Setsu Sawai

Thalidomide reduces serum VEGF levels and improves peripheral neuropathy in POEMS syndrome

Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein and skin changes (POEMS) syndrome is a rare multi-system disorder associated with plasma-cell dyscrasia. Several case series and reports have suggested that high-dose chemotherapy with autologous peripheral blood stem-cell transplantation is efficacious treatment, but this transplantation is not indicated for elderly patients and patients with renal failure. Objective: To investigate the effects of thalidomide treatment for POEMS syndrome. Methods: Nine patients, who were not indicated for high-dose chemotherapy, were treated with thalidomide. Neurological disability scores, nerve conduction studies and serum levels of vascular endothelial growth factor (VEGF) were prospectively examined. VEGF levels were measured by an enzyme-linked immunosorbent assay. Results: During follow-up periods of 8–23 months (mean, 15 months), all patients showed substantial clinical improvement (n = 6) or stabilisation of symptoms (n = 3). Serum VEGF levels decreased in all patients and were normalised in five patients. Nerve conduction velocities in the median nerve increased in seven patients. There were no serious adverse effects, including thalidomide neuropathy. Conclusion: Thalidomide treatment should be further studied as a treatment for POEMS syndrome, particularly for patients who are not indicated for transplantation therapy.

Neurologic improvement after peripheral blood stem cell transplantation in POEMS syndrome

Background: Polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome is a rare multisystem disorder associated with plasma cell dyscrasia. There is increasing evidence that high-dose chemotherapy with autologous peripheral blood stem cell transplantation (Auto-PBSCT) is an efficacious treatment. Objective: To elucidate the extent and time course of neurologic improvement after Auto-PBSCT in patients with POEMS syndrome. Methods: Clinical and electrophysiologic findings in nine patients were reviewed. The median follow-up period was 20 months (range, 8 to 49 months). Serum levels of vascular endothelial growth factor (VEGF) were measured by ELISA. Results: Serum VEGF levels rapidly decreased a month after Auto-PBSCT. Within 3 months, neurologic improvement began, and all the patients showed substantial neurologic recovery during the next 3 months. Particularly, three initially chairbound patients regained ability to walk at 6 months. Nerve conduction studies showed significant increases in conduction velocities and amplitudes within 6 months of treatment. At the end of follow-up periods, neuropathy was still improving, and no patients had recurrence of symptoms. Conclusion: Autologous peripheral blood stem cell transplantation results in obvious neurologic improvement within 6 months, presumably by extensive axonal regeneration and remyelination. This therapy could be considered as a first line treatment for patients with polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes syndrome with younger onset even if they are tetraplegic.

Markedly upregulated serum interleukin-12 as a novel biomarker in POEMS syndrome.

Objective: To systematically study abnormalities in cytokine profiles in polyneuropathy, organomegaly, endocrinopathy, M-protein, and skin changes (POEMS) syndrome, which has been increasingly recognized as a cause of demyelinating neuropathy associated with plasma cell dyscrasia and elevated serum level of vascular endothelial growth factor (VEGF). Methods: In this case-control study, we measured serum levels of 27 cytokines in patients with POEMS syndrome using a multiplex suspension array system, and compared them with those of controls. In 10 patients, serial changes after treatment were analyzed. Results: Interleukin (IL)–12 as well as VEGF levels were markedly increased (p < 0.0001) in all the patients (n = 23). Ten kinds of other proinflammatory cytokines such as IL-6 and tumor necrosis factor–α were also significantly increased in the POEMS syndrome group, but in some patients the serum levels of such cytokines remained within the normal ranges. After treatments, the IL-12 as well as VEGF levels significantly decreased with clinical improvements (p > 0.01 and p > 0.05, respectively). Conclusions: Our findings suggest that serum IL-12 is a biomarker of the disease activity in POEMS syndrome. The overproduction of IL-12, as well as VEGF, is likely to play an important role in the pathogenesis of the disorder, and could contribute to the peripheral nerve demyelination in POEMS syndrome.

Distal excitability changes in motor axons in amyotrophic lateral sclerosis

OBJECTIVE Previous axonal excitability studies in amyotrophic lateral sclerosis (ALS) have suggested that impaired potassium channel function could be responsible for the generation of fasciculations, but the ectopic activity arises predominantly from the motor nerve terminals. This study tested the hypothesis that dysfunction of potassium channels is more pronounced in the more distal parts of axons. METHODS Threshold electrotonus was used to compare accommodation at the motor point of abductor pollicis brevis, and at the wrist portion of the median nerve, between 22 patients with ALS and 19 normal subjects. As target responses for motor point stimulation, movement-related potentials were recorded using an accelerometer. RESULTS Compared to normal subjects, ALS patients showed greater threshold changes to depolarizing conditioning currents at both the motor point and wrist, suggesting less accommodation by potassium currents. Differences in the threshold electrotonus curves between the normal and ALS groups were much more prominent at the motor point than at the wrist. CONCLUSIONS In ALS, axonal potassium channels are impaired more prominently in distal portions of axons than at the nerve trunk, and this is consistent with evidence that fasciculations mostly arise from the nerve terminals. SIGNIFICANCE Excitability testing at the motor point provides additional information about the pathophysiology of ALS.

Cerebrospinal fluid interleukin-6 and glial fibrillary acidic protein levels are increased during initial neuromyelitis optica attacks.

BACKGROUND The current 2006 neuromyelitis optica (NMO) criteria is useful for diagnosing NMO, however this criteria seemed to be insufficient at early stage of NMO. Hence, the development of diagnostic marker besides anti-aquaporin 4 antibody at early stage of NMO may be required. Our main aim of this study is to test the usefulness of measuring cerebrospinal fluid (CSF) interleukin (IL)-6 and glial fibrillary acidic protein (GFAP) concentrations as early diagnostic markers during initial NMO attacks. METHODS We investigated CSF IL-6 and GFAP concentrations in 13 NMO spectrum disorder (NMOSD) patients at initial attacks, 24 idiopathic central nervous system inflammatory disease patients (9 optic neuritis, 9 myelitis and 6 encephalitis) and 20 other non-inflammatory neurological disorders (ONNDs) patients, retrospectively. RESULTS The mean CSF IL-6 and GFAP concentrations during the initial NMOSD attack were 91.4 pg/ml and 369.3 ng/ml, respectively, and were significantly higher than in ONNDs, idiopathic optic neuritis and myelitis patients (P<0.01). The sensitivity of high CSF IL-6 during initial NMO attack was 76.9% and that of high CSF GFAP was 84.6%, respectively. CONCLUSION Our data suggests that CSF IL-6 and GFAP may be useful early diagnostic markers of NMOSD.

Proteomic analysis of gingival crevicular fluid for discovery of novel periodontal disease markers.

The protein composition of gingival crevicular fluid (GCF) may reflect the pathophysiology of periodontal diseases. A standard GCF proteomic pattern of healthy individuals would serve as a reference to identify biomarkers of periodontal diseases by proteome analyses. However, protein profiles of GCF obtained from apparently healthy individuals have not been well explored. As a step toward detection of proteomic biomarkers for periodontal diseases, we applied both gel‐based and gel‐free methods to analyze GCF obtained from healthy subjects as compared with supragingival saliva. To ensure optimized protein extraction from GCF, a novel protocol was developed. The proteins in GCF were extracted with high yield by urea buffer combined with ultrafiltration and the intensity of spots with supragingival saliva and GCF was compared using agarose two‐dimensional electrophoresis. Eight protein spots were found to be significantly more intense in GCF. They included superoxide dismutase 1 (SOD1), apolipoprotein A‐I (ApoA‐I), and dermcidin (DCD). Moreover, GCF proteins from healthy subjects were broken down into small peptide fragments and then analyzed directly by LC‐MS/MS analysis. A total of 327 proteins including ApoA‐I, SOD1, and DCD were identified in GCF. These results may serve as reference for future proteomic studies searching for GCF biomarkers of periodontal diseases.

Differences in excitability properties of FDI and ADM motor axons.

The first dorsal interosseous (FDI) and abductor digiti minimi (ADM) muscles are innervated by the same ulnar nerve, but studies have shown that the former is much more severely affected in amyotrophic lateral sclerosis. In this study, threshold tracking was used to investigate whether membrane properties differ between FDI and ADM motor axons. In 12 normal subjects, compound muscle action potentials were recorded from FDI and ADM after ulnar nerve stimulation at the wrist. The strength–duration time constant was significantly longer in the FDI axons than in the ADM axons, and latent addition studies showed greater threshold changes at the conditioning–test stimulus of 0.2 ms in FDI than in ADM axons. These findings suggest that nodal persistent sodium conductances are more prominent in FDI axons than in ADM axons, and therefore excitability is physiologically higher in FDI axons. Even in the same nerve at the same sites, membrane properties of FDI and ADM motor axons differ significantly, and thus their axonal/neuronal responses to disease may also differ. Muscle Nerve 39: 350–354, 2009

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%).