Interrater agreement in the assessment of motor manifestations of Huntington's disease

Abstract

With prospects improving for experimental therapeutics aimed at postponing the onset of illness in preclinical carriers of the Huntington's disease (HD) gene, we assessed agreement among experienced clinicians with respect to the motor manifestations of HD, a relevant outcome measure for preventive trials in this population. Seventy-five clinicians experienced in the evaluation of patients with early HD and six non-clinicians were shown a videotape compiled from the film archives of the United States-Venezuela Collaborative HD Research Project. Observers were asked to rate a 2-3-minute segment of the motor examination for each of 17 at-risk subjects. The rating scale ranged from 0 (normal) to 4 (unequivocal extrapyramidal movement disorder characteristic of HD). As measured by a weighted kappa statistic, there was substantial agreement among the 75 clinicians in the judgment of unequivocal motor abnormalities comparing scale ratings of 4 with ratings that were not 4 (weighted kappa = 0.67; standard error (SE) = 0.09). Agreement among the non-clinicians was only fair (weighted kappa = 0.28; SE = 0.10). Even under the artificial conditions of a videotape study, experienced clinicians show substantial agreement about the signs that constitute the motor manifestations of illness in subjects at risk for HD. We expect these findings to translate to a similar level of interobserver agreement in the clinical trial setting involving experienced investigators examining live patients.

Are gait initiation parameters early markers of Huntington's disease in pre-manifest mutation carriers?

“…a score of 3 or 4 on the motor diagnosis confidence level taken from the Unified Huntington's Disease Rating Scale (UHDRS) [12]). This score has good levels of interrater agreement and is generally chosen as a criterion for symptomatic HD in the literature [13]. Pre-manifest mutation carriers over the age of 60 or those suffering from neurological, mental or orthopaedic pathologies that could have interfered with gait were excluded from the study.…”

Epidemiological Study of Huntington's Disease in the Province of Ferrara, Italy

“…A case of HD was defined as any individual carrying CAG expansion on the HTT gene and presenting onset with the unequivocal presence of an otherwise unexplained extrapyramidal movement disorder (i.e., chorea, dystonia, bradykinesia, rigidity) [3,19,20,21,22,23] with or without psychiatric signs or cognitive decline [23,24]. Juvenile HD (JHD; onset before age 21) and the rigid Westphal variant were also taken into consideration.…”

Huntington's Disease: Premotor Phase

“…In terms of HD diagnosis, according to the current criteria, a patient needs to have: (1) a positive genetic test for the CAG-expanded allele gene or a family history of HD and (2) motor symptoms as per the Unified Huntington's Disease Rating Scale [2]. Thus, the diagnosis of HD is centered around the presence of clear motor symptoms, i.e., involuntary choreiform movements.…”

“…This produces a ubiquitous mutant protein, i.e., huntingtin, which aggregates in intranuclear inclusions, leading to progressive cerebral degeneration. HD manifests around mid-adulthood via a triad of progressive symptoms, i.e., motor impairment, psychiatric disorders, and cognitive decline [1,2,3]. …”