Trial of Lixisenatide in Early Parkinson's Disease.

BACKGROUND: Lixisenatide, a glucagon-like peptide-1 receptor agonist used for the treatment of diabetes, has shown neuroprotective properties in a mouse model of Parkinson's disease. METHODS: In this phase 2, double-blind, randomized, placebo-controlled trial, we assessed the effect of lixisenatide on the progression of motor disability in persons with Parkinson's disease. Participants in whom Parkinson's disease was diagnosed less than 3 years earlier, who were receiving a stable dose of medications to treat symptoms, and who did not have motor complications were randomly assigned in a 1:1 ratio to daily subcutaneous lixisenatide or placebo for 12 months, followed by a 2-month washout period. The primary end point was the change from baseline in scores on the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS) part III (range, 0 to 132, with higher scores indicating greater motor disability), which was assessed in patients in the on-medication state at 12 months. Secondary end points included other MDS-UPDRS subscores at 6, 12, and 14 months and doses of levodopa equivalent. RESULTS: A total of 156 persons were enrolled, with 78 assigned to each group. MDS-UPDRS part III scores at baseline were approximately 15 in both groups. At 12 months, scores on the MDS-UPDRS part III had changed by -0.04 points (indicating improvement) in the lixisenatide group and 3.04 points (indicating worsening disability) in the placebo group (difference, 3.08; 95% confidence interval, 0.86 to 5.30; P = 0.007). At 14 months, after a 2-month washout period, the mean MDS-UPDRS motor scores in the off-medication state were 17.7 (95% CI, 15.7 to 19.7) with lixisenatide and 20.6 (95% CI, 18.5 to 22.8) with placebo. Other results relative to the secondary end points did not differ substantially between the groups. Nausea occurred in 46% of participants receiving lixisenatide, and vomiting occurred in 13%. CONCLUSIONS: In participants with early Parkinson's disease, lixisenatide therapy resulted in less progression of motor disability than placebo at 12 months in a phase 2 trial but was associated with gastrointestinal side effects. Longer and larger trials are needed to determine the effects and safety of lixisenatide in persons with Parkinson's disease. (Funded by the French Ministry of Health and others; LIXIPARK ClinicalTrials.gov number, NCT03439943.).

Hemophagocytic Lymphohistiocytosis Gene Mutations in Adult Patients Presenting With CLIPPERS-Like Syndrome.

OBJECTIVE: To determine whether adult cases of Chronic Lymphocytic Inflammation with Pontine Perivascular Enhancement Responsive to Steroids (CLIPPERS) may be related to familial hemophagocytic lymphohistiocytosis (HLH) causes, we have screened patients with adult-onset CLIPPERS for mutations in primary HLH-associated genes. METHODS: In our cohort of 36 patients fulfilling the criteria for probable or definite CLIPPERS according to the CLIPPERS-2017 criteria, we conducted a first study on 12 patients who consented to genetic testing. In these 12 patients, systemic HLH criteria were searched, and genetic analysis of 8 genes involved in primary HLH was performed. RESULTS: Four definite and 8 probable CLIPPERS were enrolled (n = 12). Mutations involved in HLH were identified in 2 definite and 2 probable CLIPPERS (4/12). Three of them had biallelic PRF1 mutations with reduced perforin expression in natural killer cells. The remaining patient had biallelic UNC13D mutations with cytotoxic lymphocyte impaired degranulation. None of the mutated patients reached the criteria for systemic HLH. During follow-up, 3 of them displayed atypical findings for CLIPPERS, including emergence of systemic non-Hodgkin lymphoma (1/3) and confluent gadolinium-enhancing lesions on brain MRI (3/3). CONCLUSIONS: In our patients presenting with adult-onset CLIPPERS, one-third have HLH gene mutations. This genetic treatable condition should be searched in patients with CLIPPERS, especially in those presenting with atypical findings.

Clinically suspected concomitant spinal cord and vertebrobasilar infarctions caused by fibrocartilaginous embolism.

Fibrocartilaginous embolism (FCE) is a rare and probably under diagnosed cause of spinal cord infarction presumably due to acute embolization of nucleus pulposus fragments into the spinal circulation. Concomitant cerebral involvement is much rarer and often asymptomatic. Although the definitive diagnosis is histologic, certain criteria have been proposed to support the diagnosis in living patients, such as absence of vascular risk factors, acute onset or antecedent of valsalva maneuver before the episode and the exclusion of potential differential diagnoses. A 56 years-old patient, without any medical history was referred for sudden back pain while carrying heavy load at work. Clinical examination showed a Brown-Sequard syndrome. Brain and spine MRI disclosed spinal cord infarction at the C4-C5 level associated with brain infarctions involving exclusively the vertebrobasilar circulation. The exhaustive etiological assessment was normal. In our case, the acute symptoms onset, the clinical and imaging data and lack of evidence for other plausible diagnoses in the setting of a valsalva-like maneuver are highly suggestive of FCE diagnosis.

Accuracy of the robot-assisted procedure in deep brain stimulation.

INTRODUCTION: The use of a robot-assisted technology becomes very competitive. The aim of this work was to define the accuracy of robotic assistance in deep brain stimulation surgery and to compare results with that in the literature. METHODS: We retrospectively reviewed the accuracy of lead implantation in 24 consecutive patients who had robot-assisted (ROSA, Zimmer-Biomet) surgery for the treatment of movement disorders. Intended stereotactic coordinates (x, y, z) of contact 0 (the most distal contact at the tip of the electrode) of each definitive lead were compared with actual coordinates obtained by a postoperative CT scan. For each lead, the euclidian 3D distance between the actual and intended location of contact 0 was calculated. RESULTS: The euclidian 3D distances between the intended and actual location of the contact 0 were 0.81 mm on the right side and 1.12 mm on the left side. DISCUSSION: Robot-assisted technology for stereotactic surgery is safe and accurate. The association with a 3D flat-panel CT scan is an optimized procedure for deep intracranial electrode implantation.

Leucoencephalopathy following abuse of sniffed heroin.

A 29-year-old man was admitted for acute cognitive impairment. Three weeks earlier, he had been admitted for coma due to sniffed heroin abuse responsive to naloxone infusion. At admission, the patient presented with apraxia, severe memory impairment and anosognosia. Brain MRI revealed symmetric hyperintensities of supratentorial white matter, sparing brainstem and cerebellum, on FLAIR and B1000 sequences. Four months later, repeated neuropsychological assessment revealed dramatic improvement of global cognitive functions. Toxic leucoencephalopathy excluding the cerebellum and brainstem is a rare complication of heroin abuse, and seems to concern especially patients that use heroin by sniff or injection. In these patients, cognitive troubles are predominant, prognosis seems better and infratentorial brain structures can be spared. In conclusion, our observation emphasizes that heroin-induced encephalopathy can have a favourable outcome and that imaging and clinical patterns can indicate the mode of drug administration.

Anti-MuSK myasthenia gravis with prolonged remission.

Myasthenia gravis (MG) with antibodies against muscle-specific tyrosine kinase (MuSK) is a rare disorder of neuromuscular transmission affecting preferentially bulbar, neck and respiratory muscles. We report the case of a 22-year-old man who presented with diplopia on lateral gaze to both sides, facial diplegia, nasal dysarthria and dysphagia. Repetitive nerve stimulation of the trapezius and orbicularis oculi muscles showed amplitude decrements of 19% and 41% respectively supporting the diagnosis of myasthenia gravis. MUsK antibodies were positive. Corticosteroids were introduced and then tapered and discontinued at 6 months after initiation. The patient remained in remission and asymptomatic for 4 years without ongoing treatment or prior treatment with rituximab after this first relapse of MuSK-MG. MuSK- MG is considered a hard-to-treat condition and patients generally remain dependent on immunosuppression or prior treatment with rituximab. Our observation highlights that patients with MuSK-MG can have a benign course and that continued immunosuppressive or immunomodulatory therapy may not always be required.

Age Limits for Deep Brain Stimulation of Subthalamic Nuclei in Parkinson's Disease.

BACKGROUND: Clinical pre-operative predictive factors of optimal STN-DBS motor outcome in Parkinson's disease (PD) have been previously reported. However, available data involving elderly patients are conflicting. OBJECTIVE: To compare early post-operative outcomes in parkinsonian patients younger than 65 years old (group 1) vs patients 65 years old or older (group 2) at the time of surgery. METHODS: The cognitive and motor effects of DBS were evaluated by comparison of different scores obtained before (baseline) and 6 months after surgery using a repeated measures analysis of variance. RESULTS: Post-operative motor improvement (UPDRS part III and UPDRS part IV scores) and drug reduction were not statistically different between groups 1 and 2 (P > 0.05). Axial motor score which was significantly worse in group 2 in the on-drug condition before surgery was also significantly worse both in off-drug/on-stimulation and on-drug/on-stimulation conditions (P < 0.05). Similarly, cognitive performances (Wisconsin Card Sorting Test, Stroop interference test, Free and Cued Selective Reminding Test with Immediate Recall, Verbal Fluency) significantly worsened post-operatively ingroup 2. CONCLUSIONS: Although effective and safe, STN-DBS has a more negative impact on cognitive functions in elderly patient, requiring a careful preoperative selection.

Subthalamic stimulation: toward a simplification of the electrophysiological procedure.

BACKGROUND: The aim of the present study was to assess the consequences of a simplification of the electrophysiological procedure on the post-operative clinical outcome after subthalamic nucleus implantation in Parkinson disease. METHODS: Microelectrode recordings were performed on 5 parallel trajectories in group 1 and less than 5 trajectories in group 2. Clinical evaluations were performed 1 month before and 6 months after surgery. RESULTS: After surgery, the UPDRS III score in the off-drug/on-stimulation and on-drug/on-stimulation conditions significantly improved by 66,9% and 82%, respectively in group 1, and by 65.8% and 82.3% in group 2 (P<0.05). Meanwhile, the total number of words (P<0.05) significantly decreased for fluency tasks in both groups. Motor disability improvement and medication reduction were similar in both groups. CONCLUSIONS: Our results suggest that the electrophysiological procedure should be simplified as the team's experience increases.

Generalized pruritus preceding paraneoplastic neuropathy.

Paraneoplastic syndromes are a group of rare disorders involving non-metastatic systemic effects accompanying malignancies, and occur remotely from the tumor itself. Chronic pruritus lasting more than 6 weeks can be from paraneoplastic origin. A 65-year-old woman was admitted for generalized pruritus lasting for 1 month, despite treatment with prednisolone, levocetirizine and hydroxyzine. General examination was normal. Biological data and gastroscopy were normal. One month later, the patient was readmitted for worsening of her pruritus and walking impairment, revealing a severe sensory neuropathy. Blood anti-Hu antibodies returned positive at a level of 400 (normal <100). Bronchoscopy and bronchial biopsies revealed small-cell lung carcinoma. To our knowledge, the association of generalized pruritus and paraneoplastic neuropathy has been rarely reported. Our observation raises the question of a pathophysiological continuum between pruritus and neuropathy in a paraneoplastic context.

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.

Does early verbal fluency decline after STN implantation predict long-term cognitive outcome after STN-DBS in Parkinson's disease?

BACKGROUNDS: An early and transient verbal fluency (VF) decline and impairment in frontal executive function, suggesting a cognitive microlesion effect may influence the cognitive repercussions related to subthalamic nucleus deep brain stimulation (STN-DBS). METHODS: Neuropsychological tests including semantic and phonemic verbal fluency were administered both before surgery (baseline), the third day after surgery (T3), at six months (T180), and at an endpoint multiple years after surgery (Tyears). RESULTS: Twenty-four patients (mean age, 63.5 ± 9.5 years; mean disease duration, 12 ± 5.8 years) were included. Both semantic and phonemic VF decreased significantly in the acute post-operative period (44.4 ± 28.2% and 34.3 ± 33.4%, respectively) and remained low at 6 months compared to pre-operative levels (decrease of 3.4 ± 47.8% and 10.8 ± 32.1%) (P < 0.05). Regression analysis showed phonemic VF to be an independent factor of decreased phonemic VF at six months. Age was the only independent predictive factor for incident Parkinson's disease dementia (PDD) (F (4,19)=3.4, P<0.03). CONCLUSION: An acute post-operative decline in phonemic VF can be predictive of a long-term phonemic VF deficit. The severity of this cognitive lesion effect does not predict the development of dementia which appears to be disease-related.

Phenotypic spectrum of probable and genetically-confirmed idiopathic basal ganglia calcification.

Idiopathic basal ganglia calcification is characterized by mineral deposits in the brain, an autosomal dominant pattern of inheritance in most cases and genetic heterogeneity. The first causal genes, SLC20A2 and PDGFRB, have recently been reported. Diagnosing idiopathic basal ganglia calcification necessitates the exclusion of other causes, including calcification related to normal ageing, for which no normative data exist. Our objectives were to diagnose accurately and then describe the clinical and radiological characteristics of idiopathic basal ganglia calcification. First, calcifications were evaluated using a visual rating scale on the computerized tomography scans of 600 consecutively hospitalized unselected controls. We determined an age-specific threshold in these control computerized tomography scans as the value of the 99th percentile of the total calcification score within three age categories: <40, 40-60, and >60 years. To study the phenotype of the disease, patients with basal ganglia calcification were recruited from several medical centres. Calcifications that rated below the age-specific threshold using the same scale were excluded, as were patients with differential diagnoses of idiopathic basal ganglia calcification, after an extensive aetiological assessment. Sanger sequencing of SLC20A2 and PDGFRB was performed. In total, 72 patients were diagnosed with idiopathic basal ganglia calcification, 25 of whom bore a mutation in either SLC20A2 (two families, four sporadic cases) or PDGFRB (one family, two sporadic cases). Five mutations were novel. Seventy-one per cent of the patients with idiopathic basal ganglia calcification were symptomatic (mean age of clinical onset: 39 ± 20 years; mean age at last evaluation: 55 ± 19 years). Among them, the most frequent signs were: cognitive impairment (58.8%), psychiatric symptoms (56.9%) and movement disorders (54.9%). Few clinical differences appeared between SLC20A2 and PDGFRB mutation carriers. Radiological analysis revealed that the total calcification scores correlated positively with age in controls and patients, but increased more rapidly with age in patients. The expected total calcification score was greater in SLC20A2 than PDGFRB mutation carriers, beyond the effect of the age alone. No patient with a PDGFRB mutation exhibited a cortical or a vermis calcification. The total calcification score was more severe in symptomatic versus asymptomatic individuals. We provide the first phenotypical description of a case series of patients with idiopathic basal ganglia calcification since the identification of the first causative genes. Clinical and radiological diversity is confirmed, whatever the genetic status. Quantification of calcification is correlated with the symptomatic status, but the location and the severity of the calcifications don't reflect the whole clinical diversity. Other biomarkers may be helpful in better predicting clinical expression.

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.

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.