Kazunori Nanri

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. J. Clin. Apheresis 30:43–45, 2015.

Selective loss of Purkinje cells in a patient with anti-gliadin-antibody-positive autoimmune cerebellar ataxia

The patient was an 84-year-old woman who had the onset of truncal ataxia at age 77 and a history of Basedows disease. Her ataxic gait gradually deteriorated. She could not walk without support at age 81 and she was admitted to our hospital at age 83. Gaze-evoked nystagmus and dysarthria were observed. Mild ataxia was observed in all limbs. Her deep tendon reflex and sense of position were normal. IgA anti-gliadin antibody, IgG anti-gliadin antibody, anti-SS-A/Ro antibody, anti-SS-B/La antibody and anti-TPO antibody were positive. A conventional brain MRI did not show obvious cerebellar atrophy. However, MRI voxel based morphometry (VBM) and SPECT-eZIS revealed cortical cerebellar atrophy and reduced cerebellar blood flow. IVIg treatment was performed and was moderately effective. After her death at age 85, the patient was autopsied. Neuropathological findings were as follows: selective loss of Purkinje cells; no apparent degenerative change in the efferent pathways, such as the dentate nuclei or vestibular nuclei; no prominent inflammatory reaction. From these findings, we diagnosed this case as autoimmune cerebellar atrophy associated with gluten ataxia. All 3 autopsies previously reported on gluten ataxia have noted infiltration of inflammatory cells in the cerebellum.In this case, we postulated that the infiltration of inflammatory cells was not found because the patients condition was based on humoral immunity. The clinical conditions of gluten ataxia have not yet been properly elucidated, but are expected to be revealed as the number of autopsied cases increases.

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.

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.

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.

Is Anti-Gliadin Antibody Pathogenic in Gluten Ataxia? Analysis using Rat Cerebellar Slices and Patch-Clamp Recording

The significance of autoantibodies associated withneurologicalsymptoms has been the focus of interest. Recentstudies emphasized the pathogenic role of anti-gliadin antibody in gluten ataxia, an important disease of autoimmune cerebellar ataxia. To examine whether autoantibodies, including anti-gliadin antibody, play a pathogenic role, we analyzed the effects of CSF samples obtained from a Japanese patient with gluten ataxia on cerebellar synaptic transmission. Patch-clamp recordings were prepared from cerebellar Purkinje cells, the output cells from the cerebellar cortex, in mice cerebellar slices. The CSF (diluted 1:100) had no effects on the excitatory postsynaptic currents, and did not affect the release mechanisms of glutamate. These results do not support an idea that CSF autoantibodies, including anti-gliadin antibody, interfere cerebellar synaptic function so as to develop ataxia

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.

Superficial siderosis with cerebrospinal fluid leakage

The patient was a 73-year-old man with a history of traffic accident in 1999. In 2004, blood patch treatment was carried out for cerebrospinal fluid (CSF) hypovolemia. In 2009, he became aware of hearing loss and dizziness. T2*-weighted magnetic resonance images showed a symmetric hypointense rim partially delineating the cerebellum. CSF analysis showed xanthochromia and elevated red blood cell count. We diagnosed superficial siderosis (SS). We carried out computed tomography myelogram and magnetic resonance imaging of the full spine, and epidural fluid accumulation was detected from the second cervical vertebra to the 11th thoracic vertebra (Fig. 1). The 24-h residual rate on cisternal scintigraphy was decreased to 20.9%, suggesting CSF leakage. In the pathogenesis of SS with epidural fluid accumulation, a dural tear might be the source of bleeding, and it might also cause CSF hypovolemia. When SS is observed, it is important to detect fluid accumulation carefully with spinal magnetic resonance imaging to locate the site of bleeding. References