Distinguishing functional from primary tics: a study of expert video assessments.

BACKGROUND: Reliably applied criteria to differentiate functional from primary tics are lacking. In the absence of biological markers, the development of new diagnostic criteria to assist clinicians is predicated on expert judgement and consensus. This study examines the level of diagnostic agreement of experts in tic disorders using video footage and clinical descriptions. METHODS: Using a two-part survey, eight experts in the diagnosis and management of tics were first asked to study 24 case videos of adults with primary tics, functional tics or both and to select a corresponding diagnosis. In the second part of the survey, additional clinical information was provided, and the diagnosis was then reconsidered. Inter-rater agreement was measured using Fleiss' kappa. In both study parts, the factors which influenced diagnostic decision-making and overall diagnostic confidence were reviewed. RESULTS: Based on phenomenology alone, the diagnostic agreement among the expert raters was only fair for the pooled diagnoses (κ=0.21) as well as specifically for functional (κ=0.26) and primary tics (κ=0.24). Additional clinical information increased overall diagnostic agreement to moderate (κ=0.51) for both functional (κ=0.6) and primary tics (κ=0.57). The main factors informing diagnosis were tic semiology, age at tic onset, presence of premonitory urges, tic suppressibility, the temporal latency between tic onset and peak severity, precipitants and tic triggers and changes in the overall phenotypic presentation. CONCLUSIONS: This study confirmed that in the absence of clinical information, the diagnostic distinction between primary and functional tics is often difficult, even for expert clinicians.

The prevalence of impulsive compulsive behaviors in patients treated with apomorphine infusion: a retrospective analysis / Prevalência de comportamentos impulsivo-compulsivos em pacientes tratados com infusão de apomorfina: análise retrospectiva

ABSTRACT Background: Impulsive compulsive behaviors (ICBs) can affect a significant number of Parkinson's disease (PD) patients. Objective: We have studied brain samples from a brain bank of PD patients who received apomorphine via continuous infusion in life to assess the prevalence and outcome of ICBs. Methods: A search on the Queen Square Brain Bank (QSBB) database for cases donated from 2005 to 2016 with a pathological diagnosis of idiopathic PD was conducted. Notes of all donors who used apomorphine via continuous infusion for at least three months were reviewed. Clinical and demographic data were collected, as well as detailed information on treatment, prevalence and outcomes of ICBs. Results: 193 PD cases, 124 males and 69 females, with an average age at disease onset of 60.2 years and average disease duration of 17.2 years were reviewed. Dementia occurred in nearly half of the sample, depression in one quarter, and dyskinesias in a little over 40%. The prevalence of ICBs was 14.5%. Twenty-four individuals used apomorphine infusion for more than three months. Patients on apomorphine had younger age at disease onset, longer disease duration, and higher prevalence of dyskinesias. The prevalence of de novo ICB cases among patients on apomorphine was 8.3%. Apomorphine infusion was used for an average of 63.1 months on an average maximum dose of 79.5 mg per day. Ten patients remained on apomorphine until death. Conclusions: Apomorphine can be used as an alternative treatment for patients with previous ICBs as it has low risk of triggering recurrence of ICBs.

RESUMO Antecedentes: Comportamentos impulsivo-compulsivos (CICs) podem acometer uma parcela significativa de indivíduos com doença de Parkinson (DP). Objetivo: Nós estudamos amostras de tecido cerebral de uma população de pacientes com DP de um banco de cérebros que receberam apomorfina por infusão contínua em vida, com a finalidade de avaliar a prevalência e o desfecho dos CICs. Métodos: Uma pesquisa no banco de dados do Banco de Cérebros de Queen Square foi conduzida à procura de doações recebidas entre 2005 e 2016 com diagnóstico anatomopatológico de DP idiopática. Os prontuários de todos os doadores que usaram apomorfina por infusão contínua por um período mínimo de três meses foram revisados. Dados clínicos e demográficos foram coletados, assim como informações detalhadas sobre o tratamento, prevalência e desfecho dos CICs. Resultados: 193 casos de DP, 124 do sexo masculino e 69 do sexo feminino, com idade média de início da doença de 60,2 anos e tempo médio de duração da doença de 17,2 anos, foram revisados. Aproximadamente metade dos casos apresentaram demência, um quarto depressão, e um pouco mais de 40% discinesias. A prevalência de CICs foi 14,5%. Vinte e quatro indivíduos usaram infusão de apomorfina por mais de três meses. Os pacientes que usaram apomorfina apresentaram DP mais cedo, maior duração da doença, e uma maior prevalência de discinesias. A prevalência de novos casos de CICs entre pacientes usando apomorfina foi de 8,3%. Infusão de apomorfina foi usada em média por 63,1 meses a um dose máxima média de 79,5 mg por dia. Dez pacientes permaneceram usando apomorfina até o óbito. Conclusões: Apomorfina pode ser usada como opção de tratamento alternativo para pacientes que apresentarem CICs no passado considerando seu baixo risco de causar recorrência de CICs.

The prevalence of impulsive compulsive behaviors in patients treated with apomorphine infusion: a retrospective analysis.

BACKGROUND: Impulsive compulsive behaviors (ICBs) can affect a significant number of Parkinson's disease (PD) patients. OBJECTIVE: We have studied brain samples from a brain bank of PD patients who received apomorphine via continuous infusion in life to assess the prevalence and outcome of ICBs. METHODS: A search on the Queen Square Brain Bank (QSBB) database for cases donated from 2005 to 2016 with a pathological diagnosis of idiopathic PD was conducted. Notes of all donors who used apomorphine via continuous infusion for at least three months were reviewed. Clinical and demographic data were collected, as well as detailed information on treatment, prevalence and outcomes of ICBs. RESULTS: 193 PD cases, 124 males and 69 females, with an average age at disease onset of 60.2 years and average disease duration of 17.2 years were reviewed. Dementia occurred in nearly half of the sample, depression in one quarter, and dyskinesias in a little over 40%. The prevalence of ICBs was 14.5%. Twenty-four individuals used apomorphine infusion for more than three months. Patients on apomorphine had younger age at disease onset, longer disease duration, and higher prevalence of dyskinesias. The prevalence of de novo ICB cases among patients on apomorphine was 8.3%. Apomorphine infusion was used for an average of 63.1 months on an average maximum dose of 79.5 mg per day. Ten patients remained on apomorphine until death. CONCLUSIONS: Apomorphine can be used as an alternative treatment for patients with previous ICBs as it has low risk of triggering recurrence of ICBs.

Longitudinal thalamic white and grey matter changes associated with visual hallucinations in Parkinson's disease.

OBJECTIVE: Visual hallucinations are common in Parkinson's disease (PD) and associated with worse outcomes. Large-scale network imbalance is seen in PD-associated hallucinations, but mechanisms remain unclear. As the thalamus is critical in controlling cortical networks, structural thalamic changes could underlie network dysfunction in PD hallucinations. METHODS: We used whole-brain fixel-based analysis and cortical thickness measures to examine longitudinal white and grey matter changes in 76 patients with PD (15 hallucinators, 61 non-hallucinators) and 26 controls at baseline, and after 18 months. We compared white matter and cortical thickness, adjusting for age, gender, time-between-scans and intracranial volume. To assess thalamic changes, we extracted volumes for 50 thalamic subnuclei (25 each hemisphere) and mean fibre cross-section (FC) for white matter tracts originating in each subnucleus and examined longitudinal change in PD-hallucinators versus non-hallucinators. RESULTS: PD hallucinators showed white matter changes within the corpus callosum at baseline and extensive posterior tract involvement over time. Less extensive cortical thickness changes were only seen after follow-up. White matter connections from the right medial mediodorsal magnocellular thalamic nucleus showed reduced FC in PD hallucinators at baseline followed by volume reductions longitudinally. After follow-up, almost all thalamic subnuclei showed tract losses in PD hallucinators compared with non-hallucinators. INTERPRETATION: PD hallucinators show white matter loss particularly in posterior connections and in thalamic nuclei, over time with relatively preserved cortical thickness. The right medial mediodorsal thalamic nucleus shows both connectivity and volume loss in PD hallucinations. Our findings provide mechanistic insights into the drivers of network imbalance in PD hallucinations and potential therapeutic targets.

Parkinson's disease determinants, prediction and gene-environment interactions in the UK Biobank.

OBJECTIVE: To systematically investigate the association of environmental risk factors and prodromal features with incident Parkinson's disease (PD) diagnosis and the interaction of genetic risk with these factors. To evaluate whether existing risk prediction algorithms are improved by the inclusion of genetic risk scores. METHODS: We identified individuals with an incident diagnosis of PD (n=1276) and controls (n=500 406) in UK Biobank. We determined the association of risk factors with incident PD using adjusted logistic regression models. We constructed polygenic risk scores (PRSs) using external weights and selected the best PRS from a subset of the cohort (30%). The PRS was used in a separate testing set (70%) to examine gene-environment interactions and compare predictive models for PD. RESULTS: Strong evidence of association (false discovery rate <0.05) was found between PD and a positive family history of PD, a positive family history of dementia, non-smoking, low alcohol consumption, depression, daytime somnolence, epilepsy and earlier menarche. Individuals with the highest 10% of PRSs had increased risk of PD (OR 3.37, 95% CI 2.41 to 4.70) compared with the lowest risk decile. A higher PRS was associated with earlier age at PD diagnosis and inclusion of the PRS in the PREDICT-PD algorithm led to a modest improvement in model performance. We found evidence of an interaction between the PRS and diabetes. INTERPRETATION: Here, we used UK Biobank data to reproduce several well-known associations with PD, to demonstrate the validity of a PRS and to demonstrate a novel gene-environment interaction, whereby the effect of diabetes on PD risk appears to depend on background genetic risk for PD.

Brain iron deposition is linked with cognitive severity in Parkinson's disease.

BACKGROUND: Dementia is common in Parkinson's disease (PD) but measures that track cognitive change in PD are lacking. Brain tissue iron accumulates with age and co-localises with pathological proteins linked to PD dementia such as amyloid. We used quantitative susceptibility mapping (QSM) to detect changes related to cognitive change in PD. METHODS: We assessed 100 patients with early-stage to mid-stage PD, and 37 age-matched controls using the Montreal Cognitive Assessment (MoCA), a validated clinical algorithm for risk of cognitive decline in PD, measures of visuoperceptual function and the Movement Disorders Society Unified Parkinson's Disease Rating Scale part 3 (UPDRS-III). We investigated the association between these measures and QSM, an MRI technique sensitive to brain tissue iron content. RESULTS: We found QSM increases (consistent with higher brain tissue iron content) in PD compared with controls in prefrontal cortex and putamen (p<0.05 corrected for multiple comparisons). Whole brain regression analyses within the PD group identified QSM increases covarying: (1) with lower MoCA scores in the hippocampus and thalamus, (2) with poorer visual function and with higher dementia risk scores in parietal, frontal and medial occipital cortices, (3) with higher UPDRS-III scores in the putamen (all p<0.05 corrected for multiple comparisons). In contrast, atrophy, measured using voxel-based morphometry, showed no differences between groups, or in association with clinical measures. CONCLUSIONS: Brain tissue iron, measured using QSM, can track cognitive involvement in PD. This may be useful to detect signs of early cognitive change to stratify groups for clinical trials and monitor disease progression.

The prediagnostic phase of Parkinson's disease.

The field of prediagnostic Parkinson's disease (PD) is fast moving with an expanding range of clinical and laboratory biomarkers, and multiple strategies seeking to discover those in the earliest stages or those 'at risk'. It is widely believed that the highest likelihood of securing neuroprotective benefit from drugs will be in these subjects, preceding current point of diagnosis of PD. In this review, we outline current knowledge of the prediagnostic phase of PD, including an up-to-date review of risk factors (genetic and environmental), their relative influence, and clinical features that occur prior to diagnosis. We discuss imaging markers across a range of modalities, and the emerging literature on fluid and peripheral tissue biomarkers. We then explore current initiatives to identify individuals at risk or in the earliest stages that might be candidates for future clinical trials, what we are learning from these initiatives, and how these studies will bring the field closer to realistically commencing primary or secondary preventive trials for PD. Further progress in this field hinges on greater clinical and biological description, and understanding of the prediagnostic, peridiagnostic and immediate postdiagnostic stages of PD. Identifying subjects 3-5 years before they are currently diagnosed may be an ideal group for neuroprotective trials. At the very least, these initiatives will help clarify the stage before and around diagnosis, enabling the field to push into unchartered territory at the earliest stages of disease.

Effects of age and cognition on a cross-cultural paediatric adaptation of the Sniffin' Sticks Identification Test.

OBJECTIVES: To study the effects of age and cognition on the performance of children aged 3 to 18 years on a culturally adapted version of the 16 item smell identification test from Sniffin' Sticks (SS16). METHODS: A series of pilots were conducted on 29 children aged 3 to 18 years old and 23 adults to produce an adapted version of the SS16 suitable for Brazilian children (SS16-Child). A final version was applied to 51 children alongside a picture identification test (PIT-SS16-Child) to access cognitive abilities involved in the smell identification task. In addition 20 adults performed the same tasks as a comparison group. RESULTS: The final adapted SS16-Child was applied to 51 children with a mean age of 9.9 years (range 3-18 years, SD=4.25 years), of which 68.3% were girls. There was an independent effect of age (p<0.05) and PIT-SS16-Child (p<0.001) on the performance on the SS16-Child, and older children reached the ceiling for scoring in the cognitive and olfactory test. Pre-school children had difficulties identifying items of the test. DISCUSSION/CONCLUSIONS: A cross-culturally adapted version of the SS16 can be used to test olfaction in children but interpretation of the results must take age and cognitive abilities into consideration.

Secondary nonresponsiveness to botulinum toxin A in cervical dystonia: the role of electromyogram-guided injections, botulinum toxin A antibody assay, and the extensor digitorum brevis test.

We studied 20 patients with cervical dystonia who had started to respond poorly to botulinum toxin A (BTXA) injections after an initial good response. All patients had extensor digitorum brevis (EDB) tests performed in addition to BTXA immunoprecipition assay (IPA) and mouse bioassay (MBA) antibody testing. The patients were reexamined and then treated with carefully placed electromyogram (EMG)-guided BTXA. Nine patients had a good clinical response to EMG-guided injections and all of these patients showed an obvious decrement on the EDB test. All were BTXA blocking antibodies (Abs)-negative via IPA and MBA (apart from one patient who had low BTXA antibodies titers using IPA but no antibodies by MBA). In the other 11 patients, there was a poor clinical response to EMG-guided BTXA injections. Seven of these 11 had small EDB decrement and BTXA antibodies using IPA, suggesting resistance to BTXA. Of the remaining four patients, two had obvious EDB decrement and low antibody titers via IPA (one of them had no antibodies via MBA), while the other two patients showed obvious decrement on the EDB test and no antibodies via IPA. This study shows that the EDB test correlates better with the clinical response than the antibody assays and that EDB decrement does not always correlate quantitatively with the BTXA antibody titers. In patients with secondary nonresponsiveness, it is recommended that an EDB test is the initial investigation of choice. In those patients where the EDB test does not demonstrate resistance to BTXA, a reexamination of the patients and carefully placed injections under EMG guidance may improve results.