Masaru Yanagihashi

Wegener Granulomatosis-associated Optic Perineuritis

Abstract Introdunction: We report two patients with optic perineuritis (OPN) and hypertrophic pachymeningitis in Wegener granulomatosis (WG). Case report: Patient 1: a 74-year-old man developed blurred vision in each eye, sequentially, over a year. In the first episode, visual acuity in the right eye was reduced to no light perception, and in the second episode, the vision in the left eye fell to 20/100. Brain and orbital magnetic resonance imaging (MRI) revealed abnormal enhancement in the meninges and the ipsilateral optic nerve sheath. T2-hyperintense lesions were found along the outer rim of the ipsilateral optic nerve. Seropositive proteinase-3-antineutrophil cytoplasmic antibody (PR3-ANCA), microhematuria and multiple pulmonary nodules suggested the diagnosis of WG. Steroid therapy was initiated 3 months after the first onset, but with no clinical response. At the 2nd episode, rapid administration of steroid ameliorated visual disturbance and MRI lesions markedly. Patient 2: a 72-year-old man developed blurred vision in each eye. Visual acuity measured no light perception in OD and 6/12 in OS. Gadolinium-enhanced MRI disclosed enhancement in the meninges and both optic nerve sheaths. T2-weighted imaging displayed hyperintense lesions along the outer rims of optic nerves. Otolaryngologic examination, seropositive PR3-ANCA and pulmonary nodules supported the diagnosis of WG. Steroid and cyclophosphamide treatment improved visual dysfunction and MRI lesions in the meninges and the optic nerve sheaths. Comment: The morphological similarity and the anatomical continuity between the meningeal and the perioptic tissues suggest that extension of granulomatous inflammation along such tissue planes accounted for visual loss in these two patients with WG.

Combined Treatment of Methylprednisolone Pulse and Memantine Hydrochloride Prompts Recovery from Neurological Dysfunction and Cerebral Hypoperfusion in Carbon Monoxide Poisoning: A Case Report

A 49-year-old healthy man developed sudden unconsciousness under inadequate ventilation. Blood gas analysis showed carboxyhemoglobin of 7.3%. After normobaric oxygen therapy, he recovered completely 7 days later. At 3 weeks after carbon monoxide (CO) exposures, memory and gait disturbances appeared. Neurological examination revealed Mini-Mental State Examination (MMSE) score of 5 of 30 points, leg hyper-reflexia with Babinski signs, and Parkinsonism. Brain fluid-attenuated inversion recovery imaging disclosed symmetric hypointense lesions in the thalamus and the globus pallidus, and hyperintense lesions in the cerebral white matter. Brain single-photon emission tomography (SPECT) scanning with (99m)Technesium-ethyl cysteinate dimer displayed marked hypoperfusion in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. He was diagnosed as CO poisoning and treated with hyperbaric oxygen therapy. The neurological deficits were not ameliorated. At 9 weeks after neurological onset, methylprednisolone (1000 mg/day, intravenous, 3 days) and memantine hydrochloride (20 mg/day, per os) were administered. Three days later, MMSE score was increased from 3 to 20 points. Neurological examination was normal 3 weeks later. Brain SPECT exhibited 20% increase of regional cerebral blood flows in the cerebellum, the thalamus, the basal ganglia, and the entire cerebral cortex. These clinicoradiological changes supported that the treatment with steroid pulse and memantine hydrochloride could prompt recovery from neurological dysfunction and cerebral hypoperfusion. Further clinical trials are warranted whether such combined therapy can attenuate neurological deficits and cerebral hypoperfusion in patients with CO poisoning.

Late-onset spinal form xanthomatosis without brain lesion: a case report

BackgroundCerebrotendinous xanthomatosis (CTX) is a rare autosomal recessive sterol storage disease caused by a mutated sterol 27-hydroxylase (CYP27A1) gene. Patients with typical CTX show neurological dysfunction including bilateral cataracts, paresis, cerebral ataxia, dementia, and psychiatric disorders, and magnetic resonance imaging (MRI) has revealed symmetrical lesions in the cerebellar white matter.Case presentationWe report the case of a patient with late-onset spinal form CTX without brain lesion. He showed pyramidal tract signs, and impaired joint position and vibration sensation in the lower limbs. Cervical sagittal MRI demonstrated a longitudinally extensive white matter abnormality in the dorsal column of the C2-C7 spinal cord; however, a brain MRI revealed an absence of lesions, including in the cerebellar white matter. Genetic analysis of CYP27A1 revealed that the patient was compound heterozygous for p.Gln85Arg in exon 1, a novel mutation, and p.Arg405Gln in exon 7, a previously reported mutation.ConclusionThis is the first report of late-onset spinal form CTX without typical neurological symptoms, and the first report of p.Gln85Arg in CYP27A1. We speculate that spinal form CTX without brain lesion is a clinically and radiologically rare variation of CTX. Therefore, spinal xanthomatosis should be included in the differential diagnosis of chronic myelopathy even with late-onset and/or no other typical neurological findings.

Clinical Profile and Changes of Serum Lipid Levels in Epileptic Patients after Cerebral Infarction

BACKGROUND Antiepileptic drugs (AEDs) may increase development of dyslipidemia and cerebrovascular disease (CVD). We examined the clinical profile and changes of serum lipid levels after AED monotherapy in patients with poststroke epilepsy (PSE) after cerebral infarction (CI). SUBJECTS AND METHODS Medical records were reviewed in consecutive 2144 CI patients. Monotherapy of valproate, carbamazepine (CBZ), phenytoin (PHT), zonisamide, levetiracetam, or lamotrigine was performed in PSE patients. Serum lipid levels were measured before and at 3 months after AED treatment. RESULTS The prevalence of PSE was 7.0% in CI patients. The TOAST etiology disclosed large-artery atherosclerosis in 68 patients (45%), cardioembolism in 63 patients (42%), and undetermined cause in 19 patients (13%). CVD risk profile showed obesity of 18 patients (12%), current smoker of 30 patients (20%), hypertension of 75 patients (50%), diabetes mellitus of 32 patients (21%), dyslipidemia of 15 patients (10%), and atrial fibrillation of 63 patients (42%). CBZ or PHT administration increased serum total cholesterol (TC) and low-density lipoprotein-cholesterol (LDL-C) levels significantly compared to baseline and AED-untreated controls. Those levels were not increased significantly in other AED and control groups. Serum high-density lipoprotein-cholesterol and triglyceride levels did not differ statistically in all groups. CONCLUSIONS The prevalence of post-CI epilepsy was 7.0%. The pathogenesis contributed to atherothrombosis and cardioembolism. CBZ or PHT administration increased serum TC and LDL-C significantly. Thus, we should pay more attention to serum lipid levels in patients receiving cytochrome P450 (CYP)-induced AEDs, and might considerer switching to non-CYP-induced AEDs in patients with unfavorable serum lipid changes.

Zonisamide cotreatment delays striatal dopamine transporter reduction in Parkinson disease: A retrospective, observational cohort study

This study examined whether zonisamide (ZNS) cotreatment delays dopamine transporter (DAT) reduction on SPECT in Parkinson disease (PD) patients. The study participants met the following criteria: (i) age ≥ 40 years; (ii) HY stage = 2 or 3; (iii) average specific binding ratio (SBR) ≥2.00; (iv) levodopa administration without a prior history of ZNS use before the first DAT-SPECT (baseline). Attending physicians initially determined whether ZNS (25 mg/day) should be used or not. Levodopa and other anti-PD medications were not restricted. The second DAT-SPECT (endpoint) was conducted 1.2 ± 0.2 years after the first DAT-SPECT. Clinicoradiological changes of HY stage, UPDRS parts II to IV, dyskinesia subscore, and SBR were calculated. Statistical differences were analyzed by Students t-test, ANOVA, or multilogistic analysis. ZNS cotreatment improved wearing off and prevented the development of dyskinesia without additional administration of selegiline, entacapone, and dopamine receptor agonists. The endpoint SBR reduced significantly in the non-ZNS group compared to the baseline (P < .01). The SBR decline rate reduced significantly in the ZNS group (P < .01). ZNS was an independent preventive factor for SBR reduction. These results suggested a beneficial potential that ZNS preserves striatal presynaptic DAT expression and slows disease progression in early-stage PD.

Preventive Treatment with Lomerizine Increases Cerebral Blood Flows during the Interictal Phase of Migraine

BACKGROUND Changes in regional cerebral blood flow (rCBF) were reported in migraineurs. However, little is known how preventive medications of migraine can influence rCBF. Lomerizine, a calcium channel blocker, has been used for migraine prophylaxis in Japan. We examined rCBF after lomerizine treatment. SUBJECTS AND METHODS Migraine was diagnosed according to the criteria of the International Classification of Headache Disorders, Third Edition beta. Migraine subtype was classified into migraine with aura (MA) and migraine without aura (MO). Lomerizine (10 mg/day, per oral) was administered for 3 months. Headache Impact Test-6 (HIT-6) and blood pressure (BP) were compared at baseline and end point. Brain single photon emission computed tomography using 99mTc-ethyl cysteinate dimer was performed at the interictal period. Brain SPECT data were analyzed according to revised version of 3-dimensional stereotaxic region of interest template. Clinic-radiological variables were analyzed by paired Students t test. RESULTS Ten migraineurs (4 men and 6 women) participated in the present study. Mean age was 54.1 (standard deviation [SD] 10.1) years. Mean duration of migraine was 25.3 (SD 9.8) years. Migraine subtype showed 4 MA and 6 MO patients. Mean score of HIT-6 was 66.3 (SD 11.7). Lomerizine treatment decreased HIT-6 scores significantly (P < .01). BP did not differ significantly after lomerizine treatment. Lomerizine treatment increased rCBF 20% approximately in the frontal, the parietal, the temporal, and the occipital region. CONCLUSIONS The present study indicated a significant increase in interictal rCBF after lomerizine treatment in migraineurs. The upregulation of rCBF could contribute to the antimigraine mechanism of lomerizine.

Ibudilast inhibits IL-17

of Tg mice already at 9 months of age, whereas we observed baseline levels of IL-1b mRNA. Flow cytometry results showed a significant increase in the number of microglia and, specifically TNFand IL-1bproducing microglia, in Tg compared to Wt mice at 12 months. This was consistent with stainings showing an ageand amyloid-plaqueassociated activation of microglia. Following treatment with endotoxin, protein levels of both oligomeric and fibrillar Ab in the neocortex fell significantly, compared to vehicle-treatedmice, while the expression of both TNF and IL-1b increased. In conclusion, the results suggest that Ab deposition induces a microglial-driven inflammatory reaction in APP695/PS1dE9 Tg mice, reminiscent to the microglial reaction observed in MCI. Interestingly, Ab levels fell after repeated injections of endotoxin. We speculate that this is mediated by supranormally activated, microglial cells, which have a known capacity to phagocytose Ab. This is part of our ongoing investigations.

Angiotensin-(1-7) inhibits NF-kappa B in glia cells of ALS model mice

infection can trigger CNS demyelination consistent with the outsidein and inside-out hypotheses of CNS demyelination. Background: The nature of the initial trigger in multiple sclerosis (MS) — primary autoimmune attack (outside-in) hypothesis or cytodegeneration (inside-out) hypothesis remains controversial. Recently, Stys and colleagues (2012) argued in favour of the cytodegenerative mechanism as the initiating event with a convolution between progressive cytodegeneration and a variably primed immune system explaining the differences in clinical presentation. Using a mouse model of Herpes simplex virus type 1 (HSV-1) induced CNS demyelination, we investigated the possibility that ‘spontaneous molecular reactivation’ of virus in the CNS can result in either a primary autoimmune attack or primary cytodegeneration depending on the mouse strain. Methods: To determine if latent HSV-1 nucleic acid (NA) is present in the brains of A/J & PL/J mice, strains developing recurrent CNS demyelination, and BALB/c mice, a strain not developing recurrent demyelination, solution phase PCR was performed during the intermediate (1–3 months PI) and late (N3 months PI) stages of infection. In-situ hybridization (ISH) was performed to identify latently infected CNS cells while immunohistochemistry (IHC) identified CNS cells expressing viral proteins. Results: Using solution phase PCR, HSV-1 NA was identified in the brains of A/J, PL/J, and BALB/c mice at week 10 and 25 PI. Individual latently infected CNS cells, identified by ISH, were associated with CNS demyelination in A/J & PL/J but not BALB/c mice. Similarly, cells stained with anti-HSV antibody, consistent with ‘spontaneous molecular reactivation’ were associated with CNS demyelination in A/J & PL/J but not BALB/c mice. Conclusions: This study provides support for ‘spontaneous molecular reactivation’ of latent HSV-1 in three strains of mice. Depending on the mouse strain, the results are consistent with the outside-in and inside-out hypotheses of CNS demyelination.

Presence of paraneoplastic antibodies in non-carcinomatous patients with neurological involvements of unknown cause

BACKGROUND Paraneoplastic antibodies (PAs) play a crucial role in the diagnostic approach of paraneoplastic neurological syndrome (PNS). We clarified the frequency and the clinical profile of PA-positive non-carcinomatous patients with neurological involvements of unknown cause. METHODS PAs were analyzed in sera of 222 consecutive non-carcinomatous patients (122 men and 100 women) defined as acute or subacute onset of unknown-causative symptoms involving the neuromuscular junction, the central and/or the peripheral nervous system between 2006 and 2009. PAs contained antineuronal nuclear autoantibody type 1, 2, 3, Purkinje cell cytoplasmic autoantibody type 1, 2, anti-Tr, amphiphysin, CRMP-5, P/Q-type, N-type voltage-gated calcium channels (VGCC), voltage-gated potassium channel complex (VGKCC) and neuronal acetylcholine receptor (nAChR) antibodies. PA-seropositive patients received detailed examination of carcinoma in the whole body for the following 2 years. RESULTS Nine patients were PA-positive. VGKCC antibodies were found in four patients, P/Q-type VGCC antibodies in two, N-type VGCC antibodies in two and nAChR antibodies in one. Neurological features revealed limbic encephalitis in four patients, sensorimotor neuropathy in three and Lambert-Eaton myasthenic syndrome in two. One year later, 2 patients developed myelodysplastic syndrome and lung adenocarcinoma (one patient each). CONCLUSION We conclude that PA-seropositive frequency is 4.1% in non-carcinomatous neurological patients at examination. VGKCC, P/Q-type and N-type VGCC, and nAChR antibodies have benefits for screening non-carcinomatous PNS patients with acute or subacute neurological deficits of unknown cause.