Symptomatology and Neuropathology of patients presenting with focal cortical signs.

Here, we describe two patients who presented with focal cortical signs and underwent neuropathological examination. Case 1 was a 73-year-old woman with progressive speech disorder and abnormal behavior. She showed agraphia of the frontal lobe type, featured by the omission of kana letters when writing, other than pyramidal tract signs, pseudobulbar palsy, and frontal lobe dementia. Neuropathological examination, including TAR DNA-binding protein 43 (TDP-43) immunohistochemistry, revealed bilateral frontal and anterior temporal lobe lesions accentuated in the precentral gyrus and posterior part of the middle frontal gyrus. Both upper and lower motor neurons showed pathological changes compatible with amyotrophic lateral sclerosis. Case 2 was a 62-year-old man with progressive speech disorder and hand clumsiness. He had a motor speech disorder, compatible with apraxia of speech, and limb apraxia of the limb-kinetic and ideomotor type. Neuropathological examination revealed degeneration in the left frontal lobe, including the precentral gyrus, anterior temporal, and parietal lobe cortices. Moreover, numerous argyrophilic neuronal intracytoplasmic inclusions (Pick body) and ballooned neurons were observed in these lesions and the limbic system. The pathological diagnosis was Pick disease involving the peri-Rolandic area and parietal lobe. In these two cases, the distribution of neuropathological changes in the cerebral cortices correlated with the clinical symptoms observed.

Late-onset autosomal recessive cerebellar ataxia and neuropathy with a novel splicing mutation in the ATM gene.

Autosomal recessive cerebellar ataxias comprise many types of diseases. The most frequent autosomal recessive cerebellar ataxias are Friedreich ataxia, but other types are relatively rare. We encountered a consanguineous family with two cases of late-onset cerebellar ataxia with neuropathy. We performed whole-exome sequencing in one patient and confirmed by Sanger sequencing in other family members. Neurological examination revealed cerebellar ataxia, hand tremor, and neck dystonia, distal muscle wasting, and diminished tendon reflexes. The patients had no conjunctival telangiectasia or immunodeficiency. Blood examination revealed slightly elevated α-fetoprotein. Brain MRI demonstrated marked cerebellar atrophy and mild brainstem atrophy. The electrophysiologic study and nerve biopsy showed axonal neuropathy. Whole-exome sequencing revealed a novel homozygous missense variant (NM_000051.3: c.496G > C) in the ataxia-telangiectasia mutated gene. This homozygous variant was found in another patient, co-segregated within the family members-this variant results in aberrant splicing (skipping exon 5) on RT-PCR analysis. We identified the ataxia-telangiectasia mutated variant in an adult, late-onset autosomal recessive cerebellar ataxias family. We should consider ataxia-telangiectasia even in late-onset autosomal recessive cerebellar ataxias without telangiectasia or immunodeficiency.

Predictive factors for prognosis following unsedated percutaneous endoscopic gastrostomy in ALS patients.

INTRODUCTION: This study aimed to determine the prognostic factors and the values that predict survival after percutaneous endoscopic gastrostomy (PEG) tube placement in patients with amyotrophic lateral sclerosis (ALS). METHODS: We retrospectively analyzed the correlations for 97 consecutive patients with ALS between clinical parameters and survival following PEG tube placement using the log-rank test and Cox proportional-hazards models. RESULTS: The log-rank test showed that an arterial carbon dioxide pressure (PaCO2 ) of ≤ 40 mmHg (P = 0.0054), a forced vital capacity (FVC) of ≥ 38% of predicted (P = 0.0003), and bulbar-onset (P = 0.0121) were significantly associated with better post-PEG survival. Multivariate analysis showed that the FVC and PaCO2 were associated with better post-PEG survival (P = 0.0081 and P = 0.0265, respectively). CONCLUSIONS: PEG tube placement in ALS is recommended when FVC is ≥ 38% of predicted and when PaCO2 is normal. Muscle Nerve 54: 277-283, 2016.

Surgery for amygdala enlargement with mesial temporal lobe epilepsy: pathological findings and seizure outcome.

OBJECTIVE: Amygdala enlargement (AE) has been suggested to be a subtype of mesial temporal lobe epilepsy (MTLE). However, most reports related to AE have referred to imaging studies, and there have been few reports regarding surgical and pathological findings. The present study was performed to clarify the surgical outcomes and pathology of AE. METHODS: Eighty patients with drug-resistant MTLE were treated surgically at the Tokyo Metropolitan Neurological Hospital between April 2010 and July 2013. Of these patients, 11 were diagnosed as AE based on presurgical MRI. Nine patients with AE underwent selective amygdalohippocampectomy, while the remaining two patients underwent selective amygdalotomy with hippocampal transection. Intraoperative EEG was routinely performed. The histopathology of the resected amygdala tissue was evaluated and compared with the amygdala tissue of patients with hippocampal sclerosis. RESULTS: Pathological findings indicated that 10 of 11 specimens had closely clustering hypertrophic neurons with vacuolisation of the background matrix. Slight gliosis was seen in nine specimens, while the remaining two showed no gliotic changes. Intraoperative EEG showed abnormal sharp waves that seemed to originate not from the amygdala but from the hippocampus in all cases. Ten patients became seizure-free during the postoperative follow-up period. CONCLUSIONS: Histopathologically, clustering hypertrophic neurons and vacuolation with slight gliosis or without gliosis were considered to be pathological characteristics of AE. Amygdalohippocampectomy or hippocampal transection with amygdalotomy is effective for seizure control in patients with AE.

A lethal intracranial Rosai-Dorfman disease of the brainstem diagnosed at autopsy.

Rosai-Dorfman disease (RDD) is a benign histiocytic proliferative disorder characterized by the accumulation of histiocytes in lymph nodes and various other organs. RDD seldom involves the central nervous system, and cases of purely intracranial RDD are particularly rare. We report a case of purely intracranial RDD involving the brainstem that was diagnosed at autopsy. A 68-year-old woman visited our hospital because of visual disturbances and loss of energy. Magnetic resonance imaging revealed an obscure mass in the brainstem. Despite exhaustive work-ups, the etiology of the intracranial mass remained unclear. The patient died of respiratory depression, and an autopsy was performed for pathological investigation. Macroscopically, a pink pale mass 2.5 cm in diameter was found in the brainstem, with no attachment to the dura. Histologically, it was composed of histiocytic cells with incorporation of small lymphocytes (emperipolesis). Immunohistochemical staining revealed that the cells were positive for CD68 and S100 and negative for CD1a, consistent with a diagnosis of RDD. Purely intracranial RDD is extremely rare and considered benign. To date, nine cases (including ours) have been reported. To our knowledge, this is the first case of intracranial RDD with autopsy. Although generally considered benign, RDD involving the brainstem might be lethal.

Autosomal-recessive complicated spastic paraplegia with a novel lysosomal trafficking regulator gene mutation.

BACKGROUND: Autosomal-recessive hereditary spastic paraplegias (AR-HSP) consist of a genetically diverse group of neurodegenerative diseases characterised by pyramidal tracts dysfunction. The causative genes for many types of AR-HSP remain elusive. We tried to identify the gene mutation for AR-HSP with cerebellar ataxia and neuropathy. METHODS: This study included two patients in a Japanese family with their parents who are first cousins. Neurological examination and gene analysis were conducted in the two patients and two normal family members. We undertook genome-wide linkage analysis employing single nucleotide polymorphism arrays using the two patients' DNAs and exome sequencing using one patient's sample. RESULTS: We detected a homozygous missense mutation (c.4189T>G, p.F1397V) in the lysosomal trafficking regulator (LYST) gene, which is described as the causative gene for Chédiak-Higashi syndrome (CHS). CHS is a rare autosomal-recessive syndrome characterised by hypopigmentation, severe immune deficiency, a bleeding tendency and progressive neurological dysfunction. This mutation was co-segregated with the disease in the family and was located at well-conserved amino acid. This LYST mutation was not found in 200 Japanese control DNAs. Microscopic observation of peripheral blood in the two patients disclosed large peroxidase-positive granules in both patients' granulocytes, although they had no symptoms of immune deficiency or bleeding tendency. CONCLUSIONS: We diagnosed these patients as having adult CHS presenting spastic paraplegia with cerebellar ataxia and neuropathy. The clinical spectrum of CHS is broader than previously recognised. Adult CHS must be considered in the differential diagnosis of AR-HSP.

A novel WDR45 mutation in a patient with static encephalopathy of childhood with neurodegeneration in adulthood (SENDA).

Static encephalopathy of childhood with neurodegeneration in adulthood (SENDA) is an X-linked dominant neurodegenerative disorder, and is classified as a subtype of neurodegeneration with brain iron accumulation. Recently, de novo heterozygous mutations in WDR45 at Xp11.23 have been reported in patients with SENDA. We report the clinical and neuroradiological findings of a patient with SENDA with a novel c.322del mutation in WDR45. In this patient, characteristic MRI findings were useful for diagnosis.

Unique combination of hyperintense vessel sign on initial FLAIR and delayed vasoconstriction on MRA in reversible cerebral vasoconstriction syndrome: a case report.

BACKGROUND: Reversible cerebral vasoconstriction syndrome is characterized by thunderclap headache and reversible cerebral vasoconstriction on angiographic findings. It can be difficult to diagnose when initial angiography is normal. CASE RESULTS: A 30-year-old woman was admitted because of sudden-onset thunderclap headache and seizure on postpartum day 7. Brain MRI on fluid-attenuated inversion recovery (FLAIR) showed hyperintense vessel sign (HVS), which usually means slow flow due to severe proximal arterial stenosis. However, magnetic resonance angiography (MRA) indicated that proximal arteries was normal. After nicardipine treatment, her symptoms improved dramatically. Follow-up FLAIR on day 7 showed complete resolution of HVS, while a series of MRAs revealed reversible multifocal segmental vasoconstriction. CONCLUSIONS: HVS on initial FLAIR is useful for an early diagnosis of reversible cerebral vasoconstriction syndrome. As the delayed vasoconstriction on MRA can be observed, reversible cerebral vasoconstriction syndrome may progress from distal small to proximal larger arteries.

Prevalence and incidence of amyotrophic lateral sclerosis in Japan.

BACKGROUND: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown. METHODS: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution. RESULTS: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females. CONCLUSIONS: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.

Prevalence and Incidence of Amyotrophic Lateral Sclerosis in Japan.

Background: Previous studies have reported a high incidence of amyotrophic lateral sclerosis (ALS) in endemic foci in the Kii Peninsula, Japan. However, little is known about the ALS frequency in the whole country. Furthermore, the presence of ethnic variation in the incidence of ALS remains unknown.Methods: We conducted a nationwide survey of ALS frequency in 2013 to estimate its annual prevalence and incidence. ALS was diagnosed based on the El Escorial Criteria. The study period was the 2009 fiscal year, from April 2009 to March 2010. To compare the incidence of ALS among prefectures, standardized incidence ratios (SIRs) and 95% confidence intervals (CIs) were calculated under the assumption of Poisson distribution.Results: The annual crude prevalence and incidence rates per 100 000 people per year were 9.9 (95% CI 9.7-10.1) and 2.2 (95% CI 2.1-2.3), respectively. The age group with the highest prevalence as well as incidence was 70-79 years, and the male-female ratio was approximately 1.5. The annual incidence rate adjusted for age and sex using the 2000 U.S. standard population was 2.3 (95% CI 2.2-2.4) per 100 000 people. Some prefectures had significantly high SIRs: Okinawa, Nara and Wakayama in the Kii Peninsula, and Niigata for males; Kumamoto for females.Conclusions: This is the first report on the annual prevalence and incidence of ALS in the representative population of Japan. We identified some prefectures with a high incidence of ALS. However, the incidence of ALS in the Japanese population was much lower than in the Caucasian populations of Europe and North America.

What can we learn from a patient on dialysis for 42 years?

We performed autopsy on a 60-year-old Japanese man who had received dialysis for 42 years. He started on intermittent peritoneal dialysis in 1968, which was combined with hemodialysis in 1969. His serum calcium-phosphate balance and his blood pressure had been controlled well. Carpal tunnel syndrome occurred in 1984. Then lumbar spinal canal stenosis (SCS) occurred in 1997, followed by cervical SCS in 2000, destructive lumbar spondyloarthropathy (DSA) in 2002, and pathological fracture of the right femoral neck due to an enlarging bone cyst in 2006. All of his surgical specimens showed dialysis-related deposition of beta2MG amyloid (dialysis-related amyloidosis: DRA). Thereafter, lumbar and cervical spinal palsy progressed. In 2009, he developed severe paralytic ileus with dilatation of the sigmoid colon, and subsequently died of peritonitis due to necrotizing cholecystitis. Autopsy showed massive DRA deposits in his intestinal blood vessels and thickened spinal dura, resulting in the above-mentioned intestinal and spinal complications. However, his arterial tree, including the aorta and coronary arteries, showed very little atheroma. Strict control of the Ca-P balance and blood pressure may have prevented cardiovascular disease, while progress in dialysis technology delayed fatal complications of DRA and allowed this patient to survive on dialysis for 42 years.

The Card Placing Test: a new test for evaluating the function of the retrosplenial and posterior cingulate cortices.

BACKGROUND/AIM: We developed a test named the Card Placing Test (CPT), which is potentially useful for evaluating a function of the retrosplenial and posterior cingulate cortices (RSC/PCC). Part A of the test assesses the ability of a subject to retain information on spatial locations of cards placed on the floor around the subject. Part B examines the subject's ability to integrate information on the spatial locations of similarly arranged cards and information on changes in body direction. The aim of this study is to identify brain regions involved in the CPT performance. SUBJECTS AND METHODS: Twenty-five subjects were recruited from our memory clinic. We analyzed the correlation between the CPT scores and resting state regional cerebral blood flow (rCBF) determined by single-photon emission tomography. RESULTS: The scores for part A correlated with rCBF in the right inferior parietal lobule. The scores for part B were associated with rCBF in the RSC/PCC. CONCLUSIONS: The right inferior parietal lobule seems to play a pivotal role in performing part A of the CPT, whereas the RSC/PCC appears to be involved in accomplishing part B of the CPT.

Cerebral small-vessel disease protein HTRA1 controls the amount of TGF-ß1 via cleavage of proTGF-ß1.

Cerebral small-vessel disease is a common disorder in elderly populations; however, its molecular basis is not well understood. We recently demonstrated that mutations in the high-temperature requirement A (HTRA) serine peptidase 1 (HTRA1) gene cause a hereditary cerebral small-vessel disease, cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL). HTRA1 belongs to the HTRA protein family, whose members have dual activities as chaperones and serine proteases and also repress transforming growth factor-ß (TGF-ß) family signaling. We demonstrated that CARASIL-associated mutant HTRA1s decrease protease activity and fail to decrease TGF-ß family signaling. However, the precise molecular mechanism for decreasing the signaling remains unknown. Here we show that increased expression of ED-A fibronectin is limited to cerebral small arteries and is not observed in coronary, renal arterial or aortic walls in patients with CARASIL. Using a cell-mixing assay, we found that HTRA1 decreases TGF-ß1 signaling triggered by proTGF-ß1 in the intracellular space. HTRA1 binds and cleaves the pro-domain of proTGF-ß1 in the endoplasmic reticulum (ER), and cleaved proTGF-ß1 is degraded by ER-associated degradation. Consequently, the amount of mature TGF-ß1 is reduced. These results establish a novel mechanism for regulating the amount of TGF-ß1, specifically, the intracellular cleavage of proTGF-ß1 in the ER.

A functional variant in ZNF512B is associated with susceptibility to amyotrophic lateral sclerosis in Japanese.

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by the selective loss of motor neurons. Several susceptibility genes for ALS have been reported; however, ALS etiology and pathogenesis remain largely unknown. To identify further ALS-susceptibility genes, we conducted a large-scale case-control association study using gene-based tag single-nucleotide polymorphisms (SNPs). A functional SNP (rs2275294) was found to be significantly associated with ALS through a stepwise screening approach (combined P= 9.3 × 10(-10), odds ratio = 1.32). The SNP was located in an enhancer region of ZNF512B, a transcription factor of unknown biological function, and the susceptibility allele showed decreased activity and decreased binding to nuclear proteins. ZNF512B over-expression increased transforming growth factor-ß (TGF-ß) signaling, while knockdown had the opposite effect. ZNF512B expression was increased in the anterior horn motor neurons of the spinal cord of ALS patients when compared with controls.  Our results strongly suggest that ZNF512B is an important positive regulator of TGF-ß signaling and that decreased ZNF512B expression increases susceptibility to ALS.

Neck weakness is a potent prognostic factor in sporadic amyotrophic lateral sclerosis patients.

OBJECTIVE: To clarify the emergence of muscle weakness in regions of the body that affect survival, and deterioration in activities of daily living (ADL) in amyotrophic lateral sclerosis (ALS) patients. METHODS: We conducted a multicentre-based prospective cohort study of patients with ALS. We enrolled 401 sporadic patients with ALS. Death or the introduction of invasive ventilation was defined as the primary endpoint, and the time to five clinical markers of ADL deterioration associated with bulbar paralysis or limb weakness were defined as ADL milestones. Muscle weakness was assessed in the neck flexor muscles; the bilateral abductors of the shoulders; the bilateral wrist extensor muscles; the bilateral flexor muscles of the hips; and the bilateral ankle dorsiflexion muscles. We performed Cox proportional hazards regression analyses for the primary endpoint and the five ADL milestones, adjusting for known covariate prognostic factors for ALS. RESULTS: The Medical Research Council (MRC) score for the neck flexors was the most significant prognostic factor for the primary endpoint (HR 0.74, p<0.001), loss of speech (HR 0.66, p<0.001), and loss of swallowing function (HR 0.73, p<0.001), and was one of the significant prognostic factors for loss of upper limb function, difficulty turning in bed, and loss of walking ability (p=0.001, 0.002, and 0.008, respectively). The MRC score for the neck flexors was also a significant prognostic factor for covariates of the previously reported prognostic factors. CONCLUSIONS: Neck weakness is an independent prognostic factor for survival and deterioration in ADL in Patients with ALS.

A homozygous mutation of C12orf65 causes spastic paraplegia with optic atrophy and neuropathy (SPG55).

BACKGROUND: Autosomal recessive hereditary spastic paraplegias (AR-HSP) constitute a heterogeneous group of neurodegenerative diseases involving pyramidal tracts dysfunction. The genes responsible for many types of AR-HSPs remain unknown. We attempted to identify the gene responsible for AR-HSP with optic atrophy and neuropathy. METHODS: The present study involved two patients in a consanguineous Japanese family. Neurologic examination and DNA analysis were performed for both patients, and a skin biopsy for one. We performed genome-wide linkage analysis involving single nucleotide polymorphism arrays, copy-number variation analysis, and exome sequencing. To clarify the mitochondrial functional alteration resulting from the identified mutation, we performed immunoblot analysis, mitochondrial protein synthesis assaying, blue native polyacrylamide gel electrophoresis (BN-PAGE) analysis, and respiratory enzyme activity assaying of cultured fibroblasts of the patient and a control. RESULTS: We identified a homozygous nonsense mutation (c.394C>T, p.R132X) in C12orf65 in the two patients in this family. This C12orf65 mutation was not found in 74 Japanese AR-HSP index patients without any mutations in previously known HSP genes. This mutation resulted in marked reduction of mitochondrial protein synthesis, followed by functional and structural defects in respiratory complexes I and IV. CONCLUSIONS: This novel nonsense mutation in C12orf65 could cause AR-HSP with optic atrophy and neuropathy, resulting in a premature stop codon. The truncated C12orf65 protein must lead to a defect in mitochondrial protein synthesis and a reduction in the respiratory complex enzyme activity. Thus, dysfunction of mitochondrial translation could be one of the pathogenic mechanisms underlying HSPs.

Pseudobulbar dysarthria in the initial stage of motor neuron disease with dementia: a clinicopathological report of two autopsied cases.

We retrospectively analyzed the clinical features of two cases of neurodegenerative disease, whose initial symptoms were motor speech disorder and dementia, brought to autopsy. We compared the distributions of pathological findings with the clinical features. The main symptom of speech disorder was dysarthria, involving low pitch, slow rate, hypernasality and hoarseness. Other than these findings, effortful speech, sound prolongation and initial difficulty were observed. Moreover, repetition of multisyllables was severely impaired compared to monosyllables. Repetition and comprehension of words and sentences were not impaired. Neither atrophy nor fasciculation of the tongue was observed. Both cases showed rapid progression to mutism within a few years. Neuropathologically, frontal lobe degeneration including the precentral gyrus was observed. The bilateral pyramidal tracts also showed severe degeneration. However, the nucleus of the hypoglossal nerve showed only mild degeneration. These findings suggest upper motor neuron dominant motor neuron disease with dementia. We believe the results indicate a subgroup of motor neuron disease with dementia whose initial symptoms involve pseudobulbar palsy and dementia, and which shows rapid progression to mutism.

Association of HTRA1 mutations and familial ischemic cerebral small-vessel disease.

BACKGROUND: The genetic cause of cerebral autosomal recessive arteriopathy with subcortical infarcts and leukoencephalopathy (CARASIL), which is characterized by ischemic, nonhypertensive, cerebral small-vessel disease with associated alopecia and spondylosis, is unclear. METHODS: In five families with CARASIL, we carried out linkage analysis, fine mapping of the region implicated in the disease, and sequence analysis of a candidate gene. We also conducted functional analysis of wild-type and mutant gene products and measured the signaling by members of the transforming growth factor beta (TGF-beta) family and gene and protein expression in the small arteries in the cerebrum of two patients with CARASIL. RESULTS: We found linkage of the disease to the 2.4-Mb region on chromosome 10q, which contains the HtrA serine protease 1 (HTRA1) gene. HTRA1 is a serine protease that represses signaling by TGF-beta family members. Sequence analysis revealed two nonsense mutations and two missense mutations in HTRA1. The missense mutations and one of the nonsense mutations resulted in protein products that had comparatively low levels of protease activity and did not repress signaling by the TGF-beta family. The other nonsense mutation resulted in the loss of HTRA1 protein by nonsense-mediated decay of messenger RNA. Immunohistochemical analysis of the cerebral small arteries in affected persons showed increased expression of the extra domain-A region of fibronectin and versican in the thickened tunica intima and of TGF-beta1 in the tunica media. CONCLUSIONS: CARASIL is associated with mutations in the HTRA1 gene. Our findings indicate a link between repressed inhibition of signaling by the TGF-beta family and ischemic cerebral small-vessel disease, alopecia, and spondylosis.

A novel adult case of juvenile-onset Alexander disease: complete remission of neurological symptoms for over 12 years, despite insidiously progressive cervicomedullary atrophy.

We present here a 25-year-old woman with genetically confirmed (p.R276L mutation in the GFAP gene) juvenile-onset AxD. Episodic vomiting appeared at age nine, causing anorexia and insufficient growth. Brain MRI at age 11 showed a small nodular lesion with contrast enhancement in the left dorsal portion of the cervicomedullary junction. Her episodic vomiting improved spontaneously at age 13, and she became neurologically asymptomatic. The enhancement of the lesion disappeared simultaneously, although the plaque remained. Longitudinal MRI observations, however, revealed insidiously progressive cervicomedullary atrophy without a signal change. This case broadens our knowledge of AxD: (1) molecular analysis of the GFAP gene is warranted in patients with MRI evidence of tumor-like lesions in the brainstem, particularly if they present with isolated episodic vomiting and/or anorexia; (2) the disease can be self-remitting for at least 12 years; (3) cervicomedullary atrophy, characteristic of the adult form, can be insidiously progressive without a signal change before the clinical symptoms appear.

[Food-borne botulism].

Botulism is a neuroparalytic disease caused by neurotoxins produced by Clostridium botulinum, and classically presents as palsies of cranial nerves and acute descending flaccid paralysis. Food-borne botulism is the most common form of botulism, and caused by preformed neurotoxins produced by Clostridium botulinum. Electrophysiological studies play an important role in the early diagnosis. Confirmation of the diagnosis is based on the detection of botulinum toxins in the patient's serum or stool. In Japan, decades ago, botulism type E occurred, though only sporadically, almost every year, but in recent years, has dramatically decreased in frequency. Botulism is a curable disease when treated early and adequately. Differential diagnosis of cranial nerves and limb muscle palsies with rapid exacerbation should include food-borne botulism.