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pmc-6205713-1
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A 49-year-old female patient described a pulsating mass on the dorsal aspect of the right foot with onset approximately 3 years earlier that had grown progressively before becoming painful a few months prior to presentation, which caused her to seek medical care. She stated that she had not suffered any traumas or undergone any surgical procedures to the foot, had no family history of aneurysms, diabetes, or dyslipidemia, but was a smoker and had hypertension as cardiovascular risk factors.
On physical examination, a pulsating mass, static and painful on palpation, was observed on the dorsal aspect of the right foot, suggestive of an aneurysm of the dorsal artery of the foot ( ). Additionally, there was a strong pulse in the posterior tibial artery, with no signs of chronic ischemia or other detectable vascular disorders.
Ultrasonography showed an oval, anechoic image along the course of the dorsal artery of the right foot, measuring approximately 1.2 × 1.6 × 2.2 cm ( ).
Exploratory surgery, under local anesthesia, was initiated with a longitudinal incision in the dorsal surface of the right foot, above the aneurysm. After careful and detailed dissection, a dilation with a saccular appearance was observed along the course of the dorsal artery of the foot. After exposure, the proximal and distal stumps of the dorsal artery of the foot were isolated and ligated and the aneurysm was resected ( ).
Reconstruction of the artery was considered unnecessary, since the foot showed no signs of ischemia and duplex scanning revealed excellent flow to the interdigital and tibial arteries. Histopathological analysis of the aneurysm sac found intimal thickening and myxoid degeneration with inflammatory infiltrate and atherosclerotic changes ( ).
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pmc-6205782-1
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We describe a 10-year old Caucasian male with diagnosed peanut and tree-nut allergy, who developed anaphylaxis to lupine flour in May 2017 in Vancouver, Canada. A few minutes after eating a small amount of pancake made with a pre-made mix, he developed oral pruritis, throat tightness, severe stomachache, lightheadedness, cough, hoarse throat, nasal congestion, sneezing, and fatigue. He refused epinephrine but was given cetirizine. The symptoms resolved after 3 h, but he was still unwell the following day. In a conversation between the mother and the allergist, it was suspected that lupine, the second ingredient on the label, was the cause of anaphylaxis, since the patient was eating the other ingredients regularly. He was brought into the BC Children’s Hospital Allergy clinic in June 2017 for skin prick testing to lupine (Fig. ). Results were consistent with lupine allergy and the patient was counseled to avoid lupine. The mother was counseled on the importance of administering epinephrine for anaphylaxis. In addition, the mother was encouraged by the allergist to report this incident to the food company and government agencies.
Subsequently, the food company performed testing on the pancake mix and confirmed that it did not contain the patient’s known allergens.
After the incident, the patient’s mother became an advocate for patient education regarding cross-reactivity between lupine and peanut, and importance of labeling lupine-containing products to warn families with peanut allergy about lupine. She contacted the Canadian Food Inspection Agency (CFIA), who issued a product recall and public information sheet (see Additional file ), and Health Canada, who issued “Information for Canadians with peanut allergy concerning lupine”, a message about peanut allergy and exposure to lupine as a food ingredient. The pancake mix company initially recalled the product from stores, but in a letter to the family a few months later, they wrote they would be putting the product back on the shelf with a warning label that lupine is a legume related to peanuts. The company promised to include warning labels for other home-brand lupine-containing products and institute a voluntary labeling system for other companies whose lupine-containing products may be sold in their stores. The mother was interviewed in magazines, e-newsletters, and blogs, aimed at educating parents of children with food allergy.
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pmc-6205787-1
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A 65-years-old female Chinese woman was admitted to our hospital with the chief complaint of abdominal pain in the right upper quadrant for the past 20 days. There was no remarkable family, medical or genetic history. The patient was in good general health and had no significant weight loss. Her vital signs (including heart rate, respiration rate, blood pressure and body temperature) were within normal limit. There were two positive signs during the physical examination, anemic conjunctiva and tenderness in the right upper quadrant. Complete blood count and serum biochemistry data on admission remained normal except hemoglobin, 9.5 g/dl. Significant abnormalities were found in the tumor marker, demonstrated by a normal serum level of alpha-fetoprotein (AFP; 4.85 ng/ml, normal: 0–8.78 ng/ml) and elevated levels of carcinoembryonic antigen (CEA; 16.3 ng/ml, normal: 0.5–5.0 ng/ml), carbohydrate antigen125 (CA125; 371.2 U/ml, normal: 1–35 U/ml) and CA19–9 (358.96 U/ml, normal: 2–37 U/ml). Multi-detector computed tomography (CT) scan of the abdomen showed distension of the gallbladder with gallbladder stones and several homogeneous high-density masses in the gallbladder fundus (intense enhancement on artery and portal venous phase, low attenuation on delayed phase), and multiple hypodensity tumorous lesions adjacent to the gallbladder (mild irregular enhancement at the periphery of the lesions on artery and portal venous phase, further enhancement on delayed phase), which were located in the lower part of segment IV of the liver (Fig.-). Magnetic resonance imaging (MRI) with perfusion-weighted imaging confirmed the presence of gallbladder stones and solitary 3 × 3 cm enhanced lesions in the gallbladder, and 6.2 × 4.5 cm hypovascular tumors in the liver (Fig. -). The data of abdominal ultrasonography was consistent with the above data. Thus, the preoperative diagnosis was GC with hepatic metastasis.
The patient was informed of the risks involved with the surgery before consent for the operation was obtained. After sufficient preoperative preparation, the patient underwent an exploratory laparotomy. During laparotomy, the gallbladder was enlarged to 16 × 6 × 6 cm and showed wall thickening (the thickness was 1 cm). There was a palpable mass felt on the surface of the gallbladder fundus portion. Exploration also showed an 8 × 6 cm rigid lesion fused by multiple masses in liver segment IVb and V and a 1 × 1 cm lesion in segment VIII. Moreover, sporadic lesions on the diaphragm and enlarged station 8 lymph nodes were seen. The patient underwent cholecystectomy, resection of liver segment V, of the lower part of segment IV and partial segment VIII, regional lymphadenectomy and resection of lesions on diaphragm.
The post-operative histopathological examination revealed synchronous double cancers in the liver and gallbladder, which were GC (well-differentiated papillary adenocarcinoma invading the muscularis propria) and CHC (Fig. and ). The examination also showed that the metastases in lymph nodes and diaphragm were both from CHC in the liver.
After 10 days of recovery, the patient was discharged without complications. Adjuvant chemoradiation therapy was not performed due to the patient’s refusal. Unfortunately, the patient died of widespread metastasis 8 months after the operation.
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pmc-6205802-1
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A 57-year-old Japanese man visited our hospital for consultation of asthma attacks with exertional dyspnea. When he was about 30 years old, he was started on asthma treatment by a local physician. However, the asthma attacks occurred frequently despite triple therapy with high-dose inhaled corticosteroids, inhaled long-acting beta-2 agonist drugs, and long-acting anticholinergic drugs. He had no history of smoking. Blood test findings showed 7.1% eosinophilia (460/μL) and an elevated total IgE level at 256 IU/mL (specific IgE for house dust: 0.97 UA/mL; for mite: 1.18 UA/mL). There was bronchial wall thickening on both lungs on plain computed tomography of the chest. Exhaled nitric oxide concentration was increased at 68 ppb. After managing the asthma attack with oral intake of prednisolone at 30 mg/day for 6 days, there was persistence of dyspnea and fluctuations in forced expiratory volume in one second (FEV1) values from 1.17 L before steroid treatment to 2.33 L after steroid treatment. The patient was diagnosed as intractable asthma based on his history and the clinical course. Using the Alair Bronchial Thermoplasty (BT) System (Boston Scientific Corporation, MA, USA), BT was performed in three treatment sessions with a different region of the lung. Each treatment was performed approximately 3 weeks apart. Because the stenosis was observed in each lobe bronchus due to bronchial mucosal thickening, total sessions consisted of 98 activations. At 1 year after BT, the resting tests for respiration showed no improvement in FEV1, but the forced oscillation technique (FOT) [, ] (MostGraph, Chest M.I., Tokyo, Japan) showed decreases in both inhalation and exhalation respiratory resistance values (Table and Fig. ). Assessment of asthma control scores [] showed improvement from 19 before BT to 25 at 1 year after BT. CPET (Aero monitor AE310S, Minato Medical Science Co., Ltd., Osaka, Japan) was performed using a similar treadmill protocol by Sheffield []. All the CPET results indicated that exercise was terminated when the target heart rate (THR), which was calculated as 220-age in years was reached; thereafter, the CPET results were evaluated (Table , Fig. ). At the end of exercise, comparison of the findings at pre-BT and at 1 year after BT showed (1) improvement in dyspnea based on the Borg scale; (2) longer exercise time to reach the THR; and (3) increase in arterial oxygen saturation (SpO2).
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pmc-6205863-1
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A 12-year-old boy admitted to the hospital with right chest pain and shortness of breath. He had no other complaints such as cough, fever, or hemoptysis. During the examination, the right hemithorax respiratory sounds were diminished and the other side was normal. He had shortness of breath during exercise. On posteroanterior chest radiograph, there was a huge well-circumscribed opacity in the right hemithorax. Magnetic resonance showed a 15 × 16-cm cystic lesion which was filling the right hemithorax totally. Mediastinum and the heart had deviated to the left hemithorax (
). Surgery was planned immediately. In the surgery, thoracic exploration was done via single-port videothoracoscopy. First, utility incision was performed and then needle aspiration was done to aspirate the cystic fluid totally. After covering around the punctured place by a gauze with povidone iodine, the cyst wall was opened. The germinative membrane was removed in pieces, and the pouch of the cyst was checked for bronchial orifice. Then cystectomy and capitonnage were performed on the cyst located in the entire right upper lobe through utility thoracotomy at the level of 4th intercostal area (
). After air leak was controlled, the expansion of the right upper lobe was provided in the postoperative period (
).
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pmc-6205870-1
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A 22-year-old male patient presented to our polyclinic with pain, deformity, and limited joint mobility in the right knee. He suffered a fall about three years ago and did not receive any kind of treatment. A physical examination showed a 10° varus deformity, a 25° flexion contracture, and a limited amount of joint movement in the patient's right knee. There was no neurological damage. Radiographs and computed tomography (CT) images showed a malunited isolated medial condyle fracture in the coronal plane with an intra-articular incongruity (Figure ).
Magnetic resonance imaging (MRI) revealed no ligaments injury in the knee. We planned for corrective osteotomy of the medial femoral condyle (Figure ).
The knee was placed in the flexed position for skin incision. An anterior skin incision was made that extends 3 cm proximal to the patella to the tibial tubercle. The medial parapatellar arthrotomy was made 2 cm proximal to the patella, curving along the medial patella and parallel to the patellar ligament to the tibial tubercle, and the distal medial femoral condyle was exposed. An approximately 5-mm step was detected in the medial femoral condyle. The chondral structures, meniscus, and ligaments were in good shape. An osteotomy line was identified with fluoroscopy using two Kirschner wires. Then, corrective osteotomy was carried out carefully. Posterior soft tissue dissection was not performed to protect the blood supply of the femur medial condyle. Therefore, a difficulty was encountered in bringing the osteotomized medial condyle to an anatomical position. This problem has been overcome by hyperflexing the knee and letting the tibial plateau push the medial condyle forward.
The condylar osteotomy fragment was fixed by inserting two 4.5-mm headless compression screws from the anterior to the posterior direction of the medial femoral condyle. Then, another screw was inserted from the medial to the lateral direction. The joint movements were checked, and it was found that the varus deformities of the knee improved. Finally, the exposure was closed (Figure ).
Postoperatively, a long-leg splint was applied to the knee joint with flexion at 30°. The cast was applied for two weeks (Figure ).
Then, physical therapy was initiated such as active and passive joint movements and other muscle-strengthening exercises. The patient was allowed to bear weight as tolerated after two months. During the nine-month follow-up, the patient returned to his normal activities. The functional outcome of the patient and knee joint alignment were improved without pain or disability (Figure ).
This study was conducted in accordance with the ethical guidelines of the Declaration of Helsinki. The patient provided written informed consent before participation.
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pmc-6205871-1
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We present a case of a 62-year-old African American female patient admitted to the intensive care unit (ICU) with profuse rectal bleeding with a hemoglobin (Hb) of 5.3 grams per deciliter (g/dL), left lower abdominal pain, nausea, chills, and dizziness. Her extensive comorbidities include diverticulosis present for over 40 years, untreated hepatitis C, end-stage renal disease (ESRD), asthma, chronic obstructive pulmonary disease, hypertension, polycystic kidney disease, diabetes, gout, history of pulmonary embolism not on anticoagulation, cerebrovascular disease, and patent foramen ovale, while family history was significant for gastric cancer. Her medications did not include anticoagulants or non-steroidal anti-inflammatory agents (NSAIDs). She had a previous colonoscopy, two years prior in 2016, that revealed severe diverticulosis and internal hemorrhoids. She presented with a Hb of 5.3 g/dL, normal platelets and coagulation panel, low-normal corrected calcium of 8.4 milligrams/deciliter (mg/dL), and an elevated creatinine and blood urea nitrogen (BUN) due to her pre-existing ESRD. While she experienced intermittent spotting before, this episode marked the first time she experienced a profuse and rapid bleed. She was transfused two units of pure red blood cells (PRBC), started on both a proton pump inhibitor (PPI) drip and a desmopressin drip. She underwent a computed tomography (CT) of the abdomen and pelvis without intravenous (IV) contrast due to poor renal function and refusal to take per oral (PO) contrast. The CT exhibited extensive diverticula mostly in the left colon with a majority of the diverticula calcified and gastric wall thickening, best observed on the axial and coronal reconstruction below (Figures -).
Calcified cysts were present in both her kidneys as well as calcified fibroids in her uterus. A previous CT without contrast, performed seven years prior, showed diverticulosis, but an absence of calcification in the above-mentioned locations at that time. She was transfused two more units of PRBC, totaling four, to eventually attain a Hb of 7.7 g/dL. The patient no longer experienced active gastrointestinal bleeding after resuscitation. Bolstered by the resolution of her symptoms in the setting of her stable Hb and vitals, she deferred an inpatient colonoscopy and endogastroduodenoscopy and agreed to follow-up as an outpatient.
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pmc-6205872-1
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A 53-years-old female with the history of morbid obesity status post-Roux-en-Y gastric bypass surgery presented with a chief complaint of dyspnea on exertion and intermittent substernal chest pain. The patient reported that for the past two months she would feel very short of breath during early 10-15 minutes of exercise, however, with continued exertion her symptoms resolved. The patient then began to develop intermittent substernal chest pain, not associated with exercise, which prompted her to present to the emergency department. On further history, the patient stated that she has had dyspnea on early exercise after massive weight loss since bariatric surgery, but her symptoms worsened after she moved to high altitude in Albuquerque two months ago. The patient had undergone bariatric procedure five years prior to presentation and subsequently lost 100 pounds with an 18-point drop in body mass index (BMI).
On emergency department visit, the patient’s physical exam revealed resting bradycardia with a heart rate (HR) of 55 beats per minute (BPM) and blood pressure at 89/54. The patient was of normal weight with a BMI of 24. The patient denied any history of tobacco abuse, excessive consumption of alcohol or drug use. She also denied being on any negative ionotropic drugs.
Electrocardiogram (EKG) revealed non-specific ST waves changes (Figure ).
High sensitivity troponin I was within normal range (<0.017). Given EKG changes and a strong family history of coronary artery disease (CAD), the patient underwent EKG exercise stress test per the Bruce protocol.
The patient’s resting HR was 68. Stage I of exercise patient’s heart rate was 81. The patient did not experience a significant rise in heart rate until later part of stage III of exercise at 10.4 metabolic equivalents (METs) where her rate increased to 133 beats per minute. The patient did not achieve target HR until stage IV of exercise when her HR did increase to 148 which was 88% of age-predicted HR. Notably, the patient did experience profound dyspnea during the test, which improved once she reached HR of 133 at the ninth minute during stage III of exercise (Table ) (Figure ).
The patient’s resting bradycardia, hypotension, and delay of appropriate heart rate response during exercise stress testing prompted patient’s chart review. Comparison of resting heart rate before and after significant weight loss revealed a marked difference. Prior to bariatric intervention, the patient’s heart rate averaged in the 80s. After 100 lb weight loss and the decrease in BMI of 46% the patient’s heart rate dropped significantly, averaging in the 50s. The patient’s blood pressure followed a similar trend (Figures , ).
Retrospective chart review also revealed that approximately one year after a Roux-en-Y procedure and 100 pounds of weight loss, the patient presented to her primary care clinician complaining of light-headedness and hypotension at home. This was deemed to be due to “dehydration” related to gastric bypass surgery. Reviewing multiple clinic visits prior to presentation, the patient suffered from a dizzy feeling intermittently for four years prior to presenting to our facility, wherein she had just recently moved to Albuquerque, New Mexico at an elevation of >5,000 feet.
Ultimately, the patient’s chest pain was determined to be due to gastroesophageal reflux disease (GERD) and a large hiatal hernia as a complication of her bariatric intervention. However, her dyspnea on exertion was determined to be secondary to the delayed chronotropic response due to overwhelming cholinergic tone and less sympathetic tone at baseline due to hormonal changes associated with massive weight loss. The patient was counseled about her condition with the plan to follow her symptoms in subsequent clinic visits.
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pmc-6205878-1
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A 33-year-old woman was admitted to psychiatry inpatient with a complaint of suicidal ideation. The patient has a past history of multiple psychiatric disorders like BPD, MDD, and anxiety issues for about last eight to 10 years. She had multiple suicide attempts in the past most recent being two weeks back when she tried to suffocate herself with the help of a medical device tubing. On inquiry, she said she just wanted to feel the pain, not kill herself. On further questioning, she was found to have passive suicidal thoughts as well as an active plan to harm herself. Her plan was to kill herself with the carbon monoxide poisoning by turning on the engines of four cars parked in the garage. According to her, she felt better at the time of the last admission and these suicidal thoughts just returned two to three days back. She had multiple admissions and emergency department (ED) visits related to her psychiatric conditions as well as five suicidal attempts. During one of her admission when she took multiple tablets of Advil® (Pfizer, New York, USA) in an attempt to kill herself, she was evaluated for ECT by a psychiatrist but the decision was made in favor of dialectical behavior therapy (DBT) as they felt these symptoms are because of her BPD. According to the patient she has been compliant with the therapy that has helped her in coping day-to-day issues. The patient also confirmed that she has never recovered from these active and passive suicidal thoughts which have progressed to even worse state in the last four months.
On further evaluation, the patient reported feelings of hopelessness and worthlessness most of the time along with a guilt of things for what she has done in the past. She also reported a decrease in sleep to about five hours per night along with difficulty in staying asleep and poor appetite and energy. Her concentration was normal. She continues to engage in her interests in reading and photography. The patient states she has been a "warrior" for years. She endorses a few prior panic attacks where she felt shaky, short of breath, and had chest pain. She could not recall how long they lasted or when her last episode was. Screening for mania, psychosis, and obsessive compulsive disorder was unremarkable. There was no reported history of alcohol, tobacco, or illicit drugs.
Minnesota multiphasic personality inventory-2 (MMPI-2) results suggested the presence of depression, anxiety, overall distress, and a personality disorder. All of these scores are in the moderate to severe ranges and are rather similar to one another. The psychologist during this visit interpreted that these results do not suggest that the personality disorder is the main factor driving her clinical presentation and that her presenting symptoms are due to MDD. She was recommended ECT as it was determined that these symptoms are due to resistant MDD.
The patient had a past history of multiple psychiatric drug trials in the last eight years which included medicines like fluoxetine, sertraline, venlafaxine, amitriptyline and even augmented therapy with antipsychotics was tried with aripiprazole and thyroxine which all proved ineffective in this patient. Considering her condition and beneficial outcomes in such a treatment-resistant patient, a trial of ECT was the consensual decision of all the panelist psychiatrists. The patient agreed to this mode of therapy.
The first session was done with the parameters mentioned in Table .
After the first session parameters were changed for the rest of the 12 sessions which are mentioned in Table .
A total of 16 sessions were conducted with a break after 13 sessions. The frequency of sessions was three per week for the first 10 sessions and then two sessions every week and last three sessions were conducted once a week. The patient was evaluated after every session and there was a remarkable improvement from the sixth session onwards. After 13 sessions there was a thorough evaluation and the patient reported improved mood and no active or passive suicidal ideations and she was discharged. She remained symptom-free for four to five months but then reported again with another suicide attempt. She was restarted on ECT, and 16 more sessions were conducted with the same frequency and same parameters.
On her recent visit, she endorsed a significant improvement in her depressive symptoms and denied active suicidal ideations. She also reported an improved quality of life.
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pmc-6205880-1
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A 61-year-old man was admitted for a one-day history of progressive bilateral ascending lower-limb weakness and sensory deficits. The patient had a 40 pack-year smoking history. Three months prior to admittance, the patient was diagnosed with squamous cell lung cancer. The patient had no neurologic complaints at the initial diagnosis of cancer. At the time of diagnosis, computed tomography (CT) scan of the chest showed 9.0 cm left upper lobe mass with central necrosis. A positron emission tomography (PET) scan revealed two hypermetabolic perivascular lymph nodes as well as periportal and aortocaval lymph node consistent with malignancy. Biopsy and staging of the cancer revealed poorly differentiated stage IV (T4, N3, M1) squamous cell carcinoma.
At initial presentation, the patient was alert and oriented with new onset of weakness in his lower extremities requiring the use of a cane. The patient also complained of sensory deficits in his legs and fingertips beginning since the morning of his admission. On physical exam, the patient was alert and responsive. Cranial nerves were intact. Strength testing demonstrated 4/5 weakness in hip flexors and extensors bilaterally. The upper extremities showed 5/5 strength. Deep tendon reflexes could not be elicited. No fasciculations of muscles were observed. Sensory testing revealed decreased response to light touch below the knee bilaterally. The patient did not exhibit dysdiadochokinesia or dysmetria.
By the afternoon of the second hospital day, the weakness had worsened to involve the arms symmetrically. The patient was intubated to protect his airway. Strength in lower extremities was 1/5 bilaterally. The upper extremities were 2/5 bilaterally. The next day, all extremities were flaccid, the patient was respirator dependent with facial weakness. The patient was still able to respond to voice through blinking and eye movements.
Imaging
Emergent magnetic resonance imaging (MRI) of whole spine without contrast showed absence of fracture, subluxation, and abnormal cord signal. Imaging was negative for both metastatic disease and spinal cord compression (Figure ). CT head scan without contrast was also negative for metastatic disease. Additional neuroimaging was unable to be obtained after intubation.
Investigation
On admission the patient had normal complete blood count. Hypokalemia was present (2.7 mEq/L). Ferritin was elevated (631.7 ng/ml). Renal, hepatic, and thyroid functions were normal. B12 was on the lower border of normal (191 pg/ml), however, the patient had normal methylmalonic acid (143 nmol/L).
Additional labs were ordered to rule out other potential causes of acute polyneuropathies such as HSV, Lyme disease, vasculitis, and sarcoidosis. Polymerase chain reaction of cerebrospinal fluid (CSF) was negative for HSV1, HSV2, and Lyme DNA. Additional lab tests within normal range included erythrocyte sedimentation rate, C-reactive protein, angiotensin converting enzyme, and anti-MAG antibodies. The patient was negative for anti-GM1 antibodies. Additional antibodies specific to other subtypes of GBS were not ordered.
Gram stain and bacterial culture of CSF fluid was negative. In addition, patient was afebrile throughout the hospitalization and did not have symptoms suggestive of bacterial meningitis.
A lumbar puncture yielded clear CSF with protein (177 mg/dL), glucose (61 mg/dL), red blood cell count (0 per/µL), and white blood cell count (0 per/µL). CSF demonstrated albuminocytologic dissociation typical of Guillain-Barre. Nerve conduction studies could not be conducted.
Treatment
A course of intravenous immunoglobulins at 2 gm/kg of body weight was started for five days beginning on day two of admission. In addition, intramuscular B12 supplementation was started due to borderline low B12 levels. The patient was monitored and did not show signs of improvement. After a period of 10 days of observation with no changes in respiratory and motor status, additional treatment was felt to be necessary. Literature suggested that subtypes of Guillain-Barre with axonal involvement may respond better to plasmapheresis [-]. Therefore, a trial with plasmapheresis was initiated due to the lack of response to the intravenous immunoglobin. The patient underwent five days of plasma exchange at 3 L/day for the first three days followed by plasma exchange every other day for two more days. Despite treatment, there were no neurologic improvements.
Outcome
The patient did not recover from his weakness and could not tolerate being weaned off of the ventilator. Hospice care was offered, however, he passed away in the intensive care unit 48 days after diagnosis after agreeing to terminate respiratory support.
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pmc-6205891-1
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A 22-year-old Caucasian male with no significant past medical history was evaluated in cardiology clinic with intermittent chest pain. Chest pain was nonexertional, located in the center of chest and nonradiating. The patient was a college athlete and denied symptoms of chest pain, palpitations, dizziness, or syncope with exertion. He had exercise nuclear stress test one month ago for similar chest pain which was normal. He denied personal history of heart problems or family history of premature coronary artery disease, inherited arrhythmias, or sudden cardiac death. Electrocardiogram (EKG) showed normal sinus rhythm with no ST or T wave changes suggestive of ischemia and three sets of troponin I were normal. Transthoracic echocardiogram showed normal ejection fraction of 60%-65% and no segmental wall motion or valvular abnormalities. He underwent coronary computed tomography (CT) angiogram (CCTA) which revealed large dominant right coronary artery (RCA) and anomalous origins of left anterior descending artery (LAD) and left circumflex artery (LCX) from right coronary sinus (Figures -). LAD had a malignant course between aorta and pulmonary artery.
The patient underwent left heart catheterization which showed a very large dominant RCA and small LAD and LCX with anomalous origin from right coronary sinus (Videos -). The coronary arteries appeared angiographically normal.
Because of chest pain and anomalous LAD with malignant course, it was decided to get noninvasive fractional flow reserve (FFR) assessment from coronary CT angiography which was hemodynamically nonsignificant (Figure ). Based on FFR findings and small size of the vessel, it was decided to treat the patient conservatively. The patient’s chest pain was considered atypical which resolved on its own. He was recommended to continue his regular physical activities with no restriction.
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pmc-6205896-1
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A 58-year-old female with a past medical history of hypertension, diabetes mellitus type 2, hyperlipidemia, vitamin D deficiency, obesity, allergic rhinitis, and uncontrolled recurrent urticaria presented to the clinic with fatigue and weight gain. Review of her medical records showed that her vitals were in the normal range, with blood pressure ranging from 132/70 mmHg, pulse rate 72/min, and weight 210 lbs with a body mass index (BMI) of 38.1 kg/m2. She denied smoking and alcohol intake. She was taking metformin 500 mg twice daily, rosuvastatin 50 mg, hydrochlorothiazide 25 mg, antihistamines, and nystatin-triamcinolone topical 100,000 units/G-0.1% ointment.
Laboratory investigations showed raised thyroid stimulating hormone (TSH) levels as 14 mlU/ml and low levels of free thyroxine (FT4) as 0.4 ng/dl. hemoglobin A1c (HbA1c) was 6.1, eosinophil count was raised 6.5% (0%-5% normal) and eosinophils (absolute) 0.53x103 (N: 0.0-0.4x103), high antithyroid peroxidase antibodies (anti-TPO) 250 IU/ml (0.0-35 IU/mL), and antithyroglobulin antibodies (anti-TG) 437 IU/ml (N: <40 IU/Ml).
Based on investigations, she was diagnosed as a case of Hashimoto’s thyroiditis. She was started on 50 mcg levothyroxine therapy, which was raised to 125 mcg to achieve euthyroid levels. She noticed that her uncontrolled recurrent urticaria started to get better, and after six months of levothyroxine therapy, her TSH was 1.77 mlU/ml and T4 level was 1.2 ng/dl, and the recurrent urticaria completely resolved. She quit taking her topical ointments and antihistamines that she had been using for urticaria. She is on regular follow-up every six months for the last two years and is symptom-free since then.
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pmc-6205900-1
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We present a case of 68-year-old Caucasian gentleman, a diagnosed case of major depressive disorder, recurrent, severe, without psychotic feature and with anxious distress. He has been suffering from major depressive disorder (MDD) for the last 40 years. He also had post-traumatic stress disorder (PTSD) along with passive suicidal thoughts for a long period of time. Multiple trials of various antidepressants including citalopram, escitalopram, sertraline, paroxetine, and mirtazapine, either used in combinations or as mono-therapy had failed to produce long-term desired effects. The patient was admitted to the psychiatric department on numerous occasions. Psychotherapy was tried but was not effective at all. Medications were discontinued by the patient on account of numerous side effects they produced ranging from a mild headache, nausea, nightmares to confusion. His current spell of depression lasted three months, exhibited by gradual worsening of symptoms, e.g., sleep disturbances, decreased appetite and increased suicidal thoughts. At that time, ECT sessions were planned but never initiated. He is married but states that his social life and family life suffers drastically because of his mood disruptions. He denied any abuse of alcohol or drugs; prescription or recreational. He was losing interest in his current job as well. Concomitantly he suffers from PTSD and anxiety. He also had family history positive for MDD in his mother.
On examination, he was oriented, distressed with prolonged low mood and labile effect. His speech was slow and full of pessimistic thoughts. No cognitive deficits were noted. Based on his history, the team of psychiatrists decided to pursue bilateral brief pulse ECT and discussed it with the patient. Complete medical and neurological investigations were carried out to rule out any comorbidities. Basic metabolic profiles (BMP) including thyroid function tests, electrocardiogram (EKG) and electroencephalogram (EEG) were normal. Informed consent was obtained. Bilateral brief pulse ECT, three times a week (total of 10 sessions), was planned. General anesthesia for a duration of 20-30 minutes was given. Following drugs were administered: Succinylcholine 100 mg, Etomidate 16 mg, Dexamethasone 4 mg and Ondansetron 4 mg for relieving nausea and vomiting post ECT. The first three sessions of ECT were uneventful with no marked post-ECT side effects except for mild headaches. The patient described an alleviation of depressive symptoms and anxiety. However, after the fourth session, the patient experienced delirium (according to diagnostic criteria of DSM-V), starting immediately and lasting for 36 hours. His confusion was characterized by varying degrees of consciousness, disorientation, and difficulty in performing daily activities. Cardiovascular and respiratory parameters like blood pressure, heart rate, and respiratory rate were within normal limits. Metabolic and neurological causes of delirium were ruled out. His delirium improved and he had his fifth ECT session that resulted in profound and prolonged delirium lasting 14 days, relieved without the use of any psychotropic medication. Again, his confusion was characterized by varying degrees of consciousness, disorientation, and difficulty in performing daily activities. A change in ECT protocol, from bilateral brief pulse to right-sided unilateral ultra-brief pulse, was opted for. The first session of unilateral ECT provided significant development. No confusion following procedure was noticed.
With successive session separated by a minimum of three to four days, the patient felt more and more improvement in his depression and anxiety. There was a mild post-ECT confusion after these sessions which improved within a day. He had five sessions of right-sided unilateral ECT. The sixth session was spaced by one week and seventh session by 15 days. He was then put on once a month maintenance ECT. His depression, suicidal ideations, and somatic complaints improved significantly and he was able to live a functional life.
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pmc-6205902-1
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Case 1: Inflammatory non-perforating internal root resorption
A 35-year-old healthy female patient presented to the Department of Conservative Dentistry and Endodontics, Army College of Dental Sciences, Secunderabad, India, with dull pain in right upper front tooth region for one week. The patient gave a history of trauma 10 years ago, and previous dental treatment with respect to the same tooth.
Clinical examination revealed previously initiated endodontic therapy in tooth 11 and 21 (Figure ). Tooth 21 showed mild sensitivity to percussion with no associated sinus formation or swelling. Radiographic examination revealed a well-defined radiolucency in the middle and apical third of tooth 21 (Figure ).
Cone beam computed tomography (CBCT) (Kodak 9500 Cone Beam 3D system, USA) was done using field of view 5 × 5 and axial, sagittal, and horizontal sections were obtained that aided in the diagnosis of inflammatory non-perforating internal resorption with symptomatic apical periodontitis for tooth 21 (Figure ) and chronic irreversible pulpitis with normal periapical tissues for tooth 11. Nonsurgical endodontic treatment was planned in relation to tooth 21 and 11.
First Appointment
Informed consent was obtained from the patient and treatment initiated by administering an infiltration of 2% Lignocaine with 1:80,000 adrenaline (Lignox, Indoco Remedies Ltd, India). The tooth was isolated using rubber dam (Hygenic Dental Dam, Coltene Whaledent, Germany) and coronal access was prepared using an Endo‑Access bur (Dentsply Maillefer, USA). The working length was determined using apex locator (Root ZX II; Morita, Tokyo, Japan) (Figure ) which was found to be 23 mm in tooth 11 and 20 mm in tooth 21.
Cleaning and shaping was performed by crown-down technique using Protaper Universal (Dentsply Maillefer, USA) up to finishing file number 3 (F3), under copious irrigation using 2.5% sodium hypochlorite (Septodont, India) and normal saline. Ultrasonic irrigation using Irrisafe ultrasonic tips (Satelec, France) (Figure ) was performed with 2.5% sodium hypochlorite and an intracanal dressing of calcium hydroxide was given and temporarily sealed using Cavit (3M ESPE, USA).
Second Appointment
On two-week recall visit, the intracanal medicament was removed using 10% citric acid (Prime Dental Products Pvt Ltd, Maharashtra, India) using ultrasonic irrigation. The tooth was asymptomatic, and prepared for obturation.
Since the resorptive defect involved the middle and apical region of tooth 21, the entire canal was obturated with thermoplasticized gutta-percha, using Obtura II (Obtura, USA) while tooth 11 was with lateral compaction technique using gutta-percha (Dentsply Maillefer, USA) and AH Plus (Dentsply Maillefer, USA) (Figure ). The tooth was clinically asymptomatic and showed successful healing radiographically at six, 12 and 18 months (Figure , , ). Figure shows the postoperative photograph of patient with satisfactory healing.
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pmc-6205902-2
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Case 2: Inflammatory perforating internal root resorption
A 20-year-old male patient presented with pain for one week and gave a history of trauma seven years back leading to fracture of tooth 21. Clinically, the tooth 21 showed grossly destructed crown, a 6 mm deep periodontal pocket distally and grade one mobility. Intra oral periapical radiograph revealed a well-defined radiolucency in the coronal third of the radicular surface (Figure ). Images of cone beam computed tomography revealed a radiolucency communicating with the external root surface, suggestive of inflammatory perforating internal root resorption (Figure , , ). Since the prognosis of the tooth was questionable, extraction was the treatment of choice, but the patient desired to save the tooth.
First Appointment
An informed consent was obtained and root canal was accessed after administration of 2% local anaesthesia with 1:80,000 adrenaline under rubber dam isolation, using an Endo‑Access bur. The intracanal bleeding was controlled by gently irrigating with 2.5% sodium hypochlorite. Working length of 23 mm was established (Figure ) and cleaning and shaping was performed with Protaper Universal up to finishing file F3. Calcium hydroxide (Prime Dental Pvt Ltd, India) was placed for a period of four weeks as an intracanal medicament and temporized with Cavit.
Second Appointment
Calcium hydroxide dressing was removed with 10% citric acid, using ultrasonic irrigation and internal walls of the canal were repaired with mineral trioxide aggregate (MTA) (Angelus, Brazil), sealed with a wet cotton pellet and temporized with Cavit, and allowed to set for 24 hours (Figure ). Sectional obturation was done followed by backfill with thermoplasticized gutta-percha, using Obtura II, till the middle third of the canal. The remaining canal was sealed with Ribbond fibres (Ribbond, USA) (Figure ) and composite (Ivoclar Vivadent, NY, USA). Figure shows the postoperative radiograph of tooth 21 after obturation.
A full thickness mucoperiosteal flap was reflected (Figure ) and the perforation defect was repaired externally using MTA (Figure ). The associated periradicular bone defect was curetted and biogen granules (Biotek, Italy) were packed into the defect with platelet rich fibrin (PRF) membrane (Figure ) and sutured (Figure ). The patient was recalled at one week, four weeks, six and 18 months for follow-up.
Figure depicts the post-operative clinical photograph and six and 18 months recall visit radiographs, showing healing of the lesion with bone formation.
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pmc-6205902-3
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Case 3: Invasive cervical external root resorption
A 43-year-old male patient presented with pain in left upper quadrant from the past one month. The patient gave a history of trauma 12 years back for which surgery was performed on the left upper lateral incisor 10 years ago. Clinically, tooth 22 was asymptomatic; however, the tooth 23 presented with an intraoral sinus and showed moderate sensitivity to percussion. Cold test and electric pulp test revealed a delayed response for tooth 23. An 8 mm deep periodontal pocket was present on the palatal surface of tooth 23 (Figure ). Radiographic analysis revealed diffuse radiolucencies in cervical and mid root region of tooth 23 and root canal treated 22 (Figure ).
To obtain specific knowledge about the three-dimensional (3D) anatomy, the patient was referred for a CBCT analysis. CBCT revealed a class 3 cervical root resorption on buccal and palatal aspects, which perforated and involved the main canal (Figure , , , ).
First Appointment
After obtaining an informed consent the tooth was isolated using rubber dam, access cavity was prepared in tooth 23 using an Endo‑Access bur. Working length of 25 mm was established using apex locator. Cleaning and shaping of canals was performed followed by placement of calcium hydroxide for a period of four weeks, and temporized with Cavit.
Second Appointment
At the recall visit, medicament was removed using 10% citric acid. A surgical intervention was planned to make the cervical defect accessible. A triangular full thickness flap was reflected buccally and palatally to expose the large defect (Figure ). The necrotic tissue was curetted, and resorptive defect was cleaned with normal saline and 17% ethylenediaminetetraacetic acid (EDTA) (Prime Dental product Limited, India) (Figure , ). The root canal was dried using paper points (Diadent, USA) and secured by inserting a 2% gutta-percha point (Diadent, USA). The defect was repaired using Biodentine (Septodont, USA) on both buccal and palatal surfaces and contoured according to the external anatomy of the root (Figure , ).
Sectional obturation was done followed by backfill using thermoplasticized gutta-percha and MTA Fillapex (Angelus, Brazil). The flap was repositioned and sutured. The patient was instructed to report after a week for suture removal. A four-year follow-up radiograph shows satisfactory periradicular healing with bone formation (Figure , ).
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pmc-6206326-1
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A 48-year-old healthy man with BMI 30 was admitted to the emergency department with a 12-h duration history of abdominal pain and distension with bilious vomiting. The patient had no history of previous similar attacks. On examination, the patient was dehydrated, afebrile with a pulse minute rate of 98 and blood pressure of 130/80. His abdomen was distended, tympanic on percussion and tinkling bowel sounds were auscultated. The clinical suspect of bowel occlusion was confirmed by an abdominal X-ray in the upright position that revealed multiple fluid levels without free air. The abdominal and pelvic CT scan with intravenous contrast identified an SBO with a transizional zone in the right lower abdomen. Below the transitional zone there was a saclike mass of clustered dilated bowel loops descending downward into the prevesical space and compressing the anterolateral wall of the bladder (). The patient, informed about the radiological suspect of internal hernia, provided informed consent to laparoscopic approach. A laparoscopy by a three trocars technique (12 mm trocar at navel and two 5 mm trocars at bilateral abdominal flank) was performed confirming the radiological diagnosis of obstructive supravesical hernia involving the terminal ileum (A). With the patient in Trendelemburg's position, the entrapped small bowel was gently reduced revealing a hernia's ring of 2 cm × 4 cm with a sac running laterally and anteriorly to the bladder (B). The segment of incarcerated intestine was found to be viable for which bowel resection was not required. The internal surface of the sac was cauterized by bipolar device and the hernia's ring was closed with 2/0 Polydioxanone (PDS) running suture. After an uneventful recovery, the patient was discharged on the four post-operative day. Two months later, the patient presented with a bulging mass in the right inguinal area and had repair of direct inguinal hernia. After 23 months follow-up the patient did not develop clinical or radiological signs of recurrences of supravesical hernia.
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pmc-6206326-2
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A 65-year-old healthy man with BMI 32 was admitted to the emergency department. He referred 6-h before symptoms, following heavy cough, mostly related to abdominal pain and nausea, with one episode of bilious vomiting but no clinical evidence of heavy abdominal distension. The patient had no history of previous similar episodes. Clinical examination revealed dehydratation, high body temperature (38.2 °C), pulse rate of 98/minute and mild hypotension (blood pressure 110/60 mmHg). His abdomen was little distended, mostly tympanic on percussion and tinkling bowel sounds were auscultated especially on the right inferior quadrants. To confirm the suspect of bowel occlusion, an abdominal X-ray in the upright position was performed revealing multiple fluid levels without free air in the peritoneal cavity. Abdominal and pelvic CT scan without intravenous contrast identified a small bowel obstruction with a transitional zone in the right lower abdomen, starting from a saclike mass of clustered dilated bowel loops descending into the prevesical space and compressing the anterolateral wall of the bladder (). The patient, informed about the radiological suspect of internal hernia, provided informed consent to a minimal invasive approach. Laparoscopy revealed a not necrotic ileal incarcerated loop in a hernia's ring of 1.5 cm × 3 cm with a sac running laterally and anteriorly to the bladder. The same surgical technique of the first case was adopted. Recovery was rapid and uneventful. After 18 months follow-up, the patient did not develop clinical or radiological signs of supravesical hernia recurrence but showed a left direct inguinal hernia for which was submitted to surgery.
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pmc-6206369-1
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Patient A is a 48-year-old female referred for investigation of progressive swelling of her right breast. The patient previously had left-sided breast cancer, for which she underwent a total mastectomy. Subsequently, she underwent breast implantation for cosmetic purposes. She was referred for a mammogram (Fig. a). Mammograms are typically used in conventional breast cancer screening but cannot accurately distinguish between an effusion and a mass [].
Patients with BIA-ALCL often present to their primary clinician with breast enlargement, asymmetry, skin rash, contracture or lymphadenopathy []. The average time frame of presentation is 7 years following breast implantation []. Initial presentation often manifests as a peri-prosthetic effusion surrounding an implant on ultrasound. Any new effusion around an implant of more than 12 months of age should prompt consideration of BIA-ALCL. Patient A subsequently underwent ultrasound assessment (Fig. b).
The most notable abnormality of BIA-ALCL is an effusion in relation to the breast implant []. These can be peri-prosthetic or even present in the subcutaneous layer []. Aspirated fluid must be sent for flow cytometry and not simply for microscopy and culture, with the pathologist alerted to the possibility of the BIA-ALCL. If ultrasound examination is indeterminate, then magnetic resonance imaging (MRI) or positron emission tomography/computed tomography (PET/CT) should be considered for further evaluation (Fig. c). The patient was subsequently admitted for implant removal with capsulectomy and adjuvant chemotherapy.
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pmc-6206369-2
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Patient B is a 64-year-old female with bilateral breast implants who presented to her GP with a painful left breast. Turbid fluid was aspirated inferior to the left breast prosthesis. It was concluded that the implant was infected and the implants were removed. Unfortunately, the aspirated fluid was not sent to pathology for assessment. The patient did not undergo a capsulectomy. She represented to her GP 2 years later with unilateral left breast swelling and underwent ultrasound assessment (Fig. a). This case highlights that BIA-ALCL can even occur from a residual fibrous capsule.
Patient B was referred for a staging PET/CT (Fig. b). Evaluation with PET can vary from diffuse [–] to focal [, ] FDG uptake surrounding the implant or its capsule. FDG uptake can also appear in regional lymph nodes, suggestive of metastatic progression [, –].
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pmc-6206369-3
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Patient C is 33-year-old female who presented to her cosmetic surgeon with a sudden and rapid increase in the size of her left breast. The patient had bilateral textured breast implants inserted 4 years previously. The patient was referred for ultrasound assessment (Fig. a).
The patient underwent MRI assessment (Fig. b). The external structure of the implant has been found to statistically influence the risk of developing BIA-ALCL, with the majority of cases occurring with textured breast implants []. There has been no significant difference in incidence between saline and silicone implants. There is also inadequate evidence to comment if implant location plays a role in developing BIA-ALCL [].
The patient was staged with CT (Fig. c). Many patients with BIA-ALCL have an effusion, mass or lymphadenopathy on CT evaluation []. Other findings can include irregularity of implant contour and capsular thickening [, , ]. The patient underwent bilateral implant removal, with bilateral capsulectomies. Subsequent PET/CT showed complete metabolic remission. Surprisingly, the patient had bilateral breast implantations the following year, despite being warned of the risk of BIA-ALCL recurrence. The patient is being closely monitored for evidence of relapse.
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pmc-6206514-1
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A 50-year-old woman presented to the Emergency Department (ED) of Chitwan Medical College, Bharatpur, Chitwan, Nepal, with the history of weakness of both lower limbs for two days that was preceded by muscle cramps of three days' duration. Her weakness was insidious in onset and gradually progressive in nature affecting the upper limbs by next day with no history of altered sensorium, seizure, and bladder or bowel involvement. Her past medical history was positive for repeated hospital admissions following episodes of weakness and fatigue associated with hypokalemia for the past three years, which was managed in the line of hypokalemic periodic paralysis that responded well to supplemental potassium alone. She also had similar problems episodically for the past three years requiring repeated hospital admissions. The lady also had a history of drooping of her bilateral eyelids, foreign body sensation in the eyes, dry mouth, and recurrent muscular weakness for the past three years. She denied history of vomiting and intake of diuretics, alcohol, or laxatives. Previous medical records revealed negative results for antibody against acetylcholine receptor that ruled out myasthenia gravis.
On physical examination, vital signs were within normal limit and higher mental functions were intact. Her oral cavity was dry and there was no lymphadenopathy. Motor power was 3/5 on the lower limbs and 4/5 on the upper limb affecting both proximal and distal group of muscles. Deep tendon reflexes were diminished bilaterally. There was no sensory deficit and cranial nerve examination was unremarkable. Cardiovascular, respiratory, gastrointestinal, and thyroid examination findings were normal.
She was found to have hypokalemia (documented serum K+ of 1.6 meq/L; normal range 3.5-5.5 meq/L) (). ECG showed a sinus bradycardia with global T wave inversion and the presence of subtle U wave.
In the Emergency Department, the patient was started on intravenous potassium supplementation at the rate of 20 meq/hour via central line and was admitted to the intensive care unit (ICU), where treatment was continued and serial monitoring of potassium level was done. Consecutive serum potassium levels at 6th, 12th, and 48th hour after initiation of treatment were 1.75 mmol/L, 2.1 mmol/L, and 3.7 mmol/L, respectively. Intravenous magnesium supplementation and injection sodium bicarbonate were also given. After 12 hours of treatment, her clinical condition improved significantly with normalization of the muscle power.
With the urinary pH of 5.0, negative urine culture, no history of diuretic usage, vomiting, and diarrhea, and the arterial blood gas (ABG) showing hyperchloremic normal anion-gap metabolic acidosis in a patient with severe hypokalemia (serum potassium 1.7 mmol/L), the diagnosis of distal renal tubular acidosis (DRTA) was made. With the history of xerostomia and xerophthalmia without any secondary causes for them, SS was suspected, which was later confirmed by the significantly raised titers of anti-Ro/SSA and/or anti-La/SSB antibodies and positive Schirmer test (4.8 mm in 5 minutes) as per the latest classification criteria [].
She was started on oral prednisolone at 1 mg/kg/day after which ptosis showed partial recovery in the first 7 days. She was discharged with the same dose of prednisolone and was advised for regular follow-up in nephrology clinic.
The patient attended the nephrology clinic after 7 days with palpable purpuric rashes in both of the lower limbs associated with minimal pedal edema (). She was reevaluated and skin biopsy was suggested, but she refused it. She was found to have normal hemogram and bleeding profile and negative perinuclear antineutrophil cytoplasmic antibodies (P-ANCA), antineutrophil cytoplasmic antibodies (C-ANCA), and cryoglobulins. Urine examination showed 2+ albumin without associated hematuria and 24-hour urinary protein was 1600 mg, for which she underwent kidney biopsy. Light microscopy showed nonproliferative glomerular morphology () with patchy acute tubular injury and multifocal chronic interstitial inflammation (). Direct immunofluorescent examination revealed no significant glomerular immune deposits. Transmission electron microscopy revealed relatively well-preserved visceral epithelial cell foot processes () and no evidence of glomerular or extraglomerular electron dense deposits. Endothelial tubuloreticular inclusions were not seen. Proximal tubular epithelial cells did not reveal abnormal inclusions or giant mitochondria.
The patient is on regular follow-up for the last eight months and the oral steroids is getting tapered gradually. She is doing well with improvement in proteinuria, resolution of acidosis, and hypokalemic episodes.
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pmc-6206516-1
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A 56-year-old woman with end-stage renal disease (ESRD) on hemodialysis (HD) was diagnosed with upper extremity deep vein thrombosis (DVT) one month prior to presentation and started on apixaban presented with dyspnea and left-sided pleuritic chest pain for two weeks that have been progressing slowly. She denied any other respiratory symptoms such as hemoptysis and cough and had no history of falls nor trauma. There was no weight loss, fever, night sweats, or recent travels. She has history of hypertension, diabetes mellitus, and prosthetic mitral valve replacement and she takes lisinopril, carvedilol simvastatin, and aspirin. Physical examination revealed tachypnea and dullness to percussion of the posterior left hemithorax along with decrease in tactile fremitus; she remained hemodynamically stable throughout her hospital stay. Laboratory tests on admission revealed the following: prothrombin time (PT) of 11.5 seconds, international normalized ratio (INR) of 1.03, activated partial thromboplastin time (aPTT) of 30.4 seconds, and hemoglobin of 7.0 g/dL. Chest radiograph (CXR) showed opacification of two-thirds of the left hemithorax with tracheal deviation to the contralateral side consistent with pleural effusion (). Bedside ultrasound of left hemithorax revealed hypoechoic fluid without loculations. Even though she was transfused one unit of packed red blood cells (PRBC), her Hb dropped to 6.7 g/dL on the second day of admission.
Apixaban was held for 48 hours and bedside ultrasound-guided thoracentesis was performed on the third day of admission. One liter of bloody fluid was drained and sent for testing (). Pleural fluid analysis was as follows: hematocrit (Hct) 22%, red blood cells (RBC) 126,000/mm3, white blood cells (WBC) 1,400/mm3; bacterial gram-stain, culture, and acid-fast bacilli smear were negative for bacteria and tuberculosis, respectively, and cytology negative for malignant cells. Serum Hct was 25% at the time of the thoracentesis. The finding of pleural fluid analysis was consistent with hemothorax (pleural Hct to serum Hct ratio 88%). A chest computed tomography (CT) with intravenous contrast was done to rule out active bleeding, vascular malformations, and other causes of spontaneous hemothorax ().
A 12-Fr pigtail catheter was inserted and another one liter was drained in the first 2 hours which then slowed down to 300ml in the next 24 hours and afterwards 20-30ml daily for 2 days. CXR after drainage showed near-total resolution of the pleural effusion (). The catheter was then removed and patient was discharged without complications.
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pmc-6206519-1
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A 3-year-old girl presented to the emergency department with eye pain and was found to be hypertensive with a blood pressure measurement of 162/126. Further workup with renal ultrasound demonstrated a heterogeneous mass measuring 9.5 x 9.1 x 8.6 cm occupying the location of the left renal fossa. Surgical resection of the left renal mass revealed a 577.9 gram, 12.0 x 10.2 x 8.0 cm grossly distorted kidney with a 12.0 x 10.0 x 8.3 cm encapsulated, fleshy, pink-gray lesion which appeared grossly to have replaced the majority of the renal parenchyma. Microscopic examination revealed a cellular proliferation of neoplastic cells arranged haphazardly, in cords (), occasional nests, and focally palisading () and separated by regularly spaced arborizing fibrovascular septa within an extracellular myxoid matrix () with occasional myxoid pool formation (). Necrotic foci were noted focally within the tumor. Immunohistochemical stains were positive for vimentin (), cyclin D1 (), CD99 (), TLE1 (), and focally positive for Bcl- 2 () in the tumor cells. SMA, desmin, CD34, cytokeratin AE1/AE3, EMA, WT-1, myogenin, and S100 were negative. The overall morphology and immunopositivity for vimentin, Bcl-2, and cyclinD1 were suggestive of clear cell sarcoma of the kidney. However, given the histologic findings and the tumor immunopositivity for CD99 and TLE1, myxoid variant of synovial sarcoma entered the differential diagnosis. FISH for SYT gene rearrangement () was performed and was negative, ruling out a synovial sarcoma. The final diagnosis was clear cell sarcoma of the kidney, COG Stage III.
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pmc-6206551-1
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A 48-year-old Indian male with no chronic medical illness in the past admitted to emergency department with history of fever, headache, dry cough, and generalized body pain for 4 days and vomiting for one day. No abdominal pain, SOB, chest pain, joint pain, skin rash, recent travel, or exposure to sick person and no significant family history were reported. Patient denied alcohol consumption or tobacco smoking. On physical examination, the patient was well built and nourished; he was icteric, conscious, and oriented to time, place, and person. Vitals were as follows: temperature: afebrile, 35.9°C; heart rate: 94/minute; respiratory rate: 20/minute; blood pressure: 121/81 mmHg; and SpO2: 98% in room air.
Systemic examination showed normal neurological findings except meningeal signs. Other systems were unremarkable. Initial investigations showed hemoglobin and platelets were normal. White blood cell (WBC) count was 12.6 × 103/microliter (normal: 4 × 103/microliter–10 × 103/microliter) with 92% neutrophils. Serum creatinine was 146 µmol per liter (normal: 64 to 110 µmol per liter), urea was 11 mmol per liter (normal: 3.2 mmol per liter to 7.4 mmol per liter), and serum electrolytes were normal. Alanine aminotransferase (ALT) was 56 units per liter (normal: 0 units per liter to 30 units per liter), aspartate aminotransferase (AST) was 38 units per liter (normal: 0 units per liter to 31 units per liter), alkaline phosphatase (ALP) was 96 units per liter (normal: 40 units per liter to 150 units per liter), albumin was 33 g per liter (normal: 35 g/L to 50 g/L), total bilirubin was 68 µmol per liter (normal: 3.4 to 20.5 µmol per liter), direct bilirubin was 34 µmol per liter (normal: 0 to 8.6 µmol per liter), C-reactive protein (CRP) was 495 mg per liter (normal: 0 to 5 mg/L), procalcitonin (PCTN) was 11 ng per milliliter (normal: 0 to 2 ng/mL), and chest X-ray was normal. His conscious level deteriorated soon after hospital admission, and the Glasgow Coma Scale (GCS) dropped from 15/15 to 12/15. Meningitis is suspected, and antibiotics were started after lumbar puncture (LP) and computerized tomography (CT) head. Initial empirical intravenous (IV) antibiotics were started: ceftriaxone, vancomycin, and acyclovir along with dexamethasone. CT head was normal, and cerebrospinal fluid (CSF) analysis showed WBC 145 per microliter (normal: 0 to 5/µL) with 96% neutrophils, protein 4.55 grams per liter (normal: 0.15 to 0.45 g/L), and Glu <0.3 mmol per liter; CSF viral panel showed Epstein–Barr virus (EBV) PCR was 326 International Units per mL, acid-fast bacilli staining was negative, and tuberculosis PCR was negative. Both CSF and blood culture showed Streptococcus pneumonia which was sensitive to ceftriaxone. So acyclovir and vancomycin were stopped, dexamethasone was given for a total of 3 days, and IV ceftriaxone 2 g every 12 hours was continued; later, the patient's condition improved and oriented to person but not oriented to time and place. There was no focal neurological deficit. However, he developed hard of hearing and though fever pattern has improved, having fever spike on and off. Repeat blood cultures were negative, CRP improved from >500 mg/L to 93 mg/L, PCTN decreased from 11 ng/mL to 0.41 ng/mL, and serum creatinine level normalized. However, liver enzymes persisted to rise (both transaminases and alkaline phosphatase), and white blood cell persisted to be in the range of 13–15. Due to presence of persistence of symptoms, magnetic resonance image (MRI) brain and repeat LP were done to rule out any complication of the disease. MRI brain (Figures and ) showed meningoencephalitis, vasculitis, and extradural fluid collection. There was right-sided fluid in the mastoid cavity without bone destruction. ENT was consulted and advised for medical management. As the patient is confused, hearing assessment could not be done properly. Repeat LP showed CSF WBC 11/µL, neutrophils 70%, lymphocytes 29%, protein 1.11 g/L, EBV PCR was negative, and CSF culture was negative. Dexamethasone was restarted with continuation of IV ceftriaxone for a total of 6 weeks as Streptococcus pneumoniae meningitis is complicated by infective vasculitis, mastoiditis, and subdural collection. Repeat MRI brain () showed significant improvement in leptomeningeal enhancement and resolution of epidural collection; however, there was a new communicating hydrocephalus. After completion of his IV ceftriaxone, the patient was repatriated to his home country. Although his condition improved on above treatment, he was discharged with mild disorientation to time and person.
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pmc-6206568-1
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A 53-year-old man who was firstly treated for diffuse large B-cell lymphoma (DLBCL) presented 45 months after induction remission treatment with abdominal and inguinal lymph node (L/N) enlargement. An excisional L/N biopsy confirmed the histological type of mixed cellularity cHL; malignant cells were positive for CD30, CD15, and PAX5 and negative for CD20, CD10, CD3, BCL-2, and EMA antigens. ESHAP (etoposide, cisplatin, methylprednisolone, and cytarabine) was given as salvage treatment, and after 2 cycles, he achieved very good partial remission. Since the treatment plan was to proceed with high-dose chemotherapy and rescue with autologous stem cells transplantation (ASCT), he received an additional 3rd cycle of ESHAP for further disease control and autologous stem cell collection. After the 3rd cycle of salvage chemotherapy, the disease further responded and the stem cells collection was successful. However, he developed acute kidney injury, and the ASCT postponed till renal function recovery; the patient, based on his previous medical history (DLBCL and cHL diagnoses), received a combination of rituximab plus brentuximab vedotin as bridge treatment to ASCT. Four months later, the renal function became normal, but evaluation with PET-CT (after six cycles of combination treatment) confirmed disease progression. Subsequently, nivolumab at the dose of 3 mg/m2 every two weeks was given as a new salvage therapy. The medication was well tolerated, and no renal or any other organ function impairment was noticed. However, after the sixth infusion of nivolumab, he presented with raised nonitchy, erythematous scaly papules with silver-white coating and some annular plaques with collarettes of scales of different sizes involving the anterolateral aspects of shins and dorsa of hands, distal forearms, and both tibias (). The Köbner phenomenon was not noticed. The clinical differential diagnosis included (1) PsV, (2) erythema annulare, or (3) tinea circinata. To confirm the diagnosis, a 5 mm punch skin biopsy was obtained from the right tibia. The epidermis findings revealed hyperkeratosis and irregular acanthosis with regular elongation of rete ridges and suprapapillary thinning (Figures and ). The upper dermis showed mild perivascular lymphocytic infiltration (). There were no evidence of Munro microabscesses and no evidence of granuloma or other specific inflammation. Although the histological findings were not the typical one, the diagnosis of PsV was made based on the clinicopathological findings and the exclusion of the other aforementioned dermatological diseases.
The patient initially received only topical treatment with steroids, and the skin lesions partially improved. He next underwent ASCT, with a conditioning regimen consisted of single-agent chemotherapy of melphalan 200 mg/m2. The skin lesions gradually improved, and 3 months after ASCT, they almost disappeared. Currently, one year after ASCT, the patient was alive in complete metabolic remission regarding his primary disease and without any evidence of residual skin lesions ().
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pmc-6206570-1
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The second case refers to a 48-year-old woman, a busy manager with a history of depression and sleep disturbance. She has had three terminations of pregnancy and one delivery by cesarean section. She smokes approximately ten cigarettes per day and has high cholesterol serum levels. She takes several medications: a selective serotonin reuptake inhibitor (escitalopram), two benzodiazepines (delorazepam and clonazepam), and a statin. She reports a four-year history of urinary symptoms: daily UUI episodes, mild stress urinary incontinence (SUI), and two episodes of nocturia per night. She wears pads every day. The urology consultation revealed some degree of pelvic pain, especially during vaginal examination. The urine dipstick was negative and there was no PVR. No specific causes of the symptoms such as urine tract infection were identified. The patient also complained of mild dyspareunia and occasional constipation. The urine culture turned out to be sterile, with no blood in urine, and the pelvic ultrasound scan and urine cytology were also negative. The cystoscopy, which was performed as a result of the presence of storage symptoms and to rule out a bladder tumor in this current smoker, was normal.
In OAB patients, it is of utmost importance to consider all comorbidities. Anxiety and depression may play a role, feeding a vicious circle. Moreover, medications to treat neurological or psychiatric disorders can influence OAB and be responsible for side effects [, ]. Gastrointestinal disorders are frequently associated with OAB, such as constipation in this case, but patients rarely raise the topic. An overlap exists between irritable bowel syndrome and OAB [].
The patient was prescribed a β3 agonist, pelvic floor muscle training (PFMT) and bladder retraining. Four months later, she noticed some degree of improvement, but had stopped the treatment as she felt that she had no time for PFMT. She was not compliant with the bladder drill either, and soon stopped the β3 agonist because she did not sense any real improvement. She also felt that she did not have the time to complete a bladder diary. She was prescribed fesoterodine 8 mg for three months. In parallel, her general practitioner asked for vaginal and urethral culture swabs, which were negative. After three months, her urinary urgency improved, but she said that the few remaining episodes of urgency were “killing her life” and that she did not want to be on pills for her whole life. Therefore, she refused to continue the treatment and requested an “easy fix”. Her reaction highlights the need for careful consideration of the consequences of incontinence in terms of QoL. A publication from Vaughan et al. [] reported that OAB and incontinence synergize to reduce QoL, especially in the domains of sleep, elimination, usual activities, discomfort, distress, vitality, and sexual activity.
Consistent efficacy on urgency symptoms with a significant decrease in UUI and urgency episodes has been reported with fesoterodine at doses of 4 and 8 mg compared to placebo () [, , , ]; however, some patients may react differently. Patient satisfaction is an important driver of treatment success []. Patient expectations should be considered carefully in the context of OAB management. The achievement of patients' goals was measured in the Study Assessing FlexIble-dose fesoterodiNe in Adults (SAFINA study) [], a 12-week multicenter open label study with 331 OAB adults, using the Self-Assessment Goal Achievement (SAGA) questionnaire. Fesoterodine treatment resulted in 81.3% of patients declaring that their goals were “somewhat achieved/achieved” or that the result “exceeded/greatly exceeded their expectation”.
Our case patient had very specific expectations; she refused to have an implant (neuromodulation), saying “I'm not going to be an android!” She accepted botox injections, and so a first set of injections was performed under local anesthesia. She found the injections “a little painful” and “a big annoyance”, but at the one-month follow-up visit after botox injection she reported no more UUI episodes and an improvement in frequency and the number of urgency episodes, as well as in QoL. Even though she stated that she did not like the idea of being a patient for the rest of her life, she accepted subsequent injections.
The clinical points that can be learned from this case are as follows:All OAB cases are different, and a thorough evaluation is mandatory to adequately address each case. It is important to assess other aspects, such as functional and psychological disorders that may influence symptoms, and to consider nonneurogenic OAB as a multifactorial disease. The major goal of initial therapy is to meet the patient's expectations regarding the reason for their visit, to improve their satisfaction, and their QoL. Due to fesoterodine's characteristics and flexible dosage, improvement of symptoms and achievement of the patients' goal are usually high with this medication. When patients have specific requirements, all options should be discussed and the patient's agreement obtained. A customized approach is a crucial factor for treatment success. OAB management should be personalized; beware of a simplistic application of a standardized treatment algorithm.
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pmc-6206662-1
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A 38- year-old man, with no psychiatric history, known to suffer from epilepsy but who stopped his antiepileptic drugs (AED) is brought into a community hospital’s emergency room by an ambulance after being found in the streets in a confused condition and with reduced awareness. The history taking in the emergency room is hampered by bradyphrenia and amnesia. The patient merely relates a vague account of a pub fight. At that instant he does not know where he lives nor is he able to provide any contact information about relatives or friends. General physical examination, neurological examination, urine toxicology, brain CAT and cerebrospinal fluid findings (proteins and cells, mainly to exclude meningitis/encephalitis) are unremarkable. Blood analysis shows slight signs of leukocytosis. The EEG shows general slowing without traces of epilepsy. The patient is admitted to the neurology department for diagnostic work-up.
The next day the patient is somewhat less slow and more aware, although still unaware of the events on the day prior to admission. He believes to have fallen as a consequence of an ES. He indicates he has not been taking his AED for some time. Valproic acid was therefore restarted at a dose of 1500mgs daily. He denies having used any drugs or alcohol, as confirmed by urine toxicology. A new blood analysis is carried out, showing a decrease in leukocytosis, an increase of CK to 521 U/L and a slight increase in CRP to 16.2 mg/L. Brain MRI is unremarkable.
Two days after his admission an ES is observed by nursing staff and is interpreted as tonic-clonic, generalized. No clear underlying cause is identified. Valproic acid blood levels are 54 mg/L (at the time of admission this was < 10 mg/L), leading us to increase the dose to 2x1000mg/d. The EEG is unchanged.
The patient then shows peculiar behaviour: he stares and speaks little, leading the neurologist to suspect a psychotic episode and therefore a psychiatrist is consulted. During the psychiatric history the patient informs him that he does not have any complaints other than noticing being somewhat slow. He himself attributes this to the restarted AED. During psychiatric examination we notice bradyphrenia. The patient does blink his eyes and moves slowly, though fluently. There is no posturing or grimacing. He is friendly and cooperative. His conscienceness is clear and his attention span is undisturbed. He is well-oriented. Perception, memory and mood appear intact. The affect is flattened. He denies having suicidal thoughts.
Given this symptomatology the differential diagnosis at that stage included side effects of the valproic acid and, although there were insufficient DSM-5 criteria for catatonia at the time, catatonia. The attending psychiatrist decided to re-evaluate the patient a few days later.
Upon that re-evaluation, the patient rubs his hands in a stereotypical manner and there is evidence of grimacing and posturing (the patient sits bent over for minutes, with hands, head and shoulders in the same position) and of ambitendency. There is no Gegenhalten, no negativism, no Mitmachen. The Bush Francis catatonia rating scale (BFCRS) scores: 0 1 0 1 2 1 0 2 0 0 0 0 0 0 2 0 0 0 3 0 0 0 0 = 12 (Table ). Again, the EEG remains without abnormalities and unchanged. Given the stereotypies, the bradyphrenia, hypoactivity, inappropriate behaviour, ambitendency and posturing combined with a BFCRS score of 12, we concluded the patient was suffering from postictal catatonia becoming more severe within 8 days following a seizure. To confirm this hypothesis, we treated him with lorazepam 3dd1mg and 1dd2.5 mg, without improvement, but the lorazepam didn’t bring about any sedation. He was then transferred to the psychiatry department for further diagnostic work-up and treatment. During the first days of his stay at the ward symptoms and signs were unchanged. A fourth EEG showed no change either. Lorazepam was increased by 3 mg every 2 days until at a total dose of 17 mg/d the patient clearly improved: he became more talkative, started moving more fluently and has not shown signs of grimacing or posturing since. His mood has remained cheerful. Then, lorazepam was gradually tapered by 1 mg/d until it could be stopped completely, with the patient remaining stable and free of symptoms. On his day of discharge at 0 mg of lorazepam an EEG showed a normal base rhythm with only a couple of short episodes of general slowing.
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pmc-6206667-1
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A 7-year-old intact female Labrador Retriever was presented because of a 1 day history of vomiting, anorexia, mild polyuria/polydipsia and signs of fatigue. The owner had noticed some discharge from the vulva, as well as mucus and helminths in the feces. The dog had been in estrus 2 weeks before presentation but was not mated. The owner reported episodes of vomiting and weakness during the dog’s previous estrus cycles. On physical examination the dog was normothermic, had a swollen vulva with a sparse amount of yellow discharge and showed signs of pain on abdominal palpation. Hematology showed mild leukocytosis (18.96 × 109 cells/L, reference 5.05–16.76 × 109 cells/L). A serum chemistry panel identified mild metabolic hypochloremia and respiratory alkalosis and mildly elevated lactate.
Left lateral (Fig. a) and ventrodorsal (Fig. b) abdominal radiographs were obtained. The lateral radiograph showed two gas-filled tubular structures, measuring up to 3.5 times the height of the body of the 5th lumbar vertebra. There was one gas-filled tubular structure in the central abdomen, dorsal and parallel to the descending colon, and one in the craniodorsal abdomen, just ventral to the caudal thoracic and cranial lumbar vertebrae. The ventrodorsal radiograph showed that the two gas-filled structures were parts of the same, slightly contracted, tubular structure. In the caudal and mid abdomen the tubular structure was medial to the descending colon and had a soft tissue/fluid opacity in this region. The tubular structure then turned to the right crossing the midline at the level of the two first lumbar vertebrae. The most cranial segment followed the right cranial abdominal/caudal thoracic wall to reach the most dorsal part of the right cranial abdomen. The difference in location of the intraluminal gas on the lateral and ventrodorsal radiograph was considered to be due to gravity as a result of positional changes of the dog. Thus, the tubular gas and fluid-filled structure could be followed almost the entire length of the abdomen, from the cranial aspect of the urinary bladder to the stomach. In the caudal abdomen on the lateral radiograph the uterine body was faintly visible between the descending colon and the urinary bladder, measuring approximately 1.3 cm in diameter, subjectively considered to be normal for the large size of the dog and the phase in the estrus cycle. Small intestines with normal diameter and content were seen in the mid-abdomen.
Because of the position and the gas content in the structure, the main radiological suspicion was small intestinal ileus likely due to mechanical intra- or extraluminal obstruction, despite that no foreign body or mass could be seen.
Following the radiographic examination, abdominal ultrasound was performed to confirm ileus and locate the suspected obstruction. In the left mid and caudal abdomen there were two thin-walled tubular structures whose content created a hyperechoic interface associated with reverberation and comet tail-artifacts, indicating gas content (Figs. and ). One of these structures had the typical appearance of an intestinal wall, with alternating hypo- and hyperechoic layers, and in some parts the interface with the content created a dirty acoustic shadow. This structure was considered to represent the descending colon. A second structure had a similar thickness but homogenously hypoechoic wall, without visible layers. The interface between the wall and the luminal content was uneven and, in some parts, hyperechoic speckles were visible within the wall, creating a faint “comet-tail” artifact, suspected to be gas within the wall, consistent with emphysema of the wall or ulceration (Fig. ). Apart from the gas there was echogenic fluid in the lumen in the second structure, visible when the gas was moving. When tracing the second structure, it followed the path of the colon but was medial to the descending and ascending colon and caudal to the transverse colon. By use of several positional changes of the dog aiming to change the location of the intraluminal gas and any superimposition of other organs, the structure could be seen reaching the right ovary from the cranial aspect, while caudally it was connected to the uterine body, confirming that this was the right uterine horn. The maximum diameter of this right uterine horn was 3.3 cm. In order to make it possible to follow the left uterine horn, positional changes of the dog were required to move the right horn from its location in the left hemiabdomen. The left uterine horn was 0.9 cm in diameter, with mild amounts of intraluminal fluid and gas. The right medial iliac lymph node was mildly hypoechoic and rounded compared to the left one, with a thickness of 2 cm, interpreted as reactive lymphadenopathy. No free fluid nor free gas were found in the abdomen. The rest of the abdominal organs were normal.
The radiological diagnosis was emphysematous pyometra, predominantly affecting the right uterine horn.
The dog underwent surgery for ovariohysterectomy immediately after being treated with supporting intravenous Ringer-acetate solution (Fresenius AG, Bad Homburg, Germany) and methadone (Meda AB, Solna, Sweden). The ultrasonographic findings were confirmed on surgery (Fig. ). The right horn measured up to 5 cm in diameter and was thin-walled, distended and fluctuant due to the gaseous and liquid content. The left horn measured 1 cm in diameter and contained mainly fluid. When cutting through the uterine wall into the lumen gas and purulent exudate were found. Fluid samples for aerobic and anaerobic bacterial cultures were taken and Escherichia coli and beta-hemolytic streptococci were isolated. The uterus was not submitted for histopathology. The other abdominal organs were grossly unremarkable. The patient was treated with antibiotics in accordance to the result of the antibiogram and recovered fully in 2 weeks.
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pmc-6206708-1
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A 34-year-old female, diagnosed with relapsing-remitting MS since the age of 26, suffered from 2008 to 2013 from recurrent attacks of optic neuritis that partially responded to corticosteroid treatment. The patient was initially treated with glatiramer acetate for 2 years, and then switched to natalizumab (NTM) treatment due to significant clinical relapses. John Cunningham virus seropositivity developed while the patient was receiving NTM intravenously and treatment was discontinued after 24 months. The patient subsequently switched to Alemtuzumab therapy (12 mg/day for 5 days). At the day prior to Alemtuzumab-initiation she had a white blood cell (WBC) count of 14,500/μL (absolute neutrophil count [ANC], 10,900/μL; lymphocytes, 2300/μL) (Additional file : Table S1). 9 weeks (Day 65) after the first Alemtuzumab induction therapy, during the standard follow-up, complete blood count revealed severe neutropenia (Grade III) (WBC count, 2000/μL; ANC, 899/μL) (Additional file : Table S1), a finding that led to her hospitalization. We tested for the presence of an underlying infection/pathology.
At the onset of neutropenia and throughout its duration, clinical, serological and ultrasonic investigation did not reveal any underlying pathology (Additional file : Table S1). At the onset of neutropenia, peripheral blood smear analysis (May-Grünwald-Giemsa staining) revealed numerous large granular cells (LGL cells) (approximately 80–90%) that had variable numbers of randomly distributed azurophilic granules in their cytoplasm (Fig. ). Neutrophils with apoptotic features were rare. To further verify the nature of LGL cells, immunophenotypic analysis of peripheral blood was performed by flow cytometry. Such analysis showed marked elevation in the percentage of a specific cell-subset that belongs to the NK lineage [CD3-CD(16 + 56+): 47%] (Additional file : Table S1). Moreover, the percentage of CD3 + CD8+ T cells was found elevated compared to the baseline levels (before Alemtuzumab initiation). Of notice, the fold increase of CD3 + CD8+ T over baseline values (fold increase: 1.5) was less than that of NK-cells (fold increase: 3.2).
At the 70th day post-Alemtuzumab initiation, neutropenia was further exacerbated (ANC = 500 /μL). The occurrence of sustained neutropenia for at least 5 days underscored the need for therapeutic intervention. The patient was placed on corticosteroids (prednisolone 25 mg for 3 days and subsequent dose tapering) and 3 days after, the values of WBC and ANC started to rise, reached normal levels (fourth day) and remained stable for 2 months (Fig. ). Neutropenia resolution is stable for at least 1 year of follow up. Peripheral blood smear analysis showed that LGL cells were markedly reduced (approximately 50%) after prednisolone initiation and were further diminished 1 month later. Flow cytometry analysis showed that the percentage of NK cells remained increased (48%), whereas the percentage of CD3 + CD8+ showed a significant reduction compared to their levels upon neutropenia development (27.3% versus 48%) (Additional file : Table S1). The constellation of neutropenia, along with normal hemoglobin and platelet counts, the expansion in the peripheral blood of LGL cells, in the absence of a common infection, and the responsiveness to corticosteroids were highly suggestive of an ensuing immune-mediated mechanism for Alemtuzumab-induced neutropenia.
During the phase of neutropenia, our patient was in disease remission, with moderate neurologic disability and an EDSS = 2 (pyramidal signs, mild ataxia). We did not perform MRI scanning during the short phase of neutropenia because there was no any disease exacerbation and our patient did not exhibit any new neurological signs. No signs of radiological disease activity were evident during alemtuzumab treatment and as shown in Additional file : Figure S1, the lesion size and signal intensity was slightly reduced after 6-months of therapy. Our patient responded well to alemtuzumab, exhibited disease stabilization and was thereof, she was placed in a follow up with neurological examination and assessment of her hematological profile every 1-month, for at least 1 year. Due to prolonged disease remission and the resolution of neutropenia we have not switched to another disease-modifying drug yet.
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pmc-6206835-1
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A 28 year-old male was referred to our Clinic of Cranio-Maxillofacial Surgery with trismus in March 2016. The patient was not able to open or to close his mouth and, moreover, he was unable to protrude or to produce a lateral excursion. So he possessed an interincisal mouth opening of 5 mm. The patient indicated that he underwent a filling therapy on the right mandible molar by his dentist 7 months ago. As according therapy a right mandibular nerve block was performed. Four weeks later the patient developed trismus. His dentist described oral antibiosis and physical examination. However, no clinical improvement was observed. Therefore, the patient was referred to a Clinic of Cranio-Maxillofacial Surgery where the diagnosis of pericoronitis of the lower right third molar was stated. Extraction of the right upper and lower third molar and a forced mouth-opening was performed under general anesthesia. Subsequently, the trismus disappeared but reappeared 2 weeks later. Because of this relapse, coronoidectomy was performed on the right side. Consequently, the trismus disappeared, but a relapse reoccurred a few weeks later. A multislice computer tomography (CT) of the head was performed and the CT revealed a calcification of the right medial pterygoid muscle (Fig. ). Due to the given diagnosis of MOT of the right medial pterygoid, the patient was finally referred to the Clinic of Cranio-Maxillofacial Surgery at the University of Münster. For excluding MOP, we referred the patient to the department of human genetics. Indeed, MOP could be excluded and also all laboratory test results ranged within normal limits, including the resulting values for calcium, phosphate, alkaline phosphatase and parathyroid hormone measurements. Thus, we decided to perform renewed surgery 6 months after the last surgical intervention. Pre-operative radiation was performed with 6 Gy as single-dose radiation. Surgical excision of the ossified right medial pterygoid muscle was performed through combined intra- and extraoral access under general anesthesia. During this intervention, solid bone mass could be excised (Fig. ). Histopathological analysis confirmed the diagnosis of MOT (Fig. ). Physical therapy was started 2 days after surgery and 1 week after surgical intervention the patient could be released. Post-operative long-term application of ibuprofen 400 mg was performed for 2 weeks. At this time point, the MIO reached 23 mm in length. The patient was instructed to perform intensive physical therapy with an functional orthodontic gadget, the so-called “Jeckel-spreader”, for exercising mouth opening. This device serves for mobilisation of the masticatory muscles. Two weeks later, the MIO still yielded 25 mm in length. Thereafter, the patient stopped physical therapy using the “Jeckel-spreader” against our recommendation. Consequently, the MIO decreased to 10 mm in length. Thus, we advised the patient strongly to restart physical therapy but he declined. Digital volume tomography (DVT) was performed which revealed renewed calcification (Fig. ). Six months after surgery, MIO exhibited a length of about 8 mm. This enabled the patient to eat, to perform and to do a small lateral excursion.
We have derived a decision tree for diagnosis and treatement of MOT (Fig. ).
The pathogenesis of MOT has not been finally clarified. In 1924, Carey [] already listed four major theories for the development of MOT: 1) Displacement of bony fragments into soft tissue and hematoma with subsequent proliferation; 2) detachment of periosteal fragments into surrounding tissue with proliferation of osteoprogenitor cells; 3) migration of subperiostal osteoprogenitor cells into surrounding soft tissue through periosteal perforations induced by trauma; 4) differentiation of extraosseous cells exposed to bone morphogenic proteins. The results of the present study confirm the assumption,that multiple processes lead to the development of MOT. If a triggering event is present at all, its nature seems to be too heterogenous from case to case to support the theory of a single initiating cause. In 12 of the cases summarized here, no specific triggering traumatic event was identified (idiopathic myositis ossificans). Nevertheless, it seems that minor traumatic lesions unnoticed by these patients could be a possible cause. According to Torres [] the intensity of the trauma may not be related to the occurrence of MOT. This statement could explain why no cases of MOT occurring in individuals that pursue the sport of boxing have been reported in the literature so far. These cases would be expected because of regularly occurring blows to the face and masticatory muscles (especially the masseter and temporal muscles) of boxers. On the other hand, a relation between dental surgery and the onset of MOT seems obvious. There are 7 case reports of MOT with previous tooth extraction [–, , , ] though it is not possible to fully differentiate whether the extraction or the dental anesthesia in the context with the extraction represents the triggering event. The latter as a cause of MOT was reported in four cases [, , , ]. Mandibular block as reported by Trautmann [] as well as in our reported case, could be a more possible triggering factor for MOT. Therefore local anesthesia cannot be excluded as a cause of MOT occurring after periodontal treatment, either []. Furthermore, three cases of MOT following repetitive wisdom tooth infection have been published [, , ]. This would represent an additional indication requiring surgical removal of wisdom teeth if normal placement in the row of teeth is not expected.
Trismus is the most frequently observed symptom of MOT in the masticatory muscles which was also presented in our case. In this respect, MOT should be considered in the differential diagnosis in case of persisting trismus without a clinically manifesting cause. In such cases, radiographic findings are being expected only 3–6 weeks after the appearance of clinical symptoms [].
So far, male patients have been considered as the main group at risk of developing MOT of the masticatory muscles with a male/female ratio of 2.4/1 []. However, our data analysis demonstrated a gender-specific difference to a lesser extent with a male/female ratio of approximately 1.5/1. Since however MOT has been frequently related to traumas (e. g. fracture, blow) a possible explanation could be: males might have experienced traumas more often than females and thus also suffer more often from MOT. Of particular interest is the view at the cases of MOT occurring after dental treatment where more women (n = 9) were concerned than men (n = 6). This means prevalence for female patients of MOT of the masticatory musculature in context of dental treatment with a 1.5/1 ratio.
In most cases of MOT of the masticatory muscles the masseter muscle is the most affected one []. However, this is not true for those cases of MOT occurring after dental treatment. Of these cases (n = 10), 66% involved the medial pterygoid muscle. Given the potential risk of damaging this muscle in the context of a mandibular nerve block, local dental anesthesia seems to be the cause of MOT here, as potentially in our case. Whether the patient has to be informed about this extremely rare complication remains questionable in view of the large numbers of local dental anesthesia administered daily. On the other hand the consequences represent a severe impairment for the patient. Nevertheless, MOT should be considered in the differential diagnosis in cases of therapy-resistant trismus developing in the weeks after local anesthesia.
Generally, excision of the affected muscle is recommended as treatment of choice []. However, there are different opinions about the time when the excision has to be done and about possible additional measures, such as the use of interpositional materials, treatment with drugs, or physical therapy. Some authors recommended [, , ] that the excision as well as the use of interpositional material should be performed after complete maturation, about 6 to 12 months after initial symptoms. In contrast, other authors prefered excision at an early stage []. There were five relapses, both, in the group of early excision (treatment less than six months after first symptoms), and in the group of excision at a later stage (treatment more than six months after first symptoms). However, the group with intervention at a later time point included 27 cases that was somewhat bigger than the early-intervention group (n = 21). Nonetheless, it is not possible to make any clear recommendation for the ideal time point of surgical intervention based on these data.
While some authors suggested aggressive physical therapy after surgical excision [], others advised against this procedure []. They feared that physical therapy stimulates bone formation with the consequence of exacerbation of MOT. Of the 22 reported cases undergoing excision combined with physical therapy, 3 cases relapsed. In the group of 23 patients who only underwent excision without physical therapy there were also 3 relapses. In consequence, no difference in the rate of recurrence was found depending on physical therapy.
In addition to excision, − with or without physical therapy, the use of interpositional materials [, , , , ] or pharmaceuticals, such as etidronate or ibuprofen [] have been proposed. Often, these additional measures were applied in clinical cases with multiple recurrences [, , , , ] so that the benefit of additional treatment cannot be assessed conclusively.
The major limitation of this review is the rarity of the evaluated condition, resulting in a lack of research sources which could offer reliable evidence-based information. With this regard, all studies selected for this review were case reports, which hampered a deeper analysis of risk of bias of each study. Nonetheless, the present study aimed to offer a guide decision for the management and diagnosis of MOT. Additionally, the case reported described the authors clinical experience regarding this condition and shows a treatment option for patients with MOT.
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pmc-6206852-1
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We present the case of a 77-year-old ambulatory man with hypertension, sarcoidosis, complete atrioventricular block status post-pacemaker implantation, chronic kidney disease due to FSGS, and right facial nerve paralysis, who presented with sporadic gait and right face numbness. He was diagnosed with sarcoidosis by biopsy of a tumor in front of the right tibia 14 years before presentation. Since the tumor and abdominal lymphadenopathy were the only manifestation of sarcoidosis and no other signs of organ involvement were present, he received no immunosuppressive treatment. The abdominal lymphadenopathy had been stable over time. Nine years before presentation, he was referred to our nephrology clinic to determine the cause of chronic kidney disease. His serum creatinine level was 1.2 mg/dL and he had proteinuria of 0.4 g per day. Hematuria was not present. Renal biopsy revealed six globally sclerotic glomeruli among all 34 glomeruli (18%) and some residual glomeruli with segmental sclerosing lesions, but no involvement of sarcoidosis. He was diagnosed with primary FSGS. Since the proteinuria was mild, he did not receive immunosuppressive treatment.
One year after that, the patient experienced palpitations and was diagnosed with complete atrioventricular block. Coronary angiography showed no significant stenosis of the coronary arteries, and he underwent pacemaker implantation. Whether sarcoidosis contributed to the complete atrioventricular block was unclear. The abdominal lymphadenopathy and the dyskinesia of the ventricular septum were stable and did not progress over time.
The patient was stable for eight years, until when he started to suffer from sporadic gait and right face numbness that occurred and resolved within a day every few weeks. Three months later, the symptoms recurred along with sudden dysarthria and left limbs weakness. Physical findings were notable for pronator drift on the left side. Perfusion computed tomography (CT) with iodinated contrast and CT angiography revealed no ischemic lesions or occlusion of major cerebral arteries. The symptoms disappeared three hours after the onset. A transient ischemic attack (TIA) was suspected, and he was admitted to the stroke unit. Ultrasonography revealed no stenosis of the internal carotid arteries, and transesophageal echocardiogram showed no abnormalities of the atrial septum. His pacemaker detected paroxysmal atrial fibrillation, which was presumed to be the etiology of the TIA. Thus, edoxaban 30 mg per day was started and he was discharged after one week of hospitalization.
One month after his discharge, his left leg started to swell and his gait worsened. Urinary protein excretion was 0.6 g per day, serum creatinine was at the baseline level of 1.6 mg/dL, and serum albumin level was 3.8 g/dL. Although no coagulopathy was found, ultrasonography revealed left femoral vein thrombosis that was 41 mm long. Edoxaban was stopped, and heparin was administered intravenously for two weeks. Low mobility due to his gait was presumed to be the cause of development of deep vein thrombosis (DVT). The patient was switched to warfarin and was discharged, but the left leg edema persisted. Three months later, he developed complications of urinary retention and constipation.
Four months after discharge, the patient presented to the emergency department with sudden left leg pain and inability to walk. The entire left lower limb was slightly pale and had slow pitting edema. The left dorsal artery was not palpable, and the left femoral artery was barely palpable. Contrast CT revealed occlusion of the left femoral and superficial femoral arteries together with the known DVT in the left femoral vein (Fig. , ). Emergency thrombectomy for acute arterial occlusion was performed and the leg perfusion resumed. The emboli (maximum of 23 mm in diameter) were sent for pathological examination. The patient was admitted to the hospital and started on heparin infusion in place of oral warfarin. The history of recent TIA implied hypercoagulable state, but again no coagulopathy was found. While malignancy screening was being planned, the pathology of the arterial emboli revealed an unusual and surprising finding: the surface of the thrombi was filled with large atypical lymphoid cells (Fig. ) and was covering the necrotic interior of the thrombi. Immunohistochemical analysis showed that the tumor cells on the surface and the necrotic interior of the thrombi were positive for CD20 and CD79a but negative for CD3 (Fig. , ), which is characteristic of B cells. Leukocytosis was absent (white blood cell, 4,000/μL; segmented neutrophil, 55%; lymphocyte, 34%; monocyte, 9%; eosinophil, 2%). Serum soluble interleukin-2 receptor level was 1,548 U/mL (normal, 122–496 U/mL); lactate dehydrogenase (LDH) level, 808 U/L (normal, 120–245 U/L); LDH-2 fraction, 39% (normal, 28–35%), and LDH-3 fraction, 32% (normal, 21–27%). These findings were consistent with large B-cell lymphoma with intravascular proliferation, but the etiology of the aortic thrombi was unclear.
The hematology consultation team considered that the patient needed further biopsy to determine the etiology. Bone marrow biopsy showed normocellular marrow with normal maturation, but with infiltration of CD79a-positive large atypical lymphoid cells within the small vessels (Fig. , ). Although no lymphadenopathy was detected on palpation, CT scan showed swollen bilateral axillary and inguinal lymph nodes, which were up to 30 mm in diameter. While surgical biopsy of the right axillary lymph node and random skin biopsy were planned for diagnosis, the patient developed a complication of sepsis presumably due to pyelonephritis on hospital day nine. Piperacillin/tazobactam and vancomycin were started. Because partial thromboplastin time was prolonged, biopsies were withheld. Although white blood cell and neutrophil counts were improving, the patient died due to sudden respiratory and cardiac arrest on hospital day twelve. The patient had a do-not-resuscitate order. His family agreed to an autopsy.
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pmc-6206890-1
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A 38-year-old previously healthy Sri Lankan woman from Colombo, Sri Lanka presented to a teaching hospital on day 5 of an acute febrile illness. On admission to the medical ward, she was afebrile, with a pulse rate of 120 beats per minute and a blood pressure of 80/60 mmHg. She also had features of a right-sided pleural effusion on examination of her lungs, and an abdomen examination revealed tender hepatomegaly with free fluid.
The results of the investigations done on presentation were as follows: white blood cell count 3400/mm3 (neutrophils 45%, lymphocytes 43%); platelets 18,000/mm3; hemoglobin 11.7 g/dl; hematocrit 49.4%; blood picture – leukopenia, lymphocytosis, and thrombocytopenia suggestive of an acute viral infection; erythrocyte sedimentation rate 06 mm/hour; alanine aminotransferase 1360 U/l; aspartate aminotransferase 2450 U/l; alkaline phosphatase 185 U/l; total bilirubin 1.4 mg/dl; direct bilirubin 0.5 mg/dl; serum protein 5.7 g/dl; serum albumin 2.9 g/dl; prothrombin time 19 seconds; international normalized ratio 1.58; serum creatinine 4.6 mg/dl; serum sodium 143 mmol/l; and serum potassium 5.5 mmol/l.
A clinical diagnosis of possible dengue hemorrhagic fever with shock leading to acute liver and kidney injury was made based on the history, examination, investigations, and the very high incidence of DF in Colombo during the time of her presentation. It was confirmed subsequently with seroconversion of dengue immunoglobulin M (IgM) antibody test (enzyme linked immunosorbent assay) on day 7 of the illness.
She was managed with intravenously administered fluid resuscitation and close monitoring of her hemodynamic status. Following initial stabilization, hemodialysis was done via right-sided femoral venous access. By day 8 of the illness, her serum creatinine declined to 2.1 mg/dl, and the femoral venous catheter was removed as she no longer required hemodialysis.
Her liver functions and platelet count improved gradually. However, by day 10 of the illness, the fever was persistent and her white cell count rose to 13,500/mm3 with 73% neutrophils. A clinical examination to identify a focus of secondary infection revealed a systolic murmur best heard at the mitral area. There were no peripheral stigmata of infective endocarditis. There were no signs of infection at the site of previous femoral venous access.
A two-dimensional echocardiogram was performed and a 0.5 × 0.3 cm sized oscillating intracardiac mass was found attached to anterior mitral valve leaflet. One blood culture was positive for methicillin-resistant Staphylococcus aureus (MRSA), which was sensitive to vancomycin with minimum inhibitory concentration (MIC) 0.5 μg/ml and linezolid, but all the other blood cultures were negative. A diagnosis of possible infective endocarditis was made according to modified Duke criteria (one major criterion – presence of vegetation, and two minor criteria – single positive blood culture and fever).
She was started on intravenously administered vancomycin 1 g daily, to which the response was poor despite adequate trough levels. Therefore, the antibiotic was changed to intravenously administered linezolid 600 mg 12 hourly, to which the response was good. Linezolid was chosen according to the sensitivity pattern of the MRSA strain and due to unavailability of daptomycin or fifth-generation cephalosporins. A repeat two-dimensional echocardiogram was done after completing 2 weeks of antibiotics; there was no vegetation, which was confirmed with a transesophageal echocardiogram. Blood cultures were negative. However, the antibiotic was continued for a total duration of 4 weeks. Blood counts were monitored closely to detect cytopenia caused by linezolid.
On day 14 of the illness, she complained of right lower limb pain, and swelling of right lower limb was noted. A venous duplex of the lower limbs revealed right proximal femoral deep vein thrombosis.
She was commenced on subcutaneous enoxaparin 60 mg twice daily, and warfarin 5 mg daily. The dose of warfarin was adjusted subsequently to 6 mg to maintain international normalized ratio between 2 and 3. Enoxaparin was stopped after the international normalized ratio reached the desirable range, and warfarin was continued for 3 months.
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pmc-6206897-1
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In August 2017, a 45-year-old woman presented to our outpatient urology clinic in consultation for intermittent gross hematuria associated with flank pain. Her medical history was significant for antiphospholipid syndrome and her surgical history was notable for previous tubal ligation; the remainder of her history was unremarkable. She had not undergone menopause. No abnormalities were noted on abdominal and pelvic physical examination. Laboratory work-up revealed a hemoglobin of 12.0 (g/dL) and an estimated glomerular filtration rate >60 (mL/min/1.73 m). Cystoscopic evaluation was unremarkable. To complete her hematuria evaluation, a triphasic CT was obtained demonstrating a 3.1 cm left upper pole heterogeneous, partially enhancing renal mass (R.E.N.A.L Nephrometry Score = 9X). Subsequent abdominal MRI was performed reaffirming the presence of the renal mass and demonstrating cystic components with parenchymal enhancement (). The differential diagnoses derived from the radiologic findings at this time included a renal malignancy, a benign renal mass, multilocular cystic nephroma, or sequelae from a prior focal pyelonephritis.
We reviewed diagnostic and treatment options, most notably active surveillance, renal biopsy, ablative therapy, and partial nephrectomy. Given the cystic nature of the lesion, along with her young age, we recommended robotic partial nephrectomy.
The patient was placed into a modified flank position and using a standard left-sided robotic kidney port placement, the left kidney was exposed, and the mass was readily identified. Intraoperative ultrasonography was used to delineate the echogenic renal mass and the single renal artery was clamped before sharp excision of the lesion. A visually appreciated negative margin was maintained throughout the resection of the mass. The mass was noted to be cystic and loculated with the deep margin penetrating toward the collecting system, requiring a larger rim of resection than normally anticipated for a 3 cm renal mass. After renorrhaphy, the mass was then extracted and sent for pathologic determination.
Pathology revealed a 2.8 × 2.6 × 1.7 cm partially cystic lesion that was encapsulated with negative margins. Immunostains for desmin, CD10, Melan-A, and HMB-45 were performed confirming a diagnosis of endometriosis with smooth muscle metaplasia.
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pmc-6206910-1
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Case 2 (Fig. ) is a 36-year-old man with a history of panic attacks and recurrent depressive episodes. He is intelligent and sensitive but has not managed to finish any degree after high school. A psychiatric evaluation at an outpatient psychotherapy unit concluded that his personality features met ICD-10 criteria for F60.6 Avoidant Personality Disorder and F60.7 Dependent Personality Disorder. Case 2 (Fig. ) grew up in a home with poor resources and a family climate characterized by emotional and physical neglect along with some emotional abuse by both parents. During adolescence, he suffered from loneliness, insecurity, poor self-worth, and self-defeating behaviors such as letting peers take advantage of him. He virtually had no friends in school and he generally felt anxious, shy, and unaccepted among peers. Accordingly, he was prone to act as an underdog or people-pleaser. These features were preserved in adulthood in terms of social withdrawal and intimacy avoidance in order not to feel criticized, ashamed, or rejected. However, today he maintains a permanent job and a couple of relationships beyond his two brothers. As displayed in the figure, Case 2’s (Fig. ) clinical presentation is classified as Mild Personality Disorder (e.g., some distortions in interpersonal appraisal, difficulty maintaining positive self-esteem, is highly submissive in relationships but at least some healthy relationships and occupational roles are maintained) with prominent features of Negative Affectivity (e.g., anxiety, shame, low self-esteem, vulnerability, and depression depressivity) and Detachment (e.g., avoidance of social interactions). Notably, when Case 2 (Fig. ) was younger, he would probably have been classified as Moderate Personality Disorder because he virtually had no friends; but he has improved since then as he now maintains a stable job and at least a couple of relationships.
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pmc-6206910-2
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Case 3 (Fig. ) is a 26-year-old man incarcerated for brutal violence (e.g., purposely injured a shop owner with a blunt instrument just to get his money). Although he claimed to feel no suffering from any symptoms or dysfunction, he sought rehabilitation for his dependency on cocaine which had caused him certain problems while imprisoned including withdrawal symptoms and symptoms of intoxication (e.g., tremor and dry mouth). A psychiatric evaluation concluded that his personality features met ICD-10 criteria for F60.2 Dissocial Personality Disorder including some characteristic psychopathic (e.g., callousness and exploitativeness) and narcissistic (e.g., entitlement) features as well as recklessness without concern for others’ safety. Case 3 (Fig. ) did not recall much from his childhood and appeared aloof and emotionally detached while mentioning that his father was extremely physically abusive towards him and his mother. He did not experience anything positive from friendships, unless they could provide him with certain favors. Moreover, he was not ashamed of admitting that he did not care about harming others, but was rather proud of it, and he generally never felt any emotional or physical pain nor remorse. Case 3’s (Fig. ) clinical presentation is classified as Severe Personality Disorder (e.g., past history and future expectation of severe harm to others, friendships have no genuine value to him, and self-view is characterized by entitlement) with prominent features of Dissociality (e.g., callousness, exploitation of others, and entitlement), Disinhibition (e.g., recklessness with no regard for others’ safety), and some Detachment (e.g., aloofness). In this case Moderate Personality Disorder would not apply because Case 3 (Fig. ) is not even interested in maintaining a single friendship and the risk of dangerous harm to others is not just “sometimes” but “often” taking place.
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pmc-6206910-3
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Case 4 (Fig. ) is a 19-year-old highschool student, who was referred for treatment of ICD-10 F41.2 mixed anxiety and depressive disorder along with symptoms of anorexia nervosa, which she had previously been treated for in a private adolescent psychiatric clinic. Case 4 (Fig. ) is from a relatively stable familiy, where the father works as physician and the mother as dentist. She has always been good at school and at finishing her duties in the home. Even though her parents have been busy with their own careers, they have persistently encouraged her to play the piano at different occasions and excel at horse riding competitions because they knew and expected that she was good at that. For that reason, her father never responded positively when she performed very well, whereas he showed disaoppointment if she did not get an A at her exams. While she was 13 her world fell apart as she discovered her father having an affair with another woman from his workplace, and she started overperforming in school and in sport while gradually developing eating disorder symptoms (restricting food leading to abnormally low weight) and even more unrelenting standards. However, she managed to maintain satisfying relationships with her friends as well as her mother and siblings. Case 4’s (Fig. ) clinical presentation is primarily classified as Anorexia Nervosa in the context of Personality Difficulty (i.e., some long-standing difficulties in her way of thinking about the self and the world, including unrelenting standards, which are insufficiently severe to cause notable disruption in school and most relationships) with prominent features of Negative Affectivity (e.g., depressivity, shame, and anxiety) and Anankastia (e.g., perfectionism, concern with meeting obligations, perseveration, deliberatetiveness, and tight control of own emotional expression). In this case Mild Personality Disorder would not apply because Case 4’s (Fig. ) habitual personality issues are not leading to any notable psychosocial impairment, whereas her problems are mainly attributable to other current mental problems.
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pmc-6206937-1
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A 69 year-old Caucasian male Army veteran was referred to a chiropractor at a Veterans Affairs Medical Center. He presented with left shoulder pain in the setting of a full thickness supraspinatus tear. A thorough history of his neck was gathered as it related to the left shoulder pain. His cervical spine was “stiff” most mornings, which abated with movement and activity. The patient had limited cervical range of motion in all planes and noted episodic neck pain secondary to injuries he sustained from multiple fragment wounds to left side of his neck in 1969.
A review of the final field hospital narrative at the time of initial trauma revealed the multiple frag wounds to the neck, shoulder and scrotum. These injuries subsequently resulted in a trachea-esophageal cutaneous fistula with left cervico-mediastinal abscess and cervical VO. During hospitalization, cervical plain films were reported on which described “prominent demineralization of the bones of the cervical spine with decrease in disk spaces C2 through C6. More demineralization anteriorly with apparent destruction of the anterior aspect of vertebral bodies with resultant reversal of normal lordotic curve. Neural foramina appear intact.” There was no mention of zygapophyseal joint fusion in the original radiographic reports following injury. He was hospitalized for 17 months following the gunshot wound with multiple surgeries to debride the region and reconstruct the left cervical musculature as well as antibiotic therapy. Cervical plain films at time of discharge described “bony healing and fusion of the mid-cervical spine with fusion of 2nd through 5th cervical bodes and calcification of the anterior ligament, C5-C6, C6-C7”. Again there was no remark of zygapophyseal joint fusion after treatment for the initial injuries and subsequent infection.
In office, he endorsed occasional axial neck pain and occipital headache that occurred 1 time per week. Neck Disability Index (NDI) score was 2 out of 50 (4%) []. Pertinent details from the review of systems revealed type 2 diabetes mellitus, carpal tunnel syndrome, hypothyroidism, and irritable bowel syndrome. His medications included tramadol and butalbital, both taken as needed. He used a Thera Cane for self-management of myofascial pain. Despite this history, the patient worked full time from his 20s and was planning to retire at the age of 70.
Physical exam findings revealed a man of anticipated age who was oriented to person, place and time. He weighed 82 kg (181.2 lbs) and measured 177 cm (70 in.). Neurologic examination of the upper and lower extremity dermatomes revealed no deficits. Romberg test was negative and failed to elicit body sway or sense of loss of balance. Biceps, triceps and brachioradialis deep tendon reflexes were 2+ when elicited bilaterally. The plantar response was down going and symmetric. Finger to nose movements were without dysmetria or tremor. Cervical rotation was found to be severely limited in both directions. Global restriction of the cervical spine was noted when assessing joint play, with no isolated segmental motion.
Radiographs of the cervical spine on file demonstrate osseous ankylosis from C2/C3 to C7/T1 with obliteration of the intervertebral discs and accompanying endplates from C2/C3 to C5/C6. (Figs. , , , , ) The C6/C7 and C7/T1 intervertebral discs and accompanying endplates are visualized, though the levels are ankylosed. The facet joints from C2-C6 are ankylosed as well. There is a mild kyphotic alignment of the cervical spine. Metallic fragments are seen in the soft tissues of the neck and upper thorax consistent with the stated history. Provided the history of osteomyelitis secondary to the treatment of the wound and multiple surgeries, the most likely diagnosis is post-infectious ankylosis from C2-T1. The initial field narrative did describe spondylodiscitis with observation of fusion of multiple segments of the cervical spine upon discharge 17 months later. No clear infection of the facet joint was described at the time. Traditional spondylodiscitis is observed to be contained to the anterior column of the spine, primarily the vertebral endplate and adjacent intervertebral disc. However, it has been reported, when infection involves a vertebral body, that it may extend into the pedicles and articular processes which may result in adjacent septic facet arthritis [].
No manual care to the cervical spine occurred following the evaluation as the patient had no complaint in addition to the NDI score of 4%. There was no indication for additional imaging or further work-up regarding the cervical spine. The patient reported complete functional independence in all activities of daily living with reasonable expectation of associated stiffness and limited cervical range of motion. Following the evaluation, the extent of care included education to the patient. Further work-up for the left shoulder and referral to physical therapy resolved left shoulder pain.
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pmc-6207173-1
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Initial presentation
The patient is a 29-year-old male of Asian Indian origin, who presented for symptoms of a viral upper respiratory infection (URI). Initial symptoms included a clear nasal discharge for the past four days, mild nasal and sinus congestion, general myalgia, and a low-grade fever of 100.3°F. Further physical examination showed erythematous nasal turbinates with a distinct lack of cervical lymphadenopathy, tonsillar exudates, sinus tenderness, or pharyngeal erythema. As such, a clinical diagnosis of viral URI was made and treated accordingly with over-the-counter (OTC) acetaminophen-nasal decongestant formulations. However, a review of past medical history showed that the patient had a similar episode of viral URI approximately two months ago that was treated in a similar manner at a different outpatient clinic. The patient also disclosed performing nasal instrumentation along with daily, consistent contact with multiple family members who had similar URI symptoms prior to each personal episode of viral URI in the last six months. As the patient was solely concerned with the resolution of his URI at this first visit, the patient was discharged at his own request but volunteered to appear for a follow-up appointment in two weeks.
Subsequent follow-up visits involved a more extensive review of symptoms along with a more thorough nasal examination. The patient noted experiencing transient non-mucoid rhinorrhea in the morning on a near-daily basis for over two years. This rhinorrhea was usually very transient, lasting approximately one hour. His familial and personal medical history was insignificant for any conditions that may predispose to recurrent infections or any other pathology, especially those pertaining to an immune-compromised state. Specifically, he lacked any severe febrile symptoms or signs of sepsis. In addition, his history did not indicate any repetitive episodes of gastrointestinal or lower respiratory infections. Further, psychologically, he displayed an intact sensorium with no significant issues regarding his decision-making capacity, understanding, mood, or memory.
The patient described that he had started picking at coarse and thick nasal hair follicles that initially irritated his internal nasal cavity. Later, the patient began a prophylactic regimen of using metal instruments to selectively remove thicker hair follicles. This regimen had a paired compulsive aspect, often with a sense of anxiety and relief. Although it did not affect his daily functioning, the patient often felt irritation at not removing coarse nasal hair follicles and relief upon doing so. The patient maintained this habit for approximately one year, often with associated internal lacerations, temporary mucoid and bloody nasal discharge, local nasal tenderness, and inflammation. Subsequently, the patient observed that with every successive episode of inflammation, his left external nare underwent greater enlargement and stenosis. At a later stage, the patient noticed a reduced hair presence in his nasal cavity and local nasal tenderness, ultimately discouraging and reducing his regimen's frequency.
On examination, the primary care team noticed that on passive breathing, both nares had sufficient and equal air flow. However, on forceful nasal expiration, the stenotic nostril had significantly reduced air flow compared to the intact nare. The patient's left nostril was significantly stenosed due to an expanded alar lobule, soft tissue facet, and a mild contralateral deviation of the columella (Figures -). The nasal mucosa was erythematous and showed patchy lichenification. Computer tomography (CT) of the sinuses showed no evidence of alteration in the superior nasal and sinus cartilage beyond the external nare. His serum testing for metabolic or electrolyte abnormalities was insignificant. Otorhinolaryngology (ENT) consultation also confirmed the absence of any nasal polyps, septum perforation, or any other abnormality in the nasal tissue. A psychiatric evaluation identified this patient to have a generalized body-focused repetitive behavior (BFRB) disorder.
The Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for rhinotillexomania are based on the same criteria as trichotillomania but with a specific focus on the nasal mucosa. It states that hair picking should be in a pattern where it may or may not be noticeable (widely distributed or localized), with possible attempts to conceal/camouflage the hair loss, and the patient has made repeated attempts to stop or decrease the hair pulling. It is also important to the diagnosis that no other psychiatric or medical condition can be responsible for the hair loss [].
Management
Given the already reduced scope of the nasal regimen, the lack of any significant respiratory impediment and the relatively greater side-effect potential of an antidepressant course, a trial of behavioral therapy was conducted. This regimen included regular nail trimming, continuous hand hygiene, and aversion conditioning (via malodorous stimuli on fingertips). Familial support was also encouraged in avoiding the same lifestyle changes. As part of his aversion therapy, the patient often dipped his second and third digits in malodorous oil. As such, any digital proximity to the nasal area produced a strong aversion response to his nasal habit. Regular digital nail trimming with sufficient hand hygiene also reduced the risk of any intranasal lacerations and its resulting infection. Finally, as the stenosis was cosmetic in nature, the patient declined any need for surgical correction. The prognosis was also improved based on the ego-dystonic nature of this case, where the patient already recognized the abnormal pattern as unhealthy. This motivated the patient to make significant attempts to correct this unhealthy behavior. Overall, while the physical nare stenosis was not reversed, the client reported a nearly complete cessation of both morning rhinorrhea episodes as well as nasal digital exploration episodes at the three-month interval of behavioral modification therapy.
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pmc-6207273-1
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A 67-year-old non-smoker man with a past medical history of non-obstructive coronary artery disease, hyperlipidemia, essential hypertension, paroxysmal atrial fibrillation, and subclinical hypothyroidism and no prior history of autoimmune disease in the family underwent permanent dual chamber pacemaker implantation for sinus node dysfunction. The patient was discharged home without any immediate procedural complications but returned to the hospital two weeks later with increasing dyspnea and chest discomfort. He had extensive testing, including workup for ischemic heart disease. A left heart catheterization was done, revealing non-obstructive coronary artery disease. A transthoracic echocardiogram revealed a small pericardial effusion without any other echocardiographic abnormalities. He was discharged home on ibuprofen with a diagnosis of pericarditis. He was admitted to our facility a month later with worsening dyspnea and non-productive cough. He denied fever, chills, or chest pain at presentation. The physical examination was consistent with decreased breath sounds in the right middle and lower lung fields. Chest radiograph (Figure ) and computerized tomography (CT) of the chest (Figure ) revealed a large right-sided pleural effusion and a small-moderate pericardial effusion. Pertinent laboratory workup showed no leukocytosis, hemoglobin of 11 g/dl, and a supratherapeutic international normalized ratio (INR) of 3.5 secondary to warfarin use. He received empiric antibiotics for a possible pulmonary infectious process. He received fresh frozen plasma and vitamin K to reverse the coagulopathy and underwent pleural fluid drainage with chest tube placement. A total of three liters of serosanguinous fluid was removed. The pleural fluid analysis was consistent with an exudative effusion using Light’s criteria with a pleural fluid/serum protein ratio of 0.625, a pleural fluid/serum lactate dehydrogenase (LDH) ratio of 1.526, and a pleural fluid LDH > 2/3 upper limit of normal plasma levels. Pleural fluid pH was elevated to 8.6 (normal: 7.60-7.65). Pleural fluid microbiology, including bacterial, fungal, and acid-fast bacilli cultures, were negative. Relevant laboratory and microbiologic data are shown in Table . A repeat CT scan of the chest following chest tube placement showed marked interval improvement in pleural effusion, and the chest tube was removed. On the chest CT scan, there was a concern for possible right atrial pacemaker lead causing the perforation of the right atrial wall due to its close proximity to the atrial wall and the associated pericardial effusion (Figure ). However, no conclusive evidence of cardiac perforation was identified on repeat imaging and the patient remained clinically stable during the hospitalization. A pacemaker interrogation was normal. He had a repeat transthoracic echocardiogram three weeks later, which didn’t reveal any evidence of atrial perforation, including no pericardial effusion. A follow-up chest radiograph demonstrated near-complete resolution of the pleural effusion. This case represents an unusual presentation of PCIS where symptoms were predominantly pulmonary, including a large unilateral pleural effusion.
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pmc-6207282-1
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A 45-year-old male without a significant past medical history presented to the emergency department (ED) as a walk-in, complaining of 10/10 intractable headaches with lightheadedness, confusion, and loss of balance, starting one day before presentation to the ED. A computed tomography (CT) scan of the head done in the ED revealed a hyperdense lesion on the right at the level of the peri- pontine cistern and magnetic resonance (MRI) of the brain done for a further evaluation of the lesion revealed a 4.1 x3.3x 3.2 cm mass with mild tonsillar herniation and a mass effect on the brainstem (Figure ).
MR signal post-COR T1 revealed a hyperintense cortical grey matter lesion with a patchy heterogenous enhancement due to possible hemorrhage or necrosis (Figure ).
On examination, he continued to complain of headaches, with the only pertinent physical findings being a positive Babinski sign bilaterally. The physical exam was negative for loss of proprioception and loss of cerebellar function (finger-to-nose test). Consequently, he was admitted for further work-up. Since an adult brain neoplasm is more likely to be a metastasis rather than a primary malignancy, CT scans of the chest, abdomen, and pelvis were obtained. The scans identified a right thyroid nodule but no lung mass on CT of the chest, and the abdomen was free of masses except for a 2.3 cm renal cyst. He had a right suboccipital craniotomy on Day 2 of admission. The intraoperative report concluded an undifferentiated neoplasm with a histological differential diagnosis of medulloblastoma, ependymoma, or other neuroepithelial neoplasms. Additionally, the CD45 marker was positive, which raised the differential diagnosis of a lymphoproliferative disorder. The case was referred for consultation to a tertiary care center, which made the diagnosis of classic medulloblastoma, world health organization (WHO) grade IV. The tumor was composed of densely packed cells with round to oval highly hyperchromatic nuclei surrounded by scanty cytoplasm most consistent with classic medulloblastoma with non-desmoplastic nodules. He subsequently developed vasogenic edema that completely occluded his fourth ventricle, producing obstructive hydrocephalus and required the emergent insertion of a frontal ventricular drain into the right lateral ventricle. He later developed a fever, headache, and neck stiffness suggestive of meningitis. Lumbar puncture was deferred due to raised intracranial pressure, and the patient was started on empiric antibiotics. Leukocytosis resolved and fever subsided. Additionally, he developed hyponatremia with urine osmolality of 384, urine sodium of 24, and serum osmolality of 284 with a differential diagnosis of syndrome of inappropriate anti-diuretic hormone (SIADH), cerebral salt wasting, or reactive elevation of the anti-diuretic hormone secondary to surgery. He was started on sodium chloride tablets, demeclocycline, and fluid restriction. Post-surgery imaging showed no metastasis and radiation oncology recommended follow-up in a tertiary center.
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pmc-6207284-1
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A 71-year-old female came to our institute after falling down from her bed in September 2016. She sustained an injury on her left thigh. She also gave a history of taking bisphosphonates (alendronate, 70 mg weekly) continuously for the past five years. On examination, she was unable to walk or put any weight on her left leg. Her left leg was in complete external rotation, and she was unable to do active straight leg raises (SLR). With the help of an X-ray, a subtrochanteric fracture of the left femur was diagnosed (Figure ). The right thigh X-ray also showed thickening of the lateral cortex, which was indicative of the changes occurring due to the bisphosphonates. The patient was a known case of controlled diabetes mellitus and hypertension.
After the necessary preoperative investigations, the patient was taken up for fixation with close proximal femoral interlock nailing of the trochanteric fracture of the left femur (Figure ). As there was no breach in the cortex seen on the right side, no operative intervention was planned. After fixation, the patient was started on partial weight-bearing walking after three weeks. After reaching the required serum calcium, serum Vitamin D, and serum parathyroid hormone (PTH) levels, the patient was started on teriparatide, 8 IU subcutaneous daily injections, along with elemental calcium, 500 mg, and Vitamin D, 60,000 IU weekly, for six months.
On the subsequent X-rays, it was seen that the bone was not uniting; after nine months, the fracture was labeled as a nonunion subtrochanteric fracture (Figure ). The patient was taken up for surgery after one year for the same. The fracture site was exposed and after freshening of the fracture ends it was seen that fixation was stable with intramedullary nail. However, additional stability and compression were achieved at the fracture site with a 6 hole 3.5 mm LC-DCP which was then fixed with four cortical screws inserted by “missing” technique. "Missing" technique entails the insertion of the plate screws so that they miss the the intramedullary nail. At the fracture site, a cortico-cancellous bone graft taken from the same side anterior superior iliac spine was impacted at the fracture site. About 60 ml of bone marrow was aspirated from the opposite iliac crest, and a 4 ml concentrate was prepared which was mixed in 10 cc granules of calcium triphosphate; the granules were placed all around the fracture site (Figure ).
Postoperative recovery was uneventful and the patient was mobilized using partial weight-bearing the next day. The fracture showed early signs of union, and three months postoperatively the fracture showed signs of complete union (Figure ). Clinically the fracture also showed signs of union with the patient able to walk without any pain.
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pmc-6207285-1
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We report a case of a 70-year-old male patient who presented to the outpatient department (OPD) with chief complain of dribbling of watery secretions from nasal mucosa on the thought of food or sight of food. Each episode of dribbling comprised of secretion of 50–100 ml of watery fluid. Past medical history was significant for hypertension for three years and type 2 diabetes mellitus for five years. There was no history of any neuro-degenerative disease in the family. Furthermore, there was a history of constipation for three months along with the presence of mucus in stool. Colonoscopy was performed which showed no significant pathology. There was no evidence of dementia or other psychiatric disturbances. Mild sleep abnormalities were present. Forward flex posture was present along with broad-based gait. A mask-like face was not present.
A provisional diagnosis of gustatory rhinorrhea was made and the patient was advised of anti-cholinergic medications and anti-histamine drugs. There was little to no benefit with these medications. The patient was further prescribed with nasal corticosteroid sprays, mucolytic medications, and nasal irrigations but these prescriptions only provided mild symptomatic improvement.
Twenty-two months later, the patient presented again in the OPD and had developed fine tremors in fingers and hands. These tremors were absent in head and lower limbs. Tremors were only evident at rest while absent on activity. Further examination revealed an altered sense of smell which was un-noticed by the patient. The patient was diagnosed with Parkinson’s disease. Dopamine-based therapy was commenced which resulted in improvement of rhinorrhea as well as motor symptoms.
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pmc-6207288-1
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A 65-year-old gentleman with past medical history significant for chronic kidney disease stage 3, liver cirrhosis, and thoracolumbar spinal stenosis presented to the hospital because of progressive dyspnea, fever, and non-productive cough for two days. He underwent laminectomy for spinal stenosis, later complicated by T5-8 vertebral osteomyelitis with epidural phlegmon, requiring drainage and debridement with hardware removal. He was started on empiric antibiotics with intravenous vancomycin and cefepime, which were replaced with daptomycin when phlegmon cultures grew methicillin-sensitive Staphylococcus aureus. He received daptomycin for three weeks.
He appeared in respiratory distress with tachypnea and was hypoxemic on arrival to the hospital with a peripheral capillary oxygen saturation (SpO2) of 90%. Pulmonary examination revealed diffuse scattered bi-basal crackles. Laboratory studies revealed a polymorphonuclear leukocytosis and eosinophilia. Pulmonary infection from other infective agents, including bacterial, fungal, mycobacterial, and viral organisms, was considered in this patient and appropriate culture and serologies were sent but reported negative. The remainder of the laboratory and microbiology data are shown in Figure . His computerized tomography (CT) chest scan with contrast at arrival revealed bilateral pulmonary infiltrates, as shown in Figure . A diagnosis of daptomycin-induced AEP was strongly suspected. Bronchoscopy and bronchoalveolar lavage (BAL) were performed the next day, which revealed an eosinophil count of >20% in lavage. He was started on intravenous solumedrol and daptomycin was discontinued. He responded to this regimen in the next 24-48 hours with subjective improvement and reduced oxygen requirements. He was discharged home on a reducing course of steroids for two weeks. A repeat CT chest scan at his three-week follow-up revealed a resolution of the pulmonary infiltrates (Figure ).
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pmc-6207488-1
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A 56-year-old Caucasian male with past medical history of a high-grade astrocytoma of the right temporal lobe presented to the oncology clinic with dyspnea and palpitations for several weeks. He had been diagnosed with high-grade astrocytoma six months prior, which was treated with surgical resection and was followed by concurrent chemotherapy and radiation for six weeks with temozolomide with subsequent maintenance temozolomide. Pathology from his original brain tumor noted mixed features of an anaplastic pleomorphic xanthoastrocytoma (PXA) with atypical features versus glioblastoma. The pathologist described an astrocytic neoplasm composed of cells with variable polymorphism, brisk mitotic activity including atypical forms, and necrosis were present. Immunohistochemistry (IHC) stains were positive for glial fibrillary acidic protein (GFAP), oligodendroglial lineage 2 (OLIG2) and cellular differentiation 34 marker (CD34). The tumor did not harbor isocitrate dehydrogenase 1 (IDH-1), methylguanine-DNA methyltransferase (MGMT) or B-raf proto-oncogene serine/threonine kinase (BRAF) mutations.
Upon presentation to our clinic, the patient was still receiving maintenance therapy with temozolomide 200 mg/m2 on days one through five every 28 days. On physical exam, he was found to be tachycardic with a heart rate in the 150s with an irregularly irregular rhythm. On physical exam, he was noted to have decreased breath sounds to auscultation on the right and dullness to percussion in the mid to lower right hemithorax. He was admitted to the hospital for further evaluation. Computed tomography (CT) of the chest showed a pulmonary embolus in the left pulmonary artery in addition to a large pleural effusion on the right with pleural thickening and a nodular appearance. There was a new hypodense lesion in the superior part of the liver measuring 2.7 x 2.3 cm with multiple lytic bone lesions on CT of the abdomen. A bone scan confirmed the metastatic nature of bone lesions. Magnetic resonance imaging (MRI) of the brain showed abnormal enhancement in the middle cranial fossa, which was thought to be related to prior treatment. Anti-coagulation with heparin was initiated for treatment of the pulmonary embolus. Thoracentesis revealed the effusion to be exudative and cytology was significant for atypical cells. Thoracoscopy was performed for pleural biopsy and on examination, classic pleural studding was noted (Figure ). Pleural biopsies were obtained using rigid optical forceps. Biopsy report showed malignant cells with initial IHC stains negative for calretinin, carcinoembryonic antigen (CEA), cytokeratin 5/6 (CK 5/6), pankeratin, thyroid transcription factor 1 (TTF-1) and Wilms tumor protein (WT-1), as is usually done to rule out lung carcinoma or mesothelioma. Because of marked pleomorphism in the sample which is normally seen in glioblastoma or high grade astrocytomas, glial fibrillary acidic protein (GFAP) by IHC was checked and found to be positive. Additionally, S100 (acidic protein, which is a common marker for neural tissue and melanoma) by IHC was also positive (Figure ). Coupled together, these findings were consistent with metastasis from his known diagnosis of high grade astrocytoma/glioblastoma. The patient had placement of a PleurxTM catheter and was discharged home on anticoagulation therapy. Upon discharge and finalization of pathology report, the patient was offered chemotherapy with bevacizumab, but the patient opted to be placed in hospice and subsequently died a few weeks later.
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pmc-6207489-1
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A 29-year-old Caucasian female was brought to the emergency department (ED) in the late afternoon by ambulance for altered mental status. Earlier that day, her mother had gone to her apartment, at which time, the patient had become more confused and lethargic, prompting the phone call to emergency services. In the ED, she was lethargic and not answering questions. As per her mother, she had confessed to taking a large bottle of ibuprofen in a suicide attempt earlier that morning. In all, she had taken approximately 300 tablets of 200 mg ibuprofen (approximately 60,000 mg in total). Of note, she had no known allergies to medications. She had a medical history, including depression, asthma, alcohol abuse, and prior drug abuse (cocaine, Percocet, and intravenous heroin). In fact, she had completed a drug rehabilitation program six months ago and had not been drinking or using illegal drugs since then. She still smoked half a pack of cigarettes per day “for years” and would occasionally have an alcoholic beverage with friends. Her surgical history included breast reduction surgery. Her father had a history of hypertension, her mother had non-alcoholic fatty liver disease (NAFLD), and her aunt (mother’s sister) had cryptogenic cirrhosis).
Her vital signs in the ED were a temperature of 98 degrees Fahrenheit, a pulse of 111 beats per minute, a blood pressure of 109/66 mmHg, a respiratory rate of 17, and an oxygen saturation of 97% on room air. Her physical exam was non-revealing other than her lethargy. Her initial complete blood count (CBC) and basic metabolic panel (BMP) were within normal limits. She was intubated for airway protection and was admitted to the medical intensive care unit (MICU) for further treatment. She was then emergently hemodialyzed overnight for ibuprofen overdose (early morning of Day 2). On the morning of Day 3, her mental status had returned to her normal baseline, so she was successfully extubated. On Day 4, the MICU team noted an elevation in her liver enzymes (LFTs). From a baseline of normal, her total bilirubin was now 2 mg/dL, aspartate aminotransferase (AST) 350 U/L, alanine aminotransferase (ALT) 383 U/L, albumin 2.3 g/dL, and international normalized ratio (INR) was 1.5. Her alkaline phosphatase (ALP) was normal. Gastroenterology was consulted at that time. She denied any history of liver disease. She stated she had not recently taken any supplements, vitamins, over-the-counter medications (other than the ibuprofen), herbal medications, or herbal teas. She denied any abdominal pain, nausea, vomiting, hematemesis, melena, or hematochezia. Vital signs were within normal limits and stable. On exam, she appeared obese, jaundiced, and had multiple tattoos on her body. She had no abdominal tenderness to palpation, no appreciable abdominal organomegaly, and had appropriate bowel sounds. She was thought to have had transaminitis due to a possible ischemic liver from her initial borderline hypotension. Ibuprofen toxicity was also considered but as a secondary differential given its rarity. Recommendations were made to start the patient on N-acetyl cysteine (NAC), trend her LFTs, and start a daily proton pump inhibitor by mouth, to obtain a right upper quadrant sonogram, to rule out other causes of hepatitis, including viral and autoimmune, and to contact the local transplant hepatology service to discuss the patient.
On Day 5, her LFTs continued to trend up. She tested immune to hepatitis A and B and negative for hepatitis C and HIV. Her ferritin was elevated to 1664 ng/mL, anti-nuclear antibody was positive (ratio of 1:18), anti-mitochondrial antibody was negative, anti-smooth muscle antibody was positive, herpes simplex 1 and 2 were both positive, cytomegalovirus antibody was positive, varicella zoster virus was negative, Epstein-Barr virus antibody was positive, alpha 1-antitrypsin was negative, and ceruloplasmin was negative. The sonogram showed an enlarged liver (17.7 cm), hypoechoic in texture and indicative of hepatitis (Figure ). The transplant hepatology service stated that she was not a candidate for emergent liver transplant at this time, given her appropriate mental status. On Day 6, her LFTs continued to trend up and she began to have intermittent, watery diarrhea, occasionally streaked with bright red blood. Her hemoglobin stayed within the normal range and she tested negative for Clostridium difficile. She was also given a total of 15 mg of vitamin K for her elevated INR of 1.9. On day 7, her LFTs peaked, with a total bilirubin of 5mg/dL, AST > 717U/L, ALT 1873U/L, and albumin 2.5g/dL. Her platelets had also steadily decreased from 278 to a low of 59. At the peak of her LFTs, her model end stage liver disease-sodium (MELD-Na) score was 31, which signifies a 19.6% chance of three-month mortality. Again, speaking to the transplant hepatology service, she was still not a candidate for emergent transplant given her appropriate mental status.
After that, her LFTs began down-trending to normal (Table ). Her renal function remained very poor and she was still requiring intermittent hemodialysis. She was downgraded from the MICU and was transferred to the psychiatric unit for further management. Upon discharge, she was to follow up with our hepatology clinic for further evaluation.
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pmc-6207490-1
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A 26-year-old African American male with a past medical history of hypertension, end-stage renal disease managed by hemodialysis presented to the emergency department with complaints of abdominal pain, nausea, and vomiting. He had been noncompliant with his antihypertensive medications which included nifedipine, hydralazine, and spironolactone. On presentation, the patient’s blood pressure was 231/123 mmHg. Laboratory workup showed a white blood count of 17.3 × 109/L (normal range: 4.5 to 11.0 × 109/L), hemoglobin 7.8 gm/dL (normal range: 13.5 to 17.5 g/dL), platelet count 46 × 109/L (normal range: 150 - 400 × 109/L), reticulocyte count 7.8%, total bilirubin 1 mg/dL (normal range: 0.1 to 1.2 mg/dL), lactate dehydrogenase 1,235 U/L (normal range: 140 to 280 U/L), haptoglobin < 10 mg/dL, and direct Coomb's test was negative. Numerous schistocytes were identified on a peripheral blood smear (Figure ).
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pmc-6207491-1
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An 82-year-old female patient with a symptomatic gallstones disease and a recent weight loss was admitted to our hospital. The patient’s past medical history was free of other diseases and on physical examination, a Murphy sign was present. The abdominal ultrasound mentioned a large gallstone in the gallbladder and a hypoechoic liver mass. Liver blood tests, including tumor markers CEA and CA 19-9 were normal. Magnetic resonance imaging-magnetic resonance cholangiopancreatography (MRI-MRCP) revealed a liver tumor mass (4.5x3.5 cm) located mainly in segments IVa and VIII of the liver with an extent to segment I (Figure ).
The tumor displaced the adjacent hepatic veins and the inferior vena cava (IVC) without any signs of vessel invasion. There were no signs of liver cirrhosis and no dilated bile ducts or capsular retraction were noted. There was no associated lymphadenopathy. At this point, imaging characteristics were controversial regarding diagnosis. The differential diagnosis tilted in favor of ICC, mainly due to the enhancement characteristics and the absence of liver cirrhosis, as seen in Figure .
The patient was scheduled for exploratory laparotomy with a provisional diagnosis of an ICC. Intraoperatively, a cholecystectomy and lymph node sampling from the hepatoduodenal ligament were performed and both specimens were negative for malignancy on frozen section. Next, the liver was mobilized and the tumor was carefully dissected free of the hepatic veins, the IVC, and the rest of the liver parenchyma. The gross morphology of the liver specimen revealed a solid, grey-yellow liver lesion with a soft consistency. In the center, a light yellow region was noted, as can be seen in Figure .
The frozen section was negative for malignancy. Histologically, the tumor was characterized by a heavy inflammatory infiltrate in myxoid collagen stroma, consisting primarily of plasma cells, lymphocytes, and eosinophils. Fibroblast cells without significant fibrosis composed the stroma. There was no evidence of malignancy in the tissue examined. The final pathology report revealed an IPT of the liver.
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pmc-6207494-1
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A 27-year-old woman with known history of GD from seven years presented at the 21st week of her first spontaneous pregnancy. She was on long-term CBZ (10 mg daily) treatment and was clinically euthyroid. Thyroid function tests were compatible with subclinical hyperthyroidism, with free thyroxine (FT4) of 19.6 pmol/L (normal range: 12-22), free triiodothyronine (FT3) of 5.2 pmol/L (normal range: 3.1-6.8), and TSH of 0.05 mIU/L (normal range: 0.25-4.5) (Figure ).
The TRAbs assay was negative. The patient remained euthyroid and the TRAbs remained negative throughout pregnancy. She delivered normally without complications (the neonate’s birth weight was 2500 gr). Postpartum the patient continued CBZ 10 mg daily.
Two months later she was pregnant again, having also symptoms of thyrotoxicosis: palpitations, heat intolerance, sleep disturbances, as well as bilateral exophthalmos. On clinical examination, she had sinus tachycardia with a heart rate of 115/min, diffuse goiter with a bruit, and fine tremor in her hands. Thyroid function tests revealed a fivefold rise of FT4 levels (FT4: 100 pmol/L, normal range: 12-22), a sixfold rise of FT3 levels (FT3: 34.6 pmol/L, normal range: 3.1-6.8) (Figure ), and a suppression of TSH levels (TSH: <0.01 mIU/L, normal range: 0.25-4.5). The TRAb levels were elevated as well (TRAbs: 16 U/L, normal range: <1.75). Treatment was changed to PTU (300 mg daily) and selenium (200 mg daily) with only partial response, as the FT4 and FT3 levels decreased to twice normal. During the second trimester, PTU was switched to 20 mg of CBZ daily; thyrotoxicosis was adequately controlled in the 36th week of pregnancy, with normal FT4 and FT3 levels and suppressed TSH. The patient delivered with a selective caesarean section (CS) at the 38th week of pregnancy. The TRAb levels remained positive throughout the second pregnancy (TRAbs at 34th week of pregnancy: 2.03 U/L, normal range <1.75). Neither the mother nor the neonate had complications (neonate birth weight: 2890 gr). Postpartum, the patient was advised to increase the dose of CBZ to 30 mg daily and thyroidectomy was scheduled.
The scheduled thyroidectomy was not performed, as within a few months the patient was pregnant for the third time. She presented with more accentuated symptoms of palpitations, tremor, heat intolerance, irritability, bilateral exophthalmos, and diffuse goiter. Thyroid function tests revealed severe thyrotoxicosis with TSH < 0.005 mIU/mL, (normal range: 0.25-4.5), FT4: 66.25 pmol/L, (normal range: 12-22), and FT3: 23.04 pmol/L, (normal range: 3.1-6.8). During the third pregnancy, the patient developed resistance to ATDs. More in detail, during the first trimester PTU was initiated. Her FT4 failed to normalize despite high doses of PTU (400 mg daily) (Figure ). In the second trimester, a switch to maximal doses of MMI (60 mg daily) had a minimal benefit on FT4, which reached 43 pmol/L (normal range: 12-22); it was discontinued and CBZ was started at maximal doses (45-60 mg daily) with no response (FT4: 52.4 pmol/L). Although the patient’s compliance was questioned, careful in-hospital observation and inspection did not disclose any infractions. Her TRAb levels remained remarkably elevated throughout pregnancy. In the 21st week of pregnancy they had reached a peak of 27.7 U/L (normal range <1.75); the elevated TRAb persisted, since in the 30th week a value of 7.48 U/L was found.
Given the poor control of maternal thyrotoxicosis, the high doses of ATDs, and the elevated TRAb levels during pregnancy, thorough fetal surveillance was performed to minimize possible complications. Serial fetal ultrasounds were performed for the assessment of fetal viability, fetal growth, amniotic fluid volume, fetal anatomy, and detection of malformations. Moreover, a fetal cardiac ultrasound in the 30th week of pregnancy excluded fetal tachycardia and signs of congestive heart failure. Propranolol was also administered to control the symptoms of thyrotoxicosis. In the 32nd week of pregnancy, the patient was hospitalized and, given the increased risk of preterm delivery, antenatal corticosteroids were administered for fetal lung maturation [].
Since a remarkable improvement in thyroid function was observed within a few days of starting corticosteroids, with FT4 levels reaching 29.3 pmol/L (normal range: 12-22), corticosteroid administration was kept along with CBZ [, ]. A 30 mg daily dose of prednisolone led to normalisation of FT4 levels within one week (FT4: 15.9 pmol/L) (Figure ).
The patient underwent CS at the 37th week without complications. The neonate weighed 2280 gr and was hospitalized for three months because of staphylococcal encephalitis unrelated to the mother’s GD. Postpartum, treatment included 20 mg of prednisolone in adjunction with 15 mg of CBZ per day. Surgical treatment was planned. Thyroidectomy was performed two months later without complications. Prednisolone was gradually withdrawn; the patient is currently treated with thyroxine and is clinically well.
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pmc-6207495-1
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A nine-year-old girl presented to the National Institute of Integrative Medicine (NIIM) Clinic in Melbourne, Australia, in June 2016 with chronic pain, extreme muscle wasting requiring a wheelchair, growth retardation, severe underweight (20 kg), swollen and painful joints, heart palpitations, loose stools, and headaches. Her condition and extreme weakness didn’t allow her to move her limbs without assistance; she was not able to feed herself, or move her legs without assistance or stand up.
The nine-year-old had not been able to attend school for several months due to the severity of her illness, and she had been in and out of hospital on a regular basis. The girl had been diagnosed with juvenile idiopathic arthritis (JIA) three years earlier and had been treated with standard medications for the potential autoimmune condition, including regular corticosteroid infusions with methylprednisolone, treatment with methotrexate, and anakinra, a recombinant and modified interleukin-one-receptor-antagonist.
Despite these conventional treatments, her condition had progressively worsened over the course of three years, and by the time she presented to the NIIM clinic her prognosis was extremely critical. The sudden onset of illness three years earlier with extremely high fever and rashes, coincided with the girl’s pet dog’s illness, sudden death and exposure to the dog’s blood into the girl’s eyes. Her pet dog had been ill with a wobbly walk, weight loss, and listlessness prior to its accidental death with open wound blood loss, suggesting a plausible path of infection.
Materials and methods
Our research lab at the National Institute of Integrative Medicine (NIIM) in Melbourne, Australia has developed a two-part Pathogen Blood Test assay combining cytological microscopy and genetic analysis of the pathogen by polymerase-chain-reaction (PCR) DNA analysis []. Fresh and processed blood is handled in air-filtered laboratory cabinets with sterilised equipment.
In the first part of this Pathogen Blood Test, the microscopic analysis, 10 ml of the patient’s blood is treated with a saponin-enriched buffer to lyse the red blood cells []. The treated blood is vacuum-filtered through a special polycarbonate filter with eight micron holes and stained with standard May-Gruenwald-Giemsa for cytological analysis using a Leica light microscope (Leica Microsystems Inc., IL. USA) with 63x10 ocular magnification. The image is captured with the Leica EC3 digital camera (Leica Microsystems Inc., IL. USA).
This first part of the Pathogen Blood Test of isolating rare cells in blood by filtration has been adapted from the cytology-based Circulating-Tumour-Cells (CTC) Isolation-by-Size-of-Epithelial-Tumour-cell (ISET) technology developed by Rarecells, France, which focuses on the isolation and identification of human cancer cells from blood [].
Using light microscopy we screen the erythrocyte-free enriched blood for human and non-human cells, including potentially pathogenic single or multicellular organisms, such as bacteria, protozoa, parasites, or fungal elements.
In this case study, the microscopy revealed the presence of a large number of fungal elements amongst inflammatory cells (Figure ).
In the second part of the Pathogen Blood Test, any non-human organisms detected in the processed blood can be further identified by genetic analysis [].
As we found an unusually large number of fungal elements in the microscopic analysis in this case, we proceeded with fungal DNA analysis as follows:
Genetic identification of fungal elements was adapted from references [] and []. DNA was extracted from 3 ml whole blood using a bead beating step to lyse tough-walled cells including fungal spores and hyphens with MP Biomedical FastPrep®-24 Instrument and Lysing Matrix B () (MP Biomedicals, LLC., CA, USA), followed by Qiagen DNeasy tissue protocol using the Qiagen blood and tissue DNA extraction kit () (Qiagen, Hilden, Germany). Subsequently, a pan-fungal PCR-assay with primers and PCR conditions as described in [] was performed, using a real-time qPCR Roche Light-cycler-1.5, (Basel, Switzerland). The PCR products were purified with the Qiagen PCR cleaning kit and Sanger-sequenced with the same primers by the Micromon DNA Sequencing Facility at Monash University, Melbourne, Australia. The acquired sequence was then analyzed by comparative genetic analysis using the Basic-Local-Alignment-Search-Tool (BLAST) search tool () [].
The amplified fungal DNA best matched Sagenomella species of the ascomycete family Trichocomaceae, which also includes Aspergillus and Penicillium.
Sequence identity of the pan-fungal PCR-product to Sagenomella and Aspergillus species was high (97% and 94%, Figure ).
Pathogenic infections with Sagenomella have been described in the literature, including a fatal systemic fungal infection in a dog with a history of listlessness, extreme weight loss, joint issues, and multiorgan involvement, as identified in the autopsy report []. The girl’s dog in this case report had also displayed similar symptoms before sudden death, and transmission of an infection appears plausible as the sick dog’s blood came in contact with the girl’s eyes according to her mother.
Prompted by these findings, we tested our patient for Aspergillus antibodies and found highly elevated serum levels of immunoglobulin E (IgE) = 8.7 kU/L (cat III; high), while the absence of elevated IgM serum levels suggested a chronic rather than an acute infection.
Our test results encouraged a radical change of the patient’s treatment plan, by which immunosuppressive therapy, which at that time consisted of prednisolone injections, was withdrawn gradually over six months. At this time the patient was too weak for any anti-fungal medications. Instead, immune system supportive treatments were provided, including immune-stimulating herbs and nutrients, such as high dose vitamin C, vitamin D, and ozone therapy [, ]. In addition, the patient was able to participate in gentle water-based physiotherapy sessions two-three times a week.
Over the next six months, the patient made a progressive recovery, including remarkable reversion of the previously swollen and painful joints, with only occasional pain in the wrist. Importantly, the patient’s appetite, energy levels, and mood improved. She returned to being able to use her hands again to feed herself and participated in regular walking exercises in water. After about six months since cessation of the treatment with regular immunosuppressant medications, the patient started to gain weight (>20kg) including muscle mass and had solid bowel movements. Her mood and energy levels continued to improve and about ten months after detection of the systemic fungal infection and the beginning of the new treatment program, she was able to return to school again firstly part-time then full-time.
A repeat Pathogen Blood Test one year after the initial test identified remaining fungal presence with Sagenomella, albeit to a lesser extent than initially. The ratio of fungal elements to immune cells determined by microscopy in June 2016 was 1/7, and at the time of the repeat testing in May 2017 the ratio was 1/20.
The repeat blood test also identified an increased number of Circulating Tumour Cells (CTC) from 0.1 CTC/ml in June 2016 to 12.6 CTC/ml in May 2017 associated with an increased risk of malignancy [], in line with findings of higher malignant potential in JIA in the literature [].
Additionally, the patient had severe anemia with thrombocytosis, high copper, low urea, and high creatinine, prompting an intravenous iron infusion as per protocol for children, which the patient tolerated well.
As a result of the remnant findings of fungal elements in her repeat blood test in May 2017 and the patient being stronger than one year prior, the patient was prescribed a 60-day course of anti-fungal medication of itraconazole.
Monthly intravenous vitamin C infusions of 15-30 grams per dose continued over the next year, as well as regular immune-stimulating nutrients, including vitamin D, B-vitamins, zinc, magnesium, and glutathione. To date, about two years after undertaking the first Pathogen Blood Test, the patient has continued to improve, has been attending school full-time, and has been able to walk unassisted for short distances.
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pmc-6207496-1
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A 67-year-old man with a history of chronic obstructive pulmonary disease, cerebral vascular accident, necrotizing pancreatitis complicated by pseudocyst requiring splenectomy and heart failure with preserved ejection fraction was transferred to our hospital following one month of treatment for pneumonia. He was a distant alcoholic but had since gone through rehabilitation and admitted to drinking one time per week and smoking four cigarettes a day. He had previously presented to his primary care physician with fever and malaise and was diagnosed with community-acquired pneumonia. He was treated with five days of azithromycin. He continued to worsen, and was admitted to an outside hospital with hypoxemia and right lower lobe pneumonia for which he was started empirically on vancomycin and piperacillin-tazobactam. His hospital course was complicated by respiratory failure requiring intubation for three days and a recurrent exudative right lung loculated effusion that required decortication and placement of a catheter that remained in place for two weeks. All blood and pleural fluid cultures were negative.
On transfer to our hospital for physical rehabilitation, the patient complained of mild shortness of breath. He denied hemoptysis, chest pain, orthopnea, nausea, chills or night sweats. Physical exam was significant for bilateral rhonchi with signs of consolidation in the right lower lobe. His labs were notable for a white blood cell count (WBC) of 17,000 cells/mcl with 87% neutrophils, and a chest radiograph revealed a right middle lobe infiltrate. He was continued on intravenous (IV) vancomycin and piperacillin-tazobactam at admission. Over the next two days his WBC climbed to 21,000 cells/mcl. Computed tomography scan of the chest revealed a right-sided empyema with extensive bilateral airspace disease consistent with severe pneumonia. A new chest tube was placed, which drained dark brown exudative fluid with gram-positive cocci on gram stain. The fluid was cultured and grew E. faecium resistant to ampicillin and vancomycin but sensitive to linezolid, gentamicin and streptomycin. The patient was started on linezolid and improved over the next two weeks, with resolution of the chest tube drainage.
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pmc-6207854-1
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We report the case of a 25-year-old female patient with a long-standing history of psychiatric disorder on medical treatment who was referred to our unit from a health centre with a history of abdominal pain, abdominal distension, and failure to pass stool and flatus for one week. On examination, the patient had disorganized speech, abnormal motor behavior, and lack of emotional expression. The abdomen was distended to below the umbilicus, irregular hard multiple masses were palpable below the umbilicus, and bowel sounds were found to be exaggerated. Abdominal pelvic ultrasound was done and revealed abnormal materials in the abdominal cavity. Barium meal X-ray was done and showed the stomach being located in the pelvic brim. It also showed stenosis in some parts of the gastrointestinal tract and irregularities in other parts (Figures and ).
Based on the clinical presentation and X-ray findings, a decision to operate was reached. Laparotomy was done, and the stomach was found to be distended reaching the pelvis. Gastrotomy was then performed ().
Different metallic and nonmetallic materials were found in the stomach and proximal part of the small intestine. They were both carefully retrieved. The instruments were of various sizes and included iron nails, arrows, wheel spokes, dinner forks, broken handles of spoons with sharp edges, and many other objects weighing a total of 780 mg (Figures –). The longest instrument was found to be approximately 80 mm long, and it was a nail. There was no evidence of either perforation or ulceration of both the stomach and proximal bowel. The final diagnosis of metalophagia was reached. The patient recovered and did well a few days postoperatively and was referred back to the psychiatric hospital.
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pmc-6207856-1
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A 62-year-old man presented to the otolaryngology clinic with a House-Brackmann grade 4 left lower motor facial nerve palsy with a 10-day history of left postauricular pain. This was preceded by 6 months of intermittent purulent discharge from the left ear for which he received multiple antibiotic courses. On examination, the patient was vitally stable; however, he was febrile. The left postauricular area was mildly tender on palpation and the overlying skin was normal. Otoscopic examination of the left ear was only significant for an erythematous and retracted tympanic membrane. The rest of the examination of the right ear along with a full head and neck exam was unremarkable. White blood count was elevated with 13900 (76% neutrophils, 16.2% lymphocytes, and 8.3% monocytes).
The patient was admitted to the hospital and had an initial diagnosis of mastoiditis with facial nerve paralysis. He was started on intravenous antibiotics. High-resolution computed tomography (HRCT) and magnetic resonance imaging were performed (Figures –).
Due to the severe complication of the facial nerve palsy a decision was made for surgical intervention; cortical mastoidectomy with facial nerve decompression and left middle ear exploration was performed. Granulation tissue in the mastoid air cells and the middle ear were encountered and removed. Biopsies were also taken and sent for histopathology.
The histopathological assessment of the tissue revealed diffuse proliferation of large monomorphic atypical lymphoid cells admixed with few medium-sized cells (centroblastic and prominent immunoblastic lymphoid cells) ().
The cells showed scant to moderate amphophilic cytoplasm, vesicular nuclei, or focal irregular chromatin clumping with prominent 1-2 nucleoli.
Frequent mitoses and few tumor giant cells were regarded along with subendothelial infiltrate and occasional pseudorosette (Figures and ).
The proliferative fraction as detected by Ki67 immunostaining is very high (80–90% positivity) ().
The patient was then transferred to the oncology unit for staging and further management. There was no distant spread and the patient was treated with courses of chemotherapy. At the most recent follow-up his ear symptoms of otalgia and persistent discharge have resolved; however, he still showed a House-Brackmann grade 3 left lower motor neuron facial palsy.
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pmc-6207865-1
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The patient is a 12-year-old Caucasian girl referred urgently to the endocrinology clinic with an expanding right neck mass. The mass had first been noted four weeks prior to their appointment and was felt to have increased in size during this time. Examination revealed a well-grown prepubertal girl with no clinical features suggestive of hyper- or hypothyroidism. On examination of the neck, a firm right sided neck mass was noted. This measured 2 cm x 1.5cm and was not tethered to any local structures. An urgent thyroid ultrasound scan revealed a round well circumscribed heterogeneous, highly vascular mass arising from the right lobe of the thyroid, measuring 21 × 17 x 17 mm (). No lymphadenopathy was noted. Chest X-ray was normal with no evidence of mediastinal lesion or lung mass. The thyroid function test showed raised FT3 (9.1pmol/L [normal range 3.6-6.4]) and normal FT4 (free T4 10.1pmol/L [normal range 9-19]), with suppressed TSH (<0.03mU/L [normal range 0.3-3.8]). After a detailed discussion with the family, hemithyroidectomy was undertaken for removal of the lesion.
Macroscopic examination of the surgical specimen showed a well circumscribed 20 mm mass. Microscopic examination of the specimen showed a predominately insular and follicular growth pattern. There were no features of papillary nuclear changes or anaplastic component. Mild to moderate nuclear pleomorphism with some mitotic features were noted (). A diagnosis of follicular thyroid carcinoma (pT1b) was made and the patient underwent completion thyroidectomy. Histological examination of the extracted left thyroid gland showed benign thyroid tissue with no evidence of residual carcinoma.
The majority of the tumour showed follicular and compact growth pattern with only few areas of more lobular appearance, although the typical insular growth was not present. The vascular invasion was limited to only four small caliber vessels (veins) within the capsule (two illustrated on the submitted images) and the capsular invasion affected 3/4 of its thickness without actually penetrating it. The insular thyroid carcinoma is rare (from 0.3 to 6.7% of all thyroid cancers) and mainly affects adults >45 years of age, although there are isolated case reports in young children []. Given the tumour cells were predominantly well differentiated, follicular carcinoma was confirmed as the diagnosis. This has been confirmed by expert review at the time of the hemithyroidectomy.
Levothyroxine was commenced postoperatively with normalisation of the thyroid function [TSH 1.7, FT4 11.9pmol/L]. Corrected calcium [2.38 mmol/L, normal range 2.15-2.74 mmol/L] and PTH [5.9pmol/L, normal range 1.1-6.9pmol/l] were stable during the postoperative period.
Three months after thyroidectomy, the patient received a course of radioactive iodine. Whole body scan showed no evidence of distant metastases. The patient is currently on thyroxine 125 micrograms once daily and the thyroid function is normal.
The Sanger sequencing of the DNA extracted from the tumour tissue revealed a missense TSHR mutation (c.1703T>C, p.Ile568Thr). The mutation was present with a frequency of 25% within the sample, representing a somatic gain of function mutation.
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pmc-6207877-1
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A fourteen-year-old 48.9 kilogram (kg) female with a history of intermittent, infrequent migraines presented to our institution's emergency department with bilateral distal leg pain, severe mechanical allodynia, and truncal rash which began two weeks previously while in Hawaii after ingestion of uncooked spinach. Initial symptoms consisted of full body itching, initially without a rash, rhinorrhea, congestion, or cough. A maculopapular rash evolved to cover her entire truncal region and thighs. She then developed intense bilateral distal lower extremity pain in a stocking-like distribution from feet to knee, which became exquisitely painful to light touch and ambulation. She described the pain as “sharp” and “shooting”. She then developed spontaneous tingling and numbness in both feet and hands, as well as tremors in all four extremities. She complained of burning pain across her abdomen at dermatome T10. Pain was rated at 10/10 and constant. She additionally complained of headache, diplopia, lightheadedness, and urinary retention. Before she was admitted to the hospital her pain was managed with acetaminophen, ibuprofen, and gabapentin. After the trial of gabapentin failed to reduce pain it was discontinued and pregabalin was started while still an outpatient.
A brain MRI, with and without contrast, was normal but the total spine MRI showed slight increased signal in the right dorsal cord especially at the level of T11-T12. A lumbar puncture revealed an opening pressure of 46 and closing pressure of 15 cm H2O, a protein of 82, and glucose of 54 mg/dL with leukocytosis of 390 cells/μL and 17% eosinophils. Cerebrospinal fluid (CSF) serology was sent. The complete blood count (CBC) was normal except for an elevated white blood cell count of 11.46. X 103 cells/μL. A diagnosis of eosinophilic meningitis was made. Prednisone, 20 milligrams (mg), every eight hours was started, as were around-the-clock acetaminophen, ketorolac, and topical 5% lidocaine patches. Additionally, hydroxyzine 12.5 mg was given, as needed, for pruritus to good effect. The hydroxyzine and clonazepam given for sleep were discontinued because of excessive sedation.
Despite the above interventions, the pain remained refractory and so the following day ketamine was started at 0.02 milligrams (mg) per kilogram (kg) per hour, which was increased over five hours to 0.05 mg per kg per hour. Duloxetine, 20 mg, was administered at bedtime and methadone 2.5 mg every twelve hours was also added for continued pain that night. The following morning, the patient reported reduction in her pain to a numeric pain score of 6/10. Her leg pain resolved with the exception of the dorsum of her feet bilaterally; however, the burning pain persisted at approximately the T10 dermatome. Pregabalin continued to be slowly titrated upward to its maximum dose of 100 mg every eight hours. She did have one report of a vivid dream, but no hallucinations, tachycardia, hypertension, or signs of serotonergic or noradrenergic syndrome were present. On day 5 of admission, albendazole was started as per the recommendations of the Hawaii Department of Health. She had no additional side effects to the analgesic medications and her mental status remained normal. Diplopia, headache, and urinary retention resolved within four days of hospitalization. Ketamine was weaned and the patient was discharged with duloxetine, methadone, pregabalin, and prednisone with plans to be tapered by Pediatric Neurology as an outpatient. Of note, within two weeks of discharge, pregabalin and methadone weaning was initiated with recrudescence of pain despite continued administration of prednisone. The weaning was then restarted the following week at a slower rate and was better tolerated. CSF serologies confirmed diagnosis of A. cantonensis infection.
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pmc-6207879-1
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This patient was a 48-year-old currently employed male with a diagnosis of bipolar 1 disorder who was admitted to our inpatient psychiatric unit for treatment of severe bipolar 1 depression. About two months prior to this admission for depression, he had been involuntarily hospitalized at another facility for mania.
Standard laboratory measures, which were within normal limits, and a urine toxicology screen, which was negative, were obtained prior to admission. During the initial days on our service, the patient endorsed depressed mood and low energy. He had profound hypersomnia and slept through the night and much of the day. He rarely would attend group therapy or socialize with staff or other patients.
The patient was started on modafinil 100 mg daily with plans to use short term to help combat hypersomnia. Psychiatric medications at the time included divalproex 2,500 mg QHS, quetiapine 300 mg QHS, and venlafaxine 225 mg once daily. Venlafaxine had been increased to 225 mg several weeks prior to initiation of modafinil. His valproic acid level prior to initiation of modafinil was found to be 79 ug/ml, confirming adequate prophylactic treatment of mania. There were no other changes made to his medication regimen at this time. Two days following the initiation of modafinil the patient begins to demonstrate symptoms of psychosis. This included seeing trees moving in his bedroom, beliefs that there were cameras in the pictures on his wall, and that a water bottle was “transmitting something” into his room. The following day the patient demonstrated more psychotic behaviors including waking his roommate up in the middle of the night to accuse his roommate of abusing his daughter and later accusing the treatment team of including him in experimental research. Following these psychotic events, the modafinil was discontinued and the psychotic features subsided within the following days.
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pmc-6207883-1
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A 69-year-old Caucasian man was admitted to our Unit from the Emergency Department. He had been suffering from fever, dyspnea, fatigue, and dizziness for 10 days. He had no relevant medical history until the previous month, when he developed intermittent fever with chills. Ceftriaxone was administered at home without benefit. A few days before hospitalization, the patient's clinical condition worsened. On admission, the patient was confused, jaundiced, and had lower-limb edema.
Physical examination revealed jugular turgor, thready pulse with tachycardia, and hypotension (heart rate, 110 beats/minute; blood pressure, 90/60 mmHg) (Beck's triad). Chest auscultation revealed tachypnea (respiratory rate, 28 breaths/minute) and bilateral basal crepitations. Abdominal palpation disclosed hepatomegaly, splenomegaly, and a dull percussion sound in the lower abdominal quadrants.
Routine blood tests showed elevated white blood cells (2146 × 10^3/μL; neutrophils, 91.1%), normal Hb and PLTs, hyperglycemia, hyperbilirubinemia (bilirubin 5.50 mg/dl; 53% direct), and signs of hepatic dysfunction (aspartate aminotransferase (AST) 93 units/L, alanine aminotransferase (ALT) 119 units/L, gamma glutamyl transferase-GGT 285 units/L, serum albumin 2.9 g/dl, and INR 1.81). NT-pro-BNP was increased (2901 pg/ml), whereas cardiac-specific troponin was in the normal range ().
Since the electrocardiogram (ECG) identified high frequency sites during atrial fibrillation, digoxin and low-molecular-weight heparin (LMWH) were administered. Abdominal ultrasonography (US) revealed signs of hepatic disease (parenchymal inhomogeneity and increased diameters), splenomegaly (longitudinal diameter = 20 cm), and ascites. Heart US showed a difficult contraction and reduced diameter of the right ventricle with right atrium diastolic collapse and no inspiratory changes in the vena cava diameter. Chest CT scan demonstrated a retrosternal mediastinal mass containing calcifications and air bubbles. This mass did not show a cleavage plane over the heart but compressed it and shifted it to the left. Bilateral pleural effusion was also observed (). Within a few hours, the blood pressure progressively decreased to 70/40 mmHg; dopamine (7 µg/kg/min) and oxygen (12 L/min) were given, and ECG monitoring was instituted. Urgent pericardiotomy was performed. Constrictive purulent-like pericardium and a firm mass with calcifications were removed. The patient rapidly improved: alertness, arterial pressure, and pulse rate normalized but he still had edema. NT-pro-BNP decreased in a couple of weeks (1430 pg/dl).
Because of the fever, antibiotic treatment was started, and insulin was administered for persistent hyperglycemia. A good response to the therapy was observed and paralleled a reduction of the WBC (11 × 103/µl) and an improvement of liver function, as indicated by a decrease of AST, ALT, and GGT. However, the Hb value (8 g/dl) and PLT count (80 × 103/µl) also decreased, with 3.1% of reticulocytes. Simultaneously, the albumin value was reduced (1.8 g/dl), whereas total bilirubin increased (9.1 mg/dl, 67% indirect), with a positive Coombs test for direct IgG. Therefore, albumin was administered.
One of the possible causes of effusive-constrictive pericarditis is tuberculosis (TBC) []. Since negative QuantiFERON ruled out classic TBC, we hypothesized atypical pericardial TBC or a fungal pericarditis. However, all viral (included HIV), microbiological, and cultural tests performed failed to reveal any infections.
Gamma-proteins were increased (30.8% vs 10–20% normal values) on serum protein electrophoresis and contained a monoclonal component (M component) accounting for 23.3% (1.64 g/dl) (). Serum immunofixation demonstrated that the M component was IgG-λ. Mild renal failure was present with proteins in the urine (1.56 g/24 h) that contained the Bence Jones as free lambda chains. Our analysis showed that the patient had had previous hepatitis A and B infections but not hepatitis C. No bacteria were demonstrated at blood cultures.
The culture test of the pericardial effusion demonstrated the Salmonella species (Salmonella suinis), so imipenem and ciprofloxacin were given. A sample of periumbilical fat was taken and histologically analyzed: amyloid AL deposits were found as positive Congo red and apple-green birefringent areas under polarized light ().
Bone marrow (BM) biopsy showed 4% plasma cells (CD138 and lambda light chain positive) but not amyloid deposits. Skeleton radiological analysis was negative for bone lesions.
PET-CT with 18 fluorodeoxyglucose (FDG) showed a low uptake only in the mediastinum behind the sternum close to the heart. Optical microscope histological examination of the mediastinal mass showed hematoxylin-eosin pink amorphous material which was Congo-red positive and apple-green birefringent and included some granulocytes and few plasma cells (CD138 and lambda light chain positive) near the vessels.
We decided to start treatment according to the chemotherapy scheme VEL/DEX (bortezomib 1.3 mg/m2 i.v. on days 1, 4, 8, and 11; dexamethasone 40 mg i.v. on days 1, 2, 4, 5, 8, 9, 11, and 12).
The patient demonstrated good compliance and had a good response. The M component progressively lowered (12.2%, 0.67 g/dl), renal function improved, and urine proteins reduced. Epoetin A treatment was started to prevent a further decrease of Hb values.
At discharge, Hb, PLT, and serum bilirubin were stable; AST and ALT levels were normal; the pleural effusion, dyspnea, tachypnea, and edema had disappeared.
The patient underwent 4 cycles of Vel/Dex yielding a good clinical response. He slowly went back to work, with a good performance status.
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pmc-6207888-1
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A 37-year-old, gravida 3, para 2 woman was referred for fetal echocardiography due to prenatal ultrasounds that showed a dichorionic/diamniotic twin gestation with the following anomalies: Twin A (female) had a thickened nuchal fold, absent nasal bone, small stomach, and complex CHD consisting of a ventricular septal defect (VSD), atrial septal defect (ASD), pericardial effusion, deviated cardiac axis, and possible AVSD; Twin B (male) had all of the above noted as well as short long bones. These findings were concerning for DS in both twins. Previous pregnancies were delivered via normal spontaneous vaginal delivery and the children did not have genetic or congenital conditions. Amniocentesis was declined during the current pregnancy due to maternal concern for associated risks.
Fetal echocardiography was performed initially at 27 weeks and 2 days gestation, showing each twin had a complete, balanced AVSD of Rastelli type A consisting of a moderate-sided inlet VSD, a small primum ASD, a probable small secundum ASD, and a single atrioventricular valve with trivial left-sided and mild central atrioventricular valve regurgitation and a small predominantly apical pericardial effusion (Figures and –). Biventricular size and qualitative systolic function were normal in both twins, as was conotruncal anatomy and aortic and ductal arch anatomy.
Follow-up obstetric ultrasound at 30 weeks gestation was notable for oligohydramnios, mild ascites, and severe growth restriction in Twin A and polyhydramnios in Twin B. Estimated fetal weight for Twin A was 18th percentile and for Twin B was 50th percentile. The mother received two treatments of betamethasone at that time. The twins were closely followed and the ascites in Twin A was noted to improve over time, but they were ultimately delivered at 33 weeks gestation via emergent cesarean section due to nonreassuring heart tracings in Twin A.
Birth measurement of Twin A was at the ∼5th percentile for length (39 cm), weight (1410 g), and occipitofrontal head circumference (27.5 cm), based on the Olsen Premature Girls Chart (which does not account for DS). Apgar scores at 1 and 5 min were 8 and 9, respectively. The patient was subsequently admitted to the neonatal intensive care unit (NICU) for low birth weight and mild respiratory distress requiring supplemental oxygen; she was noted to be 500 g smaller than her twin at birth. Notable dysmorphic features included transverse palmar crease on her left hand, tongue thrusting, a flat nasal bridge, and upslanting palpebral fissures. Her exam was also notable for suspected choanal atresia or stenosis of her right nare. Chromosomal analysis confirmed the diagnosis of DS with 47XX + 21 karyotype. Transthoracic echocardiography on day of life one confirmed the diagnosis of Rastelli type A complete AVSD with moderate atrial and ventricular septal defects, a balanced common atrioventricular valve with mild right and trace left atrioventricular valve regurgitation, and a patent foramen ovale (Figures and ). Heart size was normal with low normal qualitative right ventricular systolic function and normal left ventricular size and systolic function. There was no evidence of left ventricular outflow tract obstruction, conotruncal anatomy was normal, the aortic arch appeared unobstructed, and there was a small patent ductus arteriosus with predominantly left to right shunting.
Birth measurement of Twin B was at the ∼20th percentile for length (41.5 cm), ∼42nd percentile for weight (1905 g), and ∼55th percentile of occipitofrontal head circumference (31 cm), based on the Olsen Premature Boys Chart (which does not account for DS). Apgar scores at 1 and 5 min were 7 and 9, respectively. The patient was subsequently admitted to the NICU for persistent respiratory distress requiring supplemental oxygen. Notable dysmorphic features included transverse palmar crease, macroglossia, a flat nasal bridge, low set ears, increased skin over back of neck, a short neck, and upslanting palpebral fissures. Chromosomal analysis confirmed diagnosis of DS with 47XY + 21 karyotype. Transthoracic echocardiogram on day of life one confirmed the diagnosis of Rastelli type A complete AVSD with a large atrial septal defect and a moderate ventricular septal defect, a balanced common atrioventricular valve with mild right and trace left atrioventricular valve regurgitation, and a patent foramen ovale (Figures and ). Heart size was normal with low normal qualitative right ventricular systolic function and normal left ventricular size and systolic function. There was no evidence of left ventricular outflow tract obstruction, conotruncal anatomy was normal, the aortic arch appeared unobstructed, and there was a small patent ductus arteriosus with predominantly left to right shunting.
On day of life 25, diuretic therapy with furosemide was initiated in both twins for the management of persistent respiratory distress, consistent with pulmonary overcirculation, a common complication in AVSD. Repeat echocardiography at one month of age showed only modest changes—both twins had mild right atrial dilation, mild to moderate right ventricular dilation with moderate hypertrophy and good qualitative systolic function, normal left ventricular size, and systolic function, mild central and right atrioventricular valve regurgitation, and no evidence of a persistent PDA. The patients remained stable during their hospital course and were discharged after 41 days, and continued furosemide therapy at home.
Despite the similarities in these twins' CHD, they had divergent clinical courses. Twin B followed a typical course for AVSD and underwent complete surgical repair at seven months of age with relatively smooth postoperative course. Twin A, however, passed away from complication of presumed necrotizing enterocolitis with bowel perforation following admission for repair of her choanal atresia at three months of age.
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pmc-6207901-1
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A 51-year-old male, former smoker and former alcoholic, presented to our emergency department with a few weeks' history of headache associated with left-sided weakness, without fever, seizures, nausea, or visual impairment. A neurological exam was significant for left hemiparesis. CT head was remarkable for multiple isodense and hypodense lesions in the frontal lobes, right parietal lobes, and cerebellum suspicious for metastatic lesions. CT chest was significant for a nodular density in the medial right upper lobe and right hilar lymph node. Biopsy of the lung mass and the hilar lymph node revealed poorly differentiated adenocarcinoma. Immunohistochemistry was positive for TTF-1 (thyroid transcription factor-1), Napsin, and PDL-1 expression of >95% PDL-1. NGS (next-generation sequencing) was negative for EGFR mutation. Treatment for metastatic adenocarcinoma of the lung was initiated based on these findings.
After the completion of whole brain radiation, the patient was started on pembrolizumab as the first-line therapy. His baseline complete blood count (CBC), comprehensive metabolic panel (CMP), and thyroid stimulating hormone (TSH) were normal. In the setting of the normal liver function test and absence of symptoms, hepatitis panel was not indicated and not performed at baseline. Following the first cycle of pembrolizumab, a rise in ALT (Alanine aminotransferase) to 528 U/L (normal range: 9–52 U/L) and AST (Aspartate aminotransferase) to 342 U/L (normal range: 14–36 U/L) was noted. Consequently, pembrolizumab was held, and over the next few days, ALT peaked to 994 U/L and AST to 670 U/L. Total bilirubin and alkaline phosphatase were normal. Treatment for probable autoimmune hepatitis was started with high-dose steroids tapered over 3 weeks. The patient's liver enzymes remained elevated in spite of the steroids. Hepatitis workup was sent which revealed HBsAg positive, anti-HBsAb negative, and total anti-HBc positive while IgM anti-Hbc was negative, HbeAg was nonreactive, and HbeAb was reactive which was consistent with chronic hepatitis B. In addition to the serological markers, presence of newly elevated transaminases and HBV DNA RT-PCR (real-time polymerase chain reaction) of >8.23 log was consistent with HBV reactivation. Other tests including ANA, smooth muscle antibody, and ferritin were within normal limits.
After the initiation of tenofovir treatment, liver enzymes started to trend downward. Pembrolizumab was reintroduced and continued without any further significant events. Liver enzymes returned to normal range within a 10-week period, and HBV DNA was undetectable.
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pmc-6207954-1
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A 75-year-old man presented with dull aching new-onset low back pain for 2 weeks. His past history was significant for severe aortic stenosis necessitating bioprosthetic aortic valve placement 4 years ago, hypertension, and coronary artery disease. His physical examination was positive for point tenderness over the lower lumbar spine. At presentation, he had a fever of 38.7°C, heart rate of 96/min, blood pressure of 130/90 mm Hg, and oxygen saturation of 96% on room air. On physical examination, tenderness over lower lumber vertebra noted without deformity, skin lesion, or focal neurological deficit. A new holosystolic murmur was also noted at the mitral area.
His white blood cell count was 4.33 × 103/µL (normal = 4-10 × 103/µL), hemoglobin/hematocrit of 6.8 g/dL/20.6%, and thrombocytopenic to 100 × 103/µL (normal = 150-400 × 103/µL) with normal renal and liver function tests. His erythrocyte sedimentation rate and C-reactive protein were elevated to 107 mm/h and 205 mg/L, respectively. Magnetic resonance imaging of the spine revealed lumbar (L4-L5) epidural abscess and vertebral osteomyelitis, discitis (). He was found to be bacteremic with C hominis. He underwent a computed tomography–guided needle biopsy of L4-L5. The biopsy culture was also positive for C hominis (). A transesophageal echocardiogram showed small vegetation on the mitral valve with mild regurgitation. He was started on intravenous ceftriaxone 2 g once daily for a planned duration of 6 weeks and was discharged. However, he, unfortunately, expired at an outside facility secondary to an unknown illness 4 weeks into the treatment course.
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pmc-6208010-1
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The 24-month-old boy was the first child of healthy nonconsanguineous parents. Pregnancy and delivery were normal. He was born at term with normal measurements (birth weight: 3550 g, 50-85th percentile). The physical development seemed over growth of his infanthood, as his weight, length and head circumference was 5200 g (> 85th percentile), 59.5 cm (> 97th percentile) and 40 cm (> 97th percentile) separately at 1-month old, as well as 11.6 kg (85-97th percentile), 86 cm (> 97th percentile) and 47.5 cm (> 85th percentile) separately at 1-year old. He was irritable when kept in the crawling position at 3–4 months old presenting with crying constantly. He was neither to respond to his name nor to learn to talk since then. He presented with a general developmental delay and dysmorphic feature (Fig. and ). He started sitting at 7-months old and walking at 15-months old but had never walked on all fours. He was always found tumbling head over heels without awareness of self protection. General learning difficulties were also observed. Subsequently, there were concerns about his delayed language development and abnormal behavior. He also showed symptoms of diarrhea and constipation alternately. Half month to 20 days with a dilute stool (3–4 stools/day), alternately turn to constipation (one stool/2–3 days) after medication, without anal fissure. He further had a halitosis in the morning due to the gastroesophageal reflux. He had an initial developmental evaluation at 17-months old with a subsequent follow-up. His hearing evaluation at 20-months of age was normal. He was not found with funicular hydrocele on the right until 12-months old and received repairing operation at 20-months old. There was no similar disease in the other member of the family. In the present study, the Bayley scales was chosen as an instrument to assess his neuropsychological profiles. The scales is an individually administered instrument, which assesses the cognitive, language, and motor functioning of infants and young children aged 1–42 months. The patient was assessed at 26 months old and the cognitive score was < 50 (18-19 months) and the motor score was 56 (19 months).
We used Peabody developmental motor scales 2nd edition (PDMS-2) to assessed the patient’s motor development which including subtest scores: balance ability (19 months), locomotion (18 months), grasping (20 months), visual-motor (V-M) integration (19 months), and standardized motor quotients: gross (GMQ) (74), fine (FMQ) (82), total motor(TMQ) (75).
Autism Diagnostic Observation Schedule (ADOS) [] was used to evaluate communication, social interaction abilities, creativity and the imaginative use of objects (Table ). In the “communication” category, it was noted that he did not respond to his name, retrieve objects, initiate interactions, imitation, or point to pictures or objects. He did not differentially respond to his mother’s voice from others. He still had not developed speech appropriately. We also observed poor and limited eye contact in reciprocal social interactions during the ADOS examination. He had abnormal social interactions with repetitive patterns of behavior, poor eye contacts and restricted interests. In terms of behavior, he was hyperactive with difficulty in sustaining attention on using specific objects, and was unable to follow one-step directions. He did not respond or react to the examiner’s emotional state (ADOS Social interaction score: 13; Autism Cut-Off: 7/ASD Cut-Off: 4) []. Concerning imagination, he did not initiate any spontaneous creative actions or pretend plays, even when he was invited to do so. His behavior did not reveal any unusual sensory interests, but the examiner noted the presentation with hyperactive behavior in sustaining attention on using specific objects and not to follow one-step directions. He also chewed on and ate non-edible objects. He showed little awareness of potential dangers. These findings confirmed our primary developmental diagnosis of ASD, which has finally been aligned to the American Psychiatric Association’s Diagnostic and Statistical Manual for Mental Disorders, 5th Edition (DSM5) criteria.
MRI showed the enlargement of skull anteroposterior diameter (17.6 cm at 17-months, Fig. ), increased signal in T2 in the white matter territories adjacent to the lateral ventricles and subcortical zone, and retardation of brain development (Fig. ). EEG showed non specific slow background activity, as well as no epileptiform discharges.
Genetic analyses were performed after obtaining the patient’s signed informed consent and approved by our hospital ethical committee. Exome sequencing revealed a novel heterozygous nonsense mutations, c.2647C > A (p.E883X) in CHD8 gene which was further validated by Sanger sequencing (Fig. . E1).
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pmc-6208010-2
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The proband is a 28-month-old boy who was born full term without major prenatal complications. The patient was the second child of healthy nonconsanguineous parents. His 5-year-old sister is healthy. Pregnancy and delivery were normal (birth weight: 3200 g, 50th percentile; length: 52 cm, 50-85th percentile). There were no major postnatal complications or congenital findings. The physical development also seemed over growth of his infanthood, as the weight, length and head circumference was 5200 g (50-85th percentile), 60 cm (97th percentile), and 40.4 cm (> 97th percentile) separately at 42-days old, as well as 17.5 kg (>97th percentile), 104 cm (>97th percentile), and 52 cm (> 97th percentile) separately at 2-years old. No facial or corporeal dysmorphic features have been detected (Fig. and ). He was described by his parents as a very quiet infant who rarely crying even when receiving vaccinations. He seemed to develop normally, make eye contact, and interact spontaneously until approximately 5-months of age as he no longer made good eye contact afterward. He had gastrointestinal discomfort. The main clinical manifestation was constipation (one stool/3–4 days), with dry knot hard to discharge, and often accompanied by anal fissure. Also he showed a gastroesophageal reflux and a halitosis in the morning. His symptoms relieved after improvement of dietary habits before sleeping, stop the night milk, and improve sleep posture. He had an initial developmental evaluation at 6-months old with a subsequent follow-up. There were concerns about his delayed motor development. He exhibited developmental delays, sitting at 10-months and walking after 18-months of age. He was irritable and cried constantly. He had abnormal social interactions with poor eye contact and stereotypic behaviors. His hearing evaluation at 23-months was normal. By 18-months of age, he had not developed speech appropriately. There were no reports of clinical seizures in this patient. There was no similar disease in the other member of the family.
The patient was assessed by using Bayley scales at 30 months old and the cognitive score was < 50 (22–23 months) and the motor score was 55 (19 months).
The scores of PDMS-2: balance ability (20 months), locomotion (17 months), grasping (23 months), V-M integration (21 months), and standardized motor quotients: GMQ (53), FMQ (76), TMQ (59).
ADOS [] was used to assess communication, social interaction abilities, creativity and the imaginative use of objects (Table ). In the “communication” category, it was noted that he did not respond to his name as the patient 1. His verbal and non-verbal communication capabilities were so weak that, at that age, it was clearly observed that the quality of his eye contact, as well as social interactions, were in the autistic spectrum range. He did also have repetitive behaviors. His socialization skills were variable: did not interact with children in his same age and was unable to appreciate social cues. His ADOS scores (Table ) suggested that the child was in the range of the autistic spectrum. This finding confirmed our primary developmental diagnosis of ASD.
MRI showed the increased signal in T2 in the white matter territories adjacent to the lateral ventricles and subcortical zone, and retardation of brain development (Fig. ). EEG showed non specific slow background activity, as well as no epileptiform discharges.
Genetic analyses were performed after obtaining the patient’s signed informed consent and approved by our hospital ethical committee. Exome sequencing revealed a novel heterozygous missense mutations, c.1677C > A (p.M559I) in CHD8 gene which was further validated by Sanger sequencing (Fig. . E1). The variant (p.M559I) was determined to be pathogenic which was classified basing on American College of Medical Genetics and Genomics guideline.
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pmc-6208011-1
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In January 2018, an 85-year-old Japanese woman was referred to our hospital with vascular purpura on her lower limbs, chest, and abdomen. She was a housewife and reported no recent travel history. There was no history of urticarial or other allergic symptoms, and she had no familial history. She had no history of smoking tobacco and alcoholism. She had a previous history of hypertension treated with amlodipine besylate for 20 years and no other medication (she was not administered new drugs). She described no trigger factors for purpura. Her vital signs were as follows: temperature, 37.2 °C; pulse, 86 beats per minute; blood pressure, 120/78 mmHg; and respiratory rate, 18 breaths per minute.
A physical examination revealed significant pitting edema in both lower legs, and the confluence of palpable purpura that formed several patches of different sizes in her lower limbs, chest, and abdomen (Fig. ). There were no remarkable features in her heart, lungs, or abdominal examinations. A neurological examination revealed no abnormalities. She was afebrile and there were no signs of an infectious focus in examinations of each system. Laboratory tests showed a white blood cell count (WBC) of 23.3 × 109/L, eosinophil cell count of 13.5 × 109/L, red blood cell count (RBC) of 299 × 1010/L, hemoglobin (Hb) concentration of 9.2 g/dL, and platelet count of 152 × 109/L (Table ). The serum total protein level was 8.2 g/dL (normal range, 6.9–8.2 g/dL), the lactate dehydrogenase (LDH) level was 280 IU/L (normal range, 106–211 IU/L), the aspartate transaminase level was 50 U/L (normal range, 5–40 U/L), the alanine transaminase level was 40 U/L (normal range, 5–35 U/L), the alkaline phosphatase level was 1564 U/L (normal range, 104–338 U/L), and the C-reactive protein level was 6.6 mg/dL (normal range, below 0.3 mg/dL). The serum creatinine level was 2.1 mg/dL (normal range, 0.40–0.80 mg/dL) and nephrotic-range proteinuria was noted. Hypocomplementemia with elevated C1q levels was observed. Serum antinuclear antibodies, perinuclear anti-neutrophil cytoplasmic antibodies, and cytoplasmic anti-neutrophil cytoplasmic antibodies were all negative. Cryoglobulins and the hepatitis B and C panels were negative. The serum β2-microglobulin level was 13.5 μg/dl (normal range, < 2.0 μg/dl), and immunoglobulin G (IgG), immunoglobulin E (IgE), and κ-light chain concentrations were 43.8 g/L (normal range, 8.7–17 g/L), 2455 IU/mL (normal range, 10–340 IU/mL), and 515 mg/dL (normal range, 3.3–19.4 mg/dL), respectively. Serum protein electrophoresis disclosed a monoclonal spike in the γ-globulin region and urine electrophoresis also revealed a monoclonal spike. Serum immunofixation electrophoresis confirmed the presence of an IgG-κ chain monoclonal M component. A bone marrow (BM) examination showed that plasma cells and eosinophils were 16.2% and 28.6%, respectively (Fig. ). A karyotype analysis showed 46,XX (20/20 cells). Interphase fluorescence chromosomal in situ hybridization (FISH) of BM cells revealed no gene abnormalities in 1q21, RB1, P53, D13S319, or IgH. A skeletal survey X-ray found no osteolytic lesions. A biopsy sample of accessory salivary glands showed no amyloidosis. A skin biopsy sample revealed LV showing angiocentric, neutrophilic segmental inflammation with endothelial cell swelling and fibrinoid necrosis on blood vessel walls (Fig. ). A cellular infiltrate around the vessels showed leukocytoclasia of neutrophil nuclei. IgG or IgA deposits around the vessel walls were not clear. Although hypocomplementemia was noted, no manifestations suggesting autoimmune diseases and cryoglobulinemia were observed. Allergic purpura was less likely because of the absence of abdominal pain and arthralgia. Drug-induced purpura was also not suspected because no causative drug was being taken.
The serum level of IFN-γ, which was secreted by Th1, was lower than 0.1 IU/ml (normal range, lower than 0.1 IU/mL) (Table ). Serum levels of IL-4, IL-5, and IL-6 secreted by Th2 were 50.3 pg/mL (IL-4 normal range, lower than 6 pg/mL), 56.1 pg/mL (IL-5 normal range, lower than 3.9 pg/mL), and 76.2 pg/mL (IL-6 normal range, lower than 4 pg/mL), respectively. IL-3, granulocyte-macrophage colony-stimulating factor (GM-CSF), IL-10, and TGF-β levels were lower than 31 pg/mL (IL-3 normal range, lower than 31 pg/mL), lower than 8 pg/mL (GM-CSF normal range, lower than 8 pg/mL), 45 pg/mL (IL-10 normal range, lower than 5 pg/mL), and 8.74 ng/mL (TGF-β normal range, 1.56–0.24 ng/mL), respectively.
Our patient was diagnosed as having MM IgG-κ chain type, stage IIIA according to the Durie-Salmon system and stage II according to the International Staging System. Following a definite diagnosis, she received a VRD regimen: bortezomib, 1.0 mg/m2, days 1, 4, 8, and 11; lenalidomide, 15 mg/day, days 1–21, and dexamethasone 20 mg/day, days 1, 2, 4, 5, 8, 9, 11, and 12. After one course of the treatment, the cutaneous manifestation rapidly improved (Fig. ). Laboratory tests showed a WBC count of 5.4 × 109/L, eosinophil cell count of 0.2 × 109/L, RBC count of 305 × 1010/L, Hb concentration of 10.6 g/dL, and platelet count of 286 × 109/L (Table ). The serum total protein level was 7.6 g/dL, the LDH level was 204 U/L, the aspartate transaminase level was 15 U/L, the alanine transaminase level was 12 U/L, the alkaline phosphatase level was 332 U/L, and the C-reactive protein level was 0.13 mg/dL. The serum creatinine level was 0.82 mg/dL and serum levels of complement bodies were normalized. Serum concentrations of IgG, IgE, and the κ-light chain decreased (13.2 g/L, 218 IU/mL, and 24.2 mg/dL, respectively). The serum level of IFN-γ was elevated (6.5 IU/mL). Serum levels of IL-4, IL-5, IL-6, IL-10, and TGF-β decreased (< 6 pg/mL, < 3.9 pg/mL, 3.4 pg/mL, < 5 pg/mL, and 0.48 ng/mL, respectively). In the fluorescence-activated cell sorting (FACS) analysis of peripheral blood mononuclear cells, the ratio of Th1/Th2 increased. A BM examination showed decrease of plasma cells (3%). She achieved and maintained a very good partial response (VGPR) following VRD regimen for nine cycles without recurrence of LV and eosinophilia.
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pmc-6208032-1
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A 72-year old female melanoma patient attended our department in disease stage IV (pT2a, N3c, M1d; AJCC 2017) with a bulky ulcerated tumor mass on the right proximal upper leg, an asymptomatic singular brain metastasis, and further suspected tumor lesions pectoral, iliacal, inguinal and pulmonal. Serum lactate dehydrogenase (LDH) was elevated with 566 U/l (135–214 U/l) and S100B with 0.63 μg/l (< 0.2 μg/l). BRAF, NRAS, and KIT mutation analysis revealed gene wild-types. Based on tumor board recommendation we initiated ipilimumab (3 mg/kg body weight) and nivolumab (1 mg/kg body weight) combination therapy which was granted with accelerated approval by the FDA in 2015 for the treatment of patients with BRAF V600 wild-type, unresectable or metastatic melanoma. Radiotherapy for the brain lesion (stereotactic) and bulky mass on the right upper leg was also planned. Prior to initiation of treatment she had normal blood leucocytes and mild C-reactive protein elevation (CRP).
Two days after initiation of systemic immunotherapy she attended again our department with worsened pain on the right upper leg. Apart from her leg pain she was in good condition without history of chills, fever, weight loss or malaise. However, blood collections revealed a massive leucocytosis (68.970/μl; normal range: 4.600–9.500/μl) with neutrophilia (63.420/μl; normal range: 1.800–7.200/μl). CRP was elevated with 53 mg/l (< 0.5 mg/l). Wound swabs taken from the ulcerated tumor on right upper leg revealed Staphylococcus aureus. Hence we administered intravenously 600 clindamycine 3 times daily over 10 days. Blood smears did not reveal signs of leukemia. A bone marrow biopsy was refused by the patient. Procalcitonin was within the normal range. Repeated cultures from blood, urine, and sputum were sterile. Magnetic resonance tomography of the brain and thorax and abdomen computed tomography did not reveal evidence for an infectious focus but demonstrated progress of her tumor condition, including tumor infiltration of musculature on the right upper leg, new pulmonal lesions, and disseminated subcutaneous metastases. LDH and S100B were increased with 588 U/l and 1.27 μg/l, respectively. Granulocyte colony-stimulating factor (G-CSF) was elevated with 33 pg/ml (cut-off: < 21 pg/ml). Granulocyte macrophage-colony-stimulating factor (GM-CSF) was within the normal range. During 2 weeks after initiation of the systemic immunotherapy she developed hyperleucocytosis of 122.360/μl with massive neutrophilia (115.300/μl) as also demonstrated in Fig. . Because of her tumor progress and significant spontaneous improvement of her hyperleucocytosis we decided to carry on with nivolumab (fix dosage: 240 mg as approved by the EMA in 2018) monotherapy about 5 weeks after the initiation of the combination immunotherapy. Within the following week her leucocytes even dropped down to 9.600/μl. Since she remained in good condition we continued nivolumab monotherapy and local radiotherapy for the bulky tumor mass on the right leg. Nevertheless, after the second application of nivolumab monotherapy her general condition worsened and she refused further treatment. Two weeks after the last nivolumab infusion she died due to her progressive metastatic disease (Table ). Interestingly, hyperleucocytosis did not reoccur under her nivolumab monotherapy - her leucocytes were only mildly elevated up to 12.200/μl.
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pmc-6208046-1
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A 55 year old female patient was being treated at local hospital for 3 days symptoms suggestive of acute exacerbation of COPD. She was referred to our center for further management after she developed multiple episodes of seizure followed by loss of consciousness on the first day of hospital admission. The patient’s relatives revealed that she had history of COPD for last 5 years but was not compliant to inhaler medications. Her family history was unremarkable. She has been a smoker for the last 30 years. No other significant history was available.
On examination, the patient was drowsy, and was not obeying commands. She had a temperature of 37.6 °C, blood pressure of 130/80 mmHg, pulse rate of 96/min and respiratory rate of 26/min. She had widespread expiratory wheeze. While the patient was regaining consciousness, she reported of headache and a decreased vision. An ocular examination revealed normally reactive pupil and fundus. Cranial nerves examination was unremarkable. Motor and sensory function examination was normal. There was no any clinical sign of meningeal irritation.
Her laboratory tests on admission were as follows: hemoglobin, 17 g/dl; white blood cells, 12640 /Cumm; platelets, 155000 /Cumm; urea, 37 mg/ dl; creatinine 0.3 mg/dl; Na, 132 meq/L; K,4.6 meq/L. Chest X-radiography revealed emphysematous changes. Arterial blood gas finding showed the pH, 7.56; pCO2, 46.2; pO2, 81.0; HCO3, 41.5. Magnetic Resonance Imaging (MRI) demonstrated hyperintense lesions in the bilateral parieto-occipital region consistent with PRES (Fig.).
Our patient was treated with salbutamol and ipratropium nebulisation, hydrocortisone, levetiracetam and other supportive care. The patient was continuously monitored for hemodynamic stability in Intensive Care Unit (ICU) for 2 days and was later transferred to a general ward. The patient continued to improve clinically and was discharged home on the sixth day of hospitalization without any respiratory and neurological symptom.
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pmc-6208071-1
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A 36-year-old Afro-Caribbean woman with PCOS, according to the Rotterdam criteria [], presented a recurrent virilization syndrome during four pregnancies. The only known past medical history was a type 2 maternal diabetes. Menarche occurred at 13 years old, with irregular cycles but no sign of hyperandrogenism. Ovulation disorder persisted in adulthood, but the patient had four spontaneous pregnancies. The body mass index was 28 kg/m2. All four pregnancies are described in Table . Pregnancies were complicated by gestational diabetes. During the first pregnancy, a deepening in the voice and an enlargement of feet were described. Most of the symptoms spontaneously resolved after delivery except the deep voice. During the 3 next pregnancies, hirsutism and signs of virilization started again as described in Table . A right adnexal torsion required an adnexectomy in the postpartum of the third pregnancy. Enlargement of the face, hands and feet (two sizes of shoe), deep voice and clitoromegaly persisted after the fourth pregnancy. Only hirsutism decreased over the following weeks in postpartum. Unfortunately, no picture of patient was available. The patient’s history excluded iatrogenic causes, such as anabolic agents. Newborns did not have clitoromegaly nor ambiguous genitalia.
Serum androgen concentrations were measured in the postpartum of the second and third pregnancies and were normal. A hormonal follow up was initiated with the 4th pregnancy, in order to control the androgens’ levels. Blood investigations revealed elevated androgens’ concentrations during the 1st trimester of 4th pregnancy with a peak at the end of the pregnancy (Table ). A spontaneous decrease in testosterone and ∆4-androstenedione (∆4) levels was observed 2 weeks after the delivery and a complete resolution a month after postpartum. An adrenal etiology was excluded during the second pregnancy, based on normal concentrations of dehydroepiandrosterone sulfate (2.8 μmol/l), 17-hydroxyprogesterone (2.1 ng/ml) and urinary free cortisol (19 μg/l). Acromegaly was also excluded based on normal Insulin-like growth factor-1 (IGF1).
A pelvic ultrasound (U/S), performed in the first trimester of the 4th pregnancy to exclude ovarian causes of hyperandrogenism (luteoma, luteinic cyst or malignant causes), described the single left ovary with an area of 9,9 cm2 and multiple microfollicles. At the same time, a Pelvic Magnetic Resonance Imaging (MRI) confirmed the polycystic ovarian pattern. In the immediate postpartum, another U/S described the polycystic aspect of the left ovary, that was a larger and an anechogenic cyst of 3.5 cm diameter (Fig. ).
A second MRI was performed 1 month postpartum because of pelvic pain, suggesting a subtotal ovarian torsion (Fig. and ). The MRI described an enlarged left ovary of 16.5 × 8.2 × 10 cm, a polycystic aspect and an anechogenic cyst up to 3 cm. No detectable solid mass was observed. The ovary was twisted with a lack of vascularization within some parts of parenchyma. The MRI was non-contributive for this area. The clitoromegaly and the deep voice remained but the patient was lost to follow-up.
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pmc-6208071-2
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A 37-year-old woman originating from Niger with no medical history, presented a recurrent virilizing syndrome during her two pregnancies (Table ). A PCOS was diagnosed before the pregnancies. During the first pregnancy, the patient presented a hirsutism, an enlargement of hands and feet. Blood investigations at the end of the first pregnancy excluded differential diagnoses such as an adrenal etiology based on normal concentrations of dehydroepiandrosterone sulfate, 17-hydroxyprogesterone and urinary free cortisol (320 μg/24 h). A normal level of IGF1 (0.4 ng/l) excluded an acromegaly. After the first pregnancy, the hirsutism decreased. During the second pregnancy, symptoms of virilization worsened as described in Table . No picture of patient was available. Gestational diabetes occurred during pregnancies. Newborns did not have clitoromegaly nor ambiguous genitalia.
A hormonal follow up was designed every 2 months of the second pregnancy, showing an increase in testosterone, ∆4-androstenedione and SHBG concentrations during the 2nd trimester. Testosterone concentration rapidly returned to normal in post-partum (Table ).
A pelvic MRI, performed during the 2nd pregnancy, did not find any adrenal abnormality but only polycystic ovaries. In addition, the caesarean showed a macroscopic aspect of “polycystic” ovaries. The hirsutism improved within weeks postnatally and completely disappeared. Only the clitoromegaly and the deep voice remained. The patient was also lost to follow-up.
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pmc-6208074-1
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On 2018.01.24, a 19-year-old woman was admitted to the emergency room after taking 80 colchicine tablets (0.5 mg per tablet) 44 h previously. She had an argument with her boyfriend and ingested the colchicine to commit suicide. She was previously healthy and had no history of drug allergies. The clinical symptoms were abdominal pain, watery diarrhea and profuse vomiting. Other symptoms were muscle weakness and palpitations.
On physical examination, the temperature was 38.7 °C, pulse rate was 145, and respiration rate was 39. Her blood pressure was 122/60 mmHg, and she weighed 43 kg. Physical examination indicated upper abdominal pain.
Laboratory test results before treatment indicated the following: a white blood cell (WBC) count of 28.2 × 109/L, and other values such as red blood cell (RBC) count, hemoglobin (HGB) level and platelet (PLT) count were within the normal ranges. The levels of α-L-fructosidase (AFU), adenosine deaminase (ADA), alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP) and lactate dehydrogenase (LDH) were increased to 98, 57, 84, 408, 378 and 3494 respectively from reference values (reference range were 12–40 U/L, 0–50 U/L, 5–40 U/L, 8–40 U/L, 40–150 U/L, 109.0–245.0 U/L, respectively). Biochemical abnormalities also included hypokalemia and hypoglycemia. Plasma prothrombin time (PT) and activate part plasma prothrombin time (APTT) were significantly prolonged at 23.50 s and 52.40 s respectively. The level of N-terminal pronatriuretic peptide (NT-proBNP) was 5950 pg/mL, which is abnormal with values higher than 450 pg/mL in the populations under 50-year-old (referrence value). The Electrocardiograms revealed sinus tachycardia.
Hemoperfusion was performed to remove circulating toxins. The patients refused other treatments in Department of Emergency. After 44 h later, gastrointestinal hemorrhage, acute liver injury, acute kidney injury and acute cardiac damage were reported, along with prolonged coagulation. She was then admitted to the intensive care unit. Adequate fluid and electrolyte replacement, oxygenation and other supportive cares was initiated. Anti-inflammatory ceftriaxone sodium was used. Since the unobstructed drainage tube revealed brown fluid, gastric lavage and charcoal were not recommended.
During two days after admission, she presented with high fever, subcutaneous hemorrhage and anuria. Arterial blood gas analysis suggested hyperlactinemia. Uric convention and occult stool were positive for blood. The level of Creatine Kinase-MB had sharply increased to 182 U/L and HGB level and PLT count rapidly plunged to 49 g/L and 11 × 109 /L, respectively. APTT had increased to 72.4 s. At that time, renal function deteriorated and anuria was observed, and the levels of serum creatinine (Cr) and blood urea urea (BUN) were elevated. CRRT was used to remove metabolic wastes and poisons and promoted recovery of renal function. RBC, PLT and plasma were transfused to alleviate anemia and deficient coagulation.
Due to the high dosage of colchicine ingestion, the patient progressed to exhibit shortness of breath, high fever, and subsequent coma. The vital signs at this point were: a heart rate of 87, respiration rate of 21, and the blood pressure was 103/52 mmHg. Blood lactic acid levels were slightly increased. Hyperleukocytosis, low hemoglobin and thrombocytopenia were present. Emergency treatment with tracheal intubation via oral cavity was initiated.
On 2018-02-01, the level of BUN and CK were elevated and anuria was noted. Maintenance therapy with CRRT was initiated to clear metabolic toxins. The arterial blood gas results were generally normal, and she was extubated and provide with supplemental oxygen through a nasal tube. The WBC count returned normal levels, and blood coagulation and liver function were gradually normalized as well.
Following a month of treatment, urine volume increased, but renal function indicators remained abnormal. In addition, HGB levels gradually increased but remained low. Intermittent CRRT and diuretics were administered.
On 2018-03-06, her urine volume reached 3000 ml. Renal ultrasound showed the kidneys were full and diffusely changed (Fig. ). Urinary albumin-to-creatinine ratio (reference range of 0–200 mg/g) was also abnormal as displayed in Fig. . Intermittent hemodialysis was performed and renal function improved. Three days later, the levels of Cr and BUN were also normal, and the patient was discharged. (Blood and urine specimens, and blood biochemistry were reviewed one week later. These values and the time of CRRT treatment are shown in Table . Changes of Cr level and BUN level are presented in Figs. and . On 2018.05.28, the renal ultrasound urinary albumin-to-creatinine ratio were normal (Fig. and ). The treatment timeline is shown in Additional file : Figure S1.
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pmc-6208086-1
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Patient 1 is a girl aged 5 years and 9 months, the first child of a healthy nonconsanguineous couple. Her psychomotor milestones were profoundly delayed, with raising head at 8 months, sitting alone at 1 year old, and still unable to walk by herself at 5 years and 9 months. Poor eye contact, hand clapping, hand wringing and bruxism were observed at 1 year old, followed by deterioration of hand skills. Epileptic attack occurred at 20 months old, and she responded to valproate (VPA), oxcarbazepine (OXC), and topiramate (TPM) combined therapy. Seizure free was achieved at 5.5 years old. EEG demonstrated spike-slow waves at right medial and posterior temporal, with generalization. MRI (1 year old) revealed enlargement of frontal subarachnoid space. Above manifestations led to the diagnosis of typical RTT. However, mutational analysis of MECP2, CDKL5 and FOXG1 was negative. Through this study, a de novo missense MEF2C mutation, c.48C > G, p.Asn16Lys, was identified, which was a novel mutation.
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pmc-6208086-2
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Patient 2 is a 2.5 years old girl presented with RTT-like ID. she displayed profound psychomotor retardation, with controlling head at 5 months, sitting alone at 8 months. She remained unable to walk independently and still had no speech at 2.5 years old. She developed stereotypic hand movements and bruxism at 2 years of age. No seizure was reported, but there was epileptiform discharge on EEG at age of 2 years. Brain MRI revealed high T1 and T2 signal at posterior horn of bilateral ventricle. A nonsense mutation, c.565C > T, p.Arg189*, of MEF2C was discovered, a known disease causing mutation ().
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pmc-6208086-3
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Patient 3 is a 23-month-old girl who presented with RTT-like features. Feeding difficulties caused concern at 3 months of age. No epilepsy was observed, though she had medical history of febrile convulsions at 9 months old. There was significant delay in her developmental milestones, without obvious retrogression. She could sit alone at 1 year old, and walk at 23 months of age, with abnormal gaits. Unmeaningful language began at 12 months. She also presented with poor eye contact, stereotypic actions, breathing disturbance, and sleeping abnormalities. She suffered from recurrent respiratory infections frequently after 15 months of age. MRI revealed hypomyelination at 1 year and 10 months of age. A novel nonsense mutation, c.334G > T, p.Glu112*, in MEF2C was identified.
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pmc-6208086-4
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Patient 4 was a boy aged 7 years and 8 months. He achieved the gross motor developmental milestones somewhat delay, with rising head at 1 year old, sitting alone at 1 year and 2 months, and walking at 1.5 years. Lack of speech was another problem, that he still cannot speak a single word so far (7 years and 8 months). He was always immersed in his own world, showed little interest to the others, and lacked eye-contact. Febrile seizures attacked at 1 year, which turned into afebrile seizures at 2 years old. Partial seizures occurred 1~ 2 times per month, lasted few minutes to more than half an hour. The epilepsy was fever-sensitive. VPA was used at 2.5 years of age, and no seizures occurred after 4 years of age. EEG at 2.5 years displayed (multi-) spike and slow waves at right occipital region, with slow rhythm on the background. MRI at 3 years of age was normal. A novel mutation, c.403-1G > T, of MEF2C was identified, which arose de novo.
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pmc-6208180-1
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A 77-year-old Chinese man complained of bilateral, simultaneous onset vision loss for 5 days, accompanied by severe headache on right side and jaw pain. He was a considerable healthy man in the past. The Neuro-Ophthalmological examination revealed the patient to be alert and oriented. The visual acuities were no light perception in both eyes. The pupils were dilated with no reaction to light. Slit lamp examination showed punctate cataract and funduscopic examination revealed diffused swollen of the optic disc bilateral, with pallid “chalky white” appearance; the choroids showing diffused atrophy around the optic disc bilateral (Fig. ). The extra-ocular motility was full of both eyes. The bilateral superficial temporal arteries were palpable and tenderness.
The routine laboratory tests showed slight decreased RBC (3.09 × 1012/L, normal: 4–5.5) and Hb (92 g/l, normal:120–160),with normal platelet count (170 × 109/L, normal:100–300);dramatic elevated erythrocyte sedimentation ratio (ESR: 100 mm/h, normal: 0–15) and C-reactive protein (CRP: 39.27 mg/L, normal: 0–5). The ocular blood flow detected by color duplex ultrasonography (CDUS) revealed decrease of posterior ciliary artery, central retinal artery, ophthalmic artery in both eyes. CDUS of the bilateral superficial temporal arteries with high-frequency linear probe revealed inflammation of the vessel wall as a hypo-echoic concentric ring, which referred as the “halo sign” [] (Fig. ). The orbital fat-suppression T1-weighted magnetic resonance imaging (MRI) with contract only showed the enhancement of the optic nerve sheath in the left eye, without inflammatory and mass occupation lesions. The MRA were also unremarkable (Fig. ). The right temporal artery biopsy was performed and revealed the occlusion of the luminal owing to the intimal proliferation and infiltration (Fig. ). Methylprednisolone 1 g/d was intravenous for 3 days followed by prednisone 1 mg/kg/d. The vision acuity maintained NLP bilateral after treatment, whereas the headache and jaw pain disappeared. The oral prednisone was weaned and methotrexate was added as the immunosuppressive agent for long treatment. The patient was followed more than one year and there was no other new systematic symptoms, but with the permanent blindness eventually.
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pmc-6208288-1
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We present an unusual case of pulmonary hydatid cysts mimicking malignancy in a 10-year-old girl. A paediatric, female patient presented with acute respiratory distress, productive cough, and pleuritic chest pain. The first-line investigations included a biochemical work-up and a chest X-ray. Laboratory results showed raised C-reactive protein and leucocytosis. The supine plain radiography showed complete opacification of the left lung with widening of the intercostal spaces, right-sided cardiomediastinal shift and multiple round opacities in the right middle and lower lung fields (Figure ). A contrast-enhanced computed tomography (CT) scan (40-slice Siemens, CT Dose Index 4.25) demonstrated multiple densely packed cystic lesions, interspersed by atelectatic lung parenchyma on the left and multiple scattered cysts in the right lung, with a residual moderate amount of aerated lung. A spherical, soft tissue density lesion was seen in the left upper lobe. The liver demonstrated no involvement (Figure ).
Pulmonary malignancy, although seldomly encountered in this age group, was suspected due to the diffuse involvement of the lungs by the lesions and the soft tissue density lesion in the left upper lobe. Possible differentials included pleuropulmonary blastoma (especially type II), malignant teratoma, undifferentiated sarcoma, and diffuse pulmonary metastases. The most plausible differential was pleuropulmonary blastoma (PPB), an embryonal mesenchymal neoplasm and one of the most common primary lung malignancies in children. Type II PPB characteristically presents with both solid and cystic lesions of the lung and pleura and can be solitary or multiple []. Superinfection of the normally air-containing cysts in PPB was thought to explain the fluid content of the cysts. An atypical presentation of pulmonary hydatidosis was initially considered as a differential, but much less likely due to the presence of what appeared to be a soft tissue lesion in the left upper lobe.
Open biopsy was performed, and multiple parenchymal hydatid cysts with innumerable daughter cysts were seen (Figure ). Serology of the patient and a positive antigen test (specific for Echinococcus granulosus) on the cyst fluid confirmed the diagnosis of pulmonary hydatidosis. A large amount of cysts was surgically removed during thoracotomy. Despite release of the cyst fluid into the circulation, neither anaphylaxis nor other complication occurred during and after the operation. The patient was then treated medically with albendazole and improved significantly. Following the confirmation of pulmonary hydatidosis, the apparent soft tissue density lesion in the left upper lobe, as visualized on CT, could be identified as a complicated cyst due to super-infection and haemorrhage – not a solid mass as initially suspected. This diagnosis was confirmed on the follow-up MRI, but the causative infectious agent could not be isolated.
Follow-up chest radiograph (Figure ) two weeks later and magnetic resonance imaging (MRI) of the chest six weeks after surgery were performed to evaluate the amount of remaining cysts. A decrease of the innumerable bilateral cysts was demonstrated. On MRI, almost all of them exhibited a hyperintense signal on T2WI and a hypointense signal on T1WI reflecting simple fluid contents – except one lesion in the left upper lobe, representing the complicated hydatid cyst (Figure ).
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pmc-6208943-1
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In October 2015, in the course of a routine mammography and sonography, a 72-year-old woman was diagnosed with a centrally located carcinoma of the right breast with enlarged axillary lymph nodes. The pretherapeutic staging tests and anamnesis were unremarkable apart from hypertension, obesity and smoking and there was no history of allergy. In particular, there were no signs of an autoimmune disease.
Based on the clinically positive axilla of a cT1 tumor (invasive carcinoma of no special type, G1, hormone receptor positive, Her2/neu negative, Ki67 10%), the patient was given a 4-month neoadjuvant systemic therapy with the nonsteroidal aromatase inhibitor anastrozole (Arimidex®) and the CDK 4/6 inhibitor abemaciclib (Verzenio®), from November 2015 to March 2016, as part of a clinical trial (NeoMONARCH).
The histopathological work-up of the surgical specimen revealed stage ypT1b ypN0 R0 disease. Following segmentectomy and sentinel node dissection, adjuvant radiotherapy (RTX) of the right breast and the supraclavicular region was done in three-dimensional (3D) conformal technique up to a total dose of 50 Gy (6MV) in 25 fractions with an electron boost dosage to the tumor bed of 10 Gy (16 MeV) in 5 fractions while continuing therapy with anastrozole. Prior to radiotherapy the measured volume of the irradiated right breast revealed no difference compared with the left side (1455 vs. 1500 ccm; Fig. ). Towards the end of the course of radiation, the patient developed a moderate acute radiodermatitis with small circumscribed moist epitheliolysis in the submammary fold, which were classified as CTCAE grade 2 and treated symptomatically for the remaining period of radiotherapy.
Three months after completion of RTX, all acute skin changes had completely healed, but a new, 2 cm wide, circumscribed cutis edema was observed at 1 o’clock within the irradiated breast and was documented. Six months after RTX, this developed into an increasing local redness and induration of the skin. A cutis edema was visible in sonography, which showed that the changes were limited to the irradiation field. Nine months after RTX, the cutis edema had grown to cover the whole former irradiation field, the skin exhibited a continuous inflammatory infiltrate, hyperpigmentation and induration. A loss of breast volume was also clearly evident. To rule out a lymphangiosis carcinomatosa cutis (inflammatory carcinoma) recurrence, a targeted punch biopsy was performed. The histology showed no signs of malignant tumor cells but a pronounced dermal fibrosis with thickened dermis and fibrosis extending into the underlying fatty tissue, with corresponding panniculitis and pronounced chronic perivascular inflammation (Fig. a, b).
Based on the pronounced clinical picture (Fig. ) and the distressing situation for the patient, the histological findings from February 2017 were re-examined. Taking account of the radiation history and the clinical progression, a postradiogenic circumscribed scleroderma (morphea) was diagnosed in December 2017, 20 months after RTX.
After the diagnosis had been established all suggested treatments which included systemic immune suppression with steroids and methotrexate (MTX) were declined by our patient. She has been applying topical steroids and has undergone several weeks of lymph drainage at a specialized center. The clinical picture has remained unchanged since December 2017.
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pmc-6209514-1
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A 30-year-old African-American woman presented to our institution with a six-day history of progressively worsening neck and anterior upper chest pain radiating to the arms. The pain was excruciating, sharp and constant in nature without any alleviating or aggravating factors. She also had fever, night sweats, progressive fatigue, and shortness of breath. She had experienced an ‘intentional’ weight loss (10 lbs) with diet and exercise. Her exercise tolerance had progressively diminished from walking six miles to barely being able to walk to the bathroom without dyspnea. Her past medical history was remarkable for mixed connective tissue disease (MCTD), fibromyalgia and chronic pain syndrome. Her autoimmune condition was accompanied with elevated serum titers of rheumatoid factor, anti-Ro/Sjogren's syndrome-related antigen A (SSA), anti-cyclic citrullinated peptide, anti-ribonucleoprotein and antinuclear antibodies. Clinically, this manifested with mixed features of rheumatoid arthritis and systemic lupus erythematous over a span of 10 years. As part of her autoimmune workup, she had been tested for thyroid diseases approximately two years previously. Her previous thyroid stimulating hormone (TSH) levels had ranged from 0.56 to 0.77 international microunits/milliliter (uIU/mL) respectively (normal, 0.45–4.70 uIU/mL). She denied smoking cigarette and consuming alcohol.
A computed tomography (CT) of the chest with contrast performed to evaluate her shortness of breath revealed a lobular mass in the anterior mediastinum measuring 4.1 x 7.4 x 6.4 centimeters (cm), as represented in Figure . Her lower neck and thyroid gland were unremarkable. A percutaneous biopsy was non-diagnostic. She was discharged after recovering from her acute condition and scheduled for elective surgery. Three weeks later she underwent a thoracoscopic resection of the mass and total thymectomy. To perform the surgery, two 1 cm port sites were created. The mass was able to be dissected off the surrounding intra-thoracic structures using an ultrasonic energy device. The mass did not invade the pericardium or any other intra-thoracic structures.
On postoperative day 1, she developed fever to 38 degrees Celsius, tachycardia (150 beats per min) and tachypnea (30 breaths per min). She was agitated and tremulous. A chest CT was negative for pulmonary embolism. Over the next few hours, her condition worsened and she required intubation and mechanical ventilation. An arterial blood gas revealed an evolving mixed metabolic and respiratory acidosis (Table ).
With a high index of suspicion for thyrotoxicosis, the serum T3, free T4 and TSH concentrations were measured and revealed a significantly elevated T3 and free T4 along with suppressed TSH (Table ). In light of her clinical manifestations, laboratory findings and precipitating factors (e.g., major surgery and recent exposure to intravenous iodinated contrast), a diagnosis of thyroid storm was made (with a Burch-Wartofsky score of 65 points). Her thyroid stimulating immunoglobulin (TSI) activity was at 217% of basal level and her TSH receptor antibody titer was 6.32 (normal, ≤1.75). Both values were consistent with Graves’ disease.
She was initially treated with propylthiouracil, an esmolol drip and saturated solution of potassium iodide (SSKI). Intravenous hydrocortisone was also administered. Her clinical status gradually improved. She was successfully extubated on postoperative day 3. Her vital signs normalized by postoperative day 6. On postoperative day 8, the free T4 concentration returned to a normal range. On an outpatient follow-up one week later, she was doing well. Histopathologic analysis of the mediastinal mass was consistent with thymic hyperplasia.
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pmc-6209516-1
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An eight-year-old girl presented with massive ascites. Two months ago she developed fatigue, abdominal distention and weight loss of 10–15 pounds over a month. The patient did not have any significant previous medical history. She was taken to a primary care hospital where abdominal tuberculosis was suspected and she was started on anti-tuberculosis medications. Despite treatment her symptoms did not improve. Hence, she was transferred to a tertiary care hospital.
On examination, her vitals were normal. Abdomen was distended without any indication of peritonitis or perforation and bowel sounds were normal. There were no palpable lymph nodes.
She was given supportive care and detailed lab workup was started. Peripheral blood count was unremarkable except for hemoglobin of 14.6 g/dL with low red cell indices (consistent with iron deficiency anemia as serum iron was low as well) and a platelet count of 641,000/micro liter. Peripheral smear showed hypochromia, anisocytosis and microcytosis, few reactive lymphocytes and increased platelets. Routine lab tests were normal except for C-reactive protein test (CRP) of 24.27 mg/L (normal is up to 5 mg/L). Liver function tests and coagulation profile were normal. Ascitic tap was positive for red blood cells with a total lymphocyte count of 122/cumm (30% polymorphs and 70% lymphocytes), protein 2.6 g/dL and lactate dehydrogenase (LDH) 156. Serum-ascites albumin gradient (SAAG) was less than 1.1 g/dL. Occasional pus cells were seen on peritoneal fluid examination but no growth was observed on culture. Ascitic fluid cytology showed mature lymphocytes and reactive mesothelial cells but no atypical cells. Chest X-ray was normal and to rule out suspected abdominal tuberculosis Mycobacterium tuberculosis DNA by PCR was done which came out to be negative.
Ultimately CT abdomen showed gross ascites with omental thickening and nodularity (Figures -). A laproscopic omental biopsy was performed. Grossly omentum and gut loops appeared normal. However, omental biopsy showed atypical lymphoid infiltrate (Figure ). Immunohistochemistry showed lymphocytes positive for CD20 and Tdt while CD10 negative (Figures -). In correspondence with these results precursor B-cell lymphoblastic lymphoma was diagnosed. After discussing the biopsy report with the child’s parents CHOP therapy has been initiated.
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pmc-6210496-1
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A 21-years-old Caucasian woman presented to a private dental clinic with a chief complaint of asymptomatic swelling in the gingiva observed four years prior. A gradual increase in size and no history of previous treatment were also reported during the anamnesis. The patient signed the informed consent, which represents the ethical approval of the faculty committee. Her medical and socio-economic histories were not contributory. The extra-oral evaluation did not reveal changes. The intraoral examination revealed a sessile nodule with a color similar to that of the mucosa and a focal erythematous area with a fibro-elastic consistency measuring 1.5 cm in the largest diameter extending from the inferior right lateral incisor to the inferior right first premolar. The lesion involved the vestibular and lingual gingiva, causing displacement of the inferior right canine (Fig. ).
Panoramic reconstruction and parasagittal slices of the Cone Beam Computed Tomography (CBCT) showed a slightly superficial hypodense area between the inferior right lateral incisor and inferior right canine with reabsorption of the alveolar crest (Fig. ). Based on the clinical and immunological aspects, the main diagnosis hypotheses included peripheral ossifying fibroma, peripheral giant cell lesion, and ancient pyogenic granuloma. The peripheral odontogenic tumors were also included as a differential diagnosis. An excisional biopsy was performed and a clear separation was noted between the lesion and mandible bone during the trans-surgical approach. The histopathological analysis revealed a well-circumscribed proliferation comprising numerous islands and strands of epithelial polyhedral cells with well-defined borders and marked round nucleus in the connective tissue under the mucosal epithelium. Numerous nests, cords, and small islands of polyhedral cells with clear and vacuolated abundant cytoplasm were observed interspersed with the amorphous eosinophilic deposits (Fig. ). Immunohistochemistry was performed, which yielded positive results for CK-19 in the epithelial cells, except for the clear cells. Congo red staining showed the presence of amyloid-like deposits with apple-green birefringence under polarized light (Fig. ). A final diagnosis of a peripheral CEOT rich in clear cells was reached. No complications were observed in the postoperative appointment and a follow-up schedule was established. The patient has had no recurrence after 22 months (Fig. ).
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pmc-6210623-1
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A 32-year-old Caucasian woman came to our service with complaints of amenorrhea and
infertility. She had a history of two previous failed attempts at ovarian
stimulation with CC. She had been successfully treated for amenorrhea with progestin
(norethisterone 5 mg/day, Primolut, Bayer, Germany) for 10 days in a monthly
fashion.
Clinical examination revealed mild hirsutism (upper lip, chin, and upper abdominal
area) without other signs of virilization (she was not assigned a Ferriman-Gallwey
score due to extensive use of laser for hair removal). Pelvic examination did not
reveal clitoromegaly. Her uterus and adnexa were of normal size. Transvaginal
ultrasound evaluation confirmed the above findings; no signs of polycystic
morphology were seen in her ovaries. A uterine septum was suggested and confirmed by
hysterosalpingography (HSG). Her partner’s semen parameters were normal. Hormonal
analysis on day 3 of her menstrual cycle showed the following: estradiol 38pg/ml;
FSH 3.6 IU/l; testosterone 68ng/dl (normal range 5-52ng/dl); LH 22.8 IU/l; and
Anti-Müllerian hormone (AMH) 179pmol/l. A possible diagnosis of polycystic
ovarian syndrome (PCOS) based on the Rotterdam criteria was considered ().
After hysteroscopic resection of the septum, the patient proceeded with two
additional ovarian stimulation cycles with clomiphene citrate 100 mg/day (Clomiphene
citrate, Anfarm Hellas, Greece) for 5 days (from day 3 to day 7) with no response.
Ultrasound examination performed after the last attempt indicated her left ovary was
mildly enlarged possibly because of a solid mass. Contrast-enhanced magnetic
resonance imaging (MRI) scans confirmed the presence of an irregular, solid mass
with a diameter of 36 mm within the substance of the left ovary without additional
findings. Tumor markers (CA125: 14.7 U/ml, CEA: 1.5 ng/ml, αFP: 4.0 ng/ml)
were within normal range.
Laparoscopic examination showed her left ovary was enlarged, with no obvious surface
anomalies. After peritoneal washing cytology, her ovary was bivalved to reveal a
well-defined solid mass that was easily separated from the surrounding ovarian
tissue. The surface of the tumor was yellowish and friable. The tumor was removed
and contained in an endobag. Her right ovary and both fallopian tubes were normal.
No other signs of disease were noted in the peritoneal cavity and the procedure was
completed.
The pathology report described a borderline adult GCT. Staining by
immunohistochemistry was positive for inhibin and partly positive for calherin.
Nearly 10% of the cells stained positive for proliferation marker Κi-67.
Examination with a microscope showed 0-2 mitoses per 10 high power field. Inhibin B
serum levels measured upon histological confirmation two weeks after the procedure
were within normal range (20pg/ml).
The patient was informed of the pathology results and was scheduled for surgical
staging. On the day of the procedure, the patient had a positive pregnancy test
confirmed by serum β-hCG, and the procedure was cancelled. A singleton viable
pregnancy was confirmed by ultrasound examination two weeks later. The patient was
advised to proceed with surgical staging, with a tentative date for the procedures
somewhere around the 12th week of gestation. The risks and benefits were
explained to her, but she refused to carry on with it. During her pregnancy she had
serial ultrasound images of her ovaries taken along with measurements of inhibin B
serum levels, which remained within normal levels. The patient underwent a planned
cesarean section under epidural anesthesia at 40 weeks of gestation. During the
procedure there was no macroscopic evidence of recurrent disease on her left ovary
or anywhere else in the peritoneal cavity. Complete surgical staging, including
peritoneal washings, left adnexectomy, exploration of peritoneal cavity, multiple
peritoneal biopsies, and omentectomy were performed. Cytology and histology tests
were negative for disease.
Twelve months after delivery the patient had no obvious symptoms of disease and her
menstrual cycle was normal. Serial measurements of serum inhibin B, AMH, estrogen,
and testosterone levels were within normal range.
|
pmc-6211145-1
|
A 54-year-old Caucasian female with a history of obstructive sleep apnea presented to her regional hospital with symptoms of fever, nausea, and right lower quadrant abdominal pain. She was clinically diagnosed with acute appendicitis; however, CT scan showed a normal appendix, with no other acute abdominal findings. The decision was made to proceed with diagnostic laparoscopy. Extensive inflammatory adhesions were found in the RLQ, with an appendix that appeared acutely inflamed with surrounding phlegmon. The appendix was removed, and a Jackson-Pratt drain was left to drain any residual infection. The patient initially improved and was discharged home on the second postoperative day. Surgical pathology revealed acute appendiceal serositis with a rare small focus of mucosal inflammation and no evidence of perforation. A few days after discharge, the patient’s JP drainage increased and began to be feculent in appearance. Her symptoms of nausea, fever, and chills returned, with persistent abdominal pain and constipation.
The patient returned to the hospital due to her worsening symptoms and was transferred to our facility for continued care. Upon presentation at our facility, she was slightly febrile and hypertensive, with no tachycardia or tachypnea. Lab work revealed a white cell count of 21,500 and lactic acid of 1.0. On physical exam, she was 5 ft. and 6 in. tall and weighed 316 lbs. with a BMI of 51. She had significant lower quadrant tenderness to palpation and had developed substantial cellulitic changes around the drain site, with dark, feculent drainage within, and around the drain.
A diagnosis of appendiceal stump dehiscence vs bowel perforation was made, and the patient was taken to the operating room for an exploratory laparotomy. Upon entering the abdomen, copious amounts of enteric contents were found, with significant inflammation throughout. The cecum appeared intact, with no evidence of staple line dehiscence. A systematic examination of the viscera revealed an ileal diverticulum approximately 55 cm from the ileocecal valve, with perforation at its apex (Fig. ). A wedge resection of the diverticulum containing ileum with primary anastomosis was performed. The abdomen was washed out and closed, and a new JP drain was placed.
Extracorporeal inspection of the specimen revealed a 5-cm-long diverticulum with a narrow base. No evidence of foreign body or fecalith was found either within the diverticula or during abdominal washout and repeat inspection. Histology revealed evidence of pressure necrosis at the apex with perforation. No evidence of ectopic tissue or malignancy.
Postoperatively, the patient was managed in the intensive care unit. Her course was complicated with dehiscence of the ileo-ileal anastomosis. She required a second wash out and an end ileostomy, after which, her condition improved. She was discharged on postoperative day 16 from her diverticulum resection. She underwent ileostomy takedown 3 months later.
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pmc-6211148-1
|
A 37-year-old woman presented with intense pain in her feet while walking. She began to feel water droplets burning through her feet at age 29. Her symptoms continued to progress to an intense burning and lightening-like pain while walking, as if her feet were scraped by sandpaper and then dipped in rubbing alcohol. The pain was so severe that she thought about cutting her feet off.
Examination was significant for severe pain in her feet; a simple touch was equivalent to a “bowling ball dropped on her skin”. She had high arched feet on exam (, Case 1). There was decreased sensation to pinprick and light touch up to her ankle. Vibratory sense was decreased up to her knees. She was unable to walk on her heels and reflexes were absent. She had full strength throughout. Her Charcot-Marie-Tooth examination score was a 10 out of 28 []. Electromyography and nerve conduction studies showed evidence of chronic axonal neuropathy with normal nerve conduction velocities and absent sural and peroneal responses. Sequencing of 72 neuropathy genes [] showed a pathogenic variant, c.431T>A (p.Val144Asp) of the SPTLC1 gene.
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pmc-6211148-2
|
A 74-year-old male presented with generalized numbness. He started to have significant numbness in his legs in his forties, which progressed to above his knees. At the time of visit, he had no sensation in his hands, fingers, and toes. His legs would jump when he lied down at night and he had ankle pain when he walked. He had cramps in his thighs, calves, and left arm. He had some hearing difficulties and tremors. Family history was significant for the daughter of the subject carrying the same mutation; she also had similar symptoms of generalized numbness. The subject also has two unaffected daughters and a sister who were offered genetic testing but they declined.
On exam, he had absent light touch and pinprick sensation below his knees and elbows. He had reduced vibratory sense below his knees. He was areflexic throughout. Strengths were 4+/5 in his hands and full strength in his legs. There was atrophy of the bilateral feet and hands, and he could not walk tandem, on toes or on heels. He had high arches bilaterally and his feet could not be easily brought into a neutral position (, Case 2). His Charcot-Marie-Tooth examination score was 13/28. Electromyography and nerve conduction studies showed evidence of chronic axonal neuropathy with normal nerve conduction velocities and absent sural, peroneal, and tibial responses. Sequencing of 72 neuropathy genes [] showed a pathogenic variant, c.431T>A (p.Val144Asp) of the SPTLC1 gene.
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pmc-6211149-1
|
A 60-year-old gentleman presented in clinic complaining of dysuria and intermittent painless hematuria and severe penile pain. His comorbidities include stage 5 chronic kidney disease, peripheral vascular disease, and insulin dependent diabetes mellitus. The patient denies history of trauma, and there was no evidence of vitamin D deficiency or thrombophilia. On examination, he had a tight meatus, blackish discoloration of the tip of the glans, and tender hard gangrenous mass of the glans (), which was proven to be a calciphylaxis gangrene by histopathological assessment.
Laboratory results revealed mildly elevated inflammatory markers including ESR and PCT. Fasting blood sugar was 12.8 mmol/L on admission and then was controlled and reached 5.5 mmol/L. Serum calcium was normal 2.53 mmol/L, and serum phosphate was also normal 1.4 mmol/L, giving a high calcium phosphate product of 75.9 mg/dL (normal range: 20.6–52.5 mg/dL). In addition, parathyroid hormone level was persistently elevated 70 pg/mL (N-terminal: 8 to 24 pg/mL). Albumin was 40 g/L. Due to the history of hematuria, CT urography was done and it showed extensive calcification of the corpus cavernosa, penile vessels, and soft tissues (), obstructive calcified of bilateral internal iliac vessels both anterior and posterior branches ().
Conservative therapy was initiated in form of wound debridement, systemic antibiotics and sodium thiosulfate, and tight blood sugar control, but due to severe penile pain we proceeded with partial penectomy (). Additionally, a cystoscopy was done and showed sloughed necrotic bladder wall and diffuse hematuria uncontrolled by fulguration (). Postoperatively, he developed sepsis with persistent hematuria and was shifted to intensive care unit (ICU) for resuscitation. Sepsis parameters improved in the ICU. Trail of ALUM and dicynone instillation were unsuccessful in controlling the hematuria, so the decision for redo cystoscopy was made, and we found a diffuse uncontrollable bladder wall bleeding; therefore bilateral internal iliac angioembolization was done and it was successful in controlling the hematuria, leading finally to Hemodynamic stability of the patient. Histopathology confirmed the diagnosis of calcific uremic arteriolopathy of the penis, and bladder biopsy showed diffuse blood vessels with no evidence of malignancy.
After being discharge he presented to the clinic with sudden onset of left eye blindness. Magnetic resonance angiography (MRA) of the brain demonstrated the presence of multiple lacunar infarcts and inflammatory changes in the left optic nerve, consistent with optic nerve ischemia or inflammation. The MRA also showed multiple areas of bilateral narrowing of ACA and MCA arteries and none of the ophthalmic arteries were visualized.
|
pmc-6211211-1
|
A 32-year-old man presented with a 2-year history of a painless right-sided neck mass.
Clinical examination revealed 3 x 3 cm smooth, round, nontender, mobile mass at the right lateral of the neck, at the submandibular region. No palpable lymph node was present. Computed tomography (CT) scan neck region revealed a well-defined 3.0 x 2.2 x 2.0 cm uniloculated lesion located anteroinferior to the right submandibular gland with imperceptible wall. An 8 mm enhancing nodule was noted within the lesion at its inferior pole. Subcentimeter submental and bilateral submandibular lymph nodes are present. Bilateral enlarged cervical lymph nodes about 1 cm size at level II are identified. The thyroid is normal in appearance with no focal lesion seen (). He was admitted for further treatment under the impression of infected dermoid cyst. Intraoperatively, there was a cyst measuring 3 x 3 cm located posterior to the strap muscle and lateral to the thyroid cartilage. Excision biopsy of the lateral neck cyst was done. Grossly, the excised specimen revealed a thin-walled cyst containing chocolate-brown fluid, measuring 35 x 30 x 20 mm. The inner surface showed multiple small excrescences ranging from 2 to 3 mm in diameter. Pathologic examination revealed the specimen to be a papillary thyroid carcinoma with a prominent cystic change (). Immunohistochemical stain shows the tumour cells are reactive to TTF-1 (nucleus staining). One out of two tiny lymph nodes (2-3 mm in largest diameter) showed tumour metastasis. Postoperative fine needle aspiration (FNA) of both thyroid lobes revealed no evidence of PTC.
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pmc-6211211-2
|
A 53-year-old male presented with persistent left sided neck swelling for 2 years. Physical examination revealed a cystic mass at the left posterior triangle of the neck measuring 5 x4 cm. The CT scan of neck region revealed well-defined complex cystic lesions with foci of calcifications and small area of enhancement, measuring 4.3 x 3.8 x 5cm and 1.7 x 1.9 cm, located at posterior cervical space and appear to be extending to left supraclavicular region inferiorly. Multiple enhancing subcentimeter bilateral submental and cervical nodes are also seen. The sonographic findings showed homogenous thyroid gland with no focal lesion or abnormal vascularity seen. The thyroid function test is within normal range. Thus, the initial impression was inflammatory process involving 3rd brachial space.
He subsequently underwent excision biopsy of the cystic lesions. The histopathological findings showed papillary thyroid carcinoma which is positive TTF-1, thyroglobulin, CK19 expression and negative reaction towards Napsin A. An impression then was given as PTC with occult primary from thyroid gland cannot be completely excluded.
A month later, the patient was then undergoing total thyroidectomy and modified left radical neck dissection. The thyroid gland is of normal size with a small white nodule noted at left upper pole subcapsular region (4 x 3 mm), pale lesion at mid right lobe (4 x 4 mm), and pyramidal lobe (2 x 1 mm), in keeping with multifocal papillary microcarcinoma. The cervical lymph nodes showed metastatic papillary thyroid carcinoma involving 8 out of 19 nodes. He is currently undergoing radioactive iodine ablation.
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pmc-6211214-1
|
A 41-year-old left hand-dominant female visited the emergency room of another hospital with a small (5-mm long) laceration wound on the dorsum of the left second MCP joint due to a bite injury from her pet cat. A physical examination showed a simple laceration wound with mild tenderness, and an initial X-ray examination was not performed. A simple wound dressing was performed and the patient was discharged with a prescription for regular oral antibiotics. Three weeks later, the patient visited our hospital with noticeable swelling, erythema, and tenderness on the dorsum of the MCP joint of her second finger (). Body temperature was 37.6 °C. Laboratory tests revealed elevated white blood cells (11.25 × 109/L) and C-reactive protein (12.05 mg/L). X-ray showed focal osteopenia at the second metacarpal head. We diagnosed acute osteomyelitis in the second metacarpal bone and quickly performed surgical debridement. During surgery, a partial lesion of the second metacarpal head due to infection was found, and necrotic and infectious bone was removed completely (). An intraoperative Gram-stain wound culture did not reveal any bacteria due to the effect of the oral antibiotics from the first hospital.
The patient was treated with intravenous systematic antibiotic therapy, including a second-generation cephalosporin. One month after the initial surgery, her inflammatory symptoms improved and she showed complete resolution of the osteomyelitis. However, she could not move her right second finger MCP joint without pain due to the second metacarpal head defect (articular defect size: 13 × 10 mm) (). The motion arc was 5°, the pinch strength of the injured finger was 1.0 kg, and the DASH score was 44. Therefore, the patient was treated with a third metacarpal base osteoarticular flap for the right second metacarpal head defect [] (). This surgery was performed under general anaesthesia, and a pneumatic tourniquet was used. A 6-cm longitudinal incision was made over the second dorsal metacarpal artery (DMA), which was selected as the vascular pedicle. We identified and released the second DMA and accompanying veins, and then incised the periosteum of the third metacarpal transversely at the level of the epiphysis, which was distal to the nutrient arteries. The metacarpal was cut carefully to avoid injury to the nutrient arteries, and the osteoarticular flap was elevated (articular flap size: 12 × 10 mm, pedicle length: 40 mm). This pedicled bone flap was then transferred to the second metacarpal head defect. A pivot point was chosen at a point along the portion of the DMA proximal to the communicating artery of the palmar metacarpal artery. The vascularised bone fragment was fixed with two K-wires (1.0 mm) (), taking care to restore the continuity and contour of the articular surface as much as possible. The tourniquet was then released to check for bone flap bleeding. No other procedure was performed at the donor site after harvesting the bone flap.
A short arm splint was applied for 3 weeks postoperatively (POW 3). The K-wires fixing the vascularised bone were removed after POW 4, and active-assisted motion of fingers was then allowed. Hand therapy with active assisted motion was undergone for 6 months. Plain radiographs showed bone union after POW 8 () and the patient returned to her work (nurse) and normal daily activity at POW 18 (). At final follow up of 12 months postoperatively, the motion arc was 50°, the pinch strength of the injured finger was 6.5 kg, and the DASH score was 8. There was no donor site morbidity at final follow up.
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pmc-6211214-2
|
A 32-year-old right hand-dominant man was admitted to the Department of Dermatology in our hospital with swelling and pain of the right hand. He reported an injury with a calk at work 10 days ago. A 5-mm long wound was present over the third MCP joint with redness and swelling. A dermatologist examined the patient. A simple wound dressing was applied and the patient was discharged with a prescription for regular oral antibiotics. One week later, the patient visited our hospital with noticeable swelling, erythema, tenderness, and pus-like discharge on the dorsum of his third MCP joint (). Radiographs showed a visible tooth mark at the third metacarpal head (). Body temperature was 38.5 °C. Laboratory tests revealed an increased number of white blood cells (12.00 × 109/L) and elevated C-reactive protein (25.00 mg/L). We suspected osteomyelitis of the right third metacarpal head due to a clenched-fist injury and quickly performed wound exploration in the operation room. A partial lesion of the extensor and the second metacarpal head due to bite and infection was found ().
An intraoperative Gram-stain wound culture did not reveal any bacteria due to treatment with the initial oral antibiotics. Surgical debridement was performed three times with intravenous systematic antibiotic therapy to resolve osteomyelitis completely. A large defect of the third extensor and third metacarpal head occurred due to the repeated debridements (articular defect size: 18 × 15 mm) (). The patient could not move his third finger due to pain. The motion arc was 0°, the pinch strength of the injured finger was 1.0 kg, and the DASH score was 52. Therefore, the patient was treated with an osteochondral vascularised medial femoral trochlea (MFT) flap for the third metacarpal head defect (). The flap was harvested using the method described by Bürger et al. [,]. The width, length, and depth of the osteocartilaginous segment were 18, 15, and 12 mm respectively. This segment was harvested on the transverse branch and common descending geniculate artery (DGA) (). The length of vascular pedicle available was 6.0 cm. No other procedure was performed at the donor site after harvesting the bone flap. DGA vessels were end-to-end anastomosed to the radial artery and accompanying vein at the snuff box (). Fixation was achieved with two K-wires (1.2 mm) through a dorsal approach at the MCP joint (). The cartilage-bearing segment of the MFT provided a good counter match with the MCP joint. Third extensor reconstruction was performed with a palmaris longus tendon graft.
After surgery, the patient was immobilised in a finger splint for 4 weeks. The K-wires fixing the vascularised bone were removed after POW 8. Osseous union was detected on radiography at POW 10. Hand therapy with active assisted motion was started at 4 weeks postoperatively and undergone for 6 months. The patient returned to his work (civil engineer) and normal daily activity at 6 months postoperatively (). At final follow up of 12 months postoperatively, the motion arc was 30° (extension lag: 4°), the pinch strength of the injured finger was 8.0 kg, and the DASH score was 13. X-ray showed a thick layer of cartilage at the MCP joint without joint space narrowing at final follow up (). There was no morbidity such as pain at the knee donor site.
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pmc-6211215-1
|
An 84-year-old woman presented with painful ulcers on her bilateral index fingers visited our hospital. She had been treated for interstitial pneumonia and Raynaud’s disease by a rheumatologist. She had a 5-year history of Raynaud’s phenomenon. Two months prior to the visit, she began to demonstrate peripheral cyanosis on her fingers and developed ulcerations on bilateral index fingers (). The ulcers were severely painful and were covered with black eschar, and her fingers were cold. Angiography findings revealed poor arterial perfusion in her fingers (). Blood test results indicated slightly increased inflammatory indexes, including an erythrocyte sedimentation rate of 15 mm/h and C-reactive protein of 0.34 mg/dL. Tests for antinuclear antibody, anti-dsDNA, anti-Sm, anti-SM/RNP, anti-Scl-70, anti-Jo-1, rheumatoid factor, anticentromere antibody, cytoplasmic antineutrophil cytoplasmic antibody, and myeloperoxidase antineutrophil cytoplasmic antibody revealed normal ranges. Skin biopsy did not show any specific findings.
In the outpatient clinic, she underwent conservative therapy with a calcium-channel blocker and anti-platelet drugs: oral administrations of nifedipine (20 mg/day), cilostazol (100 mg/day), and Beraprost (60 µg/day); however, the peripheral cyanosis and digital ulcers exacerbated. Thus, she was indicated hyperbaric oxygen therapy to improve digital ischemia.
The patient was admitted to our hospital and underwent hyperbaric oxygen therapy. The treatment protocol consisted of 100% oxygen at 2.0 atm of absolute pressure for 60 min. She underwent a total of 10 sessions of this therapy during 2 weeks of hospitalization. The patient had no side effects associated with the hyperbaric oxygen therapy. The cyanosis around the ulcers disappeared after the treatment. The pain due to the ulcers was remarkably reduced, and the patient required no painkillers at discharge. The ulcer size gradually decreased, and complete healing was accomplished 6 weeks after discharge. The patient experienced no recurrence in the 12-month follow-up period ().
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pmc-6211252-1
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A 51 year old man presented to our outpatient department with an increasing swelling in the right distal upper arm. He reported about local pain without radiation. The patient´s medical history was without previous infections, surgeries or other diseases. The mass in the arm presented solid and relocatable. The examination showed full strength in all upper extremity muscles, especially in the forearm flexors, in M. pronator, M. abductor pollicis brevis, M. flexor pollcis brevis, M. opponens pollcis and Mm. lumbricales I and II. No sensory loss in the upper arm, the forearm, the palm and dorsum of the hand and the fingers could be found.
MRI of the upper arm showed a spindle-shaped homogeneously contrast enhancing mass. It was located some centimeters above the crook of the arm within the medial sulcus bicipitalis. In the imaging it showed a relationship to the median nerve main branch of the forearm or seemed to originate from part of its fibres, respectively. Its diameter was about 11 × 4 centimeters (). The primary diagnosis from the radiologist was schwannoma.
Surgical extirpation was indicated and performed. In its middle part the exposed tumour had a smooth capsule which was opened (). In its equator the surface had a good boundary to the surrounding tissue (). It did not extend to the muscles or tendons. In its distal and especially in its proximal ending the tumour showed a more infiltrative growth (). A feeding fascicle could be identified and was cut after ensuring by electric stimulation that it had no motor function. But with the intention to set no damage at the main nerve trunk approximately twenty percent residual tumour was left ().
The postoperative course was uneventful. The patient suffered a light hypesthesia in the forearm. This did not match to the supply territory of the median nerve which is the palmar hand. It rather corresponded to another skin nerve, possibly damaged by the approach. There was no new motor function deficit in the forearm flexors, in M. pronator, M. abductor pollicis brevis, M. flexor pollcis brevis, M. opponens pollcis and Mm. lumbricales I and II. A local upper arm pain vanished in the course of two weeks.
The final histological examination of the tumour showed typical criteria of the Castleman disease with an effaced architecture of a lymph node with regressed germinal centers and typical high endothelial venules (). Immunohistochemistry demonstrated regressed atrophic germinal centers () and aberrant network of follicular dendritic cells (). The combination of these features ensured the diagnosis.
To exclude a multicentric disease the patient was admitted to the internal medical department. Entire virus tests including HIV were negative. A bone marrow biopsy showed a normal hematopoiesis without evidence for an infiltration by pathologic cells. A staging PET-CT showed no further organ manifestations. An unicentric form was approved in synopsis of all findings. In regard to the tumour rest and the curative approach of an unicentric M. Castleman the patient finally underwent a selective radiation of the upper arm [].
In a 6-month follow-up, the partly sensory loss in the forearm had remained. Except for this, the patient had no nerve related problems or restrictions in everyday life except for the sensory loss in the forearm. In a 18-month follow up he reportet on full functionality of the arm. Currently, the area of the tumour is regularly examined with sonography.
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pmc-6211318-1
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A 4-year-old female infant, the daughter of a Thai mother and a Swiss father, was stung by a jellyfish during their holidays in Hua Hin, Thailand. The incident occurred at the beach in shallow water. The animal was described to be transparent and had long tentacles (approximately 1 m). The girl immediately experienced intense pain and developed reddish sting marks on her legs. Vinegar was immediately poured over the sting marks. Four hours later, the girl was treated at the local hospital with an unknown topical cream. Five days later, she was presented to the surgical department of a hospital in Bangkok (). She continued to report pain. According to information provided by the attending doctor, the skin marks were dry, without signs of infection, and there was a mild swelling of the left leg. Systemic therapy with oral prednisone and local treatment with Silvex® cream (containing sulfadiazine and silver) was initiated. The girl developed intense local itching, scabbing occurred, and perifocal redness increased.
Nine days after the injury, she presented to our emergency department. She was in poor general condition, with tachycardia and fever. Her vital signs were otherwise stable. Blood markers for inflammation were slightly elevated (c-reactive protein, 65 mg/l). At that point, some of the sting marks of the left leg showed superficial dry necrosis with mild perifocal redness (). The few smaller sting marks on the right poplit were dry. Immediate rehydration and analgesic therapy were initiated. After collecting samples for blood cultures, antibiotic therapy with intravenous amoxicillin/clavulanic acid was initiated. Topical dressing with sulfadiazine silver was applied and changed to foam dressing (MepilexAg®) the following day. Daily reassessments with dressings and stepwise debridement were performed. At day 14 after the initial event, deep, tunnel-like necrosis was observed on the left leg (). Radical debridement of the devitalized tissue under general anesthesia was performed. Vacuum assisted wound therapy (KCI V.A.C.®) was initiated. Finally, the ongoing process of deep necrosis resolved and we were able to close all skin lesions of the left leg either by direct wound closure or by split-thickness skin graft (). Two weeks after skin grafting, all wounds on the left leg healed.
Unexpectedly, the initially unimpressive dry skin mark in the right poplit developed delayed deep necrosis 19 days after the initial trauma (). The necrotic tissue was excised and vacuum assisted wound therapy was initiated. After eight days, the wound stabilized and we closed the defect with a rotation flap-plasty.
The scars were initially treated with local massage, and compression stockings were used in combination with massage therapy laters. shows the scars 8 weeks after the split-thickness skin graft of the left leg.
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pmc-6211476-1
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A 69-year-old man with a history of hypertension, bilateral thalamic hemorrhage, and decreased kidney function was admitted to our hospital because of congestive heart failure with extracellular volume overload. Volume control with drugs, such as diuretics, was unsuccessful and he was started on hemodialysis. Thereafter, he received various antibiotics for bacterial infections, including pneumoniae and urinary-tract and catheter-related infections. Simultaneously, he had continuous watery and sometimes bloody diarrhea, the etiology of which was considered to be CDAD due to a positive stool test for CD toxins. Despite treatment with metronidazole and vancomycin, the severity of the diarrhea was not ameliorated. Abdominal X-ray and computed tomography did not reveal any causal factors, and laboratory tests showed only slight elevations in the white blood cell count and C-reactive protein level. We suspected involvement of uncontrollable CDAD or other type of infection (such as mycosis, tuberculosis, or cytomegalovirus infection) and inflammatory bowel disease (IBD).
Colonoscopy showed multiple segmental ulcers in the ascending, transverse, and sigmoid colon, but not the rectum, which suggested infectious colitis or ischemic colitis (Fig. ). A biopsy specimen showed loss of glands, fibrosis, congestion, and edema, suggesting ischemia, with no findings of infection (Fig. ). Given these results and the fact that the patient was on dialysis and had severe arteriosclerosis, we provisionally diagnosed ischemic colitis caused by arteriosclerosis and hemodialysis. We stopped or adjusted enteral nutrition, avoided low blood pressure, and withdrew antibiotics; however, his diarrhea persisted. It was impractical to perform a second colonoscopy, as his performance status was severely worsened. Finally, he died of cardiac arrest 193 days after admission. The autopsy showed longitudinal and annular ulcers in the sigmoid colon. An autopsy specimen of the ulcers showed inflammatory polyposis, cryptitis with crypt abscess formation, and focally severe lymphocyte infiltration near the muscularis mucosa; these findings are fully compatible with UC (Fig. ). We retrospectively suspected that the cause of the intractable diarrhea was UC, which had been masked by the clinical course and findings of CDAD and ischemic colitis.
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pmc-6211501-1
|
A 21 year old woman with no prior medical illness presented with epistaxis and raised blood pressure of 200/142 mmHg. She consumes 20 unit of alcohol per week and is a smoker of 1 pack year. On examination, she was obese with a body mass index (BMI) of 29.7 kg/m2. Physical examination was otherwise unremarkable with no hirsutism nor cushingnoid features. There was no abdominal bruit, radio-radial, or radio-femoral delay. Laboratory investigation at presentation showed hypokalemia (potassium 2.6 mmol/L) and alkalosis. Renal function, liver function, thyroid function, fasting blood glucose and lipid profile were within normal limits. 8 am cortisol was 17.11 μg/dL. Echocardiography showed asymmetrical left ventricular hypertrophy. She was treated with prazosin 2 mg tds and amlodipine 10 mg daily as well as oral potassium chloride 1.2 g od to maintain normal blood pressure and potassium level. Further work up after normalization of potassium revealed secondary hyperaldosteronism with elevated plasma aldosterone 1100 pmol/L (Reference range 102–858) and direct plasma renin 230.10 mIU/L (Reference range 4.2–59.7); giving a aldosteorone renin ratio (ARR) of 5 pmol/mIU. There was no evidence of renal artery stenosis on renal Doppler study. Renal magnetic resonance angiography (MRA) showed normal renal arteries bilaterally but bilateral accessory renal arteries were seen superior to the main renal arteries (Fig. ). Renal angiography had no evidence of stenosis in the main or the accessory arteries bilaterally. In view of the absence of demonstrable stenosis for intervention, the patient was put on medical therapy. Her blood pressure was subsequently controlled on spironolactone 75 mg daily and amlodipine 10 mg daily.
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pmc-6211501-2
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A 41 year old lady with history of hypertension for 3 years treated with amlodipine 5 mg daily, presented with body weakness for a week and difficulty climbing stairs for a few months. She did not have any prior gastrointestinal losses and denied the use of traditional medications. Investigation done showed hypokalemia at 1.8 mmol/L and she was hospitalized. On examination, blood pressure was 145/100 mmHg with pulse rate of 85 per minutes. Her BMI was 30.5 kg/m2 but she did not appear cushingnoid. There was no abdominal bruit. Physical examination was otherwise unremarkable. Investigation showed normal thyroid function, renal function and normal serum calcium and magnesium. There was metabolic alkalosis with serum bicarbonate of 32 mmol/L. Cortisol after overnight 1 mg dexamethasone suppression was normal at 0.69 μg/dl. Hypertension was controlled with diltazem 30 mg tds but she required oral potassium chloride at 1.8 g tds to maintain normal potassium level. Serum aldosterone was 1046 pmol/L with plasma renin of 6.5 ng/ml/hour (reference range 0.2–2.8) giving an ARR of 161. Her echocardiogram was normal with no left ventricular hypertrophy or coarctation of aorta. Renal Doppler showed prolonged acceleration time of the left renal artery with spectral widening. Peak systolic velocities and resistive indices within normal limits but findings were suspicious for left renal artery stenosis. MRA of the kidneys revealed normal kidneys and normal main renal artery calibers bilaterally. However a small accessory left renal artery was seen 1 cm above the origin of the left main renal artery supplying the upper pole (Fig. ). There was no stenosis detected in the accessory artery. Her blood pressure and hypokalemia were controlled with spironolactone 50 mg daily and oral potassium chloride 1.2 g daily.
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pmc-6211544-1
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This is the case of a 75-year-old male with a history of ADPKD, hypertension, dyslipidemia, Crohn’s disease, Benign Prostatic Hyperplasia and a left nephrectomy who presented with generalized malaise, mild diaphoresis, right lower quadrant abdominal pain 10 min after tripping and falling on an outstretched arm while walking down the street. Immediately after the fall, he complained of right wrist pain, walked a short distance back home and started complaining of malaise. He was subsequently evaluated by a neighbor Emergency Medicine attending physician who suspected hypovolemic shock, and transported him in the back of a car to a nearby tertiary care Emergency Department (ED). In route to the hospital, he became pre-syncopal, improving on Trendelenburg positioning. Upon arrival to the ED, his vital signs were as follows:
Temperature = 36.2 (degrees Celsius), Blood Pressure: 100/62 mmHg (130/72 Trendelenberg), Heart Rate = 53 beats/min, Oxygen saturation = 100%, Respiratory Rate = 27 breaths/min.
On physical exam, he was profusely diaphoretic, lethargic but alert and oriented to person, place and time. He had right lower quadrant abdominal tenderness with no rebound or guarding. Due to suspicion of shock, he immediately received two boluses of 0.9% Normal Saline (1 l each). Next, 2 units of O negative packed Red Blood Cells were prepared and he was immediately transfused. The patient was not receiving anticoagulation, so reversing the latter was not envisioned. He reported that his baseline creatinine is 1.6 mg/dL.
His home medications included Irbesartan, Budesonide, Fenofibrate, Ezetimibe, Allopurinol, Nebivolol, Calcium Carbonate and Finasteride.
The risk/benefit ratio for contrast administration was evaluated and decision was made to obtain a CT angiography of the abdomen and pelvis, which revealed the following:A large hematoma measuring 11 × 7 × 7.5 cm inseparable from the medial aspect of the right lower renal pole and extending into the right perinephric space, displacing the kidney superiorly and anteriorly; with associated significant perinephric blood and associated minimal retroperitoneal bleed. Active contrast extravasation along the posterior aspect of the hematoma extending into its most dependent aspect (Figs. , ) on the arterial phase associated with contrast pooling on the venous and delayed images consistent with an acute bleed; most likely arising from a right lower segment renal artery. A 12-min delay image demonstrated pelvic contrast extravasation from the proximal ureter, indicating urinary extravasation (Additional file ).
In summary, the CT was in keeping with an acute right renal bleed likely arising from a right lower segmental artery, with an associated large right perinephric hematoma.
Laboratory results revealed a hemoglobin of 13.3 g/dL, white cell count of 9700 /cu.mm, a platelet count of 237,000 /cu.mm, an INR of 1, a lactic acid of 3.86 mmol/L, Creatinine of 1.9 mg/dL, and a GFR of 34 mL/min/1.73m2.
Urine dipstick revealed 2+ protein, 4+ qualitative hemoglobin, numerous RBCs and 8–10 WBCs.
After an urgent consultation with a multidisciplinary team including Urology, Vascular Surgery, Trauma Surgery and Interventional Radiology, a decision was made to proceed with a supra-selective right renal artery angiography and segmental artery embolization.
Successful and uneventful embolization of the active bleed of the lower pole branch of the right renal artery was performed by the interventional radiology team (Fig. ). The patient tolerated the procedure well and left the interventional unit in a stable condition. He was subsequently admitted to the surgical ICU for monitoring, IV hydration, blood transfusion and serial Creatinine level checking.
The patient subsequently developed an acute kidney injury with a Creatinine reaching 2.8 mg/dL the day after the procedure. The same day, repeated Hemoglobin levels revealed a Hemoglobin of 10.3 g/dL that dropped further 2 days later reaching a trough of 7.3 g/dL. The patient received a total of 3 units of packed RBCs during his hospital stay.
The patient was discharged 6 days later after improvement in his Hemoglobin levels and hemodynamic stabilization. His Creatinine on discharge was 1.5 mg/dL and his Hemoglobin was 9.0 g/dL. Four days after discharge the patient remained stable clinically with a Hemoglobin of 9.7 g/dL and Creatinine of 1.6 mg/dL. Follow up with CT imaging 5 days after discharge did not show any increase in peri-nephric hematoma to indicate continuous bleed or failure of embolization.
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pmc-6211551-1
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A 37-year-old Caucasian male with a known history of aplastic anemia (AA), presented to a rural hospital after a ground level fall. AA was diagnosed 10 months earlier after he was investigated for pancytopenia. A bone marrow biopsy showed cellularity of only 10% and the presence of a small paroxysmal nocturnal hemoglobinuria clone (less than 0.2%). He received standard combination treatment for AA with cyclosporine 225 mg orally twice daily, horse anti-thymocyte globulin (ATG) 40 mg/kg daily for 4 consecutive days, and prednisone 1 mg/kg daily. His other medications included daily Pantoloc 40 mg orally, daily Valtrex 500 mg orally, and daily Dapsone 50 mg orally for Pneumocystis jirovecii prophylaxis due to a reported allergy to trimethoprim/sulfamethoxazole. He had recently quit smoking and denied alcohol use but actively used other recreational drugs, including marijuana, cocaine, and methamphetamine. He was unemployed. He had no known other medical co-morbidities and was taking no other medications prior to developing AA. The etiology of AA was felt to be idiopathic because he had no improvement after an initial trial of sobriety. AA improved following immunosuppressive therapy and, although human leukocyte antigen typing was performed, a subsequent bone marrow transplant was deferred not only because of the medical therapeutic response but also due to his ongoing recreational drug use. Although he was no longer transfusion dependent a month after starting immunosuppressive therapy, his treatment compliance waned overtime due to regular ongoing recreational drug use of cocaine and methamphetamines. He routinely used unsterilized tap water for illicit drug injections, but he denied other exposure to fresh or salt water sources at home or in the community.
On presentation to the emergency department he was not in distress, with a heart rate of 90 bpm and a blood pressure of 116/59. Severe pallor was noted upon examination, as well as a petechial rash and mild ecchymoses (Fig. ). The rest of his physical assessment was normal, including a neurological examination. Admission bloodwork revealed severe pancytopenia with hemoglobin of 22 g/L, a platelet count of 1 × 109/L, a white blood cell count of 3.7 × 109/L, and an absolute neutrophil count of 0.2 × 109/L (reticulocytes were not sent at admission, but 2 weeks into his hospitalization his absolute reticulocyte count was 12 × 109/L with a reticulocyte percentage of 0.5). All other admission blood work was normal, including liver function tests (total bilirubin 9 μmol/L (reference < 21 μmol/L), alanine aminotransferase 13 μmol/L (reference < 41 μmol/L), alkaline phosphatase 66 U/L (reference 30–130 U/L)) and renal function tests (creatinine 63 μmol/L (reference 59–104 μmol/L), glomerular filtration rate 120 mL/min (reference < 59 mL/min)). He was stabilized and transferred to a tertiary care center where he was restarted on treatment for relapsed AA with a regimen that included cyclosporine (5 mg/kg/day) and prednisone 30 mg daily in addition to five doses of ATG. He remained transfusion dependent throughout his hospitalization.
On day 10 after admission, he developed generalized, mild (3/10), colicky abdominal pain with an associated fever > 38.5 °C. He was started empirically on piperacillin-tazobactam (PTZ) 3.375 gm intravenously every 6 hours. Two sets of blood cultures, each consisting of an anaerobic and aerobic BacT/Alert bottle (bioMérieux, Laval, Quebec), were collected peripherally and from his central line. E. coli grew in each bottle set at 10 and 11 hours, respectively. He then developed watery, non-bloody bowel movements, 3–4 times a day, associated with rectal pain. Real-time PCR for Clostridium difficile A/B toxin on a stool sample was negative. Computerized tomography of the abdomen and pelvis was also unremarkable. Repeat blood cultures were negative at 24 and 48 hours after the initial positive set. He improved dramatically after 7 days of intravenous PTZ and was stepped down to oral ciprofloxacin 500 mg orally twice daily to complete a further 7 days of therapy.
On day 19 of admission he developed acute continuous severe (9/10), non-radiating dull rectal pain, associated with a high-grade fever (40.4 °C). Vancomycin 1.5 g intravenously every 12 hours and metronidazole 500 mg orally twice daily were empirically started and ciprofloxacin was continued in the same dosage. Blood cultures that were collected from peripheral venipuncture and a peripherally inserted central catheter line grew A. hydrophila at 11 hours. The peripherally inserted central catheter line was immediately removed the next day (day 20 after admission). The same day he also began to complain of vague, mild, bilateral leg pain. Delayed serum sickness due to recent ATG administration was considered a possible cause for his new symptoms because clinical examination did not show erythema, edema, or deformities on either of his legs. However, sustained bacteremia was diagnosed by recovery of A. hydrophila from repeat blood cultures (i.e., one anaerobic and aerobic bottle set from two peripheral venipunctures) positive after 11 and 16 hours of incubation. Bilateral leg pain steadily worsened in intensity (10/10) over the next 48 hours, and the area of distribution of pain extended to the lateral aspect of the right thigh although physical examination remained unremarkable. Creatinine kinase was increased at 470 U/L (normal range for males, 0–195 U/L). Ultrasound venous Doppler of both legs also showed no evidence of deep venous thrombosis. However, magnetic resonance images of both legs showed extensive bilateral patchy multi-compartment muscular and fascial inflammatory changes highly concerning for NF (Fig. , ).
Urgent initial surgical debridement was performed that evening. An extensive four-compartment fasciotomy, debridement, and myomectomy were performed on both legs. Extensive ‘dishwater’ purulent material was found in multiple compartments of both legs, including (1) the superficial posterior compartment between the gastrocnemius and soleus muscles, and (2) the lateral deep compartment. There was also clinical evidence of severe muscle necrosis of the tibialis anterior muscles in the anterior compartment of both legs. He was admitted to the Intensive Care Unit post-operatively. After consultation with the Infectious Diseases service and review of the antibiotic susceptibility profile of the previously isolated A. hydrophila strain, antibiotics were changed to meropenem 1000 mg intravenously every 8 hours and clindamycin 600 mg intravenously every 8 hours. High dose intravenous immunoglobulin (2 g/kg) was also given. All prior antibiotics were discontinued.
Gram stain of tissue samples from the right tibialis anterior muscle showed no neutrophils but that gram-negative bacilli were present, and subsequently grew a heavy amount of A. hydrophila. Gram stain and anaerobic culture from the right vastis lateralis muscle also did not show the presence of neutrophils or organisms but grew scant amounts of A. hydrophila. A genus-level identification as Aeromonas was obtained for all isolates from blood and tissue samples by matrix-assisted laser desorption ionization-time of flight (MALDI-TOF) mass spectrometry using a VITEK MS (bioMérieux, Laval, Quebec, Canada); since this technique has an accuracy of identification rate of 80–90% for species-level identification of Aeromonas [], all isolates were also analyzed using in-house bi-directional 16S rRNA gene cycle sequencing of the V1-V3 (approximately first 500 bp), as previously described []. Broth microdilution susceptibility panel testing was performed and interpreted using published guidelines []. All isolates were multidrug resistant to ampicillin, ceftriaxone, ciprofloxacin, and trimethoprim/sulfamethoxazole but susceptible to meropenem and tetracycline. The isolates were confirmed to produce an extended-spectrum β-lactamase (ESBL) using published guidelines and the Mast Disc Test (Mast Group Ltd., Merseyside, UK) []. Production of an AmpC β-lactamase was shown by resistance to cefoxitin disk (30 μg) testing and the Mast Disc test (Mast Group Ltd.).
Two additional extensive surgical procedures for removal of necrotic tissue from both legs were undertaken in the next 24 hours. Bilateral above-knee amputations were performed during the last debridement as a life-saving measure because of extensive rapid progression of bilateral leg necrosis, and the patient’s rapid clinical deterioration with severe unremittent hemodynamic instability during the operation. Post-operatively, he required aggressive resuscitation for septic shock in the Intensive Care Unit with intractable hyperkalemia and severe acidosis, and anuric acute kidney failure (creatinine 210 μmol/L; normal range for males, 50–120 μmol/L). Despite all therapeutic interventions, the patient went into cardiac arrest and passed away within 2 hours after the final surgery.
Post-mortem examination at autopsy revealed findings related to the underlying AA, and evidence of septic shock secondary to extensive bilateral lower limb necrotizing myofasciitis. The bone marrow was markedly hypocellular and there was splenic enlargement at 331 g. The heart was enlarged (536 g). Cardiomegaly was likely a compensatory response to the AA due to the absence of atherosclerotic and hypertensive cardiovascular disease. In keeping with the patient’s severe septic shock, there was marked centrilobular necrosis of the liver, as well as petechial hemorrhages of the skin, heart, pleural surfaces, kidneys, and liver capsule. Histologic examination of skin and muscle from the left thigh showed necrosis of the muscle and deep subcutaneous adipose tissue, admixed with dense collections of gram-negative bacilli (Fig. , ). However, in keeping with the AA, there was notably an absence of an acute inflammatory response.
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pmc-6211840-1
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In November 2015, a 46-year-old man presented to our hospital for dyspnea on exertion and abdominal pain, since a week. He had chronic hepatitis B-related liver cirrhosis, without any other disease. On admission, his performance score (Eastern Cooperative Oncology Group performance status) was 1. Initial laboratory investigations showed a total bilirubin level of 1.93 mg/dL, albumin of 3.9 g/dL, and prothrombin time international normalized ratio of 1.13. Shifting dullness or abdominal distension was not observed, and his mental state appeared normal. The cirrhosis was classified as Child-Pugh class A6. Initial computed tomography (CT) scan of the chest and abdomen demonstrated a 12.6 × 12.2 × 11.0 cm HCC with daughter nodules in the right hepatic lobe and tumoral thrombosis in the intrahepatic and suprahepatic inferior vena cava (IVC) and right atrium (RA), as well as multiple lung metastases (Fig. ). Transthoracic echocardiography revealed a heterogeneous oscillating mass from the distal IVC to the RA. The initial alpha-fetoprotein (AFP) level was 33,989 ng/mL. The tumor conformed to the BCLC stage C, with a CLIP score of 3, American Joint Committee on Cancer TNM staging systems (AJCC TNM) stage IVB, and modified UICC stage IVB.
Immediately after the diagnosis, he was treated with entecavir 0.5 mg daily, and sorafenib 400 mg twice daily (Nexavar, Bayer, Germany, Leverkusen), which was reduced to 400 mg a day because of a grade III hand–foot skin reaction (HFSR) after 1 month. Ten days after the diagnosis, palliative radiation therapy (daily 250 cGy, 14 times, total 3500 cGy) to the hepatic mass, IVC, and RA metastasis was initiated. Three weeks later, on December 8, 2015, the first transarterial chemoembolization (TACE) was performed with Lipiodol 6 cc/Adriamycin 20 mg. After 6 weeks of treatment, on December 31, 2015, a follow-up CT was conducted to check the tumor response. The contrast medium used was iomeprol (iomeron; Bracco Imaging Korea, Ltd., Korea, Seoul), and it was the first time he had received the agent. He had no history of adverse effects from other contrast agents used previously. However, the patient complained of dyspnea and developed loss of consciousness, immediately after injection of the contrast medium iomeprol. The systolic blood pressure was 50 mm Hg, whereas the diastolic BP could not be detected. After injecting 1 mg of epinephrine, 4 mg of peniramine, 5 mg of dexamethasone, and loading 2 LL of normal saline, he gradually recovered from the anaphylactic shock. ImmunoCAP tryptase measured 1 hour after the event was increased to 19.8 μg/L (normal range: 0–11.5 μg/L). Follow-up CT revealed that the tumor mass was reduced to 9.1 × 7.5 × 7.3 cm (from 12.6 × 12.2 × 11.0 cm) in the right hepatic lobe. Necrotic changes were observed in the mass, and the extent of tumor thrombosis in the intrahepatic and suprahepatic IVC and the RA had decreased. However, multiple newly nodules in both lung (pulmonary metastasis) were detected (Fig. ). Based on the modified Response Evaluation Criteria in Solid Tumors criteria,[ overall partial response (PR) was noted. Sorafenib administration was continued and the second TACE was performed in February 2016. After 3 weeks of treatment with second TACE, a follow-up CT (February 26, 2016) revealed more regression of intrahepatic mass, IVC, and RA. However, both pulmonary metastases were aggravated. Fourteen months of sorafenib treatment, 2 sessions of TACE, and a follow-up CT (June 24, 2016) revealed the tumor burden had decreased considerably including both pulmonary metastases, with extensive necrotic areas and no tumoral enhancement, and sustained normalization of the alpha-fetoprotein level was noted (Fig. ).
The NK cell activity of our patient was checked, and the value of NK cell activity was significantly higher than normal range (CD56: 54.1%, normal range: 6%–37%). Thirty months after the initial diagnosis, the patient is still alive with no clinical or radiological evidence of tumor recurrence (Fig. ).
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pmc-6211851-1
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A 3-year-old boy with 9Q partial trisomy syndrome, PRS, obstructive sleep apnea (OSA), developmental delay, pulmonary hypertension, VSD, and G tube dependency presented to Craniofacial Clinic at Children's Hospital Colorado (CHC) for consideration of TLA takedown. The patient underwent TLA at 3 months of age at an outside hospital due to significant apnea and concern for upper airway obstruction unresponsive to prone or lateral positioning. A sleep study a year after the procedure showed mild improvement with a persistent apnea–hypopnea index of 4.3 events/h and a desaturation nadir to 83%. Due to swallow dysfunction, the patient was dependent on his G tube. On physical examination he had a sagittally short retrognathic mandible with the tongue in an anterior position secondary to his TLA.
A repeat sleep study interpreted by Otolaryngology and the Sleep team at CHC demonstrated severe sleep apnea with an apnea–hypopnea index of 31 and a nadir of 75%. Due to his severe apnea, TLA takedown at this time was considered a significant risk for worsening the condition. Nighttime oxygen was initiated; however, the patient did not tolerate CPAP. CT scan at age 3.1 years showed moderate micrognathia with slightly hypoplastic mandibular rami.
Bilateral mandibular osteotomies and distractor placement were initiated at age 3.6 years in an attempt to favorably modulate his OSA symptoms to facilitate TLA takedown. The patient was discharged on POD #4. Distraction was initiated after a latency period of 4 days. Initial X-rays obtained at 7 days demonstrated asymmetric diastasis between the sides. However, repeat X-rays 4 days later showed increased distraction on the right side compared with the previous film, so distraction was continued.
After 17 days of distraction, the patient presented for removal of external distraction arms. It was noted that he was unable to actively or passively close his mouth. CT scan showed the superior portion of the right-sided distractor in the glenoid fossa and anterior dislocation of the right mandibular condyle (Fig. ). He was taken to the operating room for removal of the right-sided mandibular distractor and was discharged the next day. The proximal portion of the distractor had fractured a portion of cortical bone away with the screws and proximal distractor limb, likely due to incomplete/unfavorable osteotomy. An attempt at reosteotomy at that time was not undertaken due to loss of outer cortical table in desired area of replacement of the distractor.
Removal of the left mandibular distractor and repeat right mandibular osteotomy with placement of a right mandibular distractor were completed at the age of 3.9 years. Left-sided consolidation was confirmed to be complete during removal of the distractor. The distractor was turned BID for 17 days without complication.
Repeat sleep study at age 4 years, 1 month after cessation of distraction, showed continued moderate-to-severe OSA with an apnea–hypopnea index of 12.8 and mild snoring with mouth breathing. Sleep endoscopy was scheduled to evaluate for adenoid enlargement at the time of right distractor removal.
The right distractor was removed at age 4.3 years. Sleep endoscopy showed 75% adenoid obstruction that was very edematous, tonsils moderately encroaching on the airway, long soft palate and uvula, and severe right nasal obstruction due to septal deviation. Due to the high degree of obstruction, adenotonsillectomy was performed by otolaryngology at the time of distractor removal. Repeat sleep study 9 months later showed no OSA with an apnea–hypopnea index of 0.2 events/h. Given the resolution of OSA, TLA takedown was scheduled.
TLA takedown was performed at age 5.2 years. Previous CT scan at age 3.6 years and lateral skull X-ray at 5 years showed severely retroclined mandibular alveolus and teeth (Fig. ). Dentistry was consulted intraoperatively and recommended consultation postoperatively with cleft palate team orthodontist for treatment of mandibular anterior ridge. On examination full complement of teeth was present in primary dentition and with no gross caries visible.
The TLA extended down to the anterior base of the tongue. Patient tolerated takedown well and was discharged on POD #2. Six days after TLA takedown the patient was admitted to the hospital due to coronavirus upper respiratory infection and difficulty managing his tongue and secretions. Otolaryngology was consulted and recommended glycopyrrolate for secretions and a course of dexamethasone. He maintained his airway throughout hospitalization without aggressive measures and was discharged after 3 days.
Four months later, per dentistry the patient's mandibular alveolus was better aligned but the teeth remained crowded and calculus was present. Repeat sleep study 5 months after surgery was essentially normal. At last follow-up, the patient has continued to do very well for the last 2.5 years (Fig. ).
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pmc-6211869-1
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A 20-year-old woman with FLT3/ITD mutation-positive relapsed/refractory acute myeloid leukemia (AML) was transferred to our institute in June 2017. Following a diagnosis of AML-M5, she received 4 cycles of primary chemotherapy and 1 cycle of unsuccessful salvage chemotherapy for recurrent disease and complex pneumonia, and voriconazole to cure a cutaneous ulceration. After admission, she developed acute appendicitis and recovered following a laparoscopic appendectomy. A computed tomography scan of the paranasal sinuses showed mucosal thickening in her maxillary sinus and a leukemic mass in her nasal cavity (Fig. A). Despite a blast ratio of >90% in her marrow and pathologically proven extramedullary disease in both her central nervous system (CNS) and nasal cavity, we performed salvage allo-HSCT with donor tissue from her father. This study was approved by the institutional Ethics Committees of China Aerospace Center Hospital and conducted in accordance with the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
For graft-versus-host disease (GVHD) prophylaxis, a total body irradiation–based myeloablative conditioning regimen comprising antithymocyte globulin (ATG), cyclosporine, mycophenolate mofetil, and a short methotrexate course was used. The patient developed febrile neutropenia, headache, nasofacial pain and swelling on day +3, and a white blood cell count of 240/mm3 and platelet count of 36,000/mm3 indicated the need for transfusion. A physical examination showed ulceration and grayish tissue necrosis in the anterior nasal cavity, with an erosion on the hard palate (Fig. B arrow). However, the leukemic mass in the nasal cavity had decreased significantly since conditioning.
Because we strongly suspected AIFR, we administered liposomal amphotericin B (L-Amp B, AmBisome, 3 mg/kg i.v. daily), imipenem (1.0 g i.v. q8 hours), and a donor-derived neutrophil transfusion. As no symptomatic improvement occurred during the first 24 hours, an experienced otolaryngologist performed an urgent aggressive endoscopic sinonasal debridement. Subsequently, a low-temperature plasma radiofrequency ablation and radical necrotic tissue excision were performed after the patient's platelet count exceeded 30,000/mm3 via transfusion (Fig. C). Pathology indicated the presence of Talaromyces marneffei in the tissue, concordant with the blood culture result (Fig. D). Although the species is known to respond well to triazole,[ L-Amp B therapy, which yields superior CNS penetration, was maintained to avoid an adverse interaction between high-dose triazole and calcineurin inhibitor therapy. After a 10-day therapeutic regimen, the maintenance therapy switched to oral voriconazole as the patient's symptoms significantly improved. Neutrophil and platelet engraftment occurred on days +11 and +14, respectively. Although the leukemia unfortunately deteriorated, no recurrence of fungal infection was observed until treatment was terminated at 4 months post-HSCT.
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pmc-6211869-2
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A 21-year-old woman with refractory relapsed FLT-3/TKD mutation–positive AML was admitted to our institute in April 2015. Although she had achieved a complete remission (CR) after the initial induction chemotherapy, this was lost after 4 additional cycles of medium-dose cytarabine consolidation therapy. Despite 2 unsuccessful cycles of standard reinduction chemotherapy, leukemic CNS involvement was controlled via intrathecal therapy. Postadmission, low-dose cytarabine-based cytoreduction chemotherapy was used to treat the rapidly progressing disease. Although magnetic resonance imaging of the paranasal sinus showed no abnormalities (Fig. A), the patient exhibited tumor lysis syndrome, disseminated intravascular coagulation, diffuse alveolar hemorrhage, and transient heart failure, which were controlled after 2 weeks of therapy. Despite a 1-year history of laparoscopic resection for a left-sided cystic kidney, normal renal function had been maintained since the onset of AML.
While receiving intravenous voriconazole treatment after cytoreduction chemotherapy, she developed fever, vision difficulty, nasofacial pain, and nasal congestion, as well as mucosal ulceration and purplish skin nodules with progressive necrosis on her bilateral legs (Fig. B arrow). We switched the patient from voriconazole treatment to L-Amp B (3 mg/kg i.v. daily) and conducted an urgent frontal sinusotomy. The biopsy specimen culture was positive for Fusarium species. This study was approved by the Institutional Ethics Committees of China Aerospace Center Hospital and conducted in accordance with the ethical guidelines of the Declaration of Helsinki. Written informed consent was obtained from the patient for the publication of this case report and accompanying images.
Despite a marrow blast ratio >90%, salvage allo-HSCT with busulfan-based myeloablative conditioning comprising ATG, cyclosporine, mycophenolate mofetil, and methotrexate for GVHD prophylaxis was performed. Despite secondary prophylaxis with continuous L-Amp B, she experienced febrile neutropenia and headache with blackish tissue necrosis in her frontal nasal cavity on day-2. Two consecutive blood and 1 pharyngeal culture identified the presence of Fusarium species.
Once multiple transfusions allowed the patient's platelet number to meet the requirement for surgery, the otolaryngologist performed another aggressive surgical debridement with low-temperature plasma radiofrequency ablation and excised the necrotic tissue (Fig. C). The patient's symptoms improved 2 days later. Pathology confirmed the diagnosis of fusarial sinusitis (Fig. D). L-Amp B maintenance therapy was not replaced with voriconazole until day +60. Neutrophil and platelet engraftment occurred on days 8 and 12, respectively. Despite the extended use of L-Amp B and unilateral nephrectomy, the patient maintained normal renal function and remained symptom-free and had sustained a CR after a 39-month follow-up at the time of this submission.
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pmc-6211882-1
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A 3-year-old male with Moroccan origins is the index case. His main query reason to consult was a disharmonic low size. He has healthy consanguineous parents and 4 healthy brothers and sisters. All of them were informed and consent was given for a familial enzymatic and genetic study for lisosomal storage diseases. The index case sent 24 hours urine, dried blood spot (DBS), and ethylene diamine tetraacetic acid (EDTA) blood. His father sent DBS sample and EDTA blood, but his mother, 2 sisters, and 2 brothers live in Morocco and the only sample sent was DBS.
Urine quantitative analysis is based on the spectrometric determination of the binding of glycosaminoglycans (GAGs) with 1,9-dimethylen blue, in 24-hour urine samples. The absorbance readings are performed at 630 nm, and the reference values depend on age.
This method allows us to detect the excretion of GAGs increased in urine, but it is not possible to differentiate the type of GAGs excreted. The qualitative analysis of urine GAGs was obtained by thin-layer chromatography to determine the predominant presence of dermatan sulfate.
In the enzymatic analysis, the action of the beta-galactosidase enzyme present in the DBS sample is determined on the fluorometric substrate 4-methylumbelliferyl-beta-D-galactopyranoside, releasing 4-methylumbelliferyl, which, at alkaline pH, produces fluorescence, proportional to the enzymatic activity. We adapted the methods of Hein et al,[ and Ho and O’Brien[ to evaluate the enzymatic activity of arylsulfatase B (ARSB, EC 3.1.6.1) and beta-galactosidase (GLB, EC 3.2.1.23), respectively. For the ARSB, measured in DBS, a 3.2-mm punch was incubated 20 hours with 50 μL substrate 4-methylumbelliferyl-sulfate, following a 20-minute preincubation with 30 μL water and 20 μL inhibitor (lead acetate). Reaction was stopped with 300 μL of ethylenediamine. Stopping buffer was added to the blanks before the substrate.
Leukocytes were separated from EDTA blood using the Wizard Genomic deoxyribonucleic acid (DNA) Purification Kit (Promega, Madison, WI), and stored at −20°C until used. The leukocyte samples were diluted in 0.9% NaCl and were sonicated in an Ultrasonic Sonicator Processor BandelinSonopuls HD 2070. The Bradford method was used for measuring protein in leukocytes. Fluorescence (excitation 355 nm; emission 460 nm) was measured on a BMG Labtech spectrofluorometer, model Fluo Star Optima. Readings were corrected for blanks, and compared with 4-methylumbelliferone calibrators. Enzyme activities were expressed in micromoles of 4-MU product formed per hour/liter of blood (DBS samples) or nanomoles per hour/mg of protein (leukocytes).
For DNA extraction from DBS samples, 6 punch of 3.2 mm of every sample were preincubated with Casework Extraction Kit (Ref:DC6745 Promega) according to DNA IQ System-Small Sample Casework Protocol #TB296 and they were automatically extracted with MagNa Pure Compact instrument (Roche Diagnostics, Manheim, Germany) with the Magna Pure Compact Nucleic Acid Isolation Kit I, according to the Total NA Plasma 100 400 V3 1 extraction protocol. Final elution of DNA was in 50 μL elution buffer and stored at −20°C until further use.
The genetic study was performed with DNA by massive sequencing of lisosomal storage diseases. Amplification was performed by multiplex PCR for coding regions and splicing sites of 81 genes with 15192 amplicons covering the 99.75% regions in a custom design Kit for Ion AmpliSeq. The sequencing was performed in an S5 Ion Torrent Platform. The ARSB and GLB1 genes coding regions were 100% covered in the index case. However, DBS DNA samples do not amplify exon 2 of the GLB1 gene, but the index case, since DNA is extracted from EDTA blood samples, does have 100% coverage of both genes and the exon 2 of GLB1 is normal.
The index case was 1 of 5 children in a healthy consanguineous family, born at term with delivery by vacuum extraction. A set of anthropometric parameters were monitored at birth such as weight (3.130 g, percentile 25, −0.68 SD), length (50.5 cm, percentile 52, 0.07 SD), cephalic perimeter (35 cm, percentile 50, −0.01 SD), and Apgar score (9/10). He had normal growth and development in the first 2 years.
During the subsequent months, the clinical manifestations became progressively severe without psychomotor retardation. At the age of 3, he had stopped growing with body height of 84.4 cm (below first percentile 1, −2.92 SD), weight of 13 kg (below 11th percentile, −1.23 SD), body mass index of 16.64 (62nd percentile, 0.33 SD), cephalic perimeter of 51 cm (60th percentile, 0.27 SD), and sitting/carving size ratio of 0.563 (40th percentile, −0.26 SD). Musculo-skeletal deformities increased with hypertelorism, flattened nasal root, macrocephaly, bell-shaped thorax, dorsal kyphosis, genu valgus, metaphyseal widening, and short and broad fingers with slight stiffness of distal interphalange. He became a mouth breather with chronic nasal snoring with sporadic breathing pauses; an obstructive sleep apnea syndrome was confirmed by nocturnal respiratory polydraphy.
Otorhinolaryngologic evaluation showed hypertrophic tonsils, macroglossia, and abundant rhinorrhea without otitis. Echocardiogram showed a slightly dysplastic mitral and tricuspid valves, normo-functioning dysplastic aortic and pulmonary valves, and signs of interventricular septum hypertrophy (8.5 mm in diastole, Z score 2.6) with normal coronary pattern. He also had progressive hepatomegaly; his liver was 5 cm below the costal margin. His intelligence and other aspects of neurodevelopment were normal.
Urine GAGs were elevated (74 mg/mmol creatinine, normal range for his age <14.1). Qualitative analysis of urine showed the presence of dermatan sulfate with the absence of keratan sulfate. Peripheral blood leukocyte ASB activity levels were completely abolished (0 nmol/h/mg, normal range 5.4–63.0). The ASB activity was also studied in dried blood spot (DBS) samples in the index case, confirming his ASB reduced activity, while both parents, his brothers and sisters, showed values at the lower end of the reference interval, compatible with the carrier state (Table ). Beta-galactosidase enzyme activity levels were found to be reduced in all the family members, although there was no clinical evidence of Morquio B syndrome (Table ).
Molecular characterization of the ARSB gene was performed for identification of all the possible deleterious and potential disease causing mutations. A single-nucleotide polymorphism (SNP) mutation was detected in homozygosis in the ARSB gene (NM_000046) at position Chr5:78280809 (c.263A > C) leading to a protein change p.Gln88Pro. Analysis of the variant was performed with Polyphen2 from, which it was described as a disease causing variant existing in homozygous state at the first exon of ARSB gene. This variant was not described in either Pubmed or the public access Human Genome Mutations Database (HGMD) (Table ). The patient has another SNP variant in heterozygosis at position Chr5:78181477, in exon5 (c.1072 G > A), producing a change p.Val358Met described as benign in ClinVar (rs1065757) and as pathological in public access HGMD (Table ). The hereditary pattern of MPS6 in this family is shown in Fig. .
Molecular characterization of the GLB1 gene (NM_000404.3) was also performed for identification of all the possible deleterious and potential diseases causing mutations (Table ). Two SNPs were detected in exon 1 of GLB1 gene (NM_000404.3). The first variant existing in homozygous state in all family was at position Chr3:33138544 (c.34T > C) without protein change (p.Leu12 = ), classified by ClinVar as benign/likely benign (rs7614776). The second variant existing was at position Chr3:33138549 (c.29C > T) leading to a protein change (p.Prp10Leu). This variant was homozygous in the mother, wild type in the father, and in heterozygous state in all children, and described by ClinVar as benign/likely benign (rs7637099). All the family had a discrete reduction in the beta-galactosidase enzyme activity with no MPS IVB symptoms (Table ).
None of the family members had symptoms of MPS VI, despite a discrete reduction in ASB activity (Table ). They all had heterozygous state for the c.263A > C novel mutation. However, the index case, showing a drastic reduction in ASB activity, presented a homozygous state in the novel mutation. Brother 1 showed a wild-type pattern in c.236A with a normal ASB activity. The second variant (c.1072G > A) was homozygous in the index case, father, and sister 1, and heterozygous in the rest of family members (Table ).
The patient was treated with galsulfase presenting a good tolerance and good clinical response. Within 1 year of treatment, he showed improvement in weight (from 13 to 15 kg; from percentile 11 to percentile 16), height (from 88.4 to 92.5 cm; still in percentile <1), and respiratory symptoms in both wakefulness and sleep. Medication for pulmonary hypertension had been withdrawn, and tonsillectomy and adenoidectomy were done with fibroscope in intensive care due to difficulty in intubation. In the last cardiology evaluation, the patient improved his interventricular septum hypertrophy (from 8.5 to 7.0 mm).
The patient's parents consented to our publishing this case report.
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