Pure Cerebellar Atrophy Research Articles

Anti-glutamic acid decarboxylase antibodies-associated cerebellar ataxia: A treatable ataxia

Abstract Background: Anti-glutamate decarboxylase 65 antibody-associated cerebellar ataxia (anti-GAD65Ab-associated CA) is the most widely studied immune-mediated CA. There are few case series evaluating the clinical, radiological, treatment profile, and outcome of anti-GAD65Ab-associated CA. Objective: To study the clinical, radiological profile, associated neoplasm, treatment outcome, and prognosis in patients diagnosed with anti-GAD65Ab-associated CA. Methods: A retrospective descriptive analysis of a cohort of patients diagnosed with anti-GAD65Ab-associated CA was performed and analyzed. Results: Thirteen patients were selected for the analysis with female predominance (70%). The mean age at presentation was 47.5 ± 11.1 years (range, 29–65 years), and the median duration of the symptoms was 4 months. All 13 patients (100%) had gait ataxia. Ten patients had limb ataxia along with gait ataxia (75%). Seven patients had cerebellar dysarthria (54%). Four patients (31%) had gaze-evoked jerky nystagmus. Five patients (39%) were diagnosed with type 2 diabetes mellitus, and one patient had hypothyroidism in addition to type 2 diabetes mellitus. Brain magnetic resonance imaging was normal in seven (54%) patients, and pure cerebellar atrophy was observed in six patients. One patient was detected with a colon neoplasm. All 13 patients received intravenous methylprednisolone, followed by oral steroids over 3 months. Six patients (50%) received plasma exchange along with intravenous methylprednisolone. Favorable outcomes (modified Rankin scale score ≤2) were observed in five patients and poor outcomes in two; six patients were lost to follow-up after the first admission. Conclusion: Anti-GAD65Ab-associated CA presents as subacute to chronic progressive CA with a favorable outcome with immunotherapy. Anti-GAD antibodies should be assessed in serum or cerebrospinal fluid in patients presenting subacute to chronic sporadic CA. The occurrence of a systemic neoplasm is rare in anti-GAD65Ab-associated CA.

Neuroradiological Findings in the Spinocerebellar Ataxias.

BackgroundThe spinocerebellar ataxias (SCAs) are a group of autosomal dominant degenerative diseases characterized by cerebellar ataxia. Classified according to gene discovery, specific features of the SCAs – clinical, laboratorial, and neuroradiological (NR) – can facilitate establishing the diagnosis. The purpose of this study was to review the particular NR abnormalities in the main SCAs.MethodsWe conducted a literature search on this topic.ResultsThe main NR characteristics of brain imaging (magnetic resonance imaging or computerized tomography) in SCAs were: (1) pure cerebellar atrophy; (2) cerebellar atrophy with other findings (e.g., pontine, olivopontocerebellar, spinal, cortical, or subcortical atrophy; “hot cross bun sign”, and demyelinating lesions); (3) selective cerebellar atrophy; (4) no cerebellar atrophy.DiscussionThe main NR abnormalities in the commonest SCAs, are not pathognomonic of any specific genotype, but can be helpful in limiting the diagnostic options. We are progressing to a better understanding of the SCAs, not only genetically, but also pathologically; NR is helpful in the challenge of diagnosing the specific genotype of SCA.

60. The effect of cerebellar degeneration on human sensori-motor plasticity

We investigated how cerebellar degeneration influences the plasticity of the tprimary motor cortex (M1) by using PAS (paired associative plasticity) technique. PAS involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimuli of the motor cortex. If the interval between peripheral and cortical stimulation is around 21–25 ms, corticospinal excitability is increased via a long-term potentiation (LTP)-like effect within M1. Our aims were: (i) to explore the presence of a time-specific influence of cerebellar degeneration on human associative plasticity; (ii) to evaluate the role of the somatosensory pathway on the cerebellar modulation of sensory-motor plasticity. We studied 10 patients with pure cerebellar atrophy and 10 age-matched healthy subjects. Motor evoked potentials amplitudes, short-afferent inhibition, motor thresholds, I/O curves, somatosensory-evoked-potentials (SEPs) were measured before, just after and 30 min after PAS at interstimulus intervals of 21.5 and 25 ms. In cerebellar patients, LTP-like effect induced by PAS was abolished at 25 ms, but not at 21.5 ms. SEPs showed that the P25 wave amplitude was markedly reduced in patients with a more severe clinical and radiological impairment of the cerebellum. Patients with cerebellar atrophy have an altered capability to process time-specific sensory volleys, influencing the M1 plasticity.

Ataxia with Oculomotor Apraxia Type 1 without Oculomotor Apraxia: A Case Report.

Dear Editor, Ataxia with oculomotor apraxia type I (AOA1) is a recessively inherited ataxic disorder that is characterized clinically by the childhood onset of progressive cerebellar ataxia, oculomotor apraxia (OMA), and peripheral axonal sensorimotor neuropathy.1 Dystonia, chorea, and cognitive impairment are commonly associated symptoms, and hypoalbuminemia and hypercholesterolemia are often observed.2 AOA1 is caused by mutations of the gene encoding aprataxin (APTX).3 AOA1 has not been reported previously in Korea.5 The first case of AOA1 in Korea is presented here. In this patient, who did not exhibit OMA but had bilateral gaze-evoked nystagmus, the condition was caused by compound heterozygous mutations of APTX. A 32-year-old man presented with slowly progressive gait disturbance and unsteadiness that developed at the age of 14 years. He was the second child of healthy unrelated Korean parents without a family history of gait disturbance. He was diagnosed as having cerebellar atrophy of unknown cause at the age of 17 years. His ataxic gait had progressively deteriorated and he had become confined to a wheelchair 2 years prior to presentation. A physical examination revealed pes cavus but no scoliosis or other musculoskeletal deformity. A neurological examination revealed mild cerebellar dysarthria without dysphagia. His limb motor powers were normal, as were light touch, pinprick, temperature, and pain sensations. However, his vibration and positional senses were decreased in the lower limbs, his deep tendon reflexes were hyporeflexic in all the limbs, Babinski signs were absent bilaterally, and he had bilateral upper and lower limb dysmetria and truncal ataxia. The patient was unable to stand still without assistance. His ranges of extraocular movement were full in all directions, and he did not exhibit OMA on reflexive saccades testing, but his optokinetic nystagmus was impaired. He presented gaze-evoked nystagmus in all directions. His Mini-Mental State Examination score was 30. The results of laboratory tests were unremarkable except for hypercholesterolemia (217 mg/dL), hypoalbuminemia (3.3 g/dL), and mildly elevated alpha-fetoprotein (7.05 ng/mL). A nerve conduction study and electromyography revealed sensorimotor axonal polyneuropathy, and brain magnetic resonance imaging revealed pure cerebellar atrophy without involvement of the pons, medulla oblongata, midbrain, or cerebral cortex (Fig. 1A and B). Sanger sequencing after PCR amplification of APTX revealed compound heterozygous mutations involving the deletion of two nucleotides (c.359_360delAC, p.Asp120Lysfs2) in exon 3, and a missense mutation (c.617C>T, p.Pro206Leu, rs121908131) in exon 5 (Fig. 1C). While the mutation of c.359_360delAC is novel, c.617C>T is a known pathogenic mutation. The patient’s father is a carrier of the single heterozygous mutation (c.617C>T); we were unable to perform genetic testing on his mother. While Friedreich’s ataxia is the most frequent cause of autosomal recessive ataxia in the Caucasian population,6 it is rare in Korea and Japan.5,7 Before discovery of the APTX mutation, AOA1 was known as early-onset ataxia with OMA and hypoalbuminemia (EAOH) in Japan Minwoo Lee Nan Young Kim Jin Young Huh Young Eun Kim Yun Joong Kim

The Effect of Cerebellar Degeneration on Human Sensori-motor Plasticity.

Plasticity of the primary motor cortex (M1) has a critical role in motor control and learning. The cerebellum facilitates these functions using sensory feedback. We investigated how cerebellar degeneration influences the plasticity of the M1 by using PAS (paired associative stimulation) technique. PAS involves repeated pairs of electrical stimuli to the median nerve and transcranial magnetic stimulation (TMS) of the motor cortex. If the interval between peripheral and TMS stimulation is around 21-25ms, corticospinal excitability is increased via a long term potentiation (LTP)-like effect within M1. Our aims were: (i) to explore the presence of a time-specific influence of cerebellar degeneration on human associative plasticity; (ii) to evaluate the role played by somatosensory pathway on cerebellar modulation of sensory-motor plasticity. We studied 10 patients with pure cerebellar atrophy and 10 age-matched healthy subjects. Motor-evoked-potentials amplitudes, short-afferent inhibition (SAI), motor thresholds, I/O curves, somatosensory-evoked-potential (SEP) were measured before, just after and 30min after PAS at ISIs (interstimulus intervals) of 21.5 and 25ms. Cerebellar patients show a selective lack of LTP-like effect induced by PAS25ms, but not at 21.5ms. SAI was overall not truly modulated by PAS but clearly differed between cerebellar patients and healthy subjects for ISIs around 25ms (+6ms and+8ms) (P<0.01). SEPs showed the amplitude of P25 wave was markedly reduced in patients with a more severe clinical and radiological impairment of cerebellum. Cerebellar patients have an altered capability of cerebellar filtering or processing of time-specific incoming sensory volleys, influencing the plasticity of M1.

Principal Component Analysis of Cerebellar Shape on MRI Separates SCA Types 2 and 6 into Two Archetypal Modes of Degeneration

Although "cerebellar ataxia" is often used in reference to a disease process, presumably there are different underlying pathogenetic mechanisms for different subtypes. Indeed, spinocerebellar ataxia (SCA) types 2 and 6 demonstrate complementary phenotypes, thus predicting a different anatomic pattern of degeneration. Here, we show that an unsupervised classification method, based on principal component analysis (PCA) of cerebellar shape characteristics, can be used to separate SCA2 and SCA6 into two classes, which may represent disease-specific archetypes. Patients with SCA2 (n=11) and SCA6 (n=7) were compared against controls (n=15) using PCA to classify cerebellar anatomic shape characteristics. Within the first three principal components, SCA2 and SCA6 differed from controls and from each other. In a secondary analysis, we studied five additional subjects and found that these patients were consistent with the previously defined archetypal clusters of clinical and anatomical characteristics. Secondary analysis of five subjects with related diagnoses showed that disease groups that were clinically and pathophysiologically similar also shared similar anatomic characteristics. Specifically, Archetype #1 consisted of SCA3 (n=1) and SCA2, suggesting that cerebellar syndromes accompanied by atrophy of the pons may be associated with a characteristic pattern of cerebellar neurodegeneration. In comparison, Archetype #2 was comprised of disease groups with pure cerebellar atrophy (episodic ataxia type 2 (n=1), idiopathic late-onset cerebellar ataxias (n=3), and SCA6). This suggests that cerebellar shape analysis could aid in discriminating between different pathologies. Our findings further suggest that magnetic resonance imaging is a promising imaging biomarker that could aid in the diagnosis and therapeutic management in patients with cerebellar syndromes.

Un nouveau cas d'ataxie cérébelleuse à anticorps anti-GAD traité par corticoïdes et initialement séronégatif

Introduction Cerebellar ataxia with antiglutamic acid decarboxylase antibodies (GAD-ab) is an exceptional newly recognized autoimmune disorder. The cerebellar ataxia may occur in isolation or be associated with stiff man syndrome another rare GAD-Ab induced disorder of central nervous system. Exegesis A 38-year-old woman with a past history of Graves disease presented with insidious cerebellar symptoms including ataxic gait, dysmetria, dysarthria, and oscillopsia. A thorough survey of markers of paraneoplastic cerebellar ataxia and collagen diseases was negative. Her serum contained high level of GAD-ab (647.2 U/ml) and MRI evidenced pure cerebellar atrophy leading to diagnosis of autoimmune cerebellar ataxia. Under corticosteroids, cerebellar symptoms partially improved, but serum GAD-ab titre dramatically decreased. Conclusion Testing for GAD-ab may be indicated in patients with idiopathic cerebellar ataxia, particularly mature women with organ-specific autoimmune diseases. Corticosteroids must be started to prevent irreversible cerebellar atrophy.

The wide spectrum of spinocerebellar ataxias (SCAs)

Spinocerebellar ataxias (SCAs) are a clinically heterogeneous group of disorders. Current molecular classification corresponds to the order of gene description (SCA1-SCA 25). The prevalence of SCAs is estimated to be 1-4/100,000. Patients exhibit usually a slowly progressive cerebellar syndrome with various combinations of oculomotor disorders, dysarthria, dysmetria/kinetic tremor, and/or ataxic gait. They can present also with pigmentary retinopathy, extrapyramidal movement disorders (parkinsonism, dyskinesias, dystonia, chorea), pyramidal signs, cortical symptoms (seizures, cognitive impairment/behavioral symptoms), peripheral neuropathy. SCAs are also genetically heterogeneous and the clinical diagnosis of subtypes of SCAs is complicated by the salient overlap of the phenotypes between genetic subtypes. The following clinical features have some specific values for predicting a gene defect: slowing of saccades in SCA2, ophthalmoplegia in SCA1, SCA2 and SCA3, pigmentary retinopathy in SCA7, spasticity in SCA3, dyskinesias associated with a mutation in the fibroblast growth factor 14 (FGF 14) gene, cognitive impairment/behavioral symptoms in SCA17 and DRPLA, seizures in SCA10, SCA17 and DRPLA, peripheral neuropathy in SCA1, SCA2, SCA3, SCA4, SCA8, SCA18 and SCA25. Neurophysiological findings are compatible with a dying-back axonopathy and/or a neuronopathy. Three patterns of atrophy can be identified on brain MRI: a pure cerebellar atrophy, a pattern of olivopontocerebellar atrophy, and a pattern of global brain atrophy. A remarkable observation is the presence of dentate nuclei calcifications in SCA20, resulting in a low signal on brain MRI sequences. Several identified mutations correspond to expansions of repeated trinucleotides (CAG repeats in SCA1, SCA2, SCA3, SCA6, SCA7, SCA17 and DRPLA, CTG repeats in SCA8). A pentanucleotide repeat expansion (ATTCT) is associated with SCA10. Missense mutations have also been found recently. Anticipation is a main feature of SCAs, due to instability of expanded alleles. Anticipation may be particularly prominent in SCA7. It is estimated that extensive genetic testing leads to the identification of the causative gene in about 60-75 % of cases. Our knowledge of the molecular mechanisms of SCAs is rapidly growing, and the development of relevant animal models of SCAs is bringing hope for effective therapies in human.

Pontine Atrophy in Spinocerebellar Ataxia Type 6

To investigate the clinical range of spinocerebellar ataxia type 6 (SCA6), we screened CAG repeat expansion in the voltage-dependent alpha 1A calcium channel gene (CACNL1A4) in 71 ataxic patients in 60 families; 54 patients in 43 families with hereditary ataxia and 17 sporadic patients. Thirteen patients with SCA6 were detected to have elongated CAG in CACNL1A4. Of these, 7 patients had been diagnosed as having hereditary cerebellar cortical atrophy, and 6 patients had been found to have sporadic occurrence. One patient showed distinct pontine atrophy with prominent horizontal or oblique gaze nystagmus which is an unusual feature in sporadic olivopontocerebellar atrophy. For the efficient screening of SCA6, we would propose testing CAG repeat expansion in CACNL1A4, in patients with one of two markers: (1) horizontal or oblique gaze nystagmus without other eye movement disorders, (2) pure cerebellar atrophy, even if occurrence is sporadic. We should note that the pontine atrophy could also be caused by CAG repeat expansion in CACNL1A4.

Autosomal dominant cerebellar ataxia: Phenotypic differences in genetically defined subtypes?

Seventy-seven families with autosomal dominant cerebellar ataxia were analyzed for the CAG repeat expansions causing spinocerebellar ataxia (SCA) types 1, 2, 3, and 6. The SCA1 mutation accounted for 9%, SCA2 for 10%, SCA3 for 42%, and SCA6 for 22% of German ataxia families. Seven of 27 SCA6 patients had no family history of ataxia. Age at onset correlated inversely with repeat length in all subtypes. Yet the average effect of one CAG unit on onset age was different for each SCA subtype. We compared clinical, electrophysiological, and magnetic resonance imaging (MRI) findings to identify phenotypic characteristics of genetically defined SCA subtypes. Slow saccades, hyporeflexia, myoclonus, and action tremor proposed SCA2. SCA3 patients frequently developed diplopia, severe spasticity or pronounced peripheral neuropathy, and impaired temperature discrimination, apart from ataxia. SCA6 presented with a predominantly cerebellar syndrome and patients often had onset after 55 years of age. SCA1 was characterized by markedly prolonged peripheral and central motor conduction times in motor evoked potentials. MRI scans showed pontine and cerebellar atrophy in SCA1 and SCA2. In SCA3, enlargement of the fourth ventricle was the main sequel of atrophy. SCA6 presented with pure cerebellar atrophy on MRI. However, overlap between the four SCA subtypes was broad.

Vestibulo-ocular function in patients with cerebellar atrophy.

Eye movement abnormalities were quantiatively assessed in four patients with clinically pure cerebellar atrophy (group A), six patients with brainstem plus cerebellar atrophy (group B), and five patients with Friedreich's ataxia (group C). Twelve patients had one or more types of spontaneous nystagmus; eight gaze nystagmus, three rebound nystagmus, wo positional nystagmus, and one vestibular nystagmus. Catoric-induced and rotatory-induced nystagmus was hyperactive in group A and diminished in group C. Group B had mixed responses. All patients demonstrated significant fixation instability and impaired smooth pursuit. There was dysmetria of voluntary saccades, with flutter and "rebound" saccades. Nine of 15 patients had significant slowing of induced saccades, including two patients in group A. It is concluded that quantitative vestibulocular tests can be useful in classifying the cerebellar atrophy syndromes.