Anti-myelin Oligodendrocyte Glycoprotein Antibodies in a Patient with Recurrent Optic Neuritis Involving the Cerebral White Matter and Brainstem.

We herein report a case of recurrent optic neuritis involving the cerebral white matter and brainstem in a patient positive for anti-myelin oligodendrocyte glycoprotein (MOG) antibodies. The patient had an initial attack at 24 years of age. Optic neuritis recurred over 14 years, and she was admitted to our neurology unit at 38 years of age. She showed bilateral optic neuritis, high-intensity lesions in the cerebral white matter and brainstem on T2 MRI with contrast enhancement, and elevated serum anti-MOG antibodies. Immunotherapy improved the MRI lesions. Recurrent optic neuritis in patients with anti-MOG antibodies may thus involve the cerebral white matter and brainstem.

[A case of corticosteroid-responsive Lemierre syndrome with clivus osteomyelitis and a mass in the cavernous sinus-suprasellar region].

Lemierre syndrome is a clinical syndrome that presents with internal jugular thrombophlebitis, septicemia and systemic abscess formations. In general, the condition is preceded by oropharyngeal infections. We report a case of a 73-year-old man with Lemierre syndrome, clivus osteomyelitis and a steroid-responsive mass in the cavernous sinus-suprasellar region. He complained of fever, occipital pain, diplopia and right ptosis. Administration of oral steroids ameliorated the ophthalmic symptoms for a period before he was admitted to our hospital. After admission, the severity of his headache advanced, and his ophthalmic symptoms progressed bilaterally. Brain magnetic resonance imaging showed contrast enhancement of the clivus and revealed a mass lesion contrast-enhancement effect in the cavernous sinus-suprasellar region. Fusobacterium nucleatum was detected by blood culture, and computed tomography revealed multiple bacterial emboli in both lung fields and thrombosis of the left internal jugular vein; thus, he was diagnosed with Lemierre syndrome. After venous administration of antibiotics, his fever and headache markedly improved, but the ophthalmic symptoms did not. We prescribed an oral steroid because the cavernous sinus-suprasellar lesion was probably an inflammatory granuloma caused by a para-infectious mechanism rather than by infection. After the series of treatments, his ophthalmic symptoms improved, and the cavernous sinus-suprasellar region mass lesion decreased. He was eventually discharged in a fully ambulatory state and had no ophthalmic difficulties. We thought that the osteomyelitis of clivus was caused by Lemierre syndrome and its inflammatory processes formed the granuloma in the cavernous sinus-suprasellar region. This was a case of Lemierre syndrome with a rare combination of clivus osteomyelitis and a steroid-responsive tumour in the cavernous sinus-suprasellar region that was successfully treated.

Variants associated with Gaucher disease in multiple system atrophy.

OBJECTIVE: Glucocerebrosidase gene (GBA) variants that cause Gaucher disease are associated with Parkinson disease (PD) and dementia with Lewy bodies (DLB). To investigate the role of GBA variants in multiple system atrophy (MSA), we analyzed GBA variants in a large case-control series. METHODS: We sequenced coding regions and flanking splice sites of GBA in 969 MSA patients (574 Japanese, 223 European, and 172 North American) and 1509 control subjects (900 Japanese, 315 European, and 294 North American). We focused solely on Gaucher-disease-causing GBA variants. RESULTS: In the Japanese series, we found nine carriers among the MSA patients (1.65%) and eight carriers among the control subjects (0.89%). In the European series, we found three carriers among the MSA patients (1.35%) and two carriers among the control subjects (0.63%). In the North American series, we found five carriers among the MSA patients (2.91%) and one carrier among the control subjects (0.34%). Subjecting each series to a Mantel-Haenszel analysis yielded a pooled odds ratio (OR) of 2.44 (95% confidence interval [CI], 1.14-5.21) and a P-value of 0.029 without evidence of significant heterogeneity. Logistic regression analysis yielded similar results, with an adjusted OR of 2.43 (95% CI 1.15-5.37) and a P-value of 0.022. Subtype analysis showed that Gaucher-disease-causing GBA variants are significantly associated with MSA cerebellar subtype (MSA-C) patients (P = 7.3 × 10(-3)). INTERPRETATION: The findings indicate that, as in PD and DLB, Gaucher-disease-causing GBA variants are associated with MSA.

[A case of late-onset cobalamin C disease (methylmalonic aciduria and homocystinuria, cobalamin C type)].

We report the case of an 18-year-old Japanese woman with cobalamin (cbl) C disease. She was born between non- consanguineous parents, and had easy fatigability from a childhood. At 14 years old, she developed renal failure, and had repeated psychosis during 2 years. At 16 old, she developed her gait disturbance and her symptoms fluctuated, but the cause of gait disturbance was unclear. At 18 years old, she was admitted with worsening of gait disturbance. Physical examination revealed spastic paraparesis and bilateral peroneal nerve paralyses. Homocystinuria and methylmalonic aciduria were detected, although serum vitamin B12 was within normal range. Gene mutation analysis revealed Gly147Asp (440G>A) and Trp157Ser (470G>C) in the MMACHC gene as a compound heterozygous mutation. We diagnosed her as having late-onset cbl C disease, and her gait disturbance and renal failure improved after intramuscular hydroxocobalamin administration. Although late-onset cbl C disease is rare in Japan, it an important to consider this congenital disease because symptoms are expected to improve by medical intervention.

A 3-year cohort study of the natural history of spinocerebellar ataxia type 6 in Japan.

BACKGROUND: Only a few prospective studies have determined which clinical symptoms and factors are associated with the disease severity of spinocerebellar ataxia type 6 (SCA6). A multicenter longitudinal cohort study was conducted to clarify both the natural history of SCA6 in Japan and the factors influencing disease progression. METHODS: Patients were consecutively recruited between 2007 and 2008. Scores from the Scale for the Assessment and Rating of Ataxia (SARA) and Barthel Index (BI) were collected prospectively each year. Additionally, data from the Japan intractable diseases research (IDR) registry were collected both retrospectively, from 2003 to 2006, and prospectively, from 2007 to 2010. As a result, we were able to collect 3 years of retrospective data and 4 years of prospective data during the course of 3 yearly visits. RESULTS: Forty-six patients were registered. The follow-up rate of the third year was 93%. The SARA scores worsened significantly each year. Over 3 years, the decline of the SARA scores was 1.33 ± 1.40 points/year. The results of multivariate analysis of the decline of the SARA score were not significant. The IDR scores correlated well with the SARA and BI scores. Kaplan-Meier curves of 7 years of data from the IDR registry illustrated the correlation between the ability to walk and the time course of the disease. CONCLUSIONS: Information regarding the progression of ataxia and the decline in the activities of daily living (ADL) in patients with SCA6 was obtained by a 3-year cohort study and a 7-year IDR study. The decline of the SARA score of patients with SCA6 was 1.33 ± 1.40 points/year. The results elucidate the natural history of SCA6, factors influencing disease severity, and utility of data from the IDR registry of Japan.

Leber's Hereditary Optic Neuropathy with Olivocerebellar Degeneration due to G11778A and T3394C Mutations in the Mitochondrial DNA.

BACKGROUND: Leber's hereditary optic neuropathy (LHON) is a mitochondrial disorder with optic nerve atrophy. Although there are no other associated neurological abnormalities in most cases of LHON, cases of "LHON plus" have been reported. CASE REPORT: The proband was a 37-year-old man who had visual and gait disturbances that had first appeared at 10 years of age. He showed horizontal gaze palsy, gaze-evoked nystagmus, dysarthria, and cerebellar ataxia. Brain and orbit MRI disclosed atrophy of the optic nerve and cerebellum, and degenerative changes in the bilateral inferior olivary nucleus. Mutational analyses of mitochondrial DNA identified the coexistence of heteroplasmic G11778A and homoplasmic T3394C mutations. CONCLUSIONS: These results suggest that the combination of G11778A and T3394C mutations leads to an atypical LHON phenotype.

Comparison of the clinical features of rapid eye movement sleep behavior disorder in patients with Parkinson's disease and multiple system atrophy.

AIMS: The aim of this study was to evaluate differences in the clinical presentation and polysomnographic characteristics of rapid eye movement sleep behavior disorder (RBD) between patients with Parkinson's disease (PD) and those with multiple system atrophy (MSA). METHODS: We conducted clinical interviews examining RBD symptoms, including violent and non-violent behaviors, in 49 patients with PD and 16 patients with MSA (as well as their bed partners) and performed polysomnography on all subject patients. RESULTS: Twenty-seven patients with PD (55.1%) and 11 patients with MSA (68.8%) had rapid eye movement sleep without atonia (RWA) on polysomnogram. The relative amounts of RWA were quite similar between the two groups. For most of the RWA-positive patients in both groups, RBD symptoms remained non-violent or silent. RBD symptoms in PD patients seemed to increase with the course of PD, while most of the RBD symptoms in the MSA patients occurred just prior to or at the onset of MSA and then disappeared within a short period. CONCLUSION: Although PD and MSA frequently accompany RWA, RBD symptoms often remain non-violent or silent. Differences in the course of RBD symptoms in patients with PD and MSA may reflect the difference in the degeneration process of the two disorders.

Clinicopathological features of acute autonomic and sensory neuropathy.

Acute autonomic and sensory neuropathy is a rare disorder that has been only anecdotally reported. We characterized the clinical, electrophysiological, pathological and prognostic features of 21 patients with acute autonomic and sensory neuropathy. An antecedent event, mostly an upper respiratory tract or gastrointestinal tract infection, was reported in two-thirds of patients. Profound autonomic failure with various degrees of sensory impairment characterized the neuropathic features in all patients. The initial symptoms were those related to autonomic disturbance or superficial sensory impairment in all patients, while deep sensory impairment accompanied by sensory ataxia subsequently appeared in 12 patients. The severity of sensory ataxia tended to become worse as the duration from the onset to the peak phase of neuropathy became longer (P<0.001). The distribution of sensory manifestations included the proximal regions of the limbs, face, scalp and trunk in most patients. It tended to be asymmetrical and segmental, rather than presenting as a symmetric polyneuropathy. Pain of the involved region was a common and serious symptom. In addition to autonomic and sensory symptoms, coughing episodes, psychiatric symptoms, sleep apnoea and aspiration, pneumonia made it difficult to manage the clinical condition. Nerve conduction studies revealed the reduction of sensory nerve action potentials in patients with sensory ataxia, while it was relatively preserved in patients without sensory ataxia. Magnetic resonance imaging of the spinal cord revealed a high-intensity area in the posterior column on T(2)*-weighted gradient echo image in patients with sensory ataxia but not in those without it. Sural nerve biopsy revealed small-fibre predominant axonal loss without evidence of nerve regeneration. In an autopsy case with impairment of both superficial and deep sensations, we observed severe neuronal cell loss in the thoracic sympathetic and dorsal root ganglia, and Auerbach's plexus with well preserved anterior hone cells. Myelinated fibres in the anterior spinal root were preserved, while those in the posterior spinal root and the posterior column of the spinal cord were depleted. Although recovery of sensory impairment was poor, autonomic dysfunction was ameliorated to some degree within several months in most patients. In conclusion, an immune-mediated mechanism may be associated with acute autonomic and sensory neuropathy. Small neuronal cells in the autonomic and sensory ganglia may be affected in the initial phase, and subsequently, large neuronal cells in the sensory ganglia are damaged.

Validation of the Parkinson's disease sleep scale in Japanese patients: a comparison study using the Pittsburgh Sleep Quality Index, the Epworth Sleepiness Scale and Polysomnography.

OBJECTIVE: Characteristic sleep disturbance in patients with Parkinson's disease (PD) was evaluated using a subjective questionnaire called the PD sleep scale (PDSS). In this study we sought to examine the relationship between the results from the PDSS with those from the Pittsburgh Sleep Quality Index (PSQI), the Epworth Sleepiness Scale (ESS), and polysomnography (PSG) in Japanese PD patients. SUBJECTS AND METHODS: Subjects were 79 PD patients and 79 age and gender matched controls. The length of morbidity in patients with PD was 8.4+/-8.0 years, and their Hoehn and Yahr grade was 2.9+/-1.0. All subjects completed the PDSS, PSQI, and ESS questionnaires, and we compared the results from patients with PD to controls. We also evaluated the correlation among the PDSS, PSQI, and ESS in patients with PD. Moreover, we performed PSG on 33 of 79 PD patients, and examined the correlation between the PDSS and PSG. RESULTS: PDSS total scores and subscales from patients with PD were significantly lower than those in controls, except for items 3, 8, and 14. PDSS scores had significant internal consistency and significant correlation with PSQI and ESS scores. The total PDSS score also correlated with sleep efficiency as measured by PSG. In subscales of the PDSS, night psychosis was negatively correlated with percentage of REM sleep without atonia on PSG. DISCUSSION: Based on our comparisons with PSQI, ESS, and PSG, the PDSS appears to be a reliable tool to evaluate the characteristics of sleep disturbances in PD patients.

[Reliability of the Japanese version of the Scale for the Assessment and Rating of Ataxia (SARA)].

BACKGROUND: The International Cooperative Ataxia Rating Scale (ICARS) is widely used as a scale for the assessment of the severity of cerebellar ataxia. However, this scale comprises several items; thus, making the application of this scale is not sufficiently practical to perform daily assessment of ataxic patients. A new rating scale--Scale for the Assessment and Rating of Ataxia (SARA)--was shown to provide highly reliable assessments; further, the scores on SARA correlated with the ICARS score and the Barthel index. After obtaining the permission, original SARA was translated into Japanese. OBJECTIVE AND METHODS: To examine the reliability and internal consistency of the Japanese version of the SARA for the assessment of cerebellar ataxia in 66 patients with spinocerebellar degeneration. RESULTS: Intraclass coefficients (ICC) were observed to be greater than 0.8 except in the case of the inter-rater "finger chase" and "fast alternating hand movement" tests. CONCLUSIONS: The Japanese version of SARA is highly reliable and very useful for the assessment of cerebellar ataxia on a daily basis.

Adherent monomer-misfolded SOD1.

BACKGROUND: Multiple cellular functions are compromised in amyotrophic lateral sclerosis (ALS). In familial ALS (FALS) with Cu/Zn superoxide dismutase (SOD1) mutations, the mechanisms by which the mutation in SOD1 leads to such a wide range of abnormalities remains elusive. METHODOLOGY/PRINCIPAL FINDINGS: To investigate underlying cellular conditions caused by the SOD1 mutation, we explored mutant SOD1-interacting proteins in the spinal cord of symptomatic transgenic mice expressing a mutant SOD1, SOD1(Leu126delTT) with a FLAG sequence (DF mice). This gene product is structurally unable to form a functional homodimer. Tissues were obtained from both DF mice and disease-free mice expressing wild-type with FLAG SOD1 (WF mice). Both FLAG-tagged SOD1 and cross-linking proteins were enriched and subjected to a shotgun proteomic analysis. We identified 34 proteins (or protein subunits) in DF preparations, while in WF preparations, interactions were detected with only 4 proteins. CONCLUSIONS/SIGNIFICANCE: These results indicate that disease-causing mutant SOD1 likely leads to inadequate protein-protein interactions. This could be an early and crucial process in the pathogenesis of FALS.

A novel cell transplantation protocol and its application to an ALS mouse model.

Amyotrophic lateral sclerosis (ALS) is a lethal neurodegenerative disease, which selectively affects motor neurons throughout the central nervous system. The extensive distribution of motor neurons is an obstacle to applying cell transplantation therapy for the treatment of ALS. To overcome this problem, we developed a cell transplantation method via the fourth cerebral ventricle in mice. We used mouse olfactory ensheathing cells (OECs) and rat mesenchymal stem cells (MSCs) as donor cells. OECs are reported to promote regeneration and remyelination in the spinal cord, while MSCs have a capability to differentiate into several types of specific cells including neural cells. Furthermore both types of cells can be relatively easily obtained by biopsy in human. Initially, we confirmed the safety of the operative procedure and broad distribution of grafted cells in the spinal cord using wild-type mice. After transplantation, OECs distributed widely and survived as long as 100 days after transplantation, with a time-dependent depletion of cell number. In ALS model mice, OEC transplantation revealed no adverse effects but no significant differences in clinical evaluation were found between OEC-treated and non-transplanted animals. After MSC transplantation into the ALS model mice, females, but not males, showed a statistically longer disease duration than the non-transplanted controls. We conclude that intrathecal transplantation could be a promising way to deliver donor cells to the central nervous system. Further experiments to elucidate relevant conditions for optimal outcomes are required.

Mitochondrial changes in motor neurons of homozygotes of leucine 126 TT deletion SOD1 transgenic mice.

We investigated the time course of ultrastructural changes of mitochondria in the spinal cord of homozygotes of Leu126TTdel SOD1 (superoxide dismutase 1) with FLAG (signal sequence at the C-terminal protein) transgenic mice (DF-homo). Non-Tg mice and wild-type human SOD1 with FLAG epitope transgenic mice (WF) were investigated as controls for non-onset Tg mice. Expansion and vacuolation of the mitochondrial matrix was exhibited in motor neurons in the anterior horns of DF-homo Tg mice at the presymptomatic stage. Such mitochondrial degeneration became severe at the postsymptomatic stage. In contrast, expansion of the mitochondrial inner-membrane space was not evident even at the terminal stage. Microvacuoles of cytoplasm and fibrillar inclusions were rarely shown from the early symptomatic stage. WF mice showed expansion and vacuolation of the mitochondrial inner membrane space at old age. Non-Tgs showed no obvious change in mitochondria. Gold-labeled human SOD1 immunoreactivity showed small amount of gold deposits in the vacuolated mitochondria. These results suggest that the expansion and vacuolation of mitochondrial matrix in the spinal cord of DF-homo transgenic mice is the first pathological change, but that it is not directly caused by the aggregation of an abnormal human SOD1 protein in intermembrane space of mitochondria.

Gene expression analysis of the murine model of amyotrophic lateral sclerosis: studies of the Leu126delTT mutation in SOD1.

The pathogenic events that lead to amyotrophic lateral sclerosis (ALS) have not been elucidated. We previously described familial amyotrophic lateral sclerosis (FALS) caused by a Leu126delTT mutation in the Cu/Zn superoxide dismutase gene (SOD1) and have produced transgenic mice (TgM) carrying the same mutation (SOD1(L126delTT) TgM), which exhibited distinct ALS-like motor symptoms and pathological findings. In this study, we analyzed gene expression in the spinal cord of SOD1(L126delTT) TgM by cDNA microarray. Eleven genes were upregulated and two genes downregulated in pre-symptomatic TgM. In post-symptomatic TgM, 54 genes were upregulated and four genes downregulated. We performed real-time polymerase chain reaction (PCR) analysis of 10 of the 54 upregulated genes in the post-symptomatic TgM. The results of real-time PCR were consistent with those obtained by microarray for micro-crystallin (Crym), heat shock protein 1 (Hspb1/HSP27), serine proteinase inhibitor clade A member 3N (Serpina3n), complement component 1q subcomponent beta polypeptide (C1qb), cathepsin H (Ctsh) and polyadenylate binding protein-interacting protein 1 (Paip1). In immunohistochemical analysis, Hsbp1/HSP27 and Ctsh expression levels were increased in reactive astrocytes at the ventral horn of the spinal cord in post-symptomatic TgM, as were Crym, some of Ctsh and Paip1 in microglial cells. Increased expression of those genes was not observed in the control mice. These four genes may be related to the pathogenesis of FALS, especially with regard to the progression of reactive astrocytes and the inflammatory response of microglial cells.

CSF orexin levels of Parkinson's disease, dementia with Lewy bodies, progressive supranuclear palsy and corticobasal degeneration.

Excessive daytime sleepiness has been widely accepted as a common problem not only in Parkinson's disease (PD) but also in other related disorders. Lowered excretion of orexin A (hypocretin 1) into the cerebrospinal fluid (CSF) is known to play a pathological role in narcolepsy and secondary hypersomnia due to hypothalamic dysfunction. Although the levels of CSF orexin in PD have been previously examined, the results have been controversial, and no systematic investigation of CSF orexin excretion has been conducted on PD related disorders. In this study, orexin was measured in CSF collected by lumbar puncture in 62 patients with PD, 13 patients with dementia with Lewy bodies (DLB), 16 patients with progressive supranuclear palsy (PSP), and 7 patients with corticobasal degeneration (CBD). Levels of CSF orexin (mean+/-SD pg/ml) were 302+/-38 in PD, 297+/-48 in DLB, 258+/-37 in PSP, 246+/-90 in CBD. The occurrence of low orexin levels (

Detection of compound heterozygous deletions in the parkin gene of fibroblasts in patients with autosomal recessive hereditary parkinsonism (PARK2).

Mutations in the parkin gene are a common cause of autosomal recessive, juvenile or early onset parkinsonism (PARK2). In this report, we use RT-PCR to detect compound heterozygous deletions of the parkin gene in fibroblasts from two cases of middle age-onset familial parkinsonism with lower extremities-dominant resting tremor and mild cogwheel rigidity. Although exonic amplification of the parkin gene showed a deletional mutation of exon 3-4, their family histories suggested that the deletional mutations were a compound heterozygous abnormality of discrete origin. Immunoblotting demonstrated that abundant Parkin protein was expressed in fibroblasts, but little expression was detected in lymphocytes. RT-PCR using RNA isolated from the patients' fibroblasts indicated a parkin mutation in this family that consisted of compound heterozygous deletions (del exon3-4/del exon3-5). These results suggest that RT-PCR using the patients' fibroblasts may be helpful for the detection of compound heterozygous abnormalities in the parkin gene.

Prevalence and clinical characteristics of restless legs syndrome in Japanese patients with Parkinson's disease.

To explore the clinical significance of restless legs syndrome (RLS) in Parkinson's disease (PD) and the causal relationship between these two disorders, we made a comparison of both the prevalence of RLS and the severity of sleep disturbance manifested on the Pittsburg Sleep Quality Index (PSQI) between patients with PD (n=165) and age- and sex-matched control subjects (n=131). The prevalence of RLS diagnosed by clinical interview was significantly higher in PD patients than in control subjects (12% vs. 2.3%). PSQI score was significantly higher in PD patients with RLS than in both patients without RLS and controls. However, PSQI score was not statistically different between the latter two groups. Among the PD patients with RLS, only 2 had a positive family history of RLS. Only 3 PD patients had requested treatment for the disorder. Our results emphasize the etiological link between RLS and PD in a Japanese cohort, and the existence of RLS is thought to be one of the most important factors aggravating sleep disturbance in PD, despite the low RLS severity.

Mouse motor neuron disease caused by truncated SOD1 with or without C-terminal modification.

Mutation of Cu/Zn superoxide dismutase (SOD1) contributes to a portion of the cases of familial amyotrophic lateral sclerosis (FALS). We previously reported on a FALS family whose members had a mutant form of SOD1 characterized by a 2-base pair (bp) deletion at codon 126 of the SOD1 gene. To investigate the cellular consequences of this mutation, we produced transgenic mice that expressed normal and mutated copies of human SOD1: wild-type SOD1 (W), wild-type SOD1 with a FLAG epitope at C-terminal (WF), mutated SOD1 with the 2-bp deletion (D), and SOD1 with the 2-bp deletion with FLAG (DF). The mice heterozygotic for the human mutated SOD1 (D and DF) showed distinct ALS-like motor symptoms, whereas the mice heterozygotic for the normal SOD1 (W and WF) mice did not. Homozygotes of D and DF lines showed the ALS symptoms at an earlier age and died earlier than the heterozygotes. By Northern blot analysis, the mRNAs for all human SOD1s were confirmed in these lines. All the human SOD1 proteins, except the D mutant, were detectable by immunoblot. The D protein was only confirmed when it was concentrated by immunoprecipitation. Neuropathologically, loss of spinal motor neurons and reactive gliosis were common features in the symptomatic lines. The remaining motor neurons in these mice also exhibited eosinophilic inclusions. The biochemical and pathological characteristics of these mice are quite similar to those of human FALS patients with same mutation. This intriguing model will provide an important source of information of the pathogenesis of FALS.