Mikito Shimizu

Herpes zoster laryngitis in a patient treated with fingolimod

Development of treatment with immunomodulatory agents has improved prognosis of various autoimmune-related diseases. A sphingosin-1-phosphate receptor modulator, or fingolimod, is the first licensed oral drug for relapsing-remitting multiple sclerosis. The agent reduces circulating lymphocytes by trapping T cells in lymph nodes, possibly leading to reactivation of latent viruses. A 41-year-old Japanese woman who had been treated with fingolimod for 2 years presented with unilateral sore throat. Laryngoscopy revealed exudates unilaterally emerging on the left side of her supraglottic region. Serum level of the varicella zoster virus (VZV)-specific IgG was markedly elevated, and a result of genome sequence using the exudates demonstrated VZV as a possible causative pathogen. Fingolimod therapy was discontinued and the patient was successfully treated with intravenous acyclovir. This is the first reported case of fingolimod-associated herpes zoster laryngitis, in which the local VZV reactivation was demonstrated by next-generation sequencing technology. The present case highlights that the occurrence of VZV reactivation should be recalled in any patients undergoing fingolimod therapy.

The Motor Unit Number Index of Subclinical Abnormality in Amyotrophic Lateral Sclerosis

Purpose: Diagnosis of amyotrophic lateral sclerosis (ALS) at an early stage is challenging, thus making the enrollment of these patients in clinical trials infeasible. In this study, we investigated the potential usability of motor unit number index (MUNIX) to detect denervation of clinically intact muscles of ALS patients. Methods: Thirty-two first dorsal interosseous muscles of 26 ALS patients were evaluated with both MUNIX and needle electromyography. Results: The mean MUNIX value of first dorsal interosseous muscles was 131 in the control group, whereas it was 48, 34, 15, and 8 for Medical Research Council scales of 5, 4, 3, and 2, respectively, in the ALS patients. The optimal cutoff point gave a sensitivity of 0.89 and a specificity of 1.0. Among 9 intact first dorsal interosseous muscles of the ALS patients, 8 showed MUNIX values below the cutoff point, whereas only 2 first dorsal interosseous muscles showed denervation on needle electromyography. Conclusions: MUNIX could serve as a sensitive technique to detect denervation of clinically intact muscles of ALS patients.

A case of anti-neurofascin 155 antibody-positive combined central and peripheral demyelination successfully treated with plasma exchange

A 21-year-old man was admitted to our hospital in June 2015. He felt paresthesia of toes in April 2015, which had been spreading upward, and he became difficult to walk in June. Nerve conduction study showed peripheral demyelinating neuropathy that met the diagnostic criteria for chronic inflammatory demyelinating polyneuropathy (CIDP), and the cerebrospinal fluid (CSF) examination revealed the remarkably increased protein level. In addition, magnetic resonance imaging of his brain showed a few plaques in white matter, so he was finally diagnosed with combined central and peripheral demyelination (CCPD). Moreover, anti-neurofascin155 (NF155) antibodies assayed in his serum and CSF turned out to be positive. Although he was treated with intravenous immunoglobulin and intravenous methylprednisolone, his symptoms were not ameliorated. However, plasma exchange therapy was apparently effective, and the titer of anti-NF155 antibody was reduced. Recently, the number of case reports of CIDP with CNS lesions has gradually been increasing, while the information about the diagnosis and the treatment responses are not enough. Thus, we reported our case with CCPD who was successfully treated with plasma exchange.

Risk of stroke early after implantation of a left ventricular assist device

Objective: Stroke is one of the major adverse events after left ventricular assist device implantation. Risk of stroke is the highest immediately after left ventricular assist device implantation and then increases again in chronic periods. There is no study that has analyzed risk factors for stroke in acute phase. We investigated the risk factors for stroke in the acute phase after left ventricular assist device implantation in the present study. Methods: Between October 2005 and December 2016, 158 consecutive patients (mean age, 43 ± 14 years; 34% were women) underwent continuous‐flow left ventricular assist device (50 HeartMate II [Abbott Medical, Abbott Park, Ill], 38 DuraHeart [Terumo Heart, Ann Arbor, Mich], 33 Jarvik2000 [Jarvik Heart, New York, NY], 23 EVAHEART [Sun Medical, Moriyama City, Japan], 14 HeartWare [Framingham, Mass]) implantation in our institution. We analyzed the risk factors for a symptomatic stroke within 90 days after left ventricular assist device implantation. Results: Stroke occurred in 28 patients in the acute phase after left ventricular assist device implantation. Multivariate analysis revealed that low cardiac output (odds ratio, 0.25; 0.07‐0.92; P = .024) during postoperative 12 to 24 hours was the only independent risk factor for stroke in the acute phase. Patients with stroke in the acute phase had higher serum lactate dehydrogenase levels at any point until postoperative 14 days. Patients with the HeartMate II device particularly showed a statistically significant negative relationship between cardiac output during postoperative 12 to 24 hours and serum lactate dehydrogenase levels at postoperative 14 days (r = −0.313, P = .03). Conclusions: Our study demonstrated that patients with perioperative lower cardiac output and higher lactate dehydrogenase level developed stroke in the acute phase after left ventricular assist device implantation. These results suggested that maintenance of sufficient left ventricular assist device flow is important in prevention of stroke, which may be related to subclinical pump thrombosis.

Beneficial effects of fingolimod in MS patients with high serum Sema4A levels

We previously demonstrated that patients with multiple sclerosis (MS) of high serum Sema4A levels are resistant to IFN-β therapy. To further elucidate the role of serum Sema4A as a biomarker for therapeutic stratification in MS patients, it is important to clarify the efficacy of other disease-modifying drugs (DMD) in those with high serum Sema4A levels. Thus, in this study we investigated whether fingolimod has beneficial effects on MS patients with high Sema4A levels. We retrospectively analyzed annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) change in 56 relapsing—remitting multiple sclerosis (RRMS) patients who had been treated with fingolimod, including those who switched from IFN-β therapy. The levels of Sema4A in the sera were measured by sandwich ELISA. The implications of Sema4A on the efficacy of fingolimod were investigated by administering recombinant Sema4A-Fc and fingolimod to mice with experimental autoimmune encephalomyelitis (EAE). Retrospective analysis of MS cohort (17 high Sema4A and 39 low Sema4A) demonstrated the effectiveness of fingolimod in those with high serum Sema4A levels, showing reduction of ARR (from 1.21 to 0.12) and EDSS progression (from 0.50 to 0.04). Consistent with this observation, improvement in the disease severity of EAE mice receiving recombinant Sema4A-Fc was also observed after fingolimod treatment. These data suggest that fingolimod could serve as a candidate DMD for managing the disease activity of MS patients with high Sema4A levels.

Febuxostat ameliorates secondary progressive experimental autoimmune encephalomyelitis by restoring mitochondrial energy production in a GOT2-dependent manner

Oxidative stress and mitochondrial dysfunction are important determinants of neurodegeneration in secondary progressive multiple sclerosis (SPMS). We previously showed that febuxostat, a xanthine oxidase inhibitor, ameliorated both relapsing-remitting and secondary progressive experimental autoimmune encephalomyelitis (EAE) by preventing neurodegeneration in mice. In this study, we investigated how febuxostat protects neuron in secondary progressive EAE. A DNA microarray analysis revealed that febuxostat treatment increased the CNS expression of several mitochondria-related genes in EAE mice, most notably including GOT2, which encodes glutamate oxaloacetate transaminase 2 (GOT2). GOT2 is a mitochondrial enzyme that oxidizes glutamate to produce α-ketoglutarate for the Krebs cycle, eventually leading to the production of adenosine triphosphate (ATP). Whereas GOT2 expression was decreased in the spinal cord during the chronic progressive phase of EAE, febuxostat-treated EAE mice showed increased GOT2 expression. Moreover, febuxostat treatment of Neuro2a cells in vitro ameliorated ATP exhaustion induced by rotenone application. The ability of febuxostat to preserve ATP production in the presence of rotenone was significantly reduced by GOT2 siRNA. GOT2-mediated ATP synthesis may be a pivotal mechanism underlying the protective effect of febuxostat against neurodegeneration in EAE. Accordingly, febuxostat may also have clinical utility as a disease-modifying drug in SPMS.

A case of chronic inflammatory demyelinating polyradiculoneuropathy presenting recurrent attacks associated with pregnancies

At 37 years of age, the patient initially presented with symptoms of chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) during her 1st pregnancy. She was treated with intravenous immunoglobulin (IVIg), and showed favorable recovery, becoming almost asymptomatic by the age of 38. At 39 years of age, during her puerperal period of her second pregnancy, she developed symmetrical muscle weakness and sensory disturbance of the upper and lower limbs. Nerve conduction studies revealed diffuse demyelination of peripheral nerves, and she was diagnosed with recurrence of CIDP. Once again, she showed remarkable improvement after IVIg therapy, and she has remained asymptomatic without the induction of preventative therapies. Recurrence of CIDP triggered in accordance with multiple pregnancies is extremely rare, and its clinical and electrophysiological features are presented in this report.

Cerebrospinal fluid mitochondrial DNA in neuromyelitis optica spectrum disorder

BackgroundNeuromyelitis optica spectrum disorder (NMOSD) is an inflammatory disease of the central nervous system. Although complement-dependent astrocyte damage mediated by anti-aquaporin 4 autoantibody (AQP4-Ab) is well acknowledged to be the core of NMOSD pathogenesis, additional inflammatory cascades may contribute to the establishment of lesion formation. Thus, in this study, we investigated the possible pathogenic role of immune-reactive mitochondrial DNA (mtDNA) in cerebrospinal fluid (CSF) of NMOSD patients.MethodsUsing quantitative polymerase chain reaction, we measured extracellular mtDNA levels in CSF of NMOSD patients positive for AQP4-Ab. Patients with multiple sclerosis or other neurological diseases were examined as controls. Pre- and post-treatment extracellular mtDNA levels were also compared in the NMOSD group. Extracellular mtDNA release from human astrocytes was analyzed in vitro utilizing NMOSD sera, and interleukin (IL)-1β production was measured in supernatants of mixed glial cells stimulated with DNA fraction of CSF derived from NMOSD patients. Furthermore, specific innate immune pathways mediating the IL-1β production by mtDNA were investigated in peripheral blood mononuclear cells with selective inhibitors of Toll-like receptor 9 (TLR9) and NOD-like receptor protein 3 (NLRP3) inflammasomes.ResultsExtracellular mtDNA level was specifically elevated in acute phase of NMOSD CSF. In vitro studies provided the evidence that mtDNA is released from human astrocytes by NMOSD sera. In addition, DNA fraction isolated from NMOSD CSF promoted secretion of IL-1β from mixed glial cells. Selective inhibition of TLR9 and NLRP3 inflammasomes revealed that mtDNA-mediated IL-1β production depends on specific innate immune pathways.ConclusionExtracellular mtDNA is specifically elevated in the CSF of patients with acute phase NMOSD, and mtDNA released by AQP4-Ab-mediated cellular damage elicits the innate immune cascades via TLR9 and NLRP3 inflammasomes pathways. Our study highlights mtDNA-mediated innate immune pathways as a novel therapeutic target for future treatment of NMOSD patients.