Multiple sclerosis (MS) is rare in Asians, but selective and severe involvement of the optic nerve and spinal cord is characteristic when it does occur. Recent epidemiological studies have demonstrated an increase in the prevalence of MS in Japan. Moreover, while there are two distinct phenotypes of MS in Asians, opticospinal (OSMS) and conventional (CMS), it is important to determine if MS phenotypes in Japanese are presently undergoing change.
Four nationwide surveys of MS have been conducted in Japan: 1972, 1982, 1989, and 2004. The most recent survey demonstrated: (1) a four-fold increase in the estimated number of clinically definite MS patients in 2003 (9,900; crude MS prevalence, 7.7/100,000) compared to the numbers in 1972; (2) a shift in the peak age at onset from the early 30s in 1989 to the early 20s in 2003; (3) a successive proportional decrease in optic-spinal involvement; (4) a significant north-south gradient for the CMS/OSMS ratio; (5) after dividing the mainland (30-45° North) into northern and southern parts at 37°N, northern-born northern-residents (northern patients) showed a significantly higher CMS/OSMS ratio and higher frequency of brain lesions fulfilling the Barkhof criteria (Barkhof brain lesions) than southern-born southern-residents; (6) among northern patients, the absolute numbers of CMS patients and those with Barkhof brain lesions rapidly increased with advancing birth year; (7) further classifications based on MRI findings demonstrated distinct demographic features with not only the CMS/OSMS phenotype but also the presence or absence of longitudinally extensive spinal cord lesions (LESCLs). In northern patients, the incidence of OSMS with LESCLs had decreased with advancing year of birth, while incidences of intermediate phenotypes, such as CMS with LESCLs and OSMS without LESCLs, had increased. Although phenotypic changes appeared to be mostly attributable to the increase in CMS patients with Barkhof brain lesions in younger northern populations, the emergence of such intermediate phenotypes may support the notion that CMS and OSMS represent opposite ends of a single spectrum of disease. These findings suggest that phenotype is drastically altered by environmental factors, such as latitude and "Westernization".
The recent discovery of a specific IgG against neuromyelitis optica (NMO) suggests that NMO is a disease entity distinct from MS. NMO-IgG targeting aquaporin-4 (AQP4) is present in 30 to 60% of Japanese OSMS patients with LESCLs. MS patients with anti-AQP4 antibodies were not responsive to interferon beta-1b while those without anti-AQP4 antibody did respond. In CSF, IL-17, IFN-gamma, granulocyte-colony stimulating factor, and IL-8 were markedly upregulated in OSMS patients, irrespective of the presence or absence of the anti-AQP4 antibody. Pathological studies of autopsy specimens of OSMS patients disclose that there are two subtypes of OSMS, with or without showing a selective AQP4 loss; although both subtypes had severe necrotic spinal cord lesions. There are also OSMS cases showing both pathological patterns at different lesions. These findings indicate that both anti-AQP4 autoimmunity-related and -unrelated OSMS occur in Japanese. Th17/Th1 cells are involved in both conditions, while additional humoral factors also act in the former.

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A 65-year-old right-handed man noted a sudden onset of numbness and weakness of the right hand. On the initial visit to our hospital, he showed severe acalculia, and transient agraphia (so called incomplete Gerstmann syndrome) and transcortical sensory aphasia.
Brain MRI revealed a fresh infarct in the left middle frontal gyrus. The paragraphia and aphasia improved within 14 days after onset, but the acalculia persisted even at seven months after onset. In an ¹²³I-IMP SPECT study, the cerebral blood flow (CBF) was found to be decreased in the infarction lesion and its adjacent wide area, the ipsilateral angular and supramarginal gyri, and contralateral cerebellar hemisphere. We speculate that inactivation in the infarction lesion caused the CBF decrease in the non-infarcted areas due to diaschisis. This case indicates that Gerstmann syndrome can be caused by not only dysfunction of the angular gyrus but also of the left middle frontal gyrus in the dominant hemisphere.

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A 40-year-old woman was diagnosed with iron deficiency anemia (hemoglobin 3.5g/dl) induced by uterine myomas, and admitted to the Department of Gynecology of our hospital. During admission, she underwent the daily intravenous administration of saccharated ferric oxide for 3 weeks, and monthly GnRH analogue administration was started. Her hemoglobin level acutely increased to 9.3g/dl over the next 18 days with normal blood pressure. Thirteen days after the 3rd administration of the GnRH analogue, she suddenly developed marked headache. Just before the onset, she had been driving a car, and spun the steering wheel to avoid a traffic accident on a busy street. This headache was so severe that she was brought to our hospital by ambulance. During transport to the hospital, her blood pressure was normal. Soon after arriving, she developed generalized convulsions, followed by status epilepticus. A brain MRI showed vasogenic edema in the posterior and parietal cortices including white matter bilaterally, and minimum subarachnoid hemorrhage was indicated in the bilateral frontal lobe and right temporal lobe. CSF analysis was unremarkable. Anticonvulsants, one course of steroid pulse therapy and glycerol were started, and status epilepticus disappeared on the same day. Abnormal areas on MRI decreased gradually. However, hyperintensity on T1- and FLAIR images remained in the right parietal lobe and bilateral occipital lobe white matter at 15 months after the onset. Judging from the clinical and radiological findings, this patient was diagnosed as reversible posterior leukoencephalopathy syndrome (RPLS) accompanied with subarachnoid hemorrhage.
This case suggests that an unexpected prompt physical activity or astonishment would induce RPLS in a patient treated with GnRH analogue.

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Adult-onset type II citrullinemia (CTLN2) is a hereditary metabolic disorder characterized by highly elevated plasma citrulline and ammonia. Recent studies have identified the "citrin gene" (SLC25A13) as the causative gene for CTLN2. Various neurobehavioral symptoms seen in this disease, such as unconsciousness, disorientation, abnormal behavior, and epilepsy, are thought to be caused by encephalopathy mostly due to hyperammonemia.
A 47-year-old woman presented with repeated unconsciousness and abnormal behavior. The high plasma anmonia level was not always associated with her neurobehavioral symptoms (unconsciousness, disorientation, abnormal behavior, and epilepsy), but paroxysmal EEG discharges were invariably associated with these symptoms. Her symptoms and abnormal EEG discharges were sometimes treated with diazepam simultaneously. Based on these findings, we considered that her symptoms were caused by nonconvulsive status epilepticus (NCSE).
Until date, neurobehavioral symptoms of CTLN2 are considered to be caused by hyperammonemia or other metabolic factors. We suggest that encephalopathy of CTLN2 is caused not only by hyperammonemia but also by NCSE. Therefore, repeated EEG monitoring is recommended in the follow up of patients with CTLN2.

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We report a 25-year-old woman who developed optic neuritis and encephalomyelitis following primary Sjögren's syndrome (SjS). SjS began with Sicca syndrome when she was 8 years old, and neurological involvement subsequently developed at the age of 10 with right hemiparesis. Based on clinical symptoms, serum positive for SS-A and SS-B antibodies and pathological findings of the salivary gland, we confirmed a diagnosis of primary SjS. Magnetic resonance imaging (MRI) revealed multiple lesions in the brain and the spinal cord. These led diagnosis of SjS with central nervous system involvement (CNS-SjS) and initiated steroid therapy.
At the age of 25, the patient developed left visual loss due to retrobulbar optic neuritis, left lower quadrantic hemianopia, numbness of the right upper limb, and weakness of both legs. Laboratory examinations showed that her serum was positive for SS-A and SS-B antibodies, and her cerebrospinal fluid had elevated levels of total protein and myelin basic protein without pleocytosis. Her brain MRI revealed multiple T2-high-intensity lesions bilaterally in the frontal subcortical white matter and in the right temporo-parietal subcortical white matter. The lesions included a tumefactive lesion and an active lesion. Additionally, the spinal MRI revealed a severely atrophied spinal cord with T2-high-intensity lesions extending longitudinally and centromedullary in the spinal cord. These findings led us to examine the patient's serum for anti-aquaporin (AQP) 4 antibodies and the test confirmed that her serum was positive for the antibodies. After administering intravenous high-dose methylprednisolone (1,000mg/day for 3 days), her symptoms markedly improved with normalization of myelin basic protein. However, her serum remained positive for AQP 4 antibodies.
We think that the patient's diagnosis belongs to the neuromyelitis optica (NMO) spectrum disorders associated with autoimmune disorders. This is a rare case in that the initial presentation was SjS and occurred at a very young age.

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Erectile dysfunction, dysuria, photophobia, and chronic cough developed insidiously in a 49-year-old man from his third decade. Severe difficulty of urination resulted in intermittent catheterization. He had six family members who had suffered similar autonomic symptoms with or without motor deficits. He presented asymmetrical tonic pupils, a neurogenic bladder, and mild sensory impairment in the distal parts of the bilateral lower limbs without orthostatic hypotension and motor deficits. Nerve conduction studies revealed mild axonal changes with slightly reduced conduction velocities in the lower limbs. His left pupil over-responded to instillation with 0.125% pilocarpine. Functional bladder tests showed an atonic bladder, suggesting postganglionic parasympathetic involvement. Autonomic evaluation for sympathetic components including head-up tilt, beat to beat responses to Valsalva's maneuver, cardiac MIBG imaging, plasma catecholamine levels and sweat tests were all normal. A genetic test disclosed a heterozygous mutation of myelin protein zero (MPZ); p.Thr124Met. Selectively distributed dysautonomia in this pedigree may indicate parasympathetic postganglionic components including the ganglion as the primary target of this mutated MPZ in the autonomic nervous system.

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A 57-year-old man suffered a generalized seizure. Brain MRI showed a Gadolinium (Gd) enhanced lesion with massive edema in the left frontal lobe. He received in a brain biopsy a diagnosis of ganglioglioma, probable. After two weeks from the biopsy, brain MRI showed spontaneous remmision of the lesion. Eighteen months after his seizure, a follow-up brain MRI showed a new lesion in the left cerebellar peduncle. However, the lesion also improved spontaneously. After 2 years from the onset, a follow-up examination showed a new lesion in the corpus callosum. At that time even though high dose corticosteroid was given with the diagnosis of multiple sclerosis, the lesion enlarged progressively and uveitis occurred at the same time. He received in the second biopsy a diagnosis of diffuse large B cell lymphoma. We report a case of primary central nervous system lymphoma preceded by cerebral and cerebellar lesion diminishing spontaneously, with consideration of two brain biopsy at the onset and after two years.

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An 83-year-old woman developed high fever and headache for four days. She had disturbance of consciousness and was admitted to our hospital. A lumbar puncture was performed and cerebrospinal fluid (CSF) analysis revealed a white blood cell count of 268/mm³ and culture became positive for Listeria monocytogenes. Six days after admission, the adenosine deaminase (ADA) level in CSF markedly elevated (43.3IU/L) with pleocytosis, but a negative PCR test for tuberculosis in CSF, sputum, gastric fluid. She recovered by antibiotics for 45 days and ADA level in CSF was normalized. She was diagnosed as listeria meningitis. High levels of ADA in CSF have high sensitivity and high specificity for tuberculous meningitis, but there are some reports that high ADA levels in CSF in other meningitis. The main biological role of ADA is related to proliferation and differentiation of lymphocytes, and specific activity of this enzyme is slightly higher in T-lymphocytes than in B-lymphocytes. Protective immunity to Listeria monocytogenes is exclusively exhibited by T-lymphocytes. We consider that increased ADA levels in listeria meningitis associated with elevation of T-lymphocytes in CSF. This report suggests that listeria meningitis must be included in the differential diagnosis of high levels of ADA in CSF.

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Both multifocal fibrosclerosis and hypertrophic pachymeningitis are rare disorders of unknown etiology, characterised by chronic inflammation leading to dense fibrosis. There have been several reports of multifocal fibrosclerosis with hypertrophic pachymeningitis. Autoimmune pancreatitis is frequently associated with various extrapancreatic lesions, their pathological similarities such as dense inflammatory fibrosis with lymphoplasmacytic infiltration strongly suggests a close relationship between autoimmune pancreatitis and multifocal fibrosclerosis. Recently, autoimmune pancreatitis including these systemic fibrosing disorders may be classified as IgG4-related systemic disease. However, the relationship between HP and IgG4-related systemic disease is still uncertain. We performed immunohistochemical examinations in autopsy specimens from a patients with HP. Histological findings can be summarized as follows: sever interstitial fibrosis and diffuse inflammatory cells infiltration, presenting nonspecific inflammatory changes. Immunohistochemically, diffuse infiltrates in the dura consisted predominantly of UCHL-1 positive T or L-26 positive B lymphocytes. ManyIgG4 positive plasma cells were also infiltrated.
To our knowledge, this may be the first report which showed IgG4 positive plasma cells infiltration in the dura in a patient with HP. It is postulated that HP may be a dural lesion of IgG4-related systemic disease.

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