A Japanese Patient with Hereditary Myopathy with Early Respiratory Failure Due to the p.P31732L Mutation of Titin.

Hereditary myopathy with early respiratory failure (HMERF) is caused by titin A-band mutations in exon 344 and is considered quite rare. Respiratory insufficiency can be the sole symptom in the disease course. We herein report the first Japanese HMERF patient with a p.P31732L mutation in titin. The patient manifested respiratory failure and mild weakness of the neck flexor muscle at 69 years old and showed fatty replacement of the bilateral semitendinosus muscles on muscle imaging. Our case indicates that HMERF with a heterozygous p.P31732L mutation should be included in the differential diagnosis of muscular diseases presenting with early respiratory failure.

[Neuropathy presenting conduction block in ANCA-negative eosinophilic granulomatosis with polyangiitis].

A 74-year-old woman with a history of asthma and allergic rhinitis rapidly developed multiple mononeuropathy. Although anti-neutrophil cytoplasmic antibodies were negative, the presence of eosinophilia and eosinophilic infiltrations in the sural nerve led to a diagnosis of eosinophilic granulomatosis with polyangiitis. A motor nerve conduction study on admission revealed conduction block, which promptly disappeared after initiating immunotherapy without findings suggestive for remyelination or axonal degeneration. This electrophysiological change distinct from that of Wallerian degeneration. A biopsy of the sural nerve showed many eosinophil infiltrations and degranulation of eosinophilic cationic protein within nerve fascicles, whereas findings of necrotizing vasculitis were absent. These findings suggest that a direct effect of eosinophilic cationic protein, rather than ischemic damage due to vasculitis, was the main mechanism of transient nerve conduction failure in this patient.

Eosinophilic Granulomatosis with Polyangiitis Presenting with Myocarditis as an Initial Symptom: A Case Report and Review of the Literature.

A 66-year-old woman with a history of bronchial asthma had shortness of breath and fatigue upon mild exercise. She was diagnosed as congestive heart failure. A blood test showed eosinophilia without the presence of anti-neutrophil cytoplasmic antibody (ANCA), and a myocardial biopsy specimen revealed eosinophilic infiltration in the myocardium. Eosinophilia was improved when she was administered short-term methylprednisolone. After that, she had numbness and pain in her lower limbs with re-elevation of eosinophils. She had dysesthesia and hypalgesia in the distal part of the limbs. Sural nerve biopsy revealed axonal degeneration and thickness of the arterial wall, indicating a diagnosis of eosinophilic granulomatosis with polyangiitis (EGPA). Two courses of steroid pulse therapy were performed, resulting in marked improvement of her sensory symptoms. ANCA-negative EGPA might be associated with myocarditis and peripheral neuropathy. A sufficient immunotherapy should have been considered to prevent rapid progression.

[Chronic inflammatory demyelinating polyradiculoneuropathy with myelopathy due to massively enlarged nerve roots].

We report a 77-year-old man who presented with numbness and weakness of the feet bilaterally, that had progressed over 13 years. He was diagnosed with chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) on the basis of nerve conduction studies and a sural nerve biopsy; however, he was inadequately treated and his weakness had progressed. At 76 years of age, he developed spasticity in the legs as well as bladder and rectal incontinences. Gd-enhanced MRI revealed severe compression of the cervical cord by massively enlarged nerve roots. A cervical laminectomy was performed to decompress the cervical cord. A fascicular biopsy of the C5 dorsal root showed a prominent lymphocyte infiltration and edema. Repeated methylprednisolone pulse therapy and IVIg ameliorated the weakness. We concluded that the main cause of nerve root hypertrophy in this patient was active inflammation.

[A women with aplastic anemia developed chronic inflammatory demyelinating polyneuropathy].

A 66-year-old female developed chronic inflammatory demyelinating polyneuropathy (CIDP) one year after the diagnosis of aplastic anemia. High-dose intravenous immunoglobulin (IVIg) therapy, followed by IVIg maintenance therapy, rapidly improved her weakness and hyperesthesia in four extremities. In addition, pancytopenia caused by aplastic anemia also improved following IVIg treatment in parallel. This is the first report to show the co-existence of CIDP and aplastic anemia, and a common pathomechanism may be present in these two rare autoimmune disorders.

[Cytomegalovirus myositis complicated with hemophagocytic lymphohistiocytosis, acute renal failure, and colitis].

A 60-years-old previously healthy man presented with acute renal failure and hemophagocytic lymphohistiocytosis (HLH). Both conditions improved after immunotherapies, but severe limb weakness with elevation of serum CK developed. Needle EMG showed myogenic changes with spontaneous activities and muscle weakness thereafter improved without adding further immunotherapies, suggesting that our patient had viral myositis. After the stabilization of limb weakness, cecal perforation occurred due to cytomegalovirus (CMV) enteritis and temporal significant change of anti-CMV IgG antibody titer was confirmed using paired serum samples. Upregulation of MHC-class I molecule and numerous regenerative muscle fibers were observed in muscle biopsy, but no evidence of direct CMV infection in muscle fibers were seen. Although CMV infection may cause either myositis, acute renal failure, HLH or colitis in individual patient, this is the first case which had been complicated by all these conditions subsequent to CMV infection.

Dermatomyositis Complicated by Digital Ischemia and Lung Adenocarcinoma in a Patient with Positive Anti-signal Recognition Particle Antibodies.

A 58-year-old Japanese woman was diagnosed with anti-signal recognition particle (SRP)-positive dermatomyositis associated with Sjögren's syndrome, rheumatoid arthritis and lung adenocarcinoma. She presented with cutaneous lesions, including ulceration of her right middle finger. Tissue specimens obtained from her right deltoid muscle were positive for CD4+ T-cell infiltration and the sarcolemma showed the upregulation of major histocompatibility complex (MHC) class I antigens. The present case suggests that overlapping autoimmune diseases or complications of malignancy may result in an atypical clinical presentations and histological findings in patients with anti-SRP antibody-positive dermatomyositis.

Charcot-Marie-Tooth disease type 2 caused by homozygous MME gene mutation superimposed by chronic inflammatory demyelinating polyneuropathy.

We report a 59-year-old Japanese male who developed gradually worsening weakness and numbness of distal four extremities since age 50. His parents were first cousins, and blood and cerebral spinal examinations were unremarkable. Homozygous mutation of MME gene was detected and thus he was diagnosed as autosomal-recessive Charcot-Marie-Tooth disease 2T (AR-CMT2T); however, electrophysiological examinations revealed scattered demyelinative changes including elongated terminal latency in several peripheral nerve trunks. Sural nerve biopsy showed endoneurial edema and a lot of thinly myelinated nerve fibers with uneven distribution of remnant myelinated fibers within and between fascicles. Immunoglobulin treatment was initiated considering the possibility of superimposed inflammation and demyelination, and immediate clinical as well as electrophysiological improvements were noted. Our findings indicate that AR-CMT2T caused by MME mutation predisposes to a superimposed inflammatory demyelinating neuropathy. This is the first report which documented the co-existence of CMT2 and chronic inflammatory demyelinating polyneuropathy (CIDP); however, in the peripheral nervous system, neprilysin, a product of MME gene, is more abundant in myelin sheath than in axonal component. The fragility of myelin sheath due to mutated neprilysin may trigger the detrimental immune response against peripheral myelin in this patient.

Steroid-responsive demyelinating peripheral neuropathy associated with chronic lymphoproliferative disorders of natural killer cells.

We herein report the findings of a 67-year-old woman with steroid-responsive multiple mononeuropathy associated with chronic natural killer (NK) cell lymphocytosis. The patient developed progressive, asymmetric weakness and numbness in all four extremities in the course of a three-month period. Nerve conduction studies revealed asymmetric demyelination in both the motor and sensory nerves, and a biopsy specimen of the sural nerve showed a conspicuous difference in the demyelination between the neighboring fascicles and the infiltration of NK cells in the endoneurium. We considered the multiple mononeuropathy in this patient to have been caused by NK cell infiltration in the endoneurium, and the observed asymmetry might have been due to differences in the NK cell intrusion among the fascicles. Corticosteroid administration resulted in a rapid neurological, electrophysiological and hematological improvement. The rapid clinical amelioration that was observed after corticosteroid therapy suggested that the neuropathy in this case had been mainly caused by the mechanical compression of the endoneurial NK cells or the inflammatory cytokines that had been released by them.

Autopsy case of the C12orf65 mutation in a patient with signs of mitochondrial dysfunction.

OBJECTIVE: To describe the autopsy case of a patient with a homozygous 2-base deletion, c171_172delGA (p.N58fs), in the C12orf65 gene. METHODS: We described the clinical history, neuroimaging data, neuropathology, and genetic analysis of the patients with C12orf65 mutations. RESULTS: The patient was a Japanese woman with a history of delayed psychomotor development, primary amenorrhea, and gait disturbance in her 20s. She was hospitalized because of respiratory failure at the age of 60. Pectus excavatum, long fingers and toes, and pes cavus were revealed by physical examination. Her IQ score was 44. Neurologic examination revealed ophthalmoplegia, optic atrophy, dysphagia, distal dominant muscle weakness and atrophy, hyperreflexia at patellar tendon reflex, hyporeflexia at Achilles tendon reflex, and extensor plantar reflexes. At age 60, she died of pneumonia. Lactate levels were elevated in the patient's serum and CSF. T2-weighted brain MRI showed symmetrical hyperintense brainstem lesions. At autopsy, axial sections exposed symmetrical cyst formation with brownish lesions in the upper spinal cord, ventral medulla, pons, dorsal midbrain, and medial hypothalamus. Microscopic analysis of these areas demonstrated mild gliosis with rarefaction. Cell bodies in the choroid plexuses were eosinophilic and swollen. Electron microscopic examination revealed that these cells contained numerous abnormal mitochondria. Whole-exome sequencing revealed the 2-base deletion in C12orf65. CONCLUSIONS: We report an autopsy case of the C12orf65 mutation, and findings suggest that mitochondrial dysfunction may underlie the unique clinical presentations.

Establishment of a new conditionally immortalized human skeletal muscle microvascular endothelial cell line.

In skeletal muscle, the capillaries have tight junctions (TJs) that are structurally similar to those in the blood-brain barrier (BBB) and blood-nerve barrier (BNB). Although many findings have been clarified in the territory of BBB and BNB, few have so far examined the TJs of capillaries in the skeletal muscle. In addition, no in vitro human skeletal muscle microvasculature models have been reported thus far. We newly established a new human skeletal muscle microvascular endothelial cell (HSMMEC) line. HSMMECs were isolated from human skeletal muscle and were infected with retroviruses harboring temperature-sensitive SV40 T antigen and telomerase genes. This cell line, termed TSM15, showed a spindle fiber-shaped morphology, an immunoreactivity to anti-factor VIII and anti-VE-cadherin antibodies, and a temperature-sensitive growth. TSM15 cells grew stably for more than 40 passages when they were cultured at 33°C, thereby retaining their spindle fiber-shaped morphology and contact inhibition at confluence. The cells expressed tight junctional molecules such as claudin-5, occludin, and zonula occludens-1, as well as transporters such as a glucose transporter 1. The transendothelial electrical resistance of TSM15 was as high as those of the human brain microvascular endothelial cell line. This novel cell line might facilitate the analyses of the pathophysiology of inflammatory myopathy, such as dermatomyositis, and can improve our understanding of the physiological and biochemical properties of the microvasculature in human skeletal muscle.

[Systemic vasculitic neuropathy diagnosed by means of (18)F-FDG PET CT].

We report a 43-year-old man experienced numbness in the distal portion of both legs, which progressed over following two months. Neurological examination showed hypesthesia and muscle weakness in the distal portion of both legs. No abnormal findings were seen on blood test and whole-body contrast enhanced computed tomography (CT). Histopathological findings of the sural nerve and the peroneus brevis muscle showed decreased myelinated nerve fibers with scattered myelin ovoids, vascular occlusion in the epineurium, and inflammatory cell around the arteriole in the muscle bundle. These findings suggested falling in the category as non-systemic vasculitic neuropathy (NSVN). (18)F-fluorodeoxyglucose (FDG) positron emission tomography (PET) revealed the increase of FDG uptake in the rectum. Inflammatory cell infiltration was found around the arteriole with fibrinoid necrosis in the histopathological specimen of the rectal mucosal biopsy. This result represented the diagnosis as systemic vasculitis. The diagnosis of NSVN may depend on the sensitivity of diagnostic procedure, and (18)F-FDG PET CT might be a useful tool to detect small or medium-sized vasculitis.

[A case of chronic progressive motor-dominant multiple mononeuritis associated with primary Sjögren's syndrome].

A 45-year-old female with a history of dry eyes presented with chronic progressive disturbance of her right finger extension, bilateral foot drops, and dysesthesia in the left lower leg. On admission, neurological examination revealed decreased tendon reflex in the right upper limb and bilateral lower limbs, and dysesthesia in the distal outer portions of the bilateral lower legs. Her vibration sensation was moderately diminished in both lower legs. Weakness ranging from moderate to severe was predominantly found in the muscles innervated by the radial (r > l), medial (r > l), ulnar (r > l), deep peroneal (r ≒ l), tibial (r < l), and medial planter nerves (r < l). Nerve conduction study showed asymmetrical axonal neuropathy, while chronic neurogenic changes were observed on needle electromyography. Cerebrospinal fluid analysis results were unremarkable, except for an elevated IgG index (1.53) and the presence of oligoclonal IgG bands. Seropositive anti-SS-A antibody and histological findings of the biopsied minor salivary gland, as well as the lack of other connective tissue disorders, indicated primary Sjögren syndrome (SjS). A left sural nerve biopsy showed inhomogeneous reductions in the myelinated fibers within fascicules, mild infiltration of CD8-positive T lymphocytes around small vessels, and no fibrinoid necrosis in the arteries. From these findings, the diagnosis of motor-dominant multiple mononeuritis associated with primary SjS was made. Therapy that comprised a single course of intravenous (IV) methylprednisolone (1 g for 3 days), followed by oral prednisolone (60 mg/day) with gradual tapering, resulted in no amelioration of her symptoms. She then received IV immunoglobulin (0.4 mg/kg/day for 5 days), which resulted in moderate improvement in the strength of several muscles and a reduction of CSF IgG index (0.89). A wide variety of peripheral nerve complications are documented in primary SjS. However, the present case is unique in the symptoms of chronic progressive, motor-dominant, multiple mononeuritic phenotype.

Rituximab-associated progressive multifocal leukoencephalopathy derived from non-Hodgkin lymphoma: neuropathological findings and results of mefloquine treatment.

A 66-year-old man with non-Hodgkin lymphoma (NHL) developed progressive multifocal leukoencephalopathy (PML) after undergoing chemotherapy including rituximab. Although the administration of mefloquine at a dose of 500 mg weekly temporarily led to a dramatic decrease in the copy number of JC Virus DNA in the cerebrospinal fluid, the patient's symptoms gradually worsened. The CD4(+) T count remained continuously low, at least until approximately five months after the last cycle of chemotherapy. A postmortem examination performed 10 months after the onset of PML disclosed a severe condition associated with rituximab-treated PML originating from NHL and a high mefloquine concentration in the brain. The accumulation of further data regarding mefloquine treatment in PML cases may help to elucidate the optimal dosage and time window for effectively treating PML.

[Leptomeningeal gliomatosis with high levels of adenosine deaminase in the cerebrospinal fluid].

A 61-year-old man developed disturbance of consciousness for 2 weeks. He showed neck stiffness and hyporeflexia. Analysis of his cerebrospinal fluid (CSF) revealed pleocytosis and markedly reduced glucose contents. Adenosine deaminase (ADA) levels in the CSF were elevated (28.8 IU/l). Brain magnetic resonance imagings showed enhancement of the leptomeninges. Tuberculous meningitis was considered, but antituberculous drug was not effective. Repeated cytological analysis of the CSF demonstrated atypical cells with enlarged unevenly distributed nuclei and immunoreactive with glial fibrillary acidic protein. We diagnosed him as leptomeningeal gliomatosis. CSF ADA may be elevated in this rare disorder, and here we emphasize that repeated cytological analysis with immunohistochemical staining was useful for diagnosis.

Sera from patients with multifocal motor neuropathy disrupt the blood-nerve barrier.

OBJECTIVE: In multifocal motor neuropathy (MMN), the destruction of the blood-nerve barrier (BNB) has been considered to be the key step in the disease process. The purpose of the present study was to ascertain whether sera from patients with MMN can open the BNB, and which component of patient sera is the most important for this disruption. METHODS: We evaluated the effects of sera from patients with MMN, patients with amyotrophic lateral sclerosis, and control subjects on the expression of tight junction proteins and vascular cell adhesion molecule-1 (VCAM-1), and on the transendothelial electrical resistance (TEER) in human peripheral nerve microvascular endothelial cells (PnMECs). RESULTS: The sera from patients with MMN decreased the claudin-5 protein expression and the TEER in PnMECs. However, this effect was reversed after application of an anti-vascular endothelial growth factor (anti-VEGF) neutralising antibody. The VEGF secreted by PnMECs was significantly increased after exposure to the sera from patients with MMN. The sera from patients with MMN also increased the VCAM-1 protein expression by upregulating the nuclear factor kappa-B (NF-κB) signalling. The immunoglobulin G purified from MMN sera decreased the expression of claudin-5 and increased the VCAM-1 expression in PnMECs. CONCLUSIONS: The sera from MMN patients may disrupt the BNB function via the autocrine secretion of VEGF in PnMECs, or the exposure to autoantibodies against PnMECs that are contained in the MMN sera. Autoantibodies against PnMECs in MMN sera may activate the BNB by upregulating the VCAM-1 expression, thereby allowing for the entry of a large number of circulating inflammatory cells into the peripheral nervous system.

NMO sera down-regulate AQP4 in human astrocyte and induce cytotoxicity independent of complement.

Autoantibodies against astrocyte water channel aquaporin-4 (AQP4) are highly specific for neuromyelitis optica (NMO). However, the molecular mechanism of NMO still remains unclear. The purpose of this study was to identify the possible humoral mechanisms responsible for the occurrence of astrocytic damage. Human primary astrocytes (AST) were immortalized by retroviral vectors harboring temperature-sensitive SV40 T antigen gene and AQP4 cDNA (M23), designated as hAST-AQP4. The effects of NMO sera on the content and localization of AQP4, including cytotoxicity and astrocytic morphology, were evaluated. In addition, this study examined whether the amount and localization of AQP4 protein in astrocytes were influenced by direct contact with the immortalized human brain microvascular endothelial cell line, TY09. NMO sera alone induced cytotoxicity and addition of complement had a more harmful effect on hAST-AQP4. NMO sera also decreased AQP4 mRNA and protein. NMO sera alone up-regulated TNFα and IL-6 in astrocytes and co-incubation with anti-TNFα and anti-IL-6 neutralizing antibodies blocked both the cytotoxicity and reduction of AQP4 in astrocytes. In the experiment using the in vitro BBB models, AQP4 protein mainly localized at the astrocytic membrane after co-culture with TY09, in contact with TY09. The future elucidation of factors that up-regulate AQP4 in astrocytes presumably released by blood brain barrier forming endothelial cells and that block the production of inflammatory cytokines may therefore lead to the development of a novel therapeutic strategy.