Romain Lefaucheur

Mutation of the PDGFRB gene as a cause of idiopathic basal ganglia calcification

Objectives: To identify a new idiopathic basal ganglia calcification (IBGC)-causing gene. Methods: In a 3-generation family with no SLC20A2 mutation, we performed whole exome sequencing in 2 affected first cousins, once removed. Nonsynonymous coding variants, splice acceptor and donor site variants, and frameshift coding indels (NS/SS/I) were filtered against dbSNP131, the HapMap Project, 1000 Genomes Project, and our in-house database including 72 exomes. Results: Seventeen genes were affected by identical unknown NS/SS/I variations in the 2 patients. After screening the relatives, the p.Leu658Pro substitution within the PDGFRB gene remained the sole unknown mutation segregating with the disease in the family. This variation, which is predicted to be highly damaging, was present in 13 of 13 affected subjects and absent in 8 relatives without calcifications. Sequencing PDGFRB of 19 other unrelated IBGC cases allowed us to detect another potentially pathogenic substitution within PDGFRB, p.Arg987Trp, also predicted to be highly damaging. PDGFRB encodes a protein involved in angiogenesis and in the regulation of inorganic phosphate (Pi) transport in vascular smooth muscle cells via Pit-1, a Pi transporter encoded by SLC20A1. Conclusion: Mutations of PDGFRB further support the involvement of this biological pathway in IBGC pathophysiology.

Rivastigmine in apathetic but dementia and depression-free patients with Parkinson's disease: a double-blind, placebo-controlled, randomised clinical trial

Background Even with optimal dopaminergic treatments, many patients with Parkinsons disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmines ability to inhibit acetyl- and butyrylcholinesterases could relieve the symptoms of apathy in dementia-free, non-depressed patients with advanced PD. Methods We performed a multicentre, parallel, double-blind, placebo-controlled, randomised clinical trial (Protocol ID: 2008-002578-36; clinicaltrials.gov reference: NCT00767091) in patients with PD with moderate to severe apathy (despite optimised dopaminergic treatment) and without dementia. Patients from five French university hospitals were randomly assigned 1:1 to rivastigmine (transdermal patch of 9.5 mg/day) or placebo for 6 months. The primary efficacy criterion was the change over time in the Lille Apathy Rating Scale (LARS) score. Finding 101 consecutive patients were screened, 31 were eligible and 16 and 14 participants were randomised into the rivastigmine and placebo groups, respectively. Compared with placebo, rivastigmine improved the LARS score (from −11.5 (−15/−7) at baseline to −20 (−25/−12) after treatment; F(1, 25)=5.2; p=0.031; adjusted size effect: −0.9). Rivastigmine also improved the caregiver burden and instrumental activities of daily living but failed to improve quality of life. No severe adverse events occurred in the rivastigmine group. Interpretation Rivastigmine may represent a new therapeutic option for moderate to severe apathy in advanced PD patients with optimised dopaminergic treatment and without depression dementia. These findings require confirmation in a larger clinical trial. Our results also confirmed that the presence of apathy can herald a pre-dementia state in PD. Registration Clinicaltrials.gov reference: NCT00767091.

Long-term Outcomes of CLIPPERS (Chronic Lymphocytic Inflammation With Pontine Perivascular Enhancement Responsive to Steroids) in a Consecutive Series of 12 Patients

BACKGROUND Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is a central nervous system inflammatory disease. OBJECTIVE To describe the disease course of CLIPPERS. DESIGN A nationwide study was implemented to collect clinical, magnetic resonance imaging, cerebrospinal fluid, and brain biopsy specimen characteristics of patients with CLIPPERS. SETTING Academic research. PATIENTS Twelve patients with CLIPPERS. MAIN OUTCOME MEASURES The therapeutic management of CLIPPERS was evaluated. RESULTS Among 12 patients, 42 relapses were analyzed. Relapses lasted a mean duration of 2.5 months, manifested frequent cerebellar ataxia and diplopia, and were associated with a mean Expanded Disability Status Scale (EDSS) score of 4. Besides typical findings of CLIPPERS, magnetic resonance imaging showed brainstem mass effect in 5 patients, extensive myelitis in 3 patients, and closed ring enhancement in 1 patient. Inconstant oligoclonal bands were found on cerebrospinal fluid investigation in 4 patients, with an increased T-cell ratio of CD4 to CD8. Among 7 available brain biopsy specimens, staining was positive for perivascular CD4 T lymphocytes in 5 samples. Thirty-eight of 42 relapses were treated with pulse corticosteroid therapy, which led to improvement, with a mean residual EDSS score of 1.9 (range, 0-7). In 1 patient with untreated relapses, scores on the EDSS progressively increased to a score of 10 at death. Among 5 patients without long-term corticosteroid therapy, the mean annualized relapse rate was 0.5 (range, 0.25-2.8). Among 7 patients taking oral corticosteroids, no relapses occurred in those whose daily dose was 20 mg or higher. No progressive course of CLIPPERS was observed. Four patients with a final EDSS score of 4 or higher had experienced previous severe relapses (EDSS score, ≥5) and brainstem and spinal cord atrophy. CONCLUSIONS CLIPPERS is a relapsing-remitting disorder without progressive forms. Long-term disability is correlated with the severity of previous relapses. Further studies are needed to confirm that prolonged corticosteroid therapy prevents further relapses.

Early verbal fluency decline after STN implantation: Is it a cognitive microlesion effect?

BACKGROUNDS Worsening of verbal fluency is reported after subthalamic nucleus deep brain stimulation in Parkinsons disease. It is postulated that these changes could reflect microlesion consecutive to the surgical procedure itself. METHODS We evaluated verbal fluency, in 26 patients (mean age, 57.9±8.5 years; mean disease duration, 11.4±3.5 years) both before surgery (baseline) and, after surgery respectively the third day (T3), the tenth day (T10) just after STN implantation before turning on the stimulation and at six months (T180). RESULTS Number of total words and switches was significantly reduced at T3 and T10, while average cluster size was unchanged. Repeated post-operative neuropsychological testing demonstrated reliable improvement from T3 to T180 on verbal fluency. CONCLUSION This study provides evidence of transient verbal fluency decline consecutive to a microlesion effect. Further studies needed to determine a putative relationship between early and long-term verbal fluency impairment.

Microsubthalamotomy effect at day 3: Screening for determinants

A microsubthalamotomy (mSTN) effect has been frequently reported after implantation that improves Parkinsons motor disability. It is usually believed that mSTN effect reflects the post‐traumatic tissue reaction within the STN. However, it has never, to our knowledge, been reported whether pre and intraoperative factors could predict this mSTN effect. Preoperative clinical characteristics, that is, age, disease duration, Mattis Dementia Rating Scale score, levodopa responsiveness, severity of motor fluctuations and dyskinesia, and intraoperative parameters, that is, the number of tracks, distance of typical STN neuronal activity recorded along all microelectrodes, and along the definitive electrodes, were assessed in 40 consecutive PD patients submitted for STN stimulation. Multiple stepwise regression analysis showed that only the number of tracks used for microelectrodes recordings was predictor of the contralateral mSTN effect (F (4,73) = 1.83, P = 0.02). This result suggests that the contralateral mSTN depends on the tissue changes along the entirety of surgical trajectories affecting both STN and its adjacent structures.

Post-Operative Edema Surrounding the Electrode: An Unusual Complication of Deep Brain Stimulation.

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Varicella-zoster virus acute myelitis in a patient with MS treated with natalizumab

Yeung et al.1 studied a case of varicella-zoster virus (VZV) myelitis in a patient with MS treated with natalizumab (NTZ). We wanted to stress another manifestation of VZV infection in NTZ-treated patients. A patient with MS recently came to …

Impact of deep brain stimulation on pharyngo‐esophageal motility: a randomized cross‐over study

Bilateral subthalamic nucleus (STN) stimulation is used to alleviate Parkinsons disease (PD) motor symptoms. Recently, it has been shown that this therapeutic also increased gut cholinergic contractions. We therefore investigated the effect of STN stimulation on esophageal motility in an interventional randomized study.

Decline in Verbal Fluency After Subthalamic Nucleus Deep Brain Stimulation in Parkinson's Disease: A Microlesion Effect of the Electrode Trajectory?

BACKGROUND Decline in verbal fluency (VF) is frequently reported after chronic deep brain stimulation (DBS) of the subthalamic nucleus (STN) in Parkinson disease (PD). OBJECTIVE We investigated whether the trajectory of the implanted electrode correlate with the VF decline 6 months after surgery. METHODS We retrospectively analysed 59 PD patients (mean age, 61.9 ± 7; mean disease duration, 13 ± 4.6) who underwent bilateral STN-DBS. The percentage of VF decline 6 months after STN-DBS in the on-drug/on-stimulation condition was determined in respect of the preoperative on-drug condition. The patients were categorised into two groups (decline and stable) for each VF. Cortical entry angles, intersection with deep grey nuclei (caudate, thalamic or pallidum), and anatomical extent of the STN affected by the electrode pathway, were compared between groups. RESULTS A significant decline of both semantic and phonemic VF was found after surgery, respectively 14.9% ± 22.1 (P < 0.05) and 14.2% ± 30.3 (P < 0.05). Patients who declined in semantic VF (n = 44) had a left trajectory with a more anterior cortical entry point (56 ± 53 versus 60 ± 55 degree, P = 0.01) passing less frequently trough the thalamus (P = 0.03). CONCLUSIONS Microlesion of left brain regions may contribute to subtle cognitive impairment following STN-DBS in PD.

Psychosis revealing familial idiopathic basal ganglia calcification

We describe the case of a 39-year-old woman presenting with auditory hallucinations and delusions responsive to antipsychotic drugs. Computerized tomography scans revealed basal ganglia calcifications in the proband and in her two asymptomatic parents. Extensive etiological clinicobiological assessment allowed us to exclude known causes of brain calcifications and diagnose familial idiopathic basal ganglia calcification (IBGC). Neurological symptoms associated with psychiatric symptoms are common in IBGC. Nevertheless, purely psychiatric presentations, as demonstrated by the present case, are possible. However, a fortuitous association between asymptomatic IBGC and schizophrenia cannot be ruled out. Only brain imaging, followed by an extensive etiological assessment, allows for diagnosis of this rare disorder.