Topiramate for essential tremor.

BACKGROUND: Essential tremor (ET) is one of the most common movement disorders. The management is primarily based on pharmacological agents and in clinical practice propranolol and primidone are considered the first-line therapy. However, these treatments can be ineffective in 25% to 55% of people and are frequently associated with serious adverse events (AEs). For these reasons, it is worthwhile evaluating other treatments for ET. Topiramate has been suggested as a potentially useful agent for the treatment of ET but there is uncertainty about its efficacy and safety. OBJECTIVES: To assess the efficacy and safety of topiramate in the treatment of ET. SEARCH METHODS: We carried out a systematic search without language restrictions to identify all relevant trials in the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (January 1966 to January 2017), Embase (January 1988 to January 2017), National Institute for Health and Care Excellence (1999 to January 2017), ClinicalTrials.gov (1997 to January 2017) and World Health Organization International Clinical Trials Registry Platform (ICTRP; 2004 to January 2017). We searched BIOSIS Citation Index (2000 to January 2017) for conference proceedings. We handsearched grey literature and the reference lists of identified studies and reviews. SELECTION CRITERIA: We included all randomised controlled trials (RCTs) of topiramate versus placebo/open control or any other treatments. We included studies in which the diagnosis of ET was made according to accepted and validated diagnostic criteria. We excluded studies conducted in people presenting with secondary forms of tremor or reporting only neurophysiological parameters to assess outcomes. DATA COLLECTION AND ANALYSIS: Two review authors independently collected and extracted data using a data collection form. We assessed the risk of bias and the quality of evidence. We used a fixed-effect meta-analysis for data synthesis. MAIN RESULTS: This review included three trials comparing topiramate to placebo (309 participants). They were all at high overall risk of bias. The quality of evidence ranged from very low to low. Compared to placebo, participants treated with topiramate showed a significant improvement in functional disability and an increased risk of withdrawal (risk ratio (RR) 1.78, 95% confidence interval (CI) 1.23 to 2.60). There were more AEs for topiramate-treated participants, particularly paraesthesia, weight loss, appetite decrease and memory difficulty. AUTHORS' CONCLUSIONS: This systematic review highlighted the presence of limited data and very low to low quality evidence to support the apparent efficacy and the occurrence of treatment-limiting AEs in people with ET treated with topiramate. Further research to assess topiramate efficacy and safety on ET is needed.

LRRK2 mutations in Parkinson's disease: confirmation of a gender effect in the Italian population.

BACKGROUND: The relative risk of developing idiopathic PD is 1.5 times greater in men than in women, but an increased female prevalence in LRRK2-carriers has been described in the Ashkenazi Jewish population. We report an update about the frequency of major LRRK2 mutations in a large series of consecutive patients with Parkinson's disease (PD), including extensive characterization of clinical features. In particular, we investigated gender-related differences in motor and non-motor symptoms in the LRRK2 population. METHODS: 2976 unrelated consecutive Italian patients with degenerative Parkinsonism were screened for mutations on exon 41 (G2019S, I2020T) and a subgroup of 1190 patients for mutations on exon 31 (R1441C/G/H). Demographic and clinical features were compared between LRRK2-carriers and non-carriers, and between male and female LRRK2 mutation carriers. RESULTS: LRRK2 mutations were identified in 40 of 2523 PD patients (1.6%) and not in other primary parkinsonian syndromes. No major clinical differences were found between LRRK2-carriers and non-carriers. We found a novel I2020L missense variant, predicted to be pathogenic. Female gender was more common amongst carriers than non-carriers (57% vs. 40%; p = 0.01), without any gender-related difference in clinical features. Family history of PD was more common in women in the whole PD group, regardless of their LRRK2 status. CONCLUSIONS: PD patients with LRRK2 mutations are more likely to be women, suggesting a stronger genetic load compared to idiopathic PD. Further studies are needed to elucidate whether there is a different effect of gender on the balance between genetic and environmental factors in the pathogenesis of PD.

Impairment of sensory-motor plasticity in mild Alzheimer's disease.

BACKGROUND: Primary motor cortex (M1) is relatively spared in the early stages of Alzheimer's disease (AD). OBJECTIVE: Aim of the present study was to investigate whether abnormal M1 synaptic plasticity is present at an early stage of AD. We employed an electrophysiological protocol, named rapid paired associative stimulation (rPAS), involving repetitive transcranial magnetic stimulation (rTMS) paired with electrical stimulation of the contralateral median nerve, that modifies corticospinal excitability and short latency afferent inhibition (SAI). METHODS: We studied 10 patients with a diagnosis of probable mild AD according to the Mini Mental State Examination score (minimum 21) and 14 age-matched control subjects. Motor evoked potentials (MEP) amplitudes and short-afferent inhibition (SAI) were measured at baseline before and for up to 60 min after 5Hz-rPAS in abductor pollicis brevis (APB). rPAS consisted of 600 pairs of transcranial magnetic stimuli, at a rate of 5 Hz for 2 min, coupled with electrical median nerve stimulation preceding TMS over the contralateral M1 at an inter-stimulus interval of 25 ms. RESULTS: Baseline SAI was significantly reduced in AD patients. In the control subjects rPAS induced a significant increase in MEP amplitudes and a decrease of SAI in the APB muscle persistently for up to 1 h. Conversely 5Hz-rPAS did not induce any significant changes in MEP amplitudes and SAI in mild AD patients. CONCLUSIONS: Sensory-motor plasticity is impaired in the motor cortex of AD at an early stage of the disease.

Treatment of essential tremor: a systematic review of evidence and recommendations from the Italian Movement Disorders Association.

Essential tremor (ET) is one of the most common movement disorders of adults, characterized by postural and kinetic tremor. It often causes embarrassment and more rarely serious disability, requiring treatment. To assess the current state of knowledge on ET therapy and produce recommendations based on the analysis of evidence the authors reviewed the literature regarding pharmacologic and surgical therapies, providing a quality assessment of the studies and the strength of recommendations for each treatment. A committee of experts selected clinical-based questions to guide the search. A systematic literature review was performed to identify all the studies conducted on patients with ET published until September 2010. Articles were classified according to GRADE evidence profile, a system for grading the quality of evidence and the strength of recommendation based on the quality of the studies. The quality of evidence was often rated as "low" or "very low" for the studies analyzed. Propranolol, long-acting propranolol, primidone, and topiramate are recommended as first-line therapy, with restrictions for their side effects. Arotinolol, sotalol, ICI 118.551 and LI 32.468 (experimental drugs), zonisamide, gabapentin, alprazolam, clozapine, and olanzapine are recommended as a second-line treatment. Botulinum toxin type A and thalamic deep-brain stimulation are recommended for refractory ET. The results highlight the need of well-designed direct comparison trials aimed at evaluating relative effectiveness and safety of the drugs currently used in clinical practice. Furthermore, additional controlled clinical trials are required to define other possible treatment strategies for ameliorating the management of ET.