Inventory of real world data sources in Parkinson's disease.

BACKGROUND: Real world data have an important role to play in the evaluation of epidemiology and burden of disease; and in assisting health-care decision-makers, especially related to coverage and payment decisions. However, there is currently no overview of the existing longitudinal real world data sources in Parkinson's disease (PD) in the USA. Such an assessment can be very helpful, to support a future effort to harmonize real world data collection and use the available resources in an optimal way. METHODS: The objective of this comprehensive literature review is to systematically identify and describe the longitudinal, real world data sources in PD in the USA, and to provide a summary of their measurements (categorized into 8 main dimensions: motor and neurological functions, cognition, psychiatry, activities of daily living, sleep, quality of life, autonomic symptoms and other). The literature search was performed using MEDLINE, EMBASE and internet key word search. RESULTS: Of the 53 data sources identified between May and August 2016, 16 were still ongoing. Current medications (81%) and comorbidities (79%) were frequently collected, in comparison to medical imaging (36%), genetic information (30%), caregiver burden (11%) and healthcare costs (2%). Many different measurements (n = 108) were performed and an interesting variability among used measurements was revealed. CONCLUSIONS: Many longitudinal real world data sources on PD exist. Different types of measurements have been performed over time. To allow comparison and pooling of these multiple data sources, it will be essential to harmonize practices in terms of types of measurements.

Development and validation of an algorithm for identifying urinary retention in a cohort of patients with epilepsy in a large US administrative claims database.

PURPOSE: The aim of this study was to develop and validate an insurance claims-based algorithm for identifying urinary retention (UR) in epilepsy patients receiving antiepileptic drugs to facilitate safety monitoring. METHODS: Data from the HealthCore Integrated Research Database(SM) in 2008-2011 (retrospective) and 2012-2013 (prospective) were used to identify epilepsy patients with UR. During the retrospective phase, three algorithms identified potential UR: (i) UR diagnosis code with a catheterization procedure code; (ii) UR diagnosis code alone; or (iii) diagnosis with UR-related symptoms. Medical records for 50 randomly selected patients satisfying ≥1 algorithm were reviewed by urologists to ascertain UR status. Positive predictive value (PPV) and 95% confidence intervals (CI) were calculated for the three component algorithms and the overall algorithm (defined as satisfying ≥1 component algorithms). Algorithms were refined using urologist review notes. In the prospective phase, the UR algorithm was refined using medical records for an additional 150 cases. RESULTS: In the retrospective phase, the PPV of the overall algorithm was 72.0% (95%CI: 57.5-83.8%). Algorithm 3 performed poorly and was dropped. Algorithm 1 was unchanged; urinary incontinence and cystitis were added as exclusionary diagnoses to Algorithm 2. The PPV for the modified overall algorithm was 89.2% (74.6-97.0%). In the prospective phase, the PPV for the modified overall algorithm was 76.0% (68.4-82.6%). Upon adding overactive bladder, nocturia and urinary frequency as exclusionary diagnoses, the PPV for the final overall algorithm was 81.9% (73.7-88.4%). CONCLUSIONS: The current UR algorithm yielded a PPV > 80% and could be used for more accurate identification of UR among epilepsy patients in a large claims database.

Parkinson's Disease Case Ascertainment in the EPIC Cohort: The NeuroEPIC4PD Study.

BACKGROUND/AIMS: Large epidemiological prospective studies represent an important opportunity for investigating risk factors for rare diseases such as Parkinson's disease (PD). Here we describe the procedures we used for ascertaining PD cases in the EPIC (European Prospective Investigation into Cancer and Nutrition) study. METHODS: The following three-phase procedure was used: (1) elaboration of a NeuroEPIC4PD template for clinical data collection, (2) identification of all potential PD cases via record linkage and (3) validation of the diagnosis through clinical record revision, in a population of 220,494 subjects recruited in 7 European countries. All cases were labelled with the NeuroEPIC4PD diagnoses of 'definite', 'very likely', 'probable', or 'possible' PD. RESULTS: A total of 881 PD cases were identified, with over 2,741,780 person-years of follow-up (199 definite, 275 very likely, 146 probable, and 261 possible). Of these, 734 were incident cases. The mean age at diagnosis was 67.9 years (SD 9.2) and 458 patients (52.0%) were men. Bradykinesia was the most frequent presenting motor sign (76.5%). Tremor-dominant and akinetic rigid forms of PD were the most common types of PD. A total of 289 patients (32.8%) were dead at the time of the last follow-up. CONCLUSIONS: This exercise proved that it is feasible to ascertain PD in large population-based cohort studies and offers a potential framework to be replicated in similar studies.

Epilepsy, suicidality, and psychiatric disorders: a bidirectional association.

OBJECTIVE: A study was undertaken to determine whether psychiatric disorders associated with suicide are more common in incident epilepsy than in matched controls without epilepsy, before and after epilepsy diagnosis. METHODS: A matched, longitudinal cohort study was conducted in the UK General Practice Research Database. A total of 3,773 cases diagnosed with epilepsy between the ages of 10 and 60 years were compared to 14,025 controls matched by year of birth, sex, general practice, and years of medical records before the index date. We examined first diagnosis of psychosis, depression, anxiety, and suicidality in each of the 3 years before and after the index date and annual prevalence of suicide. Referent diagnoses were eczema and acute surgery. The incidence rate ratio (IRR) was calculated for each year in the study period; the prevalence ratio (PR) was calculated for suicidality. RESULTS: The IRR of psychosis, depression, and anxiety was significantly increased for all years before epilepsy diagnosis (IRR, 1.5-15.7) and after diagnosis (IRR, 2.2-10.9) and for suicidality before epilepsy diagnosis (IRR, 3.1-4.5) and 1 year after diagnosis (IRR, 5.3). The PR was increased for suicide attempt before epilepsy onset (PR, 2.6-5.2) and after onset (PR, 2.4-5.6). Eczema and acute surgery were both associated with epilepsy in the first and third year after diagnosis. INTERPRETATION: Epilepsy is associated with an increased onset of psychiatric disorders and suicide before and after epilepsy diagnosis. These relations suggest common underlying pathophysiological mechanisms that both lower seizure threshold and increase risk for psychiatric disorders and suicide.

Sudden unexpected death in epilepsy in lamotrigine randomized-controlled trials.

PURPOSE: Nonrandomized studies of the relationship of antiepileptic drugs (AEDs) with sudden unexpected death in epilepsy (SUDEP) may be susceptible to confounding by tonic-clonic seizure frequency, polypharmacy, and other potential risk factors for SUDEP. We evaluated the risk of SUDEP with lamotrigine (LTG) compared to active comparators and placebo in randomized controlled clinical trials conducted by GlaxoSmithKline (GSK) between 1984 and 2009. METHODS: Among 7,774 subjects in 42 randomized clinical trials, there were 39 all-cause deaths. Ten deaths occurred >2 weeks after discontinuation of study medication and were excluded. Narrative summaries of deaths were independently reviewed by three clinical experts (TT, LH, DF), who were blinded to randomized treatment arm. The risk of definite or probable SUDEP was compared between treatment arms for each trial type (placebo-controlled, active-comparator, crossover), using exact statistical methods. KEY FINDINGS: Of 29 on-treatment deaths, eight were definite/probable SUDEP, four were possible SUDEP, and 17 were non-SUDEP. The overall, unadjusted rate of definite/probable SUDEP for LTG was 2.2 events per 1,000-patient years (95% confidence interval [95% CI] 0.70-5.4). The odds ratios (OR) for on-treatment, definite/probable SUDEP in LTG arms relative to comparator arms, adjusted for length of exposure and trial, were the following: placebo-controlled, OR 0.22 (95% CI 0.00-3.14; p = 0.26); active-comparator, OR 2.18 (95% CI 0.17-117; p = 0.89); and placebo-controlled cross-over, OR 1.08 (95% CI 0.00-42.2; p = 1.0). SIGNIFICANCE: There was no statistically significant difference in rate of SUDEP between LTG and comparator groups. However, the CIs were wide and a clinically important effect cannot be excluded.

Neuropsychiatric comorbidities in Huntington's and Parkinson's Disease: A United States claims database analysis.

OBJECTIVE: Huntington's disease is a rare, genetic, neurodegenerative disease characterized by a triad of cognitive, behavioral, and motor symptoms. The condition gradually results in increasing disability, loss of independence, and ultimately death. Our objective was to use United States claims data (which offer valuable insight into the natural history of disease) to compare the prevalent comorbidities of people with Huntington's disease against matched controls with Parkinson's disease or with no major neurodegenerative diseases (general population controls). We also assess medication use in people with Huntington's disease. METHODS: This was a retrospective, observational study using data from the IBM MarketScan® Databases. Cases and controls were matched 1:1, and comorbidities were analyzed in each group during 2017. Medications were also assessed in the Huntington's disease cohort. Eligible cases had ≥ 2 diagnostic codes for Huntington's disease; controls had ≥ 2 codes for Parkinson's disease (with no record of Huntington's disease), or, for general population controls, no record of Huntington's disease, Parkinson's disease, amyotrophic lateral sclerosis, or dementia. RESULTS: A total of 587 matched individuals were assessed in each cohort. Depression and anxiety were more common in Huntington's disease versus Parkinson's disease (odds ratios: 1.51 and 1.16, respectively). Other conditions more common in Huntington's disease included dementia, communication/speech problems, dysphagia, and falls. The use of antidepressant (59.9%) and antipsychotic (39.5%) medications was frequent among Huntington's disease cases. INTERPRETATION: These data highlight the prevalence of psychiatric, cognitive, communication, swallowing, and mobility problems in people with Huntington's disease, underscoring the need for holistic expert care of these individuals.

Exploring differential prescribing between anti-epileptic drugs in epilepsy patients with a history of mood disorders.

PURPOSE: To explore differential prescribing of anti-epileptic drugs (AEDs) to patients with epilepsy by history of mood disorder. METHODS: Epilepsy was defined as at least one diagnosis code and one AED prescription, and all patients must have been on the database 182 days before and after their first AED prescription. The Integrated HealthCare Information Services (IHCIS) insurance claims database included 44 557 patients with epilepsy between January 1997 and March 2007. The General Practice Research Database (GPRD) included 16 904 patients with epilepsy up to March 2007. Patients were categorized by their first use of specified AEDs. Mood disorders were defined as diagnosis codes for depression and bipolar disorder, or anti-depressant use. The unadjusted odds ratios and 95% confidence intervals for a history of mood disorder diagnosis ever or within the three months prior to AED use were calculated with carbamazepine and oxcarbazepine (CBZ) as the referent. RESULTS: In the US IHCIS, a history of mood disorders was significantly more common in new users of most AEDs compared to CBZ new users, indicating differential prescribing. Clonazepam and gabapentin were the most commonly prescribed AEDs in patients with epilepsy and a history of mood disorders.In the UK GPRD, there was less evidence of differential prescribing of AEDs, although gabapentin was prescribed most often to epilepsy patients with a history of mood disorders. CONCLUSIONS: Any observational studies of AEDs and suicidality would have to consider potential channeling bias by history of mood disorders, which is a major risk factor for suicide.

Estimated life expectancy of Parkinson's patients compared with the UK population.

OBJECTIVE: To calculate the best possible estimates for age specific life expectancy (LE) and anticipated age at the time of death (AAD) in patients with Parkinson's disease (PD) compared with the general population in the UK. These may be of greater value to patients than standardised mortality ratios (SMRs), which are usually reported in studies on mortality in PD. METHODS: A literature review identified articles with data on age stratified life expectancy or SMRs to calculate estimations of LE using the Gompertz function and data on mortality and LE in the UK from the Office of National Statistics and Actuarial Department for the year 2003. RESULTS: Two UK studies and four from Western Europe were used to estimate LE and AAD for patients with PD from SMRs. The mean LEs of patients with PD compared with the general population were: 38 (SD 5) years for onset between 25 and 39 years compared with 49 (SD 5) years; 21 (SD 5) years for onset between 40 and 64 years compared with 31 (SD 7) years; and 5 (SD 4) years for onset age > or = 65 years compared with 9 (SD 5) years. The average AAD of patients with PD with onset between 25 and 39 years was 71 (SD 3) years and considerably lower than that of the general population (82 (SD 2) years). The difference between average AAD for older individuals with PD (onset > or = 65 years) and the general population was smaller, with an AAD of approximately 88 (SD 7) years compared with 91 (SD 5) years. CONCLUSIONS: The calculations showed that LE and AAD in PD are reduced for all onset ages but this reduction is greatest in individuals with a young onset. While the results are average estimates, these can provide useful indications of LE and AAD.

Clinical features of Parkinson disease patients with homozygous leucine-rich repeat kinase 2 G2019S mutations.

BACKGROUND: The G2019S mutation is the most common pathogenic substitution in the leucine-rich repeat kinase 2 (LRRK2) gene, which has recently been identified in familial and sporadic Parkinson disease (PD). OBJECTIVES: To report the clinical characteristics of PD patients with homozygous LRRK2 6055G>A (G2019S) mutations and to compare them with previously published descriptions of heterozygous patients. DESIGN: Descriptive clinical report from an international consortium of studies. Subjects Patients with familial PD and homozygous LRRK2 mutations included 23 Tunisians, 2 Algerians, 2 US patients, 1 Canadian, and 1 Moroccan. RESULTS: There were no observable differences between the homozygote and heterozygote phenotypes. CONCLUSIONS: Parkinson disease related to LRRK2 is characterized by typical clinical features, and the similarities between patients with homozygous and heterozygous mutations do not support a gene dosage effect.

The frequency and validity of self-reported diagnosis of Parkinson's Disease in the UK elderly: MRC CFAS cohort.

BACKGROUND: Estimates of the incidence and prevalence of chronic diseases can be made using established cohort studies but these estimates may have lower reliability if based purely on self-reported diagnosis. METHODS: The MRC Cognitive Function & Ageing Study (MRC CFAS) has collected longitudinal data from a population-based random sample of 13004 individuals over the age of 65 years from 5 centres within the UK. Participants were asked at baseline and after a two-year follow-up whether they had received a diagnosis of Parkinson's disease. Our aim was to make estimates of the incidence and prevalence of PD using self-reporting, and then investigate the validity of self-reported diagnosis using other data sources where available, namely death certification and neuropathological examination. RESULTS: The self-reported prevalence of Parkinson's disease (PD) amongst these individuals increases with age from 0.7% (95%CI 0.5-0.9) for 65-75, 1.4% (95%CI 1.0-1.7) for 75-85, and 1.6% (95%CI 1.0-2.3) for 85+ age groups respectively. The overall incidence of self reported PD in this cohort was 200/100,000 per year (95%CI 144-278). Only 40% of the deceased individuals reporting prevalent PD and 35% of those reporting incident PD had diagnoses of PD recorded on their death certificates. Neuropathological examination of individuals reporting PD also showed typical PD changes in only 40%, with the remainder showing basal ganglia pathologies causing parkinsonism rather than true PD pathology. CONCLUSION: Self-reporting of PD status may be used as a screening tool to identify patients for epidemiological study, but inevitably identifies a heterogeneous group of movement disorders patients. Within this group, age, male sex, a family history of PD and reduced cigarette smoking appear to act as independent risk factors for self-reported PD.