Shigeki Ohmori

Different neurological and physiological profiles in POEMS syndrome and chronic inflammatory demyelinating polyneuropathy

Background POEMS (polyneuropathy, organomegaly, endocrinopathy, M protein and skin changes) syndrome, a rare cause of demyelinating neuropathy associated with multiorgan involvement, has been increasingly recognised. Polyneuropathy is often an initial manifestation and therefore the disorder can be misdiagnosed as chronic inflammatory demyelinating polyneuropathy (CIDP). Objective To elucidate whether POEMS syndrome and CIDP are differentiated based on profiles of neuropathy. Methods Clinical and electrophysiological data were reviewed in consecutive POEMS syndrome (n=51) and typical CIDP (n=46) patients in a single Japanese hospital between 2000 and 2010. Results Both POEMS and CIDP patients showed symmetric polyneuropathy, physiological evidence of demyelination (70% of POEMS patients fulfilled the electrodiagnostic criteria for definite CIDP) and albuminocytological dissociation; 49% of the POEMS syndrome patients had neuropathy onset and 60% of them were initially diagnosed as having CIDP by neurologists. Clinically, POEMS neuropathy more frequently showed severe leg pain (76% vs 7%; p<0.001), muscle atrophy (52% vs 24%; p=0.005) and distal dominant muscle weakness. Electrophysiologically, POEMS syndrome was characterised by less prolonged distal motor latency (mean 5.6 ms vs 8.1 ms; p<0.001) and higher terminal latency index (0.42 vs 0.33; p=0.006) in the median nerves, and unrecordable tibial and sural responses (p<0.001), suggesting demyelination predominant in the nerve trunk rather than in the distal nerve terminals, and axonal loss in the lower limb nerves. Conclusions Before development of typical systemic manifestations, POEMS neuropathy can be distinguished from CIDP by the clinical profile and patterns of nerve conduction abnormalities. Recognition of these features leads to early diagnosis and proper treatment for POEMS syndrome.

Antiganglioside antibodies are associated with axonal Guillain–Barré syndrome: A Japanese–Italian collaborative study

Background Whether or not antiganglioside antibodies are related to axonal or demyelinating Guillain–Barré syndrome (GBS) is still a matter of controversy, as detailed in previous studies conducted in Western and Asian countries. Objective To clarify whether antiganglioside antibodies are associated with axonal dysfunction in Japanese and Italian GBS patient cohorts. Methods Clinical and electrophysiological profiles were reviewed for 156 GBS patients collected from Japan (n=103) and Italy (n=53). Serum IgG antibodies against GM1, GM1b, GD1a and GalNAc-GD1a were measured by ELISA in the same laboratory. Electrodiagnostic criteria and results of serial electrophysiological studies were used for classification of GBS subtypes: acute inflammatory demyelinating polyneuropathy (AIDP) and acute motor axonal neuropathy (AMAN). Results In both Japanese and Italian cohorts, any of the antibodies were positive in 36% of the patients, and antibody positivity had a significant association with the AMAN electrodiagnosis. Approximately 30% of Japanese and Italian antiganglioside positive patients showed the AIDP pattern at the first examination whereas sequential studies showed that most finally showed the AMAN pattern. Clinically, seropositive patients more frequently had preceding diarrhoea and pure motor neuropathy in both Japanese and Italian cohorts; vibratory sensation was normal in 97% of Japanese and in 94% of Italian seropositive patients. Conclusions In GBS, clinical and electrophysiological features appear to be determined by antiganglioside antibodies, and the antibodies are associated with motor axonal GBS in both Japan and Italy. Classification of the GBS subtypes as a disease entity should be made, combining the results of antiganglioside assays and serial electrodiagnostic studies.

Motor axonal excitability properties are strong predictors for survival in amyotrophic lateral sclerosis

Objective The aim of this study was to investigate whether axonal excitability indices are associated with survival in patients with amyotrophic lateral sclerosis (ALS). Previous nerve excitability studies suggested increased persistent sodium currents in motor axons of patients with ALS, which lead to axonal hyperexcitability and potentially enhance neuronal death. Methods 112 patients with sporadic ALS were followed up until endpoint (death or tracheostomy). Multivariate analyses were performed using the Cox proportional hazard model. Threshold tracking was used to measure multiple axonal excitability indices in median motor axons, such as strength–duration time constant (SDTC; a measure of nodal persistent sodium current). Latent addition was also used to estimate the magnitude of persistent sodium currents. Results The overall median tracheostomy-free survival from onset was 37 months. Prolonged SDTC was strongly associated with shorter survival (adjusted HR 4.07; 95% CI 1.7 to 9.8; p=0.0018) compared with older onset age (>60 years; HR=1.80) and bulbar onset (HR=1.80). Estimated median survival was 34 months in the longer SDTC group and 51 months in the shorter SDTC group. This index was highly statistically significant even after multiple testing adjustments with age and site of onset (bulbar or limb). Latent addition study results were consistent with these findings. Conclusions Axonal persistent sodium currents, estimated by SDTC and latent addition, are strong and independent predictors for shorter survival in patients with ALS. Membrane hyperexcitability is possibly associated with motor neuronal death, and modulation of excessive sodium currents could be a novel therapeutic option for ALS.

Split hand syndrome in amyotrophic lateral sclerosis: different excitability changes in the thenar and hypothenar motor axons

Background In amyotrophic lateral sclerosis (ALS), muscle wasting preferentially affects the abductor pollicis brevis (APB) and first dorsal interosseous over the abductor digit minimi (ADM), and this is termed ‘split hand’. Previous axonal excitability studies have suggested increased nodal persistent sodium current and reduced potassium current in motor axons in ALS, but the extent of excitability changes in APB and ADM axons in ALS has never been compared. Objective To elucidate the peripheral axonal pathophysiology of split hand. Methods In both APB and ADM motor axons of 21 patients with ALS and 17 age-matched normal controls, threshold tracking was used to measure excitability indices such as strength-duration time constant (SDTC; a measure of persistent sodium current) and threshold electrotonus. Results In normal controls, SDTC was significantly longer for APB than ADM axons, suggesting that axonal excitability is physiologically higher in APB axons. Compared with normal controls, patients with ALS had longer SDTC and greater threshold changes in depolarising threshold electrotonus in both APB and ADM axons. Furthermore, the difference in extent of SDTC prolongation between normal subjects and patients with ALS was greater in APB than ADM axons. Conclusions APB axons have physiologically higher excitability than ADM axons, and, in ALS, the hyperexcitability is more prominent in APB axons. Although cortical mechanisms would also be involved, more prominent hyperexcitability of APB axons may contribute to development of split hand, and the altered axonal properties are possibly associated with motor neuronal death in ALS.

Markedly reduced axonal potassium channel expression in human sporadic amyotrophic lateral sclerosis: An immunohistochemical study

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), suggesting abnormally increased excitability of motor axons. Previous nerve excitability studies have shown reduced axonal potassium currents in ALS patients that may contribute to the hyperexcitability and thereby generation of fasciculations. To clarify changes in axonal ion channel expression in motor axons of ALS, we performed immunohistochemistry of potassium and sodium channels in the C7 and L5 ventral/dorsal roots obtained from five autopsy cases of sporadic ALS. Compared to controls, the immunoreactivity of potassium channels (Kv1.2) was markedly reduced in the ventral roots, but normal in the dorsal roots of all the ALS patients. Nodal sodium channel expression was not significantly different in ALS patients and control subjects. Our results show prominently reduced expression of axonal potassium channels, and provide the neuropathological and biological basis for decreased accommodative potassium currents in motor axons of ALS patients. The axonal hyperexcitability would lead to generation of fasciculations, and possibly enhances motor neuron death in ALS.

Bortezomib-induced neuropathy: Axonal membrane depolarization precedes development of neuropathy

OBJECTIVE Bortezomib is a proteasome inhibitor with high efficacy for multiple myeloma but with severe peripheral neurotoxicity, leading to dose modification and severe neurological disability. This study aimed to investigate the pathophysiology of bortezomib-induced neuropathy. METHODS Threshold tracking was used to assess the excitability of sensory and motor axons. Measurements were sequentially performed before and after bortezomib treatment in nine patients with newly diagnosed multiple myeloma. RESULTS In total, 67% of patients finally developed symptomatic neuropathy. Changes in sensory axonal excitability indices readily occurred after the first course of administration. Patterns of changes in excitability indices suggest membrane depolarization (decreased superexcitability, P<0.001; decreased depolarizing threshold electrotonus 90-100ms, P=0.02). Abnormalities in nerve conduction parameters suggestive of axonal degeneration appeared after the second course of treatment. CONCLUSIONS Bortezomib induces a depolarizing shift in resting membrane potential prior to the development of neuropathy. Membrane depolarization could be associated with impairment of electrogenic Na(+)-K(+)-ATPase-dependent pump caused by toxic effects of bortezomib on mitochondria. SIGNIFICANCE Axonal depolarization and hyperexcitability might enhance neurodegeneration in bortezomib-induced neuropathy.

Patterns of sensory nerve conduction abnormalities in Fisher syndrome: more predominant involvement of group Ia afferents than skin afferents.

OBJECTIVE To elucidate the features of sensory nerve involvement in Fisher syndrome (FS), this study extensively investigated sensory electrophysiology. METHODS In 47 consecutive FS patients, results of sensory nerve conduction studies in the median, ulnar and sural nerves, soleus H-reflexes, and median or tibial somatosensory-evoked potentials (SEP) were reviewed. Because of the large effects of age on amplitude of sensory nerve action potentials (SNAP), we strictly defined reduction of SNAP amplitudes by using a nomogram which age and amplitude obtained from 87 normal subjects. RESULTS In routine nerve conduction studies, SNAP amplitude was reduced only in 32% of the patients, and conduction velocity was decreased in 2%. In contrast, soleus H-reflexes were frequently absent or reduced (67%). SEPs were abnormal only in 17%. CONCLUSIONS In FS, absent soleus H-reflexes are the most frequent electrophysiologic abnormalities, whereas SNAPs amplitudes are rarely affected. The pattern is characterized by predominant involvement of group Ia afferents with relatively preserved cutaneous afferents without evidence suggestive of demyelination. SIGNIFICANCE The major targets of immune attack by anti-GQ1b antibodies in FS appear to be group Ia neurons in the dorsal root ganglia, and this is presumably responsible for ataxia and areflexia in FS.

Activity-dependent changes in impulse conduction of single human motor axons: A stimulated single fiber electromyography study

OBJECTIVE The aim of this study is to develop a novel method to assess activity-dependent hyperpolarization in human single motor axons at a constant stimulus frequency by using intra-muscular axonal stimulating single fiber electromyography (s-SFEMG). METHODS We performed s-SFEMG in the extensor digitorum communis (EDC) muscle of 10 normal subjects, and measured changes in latencies for single muscle fiber action potentials (MAPs) during 500 stimuli delivered at 5, 10 and 20 Hz. The data were analyzed with a repeated measurement analysis, and multiple comparisons were performed. RESULTS A total of 585 MAPs were examined at 5 Hz (n=190), 10 Hz (n=210), and 20 Hz (n=185) steady stimulation. There was a progressive linear prolongation of latencies, as the stimulus rate increased (F=95.6, p<0.001); the least square means (SEM) of latency change were 100.7 (0.28)% at 5 Hz, 102.3 (0.27)% at 10 Hz and 105.3 (0.28)% at 20 Hz. There were statistically significant differences between frequencies by Tukey-Kramers method. Despite the significant latency prolongation, no activity-dependent conduction block developed. A 20 Hz electric stimulation to intramuscular axons was well-tolerated in all the subjects. CONCLUSIONS Tetanic stimulation at a constant rate results in significant latency increase in single human motor axons, the extent of which depends on the stimulus frequency. The findings imply that physiological discharge rates will activate the Na(+)/K(+) pump and thereby produce axonal hyperpolarization in single motor axons. SIGNIFICANCE This technique may detect activity-dependent conduction block if the safety margin of impulse transmission is significantly reduced by demyelination or increased branching due to collateral sprouting in a variety of neuromuscular disorders.

Prominent fatigue in spinal muscular atrophy and spinal and bulbar muscular atrophy: evidence of activity-dependent conduction block.

OBJECTIVES To clarify whether patients with spinal muscular atrophy (SMA) or spinal and bulbar muscular atrophy (SBMA) suffer disabling muscle fatigue, and whether activity-dependent conduction block (ADCB) contributes to their fatigue. ADCB is usually caused by reduced safety factor for impulse transmission in demyelinating diseases, whereas markedly increased axonal branching associated with collateral sprouting may reduce the safety factor in chronic lower motor neuron disorders. METHODS We assessed the fatigue severity scale (FSS) in 22 patients with SMA/SBMA, and in 100 disease controls (multiple sclerosis, myasthenia gravis, chronic inflammatory demyelinating polyneuropathy (CIDP), and axonal neuropathy). We then performed stimulated-single fibre electromyography (s-SFEMG) in the extensor digitorum communis (EDC) muscle of 21 SMA/SBMA patients, 6 CIDP patients, and 10 normal subjects. RESULTS The FSS score was the highest in SMA/SBMA patients [4.9 ± 1.1 (mean ± SD)], with 81% of them complaining of disabling fatigue, compared with normal controls (3.5 ± 1.0), whereas patients with multiple sclerosis (4.3 ± 1.6), myasthenia gravis (4.0 ± 1.6) or CIDP (4.3 ± 1.4) also showed higher FSS score. When 2000 stimuli were delivered at 20 Hz in s-SFEMG, conduction block of single motor axons developed in 46% of patients with SMA/SBMA, and 40% of CIDP patients, but in none of the normal controls. CONCLUSION SMA/SBMA patients frequently suffer from disabling fatigue presumably caused by ADCB induced by voluntary activity. SIGNIFICANCE ADCB could be the mechanism for muscle fatigue in chronic lower motor neuron diseases.

Differences in excitability between median and superficial radial sensory axons

OBJECTIVE The aim of this study was to investigate differences in excitability properties of human median and superficial radial sensory axons (e.g., axons innervating the glabrous and hairy skin in the hand). Previous studies have shown that excitability properties differ between motor and sensory axons, and even among sensory axons between median and sural sensory axons. METHODS In 21 healthy subjects, threshold tracking was used to examine excitability indices such as strength-duration time constant, threshold electrotonus, supernormality, and threshold change at the 0.2 ms inter-stimulus interval in latent addition. In addition, threshold changes induced by ischemia for 10 min were compared between median and superficial radial sensory axons. RESULTS Compared with radial sensory axons, median axons showed shorter strength-duration time constant, greater threshold changes in threshold electrotonus (fanning-out), greater supernormality, and smaller threshold changes in latent addition. Threshold changes in both during and after ischemia were greater for median axons. CONCLUSIONS These findings suggest that membrane potential in human median sensory axons is more negative than in superficial radial axons, possibly due to greater activity of electrogenic Na(+)/K(+) pump. These results may reflect adaptation to impulses load carried by median axons that would be far greater with a higher frequency. SIGNIFICANCE Biophysical properties are not identical in different human sensory axons, and therefore their responses to disease may differ.