Hikaru Doi

Reappraisal of brain MRI features in patients with multiple sclerosis and neuromyelitis optica according to anti-aquaporin-4 antibody status

Brain lesions are not uncommon in neuromyelitis optica (NMO) patients with anti-aquaporin-4 (AQP4) antibody; however, the appearance of these lesions is said to be different from that of those in Western patients with multiple sclerosis (MS). To clarify the similarities and dissimilarities of brain lesions in anti-AQP4 antibody-positive and -negative MS and NMO patients, we examined the presence of anti-AQP4 antibody in the sera of 148 consecutive patients fulfilling Posers criteria for clinically definite MS, of whom 38 also met the revised NMO criteria, using an immunofluorescence method, and analyzed brain lesions by magnetic resonance imaging (MRI). Brain lesions fulfilling the Barkhof criteria were significantly more common in 121 patients without anti-AQP4 antibody than in 27 patients with anti-AQP4 antibody (57.0% vs. 33.3%, P=0.033), while the frequency of those that met the Paty criteria was not different between the two groups (74.4% vs. 73.5%). Ovoid lesions were detected more commonly in patients without anti-AQP4 antibody than in those with the antibody (72.3% vs. 48.2%, P=0.022). The anti-AQP4 antibody-positive patients had significantly more atypical brain lesions, such as extensive brain lesions, than the anti-AQP4 antibody-negative ones (18.5% vs. 1.7%, P=0.0023). Thus, although MS-like brain lesions are more common in anti-AQP4 antibody-negative patients than anti-AQP4 antibody-positive patients, approximately 30 to 50% of patients with anti-AQP4 antibody harbour brain MRI lesions indistinguishable from those present in typical MS patients, such as periventricular ovoid lesions, suggesting the existence of considerable overlap in brain MRI features between anti-AQP4 antibody-positive and -negative Asian patients. In the present study, NMO patients with brain lesions showed a significantly higher annualized relapse rate (P(corr)=0.017) and higher frequency of anti-AQP4 antibody (P(corr)<0.0001) than typical NMO patients without brain lesions, suggesting that development of brain lesions in NMO may reflect high disease activity and thus be a warning sign.

Hypercomplementemia at relapse in patients with anti-aquaporin-4 antibody

Objective Because Asian patients with opticospinal multiple sclerosis (OSMS) frequently have anti-aquaporin-4 (AQP4) antibody, complement-mediated disruption of astrocyte foot processes is proposed but not yet proven. We aimed to clarify whether complement consumption occurs at relapse in anti-AQP4 antibody-positive patients. Methods We analyzed serum CH50, C3, C4, and C-reactive protein (CRP) levels and their relation to clinical phases in 118 MS patients with or without anti-AQP4 antibody. Serum CH50 levels were higher in 24 patients with anti-AQP4 antibody than in 39 OSMS and 54 conventional form of MS (CMS) patients without anti-AQP4 antibody at relapse (Pcorr < 0.05) but not in remission. The frequency of hypercomplementemia at relapse was also higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative CMS patients (70.4% vs 29.0%, Pcorr < 0.05). C3 and C4 levels did not differ significantly among the three groups at relapse. In patients with anti-AQP4 antibody, the coexistence of hypercomplementemia and high CRP values was more common at relapse than in the remission phase (36.0% vs 10.5%, P < 0.05). In patients with extensive central nervous system lesions, hypercomplementemia was significantly more common in anti-AQP4 antibody-positive patients than anti-AQP4 antibody-negative ones (88.9% vs 16.7%, P < 0.01). We consider that hypercomplementemia in anti-AQP4 antibody-positive patients may reflect a systemic inflammatory reaction at relapse.

Motor neuron disorder simulating ALS induced by chronic inhalation of pyrethroid insecticides

Some agricultural chemicals are known to be neurotoxic. Pyrethroid insecticides are commonly used as they are highly toxic to a wide range of insects but have low toxicity to mammals. However, overexposure to pyrethroids can induce various neurotoxic symptoms such as numbness, seizure, tremor, and memory impairment.1 Such symptoms are usually transient, and there are no reports indicating that chronic intoxication from pyrethroid insecticides causes motor neuron damage, although a case of pathologically proven motor neuron death after acute massive ingestion of pesticides containing pyrethroids and organochlorine has been reported.2 Here, we report a case of slowly progressive motor neuron disease (MND) following chronic exposure to pyrethroids that was indistinguishable from ALS. A 44-year-old woman, a food shop proprietor, had been using cans of pyrethroid insecticides containing imiprothrin, phenotorin, d-T80-resmethrin, and d-T80-phthalthrin almost every day for 3 years in an unventilated room. Initially, she experienced tongue numbness, nausea, and rhinitis while using …

Interleukin-7 receptor alpha gene polymorphism influences multiple sclerosis risk in Asians

A recent genome-wide survey identified non–human leukocyte antigen ( HLA ) genes that are related to multiple sclerosis (MS). Among these, an association of a single nucleotide polymorphism (SNP), rs6897932, in the interleukin-7 receptor α gene ( IL-7RA ) with MS susceptibility has been widely replicated in Caucasians.1,–,3 The SNP located in the transmembrane domain of IL-7Rα is nonsynonymous and functional: the MS-susceptible CC allele increases levels of the soluble form of IL-7Rα via exon skipping, and decreases the expression of membrane-bound IL-7Rα, thereby causing decreased IL-7/IL-7R signaling.1,–,3 IL-7/IL-7R signaling induces thymic production of FOXP3+ regulatory T cells, which efficiently ameliorate experimental autoimmune encephalomyelitis,4 an animal model of MS. Thus, the rs6897932 polymorphism of the IL-7RA gene may confer MS susceptibility through decreased production of FOXP3+ regulatory T cells due to downregulated IL-7/IL-7R signaling. This polymorphism has never been reported in either MS or neuromyelitis optica (NMO) in Asians. Therefore, in the present cross-sectional study, we investigated the association of the IL-7RA SNP rs6897932 with non-NMO MS and NMO in the Japanese. ### Methods. All patients with NMO fulfilled the 2006 Wingerchuk5 criteria for NMO, while those with NMO spectrum disorders who did not completely meet the criteria were excluded. All non-NMO patients with MS satisfied …

Multimodality-evoked potential study of anti-aquaporin-4 antibody-positive and -negative multiple sclerosis patients.

Neuromyelitis optica (NMO) is claimed to be a distinct disease entity from multiple sclerosis (MS) because of its strong association with NMO-IgG/anti-AQP4 antibody; however, the in vivo role of the antibody remains unknown. Therefore, we aimed to clarify whether the presence of anti-AQP4 antibody is associated with any abnormalities in multimodality-evoked potentials in 111 patients with relapsing-remitting or relapsing-progressive MS, including the opticospinal form of MS, 18 of whom were seropositive for anti-AQP4 antibody. More patients with anti-AQP4 antibody showed a lack of the P100 component on visual-evoked potentials (VEPs) than those without the antibody (11/17, 64.7% vs. 20/84, 23.8%, p=0.003), whereas the frequency of delayed P100 latency was significantly higher in the latter group than in the former (1/17, 5.9% vs. 28/84, 33.3%, p=0.021). The frequencies of non-responses and delayed central sensory conduction times in median and posterior tibial nerve somatosensory-evoked potentials (SEPs) were not significantly different between anti-AQP4 antibody-positive and -negative patients. In terms of upper and lower limb motor-evoked potentials (MEPs), the frequencies of non-responses and delayed central motor conduction times did not differ significantly based on the presence or absence of anti-AQP4 antibody. The frequency of optic nerve lesions on MRI was significantly higher in anti-AQP4 antibody-positive patients than in anti-AQP4 antibody-negative patients (p=0.0137). Multiple logistic analyses revealed that anti-AQP4 antibody positivity (OR=8.406, p=0.02) and unevoked VEP responses (OR=35.432, p<0.001) were significantly related to development of severe visual impairment. Such an association of anti-AQP4 antibody with disability was not found for either severe motor or sensory impairment. These findings suggest a distinctive nature of optic nerve lesions between anti-AQP4 antibody-positive and -negative patients; lesions are supposed to be more necrotic in the former group and more demyelinating in the latter.

Frequency of chronic headaches in japanese patients with multiple sclerosis: With special reference to opticospinal and common forms of multiple sclerosis

Background.— Headache is common in Western patients with multiple sclerosis (MS), but its frequency has not been reported in Asian patients. In Asians, the opticospinal form of MS, showing similar characteristics to relapsing neuromyelitis optica in Westerners, is regarded as a different subtype from conventional MS.

Analysis of Cerebral Lobar Microbleeds and a Decreased Cerebral Blood Flow in a Memory Clinic Setting

OBJECTIVE Cerebral microbleeds (MBs) have been previously associated with cognitive dysfunction, including Alzheimers disease. In the present study, we aimed to clarify the relationship between cerebral lobar MBs and the regional cerebral blood flow (CBF). METHODS We investigated the data obtained from 122 patients in our memory clinic who were examined by both MRI and (99m)Tc-ethyl cysteinate dimer (ECD)-single photon emission computed tomography (SPECT). Patient brain scans were superimposed and brain regions containing both decreased CBF and MBs were visually identified. For each patient eight brain regions were evaluated, comprising the right and left frontal, temporal, parietal, and occipital lobes. RESULTS Cerebral MBs were detected in 36 of the 122 (29.5%) patients. Of these 36 patients, 23 had detectable lobar MBs, which were primarily distributed in the occipital lobe in 19 of the 46 (41.3%) regions with lobar MBs. The frequency of MBs accompanied by a decreased CBF in the parietal and occipital lobes was significantly higher than that observed in the frontal lobe (73.3% vs. 27.3%, p<0.05, and 73.7% vs. 27.3%, p<0.05, respectively). Additionally, a decreased CBF was observed significantly more frequently in the brain regions with 5 or more MBs compared to the regions with one microbleed (83.3 vs. 25.0%, p<0.0005). Among the 17 patients with observable MBs accompanied by a decreased CBF, none were initially diagnosed with either subjective complaints or mild cognitive impairment. CONCLUSION We determined that the cerebral lobar MBs located in the parietal and occipital lobes, and the lobar regions with a large number of MBs, were significantly more likely to be accompanied by a decreased CBF.

Japanese guidelines for fingolimod in multiple sclerosis: Putting into practice

Fingolimod functions as a modulator of sphingosine‐1‐phosphate (S1P) receptors expressed on the surface of T and B lymphocytes, leading to their internalization. Loss of S1P receptors results in sequestration of central memory T cells enriched by Th17 cells in lymph nodes. After successful treatment of an animal model of multiple sclerosis (MS), clinical trials of oral fingolimod in patients with relapsing‐remitting MS showed a 60% reduction in the annualized rate of relapse. The United States Food and Drug Administration approved fingolimod as a first‐line drug for MS treatment in 2010, and data have been accumulated thereafter. However, MS experts recommend that the drug should remain as a second‐line option, because the long‐term risks for infection and malignancy have not been fully elucidated. Also, because of different genetic backgrounds, Asian MS patients might require special attention regarding other infectious agents and secondary cancer as compared with those reported in Caucasian patients. Furthermore, some Japanese patients who developed severe symptoms were later shown to be positive for the anti‐aquaporin‐4 antibody. In addition, reports of some Western MS patients have noted worsening after initiation, as well as discontinuation of fingolimod treatment. Finally, the optic spinal type of MS and neuromyelitis optica spectrum disorders are more prevalent in Asian than Western countries. Thus, establishment of criteria for determining which Asian MS patients would benefit from fingolimod treatment is mandatory.

Distinct cytokine and T helper cell profiles between patients with multiple sclerosis who had or had not received interferon-beta

Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system, and is generally considered to be mediated by T helper (Th) 1/Th17 cells. Interferon‐β (IFNβ) is widely used as a disease‐modifying MS drug, but its effects on Th17 cells are still disputed. Furthermore, the effects of IFNβ on Th9 cells have not been elucidated. The present study aimed to clarify the effects of IFNβ on cytokines/growth factors in cerebrospinal fluid (CSF) and cytokine‐producing Th cells in peripheral blood.

Transient burning pain in the ipsilateral orbit as an initial manifestation of dorsal pontine hemorrhage: case report.

A 45-year-old man with a past history of hypertension and hyperlipidemia presented with right dorsal pontine hemorrhage manifesting as transient burning pain in the right orbital region, followed by numbness and mild weakness of the left side of the body. Magnetic resonance imaging showed a hyperintense lesion in the right dorsal pons on T1-weighted and T2-weighted images, but no other abnormalities suggesting vascular lesions in the midbrain, medulla, cerebellum, or cerebrum. These findings were consistent with the subacute stage of small pontine hemorrhage. He was treated to decrease his blood pressure. The symptoms gradually improved and he has suffered neither recurrence of the orbital pain nor migraine for several months after the first episode of headache. The trigeminal nociceptive system in the dorsal lateral pons may be linked to this characteristic pain, as suggested by reports of secondary migraine caused by cavernous hemangioma and arteriovenous malformation, and activation of the dorsal lateral pons during migraine attacks on positron emission tomography.