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Biomedical subjects

Satoshi Kuwabara

Publications and source records attributed to Satoshi Kuwabara.

At least 37 records · Page 2Linked to original sources
PubMed2005

The effects of mexiletine on excitability properties of human median motor axons.

OBJECTIVE: To investigate the effects of mexiletine, an analog of lidocaine, on excitability of human axons in vivo. METHODS: Threshold tracking was used to measure multiple excitability indices (strength-duration time constant, rheobase, refractoriness, supernormality, and threshold electrotonus) in median motor axons of 20 patients with neuropathic pain or muscle cramping, before and 3 months after treatment with oral 300 mg mexiletine per day. RESULTS: After treatment, there was a reduction in pain/muscle cramps, associated with decreased strength-duration time constants (P=0.01), increased rheobasic currents (P=0.06), and lower refractoriness (P=0.02), all of which were consistent with reduced nodal Na+ currents. Supernormality and threshold electrotonus did not change significantly. The changes in strength-duration properties suggest a decrease in persistent Na+ conductance. The lowered refractoriness after treatment might result from reduced transient Na+ currents, but the lack of change in supernormality and threshold electrotonus was not consistent with this hypothesis. CONCLUSIONS: Oral mexiletine in a dosage of 300 mg daily suppresses persistent Na+ currents in human motor axons. SIGNIFICANCE: Measurements of the excitability indices can be used for non-invasive assessment and monitoring of the effects of mexiletine in patients with neuropathic pain or muscle cramps.

Action Potentials↗
PubMed2005

Axonal potassium conductance and glycemic control in human diabetic nerves.

OBJECTIVE: To investigate the effects of hyperglycemia on axonal excitability and potassium conductance in human diabetic nerves. METHODS: Threshold tracking was used to measure excitability indices, which depend on potassium channels (supernormality, late subnormality, threshold electrotonus, and a current/threshold relationship) in median motor axons of 96 diabetic patients. The effects of hyperglycemia on these indices were analyzed. RESULTS: Among diabetic patients, higher serum hemoglobin A1c (HbA1c) levels were significantly associated with greater supernormality (P = 0.04) and smaller late subnormality (P = 0.02), suggestive of reduced nodal/paranodal potassium currents under hyperglycemia. Threshold electrotonus and current/threshold relationships did not correlate with HbA1c levels, but partly related with nerve conduction slowing. CONCLUSIONS: Hyperglycemia could reduce nodal potassium conductances, possibly due to reduced membranous potassium gradient or suppression of potassium channels. In contrast, internodal potassium conductances may be determined by both metabolic factors and structural changes such as exposure of internodal channels by demyelination. SIGNIFICANCE: Measurements of the excitability indices could provide new insights into nodal and internodal axonal membrane properties in human diabetic neuropathy, whereas multiple factors can affect especially internodal properties.

Adult↗
PubMed2005

Superficial radial sensory nerve potentials in immune-mediated and diabetic neuropathies.

OBJECTIVE: The pattern of abnormal median-normal sural sensory nerve action potential (SNAP) is frequently found in acute/chronic inflammatory demyelinating polyneuropathy (AIDP/CIDP), whereas sural/radial SNAP amplitude ratio is sensitive to detect dying-back degeneration. To investigate whether radial SNAP and its amplitude ratio to median or sural SNAP provide additional particular patterns of sensory nerve involvement. METHODS: Superficial radial, median, and sural SNAPs were recorded in 63 normal subjects and in 132 patients with AIDP/CIDP (n = 22), diabetic neuropathy (n = 83), or other axonal polyneuropathy (n = 27). Median/radial and sural/radial amplitude ratios were examined. RESULTS: In normal subjects, median/radial ratio was 0.96 +/- 0.05 (mean +/- SEM), and sural/radial ratio was 0.50 +/- 0.03. Compared with normal controls, the median/radial ratio was lower in patients with AIDP/CIDP (0.64 +/- 0.11; P < 0.001) or diabetic neuropathy (0.75 +/- 0.04; P = 0.08), but similar in those with other neuropathy (0.94 +/- 0.10). The sural/radial ratio was higher in the AIDP/CIDP group (0.71 +/- 0.08; P = 0.10), and lower in the diabetic (0.36 +/- 0.03; P < 0.001) and other axonal neuropathy groups (0.40 +/- 0.07; P = 0.08). CONCLUSIONS: AIDP/CIDP is associated with a reduced median/radial ratio and increased sural/radial ratio, probably reflecting demyelination predominant in the distal nerve terminals. Diabetic neuropathy is characterized by decreases in both median/radial and sural/radial ratios, presumably due to coexistence of carpal tunnel pathology and dying-back degeneration. SIGNIFICANCE: Comparison of multiple SNAP amplitudes provides information about characteristic distribution patterns of sensory nerve involvement in peripheral neuropathies.

Action Potentials↗
PubMed2004

Putaminal hemorrhage disrupts thalamocortical projection to secondary somatosensory cortex: case report.

Putaminal hemorrhage presenting pure sensory stroke is rare. We describe a case of left putaminal hemorrhage presenting contralateral hemisensory disturbance without hemiparesis. A 52-year-old man developed analgesia and thermoanesthesia in the right half of his body, but deep sensation was relatively well preserved. Neuroradiological and somatosensory evoked potential findings suggested that thalamocortical sensory pathways to the secondary somatosensory cortex (S2) were involved, whereas those to the primary somatosensory cortex (S1) were spared. In experimental animals, spinothalamic projections from the thalamic nucleus input directly to S2. In humans, thalamocortical pathways are still a subject of debate, but results of recent functional imaging studies suggest that the pathway of pain inputs directly to S2 and that of tactile sensation to S2 via S1. Our findings support these reports.

Evoked Potentials, Somatosensory↗
PubMed2004

Epilepsia partialis continua as an isolated manifestation of motor cortical dysplasia.

Cortical dysplasia has been increasingly recognized as a cause of epilepsy. We describe herein a 31-year-old female patient with epilepsia partialis continua (EPC) in the right extremities, which had lasted for 15 years without generalized seizures and other neurological deteriorations. MRI showed a focal thickening around the left motor area, indicative of cortical dysplasia, with adjacent subcortical abnormal T2 high intensity, suggestive of dysmyelination. Transcranial magnetic stimulation revealed low motor thresholds and markedly prolonged latencies of motor-evoked potentials (MEP) of the affected side, consistent with hyperexcitability of the cortical motoneurons accompanied by dysmyelination. This case demonstrates that motor cortex dysplasia can result in a mild and non-progressive form of epilepsia partialis continua, associated with the characteristic MRI and MEP abnormalities.

Adult↗
PubMed2004

Treatment and outcome of myasthenia gravis: retrospective multi-center analysis of 470 Japanese patients, 1999-2000.

To clarify the current status of treatments and outcomes of patients with myasthenia gravis (MG) in Japan, a total of 470 patients (164 men and 306 women; mean age 41 years) were recruited from 19 Japanese tertiary medical centers in 1999-2000. Thymectomy was performed in 319 (68%) of the patients. Patients who received thymectomy were younger (p = 0.01) and had more severe disabilities (p < 0.01) than patients without thymectomy. Irrespective of receiving thymectomy, most of the patients were administered corticosteroids (64%), other immunosuppressive agents (10%), or cholinesterase inhibitors (86%). Of 395 patients followed up for more than 12 months after treatment (mean 8.0 years), 30% (34% of thymectomized and 21% of non-thymectomized patients) were in remission (no symptoms with/without medication), 34% had only ocular symptoms, and the remaining 35% still had weakness of bulbar or limb muscles at the end of follow-up. The prognosis of MG in Japan was generally favorable, but despite the frequent use of thymectomy and immunosuppressive treatments, approximately one-third of patients still had generalized weakness. More effective or intensive treatments are required to improve the prognosis.

Adolescent↗
PubMed2004

Increased ability of peripheral blood lymphocytes to degrade laminin in multiple sclerosis.

T lymphocytes and macrophages probably play a role in the pathogenesis of multiple sclerosis (MS), and migration of these cells into the central nervous system is facilitated by disruption of the capillary basement membrane. Laminin is a major extracellular matrix of the basement membrane. To investigate whether ability of lymphocytes to degrade laminin correlates with disease activity in MS, we conducted a prospective study in consecutive 24 MS patients. A novel quantitative assay was developed to estimate the ability of peripheral blood mononuclear cells (PBMCs) to degrade laminin. The assay was performed every four weeks over a period of 12 months. During the study period, a total of 41 relapses were observed. The ability to degrade laminin was significantly higher in MS patients, even during clinical remission, than in normal and neurological controls, and was transiently increased further within 4 weeks before relapse (p=0.076). In MS, the ability of peripheral blood lymphocytes to degrade laminin increases, and may correlate with disease activity.

Adult↗
PubMed2004

Sensory nerve conduction in demyelinating and axonal Guillain-Barré syndromes.

Guillain-Barré syndrome is divided into acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN) based on motor nerve conduction studies. We investigated whether sensory nerve conduction studies contribute to the electrodiagnosis of AIDP and AMAN. In consecutive 59 patients with AIDP (n = 26) or AMAN (n = 33), results of sensory nerve conduction studies in the median, ulnar and sural nerves were reviewed. Sensory nerve conduction abnormalities were found for 85% of AIDP patients and for only 6% of AMAN patients. In AIDP patients, the abnormalities were present in 85% of patients in the median nerves, 85% in the ulnar nerves and 38% in the sural nerves. AMAN is very rarely associated with sensory nerve involvement. Abnormal sensory nerve conduction is supportive of AIDP and is more frequently found for the median and ulnar nerves than sural nerves.

Adolescent↗
PubMed2004

The acute effects of glycemic control on axonal excitability in human diabetics.

In diabetic nerves, the activation of the polyol pathway and a resulting decrease in Na(+)-K(+) ATPase activity lead to intra-axonal Na(+) accumulation and a smaller Na(+) gradient across the axolemma than normal. To investigate whether glycemic control is associated with acutely reversible changes in axonal excitability and Na(+) conductance, we measured the multiple excitability indices (strength-duration time constant, rheobase, refractoriness, and refractory period) of the median motor axons of 21 diabetic patients before and after intensive insulin treatment. Within 4 weeks after treatment was begun, there was a significant improvement in nerve conduction velocities, associated with increased strength-duration time constant, decreased rheobase, increased refractoriness, and prolonged refractory periods. Assuming that the strength-duration time constant partly reflects persistent Na(+) conductance, and that refractoriness/refractory periods depend on inactivation of transient Na(+) channels caused by prior depolarization (the influx of Na(+)), the patterns of changes in these indices may reflect a reduced trans-axonal Na(+) gradient during hyperglycemia and its restoration by glycemic control in diabetic patients. Measurement of the excitability indices could provide new insights into the pathophysiology of human diabetic neuropathy.

Action Potentials↗
PubMed2004

Threshold electrotonus in chronic inflammatory demyelinating polyneuropathy: correlation with clinical profiles.

Chronic inflammatory demyelinating polyneuropathy (CIDP) is characterized by multifocal demyelination along the course of the nerves, and involvement of the intermediate segments may correlate with more severe demyelination associated with breakdown of the blood-nerve barrier. Threshold electrotonus was used to study whether altered membrane properties of the median nerve at the wrist (intermediate segment) are associated with clinical profiles in 21 CIDP patients. In response to hyperpolarizing conditioning stimuli, the threshold changes were significantly greater for CIDP patients than for normal controls (n = 49). The pattern was similar to that of 11 patients with Charcot-Marie-Tooth disease type 1a, who exhibited abnormally high thresholds to hyperpolarizing currents. The abnormal threshold electrotonus was present in 48% of the CIDP patients and was associated with longer disease duration, more severe disability, poorer response to immune treatments, and slower nerve conduction velocities. Threshold electrotonus can be used to detect demyelination at the tested sites and may provide new information about pathophysiology and distribution patterns of demyelination in CIDP.

Action Potentials↗
PubMed2004

Excitability properties of human median axons measured at the motor point.

Threshold tracking was used to measure excitability indices (strength-duration properties, threshold electrotonus, and the current-threshold relationship) at the motor point of the abductor pollicis brevis, and the results were compared with those of the median nerve at the wrist. Using an accelerometer placed at the thumb tip, movement-related potentials were recorded as target responses. When stimulating at the same site, excitability measurements were no different, and their variability no greater, when the target responses were movements rather than muscle action potentials. Motor point stimulation resulted in significantly shorter strength-duration time-constant and higher rheobase than wrist stimulation. In addition, the technique of latent addition showed that a slow component was much smaller at the motor point than at the wrist. In threshold electrotonus, threshold changes in response to depolarizing and hyperpolarizing conditioning currents were significantly smaller at the motor point than at the wrist. The differences in strength-duration time-constant and latent addition suggest that persistent Na(+) current at the resting potential is smaller at the motor point. The differences in threshold electrotonus may depend in part on altered fiber geometry but suggest that inward and possibly outward rectification are increased distally. Motor point excitability testing may provide new insights into the pathophysiology of the nerve terminals in a variety of peripheral neuropathies and motor neuron disorders.

Action Potentials↗
PubMed2004

Hyperglycemia alters refractory periods in human diabetic neuropathy.

OBJECTIVE: To investigate the effects of hyperglycemia on axonal excitability in human diabetics. Diabetic nerve dysfunction is partly associated with the altered polyol pathway and Na+-K+ ATPase activity, probably resulting in a decrease in the trans-axonal Na+ gradient and reduced nodal Na+ currents. METHODS: Threshold tracking was used to measure the relative refractory periods (RPs) of median motor axons in 58 diabetic patients, 45 normal subjects, and 12 patients with non-diabetic axonal neuropathy. In diabetic patients, the relationship of RPs with hemoglobin A1c (HbA1c) levels was analyzed. RESULTS: The mean RP was similar for diabetics and normal controls as a group, but was longer in patients with non-diabetic neuropathy than in normal controls (P=0.02). Diabetic patients with good glycemic control (HbA1c levels <7%) had longer RPs than patients with poorer glycemic control and normal controls (P=0.01). RP was longest at the HbA1c level of 6%, gradually decreasing and reaching a plateau at the HbA1c level of 8-9%. CONCLUSIONS: Hyperglycemia shortens RPs, possibly because metabolic abnormalities lead to reduced nodal Na+ currents, and thereby to a lower inactivation of Na+ channels when generating an action potential. SIGNIFICANCE: RP measurements could provide new insights into the ionic pathophysiology of human diabetic neuropathy.

Adult↗
PubMed2004

Guillain-Barré syndrome: epidemiology, pathophysiology and management.

Guillain-Barré syndrome (GBS) is clinically defined as an acute peripheral neuropathy causing limb weakness that progresses over a time period of days or, at the most, up to 4 weeks. GBS occurs throughout the world with a median annual incidence of 1.3 cases per population of 100 000, with men being more frequently affected than women. GBS is considered to be an autoimmune disease triggered by a preceding bacterial or viral infection. Campylobacter jejuni, cytomegalovirus, Epstein-Barr virus and Mycoplasma pneumoniae are commonly identified antecedent pathogens. In the acute motor axonal neuropathy (AMAN) form of GBS, the infecting organisms probably share homologous epitopes to a component of the peripheral nerves (molecular mimicry) and, therefore, the immune responses cross-react with the nerves causing axonal degeneration; the target molecules in AMAN are likely to be gangliosides GM1, GM1b, GD1a and GalNAc-GD1a expressed on the motor axolemma. In the acute inflammatory demyelinating polyneuropathy (AIDP) form, immune system reactions against target epitopes in Schwann cells or myelin result in demyelination; however, the exact target molecules in the case of AIDP have not yet been identified. AIDP is by far the most common form of GBS in Europe and North America, whereas AMAN occurs more frequently in east Asia (China and Japan). The prognosis of GBS is generally favourable, but it is a serious disease with a mortality of approximately 10% and approximately 20% of patients are left with severe disability. Treatment of GBS is subdivided into: (i) the management of severely paralysed patients with intensive care and ventilatory support; and (ii) specific immunomodulating treatments that shorten the progressive course of GBS, presumably by limiting nerve damage. High-dose intravenous immunoglobulin (IVIg) therapy and plasma exchange aid more rapid resolution of the disease. The predominant mechanisms by which IVIg therapy exerts its action appear to be a combined effect of complement inactivation, neutralisation of idiotypic antibodies, cytokine inhibition and saturation of Fc receptors on macrophages. Corticosteroids alone do not alter the outcome of GBS.

Adjuvants, Immunologic↗
PubMed2004

Axonal ionic pathophysiology in human peripheral neuropathy and motor neuron disease.

Testing the excitability of axons can provide insights into the ionic mechanisms underlying the pathophysiology of axonal dysfunction in human neuropathies and motor neuron diseases. Threshold tracking, which was developed in the 1990's, non-invasively measures a number of axonal excitability indices, which depend on membrane potential and on the Na+ and K+ conductances. This paper reviews recent advances in ionic-pathophysiological studies in human subjects in vivo. Membrane potential of human axons can be estimated, because most of the ion channels expressed on the axolemma are voltage-dependent, and patterns of changes in multiple excitability indices can suggest whether axons are depolarized or hyperpolarized. This has been clearly demonstrated in a single patient with acute hypokalemia (hyperpolarization) and patients with chronic renal failure (depolarization due to hyperkalemia). Muscle cramps/fasciculations arise from hyperexcitability of the motor axons. The enhanced excitability can result from altered ion channel function; an increase in persistent Na+ conductance, a decrease in accommodative K+ conductance, and focal membrane depolarization, all of which increase excitability, have been demonstrated in amyotrophic lateral sclerosis or other disorders affecting lower motor neurons. Patients with demyelinating neuropathy often complain of muscle fatigue. During voluntary contraction, the activation of the electrogenic Na+-K+ pump and resulting membrane hyperpolarization can cause activity-dependent conduction block when the safety factor for impulse transmission is critically reduced. Studies of ion-channel pathophysiology in human subjects have recently begun. Investigating ionic mechanisms is of clinical relevance, because once a specific ionic conductance is identified, blocking or activating it may provide a new therapeutic option for a variety of neuromuscular diseases.

Animals↗
PubMed2003

Combined treatment with LDL-apheresis, chenodeoxycholic acid and HMG-CoA reductase inhibitor for cerebrotendinous xanthomatosis.

The effects of combined treatment with low-density lipoprotein (LDL)-apheresis, chenodeoxycholic acid (CDCA) and 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) reductase inhibitor were studied in 2 patients with cerebrotendinous xanthomatosis. Patient 1 was initially treated with LDL-apheresis alone: serum cholestanol levels decreased by 50% after each apheresis, but returned to their initial levels within 2 weeks. After an addition of CDCA administration, the serum cholestanol levels steadily decreased, resulting in slight improvement of neurological symptoms. Patient 2 received a combined treatment with LDL-apheresis, CDCA and HMG-CoA reductase inhibitor. This combination showed less LDL-apheresis-dependent fluctuation and more rapid decrease of serum cholestanol levels than those in Patient 1, resulting in improvement and stabilization of the symptoms. Our results suggest that LDL-apheresis in combination with CDCA and HMG-CoA reductase inhibitor may have beneficial effects and can be one of the treatment options.

Adult↗