What is the diagnosis and treatment approach for an adult patient with a history of autoimmune disorders presenting with stiffness and rigidity of the muscles, suspected to have Stiff Person Syndrome?

Stiff Person Syndrome: Diagnosis and Treatment

Diagnostic Approach

Stiff Person Syndrome (SPS) is a rare autoimmune neurological disorder characterized by progressive muscle rigidity and painful spasms affecting axial and limb muscles, requiring specific clinical, electrophysiological, and immunological confirmation for diagnosis. 1, 2

Clinical Features to Identify

• Progressive, symmetric rigidity of axial muscles (paraspinal, abdominal) with superimposed painful spasms triggered by tactile stimuli, passive stretch, volitional movement, startling noises, or emotional stimuli 3, 2
• Continuous motor unit activity on EMG in agonist and antagonist muscles simultaneously, which is pathognomonic 1, 3
• Relief of symptoms with sleep, general anesthesia, myoneural blockade, or peripheral nerve blockade 3
• Adrenergic symptoms including profuse sweating, tachycardia, and hypertension may accompany muscle rigidity 1
• Lumbar hyperlordosis from chronic paraspinal muscle contraction is common 2

Essential Diagnostic Workup

• Anti-glutamic acid decarboxylase (anti-GAD65) antibodies via radioimmunoassay in both serum and CSF—elevated titers are present in most classic SPS cases 1, 3, 2
• Polygraphic EMG from paraspinal and leg muscles demonstrating continuous motor unit activity in agonist and antagonist muscles 1
• Screen for associated autoimmune conditions: Check for diabetes mellitus (common association), thyroid disease, and other autoimmune disorders 1, 3, 2
• Rule out paraneoplastic SPS: Antiamphiphysin antibodies and screening for breast cancer, particularly in atypical presentations 2
• Additional antibody testing: GABA(A) receptor-associated protein and glycine-α1 receptor antibodies in antibody-negative cases 2
• Brain MRI and EEG to exclude other neurological disorders (typically normal in SPS) 1

Critical Diagnostic Pitfall

SPS is frequently misdiagnosed as a psychiatric illness due to phobic symptoms and anxiety that develop secondary to the unpredictable muscle spasms, leading to treatment delays averaging years. 1 Do not attribute muscle rigidity and spasms to conversion disorder or anxiety without completing the diagnostic workup above.

Treatment Algorithm

First-Line Treatment: GABAergic Therapy

Benzodiazepines are the first-line treatment for SPS, as they enhance GABAergic tone and provide symptomatic relief of rigidity and spasms. 4, 5, 3

• Diazepam is FDA-approved specifically for stiff-man syndrome (SPS), typically starting at low doses and titrating to effect 4
• Partial relief of rigidity and spasms is expected, though complete symptom resolution is uncommon 3

If symptoms persist on benzodiazepines alone, add levetiracetam or pregabalin as adjunctive GABAergic therapy. 5

• Pregabalin 150 mg three times daily has demonstrated satisfying response in case reports 1
• These agents augment GABA-mediated inhibition through different mechanisms 5

Second-Line Treatment: Oral Baclofen

For inadequate response to first-line therapy, add oral baclofen before escalating to immunotherapy. 5

• Baclofen is a GABA-B receptor agonist that reduces muscle spasticity 5
• Titrate dose gradually to minimize sedation and weakness 5

Immunotherapy Considerations

Given the autoimmune pathogenesis and association with other autoimmune diseases, early immunotherapy should be considered, particularly in patients with high anti-GAD65 titers and progressive symptoms. 6, 3

• Corticosteroids (prednisone 1 mg/kg) provide partial relief and support the autoimmune etiology 3
• Rituximab is recommended over tacrolimus for steroid-refractory cases 5
• Immunotherapy is most effective when combined with GABAergic therapy rather than as monotherapy 2

Refractory Treatment Options

For patients with refractory symptoms despite maximal oral therapy, intrathecal baclofen or intravenous immunoglobulin (IVIG) are more effective than plasmapheresis. 5

• Intrathecal baclofen delivers high CSF concentrations with minimal systemic side effects for severe, treatment-resistant rigidity 5
• IVIG targets the underlying autoimmune process and has demonstrated efficacy in refractory SPS 5
• Plasmapheresis is less effective but may be considered when other options fail 5
• Propofol may serve as temporary bridge therapy before initiating permanent treatment in acute severe exacerbations 5

Monitoring and Prognosis

• The prognosis is unpredictable and spontaneous remissions are unlikely 2
• Serial monitoring of anti-GAD65 antibody titers does not reliably correlate with disease activity 2
• Screen for malignancy in patients with atypical features or antiamphiphysin antibodies, as paraneoplastic SPS requires treatment of the underlying cancer 2
• Compartment syndrome has been reported as a rare initial presentation requiring emergency fasciotomy 7