Consensus Paper: Neuroimmune Mechanisms of Cerebellar Ataxias.

In the last few years, a lot of publications suggested that disabling cerebellar ataxias may develop through immune-mediated mechanisms. In this consensus paper, we discuss the clinical features of the main described immune-mediated cerebellar ataxias and address their presumed pathogenesis. Immune-mediated cerebellar ataxias include cerebellar ataxia associated with anti-GAD antibodies, the cerebellar type of Hashimoto's encephalopathy, primary autoimmune cerebellar ataxia, gluten ataxia, Miller Fisher syndrome, ataxia associated with systemic lupus erythematosus, and paraneoplastic cerebellar degeneration. Humoral mechanisms, cell-mediated immunity, inflammation, and vascular injuries contribute to the cerebellar deficits in immune-mediated cerebellar ataxias.

Immunoadsorption therapy for neuromyelitis optica spectrum disorders long after the acute phase.

Neuromyelitis optica (NMO) is a severe inflammatory demyelinating disease with exacerbations involving recurrent or bilateral optic neuritis and longitudinally extensive transverse myelitis. Pulse steroid therapy is recommended as the initial, acute-phase treatment for NMO. If ineffective, treatment with plasma exchange (PE) should commence. However, no evidence exists to support the effectiveness of PE long after the acute phase. Immunoadsorption therapy (IA) eliminates pathogenic antibodies while sparing other plasma proteins. With IA, side effects of PE resulting from protein substitution can be avoided. However, whether IA is effective for NMO remains unclear. We describe a patient with anti-aquaporin-4-positive myelitis who responded to IA using a tryptophan polyvinyl alcohol gel column that was begun 52 days after disease onset following the acute phase. Even long after the acute phase when symptoms appear to be stable, IA may be effective and should not be excluded as a treatment choice.

Gluten ataxia in Japan.

Gluten ataxia, a type of cerebellar ataxia caused by exposure to gluten in sensitive patients, has been considered common in the USA and Europe, and rare in Asia. We measured anti-deamidated gliadin peptide (DGP) antibody levels in 49 patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, or cancer, as well as those who were receiving oral administration of phenytoin. Anti-DGP antibody was positive in eight (16.3 %) patients, five of these patients were positive only for IgA, one was positive for both IgG and IgA, and two were positive only for IgG antibody. Intravenous immunoglobulin was administered to five of the eight patients, and was markedly effective in one, moderately effective in two, and ineffective in two. Steroid therapy was administered to four patients, but none had an apparent response. Ataxia symptoms improved in one patient treated with a gluten-free diet only. Although it had been thought to be extremely rare in Asia, we speculate that more than 10 % of cerebellar ataxia patients in Japan currently have gluten ataxia; therefore, measuring anti-DGP antibody or anti-gliadin antibody in cerebellar ataxia patients in Asia is important.

Low-titer anti-GAD-antibody-positive cerebellar ataxia.

The majority of cases of anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar ataxia are reported to have high levels of anti-GAD antibody, and the diagnostic value of low titers of anti-GAD antibody in a patient with cerebellar ataxia is still unknown. The purpose of this study was to verify the characteristics of low-titer-anti-GAD-antibody-positive cerebellar ataxia patients and the diagnostic value of low titers of anti-GAD antibody in patients with cerebellar ataxia. The subjects were six patients positive for low-titer GAD antibody (<100 U/mL). We examined them with MRI, including voxel-based morphometry, and with single-photon emission computed tomography and monitored the GAD antibody index in the cerebrospinal fluid. The levels of antineuronal, antigliadin, anti-SS-A, antithyroid antibodies, and of vitamins E, B1, and B12 were determined. Thoracic and abdominal CT scans were performed to exclude a paraneoplastic origin. We treated three patients with immunotherapy. All cases showed cortical cerebellar atrophy. The GAD antibody index in three of the five patients reviewed was >1.0. Two of the six patients were thyroid antibody-positive, and one was both antinuclear- and anti-SS-A antibody-positive. After the administration of immunotherapy to three patients, two showed clear effectiveness, and one, transient effectiveness. Effectiveness was greatest in the two patients with familial occurrence of the disease. In cerebellar ataxia, regardless of family history or isolated illness, it is critical to measure the GAD antibody level, and, even with a low titer level, if the result is positive, immunotherapy should be considered.

[Usefulness of an anti-mouse cerebellar tissue-derived antigen antibody test in predicting immunotherapy efficacy in patients with idiopathic cerebellar ataxia].

BACKGROUND: Autoimmune cerebellar ataxia (AICA) is a general term for diseases in which the cerebellum is damaged by an autoimmune mechanism. For the diagnosis of the AICA, anti-thyroid antibodies (anti-thyroid peroxidase antibody and anti-thyroglobulin antibody), anti-glutamic acid decarboxylase (GAD) antibodies, and anti-gliadin antibodies are measured. Immunotherapy is known to be effective for AICA, but some patients with effective immunotherapy lack autoantibodies associated with cerebellar ataxia. The purpose of this study was to clarify whether the effectiveness of immunotherapy in patients with suspected AICA could be predicted by anti-mouse cerebellar tissue-derived antigen antibody tests. METHODS: This study was conducted on 25 patients with idiopathic cerebellar ataxia (excluding multiple system atrophy, hereditary spinocerebellar degeneration, cancer-bearing patients, and patients taking phenytoin) who received immunotherapy from 2005 to 2016 at Tokyo Medical University Hachioji Medical Center. The patients were suspected of having AICA because they were positive for cerebellar ataxia-related autoantibodies (anti-thyroid antibody, anti-GAD antibody, anti-gliadin antibody, or anti-transglutaminase 6 antibody) or other autoantibodies. Antibodies that bind to mouse cerebellar tissue-derived antigens were defined as "anti-mouse cerebellar tissue-derived antigen antibodies" in this study, and their IgG-class antibodies were comprehensively measured using a slot blot. RESULTS: Anti-mouse cerebellar tissue-derived antigen antibody test results were correlated with immunotherapy efficacy. Furthermore, the combination of anti-mouse cerebellar tissue-derived antigen and anti-GAD antibody tests could predict the effectiveness of immunotherapy with 83% sensitivity and 100% specificity, while the combination of the anti-mouse cerebellar tissue-derived antigen, anti-GAD, and anti-gliadin (IgA class) antibody tests could predict the effectiveness of immunotherapy with 94% sensitivity and 86% specificity. CONCLUSION: Anti-mouse cerebellar tissue-derived antigen antibody tests could help to provide useful information for immunotherapy administration to patients with idiopathic cerebellar ataxia suspected to be AICA.

[A case of autoimmune polyglandular syndrome-related Parkinsonian syndrome that required differentiation from multiple system atrophy].

A 76-year-old woman experienced unsteadiness in walking in 1996. On the basis of clinical and imaging findings, the patient was diagnosed multiple system atrophy. During follow-up, her gait disturbance became aggravated leaving her unable to walk unaided. She was referred to our department in 2003. T2-weighted images on brain magnetic resonance imaging (MRI) revealed low signal intensity in both putamina and a linear high-signal-intensity area on their outsides. Single photon emission computed tomography (SPECT) disclosed a reduced blood flow in both corpora striata. These findings were consistent with the diagnosis of Parkinsonian-type multiple system atrophy. The patient had anti-glutamic acid decarboxylase (GAD) antibody-positive type 1 diabetes mellitus and a normal thyroid function, and was positive for antithyroid antibodies. She was not found to have anemia on blood tests, but was positive for intrinsic factor antibodies. Vitamin B12 was markedly reduced to below the detection limit. The findings suggested that the patient's condition was autoimmune polyglandular syndrome type 3. In 2004, treatment with intramuscular injection of vitamin B12 was initiated, after which the patient's gait disturbance was improved and she was able to walk unaided. In 2009, her unsteady gait returned and was again unable to walk unaided. Autoimmune encephalopathy was suspected, and thus high-dose intravenous immunoglobulin therapy was performed. Following treatment she was able to walk steadily. This case suggests the importance of detailed tests for autoantibodies, including endocrine autoantibodies, and the measurement of vitamin B12 and total homocysteine levels in view of the possibility of autoimmune polyglandular syndrome-related neurological disorders in diabetic patients with intractable neurological disorders that are difficult to diagnose.

[A case of lung adenocarcinoma presenting with chorea with bilateral basal ganglial lesions on MRI].

The patient, a 63-year-old man, experienced the subacute onset of chorea, for which his family doctor prescribed oral haloperidol. However, the involuntary movements gradually worsened, and the patient was referred and admitted. High-signal lesions were seen in the caudate nucleus, putamen and globus pallidus bilaterally on MRI T2-weighted and FLAIR images. Chest CT, FDG-PET and tissue biopsies also revealed that the patient had lung adenocarcinoma with multiple lymph node metastases. The patient was diagnosed as having paraneoplastic chorea associated with primary lung adenocarcinoma. Antineuronal antibodies, such as anti-CRMP-5 and anti-Yo antibodies, were absent. The patient received steroid pulse therapy, oral prednisolone therapy, and concurrent radiochemotherapy. Chorea and high-signal lesions in the corpus striatum bilaterally on MRI improved quickly, and the mediastinal lymph node swelling also improved. The patient has been stable for 3 years since the onset of his symptoms. As the prognosis of paraneoplastic chorea is relatively favorable in some patients, it should be considered in the differential diagnosis of patients with chorea.

[A case of anti-gliadin-antibody-positive cerebellar ataxia effectively treated with intravenous immunoglobulin in which voxel-based morphometry and FineSRT were diagnostically useful].

We present the case of a 51-year-old man with a 5-year history of slowly progressive gait ataxia and dysarthria who showed a wide-based gait requiring assistance. The patient's score on the Revised Hasegawa Dementia Scale (HDS-R) was 22/30 and constructional apraxia was also evident. Cerebrospinal fluid analysis showed 3 cells/microl, and the protein concentration was 58 mg/dl. Brain MRI showed no evidence of cerebellar atrophy, and SPECT-eZIS showed no decrease in cerebellar blood flow. However, voxel based morphometry (VBM) and FineSRT revealed cortical cerebellar atrophy and reduced cerebellar blood flow. In addition, the patient tested positive for anti-gliadin (IgA) and anti-SS-A/Ro antibodies, and was thus diagnosed as having autoimmune cerebellar ataxia. The patient showed positive response to intravenous immunoglobulins (IVIg) and regained the ability to walk unassisted. The HDS-R score also improved to 27/30. If cortical cerebellar atrophy can be diagnosed in the early stages in patients with progressive cerebellar ataxia by imaging techniques such as MRI-VBM and FineSRT, and if such patients test positive for anti-gliadin, anti-GAD or anti-thyroid antibodies, it is possible that they have autoimmune cerebellar ataxia. The commencement of immunotherapy including IVIg should be considered in such

Transient hemiballism caused by a small lesion of the subthalamic nucleus.

Hemiballism is most commonly caused by ischemic stroke and most cases have a favorable prognosis. Lesions directly involving the subthalamic nucleus (STN) are the cause of a minority of cases but are usually associated with poor prognosis. We report two patients with a small STN lesion who presented with transient hemiballism. A small lesion confined to and only focally affecting the STN may cause hemiballism yet may have excellent outcome. Precise evaluation of the affected region with MRI is useful in predicting the prognosis.

[Cerebellar Ataxia and Autoantibodies].

The cerebellum is one of the main targets in the central nervous system for autoimmunity. Immune-mediated cerebellar ataxias include gluten ataxia, GAD antibody-associated cerebellar ataxia, Hashimoto's encephalopathy, and paraneoplastic cerebellar degeneration. Autoimmune cerebellar ataxia may be of either insidious or subacute onset, and vertigo or transient neurological symptoms occur in some patients before the onset of the disease, in contrast to spinocerebellar degeneration. If autoimmune cerebellar ataxia is suspected, early diagnosis and introduction of treatment are very important. For diagnosis, testing for gliadin antibody, TG6 antibody, GAD antibody, thyroid antibody, and anti-neuronal antibodies, including mGluR1, is useful. Magnetic resonance imaging voxel-based morphometry is also useful because it can detect cortical cerebellar atrophy of autoimmune cerebellar ataxia, different from spinocerebellar ataxia. As for treatment, it is important to remove autoimmune triggering factors (e.g.,dietary gluten or neoplasm). When the ataxia symptoms are causing hindrances in the daily life, it is worth considering immunotherapy including IVIg, steroid therapy and so on.

[Gluten Ataxia: Anti-Transglutaminase-6 Antibody as a New Biomarker].

Gluten-related disorders (GRDs) are conditions that develop in response to the common trigger of gluten ingestion and manifest as a variety of clinical symptoms. GRDs have been considered rare in Asian countries, including Japan, because of lower consumption of wheat products than in Europe and the U.S.A. and differences in genetic background. Recently, however, GRDs, such as celiac disease and gluten ataxia, have been reported in Japan, albeit sporadically and their presence is now recognized in this country. Gluten ataxia is defined as an anti-gliadin antibody positive sporadic ataxia. Recently, it was reported that the presence of anti-transglutaminase-6 (TG6) antibody can be used to diagnose gluten ataxia. Herein, we will review evidence relating to gluten ataxia and report two cases of anti-TG6 antibody positive gluten ataxia. In patients with gluten ataxia, sensory disturbance is generally considered to be so mild that it contributes minimally to ataxia. However, our patients showed a positive Romberg sign. Deep sensory disturbance, in addition to cerebellar disturbance, may have been involved in the clinical symptoms of our cases.

[Efficacy of intravenous immunoglobulin for slowly progressive cerebellar atrophy].

In slowly progressive cerebellar atrophy, it has been difficult to suppress the progression of cerebellar symptoms because no effective therapeutic agents are available when the diagnosis of secondary cerebellar atrophy, such as drug-induced cerebellar atrophy or paraneoplastic syndrome, is denied. However, amongst the different forms of slowly progressive cerebellar atrophy, some may be associated with treatable immune abnormalities. Therefore, we investigated the therapeutic efficacy of intravenous immunoglobulin (IVIg) in 9 patients with slowly progressive cerebellar atrophy (4 sporadic atrophy; 5 hereditary atrophy). The results were as follows. With regard to the 4 cases of sporadic atrophy, gait ataxia and imbalance were markedly improved in 1 patient who had positive anti-GAD antibody. Moderate improvement was seen in 1 patient and slight improvement in 2. With regard to the 5 cases of hereditary atrophy, gait ataxia and imbalance were moderately improved in 2 patients with SCA3, although there were 3 non-responders. In conclusion, our study results suggested that not only patients with sporadic atrophy but also some with hereditary atrophy may respond to therapy. In cases of slowly progressive cerebellar atrophy in which the cause may be due to immune abnormality, we should consider instituting active immunotherapy when a pathological state caused by immune abnormality is suspected after extensive evaluations of autoantibodies, including anti-GAD, anti-thyroid and anti-gliadin antibody, malignancy, and so on.

A case considered gluten ataxia with anti-TG6 IgA antibodies.

An 81-year-old woman presented with a chief complaint of gait disturbance. Brain magnetic resonance imaging (MRI) showed mild cerebellar atrophy and cerebral blood flow scintigraphy revealed reduced blood flow in the cerebellum. The patient was diagnosed with cortical cerebellar atrophy, and was given taltirelin hydrate, but symptoms slowly progressed. Thirteen years after onset, a positive result for anti-transglutaminase 6 (TG6) IgA antibodies was identified, and gluten ataxia was diagnosed. Despite steroid therapy and gluten-free diet therapy, no improvements were seen, and independent walking became difficult for the patient. High-dose intravenous immunoglobulin therapy resulted in improvements in the Posture and Gait subscore of the International Cooperative Ataxia Rating Scale (ICARS) from 15 to 11 points, and the patient regained the ability to walk independently. Gluten ataxia are rarely reported in Japan and anti-TG6 antibodies were considered useful for its diagnosis.

Prevalence of Autoantibodies and the Efficacy of Immunotherapy for Autoimmune Cerebellar Ataxia.

OBJECTIVE: Autoimmune cerebellar ataxias were recently reported to be treatable. However, the proportion of patients with cortical cerebellar atrophy of unknown etiology with autoimmune-associated cerebellar ataxia and the actual effectiveness of immunotherapy in these diseases remain unknown. METHODS: We measured the level of autoantibodies (including anti-gliadin antibody, anti-glutamic acid decarboxylase (GAD) antibody, and anti-thyroid antibody) in 58 Japanese patients with cerebellar ataxia, excluding those with multiple system atrophy, hereditary spinocerebellar ataxia, cancer, or those who were receiving phenytoin, and the efficacy of immunotherapy was assessed. RESULTS: Thirty-one of 58 (53%) patients were positive for anti-GAD antibody, anti-gliadin antibody, or anti-thyroid antibody. Seven of the 12 anti-gliadin antibody-positive patients, three of the four anti-GAD antibody-positive patients, and three of the six anti-thyroid antibody-positive patients responded well to immunotherapy, indicating that 59% of patients with ataxia-associated antibody-positive cerebellar ataxia undergoing immunotherapy responded well. CONCLUSION: Some patients with cerebellar ataxia have autoimmune conditions and diagnosing autoimmune cerebellar ataxia is therefore an important component in the care of patients with this disease entity.

Transthyretin Val 107 in a Japanese patient with familial amyloid polyneuropathy.

A 70-year-old Japanese man with amyloid polyneuropathy associated with a Val 107 transthyretin (TTR) mutation is reported. The patient presented with carpal tunnel syndrome, cardiomyopathy, bulbar palsy, dysphonia and polyneuropathy. DNA analysis of the TTR gene revealed a point mutation responsible for substitution of valine for isoleucine at position 107 of the TTR molecule. Taken together with reports of patients with the same TTR variant, Val 107 TTR mutation is probably associated with a clinical phenotype characterized by carpal tunnel syndrome, cardiomyopathy, bulbar palsy and dysphonia. This case implies a worldwide distribution of the Val 107 TTR mutation with a common clinical phenotype, despite different ethnic background.

[A case of migrainous infarction accompanying idiopathic thrombocytopenic purpura].

We reported a 31 year-old man with repeated episodes of migraine at a frequency of about once a week on and after January, 2000. In January 2001, scintillating scotoma and pulsating headache appeared followed by left hemianopsia. His platelet count decreased to 80,000/microliter and high intensity areas were observed in the right occipital lobe and hippocampal gyrus on the FLAIR image of brain MRI. Subsequently performed brain MRA and vertebral angiography revealed segmental stenosis and obstruction in the right posterior cerebral artery. Under the diagnosis of migrainous infarction, sodium ozagrel and lomerizine hydrochloride were administered. Idiopathic thrombocytopenic purpura was additionally diagnosed based on the decreased platelet count which was then treated with predonisolone. After these treatment, his migraine attack disappeared. In this patient, platelet destruction due to idiopathic thrombocytopinic purpura and subsequent release of serotonin seemed to have involved in the occurrence of migrainous infarction.

[The utility of voxel-based morphometry in the diagnosis of spinocerebellar degeneration].

We evaluated atrophic sites in the brainstem and cerebellum in the patients with spinocerebellar degeneration by using voxel-based morphometry (VBM). Gray matter atrophy was found extensively in both the cerebellar hemispheres and vermis of subjects presenting the cerebellar variant of multiple system atrophy (MSA-C; n=9). In addition, remarkable white matter atrophy was observed in the middle cerebellar peduncle, brainstem, and cerebellar hemispheres. In contrast, gray matter atrophy was not apparent in the cerebellar hemispheres or vermis of subjects in the SCA3 group (n=6), whereas intense white matter atrophy was visible in the middle cerebellar peduncle, brainstem, and cerebellar hemispheres. White matter atrophy was also observed in the brainstem and surrounding the dentate nucleus in both cases of dentatorubral-pallidoluysian atrophy (DRPLA) (n=2), whereas gray matter atrophy of the cerebellum was not remarkable. In both the SCA6 group (n=3) and the SCA31 group (n=2), gray matter atrophy was prominent in the cerebellar hemispheres and vermis; however, white matter atrophy was not found in the middle cerebellar peduncle and brainstem, whereas symmetric atrophy of white matter was found in the vicinity of the dentate nucleus. In each of these diseases, VBM findings were consistent with the pathological findings; therefore, VBM can be considered a useful tool for the diagnosis of spinocerebellar degeneration.

[Autoantibodies associated with autoimmune-mediated cerebellar ataxia].

Various autoantibodies are associated with autoimmune-mediated cerebellar ataxia. Anti-Yo, -Zic, -CARPVIII, -Tr, -Ri, -Hu, -Ma, -CRMP-5, -ANNA-3, -PCA-2, -VGCC, and -mGluR antibodies (Abs) are found in paraneoplastic cerebellar ataxia, whereas anti-GAD, -thyroid, and -gliadin Abs are found in non-paraneoplastic cerebellar ataxia. Most of these antibodies are not pathogenic but are diagnostic markers. However, anti-VGCC, anti-mGluR, and anti-GAD Abs have been shown to cause cerebellar ataxia, because administration of these Abs mimics cerebellar ataxia in vivo. Experiments using in vitro preparations show that anti-VGCC Ab depresses excitatory synaptic transmissions, and anti-GAD Ab suppresses inhibitory synaptic transmissions. Anti-mGluR Ab interferes with the induction of synaptic plasticity. These results suggest that pathogenic Abs elicit cerebellar synaptic dysfunction, and thereby cause ataxia in patients.