Negative Myoclonus Associated With Severe Motor Implications in Progressive Myoclonus Ataxia

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Findings from a recent study suggest that the presence of negative myoclonus may serve as a diagnostic clue for progressive myoclonus ataxia, suggesting the presence of genetic disorders.

Marina A.J. Tijssen, MD, PhD  (Credit: University of Groningen)

Marina A.J. Tijssen, MD, PhD

(Credit: University of Groningen)

In a newly published study in Movement Disorders, patients with progressive myoclonus ataxia (PMA) affected by negative myoclonus (NM), an involuntary movement caused by a sudden interruption of muscular activity, demonstrated a more severe motor phenotype with frequent falls and severe gait problems than those absent of NM. These findings suggest that NM might cause a relevant impairment in this patient population, further stressing the importance of neurophysiological examination for detecting NM that could be missed on clinical examination.1

Among patients with PMA (n = 14), NM was present in 6 (NM+) patients and absent in 8 (NM-) patients. The main differences between the 2 groups were frequency of falls (NM+: 6/6 vs. NM−: 3/8 individuals), and drug resistant-myoclonus (NM+: 4/5 vs. NM−: 1/8). Notably, investigators also observed differences in severity of ataxia (NM+: 21.1 [±4.95] vs. NM−: 14.8 [±10.1]), and myoclonus (NM+: 80 [±24.3] vs. NM−: 38.4 [±13.6]). In addition, motor disability was higher in NM+ (4.3 [±0.74]) compared with NM− patients (2.5 [±1.2]).

Top Clinical Takeaways

  • Negative myoclonus may significantly contribute to motor disability in progressive myoclonus ataxia.
  • Neurophysiological examinations, including video-electromyography-accelerometry and EEG analysis, could be vital for accurately detecting negative myoclonus.
  • Further research is warranted to better understand the electrophysiological characteristics and classification of negative myoclonus.

Investigators retrospectively collected clinical, neurophysiological, and genetic data from 14 patients diagnosed with PMA based on refined criteria2 from the University Medical Centre Groningen Expertise Center Movement Disorder Groningen. Conducted by senior author Marina A.J. Tijssen, MD, PhD, professor of neurology at University of Groningen in The Netherlands, and colleagues, neurophysiological examination included video-electromyography-accelerometry assessment among all of the patients and electroencephalography (EEG) examination was performed on only 13 of the participants. Authors noted that jerk-locked or silent period-locked back-averaging and cortico-muscular coherence analysis assisted with the classification of myoclonus among the participants.

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The genetic background of patients who had NM+ included GOSR2 and SEMA6B and those who had NM- included ATM, KCNC3, NUS1, STPBN2, and GOSR2. Authors noted that NM frequently was isolated or combined with a preceding positive myoclonus (PM) in 6 of 14 patients with PMA (42.8%) and that the silent-period length revealed between 88 and 194 ms. In only 2 cases, researchers reported that EEG epileptiform discharges were associated with NM. In additional findings, investigators noted that PM was classified as cortical myoclonus in 5 NM+ patients and 2 NM- patients by performing EEG inspection, jerk-locked back-averaging, or CMC analysis.

All told, limitations of the study included the relatively small cohort of patients and only 1 genetic defect (GOSR2) was represented more compared with the other disorders. Authors also noted that although the silent period-locked was not possible or negative in some patients, it does not exclude the cortical origin of myoclonus as an EEG cortical correlate could be revealed using a higher number of jerks/silent periods. Additionally, investigators emphasized the challenge of determining the precise impact of NM on overall motor disability in patients with PMA since ataxia and PM by itself can contribute to motor disability.

Overall, authors noted that this study supports conducting neurophysiological studies for detecting NM, especially if it is in combination with PM. Tijssen and colleagues highlighted that NM in PMA arises from cortical areas but in rare cases potential cortical–subcortical interaction could play a role in its genesis. Therefore, investigators recommended that further research is needed to better delineate the electrophysiological characteristics and classification of NM. In clinical practice, authors underscored that NM should be actively sought in patients with ataxia and PM since it may significantly impact the motor phenotype and clinical burden of the patients.

REFERENCES
1. Pollini L, van der Veen S, Elting JWJ, Tijssen MAJ. Negative Myoclonus: Neurophysiological Study and Clinical Impact in Progressive Myoclonus Ataxia. Mov Disord. 2024;39(4):674-683. doi:10.1002/mds.29741
2. van der Veen S, Zutt R, Elting JWJ, Becker CE, de Koning TJ, Tijssen MAJ. Progressive myoclonus ataxia: Time for a new definition?. Mov Disord. 2018;33(8):1281-1286. doi:10.1002/mds.27412
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