The Emergency Department

With the advent in genetics, many genetic parkinsonian conditions have been described that, in some cases, share features that resemble the widely recognized Richardson's syndrome (the commonest described phenotype of progressive supranuclear palsy pathology), corticobasal syndrome and multiple system atrophy syndromes. A positive family history, an earlier age at onset, and clinical features that are unusual for or characteristic of a certain condition, may help in the differential diagnosis. The recognition of these syndromes is quite important as, in contrast to the non-genetic atypical parkinsonian syndromes, a definite diagnosis can be made, there are implications for other generations and there may be an opportunity to participate in clinical trials with genetic treatments that are well under way.

Genetic mimics of the non-genetic atypical parkinsonian disorders – the ‘atypical’ atypical

Background Several conditions represented mainly by movement disorders are associated with cardiac disease, which can be overlooked in clinical practice in the context of a prominent primary neurological disorder. Objectives To review neurological conditions that combine movement disorders and primary cardiac involvement. Methods A comprehensive and structured literature search following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses criteria was conducted to identify disorders combining movement disorders and cardiac disease. Results Some movement disorders are commonly or prominently associated with cardiac disease. Neurological and cardiac symptoms may share underlying physiopathological mechanisms in diseases, such as Friedreich's ataxia and Wilson's disease, and in certain metabolic disorders, including Refsum disease, Gaucher disease, a congenital disorder of glycosylation, or cerebrotendinous xanthomatosis. In certain conditions, such as Sydenham's chorea or dilated cardiomyopathy with ataxia syndrome (ATX-DNAJC19), heart involvement can present early in the course of disease, whereas in others such as Friedreich's ataxia or Refsum disease, cardiac symptoms tend to present in later stages. In another 68 acquired or inherited conditions, cardiac involvement or movement disorders are seldom reported. Conclusions As cardiac disease is part of the phenotypic spectrum of several movement disorders, heart involvement should be carefully investigated and increased awareness of this association encouraged as it may represent a leading cause of morbidity and mortality.

Cardiac Involvement in Movement Disorders.

BACKGROUND
- The understanding of the natural history of Friedreich's ataxia has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this work was to acknowledge the broad genetic diversity of the population, especially with respect to younger individuals and to provide analyses stratified by age to guide population selection in future studies.


METHODS
- Based on a large natural history study, the Friedreich's Ataxia Clinical Outcome Measures study (FACOMS) that at the current data cut enrolled 1115 participants, followed up for 5287 yearly visits, we present results from the modified Friedreich's Ataxia Rating Scale and its sub scores. Secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk and the 9-hole peg test. Long-term progression was modeled using slope analyses within Early, Typical, Intermediate and Late Onset Friedreich's Ataxia. To reflect recruitment in clinical trials, short term changes were analyzed within age-based sub-populations. All analyses were stratified by ambulation status.


FINDINGS
- Long term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages of onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability sub score of the mFARS. The analyses of short-term changes showed slower progression with increasing population age, as a result of decreasing genetic severity. Future clinical studies could reduce population diversity, inter-patient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification.


INTERPRETATION
- Understanding of the diversity within Friedreich's ataxia populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in Friedreich's ataxia.

Natural History of Friedreich's Ataxia: Heterogeneity of Neurological Progression and Consequences for Clinical Trial Design.

Background and Objectives The understanding of the natural history of Friedreich ataxia (FRDA) has improved considerably recently, but patterns of neurologic deterioration are not fully clarified, compromising the assessment of the clinical relevance of effects and guidance for study design. The goal of this study was to acknowledge the broad genetic diversity of the population, especially for younger individuals, and to provide analyses stratified by age to guide population selection in future studies. Methods Based on a large natural history study, the FRDA Clinical Outcome Measures study that at the current data cut enrolled 1,115 participants, followed up for 5,287 yearly visits, we present results from the modified FRDA Rating Scale and its subscores. The secondary outcomes included the patient-reported activities of daily living scale, the timed 25-foot walk, and the 9-hole peg test. Long-term progression was modeled using slope analyses within early-onset, typical-onset, intermediate-onset, and late-onset FRDA. To reflect recruitment in clinical trials, short-term changes were analyzed within age-based subpopulations. All analyses were stratified by ambulation status. Results Long-term progression models stratified by disease severity indicated highly differential disease progression, especially at earlier ages at onset. In the ambulatory phase, decline was driven by axial items assessed by the Upright Stability subscore of the mFARS. The analyses of short-term changes showed slower progression with increasing population age due to decreasing genetic severity. Future clinical studies could reduce population diversity, interpatient variability, and the risk of imbalanced treatment groups by selecting the study population based on the functional capacity (e.g., ambulatory status) and by strict age-based stratification. Discussion The understanding of the diversity within FRDA populations and their patterns of functional decline provides an essential foundation for future clinical trial design including patient selection and facilitates the interpretation of the clinical relevance of progression detected in FRDA.

https://n.neurology.org/content/neurology/early/2022/07/11/WNL.0000000000200913.full.pdf

Natural History of Friedreich Ataxia

Friedreich's ataxia is classically considered a disease with onset in the first or second decade. However, late-onset (age of onset 25-39 years) and very-late-onset (age of onset >40 years) forms do occur rarely. Misdiagnosis is common, particularly because the later onset forms of Friedreich's ataxia commonly do not show characteristic features of the disorder (areflexia, dysarthria, sensory neuropathy, extensor plantars, amyotrophy, cardiac involvement, diabetes mellitus, scoliosis). Also, there may be atypical features such as spasticity, brisk reflexes and laryngeal dystonia. We present the clinical, imaging and genetic findings of a kindred with very-late-onset Friedreich's ataxia and discuss the pitfalls and risk of misdiagnosis.

https://pn.bmj.com/content/practneurol/early/2019/08/29/practneurol-2019-002368.full.pdf

Very-late-onset Friedreich's ataxia: diagnosis in a kindred with late-onset cerebellar ataxia.

Background:Headaches represent a significant proportion of referrals to any neurology consult service, of which many are migrainous. Regular use of opioids can lead to medication overuse headache i...

https://journals.sagepub.com/doi/pdf/10.1177/2515816320980995

Damien Ferguson

Papers

Very-late-onset Friedreich's ataxia: diagnosis in a kindred with late-onset cerebellar ataxia.

The opioid epidemic and headache: Experience of a general neurology consult service: