A 56-year-old man presented to the emergency department (ED) after experiencing a fever to 101°F (38.3°C) at home. His past medical history included intermittent febrile episodes over the past seven years and hypertension. His only medication was hydrochlorothiazide.
He experienced recurrent unprovoked febrile episodes (occurring every two to three months) for the past seven years. These episodes were acute in onset, without preference for day or night, and followed a stereotypic pattern. They began with chills/rigors followed by high-grade fever, severe day/nighttime diaphoresis, nausea, and sometimes palpitations. Spontaneous resolution typically occurred within 24-48 hours and left him feeling severely fatigued the following day. The highest fever he recorded during an episode was 104.1°F (40.1°C). He denied vomiting, diarrhea, abdominal pain, dysuria, arthralgias, myalgias, or unexpected weight loss in association with these episodes. Between episodes, he felt completely asymptomatic.
Five years prior to presentation, the patient resided in China for seven years. He also endorsed travel history to Taiwan, Malaysia, Thailand, Philippines, Korea, Japan, Costa Rica, and the Dominican Republic. He reports taking appropriate preventive measures against mosquitoes such as barriers and chemical prophylaxis while traveling. His first febrile episode occurred in Taiwan within the seven-year period when he was residing in China. Initially, after returning from China, he experienced dyspnea and chest pain with a negative cardiac and pulmonary workup.
He did not endorse any illicit drug use, tobacco use, and seldomly consumed alcohol. He was up to date with his preventive health screening exams. Family history was significant for rheumatoid arthritis in his sister. There was no other history of autoimmune disease or familial fever syndromes in his family.
The patient was admitted for systemic inflammatory response syndrome (SIRS) and for a diagnostic assessment for fever of unknown origin. Diagnostic labs and imaging are summarized in Table and Table , respectively. Many of these were repeated during periods of fever without a significant difference in results. An extensive rheumatologic and infectious workup was negative and oncology was consulted with low suspicion for malignancy. The infectious disease service was consulted and reported concern for malaria (particularly Plasmodium vivax (P. vivax) and Plasmodium ovale (P. ovale)) and brucellosis due to his travel history, although there lacked typical periodicity. They noted that splenomegaly, anemia, thrombocytopenia, and mild transaminitis seemed consistent with malaria. A malaria expert was consulted at the Centers for Disease Control and recommended empiric treatment for malaria based on the patient’s history and clinical findings. Following a negative glucose-6-phosphate dehydrogenase (G6PD) deficiency screen, the patient was started on empiric treatment with oral atovaquone/proguanil 1000/400 mg for three days and primaquine 30 mg daily for 14 days.
Three weeks following discharge, the patient was seen for outpatient follow-up. The anemia was resolving with a hemoglobin of 13.3 g/dL; thrombocytopenia fully resolved with a platelet count of 169 B/L. Mild transaminitis persisted (aspartate aminotransferase (AST) 42 IU/L, alanine aminotransferase (ALT) 64 IU/L), total bilirubin had returned to normal (0.7 mg/dL), and alkaline phosphatase
(ALP) remained normal at 58 IU/L. Though the improvement in labs may have simply reflected the resolution of SIRS, the patient reported no additional fevers during a telehealth follow-up one year later.


A 66-year-old Caucasian female was referred for evaluation of subclavian artery aneurysm causing distal embolization and hand ischemia.
Her medical history was notable of hypertension and hyperlipidemia without notice of renal insufficiency. She was an ex-smoker, had myocardial infarction 20 years earlier, bilateral femoropopliteal bypasses (15 and 8 years earlier) and operative repair of right common femoral artery pseudoaneurysm 4 years earlier. A computed tomography angiography showed aneurysm of extrathoracic segment of left subclavian artery. A multidisciplinary team (MDT) decided upon endovascular treatment. Digital subtraction angiography (DSA) confirmed 9 cm long fusiform aneurysm of left subclavian artery extending into left axillary artery, with a maximal diameter of 13 mm (Fig. ). Since transfemoral approach was to be avoided due to previous bilateral groin surgeries, a 10 × 150 mm stentgraft (Viabahn, Gore, USA) was placed via a left brachial artery approach. Tubular graft was chosen based on diameter of non-diseased artery with a 1 mm difference in diameter of proximal and distal landing zone. During the procedure, the patient received 5000 IU of Heparin. Postprocedural course was uneventful, the patient was on low molecular Heparin for three days and was discharged with recommendation of dual antiplatelet therapy (Clopidogrel 75 mg/day, Aspirin 100 mg/day) for six months. The patient had a follow-up at GP office which showed good clinical outcome, as well as duplex sonography one month after the procedure which showed good graft patency.
The patient returned 3 months later with a sudden onset of left arm pain and pallor. Ultrasound showed complete graft thrombosis. The patient confirmed that she was not taking the prescribed antiagregation therapy regulary. Angiography via left transbrachial approach confirmed stent graft occlusion. After graft recanalisation, AngioJet PMT was performed after thrombus lacing with 10 mg of t-PA, with a total aspiration time of 180 s (Fig. ). Postinterventional angiography showed good graft patency (Fig. ). A total amount of 60 ml of nonionic contrast media was used. At the end of the procedure, the patient became agitated, with blood pressure 230/120 mmHg, chest pain and vomiting, they were transferred to intensive unit where myocardial infarction was excluded. The patient became oliguric with elevated serum creatinine of 285 μmol/l (prepocedural serum creatinine was 120 μmol/l, eGFR 41 ml/min/1.73m2). Blood tests at 48 h postprocedure showed significant drop in hematocrit (0,433 L/L to 0,284 L/L) as a marker of intravascular hemolysis as well as elevated LDH (1521 U/l), AST (303 U/L) and ALT (165 U/L). Due to AKI and continuous rise in serum creatinine (Fig. ), urgent renal replacement therapy was initiated. The peak value of serum creatinine was 827 μmol/l on 7th postprocedural day. After 4 session of haemodialysis within 2 weeks, the patients’ renal function entered a polyuric phase and subsequent recovery without further need for hemodyalisis. Renal duplex sonography showed normal renal vasculature. Urine tests showed no signs of nephritis. No co-medication or concomitant disease was identified as a probable cause of renal failure. The pretreatment level of pottasium was 4,7 mmol/L, which was within the normal range. On final discharge, the patient was anticoagulated with Clopidogrel 75 mg/day. During 12-months follow-up, the left subclavian and axillary artery remained patent. Unfortunately, the patient died 12 months after PMT due to traumatic incident.


A 20-year-old Caucasian male presents with difficulty swallowing for the last three years. He started to develop tightness in throat and odynophagia after ingesting foods like banana and individual salads. It takes one or two hours for the symptoms to resolve. It is not associated with dyspnea, cough, nausea, or wheezing with food ingestion. Otolaryngology consultation advised initial imaging with a barium swallow, which revealed concentric rings in the esophagus.
Past medical history comprises of seasonal allergic rhinitis since childhood with frequent episodes of itchy watery eyes, sneezing, nasal congestion, clear rhinorrhea, sinus pressure, headache, and postnasal drip during early spring and fall season. Over the counter, anti-histaminic medications provided symptomatic relief during allergic episodes. He also had a history of asthma, which was diagnosed at age 3 but was resolved by age 6. He has no known food or drug allergies. He is a non-smoker, non-alcoholic, and denies any drug abuse. The patient has no history of sublingual immunotherapy (SLIT) for allergy. A review of other systems was non-contributory, and physical examination was unremarkable.
Diagnostic endoscopy visualized benign-appearing esophageal stenosis measuring less than 1 cm in length and 1 cm in diameter, and it was found 25 cm from incisors and is non-traversable. Multiple rings were found distally (Figure ). Histological examination of the biopsy specimen revealed elongation of submucosal papillae in the squamous mucosal surface, extensive basal cell hyperplasia and abundant intraepithelial eosinophils (25 eosinophils/high power microscopic field) with occasional eosinophilic microabscesses mostly prominent in the superficial aspect of the mucosa which would favor a diagnosis of EoE (Figure ).
The patient was treated with fluticasone 250 micrograms as a multiple-dose inhaler, with four puffs swallowed twice a day for eight weeks. His symptoms improved gradually, and an upper endoscopy performed after three months showed improvement in endoscopic appearance (Figure ). Histopathological examination of the biopsy specimens also revealed a marked decrease in the number of intra-epithelial eosinophils per high power field in the esophageal mucosa. The patient remained in remission at the 12-month follow-up.


A 43-year-old male with no past medical history presented to the emergency department with eight days of fevers and cough. He reported repairing water pipes in his basement two weeks prior, but had no other environmental exposures, travel, or known sick contacts. He denied alcohol, tobacco, or illicit drug use. On presentation, his temperature was 36.5 °C, blood pressure 157/95 mmHg, pulse rate 88 bpm, respiratory rate 21 breaths/minute, and oxygen saturation 91% on room air. Leukocyte count was 7.7 cells/mm3 (normal: 4.2-11.0 cells/mm3) and procalcitonin was 0.09 ng/mL (normal: <0.10 ng/mL). Arterial blood gas was notable for partial pressure of oxygen of 67 mmHg (normal: 83-108), and two blood cultures on admission were both negative. Urine antigens for Streptococcus pneumoniae and Legionella were both negative.
A chest X-ray showed a right middle lobe infiltrate (Figure ). Subsequent CT pulmonary angiogram was negative for pulmonary embolism but significant for bilateral nodular and ground-glass opacities in the posterior left upper lobe, right middle lobe, and bilateral lower lobes, as well as patchy focal areas of consolidation in the right middle and left lower lobe (Figure ). The patient was started on ceftriaxone and doxycycline for presumed community-acquired pneumonia. He was also administered intravenous methylprednisolone due to the radiographic findings.
The patient would require oxygen via nasal cannula on the following hospital days, and so he underwent bronchoscopy with bronchoalveolar lavage (BAL) on hospital day three. It was notable for mucus plugging throughout the tracheobronchial tree that was purulent and thick with erythematous underlying mucosa (Figure ). BAL was performed in the right middle lobe (Figure ). Multiple transbronchial biopsies were also obtained.
The right lower lobe transbronchial biopsy showed marked acute and chronic inflammation of bronchial mucosa and alveoli and an aggregate of atypical epithelial cells, or cells that line organs that appear abnormal. These cells were CK7, CK5/6, and focal p40 positive (a marker often used for detection of squamous differentiation in carcinoma), as well as CD68, TTF-1, and napsin-A negative by immunohistochemical stains. A ki-67 immunohistochemical stain showed a high (85%) proliferation index, suggesting a rapidly growing lesion (Figures -). The overall morphological features, immunoprofile, and the high proliferation index suggested squamous cell carcinoma arising in a background of squamous metaplasia. However, the absence of a mass lesion, absence of significant nuclear atypicality, presence of concomitant acute and chronic inflammation, and the benign clinical course suggested inflammatory-related, atypical squamous metaplasia of bronchial mucosa.
Bronchoalveolar lavage results were negative for acid-fast bacilli, Pneumocystis jirovecii direct fluorescent antibody, and Blastomyces antigen; mycobacterial and fungal cultures and smears were pending at the time of patient discharge. Chest X-ray on the day of discharge showed improved aeration of lungs with mild residual right middle lobe airspace opacities (Figure ). He felt improved after five days of antibiotic therapy and went home with a steroid taper on oral prednisone after the resolution of acute HSP. The mycobacterial culture was subsequently positive for MAC, which was the presumed infectious etiology of the patient’s pneumonitis. Outpatient CT chest six weeks after discharge showed no evidence of the previously noted bilateral ground-glass densities, and there was no evidence of pulmonary scarring, fibrosis, or usual interstitial pneumonitis (Figure ).


The patient was a 35-year-old woman with a confirmed diagnosis of high-grade B-cell lymphoma under rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) and cyclophosphamide, vincristine, doxorubicin, high-dose methotrexate/ifosfamide, etoposide, and high-dose cytarabine (CODOX-M/IVAC) regimens. In the final phase of chemotherapy, an infectious disease consultation was requested because of fever (axillary temperature, 38.9°C) and neutropenia (absolute neutrophil count, 200 cell/mL).
On the physical examination, the patient’s left eyelid was swollen and erythematous. She also had headaches and blurred vision ().
Since opportunistic infections were highly probable, chemotherapy was immediately stopped, and broad-spectrum antibiotics, including meropenem (2 g q8h), vancomycin (1 g q12h), and LAMB (300 mg/daily), were prescribed. In addition, paranasal sinus (PNS) CT scan and brain magnetic resonance imaging (MRI) were requested. The PNS CT scan showed mucosal thickening in both maxillary sinuses (figure 2). The brain MRI images revealed an intracranial lesion (about 20×20 mm) in the left frontal cortex (MRI-T2 flair view) (figure 3). Her laboratory tests revealed C-reactive protein (CRP): +++, erythrocyte sedimentation rate (ESR): 83 mm/h, galactomannan: 0.3 and blood cultures: negative.
The findings were compatible with ROCM; accordingly, sinus endoscopic biopsy and debridement was carried out, and the specimens were sent to the laboratory. Ribbon-like hyphae, compatible with mucormycosis, were reported in the histopathological examination (). Considering the extent of ROCM, the patient was a candidate for enucleation of the left eye, orbital decompression, and sinocerebral debridement. Nevertheless, the patient refused eye enucleation and craniotomy. Therefore, multiple endoscopic sinus debridement procedures were carried out, and posaconazole (200 mg /Q 6 hours) was added to LAMB as a combination antifungal treatment.
During the third week of combination therapy, there was a remarkable improvement in the patient’s clinical signs and symptoms. Also, in the follow-up brain MRI images, the frontal lobe lesion was completely resolved (). The combination antifungal therapy continued for four weeks, and the patient was discharged in the twelfth week. In the weekly follow-ups, no relapse in ROCM was found during the first three months of discharge. However, after three months, the patient died because of relapse in hematologic disease and bleeding due to severe thrombocytopenia.


A healthy 62-year-old male hospitality worker presented to the hospital with left knee pain and an inability to walk following a mechanical fall on ice. The patient was healthy and denied previous trauma, and corticosteroid or quinolone use. Examination of the left knee revealed a compromised extensor mechanism and a palpable defect at the inferior insertion of the patellar tendon, with diffuse pain and swelling but no neurovascular or skin compromise. Radiographs demonstrated tibial tubercle avulsion fracture and patella alta (Figure ). The tubercle fragment was translated 1.5 cm proximally and rotated 90º (Figure ).
Ultrasonography demonstrated an intact quadriceps tendon and a normal patellar tendon origin at the inferior patellar pole. The distal aspect of the patellar tendon could not be fully visualized by ultrasound due to overlying hematoma, but proximal retraction was noted (Figure ).
Surgical treatment occurred 24 hours following presentation. An anterior midline approach was used. After excising hemorrhagic prepatellar bursa, evacuating overlying traumatic hematoma, and exposing the fracture donor site (Figure ), it was apparent that in addition to the tibial tubercle fracture, the patellar tendon was completely avulsed from the tubercle fragment (Figure ). To begin, provisional fixation was achieved with two Kirschner wires. Two transosseous #5 polyester sutures (one medial and one lateral) were placed from intact cortical bone into cancellous bone of the donor site through pilot holes; these sutures were then pushed through the tubercle fragment and were secured through the patellar tendon using a Krackow technique (Figure ).
At this point, slots were cut into the central two holes of a four-hole, 3.5-mm one-third tubular plate. Before tensioning the tendon, this plate was positioned over the reduced tubercle fragment by passing the transosseous sutures through the slots of the plate (Figure ). Two 4-mm cancellous screws were used to secure the plate, thereby providing fixation of the tubercle fragment (Figure ). The sutures were tensioned and locked, reducing the patellar tendon to the bony fragment and tibia. The primary fixation was reinforced using a third #5 polyester suture, placed through an additional transosseous pilot hole distal to the fracture site and secured to the tendon again using a Krackow technique (Figures , ). Medial and lateral retinacular defects were repaired.
Review of final fluoroscopic images confirmed reduction of the tubercle and showed patella baja (Figures , ). Two weeks following surgery, the patient began weight bearing in a fixed knee splint. At six weeks, the operative knee could be passively flexed with no pain to 20º so the patient began gradually increasing range of motion in a hinged knee brace, initially locked at full extension. At three months, radiographs demonstrated appropriate patellar height (Figure ); the patient had active range of motion from full extension to 120º of flexion with only mild discomfort. At one year, radiographs were unremarkable other than minimal osseous debris and/or ossification (Figure ). The patellar height ratio (0.8) was within normal limits using both Caton-Deschamps (normal 0.8-1.2) and Insall-Salvetti (0.75-0.99) methods [-]. The patient had full active range of motion (full extension to 135 degrees) and strength (5/5) equivalent to the uninjured knee, with no residual pain, hardware irritation, or bursitis.


A 25-year-old previously healthy Sri Lankan male presented to the emergency department with a history of painful swelling of the left side on the neck and odynophagia of four days duration. He denied a history of fever and had no symptoms suggestive of upper airway obstruction. He had no significant past medical history to note, except he experienced an episode of severe epigastric pain which was treated as gastritis a year ago. He was an ethanol user, consuming 15 units per week. On examination, he was neither pale nor icteric. His pulse rate was 140 bpm, and blood pressure was 120/70 mmHg. He had tachypnea at rest with a respiratory rate of 32 per minute. Abdominal examination revealed mild tenderness over epigastric region though he denied any history of abdominal pain on admission. A swollen tender area, not moving with swallowing was noted in the lateral aspect of the neck without any palpable cervical lymphadenopathy. Examination of the thyroid gland and oral cavity showed no abnormality except poor oral hygiene. Rest of the systemic examination was unremarkable.
The initial full blood count showed white cell count of 12,580/mm3 with predominant neutrophils, haemoglobin of 13.5 g/dL with a haematocrit of 44, and platelets of 206,000/mm3. Initial inflammatory markers ESR and C-reactive protein (CRP) were 97 mm/1st hour and 26 mg/L, respectively. Serum amylase was 2180 IU/L, and corrected calcium was 2.21 mmol/L. Random blood glucose on admission was 122 mg/dL, and an ABG showed hypoxemia. Ultrasound scan with Doppler study of his neck showed extensive deep vein thrombosis involving internal jugular veins, subclavian veins, axillary veins, basilic veins, and upper part of superior vena cava. Ultrasound scan of abdomen revealed mixed echogenic area seen below the spleen suspicious for haematoma or haemorrhage into the cyst. At this point, he was diagnosed with an acute pancreatitis complicated with extensive deep vein thrombosis, and he was initiated with enoxaparin along with warfarin targeting an INR of 2.5 in addition to other supportive measures for acute pancreatitis.
Subsequent contrast enhanced-computed tomography of chest, abdomen, and pelvis with venogram showed extensive venous thrombosis involving in both internal jugular veins, subclavian veins, bracheocephalic vein, and superior vena cava up to the right atrium () and pulmonary arterial thromboembolism. It also revealed moderate right-sided pleural effusion and gross ascites and features of acute-on-chronic pancreatitis with two cystic collections suggestive of pseudo cyst formation ().
The 2D echocardiography showed normal cardiac function with an ejection fraction of 55%. Extensive investigations done on him to identify an alternative cause for his deep vein thrombosis failed to show any positive results. Anticardiolipin antibody, protein C, S, Factor V Leiden mutation, hams test, and urine for haemosiderin were negative. Markers of autoimmune pancreatitis and pancreatic malignancy were normal.
On day 10 of admission, he developed a bout of severe abdominal pain associated with haemodynamic instability. An urgent ultrasonography of abdomen showed bleeding into the cyst, and it was managed with therapeutic aspiration of 2000 ml of haemorrhagic fluid and transfusion of packed cells while withholding the anticoagulant. Analysis of aspirate showed an exudative fluid with an amylase level of 10435 U/L and LDH of 6060 U/L, suggestive of haemorrhagic pancreatitis. Cytological analysis did not reveal evidence of a malignancy. Parenteral antibiotics and other supportive therapies were continued. Anticoagulant was reinstituted after few days. He made a gradual recovery and discharged from hospital on day 24.
On review at a month later, he showed significant clinical improvement with an evidence of resolving deep vein thrombosis.


A 31-year-old woman (G1, P0) had been diagnosed with Graves’ disease at 16 years of age. She discontinued treatment at her own discretion but was advised to resume treatment when she expressed her desire to become pregnant. At the time treatment had resumed, her TRAb (second generation) level was 211 IU/L (normal range: < 1.75 IU/L). Her family history was negative.
The patient became pregnant naturally, at a time when her thyroid function was not satisfactorily controlled by a high dose of propylthiouracil (PTU). An alternative treatment (isotope therapy or surgery) was being considered. Because of hyperemesis gravidarum, oral medications were no longer an option, resulting in her thyroid function deteriorating during week 13 of her pregnancy. Her TRAb level was 43.6 IU/L at that time, and a daily dose of 50 mg potassium iodide (KI) was administered. As a result, her thyroid function was under control, and KI administration was discontinued at week 17. The patient’s FT3 level fluctuated between normal and elevated, whereas her FT4 and TSH levels were low. Her TRAb level gradually declined but was still high at week 33 (18.4 IU/L).
At 33 weeks and 5 days of gestation, the amniotic pocket and the cervical lengths were 8.1 and 2.6 cm, respectively, indicating worsening hydramnios and threatened premature labor. A blood test showed that the patient’s TSH level had increased to within the normal range. Because pre-pregnancy reduction in her antithyroid medication caused sudden worsening of her thyroid function, she was prescribed a daily supplementary course of 25 μg levothyroxine. At 34 weeks of gestation, she was admitted for hydramnios management and prevention of threatened premature labor.
On admission, blood sampling showed an increased TSH level; thus, her thyroid function had improved. Because she was experiencing frequent uterine contractions, we consulted the Department of Diabetes and Endocrinology at our hospital and initiated a continuous drip of ritodrine hydrochloride under careful monitoring for aggravation of hyperthyroidism. At 34 weeks and 4 days of gestation, a transabdominal ultrasound indicated enlargement of the fetal thyroid. It showed a transverse diameter and circumference of 58.4 and 178 mm, respectively (mean values at the 35th week of pregnancy: 18.9 mm and 51.1 mm respectively []) (Fig. a). The blood flow was diffusely increased (Fig. b), and hydramnios was observed. In addition, the epiphyseal nucleus of the distal femur could not be confirmed. The fetus was in face presentation (Fig. a). We assumed that the cause of the hydramnios was the inability to swallow the amniotic fluid due to the size of the thyroid. We suspected that the PTU had crossed the placenta and migrated to the fetus, causing fetal goiter; therefore, we initiated a reduced dose of antithyroid medication for the mother at 34 weeks and 5 days of gestation. After reducing the PTU dose from 200 to 100 mg/day, neither the mother nor the fetus showed signs of hyperthyroidism. The dose of PTU was gradually reduced to 50 mg/day, while the levothyroxine dose was increased to 100 μg/day. The fetal thyroid showed a shrinking tendency, as magnetic resonance imaging (MRI) performed at 36 weeks and 3 days of gestation showed a 3-cm fetal thyroid transverse diameter (transverse section; Fig. b). The next day, an ultrasound indicated that the AFI had decreased from 24 to 15 cm, and that the fetus’ thyroid blood flow had returned to normal (restricted to the thyroid margins). The fetus had moved into a normal flexion position.
Because of the goiter, we were unable to confirm that there would be a patent airway after delivery. Therefore, we speculated that a tracheotomy would be necessary. After consultation with both the Department of Neonatal Medicine and the Department of Pediatric Surgery, an elective cesarean delivery was performed at 36 weeks and 5 days of gestation. On day 7 after delivery, the mother showed signs of hyperthyroidism, which necessitated an increase in her PTU dose.
A diagram describing the therapeutic course from pre-pregnancy to postpartum is shown in Fig. .
The infant was a male, weighing 2817 g, with Apgar scores of 8 and 9 at 1 and 5 min, respectively. His umbilical aortic blood pH was 7.26. The anterior cervical region had a transverse diameter of 40 mm, indicating an enlarged thyroid gland (Fig. ). Crying was normal, and no resuscitation was necessary. The infant was admitted to the neonatal intensive care unit (NICU) immediately after birth because of premature delivery and goiter. No bradycardia was observed, and other than the goiter, no external deformities that would suggest congenital hypothyroidism, such as megaloglossia or umbilical hernia, were observed.
A sonography indicated that the thyroid gland had a left-to-right transverse diameter of 41.4 mm (normal range [mean ± 2SD]: 13.9 ± 4.0 mm []) and an isthmus of 5.2 mm, indicating enlargement. An ultrasound showed no increased blood flow. Radiographs indicated no epiphyseal nucleus of the distal femur, which showed that fetal bone maturation was delayed because of the fetal hypothyroidism.
Thyroid function tests were conducted using the umbilical blood at delivery, and the results were as follows: FT3, 1.7 pg/mL (normal range [mean ± SD]: 1.70 ± 0.034 pg/ml); FT4, 1.6 ng/dL (normal: 1.17 ± 0.14 ng/dl); and TSH, 25.18 μIU/mL (normal: 10.27 ± 6.31 μIU/mL) []. The TRAb level was 17.4 IU/L. No treatment was given until 5 days of age, when thyroid function tests indicated a tendency toward hyperthyroidism, (FT3 = 3.5 pg/mL, FT4 = 2.7 ng/dL, and TSH = 2.56 μIU/mL). The infant was administered a course of thiamazole (MMI) (0.5 mg/kg/day). No major changes in the size of the infant’s thyroid gland were observed during the hospital stay. Because of neonatal jaundice, the infant was treated with 24-h phototherapy starting at 4 days of age. His progress was stable, and he was discharged at 18 days of age, weighing 3.1 kg. Following discharge, the MMI dose was gradually decreased as TRAb levels dropped, and it was discontinued at 51 days of age. At 10 months of age, the infant’s thyroid function was normal, despite persistent goiter. There was no evidence of any developmental delays. Currently, the infant is under the continuous care of the Department of Pediatrics.


A 21-year-old male was admitted to the hospital because of pain in the middle of his chest, radiating to his left arm and between the scapulae. He felt a tingling sensation in his arm, fingers and lips and had a sore feeling in his jaw. The patient perspired heavily and he was very short of breath. In the previous 2 months, the sore feeling in his jaw and arm had also occurred intermittently. He had no medical history. In the previous 2 years, the patient had smoked 15 cigarettes a day. Cardiovascular disease at a younger age was present in his family. His blood pressure was 128/81 mm Hg. The patient had a body mass index of 34 and on his abdomen pronounced striae distensae were visible. The electrocardiogram showed sinus rhythm with transmural ischaemia characterised by ST elevation in the anteroseptal leads and reciprocal ST depression at the inferior leads (Fig. ). During coronary angiography, a complete occlusion was visible, at the ostium of the left anterior descending coronary artery (LAD) with collaterals from the right coronary artery (Fig. a). A percutaneous coronary intervention (PCI) was performed. A drug-eluting stent was placed in the LAD (Fig. b). Afterwards, cardiac ultrasound showed reasonable left ventricular function with an ejection fraction of 45%. The patient was discharged in a good clinical condition, with medication and lifestyle advice.


A 27-year-old male was admitted to the hospital with complaints of pain in the chest radiating to both arms. In addition, the patient was nauseous and vomited. The complaints began a few minutes after he had performed motocross earlier the same day. The patient had no medical history. Cardiovascular disease at a young age did not occur in his family. He had never smoked, occasionally drank alcohol and did not use drugs. The patient had a blood pressure of 135/88 mm Hg. A troponin T test was negative; the C‑reactive protein level was low. His electrocardiogram showed a sinus rhythm with an intermediate heart axis and a prolonged QRS complex (124 ms) (Fig. a). Suddenly, ventricular fibrillation developed which required immediate resuscitation. After 10 min of resuscitation, a sinus rhythm was present with adequate cardiac output. The electrocardiogram showed precordial ST-segment elevation (Fig. b). Cardiac ultrasound showed a left ventricle ejection fraction of 56% with anterior wall movement disorders. Coronary angiography was performed and revealed a completely occluded LAD with no further signs of angiographic atherosclerosis (Fig. a). The operator refrained from further intravascular coronary imaging because of the life-threatening clinical condition and the fact that it would not have any effect on the treatment strategy in this young subject. The LAD blockade was treated with two drug-eluting stents (Fig. b). Hereafter, the patient was stabilised. He recovered in 4 days and was discharged from hospital.


A 56-year-old man with a history of asthma, sinusitis, serous otitis media, idiopathic eosinophilia, recurrent idiopathic myocarditis, and idiopathic interstitial pneumonia was treated with prednisolone (PSL) at a dose of 27.5 mg/day. He had no symptom with steroid therapy. He complained of a persistent, pulsatile, occipital headache, and general malaise 2 weeks before admission, when the dose of PSL was reduced from 27.5 mg/day to 22.5 mg/day. However, he did not exhibit symptoms such as fever, weight loss, joint pain, rash, or diarrhea. A neurological examination revealed paralysis of the left abducens nerve. Magnetic resonance imaging (MRI) of the brain showed polycystic subdural hygroma and hematoma. In addition, with contrast enhancement, a diffuse thickening of the dura mater was observed (Fig. ). Whole-body computed tomography (CT) scans showed no signs of lymphadenopathy or malignant tumors. Gallium scintigraphy revealed diffuse accumulation in the kidneys; however, there was no accumulation in the lymph nodes and joints. Urinalysis showed a tubular defect (N-acetyl-beta glucosamines 45 IU/L, beta-2-microglobulin 9156 μg/L), suggesting interstitial nephritis. Microbial analyses and immunologic bioassays were uninformative. There was no complement consumption or eosinophilia. His serum IgG4 level was slightly increased (126 mg/dL) at the PSL dose of 22.5 mg/dL. However, one year prior to the study, it was higher (332 mg/dL), although the dose of PSL was 7 mg/day. Craniotomy was performed from the left side of the head with a burr hole, made a dural incision, and collected a sample. After biopsy and dural suture, it was confirmed that was no leakage of spinal fluid by the Valsalva test, preventing low intracranial pressure syndrome from occurring. Dural biopsy confirmed that the dura was 2 mm thick, and its surface was red and edematous, and very fragile. Histopathological examination of the surgical specimen revealed a fibro-inflammatory lesion in the thickened dura due to lymphoplasmacytic infiltrates. Immunohistochemical analysis showed lymphocytic infiltration, 60 IgG4+ plasma cells per high-power field, and an IgG4+/IgG ratio greater than 50% (Fig. ). There was no evidence of a malignant tumor, histiocytic disease, or granulomatous disease. Staining for microbial pathogens was negative. We established a diagnostic of IgG4-RD based on clinical diagnostic criteria [, ], we established a diagnosis of IgG4-RD; the unexplained multiple organ disorders (as mentioned before) also suggested IgG4-RD. The symptoms improved quickly with oral PSL therapy (45 mg/day, 0.6 mg/kg/day) after 2 courses of methylprednisolone 1 g pulse therapy for 3 days, and the subsequent brain MRI showed complete regression of meningeal thickening, polycystic subdural hygroma, and hematoma. Thereafter, tacrolimus (3 mg/day) was added, and the PSL dose was reduced by 2.5–5 mg every two weeks to a final dose of 10 mg/day. The patient had no recurrence of headache with oral treatment using PSL (10 mg/day) and tacrolimus (3 mg/day), and his serum IgG4 level decreased to 9.6 mg.


The 57-year-old female patient presented together with her spouse to the Clinic for Cognitive Neurology at the University Hospital Leipzig, Germany, with visual impairment that had developed gradually over the last 3 years. The patient worked as a secretary. There, she recognized problems writing with ten fingers on the computer keyboard, using computer programs, organizing dates. Moreover, she and her husband described problems in everyday life, in particular losing the ability to identify correct time on watches, keep lines when reading and writing, open the door with a key, put a plug to a socket, switch on/off the kitchen stove and other kitchen equipment, put cutlery into the drawer, load the dishwasher, put shoes or clothing into cupboards, dressing, and word finding difficulties. The patient described visuospatial and visuoperceptual problems as “things don’t fit to each other,” “I cannot find any order.” Remarkably, three ophthalmologic investigations could not identify any specific related pathology, but recommended using glasses. One year before admission, a burn-out syndrome was diagnosed and the antidepressive drug venlafaxine administered.
Investigations with structural magnetic resonance imaging (MRI) 2 and 1 year before admission and visual evoked potentials (VEP) did not reveal any pathological findings. A lumbar puncture revealed reduced amyloid-beta 1–42 levels and normal values for total and phospho tau as well as negative protein 14-3-3 in cerebrospinal fluid (CSF).
illustrates brain imaging findings. A structural MRI revealed brain atrophy especially in parietooccipital regions and, accordingly, enlargement of posterior ventricles. Single small white matter lesions did not reach pathologically relevant extent. Positron emission tomography (PET) with F18-fluorodesoxyglucose (FDG-PET) as a neuronal injury marker revealed glucose hypometabolism bilaterally in parietooccipital cortex, more pronounced on the right side, and in the right frontotemporal cortex. PET with F18-florbetaben showed amyloid accumulation in the gray matter of the neocortex (posterior cingulate, parietooccipital, and frontal cortex).
Clinical in-depth phenotyping revealed severe Balint’s syndrome with simultanagnosia, optic ataxia, ocular apraxia and visuospatial/visuoperceptual deficits, incomplete homonymous anopsia in the left lower quadrant, hemineglect on the left side, form and object agnosia. Although the patient did not recognize therapists in clinical routine that might indicate prosopagnosia, face recognition was possible, but with a reduced speed, in a facial recognition test for unknown faces. Deficits led to an impairment of exploration and reading abilities with problems in orientation in traffic, rooms, and on pages. Related clinical symptoms included alexia, agraphia, acalculia, deficits in attention, and with a lesser extent in memory and executive functions. The patient reached 24 out of 30 possible points in the Mini Mental State Examination (MMSE) 2 months before baseline investigation, and then she scored 23 points. The patient did not show any hints for proper aphasia. The patient was impaired in everyday life activities. illustrates clinical symptoms including simultanagnosia during visual exploration and object agnosia in clinical examination, optic ataxia combined with visuospatial and visuoperceptual deficits with problems in placing a plate into the dishwasher, putting a plug to a socket, and using a water boiler, and finally tactile compensation of deficits. Although the patient had problems in recognizing a fork or spoon visually (see third movie part for object agnosia), she could easily identify these items based on tactile information without visual information (eyes had been covered by blindfold, see last movie part for tactile compensation). Interestingly, this strategy was also applied successfully by the patient spontaneously when she failed in her first attempt with putting a plug to a socket (see second movie part for optic ataxia).
Differential diagnosis of neurodegenerative diseases has to take clinical syndromes and biomarkers from imaging and CSF as surrogate indicators for histopathology into account as recently suggested in clinical diagnostic criteria (; ; ). In accordance with this conceptual shift, suggested a three-level classification framework for PCA comprising both syndrome and disease-level descriptions. On classification level 1 the patient fulfilled the core features of the PCA clinico-radiological syndrome, i.e., clinical criteria with insidious onset, gradual progression, prominent early disturbance of visual and/or other posterior cognitive functions, and the cognitive features with space perception deficit, simultanagnosia, object perception deficit, constructional dyspraxia, environmental agnosia, oculomotor apraxia, dressing apraxia, optic ataxia, alexia, acalculia, agraphia, and homonymous visual field defect. Later on (see below), further discussed PCA features, apperceptive prosopagnosia, finger agnosia, and left/right disorientation were also fulfilled (Gerstmann’s syndrome). Neuroimaging indicated predominant occipitoparietal or occipitotemporal atrophy on MRI and parietooccipital hypometabolism on FDG-PET. Classification level 2 revealed pure PCA without fulfilling core clinical criteria for any other neurodegenerative syndrome. Classification level 3 provided biomarker-evidence for Alzheimer’s disease as the underlying pathology in accordance with the suggested criteria for this disease, i.e., decreased amyloid beta 1–42 in CSF and neocortical amyloid-beta accumulation in PET (, ). There was no evidence for familial/genetic etiology and no autopsy information available. As suggested in there was evidence for both Alzheimer’s disease etiology (amyloid alterations as shown in PET and CSF) and neuronal injury (FDG-PET, structural MRI; for imaging meta-analyses see , and ). In sum, the patient suffered from PCA on a syndrome-clinical level with evidence for underlying Alzheimer’s disease on imaging and biomarker levels.
An acetylcholine-esterase-inhibitor (galantamine) starting with a daily dose of 8 mg was administered due to underlying Alzheimer’s disease. Deficits were treated in a day clinic out-patient setting with a multimodal approach including orthoptists, occupational therapists, neuropsychologists, patholinguists, and physiotherapists. Support by occupational therapy, patholinguistic therapy, and psychotherapy was recommended to be continued after discharge.
Eight months later the patient was re-examined. Dosage of galantamine was increased to 24 mg daily in the meantime. Intensive therapy by orthoptist and patholinguist improved reading of words and sentences, whereas reading of numbers and writing of words and sentences did show more mistakes. These changes were related to a decline in visuospatial and visuoperceptual functions, the left-sided hemineglect, and simultanagnosia. Whereas at first investigation the patient could perceive three objects simultaneously, at follow-up only two objects were detected. The patient was functionally blind and had to rely on support by her spouse. Prosopagnosia was detected in facial recognition test and prosopagnosia test. MMSE score reached now 22 out of 30 possible points.
During the follow-up 17 months later, the patient reported further deterioration of visuospatial and visuoperceptual abilities including reading and writing, whereas she could better compensate deficits by putting things into cupboards by using strategies. She also told that she identified persons now by their voice and/or gait instead of recognizing their face. She reported failing sitting on chairs by sitting beside it. The husband reported depressive mood. Coxarthrosis required implantation of endoprostheses in both hip joints. In the meantime, dosage of galantamine was reduced to 16 mg daily due to nausea as a side effect. Investigations revealed additionally finger agnosia, deficits in body schema, and temporal orientation. The neuropsychiatric inventory excluded changes in personality/behavior besides slightly depressive mood. As illustrated in structural MRI indicated regional atrophy with slight increase in extent but without qualitative changes. Semantic abilities were now slightly impaired. Symptoms of the Balint’s syndrome, especially simultanagnosia, and cognitive abilities showed further decline if compared with earlier investigations (patient could perceive only one object now at one time, MMSE score 18 out of 30 points). These higher deficits led to misinterpretations of everyday usage objects, persons, and stronger impairments in everyday activities. Occupational therapy was now recommended in the patient’s household.
At follow-up 17 months later, the patient and spouse reported further deterioration in higher order visual processing. According to the spouse the patient once had the illusion of people sitting in the garden, which were actually not there. This never happened again. Furthermore, the patient suspected that her husband would be interested in other women. Structural MRI revealed again severe cortical and subcortical atrophy, now with temporomesial atrophy (medial temporal lobe atrophy according to Scheltens’ 2 left/3 right; at baseline and at second follow-up 1 left/2 right). Thorough neuropsychological testing was not possible anymore due to deficits’ severity.
The patient and spouse visited the clinic 14 months later. They reported further general decline of visuospatial/visuoperceptual abilities deteriorating everyday life activities. She could not use a knife and fork during eating appropriately. The husband added that the patient used her left hand less. Symptoms suspicious for hallucinations or paranoia were not reported any more. Most remarkably, the husband now stated that the patient sometimes did not recognize him and misidentified him rather as a stranger ( taken by spouse). During these episodes she also perceived him as a threat; once or two times she even told that she had been raped. These events occurred now daily with a duration of 1 h. Such misidentifications would not happen for other persons. To interrupt such events by re-identifying the spouse as her husband he would have to call their children or the patient’s female friend by phone, to calm her and reassure her regarding the husband’s identity. Structural MRI () revealed more widespread atrophy compared with the previous MRIs, especially in temporoparietooccipital areas. Temporomesial atrophy reached now stage 3 bilaterally on the Scheltens’ scale. In the meantime, the frontal cortex was also involved. Ventricles were largely extended especially in posterior and temporal regions. Neuropsychological investigations, only possible for rough tests, showed further cognitive decline with now 4 out of 30 possible points in the MMSE. Visuospatial and visuoperceptual abilities, the Balint’s syndrome, and left-sided hemineglect were further deteriorated. Although low vision could be compensated by tactile information during previous examinations, this compensatory strategy was not applicable any more. Orientation was even impaired in their own flat. To cope with misidentification events the antipsychotic quetiapine and behavioral interventions were recommended beside respite care, occupational therapy at home, and support by assistants.
To validate the impact of structural imaging changes on the disease course and, in particular, the development of Capgras delusion quantitatively, we performed a single-subject voxel-based morphometry (VBM) analysis using MRI data. Here, progress of brain atrophy was quantitatively analyzed over time in the case-subject by comparing each timepoint of MRI scans to a healthy elderly cohort.
Voxel-based morphometry identified differences that are specific for each timepoint in the patient’s disease course compared to a healthy control cohort. Here, 42 healthy controls (mean age ± SD = 69.6 ± 6.6 years) were contrasted to the four MRI measurements of the patient (baseline, age = 57.8; second follow-up, age = 60.0; third follow-up, age = 61.2; fourth follow-up, age = 62.4 years) in four separate analyses.
Voxel-based morphometry was performed applying the CAT12 toolbox (University of Jena, Germany) with SPM12 (University College London, United Kingdom). Images were spatially normalized, segmented, modulated by the amount of linear and non-linear deformations, and smoothed with a Gaussian kernel of 8-mm full-width at half-maximum. Voxel-wise Student’s t-tests were performed to compare each timepoint of the patient with controls. Nuisance covariates were used to control for differences in age and total intracranial volume. Significant clusters were detected using an uncorrected voxel-threshold of p < 0.005 and a family-wise error (FWE) corrected cluster-threshold of p < 0.05. To visualize the disease progression, resulting gray matter volume (GMV) maps from the single timepoints comparisons were binarized and superimposed to create an overlay analysis.
As aforementioned, the Capgras delusions emerged between the last two visits. Accordingly, we regarded atrophy changes between the third and fourth follow-ups as the most informative, as they are timely coincident with the emergence of the symptoms of interest. In order to graphically display the trend over time in GMV reductions, we performed an additional data-driven region-of-interest (ROI) analysis. Using marsbar v.0.44, we extracted the average GMV values from data-driven ROIs defined according to the atrophy pattern characteristic of the case-patient during the fourth follow-up. Namely, we created three ROIs, one encompassing the overall PCA pattern (i.e., including extensively occipital and temporoparietal cortex) and two from the brain regions that emerged concurrently with the Capgras delusion in the transition between the third and fourth follow-up, i.e., posterior cingulate gyrus/precuneus and middle frontal gyrus/frontal eye field (respectively, centered on the MNI x, y, z coordinate 4, −32, 44 and 28, 0, 51). GMV values for the healthy controls were summarized in a boxplot and values for each timepoint for the patient are visualized separately. In addition, we also extracted the total GMV of the patient at each timepoint to measure overall atrophy changes.
As illustrated in and the single-subject VBM analysis revealed general progressive GMV decline in occipital and temporoparietal areas from baseline to fourth follow-up. Generally, atrophy involved more the right than the left hemisphere, especially in the beginning of imaging investigations. Atrophy was already observed in the right fusiform gyrus at baseline, whereas the left fusiform gyrus appeared relatively spared at baseline but was severely compromised at fourth follow-up. Most specific changes during transition from the third to the fourth follow-up, i.e., the appearance of the Capgras delusion, are illustrated in yellow color in the left bottom panel in and in . New GMV reduction was found at this timepoint in the posterior cingulate gyrus/precuneus, as well as in the right middle frontal gyrus/frontal eye field. The ROI analyses revealed that summarized GMV values in the healthy control group were always higher in all of the three investigated regions. GMV values declined with each follow-up in all of the three ROIs (, right panel). Of note, no sharp decline in GMV was detected in any of the three ROIs, rather a slow, progressive decrease. A similar decrease rate was also evident in the overall progression of atrophy as quantified by a gradual loss of total GMV from baseline to the last follow-up (468 cm3 450 cm3 417 cm3 403 cm3).
To further explore the significance of atrophy differences between the third and the fourth follow-up for functionally associated brain networks, we applied two additional analytical techniques via Neurosynth (; see also ): (1) meta-analytic co-activation modeling (MACM), which identifies co-activation of brain regions across studies reported in the Neurosynth database (N = 14,371 as of March 2020); and (2) seed-based resting state functional connectivity based on a sample of 1,000 healthy controls (). The seeds for both analyses were created as 6 mm radius spheres centered in the atrophy maxima of the two clusters that differentiated the patients and controls at the fourth follow-up but not at previous timepoints, i.e., in the posterior cingulate/precuneus and in the frontal gyrus/frontal eye fields (coordinates in MNI space 4, −32, 44, and 28, 0, 52).
Results from both MACM and seed-based resting-state functional connectivity were highly consistent for each seed (). The seed in the right frontal gyrus/frontal eye field showed preferential co-activations and functional connectivity with its contralateral homolog, and with the bilateral superior parietal cortex, closely resembling the architecture of the dorsal attention network. The seed in the posterior cingulum/precuneus showed to be functionally connected/co-activated with the bilateral inferior parietal cortex and medial frontal and anterior cingulate cortex, well-known components of the default mode network. The two brain networks connected/co-activated with the seeds were topographically dissociated.


A 75-year-old female patient presented to our emergency department for palpitations. Her review of system was positive for intermittent right-sided chest pain and palpitation. Her medical history revealed hypertension, PCLD, and macular degeneration. Her family history is significant for PCLD. Vital signs upon presentation were notable for heart rate of 124 beats per minute, blood pressure of 143/81 mm Hg, temperature of 97.1°F, and respiratory rate of 18 breaths per minute. Physical examination was unremarkable except for marked hepatomegaly on abdominal palpation and rapid irregular pulse. An electrocardiogram performed at presentation showed a new-onset atrial fibrillation with rapid ventricular response. The patient received 1 L of lactated ringer and was started on a beta-blocker, which resulted in heart rate control. Computed tomography (CT) scan of the abdomen and pelvis performed to evaluate for hepatomegaly revealed a markedly enlarged liver containing innumerable cysts, largest measuring 12.62 cm by 10.56 cm and compressing the right atrium (Figures , ).
Transthoracic echocardiograph performed showed a large cystic mass in the right upper quadrant compressing the right atrium (Figures , ).
Apart from an isolated mild elevation of serum alkaline phosphatase of 229 U/L, the hepatic function panel was unremarkable. Renal functions test revealed serum blood urea nitrogen of 17 mg/dL and creatinine of 0.7 mg/dL. Thyroid function test was unremarkable. Serum electrolytes including potassium and magnesium were within the normal range. A nuclear stress test was performed for the evaluation of intermittent right-sided chest pain revealed no evidence of ischemic heart disease. The patient was started on anticoagulation and beta-blocker as rate control agents. The patient declined surgical intervention. She was subsequently discharged on hospital day 3. The patient has been medically stable on conservative treatment.


A 63-year-old Vietnamese man was electively admitted to a tertiary hospital in Melbourne after undergoing an outpatient colonoscopy to investigate progressive bloody diarrhea. Symptoms over the 3 months preceding admission included acute-onset watery diarrhea, up to 10 bowel motions per day, fecal incontinence, and significant weight loss. There was no associated pain, nausea, or infective symptoms. In the community, a trial of metronidazole and an antidiarrheal agent was ineffective. Past medical history included a basal ganglia hemorrhage with residual left-sided weakness and hypercholesterolemia, and he took regular medications for secondary stroke prevention. He had no family history of bowel cancer or inflammatory bowel disease (IBD). Apart from antibiotic exposure he did not have infective risk factors such as recent overseas travel or sick contacts.
On examination, the patient was afebrile; his heart rate was 84 beats/min, and body mass index was 22.4 kg/m2, having lost 14 % of his body weight in 4 months. Abdominal examination demonstrated a soft abdomen, with no tenderness or peritonism. Severe malnutrition was present with loss of muscle mass and subcutaneous fat. There was no lymphadenopathy or clinical signs of thyrotoxicosis. Per-rectal examination was unremarkable. Laboratory investigations showed mild lymphocytopenia (1.1 × 109/L) but an otherwise unremarkable routine blood panel. A nutrition screen showed hypoalbuminemia (albumin 32 g/L). A septic screen was negative, including QuantiFERON-TB Gold and human immunodeficiency virus serology. There were moderate numbers of leukocytes and erythrocytes on a fecal specimen but no cultured bacteria and parasites, and Clostridium difficile toxin was not detected. Fecal calprotectin was mildly elevated (96.5 μg/g). Abdominal computed topography (CT) indicated thickening of the distal descending colon, favoring an infective or inflammatory colitis (Fig. ).
Initial sigmoidoscopy demonstrated severely inflamed mucosa with cobblestone appearance of the sigmoid colon and well-demarcated rectal sparing (Fig. a), although the rectum had lost its regular vascular pattern and had a scarred appearance. Histopathology was suggestive of ischemia with no evidence of dysplasia or malignancy. This prompted admission to hospital in the Gastroenterology unit. An attempted complete colonoscopy showed similar features extending proximally (Fig. b,c), and in the setting of severe inflammation, the procedure was abandoned to avoid risk of perforation. Biopsies of the descending colon demonstrated severe ulceration and granulation tissue and no amyloid deposition on Congo red stains. Viral and Giardia, Cryptosporidium, and Entamoeba polymerase chain reaction testing were negative, and there were no acid-fast bacilli detected nor was there growth of mycobacterium. A vasculitic screen was negative on laboratory testing, and a CT-angiogram demonstrated extensive colitis with dilatation of the transverse and ascending colon but no arteriopathy or evidence of mesenteric thrombus, although there was engorgement of the vessels primarily in the distal descending colon. Empirical treatment included intravenous antibiotics, corticosteroids, and total parenteral nutrition.
Failure to respond to 3 weeks of medical therapy resulted in a multidisciplinary team decision to proceed with an open Hartmann's procedure. Intraoperative findings included a grossly abnormal colon from the upper rectum to mid-descending colon. The rectum and mesentery were edematous, and the affected bowel mesentery was adherent and fixed to the retroperitoneum. There were no signs of any other disease, and blood supply to the bowel was normal. Macroscopic examination of the bowel showed diffusely thickened wall, with thickened mesenteric fat and extensive areas of ulceration (Fig. ). Histopathology of the sigmoid colon showed extensive ulceration of the bowel wall, including submucosa (Fig. ). There were extensive ischemic changes with crypt atrophy and attempted regeneration and mucosal hemorrhage. Distinctive features at the base of the ulcer, the submucosa, and even in areas with intact mucosa were: (i) capillaries with marked mural fibrous thickening, so called “arteriolization” of capillaries; (ii) focal subendothelial deposits of fibrin in small vessels); and (iii) fibrin thrombi in small vessels (Figs and ). The large veins in the mesenteric fat and in the subserosal fat showed prominent myxoid change with myointimal hyperplasia, causing prominent narrowing of the lumen (Fig. ). These veins often appeared larger than the associated arteries. One vein showed evidence of recanalization consistent with previous thrombosis. These changes were those of ischemic colitis associated with myointimal hyperplasia of mesenteric veins. The three sets of mucosal biopsies taken in the 7 weeks prior to surgery were reviewed, and all showed, in addition to the changes of ischemic colitis, the characteristic mucosal changes of this disorder—fibrin thrombi and subendothelial fibrin deposits in small vessels and the arteriolization of small vessels, which are not seen in other causes of ischemic colitis (Fig. a,b).
The patient made good postoperative recovery and was discharged home 2 weeks later, tolerating an oral diet and managing his stoma independently.


A 68-year-old man presented to our institution for the treatment with cough and chest pain which already last for 4 months. He had a medical history of chronic gastritis for 3 years, and he was a smoker (30 cigarettes/day) for 40 years. He denied other symptoms like nausea, fever, vomiting or shortness of breath. Electrocardiography shows T wave changes and echocardiography showed moderate tricuspid regurgitation. The left ventricular diastolic pressure decreased. Routine laboratory examinations found carcinoembryonic antigen (CEA) at 4.7 ng/mL (normal range, < 5 ng/mL) within normal limits, but increased level of Prostate-specific antigen (PSA) (5.1 ng/mL; normal range, < 4.4 ng/mL), cancer antigen 125 (CA-125) (41.7 U/mL; normal range, < 35 U/mL), and carbohydrate antigen 19–9 (CA19–9) (53.4.1 U/mL; normal range, < 27 U/mL) in the serum. Furthermore, the fiberoptic bronchoscopic biopsy sample was fixed with 10% neutral formalin, embedded in paraffin, routinely prepared, stained with hematoxylin-eosin, and observed under light microscope. Streptavidin-perosidase method was used for immunohistochemistry. The Immunohistochemical staining results showed that the tumor cells were positive for CK(+), P63(+), CK7(+), CK5/6(+), Ki67(+), S-100(+), Calponin(+), while negative for P40, NapsinA, TTF1, WT-1 and CR (Fig. ).
Based on the radiopathological result, he was diagnosed with stage IVB myoepithelial carcinoma accompanied by metastases in the left pulmonary hilum, mediastinal lymph nodes, and cervical vertebra. Besides, there was no measurable tumor observed from PET-CT along his salivary gland. His Eastern Cooperative Oncology Group (ECOG) performance status was 1, and his vital signs were normal.
Furthermore, the biopsy samples were tested by targeted next generation sequencing (NGS) with a 168-gene cancer panel (Burning Rock Biotech, Guangzhou, Guangdong, China). The NGS sequencing results revealed EGFR exon 19 deletion (p.E746_A750del; 0.04%) and KRAS mutation (p.G12C; 0.15%) from plasma sample, and only the KRAS mutation (p.G12C; 53.18%) from needle biopsy tissue sample of the lung (Fig. ). Subsequently, he was treated with EGFR-TKI icotinib at 125 mg orally thrice daily from July 25th 2019. After 40 days, the patient came back for reexamination of chest CT. The radiography showed a significant reduction in his primary lung lesion (6.2 × 4.7 cm vs 4.2 × 3.5 cm). There was significant improvement in clinical symptoms including chest pain. He achieved partial response (PR) under the criteria of Response Evaluation Criteria In Solid Tumors (RECIST) 1.1 (Fig. ). Unfortunately, the disease progressed after 2.5 months of EGFR-TKI treatment. The magnetic resonance imaging (MRI) revealed disseminated bone metastases and brain atrophy. On Oct 31st 2019, the patient passed away due to multiple organ failures with an overall survival (OS) of 3 months.


An 83-year-old woman came to the emergency department with a complaint of shoulder pain and incapacity to lower her arm after an accidental fall from the last step of her home staircase. According to her own report, she had put her right arm outstretched above the level of her head, in the opposite wall, causing hyperflexion of the shoulder, in order to avoid the impact of a head injury. At that moment, she experienced numbness and shock-like electrical sensations in the fingers of the ipsilateral hand. In addition, there was a clear medical history without previous shoulder dislocation or contributing pathologies.
On physical examination, her dominant arm was abducted at the shoulder and flexed at the elbow. The patient could not adduct the arm to less than 80°. Examination revealed loss of contour of shoulder and presence of the head of humerus palpable in the axilla. Vascular function was not compromised in the affected extremity, as verified through the presence of radial pulse. However, she presented a deficit attempting the “OK” sign and a positive digit abduction/adduction test, which characterizes an injury to the anterior interosseous nerve (branch of the median nerve) () and ulnar nerve, respectively.
Radiographic examination confirmed the clinical diagnosis of a complete inferior dislocation of the humeral head lying beneath the glenoid cavity, without any accompanying fracture (). Immediate reduction was done with intravenous analgesia-sedation by in-line traction-abduction and gently pushing the humeral head superiorly, while countertraction was provided by an assistant. An audible pop was heard when the humeral head was reduced (). The delay between the time of injury and reduction was 2 hours. After successfully closed reduction, the right shoulder was immobilized using an arm sling. Following reduction, the deficit in attempting the “OK” sign and digit abduction/adduction test remained. The patient was discharged under instructions to maintain the immobilization (elbow to body) for three weeks to allow soft tissue healing.
A magnetic resonance imaging (MRI) of the shoulder was carried out ten days later in order to evaluate soft-tissue structures, such as the rotator cuff and labrum, and occult skeletal pathology. The MRI revealed a Bankart lesion in the anteroinferior aspect of the glenoid labrum of the shoulder. A bone marrow contusion line in the greater tuberosity of the humerus showed a contusion-crank fracture without displacement. A complete rupture of the supraspinatus tendon was also revealed (). Although the patient was advised to treat the rotator cuff rupture surgically, she chose not to do so. Further evaluation by an electromyography study revealed the destruction of the myelin sheath of the median nerves bilaterally (carpal tunnel syndrome). In addition, the altered dynamics of the right median and ulnar nerves could be related to neurapraxia due to the nerve compression.
After three weeks, physical therapy was proposed with gentle pendulum movements of the injured upper limb. Passive range of motion and isometric deltoid exercises was proposed during the 4th and 6th weeks, respectively. After the 8th week, active/strengthening exercises were proposed. After 6 months of the reduction, the patient had a mild weakness in the little finger, with difficulty to abduct her arm above the head (over 100°). Shoulder function was assessed, and the Constant score was 69 out of 100 points. At 18 months, the patient regained a nearly full active range of motion in the shoulder and had no instability toward elevation or rotation. At the present time point, she is satisfied with her function and she is independent and able to perform activities of daily living. The Constant score was 81 out of 100 points.


A 40-year-old female with a 4-month history of polydipsia, polyuria, headache, menstrual disorder and fatigue was admitted to the hospital. Examinations revealed a urine osmolality of 63 mOsm/kg when plasma osmolality reached 307 mOsm/kg and serum sodium was 148 mmol/L, and deficiencies of adrenocorticotropic hormone, thyroid-stimulating hormone and gonadotropins. Magnetic resonance imaging (MRI) revealed homogeneous signals in the pituitary gland as well as thickening of the pituitary stalk (Fig. ), which supported a diagnosis of central diabetes insipidus. FDG PET was performed with a dose of 5.55 MBq (0.15 mCi) per kilogram of body weight to localize the pituitary and/or the pituitary stalk lesions and revealed radioactivity at both sites (Fig. ). However, the elevated FDG uptake was inadequate for an etiological diagnosis, and FDS (5.55 MBq/kg) was utilized to further explore the nature of the disease. The lesions also showed increased FDS uptake at 30 min and 120 min after FDS injection (Fig. ), both of which were significantly higher than normal brain uptake. The patient was suspected to have autoimmune or infectious pituitary inflammation based on FDG and FDS activity, and both tracers also excluded possible extracranial involvement.
Transnasal biopsy was performed for a definitive diagnosis. A lesion was found locating at posterior pituitary, while the anterior pituitary remained normal. Histopathology of the posterior pituitary lesion revealed lymphocyte infiltration and fibrosis of the pituitary gland, while no evidence of malignant elements or infection was seen, which indicated a diagnosis of autoimmune hypophysitis. The patient was then treated with oral prednisone (starting dosage of 40 mg/day, gradually decreased every 3 weeks to a maintenance dosage of 10 mg/day), desmopressin acetate (0.2 mg/8 h) and levothyroxine (50 μg/day) and showed an improvement in clinical symptoms and on radiological examination (Fig. ). However, hypopituitarism remained stable and hormonal replacement was consistently needed.


A 59-year-old woman with a medical history of decompensated cirrhosis secondary to primary biliary cholangitis underwent an elective TIPS procedure for refractory ascites. Three months before TIPS placement, a cardiac workup revealed a normal electrocardiogram. A 2-dimensional contrast-enhanced transthoracic echocardiogram (TTE) showed a left ventricular ejection fraction (LVEF) of 55%–60%. A dobutamine stress echocardiogram did not reveal evidence of inducible ischemia or systolic dysfunction.
A TIPS was placed, resulting in improvement of her hepatic venous pressure gradient from 8 to 4 mm Hg. Her ascites did not reaccumulate in the first 4 days after the procedure. However, she developed progressive respiratory distress with pulmonary edema visualized on thoracic radiograph. Cardiac evaluation performed 5 days post-TIPS placement with TTE demonstrated a newly reduced LVEF of 30%–35% and severe hypokinesis of all mid to distal segments, including the apex, along with hypercontractility of the basal segments. Electrocardiogram revealed new ST- and T-wave abnormalities in the anterolateral leads. Cardiac enzymes were not obtained. Coronary angiography revealed no significant epicardial coronary artery disease. Her new-onset cardiomyopathy was medically managed with β-blockade and diuretics. TTE 2 weeks after TIPS revealed improvement in her LVEF to 50%–55% with persistent hypokinesis of the apex and apical myocardial segments. TTE 2 months later revealed LVEF of 50%–55% and resolution of regional wall motion abnormalities. Unfortunately, the patient experienced progressively worsening hepatic encephalopathy after her TIPS procedure and required TIPS reversal. She ultimately underwent orthotopic liver transplantation.


A 40-year-old man was admitted to our hospital with a 15 cm right testicular tumor. High inguinal orchiectomy was performed, and pathological diagnosis was seminoma, pT1. A systemic survey showed no metastasis, resulting in assignment to stage I. The patient selected the option of surveillance without adjuvant therapy. One month after surgery, CT showed enlarged pelvic lymph nodes, and the patient was diagnosed as having nodal metastasis. The International Germ Cell Consensus Classification was good prognosis. Therefore three cycles of BEP chemotherapy were planned. The patient complained of nausea and constipation from day 4, without vomiting or loss of consciousness. On day 8, although hyponatremia (Na 126 mEq/L) was observed, gastrointestinal symptoms did not deteriorate, and bleomycin was administered in accordance with the regimen. On day 9, he suffered from vomiting (Common Terminology Criteria for Adverse Events v5.0, Grade 2) and disorientation (Grade 1). Serum sodium level was decreased to 110 mEq/L. Urinary and plasma osmolality were 740 and 231 mOsm/L, respectively. ADH was 10.1 pg/mL (~4.2 pg/mL). Renal, thyroid, and adrenal dysfunctions were excluded. Thus, SIADH was diagnosed. His symptoms gradually improved after administration of 3% hypertonic saline and extra salt intake (Fig. ). On day 15, febrile neutropenia prevented the administration of bleomycin. The patient recovered from febrile neutropenia with antibiotic treatment. For the second and third chemotherapy courses, serum sodium was frequently monitored (Fig. ), and hyponatremia was treated by restricting water intake to 800–1000 mL/day and prescribing salt intake of 3.0–4.5 g/day besides meals. Serum sodium was maintained at >130 mEq/L. Mild digestive symptoms without hyponatremia-related symptoms were recorded. Lymph node metastasis disappeared on CT after three courses of BEP chemotherapy.


The present study reports the case of a 41-year-old male. He had no history of tobacco or alcohol abuse, neither chronic medical condition. He was diagnosed a nonfunctioning 7 cm left-sided thyroid nodule. Fine-needle aspiration cytology reported the lesion as suspicious for a follicular neoplasm (Bethesda category IV) and subsequently underwent hemithyroidectomy, with left recurrent laryngeal nerve palsy as postoperative complication. Histopathological exam reported the presence of a follicular adenoma without any evidence of malignancy. In the follow-up visits, no evidence of illness was found within the next 36 months.
In November 2018, disabling acute symptoms emerged, such as fatigue, anorexia, and skeletal pain which required a high dose of analgesic drugs. At that moment, 18F-FDG positron emission tomography (PET)/CT scan displayed several bone lesions (vertebral bodies including C6-C7, sternum, ribs, iliac crest, right acetabulum, and both necks of the femur), with maximum standardized uptake value (SUV) of 13.4. Echography percutaneous biopsy was used to obtain a sample from rib lesion which histological examination by immunohistochemistry revealed evidence of DTC metastases as they were strongly positive for thyroglobulin and thyroid transcription factor 1 (TTF1).
After establishing diagnosis, the case was reviewed in a multidisciplinary tumour board. As the patient presented poor performance status at the moment of diagnose (ECOG 3), he was not candidate for receiving local treatments, such as completion of surgery. Also, RAI therapy at this moment was not suitable for several reasons. Firstly, bone metastasis presented 18F-FDG uptake with high SUV, for that reason less likely to concentrate radioiodine and high probability of being RAI refractory. Secondly, it was considered to be a high risk of vertebral fracture and spinal cord compression at the level of C6-C7. After a careful analysis of these clinical features, it was decided to start systemic treatment with TKI Levantinib. Oral treatment was administered continually in a 24 mg once daily-dose, for 4-week cycles.
One week after treatment initiation, the patient experienced remarkable improvement in his clinical condition, including high reduction of skeletal pain that allowed a decrease in the analgesic treatment as well as a significant improvement of patient's performance status, moving from ECOG 3 to 0. After three cycles of treatment, a new 18F-FDG PET/CT scan was performed for restaging. It was observed a reduction in the size of lesions, mainly in the soft tissue component and a decrease of maximum SUV from 13.4 to 8.1 (), which represents a 39.5% of decrease. Serum thyroglobulin levels also decreased from 49105 ng/ml to 2500 ng/ml in this period.
In view of this clinical and radiological response, conventional treatment was suitable in this case, including completion of thyroid surgery plus RAI treatment. The patient underwent resection of the thyroid gland remnant, with no post operative complications and no evidence of malignancy on the histopathological exam. After surgery, RAI treatment was performed. In the cancer uptake scan, a low dose of radioiodine detected disease only in tumour bed as well as isolated vertebral metastasis. Afterwards, when a higher dose for ablation was administered, the scan showed also multiple foci of metastasis in the axial and peripheral skeleton. This absence of RAI uptake in some but not in all lesions confirmed the presence of dedifferentiated thyroid cancer population (with low ability to uptake and concentrate radioiodine) and therefore RAI-refractory disease.
Regarding adverse events (AEs), the patient experienced hypertension within the first days of treatment, later followed by diarrhoea, both grade III according to the Common Terminology Criteria for Adverse events (CTCAE) scale. He also experienced transient low-grade stomatitis that was spontaneously resolved. With respect to hypertension, early blood pressure control was started as a method to maintain TKI dose regimen. Patient was clearly instructed to report side effects when they are still low grade in order to avoid TKI interruption. It could be optimally controlled with calcium antagonist and ACE inhibitors, and no dose reduction was needed for this reason. Due to diarrhoea, dose reduction as well as one-day dose interruption once or twice per cycle was needed, in addition to antidiarrhoeal medication such as loperamide. Late adverse events observed after one year of treatment were neutropenia grade II and moderate to severe palmar-plantar erythrodysaesthesia that lead us to a dose reduction up to 10 mg once daily-dose for 3-week cycles followed by 1 week off-treatment.


A 26-year-old man sustained a high voltage electrical injury (> 1000 V) while he was working with a concrete mixer pump that came in contact with high voltage cable of 10,000 V. The patient was disconnected from the tube immediately due to the jolt, lost consciousness and a cardiac massage was launched within 3 min by witnesses. Then, advanced life support was supplied by paramedics as ventricular fibrillation was detected. He was referred to the nearby emergency room (ER) of a secondary hospital with cardiogenic shock, being chest compressed by a LUCAS machine. In the ER, advanced cardiovascular life support continued for more than 30 min.
After resuscitation, the patient was still supported with IV Noradrenaline. He was then referred to our institute. A physical exam conducted upon his admission showed an unconscious ventilated patient with reactive dilated pupils, tachycardia and a normal bilateral vesicular breathing sound. Electrical entry point was detected on the left hand; exit points were on the feet, bilaterally. ECGs showed sinus tachycardia with PVCs. The arterial blood test showed: PH 6.8, PCO2 53mmHG, PaO2 57 mmHg, lactate 8 mmol/l, and troponin 38,000 ng/dl. The ECG showed an estimated ejection fraction (EF) of 10%, with global dysfunction and a reserved valves’ function. After the heart team consulted, the patient was then connected to the VA-ECMO within 30 min of his admission, via a right femoral approach with distal perfusion.
VA-ECMO support was supplied for 86 h (3.6 days).
During this period, multiple signs and blood tests were performed, among them those related to VA-ECMO (Tables and ).
Other points of care included: suspicion of aspiration on the day of admission; he was treated by antibiotics. Diagnosis of right pleural effusion which was drained by a chest tube. Fluid administration to prevent rhabdomyolysis induced acute kidney injury. Total parenteral nutrition for visceral electrical injury, which resulted in decreased enteral absorption. Burn wounds were treated locally by utilizing silver sulfadiazine cream (Silverol) and Granuflex dressings.
Within the first day, the patient had been weaned from noradrenaline. The lactate level declined gradually down to 0.6 mmol/L. A follow up echocardiography on the third day showed improvement in cardiac function, with an EF = 50% and normal right ventricular function. After 86 h of mechanical support, the patient underwent decannulation from VA-ECMO successfully.
The weaning process was gradual, starting with decreasing the VA-ECMO to 1 l/min for 24 h before decannulation, during this period a trans oesophageal echocardiography was completed, making sure biventricular functions were within the normal range and there was no ventricular dilatation. Chest X-rays showed no new opacities or indications of ARDS. Other parameters that we followed within this period were Central Venous Pressure (CVP), PH, lactate and target organ blood test, to endure normal function.
On the day of decannulation, we stopped heparin, once ACT was less than 160, we conducted decannulation successfully. A transthoracic echocardiography conducted 1 day after the decannulation showed normal biventricular and valves function.
Acute respiratory distress syndrome (ARDS) was diagnosed on the 6th day of hospitalization and was treated accordingly Fig. .
On the seventh day, the patient was referred to the ARDS specialized department in a primary medical centre, being anesthetised and ventilated for continuous treatment. There, he was hospitalized for almost a month. During this period he passed tracheostomy and then was gradual weaned and underwent respiratory physiotherapy up until discharge. No plastic surgery was done and the burns were treated topically. Two months after the accident, he was discharged and moved to rehabilitation centre.
His chest X-rays at the discharge from the ARDS specialized department is shown in Fig. . His blood tests at discharge were normal, especially renal functions – creatinine 0.7 mg/dl.
A follow-up transthoracic echocardiography showed – left ventricle with normal global systolic function (EF = 65%) with no regional wall abnormality. The right ventricle was found to be normal size and properly functioning. The aortic valve was normally functioning, as were the mitral, tricuspid and pulmonary valve, with minimal regurgitation.


A 30-year-old previously well man presented with a four-week history of progressive right-sided hearing loss, wide-based gait, and cognitive disturbance characterized by short-term memory loss, impaired attention span, and verbal fluency. The patient had neither a personal nor family history of pertinent medical problems, and he did not smoke, drink excessive alcohol, or take illicit drugs.
On examination, he had cerebellar signs characterized by dysdiadochokinesis and ataxia of gait.
MRI of the brain at presentation demonstrated multiple hyperintense lesions in the corpus callosum, periventricular white matter, cerebellar hemispheres, and leptomeninges ().
MRI of the spine was normal. The CSF showed a small pleocytosis with normal cytology and an elevated protein 3.06 g/L. There was an absence of oligoclonal bands in both CSF and serum. CSF microbiologic investigations revealed a Gram-negative stain, syphilis serology, and cryptococcal antigen. PCR analysis of the CSF did not detect EBV, CMV, HSV, VZV, enterovirus, M. tuberculosis, or fungal pathogens. Widespread triphasic waves consistent with encephalopathy but with no focal or generalised epileptic activity were demonstrable on an electroencephalogram (EEG). CT of the chest, abdomen, and pelvis did not reveal any lesions.
The full blood count, electrolytes, creatinine, and liver function tests were normal. The ANA, ANCA, anticardiolipin antibodies, and lupus anticoagulant were negative. Evaluation for autoimmune and paraneoplastic encephalitis with serum and CSF antibodies to NMDAR (N-methyl-D-aspartate receptor), AMPAR (α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor), LGI1 (leucine-rich glioma-inactivated 1), Caspr 2 (contactin-associated protein-like 2), GABA (gamma-aminobutyric acid) B receptor, and IgLON5 were negative, and ANNA-(antineuronal nuclear antibody-)1, ANNA-2, PCA (Purkinje cell antibody), PCA 2, Ma 1, Ma 2, CV2/CRMP5 (collapsin response mediator protein 5), Tr, and SOX antibodies were also not detected. Antiaquaporin-4 antibodies and anti-heat shock 70 antibodies were negative.
The differential diagnosis included acute disseminated encephalomyelitis, aquaporin-4 negative neuromyelitis optica [], neurosarcoidosis, and primary angiitis of the CNS.
Despite treatment with intravenous methylprednisolone 1 g daily for 3 days followed by a tapering course commenced at 1 mg/kg daily, he suffered progressive bilateral hearing loss over the following four weeks and impaired vision from the right eye. Audiometry demonstrated low-frequency sensorineural hearing loss bilaterally. Neuropsychometric assessment revealed severe global cognitive impairment including difficulties with verbal fluency, as well as deficits in short-term memory and executive function.
A biopsy of the cerebellum and meninges was performed due to disease progression and lack of response to the high-dose corticosteroid therapy. The histopathology showed mild, nonspecific perivascular inflammation and a diffuse pial infiltrate dominated by CD8 T lymphocytes and macrophages with microinfarctions in the territory of the small pial arteries. There was no evidence of vasculitis or malignancy. Culture and PCR analysis of the specimen excluded mycobacterial or fungal infection.
The patient developed painless scotomata, and a branch retinal artery occlusion (BRAO) of the right temporal retina was identified on fundal photography and retinal fluorescein angiography (). Subsequently, Susac's syndrome was diagnosed based on the triad of encephalopathy, right BRAO, and bilateral sensorineural hearing loss.
Methylprednisolone 1 g daily for 3 days was subsequently readministered followed by oral prednisolone 1 mg/kg daily concurrently with intravenous cyclophosphamide 1 g (15 mg/kg) monthly for 6 months and intravenous immunoglobulin (IVIg) 2 g/kg loading and 0.4 g/kg per month for 6 months. Adjunctive treatments included cotrimoxazole prophylaxis against Pneumocystis jiroveci, risedronate for osteoprotection, and aspirin to aid vessel patency.
Clinical remission was achieved by 6 weeks, but there was no improvement in the sensorineural deafness on the right side. Maintenance of remission was attempted with methotrexate 20 mg (0.3 mg/kg) weekly following cyclophosphamide.
Another clinical relapse, however, occurred 3 months after the maintenance therapy with methotrexate was started, characterized by recurrent bilateral hearing loss, bilateral BRAOs, and new T2 hyperintensities shown by MRI of the brain. Further remission was achieved with methylprednisolone 1 g daily for 3 days, and plasma exchange was administered daily for four consecutive days. In addition, rituximab 375 mg/m2 weekly for four weeks was used as an induction agent, and methotrexate was replaced with mycophenolate mofetil (MMF) 1.5 g BD. Prior to rituximab, enumeration of lymphocyte subsets on peripheral blood revealed 302 × 106 CD19+ cells/L with CD19 suppression (<25 × 106 cells/L) maintained for 18 months following therapy. Oral prednisolone was slowly tapered to a maintenance dose of 12.5 mg (0.18 mg/kg) daily.
Despite this treatment, the patient relapsed again two months later, i.e., 11 months following initial treatment, suffering a generalised tonic-clonic convulsion, encephalopathy, recurrent bilateral hearing loss, fresh BRAOs, and new MRI lesions. His neurological status improved after methylprednisolone 1 g daily was administered for 3 days. His dose of oral prednisolone was increased to 1 mg/kg daily, IVIg 2 g/kg monthly was recommenced, and MMF continued at a dose of 1.5 g BD. MRI brain with MR venogram demonstrated right transverse venous sinus thrombosis. A procoagulant screen was positive for the lupus anticoagulant. Review of a previous MR venogram 3 months prior showed that the thrombus had been present for some time and was not changing in morphology or size. For these reasons, aspirin rather than warfarin was continued as an anticoagulant.
A further clinical relapse occurred 3 months later, i.e., 14 months () after initial treatment was commenced, characterized by sudden painless partial visual loss in the right eye with new BRAO encroaching on the central retina, persisting hearing loss, and MRI changes demonstrating diffuse cerebellar, leptomeningeal, and parenchymal enhancement. Infliximab 5 mg/kg was started using a loading regimen at 0, 2, and 6 weeks for induction and then 8 weekly treatments for maintenance. Over the following 4 weeks, there was both clinical and radiological remission of disease. His dose of prednisone was tapered completely from 12.5 mg daily over 4 months. The thrombus resolved, and the patient returned to work. Two years after remaining on the maintenance infliximab therapy, the patient has been free of relapses, the visual acuity is normal, and there are no cognitive deficits on follow-up neuropsychological testing. He continues to be troubled by partial bilateral deafness, for which cochlear implantation has proven helpful. Consideration is being given to stepping down immunosuppression to MMF.


Here we present a 6-yr-old male with global developmental delays, microcephaly, short stature improved by growth hormone, small penis for age, plus hyperlipidemia, and dysmorphic features reminiscent of Cornelia de Lange syndrome (CdLS).
His gestation was complicated by exposure to buprenorphine and pregabalin for an initial 9 wk, alcohol for 10 wk, and tobacco throughout. Normal in utero growth was reported. Patient was born via vaginal delivery at 37 wk gestation to a 22-yr-old primigravida, with a birth weight of 6 pounds. His neonatal course was complicated by meconium aspiration associated with respiratory distress and feeding difficulty due to ankyloglossia. His early developmental milestones were delayed. He sat at 9 mo, pulled to stand at 18 mo, and began walking at around 24 mo. Developmental Assessment of Young Children-2 (DAYC-2) at age 2 indicated significant developmental delays in all domains: gross motor skills (DAYC-2 score 79), fine motor skills (69), receptive and expressive language (64 and 54), social emotional skills (71), and cognition and adaptive skills (70 and 70). He had few words and was not toilet trained by the time of his initial genetics evaluation at 3 yr and 8 mo. Patient had normal head tomography and single-nucleotide polymorphism (SNP) microarray. At the initial genetic evaluation at 3 yr and 8 mo old, his height was 89.10 cm (0.39%ile and −2.66 SDS), weight was 14.10kg (20%ile, −0.84 SDS), and head circumference was 46.1 cm, below the third percentile. His features were reminiscent of the Cornelia de Lange phenotype (see ). Using Face2Gene, a facial digital analysis tool, his gestalt score was a strong match for the CdLS (). Thus, a CdLS next-generation sequencing (NGS)-based gene panel (sequencing and copy-number variant [CNV] analysis), including NIPBL, HDAC8, RAD21, SMC1A, and SMC3, was ordered on a blood specimen, and the result was negative, with no variants of interest reported. In the interim, the patient was diagnosed with growth hormone deficiency. His initial growth velocity was 5.8 cm/year (10th percentile), but after initiating growth hormone therapy, velocity improved to 8.9 cm/year (90th percentile). The response to growth hormone has not been studied systematically on CdLS patients; however, it is consistent with the experience reported by . When the patient returned to the clinic at the age of 5 yr and 1 mo, his height was 100.2 cm, improved to the third percentile (−2.01 SDS). However, microcephaly persisted and his head circumference was 47.5 cm, remaining below the third percentile. In addition, his penis remained relatively small and the length measured at the 10th percentile. Notably, his motor abilities had significantly improved, whereas his speech delay persisted, and he only had about 10 words at 5 yr old and had received an autism spectrum disorder diagnosis. Recent assessment in the context of an individualized education plan, at age 6, reported aggression toward others, requiring constant supervision and maximum teacher cues to complete work at school. He is not toilet trained. He participates in a speech-impaired program and uses assisted technology devices, continuing to qualify for in-school speech and occupational therapy. Given his persistent delays, dysmorphic features, and the negative CdLS sequencing panel, a trio exome sequencing was ordered to look for an alternative diagnosis that mimics CdLS.
The exome identified two variants of uncertain significance, in trans, in a candidate gene, NSMCE2 (see ). The NSMCE2 gene encodes a small ubiquitin-like modifier (SUMO) ligase, which plays a role in promoting homologous recombination and DNA damage repair (). Two patients have been reported by Payne et al. with NSMCE2 compound heterozygous frameshift mutations; both presented with primordial dwarfism, gonadal failure, and insulin-resistant diabetes, with fatty liver and hypertriglyceridemia. Our patient had some overlapping features with those presented by Payne et al. such as microcephaly and linear growth deficiency. Although liver function and insulin levels on our patient were normal, his fasting lipid profile indicated hypercholesterolemia (total cholesterol 275 mg/dL, reference range <170 mg/dL and LDL cholesterol 201 mg/dL; reference range <110 mg/dL), as well as hypertriglyceridemia (160 mg/dL, reference range <75 mg/dL). But fasting lipid profiles from both parents were normal. We verified with the exome reporting laboratory that there were no reportable variants in known genes causing hyperlipidemia identifiable through exome sequencing. It is uncertain if variants on NSMCE2 contribute to his hyperlipidemia in any way. Despite some overlapping features, there were significant clinical differences between our patient and those described by Payne et al. as our patient has no signs of insulin resistance or lipodystrophy. Moreover, our patient's facial features were very divergent from those described by Payne et al. who displayed prominent midface, a small jaw, acanthosis nigricans, and skin tags.
At a follow-up clinic visit at 6 yr old, considering the relatively high mosaicism rate of up to 30% reported () in the clinically diagnosed mutation-negative CdLS patients, a CdLS gene panel (sequencing and CNV analysis), including ANKRD11, HDAC8, KMT2A, NIPBL, RAD21, SMC1A, and SMC3, on buccal swab specimens was ordered and identified a novel hemizygous variant, c.793_795delGAG, p.Glu265del, in SMC1A in 60% of sequencing reads (33 of 56 reads), finally provided a definitive molecular diagnosis ().


A 32-year-old woman presented to the emergency department with acute onset of suprapubic pain of six-hour duration and low-grade fever of 38 °C. The pain was neither radiating nor migrating to other regions of the abdomen. She denied any history of trauma or comorbid illness. She had delivered two children through a lower segment cesarean section and had not undergone any other surgery. On examination, her vital signs were stable. Her abdomen was soft with a 5-cm sized tender swelling over the suprapubic region. A subcutaneous abscess was suspected based on the initial clinical findings.
The laboratory results including renal parameters, electrolytes, blood counts, and urine analysis were normal except for leucocytosis of 13,000 cells per ml (normal range: 4,000-12,000 cells per ml). Ultrasonography revealed a 5*5*5-cm sized hypoechoic lesion in the suprapubic region closely related to the dome of the bladder with internal echoes. CT of the abdomen and pelvis showed a 5*4*5-cm sized hypodense homogenous collection in the anterior abdominal wall close to the bladder (Figure ). MRI revealed a hyperintense lesion on the T2 sequence occupying the prevesical space without communicating with the bladder (Figure ). The imaging findings aided in narrowing down the preoperative diagnosis of a urachal cyst.
Given the above findings and the acute presentation, the patient underwent emergency exploration after informed consent. A transverse skin incision was made over the swelling and exploration was done, which revealed a 5-cm sized pus-filled cavity connected to the bladder dome by a fibrotic band. The abscess with its wall and the entire tract extending to skin and bladder were excised, and the skin was closed primarily after leaving a drain. Culture of the pus revealed Escherichia coli and appropriate antibiotics were started. Histological examination showed the cyst wall lined by stratified columnar epithelium, suggestive of a urachal cyst. The postoperative course was uneventful and the patient was discharged on the seventh postoperative day.


The patient is an 82-year-old Hispanic male with a past medical history of hyperlipidemia, hypertension, diabetes mellitus, and chronic kidney disease stage IV who presented to the emergency department complaining of bilateral upper extremity and lower extremity weakness and paresthesias for two weeks preceding admission. The patient had multiple falls recently after the onset of these symptoms. His symptoms had gotten to the point where he could not use his walker or even get up from a chair to walk. He denied headaches, diplopia, fevers, chest pain, shortness of breath, nausea, vomiting, dizziness, bowel incontinence, or bladder incontinence. He also denied any recent travel or consumption of undercooked meats. Vital signs were as follows: temperature of 36.8 °C, heart rate of 58 beats per minute sinus rhythm, respiratory rate of 14 breaths/min, blood pressure of 152/65, saturating 97% on room air. His physical examination was most significant for motor weakness of the bilateral upper and lower extremity, +3/5 on the right versus +4/5 on the left. Grip strength was tested in the upper extremity while dorsiflexion and plantarflexion were tested in the lower extremity. Pronator drift exam was negative.
His laboratory studies were not significant for any acute findings. Erythrocyte sedimentation rate (ESR) and C-reactive protein (CRP) were mildly elevated and a complete blood count with differential (CBC with diff) and coagulation profile were within normal limits (Table ). Serology for cysticercosis IgG resulted as negative. CT scan of the head without contrast was negative for acute intracranial abnormalities. There was an old infarct detected in the left internal capsule region. Also noted were chronic right frontal cortical calcifications and anterior right temporal lobe calcifications that were thought to be related to an old infection or hemorrhage. CT angiogram of the head and neck revealed 60% stenosis at the left common carotid artery (CCA) origin and proximal left internal carotid artery (ICA). MR imaging of the cervical spine (c-spine) with and without contrast showed multilevel cervical spondylosis with severe C3-C4 and moderate to severe C6-C7 thecal sac stenosis. Subtle increased cord signals at C3-C4 were concerning for compressive myelopathy. A neurosurgical consultation was obtained and C3-C4 anterior spinal fusion with intervertebral cage placement was performed. MRI of the brain with and without contrast showed multiple subcentimeter parenchymal and extra-axial enhancing lesions in the frontal lobes and along the right sylvian fissure with associated calcifications concerning for active neurocysticercosis (Figure ). The largest lesion along the right insula measured 7 mm with signal characteristics of a small abscess. An Infectious Disease consult was obtained and the patient was started on albendazole and praziquantal by mouth for ten days in total with dexamethasone. His hospital course was uncomplicated with no seizure activity reported. He worked well with physical therapy postoperatively and his bilateral upper and lower extremity weakness improved.