桑原 聡

The potential therapeutic role of repetitive transcranial magnetic stimulation (rTMS) in epilepsy has been increasingly recognized. We investigated the effects of low-frequency rTMS in a patient with epilepsia partialis continua (EPC) due to cortical dysplasia. A 31-year-old female patient experienced EPC in the right upper and lower extremities, which had lasted for 15 years without generalized seizures. MRI showed focal megaencephaly around the motor cortex suggestive of cortical dysplasia. A figure of eight magnetic coil was placed over the hand motor area, and 100 stimuli with an intensity at 90% of motor threshold were given at 0.5 Hz. Immediately after rTMS, EPC was nearly abolished. The effects had continued approximately for 2 months, and the second trial resulted in the similar effects and time-course. Low-frequency rTMS was safe and well tolerated in this patient. These findings support the concept that rTMS decreases cortical excitability, and may be an effective treatment for focal partial seizures. (c) 2005 Elsevier B.V. All rights reserved.

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 Ale (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. © 2005 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All fights reserved.

Background: Little is known about the long term prognosis for patients the severe acute motor axonal neuropathy (AMAN) form of Guillain-Barre syndrome (GBS), unlike those with acute inflammatory demyelinating neuropathy (AIDP). Objective: To clarify the long term prognosis for patients with AMAN. Methods: Clinical recovery and outcome in 97 consecutive GBS patients were reviewed. Results: Electrodiagnostic criteria showed that 44 patients (45%) had AMAN, 33 (34%) had AIDP, and 20 (21%) were unclassified. Most of the severely affected patients had received plasmapheresis or immunoglobulin therapy. Slow recovery (inability to walk independently at six months after onset) was found in six of the AMAN patients (14%) and in two of the AIDP patients (6%). Of the six AMAN patients, four could walk independently one year after the onset, and the other two could walk independently at 28 and 57 months after onset. Of the two AIDP patients, one could walk at nine months after the onset while the other died of pneumonia seven months after onset. Conclusions: AMAN electrodiagnosis is not always a marker of poor recovery. Almost all the severe AMAN patients who had slow recoveries over the first six months could eventually walk independently, although some required several years.

Objectives: To compare the clinical and electrophysiological features of myasthenia gravis (MG) patients with (seropositive) or without (seronegative) antibodies to acetylcholine receptor. To investigate whether antibodies to muscle specific kinase (MuSK) and ryanodine receptor (RyR) are associated with particular features. Methods: Clinical profiles and single fibre electromyography (SFEMG) in the extensor digitorum communis (EDC) were reviewed in consecutive 57 seropositive and 13 seronegative patients. Antibodies to MuSK and RyR were measured by immunoassays. Results: Of the 13 seronegative patients, four (31%) were positive for MuSK antibodies and seven (54%) were positive for RyR antibodies, including all four MuSK positive patients. Clinical features were similar at presentation for seropositive and seronegative patients, but MuSK positive patients frequently developed myasthenic crises. Despite the similar clinical severities at the time of examination, the proportion with positive jitter (93% of seropositive patients, 50% of MuSK positive patients, and 44% of MuSK negative patients) and the extent of jitter (mean consecutive difference: 76 mu s in seropositive patients, 36 ms in MuSK positive patients, and 30 ms in MuSK negative patients) were less in seronegative MG patients compared with seropositive MG patients. Conclusions: Seronegative MG is heterogeneous with respect to the presence of antibodies to MuSK. Impairment of neuromuscular synaptic transmission in EDC is less marked in seronegative than seropositive MG despite the similar clinical severity. This discrepancy may partly reflect the distribution of affected muscles in seronegative patients, but it is possible that other factors, such as impaired excitation-contraction coupling resulting from RyR antibodies, contribute to the clinical phenotype.

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. (c) 2004 Elsevier B.V. All rights reserved.

Background: In Guillain-Barré syndrome (GBS), anti-ganglioside antibodies are strongly associated with the acute motor axonal neuropathy (AMAN) form, but there are also cases of the demyelinating form of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) with anti-ganglioside antibodies. Objective: To elucidate the patterns and sequential changes in electrodiagnostic abnormalities of anti-ganglioside-positive GBS. Methods: Detailed serial electrodiagnostic findings were reviewed for 51 patients with GBS. Anti-ganglioside antibodies were measured by ELISA. Results: Antibodies to GM1, GM1b, GD1a, or GalNAc-GD1a were present in 25 patients. Of these, 12 (48%) showed the AMAN pattern, 5 (20%) the AIDP pattern, and 3 (12%) isolated F-wave absence in the first examination. All five patients with the AIDP pattern showed prolonged distal latencies, but three eventually showed the AMAN pattern or rapid normalization. The remaining two still had similarly prolonged distal latencies in weeks 4 to 6, but the serial changes were distinct from those in the anti-ganglioside-negative AIDP patients who showed progressive increases in distal latencies over 2 months after onset. Conclusions: Besides the simple axonal degeneration pattern, patients with anti-ganglioside-positive Guillain-Barré syndrome can show transient conduction slowing/block in the distal or proximal nerve segments, mimicking demyelination, but anti-ganglioside antibodies do not appear to be associated with acute inflammatory demyelinating polyneuropathy. Copyright © 2005 by AAN Enterprises, Inc.

Objective: To investigate the influences of hyperglycemia on axonal excitability in human diabetic nerves. Hyperglycemia results in decreased Na+-K+ pump function, presumably leading to intra-axonal Na+ accumulation and thereby, reduced Na+ currents. Methods: The strength-duration time constant (tau(SD)), which partly depends on persistent Na+ conductance active at the resting membrane potential, was measured in median motor axons of 79 diabetic patients. The relationship of tau(SD) with the state of glycemic control (hemoglobin A1c [HbA1c] levels) was analyzed. Results: The mean tau(SD) was longer for diabetic patients than for normal controls, but the difference was not significant. Among diabetic patients, the subgroup of patients with good glycemic control (HbA1c < 7%) had significantly longer tau(SD) than the patient group with poor control (HbA1c > 9%; P = 0.04). The mean tau(SD) was longest at the HbA1c level of 5-6%, gradually decreasing and reaching a plateau around the HbA1c level of 9%. There was an inverse relationship between HbA1c levels and tau(SD), when the HbA1c levels ranged from 5 to 9% (P 0.04). Conclusions: In diabetic nerves, tau(SD) is generally longer than normal, but hyperglycemia is associated with paradoxically shortened tau(SD), gradient, tissue acidosis, or other because of a decrease in axonal persistent Na+ conductance, possibly related to reduced membranous Na+, metabolic factors. Significance: Measurements of tau(SD) could provide a new insight into changes in ionic conductance in human diabetic nerves. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

Objective: To investigate acute changes in nerve conduction associated with glycemic control. In diabetes, nerve dysfunction can result from reversible metabolic factors associated with hyperglycemia, as well as structural changes. Methods: Multiple nerve conduction parameters including F-wave latencies were measured in 47 diabetic patients with prominent hyperglycemia before and after intensive insulin treatment. Results: Four weeks after the start of treatment, there was a significant improvement in minimal F-wave latencies of the median (P < 0.001) and tibial (P < 0.001) nerves, and in distal latencies (P=0.01) and sensory nerve conduction velocities (P < 0.001) of the median nerves. Amplitudes of motor and sensory responses did not change significantly. These findings were similar for patients with type 1 (n = 8) and those with type 2 (n = 39) diabetes. Patients with poorer glycemic control or milder neuropathy tended to show greater changes after treatment. Conclusions: Glycemic control quickly alters the speed of nerve conduction. F-wave latencies and conduction times across the carpal tunnel are very sensitive parameters. Significance: Serial nerve conduction studies can detect reversible slowing of nerve conduction presumably caused by metabolic factors, such as decreased Na+/K+-ATPase activity, the altered polyol pathway, and tissue acidosis. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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.

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. (C) 2004 International Federation of Clinical Neurophysiology. Published by Elsevier Ireland Ltd. All rights reserved.

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.

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. (C) 2004 Elsevier B.V. All rights reserved.

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.

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 improved the prognosis. (C) 2004 Elsevier B.V. All rights reserved.

Background: Campylobacter jejuni enteritis is the most common antecedent infection in Guillain-Barre syndrome (GBS). C. jejuni-related GBS is usually acute motor axonal neuropathy (AMAN), but previous reports described many cases of the demyelinating subtype of GBS (acute inflammatory demyelinating polyneuropathy [AIDP]) after C. jejuni infection. Objective: To investigate whether C. jejuni infection elicits AIDP. Methods: In 159 consecutive patients with GBS, antibodies against C. jejuni were measured using ELISA. Antecedent C. jejuni infection was determined by the strict criteria of positive C. jejuni serology and a history of a diarrheal illness within the previous 3 weeks. Electrodiagnostic studies were performed weekly for the first 4 weeks, and sequential findings were analyzed. Results: There was evidence of recent C. jejuni infection in 22 (14%) patients. By electrodiagnostic criteria, these patients were classified with AMAN (n=16; 73%) or AIDP (n=5; 23%) or as unclassified (n=1) in the first studies. The five C. jejuni-positive patients with the AIDP pattern showed prolonged motor distal latencies in two or more nerves and had their rapid normalization within 2 weeks, eventually all showing the AMAN pattern. In contrast, patients with cytomegalovirus- or Epstein-Barr virus-related AIDP (n=13) showed progressive increases in distal latencies in the 8 weeks after onset. Conclusion: Patients with C. jejuni-related Guillain-Barre syndrome can show transient slowing of nerve conduction, mimicking demyelination, but C. jejuni infection does not appear to elicit acute inflammatory demyelinating polyneuropathy.

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. (C) 2004 Elsevier B.V. All rights reserved.

Objective: To investigate whether skin or muscle afferent input via the trigeminal nerve alters the excitability of facial motoneurons in hemifacial spasm (HFS). Methods: Botulinum toxin type A (BTX) was injected only to the orbicularis oculi (O. oculi) muscle of 21 patients with idiopathic HFS, and the excitability of the orbicularis oris ( O. oris) motoneurons was monitored. The synkinetic response (SR) of the blink reflex and abnormal muscle response (AMR) were recorded from the O. oris before and after treatment. Results: BTX injections produced marked to moderate improvement in the O. oculi of all 21 patients and in the O. oris of 17 (81%). The rectified areas of SR1 and SR2 were smaller after treatment. In particular, the AMR area showed a reduction (p = 0.02). Conclusions: The significant lessening of spasms in the O. oris after BTX injection to the O. oculi and the concomitant reduction in excitability of O. oris neurons are consistent with the hypothesis that in HFS, skin or muscle afferent volleys via the trigeminal nerve enhance the excitability of facial nerve motoneurons.

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.

Charcot-Marie-Tooth disease type 1A (CMT1A) is commonly considered a prototype of a hereditary demyelinating polyneuropathy. Apart from the myelin involvement, there has been little information on axonal membrane properties in this condition. Taking advantage of the uniform nature of the disease process, we undertook the in vivo assessment of multiple axonal excitability properties at the median nerve in nine CMT1A patients with PMP22 (peripheral myelin protein 22) gene duplication and 53 controls. The thresholds of CMT1A patients were much higher than normal, and threshold electrotonus (TE) exhibited a consistent pattern of abnormalities: early steep changes (fanning out) of both hyperpolarizing and depolarizing responses were followed by increased inward rectification to hyperpolarizing currents and unusually fast accommodation to depolarizing currents. Strength-duration 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.

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.

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. (C) 2003 Elsevier B.V. All rights reserved.

Bickerstaff reported eight patients who, in addition to acute ophthalmoplegia and ataxia, showed drowsiness, extensor plantar responses or hemisensory loss. This condition has been named Bickerstaff's brainstem encephalitis (BBE). One patient had gross flaccid weakness in the four limbs. Presumably because of the rarity of this disorder, there has been no reported study on a large number of patients with BBE. To clarify its clinical features, we reviewed detailed clinical profiles and laboratory findings for 62 cases of BBE diagnosed by the strict criteria of progressive, relatively symmetrical external ophthalmoplegia and ataxia by 4 weeks, and disturbance of consciousness or hyperreflexia. Ninety-two per cent of the patients involved had had an antecedent illness. Besides ophthalmoplegia and ataxia, disturbance of consciousness was frequent (74%), and facial diplegia (45%), Babinski's sign (40%) and pupillary abnormality and bulbar palsy (34%) were present. Almost all the patients had a monophasic remitting course and generally a good outcome. Serum anti-GQ1b IgG antibody was positive in 66%, and MRI showed brain abnormality in 30% of the patients. Another striking feature was the association with flaccid symmetrical tetraparesis, seen in 60% of the patients. An autopsy study of a BBE patient clearly showed the presence of definite inflammatory changes in the brainstem: there was perivascular lymphocytic infiltration with oedema and glial nodules. Electrodiagnostic study results suggested peripheal motor axonal degeneration. Limb weakness in the BBE cases studied was considered the result of overlap with the axonal subtype of Guillain-Barre syndrome. These findings confirm that BBE constitutes a clinical entity and provide additional clinical and laboratory feaures of BBE. A considerable number of BBE patients have associated axonal Guillain-Barre syndrome, indicative that the two disorders are closely related and form a continuous spectrum.

Background: Immune treatments are recommended for patients with Guillain-Barre syndrome (GBS) who cannot walk independently, but a considerable number of GBS patients are in the progressive phase at the first examination. Objective: To investigate whether progression patterns differ in demyelinating and axonal subtypes of GBS. Methods: Clinical, laboratory, and electrophysiologic data on 131 consecutive patients with GBS were reviewed. Patients were classified as having acute inflammatory demyelinating polyneuropathy ( AIDP) or acute motor axonal neuropathy (AMAN) based on electrodiagnostic criteria. Results: Forty-one patients had AIDP, 62 AMAN, and 28 were unclassified. Age, sex, and Hughes Functional Grading Scale score at the first medical examination did not differ for the AIDP and AMAN patients. Mean periods between neurologic onset and first examination (5.3 vs 4.2 days; p = 0.01) and neurologic onset and nadir (18.0 vs 11.5 days; p = 0.001) were longer for the AIDP group. In the subgroup of those with mild disability (able to walk independently at the first neurologic examination), 88% of the AMAN patients had reached the nadir, whereas 65% of the AIDP patients had reached it. The remaining 35% progressed to it over the next 1 to 2 weeks and were unable to walk at nadir. Conclusions: The patterns and speeds of progression differ in AMAN and AIDP, AMAN having a rapid progression and an early nadir. AIDP patients frequently have a significantly long progression after the first examination; therefore, they need to be carefully monitored.

Anti-GM1 and anti-GM1b antibodies are frequently present in patients with Guillain-Barre syndrome (GBS) and accordingly, the two antibodies often coexist in the same patient. In order to study clinical and laboratory features of anti-GM1b-positive GBS, we analyzed the data of patients with anti-GM1b IgG antibody but no anti-GM1 IgG antibody. Of 86 consecutive patients, 10 had anti-GM1b antibody alone and frequently had acute motor axonal neuropathy (AMAN, 80%) and Campylobacter jejuni infection (60%). Of 10 patients with anti-GM I antibody alone, four had AMAN, and two had C. jejuni infection. These results showed that GM1b Could be a target molecule of autoantibody in the AMAN form of GBS subsequent to C. jejuni infection. (C) 2003 Elsevier Science B.V. All rights reserved.

Objective: To determine whether the anti-GM1 antibody IgG subclass (IgG1 to 4) is associated with clinical profiles and patterns of recovery in Guillain-Barre syndrome (GBS). Methods: The IgG subclassification of anti-GM1 antibody was examined and compared with clinical data on 42 GBS patients positive for the antibody. Results: Frequent anti-GM1 antibody subclasses were IgG1 (76%) and IgG3 (31%). IgG1 antibody was associated with preceding gastroenteritis and Campylobacter jejuni serology, whereas IgG3 antibody was associated with preceding respiratory infection. Although the severity at nadir was similar for IgG1- and IgG3-positive patients, the percentage of patients, who could not walk independently was greater for the IgG1-positive group I month (42 vs 0%; p = 0.02), 3 months (28 vs 0%), and 6 months (25 vs 0%) after onset. Rapid recovery within 1 month occurred frequently in the patients with the IgG3 antibody but rarely in those with the IgG1 antibody (67 vs 11%; p = 0.003). Conclusions: The IgG1 subclass of anti-GM1 antibody is a major subtype indicative of slow recovery, whereas isolated elevation of IgG3 subclass antibody titer suggests rapid recovery. Variation in subclass patterns may depend on which pathogen precipitates GBS.

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 neurophathy (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.

We report a patient with leukocytoclastic-vasculitic neuropathy associated with chronic Epstein-Barr virus (EBV) infection. A 55-year-old man had been suffering from chronic progressive axonal polyneuropathy and skin erythema for 3 years. A skin biopsy showed capillary vasculitis with clustered leukocyte fragments. Findings of serum assays, a polymerase chain reaction for EBV-DNA, and in situ hybridization indicated chronic EBV infection. Immunosuppressive treatment resulted in the gradual lessening of his general and neurologic symptoms.

We describe a patient with acute isolated bulbar palsy following enteritis. A 29-year-old man developed dysphagia and nasal voice without limb weakness, ataxia, or areflexia. High titres of serum anti-GT1 a and anti-Campylobacter jejuni IgG antibodies were detected. He was treated with plasmapheresis, resulting in rapid clinical improvement. This case suggests that an acute isolated bulbar palsy may be caused by a pathology relating to Guillain-Barre syndrome (GBS), in which anti-GT1a IgG antibody may have a role. (C) 2002 Elsevier Science B.V. All rights reserved.

The clinical and neurophysiological features of multifocal motor neuropathy (MMN) indicate selective involvement of motor axons, but pathological abnormalities in sensory axons suggest a more widespread disease process. The present study was undertaken to determine whether the focal abnormalities are associated with widespread subclinical abnormalities in motor axons. Threshold tracking was used to measure excitability properties (stimulus-response curves, strength-duration properties, recovery cycle, and threshold electrotonus) of the median nerve in five patients with MMN with lesions proximal to the site of testing. Patients were compared with 25 healthy controls. The changes in excitability indices were similar to those in controls, and in one patient there was no alteration after treatment with intravenous gammaglobulin. In this patient, indices of axonal excitability were also measured before, during, and after ischemia of the arm for 10 min. Again no differences were detected. This study provides no evidence for a generalized subclinical abnormality in MMN, at least when disease duration is less than 6 years. (C) 2002 Wiley Periodicals, Inc.

We describe a 27-year-old woman who showed the clinical triad of Fisher syndrome (ophthalmoplegia, ataxia, and areflexia), a disturbance of consciousness, facial diplegia, and hemisensory loss. Her serum was positive for anti-GQ1b immunoglobulin G (IgG) antibody. The electroencephalographic findings (diffuse slow activity), median somatosensory evoked potential (absent cortical N20 with normal cervical N13), and blink reflex studies (absent R2) suggested central dysfunction, whereas results of facial nerve conduction studies (low amplitudes of compound muscle action potentials), F-wave and H-reflex studies (absent F-waves and soleus H-reflexes), and brainstem auditory evoked potentials (prolongation of wave I latency) suggested peripheral abnormalities. This case supports the hypothesized continuity between Fisher syndrome and Bickerstaff brainstem encephalitis. These two conditions may represent a single autoimmune disease mediated by anti-GQ1b antibody, usually involving the peripheral and occasionally the central nervous systems. (C) 2002 Wiley Periodicals, Inc.

A 21-year-old woman subacutely developed memory loss subsequent to gastroenteritis. Brain MRI with gadolinium enhancement showed symmetric involvement of the amygdala. The CSF was acellular with increased protein level. There was no evidence suggestive of neoplasm or viral infection. Combined treatment with plasmapheresis and immunoglobulin improved her clinical symptoms and lessened abnormalities manifested in the MRI. This case suggests the presence of immune-mediated limbic encephalitis without association with neoplasms or infections. (C) 2002 Elsevier Science B.V. All rights reserved.

A previous study suggested that axonal hyperpolarization produced by maximal voluntary contraction could accentuate conduction block in symptomatic patients with chronic inflammatory demyelinating polyneuropathy (CIDP). If this is so, conduction block should occur with hyperpolarization due to other causes such as the release of ischaemia. The effects of ischaemia on axonal excitability and on impulse conduction were therefore studied in 12 healthy control subjects and seven patients with symptomatic CIDP. The compound muscle action potential (CMAP) of abductor pollicis brevis was recorded in response to supramaximal stimuli to the median nerve at the wrist alternating with measurements of axonal excitability before, during and after ischaemia for 10 min produced by inflation of a sphygmomanometer cuff around the arm. During ischaemia, the amplitude/area of the maximal CMAP was reduced in the patients by 10% and, after release of ischaemia, it was attenuated by 19%. There were only slight changes in the CMAPs in the healthy controls. The attenuation of the CMAP during ischaemia presumably results from depolarization-induced inactivation of Na+ channels in axons critically dependent on the number of functioning Na+ channels for action potential generation. The attenuation of the CMAP after release of ischaemia paralleled the post-ischaemic hyperpolarization and was probably precipitated by it. This study provides suggestive evidence that axonal depolarization can produce conduction block in CIDP, in addition to providing confirmation that axonal hyperpolarization can also do so. In patients with chronic demyelinating disorders, conduction block can probably result from a wider range of physiological stresses than previously appreciated, such as natural activity, ischaemia or recovery from transient ischaemia-all of which could produce fluctuations in symptoms.

Polyneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (POEMS) syndrome is a rare cause of demyelinating and axonal neuropathy. POEMS syndrome and chronic inflammatory demyelinating polyneuropathy (CIDP) cause peripheral nerve demyelination, and the electrodiagnostic findings may therefore be similar, but the two disorders are distinct. To elucidate the electrodiagnostic features of POEMS syndrome, we reviewed nerve conduction studies of 8 patients, and compared their results with those in 42 patients with CIDP. The patients with POEMS syndrome showed (1) slowing of nerve conduction that was more predominant in the intermediate than distal nerve segments, (2) rare conduction block (6% of the tested nerves), and (3) more severe attenuation of compound muscle action potentials in the lower than upper limbs. Findings in the COP patients were characterized by multifocal conduction slowing that was occasionally dominant distally, frequent conduction block (44% of tested nerves), and less discrepancy between upper and lower limb nerves. The pattern of nerve conduction abnormalities differs between these disorders. Recognition of these typical patterns may be helpful for early diagnosis of POEMS syndrome. (C) 2002 Wiley Periodicals, Inc.

Multiple nerve excitability measurements have been proposed for clinical testing of nerve function, and an important determinant of excitability is membrane potential. We report a patient with acquired hypokalemic paralysis in whom multiple excitability indices (stimulus-response curve, strength-duration properties, threshold electrotonus, recovery cycle) were measured during and after an acute hypokalemic attack (serum K+ level, 2.1 mEq/L and 4.5 mEq/L, respectively). During hypokalemia, there was a shift of the stimulus-response curve to the right, a decrease in strength-duration time constant, a "fanning-out" of responses during threshold electrotonus, a reduction in relative refractory period, and an increase in superexcitability; all of these indicate axonal hyperpolarization, presumably due to the K+ equilibrium potential being more negative. These indices returned to normal 20 h later, associated with normalization of the serum K+ level. These results demonstrate that the changes associated with hypokalemic paralysis are not confined to muscle and that axons undergo hyperpolarization in vivo. Multiple excitability measurements can be used as a tool to identify changes in membrane potential of human axons. (C) 2002 Wiley Periodicals, Inc.

This study compared directly the post-ischaemic behaviour of sensory and motor axons in the human median nerve, focusing on the excitability changes produced by ischaemia and its release and by continuous polarizing DC. The decrease in threshold during ischaemia for 13 min was greater, the post-ischaemic increase in threshold was more rapid, and the return to the pre-ischaemic excitability took longer in sensory axons. However, a transient depolarizing threshold shift developed in sensory axons a few minutes after release of ischaemia. This pattern could not be reproduced by polarizing currents designed to mimic the probable pump-induced changes in membrane potential, even though the applied currents produced greater changes in threshold. Hyperpolarizing currents of equivalent intensity produced a greater increase in threshold for motor axons than sensory axons and, in studies of threshold electrotonus using graded hyperpolarizing DC, accommodation was greater in sensory than motor axons. The post-ischaemic changes in threshold were not uniform for axons of different threshold, whether sensory or motor, the threshold increase was usually less prominent for low-threshold axons. A transient post-ischaemic depolarization could be produced in motor axons with ischaemia of 20 min duration. Greater ischaemic and post-ischaemic changes in threshold for sensory axons could reflect greater dependence on the electrogenic Na+-K+ pump to maintain resting membrane potential and/or greater extracellular K+ accumulation in ischaemic sensory axons. Inward K+ currents due to extracellular K+ accumulation would then be more likely to trigger a depolarizing shift in membrane potential, the degree of K+ accumulation and pump activity being dependent on the duration of ischaemia. In sensory axons the greater tendency to accommodate to hyperpolarizing stimuli presumably contributes to shaping their post-ischaemic behaviour but is probably insufficient to explain why their behaviour differs from that of motor axons.