Sascha Hering

Pallidal deep brain stimulation in patients with primary generalised or segmental dystonia: 5-year follow-up of a randomised trial

BACKGROUND Severe forms of primary dystonia are difficult to manage medically. We assessed the safety and efficacy of pallidal neurostimulation in patients with primary generalised or segmental dystonia prospectively followed up for 5 years in a controlled multicentre trial. METHODS In the parent trial, 40 patients were randomly assigned to either sham neurostimulation or neurostimulation of the internal globus pallidus for a period of 3 months and thereafter all patients completed 6 months of active neurostimulation. 38 patients agreed to be followed up annually after the activation of neurostimulation, including assessments of dystonia severity, pain, disability, and quality of life. The primary endpoint of the 5-year follow-up study extension was the change in dystonia severity at 3 years and 5 years as assessed by open-label ratings of the Burke-Fahn-Marsden dystonia rating scale (BFMDRS) motor score compared with the preoperative baseline and the 6-month visit. The primary endpoint was analysed on an intention-to-treat basis. The original trial is registered with ClinicalTrials.gov (NCT00142259). FINDINGS An intention-to-treat analysis including all patients from the parent trial showed significant improvements in dystonia severity at 3 years and 5 years compared with baseline, which corresponded to -20·8 points (SD 17·1; -47·9%; n=40) at 6 months; -26·5 points (19·7; -61·1%; n=31) at 3 years; and -25·1 points (21·3; -57·8%; n=32). The improvement from 6 months to 3 years (-5·7 points [SD 8·4]; -34%) was significant and sustained at the 5-year follow-up (-4·3 [10·4]). 49 new adverse events occurred between 6 months and 5 years. Dysarthria and transient worsening of dystonia were the most common non-serious adverse events. 21 adverse events were rated serious and were almost exclusively device related. One patient attempted suicide shortly after the 6-month visit during a depressive episode. All serious adverse events resolved without permanent sequelae. INTERPRETATION 3 years and 5 years after surgery, pallidal neurostimulation continues to be an effective and relatively safe treatment option for patients with severe idiopathic dystonia. This long-term observation provides further evidence in favour of pallidal neurostimulation as a first-line treatment for patients with medically intractable, segmental, or generalised dystonia. FUNDING Medtronic.

Pallidal neurostimulation in patients with medication-refractory cervical dystonia: a randomised, sham-controlled trial

BACKGROUND Cervical dystonia is managed mainly by repeated botulinum toxin injections. We aimed to establish whether pallidal neurostimulation could improve symptoms in patients not adequately responding to chemodenervation or oral drug treatment. METHODS In this randomised, sham-controlled trial, we recruited patients with cervical dystonia from centres in Germany, Norway, and Austria. Eligible patients (ie, those aged 18-75 years, disease duration ≥3 years, Toronto Western Spasmodic Torticollis Rating Scale [TWSTRS] severity score ≥15 points) were randomly assigned (1:1) to receive active neurostimulation (frequency 180 Hz; pulse width 120 μs; amplitude 0·5 V below adverse event threshold) or sham stimulation (amplitude 0 V) by computer-generated randomisation lists with randomly permuted block lengths stratified by centre. All patients, masked to treatment assignment, were implanted with a deep brain stimulation device and received their assigned treatment for 3 months. Neurostimulation was activated in the sham group at 3 months and outcomes were reassessed in all patients after 6 months of active treatment. Treating physicians were not masked. The primary endpoint was the change in the TWSTRS severity score from baseline to 3 months, assessed by two masked dystonia experts using standardised videos, analysed by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00148889. FINDINGS Between Jan 19, 2006, and May 29, 2008, we recruited 62 patients, of whom 32 were randomly assigned to neurostimulation and 30 to sham stimulation. Outcome data were recorded in 60 (97%) patients at 3 months and 56 (90%) patients at 6 months. At 3 months, the reduction in dystonia severity was significantly greater with neurostimulation (-5·1 points [SD 5·1], 95% CI -7·0 to -3·5) than with sham stimulation (-1·3 [2·4], -2·2 to -0·4, p=0·0024; mean between-group difference 3·8 points, 1·8 to 5·8) in the intention-to-treat population. Over the course of the study, 21 adverse events (five serious) were reported in 11 (34%) of 32 patients in the neurostimulation group compared with 20 (11 serious) in nine (30%) of 30 patients in the sham-stimulation group. Serious adverse events were typically related to the implant procedure or the implanted device, and 11 of 16 resolved without sequelae. Dysarthria (in four patients assigned to neurostimulation vs three patients assigned to sham stimulation), involuntary movements (ie, dyskinesia or worsening of dystonia; five vs one), and depression (one vs two) were the most common non-serious adverse events reported during the course of the study. INTERPRETATION Pallidal neurostimulation for 3 months is more effective than sham stimulation at reducing symptoms of cervical dystonia. Extended follow-up is needed to ascertain the magnitude and stability of chronic neurostimulation effects before this treatment can be recommended as routine for patients who are not responding to conventional medical therapy. FUNDING Medtronic.

Friedreich's ataxia: clinical pilot trial with recombinant human erythropoietin

To determine the role of recombinant human erythropoietin as a possible treatment option in Friedreichs ataxia, we performed an open‐label clinical pilot study. Primary outcome measure was the change of frataxin levels at week 8 versus baseline. Twelve Friedreichs ataxia patients received 5,000 units recombinant human erythropoietin three times weekly subcutaneously. Frataxin levels were measured in isolated lymphocytes by enzyme‐linked immunosorbent assay. In addition, urinary 8‐hydroxydeoxyguanosine and serum peroxides, were measured. Treatment with recombinant human erythropoietin showed a persistent and significant increase in frataxin levels after 8 weeks (p < 0.01). All patients showed a reduction of oxidative stress markers. Ann Neurol 2007

Polymorphisms in the glial glutamate transporter SLC1A2 are associated with essential tremor

Objective: Sporadic, genetically complex essential tremor (ET) is one of the most common movement disorders and may lead to severe impairment of the quality of life. Despite high heritability, the genetic determinants of ET are largely unknown. We performed the second genome-wide association study (GWAS) for ET to elucidate genetic risk factors of ET. Methods: Using the Affymetrix Genome-Wide SNP Array 6.0 (1000K) we conducted a two-stage GWAS in a total of 990 subjects and 1,537 control subjects from Europe to identify genetic variants associated with ET. Results: We discovered association of an intronic variant of the main glial glutamate transporter (SLC1A2) gene with ET in the first-stage sample (rs3794087, p = 6.95 × 10−5, odds ratio [OR] = 1.46). We verified the association of rs3794087 with ET in a second-stage sample (p = 1.25 × 10−3, OR = 1.38). In the subgroup analysis of patients classified as definite ET, rs3794087 obtained genome-wide significance (p = 3.44 × 10−10, OR = 1.59) in the combined first- and second-stage sample. Genetic fine mapping using nonsynonymous single nucleotide polymorphisms (SNPs) and SNPs in high linkage disequilibrium with rs3794087 did not reveal any SNP with a stronger association with ET than rs3794087. Conclusions: We identified SLC1A2 encoding the major glial high-affinity glutamate reuptake transporter in the brain as a potential ET susceptibility gene. Acute and chronic glutamatergic overexcitation is implied in the pathogenesis of ET. SLC1A2 is therefore a good functional candidate gene for ET.

Neurological effects of recombinant human erythropoietin in Friedreich's ataxia: a clinical pilot trial.

In a “proof‐of‐concept” study, we demonstrated that recombinant human erythropoietin (rhuEPO) increases frataxin levels in Friedreichs ataxia (FRDA) patients. We now report a 6‐month open‐label clinical pilot study of safety and efficacy of rhuEPO treatment in FRDA. Eight adult FRDA patients received 2.000 IU rhuEPO thrice a week subcutaneously. Clinical outcome measures included Ataxia Rating Scales. Frataxin levels and indicators for oxidative stress were assessed. Hematological parameters were monitored biweekly. Scores in Ataxia Rating Scales such as FARS (P = 0.0063) and SARA (P = 0.0045) improved significantly. Frataxin levels increased (P = 0.017) while indicators of oxidative stress such as urine 8‐OHdG (P = 0.012) and peroxide levels decreased (P = 0.028). Increases in hematocrit requiring phlebotomies occurred in 4 of 8 patients. In this explorative open‐label clinical pilot study, we found an evidence for clinical improvement together with a persistent increase of frataxin levels and a reduction of oxidative stress parameters in patients with FRDA receiving chronic treatment with rhuEPO. Safety monitoring with regular blood cell counts and parameters of iron metabolism is a potential limitation of this approach.

An open trial of levetiracetam for segmental and generalized dystonia

Local botulinum toxin injections represent the treatment of choice for most patients with focal dystonia. However, patients with segmental or generalized forms require additional pharmacologic treatment which is often ineffective or limited by intolerable side‐effects. An animal study and three case reports suggested antidystonic effects of levetiracetam, a pyrrolidone derivate, whereas a recent open‐label study found no improvement in 10 patients with primary idiopathic cervical dystonia. We studied the efficacy of levetiracetam in a daily dose of 3000 mg in 10 consecutive patients with otherwise therapy refractory segmental or generalized dystonia. At 4‐week follow‐up, none of the patients showed improvement of dystonia, mild side‐effects were observed in 3 patients.

Phenotype variability in spinocerebellar ataxia type 2: A longitudinal family survey and a case featuring an unusual benign course of disease

We report a 67 years old female patient out of a multigenerational family with spinocerebellar ataxia type 2 (SCA2) with an unusually benign course of disease. Although all SCA2 gene carriers have by now developed the predominant gait ataxia and brainstem oculomotor dysfunction, the index patient presented with a very mild course of disease, scoring only six points on the Scale for the Assessment and Rating of Ataxia after a disease duration of 13 years. Otherwise, intragenerational variability within family members such as the age at onset of disease and the course of disease was low. Reinvestigation of the genetic background variables in the SCA2 gene carrier reported here showed 27 repeats in the normal allele and 37 noninterrupted repeats in the abnormal allele. Interestingly, this patient has been taking lithium‐carbonate over more than 30 years because of psychotic depression. Although anecdotic, this SCA2 case may provide promising insights into possible disease modifying mechanisms in SCA2.

Review: Friedreich Ataxia and Erythropoietin

In vitro and in vivo studies have provided evidence for neuroprotective properties of Erythropoietin in neurodegenerative disorders. Although the magnitude of effect is still controversial, very recent findings point to neuronal protection in the central nervous system by Erythropoietins. Erythropoietin is a powerful growth factor which enhances cellular size and ultimatively increases the number of mitochondria. Friedreich Ataxia (FA), an inherited neurodegenerative disorder is caused by a loss of function mutation in the first intron on chromosome 9. FA patients therefore suffer a marked reduction of Frataxin, a mitochondrial protein which is involved in mitochondrial iron homeostasis and/or assembly of iron-sulfur (FeS) proteins and heme synthesis. Mitochondrial dysfunction results in a deleterious energy deficit especially in tissues highly dependent on oxidative phosphorylation such as neurons, muscle cells or pancreatic insular cells. Beneficial effects of recombinant human Erythropoietin (rhuEPO) may derive from an increase in Frataxin levels through currently unknown post-transcriptional and/or post-translational mechanisms. Moreover, additional effects via BDNF and through mitochondrial iron chelation may complete the spectrum of rhuEPOs actions in FA and may be part of its beneficial treatment effects. However, there are clear limitations to chronic rhuEPO treatment. Apart from hematopoietic side effects, tumor growth may be enhanced by rhuEPO application. In this review we provide an overview of studies using rhuEPO in FA and discuss potential beneficial effects of Erythropoietin in FA.