We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sc... more We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the fi...
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 27, 2016
Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nico... more Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AC...
To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we ... more To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of "typical" CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients.
To evaluate the effects of bromocriptine on bladder function in Parkinson's disease (PD) patients... more To evaluate the effects of bromocriptine on bladder function in Parkinson's disease (PD) patients and compare these effects with those of (L-dopa). We recruited 8 patients with PD. Urodynamic study (UDS) was performed before and 1 hour after administering 100 mg L-dopa/decarboxylase inhibitor (DCI) and 2.5 hours after administering 7.5 mg bromocriptine. After the bromocriptine administration, urinary urgency aggravated. UDS revealed a decreased bladder volume at which detrusor overactivity (DO) was initiated, a decreased bladder volume at first sensation of bladder filling (FSV) (P < 0.05), an increased maximum Watts Factor value (WFmax) (detrusor contractility), a decreased Abrams-Griffiths (AG) number (urethral obstruction), and a decreased postvoid residual (PVR) (P < 0.01). Similarly, after the L-dopa administration, urinary urgency aggravated. UDS revealed an aggravated DO (P < 0.05), a decreased FSV and bladder capacity (P < 0.01, 0.05), an increased WFmax (P < 0.05), an increased AG number, and a decreased PVR (P < 0.01). A single dose of bromocriptine proved to exacerbate urinary urgency and DO in the storage phase, and improve bladder emptying through increased detrusor contractility and decreased bladder outlet obstruction, within hours. With the exception of bladder outlet obstruction, these effects of bromocriptine are similar to the effects of L-dopa, albeit slightly less pronounced.
Journal of Neurology, Neurosurgery & Psychiatry, 2005
Background: Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is charact... more Background: Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is characterised by anterior horn cell loss in the lower cervical cord, presumably caused by anterior displacement of the dural sac during neck flexion. A recent report suggests that atopy and IgE may contribute to anterior horn damage. Objective: To investigate whether IgE is a contributing factor in Hirayama disease. Methods: Serum total IgE and allergen specific IgE were examined in 20 consecutive patients, and their correlations with clinical profiles investigated. Results: Past or present history of allergy/atopy was found in only four patients (20%), but serum IgE was raised in 14 (70%). Patients with hyperIgEaemia had more severe clinical disabilities than those without (p = 0.01). In patients whose history of Hirayama disease was less than five years, serum total IgE was higher than in those with the disease for five years or more (p = 0.05). Conclusions: The results suggest that hyperIgEaemia is often associated with Hirayama disease and can facilitate its pathophysiology, particularly in the early phases of the disease. HyperIgEaemia does not appear to involve the anterior horn cells primarily.
Although immunosuppressive effects of antiepileptic drug are well known, serious complications of... more Although immunosuppressive effects of antiepileptic drug are well known, serious complications of antiepileptic drug are rare. We report a case of hypogammaglobulinemia associated with aplasia of B lymphocytes after carbamazepine treatment. Despite repeated intravenous immunoglobulin replacement therapy, this condition persisted for more than three months. The present case suggested that routine monitoring of the blood cell count and serum levels of immunoglobulin are important in patients treated with carbamazepine, and a lymphocyte subpopulation study is valuable in cases of hypogammaglobulinemia.
Object: To study the effects of the intravenous administration of methylcobalamin, an analogue of... more Object: To study the effects of the intravenous administration of methylcobalamin, an analogue of vitamin B12, for uremic or uremic-diabetic polyneuropathy in patients whoare receiving maintenance hemodialysis. An ultra-high dose of vitamin B12 has been reported to promote peripheral nerve regeneration in experimental neuropathy. Methods: Nine patients received a 500|ig methylcobalamin injection 3 times a week for 6 months. The effects were evaluated using neuropathic pain grading and a nerve conduction study. Results: Serum concentrations of vitamin B12 were ultra-high during treatment due to the lack of urinary excretion. After 6 months of treatment, the patients' pain or paresthesia had lessened, and the ulnar motor and median sensory nerve conduction velocities showed significant improvement. There were no side effects. Conclusion: Intravenous methycobalamin treatment is a safe and potentially beneficial therapy for neuropathy in chronic hemodialysis patients.
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, Jan 16, 2016
To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) ... more To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD). Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested. Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteri...
Background: The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, ho... more Background: The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, however this criteria seemed to be insufficient at early stage of NMO. Hence, the development of diagnostic marker besides anti-aquaporin 4 antibody at early stage of NMO may be required. Our main aim of this study is to test the usefulness of measuring cerebrospinal fluid (CSF) interleukin (IL)-6 and glial fibrillary acidic protein (GFAP) concentrations as early diagnostic markers during initial NMO attacks. Methods: We investigated CSF IL-6 and GFAP concentrations in 13 NMO spectrum disorder (NMOSD) patients at initial attacks, 24 idiopathic central nervous system inflammatory disease patients (9 optic neuritis, 9 myelitis and 6 encephalitis) and 20 other non-inflammatory neurological disorders (ONNDs) patients, retrospectively. Results: The mean CSF IL-6 and GFAP concentrations during the initial NMOSD attack were 91.4 pg/ml and 369.3 ng/ml, respectively, and were significantly higher than in ONNDs, idiopathic optic neuritis and myelitis patients (P b 0.01). The sensitivity of high CSF IL-6 during initial NMO attack was 76.9% and that of high CSF GFAP was 84.6%, respectively. Conclusion: Our data suggests that CSF IL-6 and GFAP may be useful early diagnostic markers of NMOSD.
ation time constants and the shapes of recovery cycles were normal, although refractoriness and s... more ation time constants and the shapes of recovery cycles were normal, although refractoriness and superexcitability were reduced relative to controls. The high thresholds and early fanning out of electrotonus indicated altered cable properties, such that a greater proportion than normal of applied currents reached internodal rather than nodal axolemma. The rapid accommodation to depolarizing currents suggested activation of fast K + channels, which are normally sequestered from the nodal membrane. The excitability abnormalities are therefore consistent with a demyelinating pathology and exposure or spread of K + channels from under the myelin. It remains to be seen whether the TE abnormalities in CMT1A, which resemble previous recordings from normal immature rats, can be distinguished from those in acquired demyelinating neuropathies.
Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorder... more Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.
Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of... more Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [ 11 C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6 AE 5.9 years), 12 with progressive supranuclear palsy (68.5 AE 4.1 years), eight with frontotemporal dementia (59.8 AE 6.9 years) and 16 healthy controls (61.2 AE 8.5 years). Two-tissue 30 compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k 3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k 3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k 3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k 3 values) in the paracentral region, frontal, parietal and occipital cortices (P50.05, cluster corrected). The group with pro-35 gressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P50.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P50.001), 9.4% in progressive supranuclear palsy (P50.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P50.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy. 5 Abbreviations: MMSE = Mini-Mental State Examination; MP4A = N-methylpiperidin-4-yl acetate; UPDRS = Unified Parkinson's Disease Rating Scale 80 ning, forethought, reasoning or organization; and (iii) disorders of language and communication. None of the patients had a pathology-proven diagnosis in the present study.
Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise... more Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (>5 mV). Patients with severely reduced CMAP (<1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na + conductance increases, possibly associated with collateral sprouting, and then K + conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive m... more Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to a-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis. Abbreviations: AAV = adeno-associated virus; ALS = amyotrophic lateral sclerosis; FTLD = frontotemporal lobar degeneration; HEK = human embryonic kidney; TDP-43 = transactive response DNA-binding protein 43
It is established that deep brain stimulation of the subthalamic nucleus improves motor function ... more It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of 13 CO 2 excretion (T max ) in the 13 C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of 13 CO 2 excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of 13 CO 2 excretion (T max ) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 AE 22.7 min and 42.5 AE 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of 13 CO 2 excretion (T max ) values without and with subthalamic deep brain stimulation after surgery were 44.0 AE 17.5 min and 30.0 AE 12.5 min (P 5 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the 13 CO 2 excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of 13 CO 2 excretion (T max ) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Ághrelin) and changes in T max values (ÁT max ) in the subthalamic deep brain stimulation trial after surgery (r = À 0.20), and no association between changes in other characteristics and ÁT max post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sc... more We investigated the frequency and contribution of variants of the 28 known amyotrophic lateral sclerosis (ALS)-related genes in Japanese ALS patients. We designed a multiplex, polymerase chain reaction-based primer panel to amplify the coding regions of the 28 ALS-related genes and sequenced DNA samples from 257 Japanese ALS patients using an Ion Torrent PGM sequencer. We also performed exome sequencing and identified variants of the 28 genes in an additional 251 ALS patients using an Illumina HiSeq 2000 platform. We identified the known ALS pathogenic variants and predicted the functional properties of novel nonsynonymous variants in silico. These variants were confirmed by Sanger sequencing. Known pathogenic variants were identified in 19 (48.7%) of the 39 familial ALS patients and 14 (3.0%) of the 469 sporadic ALS patients. Thirty-two sporadic ALS patients (6.8%) harbored 1 or 2 novel nonsynonymous variants of ALS-related genes that might be deleterious. This study reports the fi...
Neurotherapeutics : the journal of the American Society for Experimental NeuroTherapeutics, Jan 27, 2016
Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nico... more Most patients with myasthenia gravis (MG) have elevated levels of autoantibodies against the nicotinic acetylcholine receptor (AChR) at the neuromuscular junction, which leads to muscle weakness. We developed a fusion protein, AChR-Fc, as a novel therapeutic biomolecule for patients with MG and examined its efficacy. AChR-Fc was expressed by Chinese hamster ovary cells and purified. We examined the neutralizing activity and cellular cytotoxicity of AChR-Fc using anti-AChR antibody-producing hybridoma cells and serum samples from 16 patients with MG. The effects of AChR-Fc in vivo were also examined using rat MG models. AChR-Fc bound to anti-AChR antibodies and exhibited cytotoxicity against patient-derived antibody-producing B cells. Additionally, a dose-dependent improvement in the clinical signs of disease was observed in a rat MG model. AChR-Fc can diminish signs of MG by neutralizing anti-AChR antibodies and enhancing cytotoxicity against autoantibody-producing B cells. Thus, AC...
To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we ... more To identify the target molecules of chronic inflammatory demyelinating polyneuropathy (CIDP), we used proteomic-based approach in the extracted proteins from porcine cauda equina. Two of 31 CIDP patients had markedly elevated serum autoantibodies against vinculin, a cell adhesion protein. Both of the patients with anti-vinculin antibodies had similar clinical manifestation, which are compatible with those of &amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot;typical&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;quot; CIDP. Immunocytochemistry showed that vinculin was stained at the myelin sheath of the sciatic nerves by serum samples. Our results suggest that vinculin is a possible immunological target molecule in a subpopulation of typical CIDP patients.
To evaluate the effects of bromocriptine on bladder function in Parkinson's disease (PD) patients... more To evaluate the effects of bromocriptine on bladder function in Parkinson's disease (PD) patients and compare these effects with those of (L-dopa). We recruited 8 patients with PD. Urodynamic study (UDS) was performed before and 1 hour after administering 100 mg L-dopa/decarboxylase inhibitor (DCI) and 2.5 hours after administering 7.5 mg bromocriptine. After the bromocriptine administration, urinary urgency aggravated. UDS revealed a decreased bladder volume at which detrusor overactivity (DO) was initiated, a decreased bladder volume at first sensation of bladder filling (FSV) (P < 0.05), an increased maximum Watts Factor value (WFmax) (detrusor contractility), a decreased Abrams-Griffiths (AG) number (urethral obstruction), and a decreased postvoid residual (PVR) (P < 0.01). Similarly, after the L-dopa administration, urinary urgency aggravated. UDS revealed an aggravated DO (P < 0.05), a decreased FSV and bladder capacity (P < 0.01, 0.05), an increased WFmax (P < 0.05), an increased AG number, and a decreased PVR (P < 0.01). A single dose of bromocriptine proved to exacerbate urinary urgency and DO in the storage phase, and improve bladder emptying through increased detrusor contractility and decreased bladder outlet obstruction, within hours. With the exception of bladder outlet obstruction, these effects of bromocriptine are similar to the effects of L-dopa, albeit slightly less pronounced.
Journal of Neurology, Neurosurgery & Psychiatry, 2005
Background: Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is charact... more Background: Juvenile muscular atrophy of the distal upper extremity (Hirayama disease) is characterised by anterior horn cell loss in the lower cervical cord, presumably caused by anterior displacement of the dural sac during neck flexion. A recent report suggests that atopy and IgE may contribute to anterior horn damage. Objective: To investigate whether IgE is a contributing factor in Hirayama disease. Methods: Serum total IgE and allergen specific IgE were examined in 20 consecutive patients, and their correlations with clinical profiles investigated. Results: Past or present history of allergy/atopy was found in only four patients (20%), but serum IgE was raised in 14 (70%). Patients with hyperIgEaemia had more severe clinical disabilities than those without (p = 0.01). In patients whose history of Hirayama disease was less than five years, serum total IgE was higher than in those with the disease for five years or more (p = 0.05). Conclusions: The results suggest that hyperIgEaemia is often associated with Hirayama disease and can facilitate its pathophysiology, particularly in the early phases of the disease. HyperIgEaemia does not appear to involve the anterior horn cells primarily.
Although immunosuppressive effects of antiepileptic drug are well known, serious complications of... more Although immunosuppressive effects of antiepileptic drug are well known, serious complications of antiepileptic drug are rare. We report a case of hypogammaglobulinemia associated with aplasia of B lymphocytes after carbamazepine treatment. Despite repeated intravenous immunoglobulin replacement therapy, this condition persisted for more than three months. The present case suggested that routine monitoring of the blood cell count and serum levels of immunoglobulin are important in patients treated with carbamazepine, and a lymphocyte subpopulation study is valuable in cases of hypogammaglobulinemia.
Object: To study the effects of the intravenous administration of methylcobalamin, an analogue of... more Object: To study the effects of the intravenous administration of methylcobalamin, an analogue of vitamin B12, for uremic or uremic-diabetic polyneuropathy in patients whoare receiving maintenance hemodialysis. An ultra-high dose of vitamin B12 has been reported to promote peripheral nerve regeneration in experimental neuropathy. Methods: Nine patients received a 500|ig methylcobalamin injection 3 times a week for 6 months. The effects were evaluated using neuropathic pain grading and a nerve conduction study. Results: Serum concentrations of vitamin B12 were ultra-high during treatment due to the lack of urinary excretion. After 6 months of treatment, the patients' pain or paresthesia had lessened, and the ulnar motor and median sensory nerve conduction velocities showed significant improvement. There were no side effects. Conclusion: Intravenous methycobalamin treatment is a safe and potentially beneficial therapy for neuropathy in chronic hemodialysis patients.
Clinical neurophysiology : official journal of the International Federation of Clinical Neurophysiology, Jan 16, 2016
To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) ... more To determine the utility of the Awaji criteria in diagnosing amyotrophic lateral sclerosis (ALS) and to propose a novel modification so as to enhance sensitivity based on results of individual patient data (IPD). Individual patient data were available from 8 studies comparing the diagnostic accuracy of Awaji and revised El Escorial (rEEC) criteria. The sensitivity of a novel updated Awaji criteria, incorporating a "probable-laboratory supported" category, was also tested. Individual patient data were available from 1086 patients, consisting of 881 ALS and 205 patients with disorders mimicking ALS. Summary sensitivities based on random effects logistic regression modelling disclosed a higher sensitivity of the Awaji criteria (0.70, 95% confidence interval [CI] 0.51-0.83) and updated Awaji criteria (0.73, 95% CI 0.56-0.85) when compared to rEEC (0.58, 95% CI 0.48-0.68). Paired analysis revealed higher sensitivities of Awaji criteria in 4 studies, and of updated Awaji criteri...
Background: The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, ho... more Background: The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, however this criteria seemed to be insufficient at early stage of NMO. Hence, the development of diagnostic marker besides anti-aquaporin 4 antibody at early stage of NMO may be required. Our main aim of this study is to test the usefulness of measuring cerebrospinal fluid (CSF) interleukin (IL)-6 and glial fibrillary acidic protein (GFAP) concentrations as early diagnostic markers during initial NMO attacks. Methods: We investigated CSF IL-6 and GFAP concentrations in 13 NMO spectrum disorder (NMOSD) patients at initial attacks, 24 idiopathic central nervous system inflammatory disease patients (9 optic neuritis, 9 myelitis and 6 encephalitis) and 20 other non-inflammatory neurological disorders (ONNDs) patients, retrospectively. Results: The mean CSF IL-6 and GFAP concentrations during the initial NMOSD attack were 91.4 pg/ml and 369.3 ng/ml, respectively, and were significantly higher than in ONNDs, idiopathic optic neuritis and myelitis patients (P b 0.01). The sensitivity of high CSF IL-6 during initial NMO attack was 76.9% and that of high CSF GFAP was 84.6%, respectively. Conclusion: Our data suggests that CSF IL-6 and GFAP may be useful early diagnostic markers of NMOSD.
ation time constants and the shapes of recovery cycles were normal, although refractoriness and s... more ation time constants and the shapes of recovery cycles were normal, although refractoriness and superexcitability were reduced relative to controls. The high thresholds and early fanning out of electrotonus indicated altered cable properties, such that a greater proportion than normal of applied currents reached internodal rather than nodal axolemma. The rapid accommodation to depolarizing currents suggested activation of fast K + channels, which are normally sequestered from the nodal membrane. The excitability abnormalities are therefore consistent with a demyelinating pathology and exposure or spread of K + channels from under the myelin. It remains to be seen whether the TE abnormalities in CMT1A, which resemble previous recordings from normal immature rats, can be distinguished from those in acquired demyelinating neuropathies.
Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorder... more Machado-Joseph disease is one of the most common hereditary spinocerebellar degenerative disorders with a wide range of clinical manifestations. Pathology studies have shown mild to moderate loss of anterior horn cells and, in terms of spinal pathology, Machado-Joseph disease is regarded as a type of lower motoneuron disease. Muscle cramps are often associated with lower motoneuron disorders, but features of cramps in Machado-Joseph disease patients have never been studied. We investigated the incidence and nature of muscle cramps in Machado-Joseph disease patients, the excitability properties of motor axons [strength-duration time constant (tau(SD)), threshold electrotonus, refractoriness and supernormality] using threshold tracking and the effects of mexiletine hydrochloride on those cramps. Of 20 consecutive patients, 16 (80%) had frequent, severe muscle cramps in the legs, trunk or arms that disturbed their daily activities. The frequency of pathological muscle cramps was similar to that for patients with amyotrophic lateral sclerosis (68%) and higher than those for patients with spinal muscular atrophy (33%) or peripheral axonal neuropathy (24%). Threshold-tracking studies showed that tau(SD), which in part reflects Na(+) conductance at the resting membrane potential, was significantly greater in the Machado-Joseph disease patients than in normal subjects; severe muscle cramps were associated with a longer tau(SD). Threshold electrotonus, refractoriness and supernormality were not significantly different between Machado-Joseph disease patients and normal subjects. Eight Machado-Joseph disease patients with severe cramps, who received mexiletine treatment, experienced nearly complete relief with a partial normalization of tau(SD) (P = 0.08). Muscle cramps are a very frequent and disabling factor in Machado-Joseph disease. Pathological muscle cramps responded well to mexiletine treatment, and this is consistent with the hypothesis that they are caused by an increase in persistent Na(+) conductance, possibly associated with axonal regeneration or collateral sprouting.
Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of... more Corticobasal syndrome, progressive supranuclear palsy and frontotemporal dementia are all part of a disease spectrum that includes common cognitive impairment and movement disorders. The aim of this study was to characterize brain cholinergic deficits in these disorders. We measured brain acetylcholinesterase activity by [ 11 C] N-methylpiperidin-4-yl acetate and positron emission tomography in seven patients with corticobasal syndrome (67.6 AE 5.9 years), 12 with progressive supranuclear palsy (68.5 AE 4.1 years), eight with frontotemporal dementia (59.8 AE 6.9 years) and 16 healthy controls (61.2 AE 8.5 years). Two-tissue 30 compartment three-parameter model and non-linear least squares analysis with arterial input function were performed. k 3 value, an index of acetylcholinesterase activity, was calculated voxel-by-voxel in the brain of each subject. The k 3 images in each disease group were compared with the control group by using Statistical Parametric Mapping 2. Volume of interest analysis was performed on spatially normalized k 3 images. The corticobasal syndrome group showed decreased acetylcholinesterase activity (k 3 values) in the paracentral region, frontal, parietal and occipital cortices (P50.05, cluster corrected). The group with pro-35 gressive supranuclear palsy had reduced acetylcholinesterase activity in the paracentral region and thalamus (P50.05, cluster corrected). The frontotemporal dementia group showed no significant differences in acetylcholinesterase activity. Volume of interest analysis showed mean cortical acetylcholinesterase activity to be reduced by 17.5% in corticobasal syndrome (P50.001), 9.4% in progressive supranuclear palsy (P50.05) and 4.4% in frontotemporal dementia (non-significant), when compared with the control group. Thalamic acetylcholinesterase activity was reduced by 6.4% in corticobasal syndrome (non-significant), 24.0% in progressive supranuclear palsy (P50.03) and increased by 3.3% in frontotemporal dementia (non-significant). Both corticobasal syndrome and progressive supranuclear palsy showed brain cholinergic deficits, but their distribution differed somewhat. Significant brain cholinergic deficits were not seen in frontotemporal dementia, which may explain the unresponsiveness of this condition to cholinergic modulation therapy. 5 Abbreviations: MMSE = Mini-Mental State Examination; MP4A = N-methylpiperidin-4-yl acetate; UPDRS = Unified Parkinson's Disease Rating Scale 80 ning, forethought, reasoning or organization; and (iii) disorders of language and communication. None of the patients had a pathology-proven diagnosis in the present study.
Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise... more Fasciculations are a characteristic feature of amyotrophic lateral sclerosis (ALS), and can arise proximally or distally in the motor neuron, indicating a widespread disturbance in membrane excitability. Previous studies of axonal excitability properties (i.e. threshold electrotonus, strength-duration time constant) have suggested respectively that change in potassium or sodium channels may be involved. To reinvestigate these changes and explore their correlation with disease stage, multiple axonal excitability properties (threshold electrotonus, strength-duration time constant, recovery cycle and current-threshold relationship) were measured for the median nerve at the wrist in 58 ALS patients, and compared with 25 age-matched controls. In ALS, there were greater changes in depolarizing threshold electrotonus (i.e. less accommodation) (P < 0.001) and greater supernormality in the recovery cycles (P < 0.001). These abnormalities were more prominent in patients with moderately reduced CMAP (1-5 mV). Modelling the excitability changes in this group supported the hypothesis that axonal potassium conductances are reduced, resulting in increased supernormality despite membrane depolarization. The tendency for strength-duration time constant to be prolonged in ALS was only significant for patients with normal CMAP amplitude (>5 mV). Patients with severely reduced CMAP (<1 mV) alone showed reduced threshold changes to hyperpolarizing current. These results suggest a changing pattern of abnormal membrane properties with disease progression. First, persistent Na + conductance increases, possibly associated with collateral sprouting, and then K + conductances decline. Both changes cause axonal hyperexcitability, and may contribute to the generation of fasciculations. These serial changes in axonal properties could provide insights into the pathophysiology of ALS, and implications for future therapeutic options.
Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive m... more Amyotrophic lateral sclerosis is a fatal neurodegenerative disease characterized by progressive motoneuron loss. Redistribution of transactive response deoxyribonucleic acid-binding protein 43 from the nucleus to the cytoplasm and the presence of cystatin C-positive Bunina bodies are considered pathological hallmarks of amyotrophic lateral sclerosis, but their significance has not been fully elucidated. Since all reported rodent transgenic models using wild-type transactive response deoxyribonucleic acid-binding protein 43 failed to recapitulate these features, we expected a species difference and aimed to make a non-human primate model of amyotrophic lateral sclerosis. We overexpressed wild-type human transactive response deoxyribonucleic acid-binding protein 43 in spinal cords of cynomolgus monkeys and rats by injecting adeno-associated virus vector into the cervical cord, and examined the phenotype using behavioural, electrophysiological, neuropathological and biochemical analyses. These monkeys developed progressive motor weakness and muscle atrophy with fasciculation in distal hand muscles first. They also showed regional cytoplasmic transactive response deoxyribonucleic acid-binding protein 43 mislocalization with loss of nuclear transactive response deoxyribonucleic acid-binding protein 43 staining in the lateral nuclear group of spinal cord innervating distal hand muscles and cystatin C-positive cytoplasmic aggregates, reminiscent of the spinal cord pathology of patients with amyotrophic lateral sclerosis. Transactive response deoxyribonucleic acid-binding protein 43 mislocalization was an early or presymptomatic event and was later associated with neuron loss. These findings suggest that the transactive response deoxyribonucleic acid-binding protein 43 mislocalization leads to a-motoneuron degeneration. Furthermore, truncation of transactive response deoxyribonucleic acid-binding protein 43 was not a prerequisite for motoneuronal degeneration, and phosphorylation of transactive response deoxyribonucleic acid-binding protein 43 occurred after degeneration had begun. In contrast, similarly prepared rat models expressed transactive response deoxyribonucleic acid-binding protein 43 only in the nucleus of motoneurons. There is thus a species difference in transactive response deoxyribonucleic acid-binding protein 43 pathology, and our monkey model recapitulates amyotrophic lateral sclerosis pathology to a greater extent than rodent models, providing a valuable tool for studying the pathogenesis of sporadic amyotrophic lateral sclerosis. Abbreviations: AAV = adeno-associated virus; ALS = amyotrophic lateral sclerosis; FTLD = frontotemporal lobar degeneration; HEK = human embryonic kidney; TDP-43 = transactive response DNA-binding protein 43
It is established that deep brain stimulation of the subthalamic nucleus improves motor function ... more It is established that deep brain stimulation of the subthalamic nucleus improves motor function in advanced Parkinson's disease, but its effects on autonomic function remain to be elucidated. The present study was undertaken to investigate the effects of subthalamic deep brain stimulation on gastric emptying. A total of 16 patients with Parkinson's disease who underwent bilateral subthalamic deep brain stimulation were enrolled. Gastric emptying was expressed as the peak time of 13 CO 2 excretion (T max ) in the 13 C-acetate breath test and was assessed in patients with and without administration of 100-150 mg levodopa/decarboxylase inhibitor before surgery, and with and without subthalamic deep brain stimulation at 3 months post-surgery. The pattern of 13 CO 2 excretion curve was analysed. To evaluate potential factors related to the effect of subthalamic deep brain stimulation on gastric emptying, we also examined the association between gastric emptying, clinical characteristics, the equivalent dose of levodopa and serum ghrelin levels. The peak time of 13 CO 2 excretion (T max ) values for gastric emptying in patients without and with levodopa/decarboxylase inhibitor treatment were 45.6 AE 22.7 min and 42.5 AE 13.6 min, respectively (P = not significant), thus demonstrating levodopa resistance. The peak time of 13 CO 2 excretion (T max ) values without and with subthalamic deep brain stimulation after surgery were 44.0 AE 17.5 min and 30.0 AE 12.5 min (P 5 0.001), respectively, which showed that subthalamic deep brain stimulation was effective. Simultaneously, the pattern of the 13 CO 2 excretion curve was also significantly improved relative to surgery with no stimulation (P = 0.002), although the difference with and without levodopa/decarboxylase inhibitor was not significant. The difference in peak time of 13 CO 2 excretion (T max ) values without levodopa/decarboxylase inhibitor before surgery and without levodopa/decarboxylase inhibitor and subthalamic deep brain stimulation after surgery was not significant, although motor dysfunction improved and the levodopa equivalent dose decreased after surgery. There was little association between changes in ghrelin levels (Ághrelin) and changes in T max values (ÁT max ) in the subthalamic deep brain stimulation trial after surgery (r = À 0.20), and no association between changes in other characteristics and ÁT max post-surgery in the subthalamic deep brain stimulation trial. These results showed that levodopa/decarboxylase inhibitor did not influence gastric emptying and that subthalamic deep brain stimulation can improve the dysfunction in patients with Parkinson's disease possibly by altering the neural system that controls gastrointestinal function after subthalamic deep brain stimulation. This is the first report to show the effectiveness of subthalamic deep brain stimulation on gastrointestinal dysfunction as a non-motor symptom in Parkinson's disease.
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Papers by Satoshi Kuwabara