Alice Poisson

FXTAS: new insights and the need for revised diagnostic criteria

Objective:Fragile X–associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS. Methods:Clinical, morphologic (brain MRI, 123I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women. Results:A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal 123I-ioflupane SPECT. Unified Parkinsons Disease Rating Scale motor score was correlated to abnormal 123I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04). Conclusions:We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria. GLOSSARYAcc: accelerometerCCS: corpus callosum spleniumCMAP: compound muscle action potentialDD: disease durationDL: distal latencyDRG: dorsal root gangliaET: essential tremorF-WL: F-wave latencyFAB: Frontal Assessment BatteryFLAIR: fluid-attenuated inversion recoveryFTMa: Fahn-Tolosa-Marin adapted tremor rating scale, part AFXS: fragile X syndromeFXTAS: fragile X–associated tremor ataxia syndromeLL: lower limbMCP: middle cerebellar peduncleMMSE: Mini-Mental State ExaminationMNCV: motor nerve conduction velocityNCS: nerve conduction studyPD: Parkinson diseasePOI: primary ovarian insufficiencySARA: Scale for the Assessment and Rating of AtaxiaSNAP: sensory nerve action potentialSNN: sensory neuronopathyUL: upper limbUPDRS-III: Unified Parkinsons Disease Rating Scale motorObjective: Fragile X–associated tremor ataxia syndrome (FXTAS) is defined by FMR1 premutation, cerebellar ataxia, intentional tremor, and middle cerebellar peduncle (MCP) hyperintensities. We delineate the clinical, neurophysiologic, and morphologic characteristics of FXTAS. Methods: Clinical, morphologic (brain MRI, 123I-ioflupane SPECT), and neurophysiologic (tremor recording, nerve conduction studies) study in 22 patients with FXTAS, including 4 women. Results: A total of 43% of patients had no family history of fragile X syndrome (FXS), which contrasts with previous FXTAS series. A total of 86% of patients had tremor and 81% peripheral neuropathy. We identified 3 electroclinical tremor patterns: essential-like (35%), cerebellar (29%), and parkinsonian (12%). Two electrophysiologic patterns evocative of non-length-dependent (56%) and length-dependent sensory neuropathy (25%) were identified. Corpus callosum splenium (CCS) hyperintensity was as frequent (68%) as MCP hyperintensities (64%). Sixty percent of patients had parkinsonism and 47% abnormal 123I-ioflupane SPECT. Unified Parkinsons Disease Rating Scale motor score was correlated to abnormal 123I-ioflupane SPECT (p = 0.02) and to CGG repeat number (p = 0.0004). Scale for the assessment and rating of ataxia correlated with dentate nuclei hyperintensities (p = 0.03) and CCS hyperintensity was a marker of severe disease progression (p = 0.04). Conclusions: We recommend to include in the FXTAS testing guidelines both CCS hyperintensity and peripheral neuropathy and to consider them as new major radiologic and minor clinical criterion, respectively, for the diagnosis of FXTAS. FXTAS should also be considered in women or when tremor, MCP hyperintensities, or family history of FXS are lacking. Our study broadens the spectrum of tremor, peripheral neuropathy, and MRI abnormalities in FXTAS, hence revealing the need for revised criteria.

History of the 'geste antagoniste' sign in cervical dystonia.

The geste antagoniste is a voluntary maneuver that temporarily reduces the severity of dystonic posture or movements. It is a classical feature of focal and particularly cervical dystonia. However, the precise historical aspects of geste antagoniste still remain obscure. The goals of this review were (1) to clarify the origin of the geste antagoniste sign; (2) to identify the factors that led to its diffusion in the international literature; (3) to follow the evolution of that term across the twentieth century. We used medical and neurological French, German and English literature of the late nineteenth and early twentieth centuries, and the PubMed database by entering the terms geste antagoniste, antagonistic gesture and sensory trick. The geste antagoniste sign is a legacy of the Paris Neurological School of the end of the nineteenth century. The term was introduced by Meige and Feindel in their 1902 book on tics, written in the vein of their master, Brissaud, who first described this sign in 1893. The almost immediate translations of this book by Giese into German and Kinnier Wilson into English contributed to the rapid spreading of the term geste antagoniste, which is still in use worldwide today. The term antagonistic gesture is the translation proposed by Kinnier Wilson, which also led to the use of the term geste antagonistique. The geste antagoniste sign has long been considered a solid argument for the psychogenic origins of dystonia until the 1980s when Marsden made strong arguments for its organic nature.

Relationships between Cognitive Functions and Driving Behavior in Parkinson’s Disease

Alterations in cognitive functions in Parkinson’s disease (PD) have been reported even in mild stages of the disease. These functions may play a role in complex daily activities, such as driving. This article provides an overview on the relationships between cognitive functions and driving behavior in PD in driving simulator and on-road studies. The role of attention, executive functions, visual memory, visuospatial construction and information processing speed is discussed. In driving simulator studies, driving performances were correlated with several neuropsychological measures, especially those of Trail Making Test (TMT), Brixton and Symbol Digit Modalities Test. In on-road studies, TMT, Useful Field Of View and Block Design tests appear as good predictors of driving performances. Most of these tests are also relevant to driving in Alzheimer’s disease and traumatic brain injury.

G303V tau mutation presenting with progressive supranuclear palsy–like features

Progressive supranuclear palsy (PSP) is usually sporadic, but 7% of PSP patients have parkinsonism or dementia in their family in a pattern consistent with autosomal dominant transmission. In 2005, we reported the initial description of a family of PSP carrying the G303V mutation of the tau gene. Since then, the number of affected members in this family has increased and prospective follow-up has become available for these subjects.

Slowness in Movement Initiation is Associated with Proactive Inhibitory Network Dysfunction in Parkinson’s Disease

BACKGROUND Impairment in initiating movements in PD might be related to executive dysfunction associated with abnormal proactive inhibitory control, a pivotal mechanism consisting in gating movement initiation in uncertain contexts. OBJECTIVE Testing this hypothesis on the basis of direct neural-based evidence. METHODS Twelve PD patients on antiparkinsonian medication and fifteen matched healthy controls performed a simple reaction time task during event-related functional MRI scanning. RESULTS For all subjects, the level of activation of SMA was found to predict RT on a trial-by-trial basis. The increase in movement initiation latency observed in PD patients with regard to controls was associated with pre-stimulus BOLD increases within several nodes of the proactive inhibitory network (caudate nucleus, precuneus, thalamus). CONCLUSIONS These results provide physiological data consistent with impaired control of proactive inhibition over motor initiation in PD. Patients would be locked into a mode of control maintaining anticipated inhibition over willed movements even when the situation does not require action restraint. The functional and neurochemical bases of brain activity associated with executive settings need to be addressed thoroughly in future studies to better understand disabling symptoms that have few therapeutic options like akinesia.

Do the effects measured by intraoperative and postoperative STN macrostimulation in Parkinson’s disease match?

The aim of our study was to compare the results obtained by intraoperative and postoperative subthalamic nucleus (STN) macrostimulation in Parkinson’s disease (PD). One hundred three PD patients implanted with bilateral STN stimulation were included. The thresholds for efficacy and side effects (motor contraction; paresthesias; oculomotor signs) observed on the same trajectory and at the same depth during the intraoperative evaluation and the first postoperative setting of STN stimulation parameters were collected. The level of improvement was divided into four categories depending on the degree of rigidity reduction: 0: no effect, A (mediocre efficacy): 20–50%, B (good efficacy): 60–100%, LL: lesion-like effect (disappearance of rigidity after implantation). Efficacy of STN stimulation was analyzed in 83 patients for a total of 664 contacts. For the best effects (B, LL), the results obtained in the operative room were concordant with those of the postoperative evaluation for 81% of the contacts. For the mediocre effects (A) and absence of efficacy, the results were only concordant in 20%. Side effects were analyzed in 103 patients for a total of 824 contacts. In 35% of the tested contacts paresthesias that were absent during surgery were observed postoperatively. This discrepancy was of 17% for the motor and of 10% for oculomotor side effects. Differences between the type of electrodes used, the stimulation parameters employed and the conditions of the assessment could explain these discrepancies.

Parkinson's with tardive Creutzfeldt-Jakob disease: When there is more to it than meets the eye

des animaux de basse-cour (poulets, lapins) des voisins. Il n’a aucun contact avec des sujets voyageant en Asie ni de consommation de produits exotiques. Nous supposons donc que notre patient a été infecté en France. Aucune donnée épidémiologique n’est disponible en Europe d’où l’affection semblait virtuellement absente. Quelques cas humains importés au retour d’Asie ont été décrits [2]. La pharmacorésistance classique de cette infection impose d’emblée une polyantibiothérapie, et une exérèse complète des lésions opérables. La survie des abcès cérébraux à Cladophialophora bantiana est de 30 % [1,3]. La survie au prix d’un abcès chronique dans notre cas est donc exceptionnelle [4,5].

Additive Effect of Variably Penetrant 22q11.2 Duplication and Pathogenic Mutations in Autism Spectrum Disorder: To Which Extent Does the Tree Hide the Forest?

The 22q11.2 duplication is a variably penetrant copy number variant (CNV) associated with a broad spectrum of clinical manifestations including autism spectrum disorders (ASD), and epilepsy. Here, we report on pathogenic HUWE1 and KIF1A mutations in two severely affected ASD/ID participants carrying a 22q11.2 duplication. Based on previous studies, this CNV was originally considered as disease-causing. Yet, owing to their clinical severity, the participants were further investigated by next generation sequencing and eventually found to carry pathogenic mutations in HUWE1 and KIF1A respectively. We suggest giving consideration to additive effect of 22q11.2 duplication and pathogenic mutations when clinical presentation is either unusually severe or associated with atypical features. Caution should be exercised when delivering genetic counseling for variably penetrant CNVs, as uncertain penetrance of this CNV may lead to ignore additive pathogenic mutations. Systematic panel or exome sequencing of known ASD genes should be recommended when counseling families of patients carrying variably penetrant CNV.

Weight loss induced by quetiapine in a 22q11.2DS patient

The 22q11.2 deletion syndrome (22q11.2DS) is the most frequent known genetic risk factors for schizophrenia [1]. Here, we present an unusual weight loss in a 22q11.2DS patient given quetiapine. The patient was a 37-year-old man (5-ft 7-in. tall; 145,2 lb) with a 22q11.2DS. At the age of 20, he developed a schizophrenia and failed to benefit from treatments by atypical antipsychotics and haloperidol. Weight always remained stable. After 3 weeks of antipsychotics withdrawal, a treatment by quetiapine was progressively introduced (up to 300 mg/day). Twelve weeks later, an anorexia with worrisome weight loss (−17,6 lb) was noted. Results of the metabolic work-up (chemistry screening, leptin and ghrelin levels, CBC, CPK, thyroid function tests, oral glucose tolerance test and abdominal echography) were unremarkable. The quetiapine was discontinued and the patient recovered his initial weight two months later (145 lb). Resumption of quetiapine was proposed. As a result, an anorexia with weight loss recurred and the treatment was interrupted. Quetiapine is a second-generation antipsychotic that has affinity for D2, 5-HT2A, H1, alpha 1 and 5-HT1A receptors but its mechanism of action remains unknown. In particular, quetiapine has been shown to occupy approximately 49.1% of D2 receptors at therapeutic doses [2,3], which is lower than other antipsychotics (olanzapine: 96.5%, aripiprazole: 86.9%, risperidone: 92.4%, haloperidol: 91.9% and clozapine: 61.7%). Among the 22q11.2 genes, catechol-O-methyl-transferase haploinsufficiency decreases the degradation of dopamine, causing higher levels of catecholamines in the CNS. COMT-dependent degradation is of importance in brain regions with low expression of the presynaptic transporter, such as the prefrontal cortex [4]. This dopaminergic-rich region has been shown to be important to food-related decision-making [5]. Therefore, COMT haploinsufficiency, in addition with the atypical pharmacological profile of quetiapine, gives insights to understand appetite reduction in this case report. In conclusion, taking into account molecular diagnosis in psychiatry promises to improve patient care though advances in personalized medicine.