ALSの病態解明・治療法開発

I graduated from Tokushima University in １９９５ and trained at Hiroshima University and Sumitomo Hospital. In２０００, Professor Ryuji Kaji was appointed as the first professor of the Department of Neurology, Tokushima University. In ２００１, I graduated from Hiroshima University Graduate School and returned to Tokushima University. At the Department of Neurology, Tokushima University, we have been investigating natural history, neurophysiology including neuromuscular sonology, MRI, liquid biomarkers, genes, neuropathology, iPS cells, and new treatments as research on amyotrophic lateral sclerosis（ALS）（Tokushima ALS Research）. We have examined the effect of methylcobalamin on ALS as a new therapeutic candidate. A phase Ⅲ study, Japanese Early-stage Trial of ultra-high dose methylcobalamin for ALS（JETALS）, was carried out. Patients with ALS diagnosed within１year of onset by the updated Awaji criteria were initially enrolled. Of those, patients fulfilling the following criteria after１２‐week observation were eligible for randomization :１- or ２-point decrease in ALS Functional Rating Scale Revised （ALSFRS-R）total score, a percent forced vital capacity over ６０％, no history of noninvasive respiratory support and tracheostomy, and being ambulant. Methylcobalamin ５０ mg or placebo was intramuscularly injected twice weekly for １６ weeks. The primary endpoint was change in ALSFRS-R total score from baseline to week １６. As a result, the least-squares mean difference in ALSFRS-R total score at week １６ of the randomized period was １．９７ points greater with methylcobalamin than placebo. The incidence of adverse events was similar between the two groups. In the future, we plan to work on elucidating the pathophysiology of ALS, developing more powerful treatments for ALS, and dealing with non-motor symptoms of ALS

ニンチショウ ノ ヨボウ ト チリョウ

The incidence of dementia is on a rise. Of the several diseases that can result in dementia, Alzheimer disease（AD）is the most frequent one. Treatment based on the correct diagnosis of dementia should be performed. Although the prevention of AD is possible by certain methods, such interventions merely delay the onset of this condition without completely stopping its development. AD can be treated with both medical and non-pharmacological therapies, but the effects are limited. Early examination for the diagnosis of AD is crucial for the successful implementation of all future treatment strategies. In the case of cerebrovascular diseases, improving one’s habits will assist in the prevention of vascular dementia

セキズイ ショウノウ ヘンセイショウ ノ イデンシ イジョウ

Spinocerebellar degeration （SCD） is a neurogenerative disorder. The cardinal signs of SCD include cerebellar and spinal ataxia, extrapyramidal signs, dysautonomia, pyramidal signs, mental signs, involuntary movement. In Japan, about ３０％ of SCA cases are hereditary in nature. Recently, several forms of inherited SCD have been reported, and can be devided into four groups, three of which show autosomal dominant inheritance. Group Ⅰ : This group is caused by expansion of CAG repeats encoding polyglutamine streches, and includes SCA１，２，３ （Machado-Joseph disease）, SCA７，SCA１２，dentatorubral-pallidoluysian atrophy. The number of CAG repeats correlates with the age at onset and severity of symptoms. The expanded CAG repeats become unstable during parent-offspring transmission. Group Ⅱ SCA６）：This is caused by a mutation involving mild expansion of CAG repeats in the gene encoding the voltage-dependent Ca channel alpha１A subunit （CACNA1 A）. The pathogenic CAG repeats are fewer than in Group I and stable during parent-offspring transmission. Group Ⅲ : This group is not caused by expansion of CAG repeats, and includes SCA８ （CTG expansion）, SCA１０ （ATTCT expansion）, and SCA１４ （point mutation). Group Ⅳ : This group shows sutosomal recessive inheritance, and includes Freidreich’s ataxia, early-onset ataxia with ocular motor apraxia and hypoalbuminemia, and ataxia with isolated vitamin E deficiency

脳卒中と認知症の予防

It became an important issue how we can live long in good health. Because stroke and dementia bring physical disability and cognitive functional decline and often need care, the treatment and prevention of those diseases are important. The number of stroke patients is increasing, but treatments for acute stroke has remarkably progressed, especially those by the endovascular therapy. Managing hypertension, diabetes mellitus, dyslipidemia and atrial fibrillation is key of the prevention. Because dementia patients are increasing remarkably, the countermeasures become the important problem of the country. Of the causes of dementia, Alzheimer disease is the most frequent followed by vascular dementia. Vascular dementia occurs due to cerebrovascular diseases. Therefore, it is important to manage hypertension, diabetes mellitus, dyslipidemia and atrial fibrillation for preventing vascular dementia. The etiology of Alzheimer disease is still unknown. A recent study suggests the possibility that hypertension, diabetes mellitus and dyslipidemia are involved in an etiology of Alzheimer disease. It may be effective for the prevention of Alzheimer disease to manage hypertension, diabetes mellitus and dyslipidemia

Magnetic resonance tractography exhibiting retrograde degeneration of the corticospinal tract in a patient with a unilateral spinal cord tumor

Background: Transection-induced axonal retrograde degeneration, in contrast to Wallerian degeneration, has not been widely recognized in clinical practice. Aims of the Study: To assess a potential of corticospinal tractography for detecting axonal retrograde degeneration. Methods: We assessed the corticospinal tractography of a 74-year-old woman with monoplegia of the lower limb due to a unilateral thoracic spinal cord tumor. Results: The tractography revealed integrity reduction of the corticospinal tract in the cerebra contralateral to the spinal cord tumor. Conclusions: The present report supports that magnetic resonance tractography has the potential for detecting this under-recognized phenomenon

ギョウセイテキナ コウジ キノウ ショウガイ ノ シンダン

Diagnostic criteria of the administrative higher brain dysfunction are defined. Young people between the period of entering school and starting work occasionally suffer from brain damage. Although the patient may seem to recover, memory and attention disturbances may continue. As a result, higher brain dysfunction may interfere with return to school, and reinstatement is difficult.Patients diagnosed with higher brain dysfunction by these diagnostic criteria can continue rehabilitation and achieve functional restoration. In the Tokushima University Hospital, many patients with cerebrovascular disease, brain tumor, or traffic injury（in that order）consulted about higher brain dysfunction

The effect of istradefylline for Parkinson’s disease : A meta-analysis

Adenosine A2A receptor antagonists are an alternative treatment strategy for Parkinson’s disease. Several randomized placebo controlled studies have tested the effect of A2A receptor antagonist istradefylline, and more robust evidence has been acquired. This meta-analysis aimed to provide evidence for its efficacy and safety on patients with Parkinson’s disease. After a systematic literature search, we calculated the pooled standardized mean difference and risk ratio for continuous and dichotomous variables, respectively. Further, sensitivity analyses were performed to confirm the effect estimated by meta-analyses. Publication bias was assessed by funnel plot and deviation of intercept. Six studies satisfied our inclusion criteria. Istradefylline (40 mg/day) decreased off time and improved motor symptoms of Parkinson’s disease in homogeneous studies. Istradefylline at 20 mg/day decreased off time and improved motor symptoms, but heterogeneity was found in the analysis of the former among studies. There was a significant effect of istradefylline on dyskinesia in homogeneous studies. Publication bias, however, was observed in the comparison of dyskinesia. Other adverse events showed no significant difference. The present meta-analysis suggests that istradefylline at 40 mg/day could alleviate off time and motor symptoms derived from Parkinson’s disease. Dyskinesia might be worsened, but publication bias prevents this from being clear

Efficacy of Zolpidem for Dystonia: A Study Among Different Subtypes

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor

Medical Devices for Parkinson’s Disease

Background: Pharmacotherapy is the first-line treatment option for Parkinson’s disease, and levodopa is considered the most effective drug for managing motor symptoms. However, side effects such as motor fluctuation and dyskinesia have been associated with levodopa treatment. For these conditions, alternative therapies, including invasive and non-invasive medical devices, may be helpful. This review sheds light on current progress in the development of devices to alleviate motor symptoms in Parkinson’s disease. Methods: We first conducted a narrative literature review to obtain an overview of current invasive and non-invasive medical devices and thereafter performed a systematic review of recent randomized controlled trials (RCTs) of these devices. Results: Our review revealed different characteristics of each device and their effectiveness for motor symptoms. Although invasive medical devices are usually highly effective, surgical procedures can be burdensome for patients and have serious side effects. In contrast, non-pharmacological/non-surgical devices have fewer complications. RCTs of non-invasive devices, especially non-invasive brain stimulation and mechanical peripheral stimulation devices, have proven effectiveness on motor symptoms. Nearly no non-invasive devices have yet received Food and Drug Administration certification or a CE mark. Conclusion: Invasive and non-invasive medical devices have unique characteristics, and several RCTs have been conducted for each device. Invasive devices are more effective, while non-invasive devices are less effective and have lower hurdles and risks. It is important to understand the characteristics of each device and capitalize on these

Zolpidem therapy in dystonia

Although there are some newly developed options to treat dystonia, its medical treatment is not always satisfactory. Zolpidem, an imidazopyridine agonist with a high affinity on benzodiazepine subtype receptor BZ1 (ω1), was found to improve clinical symptoms of dystonia in a limited number of case reports. To investigate what subtype of dystonia is responsive to the therapy, we conducted an open label study to assess the efficacy of zolpidem (5–20 mg) in 34 patients suffering from miscellaneous types of dystonia using the Burke–Fahn–Marsden Dystonia Rating Scale (BFMDRS). Patients were entered into the study if they had been refractory to other medications as evaluated by BFMDRS (no change in the previous two successive visits). After zolpidem therapy, the scores in the patients as a whole were decreased from 7.2 ± 7.9 to 5.5 ± 5.0 (P = 0.042). Patients with generalized dystonia, Meige syndrome/blepharospasm, and hand dystonia improved in the scale by 27.8, 17.8, and 31.0%, respectively, whereas no improvement was found in cervical dystonia patients. Overall response rate among patients were comparable to that of trihexyphenidyl. Zolpidem may be a therapeutic option for generalized dystonia, Meige syndrome, and hand dystonia including musician’s. Drowsiness was the dose-limiting factor