SEZ6L2 Antibody-Associated Cerebellar Ataxia Responsive to Sequential Immunotherapy.

OBJECTIVES: Seizure-related 6 homolog like 2 (SEZ6L2) antibody-associated ataxia is an extremely rare disease. Six patients have been reported and none of them improved significantly with immunotherapy. Herein, we present the case of a patient with cerebellar ataxia and SEZ6L2 antibodies who benefited from immunotherapy, which dramatically altered the course of her disease. METHODS: We present a case report of a 73-year-old woman with progressive balance problems. Her condition had rapidly deteriorated in the 2 weeks before the admission to our hospital leading to repeated falls and eventually left her bed-ridden. RESULTS: She presented with severe trunk ataxia, bidirectional nystagmus, dysarthric speech, and persistent nausea. With the exception of cerebellar atrophy, extensive imaging studies revealed no pathology. SEZ6L2 antibodies were found in both CSF and serum. Over a period of 9 months, our patient received immunotherapy consisting of steroid pulse therapy, IV immunoglobulin infusions, rituximab, and cyclophosphamide. Consequently, her condition improved markedly, and she was discharged home from the neurologic rehabilitation unit. DISCUSSION: Our case report shows that intense sequential immunotherapy may considerably improve level of functioning in some patients with SEZ6L2 antibody-associated cerebellar ataxia. CLASSIFICATION OF EVIDENCE: This provides Class IV evidence. It is a single observational study without controls.

Targeted versus untargeted omics - the CAFSA story.

BACKGROUND: In 2009, untargeted metabolomics led to the delineation of a new clinico-biological entity called cerebellar ataxia with elevated cerebrospinal free sialic acid, or CAFSA. In order to elucidate CAFSA, we applied sequentially targeted and untargeted omic approaches. METHODS AND RESULTS: First, we studied five of the six CAFSA patients initially described. Besides increased CSF free sialic acid concentrations, three patients presented with markedly decreased 5-methyltetrahydrofolate (5-MTHF) CSF concentrations. Exome sequencing identified a homozygous POLG mutation in two affected sisters, but failed to identify a causative gene in the three sporadic patients with high sialic acid but low 5-MTHF. Using targeted mass spectrometry, we confirmed that free sialic acid was increased in the CSF of a third known POLG-mutated patient. We then pursued pathophysiological analyses of CAFSA using mass spectrometry-based metabolomics on CSF from two sporadic CAFSA patients as well as 95 patients with an unexplained encephalopathy and 39 controls. This led to the identification of a common metabotype between the two initial CAFSA patients and three additional patients, including one patient with Kearns-Sayre syndrome. Metabolites of the CSF metabotype were positioned in a reconstruction of the human metabolic network, which highlighted the proximity of the metabotype with acetyl-CoA and carnitine, two key metabolites regulating mitochondrial energy homeostasis. CONCLUSION: Our genetic and metabolomics analyses suggest that CAFSA is a heterogeneous entity related to mitochondrial DNA alterations either through POLG mutations or a mechanism similar to what is observed in Kearns-Sayre syndrome.

JC polyomavirus granule cell neuronopathy in a patient treated with rituximab.

IMPORTANCE: Progressive multifocal leukoencephalopathy results from lytic infection of the glia by the JC polyomavirus (JCV); JCV granule cell neuronopathy is caused by infection with a mutated form of JCV, leading to a shift in viral tropism from the glia to cerebellar granule cells. This shift results in a clinical syndrome dominated by progressive cerebellar dysfunction that might elude standard diagnostic workup strategies for ataxia. OBSERVATIONS: We present the case report of a patient receiving long-term rituximab therapy who developed progressive cerebellar ataxia and marked isolated cerebellar degeneration. This syndrome resulted from JCV granule cell neuronopathy associated with a novel JCV mutation. CONCLUSIONS AND RELEVANCE: New onset or worsening of isolated cerebellar ataxia in patients being treated with rituximab or natalizumab warrants early assessment for JCV infection.

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series.

Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

Neurological disorders associated with glutamic acid decarboxylase antibodies: a Brazilian series / Distúrbios neurológicos associadas a anticorpos anti-GAD (descarboxilase do ácido glutâmico): uma série de casos brasileira

Neurological disorders associated with glutamic acid decarboxylase (GAD) antibodies are rare pleomorphic diseases of uncertain cause, of which stiff-person syndrome (SPS) is the best-known. Here, we described nine consecutive cases of neurological disorders associated with anti-GAD, including nine patients with SPS and three cases with cerebellar ataxia. Additionally, four had hypothyroidism, three epilepsy, two diabetes mellitus and two axial myoclonus.

Distúrbios neurológicos associados com anticorpos anti-GAD são doenças pleomórficas, raras, de causa incerta, das quais a rigidez muscular espasmódica (SPR) é a mais conhecida. Neste estudo, descrevemos nove casos consecutivos de distúrbios neurológicos associados com a presença de anticorpos anti-GAD, incluindo nove pacientes com SPR e três casos com ataxia cerebelar. Adicionalmente, foram encontrados quatro casos com hipotireoidismo, três com epilepsia, dois com diabetes mellitus e dois casos com mioclonia axial.

Cytotoxic CD8+ T cells and CD138+ plasma cells prevail in cerebrospinal fluid in non-paraneoplastic cerebellar ataxia with contactin-associated protein-2 antibodies.

OBJECTIVE: The purpose of this paper is to report a patient with otherwise unexplained cerebellar ataxia with serum antibodies against contactin-associated protein-2 (CASPR-2) and provide a detailed description of the composition of cellular infiltrates in the cerebrospinal fluid (CSF) compared to the peripheral blood (PB). CASPR-2 antibodies strongly labeling axons of cerebellar granule neurons have recently been identified in sera from nine patients with otherwise unexplained progressive cerebellar ataxia with mild to severe cerebellar atrophy. DESIGN: This is a report of a single case. METHODS: The study methods used were neurologic examination, magnetic resonance imaging, fluorodeoxyglucose positron emisson tomography, lumbar puncture and multicolor flow-cytometry. RESULTS: A 23-year-old Caucasian male presented with a two-year history of a progressive cerebellar and brainstem syndrome. Magnetic resonance imaging (MRI) showed pronounced cerebellar atrophy, especially of the medial parts of the hemispheres and the vermis. Cerebral fluorodeoxyglucose positron emission tomography (FDG-PET) showed pronounced hypometabolism of the whole cerebellum. CASPR-2 antibodies were detected in the serum but not the CSF, and none of the staging and laboratory assessments revealed other causes of progressive cerebellar degeneration. Interestingly, flow-cytometry of the CSF as compared to the PB showed increased fractions of CD138+ plasma cells as well as human leukocyte antigen (HLA)-DR+ CD8+ T cells suggesting that both B cells and CD8+ T cells were preferentially recruited to and activated within the CSF- (and putatively central nervous system (CNS)-) compartment. CONCLUSION: We confirm the association of CASPR-2 serum antibodies with cerebellar ataxia and provide the first evidence for a combined humoral and cellular immune response in this novel antibody-associated inflammatory CNS disease.

A prognostic value of neuron-specific enolase in cerebrospinal fluid of acute cerebellar ataxia.

We examined 16 patients with acute cerebellar ataxia (ACA) to determine whether clinical manifestations or laboratory findings could predict the prognosis of ACA. We divided the patients into two groups: a benign group of patients whose cerebellar symptoms completely disappeared within 21 days (9 patients), and a prolonged group of patients whose cerebellar symptoms persisted for more than 22 days (7 patients). The two groups were compared on the basis of demographic and clinical characteristics, and laboratory variables. The cerebellar symptoms did not differ significantly between the two groups, except in duration. The level of neuron-specific enolase (NSE) in the cerebrospinal fluid (CSF) of the prolonged group was significantly higher than that of the benign group (p < 0.01); other parameters, including protein and cell count in the CSF, were not significantly different. The results suggest that the NSE level in CSF is of prognostic value in ACA.

Impact of cerebrospinal fluid contamination on brain metabolites evaluation with 1H-MR spectroscopy: a single voxel study of the cerebellar vermis in patients with degenerative ataxias.

PURPOSE: To investigate the impact of cerebrospinal fluid (CSF) contamination on metabolite evaluation in the superior cerebellar vermis with single-voxel (1)H-MRS in normal subjects and patients with degenerative ataxias. MATERIALS AND METHODS: Twenty-nine healthy volunteers and 38 patients with degenerative ataxias and cerebellar atrophy were examined on a 1.5 Tesla scanner. Proton spectra of a volume of interest placed in the superior vermis were acquired using a four TE PRESS technique. We calculated N-acetyl aspartate (NAA)/creatine (Cr), choline (Cho)/Cr, and NAA/Cho ratios, T(2) relaxation times and concentrations of the same metabolites using the external phantom method. Finally, concentrations were corrected taking into account the proportion of nervous tissue and CSF, that was determined as Volume Fraction (VF). RESULTS: In healthy subjects, a significant difference was observed between metabolite concentrations with and without correction for VF. As compared to controls, patients with ataxias showed significantly reduced NAA/Cr and NAA concentrations, while only corrected Cr concentration was significantly increased. The latter showed an inverse correlation with VF. CONCLUSION: CSF contamination has a not negligible effect on the estimation of brain metabolites. The increase of Cr concentration in patients with cerebellar atrophy presumably reflects the substitutive gliosis which takes place along with loss of neurons.

Cerebellar ataxia with elevated cerebrospinal free sialic acid (CAFSA).

In order to identify new metabolic abnormalities in patients with complex neurodegenerative disorders of unknown aetiology, we performed high resolution in vitro proton nuclear magnetic resonance spectroscopy on patient cerebrospinal fluid (CSF) samples. We identified five adult patients, including two sisters, with significantly elevated free sialic acid in the CSF compared to both the cohort of patients with diseases of unknown aetiology (n = 144; P < 0.001) and a control group of patients with well-defined diseases (n = 91; P < 0.001). All five patients displayed cerebellar ataxia, with peripheral neuropathy and cognitive decline or noteworthy behavioural changes. Cerebral MRI showed mild to moderate cerebellar atrophy (5/5) as well as white matter abnormalities in the cerebellum including the peridentate region (4/5), and at the periventricular level (3/5). Two-dimensional gel analyses revealed significant hyposialylation of transferrin in CSF of all patients compared to age-matched controls (P < 0.001)--a finding not present in the CSF of patients with Salla disease, the most common free sialic acid storage disorder. Free sialic acid content was normal in patients' urine and cultured fibroblasts as were plasma glycosylation patterns of transferrin. Analysis of the ganglioside profile in peripheral nerve biopsies of two out of five patients was also normal. Sequencing of four candidate genes in the free sialic acid biosynthetic pathway did not reveal any mutation. We therefore identified a new free sialic acid syndrome in which cerebellar ataxia is the leading symptom. The term CAFSA is suggested (cerebellar ataxia with free sialic acid).

Reversibility of cerebellar GABAergic synapse impairment induced by anti-glutamic acid decarboxylase autoantibodies.

Anti-glutamic acid decarboxylase autoantibodies (GAD-Abs) are found in some patients with cerebellar ataxia. We reported previously that CSF IgGs depress cerebellar GABAergic synaptic transmissions by a presynaptic mechanism. Using whole-cell recordings from rat cerebellar slices, we found in the present study that CSF IgG-induced depressive effects were abolished by absorption of GAD-Abs using recombinant GAD. Furthermore, forskolin, an activator of cAMP, recovered the CSF IgG-induced reduction of GABA release. Our results provide evidence that GAD-Abs in the CSF elicited physiopathological effects on cerebellar GABA synapses in vitro and that such synaptic impairment was reversible.

Cerebellar ataxia in non-paraneoplastic Lambert-Eaton myasthenic syndrome.

Lambert-Eaton myasthenic syndrome (LEMS) is an immune-mediated disorder of the neuromuscular junction that rarely is associated with cerebellar ataxia (CA). We describe two patients with non-paraneoplastic LEMS associated with CA who showed high levels of anti-P/Q-type voltage-gated calcium channels antibodies in the serum and cerebrospinal fluid, and reduced CMAP with increment after brief maximum voluntary contraction in electrophysiological studies. We suggest that LEMS should be considered in the differential diagnosis of patients with CA.

[The acute cerebellar ataxia, reccurrence of disease after 5 years--a case report]. / Ostra ataksja mózdzkowa, nawrót choroby po 5 latach--opis przypadku.

Acute cerebellitis, also known as acute cerebellar ataxia, is a rare inflammatory syndrome characterized by cerebellar dysfunction. It typically occurs as a primary infectious, post-infectious or post vaccination disorder, typically in early childhood. The author presents a case of recurrent, acute cerebellar ataxia in a 20-year-old woman. In the described case the first event of acute cerebellar ataxia occured at the age of 15. The disease lasted 3 weeks and symptoms disappeared entirely. The similar symptoms recurred after 5 years but they were more pronounced and accompanied by pleocytosis, high protein level and low glucose level in cerebrospinal fluid. The symptoms disappeared entirely after 2 months of treatment.

CSF analysis differentiates multiple-system atrophy from idiopathic late-onset cerebellar ataxia.

BACKGROUND: Differentiating idiopathic late-onset cerebellar ataxia (ILOCA) from ataxia due to the cerebellar subtype of multiple-system atrophy (MSA-C) can be difficult in the early stages of the disease METHODS: The authors analyzed the levels of various CSF biomarkers in 27 patients with MSA-C and 18 patients with ILOCA and obtained cut-off points for each potential biomarker to differentiate MSA-C from ILOCA. RESULTS: Increased levels of neurofilament light chain (NFL) and neurofilament heavy chain (NFHp35) and decreased levels of the neurotransmitter metabolites homovanillic acid (HVA), 5-hydroxyindoleaceticacid (5-HIAA), and 3-methoxy-4-hydroxyphenylethyleneglycol (MHPG) were observed in MSA-C compared with ILOCA patients. Receiver operating characteristic analysis showed high sensitivity and specificity levels for NFL, NFHp35, and MHPG analysis. At a cut-off of 24.4 ng/L for the NFL analysis, a sensitivity of 79% and a specificity of 94% were obtained for differentiating MSA-C from ILOCA. At a cut-off point for NFHp35 of 129.5 ng/L, sensitivity was 87% and specificity 83%. Analysis of MHPG levels (cut-off 42.5 nM) resulted in a sensitivity of 86% with a specificity of 75%. A multivariate logistic regression model selected NFL, MHPG, and tau as independent predictive biomarkers that separated the MSA-C and ILOCA groups. CONCLUSIONS: Increased levels of neurofilament light chain and tau and decreased levels of 3-methoxy-4-hydroxyphenylethyleneglycol were associated with high accuracy levels in differentiating the cerebellar subtype of multiple-system atrophy from idiopathic late-onset cerebellar ataxia (LOCA). CSF analysis may thus serve as a useful tool in early diagnostic differentiation of LOCA.

Myelinopathia centralis diffusa (vanishing white matter disease) in a four-year-old boy.

A four-year-old boy presented with moderate ataxia triggered by a minor head trauma several weeks ago. Discrepantly severe signal changes of cerebral white matter with almost CSF-isointense signal on all pulse sequences were detected at cranial MRI. Localized proton MR spectroscopy of cerebral white matter demonstrated an even decrease of all metabolites. Glycine was found elevated in CSF. This pattern of clinical history, MR imaging and spectroscopy features and elevated glycine in CSF is characteristic for a novel entity amongst the leukoencephalopathies of childhood. It was originally termed "myelinopathia centralis diffusa" and renamed "vanishing white matter disease" later.

Cerebellitis in an adult with abnormal magnetic resonance imaging findings prior to the onset of ataxia.

BACKGROUND: Brain magnetic resonance imaging (MRI) findings during acute cerebellar ataxia in cases of postinfectious cerebellitis are frequently normal. This has resulted in the use of other imaging modalities, such as single-photon emission computed tomography, to aid diagnosis. OBJECTIVE: To illustrate the chronologic occurrence of cerebellar ataxia, abnormal findings on MRI, and cerebral spinal fluid pleocytosis in an adult case of postinfectious cerebellitis. METHODS: Case report. RESULTS: A patient with a 6-week history of occipital headaches and only mild tandem gait difficulty had abnormal MRI findings that were consistent with cerebellar inflammation. As cerebellar ataxia progressed in parallel with cerebral spinal fluid pleocytosis, MRI findings indicative of cerebellar inflammation resolved, while single-photon emission computed tomography showed cerebellar hyperperfusion. Recovery of neurologic function was accompanied by clearing of the pleocytosis and residual MRI-detected cerebellar atrophy. CONCLUSION: This case demonstrates that transient abnormalities can be detected by MRI before clinical manifestations of cerebellitis appear, while hyperperfusion detected by single-photon emission computed tomography is prolonged.

Cerebellar ataxia with anti-glutamic acid decarboxylase antibodies: study of 14 patients.

BACKGROUND: Antibodies to glutamic acid decarboxylase (GAD-Ab) are described in patients with insulin-dependent (type 1) diabetes mellitus (IDDM), in stiff-man syndrome, and, recently, in a few patients with cerebellar ataxia. OBJECTIVES: To show a link between GAD-Ab and some patients with cerebellar ataxia and to clarify their clinical and immunologic profiles. METHODS: Serum samples were selected from 9000 samples of 4 laboratories. The selection criterion was an immunohistochemical pattern compatible with GAD-Ab that was confirmed by radioimmunoassay. We identified 22 patients with stiff-man syndrome and 14 with cerebellar ataxia and GAD-Ab. RESULTS: Thirteen of the 14 patients with cerebellar ataxia and GAD-Ab were women, and 11 had late-onset IDDM. Patients did not have clinical or radiologic evidence of brainstem involvement. Ten patients had oligoclonal IgG bands in the cerebrospinal fluid, and intrathecal GAD-Ab synthesis was observed in 5 of the 6 patients studied. The level of GAD-Ab of these patients was similar to those with stiff-man syndrome and significantly higher than those with IDDM or with polyendocrine autoimmunity (P<.001). However, the GAD-Ab levels of 6 of the 9 patients with polyendocrine autoimmunity overlapped with those of patients with cerebellar ataxia. CONCLUSIONS: These results suggest a link between high level of GAD-Ab and some cases of cerebellar ataxia, particularly women with IDDM. If high serum levels of GAD-Ab are detected, the cerebrospinal fluid should be evaluated for the presence of oligoclonal IgG bands and intrathecal synthesis of GAD-Ab to further prove an autoimmune origin of the syndrome.

[Cerebellar syndrome after varicella infection without virus identification in cerebrospinal fluid--an important differential ataxia diagnosis]. / Zerebelläres Syndrom nach Varizelleninfektion ohne Virusnachweis im Liquor--eine wichtige Differentialdiagnose zur Ataxie.

We report on a 35 year old female with a 26 day history of an intermittent cerebellar syndrome (dysarthria, ataxia of extremities, gait and trunk, nystagmus), mild meningism, cephalgia, recurrent emesis and nausea. Symptoms developed after typically chickenpox exanthema. Examination of the liquor showed mild pleocytosis, elevated protein and increased albumin quotient. Virus was not found by EIA or PCR. There were elevated levels of IgM- and IgG-antibodies to VZV. The EEG showed mild general changes, compatible with an encephalitis. Neuroradiological examinations were unremarkful. The neurological deficits partly regressed in the follow-up of two months. To the best of our knowledge we are the first that describe the paradox of an intermittent cerebellar syndrome after infection with chickenpox without detection of the virus in the liquor. This phenomenon can be related to the unusual combination of cerebellar ataxia and the later occurrence of mild encephalitis.