DEMENTIA RELATED MYOCLONUS

Myoclonus: clinical classification, neurophysiology, and diagnostic challenges

Executive summary

Myoclonus is defined as a sudden, involuntary, brief, shock-like movement caused by either muscular contraction (positive myoclonus) or the sudden inhibition of muscular activity (negative myoclonus or asterixis). It represents a clinical manifestation of a heterogeneous group of neurological disorders, ranging from benign physiological phenomena to life-threatening encephalopathies. Current medical consensus emphasises a three-tiered classification system based on clinical distribution, aetiology, and neurophysiological generators. While the neocortex is the most common site of origin, myoclonus can be generated at any level of the central nervous system, from the brainstem to the spinal cord. Recent critical reviews suggest that traditional "gold standard" electrophysiological markers for cortical myoclonus, such as giant somatosensory evoked potentials (SEPs) and jerk-locked back-averaging (JLBA), face significant challenges regarding sensitivity, specificity, and lack of standardised definitions. Consequently, clinicians are advised to adopt a multimodal approach, combining clinical semiology with a battery of neurophysiological tests to ensure diagnostic accuracy and guide treatment, which is increasingly shifting toward disease-modifying strategies for specific genetic disorders.

1. Defining and classifying myoclonus

Myoclonus is characterised by its brief duration (typically 10–50 ms) and non-rhythmic nature. Pathological myoclonus has an estimated annual incidence of approximately 1.3 cases per 100,000 persons.

1.1 Clinical classification (distribution and activation)

Myoclonus is categorised by how it presents on the body and what triggers it:

Body distribution: Focal, multifocal, segmental, or generalised.
Temporal pattern: Usually irregular (arrhythmic), though occasionally rhythmic.
Activation profile:
Rest: Occurs without muscle activity.
Action/posture: Induced by voluntary movement or maintaining a position.
Reflex (stimulus-sensitive): Provoked by external tactile, acoustic, or visual stimuli.

1.2 Aetiological classification

The primary aetiological categories include:

Physiologic: Normal phenomena (e.g., hypnic jerks, hiccups, anxiety-induced).
Essential: Non-progressive, isolated myoclonus (sporadic or hereditary, such as epsilon-sarcoglycan mutations).
Epileptic: Myoclonus presenting as a component of a seizure or a specific epilepsy syndrome with clear EEG correlates.
Symptomatic (secondary): Resulting from an underlying disorder (metabolic, toxic, infectious, or neurodegenerative).
Psychogenic: Occurs within the context of functional neurological disorders.

2. Neurophysiological generators and mechanisms

The anatomical source of the myoclonus dictates the clinical pattern and the necessary diagnostic testing.

2.1 Critical appraisal of electrophysiological criteria

Recent research highlights that the evidence supporting traditional "definitive" criteria for cortical myoclonus (CM) is inconsistent.

Giant somatosensory evoked potentials (SEPs): Defined by some as a P25 peak >8.6 µV or N33 >8.4 µV. However, there is no universal definition of "giant." These are found in only 21–39% of suspected CM patients and can occur in non-myoclonic conditions like Multiple Sclerosis.
Jerk-locked back-averaging (JLBA): A technique to identify EEG transients preceding jerks. While highly supportive, it is positive in only about 70% of clinically suspected cases due to technical difficulties (e.g., low frequency of jerks or EEG artefacts).
C-reflex (long-latency reflex): Often considered a hallmark of CM, but its nomenclature is ambiguous, and it can be observed in subcortical forms (e.g., reticular myoclonus).
EMG burst duration: While bursts <50 ms are traditionally associated with CM, spinal myoclonus and even normal ballistic movements in healthy subjects can produce similarly short discharges.

3. Symptomatic and secondary myoclonus

Symptomatic myoclonus is the most common group and is often associated with dominant encephalopathy.

3.1 Toxic and metabolic aetiologies

Kidney disease: Uraemia can cause a toxic effect on the medulla oblongata, leading to reticular, stimulus-sensitive myoclonus.
Hepatic encephalopathy: Characterised by diffuse triphasic waves on EEG, often associated with negative myoclonus (asterixis).
Drug-induced: Many anti-seizure medications (ASMs) at high doses can paradoxically induce or worsen myoclonus.

3.2 Post-hypoxic myoclonus (PHM)

PHM is critical for prognosis and occurs in two forms:

Acute phase: Myoclonic status epilepticus (MSE) within 72 hours of cardiac arrest; associated with high mortality.
Chronic phase: Lance-Adams Syndrome (LAS), appearing days to years after the event, characterised by action-induced or stimulus-induced myoclonus of cortical and/or subcortical origin.

3.3 Neurodegenerative disorders

Creutzfeldt–Jakob Disease (CJD): Often presents with diffuse periodic triphasic waves and generalised jerks.
Alzheimer’s Disease (AD): Particularly the fast-progressive form (presenilin-1 mutations); myoclonus is common, although EEG correlates may require JLBA for detection.
Huntington’s Disease: Juvenile forms with long CAG repeats may feature cortical reflex myoclonus.

4. Progressive myoclonus epilepsies (PMEs)

PMEs are a group of rare, genetically determined disorders characterised by the triad of action myoclonus, seizures, and progressive neurologic decline (ataxia, dementia).

5. Clinical management and diagnostic approach

A stepwise diagnostic approach is essential due to the wide range of aetiologies:

Initial assessment: Comprehensive medical history focusing on medications, toxins, infections, and family history.
Basic testing: Blood, urine, antibody testing, and brain MRI to rule out metabolic or structural causes.
Neurophysiological battery:
EEG-EMG polygraphy: Mandatory to identify burst duration and muscle synchronisation.
SSEPs: Stimuli should be low-frequency (e.g., 1 Hz) to prevent the extinction of enlarged components.
C-reflex: Evaluated both at rest and during motor activation.
Advanced testing: Jerk-locked back-averaging (JLBA) and cortico-muscular coherence (CMC) for complex cases.

Conclusion on management

Correct classification is mandatory to guide treatment. While anti-seizure medications can reduce cortical hyperexcitability and diminish markers like giant SEPs, the ultimate goal is the identification of underlying genetic or metabolic causes where disease-modifying drugs are becoming increasingly available. Diagnostic accuracy is best achieved by combining clinical observations with multiple neurophysiological tests rather than relying on a single "gold standard" marker.