Publications by authors named "Yoshimitsu Shimatani"

25 Publications

  • Page 1 of 1

A novel COL4A1 variant associated with recurrent epistaxis and glioblastoma.

Hum Genome Var 2021 May 14;8(1):18. Epub 2021 May 14.

Department of Neurology, Tokushima University Graduate School of Biomedical Sciences, Tokushima, Japan.

COL4A1-related disorders are characterized by a higher incidence of cerebral hemorrhage than other hereditary cerebral small vessel diseases. Accumulating data have shown broad phenotypic variations, and extracerebral hemorrhages have been linked to these disorders. Moreover, the coexistence of neural tumors has been described. Here, we report a Japanese family with a novel COL4A1 variant, including a patient with recurrent epistaxis and glioblastoma.
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http://dx.doi.org/10.1038/s41439-021-00150-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8121905PMC
May 2021

Compound heterozygote mutations in the SIGMAR1 gene in an oldest-old patient with amyotrophic lateral sclerosis.

Geriatr Gerontol Int 2018 10;18(10):1519-1520

Department of Epidemiology, Research Institute for Radiation Biology & Medicine, Hiroshima University, Hiroshima, Japan.

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http://dx.doi.org/10.1111/ggi.13506DOI Listing
October 2018

Implications of structural and functional brain changes in amyotrophic lateral sclerosis.

Expert Rev Neurother 2018 05 19;18(5):407-419. Epub 2018 Apr 19.

a Brain and Mind Centre , The University of Sydney , Sydney , Australia.

Introduction: Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease that causes progressive muscle weakness and disability, eventually leading to death. Heterogeneity of disease has become a major barrier to understanding key clinical questions such as prognosis and disease spread, and has disadvantaged clinical trials in search of therapeutic intervention. Patterns of disease have been explored through recent advances in neuroimaging, elucidating structural, molecular and functional changes. Unique brain signatures have emerged that have lent a greater understanding of critical disease mechanisms, offering opportunities to improve diagnosis, guide prognosis, and establish candidate biomarkers to direct future therapeutic strategies. Areas covered: This review explores patterns of cortical and subcortical change in ALS through advanced neuroimaging techniques and discusses the implications of these findings. Expert commentary: Cortical and subcortical signatures and patterns of atrophy are now consistently recognised, providing important pathophysiological insight into this heterogenous disease. The spread of cortical change, particularly involving frontotemporal networks, correlates with cognitive impairment and poorer prognosis. Cortical differences are also evident between ALS phenotypes and genotypes, which may partly explain the heterogeneity of prognosis. Ultimately, multimodal approaches with larger cohorts will be needed to provide sensitive biomarkers of disease spread at the level of the individual patient.
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http://dx.doi.org/10.1080/14737175.2018.1464912DOI Listing
May 2018

Neurologic attack and dynamic perfusion abnormality in neuronal intranuclear inclusion disease.

Neurol Clin Pract 2017 Dec;7(6):e39-e42

Institute of Biomedical Sciences (KF, YO, RM, YS, TA, YI, RK), Tokushima University Graduate School, Tokushima; and Tokyo Metropolitan Geriatric Hospital and Institute of Gerontology (HS, SM), Tokyo, Japan.

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http://dx.doi.org/10.1212/CPJ.0000000000000389DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5800705PMC
December 2017

Atypical Lipomatous Tumor/Well-Differentiated Liposarcoma Developed in a Patient with Progressive Muscular Dystrophy: A Case Report and Review of the Literature.

Case Rep Orthop 2017 29;2017:3025084. Epub 2017 May 29.

Department of Orthopedics, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima 770-8503, Japan.

Background: Atypical lipomatous tumor/well-differentiated liposarcoma (ALT/WDLS) is an intermediate or locally aggressive form of adipocytic soft tissue sarcoma. Muscular dystrophy (MD) is characterized by progressive muscle atrophy and its replacement by adipose and fibrous tissue. Recently, some authors have reported that MD genes are related to neoplastic formation, but there have been no detailed clinical reports of ALT associated with MD.

Case Presentation: A 73-year-old woman with a diagnosis of limb-girdle MD visited our department for recurrence of a huge tumor in her left thigh. She had undergone resection of a lipoma at the same site more than 20 years earlier. Imaging studies revealed a lipomatous tumor in her left thigh. We performed marginal resection including the adjacent muscles. Histological diagnosis was atypical lipomatous tumor. The postoperative course was uneventful, with no recurrence at 36 months of follow-up.

Conclusion: We encountered a huge atypical tumor in a patient with MD. This is the first detailed report to describe an association between ALT and MD. We hypothesize that degenerative changes occurring in adipose tissue during muscle atrophy can cause lipomatous neoplasms and moreover that the mutation of MD-related genes may lead to the proliferation of tumor cells or to malignancy.
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http://dx.doi.org/10.1155/2017/3025084DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5467340PMC
May 2017

Neurogenic and Myogenic Diseases: Quantitative Texture Analysis of Muscle US Data for Differentiation.

Radiology 2017 05 2;283(2):492-498. Epub 2017 Feb 2.

From the Faculty of Medicine (K.S.) and Department of Neurology (H.N., N.T., A.M., H.Y., Y.S., Y.I., R.K.), Tokushima University, 3-18-15 Kuramotocho, Tokushima 770-8503, Japan; and Department of Neurology, Vihara Hananosato Hospital, Hiroshima, Japan (N.T., Y.I.).

Purpose To assess the multiple texture features of skeletal muscles in neurogenic and myogenic diseases by using ultrasonography (US). Materials and Methods After institutional review board approval, muscle US studies of the medial head of the gastrocnemius were performed prospectively in patients with neurogenic diseases (n = 25 [18 men]; mean age, 66.0 years ± 12.3 [standard deviation]), in patients with myogenic diseases (n = 21 [12 men]; mean age, 68.3 years ± 11.5), and in healthy control subjects (n = 21 [11 men]; mean age, 70.5 years ± 8.4) between January 2013 and May 2016. Written informed consent was obtained. Muscle texture parameters were obtained, and five algorithms were used to classify the groups. Results The neurogenic and myogenic disease groups showed higher echo intensities than the control subjects. The histogram-derived texture parameters had overlaps between the neurogenic and myogenic groups and thus had a low discrimination rate. With assessment of more classes of texture parameters, three groups were correctly classified (100% correct, according to four of five classification algorithms). Tenfold cross validation showed 93.5%-95.7% correct classification between the neurogenic and myogenic groups. The run-length matrix, autoregressive model, and co-occurrence matrix were particularly useful in distinguishing the neurogenic and myogenic groups. Conclusion Texture analysis of muscle US data can enable differentiation between neurogenic and myogenic diseases and is useful in noninvasively assessing underlying disease mechanisms. RSNA, 2017 Online supplemental material is available for this article.
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http://dx.doi.org/10.1148/radiol.2016160826DOI Listing
May 2017

Choreoathetosis, Dystonia, and Myoclonus in 3 Siblings With Autosomal Recessive Spinocerebellar Ataxia Type 16.

JAMA Neurol 2016 07;73(7):888-90

Department of Clinical Neuroscience, Institute of Biomedical Sciences, Tokushima University Graduate School, Tokushima, Japan.

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http://dx.doi.org/10.1001/jamaneurol.2016.0647DOI Listing
July 2016

Sonographic evaluation of peripheral nerves in subtypes of Guillain-Barré syndrome.

J Neurol Sci 2016 May 26;364:154-9. Epub 2016 Mar 26.

Department of Neurology, Tokushima University, Tokushima, Japan.

Background: Sonography of peripheral nerves can depict alteration of nerve sizes that could reflect inflammation and edema in inflammatory and demyelinating neuropathies. Guillain-Barré syndrome (GBS). Information on sonographic comparison of an axonal subtype (acute motor [and sensory] axonal neuropathy [AMAN and AMSAN]) and a demyelinating subtype (acute inflammatory demyelinating polyneuropathy [AIDP]) has been sparse.

Material And Methods: Sonography of peripheral nerves and cervical nerve roots were prospectively recorded in patients with GBS who were within three weeks of disease onset.

Results: Five patients with AIDP and nine with AMAN (n=6)/AMSAN (n=3) were enrolled. The patients with AIDP showed evidence of greater degrees of demyelination (e.g., slower conduction velocities and increased distal latencies) than those with AMAN/AMSAN. The patients with AIDP tended to show enlarged nerves in the proximal segments and in the cervical roots, whereas the patients with AMAN/AMSAN had greater enlargement in the distal neve segment, especially in the median nerve (P = 0.03; Wrist-axilla cross-sectional ratio).

Conclusion: In this small study, two subtypes of GBS showed different patterns of involvement that might reflect different pathomechanisms.
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http://dx.doi.org/10.1016/j.jns.2016.03.042DOI Listing
May 2016

Sonographic evaluation of cervical nerve roots in ALS and its clinical subtypes.

J Med Invest 2016 ;63(1-2):54-7

Department of Neurology, Tokushima University.

Morphological assessment of peripheral nerves in amyotrophic lateral sclerosis (ALS) has been available by sonography. Detection of possible axonal atrophy could be important in predicting progression. Research on correlation between sonographic findings and clinical presentation has been sparse. The aim of the study was to assess possible motor axon loss in patients with ALS by sonography and to correlate the imaging features with clinical subtypes. Patients with either definite or probable ALS and control subjects had sonographic evaluation of the cervical nerve roots (C5, C6, and C7). Each diameter and their sums were measured. The ALS patients were classified by their clinical onset and progression (arm-onset, leg-onset, bulbar, and flail-arm variant) and the sonographic features were compared. Overall, the cervical nerve roots were thinner in ALS than in the controls, but the diagnostic sensitivity was low. The patients with arm dysfunctions tended to show thinner nerve roots than those with normal or relatively preserved arm functions. The four ALS subtypes showed similar diameters of the nerve roots. There was no correlation between the disease duration and the diameters of the nerve roots. Sonography of the cervical nerve roots showed axonal atrophy in ALS and potentially reflects subtle arm dysfunctions.
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http://dx.doi.org/10.2152/jmi.63.54DOI Listing
January 2017

Which muscle shows fasciculations by ultrasound in patients with ALS?

J Med Invest 2016 ;63(1-2):49-53

Department of Neurology, Tokushima University.

The purpose of the present study was to elucidate the relative frequencies of fasciculations assessed by sonography in a large number of muscles in patients with amyotrophic lateral sclerosis (ALS). The patients diagnosed as having ALS were retrospectively assessed by muscle sonography. The frequencies of having fasciculations were compared among the 15 muscles and the subtypes according to the initially affected body region. Overall, approximately half of the muscles had fasciculations (48.8%), in the average of 11.4 muscles per patient. The frequency of fasciculations tended to be lower in the patients with longer disease durations upon testing. Biceps brachii had the highest frequency, followed by extensor digitorum communis, whereas sternocleidomastoid and rectus abdominis had the lowest frequencies. The frequencies of fasciculations were similar among the clinical subtypes. In conclusion, in patients with ALS, fasciculations were detected most frequently in proximal arm muscles by sonography, whereas truncal muscles had lower frequencies. Fasciculations tended to be less evident in the advanced disease stage, possibly reflecting muscle degeneration. Appropriate selection of muscles to observe fasciculations is important for diagnosis of ALS.
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http://dx.doi.org/10.2152/jmi.63.49DOI Listing
January 2017

Impaired Axonal Na(+) Current by Hindlimb Unloading: Implication for Disuse Neuromuscular Atrophy.

Front Physiol 2016 16;7:36. Epub 2016 Feb 16.

Department of Neurology, Tokushima University Tokushima, Japan.

This study aimed to characterize the excitability changes in peripheral motor axons caused by hindlimb unloading (HLU), which is a model of disuse neuromuscular atrophy. HLU was performed in normal 8-week-old male mice by fixing the proximal tail by a clip connected to the top of the animal's cage for 3 weeks. Axonal excitability studies were performed by stimulating the sciatic nerve at the ankle and recording the compound muscle action potential (CMAP) from the foot. The amplitudes of the motor responses of the unloading group were 51% of the control amplitudes [2.2 ± 1.3 mV (HLU) vs. 4.3 ± 1.2 mV (Control), P = 0.03]. Multiple axonal excitability analysis showed that the unloading group had a smaller strength-duration time constant (SDTC) and late subexcitability (recovery cycle) than the controls [0.075 ± 0.01 (HLU) vs. 0.12 ± 0.01 (Control), P < 0.01; 5.4 ± 1.0 (HLU) vs. 10.0 ± 1.3 % (Control), P = 0.01, respectively]. Three weeks after releasing from HLU, the SDTC became comparable to the control range. Using a modeling study, the observed differences in the waveforms could be explained by reduced persistent Na(+) currents along with parameters related to current leakage. Quantification of RNA of a SCA1A gene coding a voltage-gated Na(+) channel tended to be decreased in the sciatic nerve in HLU. The present study suggested that axonal ion currents are altered in vivo by HLU. It is still undetermined whether the dysfunctional axonal ion currents have any pathogenicity on neuromuscular atrophy or are the results of neural plasticity by atrophy.
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http://dx.doi.org/10.3389/fphys.2016.00036DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4754663PMC
February 2016

Extranodal NK/T-cell lymphoma, nasal type, manifesting as rapidly progressive dementia without any mass or enhancing brain lesion.

Neuropathology 2016 Oct 15;36(5):456-463. Epub 2016 Jan 15.

Department of Clinical Neuroscience, Tokushima University Graduate School Tokushima, Japan.

Among the many potential etiologies for rapidly progressive dementia (RPD), primary central nervous system extranodal NK/T-cell lymphoma, nasal-type (ENKL) is a rare entity. We present the first reported case of autopsy-proven RPD due to ENKL without any mass or enhancing lesion of the brain. A 54-year-old immunocompetent man presented with RPD, myoclonus and ataxia. The mini-mental state examination (MMSE) score was 22/30. His brain MRI revealed progressive brain atrophy without gadolinium enhancement or mass lesion. Five months after the initial evaluation, cognitive impairment further worsened with an MMSE score of 3/30. At the advanced stage, lumbar MRI showed swollen cauda equina with gadolinium enhancement. The number of Epstein-Barr virus (EBV) DNA in cerebrospinal fluid had gradually increased. Twelve months after onset, the patient died of respiratory failure. Pathological findings revealed that lymphoma cells had diffusely invaded the meninges, parenchyma of the brain, spinal cord and cauda equina. Cells were positive for CD3, CD56 and EBV-encoded small RNAs and negative for CD20. No evidence of malignancy was identified in the visceral organs. This report indicates that ENKL should be recognized as one of the rare causes of RPD. Early testing for EBV-DNA in cerebrospinal fluid and imaging of cauda equina would be useful diagnostic tools.
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http://dx.doi.org/10.1111/neup.12285DOI Listing
October 2016

Upregulation of axonal HCN current by methylglyoxal: Potential association with diabetic polyneuropathy.

Clin Neurophysiol 2015 Nov 14;126(11):2226-32. Epub 2015 Mar 14.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: To describe functional changes of axonal ion channels by a metabolic derivative of glucose, methylglyoxal (MGO), and its potential contribution to diabetic neuropathy.

Methods: (1) In wild-type male mice, multiple excitability measurements of sensory nerves were performed at baseline and 1week after serial administration of MGO (50mg/kg). (2) Excitability testing in patients with diabetic neuropathy (N=17) and healthy controls (N=12) were also conducted, and data were interpreted using mathematical modeling.

Results: In the animal study, there was a decrease in threshold changes by long hyperpolarization and in superexcitability after administration of MGO. In the preliminary human study, the threshold changes by long hyperpolarizing current were decreased in patients with diabetes. Mathematical modeling showed increased hyperpolarization-activated cation current (Ih) in the MGO-treated mice and in patients with diabetes.

Conclusion: Ih was upregulated after MGO administration in normal mice.

Significance: MGO is associated with abnormal axonal excitability. Hyperexcitability in diabetic polyneuropathy may, at least in part, be caused by dysfunctional axonal hyperpolarization-activated cyclic nucleotide-gated (HCN) channels. A future study with a large sample size of the diabetic patients would clarify this hypothesis.
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http://dx.doi.org/10.1016/j.clinph.2015.02.058DOI Listing
November 2015

Effects of anesthetic agents on in vivo axonal HCN current in normal mice.

Clin Neurophysiol 2015 Oct 19;126(10):2033-9. Epub 2015 Jan 19.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: The objective was to study the in vivo effects of anesthetic agents on peripheral nerve excitability.

Methods: Normal male mice were anesthetized by either isoflurane inhalation or a combination of medetomidine, midazolam, and butorphanol intraperitoneal injection ("triple agents"). Immediately after induction, the tail sensory nerve action potential was recorded and its excitability was monitored.

Results: Under both anesthetic protocols, there was an interval excitability change by long hyperpolarizing currents. There was greater threshold reduction approximately 30min post induction, in comparison to immediately post induction. Other excitability parameters were stable over time. Modeling suggested interval suppression of internodal H conductance or leak current.

Conclusions: Anesthetic agents affected responses to long hyperpolarizing currents.

Significance: Axonal excitability during intraoperative monitoring may be affected by anesthetic agents. Interpretation of interval excitability changes under anesthesia requires caution, especially with long hyperpolarizing currents.
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http://dx.doi.org/10.1016/j.clinph.2014.12.025DOI Listing
October 2015

Focal nerve enlargement is not the cause for increased distal motor latency in ALS: Sonographic evaluation.

Clin Neurophysiol 2015 Aug 1;126(8):1632-7. Epub 2014 Nov 1.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: To elucidate the mechanism of focal conduction slowing in the median nerve in ALS.

Methods: The patients with ALS and CTS and normal control subjects were tested with sonography of the median and ulnar nerves. The cross-sectional areas (CSAs) and the wrist-forearm CSA ratios were compared with the parameters of nerve conduction study.

Results: The median motor distal latency was frequently prolonged in ALS and CTS. CSA and the wrist-forearm ratio of the median nerve were smaller in ALS than in CTS. The ulnar nerve sonography was similar in all the groups.

Conclusions: Selective conduction slowing of the median nerve at the wrist in ALS is unlikely due to secondary compressive neuropathy, as seen in carpal tunnel syndrome.

Significance: Unique vulnerability of the median nerve in ALS may explain the selective conduction slowing.
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http://dx.doi.org/10.1016/j.clinph.2014.10.152DOI Listing
August 2015

Ultrasonographic evaluation of myokymic discharges.

Clin Neurophysiol 2015 Aug 6;126(8):1638-9. Epub 2014 Nov 6.

Department of Clinical Neuroscience, Institute of Health Biosciences, Tokushima University, Tokushima, Japan.

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http://dx.doi.org/10.1016/j.clinph.2014.10.154DOI Listing
August 2015

Abnormal gating of axonal slow potassium current in cramp-fasciculation syndrome.

Clin Neurophysiol 2015 Jun 28;126(6):1246-1254. Epub 2014 Sep 28.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Cramp-fasciculation syndrome (CFS) is a heterogeneous condition with multiple underlying causes. Although dysfunction of slow K(+) channels has been reported in patients with CFS, testing all potential candidates for this problem using conventional in vitro functional analysis would be prohibitively cost- and labor-intensive. However, relatively economical and non-invasive nerve-excitability testing can identify ion channel dysfunction in vivo when combined with numerical modeling.

Methods: Patients with CFS underwent nerve conduction study, needle electromyography, and nerve excitability testing. Mathematical modeling of axonal properties was applied to identify the pathophysiology.

Results: Four patients had distinct electrophysiological findings (i.e., fasciculation potentials, doublet/multiplet motor unit potentials, and sustained F responses); excitability testing showed the following abnormalities: reduction of accommodation during prolonged depolarization, lack of late sub excitability after a supramaximal stimulation, and reduction of the strength-duration time constant. Mathematical modeling showed a loss of voltage-dependence of a slow K(+) current. None of these patients had a mutation in the KCNQ2, 3, or 5 genes.

Conclusions: This study showed that patients with CFS might have abnormal kinetics in a slow K(+) current.

Significance: Nerve-excitability testing may aid the decision to start therapeutic intervention such as administration of slow K(+) channel openers.
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http://dx.doi.org/10.1016/j.clinph.2014.09.013DOI Listing
June 2015

Are multifocal motor neuropathy patients underdiagnosed? An epidemiological survey in Japan.

Muscle Nerve 2014 Mar;49(3):357-61

Introduction: Our objective was to do an epidemiologic survey of patients with multifocal motor neuropathy (MMN) in comparison with those with amyotrophic lateral sclerosis (ALS) in Japan.

Methods: In this retrospective study, we examined 46 patients with MMN and 1,051 patients with ALS from major neuromuscular centers in Japan from 2005 to 2009. Diagnosis was based on the European Federation of Neurological Societies/Peripheral Nerve Society (EFNS/PNS) and the revised El Escorial criteria. The efficacy of intravenous immunoglobulin (IVIg) was also taken into consideration in the diagnosis of MMN.

Results: The ratio of MMN to ALS patients (0–0.10) varied among the centers, but mostly converged to 0.05. The prevalence was estimated to be 0.29 MMN patients and 6.63 ALS patients per 100,000 population.

Conclusions: The frequency of MMN patients was around 1 out of 20 ALS patients, and MMN was possibly underdiagnosed in some centers.
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http://dx.doi.org/10.1002/mus.23930DOI Listing
March 2014

Thinning of cervical nerve roots and peripheral nerves in ALS as measured by sonography.

Clin Neurophysiol 2014 Sep 24;125(9):1906-11. Epub 2014 Feb 24.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Progressive atrophy and loss of motor axons is a hallmark of amyotrophic lateral sclerosis (ALS). Limited sonographic data are available on potential detection of atrophy of peripheral nerves and nerve roots in ALS.

Methods: Patients with either definite or probable ALS and control subjects underwent sonographic evaluation of the cervical roots (C5, C6, and C7) and peripheral nerves (median and ulnar nerves) on the right. These diameters and cross-sectional areas (C6, median, and ulnar nerves) were compared.

Results: The diameters and cross-sectional areas were consistently smaller in ALS than in controls. No correlation was present between the sonographic parameters and the disease severity, disease duration, age, or gender. The overall sensitivity and specificity tended to be greater in the cervical nerve roots than in the peripheral nerves.

Conclusions: This study shows atrophy of cervical nerve roots and peripheral nerves in ALS detected by sonography. Cervical nerve roots might be more appropriate to detect motor axon loss than peripheral nerves.

Significance: Sonographic evaluation of nerve roots and peripheral nerves may be a useful disease marker in ALS to confirm the diagnosis and to potentially monitor the disease progression.
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http://dx.doi.org/10.1016/j.clinph.2014.01.033DOI Listing
September 2014

Comparison between botulinum neurotoxin type A2 and type A1 by electrophysiological study in healthy individuals.

Toxicon 2014 Apr 1;81:32-6. Epub 2014 Feb 1.

Department of Clinical Neuroscience, Institute of Health Biosciences, Graduate School of Medicine, University of Tokushima, 18-15 Kuramoto-cho, Tokushima-shi, Tokushima 770-8503, Japan.

Botulinum neurotoxin type A1 (BoNTs/A1) and type B (BoNT/B) have been used for treating hyperactive muscle contractions. In the present study, we compared the effect of botulinum neurotoxin subtype A2 (6.5 mouse LD50 units A2 neurotoxin, A2NTX) and onabotulinumtoxinA (10 mouse LD50 units BoNT/A1 product) by measuring the compound muscle action potentials (CMAPs) before and after administration. In total, 8 healthy subjects were examined in the present study. A2NTX was injected into the extensor digitorum brevis (EDB) muscle, followed by onabotulinumtoxinA injection into the contralateral EDB muscle after 16 weeks. The CMAP amplitudes from the EDB, abductor hallucis (AH), and abductor digiti minimi pedis (ADM) muscles were measured after each BoNT injection on days 1, 3, 7, 14, 28, 56, 84, and 112 to assess the effect of the toxin. On day 14, both A2NTX and onabotulinumtoxinA produced an approximately 70% decline in EDB CMAP amplitude compared to the baseline values; significant reduction of the CMAP continued through day 112. The CMAP amplitudes from neighboring muscles (AH and ADM) remained intact throughout the study period, except for a slight but significant drop at day 28 after onabotulinumtoxinA injection compared to A2NTX. The current findings indicate that small doses (6.5 units and 10 units) of A2NTX and onabotulinumtoxinA have at least comparable onset and duration of action, although similar clinical effects were obtained with lower dose using A2NTX.
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http://dx.doi.org/10.1016/j.toxicon.2013.12.012DOI Listing
April 2014

Increased variability of axonal excitability in amyotrophic lateral sclerosis.

Clin Neurophysiol 2013 Oct 29;124(10):2046-53. Epub 2013 May 29.

Department of Neurology, Tokushima University, Tokushima, Japan.

Objective: Amyotrophic lateral sclerosis (ALS) is characterised by the increased excitability of motoneurons and heterogeneous loss of axons. The heterogeneous nature of the disease process among fibres may show variability of excitability in ALS.

Methods: Multiple nerve excitability tests were performed in 28 ALS patients and 23 control subjects, by tracking at the varying threshold levels (10%, 20%, 40% and 60% of maximum amplitudes).

Results: In normal controls, excitability measures at low target levels have the following characteristics compared to those at high target levels: longer strength-duration time constant, greater threshold reduction during depolarising currents and smaller threshold increase to hyperpolarising currents. ALS patients had less clear amplitude dependency of the parameters than the controls, indicating variability of axonal excitability. Three ALS patients demonstrated greater target-amplitude-dependent threshold changes in threshold electrotonus than controls, suggesting selective axonal hyperexcitability.

Conclusions: Some of the ALS patients had variable axonal excitability at different target amplitudes, suggesting preferential hyperexcitability in the axons with low target amplitude levels.

Significance: Variable membrane potentials of motor axons in ALS may be assessed by recording excitability testing at different target amplitude levels.
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http://dx.doi.org/10.1016/j.clinph.2013.02.117DOI Listing
October 2013

[Increased variability of membrane potentials in amyotrophic lateral sclerosis].

Rinsho Shinkeigaku 2011 Nov;51(11):1114-7

Department of Neurology, Tokushima University.

Amyotrophic lateral sclerosis (ALS) is characterized by increased excitability of motor neurons and early involvement of large motor fibers that have low electrical thresholds. Despite the advent of new techniques of threshold tracking, exploration of this abnormal excitability has not been straightforward, by tracking at the single target level as previous reported, because of the heterogeneous nature of the disease process among fibers that have variable thresholds. We have assessed different populations of motor axons by tracking at four different target response levels (10, 20, 40 and 60% of maximum compound muscle action potentials), and conducted multiple nerve excitability tests in 27 ALS patients and 23 control subjects. In normal controls, axons with low thresholds have the following characteristics compared to those with high thresholds: greater threshold reduction during depolarizing currents and smaller threshold increase to hyperpolarizing currents, reflecting the order of the fiber size. In contrast, ALS patients lacked these relationships, suggesting increased variability of axonal membrane potentials. Three ALS patients demonstrated changes in threshold electrotonus, consistent with overt membrane depolarization, as seen in ischemic nerves. The variability of motor nerve excitability accounts for fasciculations, confirms previously reported dysfunction of potassium channels, and suggests failure of Na(+)/K(+)pumps, possibly caused by mitochondrial dysfunctions at the early stage.
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http://dx.doi.org/10.5692/clinicalneurol.51.1114DOI Listing
November 2011

[Threshold tracking for beginners].

Brain Nerve 2011 Jun;63(6):531-8

Department of Neurology, Tokushima University Hospital, Tokushima, Japan.

Nerve excitability has been studied for a longer time than has nerve conduction. Prof. Joseph Bergmans pioneered the use of threshold current measurement for studying axonal excitability. However nerve excitability testing has not been used because of technical difficulties. Prof. Hugh Bostock developed a semiautomatic program called QTRAC. This program enables the examiner to perform various nerve excitability tests within 15 min. Nerve excitability testing can provide information regarding physiological conditions, ion channels and the functions of energy-dependent pumps in normal controls and in individuals with diseases such as amyotrophic lateral sclerosis (ALS) and multifocal motor neuropathy (MMN). For understanding threshold tracking, information regarding basic physiological principles including the function of ion channels is required. This review provides important insights on the function of axonal ion channels and investigational methods.
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June 2011

Can Awaji ALS criteria provide earlier diagnosis than the revised El Escorial criteria?

J Neurol Sci 2011 Mar 6;302(1-2):29-32. Epub 2011 Jan 6.

Department of Neurology, Tokushima University, Tokushima, Japan; Kansai Rehabilitation College, Hyogo, Japan.

Background: Recently, new electrophysiological ALS criteria incorporating fasciculation potentials (FPs) as evidence for lower motor neuron signs (Awaji Criteria (AC)) was proposed to provide earlier detection of early-stage ALS than revised El Escorial electrophysiological criteria (REEC). However, serial electrophysiological analysis is lacking to ascertain the original intention. The objective for this study was to elucidate whether electrophysiological criteria set for AC detects ALS earlier than REEC's counterpart in patients with ALS.

Methods: Of the 51 patients who were clinically suspected of ALS, 35 patients prospectively received serial electrophysiological studies every 3 months until (1) both electrophysiological AC and REEC criteria were met in more than two muscles representing both of the cervical and lumbosacral segments or (2) either clinically definite or clinically probable REEC criteria was met. The intervals were determined between the initial disease onset and when the respective electrophysiological criteria were met.

Results: Electrophysiological diagnostic criteria were met in 94.3% by AC and 40% by REEC at the initial visits. The intervals between the disease onset and the time of meeting the electrophysiological criteria were shorter in AC (mean: 9.0 months) than in REEC (mean: 15.2 months) (P<0.01). Eleven patients who met only AC electrophysiological criteria on the initial study subsequently met REEC electrophysiological criteria with the mean interval of 3.8 months. A higher percentage of bulbar-type ALS (83.3%) met AC than limb-onset ALS (43.4%) (P<0.05). FPs tended to be more frequently observed than fib/psw in the muscles outside the region of initial clinical onset.

Conclusion: Electrophysiological criteria of AC were met earlier than that of REEC in ALS patients, especially in patients with bulbar onset. Early recognition of ALS by AC may allow effective therapeutic intervention in the early disease stage.
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http://dx.doi.org/10.1016/j.jns.2010.12.007DOI Listing
March 2011