What are the appropriate next diagnostic and treatment steps for a 32‑year‑old woman presenting with dystonia, frequent falls, and lower‑leg paresthesias, whose electromyography and brain and cervical spine magnetic resonance imaging are normal and who has a negative workup for multiple sclerosis and myasthenia gravis?

Diagnostic Approach for 32-Year-Old Woman with Dystonia, Falls, and Lower-Leg Paresthesias

This patient requires immediate lumbar puncture with comprehensive CSF analysis and spinal MRI with contrast to evaluate for inflammatory/demyelinating conditions, followed by targeted genetic testing if initial workup remains negative.

Immediate Priority: Rule Out Treatable Inflammatory/Demyelinating Disorders

Despite negative brain/cervical MRI, this presentation warrants urgent investigation for conditions that may not be captured by standard imaging:

Lumbar Puncture with Comprehensive CSF Analysis

• CSF cell count and differential to detect pleocytosis suggesting inflammatory process 1
• CSF protein and glucose levels, as elevated protein can indicate inflammatory neuropathy 1
• Oligoclonal bands (OCBs) testing, noting that OCB-negative presentations can still represent demyelinating disease 1
• Cytology for malignant cells to exclude paraneoplastic syndromes 1
• Viral/bacterial cultures and PCR for infectious etiologies 1

Spinal MRI with and without Contrast

• Thoracic and lumbar spine imaging is critical, as cervical-only MRI misses lesions causing lower extremity symptoms 1
• Evaluate for nerve root enhancement/thickening suggesting inflammatory radiculopathy 1
• Assess for longitudinally extensive lesions that may indicate MOG-antibody disease or other demyelinating conditions 1
• Look for conus involvement which can cause lower extremity paresthesias and gait disturbance 1

Serologic Testing for Autoimmune/Inflammatory Etiologies

Myelin Oligodendrocyte Glycoprotein (MOG) Antibody Testing

• MOG-IgG testing via cell-based assay is essential, as this can present with dystonia, ataxia, and sensory symptoms without typical MS features 1
• MOG encephalomyelitis can manifest with OCB-negative CSF and atypical presentations including movement disorders 1
• Testing should use full-length human MOG with Fc-specific secondary antibodies to avoid false positives 1

Paraneoplastic Antibody Panel

• ANNA-1 (anti-Hu) antibodies for paraneoplastic encephalomyelitis 1
• Anti-ganglionic acetylcholine receptor antibodies for autoimmune dysautonomia 1
• Antiganglioside antibodies (anti-GQ1b, anti-GM1) for atypical neuropathy presentations 1

Additional Autoimmune Markers

• ANA, anti-dsDNA, SSA/SSB, RNP to screen for systemic autoimmune disease 1
• ANCA for vasculitic neuropathy 1
• Inflammatory markers (ESR, CRP) to assess systemic inflammation 1

Metabolic and Endocrine Evaluation

Thyroid and Calcium-Phosphate Metabolism

• Thyroid function tests (T3/FT3, T4/FT4, TSH) as hyperthyroidism can cause paroxysmal dystonia 1
• Serum calcium, phosphorus, parathyroid hormone to exclude hypoparathyroidism and related disorders 1
• Head CT without contrast to assess for basal ganglia calcification if calcium metabolism abnormal 1

Other Metabolic Screening

• HbA1c for diabetic neuropathy 1
• Vitamin B12, B6, folate, thiamine levels for nutritional neuropathies 1
• Serum ceruloplasmin to exclude Wilson disease in young adult with dystonia 1
• Serum protein electrophoresis with immunofixation for paraproteinemic neuropathy 1

Electrodiagnostic Studies

Nerve Conduction Studies (NCS)

• Comprehensive NCS of upper and lower extremities to characterize neuropathy pattern, as standard EMG may miss small fiber or sensory neuropathies 1
• Evaluate for demyelinating versus axonal patterns to guide differential diagnosis 1

Specialized Neurophysiologic Testing

• Somatosensory temporal discrimination threshold (STDT) has the greatest evidence for identifying dystonia patients 2
• Consider autonomic testing given falls and lower extremity symptoms suggesting possible dysautonomia 1

Genetic Testing Strategy

Genetic testing is indicated in this case because the patient presents with adult-onset combined dystonia (with gait disturbance and sensory symptoms) rather than isolated focal dystonia 3.

When to Pursue Genetic Testing

• Adult-onset dystonia with additional neurological features (falls, paresthesias) warrants genetic evaluation 3
• Isolated focal or segmental dystonia in adults typically does NOT require genetic testing 3
• Combined movement disorders or multisystem involvement increases likelihood of genetic etiology 3

Recommended Genetic Approach

• Exome sequencing (ES) or whole genome sequencing (WGS) should be considered as first- or second-tier testing for unexplained dystonia with additional neurological features 1
• Targeted dystonia gene panels if specific phenotype suggests particular genetic syndrome 2
• Consider chromosomal microarray (CMA) if developmental history suggests possible genetic syndrome 1

Critical Differential Diagnoses to Exclude

Guillain-Barré Syndrome (GBS) or Variant

• Ascending sensory changes with gait difficulty can represent atypical GBS 1
• CSF typically shows elevated protein by week 2, though may be normal early 1
• Requires urgent recognition as respiratory compromise can develop rapidly 1

MOG-Antibody Associated Disease

• Can present with ataxia, dystonia, and sensory symptoms without classic NMOSD features 1
• Brainstem and spinal cord involvement can cause falls and lower extremity paresthesias 1
• OCB-negative CSF with pleocytosis is characteristic 1

Paroxysmal Kinesigenic Dyskinesia (PKD)

• Kinesigenic triggers (movement-induced) with brief dystonic attacks (<1 minute) 1
• High-knee exercise test can provoke attacks for diagnostic confirmation 1
• Excellent response to carbamazepine/oxcarbazepine is characteristic 1

Atypical Multiple Sclerosis Presentation

• Paroxysmal dystonia can be initial MS manifestation, sometimes preceding other symptoms by years 4, 5
• Repeat MRI brain with contrast may be needed if initial imaging negative, as early lesions can be subtle 4, 5
• Paroxysmal symptoms in MS result from demyelinated axon irritation by inflammatory mediators 5

Treatment Considerations Pending Diagnosis

Symptomatic Management

• Avoid empiric immunosuppression until inflammatory etiology confirmed, as this may obscure diagnosis 1
• Consider trial of carbamazepine if paroxysmal dystonia suspected, as response supports PKD diagnosis 1
• Gabapentin or pregabalin for neuropathic pain from paresthesias 1

Monitoring for Progression

• Serial neurological examinations every 4-6 weeks to assess for evolution of symptoms 1
• Pulmonary function testing if any suggestion of bulbar or respiratory involvement 1, 6, 7
• Repeat imaging in 3-6 months if initial workup negative but symptoms progress 3

Common Pitfalls to Avoid

• Do not assume negative brain/cervical MRI excludes demyelinating disease—thoracolumbar spine lesions cause lower extremity symptoms 1
• Do not dismiss OCB-negative CSF—MOG disease and other inflammatory conditions can be OCB-negative 1
• Do not delay lumbar puncture—CSF analysis is critical for inflammatory/infectious etiologies that require urgent treatment 1
• Do not order genetic testing before excluding acquired causes—metabolic, inflammatory, and structural etiologies must be ruled out first 3
• Do not overlook paraneoplastic syndromes—dystonia with sensory symptoms can represent occult malignancy 1