A 79-year-old Caucasian female with a past medical history of hypertension, degenerative disc disease, and no documented history of COVID-19 received two doses of Pfizer-BioNTech COVID-19 mRNA vaccination. Two weeks thereafter, the patient presented to our emergency department with weakness and upper thigh pain. Vital parameters were stable, and physical examination was unremarkable. The patient had no allergies and denied illicit drug use. External routine laboratory assessments obtained 1 week prior to admission were normal for serum creatinine of 0.71 mg/dl (reference range: 0.5–0.95), estimated glomerular filtration rate (eGFR) of 84.4 ml/min/1.73 m2, and urinalysis with the absence of hematuria or proteinuria. Repeat reverse transcription polymerase chain reaction (RT-PCR) testing for SARS-CoV-2 RNA from nasopharyngeal swabs was negative. Laboratory assessments at admission showed massive rhabdomyolysis with creatinine kinase (CK) levels of 14,243 U/L (reference range: 29–168), myoglobinemia of >12,000 µg/L (reference range: ≤106, ), and acute kidney injury (AKI) with serum creatinine levels of 1.38 mg/dl (reference range: 0.7–1.2, ) and an estimated glomerular filtration rate (eGFR) of 33.5 ml/min/1.73 m2. Urinary analysis revealed leukocyturia, hematuria (no dysmorphic erythrocytes), few renal tubular epithelial cells, and nephrotic range proteinuria of >18,000 mg/g creatinine and albuminuria of <5,000 mg/g creatinine (reference range: <30 mg/g, ). The patient received intravenous crystalloids with decreasing CK levels and myoglobinemia (). However, progressive deterioration of kidney function with worsening of serum creatinine levels up to 6.57 mg/dl (reference range: 0.7–1.2 mg/dl, ) and an eGFR of <15 ml/min/1.73 m2 occurred. ANCA immunofluorescence (IF) was positive at 1:1,000 (reference range: <1:10) with elevated MPO-ANCA levels >134 IU/ml (reference range: <3.5 IU/ml), while myositis antibodies, complement levels, and other serologic parameters were all tested negative (). Because of leukocytosis, a white blood differential was conducted revealing prominent peripheral blood eosinophilia ().
Based on suspected MPO-positive AAV, the patient received a steroid pulse with intravenous methylprednisolone for 3 days (250 mg per day) and oral prednisone 1 mg/kg daily thereafter (60 mg per day, ). A kidney biopsy confirmed severe acute tubular injury with pauci-immune crescentic GN and interstital nephritis: cellular crescents in 1/15 (6.7%) glomeruli, global glomerular sclerosis in 2/15 (13.3%), mild (5%) interstitial fibrosis and tubular atrophy (IF/TA), interstitial inflammation (25%) with prominent eosinophilic infiltration, and severe acute tubular injury with myoglobin casts ( and ). According to histopathological scoring, focal class ANCA GN and intermediate risk ANCA renal risk score (ARRS) were present () (, ). Based on the diagnosis of AAV presenting with massive rhabdomyolysis and pauci-immune crescentic GN, intravenous cyclophosphamide (CYC) was initiated at 10 mg/kg (per CYCLOPS trial dosing, ) (). Thereafter, kidney function normalized without requirement of dialysis and proteinuria decreased to 1,603 mg/g creatinine and albuminuria to 351 mg/g creatinine (reference range: <30 mg/g, ). Repeat serological testing confirmed that ANCA IF turned negative. Thereafter, oral prednisone was tapered down (currently 50 mg per day), and we do not plan to repeat administration of intravenous cyclophosphamide because rhabdomyolysis ceased and kidney function normalized.


A 5-month-old male infant was referred to Shenzhen Children’s Hospital on July 15, 2019 with recurrent skin swellings for more than 4 months and juvenile cells in the peripheral blood of the patient were detected 24 h ago. His birth history, feeding history, growth history, vaccination history and family history are normal.
The patient was diagnosed as acute myeloid leukemia (AML, M5) based on the clinical examination of blood routine and bone marrow cytology on July 18, 2019. Physician examination at admission showed numerous hard magenta nodules with an indistinct boundary and poor mobility in the head and neck, torso, and limbs, with a maximum diameter of about 6 cm. Skin mass pathology revealed juvenile yellow granulomas. His lips were swollen and not ruddy, especially the upper lip. The lips could not be closed, and he breathed through his mouth. There were numerous white membranes in his mouth. Three days after admission, oral mucosa erosion and oral ulcers appeared, and then 10 maggots were found in the mouth, each about 3 to 5 mm in length, as shown in an additional video file [see Additional file ]. Meanwhile, a wriggling larva was found in his right ear canal with an outflow of pus. All of them were removed by using sterile tweezers. One of the larvae collected from the patient’s mouth was sent to the Diagnostic Section in the Department of Parasitology of Zhongshan School of Medicine, Sun Yat-sen University.
The larva (1 mg) was white and about 5 mm in length. The larva collected showed the morphological characteristics of the third instar larva of Brachycera (Fig. ). Next, we extracted total DNA of the larva using a Hipure Insect DNA Kit (Magen, China) and amplified the cytochrome oxidase subunit 1 (COX1) gene by Polymerase Chain Reaction (PCR) using dipteran-specific primer pairs: LCO1490, 5’-TAAACTTCAGGGTGACCAAAAAATCA-3’ and HCO2198, 5’-GGTCAACAAATCATAAAGATATTGG-3’ [] (Fig. ) followed by sequencing (Tsingke Co.). BLASTn search for homology in the National Center for Biotechnology Information (NCBI) database () showed that the sequence had 100% homology with the COX1 gene of Sarcophaga ruficornis. We constructed phylogenetic trees by MEGA 6.0 software, based on 1000 bootstrap replicates from sequences we obtained. Sequences of the homologous genes, with accession numbers of MH937749.1, JQ582053.1, JQ582085.1, KT272859.1, KR819910.1, JQ806820.1, JQ582089.1, KX094928.1, KM279656.1, JQ582078.1 and KF038009.1, of Genus Sarcophaga and Genus Neobellieria were downloaded from NCBI. The results of the similarity analyses on the basis of the above sequences revealed that the maggots were accurately identified as S. ruficornis with 100% sequence matching identities (Fig. ).
After removal of the maggots in the mouth and strengthening oral care, the oral health of the patients improved and no maggot infection recurred. Moreover, the patient received subsequent chemotherapy with the DAE regimen (cytarabine, daunorubicin, and VP-16), anti-infection and ventilator-assisted respiratory therapy, continuous renal replacement therapy (CRRT) support therapy, and correction of coagulation function. The patient gradually improved following 2 months of symptomatic treatment, and was discharged on September 24, 2019.


A 28-year-old male was admitted to the respiratory department of Jian'ou Hospital (Fujian, China) with repeated coughing and yellow phlegm in 2018. Family members complained that the patient had a history of ketamine abuse of about five to seven times monthly for 8 years. The last ketamine inhalation was the day before he was admitted to the hospital, according to a family member. During the past 5 years, he had been experiencing weakness of the lower limbs, numbness, sensory disorder, decreased muscle strength, difficulty climbing stairs, recurrent frequent urination and urgency and pain during urination. These symptoms persisted and were not significantly relieved by several conservative treatments but were worsened by repeated convulsions, aching in the hepatic region and jaundice 2 years ago. Then, he was diagnosed with “autoimmune hepatitis, chronic cholecystitis and cholangitis.” At that time, a craniocerebral computed tomography (CT) scan revealed a widened and deepened cerebral sulcus, the cerebral palsy became flattened, the ventricles expanded, the cerebellum was thickened, and brain volume decreased (). Electromyography revealed a central motor and sensory conduction disorder, and the motor nerve conduction velocity of bilateral tibial nerves was slower, indicating ketamine-related brain atrophy. His liver function normalised completely after dexamethasone treatment (15 mg for treatment and 5 mg for maintenance for more than 3 months). The patient planned to have cholecystectomy surgery 1 year later, but the operation was cancelled due to abnormal liver function and the development of renal failure. A CT examination revealed a constricted bladder with dilatation of the bilateral upper urinary tract, moderate hydronephrosis and medullary sponge kidney with multiple renal papillary calcifications. Subsequently, the patient's urine volume decreased gradually until he was not producing urine. He underwent haemodialysis treatment twice per week. After a sudden fall about 2 months before this hospitalisation, the patient was unable to walk and was confined to a wheelchair. He could not speak but made some slurred sounds, and he was conscious 2 weeks before admission.
The patient and his family members denied a history of cerebral disease or alcohol abuse. He was somnolent and jaundiced at admission. A physical examination revealed that muscle strength of both lower limbs was 0 and that of the upper limbs was 3. Routine blood testing revealed an increase in the number of leukocytes and a decrease in the number of erythrocytes. The haemoglobin value was 65 g/l. A faecal occult blood test was positive at 3+. His liver function tests (LFTs) were abnormal (serum bilirubin 283.3 mol/L, alkaline phosphatase 1,804 IU/L, alanine transaminase 19 IU/L, yGT 762 IU/L, and albumin 28.2 g/dL). Other blood tests revealed renal failure (urea 26.97 mmol/L and creatinine 375 μmol) and myocardial failure (NT-pro BNP >35,000 ng/L). Cerebrospinal fluid (CSF) was tested three times, but the routine test, culture test, and syphilis test were all negative. A chest and abdominal CT scan demonstrated pneumonia and bilateral kidney abnormalities. The patient's condition deteriorated rapidly with regular pneumonia, blood transfusions and haemodialysis treatments. During treatment, he presented with sweating, clammy limbs and repeated convulsions. Then, he required intensive care support. Symptoms improved initially with symptomatic treatment, but worsened quickly, accompanied by dyspnoea and purple lips. After convulsing again, the patient slipped into a deep coma and was intubated and maintained on a ventilator. In the end, he died from brain damage and dysfunction with other multiple organ dysfunctions.


A 5-year-old girl with a clinical diagnosis of Usher syndrome was referred for initial retinal evaluation in our clinic. Her past ocular history was significant for left-sided esotropia treated with patching and atropine penalization of the dominant eye. She had a history of developmental delay, seizures, and significant hearing impairment. At the age of four months, she presented with severe hepatic dysfunction, with elevated serum levels of transaminases, and liver biopsy results were consistent with Alagille syndrome or a peroxisomal storage disorder. Previous workup included negative skin biopsy and no evidence of TORCH infection or renal dysfunction. Her enzyme levels improved spontaneously. The mother had a history of fetal demise at about 16 weeks of gestation secondary to cystic hygroma. The family history was otherwise unremarkable for congenital anomalies or known genetic disorders.
Her physical exam upon our initial evaluation at age 5 years revealed the presence of epicanthal folds, upper lid ptosis, and bilateral single transverse palmar creases. She had approximately 15 degrees of residual left esotropia at presentation. Snellen visual acuity and intraocular pressure could not be obtained during the initial visit due to poor cooperation. The patient was able to fix and follow with each eye. Fundoscopic examination revealed bilateral “salt and pepper” changes, a hypopigmented patch in the macula of both eyes, and bilateral nummular patches of hyperpigmentation in the periphery, without significant ocular nerve pallor or vascular attenuation. OCT revealed few cystic changes in the macula with loss of foveal depression and ellipsoid zone in the right eye ().
Given the involvement of both the central and peripheral retinas with atypical hypopigmented nummular patches, the absence of disc pallor or significant vascular attenuation, and the absence of typical bone spicules, the previous diagnosis of Usher syndrome was questioned. Measurement of serum very long chain fatty acids showed elevation of C26:0 and C22:0 puritanic acid and phytanic acid, suggestive of a possible peroxisomal biogenesis disorder. Review of an electroretinogram (ERG) obtained under anesthesia at an outside facility revealed complete extinction of scotopic and photopic responses. Chromosomal microarray testing and Usher syndrome mutation panel were unremarkable. Genetic evaluation revealed that she was homozygous for a PEX1 mutation (c.2528 G>A, p. GLY843ASB) consistent with infantile Refsum disease.
Following the diagnosis, the patient was started on a phytanic acid-restricted diet and underwent audiology evaluation with subsequent hearing aid prescription for severe sensorineural hearing loss. At 6 years of age, she was noted to develop new bilateral cystoid macular edema, a finding not previously reported in this syndrome (). At the age of 9, she began therapy with 200 mg daily docosahexaenoic acid and 350 mg daily cholic acid (Cholbam). The patient's developmental delay improved on this treatment regimen, and the patient began excelling in schoolwork. However, despite long-term therapy with topical dorzolamide for 5 years, her macular edema persisted () through her most recent follow-up at 13 years of age. At this time, 8 years after initial presentation, her Snellen visual acuity was 20/100 in the right eye and 1/200 E in the left. No cataracts were noted. Retinal autofluorescence revealed a diffuse spotted pattern of hyperautofluorescence in the midperiphery (). Fundus photos demonstrated stable bilateral salt and pepper changes, with bilateral nummular patches of hyperpigmentation with a hypopigmented patch in the macula of each eye (Figures and ). The patient has some dental enamel irregularities but is currently doing well with no further complications due to her condition.


A 35-year-old male presented to the emergency of a tertiary care hospital in Central India with complaints of fever with cough and breathlessness for three days. The patient was conscious and oriented but had labored breathing with oxygen saturation of 43% on room air. Non-invasive ventilation (NIV) was initiated with 100% FiO2, following which his saturation improved to 90%. He was intubated and initiated on mechanical ventilation due to impending respiratory failure with the arterial blood-gas analysis showing a PaO2/FiO2 (P/F) ratio of 70. Laboratory investigations were done and a nasopharyngeal swab for COVID-19 reverse transcription-polymerase chain reaction (RT-PCR) was sent. Point-of-care ultrasonography of lungs was done, which showed B profile with basal consolidation in both lungs. The bedside chest X-ray revealed bilateral alveolar consolidation with peripheral distribution suggestive of COVID-19-related ARDS. He was started on injection piperacillin-tazobactam, injection Clexane, and injection methylprednisolone 500 mg intravenous once daily. Prone ventilation was commenced, and subsequently, his P/F ratio improved to 125.
Laboratory reports on day one were notable for severe lymphopenia (4%) and a very high neutrophil-to-lymphocyte ratio (NLR) of 23, suggestive of severe physiologic stress level. RT-PCR assay returned positive and the patient was started on injection remdesivir 200 mg on day one followed by 100 mg for 10 days.
The patient's young age and lack of comorbidities were pointing against the rapid progression of the disease and clinical deterioration. Thus, the HIV ELISA test was sent, which came back positive. Past history revealed that he was a known HIV-positive case and was on antiretroviral therapy (ART) for the last five months. He was on a combination regimen of dolutegravir, lamivudine, and tenofovir. CD4 counts were 177 cells/mm3 with a viral load of 24,000 copies/ml. Methylprednisolone was stopped, and injection dexamethasone 8 mg IV twice daily along with Septran-DS (prophylaxis for Pneumocystis jirovecii) was added to the treatment protocol. After three proning sessions in four days, lung compliance markedly improved. However, on day five, the patient developed sepsis and hemodynamic instability, requiring vasopressors. Blood cultures were sent and antibiotics were escalated empirically to injection meropenem 1 gm, injection colistin 3 MIU thrice daily, and injection caspofungin 50 mg once daily. Blood cultures revealed Candida and Acinetobacter, which was pan-sensitive. The tracheal culture was sterile for bacteria and Pneumocystis jirovecii. On day seven of illness, percutaneous tracheostomy (PCT) was done as the patient's P/F ratio was maintained at 180-200. He was weaned off sedation and put on spontaneous/continuous positive airway pressure (CPAP) mode. Subsequently, he was switched to a high-flow cannula through a tracheostomy tube. On day 11, a T-piece trial was given with minimal oxygen flow of 3 l/minute, followed by a trach-vent filter on room air. As he was maintaining oxygen saturation with adequate cough and intact sensorium, he was decannulated on day 12. Paired nasopharyngeal and throat swab for COVID-19 RT-PCR was repeated, which returned negative. The patient was thus discharged and advised to follow up after 10 days.


Patient 1 was a 64-year-old female who presented as an HH4F4 (Hunt-Hess 4 and Fisher grade 4) SAH (Figure ). Given a poor examination on presentation, an EVD was placed. Subsequent angiogram revealed a large right pericallosal aneurysm that was judged not to be amenable to coil embolization (Figure ). She was taken emergently to the operating room (OR) for a bifrontal craniotomy and clip ligation. Post-operatively, she developed intermittently elevated ICP, which was managed with first-line interventions until her EVD developed a poor wave form with unreliable ICP measurements. A head CT demonstrated collapsed ventricles and diffuse edema. A Licox® ICP monitor (Integra, Billerica, Massachusetts, United States) was placed, which confirmed elevated ICP (>30mmHg), and a pentobarbital infusion was started. The patient’s ICP became resistant to pentobarbital infusion, and a decision was made to take the patient to the OR for removal of the bifrontal craniotomy and extension of the previous craniotomy into an extended bifrontal craniectomy (Figure ). Post-operatively, her ICP remained well controlled, with all measurements of less than 20mmHg. After a prolonged ICU admission, the patient’s neurological examination slowly improved, and she was ultimately discharged to a skilled nursing facility after placement of a tracheostomy and gastrostomy tube (G-tube). At the six-month follow-up, the patient’s tracheostomy and G-tube had been removed, but she remained with a modified Rankin score (mRS) of 4.


Patient 2 is a 48-year-old female who presented as an HH3F3 SAH secondary to a basilar tip aneurysm (Figure ). On arrival, an EVD was placed and the basilar tip aneurysm was successfully embolized with coils (Figure ). Initially, the patient had intermittent elevated ICP that was effectively managed with first-line interventions. On post-embolization day 6, the patient developed sustained refractory elevated ICP (>30mmHg), and a head CT demonstrated diffuse cerebral edema. A pentobarbital infusion was started, to which ICP remained refractory elevated. She was then taken to the OR for a bilateral DCHC (Figure ). Her ICP remained well controlled post-operatively. After a prolonged ICU stay complicated by vasospasm, she was discharged to a rehabilitation facility. At the nine-month follow-up, she was living at home independently with an mRS of 1 and requested clearance to return to work.


Patient 3 is a 34-year-old female who presented as an HH3F4 SAH secondary to an anterior communicating aneurysm rupture (Figure ). On arrival, an EVD was placed and the aneurysm was successfully coiled (Figure ). On post-embolization day 10, she developed elevated ICP that was resistant to first-line intervention, and a head CT revealed diffuse cerebral edema. ICP remained refractory to a subsequent pentobarbital coma, and the patient was then taken to the OR for a bilateral DCHC. ICP remained well controlled post-operatively. After a prolonged ICU and hospital admission, her tracheostomy and G-tube were removed, and she was discharged to a rehabilitation facility with an mRS of 2. Unfortunately, she died five months later from complications of a urinary tract infection.


Patient 4 is a 55-year old female that presented as an HH4F3 SAH secondary to a presumed anterior communicating aneurysm rupture (Figure ). On arrival, an EVD was placed and an angiogram demonstrated a large irregular anterior communicating artery aneurysm as well as a left middle cerebral artery aneurysm (Figure ). She was then taken to the OR for an orbitozygomatic craniotomy for clip ligation of the two aneurysms. On post-operative days 1-5, she had elevated ICP that was responsive to first-line therapy. On post-operative day 6, a pentobarbital infusion was started for refractory ICP, which was unsuccessful. She was taken to the OR for a bifrontal and left DCHC (Figure ). After the DCHC, the patient’s ICP was remained controlled. After a prolonged course, she was discharged to a skilled nursing facility with an mRS of 4. She is now followed up annually to monitor an MCA aneurysm but is doing well at the skilled nursing facility. At her last follow-up (20 months post-aneurysm rupture), she was fully oriented and able to easily follow commands.


We present the case of a 42-year-old male patient who presented to the emergency department complaining of low back pain for two days before presentation. He reported that the pain was started suddenly while he was playing golf. He described the pain as burning in character and has gradually increased in its severity. The back pain was localized and was not radiating to the lower limbs. He reported that the pain partially improved with simple oral analgesics like paracetamol. The pain was not related to posture or activity and the patient did not identify any exacerbating factors. He scored the pain as 7 out of 10 in severity and it often awakes him from sleep. There was no history of night sweat, fever, weight loss, urinary or bowel symptoms.
The patient reported that this was the first emergency visit for him with this complaint. He did not have any history of chronic back pain. His past medical history was remarkable for hypertension, dyslipidemia, and diabetes mellitus. However, his diseases were well-controlled. Most of his blood pressure measurements were below 140/90 mmHg. His last hemoglobin A1c level was 6.1%. Notably, the patient did not receive the vaccination for COVID-19 and he had a history of severe COVID-19 pneumonia requiring endotracheal intubation and mechanical ventilation. He stayed in the intensive care unit for eight days and was discharged home three days before the onset of his back pain.
The patient has not undergone any surgical operation in the past. His medication history includes metformin 500 mg twice a day, amlodipine 5 mg once a day, and simvastatin 20 mg once a day. He reported good compliance with his medication. He does not smoke or drink alcohol. His family history is remarkable for cystic fibrosis.
On examination, the patient was in distress due to the pain. His vital signs on presentation were as follows: pulse rate of 110 bpm, blood pressure of 124/82 mmHg, respiratory rate of 16 bpm, the temperature of 36.8℃, and oxygen saturation of 97% on room air. Examination of his back did not reveal any deformities and there was no focal tenderness. The range of motion was normal. The pain was not related to the motion. Importantly, the straight leg raise test was negative bilaterally. Examination of the cardiorespiratory system was unremarkable for any abnormality. However, the lower limb examination showed decreased temperature with absent pulses bilaterally.
A basic laboratory investigation revealed a hemoglobin level of 13.9 g/dL, a white blood cell count of 7200/µL, and a platelet count of 350,000 µL. Other biochemical investigations, including renal and hepatic profiles, were normal. However, the D-dimer was slightly elevated with a level of 550 ng/ml (Table ).
In view of the clinical and laboratory markers, the patient underwent computed tomography angiography of the abdomen and pelvis which unexpectedly demonstrated occlusion of the lower abdominal aorta at its bifurcation with extension to both the common iliac arteries (Figures -). Such findings are consistent with aortic saddle embolism. Subsequently, the 12-lead electrocardiography showed a normal sinus rhythm and the transthoracic echocardiography showed no intracardial thrombus.
Anticoagulant therapy with low-molecular-weight heparin was initiated immediately following the diagnosis. The patient was prepared for emergency endovascular treatment. A bilateral femoral artery catheterization was performed. The thrombus was completely aspirated by the guiding catheter. The patient tolerated the procedure without any complications. His symptoms showed significant improvement after the procedure. He was discharged on the third post-intervention day and was kept on aspirin as prophylaxis.


A 13-year-old boy was referred to the local hospital with a 6-month history of headache and dizziness with no obvious predisposing causes. He denied any familiar history of hypertension, psychosocial history including genetic information, or other cardiac health comorbidities. Nonetheless, the local physician prescribed Amlodipine (25 mg, qd) for hypertension treatment. The patient was eventually transferred to our center with an explosive onset of headache, vomiting, dyspnea, and fatigue. Physical examination showed normal body development. The upper and lower limbs' blood pressure was 200/130 and 98/78 mmHg, respectively. A heart rate of 85 bpm with significant pulsation in the suprasternal fossa was detected. A systolic murmur was audible at the paravertebral area. Radial pulse was palpable, whereas the dorsal pedal artery was not.
Electrocardiogram results showed sinus rhythm, incomplete right bundle branch block, and potential ventricular hypertrophy. Chest X-ray showed no remarkable findings with a standard cardiothoracic index. However, transthoracic echocardiography showed a peak systolic gradient of 64 mmHg at the coarctation site of the descending aorta. A hypoplastic artery was also noted distally to the coarctation (13 mm). Cerebral computed tomography scan and angiography (CTA) were performed to detect the cause of headaches and dizziness. The results indicated an aneurysmal rupture of the anterior cerebral artery. A cardiac CT scan was further performed, and a 3 mm coarctated descending aorta (, arrow), with over eight collateral vessels between the proximal and radial coarctated tissue () was revealed. An aneurysmal clip (, arrow) was successfully applied, followed by balloon angioplasty and endovascular stent implantation in the coarctated site of the descending aorta ().
The postoperative outcomes were satisfactory. The blood pressure was also significantly alleviated on both upper and lower limbs. Systolic and diastolic blood pressures were at 116/77 and 123/79 mmHg, respectively. The constricted segment of descending aorta was dilated up to 16 mm, which was detected by the chest CTA 3 days after the endovascular procedure (). The patient recovered without complications and was discharged on the seventh post-operative day in a stable condition with a recommendation of subsequent follow-up.


A 60-year-old gentleman who was previously diagnosed with type 2 diabetes mellitus, hypertension, and a cerebrovascular accident, which he suffered two years prior to presentation, which left him with residual right-sided upper and lower limbs weakness, for which he is undergoing physiotherapy with continuous improvement, presented with a history of right eye sudden painless drop in the vision of one-day duration. He denied any history of trauma to the eye or head and gave no history of previous eye symptoms or surgeries. Apart from the right-sided upper and lower limb weakness, his general and systemic examination was unremarkable.
His ophthalmic examination showed visual acuity of hand movement in the right eye and 6/6 in the left eye, with normal intraocular pressure in both eyes (18 mmHg in the right and 12 mmHg in the left). Slit-lamp biomicroscopy showed grossly normal anterior segments of both eyes with immature cataracts. Fundus examination of the right eye by binocular indirect ophthalmoscopy showed no view of the retina due to a grade 4 vitreous hemorrhage, while fundus examination of the left eye was unremarkable.
B-scan ultrasonography of the right eye showed a large mushroom-shaped mass invading the choroid and retina, and protruding into the vitreous cavity in the inferior aspect of the posterior pole (Figure ) with a shallow exudative retinal detachment observed in the peripheral rim of the mass, with dense vitreous hemorrhage (Figure ).
Magnetic resonance imaging (MRI) of the orbits was also done and showed a small mass suggestive of a choroidal melanoma along the posterior aspect of the right globe extending into the vitreous and measuring 8 x 6 mm. The lesion appears of high signal intensity on T1-weighted images and low intensity on T2-weighted images and shows mild contrast enhancement in the post-contrast images. The vitreous body shows an abnormal V-shaped appearance with abnormal high signal intensity on T2-weighted images mostly suggestive of vitreous hemorrhage with posterior vitreous detachment (Figures -).
Additional testing included positron emission tomography (PET) scan, chest X-ray, and laboratory studies, which included complete blood count (CBC), serum electrolytes, and liver function test (LFT), which were all within normal limits, excluding the possibility of metastasis to the lungs and liver, and confirming that the choroidal mass is a localized primary ocular mass.
After discussing the treatment options with the patient, and due to the unavailability of plaque brachytherapy and the concurrent presence of a vitreous hemorrhage, which would already mandate a pars-plana vitrectomy, a decision was made to book the patient for an early surgical transretinal endoresection via the pars plana route.
Under local anesthesia (peribulbar block), routine phacoemulsification complicated by a posterior capsular rent was first done with the implantation of a sulcus intraocular lens. Then, a standard 23-gauge three-port pars plana vitrectomy was performed to clear the vitreous hemorrhage, after which a mushroom-shaped mass measuring approximately 6 disc diameter in size (Figure ) was seen protruding into the vitreous cavity inferior to the fovea (the base of which was 1 disc diameter inferior to the inferior vascular arcade). Micro scissors were used to obtain two biopsy specimens from the mass. After that, complete tumor transretinal endoresection using the vitrector was performed, during which endodiathermy was used frequently to stop bleeding from the mass to ensure adequate visibility at all times. Perfluorocarbon liquid was injected for foveal protection, drainage of subretinal fluid, and stabilization of the retina, while the edges of the resultant retinotomy were carefully cauterized using endodiathermy (Figure ). This was followed by argon laser photocoagulation peripheral to the endodiathermy marks, placing three rows of laser photocoagulation around the retinotomy (Figure ). Finally perfluorocarbon liquid/air exchange was performed and 1000cs silicone oil was injected as a tamponade.
Both solid biopsy specimens and diluted vitreous samples from the aspirated fluid were sent to the lab for histopathological examination. However, the pathologist report showed that there was not enough sample for adequate histopathological grading, with mainly melanocytes in the slide.
At one week post-operation, the best-corrected visual acuity of the right eye had improved to 6/36 with remaining anterior uveitis and fundus examination showed a flat retina with white laser marks around the retinotomy. At one month post-operative, the visual acuity had further improved to 6/9 with a flat retina and silicone oil tamponade in situ. Optical coherence tomography (OCT) of the macula (Figure ) and fundus photography (Figure ) at one month post-operative are shown below.
Post-operative MRI, which was done at one week post-operative to ensure complete resection, showed no evidence of residual tumor, and complete resolution of the exudative retinal detachment was seen pre-operatively, with a visible silicone oil bubble in the globe (Figure ).
The patient was also referred to the oncology department to continue monitoring tumor control in liaison with the ophthalmology department with regular follow-up appointments, and he will be posted for silicone oil removal after six to nine months.


A 75-year-old female patient (Han Chinese ethnicity) weighing 55 kg with cardiogenic shock was admitted to our critical care department. After regular treatment was unsuccessful, she was treated with venoarterial extracorporeal membrane oxygenation (VA-ECMO) on January 19, 2021, for acute myocardial infarction complicated by cardiogenic shock. MAQUET ECMO equipment was used. The ECMO catheter was implanted into the right femoral vein and left femoral artery under ultrasound guidance. The end of the catheter was confirmed to the level of the right atrium by ultrasound. VA-ECMO was established with a rotational speed of 3500/minute, flow rate of 3.2 L/minute, fraction of inspired oxygen [FiO2] of 100%, gas flow rate of 4 L/minute, and vasoactive drugs dobutamine 6 μg/(kg/minute) and norepinephrine 0.1 μg/(kg/minute) The parameters of the ventilator were adjusted as follows: oxygen concentration 50%, respiratory rate 10 times/minute, tidal volume 5 mL/kg, and positive end-expiratory pressure 8 cmH2O. When ECMO was established, due to abnormal coagulation function (activated clotting time [ACT] > 200 seconds, activated partial thromboplastin time [APTT] > 160 seconds), anticoagulation was temporarily delayed. A total of 600 mL of plasma and 4 U of red blood cell suspension were supplemented. ACT was monitored every 2 hours. When ACT decreased to less than 200 seconds, heparin anticoagulation was started at APTT of 60 seconds (Fig. ). We conducted a physical examination at the bedside, and we found that the pupil size of the patient’s eyes were not equal, so we performed a computed tomography (CT) examination. The CT report showed cerebral infarction and possibly a small amount of bleeding after infarction in the right parietal lobe. The right frontal lobe showed basal ganglia cavity infarction and elderly brain changes (Fig. ). Because of the risk of intracerebral hemorrhage, we used a low-intensity heparin anticoagulation strategy. With the assistance of ECMO, the patient underwent coronary angiography + percutaneous coronary angioplasty + stent implantation aided by digital subtraction angiography (DSA) on January 20 at 08:20–09:35. After the operation, the cardiac function gradually recovered and the hemodynamics improved. On January 21, dopamine was stopped, and low-dose norepinephrine combined with dobutamine was continued. Because of the progressive decrease in platelets and the low activity of antithrombin III, the anticoagulation efficiency of unfractionated heparin was considered to decrease, and heparin-induced thrombocytopenia was not excluded. Argatroban anticoagulation was used to maintain APTT of between 50 and 70 seconds. On January 26, ECMO parameters were adjusted to a rotation speed of 2795 r/minute, blood flow 1.61 L/minute, FiO2% 21%, air flow 1.5 L/minute, and mean arterial pressure (MAP) 90 mmHg. Bedside echocardiography showed that the patient's cardiac systolic function was improved, left ventricular ejection fraction (LVEF) (biplane Simpson method) was 35%, and hemodynamics were stable. As the patient's cardiac function improved, we discussed with caregivers and family about the discontinuation of ECMO therapy, and the ECMO was removed after evaluation. On January 27, 2021, color Doppler ultrasound showed 34% LVEF (biplane Simpson method) and thrombosis from the IVC to the atrium (about 70 mm in length, 8 mm in width, with a floating tail end, Fig. a). Enoxaparin was given immediately for 1 mg/kg every 12 hours ih. On February 5, 2021, color Doppler echocardiography showed thrombosis from the IVC to the right atrium entrance (compared with January 27, 2021, volume reduced, shape changed, length about 48 mm, width about 4 mm, tail end floating, Fig. b). On February 19, 2021, color Doppler echocardiography showed no obvious abnormal echo in the IVC; combined with medical history, thrombus disappeared after anticoagulant therapy (Fig. c). Later, the patient's condition gradually stabilized. On the 30th day, she was taken off the ventilator and administered oral rivaroxaban instead of anticoagulants. Due to decreased muscle strength of her limbs, she received rehabilitation exercise and was discharged on the 60th day. Her level of consciousness returned to normal without residual central nervous system-related complications.


The patient is a 28-year-old male from Ghana with no medical history who presented to the emergency room with fevers, “on and off” generalized arthralgias, and morning stiffness for 1.5 years. This was associated with occasional swelling of the fingers “like sausages” that would resolve over the course of the day with movement and with acetaminophen or non-steroidal anti-inflammatory drugs. He did not report erythema of the joints. The pain was located in small joints (hands > feet), wrists, and knees. The patient also complained of anterior chest discomfort triggered by cough for 4-5 days prior to presentation. He reported subjective weight loss, decreased appetite, and fatigue for the last month, but denied night sweats and rash. He also denied oral ulcers and urethral discharge. He last traveled to Ghana two months before the presentation.
In triage, he was febrile with a temperature of 101.8 F and tachycardic at 128 beats per minute, with a blood pressure of 105/54 mmHg. Physical exam was notable for dehydrated oral mucosa, but otherwise unremarkable. No hepatosplenomegaly, nail, or joint changes were noted. Erythrocyte sedimentation rate (ESR) was 105 mm/hr. The patient was also found to have anemia, with a hemoglobin of 7.7 g/dL and a mean corpuscular volume of 63 fL. CT scan of the chest without contrast showed small right pleural effusion with bibasilar patchy airspace opacities concerning pneumonia. He also had axillary, mediastinal, and hilar lymphadenopathy concerning lymphoma, and a small pericardial effusion with mild cardiac enlargement. CT scan of the abdomen and pelvis was notable for hepatosplenomegaly, no retroperitoneal masses or lymphadenopathy, and numerous prominent bilateral inguinal lymph nodes. An echocardiogram showed minimal pericardial effusion, normal valves, and no vegetations. He was admitted to the general medical floor for further workup. The differential diagnosis at this time was large, including lymphoma, sarcoidosis, AOSD, Kikuchi disease, Whipple’s disease, IgG4-related disease, in addition to infectious causes such as histoplasmosis, tuberculosis, cryptococcosis, syphilis, Coxiella burnetii, and paracoccidioidomycosis.
On the floor, the patient had repeated spiking fevers, with temperature ranging from 97.4 to 102.9 F, while on antipyretic medicine (Table ). The temperature was not continuously measured, and there are gaps from evening to morning (as per hospital norm), so it is difficult to determine a fever pattern. He was also tachycardic, with heart rates ranging from 106 to 131 beats per minute. The patient had diagnostic and rheumatologic workup as described in Tables , .
Axillary lymph node biopsy was performed and the pathology report supported a reactive etiology. Axillary lymph node flow cytometry was also normal, without evidence of B- or T-cell lymphoma. The patient was ultimately diagnosed with AOSD and was started on 60mg of prednisone once daily, with a resolution of his fevers during the last three days of his hospital stay. He was discharged with 50mg of prednisone once daily for three weeks. In outpatient follow-up, he was doing well, with decreased joint pains, especially in the small joints of the hand. His anemia improved, with hemoglobin of 10 g/dL. Ferritin decreased to 400 ng/mL, LDH decreased to 282 U/L, and CRP decreased to 6.32 mg/L. Repeat CT scan of the abdomen and pelvis showed decreasing splenomegaly. The patient will likely require a DMARD for further treatment after the completion of his taper.


A 56-year-old man presented to the emergency department with pelvic pain, rectal tenesmus, and fatigue. In the past four months, he experienced some episodes of low urinary tract symptoms and initiated treatment for hypertension.
Computed tomography (CT) documented a large heterogenic prostatic mass (59 x 35 x 33 mm) with loss of cleavage planes, numerous adenomegalies, multiple pericentimetric hepatic hypocaptating lesions, suggestive of secondary lesions, and evidence of bone involvement (Figures , ).
A urinary catheter was placed due to urinary retention. PSA was elevated with 223 ng/ml (normal <4 ng/ml) and the patient was admitted for pain control and investigation.
At admission, the patient was hypertensive (165/89 mmHg). Laboratory tests evidenced metabolic alkalosis (pH 7.58; HCO3 42 mEq/L), normal sodium of 140 mEq/L, and severe hypokalemia (2.1 mEq/L; normal 3.5-4.5 mEq/L), that showed to be refractory to adequate replacement measures. Hypokalemia investigation showed high levels of morning plasma cortisol (58 𝜇g/L; normal 3.7-19.4 𝜇g/L), high levels of 24 h urinary cortisol (12,333 𝜇g/24 h; normal range 4.3-176) with a negative overnight 8 mg dexamethasone suppression test (81 𝜇g/L; normal <19 𝜇g/L) and elevated levels of plasma ACTH (253 pg/mL; normal 7.2-63.3 pg/mL). A diagnosis of paraneoplastic ACTH-dependent CS was made. The patient was initiated on 250 mg metyrapone daily. The patient's potassium levels increased and 24 h urinary cortisol, after one week on metyrapone, decreased to 3254 𝜇g/24 h. A brain magnetic resonance imaging confirmed the absence of any pituitary abnormality and CT excluded nodules on the thyroid or adrenal gland, confirming ectopic ACTH production.
A prostatic biopsy revealed a small cell neuroendocrine carcinoma, positive for synaptophysin and focally for CAM5.2 and PSA, and negative for chromogranin A with a very high Ki67 expression (90%-100%) (Figures -).
Bone scintigraphy showed foci of hyperfixation, suggestive of osteoblastic metastization pattern dispersed along the axial and appendicular skeleton.
Diagnosis of stage IV (cT4N1M1b) NEPC was made. Fluorodeoxyglucose (FDG) positron emission tomography (PET) and 68Ga-DOTA-(Nal3)-octreotide (DOTA-NOC) PET were planned to complete the investigation and palliative chemotherapy was scheduled.
Days after diagnosis, the patient’s condition started to decline and repeated CT scans showed the disease’s progression. The patient developed a nosocomial urinary tract infection with Escherichia coli bacteremia that failed to respond to therapy and died within days with multiple organ dysfunctions.


The patient was a 37-year-old primigravida who had no medical history. Her pregnancy was achieved using fertility treatment and she was carrying dichorionic diamniotic twins. She also had placenta previa. Both of the patient’s fetuses were well developed, and their condition was good.
She underwent a cesarean section at 35 weeks of gestation because she complained of frequent uterine contractions and we were concerned about heavy genital bleeding. She delivered healthy male and female neonates (2426 g, Apgar score of 8 at 1 min; and 2196 g, Apgar score of 8 at 1 min) through a transverse incision of the uterine body, to avoid making an incision in the low placenta. She experienced extensive intraoperative bleeding owing to uterine atony and placenta previa, with 4950 mL of blood loss. We inserted an intrauterine balloon tamponade device and sutured the uterine incision in two layers, with successful hemostasis. We transfused 6 units of red blood cells (RBCs) and 4 units of fresh frozen plasma (FFP) during surgery.
The patient’s postoperative course is shown in Fig. . Postoperative blood tests showed a hemoglobin concentration of 4.5 g/dL, platelet count of 9.6 × 104/µL, fibrinogen concentration of 130 mg/dL, and fibrin degradation product (FDP) concentration of 44 µg/mL. Her DIC score was 4 points according to the diagnostic criteria of the International Society for Thrombosis and Hemostasis (ISTH). Her systolic blood pressure was 123 mmHg and her pulse rate was 90 beats/min. Her hemodynamics were stable, her uterus was contracting well, and there was no bleeding. We performed blood transfusions with 12 units of RBCs and 10 units of FFP.
However, she experienced further excessive bleeding 5 h after surgery and received 10 U oxytocin, 0.2 mg methyl ergometrine, and 1 g tranexamic acid intravenously. However, these treatments were ineffective, and her blood loss was 2400 mL. Blood tests showed a hemoglobin concentration of 4.9 g/dL, platelet count of 6.0 × 104/µL, fibrinogen concentration of 100 mg/dL, and FDP concentration of 40 µg/mL. According to the ISTH diagnostic criteria, her DIC score was 5 points, which indicated overt DIC. We performed UAE and embolized both uterine arteries with gelatin sponges. Postembolization arteriography showed occlusion of both uterine arteries, and her bleeding subsided. We continued blood transfusions, and blood tests at 10 and 14 h after surgery showed an improvement in DIC.
However, the patient experienced further excessive bleeding 18 h after surgery. Dynamic computed tomography was performed to identify the source of bleeding, and extravasation from both uterine arteries to the lumen of the uterus was observed in the arterial phase (Fig. ). There were no findings indicating retroperitoneal hematoma or uterine rupture. Her blood loss was 1300 mL. Blood tests showed a hemoglobin concentration of 7.4 g/dL, platelet count of 7.5 × 104/µL, fibrinogen concentration of 233 mg/dL, and FDP concentration of 6.5 µg/mL, and her DIC score was 1 point. Her DIC was treated successfully by blood transfusions. Her hemodynamics were stable.
We decided to perform repeated UAE. The uterine arteries on both sides were completely recanalized. We found extravasation only in the left uterine artery. We re-embolized both uterine arteries with gelatin sponges, and postembolization arteriography showed occlusion of both uterine arteries (Fig. ). No further bleeding was observed.
The total estimated blood loss throughout the process was approximately 9000 mL. The patient received 26 units of RBCs and 22 units of FFP. The patient’s condition after UAE was good and she was discharged on the 7th day postoperatively.
UAE is the preferred treatment for refractory PPH because of its high efficacy and safety, low invasiveness, and preservation of fertility. The success rate of temporary hemostasis is reported to be 99 %, and the success rate with no additional treatment is 90 % []. However, while UAE is usually highly effective, it can fail. Little is known about the risk factors associated with the failure of UAE.
We reviewed the factors associated with the failure of UAE. We identified articles in PubMed using the following search string: (Uterine Artery Embolization[MeSH] OR pelvic-embo* OR artery-embo* OR arterial-embo*) AND (postpartum hemorrhage[MeSH]). All included articles were peer reviewed, were published in English from 1 to 2000 to 31 August 2021, and also included relevant articles identified by manual searching. We extracted information on factors associated with the failure of UAE from the manuscripts. We excluded studies where the definition of success or failure was ambiguous and no significant difference was found in any factors. The 15 included articles are shown in Table [–].
Kim et al.’s study [] included the largest number of cases and identified DIC as an independent failure factor for UAE. Other studies also reported that DIC and coagulation disorders were risk factors for the failure of UAE [–]. However, the definitions of DIC differed among these reports. Kim et al., Cheong et al., and Zhang et al. [, , ] used the ISTH definition of DIC, while Lee et al. [] described the diagnostic criteria in their report, and Bros et al. [] did not define coagulation disorders. To use DIC as a clinically useful factor, it should be defined according to the ISTH criteria, rather than using a vague term such as coagulation disorders.
In the current case, we used the ISTH definition of 5 points for the first UAE and 1 point for repeated UAE, which indicated an improvement in DIC. We consider that this improvement in DIC led to the success of repeated UAE.
Some studies [, , , –] have suggested that estimated blood loss, hemoglobin concentrations, and total blood transfusion volume might be associated with the failure of UAE. The amount of blood loss during the perinatal period may be underestimated []. Additionally, the volumes of blood loss and blood transfused are based on the final state of the patient, and are not useful for predicting the failure of UAE. We believe that DIC results in an increase in blood loss and blood transfused. DIC is easily diagnosed using tests and may be a useful clinical predictor of UAE failure. Hemodynamic instability has also been reported as a factor for the failure of UAE [, , ]. Therefore, hemodynamic stabilization and treatment of DIC using adequate fluids, RBCs, FFP, and platelet transfusions are important to increase the success rate of UAE.
A limitation of this review is that each study had a different success rate. There are some important differences between the studies, including the cause and severity of PPH, and the presence or absence of DIC. A multicenter prospective study with a larger sample size with unified conditions is required to further clarify the factors associated with the failure of UAE.
We considered the possible reasons for the low success rate of UAE for PPH with DIC. Gelatin sponges are generally the preferred embolic material. A gelatin sponge is absorbed within approximately 2–6 weeks and is thus classified as a temporary embolic material. A gelatin sponge achieves vascular occlusion by filling the blood vessel, resulting in physical stagnation of blood flow and the formation of a thrombus around the sponge []. Therefore, the ability of the gelatin sponge to cause an embolism depends on the patient’s coagulation ability, suggesting that the material is more likely to fail when used in patients with DIC.
DIC is a common complication of PPH, and untreated DIC can lead to further massive uncontrolled bleeding. Successful UAE in patients with DIC requires their DIC to be corrected first, or an embolic material that does not depend on the patient’s coagulation ability, such as N-butyl cyanoacrylate (NBCA), needs to be used. NBCA achieves embolization by entering the vessel and polymerizing with cations, thereby occluding the vessel lumen []. Unlike a gelatin sponge, NBCA is a permanent embolization material.
Several studies have reported that NBCA for PPH with DIC is effective [–]. However, the number of these reports is limited. Complications, including the effect of NBCA on future pregnancies, are also unclear. Additionally, this technique requires specific skills. Therefore, we consider that the use of NBCA should be restricted until further evidence is provided.
In a recent review, prior UAE was associated with PPH and the placenta previa spectrum during the next pregnancy []. UAE may reduce blood flow to the uterus and damage the endometrium. Additionally, repeated UAE may be associated with higher complication rates because the use of a large volume of embolic agents blocks blood flow in the uterus and damages it [].
We propose the strategy of repeated UAE for PPH with DIC (Fig. ). UAE using a gelatin sponge is initially applied. If further bleeding occurs, repeated UAE using a gelatin sponge will probably achieve hemostasis if the DIC has improved, as in the current case. However, NBCA may be considered if the patient’s DIC has not improved. A recent review showed that UAE was beneficial for reducing blood loss and the operation time compared with peripartum hysterectomy, and it had a comparable hemostatic efficacy rate []. We recommend using repeated UAE before hysterectomy.
In conclusion, the success rate of UAE is reduced in patients with PPH with DIC, and requires careful consideration. Repeated UAE is an effective procedure and should help to avoid a hysterectomy.


A 71-year-old homeless man reported to the emergency department on 25 May 2020 due to general weakening, cough with expectoration of greenish sputum of over a week, and atrial fibrillation of undetermined duration. He had a fever of 39.6 °C and a sore throat. His general condition was moderately severe; he was conscious, in logical contact, cachectic (body mass index: 15.59), and with severe dyspnoea. Vital signs were an average heart rate of 128 beats per minute, blood pressure 91/67 mmHg, tachypnea, with a respiratory rate of 44 breaths/min, oxygen saturation (spO2) on room air 76–89%, with an increase in spO2 up to 96% after oxygen therapy through a mask with a flow of 5 Lt/min. The medical history revealed smoking (more than 20 cigarettes/day) for most of his life. The patient was treated for tuberculosis in 1981.
A test for SARS-CoV-2 was performed using a throat and nasal swab taken on 27 May 2020. The Vitassay qPCR SARS-CoV-2 test was positive for SARS-CoV-2 RNA. A chest X-ray revealed bilateral areas of confluent parenchymal and interstitial densities in the lungs, predominantly in the upper and middle fields. Computed tomography, completed on 28 May 2020, showed lesions typical of pulmonary tuberculosis (). Antimycobacterial treatment was initiated empirically in the following scheme: isoniazid (INH), rifampicin (RMP), pyrazinamide (PZA), and ethambutol (EMB).
For further TB diagnosis, sputum was sampled from the patient and sent to the NRLT. The analysis of the fluorescent-stained microscopic smear using the Ziehl–Neelsen technique revealed the presence of acid-fast bacilli (AFB+++) (A). The GeneXpert assay confirmed the presence of genetic material from MTBC. An identification and drug sensitivity test for the isolated strain confirmed it belonged to the species Mycobacterium tuberculosis and was sensitive to streptomycin (SM), INH, RMP, EMB, and PZA.
From the third day of hospitalisation, respiratory failure was increasing, with no improvement after the use of high-flow oxygen therapy (helmet-based CPAP/continuous positive airway pressure). Mechanical ventilation was applied, and an infusion of norepinephrine and dobutamine was initiated due to circulatory decompensation. Cardiac arrest by asystole occurred after a few hours and the patient was pronounced dead.


The patient was an 8-year-old boy who visited the department of pediatric dentistry, SNUDH, with a complaint of an abnormal crown protrusion of the maxillary central incisors. The pregnancy and delivery by his mother were uneventful; however, he suffered from aseptic cerebral meningitis two days after birth. Two weeks later, he was hospitalized for a month due to bacterial meningitis. Clinical and radiographic examination revealed extremely short and malformed roots in all PFMs and severe constriction and dilaceration at the cervical region of the maxillary central incisors (). Nonvital pulp treatment was performed for the maxillary central incisors; however, the left central incisor was fractured at age 15 years 5 months. Pain and discomfort were reported on the maxillary PFM at age 9 years 3 months. The development of the third molars was observed using a panoramic radiograph, even though the maxillary third molars seemed a little bit small. The right PFMs were extracted at age 9 years 7 months, and the left PFMs were extracted three weeks later. The maxillary fixed orthodontic treatment was performed to correct the anterior crossbite for 22 months from age 11 years 4 months. The maxillary third molars were small, especially the left one, but fully erupted at age 19 years 1 month ().


The patient was a 9-year-old boy who was referred to the department of pediatric dentistry, SNUDH, for the management of root malformations in the maxillary central incisors and all PFMs. The pregnancy and delivery by his mother were uneventful, as in case 1; however, this patient also was hospitalized for 25 days due to bacterial meningitis a week after birth. During his hospitalization, magnetic resonance imaging scans were performed twice. He also had surgery for the management of otitis media at age 1 year. There were no clinical symptoms in the PFMs, but the maxillary left central incisor was fractured at the constricted part of the cervical area due to trauma four months prior to his visit. A panoramic radiograph revealed that the third molars were developing in the maxilla but not in the mandible (). Eruption of the maxillary permanent second molars was hindered by the abnormal form of the maxillary PFMs, and the eruption space for the maxillary second premolars was not enough. Therefore, the maxillary right PFM was extracted at age 9 years 10 months, and the contralateral PFM was extracted 6 weeks later.


The patient was a 9-year-old boy who was referred to the department of pediatric dentistry, SNUDH, for the management of root malformations in the maxillary central incisors and all the PFMs. There were no similar symptoms among the other family members, including his older brother. He was born 2 months early and hospitalized for 2 weeks due to a hydrocephalus symptom one month after birth. The development of the mandibular third molars was observed; therefore, the mandibular PFMs were extracted at age 9 years 1 or 2 months (). The maxillary right central incisor was extracted due to infection and severe dilaceration and malformation about 7 months later. The maxillary PFMs were extracted at age 11 years 2 months after observation of the development of the maxillary third molars. The maxillary third molars were relatively small and complete eruption proceeded further at age 17 years 4 months ().


The patient was a 15-year-old boy whose mandibular right PFM was extracted, and the space was maintained with a band and loop appliance. He was born 6 days later than the expected date of birth and hospitalized in an incubator for a month due to dyspnea and intracranial hemorrhage a few days after birth. The mandibular left PFM had a poor prognosis, and the development of third molars was observed in all four quadrants; therefore, orthodontic treatment was planned with the extraction of the remaining PFMs (). Fixed orthodontic treatment for the mandible was started at age 16 years 6 months, and a fixed appliance for the maxilla was placed at age 18 years 3 months. Treatment was finished and the appliances were debonded at age 20 years 3 months ().


The patient was an 8-year-old girl who was referred to the department of pediatric dentistry, SNUDH, for the management of root malformations. She was born prematurely at 27 weeks gestation and was hospitalized in an incubator for 2 months, but there were no other complications. She complained of cold sensitivity on her posterior teeth. Clinical and radiographic examination revealed root malformations in all four PFMs and deciduous second molars (). All four third molars were observed in the panoramic radiograph; therefore, the mandibular PFMs were extracted at age 9 years 2 or 4 months. The maxillary PFMs were extracted at age 11 years 4 months, and fixed orthodontic treatments began to gain eruption spaces and to align the maxillary canines. The mandibular appliances were placed at age 11 years 11 months. Orthodontic treatment was finished at age 13 years and 2 months ().


A 30-year-old Pakistani female, married, mother of two children, presented to the emergency department in May 2021 with complaint of headache, vomiting, and generalized weakness for 3 weeks. She had an episode of seizure-like activity at home, and so was rushed to the emergency department. Headache is defined as generalized pain mainly over the vertex that has gradual onset and is dull in nature, nonradiating, intermittent in duration with days going through worst pain followed by days without pain, moderate in severity ranging from 7 to 8 on a pain scale, and associated with nausea, vomiting, and generalized weakness. It was only temporarily relieved with pain medications. There was no stress precipitant in her life to induce a headache. The single episode of seizure-like activity included up-rolling of eyes and drooling of saliva, with no generalized recognizable altered limb movements and no urinary or fecal incontinence. It was followed by a few minutes of unconsciousness. After gaining consciousness, she exhibited confusion and altered mental status. She also had an undocumented fever, without chills and rigors, which was relieved with antipyretic. The patient denied any neck stiffness, irrelevant behavior and mood changes, vision alteration, excess lacrimation, and photo- or phonosensitivity. In addition to this, she lost her appetite and felt like she was losing weight, although her bowel and urine habits were usual. The rest of the systemic review was unremarkable. Her past medical history was significant for two cesarean sections, with the last-born child in January 2021. She had no menstruation after the delivery. Occasionally, she took paracetamol (acetaminophen) for pain relief and fever. She negated smoking or any other addictions. There was no history of allergies to particles, food, or any medications.
On physical examination, she was agitated and acutely anxious but still awake, alert, and oriented to time, place, and person. Her Glasgow Coma Scale score was 15 over 15. Initial blood pressure was 138/72 mmHg, heart rate was 105 beats per minute, respiratory rate was 22 breaths per minute, and temperature was 38.0 °C. Jugular venous pressure was not distended, and there was no appreciable peripheral edema and lymph node enlargement. Cardiac examination showed tachycardia with a regular pulse, and there were no added sounds. Respiratory examination revealed distant air entry in bilateral lung fields. No crepitation or wheezes were noted. Abdominal examination was insignificant with no organomegaly. Neurological examination depicted confusion with normal speech, delay to response, equally reactive pupils, intact cranial nerves, no motor or sensory deficit, normal reflexes, and down-going plantar response. A detailed thyroid examination revealed a soft, nontender gland with no enlargement or bruit and no exophthalmos. Gynecological examination revealed a horizontal scar in the pelvis of the previous C-section, with normal external genitalia and no vaginal mass, discharge, or atrophy on speculum examination. The uterus was anteverted and had multiple blood clots in the cervical canal.
Based on history and examination, she underwent an extensive investigation to identify the cause of her illness. Due to the ongoing pandemic, severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antigen test and polymerase chain reaction were done, which came back negative. Initial complete blood count and metabolic panel were insignificant (Table ).
Her thyroid-stimulating hormone (TSH) was extremely low, with high free triiodothyronine (T3) and thyroxine (T4), warranting us to perform more investigations to identify the cause. Thyroglobulin was 425 ng/ml (normal reference range ≤ 55 ng/ml), and TSH receptor antibody (TRAb) was 0.87 IU/L (normal reference range 0–1.75 IU/L). Due to high levels of beta-hCG hormone on initial presentation, she underwent a transvaginal ultrasound that showed no intrauterine pregnancy but an echogenic focus adherent to the right ovary with no vascularity. The finding could be secondary to ectopic pregnancy versus neoplastic lesion (Fig. ). With the chief complaint of headache, she underwent magnetic resonance imaging (MRI) of the brain that showed multiple scattered hemorrhagic lesions in supratentorial and infratentorial brain parenchyma that were highly suspicious for metastases with an unknown primary (Fig. ). Computed tomography (CT) scans of the chest, abdomen, and pelvis were done to identify the primary tumor and for the staging of the disease. The scan revealed multiple neoplastic lesions in the lung, liver, spleen, and kidneys (Fig. a, b). She then underwent a Tru-Cut liver biopsy that showed linear cores of liver tissue with metastatic carcinoma with morphological features consistent with choriocarcinoma.
Thyroid storm was diagnosed based on the clinical scoring system proposed by Burch and Wartofsky, which is the most widely used []. Our patient scored 65 on the Burch–Wartofsky point scale (Table ). A score of more than 45 is highly suggestive of thyroid storm. As per the Japanese Thyroid Association scoring system [], our patient met the criteria for “definite thyroid storm” with thyrotoxicosis and one feature of the central nervous system (seizures) along with fever and gastrointestinal manifestations.
The patient was initially admitted to a special care unit, but later she developed generalized tonic–clonic seizures that were not aborted with diazepam and antiepileptic medications. The patient went into status epilepticus and so was electively intubated, was sedated with propofol and midazolam, and was shifted to the intensive care unit. The oncology team was called and advised of additional work-up before proceeding towards chemotherapy. Her serum alpha-fetoprotein was 2.0 IU/ml (normal reference range < 6.7 IU/ml), whereas human immunodeficiency virus (HIV) serology and hepatitis B and C came out to be nonreactive. Interestingly, echocardiography was done showing preserved ejection fraction (60%) with no segmental wall motion abnormality. A mobile, finger-like echogenic density was noted in the left atrium, probably attached to the pulmonary vein, which is suggestive of thrombus or mass or vegetation (Fig. ). Her blood cultures were negative, and there was no history of joint pain and rash, making infective endocarditis less likely. The cardiology team was called, and they considered it as a part of ongoing systemic disease. Her creatinine clearance was 73 ml/minute (normal reference range 65–123 ml/minute). For choriocarcinoma, she was started on multiple chemotherapy regimen of methotrexate and etoposide.
Endocrine team was consulted during the intensive care unit (ICU) stay. She had already been initiated on propranolol 20 mg every 8 hours to achieve adequate control of her heart rate and dexamethasone 10 mg every 8 hours by the ICU team. She was also started on carbimazole 15 mg every 12 hours. She was then started on cholestyramine 4 g every 6 hours to help bind and excrete excess thyroid hormone and Lugol’s iodine solution (ten drops every 8 hours). The results of her thyroid function test repeated after 2 weeks of treatment are presented in Table .
During ICU stay, her Glasgow Coma Scale (GCS) score dropped from 15/15 to 5/15, so urgent CT of the head was done, which showed diffuse cerebral edema with midline shift. Neurosurgery team was called, and she was started on hypertonic saline. Later, she underwent decompressive craniotomy for her brain lesion to reduce mass effect and tracheostomy for prolonged respiratory support. She was then transitioned to a portable ventilator, which she tolerated well and so was shifted out of the intensive care unit.
She made a good recovery and was gradually tapered off the sedation. Antiepileptic medications were further optimized by the neurology team, and she was gradually weaned off the ventilator. She was successfully discharged home and planned to undergo rehabilitation along with ongoing chemotherapy (methotrexate and etoposide weekly till beta-hCG level normalize). Unless her source of beta-HCG is carefully under control, she will continue to take anti-thyroid medications.


A 66-year-old man with type 2 diabetes mellitus presented with a 3-day history of painful blurry vision in his left eye. The left eye examination showed microcystic edema of the cornea, hyphema with iris neovascularization, and marked IOP elevation (11 mmHg in the right eye and 33 mmHg in the left eye, measured by pneumatic tonometer) (). He was diagnosed with NVG in the left eye. The visual acuity of the left eye was 20/200 at the time of presentation. The anterior segment examination of the right eye was unremarkable. Fundus examination of the left eye was obscured by microhyphema and microcystic corneal edema, and the right eye was diagnosed with non-proliferative diabetic retinopathy. The IOP of the left eye did not improve despite maximal intravenous mannitol usage, the combination of topical brinzolamide/timolol in the left eye twice a day and 500 mg of acetazolamide orally twice a day. Paracentesis of the left eye was then performed, and the IOP in the left eye decreased to 9 mmHg. One day after the procedure, the cornea became clear. Dilated fundus examination revealed several intraretinal hemorrhages and subhyaloid hemorrhages in the posterior pole and mid-peripheral retina () and Roth spots in the peripheral retina of the left eye. Optical coherence tomography of the left eye revealed a superficial retinal hemorrhage and dense pre-macular hemorrhage (). Fluorescein angiography of the left eye showed multiple areas of fluorescein blockage, corresponding to hemorrhage in the fundus. Scattered hyperfluorescent microaneurysms were also observed in the fundus of both eyes (). The visual acuity of the left eye decreased to hand motion. The peripheral retina of left eye showed multiple non-perfusion areas in fluorescein angiography (), indicated retinal ischemia. Panretinal photocoagulation was performed. One week later, an intravitreal anti-vascular endothelial growth factor agent was injected to treat NVG. Topical timolol was prescribed to control the IOP. During the follow-up fundus examination three months later, retinal hemorrhages were minimally reabsorbed. His best-corrected visual acuity of the left eye improved to 20/400. The left eye retinopathy was likely ODR because of the rapid decline in IOP.


A 21-year-old female was admitted to our hospital with abdominal pain, tenesmus, and bloody diarrhea for more than 10 days. Physical examination revealed tenderness localized to the left lower abdomen. The patient had no prior history of similar symptoms and no prior history of surgery, trauma, or connective tissue disorders. On admission, initial laboratory examinations revealed an elevated level of white blood cell count (18,700/mm3), C-reactive protein (14.6 mg/L), D-dimer (6820 μg/L), and carbohydrate antigen 125 (CA125, 60.6 U/mL). Colonoscopy at initial workup revealed edematous wall thickening, hyperemia and shallow ulceration with continuous involvement from rectum to sigmoid colon. The friable mucosa was difficult to identify and was easily bleeding (Fig. ). No obvious abnormalities in transverse colon, ascending colon, and ileocecum was identified.
Multiphase contrast-enhanced abdominopelvic CT were performed on the second day of admission. The CT imaging showed a long segment of marked wall thickening extending from the sigmoid colon to the distal rectum with poor mural enhancement, multiple ulcers, pericolic fat stranding, and free fluid. The colonic wall thickened to 1.6 cm and the marked submucosal edema caused the target sign of colonic wall. Thickening of the omentum was also noted while multiple enlarged lymph nodes could be seen in the retroperitoneum (Fig. A–C). The arterial phase images demonstrated the inferior mesentery artery with enlarged tortuous pericolic arteries and submucosal pseudoaneurysm (Fig. A, D). The portal phase image showed that the inferior mesenteric vein (IMV) was patent without filling defects or luminal irregularities (Fig. E). However, the ovarian veins were tortuous and dilated on the delayed phase images (Fig. B).
Based on the clinical symptoms, acute IBD was clinically suspected, and the patient was treated with empirical antibiotics (Sulperazon). However, the diarrhea and abdominal pain worsened overnight and resulted in sleep disturbance of the patient. Mesalazine and methylprednisolone sodium succinate were administrated after 4 days though did not offer symptomatic relief. Ten days after admission, the patient developed fever, massive hematochezia with decreased hemoglobin (from 123–57 g/L), and elevated white blood cell count and C-reactive protein (30,500/mm3 and 63.5 mg/L, respectively). The patient went into shock on her way to the second CT scan and was transferred to the emergency room immediately.
The clinician explained the necessity of surgical resection to the patient. Total proctocolectomy with ileal pouchanal anastomosis with ileostomy was performed on the same day. Intra-operative exploration revealed multiple ulcerative lesions in the colon and rectum, with diffuse bleeding and local necrosis and perforations. Microscopically, mucosal ulcer, sub-mucosal edema with hemorrhage, and chronic serositis with fat necrosis were observed in the involved colon. Importantly, fibrous intimal thickening and luminal occlusion of mesentery and subserosal vascular could be observed, while there were no findings of surrounding venulitis or thrombi within veins. These findings were consistent with IMHMV. Additionally, Elastica van Gieson staining confirmed the presence of elastic fiber at the site of the thickened venous intima and the final diagnosis has been confirmed as IMHMV.
The patient was discharged 10 days after the surgery with no postoperative complications. At 4 months after the operation, the patient had a swift recovery without any additional medication. During the 2-years follow-up period, there was no evidence of disease recurrence. Postoperative contrast-enhanced abdominopelvic CT imaging indicated no abnormality.


A 25-year-old unmarried Hindu female student from Dharan, Nepal, was brought to the emergency department of BPKIHS on 24 December 2019 at 4 pm with a 2 hour history of facial twitching, slurred speech, and 24 hour history of abnormal tongue protrusion. There was no documented history of any drug allergies or other abnormal body movements. She also did not have any relatives with seizure disorders. On 23 December, her local physician prescribed oral tablet metoclopramide 10 mg three times a day for 7 days and tablet pantoprazole 40 mg once every day for 7 days to prevent gastric acid and basal acid secretion for acid peptic disease (APD). On examination, her Glasgow Coma Scale (GCS) was 15, blood pressure 120/90 mmHg, pulse rate 102/min, and partial pressure oxygen saturation (SpO2) 99% on room air. Her arterial blood gas (ABG) revealed potential of hydrogen (PH)of 7.43, partial pressure of carbon dioxide (PCO2) at 31.1 mmHg; sodium ion (Na+) 140.3 mmol/L, potassium ion (K+) 3.87 mmol/L, concentration of hydrogen carbonate (HCO3−) 21.2 mmol/L. The Naranjo Adverse Drug Reaction Probability Scale scored 6 and classified as a “probable” adverse drug reaction []. Metoclopramide-induced acute dystonic reaction was diagnosed, and she was triaged as Australasian Triage Score (ATS) 2. She was resuscitated right away with intravenous fluids, oxygen via face mask, and a 25 mg intravenous dose of chlorpheniramine. After 2 hours, the symptoms subsided, and she was able to return home the same day. The patient was recommended to stop taking metoclopramide in the future.


A 52-day-old Iranian girl was referred to us due to lethargy, fever, and poor feeding, which had started 5 days earlier. She was the first child of unrelated healthy parents. There was no family history of diabetes before 25 years of age in three generations. She was born on March 21, 2011, full term by cesarean section (CS), with birth weight of 2.600 kg and height of 48 cm. On physical examination, she was conscious but had drowsiness, dehydration, tachycardia, tachypnea, and sighing Kussmaul respiration. Her weight was 3.700 kg, with height of 52 cm (at the third percentile of the Centers for Disease Control and Prevention [CDC] 2000 clinical growth chart curves), respiratory rate 40 breaths/minute, pulse rate 197/minute, body temperature 38.2 °C, and blood pressure 97/49 mmHg.
Laboratory data showed severe DKA (Table ). Fluid therapy and low-dose insulin infusion improved DKA, after which maintenance therapy with insulin was commenced. Eleven days later, we decreased the amount of insulin so that blood glucose was maintained between 200 and 300 mg/dL, and glibenclamide was administered to test its effect. It was effective in lowering blood glucose, so it was gradually substituted for insulin. Blood glucose was monitored before and 2 hours after every meal. She received glibenclamide until 2.4 years of age, but frequent monitoring of blood glucose showed some hypoglycemia before meals (minimum = 50 mg), while postprandial glucose was normal or high. Treatment was therefore switched to repaglinide (Novonorm, Novo Nordisk, Denmark), which is short-acting and is claimed to have no effect on insulin release at low blood glucose levels. The time course of treatment and follow-up is shown in Table .
Because one tablet of repaglinide is 0.5 mg, compared to 5 mg glibenclamide, and the dosage of glibenclamide is 0.4 mg/kg/day [], repaglinide dosage was calculated according to its potency as 0.04 mg/kg/day divided into three or more doses before each meal based on the patient’s age and frequency of meals. Preparations of the medicine were made by dissolving one tablet in 10 ml of water and calculating the dosage by volume of solution in every administration and spill-out of the extra. Adjustment of the dosage with weight was done during the follow-up period, which was effective for normal glucose maintenance.
Genetic analysis was done in the molecular genetics laboratory of the Medical School of the University of Exeter in the UK. Sequence analysis of the ABCC8, KCNJ11, and INS genes was performed. Analysis of coding and flanking intronic regions of the KCNJ11, INS, and ABCC8 genes (NM_000525.3, NM_000207.2, NM_001287174.1) was done by Sanger sequencing. A heterozygous missense mutation was identified, with details as follows: gene: KCNJ11; location: exon 1; DNA description: c.602G>A; protein description: p.Arg201His (p.R201H). Therefore, a diagnosis was PNDM was made.
At the last visit, she was 10 years old, with height of 143 cm (75th percentile) and weight of 50 kg (97% of the CDC 2000 curves). Hemoglobin A1C (HbA1C) was measured every 3 months during the follow-up period, with mean ± SD of all of the measurements calculated as 4.6 ± 0.7 (range 3.6–6.4). The blood glucose level from 59 recent self-monitored measurements was 123.36 ± 18 mg/dL (90–173). Neurodevelopmental assays were normal by both physical examination and questions of the parents. Ophthalmic examination was done and found to be normal.


A 3.5-month-old Iranian girl was referred due to vomiting, respiratory distress, fever, and lethargy. She had some of the signs since 10 days before presentation. She was the second child of a family with two children, and the other sibling was healthy. Both parents were healthy and first cousins. There was no family history of diabetes before 25 years of age in three generations. She was born on May 12, 2012, full term by elective CS, with birth weight of 2.500 kg. At the time of admission, she was in a light coma and dehydrated. Her weight was 5 kg (10th percentile) and height 53 cm (under the fifth percentile). Respiratory rate was 50, and pulse rate 170, with normal blood pressure and temperature. She had severe DKA (Table ). DKA improved after 26 hours of fluid therapy and low-dose insulin infusion. Glibenclamide was substituted for insulin after 5 days, with a dosage of 0.4 mg/kg once daily. The treatment was changed to repaglinide 1 month later because some hypoglycemia (minimum = 52 mg/dL) occurred, in an effort to keep 2-hour postprandial blood glucose at normal levels. The daily dosage was 0.04 mg/kg, and the method of preparation was the same as in the first case. It was divided into eight separate doses before each milk feeding, and when she became older, the daily dose was divided before every meal. During the last visit, she was 9 years old, with weight of 22.5 kg and height of 122 cm. The time course of treatment and follow-up is shown in Table .
Weight and height were always in the third percentile of the CDC 2000 curves during follow-up. HbA1C was measured every 3 months, with a mean ± SD of 4.7 ± 0.5 (4.2–6.3). The blood glucose level from 93 recent self-monitored measurements was 118.7 ± 16.4 mg/dL (88–167). Genetic analysis was done in the genes mentioned above and also on the EIF2AK3 gene in the same center. The result was the same as in the first case. The patient showed normal neurological and ophthalmological examination results.


An 86-year-old male patient presented to Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, because of the increase of CA-199 level to 282.9 U/mL in regular physical examination, without nausea, vomiting, acid reflux, belching, or other symptoms with an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 1. First, abdominal contrast-enhanced CT was performed, and showed that the gastric wall of cardia was thickened with abnormal enhancement in arterial phase, the outer margin of gastric wall was rough, and multiple nodules were scattered in hepatogastric ligament, retroperitoneum, peritoneum, omentum majus and mesangium. The malignant tumor infiltrated the entire layer of gastric cardia, and multiple round lymph node were highly suspicious for metastasis in the abdominal cavity. Second, the upper GI endoscopy subsequently identified proliferative ulcers in the region of the cardia, and signet ring cell carcinoma was confirmed by pathology. PET/CT was also demonstrating obvious cardia thickening with significant FDG uptake (SUvmax 14.3), as well as increased metabolic activities in the enlarged abdominal lymph nodes (SUvmax 4.9 to 6.8), and nodular thickening of the right retroperitoneum (SUvmax 3.8). Immunohistochemical stainings of the gastric tissue demonstrated positive expressions of MLH1, PMS2, MSH2, and MSH6, PD-L1 combined positive score (CPS) of 20, Ki-67 expression level of 90%, and negative HER-2 expression (). He was diagnosed with metastatic gastric cancer with multiple abdominal cavity lymph node and peritoneal metastases (HER2 negative, pMMR, and PD-L1 CPS 20). Chemotherapy was recommended as the first-line treatment, but the patient and his family refused due to his old age and frailty. Given his high PD-L1 CPS and the significant overall survival (OS) improvement in patients with CPS ≥ 10 treated with pembrolizumab compared to those with chemotherapy in the KEYNOTE-062 trail (), he was recommended and administered with 100 mg pembrolizumab as the first-line chemotherapy every 2 weeks for 5 cycles (). Ten days after the last dose, the patient presented for icteric sclera and skin and generalized pruritus. He was administrated with the ursodeoxycholic acid (250 mg, bid) in other hospitals for 1 week before admission to our hospital, but the above symptoms did not improve. After addimission, the patient remained hemodynamically stable and the abdominal exam findings were benign. On serum biochemical testing, a marked increase in total and direct bilirubin and slight increase in γ-glutamyl transferase were identified, the level of alkaline phosphatase (ALP; range, 30–120 IU/L) also increased, but alanine aminotransferase (ALT; range, <50 IU/L) and aspartate aminotransferase (AST; range <50 IU/L) were within normal limits (). We assessed the tumor status, and a partial response (PR) was assigned according to RECIST criteria. Neither magnetic resonance cholangiopancreatography (MRCP) nor abdominal computed tomography (CT) showed significant biliary obstruction or bile duct dilatation (). Tumor progression, and biliary inflammation and obstruction were ruled out. We suggested liver biopsy for differential diagnosis, but the patient and his family refused due to his old age and poor physical condition on admission. Given the patient's PD-1 treatment history, we therefore diagnosed him with immune-related cholestatic hepatitis was diagnosed, and ICI treatments were suspended. The patient received pulse therapy with 80 mg methylprednisolone. Simultaneously, ursodesossicolic acid was administrated to this patient daily. Icterus resolved after 3 days, and the pruritus significantly improved. Total bilirubin decreased from 171.4 to 139.3 μmol/L and direct bilirubin decreased from 114.3 to 88.4 μmol/L after 3-day high-dose steroids treatment. Therefore, oral dexamethasone replaced the methylprednisolone with a tapered dose (dexamethasone 7.5 mg for 4 days, 6 mg for 4 days, and 3 mg for 4 days). Total and direct bilirubins continued to decreasedecreasing, and he was discharged from hospital on day 36 (see ). One month later, the patient developed asthma with a low-grade fever that increased slightly (37.8–38.5°C) in the hospital. Oxygen saturation was low at 78–90%, and a decreased white cell count (1.56 × 109/L; range [4–10 × 109/L]), high levels of C-reactive protein (72 mg/L; range, <10 mg/L), and procalcitonin (0.1 ng/ml; range, <0.5 ng/mL) were found on blood tests. The 1, 3-β-D-glucan detection (G test) and galactomannan antigen detection (GM test) were performed using blood samples, while bacterial and fungal cultures were performed on sputum and blood. In addition, SARS-CoV-2 nucleic acid test through throat swab specimens and tuberculosis -related sputum and blood tests were also performed. All tests were negative and the antibiotic, Cefoperazone Sodium and Sulbactam Sodium(sulperazone), was administered with granulocyte-colony stimulating factor to promote leucocyte production; however, no significant symptomatic improvement was seen. Another chest CT showed interstitial changes, and interstitial pneumonia was considered probable (). He was diagnosed with type 1 respiratory failure based on the report of arterial blood gas examination and treated with high-flow nasal oxygen. A multi-disciplinary consultation was completed, and since the patient had received a PD-1 inhibitor, a consensus considered immune-related pneumonia to be likely. However, because the patient was elderly and treated with glucocorticoids for a considerable time, opportunistic infections could not be excluded. Therefore, the patient was given pulse therapy with 80 mg methylprednisolone and levofloxacin, meropenem, and sulfamethoxazole/trimethoprim. No significant improvements were seen after 3 days, and the patient was transferred to ICU for high-flow oxygen and intravenous immunoglobulin (25 g/day) therapy. An antifungal drug, caspofungin(coses), was also added. Symptoms improved 6 days later, and resolution of the interstitial lung changes was seen on CT (). The patient was discharged, and antibiotics were discontinued. At a 1 month recheck, the patient was in good general health with an ECOG PS of 1, and bilirubin levels were within normal limits (). Enhanced CT of the abdominopelvic cavity showed that PR was maintained () with progression-free survival (PFS) of 7 months.


In September 2019, a 74-year-old Japanese woman visited the Tsuji Dental and Oral Surgery Clinic (Fukuoka, Japan) complaining of a tingling pain and dryness in the tongue and a salty taste in the mouth when at rest; the symptoms had begun about five to six years ago (2013–2014). She had frequently consulted her family physician and dentist before visiting our clinic but did not receive any proper advice or treatment for the symptoms. No organic abnormalities were observed in the oral cavity. Evaluation of the tongue dryness using an oral moisture-checking device (Mucus®; Life Co. Ltd., Saitama, Japan) [] resulted in normal values (30.1). In the taste test using the salt-impregnated test paper, SALSAVE® (Advantec Toyo Co. Ltd., Tokyo, Japan), which was prepared with various salt concentrations (0.6, 0.8, 1.0, 1.2, 1.4, and 1.6 mg/cm2), she was unable to distinguish the saltiness, even at high concentrations. The patient was not in the habit of drinking or smoking. No signs of gingival inflammation, oral lichen planus, Sjögren's syndrome, Candida albicans, or oral cancer were found in the mouth. Serum anti-SS-A and anti-SS-B antibodies were negative, and there were no clinical signs of Candidiasis which was also confirmed with mycological swab and fungal culture. Subsequently, the patient was diagnosed with BMS by an oral surgeon at our clinic. shows the medications that the patient was taking at the time of the first visit to our clinic. Some of these drugs had been reported to have oral side effects, but the drugs could not be systemically changed or discontinued.
She had developed depression, hypertension, angina pectoris, and idiopathic atrial fibrillation about 25 years ago (at the age of 50), cervical and lumbar stenosis at the age of 55, and reflux esophagitis at the age of 65, for which she was treated by various specialists. Her depression was triggered by the illness and death of her mother when she was 50 years old and later exacerbated by the illness and death of her son when she was 57 years old. The depression was left untreated since February 2019 due to relocation. Furthermore, the patient had undergone cholecystectomy for a benign gallbladder tumor at the age of 39 and an endoscopic polypectomy for colon cancer at 66 years of age.
The pathogenesis of BMS was explained to the patient in detail. She was instructed to brush her teeth after meals and apply REFRECARE-H® to the oral mucosa. Additionally, preventive treatment for periodontal disease and denture prosthesis for the missing teeth were provided at the clinic. The patient had not been treated for depression for over six months; hence, she was referred to a psychiatric clinic and started on antidepressants. In October 2019, the following three medications were administered by the psychiatrist: escitalopram oxalate, a selective serotonin reuptake inhibitor (SSRI), triazolam, and flunitrazepam as benzodiazepine.
The visual analogue scale (VAS) is a simple and frequently used method to evaluate variations in pain intensity []. It is represented by a horizontal line, 100 mm in length, anchored by word descriptors at each end, as illustrated in ; the patients marked the point that they felt most accurately represented their perception of their current state. The VAS score was determined by measuring in mm from the left end of the line to the point that was marked by the patient. The VAS was measured 5 months prior to the patient's visit to our clinic (April 2019) and periodically between September 6, 2019, when the patient first visited our clinic, and May 21, 2021. The mean and changes in the score are shown in and , respectively. Application of REFRECARE-H® improved the QOL such as dry mouth, breath odor, refreshing mouth, oral pain during rest, oral pain at a mealtime, taste disorder, loss of appetite, sleep disorder, depressive moodiness, and jitteriness.
In October 2019, the patient's tongue pain symptoms had decreased and regular monthly follow-up showed an improving trend. However, since the beginning of 2020, following the prevalence of SARS-CoV-2 infection in the country, a nationwide state of emergency was declared in April and news of the suicides of several celebrities was reported in July. Consequently, she began to admit to suicidal ideation by August 2020, saying “I want to die too” every time she had a dental revisit. Therefore, the frequency of visits to our clinic was increased, information was shared with the psychiatrist and gastroenterologist, and oral care was implemented through medical cooperation. At each visit, we, the dentists, made sure that there were no physical problems in the oral cavity or head and neck areas and explained these to the patient, as well as instructed her to eat, sleep, and exercise regularly. We also listened to and supported the psychosocial issues behind the patient's symptoms. At each visit, we displayed the VAS score visualized over time and explained the clear improvement in BMS and depressive symptoms compared to that before treatment. The application of REFRECARE-H® to the oral mucosa was continued daily. Eventually, the suicidal thoughts disappeared in December 2020. On December 26, she suffered a thoracic vertebrae fracture in a traffic accident and was required to undergo rest therapy but she never complained of wanting to die. In March 2021, the symptoms of BMS completely disappeared and have not recurred since.
From the initial visit to the present, the results of the tongue dryness assessments were normal. However, in the taste test using SALSAVE®, she was still unable to distinguish the saltiness in December 2020. Subsequently, about two months later (February 2021), she was able to recognize the taste naturally (value, 1.4), and in March, she could recognize the saltiness at low concentrations (value, 0.8). She presented with a low serum zinc level (67 μg/dL) on March 26, 2021 (), and was treated with zinc acetate dihydrate (NOBELZIN®, Nobelpharma Co. Ltd., Tokyo, Japan) in April. The normal range of serum zinc concentration is from 80 μg/dL to 130 μg/dL. However, oral administration of NOBLEZIN was discontinued after 3 weeks due to adverse drug reactions such as diarrhea and itching. On May 7, the serum zinc level had been reduced to 70 μg/dL (below normal) but the taste sensitivity remained improved and she was able to recognize low concentrations of saltiness (value, 0.6). As shown in , free thyroxine 4 (FT4), thyroid-stimulating hormone (TSH), HbA1c, and blood glucose levels were normal, indicating no abnormal thyroid function or diabetes mellitus in this patient.


A 55-year-old female with a past history of alcoholic cirrhosis, Wernicke's encephalopathy, tobacco abuse, and hypertension, presented to the emergency department for abdominal pain. Laboratory investigations revealed elevated total bilirubin (2.1 mg/dl; reference range[RR]: 0.3 to 1.2 mg/dl) and alkaline phosphatase (237 U/L; RR: 25 to 110 U/L). Abdominal ultrasonography revealed elongated nondistended gallbladder with mild wall thickening, trace pericholecystic fluid, and dependent layering sludge. No gallstones were identified. Mild intrahepatic and moderate extrahepatic biliary ductal dilatation with the common bile duct measuring up to 1.9 cm was noted. No obstructing choledocholith or mass was identified. Subsequently, multisequence and multiplanar MR imaging was obtained through the abdomen before and following the administration of gadolinium contrast material which showed, choledocholithiasis with associated marked biliary and mild pancreatic ductal dilatation, mild peribiliary hyperenhancement, and marked gallbladder wall distention with wall thickening. The hepatobiliary surgery team was consulted for surgical evaluation and management. The patient underwent cholecystectomy with choledochoduodenostomy. The gallbladder was sent for routine histologic evaluation.
Grossly the gallbladder was intact with a wall thickness ranging from 0.4-0.6 cm. The serosa was pink-tan smooth, with a roughened hepatic bed. Mucosa was tan-gray and hemorrhagic. No gallstones were identified. Histologic evaluation showed diffuse bulbous expansion of the mucosa with cells with spindly nuclei and indistinct cytoplasmic margins (-).The proliferation was diffuse, unencapsulated, and diffusely replaced the lamina propria. Immunohistochemical stains showed that the lesional cells were positive for S100p while were negative for EMA, CD34, and CD68 (-). Diagnosis of diffuse Schwann cell proliferation most compatible with Schwann cell hamartoma was rendered.


Patient consent has been obtained for the publication of the case and associated images.
A 34-year-old male patient with no particular history was seen in consultation for swelling of the face with deformation and the presence of a nodule in the nose, cheeks, and ears accompanied by purpuric purplish lesions on the right leg consistent with lupus pernio (Figure ) slowly evolving over the last eight years. There was no notion of fever, nor of respiratory, cardiovascular, or arthralgic symptoms. The diagnosis of sarcoidosis was made on the basis of epidemiological arguments, clinical data, and imaging results and confirmed by skin biopsy, which showed numerous epithelioid granulomas surrounded by a non-caseous inflammatory crown. In May 2016, the patient developed chronic polysynovial arthritis progressing with relapses interspersed with remissions, deforming bilaterally and symmetrically, affecting the metacarpophalangeal (MCP), proximal interphalangeal (PIP), distal interphalangeal (DIP), and the first metatarsophalangeal (MTP) joints. On physical examination, the patient was in good general condition. There were pain and swelling (swelling and dactylitis appearances) of the MCP, PIP, DIP, and MTP2-3 bilaterally (Figures , ). Dermatologically, there were purplish, painless, hardened plaques located on the nose, cheeks, and lips (Figures , ) and the medial surface of the right leg (Figure ). Cardiopulmonary, abdominal, and ophthalmologic examinations were normal.
Biological evaluation showed an inflammatory syndrome with a sedimentation rate of 104 mm/h and a C-reactive protein concentration of 10.1 mg/L, associated with polyclonal hypergammaglobulinemia. The angiotensin-converting enzyme level elevated to 64 IU/L (normal value: 20-60 IU/L), and the calcium level increased to 3 mmol/L (normal value: 2.2-2.6 mmol/L), suggesting hypercalcemia. There was also an increase in immunoglobulin G4 (IgG4) to 298 mg/dL. Renal and hepatic functions were normal. Antinuclear antibodies, rheumatoid factor, and anti-cyclic citrullinated peptide antibodies were negative. A pulmonary function test found a slight restrictive deficit with a significant decrease in diffusion. X-ray of the hands and feet (Figures , ) showed destructive arthropathy with multiple subchondral geodes and bone erosion, with acro-osteolysis of the MCP, PIP, DIP, and MTP1-2.
Ultrasound of the hands and feet (Figures -) showed inflammatory synovitis, inflammatory tenosynovitis, and major dactylitis in the MCP, PIP, DIP, and MTP1-2 bilaterally. Chest CT scan (Figure ) showed several bilateral subpleural and diffuse perifissural micronodules predominantly on the right. We, therefore, retained the diagnosis of chronic sarcoidosis with lupus pernio. Medrol treatment has been initiated.