Takafumi Hosokawa

Onset and spreading patterns of lower motor neuron involvements predict survival in sporadic amyotrophic lateral sclerosis

Objective To define patterns of spread through the order of lower motor neuron involvement (first, second or third order), relationships between interval or sites of affected areas from onset to involvement of a second region, and prognosis, including 5 year survival, normal preservation of motor function at onset of respiratory symptoms and cumulative occurrence of each region and direction of spread. Method 150 patients with sporadic amyotrophic lateral sclerosis (ALS) underwent follow-up at 3 month intervals until the appearance of respiratory symptoms. Symptom appearances were determined using the revised version of the ALS Functional Rating Scale. Result Median survival with combined type onset (two regions simultaneously) was shorter (18 months) than with bulbar onset (26 months, p=0.01). The interval from onset to involvement of the second region correlated significantly with survival, independent of particular combinations. 5 year survival rate was 21% for lower limb onset, 18% for upper limb onset and 16% for bulbar onset. No patient with a rapid spread pattern (two regions within 3 months from onset) survived >5 years. Early manifestations of bulbar symptoms within 1 year were associated with worse survival (p<0.001) although no significant difference in survival was seen between groups with and without bulbar symptoms (p=0.51). In terms of cumulative occurrence, symptoms spread longitudinally to adjacent regions. Bulbar function remained preserved in 27%, lower limb function in 10% and upper limb function in 2.7%. Conclusion The interval between onset and involvement of the second region is an important predictor of survival. The data support the contiguous anatomical propagation of lower motor neuron involvement in sporadic ALS.

Visual field defects of optic neuritis in neuromyelitis optica compared with multiple sclerosis

BackgroundNeuromyelitis optica (NMO) is an inflammatory demyelinating disease that predominantly affects the optic nerves and the spinal cord, and is possibly mediated by an immune mechanism distinct from that of multiple sclerosis (MS). Central scotoma is recognized as a characteristic visual field defect pattern of optic neuritis (ON), however, the differing pathogenic mechanisms of NMO and MS may result in different patterns of visual field defects for ON.MethodsMedical records of 15 patients with NMO and 20 patients with MS having ON were retrospectively analyzed. A thorough systemic and neurological examination was performed for evaluating ON. The total number of relapses of ON and visual fields was investigated. Visual fields were obtained by Goldmann perimeter with each ON relapse.ResultsAll MS patients experienced central scotoma, with 90% of them showing central scotoma with every ON relapse. However, 53% of NMO patients showed central scotoma with every ON relapse (p = 0.022), and the remaining 47% of patients experienced non-central scotoma (altitudinal, quadrant, three quadrant, hemianopia, and bitemporal hemianopia). Thirteen percent of NMO patients did not experience central scotoma during their disease course. Altitudinal hemianopia was the most frequent non-central scotoma pattern in NMO.ConclusionsNMO patients showed higher incidence of non-central scotoma than MS, and altitudinal hemianopia may be characteristic of ON occurring in NMO. As altitudinal hemianopia is highly characteristic of ischemic optic neuropathy, we suggest that an ischemic mechanism mediated by anti-aquaporin-4 antibody may play a role in ON in NMO patients.

Increased serum matrix metalloproteinase-9 in neuromyelitis optica: implication of disruption of blood-brain barrier.

Matrix metalloproteinase-9 (MMP-9) plays an important role in some neuroinflammatory diseases through the blood-brain barrier (BBB) disruption. To investigate the pathogenicity of MMP-9 in neuromyelitis optica (NMO), serum and CSF MMP-9 concentrations were measured in 13 NMO and 15 multiple sclerosis (MS) patients and 14 healthy controls, and correlated with clinical and laboratorial parameters. Serum MMP-9 concentrations were significantly higher in NMO than MS and controls, and correlated with EDSS score, CSF/serum albumin ratio, and CSF IL-8 concentrations. Our results indicate that MMP-9, promoted by elevated IL-8 activation, plays a crucial role in the pathogenesis of NMO through the BBB disruption.

Eicosapentaenoic acid (EPA) induces peroxisome proliferator-activated receptors and ameliorates experimental autoimmune encephalomyelitis

Eicosapentaenoic acid (EPA), one of the n-3 polyunsaturated fatty acids, is a neuroprotective lipid with anti-inflammatory properties. We investigated the possible therapeutic effect of EPA on experimental autoimmune encephalomyelitis (EAE). EAE mice were fed a diet with or without EPA. The clinical EAE scores of the EPA-fed mice were significantly lower than those of the non-EPA mice. In the EPA-treated mice, IFN-γ and IL-17 productions were remarkably inhibited and the expression levels of peroxisome proliferator-activated receptors were significantly enhanced in the CNS-infiltrating CD4T cells. Thus EPA shows promise as a potential new therapeutic agent against multiple sclerosis.

Anhedonia in Japanese patients with Parkinson's disease

Aim:  Anhedonia has been proposed as a specific mood disorder related to the dopaminergic nerve dysfunction seen in Parkinsons disease (PD). This study examined hedonic tone in patients with PD using the Snaith–Hamilton Pleasure Scale (SHAPS) and investigated the associations with depressive mood by the Self‐Rating Questionnaire for Depression (SRQ‐D).

Postural Abnormality as a Risk Marker for Leg Deep Venous Thrombosis in Parkinson’s Disease

Background Pulmonary thromboembolism is a common cause of death in patients with autopsy-confirmed Parkinsonism. This study investigated the incidence of leg deep vein thrombosis in Parkinson’s disease and relationships between deep vein thrombosis and clinical/laboratory findings, including postural abnormalities as assessed by photographic measurements. Methods This cross-sectional study assessed the presence of deep vein thrombosis using bilateral leg Doppler ultrasonography in 114 asymptomatic outpatients with Parkinson’s disease. Results Deep vein thrombosis was detected in 23 patients (20%) with Parkinson’s disease. Deep vein thrombosis was located in the distal portion in 18 patients and in the proximal portion in 5 patients. No significant differences in age, sex, body mass index, disease duration, Hoehn-Yahr stage, anti-Parkinson’s drugs, or daily levodopa-equivalent dose were seen between deep vein thrombosis-positive and -negative groups. Univariate analysis for developing deep vein thrombosis in patients with Parkinson’s disease identified the following markers: long-term wheelchair use, bent knee, bent spine, and D-dimer elevation. Bending angles were significantly greater in the deep vein thrombosis-positive group at the knee and spine than in the deep vein thrombosis-negative group. Half of Parkinson’s disease patients with camptocormia had deep vein thrombosis. Among diabetes mellitus cases, long-term wheelchair use, bent knee over 15°, camptocormia, D-dimer elevation, the more risk markers were associated with a higher incidence of DVT. The presence of risk markers contributed to the development of deep vein thrombosis. On multivariate logistic regression analysis, a bent knee posture was strongly associated with an increased risk of deep vein thrombosis. Conclusion Presence of leg deep vein thrombosis correlated with postural abnormalities in Parkinson’s disease. We recommend non-invasive ultrasonographic screening for leg deep vein thrombosis in these high-risk patients with Parkinson’s disease.

Interferon-β1b Increases Th2 Response in Neuromyelitis Optica

A Japanese randomized controlled study showed that Interferon â (IFN-â1b) therapy is clinically effective in decreasing the frequency of attacks in multiple sclerosis (MS), even in optico-spinal MS (OSMS). However, recent studies have shown that IFN-â (IFN-â1a/IFN-â1b) treatment was not effective in neuromyelitis optica (NMO) patients and that the diminished benefit of IFN-â treatment in NMO may be due to different immune responses to IFN-â. We determined longitudinally the expression of CCR5, CXCR3 and CCR4 on CD4+ T and CD8+ T cells in the blood from patients with NMO and MS treated with IFN-â1b. During a 12-month period of IFN-â1b therapy, the annualized relapse rate decreased in MS patients but not in NMO patients. There was no significant difference in the expression of the chemokine receptors between NMO and MS at baseline. The percentages of CD4+CCR5+ and CD4+CXCR3+ T cells, representative of the Th1 response, were decreased in both NMO and MS after treatment. The percentage of CD4+CCR4+ T cells, representative of the Th2 response, was decreased in MS, but those for NMO was significantly increased compared with the pretreatment levels. Our results indicate that IFN-â1b-induced up-modulation of the Th2 response in NMO patients may be the source of differences in the therapeutic response to IFN-â1b therapy. In the present study, Th2 predominance is involved in the pathogenesis of NMO.

Human herpes virus 6 brainstem encephalitis in a patient with primary macroglobulinemia

Human herpes virus 6 (HHV-6) belongs to the b herpes virus subfamily as cytomegalovirus (CMV), an important pathogen that causes opportunistic infections. The primary infection by HHV-6 manifests in the form of exanthema subitum in the early childhood. Although exanthema subitum generally has a good prognosis, it is complicated by the occurrence of febrile convulsions in some cases. It can also cause encephalitis/encephalopathy, albeit rarely. Similar to infections by other herpes viruses, the primary infection by HHV-6 leads to a latent infection, and when the host immunity is suppressed, the virus is reactivated, causing encephalitis and other various forms of infection of the central nervous system. Of these infections, posttransplant acute limbic encephalitis is the most well known, whereas other forms rarely occur. Here, we report a case of brainstem encephalitis caused by HHV-6 in a patient with primary macroglobulinemia. A 73-year-old man experienced vertigo, diplopia, and dysphagia that lasted for 2 weeks. The patient suffered from hypertension and diabetes since 5 years but otherwise had no medical history of any significance. He did not have fever or any antecedent infection. Although he was lucid at the time of admission, his neurologic findings included left gaze palsy, right gaze-evoked nystagmus, mild left facial nerve paralysis, and defective lifting of the left soft palate. His tongue movement was normal without atrophy. The motor and sensory system of his limbs, his reflexes, and coordinated movements was also normal. Blood test findings revealed elevated leukocyte count (14,040/mm), AST (111 IU/L), ALT (277 IU/L), c-GTP (225 U/L), and HbA1c (8.3 %). Results for the HCV antibody test were negative. IgM level was elevated (859 mg/dL), and IgMjM protein was detected. Tests for antibodies to gangliosides (GQ1b, GM1), acetylcholine receptor, Hu, and Yo were all negative. Whole body CT showed no abnormalities, such as tumor lesions or lymphadenopathy. Brain MRI revealed no abnormalities present in the brainstem, cerebellum, and cerebral parenchyma. Nerve conduction studies of the left upper and lower extremities showed normal motor and sensory function. Cerebrospinal fluid (CSF) examination revealed a cell count of 5/mm, a protein concentration of 59.0 mg/dL, an IgG index of 0.599, and the presence of oligoclonal bands. Herpes simplex virus (HSV) DNA, varicella-zoster virus (VZV) DNA, and Mycobacterim tuberculosis DNA were negative in CSF. On day 3 of hospitalization, the left and right lateral gazeevoked nystagmus and intractable hiccups developed, and intravenous immunoglobulin (IVIG) therapy was initiated. However, IVIG therapy was discontinued after 3 days because of an adverse reaction in the form of systemic skin rash. Thereafter, the patient exhibited ptosis and external ophthalmoplegia as well as worsening dysphagia. Furthermore, bilateral vocal cord paralysis appeared. He underwent a tracheotomy on day 7 of hospitalization. Blood samples taken on days 14 and 23 of hospitalization were positive for CMV antigens. Real-time PCR performed on the CSF specimens was positive for HHV-6 (1400 copies/mL) but negative for HSV type 1, HSV type 2, & Hideto Nakajima in1045@osaka-med.ac.jp

Neurologic disorders associated with anti-glutamic acid decarboxylase antibodies: A comparison of anti-GAD antibody titers and time-dependent changes between neurologic disease and type I diabetes mellitus

To determine clinical features of neurologic disorders associated with anti-glutamic acid decarboxylase antibodies (anti-GAD-Ab), we examined titers and time-dependent changes of anti-GAD-Ab. Six patients, stiff person syndrome (2), cerebellar ataxia (1), limbic encephalitis (1), epilepsy (1), brainstem encephalitis (1), were compared with 87 type I diabetes mellitus (T1DM) patients without neurologic disorders. Anti-GAD-Ab titers and index were higher in neurologic disorders than in T1DM, suggesting intrathecal antibody synthesis. Anti-GAD-Ab titers in T1DM decreased over time, whereas they remained high in neurologic disorders. Immunotherapy improved neurological disorders and anti-GAD-Ab titers and index provide clinically meaningful information about their diagnostic accuracy.

Acute Cerebellar Ataxia Associated with Anti-glutamic Acid Decarboxylase Antibodies Mimicking Miller Fisher Syndrome: A Case Report

We herein report the case of a 53-year-old man with cerebellar ataxia with anti-glutamic acid decarboxylase antibody (GAD-Ab) who mimicked Miller Fisher syndrome (MFS). He developed ophthalmoplegia, diplopia, and gait ataxia for one week. The serum and cerebrospinal fluid GAD-Ab titers were greatly increased, and the GAD-Ab index suggesting intrathecal antibody synthesis was elevated, while GQ1b-Ab was negative. After steroid pulse therapy and following prednisolone, his symptoms dramatically improved over the course of 11 months with the simultaneous decline of GAD-Ab titers. This case indicates that cerebellar ataxia with GAD-Ab can present with acute neurological findings mimicking MFS, and that steroid therapy has an excellent therapeutic effect.