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A 36-year-old man with ulcerative colitis presented with bloody stools at the beginning of October 2020. His condition had been stable without treatment since diagnosis 4 years prior. He was administered 4,000 mg of salazosulfapyridine orally and the bloody stools resolved. Fifteen days after treatment, he was admitted to our hospital with swelling and pain in his right lower leg. Laboratory results revealed an elevated erythrocyte sedimentation rate (43 mm/hr) and mildly elevated C-reactive protein levels (4.08 mg/dl). His D-dimer level was also elevated at 7.6 μg/ml. MRI using fat saturated T

© 2020 Elsevier Ltd. All rights reserved., Background: Hereditary transthyretin-mediated amyloidosis is a rare, inherited, progressive disease caused by mutations in the transthyretin (TTR) gene. We assessed the safety and efficacy of long-term treatment with patisiran, an RNA interference therapeutic that inhibits TTR production, in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Methods: This multicentre, open-label extension (OLE) trial enrolled patients at 43 hospitals or clinical centres in 19 countries as of Sept 24, 2018. Patients were eligible if they had completed the phase 3 APOLLO or phase 2 OLE parent studies and tolerated the study drug. Eligible patients from APOLLO (patisiran and placebo groups) and the phase 2 OLE (patisiran group) studies enrolled in this global OLE trial and received patisiran 0·3 mg/kg by intravenous infusion every 3 weeks with plans to continue to do so for up to 5 years. Efficacy assessments included measures of polyneuropathy (modified Neuropathy Impairment Score +7 [mNIS+7]), quality of life, autonomic symptoms, nutritional status, disability, ambulation status, motor function, and cardiac stress, with analysis by study groups (APOLLO-placebo, APOLLO-patisiran, phase 2 OLE patisiran) based on allocation in the parent trial. The global OLE is ongoing with no new enrolment, and current findings are based on the interim analysis of the patients who had completed 12-month efficacy assessments as of the data cutoff. Safety analyses included all patients who received one or more dose of patisiran up to the data cutoff. This study is registered with ClinicalTrials.gov, NCT02510261. Findings: Between July 13, 2015, and Aug 21, 2017, of 212 eligible patients, 211 were enrolled: 137 patients from the APOLLO-patisiran group, 49 from the APOLLO-placebo group, and 25 from the phase 2 OLE patisiran group. At the data cutoff on Sept 24, 2018, 126 (92%) of 137 patients from the APOLLO-patisiran group, 38 (78%) of 49 from the APOLLO-placebo group, and 25 (100%) of 25 from the phase 2 OLE patisiran group had completed 12-month assessments. At 12 months, improvements in mNIS+7 with patisiran were sustained from parent study baseline with treatment in the global OLE (APOLLO-patisiran mean change -4·0, 95 % CI -7·7 to -0·3; phase 2 OLE patisiran -4·7, -11·9 to 2·4). Mean mNIS+7 score improved from global OLE enrolment in the APOLLO-placebo group (mean change from global OLE enrolment -1·4, 95% CI -6·2 to 3·5). Overall, 204 (97%) of 211 patients reported adverse events, 82 (39%) reported serious adverse events, and there were 23 (11%) deaths. Serious adverse events were more frequent in the APOLLO-placebo group (28 [57%] of 49) than in the APOLLO-patisiran (48 [35%] of 137) or phase 2 OLE patisiran (six [24%] of 25) groups. The most common treatment-related adverse event was mild or moderate infusion-related reactions. The frequency of deaths in the global OLE was higher in the APOLLO-placebo group (13 [27%] of 49), who had a higher disease burden than the APOLLO-patisiran (ten [7%] of 137) and phase 2 OLE patisiran (0 of 25) groups. Interpretation: In this interim 12-month analysis of the ongoing global OLE study, patisiran appeared to maintain efficacy with an acceptable safety profile in patients with hereditary transthyretin-mediated amyloidosis with polyneuropathy. Continued long-term follow-up will be important for the overall assessment of safety and efficacy with patisiran.

Huntington's disease (HD) is an inherited neurodegenerative disease caused by a polyglutamine repeat expansion in the huntingtin protein. Immunohistochemical studies using the 1C2 antibody for polyglutamine expansion have detected characteristic intranuclear inclusions (INIs) in affected neurons in HD. Further, in vitro and mouse models of HD have shown that the INIs recruit several proteins relating to RNA splicing and translation. In the present study, we immunohistochemically investigated the association of INIs with various heterogeneous nuclear ribonucleoproteins in the cerebral cortex of four autopsy cases of HD. Fused in sarcoma (FUS) was colocalized with 1C2-positive nuclear inclusions in all examined cases. Localization of poly (rC)-binding protein 1 (PCBP1) in 1C2-positive nuclear inclusions was also observed. Double immunofluorescence revealed complete or partial loss of the normal, diffuse nuclear distribution of FUS or PCBP1 in neurons with 1C2-positive nuclear inclusions. This maldistribution of FUS in cortical neurons suggests a severe disturbance of messenger RNA processing, which may be a common pathogenetic mechanism of FUS-related familial amyotrophic lateral sclerosis.

Background and objectives Meta-iodobenzylguanidine (MIBG) myocardial scintigraphy is an effective tool for distinguishing Parkinson's disease (PD) from other diseases accompanied by parkinsonism. Unlike other Parkinsonian diseases, in PD, MIBG accumulation in the heart tends to decrease. However, previous studies have reported that a decrease in MIBG accumulation also occurs in progressive supranuclear palsy (PSP). Thus, we analyzed the relationship between the degree of MIBG accumulation decrease, clinical symptoms, and brainstem atrophy in PSP. Methods We retrospectively collected data from patients who underwent MIBG myocardial scintigraphy and compared MIBG indices (heart to mediastinum [H/M] ratio, washout rate) between subjects with PSP and other diseases including PD. In addition, we evaluated the relationship between clinical characteristics, MIBG accumulation, and brainstem atrophy in patients with PSP. Results Patients with PSP had a significantly lower early H/M ratio compared with multiple system atrophy with predominant parkinsonism (MSA-P) patients, and a control group. In PSP patients there was a correlation between the decrease in delay H/M ratio, atrophy of the pons, and clinical severity as evaluated by Hoehn and Yahr score. Conclusion Unlike in PD, PSP patients exhibited a mild decrease in MIBG accumulation in MIBG myocardial scintigraphy, which may be related to brainstem atrophy.

Spastic paraplegia type 11 (SPG11) is the most common autosomal recessive hereditary spastic paraplegia with thinning of the corpus callosum. Spatacsin, a protein encoded by the SPG11 gene, is associated with autophagy. SPG11 patients show spastic paraplegia, intellectual disability, dementia, and parkinsonism. A previous neuropathological analysis of SPG11 cases reported neurodegeneration mimicking amyotrophic lateral sclerosis without transactivation response DNA-binding protein of 43 kDa (TDP-43) deposits and unique sequestosome 1 (SQSTM1)-positive neuronal inclusions. We performed a neuropathological examination of two Japanese patients with complicated spastic paraplegia with thinning of the corpus callosum from different families, and one was genetically diagnosed as having SPG11. Both cases showed diffuse atrophy of the brain and spinal cord. Depigmentation of the substantia nigra was also observed. Immunohistochemistry revealed widespread distribution of areas showing TDP-43 aggregation in the central nervous system. The TDP-43 deposits in the thalamus and substantia nigra especially resembled skein-like inclusions. Unique SQSTM1-positive neuronal inclusions, as previously reported, were widespread in the whole central nervous system as well as the dorsal root ganglia. Double-labeling immunofluorescence of the dorsal root ganglia revealed that the unique, large SQSTM1-positive cytoplasmic inclusions of the ganglion cells were labeled with lysosome-associated membrane protein 1 and lysosome-associated membrane protein 2. This is the first report showing TDP-43 pathology in SPG11. The common neuropathological findings of TDP-43-positive inclusions in both the cases imply a causal connection between the TDP-43 proteinopathy and autophagy dysfunction in SPG11.

There are no specific radiologic features in MOG-Ab (autoantibodies directed against myelin oligodendrocyte glycoprotein)-associated diseases. We present two MOG-Ab-positive patients with symmetrical lesions in the bilateral cingulate cortex of the frontal and parietal lobes. Those lesions showed hyperperfusion in acute phase and hypoperfusion in chronic phase on brain SPECT. In both patients, steroid therapy was effective in acute phase and for prevention of recurrence. High signal in the bilateral cingulate cortex on MR T2-weighted and FLAIR images might to be one of the unique findings considered MOG-Ab associated diseases.

Rett syndrome (RTT) is a neurodevelopmental disorder mainly caused by mutations in the gene encoding the transcriptional regulator Methyl-CpG-binding protein 2 (MeCP2), located on the X chromosome. Many RTT patients have breathing abnormalities, such as apnea and breathing irregularity, and respiratory infection is the most common cause of death in these individuals. Previous studies showed that MeCP2 is highly expressed in the lung, but its role in pulmonary function remains unknown. In this study, we found that MeCP2 deficiency affects pulmonary gene expression and structures. We also found that Mecp2-null mice, which also have breathing problems, often exhibit inflammatory lung injury. These injuries occurred in specific sites in the lung lobes. In addition, polarizable foreign materials were identified in the injured lungs of Mecp2-null mice. These results indicated that aspiration might be a cause of inflammatory lung injury in Mecp2-null mice. On the other hand, MeCP2 deficiency affected the expression of several neuromodulator genes in the lower brainstem. Among them, neuropeptide substance P (SP) immunostaining was reduced in Mecp2-null brainstem. These findings suggest that alteration of SP expression in brainstem may be involved in autonomic dysregulation, and may be one of the causes of aspiration in Mecp2-null mice.

We describe two cases of typical essential tremor with aspartic acidemia and mildly increased concentrations of plasma glutamic acid. Although this is a preliminary report, we emphasize the possibility of using amino acids, including aspartic acid, as biomarkers for the detection of essential tremor.

Many claim that they do not have enough neurologists in Japan, but supply and demand of neurologists remains to be analyzed. To investigate the recruitment for the Japanese Society of Neurology (JSN), the subcommittee of JSN for education performed a questionnaire-based survey in 80 medical universities and 271 board-certified education facilities throughout Japan. The response rate to the questionnaire was 77.5% in medical universities and 42.4% in education facilities. It was shown that each department of neurology in university recruits average 2.2 doctors, while they supposed that more than 4 doctors to be recruited every year. The questionnaire survey included what measures JSN should take in order to promote recruitment for JSN.

Distal hereditary motor neuropathies (dHMNs) comprise a group of clinically and genetically heterogeneous inherited lower motor neuron syndromes mainly characterized by a distal-predominant pattern of progressive muscle atrophy, weakness and hyporeflexia, without sensory dysfunction. Although at least 21 causative genes for dHMN have been reported, mutational scanning of these genes often fails to identify the causative variants in dHMN cohorts, suggesting that additional causative genes remain to be identified. We studied a four-generation pedigree of a Japanese family with autosomal dominant dHMN to provide insight into the pathogenetic basis of the disease. Neurological examinations were performed on all six family members enrolled in this study. Whole-exome sequencing (WES) was used to identify the causative gene for dHMN. The clinical features of the patients included muscle weakness with distal extensor dominancy in the lower extremities, accompanied by facial and neck flexor muscle impairment, no sensory involvement, and areflexia. Nerve conduction studies demonstrated axonal changes mainly in the peroneal nerve. WES combined with rigorous filtering revealed three missense variants (NM_001083964: c.851G > A [p.Arg284His] in TDRKH, NM_002858: c.1654G > T [p.Gly552Cys] in ABCD3, NM_001005164: c.898A > T [p.Ile300Phe], in OR52E2). The variant in TDRKH is located in a conserved region of the tudor domain which is also present in the survival of motor neuron (SMN) protein, encoded by the SMN1 gene. Therefore, we concluded the variant in TDRKH is likely to be responsible for dHMN in our pedigree.

Spinocerebellar ataxia 27 (SCA27) is an autosomal dominant SCA caused by variants in the fibroblast growth factor 14 (FGF14) gene. We examined a Japanese SCA patient whose deceased father also suffered from SCA. The patient was a 63-year-old male. He graduated from junior high school but received no further education. The predominant complaint was slowly progressive dysarthria and gait disturbance, which appeared at age 47. He showed pathological saccadic dysmetria, saccadic intrusions into smooth pursuit eye movements, dysarthria, and limb and truncal ataxia. His gait was wide-based but he did not require a walking stick. Limb muscle strength was intact. Deep tendon reflexes were normal or slightly reduced. Pathological reflexes were absent. He demonstrated mildly impaired vibration sense in the lower limbs. There was no urinary dysfunction. Brain MRI showed cerebellar atrophy without brainstem involvement. We first confirmed the absence of repeat expansion in genes known to be responsible for SCAs 1-3, 6-8, 10, 12, 17, 36 and dentatorubral-pallidoluysian atrophy. By exome analysis, we identified a novel heterozygous variant (NM_004115, c.529A>T; Lys177X) in exon 4 of the FGF14 gene. This variant is expected to generate a truncated FGF14 protein lacking the heparin binding sites, those are likely to modify the activity of FGF14. We confirmed the absence of the variant in 502 healthy Japanese individuals by Sanger sequencing. There is no record of the variant in public databases. We conclude that the novel variation in FGF14 is causative for SCA27 in this patient.

Dominant intermediate Charcot-Marie-Tooth disease F (CMTDIF) is an autosomal dominant hereditary form of Charcot-Marie-Tooth disease (CMT) caused by variations in the guanine nucleotide-binding protein, subunit beta-4 gene (GNB4). We examined two Japanese familial cases with CMT. Case 1 was a 49-year-old male whose chief complaint was slowly progressive gait disturbance and limb dysesthesia that appeared at the age of 47. On neurological examination, he showed hyporeflexia or areflexia, distal limb muscle weakness, and distal sensory impairment with lower dominancy. Nerve conduction studies demonstrated demyelinating sensorimotor neuropathy with reduced action potentials in the lower limbs. Case 2 was an 80-year-old man, Case 1's father, who reported difficulty in riding a bicycle at the age of 76. On neurological examination, he showed areflexia in the upper and lower limbs. Distal sensory impairment in the lower limbs was also observed. Nerve conduction studies revealed mainly axonal involvement. Exome sequencing identified a novel heterozygous nonsynonymous variant (NM_021629.3:c.659T > C [p.Gln220Arg]) in GNB4 exon 8, which is known to be responsible for CMT. Sanger sequencing confirmed that both patients are heterozygous for the variation, which causes an amino acid substitution, Gln220Arg, in the highly conserved region of the WD40 domain of GNB4. The frequency of this variant in the Exome Aggregation Consortium Database was 0.000008247, and we confirmed its absence in 502 Japanese control subjects. We conclude that this novel GNB4 variant is causative for CMTDIF in these patients, who represent the first record of the disease in the Japanese population.

To understand the status of postgraduate education in neurology in Japan, the Committee for the Education of Undergraduate Students and Junior Residents within the Japanese Society of Neurology investigated the four-year trend at 80 medical schools from 2009 to 2012. The mean number of new students to each postgraduate school increased from 1.24 to 1.67 during these four years. After training clinical neurology, more than half of the neurological residents entered the postgraduate schools. Students in the postgraduate schools seemed to be researching major neurological diseases using various methods at each neurology laboratory. However, some problems were suggested. First, the mean number of newcomers to the neurology departments of the universities decreased gradually from 2.29/year to 1.96/year. Second, many of the postgraduate students were working in patient services at university hospitals or as part-time workers at other hospitals, and may not have sufficient time for their research projects. Third, many of the postgraduate students were carrying out research at each affiliated department of neurology, and may not have the opportunity to work in laboratories specializing in basic science. Finally, there may not be sufficient opportunities for further research at other laboratories in Japan or overseas after they finished their work at postgraduate school.

Parkinson's disease (PD) reportedly includes altered connectivity of neural loops involving the basal ganglia and cerebellum, although little is known regarding any changes in the connectivity of motor loops. The goal of this study was to further understand the connectivity within the basal ganglia–thalamo-motor (BGTM) and cerebro-cerebellar (CC) loops in PD. Twelve PD patients and 12 age-matched control subjects performed a protocol involving self-initiated (SI) and externally-triggered (ET) finger movements, while being scanned with functional magnetic resonance imaging. Compared with the control subjects, the PD subjects showed hypo-activation in the bilateral putamen, right supplementary motor area and hyper-activation in the right premotor cortex. In the sensorimotor cortex and cerebellar hemisphere, PD subjects tended to show hyper-activation in a main effects analysis, but hypo-activation in a linear effects analysis. Analysis using structural equation modeling (SEM) revealed significant positive interactions within the right BGTM loop during the SI task and within the right (right cerebral hemisphere–left cerebellum) CC loop during the ET task. SEM also revealed task-related quantitative changes between the thalamus and the motor cortices in the control subjects. We found that the PD patients showed reduced connectivity in the right BGTM loop and inter-hemispheric connections in SEM, which is the first demonstration of this phenomenon. Interestingly, PD patients exhibited preserved connectivity within the right CC loop during the ET task. These results suggest disruption of cortico-striatal processing and preservation of relatively intact neural circuits that do not involve the basal ganglia in PD.

Background Anhedonia, a lowered ability to experience physical or social pleasure, has recently been recognized as a non-motor symptom of Parkinson's disease. Objective To identify the frequency of anhedonia and the factors influencing hedonic tone in Japanese patients with Parkinson's disease. Patients and methods We recruited 86 consecutive outpatients with a clinical diagnosis of PD attending two Japanese hospitals (one university hospital and one community hospital) in February 2010. We used the self-rating Snaith–Hamilton Pleasure Scale (SHAPS) translated into Japanese language from the original English version to assess and quantify hedonic tone as a subjectively experienced phenomenon. We studied the association of anhedonia with the variables age, age at onset, gender, disease duration, disease severity and antiparkinsonian drugs. Results Thirty-nine patients (45%) were male and 47 (55%) were female. Mean age was 72.01 ± 9.07 (49–89) years, with mean age at onset of 64.93 ± 11.42 (31–88) years. Mean disease duration was 7.20 ± 5.54 (1–23) years. The mean Hoehn and Yahr scale was 2.76 ± 0.78. The mean SHAPS score of the total sample was 1.19 ± 1.86. The SHAPS score of 14 patients (16.3%) was 3 or more, indicating anhedonia. The mean SHAPS score was lower in patients taking pramipexole (0.58 ± 0.97) than in patients not taking pramipexole (1.57 ± 2.16). Multiple linear regression analysis identified pramipexole as a significant negative influencing factor on the SHAPS score, while disease severity and entacapone treatment were identified as positive influencing factors. The age, onset age, gender, disease duration, and use of pergolide, amantadine, zonisamide, selegiline, anticholinergic agents and droxidopa did not significantly affect the SHAPS score. Conclusion Anhedonia is not rare non-motor symptom in Japanese patients with Parkinson's disease. This study suggests an anti-anhedonic property of pramipexole.

Presenilin 1 (PS1) gene mutations are the major causes of early-onset familial Alzheimer's disease and are known to increase amyloid-beta42 (Abeta42) production as well as to promote apoptosis. We have recently reported that intracellular Abeta42 activates p53 mRNA expression and promotes p53-dependent apoptosis. Here, we examined the p53 mRNA and protein levels in cells transfected with wild-type and I143T/G384A mutant PS1 genes. Although the baseline p53 mRNA levels remained unaltered, the p53 protein levels were significantly elevated in mutant PS1-transfected cells. Treatments with apoptosis-inducing agents induced significant elevation of the p53 protein but not p53 mRNA levels in mutant PS1-transfected cells. Treatment with a beta-secretase inhibitor and gamma-secretase inhibitor decreased the intracellular Abeta levels in amyloid-beta protein precursor (AbetaPP) and PS1-double transfected cells, and restrained upregulation of the p53 protein levels in the mutant PS1-transfected cells. Also, we found that proteasome activity was decreased in mutant PS1-transfected cells compared to wild-type PS1-transfected cells. Proteasome activity was further decreased in AbetaPP/PS1-double transfected cells. Taken together, p53-dependent apoptosis upregulated by the I143T/G384A mutant PS1 gene may be associated, at least in part, with intracellular Abeta and proteasome impairment.

Two cases of spinocerebellar ataxia type 14 (SCA14) with a G128D mutation in the protein kinase C gamma gene (PRKCG) without a definite family history have been reported previously. Here, we describe the first familial cases of SCA14 with a G128D mutation in PRKCG. Among three family members, the chief complaints varied and included ataxic gait, cervical dystonia, and positional vertigo. Moreover, retinal degeneration and facial muscle weakness were observed, although these are not expected to be present in SCA14. Cerebral blood flow evaluation using single photon emission computed tomography (SPECT) also differed among family members. It is possible that patients with the G128D mutation suffering from SCA14 may sometimes be classified as unaffected due to the varying clinical signs among family members.

It is not fully understood how the stimulus/response curves obtained by transcranial magnetic stimulation (TMS) reflect the function of the cortico-motoneuronal (CM) and spinal motoneuronal (SM) systems in healthy subjects. To understand these response functions, we studied patients with amyotrophic lateral sclerosis (ALS) whose upper but not lower motor neurons were affected.First, we determined the effects of voluntary muscle contraction and intensity of TMS on the motor evoked potentials (MEPs) of the first dorsal interossei (FDI) muscle in ten healthy control subjects (mean age: 35.1 +/- 6.7 years) and two older female subjects (60 and 64 years old). Second, we investigated whether this relationship was altered in two ALS patients (60-year-old woman and 69-year-old man). The MEPs were recorded at different degrees of voluntary contraction by threshold stimulus intensities (TSIs) or at different levels of TMS with the muscle at rest.In the controls, the MEP amplitudes of the FDI muscle elicited by TSI increased linearly with muscle contraction (right: Y = 0.068X + 0.754; left: Y = 0.0670X + 0.807), whereas the MEP amplitudes elicited by different TMS intensities increased sigmoidally with a flexion point at 1.10-1.15 TSI: right: Amp = 2.21/[1 + exp[(S50-Stim)/K]], S50 = 10.73, K = 4.70; left: Amp = 2.90/[1 + exp[(S(50)-Stim)/K]], S50 = 13.64, K = 5.98. The latter was abnormal only on one side of each ALS patient.From these results, we suggest that the sigmoidal TMS intensity-size curves reflect mainly CM activities, while the linear contraction-size curves reflect SM activities.

We studied a four-generation pedigree of a Japanese family with hereditary neuropathy to elucidate the genetic basis of this disease. Twelve members of the family were enrolled in this study. The clinical features were neurogenic muscle weakness with proximal dominancy in the lower extremities, sensory involvement, areflexia, fine postural tremors, painful muscle cramps, elevated creatine kinase levels, recurrent paroxysmal dry cough, and neurogenic bladder. We performed a genome-wide search using genetic loci spaced at about 13 Mb intervals. Although nine chromosomes (1, 3, 4, 5, 6, 10, 17, 19, and 22) had at least one region in which the logarithm of odds (LOD) score was over 1.0, no loci fulfilled the criteria for significant evidence of linkage. Moreover, we analyzed an extra 14 markers on 3p12-q13 (the locus of hereditary motor and sensory neuropathy, proximal dominant form) and an extra five markers on 3p22-p24 (the locus of hereditary sensory neuropathy with chronic cough) and observed LOD scores of

We have previously mapped autosomal dominant spinocerebellar ataxia (SCA) 16 to 3p26, overlapping with the locus of SCA15. Recently, partial deletions of ITPR1 and the neighbouring SUMF1 in the SCA15 and two additional families were reported. In the present study we determined the copy number of these genes by real time quantitative polymerase chain reaction (PCR) and found a heterozygous deletion of exons 1-48 of ITPR1, but not SUMF1 in SCA16. Breakpoint analysis revealed that the size of the deletion is 313,318 bp and the telomeric breakpoint is located in the middle of their intergenic region. Our data provide evidence that haploinsufficiency of ITPR1 alone causes SCA16 and SCA15.

Amyloid beta-protein ending at 42 (Abeta42) is the major peptide deposited in Alzheimer's disease (AD) brain. In immunocytochemical studies, formic acid treatment is used to dramatically enhance Abeta immunoreactivity. Recently, Abeta42 has been reported to accumulate in AD neurons. Since heating is known to enhance intracellular protein immunoreactivity, we used an autoclaving protocol to enhance intraneuronal Abeta42 immunoreactivity. Using this protocol, both anti-Abeta42 N-terminal and C-terminal antibodies, but not anti-Abeta40 C-terminal antibody, labeled AD neurons. Moreover, formic acid treatment counteracted such effects of autoclaving. Thus, intraneuronal Abeta42 accumulation may have been underestimated by conventional methods using formic acid only.

Persistent elevation of serum creatine kinase (CK) without any symptoms has been called idiopathic hyper CK-emia (IHCK). We examined a four-generation Japanese pedigree of familial IHCK. The multipoint linkage analysis of the pedigree showed seven clear peaks of logarithm of odds (LOD) scores (>1.4). By the exome sequencing followed by multiple filtering processes, we identified one novel heterozygous nonsynonymous single nucleotide variant (SNV), c.7034G>C, p.S2345T in the ryanodine receptor 1 gene, RYR1 cosegregated with IHCK in the pedigree. Mutation Taster predicted this substitution as "disease causing" (p=0.999). The PolyPhen-2 and PANTHER subPSEC scores for the substitution are 0.911 (possibly damaging) and -3.56 (probably damaging), respectively. We confirmed the absence of the SNV in 511 healthy Japanese individuals excluding the possibility of a normal variant with a very low frequency. Immunohistochemistry and Western blotting of biopsy samples consistently showed the expression level of RYR1 reduced in the patient. In real-time RT-PCR, the mRNA expression level of RYR1 was also significantly reduced in the patient (p=0.009). These results suggest that the novel nonsynonymous SNV contribute to the vulnerability of the RYR1 protein through the dominant negative effect. We conclude that the SNV in the RYR1 gene is one of the responsible genes of IHCK.

Objective: To identify of the gene responsible for the onset of spinocerebellar ataxia type 16 (SCA16). Methods: We reanalyzed the linkage of the original Japanese pedigree using updated information, including three additional subjects. We then screened all exons located in the critical region. Results: We reassigned the locus of SCA16 to 3p26.2-pter (maximum logarithm-of-odds score = 5.177) and identified only one point mutation (4,256C→T) in the 3′ untranslated region of the contactin 4 gene (CNTN4) on chromosome 3p26.2-26.3, which cosegregated with the disease. This mutation was not detected in 520 control subjects; moreover, we revised the phenotype of SCA16 from pure to complicated SCA. Conclusion: The contactin 4 gene (CNTN4) is associated with cerebellar degeneration in spinocerebellar ataxia type 16. Additional studies are necessary to prove 4,256C→T to be a causative mutation.

A 66-year-old man with idiopathic cranial pachymeningoencephalitis was described. He suffered from left orbital pain, and character changes. He became short tempered, and was very attached to trifles. Two years prior to these symptoms, he had developed transient left abducent nerve palsy. Head MRI showed a thickening and enhancement of the dura mater on gadolinium-enhanced T1-weighted images, and high signal intensity lesions at bilateral frontal lobes predominantly in the white matter on T2-weighted images. Biopsies revealed microglial proliferation in the cerebral parenchyma, and mild lymphocytic perivascular infiltration. No evidence of intracranial infection was detected. We therefore treated him with methylprednisolone pulse therapy followed by oral prednisolone. His character became gradually normalized, and bilateral frontal lobe lesions seen on MRI disappeared. This is the first case to describe recurrent pachymeningoencephalitis with character changes, and symptoms were probably due to frontal lobe dysfunction.

Vascular permeability changes precede the development of demyelinating lesions in multiple sclerosis (MS), and vessel wall thickening and capillary proliferation are frequently seen in autopsied MS lesions. Although vascular growth factors are critical for inducing such vascular changes, their involvement in MS has not been extensively studied. Thus, we examined the involvement of various vascular growth factors in MS according to their clinical phase and subtype. We measured serum levels of vascular endothelial growth factor (VEGF), acidic and basic fibroblast growth factors (FGF) and platelet-derived growth factors (PDGFs)-AA, -AB and -BB in 50 patients with MS (27 opticospinal MS and 23 conventional MS patients) and 33 healthy controls using sandwich enzyme immunoassays. Correlations between growth factor changes and brain and spinal cord MRI findings were then analyzed. Serum VEGF concentrations were significantly higher in MS patients in relapse than in controls (p = 0.0495) and in MS patients in remission (p = 0.0003), irrespective of clinical subtype. Basic FGF was significantly increased in conventional MS patients, but not opticospinal MS patients compared with controls (p = 0.0291), irrespective of clinical phase. VEGF at relapse showed a significant positive correlation with the length of spinal cord lesions on MRI (r = 0.506, p = 0.0319). The results suggest that an increase in serum VEGF concentration might be involved in MS relapse and the formation of longitudinally extensive spinal cord lesions.

We recorded conjugate eye movements to elucidate whether ocular dominancy was present at reading distance in 21 normal volunteers with the right-handedness by using a video-oculographic (VOG) measurement. This included the velocity of smooth pursuits, and the latency and velocity of saccades. We defined the dominant eye for each subject by means of the near-far alignment test and 20 subjects showed the right dominant eyes. Although the ocular dominancy was not found in the velocity of smooth pursuit and vertical saccades, the velocity of horizontal saccades in the dominant eyes was faster than that in the non-dominant eyes. These results suggest that the dominant eye is functionally activated prior to non-dominant eye in horizontal saccades at reading distance, which thus indicates the functional dominancy of the dominant eye in conjugate eye movements.

To clarify the relationship between D2 receptor binding and the cerebral metabolic rate for glucose (CMRGlu) in patients with parkinsonism, we simultaneously measured both of these factors, and then compared the results.The subjects consisted of 24 patients: 9 with Parkinson's disease (PD), 3 with Juvenile Parkinson's disease (JPD), 9 with multiple system atrophy (MSA), and 3 with progressive supranuclear palsy (PSP). The striatal D2 receptor binding was measured by the C-11 raclopride transient equilibrium method. CMRGlu was investigated by the F-18 fluorodeoxyglucose autoradiographic method.The D2 receptor binding in both the caudate nucleus and putamen showed a positive correlation with the CMRGlu in the PD-JPD group, but the two parameters demonstrated no correlation in the MSA-PSP group. The left/right (L/R) ratio of D2 receptor binding in the putamen showed a positive correlation with that of CMRGlu in the MSA-PSP group, while the two demonsrated no correlation in the PD-JPD group.Our PET study showed striatal D2 receptor binding and the CMRGlu to be closely related in patients with parkinsonism, even though the results obtained using the L/R ratios tended to differ substantially from those obtained using absolute values. The reason for this difference is not clear, but this finding may reflect the pathophysiology of these disease entities.

There are two distinct subtypes of multiple sclerosis in Asians, opticospinal (OS-multiple sclerosis) and conventional (C-multiple sclerosis). In OS-multiple sclerosis, selective and severe involvement of the optic nerves and spinal cord is characteristic, though its mechanisms are unknown. The present study aimed to find out possible differences in the cytokine/chemokine profiles in CSF between OS-multiple sclerosis and C-multiple sclerosis and to delineate the relationships between these profiles and neuroimaging and pathological features. Sixteen cytokines/chemokines, namely interleukin (IL)-1beta, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12 (p70), IL-13, IL-17, interferon (IFN)-gamma, tumour necrosis factor (TNF)-alpha, granulocyte colony-stimulating factor (G-CSF), monocyte chemoattractant protein-1 (MCP-1) and macrophage inflammatory protein-1beta (MIP-1beta), were measured simultaneously in CSF supernatants from 40 patients with relapsing-remitting multiple sclerosis (20 OS-multiple sclerosis and 20 C-multiple sclerosis) at relapse and 19 control patients with spinocerebellar degeneration (SCD), together with intracellular production of IFN-gamma and IL-4 in CSF CD4+ T cells. In CSF supernatants relative to controls, IL-17, MIP-1beta, IL-1beta and IL-13 were only significantly increased in OS-multiple sclerosis patients, while TNF-alpha was only significantly increased in C-multiple sclerosis patients, using a cut-off level of 1 pg/ml. IL-8 was significantly elevated in both OS-multiple sclerosis and C-multiple sclerosis patients. MCP-1 was significantly decreased in both OS-multiple sclerosis and C-multiple sclerosis patients, while IL-7 was only significantly decreased in C-multiple sclerosis patients. IL-17, IL-8 and IL-5 were significantly higher in OS-multiple sclerosis patients than in C-multiple sclerosis patients. The increases in IL-17 and IL-8 in OS-multiple sclerosis were still significant even after exclusion of the patients undergoing various immunomodulatory therapies. Assays of intracellular cytokine production revealed that both the IFN-gamma+IL-4- T-cell percentage and intracellular IFN-gamma/IL-4 ratio in CSF cells were significantly greater in C-multiple sclerosis patients than in controls. Contrarily, OS-multiple sclerosis patients showed not only a significantly greater percentage of IFN-gamma+IL-4- T cells than controls but also a significantly higher percentage of IFN-gamma-IL-4+ T cells than C-multiple sclerosis patients. Among the cytokines elevated in multiple sclerosis, only IL-8 showed a significant positive correlation with the Expanded Disability Status Scale of Kurtzke score. Both the length of the spinal cord lesions on MRI and the CSF/serum albumin ratio had a significant positive correlation with IL-8 and IL-17 in multiple sclerosis, in which the spinal cord lesions were significantly longer in OS-multiple sclerosis than in C-multiple sclerosis. Three of six spinal cord specimens from autopsied OS-multiple sclerosis cases demonstrated numerous myeloperoxidase-positive neutrophils infiltrating necrotic lesions. These findings strongly suggest that in OS-multiple sclerosis, in addition to the Th1 cell upregulation seen in C-multiple sclerosis, intrathecal activation of the IL-17/IL-8 axis inducing heavy neutrophil infiltration contributes to extensive spinal cord lesion formation.

Juvenile muscular atrophy of the distal upper extremity (JMADUE) is considered to be a type of flexion myelopathy; however, we recently reported cases of JMADUE associated with airway allergy successfully treated by plasma exchange. To further characterize the allergo-immunological features of JMADUE, 11 consecutive JMADUE patients in the neurology clinic at Kyushu University Hospital were studied. Past and present together with family histories of common allergic disorders were investigated. Total serum IgE was measured by an enzyme linked immunosorbent assay (ELISA) and allergen-specific IgE by a liquid phase enzyme immunoassay. Intracellular interferon (IFN) gamma-, interleukin (IL)-4-, IL-5- and IL-13-producing T cells in peripheral blood were analyzed by flow cytometry. Data from 42 healthy subjects were used as controls for allergological studies. Flow cytometric data from 21 healthy subjects were also used for comparison. The patients exhibited significantly higher frequencies of coexisting airway allergies such as allergic rhinitis (p=0.0057) and pollinosis (p=0.0064), family histories of allergic disorders (p=0.0075), and mite antigen specific IgE (p=0.0361) compared with the healthy subjects. Patients with JMADUE had a significantly higher percentage of IFNgamma-IL-4+CD4+T cells (p=0.0017), but not IL-5- or IL-13-producing CD4+T cells, and a reduced intracellular IFNgamma/IL-4 ratio in CD4+T cells (p=0.002) compared to the controls. These findings suggest that JMADUE has a significant T helper 2 (Th2) shift, which may in part contribute to the development of spinal cord damage.

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.

Objective A recent nationwide survey of myelitis with atopic diathesis in Japan disclosed that the disease frequently shows a chronic persistent course. A neuropathological study of the spinal cord also revealed chronic active inflammation. Since the effects of various immunotherapies have not been studied extensively in this condition, we evaluated the efficacies of various immunotherapies in patients with myelitis with atopic diathesis. Patients and methods Forty-two treatments in 26 patients with myelitis with atopic diathesis were retrospectively analyzed. One of the following therapies was administered: (1) corticosteroids (CS) (pulse therapy followed by oral administration with gradual tapering); (2) intravenous immunoglobulin (IVIG) (400 mg/kg/day for 5 consecutive days); (3) plasma exchanges (PE); or (4) PE followed by IVIG or CS (PE+IVIG/CS). The therapeutic efficacies were evaluated by thorough neurological examination and laboratory tests including MRI, somatosensory evoked potentials (SEPs) and motor evoked potentials (MEPs). Results Objective neurological findings improved in 89% of the PE group and 90% of the PE+IVIG/CS group, compared with only 72% of the CS and 60% of the IVIG groups. Improvement determined by laboratory tests was seen in 57% of the PE and 57% of the PE+IVIG/CS groups, compared with only 15% of the CS and none of the IVIG groups. Thus, the improvement rate determined by laboratory tests was significantly greater for therapies including PE than for those without PE ( p= 0.0187). Conclusions These data suggest that immunotherapy is effective in myelitis with atopic diathesis despite a chronic persistent course, and that PE is the most beneficial immunotherapy.

The amyloid beta-protein (Abeta) ending at 42 plays a pivotal role in Alzheimer's disease (AD). We have reported previously that intracellular Abeta42 is associated with neuronal apoptosis in vitro and in vivo. Here, we show that intracellular Abeta42 directly activated the p53 promoter, resulting in p53-dependent apoptosis, and that intracellular Abeta40 had a similar but lesser effect. Moreover, oxidative DNA damage induced nuclear localization of Abeta42 with p53 mRNA elevation in guinea-pig primary neurons. Also, p53 expression was elevated in brain of sporadic AD and transgenic mice carrying mutant familial AD genes. Remarkably, accumulation of both Abeta42 and p53 was found in some degenerating-shape neurons in both transgenic mice and human AD cases. Thus, the intracellular Abeta42/p53 pathway may be directly relevant to neuronal loss in AD. Although neurotoxicity of extracellular Abeta is well known and synaptic/mitochondrial dysfunction by intracellular Abeta42 has recently been suggested, intracellular Abeta42 may cause p53-dependent neuronal apoptosis through activation of the p53 promoter; thus demonstrating an alternative pathogenesis in AD.

Background: Superantigens are considered to exacerbate autoimmune inflammation through the expansion of autoreactive T cells; however, the immune response to bacterial superantigens has not been extensively studied in any type of myelitis. We recently reported the occurrence of a distinct type of myelitis in patients with atopic diathesis, which in a recent nationwide survey was reported to be widespread in Japan. The aim of this study was to investigate the presence of IgE antibodies to bacterial superantigens and the proportion of IL-13- or IL-5-producing CD4+ or CD8+ T cells in patients with myelitis and atopic diathesis. Methods: Twenty-four myelitic patients with and 12 myelitic patients without hyperIgEemia, 28 patients with multiple sclerosis (MS) and 34 healthy controls were enrolled in this study. IgE antibodies to staphylococcal enterotoxins A (SEA) and B (SEB) in sera were measured using a liquid-phase enzyme immunoassay, and the intracellular production of IL-5 and IL-13 in peripheral blood CD4+ and CD8+ T cells was measured by flow cytometry. Results: The myelitic patients with hyperIgEemia showed significantly higher positive rates of serum SEA/SEB-specific IgE antibodies (41.7 and 62.5%, respectively) than the healthy controls (5.9 and 8.8%), patients with MS (0 and 21.4%) and those with normoIgEemic myelitis (0 and 0%). Moreover, IL-13-producing CD4+ T cells and CD8+ T cells increased significantly in the myelitic patients with hyperIgEemia compared to the controls, while IL-5-producing CD4+ or CD8+ T cells did not. Conclusions: The IgE response to staphylococcal superantigens is heightened in myelitic patients with atopic diathesis, which might contribute to increases in IL-13-producing T cells and thus the development of myelitis.

The importance of the basal ganglia in controlling motor function is well known. However, neuroimaging studies have failed to show either movement-rate dependence or different activation patterns caused by self-initiated (SI) and externally triggered (ET) movements in the basal ganglia–thalamo-motor loop. We herein report the functional magnetic resonance image (fMRI) mapping of sequential left-hand finger movements at five different rates under SI and ET conditions. Significant movement-rate dependence was found in the whole right basal ganglia–thalamo-motor loop only during the SI task. Network analysis also showed strong interactions within this loop during SI movement, whereas interactions were present only from the premotor cortex to the putamen via the sensorimotor cortex during the ET task. Furthermore, psychophysiological interaction analysis confirmed the different modulation between the two tasks in the putamen. fMRI provides evidence that the basal ganglia–thalamo-motor loop plays a key role in controlling the rate of sequential finger movements in SI movement but not in ET movement.

Previous positron emission tomography (PET) studies have shown widespread hypometabolism in the brain of advanced MSA but the time course of these metabolic abnormalities is largely unknown. In order to clarify the principal disease processes in multiple system atrophy (MSA) in the early stage, we investigated regional cerebral glucose metabolism (rCMGglc) and nigral dopaminergic function in nine patients with early stage of MSA using [18F]fluorodeoxyglucose (FDG) and 6- l -[18F]fluorodopa (18F-Dopa) positron emission tomography (PET) (two men and seven women; age, 59.3±5.4 years; disease duration, 29.7±14.6 months). The rCMRglc in the early MSA patients significantly decreased in the cerebellum, brainstem, and striatum compared with that in nine normal subjects. A significant correlation was found between the severity of autonomic dysfunction and rCMRglc within the brainstem. The severity of extrapyramidal signs also correlated with the decline of F-Dopa uptake but not that of rCMRglc within the striatum. The degree of atrophy on MRI has correlated with neither the clinical symptoms nor rCMRglc at the cerebellum and the brainstem. Our PET studies demonstrated widespread metabolic abnormalities except for the cerebral cortex in the brain of MSA even in the early stage. The hypometabolism in the brainstem was tightly linked to the autonomic dysfunction. Not the striatal dysfunction but the nigral damage may be responsible for the extrapyramidal symptoms in early MSA.

Our aim was to localize the generator site of parasagittal epileptiform discharges in a patient with epilepsia partialis continua (EPC) in the right leg. We examined a 32-year-old woman with EPC whose conventional EEG did not show any epileptic discharge. We performed the jerk-locked back averaging (JLA) of EEG and magnetoencephalography (MEG) to localize the dipole source of sharp transients. The myoclonic discharges in the right soleus muscle were used as a trigger pulse. JLA revealed consistent EEG and MEG sharp transients that coincided consistently and constantly preceded the myoclonic jerks. JLA of EEG demonstrated sharp waves paradoxically distributed over the vertex and right hemisphere. However, the estimated dipoles of MEG were localized in a restricted area in the primary leg motor area in the left hemisphere, which was closely located in the abnormal lesion on the brain MRI. JLA of MEG is considered to be a useful non-invasive method for localizing the epileptogenic area in EPC even when paradoxical lateralization of electroencephalographic discharges was noted.

To investigate the need for pre- and post-graduate education for neurologists, the subcommittee of the Japanese Society of Neurology for education performed a questionnaire-based survey in 80 medical universities throughout Japan. The response rate to the questionnaire was 82.5%. Textbooks for lectures for medical students were used in only 22.7% of those universities. If the Japanese Society of Neurology (JSN) made a standard text, 77.8% of universities would like to use it. Most of the training programs for residents were compatible with the minimum requirements of the JSN. Just 66.7% of those training programs were completed in their own institute, and 77.3% of universities required help from the JSN.

To evaluate postgraduate neurological education, a questionnaire-based survey regarding junior and senior doctor-in-training and the Board Certification Examination in Neurology was carried out on the training supervisors of 690 insitutes, excluding 80 university hospitals. The institutes included 243 teaching hospitals, 326 semi-teaching hospitals and 121 education-associated institutes authorized by the Japanese Society of Neurology (JSN). The results were obtained from 388 institutes, and the response rate was 56.2%. The percentage of junior doctors-in-training that received training in neurology was 68.6% (the average of 2.1 months during 2 years). More than half of the institutes did not have any teaching programs for junior doctors-in-training who did not train in neurology. In senior doctors-in-training, the number of senior doctors-in-trainings per year per institute was 0.44 and was only able to experience limited types of disorders. Also, many institutes could not achieve training goals by the institutes themselves (56%). The problems were due to lack of teaching staffs and manpower, and there were many requests to the Society regarding training methods. As for the Board Certification Examination in Neurology by the Society, it was revealed that there were small number of candidates per year per institute, and over half of institutes could not sufficiently teach and support them. Most requests to the Society were regarding teaching seminars and hands-on courses, and some institutes asked small group meetings for arts and techniques of neurology to be held the Regional Society. In conclusion, there are problems that cannot be solved by individual institutes alone, and we need procedures for postgraduate training in neurology that is organized by the Regional and JSN working as the central organization.

Objectives : We studied the origin and underlying mechanism of the soleus late response (SLR) at a mean latency of 90ms following transcranial magnetic stimulation. Methods : The soleus primary response (SPR) and SLR were recorded from the soleus (SOL) muscle in 27 normal subjects under various conditions using a double-cone coil. We also tested 28 patients demonstrating neurological disorders with postural disturbance. Results : The amplitude of the SPR gradually increased and its latency gradually decreased against the voluntary contraction (0–80%) of the tibialis anterior (TA) muscle. In contrast, the SLR amplitude was the greatest at a 20% TA contraction while the SLR latency was the shortest at a 40% TA contraction. The preactivation of SOL enhanced the SPR response but did not evoke the SLR. The SPR amplitude was significantly augmented while standing, however, the SLR amplitude tended to decrease. The SLR was never obtained following the stimulation of the brainstem, lumbar roots and peroneal nerve. The SLR was abnormal in patients with cerebellar ataxia and Parkinson's disease while the SPR was normal. Conclusions : A lack of any correlation between the SPR and SLR suggests that the SLR does not originate in the corticospinal tract. The SLR may thus be a polysynaptic response related to the postural control of the agonist and antagonist organization between the TA and SOL.

Objective: To characterize a distinct form of autosomal dominant cerebellar ataxia (ADCA) clinically and genetically. Background: ADCAs are a clinically, pathologically, and genetically heterogeneous group of neurodegenerative disorders. Nine responsible genes have been identified for SCA-1, -2, -3, -6, -7, -8, -10, and -12 and dentatorubral-pallidoluysian atrophy (DRPLA). Loci for SCA-4, -5, -11, -13, and -14 have been mapped. Methods: The authors studied a four-generation Japanese family with ADCA. The 19 members were enrolled in this study. The authors performed the mutation analysis by PCR and a genome-wide linkage analysis. Results: Nine members (five men and four women) were affected. The ages at onset ranged from 20 to 66 years. All affected members showed pure cerebellar ataxia, and three patients also had head tremor. Head MRI demonstrated cerebellar atrophy without brain stem involvement. The mutation analysis by PCR excluded diagnoses of SCA-1, -2, -3, -6, -7, -8, and -12 and DRPLA. The linkage analysis suggested linkage to a locus on chromosome 8q22.1-24.1, with the highest two-point lod score at D8S1804 (Z = 3.06 at θ = 0.0). The flanking markers D8S270 and D8S1720 defined a candidate region of an approximately 37.6-cM interval. This candidate region was different from the loci for SCA-4, -5, -10, -11, -13, and -14. Conclusion: The family studied had a genetically novel type of SCA (SCA-16).

To clarify the Th1/Th2 balance in spinal cord inflammation, we used ELISA to measure the total and allergen-specific IgE in 69 patients with clinically definite multiple sclerosis (MS), including 24 patients with the optico-spinal form of MS, 45 with HAM/TSP, 30 HTLV-I carriers without HAM/TSP, 40 patients with acute myelitis, 43 with neurodegenerative disorders, and 42 healthy subjects, and flow cytometry to study the intracellular IFNgamma-positive versus IL-4-positive cell ratio (intracellular IFNgamma/IL-4 ratio) in peripheral blood CD4(+) T cells in 40 patients with MS, including 17 patients with the optico-spinal form of MS, 23 with HAM/TSP, 22 with acute myelitis, 23 with neurodegenerative disorders, and 36 healthy subjects. Patients with HAM/TSP showed a significantly higher intracellular IFNgamma/IL-4 ratio, lower IL-4(+)/IFN-gamma(-) cell percentages, lower total IgE level, and lower frequency of cedar pollen-specific IgE than did the controls. The patients with optico-spinal MS showed a significantly higher intracellular IFNgamma/IL-4 ratio and higher IL-4(-)/IFN-gamma(+) cell percentages than the controls even at remission or in the convalescence phase. In contrast, in the patients with acute myelitis, the total serum IgE level and the frequency of mite antigen-specific IgE were significantly elevated in comparison to the controls, while those having mite antigen-specific IgE myelitis showed a significantly lower IFNgamma/IL-4 ratio in the CD4(+) T cells in comparison to the controls. These findings suggest that the Th1 cell response is predominant in HAM/TSP and optico-spinal MS, whereas the Th2 cell response is predominant in mite antigen-specific IgE myelitis.

A positron emission tomography (PET) study on the regional cerebral glucose metabolism (rCMRglc) was performed in six patients with corticobasal degeneration (CBD). The clinical features included asymmetrical parkinsonism with apraxia, were related to the cerebral cortical and basal ganglionic dysfunction. An MRI study showed all cases to have asymmetrical atrophy in the front-parietal cortex contralateral to the dominantly affected limb; however, no case was pathologically verified. A PET study revealed three cases to have asymmetrical glucose hypometabolism in the parietal lobe and thalamus, which was compatible with the results of previous reports. However, two patients demonstrated symmetrical glucose hypometabolism in the frontal lobe, striatum and parietal lobe while one case had a diffuse hypometabolism, in spite of a marked asymmetry of the neurological findings. These results therefore suggest the heterogeneity of the glucose hypometabolism in CBD based on the PET findings.

Meningitis is the most common feature of cryptococcal infection of the nervous system. We herein describe the case of a 48-year-old man with fulminant cryptococcal myeloradiculitis, whose initial symptoms were impotence, dysuria and weakness of the lower extremities. He had been administered prednisolone and azathioprine for 7 years for ulcerative colitis before onset of myeloradiculitis. He finally developed meningoencephalitis and died 2 months after onset despite treatment with amphotericin B and flucytosine. Post-mortem examination revealed numerous infiltrations of cryptococci in the spinal roots as well as in the meninges and subarachnoid space. Inflammatory cells and cryptococci had infiltrated the vessel walls in the spinal cord, and this was accompanied by necrotizing myelopathy. Myeloradiculitis is rare in cryptococcal infection, and this is the first case report to demonstrate direct cryptococcal infection in the spinal roots. Cryptococcal infection should be considered while managing myeloradiculopathy of unknown etiology, especially in immunocompromised patients.

症例は45歳男性. 42歳時に噴門側部分胃切除を施行.術後,眼球運動障害と四肢脱力,体幹失調を2回繰り返した.頭部MRIで両側視床および中脳水道周囲に異常信号域を認め,血中ビタミンB1が著明に低下していた.入院当日よりビタミンB1を投与開始したところ2日目には眼球運動障害は消失, 2週間後には歩行可能となった.大酒家でなくても胃切除の既往を有する例では少量のアルコール摂取でも繰り返しWernicke脳症を起こす可能性が考えられた.

Impairment of orientation for time (OT) is a characteristic symptom of Alzheimer disease (AD). However, the brain regions underlying OT remain to be elucidated. Using single photon emission computed tomography (SPECT), we examined the brain regions exhibiting hypoperfusion that were associated with OT.We compared regional cerebral blood flow (rCBF) differences between AD and amnesic mild cognitive impairment (aMCI) or normal subjects using 3-dimensional stereotactic surface projection (3D-SSP) analysis. AD patients were divided into OT good and poor groups according to their mean OT scores, and rCBF then compared between the groups to elucidate OT-specific brain areas.3D-SSP analysis showed reduced rCBF in the left superior parietal lobule (SPL) and bilateral inferior parietal lobule (IPL) in AD patients. In the poor OT group, 3D-SSP analysis revealed hypoperfusion in the bilateral SPL, IPL, posterior cingulated cortex (PCC), and precuneus. Among these areas, region of interest analysis revealed a significant higher number of hypoperfused pixels in the left PCC in the OT poor AD group.Our SPECT study suggested that hypoperfusion in the left SPL and bilateral IPL was AD specific, and reduced rCBF in the left PCC was specifically associated with OT.

Two adult females developed HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and psoriasis. Both showed chronic progressive paraparesis and sharply demarcated erythematous scaling plaques on their extremities and trunk. One patient had polymyositis while in the other anti-thyroid antibodies, antinuclear antibodies and SS-A antibody, all autoantibodies, were positive. Both patients were treated by intramuscular injections of interferon-alpha for 2 to 4 weeks, resulting in amelioration of paraparesis. After the therapy psoriasis and polymyositis markedly improved in one patient without any additional therapy, while in the other simultaneous use of topical corticosteroids was effective. This is the first report to describe occurrences of psoriasis in HAM/TSP patients. Although there are several reports indicating interferon-alpha induces or exacerbates psoriasis, our experience suggests that psoriasis associated with HAM/TSP can be successfully managed even during interferon-alpha therapy.

A 36-year-old man with mucolipidosis type III alpha/beta presented with hypoactivity, mutism, muscle rigidity, and involuntary movement. The involuntary movement was interpreted to be tremor at rest on physical examination and surface electromyography, which revealed mostly asynchronous contractions at 3-4 Hz of the biceps and triceps brachii muscles. All these symptoms were consistent with abnormalities of parkinsonism, which is caused by an insult to the basal ganglia that permeates the entire basal ganglia-thalamocortical circuitry. This report is the first to present a case of mucolipidosis type III alpha/beta in association with parkinsonism.

Spastic paraplegia type 4 (SPG4) is the most common autosomal dominant hereditary SPG caused by mutations in the SPAST gene. We studied the four-generation pedigree of a Japanese family with autosomal dominant hereditary SPG both clinically and genetically. Twelve available family members (ten affected; two unaffected) and two spouses were enrolled in the study. The clinical features were hyperreflexia in all four limbs, spasticity of the lower extremities, impaired vibration sense, mild cognitive impairment confirmed by the Wechsler Adult Intelligence Scale—Third Edition, and peripheral neuropathy confirmed by neurophysiological examinations. All four female patients experienced miscarriages. The cerebrospinal fluid tau levels were mildly increased in two of three patients examined. Linkage analyses revealed the highest logarithm of odds score of 2.64 at 2p23-p21 where the SPAST gene is located. Mutation scanning of the entire exonic regions of the SPAST gene by direct sequencing revealed no mutations. Exonic copy number analysis by real-time quantitative polymerase chain reaction revealed heterozygous deletion of exons 1 to 4 of the SPAST gene. Breakpoint analysis showed that the centromeric breakpoint was located within intron 4 of SPAST while the telomeric breakpoint was located within intron 3 of the neighboring DPY30 gene, causing a deletion of approximately 70 kb ranging from exons 1 to 3 of DPY30 to exons 1 to 4 of SPAST. To our knowledge, this is the first report of SPG4 associated with partial deletions of both the SPAST and DPY30 genes. The partial heterozygous deletion of DPY30 could modify the phenotypic expression of SPG4 patients with this pedigree.

We describe a case of recurrent invasive thymoma associated with myasthenia gravis that responded to combined treatment with prednisolone and tacrolimus. The patient suffered from a myasthenic crisis and received methylprednisolone pulse therapy and partial thymomectomy. Low maintenance doses of prednisolone and tacrolimus shrank the size of the invasive thymoma and maintained the patient without any myasthenic symptoms. We stress the usefulness of combined treatment with tacrolimus and prednisolone for invasive thymoma, especially for unresectable tumors.

Positron emission tomography (PET) studies on regional cerebral glucose metabolism and [ 18 F]fluorodopa uptake were performed on 3 patients with “pure akinesia without rigidity and tremors”, 3 progressive supranuclear palsy (PSP) patients, and 5 patients with Parkinson's disease. The “pure akinesia” and PSP patients showed a marked decrease in glucose metabolism in the frontal cortex and striatum, and a decreased uptake of [ 18 F]fluorodopa in the striatum. While the Parkinson's disease patients had a decreased uptake of [ 18 F]fluorodopa in the striatum but no abnormality in the glucose metabolism. Magnetic resonance imaging (MRI) showed atrophy of the pretectum and dorsal pons in “pure akinesia” and PSP patients, but there was no such abnormality in the Parkinson's disease patients. As described above, patients with “pure akinesia” and PSP patients revealed similar findings on PET and MRI studies, while Parkinson's disease patients showed substantially different results.