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This 18-year-old boy presented to the hospital with symptoms of cerebellar dysfunction preceded by an acute febrile illness with rash. Examination showed evidence of left-sided cerebellar dysfunction and polyneuropathy. Empirical treatment for leptospirosis and scrub typhus was initiated. MRI was normal. Other organ dysfunctions in the form of thrombocytopenia and transaminitis were also observed. He recovered without sequelae. A diagnosis of acute cerebellar ataxia and polyneuropathy due to scrub typhus was made.

Hereditary ataxias are a group of devastating neurological disorders that affect coordination of gait and are often associated with poor coordination of hands, speech, and eye movements. Ataxia with Ocular Apraxia type 1 (AOA1) (OMIM: 606350.0006) is characterized by slowly progressive symptoms of childhood-onset and pathogenic mutations in APTX; the only known cause underpinning AOA1. APTX encodes the protein Aprataxin, composed of three domains sharing homology with proteins involved in DNA damage, signaling, and repair. We present four siblings from an endogamic family in a rural, isolated town of Colombia with ataxia and ocular apraxia of childhood-onset and confirmed molecular diagnosis of AOA1, homozygous for the W279* p.Trp279Ter mutation. We predicted the mutated APTX with Alpha Fold to demonstrate the effects of this stop-gain mutation that deletes three beta helices encoded by amino acid 270 to 339 rescinding the C2H2-type zinc fingers (Znf) (C2H2 Znf) DNA-binding and DNA-repair domain and the whole tridimensional structure of the APTX. All siblings exhibited different ages of onset (4, 6, 8, and 11 y/o) and heterogeneous patterns of dysarthria (ranging from absence to mild-moderate dysarthria). Neuropsychological evaluation showed no neurocognitive impairment in three siblings, but one sibling showed temporospatial disorientation, semantic and phonologic fluency impairment, episodic memory affection, constructional apraxia, moderate anomia, low executive function, and symptoms of depression. This heterogeneous phenotype suggests genetic interactions can shape the natural history of AOA1. To our knowledge, this report represents the most extensive series of siblings affected with AOA1 in Latin America, and the genetic analysis completed adds important knowledge to outline this family’s disease and general complex phenotype of hereditary ataxias.

Unverricht-Lundborg disease (ULD), also called progressive myoclonic epilepsy type 1, is usually characterized by the presence of ataxia associated with myoclonus and epileptic seizures without progressive cognitive deficit, presenting during late childhood and early adolescence. Currently, there is a growing body of evidence for atypical presentations of the disease with a milder phenotype or without the full symptomatology. We describe a case report of a late-onset phenotype with progressive myoclonus-ataxia syndrome accompanied by initial recurrent falls, resulting in specific phobia and agoraphobia starting at the age of 50 years old. The examination revealed multifocal myoclonus with cerebellar ataxia and electroencephalogram showed generalized polyspikes and spike-wave discharges. Electromyogram revealed positive myoclonus of 60-ms duration in the face and the presence of C reflex. A genetic study confirmed the diagnosis of ULD in the patient and other additional family members, presenting a wide range of intra-familial variability. We discuss the challenging differential diagnosis for such a misleading presentation and its possible underlying pathophysiological mechanisms. Our case report may contribute to broadening the age and clinical boundaries for this disease and emphasizes the intra-familial age and symptom variability. Based on a suggestive family history, the diagnosis of ULD should be considered in this context, even in older patients.

Cerebellar ataxia (CA) is a condition in which cerebellar dysfunction leads to movement disorders such as dysmetria, asynergy and dysdiadochokinesia. This study investigates the therapeutic effects of Melittin (MEL) on 3-acetylpyridine-induced (3-AP) cerebellar ataxia (CA) rat model. Initially, CA rat models were generated by 3-AP administration followed by the intraperitoneal injection of MEL. Then, motor performance and electromyography (EMG) activity were assessed. Afterwards, the pro-inflammatory cytokines were analyzed in the cerebellar tissue. Moreover, the anti-apoptotic role of MEL in CA and its relationship with the protection of Purkinje cells were explored. The findings showed that the administration of MEL in a 3-AP model of ataxia improved motor coordination (P 0.001) and neuro-muscular activity (p 0.05), prevented the cerebellar volume loss (P 0.01), reduced the level of inflammatory cytokines (p 0.05) and thwarted the degeneration of Purkinje cells against 3-AP toxicity (P 0.001). Overall, the findings imply that the MEL attenuates the 3-AP-induced inflammatory response. As such, it could be used as a treatment option for CA due to its anti-inflammatory effects.

Item does not contain fulltext Spinocerebellar ataxias (SCA) comprise a rare, genetic subgroup within the degenerative ataxias and are dominantly inherited, with up to 48 recognized genetic subtypes. While an updated review on the management of degenerative ataxia is published recently, an evidence-based review focussed on the management of SCA is lacking. Here, we reviewed the pharmacological and non-pharmacological management of SCA by conducting a systematic review on Medline Ovid and Scopus. Of 29,284 studies identified, 47 studies (pharmacological: n = 25; non-pharmacological: n = 22) that predominantly involved SCA patients were included. Twenty studies had a high risk of bias based on the Cochrane's Collaboration risk of bias tool. As per the European Federation of Neurological Societies 2004 guideline for therapeutic intervention, the remaining 27 studies were of Class I (n = 4) and Class II (n = 23) evidence. Only two therapies had Level A recommendations for the management of ataxia symptoms: riluzole and immediate in-patient neurorehabilitation. Ten therapies had Level B recommendations for managing ataxia symptoms and require further investigations with better study design. These include high dose valproate acid, branched-chain amino acid, intravenous trehalose; restorative rehabilitation using cycling regimen and videogame; and cerebellar stimulations using transcranial direct current stimulation and transcranial magnetic stimulation. Lithium and coaching on psychological adjustment received Level B recommendation for depressive symptoms and quality of life, respectively. Heterogeneous study designs, different genotypes, and non-standardized clinical measures alongside short duration and small sample sizes may hamper meaningful clinical translation. Therefore, rating of recommendations only serve as points of reference. 23 p.

Introduction: The impact of deep brain stimulation (DBS) on speech rhythm and its mechanism remains unclear. We investigated speech rhythm characteristics of patients with Parkinson's disease (PD) treated with subthalamic nucleus (STN) DBS to understand the underlying pathophysiology better. Methods: We enrolled a total of 105 participants and evaluated speech rhythm performances among patients with PD who had undergone STN-DBS (the PD-DBS group), patients with PD treated only with medication (the PD-Med group), patients with cerebellar ataxia (the CA group), and healthy controls (the HC group). Each participant was asked to repeat the syllable/pa/at a comfortable self-chosen steady pace. A widely-used software (the Motor Speech Profile) program performed an acoustic analysis. Results: Compared to the PD-Med and HC groups, speech rate instability (DDKjit) was significantly higher in the PD-DBS and CA groups (p < 0.01). However, after DBS was turned off, the DDKjit of the PD-DBS group improved to a level comparable to that of the PD-Med and HC groups. In contrast to the significantly higher variability of speech volume (DDKcvi) in the CA group, the PD-DBS group showed similar DDKcvi to the PD-Med and HC groups. Conclusions: STN-DBS affects the speech rate stability of patients with PD. Speech rhythm disorders caused by STN-DBS were phenotypically similar to that in CA in terms of interval variability but different regarding amplitude variability. Further studies are warranted to elucidate the underlying pathophysiology of speech rhythm disorders in PD patients treated with DBS.

A 60-year-old patient had progressive imbalance. Examination revealed saccadic smooth pursuit, downbeat nystagmus, ataxia of stance and gait, and reduced vibration sense. Video head impulse and caloric testing both showed vestibulo-ocular reflex (VOR) deficits (figure). The patient has cerebellar ataxia with neuronopathy and vestibular areflexia syndrome.1,2 Slow head turns while looking at an earth-fixed target produce saccadic rather than smooth compensatory eye movements (Videos 1) due to impairment of both the VOR and smooth pursuit (the visually enhanced VOR): 1 simple bedside test, 2 clinical signs, and 1 precise diagnosis.

Fragile X-associated tremor/ataxia syndrome (FXTAS) is an adult-onset neurodegenerative disorder caused by FMR1 premutation expansion of CGG repeats. FXTAS can be misdiagnosed with many neurodegenerative disorders manifesting with cerebellar ataxias owing to their overlapping clinical and radiological features. The frequency of the FMR1 premutation allele in Japan has not been fully determined. Herein, we aimed to determine the frequency of FMR1 premutation alleles in Japanese patients with undiagnosed cerebellar ataxia and multiple system atrophy, using repeat-primed PCR in 186 patients with adult onset of undiagnosed cerebellar ataxia and 668 patients with multiple system atrophy, to identify expanded CGG repeats as well as to detect AGG interruptions within the expanded alleles. The size of expansions was estimated using fragment length analysis of PCR products obtained by conventional PCR employing a pair of unique primers flanking the repeat sequence. We identified FMR1 premutation alleles in three male patients. One patient revealed 84 repeat units with one AGG interruption and another patient showed 103 repeat units. Both had presented with sporadic cerebellar ataxia, giving an estimated frequency of 3.7% among Japanese male patients with sporadic cerebellar ataxia with age at onset above 50 years. One patient with the clinical diagnosis of multiple system atrophy harbored 60 repeat units with four AGG interruptions. FMR1 intermediate alleles were observed in two males and one female among the multiple system atrophy patients. We found that genetic tests for FMR1 premutation should be considered in Japanese male patients with cerebellar ataxia with the age at onset above 50 years.

Spastic ataxia is characterized by the combination of cerebellar ataxia with spasticity and other pyramidal features. It is the hallmark of some hereditary ataxias, but it can also occur in some spastic paraplegias and acquired conditions. It often presents with heterogenous clinical features with other neurologic and non-neurological symptoms, resulting in complex phenotypes. In this review, the differential diagnosis of spastic ataxias are discussed and classified in accordance with inheritance. Establishing an organized classification method based on mode inheritance is fundamental for the approach to patients with these syndromes. For each differential, the clinical features, neuroimaging and genetic aspects are reviewed. A diagnostic approach for spastic ataxias is then proposed.

BACKGROUND AND PURPOSE The aim of this study was to identify the long-term radiological changes, autoantibody specificities, and clinical course in a patient with kelch-like protein 11 (KLHL11)-associated paraneoplastic neurological syndrome (PNS). METHODS Serial brain magnetic resonance images were retrospectively assessed. To test for KLHL11 autoantibodies, longitudinal cerebrospinal fluid (CSF) and serum samples were screened by Phage-display ImmunoPrecipitation and Sequencing (PhIP-Seq). Immunohistochemistry was also performed to assess for the presence of KLHL11 in the patient's seminoma tissue. RESULTS A 42-year-old man presented with progressive ataxia and sensorineural hearing loss. Metastatic seminoma was detected 11 months after the onset of the neurological symptoms. Although immunotherapy was partially effective, his cerebellar ataxia gradually worsened over the next 8 years. Brain magnetic resonance imaging revealed progressive brainstem and cerebellar atrophy with a "hot-cross-bun sign", and low-signal intensity on susceptibility-weighted imaging (SWI) in the substantia nigra, red nucleus and dentate nuclei. PhIP-Seq enriched for KLHL11-derived peptides in all samples. Immunohistochemical staining of mouse brain with the patient CSF showed co-localization with a KLHL11 commercial antibody in the medulla and dentate nucleus. Immunohistochemical analysis of seminoma tissue showed anti-KLHL11 antibody-positive particles in cytoplasm. CONCLUSIONS This study suggests that KLHL11-PNS should be included in the differential diagnosis for patients with brainstem and cerebellar atrophy and signal changes not only on T2-FLAIR but also on SWI, which might otherwise be interpreted as secondary to a neurodegenerative disease such as multiple system atrophy.

Vanishing White Matter Disease (VWMD) is a rare autosomal recessive leukoencephalopathy . The classical presentation is characterized by a severe cerebellar ataxia, spasticity, neurological deterioration with a chronic progressive course and episodes of acute neurological deterioration after stress conditions.We report a 52-year-old man with VWMD and atypical features who manifested two major events of transient aphasia eleven years apart with complete recovery in 48 hours. No cognitive decline was present. Brain MRI revealed typical aspects of VWMD including diffuse leukoencephalopathy with relative sparing of U-fibers. We identified the presence of c.592G>A (p.Glu198Lys) and c.1360 C>T (p.Pro454Ser) mutations in EIF2B5.

Background L-2-hydroxyglutaric aciduria (L2HGA) is a rare neurometabolic disorder that occurs due to accumulation of L-2-hydroxyglutaric acid in the cerebrospinal fluid (CSF), plasma and urine. The clinical manifestation of L2HGA includes intellectual disability, cerebellar ataxia, epilepsy, speech problems and macrocephaly. Methods In the present study, we ascertained a multigenerational consanguineous Pakistani family with 5 affected individuals. Clinical studies were performed through biochemical tests and brain CT scan. Locus mapping was carried out through genome-wide SNP genotyping, whole exome sequencing and Sanger sequencing. For in silico studies protein structural modeling and docking was done using I-TASSER, Cluspro and AutoDock VINA tools. Results Affected individuals presented with cognitive impairment, gait disturbance, speech difficulties and psychomotor delay. Radiologic analysis of a male patient revealed leukoaraiosis with hypoattenuation of cerebral white matter, suggestive of hypomyelination. Homozygosity mapping in this family revealed a linkage region on chromosome 14 between markers rs2039791 and rs781354. Subsequent whole exome analysis identified a novel frameshift mutation NM_024884.3:c.180delG, p.(Ala62Profs*24) in the second exon of L2HGDH. Sanger sequencing confirmed segregation of this mutation with the disease phenotype. The identification of the most N-terminal loss of function mutation published thus far further expands the mutational spectrum of L2HGDH.

In recent years, with advances in molecular genetics, many new mutations with various ataxic syndromes have been identified. Recently, homozygous sequestosome 1 (SQSTM1) gene variant with a progressive childhood-onset cerebellar ataxia, dystonia and gaze palsy was described. Here we describe a patient with progressive cerebellar ataxia and gaze palsy, as well as myoclonus, cognitive impairment and growth retardation with a homozygous SQSTM1 variant NM_003900.5:c.55G > T (p.Glu19*). Our case had brainstem lesions on brain magnetic resonance imaging that have not been previously reported. This novel finding expands the SQSTM1 gene-associated neuroradiologic spectrum. Homozygous SQSTM1 variant should be considered in the differential diagnosis in patients presenting with cerebellar findings, gaze palsy, and cognitive impairment to facilitate early diagnosis and genetic counseling.

INTRODUCTION Wolfram syndrome is a rare autosomal recessive genetic disease characterized by diabetes insipidus, diabetes mellitus, optic atrophy and deafness. A neurodegenerative syndrome is usually associated, including cerebellar ataxia. A few cases of central apnea have been reported in the literature. Here, we report a case of Wolfram syndrome with respiratory symptoms that led to the discovery of central apneas as well as complicated and delayed weaning in an intensive care unit (ICU). OBSERVATION The patient is a 39-year-old woman diagnosed with Wolfram syndrome who was admitted to an ICU for septic shock. She experienced difficult weaning before central apneas were observed while spontaneous ventilation was being attempted. After two extubation failures, cerebral MRI was performed and revealed parenchymatous atrophy of the posterior brain fossa involving the cerebral trunk, cerebellar peduncles, as well as both cerebellum hemispheres and the cerebellar vermis. Even after the patient was tracheotomized, central apneas persisted when the patient breathed spontaneously with her tracheotomy, necessitating nocturnal ventilation. CONCLUSION While central apneas Wolfram syndrome remain rare, they should be systematically investigated due to their association with severe morbimortality.

BACKGROUND: In clinical practice, eye movements can provide an early diagnostic marker for early onset ataxia (EOA). However, quantitative oculomotor assessment is not included in the most frequently used and age-validated ataxia rating scale in children, the Scale for the Assessment and Rating of Ataxia (SARA). We aimed to investigate the applicability of semi-quantitative eye movement assessment by the International Cooperative Ataxia Rating Scale (ICARSOCM) and Ocular Motion Score (OMS7-10) complementary to SARA measurements in children.METHODS: In 52 typically developing children (aged 4-16 years; n = 4 per year of age), three independent assessors scored saccadic eye movements and ocular pursuit according to the ICARSOCM and matching parameters from the OMS7-10. For ICARSOCM, we determined 1) construct validity for coordinated eye movements by correlation with OMS7-10, ICARSEYE-HAND-COORDINATION and SARA subscale scores, 2) agreement percentage and inter-rater agreement (Fleiss Kappa) and 3) age-dependency.RESULTS: Spearman's rank correlations of ICARSOCM with OMS7-10 and ICARS- and SARA subscales were moderate to fair (all p < .001). Inter-rater agreement of ICARS-OCM was 80.8%; (Fleiss Kappa: 0.411). ICARSOCM scores revealed a similar exponentially decreasing association with age as the other SARA (sub)scores, reaching a plateau at 10 years of age.INTERPRETATION: ICARSOCM has a valid construct for the measurement of coordinated eye movement performance and is reliably assessable in children. ICARSOCM reveals a similar age-dependent relationship as the other ataxia subscales, reflecting the physiological maturation of the cerebellum. In children, these data may implicate that ICARSOCM can reliably contribute to coordination assessment, complementary to the SARA subscales.

To explore the use of wearable sensors for objective measurement of motor impairment in spinocerebellar ataxia (SCA) patients during clinical assessments of gait and balance. In total, 14 patients with genetically confirmed SCA (mean age 61.6 ± 8.6 years) and 4 healthy controls (mean age 49.0 ± 16.4 years) were recruited through the Massachusetts General Hospital (MGH) Ataxia Center. Participants donned seven inertial sensors while performing two independent trials of gait and balance assessments from the Scale for the Assessment and Rating of Ataxia (SARA) and Brief Ataxia Rating Scale (BARS2). Univariate analysis was used to identify sensor-derived metrics from wearable sensors that discriminate motor function between the SCA and control groups. Multivariate linear regression models were used to estimate the subjective in-person SARA/BARS2 ratings. Spearman correlation coefficients were used to evaluate the performance of the model. Stride length variability, stride duration, cadence, stance phase, pelvis sway, and turn duration were different between SCA and controls (p

Cerebellar ataxia is a genetically heterogeneous disorder. GEMIN5 encoding an RNA-binding protein of the survival of motor neuron complex, is essential for small nuclear ribonucleoprotein biogenesis, and it was recently reported that biallelic loss-of-function variants cause neurodevelopmental delay, hypotonia, and cerebellar ataxia. Here, whole-exome analysis revealed compound heterozygous GEMIN5 variants in two individuals from our cohort of 162 patients with cerebellar atrophy/hypoplasia. Three novel truncating variants and one previously reported missense variant were identified: c.2196dupA, p.(Arg733Thrfs*6) and c.1831G > A, p.(Val611Met) in individual 1, and c.3913delG, p.(Ala1305Leufs*14) and c.4496dupA, p.(Tyr1499*) in individual 2. Western blotting analysis using lymphoblastoid cell lines derived from both affected individuals showed significantly reduced levels of GEMIN5 protein. Zebrafish model for null variants p.(Arg733Thrfs*6) and p.(Ala1305Leufs*14) exhibited complete lethality at 2 weeks and recapitulated a distinct dysplastic phenotype. The phenotypes of affected individuals and the zebrafish mutant models strongly suggest that biallelic loss-of-function variants in GEMIN5 cause cerebellar atrophy/hypoplasia.

Background Primary Sjogren's syndrome (pSS) is a chronic autoimmune disorder characterized by lymphocytic infiltrates of the exocrine glands, particularly the salivary and lacrimal glands, resulting in oral and ocular dryness. pSS has been linked to various neurological manifestations, including cerebellar dysfunction. We aimed to provide a comprehensive analysis of the currently available evidence regarding pSS-related cerebellar ataxia. Methods A systematic literature search in the PubMed database was performed and 19 papers were eligible to be included in this paper. Results The pooled prevalence of cerebellar ataxia in pSS is estimated to be 1.5% (95% CI 0.3-6.8%). pSS patients with cerebellar involvement have a female-to-male ratio of 6:1. Although most of the patients are adults in their fifth decade of life when diagnosed, cases of children with pSS and cerebellar involvement have been reported. Typical cerebellar ataxia related to pSS manifests with vermian dysfunction, namely gait ataxia and/or cerebellar speech. Cerebellar ataxia due to pSS may also mimic degenerative cerebellar ataxia, especially when the onset is progressive. Conclusions The diagnostic approach to a patient with cerebellar ataxia of unknown etiology should include evaluation for an underlying pSS. A thorough history and clinical examination, antibody testing, brain MRI imaging and/or MRS of the cerebellum will assist in establishing the diagnosis. Setting up a joint neuro-rheumatology clinic can be valuable given that rheumatic and neurological diseases share comorbidities.

Background This study aimed to describe lower limbs impairments, balance and activity limitations related to indoor mobility in adult walkers with autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS). Results Twenty-five participants were recruited with a mean age of 32.2 (± 10.4) years with 45.7% using a walking aid. There is a significant difference between participants with and without a walking aid in terms of lower limbs coordination, balance and mobility. Although participants who walk without a walking aid perform better than the others and they are below predictive or reference values. Despite significant mobility limitations, only mild spasticity and passive range of motion limitations were observed. However, there is a significant difference between unaffected individuals and participants with ARSACS for lower limb muscle cocontraction. Conclusions Results show a high level of lower limb impairments, balance and mobility limitation in adults’ participants with ARSACS that are still walking, including people not using a walking aid. One of the most original finding is the presence of excessive cocontraction and a relatively mild level of spasticity in the lower limbs muscles. Results of this study better circumscribes the impairments and activities that should be the focus of intervention including rehabilitation in ARSACS.

Methods of rehabilitation of patients with ataxia syndrome, which is a difficult task due to severe disorders in the performance of everyday activities , have been considered. Objective. To study the problems of restoring motion coordination during ataxia of cerebellar genesis through the use of high-intensity physical therapy and video games. Methods. Theoretical analysis, synthesis and generalization of modern data of scientific and scientific-methodical literature. Results. The results of studies of different level have been analyzed. The generalization of researches, which included the combined physiotherapeutic strategy with ergotherapy, programs of high-intensity physical therapy with certain coordination exercises has been carried out, and the training program based on video games has been investigated. The obtained information allows forming the basic principles of the organization of rehabilitation intervention for patients with cerebellar ataxia. The described studies prove that high-intensity physical therapy can be effective in degenerative ataxia, the use of video games can help improve the functional state of the patient, which is equivalent to one or more years of natural disease progression. Keywords: cerebellar ataxia, coordination impairment, ergotherapy, physical therapy, rehabilitation.

An expansion of the age range of multiple sclerosis (MS) manifestation has been reported recently. Considering the multifactorial etiology, high heterogeneity of the clinical symptoms, and the difficulties of early MS diagnosis in young people, the onset and course of this disease in students can be considered as one of the significant medical and social problems.Objective: to analyze the clinical and epidemiological characteristics of MS in university and secondary specialized educational institutions students in the Republic of Bashkortostan (RB).Patients and methods. This case-control study included 32 patients aged 15 to 24 years studying in universities and secondary schools of the RB. The clinical and epidemiological indicators analysis was carried out based on data from the register of MS patients in the RB. 32 sex-, age-, place of birth and residence-matching patients with MS, who were not students, were included in the control group.Results and discussion. The median age of disease manifestation in students was 18 [16.5; 20] years, in the control group – 16 [14; 19] years (p=0.010). We found a lower «disease onset – diagnosis» in the students group of revealed a lower interval «disease onset – diagnosis» (0.5 [0; 1] years, p=0.006), and a shorter duration of MS compared to the control group ((2.8 [2; 4] years and 4 [2; 7] years, respectively, p=0.020). Students with MS predominantly had movement disorders: central paresis and cerebellar ataxia. Students also had a faster MS progression (0.4 [0.2; 0.6] EDSS scores per year, p=0.001), despite of the disease-modifying therapies.Conclusion. MS manifestation and course in students receiving disease-modifying therapies indicate the need for close follow-up, adherence control, and psychological support in the educational process.

Cerebellar symptoms remain orphan of treatment options despite being prevalent and incapacitating. Investigate whether dentate nucleus deep brain stimulation (DN DBS) is safe and leads to improvements in cerebellar symptoms when compared to sham stimulation. This randomized double-blind crossover pilot trial enrolled five patients with spinocerebellar ataxia type 3 or post-lesion ataxia. Active or sham phases were randomly performed three months apart. The primary outcome was ataxia improvement as measured by the Scale for the Assessment and Rating of Ataxia (SARA) after the active compared to the sham period. Secondary outcome measures included safety and tolerability, the Fahn-Tolosa-Marin Tremor Rating Scale (FTMRS), quality of life measurements, and patients' global impression of change. The effects on ataxia were numerically better in four out of five patients after active versus sham stimulation. The composite SARA score did not change after comparing active to sham stimulation (8.6 ± 3.6 versus 10.1 ± 4.1; p = 0.223). The FTMRS showed significant improvement after active stimulation versus sham (18.0 ± 17.2 versus 22.2 ± 19.5; p = 0.039) as did patients' global impression of change (p = 0.038). The quality of life was not modified by stimulation (p = 0.337). DN DBS was well tolerated without serious adverse events. One patient had the electrode repositioned. DN DBS is a safe and well tolerated procedure that is effective in alleviating cerebellar tremor. In this small cohort of ataxic patients, DN DBS did not achieve statistical significance for ataxia improvement.

Background Spinocerebellar ataxias (SCAs) are a diverse group of progressive neurodegenerative disorders. Until now, more than 20 genes have been implicated to be associated with this phenotype and TGM6 is one of these genes, associated with spinocerebellar ataxia-35 (SCA-35). The majority of disease-causing variants in the TGM6 gene predominantly have been reported from China and Taiwan and the association with Parkinson's disease (PD) have also been reported recently. Methods We report the first Indian case with SCA-35 in a 16-year-old-boy with atypical age of onset at 9 years, prominent extrapyramidal features, intellectual disability, and a novel missense mutation in the TGM6 gene. We also reviewed and collated all previously published cases with pathogenic TGM6 variants. Results Including the index case, 54 cases were identified from 10 relevant articles in literature and 48 cases had adequate clinical details to be included in the pooled analysis. Around two-thirds of reported cases had SCA-35 phenotype, with cerebellar atrophy. Onset in the majority of cases was the fourth decade of life onwards. A proportion of SCA-35 cases also had spasmodic torticollis, impaired proprioception, extrapyramidal features, and myoclonic jerks. The patients with PD had often early-onset milder symptoms, slower progression, and favorable response to levodopa/carbidopa. One patient each presented with episodic ataxia and dystonic tremor of the upper limb. Most of the cases had missense mutations, without any definite hotspot or genotype–phenotype correlation. Conclusions TGM6 mutation should be suspected in patients with SCA like presentation, especially when it is accompanied by extrapyramidal features, spasmodic torticollis, impaired proprioception, or myoclonus.

Background Brain magnetic resonance imaging (MRI) rarely reveals structural changes in patients with suspected anti-Tr/DNER encephalitis and thus provides very limited information. Here, we combined structural MRI, functional MRI, and positron emission tomography-computed tomography (PET-CT) findings to characterize this rare disorder in a patient. Case presentation A 43-year-old woman presented with progressive cerebellar ataxia, memory impairment, anxiety, and depression. Anti-Tr antibodies were detected in both her serum (1:10) and cerebrospinal fluid (1:10). A diagnosis of anti-Tr-positive autoimmune cerebellar ataxia was established. The patient’s symptoms were worse, but her brain MRI was normal. Meanwhile, voxel-based morphometry analysis showed bilateral reduced cerebellar volume, especially in the posterior lobe and uvula of the cerebellum and the middle of the left temporal lobe compared with 6 sex- and age-matched healthy subjects (6 females, 43 ± 2 years; p p Conclusions A combination of structural MRI, functional MRI, and brain PET-CT has higher diagnostic and prognostic value than conventional MRI in patients with suspected anti-Tr/DNER encephalitis.

Background: Early Onset Ataxia (EOA) and Developmental Coordination Disorder (DCD) share several phenotypical characteristics, which can be clinically hard to distinguish. Aim: To combine quantified movement information from three tests obtained from inertial measure-ments units (IMUs), to improve the classification of EOA and DCD patients and healthy controls compared to using a single test. Methods: Using IMUs attached to the upper limbs, we collected data from EOA, DCD and healthy control children while they performed the three upper limb tests (finger to nose, finger chasing and fast alter -nating movements) from the Scale for the Assessment and Rating of Ataxia (SARA) test. The most relevant features for classification were extracted. A random forest classifier with 300 trees was used for classification. The area under the receiver operating curve (ROC-AUC) and precision-recall plots were used for classification performance assessment. Results: The most relevant discerning features concerned smoothness and velocity of movements. Classification accuracy on group level was 85.6% for EOA, 63.5% for DCD and 91.2% for healthy control children. In comparison, using only the finger to nose test for classification 73.7% of EOA and 53.4% of DCD patients and 87.2% of healthy controls were accurately classified. For the ROC/precision recall plots the AUC was 0.96/0.89 for EOA, 0.92/0.81 for DCD and 0.97/0.94 for healthy control children. Discussion: Using quantified movement information from all three SARA-kinetic upper limb tests improved the classification of all diagnostic groups, and in particular of the DCD group compared to using only the finger to nose test. (c) 2021 The Authors. Published by Elsevier Ltd on behalf of European Paediatric Neurology Society. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).

Background\ud \ud Although non-invasive central and peripheral stimulations are accruing support as promising treatments in different neurological conditions, their effects on dysarthria have not been systematically investigated.\ud \ud \ud \ud Objective\ud \ud The purpose of this review was to examine the evidence base of non-invasive stimulation for treating dysarthria, identify which stimulation parameters have the most potential for treatment and determine safety risks.\ud \ud \ud \ud Methods\ud \ud A systematic review with meta-analysis, when possible, involving publications indexed in MEDLINE, PsychINFO, EMBASE CINHAL the Linguistics and Language Behavioral Abstracts, Web of Science, Cochrane Register of Control Trials and 2 trial registries was completed. Articles were searched in December 2018 and updated in June 2021 using keywords related to brain and electrical stimulation, dysarthria and research design. We included trials with randomised, cross-over or quasi-experimental designs; involving a control group; and investigating treatment of neurogenic dysarthria with non-invasive stimulation. Methodological quality was determined with the Cochrane's Risk of Bias-2 tool.\ud \ud \ud \ud Results\ud \ud In total, 6186 studies were identified; 10 studies (6 randomised controlled trials and 4 cross-over studies) fulfilled the inclusion criteria. All 10 trials (268 adults with Parkinson's disease, stroke and neurodegenerative cerebellar ataxia) focused on brain stimulation (6 repetitive transcranial magnetic stimulation; 3 transcranial direct current stimulation; and 1 repetitive transorbital alternating current stimulation). Adjunct speech-language therapy was delivered in 2 trials. Most trials reported one or more positive effects of stimulation on dysarthria-related features; however, given the overall high risk of bias and heterogeneity in participant, trial and outcome measurement characteristics, no conclusions can be drawn. Post-treatment size effects for 2 stroke trials demonstrated no statistically significant differences between active and sham stimulation across 3 dysarthria outcomes.\ud \ud \ud \ud Conclusions\ud \ud Evidence for use of non-invasive brain stimulation in treating dysarthria remains inconclusive. Research trials that provide reliable and replicable findings are required.

Clinical case of unusual presentation is introduced, with evidence of cerebellar ataxia and Guillain-Barre syndrome of axonal type, in a pediatric patient, related to the appearance of SARS-CoV-2 infection. We also carry out a review of recent medical literature. © 2021 Sociedad Neurologica Argentina

Spinocerebellar ataxias type 3 (SCA3) patients are clinically characterized by progressive cerebellar ataxia combined with degeneration of the cerebellum. Previous neuroimaging studies have indicated ataxia severity associated with cerebellar atrophy using univariate methods. However, whether cerebellar atrophy patterns can be used to quantitatively predict ataxia severity in SCA3 patients at the individual level remains largely unexplored. In this study, a group of 66 SCA3 patients and 58 healthy controls were included. Disease duration and ataxia assessment, including the Scale for the Assessment and Rating of Ataxia (SARA) and the International Cooperative Ataxia Rating Scale (ICARS), were collected for SCA3 patients. The high-resolution T1-weighted MRI was obtained, and cerebellar grey matter (GM) was extracted using a spatially unbiased infratentorial template toolbox for all participants. We investigated the association between the pattern of cerebellar grey matter (GM) loss and ataxia assessment in SCA3 by using a multivariate machine learning technique. We found that the application of RVR allowed quantitative prediction of both SARA scores (leave-one-subject-out cross-validation: correlation = 0.56, p-value = 0.001; mean squared error (MSE) = 20.51, p-value = 0.001; ten-fold cross-validation: correlation = 0.52, p-value = 0.001; MSE = 21.00, p-value = 0.001) and ICARS score (leave-one-subject-out cross-validation: correlation = 0.59, p-value = 0.001; MSE = 139.69, p-value = 0.001; ten-fold cross-validation: correlation = 0.57, p-value = 0.001; MSE = 145.371, p-value = 0.001) with statistically significant accuracy. These results provide proof-of-concept that ataxia severity in SCA3 patients can be predicted by the alteration pattern of cerebellar GM using multi-voxel pattern analysis.

Spinocerebellar ataxia 38 (SCA 38) is an autosomal dominant disorder caused by conventional mutations in the ELOVL5 gene which encodes an enzyme involved in the synthesis of very long fatty acids, with a specific expression in cerebellar Purkinje cells. Three Italian families carrying the mutation, one of which is of Sardinian descent, have been identified and characterized. One session of cerebellar intermittent theta burst stimulation (iTBS) was applied to 6 affected members of the Sardinian family to probe motor cortex excitability measured by motor-evoked potentials (MEPs). Afterwards, patients were exposed to ten sessions of cerebellar real and sham iTBS in a cross-over study and clinical symptoms were evaluated before and after treatment by Modified International Cooperative Ataxia Rating Scale (MICARS). Moreover, serum BDNF levels were evaluated before and after real and sham cerebellar iTBS and the role of BDNF Val66Met polymorphism in influencing iTBS effect was explored. Present data show that one session of cerebellar iTBS was able to increase MEPs in all tested patients, suggesting an enhancement of the cerebello-thalamo-cortical pathway in SCA 38. MICARS scores were reduced after ten sessions of real cerebellar iTBS showing an improvement in clinical symptoms. Finally, although serum BDNF levels were not affected by cerebellar iTBS when considering all samples, segregating for genotype a difference was found between Val66Val and Val66Met carriers. These preliminary data suggest a potential therapeutic use of cerebellar iTBS in improving motor symptoms of SCA38.

Introduction: Multiple system atrophy (MSA) is a progressive degenerative disorder of the central and autonomic nervous systems characterized by parkinsonism, cerebellar ataxia, dysautonomia, and pyramidal signs. The confirmatory diagnosis is pathological, but clinical-diagnostic criteria have been developed to help clinicians. To date, the early diagnosis of MSA is challenging due to the lack of reliable diagnostic biomarkers. Areas covered: The authors reappraised the main clinical, neurophysiological, imaging, genetic, and laboratory evidence to help in the early diagnosis of MSA in the clinical and in the research settings. They also addressed the practical clinical issues in the differential diagnosis between MSA and other parkinsonian and cerebellar syndromes. Finally, the authors summarized the unmet needs in the early diagnosis of MSA and proposed the next steps for future research efforts in this field. Expert opinion: In the last decade, many advances have been achieved to help the correct MSA diagnosis since early stages. In the next future, the early diagnosis and correct classification of MSA, together with a better knowledge of the causative mechanisms of the disease, will hopefully allow the identification of suitable candidates to enroll in clinical trials and select the most appropriate disease-modifying strategies to slow down disease progression.