What are the diagnostic criteria and treatment options for stiff person syndrome?

Diagnosis and Treatment of Stiff Person Syndrome

Stiff person syndrome (SPS) is diagnosed based on progressive muscle rigidity and painful spasms affecting axial and limb muscles, combined with continuous motor unit activity on EMG and high-titer anti-GAD65 antibodies in serum or CSF. 1

Diagnostic Criteria

Clinical Features Required for Diagnosis

• Progressive muscle rigidity affecting the axial muscles (paraspinal and abdominal) with superimposed painful spasms that are precipitated by tactile stimuli, passive stretch, volitional movement, startling noises, or emotional stimuli 1, 2

• Characteristic spasm triggers: The spasms are relieved by sleep, general anesthesia, myoneural blockade, and peripheral nerve blockade 2

• Electromyographic findings: Continuous normal motor unit potentials in affected muscles during waking hours, demonstrating persistent motor unit activity in both agonist and antagonist muscles 3, 1

Laboratory Confirmation

• Anti-GAD65 antibodies: Present in up to 80% of classic SPS cases, detectable in both serum and CSF using radioimmunoassay technique 4, 3, 1

• Serum ferritin: Check to exclude iron deficiency, though this is more relevant for restless leg syndrome differential 5

• Additional antibody testing: Screen for GABA(A) receptor-associated protein antibodies, glycine-α1 receptor antibodies, and antiamphiphysin antibodies (the latter suggests paraneoplastic SPS associated with breast cancer) 1

Exclusion of Mimics

The diagnosis requires ruling out other conditions. A thorough neurological examination is essential to exclude peripheral neuropathy, radiculopathy, or other movement disorders 5, 3. Brain MRI and EEG should be normal 3.

Clinical Variants to Recognize

SPS presents in several forms 1:

• Classic SPS: Symmetric axial and limb rigidity with spasms
• Focal or segmental SPS: Limited distribution
• Jerking SPS: Prominent myoclonic features
• Progressive encephalomyelitis with rigidity and myoclonus (PERM): Most severe variant

Common diagnostic pitfall: SPS is frequently misdiagnosed as a psychiatric illness due to the presence of anxiety symptoms and phobic behaviors that develop secondary to the fear of triggering painful spasms 3. The key distinguishing feature is the objective finding of continuous motor unit activity on EMG and the presence of anti-GAD65 antibodies.

Paraneoplastic Screening

Screen for malignancy in all SPS patients, particularly if antiamphiphysin or anti-SOX1 antibodies are present 4, 1. Paraneoplastic SPS comprises approximately 5% of cases and is associated with lung, thymus, breast, colon, and lymph node malignancies 4.

Treatment Algorithm

First-Line Treatment: GABAergic Therapy

Start with benzodiazepines as initial therapy 6:

• Diazepam is the traditional first-line agent, as it enhances GABAergic tone and provides partial relief of rigidity and spasms 2
• If symptoms persist, add levetiracetam or pregabalin 6
• Pregabalin at 150 mg three times daily has shown satisfying response in documented cases 3

Second-Line Treatment

If first-line GABAergic therapy is insufficient, add oral baclofen 6:

• Oral baclofen is recommended over rituximab and tacrolimus as second-line therapy 6
• Rituximab is preferred over tacrolimus if baclofen fails 6

Immunotherapy

Combine GABAergic drugs with immunotherapy for optimal outcomes 1:

• Corticosteroids provide partial relief and support the autoimmune etiology 2
• The association with other autoimmune diseases (present in approximately one-third of patients with the stiff-man syndrome variant) supports early immunotherapy 5

Refractory Treatment Options

For patients who fail first- and second-line therapies, use intrathecal baclofen or intravenous immunoglobulin (IVIG) 6:

• Intrathecal baclofen and IVIG are more effective than plasmapheresis in refractory cases 6
• IVIG has been employed as main treatment with complete remission documented in cases with high-titer anti-GAD combined with anti-SOX1 antibodies 4
• Plasmapheresis is a third option for refractory symptoms 6

Bridge Therapy

Propofol may be used as temporary bridge therapy before initiating permanent treatment in severe cases 6.

Key Clinical Caveats

• Autonomic dysfunction can occur, including profuse sweating, tachycardia, and hypertension 3
• Metabolic complications: Monitor for hyperglycemia, as high blood glucose levels have been reported in SPS patients 3
• Bone fractures: Severe cases can present with multiple bone fractures due to the intensity of muscle spasms 4
• Prognosis is unpredictable and spontaneous remissions are unlikely, requiring long-term management 1
• Diagnosis delay is common: The average time to diagnosis can exceed 10 years due to misdiagnosis as psychiatric illness 3