Extrapyramidal Motor Features Research Articles

Editors' Note: Timing and Impact of Psychiatric, Cognitive, and Motor Abnormalities in Huntington Disease

Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources. Dr. McAllister and colleagues retrospectively analyzed the prevalence, timing, and functional impact of psychiatric, cognitive, and motor abnormalities in Huntington disease (HD) gene carriers in 6,316 individuals in the European HD Network (REGISTRY). They found that psychiatric and cognitive symptoms were common and functionally debilitating in HD gene carriers, with 42.4% of patients with HD reporting at least 1 psychiatric or cognitive symptom before motor symptoms, most commonly depression. However, the initial manifestation of HD was increasingly likely to be motor and less likely to be psychiatric as the age at presentation increased. The authors concluded that nonmotor symptoms should not be used to make a clinical diagnosis of HD because it was impossible to distinguish confidently between nonmotor symptoms arising from HD vs primary psychiatric disorders, particularly in younger premanifest patients. In response, Dr. Bird et al. argue that such a conclusion is too broad and negative, while agreeing that caution is needed and depression should not be used as a diagnostic factor. They argue that psychiatric, behavioral, and cognitive symptoms can be diagnostically meaningful in the setting of a positive genetic test, noting examples like the onset of auditory hallucinations, paranoid delusions, a sustained personality change, or decreased work performance with impaired cognition. They note that such symptoms are part of the diagnostic process for genetic forms of behavioral frontotemporal dementia, which is phenotypically similar to HD, and that earlier diagnosis can help connect patients and families to critical services. Responding to these comments, the authors note that clinical onset of HD is typically diagnosed using the emergence of specific extrapyramidal motor features. They agree that certain neuropsychiatric symptoms like apathy and increased aggression are more strongly suggestive of HD pathology. However, they caution that other commonly reported symptoms may reflect environmental sequelae or those related to the knowledge of their genetic status and should not be used on their own to make an HD diagnosis. This exchange highlights the clinical challenges of defining the onset of a complex neuropsychiatric disease like HD when one already knows the patient's genetic status. Nonetheless, the early diagnosis of HD in the appropriate clinical and genetic setting may allow for deployment of important patient resources.

Phenotype-genotype discrepancies in the prospective Huntington at-risk observational study.

ObjectiveTo examine phenotype–genotype discrepancies (PGDs) wherein genotype‐concealed and prospective judgments of the motor onset of Huntington disease (HD) occurred among at‐risk adults who had nonexpanded (<37) cytosine–adenine–guanine (CAG) trinucleotide DNA repeats.MethodsWe examined the prospective clinical assessments of investigators who were kept unaware of individual CAG lengths in the Prospective Huntington At‐Risk Observational Study (PHAROS) who enrolled and followed undiagnosed adults at risk for HD who chose not to learn their gene status. Subjects (n = 1001) at 43 Huntington Study Group research sites in the US and Canada were evaluated prospectively and systematically between 1999 and 2009. At each site, an investigator was designated to perform comprehensive clinic assessments and another investigator to rate only the motor examination. Phenoconversion from a “premanifest” status to a confidently “manifest” status was based on investigator judgment (diagnostic confidence level) of the extrapyramidal motor features of HD.ResultsThere were 20 PGDs that over time had less severe motor scores than the 101 phenoconversions with CAG ≥37, but more severe motor scores than nonconversions. Following conversion, subjects with CAG ≥37 expansions worsened more motorically and cognitively than PGD subjects in the < 37 group. PGDs were concentrated among three sites and a few investigators, especially raters who only assessed the motor examination.InterpretationThe ability to detect the clinical onset of HD in a timely and reliable fashion remains the key for developing experimental treatments aimed at postponing the clinical onset of HD. Comprehensive clinical evaluation is a more accurate and reliable basis for determining HD clinical onset than sole reliance on judging the extrapyramidal features of HD.

Clinical prodromes of neurodegeneration in Anderson-Fabry disease.

Objective:To estimate the prevalence of prodromal clinical features of neurodegeneration in patients with Anderson-Fabry disease (AFD) in comparison to age-matched controls.Methods:This is a single-center, prospective, cross-sectional study in 167 participants (60 heterozygous females and 50 hemizygous males with genetically confirmed AFD, 57 age-matched controls) using a clinical screening program consisting of structured interview, quantitative tests of motor function, and assessments of cognition, depression, olfaction, orthostatic intolerance, pain, REM sleep behavior disorder, and daytime sleepiness.Results:In comparison to age-matched controls (mean age 48.3 years), patients with AFD (mean age 49.0 years) showed slower gait and transfer speed, poorer fine manual dexterity, and lower hand speed, which was independent of focal symptoms due to cerebrovascular disease. Patients with AFD were more severely affected by depression, pain, and daytime sleepiness and had a lower quality of life. These motor and nonmotor manifestations significantly correlated with clinical disease severity. However, patients with AFD did not reveal extrapyramidal motor features or signs of significant cognitive impairment, hyposmia, orthostatic intolerance, or REM sleep behavior disorder, which commonly precede later neurodegenerative disease. In our cohort, there were no differences in neurologic manifestations of AFD between heterozygous females and hemizygous males.Conclusions:Aside from cerebrovascular manifestations and small fiber neuropathy, AFD results in a distinct neurologic phenotype comprising poorer motor performance and specific nonmotor features. In contrast to functional loss of glucocerebrosidase in Gaucher disease, α-galactosidase deficiency in AFD is not associated with a typical cluster of clinical features prodromal for neurodegenerative diseases, such as Parkinson disease.

PLA2G6-associated neurodegeneration (PLAN): Further expansion of the clinical, radiological and mutation spectrum associated with infantile and atypical childhood-onset disease

Phospholipase A2 associated neurodegeneration (PLAN) is a major phenotype of autosomal recessive Neurodegeneration with Brain Iron Accumulation (NBIA). We describe the clinical phenotypes, neuroimaging features and PLA2G6 mutations in 5 children, of whom 4 presented with infantile neuroaxonal dystrophy (INAD). One other patient was diagnosed with the onset of PLAN in childhood, and our report highlights the diagnostic challenges associated with this atypical PLAN subtype. In this series, the neuroradiological relevance of classical PLAN features as well as apparent claval hypertrophy’ is explored. Novel PLA2G6 mutations were identified in all patients. PLAN should be considered not only in patients presenting with a classic INAD phenotype but also in older patients presenting later in childhood with non-specific progressive neurological features including social communication difficulties, gait disturbance, dyspraxia, neuropsychiatric symptoms and extrapyramidal motor features.

Diminished Activation of Motor Working-Memory Networks in Parkinson's Disease

Parkinson's disease (PD) is characterized by typical extrapyramidal motor features and increasingly recognized non-motor symptoms such as working memory (WM) deficits. Using functional magnetic resonance imaging (fMRI), we investigated differences in neuronal activation during a motor WM task in 23 non-demented PD patients and 23 age- and gender-matched healthy controls. Participants had to memorize and retype variably long visuo-spatial stimulus sequences after short or long delays (immediate or delayed serial recall). PD patients showed deficient WM performance compared to controls, which was accompanied by reduced encoding-related activation in WM-related regions. Mirroring slower motor initiation and execution, reduced activation in motor structures such as the basal ganglia and superior parietal cortex was detected for both immediate and delayed recall. Increased activation in limbic, parietal and cerebellar regions was found during delayed recall only. Increased load-related activation for delayed recall was found in the posterior midline and the cerebellum. Overall, our results demonstrate that impairment of WM in PD is primarily associated with a widespread reduction of task-relevant activation, whereas additional parietal, limbic and cerebellar regions become more activated relative to matched controls. While the reduced WM-related activity mirrors the deficient WM performance, the additional recruitment may point to either dysfunctional compensatory strategies or detrimental crosstalk from “default-mode” regions, contributing to the observed impairment.

Neuropsychiatry of corticobasal degeneration and progressive supranuclear palsy

Corticobasal syndrome (CBS) and progressive supranuclear palsy syndrome (PSPS) are two of the atypical Parkinsonism syndromes, in that patients exhibit rigidity, occasional tremor and postural instability, but do not symptomatically respond to dopamine replacement. CBS and PSPS can often present with complex cognitive difficulties and neuropsychiatric disturbances. Symptoms of depression, apathy, or agitation can be subtle and are often overlooked as reactions to learning a new diagnosis of Parkinsonism. These symptoms may be the earliest presenting evidence of CBS or PSPS, and these syndromes can be misdiagnosed with a primary psychiatric disorder rather than a neurodegenerative condition. Patients may be inappropriately treated with antipsychotic medications that exacerbate the extra-pyramidal motor features of the syndromes. When symptoms are considered to comprise a neurodegenerative syndrome, it may be an inaccurate diagnosis as many features of CBS and PSPS not only overlap with each other, but also with other dementia syndromes. This review discusses similarities and differences between the syndromes of CBS and PSPS in terms of neuropsychiatric features. Improved characterization of the clinical syndromes is necessary to better predict underlying pathology. Improved education about these diseases would help patients, caregivers and clinicians to anticipate symptom progression and avoid premature nursing home placement.

Development of a Novel fMRI Compatible Visual Perception Prototype Battery to Test Older People With and Without Dementia

Visuoperceptual deficits in dementia are common and can reduce quality of life. Testing of visuoperceptual function is often confounded by impairments in other cognitive domains and motor dysfunction. We aimed to develop, pilot, and test a novel visuocognitive prototype test battery which addressed these issues, suitable for both clinical and functional imaging use. We recruited 23 participants (14 with dementia, 6 of whom had extrapyramidal motor features, and 9 age-matched controls). The novel Newcastle visual perception prototype battery (NEVIP-B-Prototype) included angle, color, face, motion and form perception tasks, and an adapted response system. It allows for individualized task difficulties. Participants were tested outside and inside the 3T functional magnetic resonance imaging (fMRI) scanner. Functional magnetic resonance imaging data were analyzed using SPM8. All participants successfully completed the task inside and outside the scanner. Functional magnetic resonance imaging analysis showed activation regions corresponding well to the regional specializations of the visual association cortex. In both groups, there was significant activity in the ventral occipital-temporal region in the face and color tasks, whereas the motion task activated the V5 region. In the control group, the angle task activated the occipitoparietal cortex. Patients and controls showed similar levels of activation, except on the angle task for which occipitoparietal activation was lower in patients than controls. Distinct visuoperceptual functions can be tested in patients with dementia and extrapyramidal motor features when tests use individualized thresholds, adapted tasks, and specialized response systems.

Role of cholinesterase inhibitors in Parkinson's disease and dementia with Lewy bodies.

This article reviews the cholinergic changes in Parkinson's disease and dementia (PDD) and dementia with Lewy bodies (DLB), their potential clinical implications, and the available evidence for cholinesterase inhibitors in the treatment of PDD and DLB. Marked neuronal loss of cholinergic nuclei, reduced cholinergic markers in the neocortex, hippocampus, and selected thalamic nuclei, and receptor changes have been reported. One large and 2 small placebo-controlled trials and nearly 20 open-label studies suggest that cholinesterase inhibitors have a positive effect on cognition, psychiatric symptoms, and global function in patients with DLB and PDD. The treatment is well tolerated in most patients without any apparent worsening of extrapyramidal motor features. Given the high risk of severe sensitivity reactions and increased risk of cerebrovascular incidents during treatment with neuroleptics, more clinical trials of cholinesterase inhibitors are encouraged to establish their precise role in DLB and PDD.

Current treatment of dementia with Lewy bodies and dementia associated with Parkinson's disease.

Dementia in Parkinson's disease (PDD) is a frequent and distressing complication with major consequences. Clinical and pathological features closely link PDD and dementia with Lewy bodies (DLB), suggesting they represent part of the same disease spectrum. Although dopaminergic deficiency primarily determines the akinetic-rigid symptoms of PDD and DLB, there is overwhelming evidence that cholinergic dysfunction underpins many of the cognitive impairments and psychotic features. Open-label studies have suggested that cholinesterase inhibitor drugs may exert positive effects upon all aspects of the neuropsychiatric syndrome in PDD and DLB but particularly apathy, anxiety, impaired attention, hallucinations, delusions, sleep disturbance, and cognitive test performance. Worsening of extrapyramidal motor features is reported only rarely. Initial double-blind, placebo-controlled studies in PDD and DLB have so far confirmed these encouraging results. Early identification of PD patients at greatest risk of developing dementia would permit early use of disease modifying treatments which represent the "golden fleece" management approach to these groups.

Catatonia as a psychomotor syndrome: a rating scale and extrapyramidal motor symptoms.

Catatonia was first described by Kahlbaum as a psychomotor disease with motor, behavioral, and affective symptoms. In keeping with this concept, we developed a rating scale for catatonia (Northoff Catatonia Scale [NCS]) with three different categories of symptoms (i.e., motor, behavioral, affective). Furthermore, the question of the relationship among catatonic symptoms, extrapyramidal motor symptoms, and neuroleptics was addressed in the present study. 34 acute catatonic patients and 68 age-, sex-, diagnosis-, and medication-matched psychiatric control subjects were investigated on days 0, 1, 3, 7, and 21 with the NCS, with other already validated catatonia rating scales by Rosebush, Bush (BFCRS), and Rogers (MRS), as well as with scales for hypokinetic (SEPS) and dyskinetic (AIMS) extrapyramidal motor features. Validity and reliability of the new scale, factor analysis, correlational analysis, and differences between catatonic patients and psychiatric control subjects were statistically calculated. NCS showed high validity (i.e., significant positive correlations [p <0.0001] with the other scales, significant differences between catatonic and control subjects), high intra-and interrater reliabilities (r = 0.80-0.96), and high affective subscores. Factor analysis revealed four factors best characterized as affective, hypoactive, hyperactive, and behavioral. Catatonic scores in NCS correlated significantly with AIMS on day 0 and SEPS on days 7 and 21. There were no significant differences in catatonic (i.e., NCS, MRS, BFCRS) and extrapyramidal (i.e., AIMS, SEPS) scores between neuroleptically treated and untreated catatonic subjects. The following conclusions were drawn: (1) the NCS has to be considered as a valid and reliable rating instrument for catatonia; (2) catatonia can be characterized by psychomotor symptoms encompassing motor, affective, and behavioral alterations; and (3) extrapyramidal hyperkinesias like dyskinesias are apparently closely related to catatonic symptoms which, in general, seem to be relatively independent of previous neuroleptic medication.