桑原 聡

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.

Objective To investigate whether glycemic control is associated with reversible changes in axonal excitability in human diabetic nerves. It is known that voluntary contraction or compression ischemia alters nerve Na+/K+ pump activity, and axonal excitability changes due to the pump activity can be estimated by threshold tracking. Methods Threshold, the current required to produce a compound muscle action potential 50% of maximum, was determined from the stimulus-response curve, and threshold changes produced by maximal voluntary contraction or ischemia were measured before and after insulin treatment in 10 diabetic patients. Results Within 3 weeks of the start of treatment, the threshold changes became greater following voluntary contractions (+13+/-4% versus +23+/-5%; mean+/-SEM; p=0.04) and during ischemia (-5+/-2% versus -11+/-2%; p=0.04). Conclusions The extent of threshold fluctuation depends on multiple metabolic factors associated with diabetes such as decreased Na+/K+ ATPase activity, increased anaerobic glycolysis, and tissue acidosis, and nerve excitability can respond quickly to glycemic control in diabetic patients.

To investigate whether there are inter-nerve differences in the extent and pattern of axonal excitability changes produced by voluntary contractions of tibialis anterior (TA) and abductor pollicis brevis (APB), threshold tracking was used to measure axonal excitability parameters [threshold, supernormality and strength-duration time constant (tau(SD))] of peroneal and median motor axons in 11 healthy subjects. Maximal contractions for 1 min resulted in an increase in threshold, an increase in supernormality, a decrease in tau(SD) and an increase in latency, all of which indicate axonal hyperpolarization. The increase in threshold was less in peroneal axons (18 +/- 4%) than median axons (37 +/- 6%, mean SEM, P < 0.001), and was accompanied by smaller absolute changes in latency, supernormality, and tau(SD). Peroneal axons had less supernormality at rest but a greater change in supernormality for the change in threshold. There were major contraction-induced changes in the compound muscle action potential of TA but not that of APB. Voluntary contractions depress axonal excitability, but the changes are quantitatively different for motor axons innervating different muscles. There are three clinical implications. First, weakness and fatigue due to activity-dependent conduction block may vary for different muscles, independent of disease severity, and therapeutic strategies to overcome activity-dependent conduction block may not be equally effective for different muscles. Second, in motor control studies using the H reflex to document motoneuron excitability, a constant stimulus will not produce a constant neural volley if the stimulated axons have been activated by, for example, a voluntary contraction. Third, TA is probably not optimal for testing for activitydependent conduction block. (C) John Wiley Sons, Inc.

Objectives: To investigate the properties of mechanoreceptors in patients with peripheral neuropathy. The skin mechanoreceptor is a terminal organ of the primary sensory neuron, which is likely to be affected earlier and more severely than is the nerve trunk by peripheral neuropathies. Methods: Single sensory unit responses to air-puff and electric stimulation were recorded using the microneurographic technique in the glabrous skin of the hand, Receptor transduction time was estimated by a latency difference between electric- and air-puff-induced responses. Results: A total of 38 mechanoreceptive units were obtained from 14 normal subjects. All the units responded to air-puff stimuli irrespective of the receptor type, and receptor transduction time was approximately 2 ms. A total of 32 units were recorded from 11 patients with neuropathy of variable causes. Seven (22%) of the 32 neuropathic units did not respond to air-puffs despite their ability to respond to electric stimulation. Compared to normal ones. units from patients with peripheral neuropathy had significantly higher mechanical thresholds, but receptor transduction times did not differ significantly. Conclusions: Changes in receptor properties in human neuropathy are characterized by increased mechanical threshold without prolongation of receptor transduction time. possibly due to a high threshold for generating receptor potentials. (C) 2002 Elsevier Science Ireland Ltd. All rights reserved.

Background: Chronic inflammatory demyelinating polyneuropathy (CIDP) is a heterogeneous disorder having a wide clinical range, and is characterised by multifocal demyelination that can involve the distal nerve terminals, intermediate nerve segments, and nerve roots. Objective: To investigate whether the distribution patterns of demyelination along the course of the nerve correlate with clinical profiles in patients with CIDP. Methods: Motor nerve conduction studies were carried out on 42 consecutive patients. According to the physiological criteria for demyelination, the presence of a demyelinative lesion was determined in the distal nerve segments (distal pattern) or intermediate nerve segments (intermediate pattern), or in both (diffuse pattern). The serum concentration of tumour necrosis factor (TNF)-alpha was measured by immunoassay. Results: Patients were classified as having a distal (n= 10), intermediate (n= 13), or diffuse (n= 15) pattern, or were unclassified (n= 4). Patients with the distal or diffuse pattern had common clinical features such as subacute onset, symmetric symptoms, and weakness involving proximal as well as distal muscles. Patients with the distal pattern had a good response to treatment and a monophasic remitting course, but the diffuse pattern was associated with a treatment dependent relapsing course, reflecting longer disease activity. The serum TNF-alpha concentrations increased only in the "diffuse" subgroup of patients, and this might be associated with breakdown of the blood-nerve barrier and therefore, involvement of the intermediate segments. The intermediate pattern was characterised by a chronic course, asymmetric symptoms, less severe disability, and refractoriness to treatments. Conclusions: COP consists of subtypes with varying predilections for lesions along the course of the nerve. The distribution patterns of conduction abnormalities may be useful in the prediction of outcome of patients with CIDP.

Objectives - To investigate whether or not the pattern and extent of autonomic involvement differ between the two subtypes of Guillain-Barre syndrome (GBS), namely acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Methods - Head-up tilt test. R-R interval variation, plasma noradrenaline concentration, skin vasomotor reflex (SVR) and sympathetic sweat response (SSwR) were used to estimate autonomic function in seven AIDP and eight AMAN patients. Results - Heart rate and plasma noradrenaline concentration were significantly high in the AIDP group but not in the AMAN group. Skin vasomotor reflexes were generally preserved and SSwRs were impaired in patients with severe neurological deficits for both AIDP and AMAN groups. Conclusion - The patterns of autonomic involvement are qualitatively different between AIDP and AMAN. Acute inflammatory demyelinating polyneuropathy is characterized by cardio-sympathetic hyperactivity, excessive or reduced sudomotor function and preserved skin vasomotor function, while AMAN is not necessarily generally associated with marked autonomic dysfunction except for the sudomotor hypofunction seen in patients with severe neurological deficits.

Threshold tracking was used to compare excitability properties (stimulus-response curves, strength-duration properties, recovery cycle and threshold electrotonus) of the median nerve in 11 patients with chronic inflammatory demyelinating polyneuropathy (CIDP) and 25 healthy controls. Stimulus-response curves were significantly different: threshold was much higher, the slope of the curves reduced and the spread of the thresholds greater in the CIDP group. The strength-duration time constant (tau (SD)) was significantly shorter and the rheobase higher in the CIDP group. In the recovery cycle, the CIDP group had less refractoriness, supernormality and late subnormality than healthy controls, but the duration of the relatively refractory period was normal. These changes in tau (SD) and the recovery cycle were not those previously predicted. There were no consistent changes in threshold electrotonus, suggesting that, for the studied axons, there are no consistent changes in accommodation properties that depend on internodal conductances. It is difficult to explain these changes in excitability on the basis of a change in membrane potential, or solely as the result of demyelination, and it is possible that other morphological factors such as variable remyelination and inflammatory oedema affected axonal excitability in the patients.

Recent evidence suggests that two conductances responsible for accommodation to changes in membrane potential (a slow K+ conductance and inward rectification [I-H]) are less active on cutaneous afferents in the sural nerve than on those in the median nerve, and it has been suggested that these axons would therefore respond differently to stress, whether natural or due to disease. The present study was undertaken in eight healthy volunteers to determine whether these afferents respond differently to the depolarizing and hyperpolarizing stresses that accompany ischemia for 13 min and subsequent recovery. During ischemia, the decrease in threshold was quantitatively less for the sural afferents, as were the changes in the other indices of axonal excitability, presumably because the ischemic depolarization was less for sural afferents. Following release of ischemia, there was, as predicted, a divergence in the pattern of threshold change. With median afferents there was evidence of a transient depolarization, believed to be due to inward rectification, superimposed on a longlasting hype rpolarization. The response of sural afferents lacked this transient depolarizing threshold change. Cutaneous afferents in the median and sural nerves behave differently in response to ischemic and postischemic stresses, and it is likely that they will also respond differently to disease processes. in a number of respects the differences between sural and median afferents are analogous to differences between diabetic and normal nerves. (C) 2001 John Wiley & Sons, Inc.