Dopa Responsiveness in Parkinson's Disease.

BACKGROUND: Dopaminergic responsiveness is a defining feature of Parkinson's disease (PD). However, there is limited information on how this evolves over time. OBJECTIVES: To examine serial dopaminergic responses, if there are distinct patterns, and which factors predict these. METHODS: We analyzed data from the Parkinson's Progression Markers Initiative on repeated dopaminergic challenge tests (≥24.5% defined as a definite response). Growth-mixture modeling evaluated for different response patterns and multinomial logistic regression tested for predictors of these clusters. RESULTS: 1525 dopaminergic challenge tests were performed in 336 patients. At enrolment, mean age was 61.2 years (SD 9.6), 66.4% were male and disease duration was 0.5 years (SD 0.5). 1 to 2 years after diagnosis, 48.0% of tests showed a definite response, but this proportion increased with longer disease duration (51.1-74.3%). We identified 3 response groups: "Striking" (n = 29, 8.7%); "Excellent" (n = 110; 32.7%) and "Modest" (n = 197, 58.6%). Significant differences were as follows: striking responders commenced treatment earlier (P = 0.02), were less likely to be on dopamine agonist monotherapy (P = 0.01), and had better cognition (P < 0.01) and activities of daily living (P = 0.01). Excellent responders had higher challenge doses (P = 0.03) and were more likely to be on combination therapy (P < 0.01). CONCLUSION: Three distinct patterns of the dopaminergic response were observed. As the proportion of PD cases with definite dopa responsiveness increased over time, the initial treatment response may be an unreliable diagnostic aid.

Motor Complications in Parkinson's Disease: Results from 3343 Patients Followed for up to 12 Years.

BACKGROUND: Motor complications are well recognized in Parkinson's disease (PD), but their reported prevalence varies and functional impact has not been well studied. OBJECTIVES: To quantify the presence, severity, impact and associated factors for motor complications in PD. METHODS: Analysis of three large prospective cohort studies of recent-onset PD patients followed for up to 12 years. The MDS-UPDRS part 4 assessed motor complications and multivariable logistic regression tested for associations. Genetic risk score (GRS) for Parkinson's was calculated from 79 single nucleotide polymorphisms. RESULTS: 3343 cases were included (64.7% male). Off periods affected 35.0% (95% CI 33.0, 37.0) at 4-6 years and 59.0% (55.6, 62.3) at 8-10 years. Dyskinesia affected 18.5% (95% CI 16.9, 20.2) at 4-6 years and 42.1% (38.7, 45.5) at 8-10 years. Dystonia affected 13.4% (12.1, 14.9) at 4-6 years and 22.8% (20.1, 25.9) at 8-10 years. Off periods consistently caused greater functional impact than dyskinesia. Motor complications were more common among those with higher drug doses, younger age at diagnosis, female gender, and greater dopaminergic responsiveness (in challenge tests), with associations emerging 2-4 years post-diagnosis. Higher Parkinson's GRS was associated with early dyskinesia (0.026 ≤ P ≤ 0.050 from 2 to 6 years). CONCLUSIONS: Off periods are more common and cause greater functional impairment than dyskinesia. We confirm previously reported associations between motor complications with several demographic and medication factors. Greater dopaminergic responsiveness and a higher genetic risk score are two novel and significant independent risk factors for the development of motor complications.

The phenotypic and genotypic features of a Scottish cohort with McArdle disease.

This retrospective study evaluated the phenotypic and genotypic features of 14 patients with McArdle disease attending the West of Scotland adult muscle clinic. Although all patients experienced exercise-induced cramps, exercise intolerance and hyperCKaemia, only 71% (n = 10) experienced the second wind phenomenon, rhabdomyolysis and/or myoglobinuria. We observed a high rate of fixed muscle weakness (50%; n = 7), coronary artery disease (36%; n = 5), and psychological comorbidity (50%; n = 7). Although 79% had symptom onset in the first decade of life, the mean age at presentation and at genetic diagnosis was 43.8 years and 47.7 years, respectively. 93% had at least one copy of the common PYGM pathogenic variant, c.148C > T, p.(Arg50*), with 50% (n = 7) of the cohort being homozygous. Our cohort highlights the phenotypic variability seen in McArdle disease and underscores the potential for late-onset presentations. It emphasises the need for improved awareness and recognition of this condition amongst neurologists, rheumatologists and general physicians. A history of exercise intolerance and second wind phenomenon may not always be volunteered by the patient, underscoring the need to ask specific questions in clinic to extrapolate the relevant symptoms in this patient cohort.

Emergency presentations of movement disorders.

Movement disorders are typically perceived as being gradually progressive conditions that are managed in outpatient settings. However, they may manifest de novo with an acute severe phenotype or an acute decompensation. A movement disorder becomes an emergency when it evolves acutely or subacutely over hours to days; delays in its diagnosis and treatment may cause significant morbidity and mortality. Here we address the clinical presentation, diagnosis and management of those movement disorder emergencies that are principally encountered in emergency departments, in acute receiving units or in intensive care units. We provide practical guidance for management in the acute setting where there are several treatable causes not to be missed. The suggested medication doses are predominantly based on expert opinion due to limited higher-level evidence. In spite of the rarity of movement disorder emergencies, neurologists need to be familiar with the phenomenology, potential causes and treatments of these conditions. Movement disorder emergencies divide broadly into two groups: hypokinetic and hyperkinetic, categorised according to their phenomenology. Most acute presentations are hyperkinetic and some are mixed.

Real world use of a neurophysiology service for the differential diagnosis of hyperkinetic movement disorders.

INTRODUCTION: Clinical neurophysiology constitutes a potentially useful aid in differentiating hyperkinetic movement disorders (HMD). Parameters including presence of a Bereitschaftspotential on back-averaged electroencephalography (EEG) have been demonstrated to help distinguish between these disorders. In 2008, a Movement Disorder neurophysiology service was established in Greater Manchester to aid in the diagnostic process. METHODS: We retrospectively reviewed records of patients with HMD who underwent EEG back-averaging through this service from January 2009 until January 2018. The aim was (i) to characterise the clinical features of our patient cohort and (ii) to determine how frequently neurophysiological testing altered the final diagnosis. RESULTS: A total of 39 patients (23 females, 16 males), with a mean age at onset of 42.6 years and mean disease duration of 2.0 years underwent neurophysiological examination. The clinical diagnosis was changed in 16 cases (41%) and refined in a further seven. Distractibility (P = 0.001), variability (P = 0.002), the presence of a Bereitschaftspotential (P < 0.0001), and electromyography burst duration > 300 ms (P = 0.012) were more frequent in those with an eventual diagnosis of functional movement disorder (n = 24) compared to other HMDs (n = 15). CONCLUSION: Neurophysiology is an invaluable adjunct in complex HMD, altering the diagnosis and treatment options for a significant proportion of patients. Our data also demonstrate, consistent with previous studies, that the majority of patients referred for jerky HMDs to a tertiary movement disorder service have a functional movement disorder.

Surgery for epilepsy.

BACKGROUND: This is an updated version of the original Cochrane review, published in 2015.Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary between at least 20% and up to 70%. If the epileptogenic zone can be located, surgical resection offers the chance of a cure with a corresponding increase in quality of life. OBJECTIVES: The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials.Secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence, and to identify the factors that correlate with remission of seizures postoperatively. SEARCH METHODS: For the latest update, we searched the following databases on 11 March 2019: Cochrane Register of Studies (CRS Web), which includes the Cochrane Epilepsy Group Specialized Register and the Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE (Ovid, 1946 to March 08, 2019), ClinicalTrials.gov, and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP). SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs) that included at least 30 participants in a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), with an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome related to postoperative seizure control. Cohort studies or case series were included in the previous version of this review. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportions of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RRs) and 95% confidence intervals (95% CIs). MAIN RESULTS: We identified 182 studies with a total of 16,855 included participants investigating outcomes of surgery for epilepsy. Nine studies were RCTs (including two that randomised participants to surgery or medical treatment (99 participants included in the two trials received medical treatment)). Risk of bias in these RCTs was unclear or high. Most of the remaining 173 non-randomised studies followed a retrospective design. We assessed study quality using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses, we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across domains.In terms of freedom from seizures, two RCTs found surgery (n = 97) to be superior to medical treatment (n = 99); four found no statistically significant differences between anterior temporal lobectomy (ATL) with or without corpus callosotomy (n = 60), between subtemporal or transsylvian approach to selective amygdalohippocampectomy (SAH) (n = 47); between ATL, SAH and parahippocampectomy (n = 43) or between 2.5 cm and 3.5 cm ATL resection (n = 207). One RCT found total hippocampectomy to be superior to partial hippocampectomy (n = 70) and one found ATL to be superior to stereotactic radiosurgery (n = 58); and another provided data to show that for Lennox-Gastaut syndrome, no significant differences in seizure outcomes were evident between those treated with resection of the epileptogenic zone and those treated with resection of the epileptogenic zone plus corpus callosotomy (n = 43). We judged evidence from the nine RCTs to be of moderate to very low quality due to lack of information reported about the randomised trial design and the restricted study populations.Of the 16,756 participants included in this review who underwent a surgical procedure, 10,696 (64%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to recording of adverse events to be very poor.In total, 120 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography, history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection, and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation, and presence of postoperative discharges were prognostic factors of outcome.Twenty-nine studies reported multi-variable models of prognostic factors, and showed that the direction of association of factors with outcomes was generally the same as that found in univariate analyses.We observed variability in many of our analyses, likely due to small study sizes with unbalanced group sizes and variation in the definition of seizure outcome, the definition of prognostic factors, and the influence of the site of surgery AUTHORS' CONCLUSIONS: Study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcomes. Future research should be of high quality, follow a prospective design, be appropriately powered, and focus on specific issues related to diagnostic tools, the site-specific surgical approach, and other issues such as extent of resection. Researchers should investigate prognostic factors related to the outcome of surgery via multi-variable statistical regression modelling, where variables are selected for modelling according to clinical relevance, and all numerical results of the prognostic models are fully reported. Journal editors should not accept papers for which study authors did not record adverse events from a medical intervention. Researchers have achieved improvements in cancer care over the past three to four decades by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.

Surgery for epilepsy.

BACKGROUND: Focal epilepsies are caused by a malfunction of nerve cells localised in one part of one cerebral hemisphere. In studies, estimates of the number of individuals with focal epilepsy who do not become seizure-free despite optimal drug therapy vary according to the age of the participants and which focal epilepsies are included, but have been reported as at least 20% and in some studies up to 70%. If the epileptogenic zone can be located surgical resection offers the chance of a cure with a corresponding increase in quality of life. OBJECTIVES: The primary objective is to assess the overall outcome of epilepsy surgery according to evidence from randomised controlled trials.The secondary objectives are to assess the overall outcome of epilepsy surgery according to non-randomised evidence and to identify the factors that correlate to remission of seizures postoperatively. SEARCH METHODS: We searched the Cochrane Epilepsy Group Specialised Register (June 2013), the Cochrane Central Register of Controlled Trials (CENTRAL 2013, Issue 6), MEDLINE (Ovid) (2001 to 4 July 2013), ClinicalTrials.gov and the World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) for relevant trials up to 4 July 2013. SELECTION CRITERIA: Eligible studies were randomised controlled trials (RCTs), cohort studies or case series, with either a prospective and/or retrospective design, including at least 30 participants, a well-defined population (age, sex, seizure type/frequency, duration of epilepsy, aetiology, magnetic resonance imaging (MRI) diagnosis, surgical findings), an MRI performed in at least 90% of cases and an expected duration of follow-up of at least one year, and reporting an outcome relating to postoperative seizure control. DATA COLLECTION AND ANALYSIS: Three groups of two review authors independently screened all references for eligibility, assessed study quality and risk of bias, and extracted data. Outcomes were proportion of participants achieving a good outcome according to the presence or absence of each prognostic factor of interest. We intended to combine data with risk ratios (RR) and 95% confidence intervals. MAIN RESULTS: We identified 177 studies (16,253 participants) investigating the outcome of surgery for epilepsy. Four studies were RCTs (including one that randomised participants to surgery or medical treatment). The risk of bias in the RCTs was unclear or high, limiting our confidence in the evidence that addressed the primary review objective. Most of the remaining 173 non-randomised studies had a retrospective design; they were of variable size, were conducted in a range of countries, recruited a wide demographic range of participants, used a wide range of surgical techniques and used different scales used to measure outcomes. We performed quality assessment using the Effective Public Health Practice Project (EPHPP) tool and determined that most studies provided moderate or weak evidence. For 29 studies reporting multivariate analyses we used the Quality in Prognostic Studies (QUIPS) tool and determined that very few studies were at low risk of bias across the domains.In terms of freedom from seizures, one RCT found surgery to be superior to medical treatment, two RCTs found no statistically significant difference between anterior temporal lobectomy (ATL) with or without corpus callosotomy or between 2.5 cm or 3.5 cm ATL resection, and one RCT found total hippocampectomy to be superior to partial hippocampectomy. We judged the evidence from the four RCTs to be of moderate to very low quality due to the lack of information reported about the randomised trial design and the restricted study populations.Of the 16,253 participants included in this review, 10,518 (65%) achieved a good outcome from surgery; this ranged across studies from 13.5% to 92.5%. Overall, we found the quality of data in relation to the recording of adverse events to be very poor.In total, 118 studies examined between one and eight prognostic factors in univariate analysis. We found the following prognostic factors to be associated with a better post-surgical seizure outcome: an abnormal pre-operative MRI, no use of intracranial monitoring, complete surgical resection, presence of mesial temporal sclerosis, concordance of pre-operative MRI and electroencephalography (EEG), history of febrile seizures, absence of focal cortical dysplasia/malformation of cortical development, presence of tumour, right-sided resection and presence of unilateral interictal spikes. We found no evidence that history of head injury, presence of encephalomalacia, presence of vascular malformation or presence of postoperative discharges were prognostic factors of outcome. We observed variability between studies for many of our analyses, likely due to the small study sizes with unbalanced group sizes, variation in the definition of seizure outcome, definition of the prognostic factor and the influence of the site of surgery, all of which we observed to be related to postoperative seizure outcome. Twenty-nine studies reported multivariable models of prognostic factors and the direction of association of factors with outcome was generally the same as found in the univariate analyses. However, due to the different multivariable analysis approaches and selective reporting of results, meaningful comparison of multivariate analysis with univariate meta-analysis is difficult. AUTHORS' CONCLUSIONS: The study design issues and limited information presented in the included studies mean that our results provide limited evidence to aid patient selection for surgery and prediction of likely surgical outcome. Future research should be of high quality, have a prospective design, be appropriately powered and focus on specific issues related to diagnostic tools, the site-specific surgical approach and other issues such as the extent of resection. Prognostic factors related to the outcome of surgery should be investigated via multivariable statistical regression modelling, where variables are selected for modelling according to clinical relevance and all numerical results of the prognostic models are fully reported. Protocols should include pre- and postoperative measures of speech and language function, cognition and social functioning along with a mental state assessment. Journal editors should not accept papers where adverse events from a medical intervention are not recorded. Improvements in the development of cancer care over the past three to four decades have been achieved by answering well-defined questions through the conduct of focused RCTs in a step-wise fashion. The same approach to surgery for epilepsy is required.