Hiroaki Yokote

NKT Cell-Dependent Amelioration of a Mouse Model of Multiple Sclerosis by Altering Gut Flora

Improved hygiene has been suggested to influence certain autoimmune disorders, such as multiple sclerosis. In this study, we addressed whether altering the composition of gut flora may affect susceptibility to experimental autoimmune encephalomyelitis (EAE), an animal model of MS. We administered a mixture of non-absorbing antibiotics, kanamycin, colistin, and vancomycin (KCV), orally to mice induced to develop EAE. The antibiotic treatment, beginning 1 week prior to sensitization, altered the composition of gut flora and, intriguingly, also ameliorated the development of EAE. While this result was associated with a reduced production of pro-inflammatory cytokines from the draining lymph node cells, a reduction of mesenteric Th17 cells was found to correlate with disease suppression. In addition, we found that Valpha14 invariant NKT (iNKT) cells were necessary for maintaining the mesenteric Th17 cells. The homologous effects of KCV treatment and iNKT cell depletion led us to speculate that KCV treatment may suppress EAE by altering the function of iNKT cells. Consistent with this hypothesis, KCV treatment did not suppress EAE that was induced in iNKT cell-deficient mice, although it was efficacious in mice that lacked Valpha19 mucosal-associated invariant T cells. Thus, gut flora may influence the development of EAE in a way that is dependent on iNKT cells, which has significant implications for the prevention and treatment of autoimmune diseases.

Suppression of Experimental Autoimmune Encephalomyelitis by Ghrelin

Ghrelin is a recently identified gastric hormone that displays strong growth hormone-releasing activity mediated by the growth hormone secretagogue receptor. While this unique endogenous peptide participates in the regulation of energy homeostasis, increases food intake, and decreases energy expenditure, its ability to inhibit the production of proinflammatory cytokines in vitro indicates its role in the regulation of inflammatory process in vivo. Here we examine the effect of exogenous ghrelin on the development of experimental autoimmune encephalomyelitis (EAE), a representative model of multiple sclerosis. In the C57BL/6 mouse model of EAE induced by sensitization to myelin oligodendrocyte glycoprotein 35–55 peptide, we found that alternate-day s.c. injections of ghrelin (5 μg/kg/day) from day 1 to 35 significantly reduced the clinical severity of EAE. The suppression of EAE was accompanied by reduced mRNA levels of proinflammatory cytokines such as TNF-α, IL-1β, and IL-6 in the spinal cord cellular infiltrates and microglia from ghrelin-treated mice at the peak of disease, suggesting the role of ghrelin as an antiinflammatory hormone. Consistently, ghrelin significantly suppressed the production of proinflammatory cytokines in LPS-stimulated microglia in vitro. These results shed light on the new role of ghrelin in the regulation of inflammation with possible implications for management of human diseases.

Serum amyloid A level is increased in neuromyelitis optica and atypical multiple sclerosis with smaller T2 lesion volume in brain MRI

Serum amyloid A (SAA) is known to promote the development of T helper 17 cells (Th17) and can be a critical mediator of disease pathogenesis. We analyzed SAA levels in 40 patients with multiple sclerosis (MS) and related disorders, and 10 with non-inflammatory neurological disease (NIND) as controls. We found that SAA levels were significantly increased in neuromyelitis optica (NMO) patients and relapsing and remitting MS (RRMS) patients showing atypical phenotype with spinal cord lesions and smaller T2 lesion volume in brain MRI, resembling NMO. Therefore, SAA levels can be associated with clinical phenotypes in MS and NMO.

Multiple sclerosis and neuromyelitis optica spectrum disorders: some similarities in two distinct diseases.

Neuromyelitis optica spectrum disorder (NMOSD) is a chronic inflammatory disorder of the central nervous system that particularly involves the optic nerve and spinal cord. It is pathologically characterized by astrocytopathy, followed by tissue destruction (Fujihara, 2011). Historically, NMOSD has been considered to be an Asian optic-spinal form of multiple sclerosis (MS), as patients with NMOSD were distributed predominantly in Asian rather than in Western countries.

Taste impairment in Miller Fisher syndrome

Miller Fisher syndrome (MFS) was first described by Charles Miller Fisher in 1956 [1]; its cardinal clinical features are external ophthalmoplegia, ataxia, and areflexia. Taste impairment is considered to be an extremely rare clinical feature of MFS [2]. Here, we report a case of MFS with taste impairment and review the previously reported similar cases. A 53-year-old male was referred to our department because of taste impairment, diplopia, and gait disturbance. About 1 month before these symptoms emerged, he had experienced symptoms of an upper respiratory infection which spontaneously resolved. On admission, he was fully alert, his body temperature was 36.5 C and his blood pressure was 171/113 mmHg. He complained of diplopia, but neurological examination did not reveal obvious ocular movement abnormalities. He also complained of dysesthesia around his mouth and taste impairment, but did not have facial nerve palsy. He did not recognize sourness well, especially on his palate. He did not complain of lacrimal hyposecretion. He had no weakness in his extremities, but deep tendon reflexes were absent. He had ataxia in his extremities and trunk, and performed tandem gait with difficulty. Immunoglobulin (Ig) G anti-GQ1b antibodies were detected in the patient’s serum. Cerebrospinal fluid examination revealed a mild elevation of protein without pleocytosis: cell 1.3/ll, protein 50.2 mg/ dl, glucose 59 mg/dl, and oligoclonal bands were present. Brain magnetic resonance imaging operated on days 2 and 5 after disease onset revealed no abnormalities which could explain his neurological symptoms. Nerve conduction studies of his upper and lower extremities were normal. Electrogustometry revealed elevated thresholds in his right and left soft palates, but normal thresholds in the anterior two-thirds and posterior one-third of his tongue, suggesting dysfunction of the bilateral greater petrosal nerves. Four days after admission, neurological examination revealed obvious ocular movement abnormalities, impairment of abduction, adduction and supraduction of both eyes, resulting in a diagnosis of MFS. Intravenous immunoglobulin (0.4 g/kg/day) was immediately administered and his symptoms, including taste impairment, gradually improved. On day 35 after disease onset, electrogustometry revealed normal thresholds in his right and left soft palates. The frequency of taste impairment in patients with Guillain–Barré syndrome has been reported to be 0.6–2 % [3, 4]. Since only two other cases with MFS presenting with taste impairment have been reported in the literature [2, 5], taste impairment is a very rare clinical feature of MFS. Clinical features of these two patients and the present case are summarized in Table 1. Taste impairment in MFS could independently occur without facial nerve palsy and could be an initial symptom of MFS. Uchibori et al. [2] postulated that the presence of specific antibodies, including anti-GQ1b antibodies, might affect peripheral nerves associated with taste and taste buds in MFS patients with taste impairment. Since taste disturbance emerged without facial nerve palsy, a similar mechanism might be associated with the symptom in the present case. Because a continuous spectrum was suggested to exist between MFS Y. Yagi (&) H. Yokote Y. Watanabe T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Pure pandysautonomia associated with interferon-alpha therapy

Sirs: Young et al. described a patient with pure pandysautonomia characterized by severe postganglionic sympathetic and parasympathetic dysfunction, with relative or complete sparing of motor and sensory function [10, 11]. We describe here a patient who developed a subacute pure pandysautonomia associated with the injection of interferonalpha. A 56-year-old woman had received interferon-alpha as a consolidation therapy for left renal cell carcinoma after a nephrectomy in 1999. About 1 month later, she developed dizziness and impaired sweating. Three months after completion of interferon therapy, she developed salivary hyposecretion and severe constipation. Her blood pressure was 140/63 mmHg supine and 60/mmHg standing. There was no resting tachycardia. Pupils were slightly dilated bilaterally in normal room light being 4 mm in diameter. The pupillary light and convergence reflexes were absent. Mild left peroneal nerve palsy caused by old left knee trauma was detected, but otherwise no motor or sensory deficits were observed. Muscle stretch reflexes were normal. To clarify the exact location of involvement and choose the appropriate drug, the following investigations were performed with the informed consent of the patient. Routine laboratory tests were all normal. Anti-nuclear, anti SS-A/-B, anti-ganglioside and antineuronal antibodies were not detected. Cerebrospinal fluid (CSF) was normal and repeated CSF cytology was negative. Wholebody CT showed no evidence of malignancy. Nerve conduction studies were normal except for reduced CMAP of the left peroneal nerve. Head-up tilt test demonstrated definite orthostatic hypotension with a decline of 77 mmHg in systolic blood pressure, while heart rate showed a slight increase, which was less than 10 beats / minute. Noradrenaline infusion test revealed denervated hypersensitivity. Sympathetic skin responses were absent. The heart rate coefficient of variation at rest (CVR-R) was lower than normal controls. The quantitative sudomotor axon reflex test showed no sweat responses. Response of her pupils to 0.1% l-epinephrine, 5.0% tyramine, 5.0% cocaine and 0.125% pilocarpine revealed denervated supersensitivity. In a sural nerve biopsy specimen, myelinated (6,420/mm) and unmyelinated (22,320/mm) nerve fiber densities were within normal limits; however, the latter was approximately a 20 % reduction compared with mean value of normal control (27250 ± 1070/mm) [5]. This subtle reduction of unmyelinated nerve fiber density may support notion of the selective disappearance of sympathetic efferent fibers, because the percentage of sympathetic ganglia-derived unmyelinated axons in the sural nerve is estimated to be 20–25 % in the rat [1]. Electron microscopic study demonstrated collagen pocket clusters (CPCs) (Figure 1). This structure probably reflected a recent dropout of a group of sympathetic efferent fibers [4]. These pathological and electrophysiological findings suggested that postganglionic sympathetic and parasympathetic function were severely impaired in this patient as well as the patient with pure pandysautonomia previously reported [11]. The patient received intravenous immunoglobulin at a dose of 0.4 g/kg body weight per day for 5 days, but there was only minor improvement of her symptoms. We could not completely exclude a possibility that the patient’s dysautonomia was caused by cancer-related autonomic neuropathy. However, since the complete surgical resection of her left renal cell carcinoma was successfully performed without any remote or lymph node metastasis and no recurrence has been detected after six years’ follow-up, we concluded that the dysautonomia was related to the interferonalpha therapy. Although the underlying mechanism of pure pandysautonomia is unknown, there is some suggestive evidence of an immune-mediated pathogenesis [2, H. Yokote, MD Æ Y. Saitou, MD, PhD T. Kanda, MD, PhD (&) H. Mizusawa, MD, PhD Dept. of Neurology and Neurological Science, Tokyo Medical and Dental University, Graduate School of Medicine Tokyo, Japan

Cervical dystonia in an Alzheimer's disease patient treated with donepezil.

The cholinesterase inhibitor donepezil is a safe, effective, and widely used drug for the long-term symptomatic treatment of Alzheimer’s disease (AD) [1]. Dystonia is a rare complication of donepezil treatment, and some authors have reported dystonia, including Pisa syndrome, in patients treated with this drug [2]. Here, we report an AD patient treated with donepezil who developed cervical dystonia. A woman in her late 70s was referred to our department because of progressive forgetfulness. She had impaired episodic memory for recent events and her mini-mental state examination score was 12. Eye movement was normal, and she did not have akinesia or rigidity in her extremities that would suggest parkinsonism. Brain magnetic resonance imaging showed mild brain atrophy, and 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both temporal and parietal lobes, but this was more severe in the left hemisphere. She was diagnosed with AD and was started on a 5-mg dose of donepezil. Within 1 month of beginning the donepezil regimen, she developed severe torticollis and complained of difficulty in walking and eating. Physical examination revealed no abnormality other than torticollis to the left side. Physical examination and imaging studies did not provide any evidence of Parkinson’s disease or dementia with Lewy bodies, and she did not take other dopaminergic or psychotropic drugs. Therefore, we suspected that her torticollis was a side effect of donepezil. Treatment with memantine did not affect her torticollis, and we decided to discontinue donepezil treatment. Several weeks later, she experienced relief of her torticollis. She was then treated with memantine alone and had a good outcome. Dystonia is considered a rare complication of treatment with donepezil, and previous case reports and the present findings provide evidence that this complication can be due to drugs that act on the cholinergic system. Kwak et al. [2] previously reported Pisa syndrome in an AD patient treated with donepezil, and Huvent-Grelle et al. [3] reviewed Pisa syndrome in AD patients treated with 3 cholinesterase inhibitors: donepezil, rivastigmine, and galantamine. Villarejo et al. [4] suggested that cholinergic excess may induce Pisa syndrome. Although dystonia is a rare complication of cholinesterase inhibitors, clinicians must be aware of this phenomenon because of the increasing number of dementia patients and the growing use of cholinesterase inhibitors to treat them. Because cholinergic excess induced by cholinesterase inhibitors seems to be a cause of dystonia, treatment with the noncompetitive N-methyl-D-aspartate receptor antagonist memantine [5] is an alternative for AD patients who experience side effects on cholinesterase inhibitors.

Transient Charles Bonnet syndrome in a patient with reversible cerebral vasoconstriction syndrome

Charles Bonnet syndrome (CBS) was first described by a Swiss philosopher named Charles Bonnet in 1760. For a long time, this syndrome was considered to be rare; however, in 1996, Teunisse et al. [1] reported psychopathological characteristics of 60 patients with CBS and questioned the rarity of CBS. CBS is diagnosed if the following criteria are fulfilled: (a) the presence of formed and complex, persistent, or repetitive visual hallucinations; (b) full or partial retention of insight; (c) the absence of delusions; (d) and the absence of hallucinations in other modalities [2]. Reversible cerebral vasoconstriction syndrome (RCVS) is a disorder characterized with reversible segmental and multifocal vasoconstriction of cerebral arteries and severe headaches with or without focal neurological deficits or seizures. Calabrese et al. described the following features for RCVS: (a) transfemoral angiography or indirect [computed tomography (CT) or magnetic resonance (MR)) angiography showing segmental cerebral artery vasoconstriction; (b) no evidence for aneurysmal subarachnoid hemorrhage; (c) normal or near-normal findings for cerebrospinal fluid analysis (protein level \80 mg/dL, white blood cell count\10 cells/lL, normal glucose level); (d) severe, acute headache with or without additional neurological signs or symptoms; and (e) the diagnosis cannot be confirmed until reversibility of the angiographic abnormalities is documented within 12 weeks after onset and if death occurs before the follow-up examinations are completed, the autopsy rules out conditions such as vasculitis, intracranial atherosclerosis, and aneurysmal subarachnoid hemorrhage, which can also manifest with headache and stroke [3]. Here, we report transient visual hallucinations resembling the ones in CBS in a patient with RCVS. A 64-year-old woman experienced severe thunderclap headache when she was skiing. CT and MR imaging (MRI) of her brain performed at that time revealed no abnormality. MRI and magnetic resonance angiography (MRA) conducted about 3 weeks later revealed convexity subarachnoid hemorrhage in the right frontal lobe and multiple segmental cerebral artery vasoconstrictions (Fig. 1). Her blood pressure was 130/96 mmHg, her body temperature was 36.2 C, and she was alert. She had no visual loss but experienced formed and complex visual hallucination such as ‘‘people walking down the street’’ or ‘‘people acting in a theater’’ only when she closed her eyes, and she had full retention of insight. Her visual hallucinations began about 3 weeks after the onset of headache, and lasted for about a week. 99mTc-ECD single-photon emission computed tomography showed diminished blood flow in both the occipital lobes (Fig. 2). Her headache eventually resolved without any neurological deficit. MRA performed at about 5 weeks after the onset of headache showed more cerebral artery vasoconstrictions, but the vasoconstrictions resolved 2 weeks after that, and the patient was diagnosed with RCVS. Y. Yagi (&) Y. Watanabe H. Yokote T. Amino T. Kamata Department of Neurology, Musashino Red Cross Hospital, Kyonancho 1-26-1, Musashino, Tokyo 180-8610, Japan e-mail: yyagi-tmd@umin.ac.jp

Lacunar thalamic infarction with isolated dysesthesia in contralateral fingers

Cerebral infarctions in the thalamus cause various neurological symptoms. Of these, the cheiro-oral syndrome is a pure sensory stroke (PSS) in which sensory disturbance is observed around the corner of the mouth and in the palm on the same side of the body [1]. Here, we report a case of thalamic infarction with sensory disturbance restricted to the thumb and index that mimicked an incomplete form of the cheiro-oral syndrome. A man in his 70s was referred to our department because of a 2-month history of sensory disturbance in his right thumb and index. His symptom developed suddenly and did not improve for 2 months. Neurological examination revealed dysesthesia restricted to the distal phalangeal region on the palmar side of his right thumb and index (Fig. 1a). He had no weakness or sensory disturbance in his face or lower extremities. Motor and sensory nerve conduction studies of his bilateral median nerves yielded normal results. Magnetic resonance imaging (MRI) of the cervical spine revealed only mild cervical spondylosis and no stenosis in the spinal canal or the intervertebral foramen. Brain MRI revealed a small T2-weighted hyperintense lesion in his left thalamus (Fig. 1b). Based on these findings, we concluded that the patient had cerebral infarction in the contralateral thalamus. PSS accounts for 17.4 % of the cases of lacunar syndromes; the thalamus is responsible for the symptoms in

Autoimmune polyendocrine syndrome-3 in a patient with late-onset multiple sclerosis.

We present here the rare case of a 73-year-old patient with very late-onset multiple sclerosis who developed autoimmune polyendocrine syndrome (APS)-3. Despite only a few reports describing the association between multiple sclerosis and APS, both of these diseases have been shown to be associated with HLA-DR4. Intriguingly, the HLA genotype profile of this patient included HLA-DR4 which, fine mapped to the DRB1*0405-DQA1*0303-DQB1*0401 extended haplotype, reported to be a susceptibility haplotype for APS-3 in Japan. This unique genetic background might explain the clinical picture of this patient.