Motoharu Kawai

Hydrocortisone Enhances the Function of the Blood-Nerve Barrier Through the Up-Regulation of Claudin-5

In autoimmune disorders of the peripheral nervous system (PNS), including Guillain–Barré syndrome and chronic inflammatory demyelinating polyradiculoneuropathy, breakdown of the blood-nerve barrier (BNB) has been considered to be a key step in the disease process. Although glucocorticoids (GCs) have been shown to effectively restore the blood–brain barrier (BBB) in some inflammatory central nervous system diseases such as multiple sclerosis, their action against the BNB has not yet been examined. To elucidate the role of GCs on the BNB, we established a novel human immortalized endothelial cell lines derived from the BNB. The established cell line termed “DH-BNBs” expresses two important tight junction proteins, claudin-5 and occludin. Using DH-BNBs, we analyzed how GCs affect BNB function. We herein report that GCs up-regulate the expression of claudin-5 and increase the barrier properties of the BNB. This is the first report which indicates how GCs affect the blood-nerve barrier.

A serological analysis of viral and bacterial infections associated with neuromyelitis optica

To evaluate the role of infections in the development of neuromyelitis optica (NMO), 19 patients positive for anti-aquaporin-4 antibody were screened for 24 viral and bacterial infections. Serological evidence of recent viral infection was found in 7 of 15 patients screened during the acute phase of the neurologic illness, which was a significantly more frequent rate of infection than seen in the control group of 33 patients with neurodegenerative, metabolic, or vertebral diseases (47% versus 15%). Mumps virus and human herpes viruses were the frequent causal agents, although there was no statistical difference in frequency between the two groups. Most patients with identified recent infection had monophasic or recurrent myelitis without evidence of optic nerve involvement and small number of total clinical relapses. Disease history tended to be shorter in patients with identified recent infection than those without, and an expanded long spinal cord lesion in magnetic resonance imaging was rarely found in patients with identified recent infection, although statistical significance could not be shown. These findings indicate that, not single, but various viral infections, can be associated with the development of NMO during the early stages of the illness, although the exact pathogenesis of NMO has yet to be clarified.

A Case of Postprandial Cluster-Like Headache With Prolactinoma: Dramatic Response to Cabergoline

A 17‐year‐old boy without a significant past medical history presented with recurrent cluster‐like headaches induced by meals for 3 years. Magnetic resonance images showed a pituitary tumor. Just after starting treatment with cabergoline, the headaches resolved completely and the patient has been absolutely free from such headache attacks for 2 years.

A new diagnostic test for VLCAD deficiency using immunohistochemistry

Background: Muscle pathology is often unhelpful in elucidating the specific underlying abnormality in patients with metabolic myopathy with rhabdomyolysis, including very-long chain acyl-CoA dehydrogenase (VLCAD) deficiency. Biochemical analyses require large amounts of biopsy samples for each enzyme assay. Objective: To develop a more efficient diagnostic method for VLCAD deficiency. Methods: The authors performed immunohistochemical analysis using an antibody to VLCAD on muscles from 344 patients (226 men and 118 women) without a specific diagnosis who had at least one of the following symptoms: myoglobinuria, high CK level, muscle pain, muscle stiffness, sudden infant death syndrome, and Reye-like syndrome. Results: Immunoreactivity to VLCAD was absent or markedly reduced in 13 patients. Biochemical analyses confirmed that all these patients had low enzymatic activity and reduced amount of protein. They all had the myopathic phenotype. The authors identified homozygous or compound heterozygous mutations in all of them. All recombinant proteins had reduced enzymatic activity except for 128G>A (G43D) and 796C>G (P266A) mutants, indicating that they are neutral polymorphisms. Conclusions: The new screening method for the detection of VLCAD deficiency using an immunohistochemical technique identified 13 new Japanese patients with VLCAD deficiency.

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 patients 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.

Autosomal dominant tauopathy with parkinsonism and central hypoventilation

Frontotemporal dementia and parkinsonism linked to chromosome 17 (FTDP-17T) can show various clinical phenotypes.1 We describe Japanese siblings with the intronic 10 + 14 splice site mutation of the microtubule-associated protein tau (MAPT) gene, showing parkinsonism, depression, weight loss, and central hypoventilation with reduced serotonin concentration suggested by low 5-hydroxyindole acetic acid (5-HIAA) in CSF. These clinical and biochemical features are just shared by Perry syndrome,2–4 although neither DCTN1 gene mutation nor TDP-43 proteinopathy was found. ### Case reports. A Japanese woman (III-5) (figure, A) developed clumsiness, tremor of the upper limbs, appetite loss, and apathy at age 44. She had lost 14 kilograms of body weight during 10 months. Mask-like face, hypophonic voice, bradykinesia, and muscle rigidity with predominance on the right side were observed. Deep tendon reflexes were hyperactive, especially in the right extremities with the Babinski sign. Despite levodopa treatment, her parkinsonism progressed and memory loss, disorientation, and cyanosis became apparent. Blood tests, EKG, and chest X-ray were not remarkable. Arterial blood gases showed reduced oxygen (60.3 Torr) and increased carbon dioxide (55.5 Torr). CSF analysis showed reduced 5-HIAA (5.6 ng/mL [normal 28.5 ± 7.2 ng/mL]). Brain MRI demonstrated mild atrophy in the brainstem tegmentum. Polysomnography revealed central hypoventilation with hypoxia. Although memory loss, disorientation, and …

Neuropathy in chronic graft‐versus‐host disease caused by Donor T cells

Chronic graft-versus-host disease (cGVHD) affects diverse organs, including peripheral nerves. Previous cases of neuropathy accompanied by cGVHD were diagnosed primarily based on electrophysiological studies and showed a favorable response to intravenous immunoglobulins. A case demonstrating infiltration of T cells in the sural nerve has been reported, but it remained unclear whether such neuropathy was caused by cGVHD or was coincidentally coexistent with other autoimmune diseases, including chronic inflammatory demyelinating polyneuropathy (CIDP). We describe direct invasion of the peripheral nervous system by the donor’s T cells in a recipient. A 29-year-old woman, after being diagnosed with acute lymphocytic leukemia (ALL), underwent a gendermismatched allogeneic bone marrow transplantation from her HLA-identical brother. Five months later, she developed cGVHD manifested by hyperkeratotic plaques of mouth ulceration and skin eruption, fulfilling the criteria for GVHD. She was treated with cyclosporine and prednisolone, after which all findings gradually lessened. Seven months later, she felt leg weakness and also noted numbness of all extremities, alopecia, dry eyes, and mouth ulcers. The neurological examination revealed distal-dominant muscle weakness in all limbs with areflexia. Tactile and pain sensations were diminished in all 4 limbs. Cerebrospinal fluid (CSF) analysis showed 13 mononuclear cells per microliter and elevated protein (264 mg/dl). Electromyography (EMG) revealed reduction of motor and sensory action potential amplitudes, decreased conduction velocities, and prolonged latencies with conduction block and abnormal temporal dispersion. The findings were consistent with a diagnosis of demyelinating neuropathy. After intravenous immunoglobulin treatment (400 mg/kg/day for 5 consecutive days), limb weakness gradually improved, and numbness of her extremities resolved. Thereafter, her demyelinating neuropathy relapsed 3 times, and she was treated with intravenous immunoglobulin, resulting in partial remission. After a fourth deterioration of the neurological and electrophysiological abnormalities, she was admitted to our department for a nerve biopsy. Sural nerve specimens showed a severe loss of large fibers and scattered thinly myelinated fibers. The teased fiber analysis showed segmental demyelination and irregular internode length. According to Dyck’s classification, a demyelinating process was seen in 8% of the fibers. Immunohistochemically, scattered CD4þ and CD8þ T cells were observed in the nerve bundles (Fig. 1A and B). The density of lymphocytes in the endoneurial space was 3.1/mm. Fluorescence in situ hybridization (FISH) showed that 15% of the infiltrating T cells carried both Xand Y-chromosomes (Fig. 1C and D), whereas others had two X-chromosomes. These data conclusively demonstrate that the infiltrating T cells were of donor origin, that is, from her brother. Periodic administration of immunoglobulin was effective in maintaining remission of the patient’s neuropathic deficits for 1 year thereafter. Gender-mismatched transplantation allowed us to distinguish the separation of donor and recipient cells using FISH, leading to the diagnosis of cGVHD-related neuropathy, and not CIDP. Arthritis with synovitis that developed in cGVHD after gender-mismatched transplantation for acute myelogenous leukemia has been reported. As in our patient, FISH analysis identified the donor origin of the inflammatory infiltrating T cells within the synovial tissues and confirmed the diagnosis of cGVHD.

Combined immunomodulatory therapies resulted in stepwise recovery in autoimmune autonomic ganglionopathy

Some intractable cases of autoimmune autonomic ganglionopathy are treated with diverse combinations of immunomodulatory therapies. However, it is unclear which of the immunotherapies directly contributed to the relief of dysautonomia when several immunotherapies have been utilized. To evaluate which of the immunomodulatory therapies are effective, we describe a 60‐year‐old man with autoimmune autonomic ganglionopathy who was successfully treated by combined immunomodulatory therapies. The patient showed subacute pure autonomic failure without antecedent infectious symptoms, and was admitted to Yamaguchi University Hospital, Yamaguchi, Japan. He demonstrated involvement of cardiovascular, pupillary, sudomotor, gastrointestinal and bladder functions. Serum ganglionic acetylcholine receptor autoantibody titer was highly elevated. The diagnosis of autoimmune autonomic ganglionopathy was made. Plasma exchange was repeated nine times, resulting in minimal improvement. Subsequently, intravenous immunoglobulin therapy followed by steroid administration was initiated, after which his symptoms gradually improved. Plasma noradrenaline levels showed a stepwise elevation after each treatment, including plasma exchange. Our case adds to the evidence that combining several immunomodulatory therapies is beneficial for some intractable cases of autoimmune autonomic ganglionopathy that do not adequately respond to a single immunomodulatory therapy. Each immunomodulatory therapy should be effective even though they are not enough to show clinical improvement.

Cloning and characterization of the gene encoding Halobacterium halobium adenylate kinase

The gene (AK) encoding adenylate kinase (AK) of Halobacterium halobium was cloned. AK consisted of 648 bp and coded for 216 amino acids (aa). S1 mapping and primer extension experiments indicated that the transcription start point (tsp) was located immediately upstream from the start codon. The TAT-like promoter sequence was found at a position 20-24 bp upstream from tsp. The most striking property of the enzyme was a putative Zn finger-like structure with four cysteines. It might contribute to the structural stability of the molecule in high-salt conditions. Phylogenetic analysis indicated two lineages of the AK family, the short and long types which diverged a long time ago, possibly before the separation of prokaryotes and eukaryotes. Although the H. halobium AK belongs to the long-type AK lineage, it is located in an intermediary position between the two lineages of the phylogenetic tree, indicating early divergence of the gene along the long-type lineage.

Proton magnetic resonance spectroscopy in corticobasal degeneration and progressive supranuclear palsy

Background:  Corticobasal degeneration (CBD) and progressive supranuclear palsy (PSP) each have distinctive clinical features, but diagnosis is often uncertain. Our purpose was to evaluate whether localized, single‐voxel proton magnetic resonance spectroscopy (1H‐MRS) could distinguish between typical CBD and PSP patients.