[Cryopyrin-associated periodic fever syndrome (CAPS) presenting as early-onset dementia, lacking typical recurrent fever or skin rash: a case report].

A 54-year-old man with a university degree was admitted to our hospital because of a two-year history of progressive dementia. He had familial sensorineural hearing loss and had been treated for epilepsy since his 30s. On admission, he showed severe dementia and parkinsonism without fever or skin rash. Systemic inflammation was evident, and the CSF cell count and IL-6 level were elevated to 53/µl and 307 |pg/ml, respectively. Brain MRI demonstrated diffuse brain atrophy. More detailed anamnesis revealed a history of rheumatoid arthritis in childhood and aseptic meningitis in his 20s. Genetic examination for autoinflammatory diseases demonstrated compound heterozygotic mutations in the NLRP3 gene, causing cryopyrin-associated periodic fever syndrome (CAPS). This case was atypical CAPS presenting as early-onset progressive dementia, without recurrent fever or urticaria-like eruption which are usually seen in this disease.

[Juvenile-onset anti-nuclear matrix protein 2 (NXP-2) antibody-positive dermatomyositis with joint contractures before manifestation of myositis: a case report].

A 23-year-old man was admitted to our hospital with a one-year history of muscle weakness and atrophy. He had noticed contractures of the fingers of both hands from the age of 18. Examination revealed a skin rash including heliotrope rash and Gottron's sign, joint contractures in the extremities, dysphagia, extensive muscle weakness and marked muscle atrophy. The serum creatine kinase level was 272 |IU/l and muscle biopsy showed typical perifascicular atrophy but little lymphocyte invasion. There was no interstitial pneumonia or malignancy, but muscle tendons showed elevated CT values suggesting calcification or fibrosis. Anti-nuclear matrix protein 2 (NXP-2) antibody-positive dermatomyositis was diagnosed on the basis of the serum antibody level. Methylprednisolone pulse therapy ameliorated the skin rash and bulbar palsy, but muscle weakness, atrophy and joint contractures were resistant to the treatment. There have been no previous reports of young adults with anti-NXP-2 antibody-positive dermatomyositis in whom joint contracture became evident as early as 4 years beforehand, which is a important feature for differential diagnosis of dermatomyositis.

Progressive conus medullaris lesions are suggestive of intravascular large B-cell lymphoma.

BACKGROUND AND PURPOSE: Spinal cord lesions are observed in 40% of all central nervous system lesions in intravascular large B-cell lymphoma (IVLBCL). However, because IVLBCL is a very rare disease, its clinical features are not well defined, which may delay appropriate diagnosis and treatment, whilst the acute to subacute course of brain lesions in patients with IVLBCL is well established. Therefore, this study aimed to clarify the clinical features of spinal cord lesions in patients with IVLBCL. METHODS: The medical records of patients with IVLBCL admitted to our hospital between 2010 and 2020 were searched. The inclusion criteria were preceding neurological symptoms without non-neurological symptoms and pathologically confirmed IVLBCL in various organs. Clinical features of spinal cord involvement in patients with IVLBCL were assessed and distinguished from those of brain involvement. RESULTS: Sixteen consecutive patients with IVLBCL were divided into two groups: six patients with spinal involvement (spinal cord type) and 10 patients with brain involvement (brain type). In the spinal cord type, four patients had chronic progression and two had subacute progression. Acute progression (0% vs. 80.0%) and sudden onset (0% vs. 50.0%) occurred significantly less frequently in the spinal cord than in the brain. All spinal cord lesions involved the conus medullaris. CONCLUSIONS: Spinal cord involvement in IVLBCL has a predominantly chronic progressive course that is exclusive to brain involvement. Conus medullaris lesions are suggestive of IVLBCL and are useful for early and accurate diagnosis and treatment.

[A case of intravascular large B-cell lymphoma manifested as lacunar infarction].

A 79-year-old man was admitted to our hospital because of sudden onset of left ataxic hemiparesis. Brain MRI diffusion weighted images showed typical lacunar infarction on the right internal capsule. He had no risk factors of cerebrovascular disorder such as hypertension, diabetes mellitus, hyperlipidemia and arrhythmia. On admission, he had a slight fever and his laboratory data showed anemia, thrombocytopenia and elevation of CRP and LDH. Intravascular large B-cell lymphoma (IVLBCL) was suspected because the serum level of soluble IL-2 receptor was also elevated. Pathological diagnosis of IVLBCL was underwent by the skin biopsy from his senile hemangiomas. Although IVLBCL was known to demonstrate various CNS lesions, it is extremely rare to be manifested as a single lacunar infarction, and this case must be important for the differential diagnosis.

[A case of neuromyelitis optica associated with pulmonary Mycobacterium avium complex disease].

A 62-year-old woman suffering from pulmonary Mycobacterium avium complex (MAC) disease was admitted to our hospital with fever, visual impairment, and lower limb weakness. MRI detected lesions in the optic chiasm and spinal cord extending the length of 6 vertebrae. The anti-aquaporin 4 (AQP4) antibody titer determined by ELISA was elevated to 8.3 IU/l. On the basis of these findings, the patient was diagnosed as having neuromyelitis optica (NMO), when chest CT also demonstrated exacerbation of pulmonary lesions. Methylprednisolone pulse therapy and double-filtered plasma exchange ameliorated the symptoms, and the EDSS score improved from 8.5 to 6.5. Six months later, visual impairment recurred, although ELISA showed that the anti-AQP4 antibody titer had become undetectable. Also, the CSF interleukin-6 (IL-6) level was elevated to 34.8 pg/ml. There have been few reports of NMO associated with pulmonary MAC disease. An increase of IL-6 is considered to exacerbate the clinical picture of NMO, whereas it may suppress progression of the pulmonary MAC disease. Exacerbation of the pulmonary MAC disease and the following internal counteraction with IL-6 may have resulted in a NMO relapse. The present patient was therefore administered eculizumab but not satralizumab, a humanized anti-IL-6 receptor antibody, for prevention of NMO recurrence.

[Selenoprotein-related myopathy in a patient with old-age-onset type 2 respiratory failure: a case report].

A 71-year-old woman was admitted to our hospital with type2 respiratory failure. Her daily life activities had been normal, although she had noticed mild truncal weakness in her sixties. Her parents were consanguineous, and her sister had suffered similar symptoms. Although Pompe disease was suspected on the basis of the clinical course and CT findings of selective muscular atrophy in the paraspinal, thigh flexor and sartorius muscle, acid alpha-glucosidase activity was normal. The serum creatine kinase level was not elevated, and muscle biopsy showed no specific change. Genetic analysis revealed a novel homozygous variant c.227T>C (p.Phe76Ser) in the SELENON gene, and she was suspected to have selenoprotein-related myopathy, which is reported to develop in childhood. Selenoprotein-related myopathy should be considered as a differential diagnosis in aged patients presenting with respiratory failure of unknown origin.

[Paraneoplastic anti-gamma aminobutyric acid (GABA)B receptor antibody limbic encephalitis associated with small cell lung cancer presenting as new-onset status epilepticus: a case report].

An 84-year-old man was admitted to our hospital with new-onset refractory status epilepticus of unclear etiology. On the third day, diffusion-weighted brain MRI demonstrated lesions in the right medial temporal and parietal lobes. As a CSF sample showed pleocytosis, paraneoplastic limbic encephalitis (PLE) associated with small cell lung cancer (SCLC) was suspected. The patient was also positive for anti-gamma aminobutyric acid (GABA)B receptor antibody in the CSF, which has recently been reported in elderly patients with SCLC-related PLE. Methylprednisolone pulse therapy ameliorated the symptoms. It is noteworthy that immune therapy often improves the symptoms of PLE with anti-GABAB receptor antibody, even though radical therapy for the lung cancer may be difficult.

[A case of thyrotoxic myopathy with generalized body muscular atrophy including the tongue muscle, lacking physical manifestations of Basedow disease].

We report a 74-year-old man with a 2-year history of proximal limb pain, body weight loss of 15 kg, and muscle weakness. Muscle atrophy was evident in the limbs and trunk, as well as the tongue. He was admitted to our hospital with suspected amyotrophic lateral sclerosis (ALS). Although he had no physical manifestations of Basedow disease such as palpitations, hyperhidrosis, hand tremor, exophthalmos, and an enlarged thyroid, he was diagnosed as having thyrotoxic myopathy as laboratory examinations indicated hyperthyroidism and positivity for TSH receptor antibody. The serum level of soluble IL-2 receptor was also elevated. Despite the severe muscle atrophy, the serum CK level was normal. A biopsy from the left quadriceps muscle revealed Type 1 fibers atrophy. Administration of anti-thyroid drugs normalized his thyroid function and the level of soluble IL-2 receptor, leading to improvement of the generalized muscle atrophy.

[A case of meningeal melanomatosis diagnosed by immunostaining of cerebrospinal fluid].

A 49-year-old woman was admitted to our hospital with suspected hypertensive encephalopathy. On the basis of MRI showing leptomeningeal enhancement and Class V cytology of the CSF, she was diagnosed as having leptomeningeal carcinomatosis. Although no primary site was detected, a few melanin granules were observed at the third CSF examination. The atypical cells in the CSF demonstrated immunoreactivity for HMB-45 and S-100, which are specific markers of malignant melanoma. There have been few reports of meningeal melanomatosis in Japan. This case illustrates that immunostaining is diagnostically useful in patients with leptomeningeal carcinomatosis from neoplasms with unknown primary sites.

[A case of anti-titin antibody positive nivolumab-related necrotizing myopathy with myasthenia gravis].

A 53-year-old man suffering from squamous cell lung cancer presented with bilateral ptosis and bulbar palsy a month after initial treatment with the immune checkpoint inhibitor nivolumab. The symptoms showed worsening from midday, suggesting myasthenia gravis (MG), although anti-AChR antibody was negative. Although no muscle weakness was detected, the CK level was elevated to 5,255 IU/l, and MRI of the thigh revealed inflammation of the bilateral rectus femoris muscle. A muscle biopsy showed signs of necrotizing myopathy with expression of sarcolemmal HLA class I and accumulation of macrophages, CD4, CD8, and CD20-positive lymphocytes. Positivity for anti-titin antibody, one of the anti-striated muscle antibodies, was evident. The patient was diagnosed as having nivolumab-related necrotizing myopathy with myasthenia gravis, an immune-related adverse event (irAE). Treatment with prednisolone rapidly ameliorated the symptoms, and the serum CK level normalized. There have been several reports of nivolumab-related myositis with MG. On the basis of the muscle pathology and antibody data, we were able to clarify that necrotizing myopathy was related to the pathogenesis of this case.

[A case of chordoma presenting as recurrent bacterial meningitis with cerebrospinal fluid leakage].

A 52-year-old man was admitted to our hospital because of two episodes of bacterial meningitis within a 6-month period. CSF examination showed neutrophilic pleocytosis with marked elevation of protein and hypoglycorrhachia, but the inflammatory reaction was mild and blood and CSF cultures were negative. At the time of the second admission, intermittent watery nasal discharge caused by CSF rhinorrhea was evident. CT and MR imaging revealed a tiny clival bone defect, and transnasal endoscopic repair was performed successfully. The pathological diagnosis was chordoma based on immunohistochemical staining for brachyury. Although chordoma presenting as recurrent bacterial meningitis occurs extremely rare, asking patients detailed questions about the CSF rhinorrhea must be essential for disclosing unclear infection sources.

[A case of multiple cerebral hemorrhage caused by sudden increase of eosinophil in a patient with eosinophilic granulomatosis with polyangiitis].

A 42-year-old woman with bronchial asthma was admitted to our hospital due to sensory dominant mononeuritis multiplex lasting for more than 6 months. At that time, her eosinophil count was 761/µl and her sural nerve biopsy showed no findings suggestive of vasculitis. Four months later, she experienced sudden convulsions and right hemiparesis due to left lobular parietal subcortical hemorrhage, when her eosinophil count was elevated to 3,257/µl. Numerous microbleeds and small infarctions were also detected in the intracerebral areas of different regions with MRI. Eosinophilic granulomatosis with polyangiitis (EGPA) is a systemic necrotizing vasculitis of the small vessels, commonly affecting the peripheral nerves. Subarachnoid hemorrhage in patients with EGPA is extremely rare. Steep elevation of the eosinophil count may release certain cytokines, causing cerebral hemorrhage.

[A case of Behçet disease developing recurrent ischemic stroke with fever and scrotal ulcers].

A 30-year-old man, who was diagnosed with Behçet disease at 10 years of age, was hospitalized because of transient right hemiparesis after presenting with high fever and scrotal ulcers. Brain MRI revealed ischemic lesions in the area supplied by the anterior cerebral arteries. Analysis of cerebrospinal fluid (CSF) showed pleocytosis and a high interleukin-6 (IL-6) concentration (668 pg/ml). The patient was diagnosed with acute ischemic stroke associated with exacerbation of Behçet disease. After initiation of corticosteroid therapy, his clinical symptoms improved, and the CSF IL-6 concentration decreased. One year later, the patient developed high fever and scrotal ulcers after the onset of transient left upper limb plegia. Brain MRI showed an acute ischemic lesion in the right putamen, and CSF analysis showed an elevated IL-6 concentration (287 pg/ml). Brain CT angiography revealed stenosis of the left anterior cerebral artery and occlusion of the right anterior cerebral artery, which had been well visualized one year previously. Involvement of the intracranial cerebral arteries in Behçet disease is extremely rare. To the best of our knowledge, this is the first case report of a patient with recurrent symptomatic ischemic stroke associated with high fever and scrotal ulcers, which suggests exacerbation of Behçet disease.

New treatment strategy for cupulolithiasis associated with benign paroxysmal positional vertigo of the lateral canal: the head-tilt hopping exercise.

This study was performed to determine whether a novel treatment was effective against cupulolithiasis associated with benign paroxysmal positional vertigo (BPPV) of the lateral semicircular canal, which is characterized by apogeotropic direction-changing nystagmus. We herein describe our head-tilt hopping (HtH) exercise, which is designed to release otoconial debris strongly adhered to the cupula. The subjects were trained to hop while tilting their heads laterally. They completed 3 to 5 exercise sessions per day over a 4-week period. Each session ended with a 20-hop trial. The HtH exercises were performed by 27 patients with intractable lateral canal BPPV who exhibited positional vertigo and persistent nystagmus beating toward the uppermost ear for more than 4 weeks, despite performing therapeutic head shaking in the horizontal plane maneuver. All the patients were subjected to the supine roll test before and immediately after the first trial as well as after 1 and 4 weeks of the program to evaluate the effect of the treatment on their apogeotropic nystagmus. Nystagmus of 9 (33.3 %) patients disappeared immediately after the first training session. After 1 and 4 weeks of the training, the number of patients that had experienced either of these improvements had increased to 15 (55.6 %) and 19 (70.4 %) subjects, respectively. These results suggest that HtH exercises aimed at releasing otoconial debris from the cupula are feasible as a new therapy for cupulolithiasis associated with intractable lateral canal BPPV. However, further studies for comparison with control are required to confirm these preliminary results.

[Neurolymphomatosis presenting as bilateral tongue atrophy: a case report].

A 62-year-old woman had progressive dysarthria for 2 months and was suspected of having amyotrophic lateral sclerosis because of the presentation of bilateral tongue atrophy and fasciculation. Brain magnetic resonance imaging (MRI) showed enlargement of the left hypoglossal nerve, and whole-body gallium scintigraphy showed abnormal uptake in the left pelvic cavity and left thigh. On the basis of the findings of biopsy of the mass lesion in the left thigh, she was diagnosed with diffuse large B-cell lymphoma. After chemotherapy for diffuse large B-cell lymphoma, the tongue atrophy improved. The patient subsequently developed left oculomotor nerve palsy, weakness of the right arm, and weakness of the right leg. The cause of these symptoms was thought to be neurolymphomatosis on the basis of the typical MRI findings observed. We report a rare case of neurolymphomatosis presenting as bilateral tongue atrophy, mimicking amyotrophic lateral sclerosis.

Vertebral basilar system dolichoectasia with marked infiltration of IgG4-containing plasma cells: a manifestation of IgG4-related disease?

We report the histopathological features of vertebral basilar system dolichoectasia (VBD) in a 68-year-old man who died as a result of accompanying infarction of the medulla oblongata on day 6 of admission. During hospitalization, the patient was also found to have an elevated serum IgG level and tumors of the renal pelvis. A possible clinical diagnosis of VBD associated with IgG4-related disease was considered postmortem. Autopsy examination, limited to the intracranial tissues, revealed marked infiltration of IgG4-containing plasma cells in the adventitia and media of the vertebral and basilar arteries. Multiple fibrous nodules forming pseudotumors were also evident on the outer surface of the affected arteries. These histological features were very similar to those of arteriopathy, such as inflammatory aortic aneurysm, which has been described in patients with IgG4-related disease, suggesting that autoimmune mechanisms, known to be involved in the pathogenesis of visceral lesions in the disease, also played a role in the etiology of VBD in the present patient. In conclusion, we consider that the present case may represent VBD as a manifestation of IgG4-related disease.

[A case of CADASIL without characteristic anterior temporal pole lesion diagnosed by skin biopsy].

A 40 year-old man with migraine presented cerebral ischemic attacks several times in one year. He had no risk factors for cerebrovascular disease including hypertension, but had strong family history suggesting autosomal dominant inheritance. A brain MRI on T(2) weighted and FLAIR images revealed patchy and confluent hyper intensity areas in the subcortical white matters and bilateral external capsules, while no anterior temporal pole lesions characteristic of CADASIL (cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy) were detected. His skin biopsy demonstrated granular osmiophilic materials (GOM) on the basement membrane of the vascular smooth muscle cells in dermis as shown by an electron microscope. The following mutational analysis of the Notch3 gene disclosed a missense mutation of p.Arg133Cys in exon 3. Molecular diagnosis of CADASIL may be time consuming because Notch3 is a huge gene and mutations may occur at multiple sites. GOM on skin biopsy is diagnostic especially in cases where anterior temporal pole involvement on MRI is negative.

[A case of inflammatory myopathy with widely skin rash following use of supplements containing Spirulina].

A 49-year old woman noticed her skin rash several days after taking supplements containing Spirulina, a planktonic blue-green alga. Her skin rash was spreading over large parts of her body, even after stop ingestion two months later. Five months later, she developed muscle weakness of neck flexor and left proximal upper extremity. On admission, creatine kinase (CK) was elevated to 1,268 IU/ml in the serum. A muscle specimen revealed many necrotizing muscle fibers and the infiltration of mononuclear cells in the peri- and endomysium including a lot of eosinophils. Immunohistochemical staining showed the infiltration of CD4 positive cells in the peri- and endomysium and that of CD20 positive B cells in the perivascular regions. She was diagnosed as having inflammatory myopathy with widely skin rash. Therapy with administration of prednisolone and cyclophosphamide followed by methyl-prednisolone pulse improved her clinical symptoms. There is a similar report describing a case of dermatomyositis after ingestion of Spirulina, which is known to have immune-stimulating property such as accelerating tumor necrosis factor (TNF)-alpha production. Also, TNF-alpha single nucleotide polymorphisms (TNF-308A) was demonstrated to have strong association with onset of myositis in Caucasians. The use of Spirulina could result in inflammatory myopathy under some specific conditions.

[Case of orbital apex syndrome caused by invasive aspergillosis successfully treated during the diagnostic procedure by the use of voriconazole].

A 75-year-old woman developed loss of vision and decreased ocular motility in all directions. She exhibited a left orbital apex syndrome, accompanied by sphenoiditis and hypertrophic pachymeningitis. Voriconazole treatment was initiated on the basis of clinical suspicion, although use of the serum beta-D glucan had negative results and a biopsy was not performed. Five days later, the left eye movements started to improve, and at that time the use of the serum aspergillus galactomannan antigen proved to have positive results. Six months later, the patient was neurologically intact and stable, except for a lack of visual acuity in counting fingers. Earlier prognoses of invasive sino-orbital aspergillosis were dismal, especially when corticosteroid therapy was done before diagnosis. This case suggests the usefulness of antifungal agents during the diagnostic procedure even when localized invasive aspergillosis is not ruled out.

[A case of dermatomyositis associated with chronic idiopathic myelofibrosis].

A 74-year old woman had been suffering from chronic idiopathic myelofibrosis (CIMF) for three years before noticing skin rash and subsequent muscle weakness. On admission, purplish and erythematous skin rash was seen spreading over large parts of her body, including the face, chest, back and extremities. She could not stand up without assistance due to weakness. On laboratory examination, her hemoglobin was found to be 11.8g/dl, platelet 17,000/microl, WBC 22,500/microl (with blast cells), and CK 1,757 IU/I. Auto-antibodies including antinuclear antibody, Jo-I antibody and rheumatoid factors were negative. Abdominal CT revealed giant splenomegaly. She was diagnosed as having dermatomyositis (DM) associated with CIMF. Although administration of prednisolone followed by methyl-prednisolone pulse therapy ameliorated the weakness and skin rash, WBC increased to 35,000/ microl. In case of worsening of CIMF, azathioprine (AZP) administered. This decreased the WBC count to 13,700/microl and the CK to 49 IU/I 40 days after the administration. Patients with CIMF have an increased incidence of complications of other autoimmune diseases, indicating that the immunological mechanism plays some roles in the progression of the disease. There has been only one other reported case of DM complication. This case suggests usefulness of AZP treatment combined with prednisolone in these patients.