Minako Beppu

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.

Direct application of MALDI-TOF mass spectrometry to cerebrospinal fluid for rapid pathogen identification in a patient with bacterial meningitis.

BACKGROUND Bacterial meningitis is a neurological emergency. Early diagnosis and rapid initiation of antimicrobial therapy are vital. METHODS Matrix-assisted laser desorption/ionization time of flight mass spectrometry (MALDI-TOF MS) is increasingly used as a rapid and accurate microbial diagnostic method for species identification of pathogens. Although this technology requires a growth step to obtain bacterial colonies for the acquisition of substantial spectra in most cases, it can also be used to analyze clinical specimens such as urine and cerebrospinal fluid for direct bacterial identification. There are very few reports describing the use of MALDI-TOF MS for the direct detection of microorganisms causing bacterial meningitis. RESULTS We describe a case of bacterial meningitis caused by Klebsiella pneumoniae in which MALDI-TOF MS provided a rapid bacteriological diagnosis, thus enabling early and appropriate treatment. CONCLUSIONS Identification of microbes based on MALDI-TOF MS is now an important technology in clinical microbiology laboratories that are required to provide a rapid diagnosis of bacterial meningitis.

Ambiguous effects of anti-VEGF monoclonal antibody (bevacizumab) for POEMS syndrome

Objective Vascular endothelial growth factor (VEGF) plays an essential role in the pathophysiology of polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome. Anti-VEGF antibody (bevacizumab) appears to be an attractive therapeutic option. The aim of this study is to investigate the effects of bevacizumab for patients with POEMS syndrome. Methods We reported six POEMS patients treated with bevacizumab and reviewed the literature. Results The serum VEGF levels decreased immediately after bevacizumab administration in all six patients. However, four patients had entirely no clinical response, and two of them died. The remaining two showed improvement that could be explained by combined treatments. We also reviewed the literature and found 11 patients treated with bevacizumab; of these, only one was treated with bevacizumab alone. 10 had combined treatments, and four died without any response. Conclusions Both our experience and the literature suggest ambiguous effects of bevacizumab; inhibition of VEGF alone may be insufficient because multiple cytokines are upregulated, or aberrant neo-vascularization may have already fully developed in the advanced stage of POEMS syndrome.

Moesin is a possible target molecule for cytomegalovirus-related Guillain-Barré syndrome

Objective: Previous histochemical studies in the demyelinating form of Guillain-Barré syndrome (GBS), acute inflammatory demyelinating polyneuropathy (AIDP), have shown complement deposition on the surface of Schwann cells, and therefore unknown epitopes would be present on the outer surface of Schwann cells. Methods: We used a proteomic-based approach to search for the target molecules of AIDP in the extracted proteins from schwannoma cells. Sera were obtained from 40 patients with GBS, 31 controls with inflammatory disease, and 46 normal controls. Results: We found that patients with AIDP after cytomegalovirus (CMV) infection have serum autoantibodies against membrane-organizing extension spike protein (moesin), which is expressed in the Schwann cell processes at the nodes of Ranvier and is crucial for myelination. Of the 40 patients with GBS, 6 had recent CMV infection and 5 of them (83%) had high levels of serum immunoglobulin G antibodies against moesin. The anti-moesin antibodies were found in none of the control subjects with disease including 5 with CMV infection but no neuropathy, and only 2 (4%) of the 46 normal control subjects. Immunocytochemistry showed that moesin was stained at the distal tips of schwannoma cells by sera from the patients with CMV-related AIDP but not by sera from controls. Conclusion: Moesin is a possible immunologic target molecule of pathogenic autoantibodies in patients with CMV-related AIDP. Classification of evidence: This study provides Class II evidence that levels of serum anti-moesin antibodies accurately distinguishes CMV-related AIDP from non–CMV-related AIDP (sensitivity 83%, specificity 93%).

Different electrophysiological profiles and treatment response in ‘typical’ and ‘atypical’ chronic inflammatory demyelinating polyneuropathy

Background Chronic inflammatory demyelinating polyneuropathy (CIDP) is currently classified into ‘typical’ CIDP and ‘atypical’ subtypes such as multifocal acquired demyelinating sensory and motor neuropathy (MADSAM). Objectives To assess the frequency of CIDP subtypes, and to elucidate clinical and electrophysiological features, and treatment response in each subtype. Methods We reviewed data from 100 consecutive patients fulfilling criteria for CIDP proposed by the European Federation of Neurological Societies and the Peripheral Nerve Society. The Kaplan-Meier curve was used to estimate long-term outcome. Results Patients were classified as having typical CIDP (60%), MADSAM (34%), demyelinating acquired distal symmetric neuropathy (8%) or pure sensory CIDP (1%). Compared with patients with MADSAM, patients with typical CIDP showed more rapid progression and severe disability, and demyelination predominant in the distal nerve segments. MADSAM was characterised by multifocal demyelination in the nerve trunks. Abnormal median-normal sural sensory responses were more frequently found for typical CIDP (53% vs 13%). Patients with typical CIDP invariably responded to corticosteroids, immunoglobulin or plasmapheresis, whereas patients with MADSAM were more refractory to these treatments. The Kaplan-Meier analyses showed that 64% of patients with typical CIDP and 41% of patients with MADSAM had a clinical remission 5 years later (p=0.02). Conclusions Among the CIDP spectrum, typical CIDP and MADSAM are the major subtypes, and their pathophysiology appears to be distinct. In typical CIDP, the distal nerve terminals and possibly the nerve roots, where the blood–nerve barrier is anatomically deficient, are preferentially affected, raising the possibility of antibody-mediated demyelination, whereas cellular immunity with breakdown of the barrier may be important in MADSAM neuropathy.

Multiple angiogenetic factors are upregulated in POEMS syndrome

Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a multisystem disorder associated with plasma cell dyscrasia. Elevated serum levels of vascular endothelial growth factor (VEGF), which strongly promotes neovascularization and vasopermeability, are considered to be responsible for the characteristic symptoms such as angiomata, pleural effusion/ascites, edema, and organomegaly in the disorder. To study whether other angiogenetic factors are upregulated in POEMS syndrome, we measured serum levels of basic fibroblast growth factor and hepatocyte growth factor (HGF), as well as VEGF, in 17 patients with POEMS syndrome. All these factors were significantly upregulated in the POEMS syndrome patients. After the treatment with anti-VEGF antibody, the levels of HGF did not change, suggesting that elevation of HGF levels is not secondary to VEGF overproduction. These results suggest that different angiogenetic factors might contribute to the pathogenesis of POEMS syndrome, and this fact might contribute to the insufficient clinical effects obtained by suppression of VEGF alone.

A single blind randomized controlled clinical trial of mexiletine in amyotrophic lateral sclerosis: Efficacy and safety of sodium channel blocker phase II trial

Fasciculations are characteristic features of amyotrophic lateral sclerosis (ALS), and suggest motor nerve hyperexcitability. Recent reports have shown that an increase in persistent nodal sodium current is associated with shorter survival in ALS patients. This objective of this trial is to study the efficacy and safety of mexiletine, a sodium channel blocker, for ALS. Sixty eligible participants were randomly allocated (1:1) to riluzole 100 mg or riluzole plus mexiletine 300 mg. The primary endpoint was change in the revised ALS functional rating scale (ALSFRS-R) scores during six months. We also monitored strength-duration time constant (SDTC, a measure of persistent sodium current) in median motor axons. Results showed that during six months of treatment, changes in the ALSFRS-R score and SDTC were –7.0 ± 7.1 and –0.04 ± 0.1, respectively, in the riluzole group and –6.9 ± 6.4 and 0.04 ± 0.1, respectively, in the mexiletine group (p = 0.96 and 0.049). Adverse events amounted 20% in the riluzole and 33% in the mexiletine groups. In conclusion, the results suggest that daily 300 mg mexiletine has no effects on axonal sodium current and ALSFRS-R deterioration in ALS. We have to attempt another trial using a higher dose of mexiletine or other agents to suppress sodium currents and ALS progression in the future.

How often and when Fisher syndrome is overlapped by Guillain-Barré syndrome or Bickerstaff brainstem encephalitis?

Fisher syndrome (FS) may overlap with Guillain–Barré syndrome (GBS), in particular the pharyngeal–cervical–brachial variant form (PCB‐GBS), or Bickerstaff brainstem encephalitis (BBE). Our aim was to elucidate the frequency of this overlap and the patterns of clinical progression in patients with FS.

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.

Vascular endothelial growth factor as a predictive marker for POEMS syndrome treatment response: retrospective cohort study

Objective POEMS (polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes) syndrome is a rare multisystem disease characterised by plasma cell dyscrasia and overproduction of vascular endothelial growth factor (VEGF). VEGF is assumed to be useful in monitoring disease activity, because VEGF levels usually decrease after treatment. However, there is no study to investigate whether the extent of decrease in VEGF correlates with clinical outcome. We tested the predictive efficacy of serum VEGF levels in POEMS syndrome. Method This was an institutional review board approved retrospective observational cohort study of 20 patients with POEMS monitored regularly for more than 12 months (median follow-up, 87 months) after treatment onset using our prospectively accumulated database of POEMS from 1999 to 2015. Patients were treated by autologous peripheral blood stem cell transplantation or thalidomide administration. Serum VEGF was measured by ELISA. Outcome measures included clinical and laboratory findings and relapse-free survival. Results Serum VEGF levels decreased rapidly after treatment, and stabilised by 6 months post treatment. Patients with normalised serum VEGF levels (<1040 pg/mL) at 6 months showed prolonged relapse-free survival (HR=12.81, 95% CI 2.691 to 90.96; p=0.0001) and greater later clinical improvement. The rate of serum VEGF reduction over the first 6 months post treatment correlated with increased grip strength, serum albumin levels, and compound muscle action potential amplitudes at 12 months. Conclusions Serum VEGF level at 6 months post treatment is a predicative biomarker for disease activity and prognosis in POEMS syndrome. Serum VEGF could be used as a surrogate endpoint for relapse-free survival or clinical or laboratory improvement of POEMS syndrome for clinical trials.