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Here, an overview of progressive multifocal leukoencephalopathy (PML) and its drug associations, especially the disease-modifying drug (DMD)-associated PML for multiple sclerosis (MS) were discussed. Additionally, along with presenting the current status of PML in MS caused by natalizumab, fingolimod, and dimethyl fumarate, the possibility of PML onset with siponimod and ofatumumab, the two newly proposed DMDs for MS, was provided. PML treatment in the era of DMD-associated PML, especially PML in MS, is an important issue. With respect to the treatment of PML, to date, there are no specific antiviral drugs against the JC virus; some drugs, that may have therapeutic potential reported recently, were also mentioned.

To understand tuberculous meningitis (TBM), its clinical features and standard therapy were briefly reviewed. In addition, to determine the therapeutic strategies for treatment-resistant TBM, several clinical cases, including those with paradoxical reaction, ventriculitis, cerebral tuberculoma, and human immunodeficiency virus (HIV) co-infection, are presented. Steroid pulse therapy and intrathecal isoniazid administration are discussed as specific therapeutic strategies. Immune reconstitution inflammatory syndrome in patients with TBM suffering from HIV co-infection and alternative drug selection for drug-resistant TBM cases are also introduced. Although TMB is a rare central nervous system infection, it remains a serious disease with high rates of mortality and neurological sequelae. Knowing therapeutic strategies for treatment-resistant TBM is necessary to prevent a devastating prognosis.

A 58-year-old man was diagnosed with mycosis fungoides (MF) confirmed by skin biopsy for systemic erythema that appeared in 2006 and had been on psoralen plus ultraviolet A (PUVA) therapy and topical steroids. In September 2017, he had diffuse large B-cell lymphoma and received chemotherapy. Since March 2019, tumor stage MF with large cell transformation was observed, and chemotherapy containing brentuximab vedotin (BV) was performed, which yielded a remarkable response. During the preparation for allogeneic hematopoietic stem cell transplantation, bradykinesia, delayed response, and cognitive decline were observed. Head magnetic resonance imaging fluid-attenuated inversion recovery images showed hyperintensity in the deep white matter below the bilateral frontal cortex. The general cerebrospinal fluid test revealed no abnormalities and was below the sensitivity of JC virus (JCV) quantitative PCR. As progressive multifocal leukoencephalopathy (PML) was strongly suspected from clinical symptoms and radiographic signs, ultrasensitive JCV testing was performed. The test result was positive; hence, the patient was diagnosed with PML. Chemotherapy was discontinued, but his central nervous system symptoms worsened, and he died on the 135th day of illness. We considered that PML developed based on the underlying disease and immunodeficiency caused by chemotherapy such as BV.

Here, progressive multifocal leukoencephalopathy (PML) and PML in systemic lupus erythematosus (SLE) are reviewed. Disease-modifying therapy (DMT) associated PML is an emerging condition, particularly in multiple sclerosis patients. Although PML is a rare adverse event in SLE, we should consider development of PML more carefully in not only conventional drug-induced PML but also DMT associated PML during SLE treatment in the era of DMT associated PML.

Background: The clinical importance of ovarian teratoma in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been established, however investigations of ovarian teratoma in patients with anti-NMDAR encephalitis remain limited. Objective: To clarify differences in NMDAR distribution and lymphocyte infiltration in ovarian teratoma between patients with and without anti-NMDAR encephalitis. Methods: Participants initially comprised 26 patients with ovarian teratomas. NMDAR distribution and lymphocyte infiltration in ovarian teratomas were examined using immunopathological techniques. Clinical, laboratory, and radiological data were compared between patients showing the features of encephalitis. Anti-NMDAR antibodies in the serum and cerebrospinal fluid were also measured in encephalitis patients. Results: Neuronal tissues were obtained from ovarian teratomas in 22 patients (after excluding 4 patients who did not satisfy the inclusion criteria), and the presence of NMDA receptor subunits was revealed in all patients. Lymphocyte infiltration was more frequent in the encephalitis group (n = 3) than in the non-encephalitis group. In particular, dense B-lymphocyte infiltration near neural tissues was observed in the encephalitis group. Conclusions: Differences in lymphocyte infiltration in ovarian teratomas between anti-NMDAR encephalitis and non-encephalitis patients suggest the immunological importance of the ovarian teratoma as the site of antigen presentation in anti-NMDAR encephalitis.

It is unclear when and which neurologic deficits should be examined within 24 hours after intravenous recombinant tissue plasminogen activator (rt-PA) therapy for acute ischemic stroke. Relationships between serial changes in National Institutes of Health Stroke Scale (NIHSS) subscores and neurologic deterioration (ND) within the first 24 hours after therapy were investigated in 43 consecutive patients. The NIHSS score was measured by neurologists 28 times within 24 hours after therapy. Assessments of subscores associated with ND, defined as the first change 4 or more points from baseline, were performed at 15 minutes (most frequent time of the first ND), 120 minutes (median time of the first ND), and 24 hours after therapy. Seventeen of 43 patients (age range, 55-94 years) showed ND. Of the NIHSS subscores, increases in scores for loss of consciousness (15 minutes, P = .001; 120 minutes, P = .026; 24 hours, P = .018) and motor limbs total (15 minutes, P = .014; 120 minutes, P = .031) were related to deterioration. Items such as questions, gaze, visual fields, ataxia, language, dysarthria, and extinction/inattention were not related to deterioration at any time. In conclusion, ND of ischemic stroke patients treated with intravenous rt-PA therapy was frequently seen within 120 minutes after therapy. Items such as loss of consciousness and motor limbs total may be considered indices for monitoring neurologic deficits after therapy.

A 39-year-old man suffering from progressive dysarthria, gait disturbance, and sensorineural deafness for 2 years was admitted to our hospital. He scored 28 points on the mini-mental state examination. He had previously undergone surgery at 24 years and 39 years of age for a cerebellar tumor (pilocytic astrocytoma). Superficial siderosis (SS) was diagnosed based on bloody cerebrospinal fluid (CSF) and the findings of T2-weighted head MRI that revealed marginal hypointensity of the surface of the cerebellum, brainstem, and cerebral cortex. After intravenous infusion and the oral use of hemostatic drugs (carbazochrome, tranexamic acid), the CSF became watery clear and his condition improved. Hemostatic drug therapy should be considered for SS.

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.

症例は66歳，男性．耕運機の操作を誤り，後進してきたハンドル部で左下顎を強く圧迫され，一時的に頸部過伸展状態となった．その後，左後頸部痛が持続し，受傷10週後に激しい後頸部痛・左不全麻痺・意識障害を生じ当院へ搬送された．拡散強調画像では上位頸髄と左後下小脳動脈領域に急性梗塞を認めた．左椎骨動脈のMRAとbasi-parallel anatomical scanning画像の所見にミスマッチがあったこと，頭部単純CTで左椎骨動脈から脳底動脈にかけて壁内血栓を示唆する高吸収域を認めたことから10週前の鈍的頸部外傷に関連した椎骨動脈損傷に伴う解離・閉塞が生じたと考えた．本例を通じ椎骨動脈損傷の受傷機転には多様性があること，詳細な問診の重要性を改めて認識した．また頸部外傷後に慢性的な後頸部痛を訴える患者と遭遇した場合には，受傷からの期間があったとしても椎骨動脈損傷の可能性を考慮すべきと思われた．

Objective To clarify the incidence and clinical significance of HTLV-I associated myelopathy/tropical spastic paraparesis (HAM/TSP) showing T2 hyperintensity in the spinal cord on magnetic resonance images (MRI). Patients and Methods We reviewed the spinal cord MRI of 38 HAM/TSP patients and analyzed them in relation to clinical and laboratory findings. Analyzed data were: age at onset, disease duration, disability status, responsiveness to interferon therapy, brain abnormalities on MRI, serum anti-HTLV-I titers, and cerebrospinal fluid (CSF) findings. Results MRI findings of the spinal cord were classified into 3 types, "normal" (n=22, 57.9%), "atrophy" (n=13, 34.2%) and "T2-hyperintensity" (n=3, 7.9%). Patients in the normal and atrophy types showed slowly progressive paraparesis. Significant differences were not found between the normal and atrophy types in any clinical or laboratory data, including disease duration, disability status and responsiveness to interferon-alpha therapy. Meanwhile, all patients showing T2-hyperintensity had severe paraparesis of a rapid progressive nature, with CSF IgG elevation. Conclusion HAM/TSP with T2-hyperintensity on spinal MRI shows a rapid progressive clinical course with severe motor impairment. The incidence of this malignant form of HAM/TSP is estimated to be around 7.9%.

It has been reported that antibodies (Abs) against heterogeneous nuclear ribonucleoproteins (hnRNPs) are associated with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) and multiple sclerosis (MS). However, these studies were done under nonmasked conditions. In order to determine whether Abs against hnRNPs associate with HAM/TSP and MS, the authors assayed Abs against two major hnRNPs, hnRNP A1 and A2/B1, in 105 cerebrospinal fluid (CSF) samples under fully masked conditions. Samples included 40 cases of HAM/TSP, 28 of MS, and 37 of other neurological diseases. Anti-hnRNP A1 Abs, and especially anti-hnRNP A2/B1 Abs, were found significantly more often in the CSF of MS patients than in other groups. However, there was no difference in the incidence of anti-hnRNP A1 Abs between HAM/TSP and other disease groups.

Hereditary spastic paraplegia (HSP) is a group of genetically heterogeneous neurodegenerative disorders characterized by slowly progressive spasticity and weakness of the lower limbs. HSP is caused by failure of development or selective degeneration of the corticospinal tracts, which contain the longest axons in humans. The most common form of HSP is caused by mutations of the spastin gene (SPAST), located on chromosome 2p21-p22, which encodes spastin, one of the ATPases associated with diverse cellular activities (AAA). In this study, we detected four causative mutations of SPAST among 14 unrelated patients with spastic paraplegia. Two missense mutations (1447A-->G, 1207C-->G) and two deletion mutations (1465delT, 1475-1476delAA) were located in the AAA cassette region. Three of these four mutations were novel. Previous reports and our results suggest that the frequency of SPAST mutations is higher among Japanese patients with autosomal dominant HSP, although SPAST mutations are also observed in patients with sporadic spastic paraplegia.

Heterogeneous nuclear ribonucleoproteins (hnRNPs) play an important role as the autoantigens in certain autoimmune disorders including neurological diseases such as HTLV-1–associated myelopathy/tropical spastic paraparesis and paraneoplastic neurological syndromes. To clarify their implication in multiple sclerosis (MS), we assayed antibodies (Abs) against hnRNP A and B proteins in sera and cerebrospinal fluid (CSF) of MS patients and compared the results with 25 patients with other neurological diseases (ONDs). Using recombinant hnRNP A1, A2, and B1 proteins and Western blotting for the assay, we found Abs against hnRNP B1 in CSF from 32 of 35 MS patients (91.4%) but not in any sera or CSF of the 25 OND patients. Most notably, no Abs against hnRNP B1 were found in sera of all 22 MS patients examined. Although Abs against hnRNP A1 and A2 were concomitantly found in CSF reacting with B1, their incidence and immunoreactivity were lower or weaker than those of anti–hnRNP B1 Abs. There was no correlation between the reactivity of CSF with hnRNP B1 and CSF parameters—such as the number of the cells and the IgG level—or clinical parameters—such as duration of illness and disease activity. The selective generation of Abs against hnRNP B1 in CSF was shown to be highly specific for MS, which makes them a disease marker. Ann Neurol 2004

To study the mechanism underlying the selective degeneration of Purkinje cells in the cerebellum of the Nagasaki (Ngsk) prion protein-deficient (PrP −/− ) mice, the mRNA levels of glutamate transporter EAAT4, the marker highly specific for Purkinje cell synapses, were analyzed by semi-quantitative reverse transcription–polymerase chain reaction. EAAT4 mRNA was expressed in the cerebellum of PrP −/− mice presenting with cerebellar ataxia, at the levels identical to those in the cerebellum of non-ataxic PrP +/− mice. Furthermore, EAAT4 mRNA was identified in the cerebrum of both PrP −/− and PrP +/− mice, although its levels were much lower than those in the cerebellum. These results indicate that Purkinje cell degeneration found in the cerebellum of PrP −/− mice is not primarily caused by glutamate neurotoxicity, although it remains to be investigated whether preserved expression of EAAT4 might represent a compensatory mechanism for protecting against Purkinje cell degeneration in the PrP −/− mice cerebellum.

The 14-3-3 protein belongs to a family of 30-kD proteins originally identified by two-dimensional analysis of brain protein extracts. Recently, the detection of the 14-3-3 protein in the cerebrospinal fluid (CSF) is utilized as a highly reliable test for the premortem diagnosis of prion diseases such as Creutzfeldt-Jakob disease. For the initial step, to clarify the biological implication of the CSF 14-3-3 protein in these diseases, its expression was investigated in neural tissues and cultures and CSF samples from patients with a variety of neurological diseases by Western blot analysis and immunocytochemistry. The constitutive expression of the 14-3-3 protein was identified in all neural and nonneural tissues examined. It was expressed in all neurons, astrocytes, oligodendrocytes, and microglia in culture with its location in both cytoplasmic and nuclear regions. The 14-3-3 protein was detected in the CSF of 8 out of 71 patients, including 1 Gerstmann-Sträussler-Scheinker disease patient and 7 patients with prion-unrelated neurological diseases, such as meningoencephalitis of viral, bacterial, or tuberculous origin, multiple sclerosis, and mitochondrial myopathy, encephalopathy, lactic acidosis, and strokelike episodes. These results suggest that the 14-3-3 protein expressed constitutively at substantial levels in both neurons and glial cells might be released into the CSF as a disease-nonspecific consequence of the extensive brain damage and indicate that the analysis of the 14-3-3 protein in the CSF is not useful as a screening test for prion diseases.

Recent evidence has suggested that molecular chaperones participate in the conformational change between the normal cellular prion protein (PrPC) and its scrapie isoform (PrPSc). To study a role of PrPC in the regulation of expression of heat shock proteins (HSPs), a group of molecular chaperones, heat-induced expression of major HSPs (HSP105, HSP90alpha, HSP72, HSC70, HSP60, and HSP25) was investigated in cultured skin fibroblasts isolated from the mice homogeneous for a disrupted PrP gene (PrP-/- mice) by Western blot analysis and immunocytochemistry. Two lines of fibroblasts were established and designated SFK derived from the PrP-/- mice and SFH derived from the PrP+/+ mice, respectively. In both SFK and SFH cells, HSP105, HSP72, and HSP25 were expressed at low levels under unstressed conditions but they were induced markedly following exposure to heat stress (43 degreesC/20 min) at 3-72 h postrecovery. In both cell types, HSC70 and HSP60 were expressed at high levels under unstressed conditions and their levels remained unchanged after heat shock treatment. HSP90alpha was undetectable in both cell types under any conditions examined. The pattern of expression, induction, and subcellular location of HSP105, HSP72, HSC70, HSP60, and HSP25 was not significantly different between SFK and SFH cells under unstressed and heat-stressed conditions. Furthermore, the levels of constitutive expression of HSP105, HSC70, HSP60, and HSP25 were similar between the brain tissues isolated from the PrP-/- and PrP+/+ mice. These results indicate that HSP induction is not affected by either the existence or the absence of PrPC in the cells.

We describe the MRI findings in three Japanese patients with spinocerebellar ataxia type 6 (SCA6) in which a polymorphic CAG repeat was identified in the gene encoding the alpha 1A voltage-dependent P/Q-type Ca2+ channel subunit (CACNL1A4). All showed slowly progressive cerebellar ataxia and mild pyramidal signs. Neuroradiologically, they had moderate cerebellar atrophy, most prominently in the superior vermis, whereas the brain stem appeared to be spared. No abnormal signal intensity was identified.

Interleukin-15 (IL-15) is a novel cytokine which shares activities and receptor components with IL-2. To investigate the biological roles of IL-15 in the human nervous system, we examined the expression of mRNAs for IL-15 and the IL-15 receptor three subunits (IL-15alpha, IL-2Rbeta and IL-2Rgamma) in human neural cell lines and tissues using reverse transcription-polymerase chain reaction and Southern blot analysis. The constitutive expression of high levels of IL-15 mRNA was observed in all the cell lines examined, including Y79 retinoblastoma, IMR-32 neuroblastoma, SK-N-SH neuroblastoma, U-373MG glioma, KG-1-C glioma, NTera2 teratocarcinoma and neurons derived from NTera2 cells following treatment with retinoic acid (RA). Among these cell lines, IL-15 protein was detectable at high levels in culture supernatants of SK-N-SH cells and NTera2-derived neurons. The expression of an alternatively-spliced transcript of the IL-15 gene was up-regulated in NTera2 cells during RA-induced neuronal differentiation, suggesting the existence of differentiation-dependent transcriptional regulation. The expression of IL-15 mRNA was also identified in the human cerebral and cerebellar tissues, peripheral nerve and skeletal muscle, while the mRNAs for the complete set of IL-15R components were detectable only in U-373MG cells, cerebral and cerebellar tissues at significant levels. These results indicate that the expression of IL-15 but not of IL-15R mRNA is universal in human neural cell lines and tissues and raise the possibility that IL-15 acts as a neuroimmune regulatory factor in the human central nervous system.

A 51-year-old woman developed a slowly progressive spastic paraparesis and diminished vibration sense beginning at age 38. Intellectual capacity was normal. Krabbe disease was confirmed by markedly reduced leukocyte galactocerebrosidase (GALC) activity, typical inclusions in Schwann cell cytoplasm, and an identification of the homozygous point mutation T1835C(Leu618Ser) in the GALC gene. T2-weighted MRI of the brain showed symmetric high-signal-intensity lesions in the bilateral frontoparietal white matter, the centrum semiovale, and the posterior limb of the internal capsule with sparing of the periventricular white matter. This case is unusual because of the late onset, protracted clinical course, and MRI findings of demyelination confined to the corticospinal tracts.

The expression of mRNAs for neurotrophins and neurotrophin receptors was examined in NTera2/cl.D1 (NT2) human embryonal carcinoma cells at various stages of retinoic acid (RA)-induced neuronal differentiation using reverse transcription-polymerase chain reaction and southern blot analysis in order to investigate the biological role of neurotrophins in the human neuronal differentiation. The expression of high steady levels of BDNF, NT-3, NT-4, and low-affinity NGF receptor mRNAs was observed in both untreated NT2 cells and NT2-derived differentiated neurons induced by RA treatment. The lower levels of expression of NGF, trkA, trkB, and trkC mRNAs were identified in untreated NT2 cells and their expression was elevated markedly following 4 week treatment with RA. The increased expression of NGF, trkB, and trkC mRNAs were stable in NT2-derived differentiated neurons, while the expression of trkA mRNA was reduced substantially in these cells. These results indicate that mRNAs for a battery of neurotrophins and their receptors are coexpressed in NT2 cells and their expression is regulated by RA-induced neuronal differentiation.

The clinical importance of ovarian teratoma in anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis has been established, however investigations of ovarian teratoma in patients with anti-NMDAR encephalitis remain limited.To clarify differences in NMDAR distribution and lymphocyte infiltration in ovarian teratoma between patients with and without anti-NMDAR encephalitis.Participants initially comprised 26 patients with ovarian teratomas. NMDAR distribution and lymphocyte infiltration in ovarian teratomas were examined using immunopathological techniques. Clinical, laboratory, and radiological data were compared between patients showing the features of encephalitis. Anti-NMDAR antibodies in the serum and cerebrospinal fluid were also measured in encephalitis patients.Neuronal tissues were obtained from ovarian teratomas in 22 patients (after excluding 4 patients who did not satisfy the inclusion criteria), and the presence of NMDA receptor subunits was revealed in all patients. Lymphocyte infiltration was more frequent in the encephalitis group (n = 3) than in the non-encephalitis group. In particular, dense B-lymphocyte infiltration near neural tissues was observed in the encephalitis group.Differences in lymphocyte infiltration in ovarian teratomas between anti-NMDAR encephalitis and non-encephalitis patients suggest the immunological importance of the ovarian teratoma as the site of antigen presentation in anti-NMDAR encephalitis.

A case of a small left pontine tegmental hemorrhage that presented as cheiro-oral syndrome with a bilateral perioral sensory disturbance is described. An 83-year-old man suddenly developed numbness in his bilateral perioral area and right hand. Head CT and MRI (T(2)*-weighted image) revealed a small left pontine tegmental hemorrhage. The patient was diagnosed as having cheiro-oral syndrome with bilateral perioral sensory disturbance, probably due to unilateral pontine tegmental hemorrhage. All residual symptoms disappeared within a month.In the present case, the following clinicopathological hypothesis was considered. The hematoma located in the left pontine tegmentum impaired the sensory fibers from the contralateral medial lemniscus (from the right hand) and the ventral trigeminothalamic tract (from the right perioral region). In addition, the ipsilateral trigeminothalamic tract (from the left perioral region) was also impaired. It is important to know that a small unilateral lesion in the brainstem (especially the pons) can cause cheiro-oral syndrome with a bilateral perioral sensory disturbance, and a small brainstem hematoma is the most frequent etiology of this disease.

Spinocerebellar ataxia 36 is caused by the expansion of the intronic GGCCTG hexanucleotide repeat in NOP56. The original article describing this condition demonstrated that patients with spinocerebellar ataxia 36 present with tongue atrophy, a finding that had not been seen in previous types of spinocerebellar ataxias. A total of 2121 patients with clinically diagnosed spinocerebellar ataxia participated in the study. We screened our patient samples for spinocerebellar ataxia 36 using the repeat-primed polymerase chain reaction method and also determined the clinical features of spinocerebellar ataxia 36. Of the ataxia cases examined, 12 were identified as spinocerebellar ataxia 36. Of these, 7 cases (6 families) were autosomal dominant, 4 cases (three families) had a positive family history but were not autosomal dominant, and 1 case was sporadic. The average age of onset was 51.7 years, and disease progression was slow. The main symptoms and signs of disease included ataxia, dysarthria, and hyperreflexia. Approximately half the affected patients demonstrated nystagmus, bulging eyes, and a positive pathological reflex, although dysphagia, tongue atrophy, and hearing loss were rare. Moreover, the observed atrophy of the cerebellum and brain stem was not severe. The patients identified in this study were concentrated in western Japan. The frequency of spinocerebellar ataxia 36 was approximately 1.2% in the autosomal dominant group, and the age of onset for this condition was later in comparison with other spinocerebellar ataxia subtypes.

膵島炎による糖尿病性ケトアシドーシスからrhabdomyolysisによる腎性腎不全を呈した興味ある1例を報告する.症例は糖尿病の既往のない67歳の男性. 1990年11月下旬より嘔吐・下痢症状のあと, 異常行動が出現し意識不明となる. 収縮期血圧50mmHg, BUN 78mg/dl, Cr 6.2mg/dl, 血糖値1,650mg/dl, および血清アミラーゼ, CPKの高値を示した. 近医で高血糖と急性腎不全の治療を受け, 一時腎機能の改善が見られたが再び悪化し当科に入院, 抗ラ氏島抗体が陽性のため, 急性発症のIDDMと診断した. 腎機能は血液透析を施行後, 正常になったがIDDMは残存した. また, 入院時血清ミオグロビンの高値を認めた. 本例は膵島炎による著明な糖尿病性ケトアシドーシスとそれに伴う低血圧による腎前性腎不全を生じ, さらに, rhabdomyolysisによる腎性腎不全が生じたものと考えられた.

A 62-year-old man was admitted to our hospital because of rapidly progressive dysarthria, truncal ataxia, and gait disturbance. High titers of the ProGRP and anti-P/Q-type VGCC antibody were detected in the serum. High accumulation of [18F] was detected at the hilus of the left lung on [18F]-FDG-PET scan. A high-frequency repetitive stimulation test of the median nerve yielded an incremental response. On the basis of these findings, a diagnosis of paraneoplastic cerebellar degeneration (PCD) and Lambert-Eaton myasthenic syndrome (LEMS) associated with small cell lung carcinoma (SCLC) was diagnosed. After intravenous immunoglobulin therapy (IVIg), methylprednisolone (m-PSL) pulse therapy, and other multidisciplinary concurrent treatments, a partial regression of the SCLC and a significant improvement in neurological symptoms were observed. However, ataxia relapsed and brainstem encephalitis developed 6 months later. A marginal improvement in neurological symptoms was observed with IVIg, m-PSL pulse therapy, and intravenous cyclophosphamide pulse therapy (IVCY). SCLC also recurred later. We hypothesized that VGCC of the brainstem was damaged by anti-P/Q-type VGCC antibody.

Objective To examine the long-term effects of tacrolimus in steroid-dependent myasthenia gravis (MG) patients. Patients and methods We administered tacrolimus at 3 mg/day to 10 generalized MG patients presented with clinical worsening by a reduction in dose of prednisolone. The effects of tacrolimus were assessed by using the MG activities of daily living (MG-ADL) profile and the post-intervention status criteria provided by the Myasthenia Gravis Foundation of America (PSC-MGFA). Results Seven patients were able to use tacrolimus without serious adverse effects for 1.0-5.1 years (mean 3.1 years). Further, its administration improved myasthenic symptoms to the level of pharmacologic remission or minimal manifestations of PSC-MGFA in 5 patients and made it possible to discontinue prednisolone administration in 4 of those 5. However, despite improvements caused by tacrolimus, the reduction in dose of prednisolone caused worsening of symptoms in another 2 patients. In addition, blood trough levels of tacrolimus lower than the recommended range were effective to maintain long-term improvements in 2 patients. Conclusions Administration of tacrolimus induced long-term improvements and enabled replacement of prednisolone in patients with intractable steroid-dependent MG.

A 55-year-old man with chronic alcoholism was first referred to us in 1992 because of spastic quadriparesis. T2-weighted images of MRI showed pontine and extracapsule lesions as central pontine and extrapontine myelinolysis (CPM/EPM). He had macrocytic anemia with normal serum level of vitamin B12 (B12). Gait disturbance was progressively worsened from the end of 2004 and dysuria appeared from June, 2005. Neurological examination on admission in November, 2005, showed mild impairment of recent memory, spastic paraparesis with hyperreflexia in all limbs, loss of deep sensations in lower limbs and urinary disturbance. The low serum level of B12 with marked macrocytic anemia was noted. On MRI. the pontine lesion extended to the midbrain but no abnormality was found in the spinal cord. We intramuscularly administered B12, resulting in marked improvement of both anemia and neurological symptoms. The brainstem lesion on MRI, however, was unchanged. We assume that B12 deficiency was involved in the formation of CPM/EPM and the neurological symptoms in our patient.

A 79-year-old woman was admitted to our hospital because of forgetfulness for a month followed with rapid development of consciousness disturbance. After admission, the depressed consciousness level fluctuated but continued for more than a month. Thyroid function tests showed increased free T3 and T4 level, lowered level of TSH, and increased anti-TSH receptor antibody titer. A diagnosis of Graves' disease was made but we could find none of thyrotoxic manifestations such as goiter, exophthalmos, tachycardia, high body temperature, or sweating. Administration of thiamazole rapidly improved her consciousness level. It should be kept in mind that hyperthyroidism in elderly could present solely with psychoneurologic symptoms or consiousness disturbance.

A 76-year old man was referred to our department because of several episodes of generalized convulsion followed by a loss of consciousness and the right hemiparesis. The disturbed consciousness and hemiparesis disappeared soon but the personal change persisted thereafter. T2 and diffusion weighted images of MRI taken on the admission showed high intensity lesions in the left medial temporal lobe including the hippocampus. Antibodies (Abs) against herpes simplex virus were not elevated, however, serum titers of antinuclear and anti-SS-A/Ro Abs were extremely elevated. CSF IgG level and IgQ index were increased, and the CSF reacted with 78-kd bands on Western blots of rat brain homogenate. He died of bacterial pneumonia on the 28th day of illness and was autopsied. Malignant tumors were not found in any organs. In the left hippocampus, degeneration and loss of neurons, infiltration of macrophages, and microgliosis were observed. Vasculitis, however, was not found in the lesion. The immunohistochemical study showed that the CSF recognized the cytoplasm of neurons in the human hippocampus and also Purkinje cells. Those immunological and pathological findings thus suggest an antibody-mediated autoimmune limbic encephalitis in our case.

Although an immune-mediated theory has been proposed for the pathogenesis of inclusion body myositis (IBM),1,2⇓ immunosuppressive treatment is not beneficial. We report a case of IBM occurring in a hepatitis C virus (HCV) carrier and showing improvement with the administration of a high dose of interferon-β (IFNβ). A 68-year-old man was admitted because of generalized muscle weakness that progressed for over 8 years. Eight years earlier, he had developed chronic renal failure due to hyperuricemia and was treated with hemodialysis three times a week. At the induction of hemodialysis he was found to be a HCV carrier. Family history was unremarkable. General physical examination revealed no abnormalities other than hepatomegaly. On neurologic examination, symmetric weakness and atrophy of muscles were noted in all extremities. He was unable to stand, remain standing, or walk. Evaluation using manual muscle testing (MMT) scores included scores of 5 (normal) to 0 (complete paralysis). The results were …

A 68-year-old man receiving four times of injection of botulinum toxin type A for cervical dystonia developed acute polyradiculoneuritis 10 weeks after the final injection. He had been complaining of paresthesia in four limbs after the second injection of the treatment. On neurological examination, bilateral facial palsy, bulbar palsy, difficulty of breath, flaccid paralysis of all limbs, sensory disturbance of all modality and areflexia in all limbs, and positive Lasèque sign were noted. Albuminocytological dissociation was present in the CSF and the conduction velocity was significantly impaired in all peripheral nerves examined. After receiving two times of intravenous highdose IgG and two times of pulse therapy, his neurological deficits gradually improved. To our knowledge, this is the third case report of acute polyradiculoneuropathy developing after botulinum toxin therapy, suggesting that botulinum toxin therapy is involved in the pathogenesis in our case.

We followed 24 patients with HTLV-I-associated myelopathy (HAM) for 4-12 years (mean 7 years) and assessed longitudinal changes of their spastic paraparesis by Kurtzke's Disability Status Scale (DSS). The DSS score of spastic paraparesis was unchanged in 18 patients (75%), advanced (worsened) by two in 1 patient and by one in 3 patients, and declined (improved) by one in 2 patients during the follow-up period. The results demonstrated that HAM presents with a variety of clinical courses including spontaneous improvement.

We report a case of acute cervical epidural hematoma clearly demonstrated by fat suppression MR image. A 64-year-old woman was admitted because of quadriparesis with neck pain, both occurred suddenly. She had been healthy except for mild hypertension. No drug was administrated previously. Neurological examination suggested cervical myelopathy. MRI of the cervical spine was performed fifteen hours after the onset. Although no significant intensity change was observed on T1 or T2 image, fat suppression image clearly demonstrated epidural hematoma at the level of C4 to C5 cervical spine. Her symptoms were disappeared spontaneously within seven days. No vascular abnormality was observed by MR angiography. Although MRI is useful to detect epidural hematoma, signal intensity of the hematoma on T1 and T2 image may be unclear within 24 hours, which was shown in our case. We recommend that fat suppression image is helpful to detect epidural hematoma clearly, especially in acute phase.

A 69-year-old woman suffering from Parkinson's disease for 22 years was admitted because of frequent occurrence of paroxysmal dyspnea for 3 months. Her dyspneic attacks consisting of inspiratory stridor and cyanosis occurred mainly during the wearing-off time and continued for less than 30 min. During nonictal period her respiration and phonation were normal and endoscopic investigation of the vocal cord and upper respiratory tract revealed no abnormality. Based on these findings, she was diagnosed to have focal laryngeal dystonia. The 24-hr monitoring with pulseoxymeter recorded frequent occurrence of paroxysmal asymptomatic hopoxemia during both daytime and sleep. With the treatment of tracheostomy and the reduction and alteration of anti-Parkinsonian drugs, dyspneic attacks disappeared gradually. We also confirmed the complete disappearance of paroxysmal asymptomatic hopoxemia with the 24-hr monitoring by pulseoxymeter, which is considered to be a useful method for early detection of asymptomatic focal laryngeal dystonia.

Recent studies showed that the 14-3-3 protein is detectable in the cerebrospinal fluid (CSF) of prion-unrelated neurological diseases, such as meningoencephalitis and myelitis. To investigate the possible association between the amounts of the 14-3-3 protein in the CSF and the clinical severity of multiple sclerosis (MS), its levels were determined by Western blot in the CSF of the patients with relapsing-remitting MS (RRMS) (n=10), secondary progressive MS (SPMS) (n=7), primary progressive MS (PPMS) (n=2), and non-MS inflammatory diseases of the CNS (n=5). The 14-3-3 protein was identified in seven CSF samples, including four patients with SPMS in acute relapse, one with SPMS in remission accompanied by fresh cerebral infarction, one with RRMS in acute relapse, and one with human T-lymphotropic virus type I (HTLV-I)-associated myelopathy. The patients positive for the CSF 14-3-3 protein immunoreactivity showed more severe disability and higher levels of pleocytosis, protein, IgG, beta2-microglobulin, and neuron-specific enolase in the CSF, compared with those negative for its immunoreactivity. Four of these patients exhibited extensive lesions distributed along multiple vertebral segments in the spinal cord on MRI. In contrast, none of the MS patients without an extensive involvement of the spinal cord showed the CSF 14-3-3 protein immunoreactivity. These results suggest that detection of the 14-3-3 protein in the CSF provides a marker for severe inflammation-induced extensive damage of the central nervous system tissues responsible for poor therapeutic responses and irreversible neurological deficits in MS.

Myelin oligodendrocyte glycoprotein (MOG) has attracted considerable attention due to its possible role in multiple sclerosis (MS). Previous studies have shown that MOG-reactive T cells are more commonly detected in MS patients than controls. In this report, we studied human MOG-reactive T cell clones generated from healthy individuals as well as MS patients. Our results indicate that immunoaffinity-purified MOG, which was routinely used in prior studies, is contaminated by anti-MOG antibody (mouse IgG), despite the inability to detect IgG by Western blotting. Here, we used continuous SDS-PAGE, which enabled us to isolate highly purified MOG devoid of contaminating mouse IgG.

The constitutive and heat-inducible expression of HSP105 was investigated in newborn mouse brain cell cultures by Northern blotting, Western blotting and immunocytochemistry. HSP105 was expressed most abundantly in the brain among the various tissues examined. HSP105 mRNA and protein were both present at substantial levels in brain cell cultures under unstressed conditions and up-regulated greatly during 3-48 h following exposure to heat stress (43 degrees C/20 min). HSP105 was expressed in nearly all neurons, oligodendrocytes, microglia and astrocytes with its location of both cytoplasmic and nuclear regions under unstressed and heat-stressed conditions. HSP105 expression was significantly down-regulated in astrocytes following treatment with IL-beta or TNF-alpha (50 ng/ml for 6 days), both of which are known growth-stimulatory cytokines for astrocytes. These results indicate that HSP105 is constitutive and heat-inducible HSP in neurons and glial cells in which its expression is under the control of both stressful stimuli and growth-regulatory factors.

Prion diseases are a group of neurodegenerative disorders characterized by intracerebral accumulation of a protease-resistant prion protein (PrP(Sc)) that causes extensive neuronal degeneration and astrogliosis. The regulation of prion protein (PrP) gene expression by a panel of glial and neuronal cytokines (TNF-alpha, IFN-gamma, IL-1beta, IL-10, and TGF-beta1) was investigated in human neural cell lines by reverse transcription-polymerase chain reaction and Northern blot analysis. The constitutive expression of PrP mRNA was identified in all human neural cell lines and tissues examined including Y79 retinoblastoma, IMR-32 neuroblastoma, SK-N-SH neuroblastoma, U-373MG astrocytoma, KG-1-C glioma, NTera2 teratocarcinoma, NTera2-derived differentiated neurons (NTera2-N), peripheral nerve, and cerebral and cerebellar tissues. In SK-N-SH cells, a 48 hour (h) treatment with 100 ng/ml IL-1beta, 100 ng/ml TNF-alpha, or 100 nM phorbol 12-myristate 13-acetate induced a 2.7- to 4.2-fold increase in the level of PrP mRNA, while the exposure to 100 ng/ml IFN-gamma resulted in a 50% decrease. By contrast, none of these cytokines significantly altered the levels of PrP mRNA in IMR-32, NTera2-N, or U-373MG cells. These results indicate that the PrP gene expression is constitutive in a wide range of human neural cell lines and tissues where it is controlled by cell type-specific regulatory mechanisms.

We report a 64-year-old Japanese man with oculo-neuroborreliosis. His clinical features consisted of polyarthralgia, keratoconjunctivitis, chorioretinitis, optic neuritis, confusion, and polyradiculitis. Assay of antibodies to Borrelia species detected IgG-antibody to B. garinii in both serum and CSF. Progressive declining of serum IgG antibody titer against Borrelia garinii, in parallel with clinical improvement, was observed after administration of ceftriaxone.

Article abstract-We evaluated the usefulness of the MRI criteria for multiple sclerosis (MS) proposed by Paty et al and Fazekas et al in 36 Japanese MS patients, using HTLV-I-associated myelopathy (HAM)/tropical spastic paraparesis (TSP) as the control. Although 30 of 36 HAM/TSP patients had multiple white matter lesions on T2-weighted cranial MRI, only two fulfilled the MRI criteria for MS. At the same time, 31 of the 36 MS patients fulfilled the primary MRI criterion, yielding 93% specificity and 86% sensitivity for the criterion. MS has disease-specific MRI abnormalities.NEUROLOGY 1995;45: 30-33

We report the development of rapid progressive HTLV-I-associated myelopathy (HAM) afte blood transfusion in two immunosuppressed patients, one of whom had aplastic anemia and the other was the recipient of a renal transplant receiving immunosuppressive chemotherapy. Spastic paraparesis developed 11 or 16 months after transfusion and rapidly progressed to a wheelchair-bound state. The present 2 cases suggest that the coexistent immunosuppression may play an important role in the rapid development of HAM in transfusion-acquired cases.

We report a family with autosomal recessive spastic paraplegia. Patient 1 was a 37-year-old woman and patient 2 was her 35-year-old sister. They showed spastic paraplegia with mild truncal ataxia and dysarthria but no dementia, epilepsy, myoclonus, or other involuntary movements. They were the products of a consanguineous marriage but the parents were neurologically normal. We analyzed the CAG repeats of the dentatorubral-pallidoluysian atrophy (DRPLA) gene in the family members. The patients were homozygous for an allele carrying an intermediate size of CAG repeats (41 or 40 repeats) in the DRPLA gene; the parents were heterozygous for an intermediate allele and a normal allele in this gene. Homozygosity for an intermediate allele in the DRPLA gene appears to have resulted in spastic paraplegia different from any DRPLA phenotype.