What is the initial treatment for Stiff Person Syndrome?

Initial Treatment for Stiff Person Syndrome

Begin treatment immediately with benzodiazepines, specifically diazepam, as first-line therapy for Stiff Person Syndrome, as this is the FDA-approved and most established treatment for enhancing GABAergic transmission to relieve muscle rigidity and spasms. 1

First-Line Treatment: GABAergic Therapy

Benzodiazepines (Primary Initial Treatment)

• Diazepam is the cornerstone initial therapy and is FDA-indicated specifically for stiff-man syndrome as a useful adjunct for relief of skeletal muscle spasm 1
• Benzodiazepines enhance GABA neurotransmission, directly addressing the underlying pathophysiology of reduced GABA levels in SPS 2, 3
• These agents provide symptomatic relief of both the continuous muscle rigidity and the episodic painful spasms 3, 4
• The rigidity and spasms characteristically respond to GABAergic enhancement, as symptoms are relieved by sleep and general anesthesia (which increase GABA activity) 4

Additional GABAergic Options if Benzodiazepines Insufficient

• Add levetiracetam or pregabalin if symptoms persist despite benzodiazepine therapy 2
• Pregabalin at 150 mg three times daily has demonstrated satisfying response in documented cases 5
• Other GABA-enhancing agents (valproate, vigabatrin, tiagabine, gabapentin) can provide symptomatic relief 3

Second-Line Treatment: Oral Baclofen

• Oral baclofen is recommended as second-line therapy when first-line GABAergic agents are inadequate 2
• Baclofen enhances GABAergic transmission and provides modest relief of clinical symptoms 4
• This should be prioritized over immunotherapies like rituximab or tacrolimus as the next step 2

Rationale for This Approach

Why Start with Benzodiazepines

The pathophysiology of SPS involves antibodies against glutamic acid decarboxylase (GAD), which is the rate-limiting enzyme for GABA synthesis 3, 4. This results in:

• Reduced GABA levels in brain and cerebrospinal fluid 3
• Loss of inhibitory neurotransmission causing continuous motor unit firing at rest 3, 4
• Co-contraction of agonist and antagonist muscles producing the characteristic stiffness 3

Clinical Confirmation Before Treatment

While initiating treatment, confirm the diagnosis with:

• Electromyography showing continuous motor unit activity at rest in both agonist and antagonist muscles simultaneously 3, 5
• High serum titers of anti-GAD65 antibodies (though GAD-negative cases exist) 3, 5
• Clinical features: axial muscle stiffness, episodic spasms triggered by tactile stimuli/noise/movement, and symptoms relieved by sleep 3, 4

Important Caveats

Limitations of Symptomatic Therapy Alone

• GABAergic agents provide symptomatic relief only and do not address the underlying autoimmune process 3, 4
• Many patients will require escalation to immunotherapy for substantial improvement 4
• The FDA label notes that effectiveness of diazepam in long-term use (>4 months) has not been systematically assessed, requiring periodic reassessment 1

When to Escalate Beyond Initial Treatment

If symptoms remain refractory to oral GABAergic therapy and baclofen, consider:

• Immunomodulatory therapy (steroids, intravenous immunoglobulin, plasmapheresis) which offers substantial improvement by addressing the autoimmune pathogenesis 3, 4
• Intrathecal baclofen for severe refractory spasticity uncontrolled by oral medications 2, 6
• IVIG and intrathecal baclofen are more effective than plasmapheresis for refractory symptoms 2

Diagnostic Pitfalls to Avoid

• SPS is frequently misdiagnosed as a psychiatric illness due to phobic symptoms and anxiety that can accompany the adrenergic symptoms (sweating, tachycardia, hypertension) 5
• Diagnosis delays of many years are common when psychiatric symptoms predominate 5
• The diagnosis requires high clinical suspicion and should be considered in any patient with unexplained progressive stiffness and spasms 4