CU is a Caucasian female, aged 16 years old at presentation, with moderate ID (IQ =40–54), no previous psychiatric history, and a family history of anxiety in a first-degree relative. At baseline, CU attended school and functioned at preschool level. Recent stressors included parental marital stress and family relocation. Symptoms were first noted 2.5 years prior to presentation, when she was diagnosed with a presumed Hashimoto’s encephalopathy at an outside institution. At that time, her symptoms included grimacing, eye blinking, and decline in functioning. She was noted to have elevated thyroglobulin antibodies (711 IU/mL) and marginally increased thyroid peroxidase antibodies (45 units/mL) but normal thyroid stimulating hormone, and free T4 and T3 levels. Routine spinal fluid analysis, EEGs, and brain MRI were normal. Oral prednisone was initiated with some improvement, although it is unclear how long she remained well. Two years later, she presented to our institution, with reoccurrence of symptoms of 7 months’ duration. Symptoms included periods of prolonged immobility, agitation, repetitive and darting eye movements, involuntary movements of the mouth and flicking movements of her fingers, depressed mood, decline in ADL, apparent loss of hedonic capacity, staring, and decreased speech output.
In addition to routine medical tests, thyroid functions, thyroglobulin antibody, and thyroid microsomal antibody; single-nucleotide polymorphism chromosomal microarray; creatinine phosphokinase; hepatitis A, B and C antibodies; paraneoplastic antibody (immunoglobulin G N-methyl-D-aspartate receptor); 25 hydroxy vitamin D; brain MRI; and, EEG disclosed no significant abnormalities.
CU was diagnosed with unspecified catatonia. Symptoms supporting the catatonia diagnosis included reduced motor activity, episodes of increased activity, grimacing, stereotyped finger movements, staring, reduced speech, and decline in skill level. Mood symptoms, not specific to the catatonia diagnosis, were also noted. An oral challenge dose of lorazepam 1 mg resulted in an immediate but short-lived improvement. Lorazepam was gradually increased to a maximum dose of 5.5 mg four times daily with limited improvement in symptoms. Lamotrigine was later added and titrated up to 150 mg daily for mood stabilization with no significant impact. Due to progressive decline, ECT was initiated. At the time of writing this report, CU has received 86 bilateral ECT treatments over a 6-month period with notable improvement. Her mother believes CU has regained 100% of her baseline functioning. There are no reported symptoms 5 months after discontinuing ECT. She continues to receive lorazepam 10 mg/day and memantine 20 mg/day and is closely monitored for recurrence of symptoms.


SH is a biracial male, aged 16 years old at presentation, with moderate ID (IQ =40–54) whose only medical problems were hypothyroidism diagnosed at age 5 years, constipation, and mild congenital right-sided cerebral palsy. At 13 years of age, SH developed uncharacteristic aggression and an inability to perform previously mastered tasks. Numerous antipsychotic agents were tried, all of which failed to stop his progressive decline. His parents and referring clinician attributed his decline to a trial of fluoxetine that they associated with periods of immobility lasting several minutes, chewing but not swallowing, inability to complete simple tasks, and high-frequency self-injurious behaviors. These symptoms improved but did not reverse upon discontinuation of fluoxetine. At 16 years of age, SH presented for a second opinion due to acute exacerbation of symptoms in the previous 8 to 10 weeks. Presenting symptoms included increased motor activity interspersed with episodic cessation of all activity for a few seconds, vocal stereotypies, staring spells, jerky head movements (tics), unprovoked aggression, reduced sleep, slowed and reduced food intake, and weight loss.
SH was diagnosed with unspecified catatonia. Symptoms supporting the diagnosis included episodes of both reduced and increased activity, periodic cessation of all motor activity, repetitive and meaningless utterances (also known as “verbal stereotypies” or “verbigeration”), staring, decline in skills, and a markedly slow food intake rate that resulted in progressive weight loss. Laboratory tests (complete blood count, comprehensive metabolic panel, thyroid and liver function tests, antinuclear antibodies, thyroid antibodies, 24-hour EEGs with video recording, and MRI) were within normal limits.
Lorazepam treatment was initiated but a maximum dose of 11 mg/day did not result in consistent improvement. Subsequently, he was treated with bilateral ECT with excellent response. The parents believe that he has regained 100% of his baseline function. At the time of writing this report, he has received a total 76 bilateral electrode placement (BL ECT) over the past 18 months and continues to receive weekly maintenance treatment. So far, attempts to taper the frequency of ECT have resulted in return of symptoms. A trial of lithium, administered at a therapeutic dose and over a 1-year period, was discontinued due to the lack of additional benefit. A future trial with memantine may be considered, although this agent was not helpful in the past when administered concurrently with an antipsychotic agent.


BN is a Caucasian male with no previous psychiatric problems, who was aged 18 years old at presentation. His only medical problems were alopecia areata successfully treated at age 12 years and mild Raynaud’s phenomenon. Despite moderate-range ID (based on IQ testing), he demonstrated higher-than-expected adaptive functioning, including playing the piano, reading, and working part-time. Family history was positive for adult-onset hypothyroidism and Raynaud’s in the father. There was no history of stressors.
Symptoms emerged at age 17 years, 5 months, with progressive psychomotor slowing, episodic immobility, freezing, reduced speech and eye-blink rate, loss of hedonic capacity, grimacing and holding his tongue out, repeated shrugging and turning of the shoulders, slow eating, and stereotyped movements of the fingers. There were no sleep problems and minimal snoring. Neurological examination was normal except for overall motor slowing. Neurologic testing was unremarkable, including brain MRI, routine and 24-hour EEGs. Laboratory testing included comprehensive metabolic profile (CMP), complete blood count, B12, B6, and folate levels; iron, total iron binding capacity, and iron saturation; thyroid panel including anti-thyroglobulin and thyroid peroxidase antibodies; rapid plasma reagin (RPR); creatinine phosphate; ceruloplasmin; sedimentation rate; and a comprehensive immune function evaluation. Immune studies were positive for mildly elevated antinuclear, anti-streptococcal, and anti-Mycoplasma antibodies; elevated serum immunoglobulin G levels against dopamine D1 receptor, dopamine D2 receptor, and tubulin; and elevated serum induction of Ca2+/calmodulin-dependent kinase II in human neuronal cell lines.
A lorazepam (1.5 mg, IV) challenge resulted in marked improvement in motor symptoms lasting approximately 24 hours. Based on these findings and due to the lack of evidence to suggest another underlying medical or neuropsychiatric disorder, BN was diagnosed with unspecified catatonia. Symptoms supporting the catatonia diagnosis were progressive motor slowing, periodic cessation of all motor activity (freezing episodes), grimacing, posturing (a posture or movement maintained for a prolonged period), staring, loss of previously gained skills, markedly slowed food intake, negativism, and a loss of hedonic capacity. Lorazepam was titrated to a maximum dose of 20 mg/day resulting in 80% of baseline function. ECT was initiated due to failure to achieve baseline. At the time of writing, the patient has had an immediate and robust response to 12 bilateral treatments, with more spontaneous speech and fluidity of movement. The plan is to continue ECT until return to baseline function is attained.


A 43-year-old male was transferred to our hospital with complaints of dizziness, dyspnea-on-exertion, and mild chest pain for 2 weeks. He had been diagnosed hypertension two years ago, but he did not take antihypertensives for two months. Otherwise he had no medical or surgical history. He smoked 2 packs per day for 20 years. He denied any previous history of syncope, palpitation and peripheral edema except dyspnea-on-exertion for 2 weeks. He also complained intermittent dizziness which was not related with specific situation or position. On admission, his blood pressure was 156/80 mm Hg and grade 2 systolic murmur was audible in pulmonic area. Electrocardiogram showed complete AV block with severe bradycardia, 45 beats/min. Complete AV block was confirmed by Holter monitoring (). Thyroid function test was normal (thyroid stimulating hormone 1.24 uIU/mL and free T4 1.21 ng/dL) and coronary angiography was followed to rule out coronary artery disease. There was no significant stenosis in left coronary arteries. Right coronary artery could not be examined due to engagement failure. Right-sided aortic arch was suspected during coronary angiography (). Thus, we had implanted a permanent pacemaker (). Complete AV block at relatively younger age, engagement failure of right coronary artery, right-sided aortic arch in coronary angiography could suggest congenital heart disease. Transthoracic echocardiography revealed coarse trabeculations of functional LV and fine trabeculations and smooth surfaced functional RV, which correspond with L-TGA. Left-sided systemic AV valve was displaced inferiorly closer to the cardiac apex than right-sided AV valve, which is consistent with tricuspid and mitral valve respectively. Estimated ejection fraction was 57%. In color Doppler study, there was no significant valvular dysfunction in right-sided mitral valve, aortic valve, and pulmonary valve except mild left-sided tricuspid regurgitation. Systolic murmur in pulmonic area could be explained by left-sided grade 2 tricuspid regurgitation (). Following cardiac computed tomography showed congenitally corrected transposition of great arteries with AV, ventriculoarterial discordance. Right-sided aortic arch with diverticulum of Kommerell was also detected (). After implanting permanent pacemaker, the patient's symptom was resolved and he was discharged with prescription of angiotensin converting enzyme (ACE) inhibitor without any complication.


In 2012, a 32-year-old man with 5-year history of classic PG was admitted to the Intensive Care Unit of Shafa Hospital (Sari, Iran) with a complaint of cough, sputum and dyspnea in the last 4 days. The patient had received methylprednisolone pulses 1 week prior to admission. His current medication was oral prednisolone, cyclosporine and surgical wound therapy. The diagnosis of PG was confirmed by biopsy, but the cause was left unknown. On physical examination, the patient had respiratory rate of 30 breaths/min, temperature of 39°C, heart rate of 150 beats/min, oxygen saturation (below 90%). Large and deeply diffuse necrotic skin lesions appeared on the upper limbs and over the chest and back []. During dermatology examination, skin lesions were observed, and initial lung and heart examinations were unremarkable. Initial laboratory evaluation showed: White blood cell count was 9.8 × 109/l with a differential of 79% neutrophils, 22% lymphocytes, 3% monocytes, and 1% eosinophil. Platelets were 25 × 109/L. No vegetation was found in transthoracic echocardiogram. A computed tomography (CT) scan of the lungs revealed multiple 1-2 cm nodules in various stages with feeding vessels sign and cavitations in some of them, well as the halo sign, an area of low attenuation surrounding a nodular lesion, and the air-crescent signs with small size left pleural effusion [Figures and ]. Respiratory failure developed 2 days after admission, and patient was intubated and mechanically ventilated. Bronchoscopy was performed, and bronchoalveolar lavage (BAL) specimen was obtained. The diagnosis of probable invasive pulmonary aspergillosis (IPA) was made on based on European Organization for Research and Treatment of Cancer/IFIs Cooperative Group and the National Institute of Allergy and Infectious Diseases Mycoses Study Group (EORTC/MSG) Consensus Group definitions.[] Direct microscopy examination of endobronchial washing and BAL samples demonstrated acute branching septate hyphae, consistent with aspergillosis and the culture of the samples revealed Aspergillus flavus. The diagnosis of cutaneous fusariosis was made on Fusarium proliferatum is isolated from skin lesion biopsy in multiple media. The polymerase chain reaction assays have been performed with BAL sample and tissue biopsy. The fungal internal transcribed spacer (ITS) region of rRNA gene in these samples were amplified and sequenced for accurate identification of the fungal species. The ITS sequences of A. flavus and F. proliferatum were submitted to the NCBI GenBank and received the accession no. KJ000075 and KJ000076, respectively. The voriconazole (6 mg/kg body weight IV. BD) and antimicrobial drugs such as linezolid (600 mg BD), meropenem (1 g IV. TDS), and ciprofloxacin (400 mg BD) were administered to treat fungal and bacterial infection. The dose of these drugs was adjusted based on creatinine clearance. The treatment failed, and the patient expired 12 days following hospitalization due to sepsis.


The present case report is about a 61-year-old woman who reported to us with a growth in the floor of mouth that gradually increased in size since last 3 years, without pain. On examination, a 3 cm × 2.5 cm ovoid swelling was palpated lingual to the edentulous alveolar ridge, extending from midline (lingual frenum) to the right premolars []. It was a firm, non-tender, non-compressible, non-reducible, did not move with deglutition and showed no change in size with meals. No pulsations were felt over the mass and no vascular channels seen. The swelling was not fixed to underlying tissues and salivary secretions were normal. Some cervical lymph nodes were palpable but not tender. There was no neural involvement or sudden increase in size. Complete hemogram, serum electrolyte levels, kidney function test and liver function test had all values within the normal range, but for a raised erythrocyte sedimentation rate (50 mm/h). Fine needle aspiration cytology (FNAC) of the lesion suggested PA. Node Ib was palpable, but non-reactive on FNAC. Magnetic resonance imaging revealed a 20 mm × 18 mm × 15 mm well defined well-marginated lesion in right sublingual space in the region of anterior aspect of sublingual gland []. It indented the inferior surface of tongue and right genioglossus muscle and did not cross midline. Multiple mildly enlarged bilateral level Ib, II and III lymph nodes were noted. A provisional diagnosis of PA of sublingual gland was made and local excision of the lesion along with the gland was planned under L.A. Incision was placed from midline extending posteriorly near the alveolar ridge in order to protect the Wharton's duct. With careful dissection, lingual nerve was identified and protected. On surgical exploration, it was found that the mass involved the deep part of submandibular gland and duct with the sublingual gland being compressed by the mass. It was difficult to delineate the exact origin of the pathology (sublingual or submandibular gland); hence it was decided to sacrifice the sublingual gland, deep part of submandibular gland and its duct on the affected side []. Excision was done with a cuff of healthy overlying mucosa. Neck dissection was not indicated, hence not done. Initial histopathological examination, revealed a solid tumor tissue composed of myoepithelial and ductal cells presenting as double layered duct like structures with hyalinization of stroma. The epithelial component showed diversity in the form of sheets, nests and cords with different patterns of ductal arrangements and large areas of secretory material in the intervening areas, suggestive of cellular PA []. However since most of the tumors of submandibular and sublingual gland are malignant, a second examination of the specimen was undertaken. It showed that the entire tumor mass was covered by dense band of fibrous connective tissue. Tumor cells were arranged in a background of predominantly mucous acini, as small tubules lined by cuboidal to oval cells containing prominent nuclei and eosinophilic cytoplasm and surrounded by clear cells and increased hyalinization []. On the basis of this dual cell population, a provisional diagnosis of EMC was suggested. Some focal areas were also observed with cells arranged in a cribriform pattern with pseudocystic spaces that pointed toward Ad CC. Immunohistochemistry showed p-63 reactivity in outer clear cells, S-100 and smooth muscle actin were focally positive and C-kit for Ad CC was negative. Hence, a diagnosis of hybrid carcinoma was ruled out and a final diagnosis of epi-myoepithelial carcinoma was made. There is a chance that being a long-standing tumor; initial PA may have turned into EMC. Patient denied adjuvant Radiotherapy; is being followed-up since last 1 year and has no fresh complains or signs of recurrence until now [].


A 2-year-old boy presented to the pediatric surgical Out Patient Department (OPD) with 5 days history of a right sided abdominal mass. On examination the lump was 5 cm × 5 cm in size, firm in consistency with restricted mobility. It was situated in the right lumbar and iliac regions. Clinically, diagnosis of a renal mass? Wilm's tumor was suggested. On ultrasound, a tumor was noticed at the right renal hilum, causing ureteric narrowing with resultant hydronephrosis along with presence of multiple, large oval, heteroechoic lesions in the right iliac region and reteroperitoneum. Possibility of lymphoma was suggested. Due to the absent testis in the right scrotum, testicular neoplasm was not excluded. Ultrasound guided FNAC was performed. A blood mixed mucoid aspirate was obtained. Smears were highly cellular showing tumor cells in variably sized loose clusters with occasional cells forming glomeruloid structures []. The tumor cells were seen embedded in metachromatic basement membrane like material. Individual cells were large, showing moderate anisocytosis, high nucleocytoplasmic ratio. The nuclei were round to oval with irregular nuclear membranes, coarsely clumped chromatin and 0-1 nucleoli. Cytoplasm was moderate in amount and vacuolated in a few cells. There was abundant mucoid material in the background with presence of intracytoplasmic as well as extracellular periodic acid-Schiff (PAS) positive hyaline globules. Diagnosis of yolk sac tumor was made. This was corraborated by the raised alpha feto-protein (AFP) levels (>2000 ng/mL). Beta human chorionic gonadotropin (hCG) levels were within normal limits (1.61 mIU/mL). contrast-enhanced computed tomography (CECT) of the chest and abdomen were performed and revealed an elongated nearly oval shaped heterogeneously enhancing lesion in the right lower abdomen. Multiple heterogeneously enhancing retroperitoneal lymph nodes, right sided hydroureteronephrosis with left sided pleural deposits was also seen. In view of undescended testis, possibility of germ cell malignancy was suggested. Excision of the lump was carried out. A solid globular mass was received. It was gray to yellow in colour with some myxoid areas. Also present in the specimen were attached epididymis and spermatic cord. Sections were taken extensively and showed features consistent with yolk sac tumor with cells arranged in microcystic-reticular, myxomatous and focal macrocystic, alveolar-glandular and papillary patterns []. The rete testis, epididymis and surgically resected end of the spermatic cord were free of tumor. A single focus of lymphovascular invasion was identified. The tumor was seen reaching upto the tunica albuginea and showed a focal breach. Intracytoplasmic and extracellular hyaline globules present in the tumor were PAS positive and diastase resistant. The individual tumor cells were positive for pancytokeratin on immunohistochemistry. CD30, epithelial membrane antigen (EMA) and carcinoembryonic antigen (CEA) were negative ruling out embryonal carcinoma and choriocarcinoma. The patient was started on chemotherapy and is currently under follow-up.


This case describes a 17-year-old boy who was electively operated for VSD closure and aortic valve replacement for aortic regurgitation with a 25 St. Jude nonrotatable valve. He was readmitted 1 year later with gradually enlarging pulsatile swelling of the chest, off and on episodes of chest pain, pedal edema and raised liver enzymes suggestive of right heart failure. Transthoracic ECHO showed a large PAA with peripheral thrombus, and compression of RV outflow tract (RVOT) [], mild to moderate RV dysfunction. CT angiography confirmed the presence of a 10.5 cm × 5.9 cm × 11.2 cm pseudoaneurysm arising from the anterior wall of ascending aorta with a small neck (7 mm) []. It was abutting the ostioproximal right coronary artery (RCA) with significant compression []. Bony erosion of sternum by aneurysm was also noted. Anesthesia was induced with fentanyl 200 mcg, midazolam 3 mg, sevoflurane and intubated with rocuronium 30 mg. Induction of anesthesia and intubation were uneventful. Femorofemoral bypass was established before commencing sternotomy so that in the event of PAA rupture during sternotomy immediate circulatory arrest can be instituted. The patient was gradually cooled to 24° while avoiding ventricular fibrillation and thus ventricular distension. Unfortunately, pseudoaneurysm ruptured during sternotomy and a circulatory arrest was immediately instituted. The ostium of the PAA could be accessed within 5 min, and a finger was insinuated into the aneurysm cavity to occlude it. The aorta was cross-clamped and cardioplegia could be administered through both the coronaries as the aneurysm was decompressed. The neck of pseudoaneurysm was closed with bovine pericardium patch. Injection milrinone infusion was started in the rewarming period in view of the RV dysfunction. The patient was successfully weaned off bypass. The postoperative course was uneventful. The patient was extubated on 2nd postoperative day and was discharged on 10th postoperative day.


A 28-year-old multiparous (P4 + 0L4) female, presented to the Gynecology Outpatient Services, with a chief complaint of painless hematuria for two months. She had open tubal ligation done three years back. An abdominal examination showed no significant finding. On vaginal examination, a nontender mass was felt in the right fornix. Routine investigations showed low hemoglobin (8 gm %) and few red blood cells (RBCs) in the urine.
Transabdominal USG (iU22; Philips Medical System, Andover, MA, USA) showed an ill-defined, predominantly hypoechoic lesion involving the right adnexa, infiltrating the right lateral wall of the urinary bladder, with a normal ipsilateral ureter. Extension into the lumen of the bladder could not be ruled out. The right ovary was seen separate from the lesion. On account of the young age of the patient and a background history of tubal ligation, the possibility of pelvic endometriosis (predominantly tubal, with infiltration into the bladder) was considered. Cystoscopy revealed solid-looking, round-shaped protrusions from the dome and anterior wall of the urinary bladder, without any mucosal breach or intraluminal extension. However, mucosal congestion was appreciated overlying the protrusions. Contrast-enhanced computed tomography (GE Light Speed VCT 64 slice CT, New Jersey, USA) of the abdomen revealed the mass to be heterogeneous, mildly enhancing, and invading into the dome and right anterolateral wall of the urinary bladder [Figure and ], with surrounding fat stranding. There was no significant lymphadenopathy or ascites. An MRI (Siemens Magnetom Avanto 1.5 Tesla, Erlangen, Germany) was done, as a further workup, which revealed no intralesional T1 hyperintensities [], but few cystic foci [], lowering the possibility of endometriosis. The right fallopian tube was found to be involved in the mass. Invasion of the urinary bladder was noticeable as on CECT; with no obvious intraluminal extension, but with edematous adjacent mucosa [Figure and ]. A mild amount of fluid was also seen in the vicinity, posterior to the right ovary []. Overall the features on CECT and MRI made us think of a possibility of right tubal malignancy invading into the urinary bladder (intramural extension).
Exploratory laparotomy unveiled the presence of an approximately 6 × 6 cm mass, infiltrating the dome and right anterolateral wall of the urinary bladder []. The right fallopian tube was found to be adherent only to the mass and was separated. With an operative diagnosis of primary bladder mass, it was excised with partial cystectomy.
However, on sectioning the excised mass, multiple cotton threads were seen [], thus altering the diagnosis to that of a gossypiboma. Histopathological examination confirmed it to be a foreign body granuloma.


A 41-year-old male injection drug user was brought to the emergency department unresponsive, febrile and hypotensive. Physical examination showed numerous track marks but no obvious source of infection. Initial investigations revealed a white blood cell count of 19.3×109/L; urinalysis, chest x-ray and abdominal computed tomography were all unremarkable. Fluid resuscitation, vasopressor support and empirical antibiotic therapy with intravenous (IV) piperacillin/tazobactam, vancomycin and clindamycin were initiated. Following resuscitation, the patient provided a vague history: he was well until the day of admission, at which time he developed a headache, severe fatigue and generalized malaise. His most recent heroin use had been the night before symptom occurrence. His medical history was significant for hepatitis C and previous episodes of bacteremia related to injection drug use. Blood cultures collected on admission grew B cereus (four of four bottles) and Serratia marcescens. The patient’s antibiotics were changed to IV vancomycin and ciprofloxacin. Blood cultures were persistently positive for B cereus until day 14 of admission. On day 29, the patient developed a small antecubital abscess that was drained and cultured B cereus. A transthoracic echocardiogram showed no signs of endocarditis. The patient received a total of six weeks of IV vancomycin and was discharged home.


Nine days following the admission of case 1, a 49-year-old man with a history of daily heroin and crystal methamphetamine injection drug use presented to hospital with confusion and agitation. He was afebrile, with no obvious focus of infection on history or physical examination. His medical history was significant for recently diagnosed HIV infection and hepatitis C. Initial laboratory results showed a white blood cell count of 13.1×109/L. Empirical therapy with IV piperacillin/tazobactam and vancomycin was initiated. Blood cultures collected on admission grew B cereus and Lactobacillus, and the patient was switched to IV vancomycin and ciprofloxacin. A transthoracic echocardiogram showed evidence of a vegetation on the mitral valve. Three subsequent blood cultures were positive for B cereus; blood cultures eventually cleared on day 14 of admission. IV vancomycin was continued for a total duration of eight weeks and the patient was discharged.


Twenty days after case 1 was admitted to hospital, a 33-year-old man with a history of heroin and cocaine injection drug use presented to the emergency department with confusion. He was afebrile and his physical examination was unremarkable. His medical history included hepatitis C and previous episodes of methicillin-resistant Staphylococcus aureus infective endocarditis, one of which necessitated a tricuspid valve replacement. The patient left hospital against medical advice, but was called to return the following day when blood cultures returned positive for Gram-positive bacilli, subsequently identified as B cereus. Repeat blood cultures were drawn and IV vancomycin therapy was initiated. Only the initial blood culture (one of two bottles) grew B cereus, and all subsequent blood cultures were negative. A transthoracic echocardiogram showed no evidence of endocarditis. The patient received a total of two weeks of IV vancomycin and was discharged home.


A 54-year-old male presented with a sore throat, arthralgia and fever for 1 week. He had an erythematous rash predominantly involving his lower back and legs bilaterally. He was a heavy smoker for 30 years but had no previous medical problems. On examination he was afebrile and the rash was purpuric in nature. Initial blood tests and mid-stream urine (MSU) were unremarkable. A skin biopsy of the rash showed a leukocytoclastic vasculitis but no tissue was sampled for immunofluorescence. Blood cultures and other serum investigations including anti-nuclear antibody (ANA), anti-neutrophil cytoplasmic antibody (ANCA) and Hepatitis B and C serology were all negative. He was commenced on a non-steroidal anti-inflammatory medication.
One week later, he re-presented with severe colicky abdominal pain with associated nausea and vomiting. He was hypertensive but hypovolaemic and the lower limb rash was still present with moderate peripheral oedema bilaterally. Abdominal X-rays were consistent with a small bowel obstruction and serum creatinine (Cr) was 180 μmol/L (previously 100 μmol/L). MSU demonstrated >1000 × 106/L glomerular red blood cells and a 24-h urine collection 3.6 g/day proteinuria. Repeat vasculitis serology was negative. The management involved intravenous (IV) rehydration, analgesia and naso-gastric tube insertion. A renal biopsy revealed a segmental necrotising glomerulonephritis with small cellular crescents and associated diffuse endocapillary proliferation (Figure ). Direct immunofluorescence microscopy showed strong granular mesangial and peripheral capillary wall staining for IgA and C3. Electron microscopy showed scattered mesangial, subendothelial and occasional subepithelial ‘hump-like’ deposits.
A diagnosis of HSP was made and treatment with IV methylprednisolone initiated. Over the next few days serum Cr increased and he became oliguric despite hydration. On Day 6 post-renal biopsy he became acutely dyspnoeic with severe hypoxia. Chest X-ray (CXR) revealed patchy interstitial and alveolar infiltrates bilaterally. With minimal response to diuretics, acute haemodialysis was commenced for fluid removal. He symptomatically improved and a CXR repeated 2 days later had markedly reduced infiltrates. A chest computed tomography (CT) scan was performed that demonstrated diffuse ground-glass opacity bilaterally consistent with pulmonary haemorrhage (Figure ). A lung biopsy showed extensive fresh intra-alveolar haemorrhage and fibrin with haemosiderin-laden macrophages (Figure ). Occasional small arteries showed features of a vasculitis with fibrinoid necrosis within the wall (Figure ); some also showed superimposed luminal thrombus. No viral cyto- pathic effects were found.
Oral cyclophosphamide was started (2 mg/kg/day) with a further 3 days of IV methylprednisolone. Blood transfusion was given and intermittent haemodialysis was continued. After 3 weeks of cytotoxic therapy, renal function improved and dialysis was ceased with a stable serum Cr 350 μmol/L. Immunosuppression and anti-hypertensive treatment were continued. He was discharged home with portable O2, required for a further 2 months. Three years after initial presentation, his renal function remained stable with serum Cr 200 μmol/L and he had good exertional tolerance. Immunosuppression included prednisolone (5 mg daily) and mycophenolate mofetil, the latter started after 4 months of cyclophosphamide was completed.


A 33-year-old obese aboriginal woman with ESRD secondary to type II diabetes who had been on haemodialysis for 7 years presented on 9 February 2006 with a 3-day history of back pain and progressive leg weakness after a minor fall. She had a known history of severe hyperparathyroidism despite treatment with calcium carbonate 500 mg four times daily, calcitriol 1 mcg three times weekly and sevelamer up to 8 g per day. She had been scheduled for a parathyroidectomy 10 months previously. Her parathyroidectomy was subsequently cancelled after her parathyroid hormone level (PTH) had decreased from 1616 pg/mL (normal 7–50 pg/mL) to 629 pg/mL with the addition of cinacalcet (90 mg orally once a day) over a 3-month period. However, despite maximal doses of sevelamer, calcium carbonate, calcitriol and cinacalcet, her PTH was 615 pg/mL when she presented with spinal cord compression. Physical examination demonstrated normal vitals and cardiac, respiratory and abdominal examinations were also non-contributory. Neurologic examination revealed bilateral hip flexor weakness (left 2/5, right 3/5), patchy saddle anaesthesia and minimal rectal tone. Sensation and proprioception were intact distally. Plantar reflex was flexor on the left, and the right side was not tested due to the presence of a cast for a non-pathological ankle fracture. Laboratory results included calcium 1.83 mmol/L (7.32 mg/dL), phosphate 1.29 mmol/L (3.99 mg/dL), albumin 37 g/L (3.7 g/dL) and alkaline phosphatase of 970 u/L. MRI revealed multiple lesions involving T1 (first thoracic), T7–T11, and L1–S1 (first lumbar to first sacral) vertebrae (Figure a). Significant spinal cord compression was identified at the T7 and T11 levels (Figure b). Open surgical biopsy revealed haemosiderin-containing macrophages, collagenous tissue and abundant isomorphic giant cells consistent with a brown tumour (Figure c). The patient underwent urgent surgical spinal cord decompression and parathyroidectomy. As the lesion was highly vascular, only a partial laminectomy was performed and the T7 level and the remainder of the lesions were treated conservatively. Post-parathyroidectomy her PTH rapidly decreased to 26 pg/mL by 21 March. Her hospital course was complicated by an intensive care unit admission for non-malignant, hemorrhagic pericardial tamponade. Follow-up MRI 80 days later showed significant improvement at all spinal cord levels with some mild residual cord compression at T9–T11. The patient's symptoms have improved but she remains wheelchair bound.


A 36-year-old 5-week postpartum woman presented to the emergency room with complaints of nausea and vomiting for 48 h. She also reported a 2-day history of general malaise and worsening dyspnoea. She denied chest pain, palpitations, diarrhoea or headaches. She reported eating; however, she limited herself to several small high-protein carbohydrate-free meals in an attempt to quickly return to her prepartum weight. Since her delivery, she had achieved an intentional weight loss of 30 lbs. Initial vital signs were: temperature 37 °C, blood pressure 140/63 mmHg, heart rate 84, respiratory rate 20 and a weight of 59.8 kg. She appeared unkempt and lethargic. Head and neck examinations were benign. Chest auscultation was clear with no adventitious sounds; heart examination was unremarkable. The abdomen was benign with a well-healed surgical C-section scar; there was no costovertebral angle tenderness. The extremities were without tenderness or oedema. She had no neurologic defects other than her blunted mentation.
Her past medical history was significant for a cesarean section, complicated by bladder damage, now resolved. Her only medication was percocet to manage post-surgical visceral pain. She denied alcohol or illicit substance use.
Initial laboratory data include sodium of 144 mEq/L, potassium 4.8 mEq/L, chloride 104 mEq/L and bicarbonate <5 mEq/L that is the lowest available determination possible at our institution. Her BUN was 3 mg/dL, creatinine was 1.1 mg/dL and glucose was 133 mg/dL. Serum lactate was 2.1 mmol/L, phosphate 1.0 mg/dL and magnesium 1.6 mg/dL. Arterial blood gas drawn on room air showed a pH of 6.9, PCO2 of 19 mmHg, PaO2 of 137 mmHg and SaO2 of 100%. White blood cell count was 17 600/mm3 with 88.2% segmented neutrophils, Hg 13.7 g/dL, haematocrit 43.1% and platelets of 340 000/mm3. Urinalysis had a pH of 5.5 with <80 mg/dL ketones. The serum osmolar gap was 7. A comprehensive drug screen was negative including salicylates and acetaminophen. Chest radiograph was normal. Blood and urine cultures were negative.
The patient was volume-depleted with a metabolic acidosis and a serum anion gap of 35. Fluid resuscitation with three ampules of sodium bicarbonate per litre of D5W at 100 cc/h was initiated for 24 h. Improvement in laboratory values occurred within 12 h with serum bicarbonate improving to 12 mEq/L. The serum bicarbonate improved to 20 mEq/L with normalization of the anion gap at 24 h. Symptomatic improvement occurred likewise. The patient was started on an 1800 kcal diet during her hospitalization, supplemented with a regular diet of home food provided by the husband. Breast feeding was stopped on advice from a lactation consultant and the acidosis did not reoccur. The patient's baby was reported to be in the 90th percentile for weight and height.


A 29-year-old Caucasian man was referred for nephrotic syndrome. In the last 2 months, he had received treatment with amoxicilline clavulanate and prednisone (1 mg/kg/day during 5 days) for common acquired pneumonia. The blood pressure was 120/60 mmHg. Clinical examination revealed anasarca and cervical and inguinal lymphadenopathies.
The urinary protein excretion was 12 g/day, with selective albuminuria. There was no haematuria. The plasma albumin level was 6 g/L, and renal function was normal. Leukocyte count was normal, including eosinophils and haemoglobin level (153 g/L). The platelet count was 55 G/L. HIV and HCV tests were negative, and HBV serology showed a vaccinal profile. CMV, parvovirus B19, HTLV1 serologies were negative, and EBV tests showed past infection, without replication. Antinuclear antibodies were positive (1/500). Anti-DNA, anti-ECT, anti-glomerular basement membrane and anti-neutrophil cytoplasmic antibodies were negative. Complement components were normal [C3 1.17 g/L (N, 0.8–1.4 g/L), C4 0.24 g/L (N, 0.16–0.38 g/L)]. Bone-marrow aspirate showed a slight hypereosinophilia (3%) and the presence of megakaryocytic lineage, which confirmed peripheral immune thrombocytopenia (ITP). Total plasmatic IgE concentration was dramatically increased (3900 UI/mL, N <20).
CT-scan showed centimetric lombo-aortic and inguinal lymphadenopathies and hepatosplenomegaly. A 18-fluoro-deoxy-glucose positron emission tomography (FDG-PET) was negative.
The biopsy of the submandibular mass revealed a 30 mm diameter lymphadenopathy. Histologic analysis and immunohistochemistry (CD3, CD5, CD10, CD15, CD30, CD20, EMA, EBV-LMP, BCL2) excluded tumoral proliferation. We found a preserved nodal architecture with hyperplastic follicules (figure not shown), many eosinophilic infiltrates and vascular hyperplasia consistent with Kimura disease (Figure ). Immunophenotyping of blood lymphocytes was normal. No clonal T-cell rearrangement was found, neither in the peripheral blood lymphocytes nor in the lymph node.
The renal biopsy specimen contained 18 glomeruli, and revealed segmental glomerular sclerosis in two of them (Figure ). There was no mesangial proliferation, nor evidence of capillary basement membrane thickening or membranous spikes. Tubules and interstitium were normal. Immunofluorescence was negative.
A diagnosis of Kimura's disease associated with focal segmental glomerulosclerosis (FSGS) and immune thrombocytopenia was retained.
The patient was treated with oral corticosteroids (prednisone, 1 mg/kg/day), associated with an ACE inhibitor (ramipril). After 1 month of treatment, while the nephrotic syndrome was in remission, antinuclear antibodies increased (1/1600), and anti-DNA antibodies appeared (IgG: 175 UI/L; N <10 UI/L). Complement component C4 decreased to 0.10 g/L, whereas C3 remained in the normal range (0.85 g/L). There were no SLE-like manifestations except ITP. Autoantibodies and complement concentration normalized lastingly in a few months.
Steroid dose was progressively tapered. The nephrotic syndrome relapsed twice, 12 and 18 months after the onset of steroid therapy when he was still receiving 20 mg prednisone per day. Mycophenolate mofetil 1 g twice per day was added after the first relapse. Nephrotic syndrome remission was acquired 4 weeks later. The second relapse was concomitant of an upper respiratory viral infection. So far, the patient has no sign of malignant lymphoproliferative disorder, and no systemic autoimmune disease.


A 56-year-old Caucasian woman, a past heavy smoker (40 pack years), was first evaluated in 2001 for resistant hypertension of 5-year duration. A year before, duplex sonography of the carotid arteries, performed because of visual disturbances, had demonstrated critical stenosis of the left internal carotid artery and she successfully underwent endarterectomy. During the previous years, the patient had gained 10 kg weight and had noticed the appearance of facial hirsutism and wide purple striae on her lower abdomen. Her blood pressure was 180/100 mmHg, and she was moonfaced with a buffalo hump, abdominal obesity and relative wasting of limb musculature. Fundoscopy showed grade II hypertensive retinopathy, and echocardiography revealed mild left ventricular hypertrophy. Relevant laboratory data are shown in Table . The patient's clinical picture and biochemical profile were consistent with a diagnosis of Cushing's syndrome either of pituitary origin or an ectopic, indolent source. On magnetic resonance imaging (MRI) of the sella turcica, the existence of a 6–7 mm pituitary microadenoma was suspected. Inferior petrosal sinus sampling clearly showed excessive pituitary ACTH excretion. In October 2002, a 1 cm ACTH staining adenoma adherent to the cavernous sinus was surgically removed. A day following the surgery, serum cortisol was undetectable necessitating maintenance prednisone treatment. Over the next 2 years, there was a gradual but complete regression of the patient's cushingoid habitus. However, her blood pressure remained elevated and fluctuated between extremes of high to low (Table ).
Twenty-four-hour urinary excretion of catecholamines as well as plasma metanephrines was all within normal limits. An MIBG scan showed no abnormal findings. In January 2003, renal ultrasound revealed the left kidney to be 11.2 cm in length (longitudinal axis) versus 9.5cm of the right kidney. Duplex sonography of the renal arteries demonstrated a systolic peak (500 cm/s) at the origin of the right renal artery with a parvus tardus pattern over the right intrarenal arteries. Magnetic resonance angiography confirmed the presence of a significant 7 mm stenosis of the right main renal artery beginning 0.5 cm from its origin. In February 2003, PTRA with stent insertion was successfully performed.
Despite the success of the PTRA, the patient's blood pressure continued to fluctuate widely while being treated with maximal doses of five anti-hypertensive drugs and a pharmacological replacement dose of prednisone (15 mg/day) (Table ). In view of her carotid surgery and the nature of her blood pressure profile, baroreflex failure was suspected. Noninvasive measurements of beat-to-beat blood pressure and heart rate were done by using a finger pulse photoplethysmographic device (Portapres, TNO Institute of Applied Physics Biomedical Instrumentation). The patient performed a Valsalva manoeuvre, maintaining an airway pressure of 30 mmHg for 12 s. During the manoeuvre, blood pressure decreased during phase 2 with an overshoot during phase 4. Baroreflex-cardiovagal gain was estimated from the relationship between interbeat interval and systolic blood pressure during phase 2 of the Valsalva manoeuvre, beginning with the peak pressure and ending with the nadir blood pressure. A scatterplot was constructed relating the interbeat intervals to the systolic pressures with a 1-beat delay from the previous heartbeat. The baroreflex-cardiovagal gain (as defined by the slope of the regression line of best fit) was 0.07 ms/mmHg. Supine and upright blood pressure and heart rate were 145/78 mmHg; 71 bpm and 142/77 mmHg; 79 bpm, respectively. Norepinephrine levels were high normal at baseline, 487 pg/ml, and markedly increased to 927 pg/ml after 5 min of standing up. These results are indeed compatible with the diagnosis of baroreflex failure.


In 1989, a 35-year-old female presented acutely with heavy proteinuria (22 g/24 h) and normal renal function. Renal histology was compatible with minimal change nephropathy (MCN). She was commenced on oral prednisolone (60 mg od), and achieved complete remission within weeks. However, multiple relapses followed on reduction of the corticosteroid dose. Azathioprine, cyclosporin, mycophenolate mofetil, tacrolimus and chlorambucil were all tried unsuccessfully, but neither the relapse rate nor the steroid requirements improved.
In 2003, cyclosporin was re-introduced to minimize steroid exposure with trough plasma levels of 149 μg/L. In the preceding 14 years, the prednisolone dose had rarely been below 15 mg/day, and there had typically been two to three relapses per year. In 2006, sirolimus 2 mg/day was added to her prednisolone (15 mg/day), and cyclosporin (6 mg/kg/day)—she was also prescribed primidone since childhood for epilepsy. At review, the trough plasma levels of cyclosporin and sirolimus were 153 μg/L and 2.9 μg/L, respectively. Steroids were gradually reduced and subsequently completely discontinued 24 months after sirolimus was added with no relapses in the last 30 months.


A 75-year-old woman presented to the emergency room with acute rectorragia, pain in the right lower abdominal quadrant, nausea and vomiting. She complained of a persistent non-productive cough and intermittent fever reaching 38°C during the last month. She had undergone a hysterectomy 8 years earlier due to endometrial cancer staged T1, N0, M0 and was treated with interferon for 15 years for multiple sclerosis.
On examination, her temperature was 36.8°C. There was severe pain upon palpation of the right lower abdominal quadrant without defence. Blood analysis revealed an elevated C-reactive protein of 160 mg/l (<5 mg/l) and a normochromic anaemia of 83 g/l. The patient was hospitalized in the surgery unit. A colonoscopy revealed inflammatory lesions. In the ascendant colon, a histological examination disclosed acute erosive colitis. Antibiotic therapy was started with cefepime (2 g b.i.d.) and metronidazole (500 mg t.i.d.). The bleeding stopped, the inflammatory parameters decreased and partial relief of the abdominal pain was noted; however, the cough still persisted.
A week after hospitalization, a pneumological consultant was asked to examine the patient. The chest x-ray showed multiple small alveolar opacities, and a chest CT scan confirmed multiple nodular and slightly cavitating lesions (Figure ). After the introduction of clarithromycin, fever and inflammatory markers improved. Pulmonary function tests revealed a moderate, non-reversible obstruction with mild restriction, but the patient had never smoked and had never previously experienced pulmonary disease. The differential diagnosis at that time included pneumonia, septic embolism, sarcoidosis, tuberculosis, cryptogenic organizing pneumonia, metastasis and Wegener granulomatosis. A bronchoscopy was performed. Extensive search for an infective agent (including tuberculosis, fungi, and pneumocystis among others) in the bronchoalveolar lavage and transbronchial biopsies was found to be negative. The cellular distribution of the lavage showed mild neutrophilia (15%, normal range <2%) and very mild eosinophilia (2%, normal range <0.5%), but no malignant cells were found. Histology showed acute inflammation without granulomas or signs of vasculitis.
The next day, the patient was transferred to our medical unit. Reviewing the case history, we noted that a urine analysis had never been performed. The sediment showed 10–20 erythrocytes per field with glomerular features, 5–10 leucocytes per field and hyaline and granular casts. The patient's proteinuria was estimated to be 800 mg/24 h. Her creatinine level was moderately elevated at 96 μmol/l, with a measured clearance of 47 ml/min. These results, coupled with an elevated MPO-ANCA titre (100 U/ml, normal range <15 U/ml), raised the suspicion of systemic vasculitis with glomerular involvement. Therefore, a renal biopsy performed on the 19th day depicted focal and segmental necrotizing glomerulonephritis, with early crescent formation (the renal sample contained 15 glomeruli, 4 of which were globally sclerotic; one showed the signs of a recent fibrinoid necrosis and three others showed cellular crescents) associated with arteriolar sclerotic lesions.
Based upon all collected data, a diagnosis of ANCA-positive microscopic polyangiitis extended disease was made with renal, gastro-intestinal and pulmonary involvement. A therapy comprising high-dose steroids (1 g methylprednisolone i.v./day for 3 days followed by prednisone oral 1 mg/kg BW) and cyclophosphamide (2 mg/kg BW/day) was started and produced sudden and progressive improvement of the clinical situation (serum creatinine 80 μmol/l, urine sediment with 0–2 erythrocytes per field, no casts and proteinuria <150 mg/24 h) 3 months after diagnosis.
The radiological abnormalities of the chest disappeared, and follow-up lung function tests showed complete resolution of the obstructive and restrictive changes.


A 78-year-old man on haemodialysis for 6 years presented with a 1-day history of haematemesis and melaena. His past medical history includes chronic pyelonephritis, gastric ulceration on the greater curvature of the stomach (2008) and hypertension. There was no history of excess alcohol intake or non-steroidal anti-inflammatory use. He was fluid-resuscitated and underwent an emergency oesophagogastroduodenoscopy (OGD) which demonstrated blood in the stomach but no bleeding source. He had a further drop in haemoglobin 24 h later, and repeat OGD was unremarkable. He went on to have a CT angiogram with a view to embolization, which failed to identify a bleeding vessel. Surgical review excluded the possibility for surgical intervention due to lack of an identifiable lesion.
The patient was discharged home after several days of observation but presented 12 h later with recurrent haematemesis. Emergency endoscopy with pre-procedure prokinetics demonstrated a Dieulafoy lesion in the cardia (see ) which was successfully treated with endoclips and adrenaline injection. He had a further haematemesis 36 h later with repeat endoscopy demonstrating another Dieulafoy lesion in the anterior wall of the fundus which was treated as before (see ).


A 73-year-old female patient with hypertensive nephrosclerosis was started on haemodialysis via a tunnelled line in July 2008. Her other comorbid conditions included atrial fibrillation and right heart failure with severe pulmonary hypertension (pulmonary artery pressure 83 mmHg) due to pulmonary emboli. Her medication included ramipril 5 mg once daily (OD), bisoprolol 3.75 mg OD (evenings) and sildenafil 25 mg three times daily. Following implantation of her tunnelled line, she underwent three uneventful haemodialysis sessions. The fourth haemodialysis session was started with the patient in good mood and with a blood pressure of 123/71 mmHg. After 8 min of dialysis the patient became unresponsive without peripheral pulse. Dialysis was stopped, and resuscitation was just being initiated when the patient regained consciousness after administration of 1L of fluid. There had been no kinking of any of the tubing. The chest was clear and there was no cardiac murmur; the abdomen was soft. The patient was afebrile. Dialysis was stopped. An electrocardiogram showed no new changes and troponin T was normal. A bedside ultrasound excluded pleural and pericardial effusion and showed no free intra-abdominal fluid. The inferior vena cava was dilated, in keeping with known right-sided heart failure. Dialysis was discontinued and the patient received oxygen. During that day she made an uneventful recovery. Her C-reactive protein was normal and serum haemoglobin was unchanged. Serum potassium was not elevated. We continued to search for something that was different on the day she had her fourth haemodialysis session and came up with the timing: the uneventful sessions had started at 17.00 p.m., 10.45 a.m. and 15.00 p.m., respectively. The fourth haemodialysis session had been started at 9.00 a.m. We hypothesized that her medication was at fault and ascertained that it had been the only session in close vicinity to sildenafil ingestion (given at 8.00 a.m., lunchtime and 18.00 p.m.). We then tried to schedule all dialysis sessions 3 h after the last sildenafil dose. No further episodes occurred. However, several sessions later the patient was inadvertently called for dialysis again at around 9.00 a.m. and sustained an episode similar to the first although less severe. Sildenafil was stopped entirely, the patient was discharged and no further episodes occurred.


A 33-year-old man suffering from hypoplastic kidney of unknown origin had been treated with haemodialysis since 1992. On 11 May 2004 severe tertiary hyperparathyroidism (PTH level 3000 ng/l, normal: 15–65 ng/l) required total parathyroidectomy. The procedure included an autotransplantation of parathyroid tissue into the upper leg, but the autotransplant failed to secrete PTH (PTH levels between 1.4 and 10.4 ng/l determined with chemiluminometric technology, Centaur, Bayer, Newbury, UK). Hypocalcaemia developed despite daily supplementation with calcium (calcium acetate 3 × 700 mg), calcitriol (0.5 μg) and dihydrotachysterol (3 × 0.5 mg). The patient developed hypocalcaemic tremor, agitation and muscle cramps. A therapy with teriparatide (20 μg administered daily, subcutaneously) was started from December 2005 until July 2007. The complaints totally diminished after a therapy with teriparatide, and did not relapse. Values of serum calcium, serum phosphate and PTH over the course of the disease are shown in Figure . Additional treatment consisted of phosphate-binding agents sevelamer (3 × 800 mg) and calcium acetate (2 × 1.8 g). Cholecalciferol (800 U) was given orally once a day and calcitriol (0.5 μg) was given orally twice weekly.
To further gain insight into the exact bone disease, a biopsy was performed 15 months after parathyroidectomy and before the initiation of teriparatide therapy in 2005.
Based on results obtained in normal controls, histomorphometric diagnosis was defined according to the amount of fibrosis, and static and dynamic parameters as previously described [].
The first bone biopsy taken in December 2005. It represents typical characters of an adynamic bone disease including massive reduction in bone volume (bone volume/tissue volume 11.6%, normal: >20%), extremely reduced number and sites of osteoclastic resorption, missing osteoblasts (osteoclast- and osteoblast-covered surface/bone surface 0, normal 2.5 resp. 4.5%) and lack of peritrabecular or marrow fibrosis (Figure A).
The second bone biopsy performed 8 months after cessation of a teriparatide treatment period over 18 months shows a considerable increase in mineralized bone volume (bone volume/tissue volume 30.2%) and also an increase in bone remodelling. Flat and plumper lining cells (osteoblast progenitors) as well as mature osteoblasts are arranged in single and double layer along the trabecular surface. The osteoblast-covered surface/bone surface reached 2.6%. In a couple of trabeculae, they cover the boundary on both sides (Figure B) and they are even present in former resorption lacunae. There is no detectable osteoid. Osteoclasts are rare and apart from the trabecular surface (osteoclast-covered surface/bone surface 0.4%). The arrangement of cement lines in trabecular bone is distinct and lamellar.


A 69-year-old Japanese woman visited our emergency room complaining of sudden headache, nausea and left haemiplegia. She had been undergoing chronic haemodialysis therapy for 17 years due to the advancement of chronic glomerulonephritis. A subtotal parathyroidectomy had been performed due to medical therapy-resistant secondary hyperparathyroidism 15 years previously. The secondary hyperparathyroidism had relapsed in the residual parathyroid gland 2 years previously, and since then 10 μm of maxacalcitol three times a week had been administered. Ticlopidine chloride 100 mg and aspirin 100 mg had also been applied since the symptoms of arterial sclerotic obliterans at her left femoral artery had become overt. Simple X-ray and X-ray computed tomographic examinations revealed obvious calcification around the thoracic aorta, abdominal aorta, bronchial wall and bilateral femoral arteries. No remarkable events had been noticed before the onset of her current symptoms.
Her height was 145 cm and body weight was 35.8 kg. Her blood pressure was 169/76 mmHg. Despite the left haemiplegia, her consciousness was clear and sensation was intact. The red-eye finding was absent. No remarkable findings were noted at her chest or abdomen. The laboratory results were as follows: haemoglobin 9.6 g/dL, serum creatinine 5.65 mg/dL, urea nitrogen 40.7 mg/dL, sodium 137 mEq/L, potassium 4.0 mEq/L, chloride 108 mEq/L, calcium 10.7 mg/dL, inorganic phosphate 4.1 mg/dL, magnesium 2.0 mg/dL and intact parathyroid hormone 1458 pg/mL. An ultrasonic examination detected a swollen parathyroid gland at her left frontal neck. Cranial computed tomography demonstrated a right subdural haematoma (Figure A) in addition to the calcification at the tentorium cerebella and falx cerebri (Figure B).
An emergency operation for the subdural haematoma was performed. Sclerotic lesions that looked like many rock barnacles sticking to sea rocks were found in the dura mater (Figure A). Adhesions of those sclerotic lesions and cerebral superficial arteries were observed (Figure B). Although the artery responsible for the subdural haematoma was not confirmed, the haemorrhage was likely to have been caused in part by such an adhesion. No obvious brain damage was observed.
By histological observation, calcified tissues were found in such sclerotic lesions with a rock barnacle-like appearance, and cells forming a single layer were found on the surface of this tissue (Figure A). An obvious lamellar structure was demonstrated in the calcified tissue by a polarization microscopic observation (Figure B and C). Osteopontin immunoreactivity was found around the calcified tissue (Figure A). Multinucleated giant cells infiltrated near the tissue, and a tartrate-resistant acid phosphatase immunoreactivity was demonstrated in those cells (Figure B).
The patient recovered after the emergency operation and was discharged a few days later only presenting lower limb muscle weakness.


A 51-year-old male previously in excellent health developed increasing fatigue and decreased exercise tolerance in 2002. Other symptoms included recurrent sinusitis, transient cough, arthralgias, hives and swollen tender feet. The hives and swelling initially responded to diphenhydramine. He particularly noted that his fatigue worsened with exposure to the cold weather. In September 2003, a purpuric rash appeared on his legs that developed into an ulcer. A skin biopsy revealed a vasculitis with fibrinoid necrosis. In February 2004, the patient was hospitalized for extreme shortness of breath and a serum creatinine (Scr) of 4.1 mg/ dL (362 μmol/L). A renal biopsy was performed.
The renal biopsy (Figure ) showed eosinophilic immunoglobulin thrombi within many of the arterioles and glomerular capillaries, including the vascular pole of the glomerulus. This material was variably pale to somewhat positive on a PAS stain and was negative on a Congo red stain. Many of the immunoglobulin thrombi were crystalline in shape. Occasional neutrophils were present within the glomerular capillary loops. No true thrombi were noted. The glomeruli did not show mesangial hypercellularity or mesangial matrix expansion, no glomerular basement membrane thickening or duplication was identified and no crescents were present. The biopsy showed focal mild interstitial fibrosis and tubular atrophy. No fibrinoid necrosis of vessels was identified. By immunofluorescence, the immunoglobulin thrombi showed bright staining for IgG, C3, fibrinogen and kappa light chain, lesser staining for C1q and no staining for IgM or lambda light chain.
Laboratory investigation included testing for cryoglobulins, which were repeatedly negative. Serum protein electrophoresis showed a small monoclonal band in the gamma region, but immunofixation was not performed. A bone marrow biopsy at that time showed no definite evidence of a plasma cell disorder. The peripheral blood count and differential were normal. The serum C3 level was slightly decreased (0.78 g/L, normal range 0.90–1.80 g/L) and the serum C4 level was normal. Tests for HIV, hepatitis B and C infection were negative. Testing for hypercoagulable states was not performed.
The patient's cough and purpura improved significantly with high-dose steroids. Renal function also improved [Scr = 1.9 mg/dL (168 μmol/L)], but he continued to have fatigue. In September 2004, another leg ulcer developed. Another skin biopsy showed leucocytoclastic vasculitis by report. He was treated with azathioprine 50–100 mg/day and prednisone 50 mg/day that was tapered to 5 mg twice a day over 6 months.
In February 2006, the patient presented with rash, fatigue, nausea and vomiting. He had noted dark-coloured urine and quickly became anuric. His blood pressure was 200/100 mmHg and a Scr was 8.2 mg/dL (725 μmol/L). The LDH was elevated at 1253 U/L, but creatinine kinase was normal. Laboratory evaluation including cryoglobulins, ANA, ANCA and ENA were negative, and serum C3 and C4 were normal. Haemoglobin was 14.3 g/dL (143 g/L) with WBC of 8.5 × 109/L, but the platelet count was 12 × 109/L. The peripheral blood smear showed normal red blood cell morphology and no schistocytes.
The patient's thrombocytopaenia prevented a renal biopsy at the time and high-dose intravenous methylprednisolone was started empirically. No other causes of acute renal failure, such as initiation of a new drug, were identified. The patient remained anuric, and a renal angiogram (Figure ) was performed which showed abnormalities of the main, tertiary and quaternary branches with no cortical perfusion. Alteplase was infused for 12 h without any improvement. Thrombophilia testing for factor V Leiden, G20210A prothrombin gene variant and anti-phospholipid antibodies was not performed. He was started on dialysis and remained dialysis dependent. Since starting dialysis, he has not experienced another episode of purpura.
In September 2007, patient presented for a second opinion. His total urinary protein level was 133 mg/day in 182 ml of urine a day. Cryoglobulins were again negative along with a test for cryofibrinogenaemia. Serum immunofixation did reveal a monoclonal IgGκ in the serum with an M-spike of 0.4 g/dL (4 g/L). His serum IgA and IgM were suppressed at 35 mg/dL (normal range, 50–400 mg/dL) [0.35 g/L (normal range, 0.05–0.40 g/dL)] and 48 mg/dL (50–300 mg/dL) [0.48 g/L (0.05–0.30 g/L)], respectively. The serum total IgG was normal at 837 mg/dL (normal range, 600–1500 mg/dL (8.37 g/L (6–15 g/L))]. The kappa free light chain was 33.9 mg/L (normal range, 3.3–19.4 mg/L) and lambda was 42.7 mg/L (5.7–26.3 mg/L) with a ratio of 0.79 (0.26–1.65).
The previous renal biopsy was reviewed and additional staining was performed on paraffin-embedded tissue. In addition to positive staining for fibrinogen by immunofluorescence, the immunoglobulin thrombi were also positive on a phosphotungstic acid-haematoxylin (PTAH) stain. No linear staining of glomerular or tubular basement membranes for a monoclonal immunoglobulin was present. Electron microscopy (EM) revealed the immunoglobulin thrombi to be composed of crystalline structures with an organized substructure showing a periodicity of ∼20 nm. In areas of the immunoglobulin thrombi, the endothelial cells appeared reactive, with enlargement of the cells and loss of fenestrations. Widespread podocyte foot process effacement was present. No finely granular deposits suggestive of monoclonal immunoglobulin deposition disease were identified within basement membranes.
Because the renal biopsy showed co-localized monotypic immunoglobulin and fibrinogen, the patient's serum was evaluated by immunoprecipitation for the presence of fibrinogen and was found to be negative. A bone survey was negative. A repeat bone marrow biopsy and aspirate showed minimal involvement by a kappa light chain-restricted plasma cell proliferative disorder based on flow cytometry, with ∼1% plasma cells in the marrow. Bone marrow cytogenetic studies were normal.


A 63-year-old Caucasian man with a past medical history of hypertension and Graves’ disease was initially admitted to another hospital for a 30-pound weight gain, lower extremity edema and shortness of breath. There, he was treated for congestive heart failure with intravenous furosemide. His creatinine increased from a baseline of 1.1 mg/dL (97.2 μmol/L) to 1.7 mg/dL (150.2 μmol/L). Further workup revealed 7 g/day of proteinuria. The patient was transferred to our hospital for further evaluation and treatment. He was diagnosed with Graves’ disease 2 years prior to admission when he experienced a 50-pound weight loss, weakness and fatigue. He was also noted to have exophthalmose, which was treated with radiation therapy. He has been on varying doses of methimazole for the last 2 years and on a dose of 5 mg daily for the last 8 months. His mother also had Graves’ disease, and his father was diabetic. The patient himself had no history of diabetes, and his glycosylated hemoglobin A1c was 5.9%. He denied any prolonged use of nonsteroidal anti-inflammatory drugs.
Physical examination revealed an obese man with a blood pressure of 170/88 mmHg, a pulse rate of 52 beats/min and regular cardiac rhythm. Pertinent findings on systemic examination were right eye exophthalmose, lower extremity edema and clear lungs. The thyroid gland was not enlarged. No bruit was detected over the thyroid gland.
Laboratory evaluation revealed mildly elevated thyroid stimulating hormone of 5.59 mIU/L (normal, 3.5–5.5 mIU/L), normal free thyroxine (T4) of 1.01 ng/dL (12.99 pmol/L) (normal, 0.80–1.80 ng/dL) and a normal free triiodothyronine (T3) of 264 pg/dL (4.06 pmol/L) (normal, 230–420 pg/dL). Results of additional tests showed a mild normochromic, normocytic anemia; albumin 2.4 g/dL (24 g/L); normal lipid profile (on a statin) and creatinine 1.7 mg/dL (150.2 μmol/L). Urinalysis showed only one red blood cell (RBC)/high power field and no casts. Spot urine protein-to-creatinine ratio was 6.62 g/day. His chest X-ray was normal and echocardiogram showed a left ventricular ejection fraction of 60%. Antinuclear antibodies, cryoglobulin, anti-streptolysin O, anti-glomerular basement membrane, serum complement (C3) level, hepatitis and antineutrophil cytoplasmic autoantibody (ANCA) screen were normal. Spun urine sediment was significant for dysmorphic RBCs, occasional hyaline casts containing RBCs and white blood cells and renal tubular epithelial cells.
A kidney biopsy was performed. Light microscopy revealed 12 glomeruli, none of which were globally or segmentally sclerotic. Glomeruli showed up to mild mesangial proliferation, with occasional foci of increased cells within capillary lumens (). No endocapillary foam cells or podocyte hyperplasia/capping were noted. Some tubules showed focal acute injury but there were only minimal chronic changes in the vasculature and tubulointerstitium. Immunofluorescence microscopy (10 glomeruli present) showed no immunopositivity. Electron microscopy of two glomeruli confirmed the above findings and revealed near total podocyte foot process effacement with associated microvillous transformation (). While occasional small electron-dense deposits were identified in the mesangium, no subepithelial or subendothelial deposits were seen. Endocapillary cellularity was somewhat increased, associated with swollen endothelial cells (pathologist thinks this could be an artifact). A minute focus of podocyte stripping with reparative changes of the basement membrane and a possible adhesion was present. However, no unequivocal changes of segmental sclerosis were seen. The findings were therefore felt to be consistent with MCD.
The patient was started on prednisone (1 mg/kg) but heavy proteinuria persisted (11 g/day) despite being on steroids for 2 weeks. Three weeks after the presentation, the patient underwent near total thyroidectomy and repeat laboratory work 2 weeks later showed a significant reduction in proteinuria (0.44 g/day). His creatinine also improved to 1.0 mg/dL (88.4 μmol/L). Methimazole was stopped. The patient remained on prednisone for 6 months with resolution of edema, nephrotic range proteinuria and atypia of the urine sediment. The clinical course and response to treatment was felt to confirm the diagnosis of MCD.


A 27-year-old woman with end-stage renal disease secondary to focal segmental glomerular sclerosis (FSGS) who had a haemodialysis history of 6.5 months received an ABO compatible and HLA haploidentical graft from her father. Patient’s HLA and MICA typing was performed using DNA. The recipient had no history of sensitization. No sign of anti-HLA or MICA antibodies was seen when tested with Single Antigen Bead technique (One Lambda, Inc. Canoga Park, CA). To avoid FSGS recurrence, the patient underwent three immunoadsorptions in the peri-operative period. Immunosuppressive treatment consisted of mycophenolate mofetil, cyclosporine and methylprednisolone as well as basiliximab on Day 0 and Day 4. Autologous and heterologous IgG and IgM CDC augmented and FC crossmatches performed before transplantation were negative.
The surgery was uneventful but the immediate post-operative course was complicated with slow graft function. The patient did not produce any urine on the day of transplantation. The diethylenetriamine pentaacetic acid scan on the first post-operative day showed good uptake but no excretion. The patient produced ∼150 mL of urine/day. At Day 5, she developed acute abdominal pain. The triplex of renal vessels showed thrombosis of renal vein and the patient underwent emergent graftectomy. Histological examination revealed transmural infiltration of the arteriolar wall by neutrophils and severe intimal arteritis with massive collections of neutrophils into the oedematous intima of small and medium size vessels lifting the endothelium suggestive of severe vascular rejection. Large vessels showed evidence of endarteritis with lymphocytes in the arterial intima in association with focal lymphocytic interstitial infiltrates and focal mild tubulitis. Additional findings were focal cortical haemorrhages, neutrophilic margination in peritubular capillaries and an area of ischaemic necrosis. Although C4d immunohistochemical stain was negative, the histological findings were strongly suggestive for acute antibody-mediated rejection accompanied by cellular rejection.
Retrospectively, a heterologous and autologous IgG and IgM FC crossmatch with Tie-2+ donor cells (XM-One; Absorber AB, Stockholm, Sweden) was performed with the same pre-transplant serum sample used for the decisive crossmatch. The heterologous IgM-Tie-2 crossmatch was positive with 139 channels shift. The IgM-Tie-2 crossmatch remained positive 5 months post-nephrectomy and was positive when serum was tested against a pool of three unrelated donors. The IgG-Tie-2 crossmatch was negative with the same serum and became positive only after nephrectomy. In that case, the patient had developed de novo IgG donor HLA antibodies identified only with solid-phase assays.
For the retrospective Tie-2 crossmatch, Institutional Review Board approval was obtained from Laikon Hospital and informed consent was obtained from recipient and donor prior to bleeding.


A 68-year-old woman presented with 1-week of weakness, dyspnea and several episodes of hemoptysis. Her medical history included hypertension, aortic stenosis [aortic valve area of 1.09 cm, mean gradient 19.74 mmHg on two-dimensional echocardiography (2DE)] and chronic obstructive pulmonary disease related to a 60-year smoking history. One month prior to presentation, she had experienced stiffness in her shoulders and was started on a corticosteroid, sulfasalazine and methotrexate for presumed rheumatoid arthritis. She had no recent history of a gastrointestinal illness.
At presentation, she was normotensive (121/76 mmHg). Her hemoglobin was 13.3 g/dL (133 g/L), platelets 241 × 109/L and serum creatinine 1.7 mg/dL (150 μmol/L). Blood cultures were negative, and chest X-ray showed non-specific bilateral interstitial markings. She was admitted with a presumptive diagnosis of congestive heart failure and pneumonia. Her sulfasalazine and methotrexate were held.
Transthoracic 2DE revealed normal left ventricular function and unchanged aortic stenosis. Her right ventricular systolic pressure was estimated to be 57 mmHg. Urinalysis showed trace protein and moderate blood. Abdominal ultrasound revealed normal-sized kidneys without evidence of obstruction.
By her 12th day of admission, her hemoglobin was 9.9 g/dL (99 g/L), platelets 63 × 109/L, serum creatinine 5.9 mg/dL (523 μmol/L) and blood urea nitrogen 120 mg/dL (43 mmol/L). Her LDH was 442 U/L, haptoglobin 1.1 mg/dL (0.11 g/L) and reticulocyte count 143 × 109/L. An autoimmune workup was positive for anti-nuclear antibody (ANA) in anti-centromere pattern (1:320). Her C4 was normal at 0.18 g/L, and C3 was mildly decreased at 0.87 g/L. Antineutrophil cytoplasmic antibodies, rheumatoid factor and antiextractable nuclear antigen antibodies were negative. Red blood cell fragmentation was noted on her blood film, prompting a renal biopsy that was consistent with a TMA (). She was transferred to a tertiary care hospital for PLEX.
Her ADAMTS-13 activity (drawn prior to the first cycle of PLEX) was estimated by qualitative collagen binding assay and was normal []. She was started on an angiotensin receptor blocker that was eventually changed to an angiotensin-converting enzyme-inhibitor following discontinuation of PLEX. She required ongoing hemodialysis and platelet transfusions. Bone marrow biopsy was normal. She received nine daily 1–1.5 plasma volume exchanges with cryosupernatant plasma, without a response in platelet count [platelets were 49 × 109/L and hemoglobin 8.4 g/dL (84 g/L) on Day 9]. PLEX was discontinued due to lack of response.
A thoracic computed tomography scan demonstrated a 4.4 cm by 3.1 cm mediastinal mass which was not seen on chest X-ray as well as enlarged mediastinal lymph nodes (largest 1.5 cm) and pleural effusions (). A biopsy was not pursued because of her deteriorating status. She died on her 31st day of admission following sudden onset of confusion and hepatitis.
Autopsy findings included an acute organized lung injury, extensive steatohepatitis and renal cortical infarctions. A high-grade malignancy was found in her mediastinum involving multiple lymph nodes. Tumor cells showed marked variability in size and shape, with nuclei having a characteristic ‘salt and pepper’ pattern by hematoxylin and eosin staining (). Immunostaining on the largest node was positive for CD56, synaptophysin, chromogranin (), low-molecular weight cytokeratin and pan-keratin but was negative for TTF-1, S100 and CD45. Transmission electron microscopy revealed intracytoplasmic membrane-bound neuroendocrine granules within tumor cells (). Overall, these findings were consistent with neuroendocrine carcinoma and did not support a diagnosis of melanoma, lymphoma or bronchogenic carcinoma. No definitive primary lesion was identified.
A post-mortem quantitative enzyme immunoassay for ADAMTS-13 activity using frozen serum demonstrated actually revealed mild deficiency prior to PLEX at 0.45 U/mL [].


A 75-year-old woman was referred to our Emergency Department in a lethargic state, with acute onset of lightheadedness and diaphoresis. Serum glucose level was 30 mg/dL. The patient was given an intravenous bolus of 35% glucose solution and then continuous infusion of 10% dextrose. The patient reported similar but less severe episodes for the last 6 months that gradually increased in frequency.
Her past medical history was significant for heart failure, atrial fibrillation, hypothyroidism and osteoporosis and her medications included amiodarone, acenocoumarol, nitroglycerin, furosemide, spironolactone, levothyroxine and calcium carbonate. She had previously undergone cholocystectomy and total abdominal hysterectomy.
Our clinical examination was unremarkable. Her abdomen was soft and nontender. In deep palpation a fullness of the left upper quadrant of the abdomen was appreciated, but no definite masses were palpated.
To confirm the diagnosis of endogenous hyperinsulinemia from insulinoma, the patient underwent a supervised overnight fast during which she developed symptomatic hypoglycemia with serum glucose of 50 mg/dL. Insulin was 26 µIU/mL and C-peptide was 5.7 ng/mL. The contrast abdominal CT scan revealed a large heterogeneously enhancing lobulated mass located in the body and tail of the pancreas, with central necrosis and coarse calcifications. Similar large enhancing masses were also present at the left renal hilum and the left retrocrural space (). Multiple hypervascular metastases were also present in the liver. A preliminary diagnosis of malignant insulinoma was established (, ).
Intraoperatively, a bulky tumor in the body and tail of the pancreas was identified that was firmly adherent to the omentum and the transverse colon. A second multilobular mass was firmly adherent to the left kidney and adrenal gland causing pressure signs and hydronephrosis. Metastatic lesions were identified at the left paraaortic area and the liver.
The patient underwent distal pancreatectomy, splenectomy, left nephrectomy and adrenalectomy and resection of the paraaortic masses, whereas the four hepatic lesions were treated with radiofrequency ablation.
Pathological exam revealed a 17 × 15 × 7-cm mass identified as a pancreatic insulinoma with malignant potential. Immunohistochemical staining revealed positivity for insulin, expression of CEA from tumor cells and 10 mitoses per 10 high-power fields. Vascular invasion, invasion of perinephric fat tissue and tumor necrosis were present. There was also invasion of the omentum and of the six lymph nodes in the spleen area (, , , ).
During the first postoperative week, the patient was put on continuous intravenous infusion of 10% dextrose and subcutaneous administration of octreotide with serum glucose maintained above 65 mg/dL. The following week the patient remained euglycemic, with serum glucose levels ranging between 73-135 mg/dL, without glucose or octreotide administration and exited the hospital on the 12th postoperative day. At her routine follow-up visit 3 months postoperatively, she reported mild hypoglycemic symptoms and was put on diazoxide. The patient remains asymptomatic and disease-free after five years of follow-up.


A 40-year-old man disclosed a 6-months history of aggravated lumbago and pain that radiated to the left buttock and the leg. The patient also had complaint of numbness and tingling sensations below the knee. However, there was no history of trauma or constitutional symptoms. On examination, he showed paravertebral tenderness in the lower lumbar spine with lumbar motion limitation secondary to pain. A neurologic examination was remarkable for a grade 3/5 dorsiflexion weakness in his left ankle. His extensor hallucis longus showed a grade 4/5 dorsiflexion weakness. Otherwise, motor examinations of the remaining muscles were within normal levels.
He had sensory abnormalities on the L4 dermatome area of the left leg. The straight leg raising test on the left was positive at an angle of 45 degrees (45°). There were no bladder or bowel disturbances. The VAS score of lumbago was 4 (pain was scored on a VAS from 0=no pain to 10=strongest pain imaginable) and that of radiating pain was 8. Lumbar radiography showed a minimal degenerative change. An MRI scan revealed a disc extrusion at L3/4 and a large spherical lesion behind the L4 vertebral body. A mass lesion revealed a low signal intensity on T1-weighted image and high signal intensity on T2-weighted images, which were located in the left ventromedial aspect of the extradural space at the L4 body level, compressing the thecal sac and left L4 nerve root dorsally (). There was a central disc bulging with a ligamentum flavum thickening at the L4/5 intervertebral disc levels, while a narrowing was detected at the left L4/5 intervertebral foramen. Based on further enhanced imaging studies, the cystic mass was well enhanced and seemed to be connected like a stalk between the L3/4 intervertebral disc spaces.
The EMG(Electromyography)/NCV(Nerve conduction velocity) was consistent with left L4 radiculopathy. This patient unsuccessfully underwent a conservative treatment with rest, NSAIDs (Non-Steroridal Anti-Inflammatory Drugs) and an epidural steroid injection at a local clinic. Owing to worsening of sensory and motor abnormalities in the lower extremities, surgery was indicated. A left partial laminectomy was performed at L4 (due to the location of a mass lesion behind the L4 body). A darkish red cyst was seen underneath the left L4 nerve root, compressing the thecal sac and displacing the left L4 nerve root dorsally. A meticulous dissection was necessary for the severe adhesions between the cystic mass and nerve root as well as dura mater (). Grossly, the cystic mass was round and 1.2×1.1 cm in size. Serous hemorrhagic fluid was aspirated with a 22-gauge syringe and sent for both pathologic study and culture (). After removal of the cyst, the channel-like soft tissues adjoining the intervetebral disc were identified and cauterized. Then, disectomy was performed at L3/L4. Histologically, the cyst walls were constituted with dense fibrous connective tissues without cell linings or disc materials. () Cultures of the cystic hemorrhagic fluid were negative. The patient's radicular pain resolved promptly after surgery and only slight numbness overlying his left anterior thigh was reported during the follow-up observation period of two (2) years.


A 47-year-old woman with a known medulloblastoma (diagnosed 2 years previously) went to see her oncologist for a scheduled check-up. Her existing medications included temsirolimus for her tumor; she was also receiving treatment with the anticonvulsant valproate because she had experienced a number of seizures over the past year. At her check-up, she reported that she had not been feeling well for the previous few days with symptoms including drowsiness, lethargy and headaches.
A clinical assessment revealed a fever (38.5°C) but otherwise no other apparent issues; she had no signs of edema, her jugular venous pressure was normal and her heart and lungs were normal during auscultation (Table ). Her blood analysis reported that her serum [Na+] was low at 123 mmol/L with a correspondingly low serum osmolality of 253 mOsm/kg, low creatinine (44.2 µmol/L [0.5 mg/dL]), low blood urea nitrogen (BUN; 3.9 mmol/L [11 mg/dL]) and low uric acid (125 µmol/L [2.1 mg/dL]; Table ). Correspondingly, her urinary osmolality was high at 599 mOsm/kg and urinary [Na+] was high at 99 mmol/L.
Her physician determined that her hyponatremia was most likely being caused by SIADH. To normalize her serum [Na+], she was admitted to the ward and fluid restriction (1.2 L/day) was initiated. The following day, the patient experienced ongoing motor convulsions, which were believed to be due to a focal status epilepticus so had to be transferred to the intensive care unit (ICU). After she arrived at the ICU, it was discovered that her serum [Na+] had not increased as expected but had in fact dropped further to 116 mmol/L (Figure )—this drop was therefore very likely to be the reason for her clinical deterioration.
Given the severity of her symptoms, treatment with hypertonic (3% NaCl) saline was commenced immediately. Within <24 h, sodium levels rose to 123 mmol/L. Hence, treatment with hypertonic saline was stopped and replaced with the oral vasopressin V2 receptor antagonist tolvaptan 15 mg/day (Figure ). This resulted in a further increase in serum [Na+] with the patient exhibiting a rapid and marked clinical improvement, which allowed her to be discharged from the ICU 1 day later. Further work-up of the patient's initial feverish presentation revealed a pneumonia, which was treated successfully with antibiotics. It subsequently was suspected that the patient's SIADH had, in fact, been caused by the underlying pneumonia rather than her medulloblastoma as was initially assumed. Hence, tolvaptan administration was discontinued 5 days later when the patient's serum [Na+] had normalized at 137 mmol/L. The patient was discharged from hospital by Day 13 and her serum [Na+] has remained normal since the resolution of the pneumonia, without the need for further tolvaptan administration.


A 47-year-old man was transferred from a secondary hospital to a university hospital following suspicious magnetic resonance imaging (MRI) findings, which suggested a recurrence of his known anaplastic oligoastrocytoma and intracerebral bleeding (Figure ). The tumor (classified as WHO grade III) had been resected 3 years previously but the patient had subsequently developed a subdural hygroma. Following several unsuccessful attempts to surgically resolve the hygroma, he had received a subdural-peritoneal shunt, which had proved successful. The patient was also coinfected with HIV and chronic hepatitis C, and had a history of alcohol abuse. He was receiving chronic treatment with antiretrovirals, carbamazepine and neuroleptics.
Following admission, the patient's clinical picture deteriorated over the course of a few days, and a steady increase in intracranial pressure mandated surgical intervention. Eight days after surgery, the patient lost consciousness; he was diagnosed with acute hyponatremia with his serum [Na+] having dropped to 116 mmol/L from a reading of 134 mmol/L just 32 h previously. The patient was therefore rushed to the ICU where hypertonic saline was administered, which led to an improvement in his clinical state.
Unfortunately, his serum [Na+] rose from 116 to 129 mmol/L within 16 h, which is considered overcorrection. Subsequently, collected urinary specimens revealed an extremely high urinary [Na+] of 222 mmol/L. This high urinary sodium output was found to have mirrored the high sodium intake caused by the administration of hypertonic saline. Several subsequent attempts to withdraw the hypertonic saline resulted in dramatic drops in serum [Na+] (e.g. falls from 133 to 119 mmol/L were observed in 24 h) thereby necessitating its continuation.
Based on the assumption that SIADH was the most likely cause of the hyponatremia, tolvaptan was initiated at a dose of 15 mg/day on Day 5 after prior discontinuation of his saline infusion (Figure ). This resulted in an increase in serum [Na+] from 120 to 130 mmol/L in 24 h and the patient reported feeling well. He was subsequently transferred from the ICU to the neurosurgery ward 1 day later and was kept on tolvaptan without adverse effects. The patient was discharged from the hospital 8 days later. A recent attempt to withdraw the drug resulted in an aggravation of the hyponatremia; therefore, the patient is currently receiving chronic therapy with tolvaptan.


An 81-year-old Caucasian woman was brought in to the emergency department of the University Hospital in Florence suffering from mental confusion. Her past medical history showed that she had hypertension, peripheral atheromatosis, and had experienced a previous transitory ischemic attack. Over the last year, she complained of an inability to perform normal cognitive functions and had experienced frequent falls. Her existing medications included ramipril 2.5 mg/day, lansoprazole 30 mg/day and acetylsalicylic acid 100 mg/day.
The patient's blood pressure was 170/100 mmHg and heart rate 70 b.p.m.; routine laboratory testing revealed that her serum [Na+] was only 120 mmol/L (Table ). At this point, her son recalled that the patient's serum [Na+] had been frequently documented below the normal range over the last year.
No further diagnostic tests were performed at this stage and the patient was administered intravenous isotonic saline in the emergency department in order to correct her low serum [Na+]. Unfortunately, there was no change in serum [Na+] and the patient's condition showed no improvement.
The patient was subsequently admitted to the internal medicine unit where she was given a comprehensive diagnostic work-up (Table ). The patient was shown to be clinically euvolemic. A cranial computed tomography (CT) scan showed no signs of intracranial bleeding or subcortical ischemic encephalopathy, but a chest X-ray revealed that she had pneumonia (Figure ). Consequently, the patient was diagnosed with hyponatremia secondary to SIADH caused by underlying pulmonary disease.
The patient was treated with hypertonic saline (3% NaCl); her existing lansoprazole was stopped following a negative gastroduodenoscopy and acetylsalicylic acid replaced by ticlopidine 250 mg/day. For her pneumonia, she was prescribed antibiotics (levofloxacin 500 mg/day orally and ceftriaxone 2 g/day intramuscularly).
Following 24 h, the patient's serum [Na+] rose to 127 mmol/L, at which point her infusion was stopped. Fluid restriction was then considered. However, calculations based on the patient's ratio of electrolytes in the urine and serum (according to the formula: urinary [Na+] + urinary [K+]/serum [Na+]) [] gave a result >1.0, which implied that the free water clearance of the patient was nil. Thus, fluid restriction was unlikely to improve serum [Na+] in this patient; therefore, therapy with tolvaptan 15 mg/day was started. This raised her serum [Na+] to 132 mmol/L after 24 h and marked clinical improvement was observed on the second day, when her serum [Na+] was 138 mmol/L. The patient was eventually discharged after 6 days on tolvaptan.
At a follow-up assessment 1 week after discharge, the patient's sodium levels remained within the normal range, her clinical condition was good and a further chest X-ray showed no evident radiological signs of pneumonia. Tolvaptan treatment was therefore stopped at a serum [Na+] of 141 mmol/L. Serum [Na+] remained within the normal range at follow-up.


A 74-year-old Caucasian man presented with a cough and hemoptysis, with which he had been suffering for the last 3 months. Although he had previously been prescribed antibiotics, they had proved ineffective. He was a long-term heavy smoker (smoking 40 cigarettes per day over the last 40 years); although his medical history included surgery for an inguinal hernia in 1987 and a diagnosis of benign prostatic hyperplasia in 2009, he was not receiving any chronic medications. The patient also complained of a slightly elevated temperature and asthenia. For this reason, his physician sent him to the emergency department of the University Hospital in Florence from which he was referred to the pneumology unit.
At the time of admission, the patient's laboratory findings showed a normal serum [Na+] of 141 mmol/L (Table ). A few days following admission, the patient started complaining of chest pain for which he was prescribed an opiate (oxycodone 5 mg o.d.) together with paracetamol 325 mg t.i.d.; at this stage, he was also receiving methylprednisolone 16 mg o.d., lansoprazole 30 mg o.d. and tranexamic acid 500 mg b.i.d. for his hemoptysis.
Over the following 15 days, the patient experienced a progressive reduction in serum [Na+] down to 123 mmol/L. His plasma osmolality was low (267 mOsm/kg), urinary osmolality was 646 mOsm/kg and urinary [Na+] 130 mmol/L; other measurements such as uric acid and potassium concentration were in the normal range (Table ). The patient was apparently asymptomatic, he was clinically euvolemic and his profile fitted that of a person with hyponatremia secondary to SIADH (Table )—the most common cause of euvolemic hyponatremia [].
A CT scan revealed a large mediastinal mass, which turned out to be small-cell lung carcinoma (SCLC) (Figure A). Fluid restriction was initiated in an effort to resolve the hyponatremia; this resulted in an initial increase in serum [Na+], however, the concentration remained below the normal range of 135 mmol/L after 15 days. Because the patient required chemotherapy with etoposide and carboplatin—drugs that may also cause SIADH—it was important to fully resolve the patient's hyponatremia before chemotherapy could be initiated. Fluid restriction was therefore discontinued and the oral vasopressin antagonist tolvaptan 15 mg/day initiated, thus making this the first person to be treated with tolvaptan in Italy.
Within 24 h, the patient's serum [Na+] had normalized allowing the prompt initiation of chemotherapy. However, over the next month the patient's serum [Na+] continued to steadily increase to 147 mmol/L at which point tolvaptan therapy was stopped (the only case in our clinic where overcorrection with tolvaptan has been observed, so far). Sodium concentrations then promptly returned to normal concentrations (Figure ).
After 3 months of chemotherapy, a CT scan showed a large reduction in a tumor mass (Figure B) and the patient's serum [Na+] remained stable. The patient was subsequently regularly monitored; serum [Na+] remained within the normal range and the patient reported a rather good quality of life at follow-up. Unfortunately, as expected, disease progression occurred after 8 months of clinical remission and the patient passed away ∼1 year after the initial diagnosis.


A 51-year-old man previously in good health except for hyperlipidemia was found unconscious in his bathroom. After awakening, he complained of a severe headache. A CT scan of the head showed a subarachnoid hemorrhage (SAH) with blood in the cisterns bilaterally. On transfer to a university hospital, he was awake and oriented with no focal neurological deficits but was noted to be drowsy and lethargic with intermittent nausea and vomiting. A physical exam was unremarkable except for a blood pressure of 149/76 mmHg, and the patient was felt to be clinically euvolemic. Admission laboratory values were all within normal limits, including electrolytes with a serum [Na+] of 139 mmol/L.
The patient was admitted to the neurosurgical ICU, where his blood pressure was controlled with labetalol and hydralazine drips. A cerebral angiogram revealed an anterior communicating artery aneurysm, which was successfully occluded by insertion of a coil by interventional neuroradiology. He was started on nimodipine for vasospasm prophylaxis and diphenylhydantoin for seizure prophylaxis. An external ventricular drain was placed to control intracranial pressure. Triple-H therapy (i.e. the induction of hypertension, hypervolemia and hemodilution to decrease the risk of vasospasm []) was begun for the SAH, including volume expansion via intravenous fluid administration with isotonic (0.9%) saline at rates varying between 125 and 175 mL/h. Total fluid intake ranged between 5 and 7 L/24 h over the first week of hospitalization.
The patient stabilized neurologically; but by Day 4, his serum [Na+] was noted to be intermittently low and the patient was started on NaCl tablets 8 g daily in divided doses (Figure ). Despite this therapy, sodium levels continued to fall to the 125–127 mmol/L range and the patient became confused and lethargic. The oral NaCl was supplemented with an intravenous infusion of hypertonic (3%) NaCl, initially at 50 mL/h then increasing to 70 mL/h. By Day 8, the endocrinology service was consulted because of persistent hyponatremia and worsening neurological status despite aggressive NaCl administration, which by that time totalled as high as 62 g/day.
On evaluation by the endocrinology department, the patient was clinically euvolemic. Serum [Na+] was in the range of 125–126 mmol/L with a plasma osmolality of 266 mOsm/kg and urine osmolalities ranging from 283 to 369 mOsm/kg. Urine [Na+] was noted to be 83 mmol/L with urine [K+] = 8.5 mmol/L prior to the start of oral NaCl tablets, and increased to 162 mmol/L with urine [K+] = 12.1 mmol/L following oral NaCl therapy. BUN was 2.1 mmol/L (6 mg/dL) and creatinine 53 µmol/L (0.6 mg/dL), with normal glucose levels. Thyroid function was normal: free T4 was 12.1 pmol/l (0.94 ng/dL) (normal range 0.58–1.64) and thyroid-stimulating hormone was 2.96 µIU/mL (normal range 0.35–5.5). A random measurement of cortisol levels showed an elevation at 792 nmol/L (28.7 µg/dL). Serum uric acid was low at 155 µmol/L (2.6 mg/dL) (normal range 208–387). Analysis of the intakes and outputs showed that the patient had been in a positive fluid balance each day over the first week of hospitalization.
Based on the patient's physical exam, laboratory values and clinical course, he was assessed to have euvolemic hyponatremia that was unresponsive to NaCl administration, which met the criteria for a diagnosis of SIADH (Table ). Because the neurosurgeons would not consider instituting fluid restriction due to the risk of vasospasm from the SAH [], therapy with tolvaptan was recommended at a starting dose of 15 mg/day. Although fluid restriction was relatively contraindicated in this case, it likely would not have been effective even if employed in view of the high urine to plasma electrolyte ratio that ranged from 0.73 to 1.39 (Table ). After the first 15 mg dose, the patient developed a negative fluid balance of −2.5 L and his serum [Na+] increased from 126 to 132 mmol/L. Despite recommendations that the 3% NaCl infusion be stopped once an increase in serum [Na+] of 5 mmol/L had occurred, the 3% NaCl infusion was continued. After the second 15 mg tolvaptan dose, the patient developed a negative fluid balance of −4.2 L and his serum [Na+] increased further to a maximum of 144 mmol/L. The 3% NaCl was subsequently discontinued and serum [Na+] stabilized between 132 and 135 mmol/L. After 5 days, the tolvaptan dose was increased to 30 mg/day with normalization of serum [Na+] to 138–140 mmol/L; the patient was discharged on this dose on Day 16. His serum [Na+] remained normal at subsequent outpatient follow-up, and tolvaptan was discontinued 4 weeks after discharge without recurrence of the hyponatremia.