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.).

Bilateral facial palsy in an older person.

Lyme disease is an infectious disease caused by the Borrelia burgdorferi spirochetes and other related species that are transmitted through an infected tick bite. We report the case of an older patient presenting with bilateral facial palsy due to Lyme disease. Multiple non-specific clinical signs preceded facial palsy with falls, fatigue and pain of both legs especially during the night. Our case illustrates the difficulty to diagnose this infectious disease, especially in older patients who have rare outdoor activities and a low risk of tick exposure.

A case of right internal carotid agenesis with associated transcavernous anastomosis revealed by transient ischemic attack.

Agenesis of the internal carotid artery (ICA) is a rare congenital vascular disorder of the cerebral circulation. CT scan of the skull base disclosing complete absence of the bony carotid canal helps to differentiate an agenesis from aplasia or hypoplasia. Although most of the patients remain asymptomatic (thanks to the sufficient collateral circulation provided by the circle of Willis) cerebral infarcts, transient ischemic attacks or intracranial aneurysms have been rarely described in association with agenesis of the ICA. Most often, the vascular territory of the involved ICA is supplied by the contralateral carotid artery and from the vertebrobasilar circulation through the anterior and posterior communicating arteries, respectively. However, collateral supply can also be provided thanks to a transcavernous anastomosis, an aberrant vascular communication between the cavernous portions of the ICAs coursing through the sella turcica. We report here the case of a 55-year-old man with right carotid agenesis and associated transcavernous anastomosis revealed by transient ischemic attack. Embryogenesis, imaging findings, possibilities of collateral circulation and potential complications have also been discussed.

Invasive meningoencephalitis as the first manifestation of hepatitis A.

Since mid-2016, Europe has been facing a major hepatitis A epidemic, with more than 25 000 cases reported to the European CDC, in 2018. We describe herein a rare case of invasive HAV meningoencephalitis as a prodrome of the classic hepatitis, which largely explains a delay in diagnosis.

Trigeminal Neuralgia and Charcot-Marie-Tooth Disease: An Intriguing Association. Lessons From a Large Family Case Report and Review of Literature.

We report a case of familial trigeminal neuralgia (TN) and Charcot-Marie-Tooth disease (CMT) caused by an identified MPZ mutation with a review of previous cases described in the literature. BACKGROUND: The association of TN in CMT patients has previously been reported in a few cases. The pathophysiological link can be detailed with recent use of genetic analysis in CMT. METHODS: We report a large family including 7 members affected by CMT, 4 of whom also presented with TN. We then performed a literature review of literature by search of Pubmed from 1950 to September 2018, using the search terms "trigeminal neuralgia" and "Charcot-Marie-Tooth" and the references of relevant articles. RESULTS: Overall, we found 29 previously published TN cases in 12 CMT families. Among them, only 7 families (69%) included several affected members, suggesting that not all mutations involved in CMT predispose to TN. TN in this context seems to present with specific characteristics, including earlier age of onset, bilateral presentation, and poor tolerance to preventive treatments with gait disturbance exacerbated by the underlying neuropathy. CONCLUSION: This report of familial TN in CMT with identified MPZ mutation highlighted specific characteristics of this association. Considered as a rare association in the literature, it may be underestimated and the clinician should be aware of its specific pattern, including earlier age of onset, bilateral presentation, and poor tolerance to preventive treatments.

Pathological Laughter as a Symptom of Middle Cerebral Artery Stroke.

BACKGROUND: Pathological laughter is defined as uncontrollable and inappropriate laughter unrelated to an emotion or a mood. This symptom can reveal a stroke. CASE REPORT: We described the case of a 57-year-old patient who presented to the emergency department 2 h after a sudden onset of left hemiparesis preceded by pathological laughter. The left motor weakness was very discrete and underestimated because of severe behavioral changes, that is, laughter, joviality, and motor restlessness. Despite abnormal brain imaging results, symptoms were considered as atypical to evoke a stroke. The patient did not receive intravenous thrombolysis. Brain magnetic resonance imaging performed 2 days after admission confirmed the diagnosis of stroke. WHY SHOULD AN EMERGENCY PHYSICIAN BE AWARE OF THIS?: Emergency physicians are at the forefront of stroke management. They should be aware that the initial symptom of a stroke can be atypical and lead to misunderstanding the diagnosis. Because the treatment of stroke requires the fastest care, it is important for emergency physicians to know that sudden behavioral troubles and pathological laughter can reveal strokes.

Bath-related thunderclap headache: Case report of a male patient.

Bath-related thunderclap headache (BRTH) is a rare entity, closed to reversible cerebral vasoconstriction syndrome. It is only described in middle-aged women and mainly Asiatic ethnic origins. Role of estrogen is consequently discussed. We report here a case of a 36-year-old man, admitted for five episodes of thunderclap headaches, triggered by hot shower. This is the first male case of BRTH, opposing only a hormonal hypothesis. Furthermore, this African patient consolidates the non-exclusivity of this affection to Asian ethnic origins.

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 Parkinson's disease (PD) are frequently incapacitated by apathy prior to the development of dementia. We sought to establish whether rivastigmine's 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.

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.

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.

Nucleus Basalis of Meynert Stimulation for Lewy Body Dementia: A Phase I Randomized Clinical Trial.

OBJECTIVES: Nucleus basalis of Meynert deep brain stimulation (NBM-DBS) has been proposed for patients with dementia. Here, we aim to assess the safety and effects of NBM-DBS in patients with Lewy body dementia (LBD), in a randomized, double-blind, crossover clinical trial. METHODS: Six patients with mild to moderate LBD (mean [SD] age, 62.2 [7.8] years) were included, operated on for bilateral NBM-DBS, and assigned to receive either active or sham NBM-DBS followed by the opposite condition for 3 months. The primary outcome was the difference in the total free recalls of the Free and Cued Selective Reminding Test (FCSRT) between active and sham NBM-DBS. Secondary outcomes were assessments of the safety and effects of NBM-DBS on cognition, motor disability, sleep, and PET imaging. RESULTS: There was no significant difference in the FCSRT score with active vs sham NBM-DBS. The surgical procedures were well tolerated in all patients, but we observed significant decreases in Stroop and Benton scores after electrode implantation. We observed no significant difference in other scales between active and sham NBM-DBS. With active NBM-DBS relative to baseline, phonemic fluency and motor disability significantly decreased. Lastly, the superior lingual gyrus metabolic activity significantly increased with active NBM-DBS. CONCLUSIONS: NBM-DBS does not appear to be totally safe for patients with LBD with no evidence of cognitive benefit. CLINICALTRIALSGOV IDENTIFIER: NCT01340001. CLASSIFICATION OF EVIDENCE: This study provides Class II evidence that, for patients with LBD operated on for bilateral NBM-DBS, active NBM-DBS stimulation compared to sham stimulation did not significantly change selective recall scores.

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.

Increased diagnostic yield in complex dystonia through exome sequencing.

INTRODUCTION: A strategy based on targeted gene panel sequencing identifies possibly pathogenic variants in fewer than 20% of cases in early-onset and familial form of dystonia. By using Whole Exome Sequencing (WES), we aimed to identify the missing genetic causes in dystonic patients without diagnosis despite gene panel sequencing. MATERIAL AND METHODS: WES was applied to DNA samples from 32 patients with early-onset or familial dystonia investigated by sequencing of a 127 movement disorders-associated gene panel. Dystonia was described according to the familial history, body distribution, evolution pattern, age of onset, associated symptoms and associated movement disorders. Rate of diagnoses was evaluated for each clinical feature. RESULTS: We identified causative variants for 11 patients from 9 families in CTNNB1, SUCLG1, NUS1, CNTNAP1, KCNB1, RELN, GNAO1, HIBCH, ADCK3 genes, yielding an overall diagnostic rate of 34.4%. Diagnostic yield was higher in complex dystonia compared to non-complex dystonia (66.7%-5.9%; p < 0.002), especially in patients showing intellectual disability compared to the patients without intellectual disability (87.5%-16.7%; p < 0.002). CONCLUSION: Our approach suggests WES as an efficient tool to improve the diagnostic yield after gene panel sequencing in dystonia. Larger study are warranted to confirm a potential genetic overlap between neurodevelopmental diseases and dystonia.

Microsubthalamotomy effect at day 3: screening for determinants.

A microsubthalamotomy (mSTN) effect has been frequently reported after implantation that improves Parkinson's 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.

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.

Four Cases of Parkinson Disease Diagnosed During the Postpartum Period.

BACKGROUND: There is little experience with the effect of pregnancy on Parkinson disease because the number of women with Parkinson disease who are of childbearing age is small. We report four cases beginning during the postpartum period and discuss the potential contribution of different factors that may influence the occurrence of Parkinson disease in this time period. CASES: Four women aged 29-35 years developed arm tremor, shoulder pain, dizziness, or decreased dexterity of the hand in the first few days or months after childbirth. They were initially diagnosed with postpartum depression or psychogenic parkinsonism. Finally, dopamine transporter imaging confirmed the diagnosis of young-onset Parkinson disease. CONCLUSION: Early-onset Parkinson disease may present in postpartum women. In women with atypical motor symptoms in addition to depression, this diagnosis should be considered.