[Show abstract][Hide abstract] ABSTRACT: The ataxias are a challenging group of neurological diseases due the aetiological heterogeneity and the complexity of the genetic subtypes. This guideline focuses on the heredodegenerative ataxias. The aim is to provide a peer-reviewed evidence-based guideline for clinical neurologists and other specialist physicians responsible for the care of patients with ataxia.
This guideline is based on systematic evaluations of the relevant literature and on three consensus meetings of the task force.
If acquired causes are ruled out, and if the disease course is rather slowly progressive, a (heredo)degenerative disease is likely. A positive family history gives much guidance. In the case of a dominant family history, first line genetic screening is recommended for spinocerebellar ataxia (SCA) 1, 2, 3, 6, 7 and 17 (level B), and in Asian patients also for dentatorubral-pallidoluysian atrophy (DRPLA). In the case of recessive disease, a stepwise diagnostic work-up is recommended, including both biochemical markers and targeted genetic testing, particularly aimed at Friedreich's ataxia, ataxia telangiectasia, ataxia due to vitamin E deficiency, polymerase gamma gene (POLG gene, various mutations), autosomal recessive spastic ataxia of Charlevoix-Saguenay (ARSACS) and ataxia with oculomotor apraxia (AOA) types 1 and 2. If family history is negative, we still advise to screen for the more common dominant and recessive ataxias. In addition, if onset is below 45 years we recommend the full work-up for recessive ataxias; if onset is above 45 years we recommend to screen for fragile X mental retardation 1 FMR1 premutations (good practice points). In sporadic cases with an onset after 30 years, a diagnosis of multiple system atrophy should be considered (good practice point). In particular the genetic work-up will change over the upcoming years due to the diagnostic utility of new techniques such as gene panel diagnostics based on next generation sequencing for routine work-up, or even whole exome and genome sequencing for selected cases.
Some of the rare recessive ataxias are treatable, but for most of the heredodegenerative ataxias treatment is purely symptomatic. Idebenone is not effective in Friedreich's ataxia (level A). Riluzole (level B) and amantadine (level C) might provide symptomatic relief, irrespective of exact etiology. Also, varenicline for SCA3 patients (level B) can be considered. There is level Class II evidence to recommend physiotherapy, and Class III data to support occupational therapy.
European Journal of Neurology 01/2014; · 4.16 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Polyglutamine-coding (CAG)n repeat expansions in seven different genes cause spinocerebellar ataxias. Although the size of the expansion is negatively correlated with age at onset, it accounts for only 50–70% of its variability. To find other factors involved in this variability, we performed a regression analysis in 1255 affected individuals with identified expansions (spinocerebellar ataxia types 1, 2, 3, 6 and 7), recruited through the European Consortium on Spinocerebellar Ataxias, to determine whether age at onset is influenced by the size of the normal allele in eight causal (CAG)n-containing genes (ATXN1–3, 6–7, 17, ATN1 and HTT). We confirmed the negative effect of the expanded allele and detected threshold effects reflected by a quadratic association between age at onset and CAG size in spinocerebellar ataxia types 1, 3 and 6. We also evidenced an interaction between the expanded and normal alleles in trans in individuals with spinocerebellar ataxia types 1, 6 and 7. Except for individuals with spinocerebellar ataxia type 1, age at onset was also influenced by other (CAG)n-containing genes: ATXN7 in spinocerebellar ataxia type 2; ATXN2, ATN1 and HTT in spinocerebellar ataxia type 3; ATXN1 and ATXN3 in spinocerebellar ataxia type 6; and ATXN3 and TBP in spinocerebellar ataxia type 7. This suggests that there are biological relationships among these genes. The results were partially replicated in four independent populations representing 460 Caucasians and 216 Asian samples; the differences are possibly explained by ethnic or geographical differences. As the variability in age at onset is not completely explained by the effects of the causative and modifier sister genes, other genetic or environmental factors must also play a role in these diseases.
[Show abstract][Hide abstract] ABSTRACT: In a previous retrospective study, we demonstrated that falls are common and often injurious in dominant spinocerebellar ataxias (SCAs) and that nonataxia features play an important role in these falls. Retrospective surveys are plagued by recall bias for the presence and details of prior falls. We therefore sought to corroborate and extend these retrospective findings by means of a prospective extension of this fall study. 113 patients with SCA1, SCA2, SCA3 or SCA6, recruited from the EuroSCA natural history study, were asked to keep a fall diary in between their annual visits to the participating centres. Additionally, patients completed a detailed questionnaire about the first three falls, to identify specific fall circumstances. Relevant disease characteristics were retrieved from the EuroSCA registry. 84.1% of patients reported at least one fall during a time period of 12 months. Fall-related injuries were common and their frequency increased with that of falls. The presence of nonataxia symptoms was associated with a higher fall frequency. This study confirms that falls are a frequent and serious complication of SCA, and that the presence of nonataxia symptoms is an important etiological factor in its occurrence.
European Neurology 11/2012; 69(1):53-57. · 1.50 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Although ataxia is by definition the prominent symptom of ataxia disorders, there are various neurological signs that may accompany ataxia in affected patients. Reliable and quantitative assessment of these signs is important because they contribute to disability, but may also interfere with ataxia. Therefore we devised the Inventory of Non-Ataxia Signs (INAS), a list of neurological signs that allows determining the presence and severity of non-ataxia signs in a standardized way. INAS underwent a rigorous validation procedure that involved a trial of 140 patients with spinocerebellar ataxia (SCA) for testing of inter-rater reliability and another trial of 28 SCA patients to assess short-term intra-rater reliability. In addition, data of the ongoing EUROSCA natural history study were used to determine the reproducibility, responsiveness and validity of INAS. Inter-rater reliability and short-term test-retest reliability was high, both for the total count and for most of the items. However, measures of responsiveness, such as the smallest detectable change and the clinically important change were not satisfactory. In addition, INAS did not differentiate between subjects that were subjectively stable and those that worsened in the 2-year observation period. In summary, INAS and INAS count showed good reproducibility, but unsatisfactory responsiveness. The present analysis and published data from the EUROSCA natural history study suggest that INAS is a valid measure of extracerebellar involvement in progressive ataxia disorders. As such, it is useful as a supplement to the measures of ataxia, but not as a primary outcome measure in future interventional trials.
[Show abstract][Hide abstract] ABSTRACT: Among the hereditary ataxias, autosomal recessive cerebellar ataxias (ARCAs) encompass a diverse group of rare neurodegenerative disorders in which a cerebellar syndrome is the key clinical feature. The clinical overlap between the different cerebellar ataxias, the occasional atypical phenotypes, and the genetic heterogeneity often complicate the clinical management of such patients. Despite the steady increase in newly discovered ARCA genes, many patients with a putative ARCA cannot be genotyped yet, proving that more genes must be involved. This review presents an updated overview of the various ARCAs. The clinical and genetic characteristics of those forms with a known molecular genetic defect are discussed, along with the emerging insights in the underlying pathophysiological mechanisms.
Journal of Medical Genetics 08/2011; 48(10):651-9. · 5.70 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To compare the effect of endplate-targeted injections of a low Botulinum neurotoxin type A (BoNT-A) dose with that of injections at defined distances from the motor endplate zone.
In eight healthy volunteers, the main endplate zones of the right and left extensor digitorum brevis (EDB) muscles were localized using high-density surface EMG. On the study side BoNT-A was injected at fixed distances from the endplate zone. On the control side, BoNT-A was administered into the endplate zone. Compound muscle action potential (CMAP) prior to the injection and 2, 12, and 24 weeks later were recorded.
On the control side, the mean CMAP reduction 2 weeks after BoNT-A injection was 79.3%. The difference in CMAP reduction between both EDB muscles was significantly related to the injection distance from the endplate zone. Increasing the injection distance by 1cm reduced the effect of BoNT-A by 46%.
Guided injection of a reduced BoNT-A dose into the muscle's endplate zone(s) is a promising strategy for optimizing the therapeutic effectiveness of BoNT-A and for minimizing side-effects such as unwanted weakness of adjacent muscles.
Precise endplate-targeted injections increase the effect of BoNT-A and may thus prove to reduce required dosage and treatment costs.
Clinical neurophysiology: official journal of the International Federation of Clinical Neurophysiology 12/2010; 122(8):1611-6. · 3.12 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Five patients with adult-onset metachromatic leukodystrophy (MLD) underwent allo-SCT. Conditioning was reduced in intensity and grafts were obtained from voluntary unrelated donors. All but one graft were depleted of T-lymphocytes. Patient age at transplantation varied from 18 to 29 (median, 27) years. Two patients rejected their graft and MLD progressed. The recipient of the unmanipulated graft converted to complete donor chimerism with normalization of arylsulphatase A (ARSA) levels. Despite ARSA normalization, he deteriorated. Another patient was a mixed chimera. Following escalated doses of donor lymphocyte infusions he converted to complete donor chimerism. His levels of ARSA correlated positively with the percentage of donor cells and MLD was not progressive. The fifth patient died after 35 days from complications associated with GVHD. We conclude that results of allo-SCT in symptomatic MLD patients are poor. However, allo-SCT may stop progression of MLD in selected patients.
Bone marrow transplantation 11/2010; 46(8):1071-6. · 3.00 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In the clinically and genetically heterogeneous group of the hereditary spastic paraplegias (HSPs), mutations in the SPAST gene are most frequently found and cause a pure autosomal dominant form.
To provide the clinical and genetic characteristics of Dutch patients with HSP due to a SPAST mutation (SPG4).
SPAST mutation carriers were identified through a comprehensive national database search. Available medical records were reviewed.
151 mutation carriers carried 60 different changes in the SPAST gene, of which one was a known polymorphism, and 27 were novel. Missense mutations were most frequently found (39%). Clinical information was available from 72 mutation carriers. Age at onset ranged from 1 to 63 years with a bimodal peak distribution in the first decade and above age 30. The predominantly pure spastic paraplegia was accompanied by deep sensory disturbances and sphincter problems in almost 50%. An additional hand tremor was found in 10%. Patients with missense mutations and exon deletions did not reveal a distinctive phenotype.
Dutch SPAST mutation carriers show a broad mutation spectrum, with 27 novel mutations in the present series. A bimodal peak distribution in age at onset was found and an accompanying tremor as peculiar feature of SPG4. The pathogenicity of S44L, the first exon 4 mutation, and a possible autosomal recessive mode of inheritance are discussed.
Journal of neurology, neurosurgery, and psychiatry 10/2010; 81(10):1073-8. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Sandhoff disease is a lipid-storage disorder caused by a defect in ganglioside metabolism. It is caused by a lack of functional N-acetyl-beta-d-glucosaminidase A and B due to mutations in the HEXB gene. Typical, early-onset Sandhoff disease presents before 9 months of age with progressive psychomotor retardation and early death. A late-onset form of Sandhoff disease is rare, and its symptoms are heterogeneous. As drug trials that aim to intervene in the disease mechanism are emerging, the recognition and identification of Sandhoff disease patients-particularly those with atypical phenotypes-are becoming more important. The authors describe six new late-onset Sandhoff cases demonstrating cerebellar ataxia or lower motor neuron (LMN) involvement combined with, mostly subclinical, neuropathy. Two different mutations were found: IVS 12-26 G/A and c.1514G-->A. In patients with either progressive cerebellar ataxia or LMN disease in the setting of a possibly recessive disorder, Sandhoff disease should be suspected, even when the onset age is over 45 years.
Journal of neurology, neurosurgery, and psychiatry 09/2010; 81(9):968-72. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To determine the longitudinal metric properties of recently developed clinical assessment tools in spinocerebellar ataxia (SCA).
A subset of 171 patients from the EUROSCA natural history study cohort (43 SCA1, 61 SCA2, 37 SCA3, and 30 SCA6) were examined after 1 year of follow-up. Score changes and effect size indices were calculated for clinical scales (Scale for the Assessment and Rating of Ataxia [SARA], Inventory of Non-Ataxia Symptoms [INAS]), functional tests (SCA Functional Index [SCAFI] and components), and a patient-based scale for subjective health status (EQ-5D visual analogue scale [EQVAS]). Responsiveness was determined in relation to the patient's global impression (PGI) of change and reproducibility described as retest reliability for the stable groups and smallest detectable change.
Within the 1-year follow-up period, SARA, INAS, and SCAFI but not EQVAS indicated worsening in the whole group and in the groups with subjective (PGI) worsening. SCAFI and its 9-hole pegboard (9HPT) component also deteriorated in the stable groups. Standardized response means were highest for 9HPT (-0.67), SARA (0.50), and SCAFI (-0.48) with accordingly lower sample size estimates of 143, 250, or 275 per group for a 2-arm interventional trial that aims to reduce disease progression by 50%. SARA and EQVAS performed best to distinguish groups classified as worse by PGI. All scales except EQVAS reached the criterion for retest reliability.
While both the Scale for the Assessment and Rating of Ataxia and the SCA Functional Index (SCAFI) (and its 9-hole pegboard component) had favorable measurement precision, the clinical relevance of SCAFI and 9-hole pegboard score changes warrants further exploration. The EQ-5D visual analogue scale proved insufficient for longitudinal assessment, but validly reflected patients' impression of change.
[Show abstract][Hide abstract] ABSTRACT: A 46-year-old man receiving tube feeding because of anorexia and weight loss developed progressive neurological symptoms initially resembling Guillain-Barre syndrome. Eventually axonal neuropathy due to severe hypophosphatemia was diagnosed. Hypophosphatemia can be caused by the so-called refeeding syndrome, which may occur in patients who start feeding after prolonged fasting. The neurological manifestations of hypophosphatemia are reversible if oral or intravenous suppletion of phosphate is started in time. Recognizing the refeeding syndrome is crucial in making a timely diagnosis.
Nederlands Tijdschrift Voor Geneeskunde - NED TIJDSCHR GENEESKD. 01/2010;
[Show abstract][Hide abstract] ABSTRACT: The syndrome of fixed dystonia includes both CRPS-dystonia and psychogenic dystonia. The underlying mechanisms are unclear, but a high prevalence of neuropsychiatric illness has previously been reported.
Clinical and neuropsychiatric follow-up study by telephone and self-administered instruments (HADS, SDQ-20, DES II, EQ-5D), on 41 patients with fixed dystonia after a mean of 7.6 (+/-3.6) years.
We obtained information on clinical outcome in 35 (85.4%) patients and neuropsychiatric questionnaire data in 22 (53.7%). Eighty-three percent were women. Thirty-one percent had worsened, 46% were the same and 23% had improved, of whom 6% had major remissions. At follow-up, mean duration of illness was 11.8 (+/-4.9) years and mean age 43.2 (+/-14.8) years. Except for 1 patient who was re-diagnosed with corticobasal degeneration, the diagnosis remained unchanged in others. Forty-one percent had scores indicating anxiety and 18% indicating depression; 18% scored within the range of dissociative/somatoform disorders on DES II and 19% on SDQ-20. The mean EQ-5D index and VAS scores were 0.34 and 56.1%. Comparison between the 3 outcome groups revealed significant difference only in the EQ-5D (p=0.003). Only baseline CRPS predicted a worse outcome (chi(2)=0.006).
Our findings revealed that the prognosis of this syndrome is poor, with improvement in less than 25% of patients, major remission in only 6% and continued worsening in a third. A high rate of neuropsychiatric findings was noted and new neuropsychiatric features had occurred in some. Average health status was poor. Of the baseline parameters, only CRPS predicted poorer outcome.
Parkinsonism & Related Disorders 06/2009; 15(8):592-7. · 3.27 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Recent studies have suggested that there may be functional and structural changes in the cerebellum of patients with adult onset primary focal dystonia. The aim of this study was to establish whether there is any neurophysiological indicator of abnormal cerebellar function, using the classic eyeblink conditioning paradigm. This paradigm at short intervals is dependent on the olivo-cerebellar circuit and does not require cerebral and basal ganglia structures. Eyeblink conditioning was performed by pairing an auditory tone with a supraorbital nerve stimulus with a delay interval of 400 ms in 12 patients with primary focal dystonia (seven cervical dystonias, five focal hand dystonias) and eight healthy controls. Healthy controls produced more conditioned eyeblink responses than patients with focal dystonia, indicating an abnormality of associative learning in this patient population. This study provides neurophysiological evidence for functional changes in the olivo-cerebellar pathway of patients with primary focal dystonia. Further work needs to be done to determine if these changes are primary, secondary or epiphenomenal to the disease.
Journal of neurology, neurosurgery, and psychiatry 02/2009; 80(1):80-3. · 4.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: The aim of this study was to investigate the correlations between body segment movements and center of mass (COM) velocity during pathological balance corrections of spinocerebellar ataxia (SCA) patients compared with controls, and to relate correlations indicating instability to EMG activity differences. Eighteen SCA patients and 21 age-matched controls were tested. Upright standing was perturbed using rotations of the support surface. We recorded body motion and surface EMG. For lateral perturbations peaks in COM lateral velocity were larger in SCA patients than controls. These peaks were correlated with increased ("hypermetric") trunk roll downhill and reduced uphill knee flexion velocity. Subsequent arm abduction partially corrected the lateral instability. Early balance correcting responses in knee and paraspinal muscles showed reduced amplitudes compared with normal responses. Later responses were consistent with compensation mechanisms for the lateral instability created by the stiffened knee and pelvis. We conclude that truncal hypermetria coupled with insufficient uphill knee flexion is the primary cause of lateral instability in SCA patients. Holding the knees and pelvis more rigid possibly permits a reduction in the controlled degrees of freedom and concentration on arm abduction to improve lateral instability. For backwards perturbations excessive posterior COM velocity coincided with marked trunk hypermetric flexion forwards. We concluded that this flexion and the ensuing backwards shift of the pelvis result from rigidity which jeopardizes posterior stability. Timing considerations and the lack of confirmatory changes in amplitudes of EMG activity suggest that lateral and posterior instability in SCA is primarily a biomechanical response to pelvis and knee rigidity resulting from increased muscle background activity rather than changed evoked responses.
[Show abstract][Hide abstract] ABSTRACT: To evaluate the usefulness of functional measures in patients with spinocerebellar ataxia (SCA).
We assessed three functional measures-8 m walking time (8MW), 9-hole peg test (9HPT), and PATA repetition rate-in 412 patients with autosomal dominant SCA (genotypes 1, 2, 3, and 6) in a multicenter trial.
While PATA rate was normally distributed (mean/median 21.7/20.5 per 10 s), the performance times for 8MW (mean/median 10.8/7.5 s) or 9HPT (mean/median 47.2/35.0 s in dominant, 52.2/37.9 s in nondominant hand) were markedly skewed. Possible learning effects were small and likely clinically irrelevant. A composite functional index (SCAFI) was formed after appropriate transformation of subtest results. The Z-scores of each subtest correlated well with the Scale for the Assessment and Rating of Ataxia (SARA), the Unified Huntington's disease Rating Scale functional assessment, and disease duration. Correlations for SCAFI with each of these parameters were stronger (Pearson r = -0.441 to -0.869) than for each subtest alone. Furthermore, SCAFI showed a linear decline over the whole range of disease severity, while 9HPT and 8MW had floor effects with respect to SARA. Analysis of possible confounders showed no effect of genotype or study site and only minor effects of age for 8MW.
The proposed functional measures and their composite SCAFI have favorable properties to assess patients with spinocerebellar ataxia.
[Show abstract][Hide abstract] ABSTRACT: To identify factors that determine disease severity and clinical phenotype of the most common spinocerebellar ataxias (SCAs), we studied 526 patients with SCA1, SCA2, SCA3. or SCA6.
To measure the severity of ataxia we used the Scale for the Assessment and Rating of Ataxia (SARA). In addition, nonataxia symptoms were assessed with the Inventory of Non-Ataxia Symptoms (INAS). The INAS count denotes the number of nonataxia symptoms in each patient.
An analysis of covariance with SARA score as dependent variable and repeat lengths of the expanded and normal allele, age at onset, and disease duration as independent variables led to multivariate models that explained 60.4% of the SARA score variance in SCA1, 45.4% in SCA2, 46.8% in SCA3, and 33.7% in SCA6. In SCA1, SCA2, and SCA3, SARA was mainly determined by repeat length of the expanded allele, age at onset, and disease duration. The only factors determining the SARA score in SCA6 were age at onset and disease duration. The INAS count was 5.0 +/- 2.3 in SCA1, 4.6 +/- 2.2 in SCA2, 5.2 +/- 2.5 in SCA3, and 2.0 +/- 1.7 in SCA6. In SCA1, SCA2, and SCA3, SARA score and disease duration were the strongest predictors of the INAS count. In SCA6, only age at onset and disease duration had an effect on the INAS count.
Our study suggests that spinocerebellar ataxia (SCA) 1, SCA2, and SCA3 share a number of common biologic properties, whereas SCA6 is distinct in that its phenotype is more determined by age than by disease-related factors.
[Show abstract][Hide abstract] ABSTRACT: Two patients, a 38-year-old man and a 32-year-old woman, were admitted to a psychiatric ward. The first patient suffered from a mood disorder, personality changes and complained of several, hitherto unexplained physical symptoms. Finally the patient was diagnosed with paraneoplastic cerebellar degeneration associated with Hodgkin's disease. The second patient presented with psychosis and panic disorders, but the condition was later found to be caused by paraneoplastic limbic encephalitis due to ovarian teratomas. These cases illustrate that patients with paraneoplastic neurological syndromes may present with psychiatric symptoms which can hamper an early diagnosis.
Tijdschrift voor psychiatrie 02/2008; 50(9):603-9.