Autoantibodies in Japanese patients with ocular myasthenia gravis.

INTRODUCTION: The majority of patients with myasthenia gravis (MG) initially present with ocular symptoms, but it is difficult to predict which cases will remain as ocular MG (OMG) or will progress to generalized MG. Herein we evaluated the serologic profile of Japanese OMG and its relationship with clinical features. METHODS: Seventy-three patients with OMG from five Japanese myasthenia gravis (MG) centers were enrolled. Live cell-based assays (CBAs) were used to determine the presence of autoantibodies (Abs) to clustered adult (2α, ß, δ, ε) and fetal (2α, ß, δ, γ) acetylcholine receptor (AChR) isoforms, muscle-specific receptor tyrosine kinase (MuSK), and lipoprotein receptor-related protein-4 (LRP4). RESULTS: Thirty-four of 73 (46.5%) serum samples were positive for Abs against both the adult-type and fetal-type AChR, as expected, but 7 (9.6%) and 2 (2.7%) were positive only for fetal or adult AChR-Abs, respectively. Four (5.4%) samples were positive for MuSK-Abs, but two of these also contained antibodies to fetal AChR or LRP4. Twenty-six (35.6%) samples were seronegative. DISCUSSION: Abs against fetal-specific AChR, MuSK, and LRP4 are found in some patients with OMG. Future studies attempting to predict conversion from ocular symptoms to generalized MG may benefit from measurement of these antibodies.

Very late onset neuromyelitis optica spectrum disorders.

BACKGROUND AND PURPOSE: Neuromyelitis optica spectrum disorder (NMOSD) often presents in the elderly with an insidious onset of symptoms and aggressive progression. There have been anecdotal cases of very late onset (VLO)-NMOSD, but case series reports are rare. The aim of this retrospective study was to clarify the clinical features of VLO-NMOSD. METHODS: According to the age at onset, we classified patients with NMOSD into three subgroups: ≤49 years, early onset NMOSD (EO-NMOSD); 50-69 years, late onset NMOSD (LO-NMOSD); and ≥70 years, VLO-NMOSD. We evaluated the clinical characteristics, magnetic resonance imaging (MRI) findings, laboratory data, and immunotherapies of the groups. RESULTS: Overall, 12 men and 64 women with a median (interquartile range) age at onset and duration of disease of 42.0 (29.0-55.8) years and 70.0 (16.3-143.0) months, respectively, were included. Eight (11%) patients had VLO-NMOSD, 22 (29%) had LO-NMOSD, and 46 (61%) had EO-NMOSD. Patients with EO-NMOSD had a significantly longer interval between episodes as well as time between the first symptom and diagnosis of NMOSD than did those with VLO-NMOSD and LO-NMOSD (p = 0.046). Optic neuritis and nerve lesions on MRI were significantly less frequent in patients with VLO-NMOSD than in those with LO-NMOSD and EO-NMOSD (p = 0.002 and p = 0.028, respectively). In contrast, patients with VLO-NMOSD had higher nadir Expanded Disability Status Scale and Nurick scale scores and a significantly longer spinal lesion length than did those with LO-NMOSD and EO-NMOSD (p = 0.029, p = 0.049, and p = 0.032, respectively). CONCLUSIONS: Patients with VLO-NMOSD tend to develop severe myelitis with long cord lesions but not optic neuritis.

Myasthenia gravis AChR antibodies inhibit function of rapsyn-clustered AChRs.

OBJECTIVE: Direct inhibition of acetylcholine receptor (AChR) function by autoantibodies (Abs) is considered a rare pathogenic mechanism in myasthenia gravis (MG), but is usually studied on AChRs expressed in cell lines, rather than tightly clustered by the intracellular scaffolding protein, rapsyn, as at the intact neuromuscular junction. We hypothesised that clustered AChRs would provide a better target for investigating the functional effects of AChR-Abs. METHODS: Acetylcholine-induced currents were measured using whole-cell patch clamping and a fast perfusion system to assess fast (<2 min) functional effects of the serum samples. The sensitivity, specificity and rapidity of the system were first demonstrated by applying maternal AChR-Ab positive plasmas known to inhibit fetal AChR function in TE671 cells. Eleven previously untested AChR-Ab positive MG sera, 10 AChR-Ab negative MG sera and 5 healthy control sera were then applied to unclustered and rapsyn-clustered human adult AChRs in CN21 cells. RESULTS: The maternal AChR-Ab positive plasmas reduced fetal AChR currents, but not adult AChR currents, by >80% within 100 s. Only 2/11 AChR-Ab positive sera inhibited AChR currents in unclustered AChRs, but 6/11 AChR-Ab positive sera compared with none of the 10 AChR-Ab negative sera (p=0.0020) inhibited rapsyn-clustered AChR currents, and current inhibition by the AChR-Ab positive sera was greater when the AChRs were clustered (p=0.0385). None of the sera had detectable effects on desensitisation or recovery from desensitisation. CONCLUSION: These results show that antibodies can inhibit AChR function rapidly and demonstrate the importance of clustering in exploring pathogenic disease mechanisms of MG Abs.

Efficacy of intravenous methylprednisolone pulse therapy in patients with multiple sclerosis and neuromyelitis optica.

BACKGROUND: No large-scale studies have compared the efficacy of intravenous methylprednisolone pulse therapy (IVMP) for multiple sclerosis (MS) and neuromyelitis optica (NMO). OBJECTIVE: To explain differences in treatment responses of MS and NMO patients to IVMP. METHODS: Changes in neurological symptoms/signs and Expanded Disability Status Scale (EDSS) scores before and within 1 week of IVMP completion were obtained in 2010 at 28 institutions, and retrospectively collated from 271 MS (478 courses) and 73 NMO (118 courses) cases. RESULTS: In MS patients, decreased EDSS score was significant after the first (-0.8 ± 0.9), second (-0.7 ± 0.9), and third (-0.7 ± 0.8) courses (p < 0.05), but not after the fourth (-0.3 ± 0.7) and fifth (-0.5 ± 0.6). However, decreased EDSS score was only significant after the first course (-0.5 ± 1.5, p < 0.05) in NMO patients. EDSS score was significantly decreased in MS compared with NMO patients at the first course (p < 0.05), but not thereafter. Model analysis for EDSS score improvement at the first course, adjusting for covariates, showed significantly greater decreases in MS compared with NMO patients (p < 0.05). CONCLUSION: IVMP is effective in MS from the first to third courses, and in NMO at the first course. Additionally, IVMP is more efficacious in MS than NMO patients, even at the first course.

Effects of a polymorphism in the GFAP promoter on the age of onset and ambulatory disability in late-onset Alexander disease.

Alexander disease (AxD) is a rare neurodegenerative disorder. Most patients with AxD have a de novo dominant missense mutation in the glial fibrillary acidic protein (GFAP) gene. Patients with late-onset AxD exhibit a more variable onset and severity than patients with early-onset AxD, suggesting the existence of factors that modify the clinical phenotype of late-onset AxD. A -250-bp C/A single-nucleotide polymorphism (SNP) of the GFAP promoter (rs2070935) in the activator protein-1 binding site is a candidate factor for modification of the clinical phenotype. We analyzed the SNP in 10 patients with late-onset AxD and evaluated the effects of the SNP on the clinical course of late-onset AxD. Three of four cases with the C/C genotype lost the ability to walk in their 30s or 40s, whereas all six cases with the other genotypes retained the ability to walk throughout their 30s. The age of onset in patients with the C/C genotype was significantly earlier than in patients with the other genotypes (P<0.05). A more severe phenotype was observed in the patient in whom the C allele of rs2070935 was in cis with the GFAP mutation compared with the patient in whom the C allele of rs2070935 was in trans with the GFAP mutation. Our investigation revealed the possibility that the C/C genotype at rs2070935 of the GFAP promoter in late-onset AxD was associated with an earlier onset and a more rapid progression of ambulatory disability compared with the other genotypes.

[Novel autoantibodies in myasthenia gravis].

Patients with myasthenia gravis(MG) are divided into three groups: (1) acetylcholine receptor antibody positive MG: 80%, (2) muscle-specific receptor tyrosine kinase (MuSK) antibody positive MG: 5-10%, and (3) double seronegative MG. In 2011, autoantibodies (Abs) against low-density lipoprotein receptor-related protein 4(Lrp4) were identified in Japanese MG patients and thereafter have been reported in Germany and USA. In other Lrp4 Ab papers, Lrp4 Ab positive sera inhibited agrin-induced aggregation of AChRs in cultured myotubes, suggesting a pathogenic role regarding the dysfunction of the neuromuscular endplate. Anti-MuSK autoantibodies were revealed to block binding of collagen Q (ColQ) to MuSK. Anti-Kv1.4 antibodies targeting alpha-subunits(Kv1.4) of the voltage-gated potassium channel occurs frequently among MG patients with thymoma. Further understandings of neuromuscular junction structure and functions through newly discovered autoantibodies may provide more specific clinical information and treatments in MG.

Immunotherapy for ocular myasthenia gravis: an observational study in Japan.

Background: Treatment for ocular myasthenia gravis (OMG) has not yet been well established. Few reports have been published on the clinical practice and outcomes of OMG. Objectives: We investigated treatment of OMG and its outcomes in Japan.We investigated treatment of OMG and its outcomes in Japan. Design: We performed a retrospective cross-sectional survey of OMG patients from eight hospitals in Japan. Methods: Clinical information, including sex, age at onset, initial symptoms, autoantibodies, clinical course, treatment history, complications, and outcomes, was obtained. In addition, we recorded the total number of patients with MG and OMG separately. Results: In total, 135 patients with OMG (67 men, 68 women) were included. Treatment of OMG was not simple and involved various immunotherapeutic strategies. Eight patients went into remission spontaneously without immunotherapy. A total of 117 patients showed improvements after treatment, whereas 10 patients showed refractory responses to treatment. Overall outcomes were good; however, symptoms persisted in 60.7% of patients even after treatment. Among 90 patients who received immunotherapy, only two showed a refractory response. Meanwhile, for 45 patients who did not receive immunotherapy, 8 were refractory. Thus, the rate of refractory disease in the group with immunotherapy was significantly lower (p = 0.001, u-test) than in the group without immunotherapy. The proportion of generalized MG patients among all MG cases was low in medical centers where immunotherapy for OMG was frequently performed. Conclusion: Although the overall prognosis for patients with OMG was good, symptoms remained in more than half of the patients. Immunotherapy, including corticosteroids, may be beneficial for patients with OMG. Plain language summary: Is immunosuppressive therapy beneficial for myasthenia gravis patients with ocular symptoms only? Patients with ocular myasthenia gravis (OMG) have only eye symptoms for more than 2 years. Whether this condition is an initial stage of the disease before eventually progressing to generalized myasthenia gravis (gMG) is still uncertain. Different from gMG, OMG is not life-threatening. But eye symptoms often cause troublesome problems in life. Doctors have treated OMG patients similarly to patients with gMG. There is no standard clinical practice for OMG. In this study, we examined how patients with OMG were treated at eight different specialist centers in Japan. In 135 patients with OMG, 8 patients became symptom free without treatment, 117 patients showed improvements after treatment, whereas 10 patients did not get well. Overall outcomes were good, but symptoms remained in 60.7% of patients even after treatment. Among 90 patients who received one or more immunotherapies, only 2 did not get well. Meanwhile, for 45 patients who did not receive immunotherapy, 8 remained ill. We found that treatment of OMG was not simple and often needed multiple immunotherapies. Administering immunotherapy, including corticosteroids, may be beneficial for patients with OMG.

Clinical features of neuromyelitis optica in a large Japanese cohort: comparison between phenotypes.

OBJECTIVE: To analyse clinicoepidemiological features of neuromyelitis optica in a large cohort and to compare the differences between onset age, gender and clinical phenotypes. METHODS: Antiaquaporin-4 antibody (AQP4-ab) levels were tested in 2366 serum samples of patients diagnosed as having central nervous system inflammatory demyelinating disorders by their referring physicians. AQP4-ab was measured by indirect immunofluorescence staining using human AQP4-transfected HEK 293 cells. A blinded analysis was performed and was combined with clinical information. RESULTS: A total of 583 patients (91.4% women) were AQP4-ab-positive. The average onset age was 42.9±15.9 years. According to MRI studies, spinal-cord lesions were detected in 85.3% of the patients, longitudinally extensive transverse myelitis in 72.7% and cerebral lesions in 51.1%. Unilateral or bilateral blindness was observed in 16.2% of patients, 19.8% were associated with Sjögren syndrome, and 13.6% were associated with thyroid diseases. Myelin basic protein was detected in the cerebrospinal fluid of 57.5% patients. In addition, men presented with an older onset age, a greater number of brainstem MRI lesions and positive myelin basic protein in the cerebrospinal fluid. All child-onset patients (<15 years, n=9) presented with optic neuritis as the first symptom, while older-onset patients presented with myelitis. Twenty patients initially developed limited brain lesions, and seven of these patients did not develop optic or spinal lesions during the 1-5-year follow-up period. CONCLUSIONS: The clinical characteristics of AQP4-ab-positive patients were similar. However, optic neuritis was more common in paediatric patients, while myelitis was more common in older patients. A small number of patients exhibited only cerebral, brainstem, or cerebellar lesions during the initial several years and lower Extended Disability Status Scale scores.

HLA genotype-clinical phenotype correlations in multiple sclerosis and neuromyelitis optica spectrum disorders based on Japan MS/NMOSD Biobank data.

HLA genotype-clinical phenotype correlations are not established for multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). We studied HLA-DRB1/DPB1 genotype-phenotype correlations in 528 MS and 165 NMOSD cases using Japan MS/NMOSD Biobank materials. HLA-DRB1*04:05, DRB1*15:01 and DPB1*03:01 correlated with MS susceptibility and DRB1*01:01, DRB1*09:01, DRB1*13:02 and DPB1*04:01 were protective against MS. HLA-DRB1*15:01 was associated with increased optic neuritis and cerebellar involvement and worsened visual and pyramidal functional scale (FS) scores, resulting in higher progression index values. HLA-DRB1*04:05 was associated with younger onset age, high visual FS scores, and a high tendency to develop optic neuritis. HLA-DPB1*03:01 increased brainstem and cerebellar FS scores. By contrast, HLA-DRB1*01:01 decreased spinal cord involvement and sensory FS scores, HLA-DRB1*09:01 decreased annualized relapse rate, brainstem involvement and bowel and bladder FS scores, and HLA-DRB1*13:02 decreased spinal cord and brainstem involvement. In NMOSD, HLA-DRB1*08:02 and DPB1*05:01 were associated with susceptibility and DRB1*09:01 was protective. Multivariable analysis revealed old onset age, long disease duration, and many relapses as independent disability risks in both MS and NMOSD, and HLA-DRB1*15:01 as an independent risk only in MS. Therefore, both susceptibility and protective alleles can influence the clinical manifestations in MS, while such genotype-phenotype correlations are unclear in NMOSD.

[Case of non-alcoholic pellagra following gastrectomy].

A 67-year-old man was admitted to our hospital in May 2006 because of gait disturbance, delirium and myoclonus along with dermatitis and diarrhea. Those symptoms became worse in 3 months. He had undergone a gastrectomy, including a fundectomy and jejunal pouch interposition, for early gastric cancer at the age of 65 years. He had no habit of drinking alcohol or unbalanced diet. The triad of typical dermatitis, delirium, and diarrhea led to a diagnosis of pellagra, and all the symptoms disappeared after intravenous administration of nicotinate and vitamins. With a gastrectomy, fundectomy performed with jejunal pouch interposition has been regarded as a superior method for postoperative nutrition, but may cause vitamin deficiency. Thus, vitamin deficiency must be considered as a potential cause in neurologic patients who underwent surgical treatment for disorders of digestive tract, regardless of the procedure utilized.

Serological and experimental studies in different forms of myasthenia gravis.

Antibodies to the acetylcholine receptor (AChR) have been recognized for over 40 years and have been important in the diagnosis of myasthenia gravis (MG), and its recognition in patients of different ages and thymic pathologies. The 10-20% of patients who do not have AChR antibodies are now known to comprise different subgroups, the most commonly reported of which is patients with antibodies to muscle-specific kinase (MuSK). The use of cell-based assays has extended the repertoire of antibody tests to clustered AChRs, low-density lipoprotein receptor-related protein 4, and agrin. Autoantibodies against intracellular targets, namely cortactin, titin, and ryanodine receptor (the latter two being associated with the presence of thymoma), may also be helpful as biomarkers in some patients. IgG4 MuSK antibodies are clearly pathogenic, but the coexisting IgG1, IgG2, and IgG3 antibodies, collectively, have effects that question the dominance of IgG4 as the sole pathologic factor in MuSK MG. After a brief historical review, we define the different subgroups and summarize the antibody characteristics. Experiments to demonstrate the in vitro and in vivo pathogenic roles of MuSK antibodies are discussed.

[A case of alcoholic with vitamin B12 deficiency presenting central pontine and extrapontine myelinolysis on MRI].

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.

The Cross-Sectional Area of Paraspinal Muscles Predicts the Efficacy of Deep Drain Stimulation for Camptocormia.

BACKGROUND: Camptocormia, a disturbance of posture, is a well-described clinical feature of PD and other parkinsonian syndromes. Previous reports have shown that DBS of the subthalamic nucleus (STN) or globus pallidus internus is effective in treating camptocormia. However, the efficacy of DBS for camptocormia varies. OBJECTIVE: To determine a clinical marker for selecting an appropriate therapy for camptocormia, a disabling manifestation of Parkinson's disease (PD) that has a variable response to systemic and local therapies. METHODS: We obtained pre-operative lumbar magnetic resonance imaging of 14 consecutive PD patients with camptocormia who underwent subthalamic nucleus deep brain stimulation (STN-DBS) in this retrospective-designed study. Lumbar MRI was performed three to six months prior to the operation. We measured the cross-sectional area (CSA) and width of each participant's paraspinal muscles. RESULTS: Four (28.6%) patients were effective (EF), five (35.7%) were partially effective (PE), and five (35.7%) were non-effective (NE) to STN-DBS. The lumbar paraspinal CSA and width were significantly larger in the EF group than in the PE and NE groups. CONCLUSIONS: The CSA of paraspinal muscles and erector spinae width can be good predictive markers for improving camptocormia in patients with PD after deep brain stimulation.

[Case of Graves' disease presenting only with rapid consciousness disturbance].

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.

[An autopsied case of limbic encephalitis associated with extremely high titers of anti-SS-A antibodies in serum and anti-neuronal antibodies in CSF].

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.

The Effectiveness of the Stereotactic Burr Hole Technique for Deep Brain Stimulation.

Deep brain stimulation (DBS) is performed by burr hole surgery. In microelectrode recording by multi-channel parallel probe, because all microelectrodes do not always fit in the burr hole, additional drilling to enlarge the hole is occasionally required, which is time consuming and more invasive. We report a stereotactic burr hole technique to avoid additional drilling, and the efficacy of this novel technique compared with the conventional procedure. Ten patients (20 burr holes) that received DBS were retrospectively analyzed (5 in the conventional burr hole group and 5 in the stereotactic burr hole group). In the stereotactic burr hole technique, the combination of the instrument stop slide of a Leksell frame and the Midas Rex perforator with a 14-mm perforator bit was attached to the instrument carrier slide of the arc in order to trephine under stereoguidance. The efficacy of this technique was assessed by the number of additional drillings. Factors associated with additional drilling were investigated including the angle and skull thickness around the entry points. Four of the 10 burr holes required additional drilling in the conventional burr hole group, whereas no additional drilling was required in the stereotactic burr hole group (p = 0.043). The thicknesses in the additional drilling group were 10.9 ± 0.9 mm compared to 9.1 ± 1.2 mm (p = 0.029) in the non-additional drilling group. There were no differences in the angles between the two groups. The stereotactic burr hole technique contributes to safe and exact DBS, particularly in patients with thick skulls.

[Left-sided metamorphopsia of the face and simple objects caused by an infarction at the right side of the splenium of the corpus callosum].

A 78-year-old woman noticed that people's eyes and the right nasal foramens located in her left visual field looked smaller than those observed in the right. The woman reported no change in shape regarding facial outlines or scenic objects. Magnetic resonance imaging revealed an acute infarction of the right side of the splenium of the corpus callosum. Close examination revealed that her metamorphopsia affected the left side of her visual field, especially influencing facial components, particularly the eye. The woman had similar reactions to photographs of several kinds of animals, realistic portraits of humans, and caricatured humans. Meanwhile, presentings caricature human face at a 90° rotation elicited metamorphopsia in eyebrows located on the left side of a picture, but not the eyes. She also reported a change of shape or color tone for geometric objects. The patient's only symptom was metamorphopsia, and she did not show any other neurological defects such as callosal disconnection syndrome. Furthermore, objects that were affected by the patient's metamorphopsia (e.g. facial component especially the eye, and simple geometric figures) may be easy images to use in order to detect this type of distorted vision.

[A case of subacute combined degeneration with normal serum vitamin B12 level].

A 40-year-old woman was admitted to our hospital because of pancytopenia with megaloblastic anemia. Two months later she complained of rapidly progressive gait disturbance and numbness in the distal part of limbs. She also told that her hair had turned totally gray in the third decade. Neurologically, mental state, cranial nerves and cerebellar functions were normal. Superficial sensations were impaired below the lower thoracic level and deep sensations were completely lost in the lower limbs. Moderate weakness was found in the lower limbs, symmetrically. Deep tendon reflexes were diminished in the upper limbs and absent in the lower limbs. Babinski's reflex was positive bilaterally. MR images of the spinal cord showed hyperintensity in the posterior column below the thoracic cord. Although the serum level of vitamin B12 was within normal range, serum homocysteine level was elevated markedly. Under the diagnosis of subacute combined degeneration (SCD) due to possible vitamin B12 deficiency, the treatment with intravenous injections of 500 micrograms/day of mecobalamin was undertaken. Muscle strength and sensory impairment improved progressively and she became able to walk with a cane. The coloration of her gray hair was also noted. After treatment, pancytopenia and megaloblastic anemia also markedly improved. Vitamin B12 became high in serum concentration and the serum level of homocysteine became normal. These clinical and laboratory findings support the diagnosis of SCD with normal serum level of vitamin B12 in our case, suggesting that the level of vitamin B12 in serum does not always correlate with that in tissue and, therefore, SCD should not be excluded just only by the reason of normal serum vitamin B12 level.

[A case report of acute polyradiculoneuritis developing after multiple injections of botulinum toxin for cervical dystonia].

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.

[A case of Alexander disease suspected juvenile-onset and exacerbating after long stationary state].

We report the case of a 40-year-old woman with Alexander disease. She experienced single seizure as 1-year-old, and became less active after that. Her academic records in elementary school were poor. However, she graduated from junior college and was later employed as a clerk for a short duration. Her parents, who lived with her noticed her apathy when she was 38, and gait disturbance soon after. At the age of 40, she was admitted to a hospital because of a fall and was referred to us. Brain magnetic resonance imaging (MRI) showed significant leukodystrophy with frontal predominance, and cervical MRI revealed mild cervical cord atrophy with dilated central canal. We performed genetic analysis and found the R79H variant of the gene encoding the glial fibrillary acidic protein. The patient was diagnosed with Alexander disease and suspedted juvenile-onset on the basis of the genetic analysis and MRI findings. Patients with juvenile Alexander disease have been previously reported to have variable survival, ranging from the early teens to the 20's and 30's. Our patient may suggest that natural history of this disease is more variable than previously thought.