Treatment of primary autoimmune cerebellar ataxia with mycophenolate

Immune-mediated ataxias account for a substantial number of sporadic otherwise idiopathic ataxias. Despite some well-characterised entities such as paraneoplastic cerebellar degeneration where diagnostic markers exist, the majority of immune ataxias remained undiagnosed and untreated. We present here our experience in the treatment of suspected primary autoimmune cerebellar ataxia (PACA) using mycophenolate. All patients reported attend the Sheffield Ataxia Centre on a regular basis and had undergone extensive investigations, including genetic testing using next-generation sequencing, with other causes of ataxia excluded. The diagnosis of PACA was strongly suspected based on investigations, pattern of disease progression, and cerebellar involvement. Patients were treated with mycophenolate and monitored using MR spectroscopy of the cerebellar vermis. Thirty patients with PACA are reported here. Of these, 22 received mycophenolate (group 1). The remaining 8 were not on treatment (group 2-control group). Out of the 22 treated patients, 4 underwent serial MR spectroscopy prior to starting treatment and thus were used as controls making the total number of patients in the control group 12. The mean change of the MRS within the vermis (NAA/Cr area ratio) in the treatment group was + 0.144 ± 0.09 (improved) and in the untreated group − 0.155 ± 0.06 (deteriorated). The difference was significant. We also demonstrated a strong correlation between the spectroscopy and the SARA score. We have demonstrated the effectiveness of mycophenolate in the treatment of PACA. The results suggest that immune-mediated ataxias are potentially treatable, and that there is a need for early diagnosis to prevent permanent neurological deficit. The recently published diagnostic criteria for PACA would hopefully aid the diagnosis and treatment of this entity

Indirect immunofluorescent assay as an aid in the diagnosis of suspected immune mediated ataxias

Background and purpose Immune mediated cerebellar ataxias account for a substantial proportion of all progressive ataxias. A diagnostic serological test is not always available. This is particularly problematic in Primary Autoimmune Cerebellar Ataxia, hence the necessity for diagnostic criteria recently devised and published by an International Task Force. We present our experience in the use of a commercially available indirect immunofluorescence assay, intended to be used for the detection of antibodies associated with paraneoplastic neurological syndromes. Methods Retrospective review of patients with ataxia who underwent serological testing using this assay as part of their diagnostic evaluation. We were interested in 3 groups: suspected immune mediated ataxias, genetically confirmed ataxias and patients with cerebellar variant of multi-system atrophy (MSA-C). The indirect immunofluorescence assay was performed using commercially available monkey cerebellum slides and anti-human IgG FITC conjugated antiserum. Results A total of 300 patients that had this test and fitted into one of these 3 groups (immune ataxias 190, genetic ataxias 60, MSA-C 50) were identified. The prevalence of positive immunofluorescence but negative immunoblot was 172/190 (91%) in the suspected immune ataxia group, 3/60 (5%) in the genetic group and 2/50 (4%) in the MSA-C group. The difference between the first and the other groups was significant χ2 (1, N = 291) = 64.2, p < 00001. Conclusions This report demonstrates that a commercially available immunofluorescence assay can be used to provide additional diagnostic aid for suspected immune mediated ataxias and in particular Primary Autoimmune Cerebellar Ataxia where no diagnostic marker exists

A Novel Pathogenic Variant in MT-CO2 Causes an Isolated Mitochondrial Complex IV Deficiency and Late-Onset Cerebellar Ataxia

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A&gt;G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxi

Consensus Paper: Latent Autoimmune Cerebellar Ataxia (LACA)

Immune-mediated cerebellar ataxias (IMCAs) have diverse etiologies. Patients with IMCAs develop cerebellar symptoms, characterized mainly by gait ataxia, showing an acute or subacute clinical course. We present a novel concept of latent autoimmune cerebellar ataxia (LACA), analogous to latent autoimmune diabetes in adults (LADA). LADA is a slowly progressive form of autoimmune diabetes where patients are often initially diagnosed with type 2 diabetes. The sole biomarker (serum anti-GAD antibody) is not always present or can fluctuate. However, the disease progresses to pancreatic beta-cell failure and insulin dependency within about 5 years. Due to the unclear autoimmune profile, clinicians often struggle to reach an early diagnosis during the period when insulin production is not severely compromised. LACA is also characterized by a slowly progressive course, lack of obvious autoimmune background, and difficulties in reaching a diagnosis in the absence of clear markers for IMCAs. The authors discuss two aspects of LACA: (1) the not manifestly evident autoimmunity and (2) the prodromal stage of IMCA’s characterized by a period of partial neuronal dysfunction where non-specific symptoms may occur. In order to achieve an early intervention and prevent cell death in the cerebellum, identification of the time-window before irreversible neuronal loss is critical. LACA occurs during this time-window when possible preservation of neural plasticity exists. Efforts should be devoted to the early identification of biological, neurophysiological, neuropsychological, morphological (brain morphometry), and multimodal biomarkers allowing early diagnosis and therapeutic intervention and to avoid irreversible neuronal loss

Medical and Paramedical Care of Patients With Cerebellar Ataxia During the COVID-19 Outbreak: Seven Practical Recommendations of the COVID 19 Cerebellum Task Force

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV2), the cause of the current pandemic coronavirus disease 2019 (COVID-19), primarily targets the respiratory system. Some patients also experience neurological signs and symptoms ranging from anosmia, ageusia, headache, nausea, and vomiting to confusion, encephalitis, and stroke. Approximately 36% of those with severe COVID-19 experience neurological complications. The virus may enter the central nervous system through the olfactory nerve in the nasal cavity and damage neurons in the brainstem nuclei involved in the regulation of respiration. Patients with cerebellar ataxia (CA) are particularly vulnerable to severe outcome if they contract COVID-19 because of the complexity of their disease, the presence of comorbidities, and their use of immunosuppressive therapies. Most CA patients burdened by progressive neurologic deficits have substantially impaired mobility and other essential functions, for which they rely heavily on ambulatory services, including rehabilitation and psychosocial care. Cessation of these interventions because of isolation restrictions places the CA patient population at risk of further deterioration. This international panel of ataxia experts provides recommendations for neurologists caring for patients with CA, emphasizing a pro-active approach designed to maintain their autonomy and well-being: continue long-term medications, promote rehabilitation efforts, utilize the technology of virtual visits for regular contact with healthcare providers, and pay attention to emotional and psychosocial health. Neurologists should play an active role in decision-making in those CA cases requiring escalation to intensive care and resuscitation. Multi-disciplinary collaboration between care teams is always important, and never more so than in the context of the current pandemic

Spectrum of gluten-related disorders: consensus on new nomenclature and classification

A decade ago celiac disease was considered extremely rare outside Europe and, therefore, was almost completely ignored by health care professionals. In only 10 years, key milestones have moved celiac disease from obscurity into the popular spotlight worldwide. Now we are observing another interesting phenomenon that is generating great confusion among health care professionals. The number of individuals embracing a gluten-free diet (GFD) appears much higher than the projected number of celiac disease patients, fueling a global market of gluten-free products approaching $2.5 billion (US) in global sales in 2010. This trend is supported by the notion that, along with celiac disease, other conditions related to the ingestion of gluten have emerged as health care concerns. This review will summarize our current knowledge about the three main forms of gluten reactions: allergic (wheat allergy), autoimmune (celiac disease, dermatitis herpetiformis and gluten ataxia) and possibly immune-mediated (gluten sensitivity), and also outline pathogenic, clinical and epidemiological differences and propose new nomenclature and classifications

Preserved central cholinergic functioning to transcranial magnetic stimulation in de novo patients with celiac disease

Background Celiac disease (CD) is now viewed as a systemic disease with multifaceted clinical manifestations. Among the extra-intestinal features, neurological and neuropsychiatric symptoms are still a diagnostic challenge, since they can precede or follow the diagnosis of CD. In particular, it is well known that some adults with CD may complain of cognitive symptoms, that improve when the gluten-free diet (GFD) is started, although they may re-appear after incidental gluten intake. Among the neurophysiological techniques, motor evoked potentials (MEPs) to transcranial magnetic stimulation (TMS) can non-invasively probe in vivo the excitation state of cortical areas and cortico-spinal conductivity, being also able to unveil preclinical impairment in several neurological and psychiatric disorders, as well as in some systemic diseases affecting the central nervous system (CNS), such as CD. We previously demonstrated an intracortical disinhibition and hyperfacilitation of MEP responses to TMS in newly diagnosed patients. However, no data are available on the central cholinergic functioning indexed by specific TMS measures, such as the short-latency afferent inhibition (SAI), which might represent the neurophysiological correlate of cognitive changes in CD patients, also at the preclinical level. Methods Cognitive and depressive symptoms were screened by means of the Montreal Cognitive Assessment (MoCA) and the 17-item Hamilton Depression Rating Scale (HDRS), respectively, in 15 consecutive de novo CD patients and 15 healthy controls. All patients were on normal diet at the time of the enrolment. Brain computed tomography (CT) was performed in all patients. SAI, recorded at two interstimulus intervals (2 and 8 ms), was assessed as the percentage amplitude ratio between the conditioned and the unconditioned MEP response. Resting motor threshold, MEP amplitude and latency, and central motor conduction time were also measured. Results The two groups were comparable for age, sex, anthropometric features, and educational level. Brain CT ruled out intracranial calcifications and clear radiological abnormalities in all patients. Scores at MoCA and HDRS were significantly worse in patients than in controls. The comparison of TMS data between the two groups revealed no statistically significant difference for all measures, including SAI at both interstimulus intervals. Conclusions Central cholinergic functioning explored by the SAI of the motor cortex resulted to be not affected in these de novo CD patients compared to age-matched healthy controls. Although the statistically significant difference in MoCA, an overt cognitive impairment was not clinically evident in CD patients. Coherently, to date, no study based on TMS or other diagnostic techniques has shown any involvement of the central acetylcholine or the cholinergic fibers within the CNS in CD. This finding might add support to the vascular inflammation hypothesis underlying the so-called “gluten encephalopathy”, which seems to be due to an aetiology different from that of the cholinergic dysfunction. Longitudinal studies correlating clinical, TMS, and neuroimaging data, both before and after GFD, are needed

Neither a novel tau proteinopathy nor an expansion of a phenotype: Reappraising clinicopathology-based nosology

The gold standard for classification of neurodegenerative diseases is postmortem histopathol-ogy; however, the diagnostic odyssey of this case challenges such a clinicopathologic model. We evaluated a 60-year-old woman with a 7-year history of a progressive dystonia–ataxia syndrome with supranuclear gaze palsy, suspected to represent Niemann–Pick disease Type C. Postmortem evaluation unexpectedly demonstrated neurodegeneration with 4-repeat tau deposition in a distribution diagnostic of progressive supranuclear palsy (PSP). Whole-exome sequencing revealed a new het-erozygous variant in TGM6, associated with spinocerebellar ataxia type 35 (SCA35). This novel TGM6 variant reduced transglutaminase activity in vitro, suggesting it was pathogenic. This case could be interpreted as expanding: (1) the PSP phenotype to include a spinocerebellar variant; (2) SCA35 as a tau proteinopathy; or (3) TGM6 as a novel genetic variant underlying a SCA35 phenotype with PSP pathology. None of these interpretations seem adequate. We instead hypothesize that impairment in the crosslinking of tau by the TGM6-encoded transglutaminase enzyme may compromise tau functionally and structurally, leading to its aggregation in a pattern currently classified as PSP. The lessons from this case study encourage a reassessment of our clinicopathology-based nosology.Fil: Marsili, Luca. University of Cincinnati; Estados UnidosFil: Sharma, Jennifer. University of Cincinnati; Estados UnidosFil: Espay, Alberto J.. University of Cincinnati; Estados UnidosFil: Migazzi, Alice. Universita degli Studi di Trento; ItaliaFil: Abdelghany, Elhusseini. University of Cincinnati; Estados UnidosFil: Hill, Emily J.. University of Cincinnati; Estados UnidosFil: Duque, Kevin R.. University of Cincinnati; Estados UnidosFil: Hagen, Matthew C.. University of Cincinnati; Estados UnidosFil: Stephen, Christopher D.. Harvard Medical School; Estados UnidosFil: Kovacs, Gabor G.. University of Toronto; CanadáFil: Lang, Anthony E.. University of Toronto; CanadáFil: Hadjivassiliou, Marios. University Of Sheffield (university Of Sheffield);Fil: Basso, Manuela. Universita degli Studi di Trento; ItaliaFil: Kauffman, Marcelo Andres. Universidad Austral. Facultad de Ciencias Biomédicas. Instituto de Investigaciones en Medicina Traslacional. Consejo Nacional de Investigaciones Científicas y Técnicas. Oficina de Coordinación Administrativa Parque Centenario. Instituto de Investigaciones en Medicina Traslacional; ArgentinaFil: Sturchio, Andrea. University of Cincinnati; Estados Unido

A novel pathogenic variant in MT-CO2 causes an isolated mitochondrial complex IV deficiency and late-onset cerebellar ataxia

Both nuclear and mitochondrial DNA defects can cause isolated cytochrome c oxidase (COX; complex IV) deficiency, leading to the development of the mitochondrial disease. We report a 52-year-old female patient who presented with a late-onset, progressive cerebellar ataxia, tremor and axonal neuropathy. No family history of neurological disorder was reported. Although her muscle biopsy demonstrated a significant COX deficiency, there was no clinical and electromyographical evidence of myopathy. Electrophysiological studies identified low frequency sinusoidal postural tremor at 3 Hz, corroborating the clinical finding of cerebellar dysfunction. Complete sequencing of the mitochondrial DNA genome in muscle identified a novel MT-CO2 variant, m.8163A>G predicting p.(Tyr193Cys). We present several lines of evidence, in proving the pathogenicity of this heteroplasmic mitochondrial DNA variant, as the cause of her clinical presentation. Our findings serve as an important reminder that full mitochondrial DNA analysis should be included in the diagnostic pipeline for investigating individuals with spinocerebellar ataxia