Ouhaid Lagha-Boukbiza

Methylphenidate for gait hypokinesia and freezing in patients with Parkinson's disease undergoing subthalamic stimulation: a multicentre, parallel, randomised, placebo-controlled trial

BACKGROUND Despite optimum medical management, many patients with Parkinsons disease are incapacitated by gait disorders including freezing of gait. We aimed to assess whether methylphenidate--through its combined action on dopamine and noradrenaline reuptake--would improve gait disorders and freezing of gate in patients with advanced Parkinsons disease without dementia who also received subthalamic nucleus stimulation. METHODS This multicentre, parallel, double-blind, placebo-controlled, randomised trial was done in 13 movement disorders departments in France between October, 2009, and December, 2011. Eligible patients were younger than 80 years and had Parkinsons disease, severe gait disorders, and freezing of gate despite optimised treatment of motor fluctuations with dopaminergic drugs and subthalamic stimulation. We randomly assigned patients (1:1 with a computer random-number generator in blocks of four) to receive methylphenidate (1 mg/kg per day) or placebo capsules for 90 days. Patients, their carers, study staff, investigators, and data analysts were masked to treatment allocation. To control for confounding effects of levodopa we assessed patients under standardised conditions with an acute levodopa challenge. Our primary outcome was a change in the number of steps during the stand-walk-sit (SWS) test without levodopa. We compared the respective mean numbers of steps at day 90 in the methylphenidate and placebo groups in a covariance analysis and adjusted for baseline differences. This trial is registered with ClinicalTrials.gov, number NCT00914095. FINDINGS We screened 81 patients and randomly assigned 35 to receive methylphenidate and 34 to receive placebo. 33 patients in the methylphenidate group and 32 patients in the placebo group completed the study. Efficacy outcomes were assessed in the patients who completed the study. Compared with patients in the placebo group (median 33 steps [IQR 26-45]), the patients in the methylphenidate group made fewer steps at 90 days (31 [26-42], F((1, 62))=6·1, p=0·017, adjusted size effect 0·61). Adverse events were analysed in all randomly assigned patients. There were significantly more adverse events in the methylphenidate group compared with placebo. Patients on methylphenidate had a significant increase in heart rate (mean 3·6 [SD 7·2] beats per min) and decrease in weight (mean 2·2 [SD 1·8] kg) compared with the placebo group. INTERPRETATION Methylphenidate improved gait hypokinesia and freezing in patients with advanced Parkinsons disease receiving subthalamic nucleus stimulation. Methylphenidate represents a therapeutic option in the treatment of gait disorders at the advanced stage of Parkinsons disease. The long term risk-benefit balance should be further studied. FUNDING French Ministry of Health and Novartis Pharma.

Polymorphism of the dopamine transporter type 1 gene modifies the treatment response in Parkinson’s disease

After more than 50 years of treating Parkinsons disease with l-DOPA, there are still no guidelines on setting the optimal dose for a given patient. The dopamine transporter type 1, now known as solute carrier family 6 (neurotransmitter transporter), member 3 (SLC6A3) is the most powerful determinant of dopamine neurotransmission and might therefore influence the treatment response. We recently demonstrated that methylphenidate (a dopamine transporter inhibitor) is effective in patients with Parkinsons disease with motor and gait disorders. The objective of the present study was to determine whether genetic variants of the dopamine transporter type 1-encoding gene (SLC6A3) are associated with differences in the response to treatment of motor symptoms and gait disorders with l-DOPA and methylphenidate (with respect to the demographic, the disease and the treatment parameters and the other genes involved in the dopaminergic neurotransmission). This analysis was part of a multicentre, parallel-group, double-blind, placebo-controlled, randomized clinical trial of methylphenidate in Parkinsons disease (Protocol ID:2008-005801-20; ClinicalTrials.gov:NCT00914095). We scored the motor Unified Parkinsons Disease Rating Scale and the Stand-Walk-Sit Test before and after a standardized acute l-DOPA challenge before randomization and then after 3 months of methylphenidate treatment. Patients were screened for variants of genes involved in dopamine metabolism: rs28363170 and rs3836790 polymorphisms in the SLC6A3 gene, rs921451 and rs3837091 in the DDC gene (encoding the aromatic L-amino acid decarboxylase involved in the synthesis of dopamine from l-DOPA), rs1799836 in the MAOB gene (coding for monoamine oxidase B) and rs4680 in the COMT gene (coding for catechol-O-methyltransferase). Investigators and patients were blinded to the genotyping data throughout the study. Eighty-one subjects were genotyped and 61 were analysed for their acute motor response to l-DOPA. The SLC6A3 variants were significantly associated with greater efficacy of l-DOPA for motor symptoms. The SLC6A3 variants were also associated with greater efficacy of methylphenidate for motor symptoms and gait disorders in the ON l-DOPA condition. The difference between motor Unified Parkinsons Disease Rating Scale scores for patients with different SLC6A3 genotypes was statistically significant in a multivariate analysis that took account of other disease-related, treatment-related and pharmacogenetic parameters. Our preliminary results suggest that variants of SLC6A3 are genetic modifiers of the treatment response to l-DOPA and methylphenidate in Parkinsons disease. Further studies are required to assess the possible value of these genotypes for (i) guiding l-DOPA dose adaptations over the long term; and (ii) establishing the risk/benefit balance associated with methylphenidate treatment for gait disorders.

Mini-Exome Coupled to Read-Depth Based Copy Number Variation Analysis in Patients with Inherited Ataxias.

Next‐generation sequencing (NGS) has an established diagnostic value for inherited ataxia. However, the need of a rigorous process of analysis and validation remains challenging. Moreover, copy number variations (CNV) or dynamic expansions of repeated sequence are classically considered not adequately detected by exome sequencing technique. We applied a strategy of mini‐exome coupled to read‐depth based CNV analysis to a series of 33 patients with probable inherited ataxia and onset <50 years. The mini‐exome consisted of the capture of 4,813 genes having associated clinical phenotypes. Pathogenic variants were found in 42% and variants of uncertain significance in 24% of the patients. These results are comparable to those from whole exome sequencing and better than previous targeted NGS studies. CNV and dynamic expansions of repeated CAG sequence were identified in three patients. We identified both atypical presentation of known ataxia genes (ATM, NPC1) and mutations in genes very rarely associated with ataxia (ERCC4, HSD17B4). We show that mini‐exome bioinformatics data analysis allows the identification of CNV and dynamic expansions of repeated sequence. Our study confirms the diagnostic value of the proposed genetic analysis strategy. We also provide an algorithm for the multidisciplinary process of analysis, interpretation, and validation of NGS data.

SPG15: a cause of juvenile atypical levodopa responsive parkinsonism

Autosomal recessive hereditary spastic paraplegias with thin corpus callosum (AR HSP-TCC) are rare and complex neurodegenerative disorders characterized by a genetic heterogeneity of which several genes (SPG11 and SPG15, SPG21, SPG47) or loci (SPG32, SPG46) have been identified. In SPG15, additional features have been described [1]: mental retardation, motor neuropathy, dysarthria and pigmentary maculopathy and recently, in a single family with a new homozygous mutation, parkinsonism [2]. In order to further confirm that SPG15 should be considered in the diagnosis of juvenile atypical parkinsonism, we describe another patient affected with SPG15, including juvenileonset levodopa-responsive parkinsonism. A female of Portuguese origin with consanguinity was 17 years old when referred to our center following 12 months of gait difficulties. The patient’s history included mild dysarthria and scholarly delay. Clinical examination demonstrated spastic paraplegia with bilateral extensor plantar reflexes and mild proximal motor deficit in the lower limbs. Vertical saccades were slightly hypometric. By age 19, a left upper limb rest tremor had developed as well as moderate bilateral akinesia, hypertonia, and hypomimia (video). An acute levodopa challenge (250 mg) led to a 60 % improvement of United Parkinson disease rating scale motor score (UPDRSIII) devoted to upper limbs (items 20–25, from 8/24 to 3/24). Rest tremor disappearance was sustained with a levodopa daily dose of M. Anheim and C. Tranchant contributed equally to the work and should be considered as co-last authors.

L-2-hydroxyglutaric aciduria diagnosed in a young adult with progressive cerebellar ataxia and facial dyskinesia.

INTRODUCTION L-2-hydroxyglutaric aciduria is a rare metabolic disorder with quite typical radiological abnormalities and various clinical symptoms. OBSERVATION A 19-year-old girl presented with ataxia, facial dyskinesia, and mild cognitive impairment. Cerebral magnetic resonance imaging demonstrated subcortical white matter T2 abnormalities and a suggestive rim hyperintensity around the caudate nuclei and the putamen. Diagnosis was confirmed by increased 2-hydroxyglutaric acid in urine and a genetic study (Gly260Ala mutation in the L-2-hydroxyglutarate dehydrogenase (L2HGDH) gene). DISCUSSION This case highlights the movement disorder onset and radiological aspects that should indicate the L-2-hydroxyglutaric aciduria diagnosis.

Prospective study of relevance of 123 I-MIBG myocardial scintigraphy and clonidine GH test to distinguish Parkinson’s disease and multiple system atrophy

Background123I-MIBG myocardial scintigraphy and clonidine growth hormone test (CGH test) may help to distinguish multiple system atrophy (MSA) from Parkinson’s disease (PD). Their relevance in the first-stage parkinsonism of uncertain etiology is unknown.MethodsPatients experiencing parkinsonism of ambiguous etiology were clinically classified into the PD group or the MSA group as initial clinical diagnosis (ICD). Then, CGH test and myocardial scintigraphy were performed. Clinical assessment was repeated throughout the disease course until the final clinical diagnosis (FCD) could be established according to the criteria of PD and MSA, respectively.ResultsTwenty-five patients with uncertain diagnosis were included (15 MSA and 10 PD as ICD). At the end of a 6-year follow-up, FCD was MSA in 11/25 patients and PD in 14/25. The CGH test and the scintigraphy showed a sensitivity of 82%, and a specificity of 71 and 93%, respectively, for the diagnosis of MSA. The combination of a normal scintigraphy (i.e., with myocardial MIBG uptake) with genitourinary dysfunction was the most relevant test to diagnose MSA, whereas an abnormal scintigraphy with a levodopa response of > 30% or an abnormal scintigraphy with the absence of OH was the most relevant combinations to diagnose PD. All these combinations had an accuracy superior than 90% and a specificity of 100%.ConclusionCombinations of myocardial scintigraphy with genitourinary dysfunction, levodopa response of > 30%, or orthostatic hypotension could be of interest for the distinction between PD and MSA when the clinical diagnosis remains ambiguous at the first stage of the disease.

Subacute parkinsonism as a complication of Lyme disease

Lyme disease is a tickborne multisystemic bacterial infection due to Borrelia Burgdorferi (BB). Diagnostic criteria for neuroborreliosis are controversial but cerebrospinal fluid (CSF) analysis which demonstrates lymphocytic meningitis, positive ELISA BB serology, and positive anti-BB antibody index (AI) [defined by ratio of (ELISA titer in CSF/ELISA titer in serum) to (total IgG in CSF/total IgG in serum)] in a patient with no past history of neuroborreliosis allow, in most of the cases, the diagnosis [1], which will be supported by rapid improvement with doxycycline, ampicilline, or in neurological complications, ceftriaxone [2]. Parkinsonism has been reported in a few patients with a positive BB serology, but the relationship between BB infection and parkinsonism remains doubtful [3]. Herein, we report two patients who developed reversible subacute parkinsonism due to Lyme basal ganglia ischemic or inflammatory lesions. A 63-year-old woman developed severe walking disorders deteriorating rapidly over 6 months. Clinical examination revealed lower limbs weakness, increased reflexes, bilateral extensor plantar, and dysuria, as well as a left akineto-hypertonic syndrome (UPDRSIII 27/108) and a bilateral peripheral facial palsy. Brain MRI identified several high signal intensities on T2-weighted (T2WI) and FLAIR images in the pons, and the periventricular and subcortical white matter, consistent with vascular demyelination. Similar lesions were observed in the right lenticular nucleus and the bilateral posterior limb of the internal capsules, rather consistent with chronic infarcts (Fig. 1a, b). Spinal cord MRI showed intramedullary high signal on T2WI at the T5/T6 level (Fig. 1c), without enhancement on post-gadolinium T1-weighted images. CSF study found 17 lymphocytes/mm, 1.33 g protein/l, a 0.35 g glucose/l, and an intrathecal anti-BB antibodies synthesis with an AI at 8 (normal\2). Lyme blood serology (IgG 1160 U/ml; IgM 20 U/ml) and Western Blot (22, 41, 60, 83 kDa bands) were positive. Complete blood count, C-reactive protein, vitamins B9B12, angiotensin-converting enzyme, and ANCA levels were normal. Blood Syphilis serology and CSF BK cultures were negative. DaTscan showed a presynaptic dopaminergic denervation on the right striatum (striatum/ occipital right ratio = 2.0 and striatum/occipital left ratio = 2.7; normal [2.5). Although the patient did not reported tick bite or erythema migrans, the diagnostic of neuroborreliosis was considered very likely and she received intravenously 2 g of ceftriaxone per day for 21 days. Nevertheless, clinical improvement was weak. Follow-up brain MRI 1 month later showed new high signal intensities on T2-weighted and FLAIR images on the head of the right caudate and the anterior part of the right lenticular nuclei. These lesions demonstrated high signal intensity on diffusion-weighted images (DWI) with low ADC values, and contrast enhancement on postgadolinium T1-weighted images. These signal abnormalities were consistent with subacute infarction (Fig. 1d). Additional intramedullary high signal intensities were observed on T2-WI at C4, T3–T4, T5–T6, T7–T8, and T9, with enhancement on post-contrast T1-weighted imaging, consistent with subacute inflammatory lesions (Fig. 1e, f). Ceftriaxone treatment was extended by 21 days, & Christine Tranchant christine.tranchant@chru-strasbourg.fr

C - 5 Dystonie évolutive symptomatique de calcifications pallidales post-radiques

Introduction Les lesions symetriques des ganglions de la base peuvent causer des dystonies secondaires. Des calcifications sont presentes dans la maladie de Fahr et certaines maladies metaboliques. L’origine post-radique est exceptionnelle. Observations Une patiente avait presente a 6 ans un craniopharyngiome intra-sellaire revele par un retard staturo-ponderal et traite par chirurgie suivie d’une radiotherapie. L’evolution s’etait compliquee d’un panhypopituitarisme puis d’une dilatation ventriculaire necessitant l’installation d’une derivation ventriculo-peritoneale. La patiente ne presentait aucune sequelle neurologique. A 9 ans s’est installee graduellement aux membres inferieurs puis au tronc une dystonie d’aggravation progressive. Le scanner X cerebral revela des calcifications bilaterales des noyaux lenticulaires. Un traitement par anticholinergiques permit une amelioration partielle des symptomes mais la dystonie continua a s’aggraver : incapable de tenir assise, la patiente devint dependante pour la plupart des gestes de la vie quotidienne. L’IRM cerebrale confirma la presence de calcifications cerebrales et le Dat-scan ® montra une atteinte du systeme dopaminergique au niveau du striatum gauche. Le traitement fut augmente progressivement jusqu’a 45 mg d’Artane ® associe a 8 mg de Rivotril ® et 100 mg de tetrabenazine. La diminution des posologies etait a l’origine d’une reaggravation des symptomes d’une perte de la marche et d’une grabatisation immediate avec un opisthotonos majeur. Discussion Les complications cerebrales tardives de la radiotherapie les mieux decrites sont les encephalopathies avec lesions diffuses de la substance blanche et demence. Les calcifications de la substance grise decrites chez des enfants ayant subi une irradiation cerebrale sont le plus souvent asymptomatiques. L’interet d’une stimulation bi-pallidale doit etre discute malgre l’existence de calcifications. Conclusion Cette observation rapporte une cause exceptionnelle de dystonie generalisee secondaire evolutive et fait discuter son traitement.