Introduction

COVID-19 has expanded the spectrum of post-infectious neurological syndromes. While Guillain–Barré syndrome and encephalitis are well recognized, movement disorders remain comparatively uncommon. Among these, the combination of generalized myoclonus and cerebellar ataxia represents a particularly distinctive syndrome.

The following case illustrates how careful localization and neurophysiologic testing can reveal the origin of myoclonus and guide effective immunotherapy.

Learning Objectives

After completing this exercise, readers should be able to:

1. Develop a differential diagnosis for acute generalized myoclonus.
2. Recognize the clinical features of post-infectious myoclonus-ataxia syndrome.
3. Localize myoclonus anatomically using neurophysiology.
4. Distinguish cortical from subcortical myoclonus.
5. Understand the rationale for immunotherapy in post-COVID neurological syndromes.

Case Presentation

A 52-year-old woman developed low-grade fever, fatigue, myalgias, mild diarrhea, and cough. COVID-19 was diagnosed and treated symptomatically.

Two weeks later, she noticed involuntary jerking movements involving her trunk and proximal limbs. The movements worsened with action and were triggered by tactile and auditory stimuli. Her gait became increasingly unsteady.

Over several days, the jerks intensified. By the fifth day of neurological symptoms, she had become unable to walk independently and developed slurred speech. She presented to the emergency department because of rapidly progressive disability.

Clinical Reasoning Pause

The combination of:

• Acute to subacute progression
• Stimulus-sensitive generalized myoclonus
• Ataxia
• Dysarthria

raises several possibilities:

Infectious encephalitis

Autoimmune encephalitis

Toxic-metabolic disorders

Drug-induced myoclonus

Prion disease

Paraneoplastic syndromes

Post-infectious immune-mediated syndrome

The two-week interval after systemic infection is particularly suggestive of a post-infectious process.

Neurological Examination

The patient demonstrated:

• Generalized myoclonus involving predominantly the upper extremities
• Wide-based gait
• Dysmetria during finger-to-nose testing
• Impaired rapid alternating movements
• Dysarthria
• Horizontal nystagmus

Importantly:

• Strength was normal.
• Sensory examination was normal.
• Reflexes were preserved.
• Plantar responses were flexor.
• Cognitive function was intact.

Localization

The coexistence of:

• Dysmetria
• Nystagmus
• Ataxia
• Dysarthria

strongly implicates cerebellar pathways.

The stimulus-sensitive generalized myoclonus suggests involvement somewhere along the cortical-subcortical-brainstem motor network.

The next question becomes:

Where does the myoclonus originate?

Clinical Reasoning Pause

Myoclonus can arise from:

Cortex

• Most common
• Often associated with epilepsy
• Giant somatosensory evoked potentials
• EEG correlates

Subcortical structures

• Brainstem
• Cerebellothalamic pathways

Spinal cord

Peripheral nervous system

Determining the anatomical origin has important implications for diagnosis and pathophysiology.

Diagnostic Workup

MRI brain was normal.

PET-CT was unrevealing.

CSF studies were normal.

Autoimmune encephalitis antibodies were negative.

Paraneoplastic antibodies were negative.

Inflammatory markers were normal.

No alternative infectious process was identified.

Thus, conventional testing failed to provide an explanation.

Neurophysiology Becomes the Key

EMG demonstrated synchronized rhythmic bursts corresponding to the jerks.

Simultaneous EEG recording showed no epileptiform discharges.

Back averaging revealed no jerk-locked cortical potential.

Somatosensory evoked potentials were not enlarged.

These findings argued strongly against cortical myoclonus.

Teaching Point

Absence of EEG-EMG correlation and lack of giant somatosensory evoked potentials suggest a subcortical origin.

The brainstem is thought to be the most likely source.

This localization fit remarkably well with the associated cerebellar syndrome.

Differential Diagnosis Revisited

Prion disease

Unlikely because:

• Rapid progression was absent.
• MRI was normal.
• Recovery occurred.

Autoimmune encephalitis

Less likely:

• Normal CSF
• Negative antibodies
• No encephalopathy

Drug-induced myoclonus

No offending medications were identified.

Structural lesion

MRI and PET-CT were unrevealing.

Post-infectious immune-mediated syndrome

Supported by:

• Two-week latency after infection.
• Progressive neurological syndrome.
• Lack of alternative causes.
• Dramatic steroid responsiveness.

Final Diagnosis

Post-COVID Myoclonus-Ataxia Syndrome

with electrophysiologic evidence supporting a subcortical (brainstem) origin of the myoclonus.

Management

Because intravenous immunoglobulin was financially prohibitive, treatment consisted of:

• Intravenous methylprednisolone 1 g/day
• Clonazepam
• Levetiracetam

Gradual improvement followed.

Three weeks later, she was discharged.

At two months, she reported approximately 90% recovery and no longer required medication.

Why Did Steroids Work?

The delayed onset following infection suggests a para-infectious or post-infectious immune process rather than direct viral invasion.

Current evidence increasingly supports cytokine-mediated neuroinflammation and autoimmune mechanisms.

This parallels other post-infectious neurological disorders, including:

• Guillain–Barré syndrome
• Acute disseminated encephalomyelitis
• Opsoclonus-myoclonus syndrome

Clinical Pearls

Pearl #1

Myoclonus and ataxia developing 1–3 weeks after COVID-19 should raise suspicion for a post-infectious syndrome.

Pearl #2

Normal MRI and CSF do not exclude an immune-mediated neurological disorder.

Pearl #3

Neurophysiology may be the most important diagnostic study in unexplained myoclonus.

Pearl #4

Absence of EEG correlates points away from cortical myoclonus.

Pearl #5

Prompt immunotherapy is associated with excellent outcomes.

Clinical Pitfalls

Mistaking the jerks for seizures.

Assuming a normal MRI excludes serious neurological disease.

Failing to recognize stimulus sensitivity.

Delaying immunotherapy while awaiting antibody studies.

Attributing symptoms solely to anxiety or functional neurological disorder.

Board-Style Questions

Question 1

A 52-year-old woman develops generalized stimulus-sensitive myoclonus and gait ataxia two weeks after recovering from mild COVID-19. Brain MRI and cerebrospinal fluid studies are unrevealing. Which mechanism is most strongly suggested by the temporal course and clinical presentation?

A. Direct viral invasion of the central nervous system

B. Hypoxic brain injury

C. Post-infectious immune-mediated neuroinflammation

D. Prion disease

E. Drug-induced serotonin syndrome

Answer

C. Post-infectious immune-mediated neuroinflammation

Explanation

The correct answer is C.

The approximately two-week interval between systemic COVID-19 symptoms and the onset of neurological manifestations strongly suggests a post-infectious autoimmune process. Similar delays are seen in Guillain–Barré syndrome and acute disseminated encephalomyelitis. Direct viral invasion would be expected to occur during the acute phase of infection rather than after clinical recovery. The absence of hypoxia, encephalopathy, and exposure to serotonergic medications further argues against the other possibilities. The patient's excellent response to corticosteroids also supports an immune-mediated mechanism.

Question 2

Which electrophysiological finding most strongly argues against cortical myoclonus?

A. Presence of dysarthria

B. Generalized jerking movements

C. Absence of EEG-EMG correlation

D. Action-induced myoclonus

E. Stimulus sensitivity

Answer

C. Absence of EEG-EMG correlation

Explanation

The correct answer is C.

Cortical myoclonus is characterized by electrophysiological evidence of cortical involvement, including EEG correlates, giant somatosensory evoked potentials, and jerk-locked cortical potentials. In this case, simultaneous EEG and EMG recordings failed to demonstrate any correlation, making a cortical origin unlikely. Instead, these findings point toward subcortical or brainstem myoclonus.

Stimulus sensitivity and action-induced jerks can occur in either cortical or subcortical forms and therefore are less specific. Dysarthria simply reflects associated cerebellar involvement and does not localize the myoclonus itself.

Question 3

The coexistence of dysarthria, nystagmus, dysmetria, and wide-based gait localizes primarily to which structure?

A. Basal ganglia

B. Cerebellum

C. Frontal lobe

D. Peripheral nervous system

E. Spinal cord

Answer

B. Cerebellum

Explanation

The correct answer is B.

Dysmetria, impaired rapid alternating movements, gait ataxia, dysarthria, and nystagmus are classic signs of cerebellar dysfunction. Together, these findings localize to the cerebellum and its connections.

Basal ganglia disease typically causes bradykinesia, rigidity, or chorea rather than limb dysmetria and nystagmus. Peripheral nerve and spinal cord disorders do not produce ocular movement abnormalities or cerebellar signs. Recognition of cerebellar involvement is important because the combination of cerebellar dysfunction and generalized myoclonus forms the characteristic myoclonus-ataxia syndrome.

Question 4

Which treatment is most appropriate for suspected post-infectious COVID-19-associated myoclonus-ataxia syndrome?

A. Carbidopa-levodopa

B. Acetazolamide

C. Intravenous methylprednisolone

D. Donepezil

E. Haloperidol

Answer

C. Intravenous methylprednisolone

Explanation

The correct answer is C.

High-dose intravenous corticosteroids represent first-line immunotherapy for many post-infectious neurological disorders. Intravenous immunoglobulin and plasma exchange are alternative therapies when corticosteroids are ineffective or contraindicated.

In this patient, treatment with intravenous methylprednisolone, along with symptomatic therapy using clonazepam and levetiracetam, resulted in dramatic improvement and near-complete recovery. Dopaminergic agents, acetazolamide, acetylcholinesterase inhibitors, and antipsychotics have no established role in treating post-COVID myoclonus-ataxia syndrome.

Question 5

A patient presents with generalized myoclonus, ataxia, and dysarthria two weeks after COVID-19 infection. MRI, PET imaging, and cerebrospinal fluid studies are normal. What is the most important next diagnostic study?

A. Muscle biopsy

B. Temporal artery biopsy

C. Video EEG with electromyography

D. Skin biopsy for small fiber neuropathy

E. Carotid ultrasonography

Answer

C. Video EEG with electromyography

Explanation

The correct answer is C.

When structural imaging and routine laboratory studies are unrevealing, neurophysiological testing becomes essential. Simultaneous EEG and EMG recordings allow clinicians to determine whether the myoclonus originates from the cortex or from subcortical structures.

In this case, the absence of EEG correlates established a subcortical origin and provided important insight into the underlying pathophysiology. Neurophysiology often provides information that conventional MRI cannot and is one of the most valuable diagnostic tools in the evaluation of unexplained myoclonus.

Teaching Pearl

Normal MRI and cerebrospinal fluid studies do not exclude significant neurological disease. In patients with unexplained myoclonus, neurophysiological testing may provide the most important clue to anatomical localization and ultimately guide diagnosis and treatment.