Stiff-Person Syndrome

Stiff person syndrome is a rare autoimmune disorder of the central nervous system with progressive muscle rigidity of the axial and proximal limb muscles and episodic painful spasms triggered by noise, touch or emotion. It is associated with antibodies to glutamic acid decarboxylase (GAD65) in 60 to 80% of cases.

The prevalence is about 1 to 2 in every million people. It occurs in adults aged 30 to 60 years, and women are affected about twice as often as men. Autoimmune disease is common in patients, particularly type 1 diabetes (30 to 35%), thyroid disease and pernicious anaemia.

Variants. Classic stiff person syndrome, stiff limb syndrome (focal, often distal), progressive encephalomyelitis with rigidity and myoclonus (anti-glycine receptor antibodies), and paraneoplastic forms with amphiphysin antibodies (breast cancer, small cell lung cancer).

Course. Slowly progressive over years, leading to disability, falls and fractures. Sudden death from autonomic crises occurs in a small number.

Pathophysiology.

Antibodies to GAD65 and related synaptic proteins impair GABAergic and glycinergic inhibition in the brainstem and spinal cord, so that motor neurons fire without restraint.

The result is continuous motor unit activity and exaggerated startle.

• Gradual stiffness and tightness of the back, abdomen and proximal legs, with a board like lumbar hyperlordosis and a stiff gait.
• Painful spasms triggered by noise, touch, emotion or sudden movement, with falls (like a falling log).
• Anxiety, task specific phobias (street phobia) and exaggerated startle.
• Normal strength and sensation; hyperreflexia in some; rare brainstem signs, myoclonus and dysautonomia in encephalomyelitis.
• Spasms can cause fractures, ventilatory compromise or autonomic crises.

Red flags.

• Autonomic crisis (sweating, tachycardia, hypertension, fever), respiratory difficulty or laryngospasm.
• Encephalopathy, seizures or brainstem signs (progressive encephalomyelitis with rigidity and myoclonus).
• Weight loss, cough or a breast lump (paraneoplastic).

• Clinical diagnosis with electromyography showing continuous motor unit activity in axial muscles that is reduced by diazepam.
• Serum anti-GAD65 antibodies (high titre, typically over 2000 IU/mL, with the cerebrospinal fluid showing intrathecal synthesis and oligoclonal bands); anti-glycine receptor, amphiphysin and DPPX antibodies if GAD65 is negative.
• Glucose, HbA1c, thyroid function, vitamin B12 and other autoantibodies; MRI of the brain and spine to exclude other causes.
• Screen for cancer (CT chest, abdomen and pelvis, mammography) in amphiphysin antibody or seronegative disease.
• Exclude hyperekplexia, tetanus, neuromyotonia, dystonia and functional movement disorder.

Differential diagnosis. Functional movement disorder, dystonia, hyperekplexia, tetanus, neuromyotonia (Isaacs syndrome), spinal cord disease, Parkinson disease, muscle disease and anxiety with spasm.

• Diazepam, first line: 5 mg orally three times daily, increased by 5 mg each day every few days to a usual 20 to 60 mg daily in divided doses. Maximum 100 mg daily under specialist care. Monitor sedation, falls, dependence, respiratory depression and mood. Avoid in sleep apnoea, severe respiratory disease, myasthenia gravis and severe hepatic impairment; use lower doses in older adults and renal impairment; avoid in pregnancy and breastfeeding unless essential; withdraw slowly.
• Baclofen: 5 mg orally three times daily, increased by 5 mg every 3 days to a usual 30 to 75 mg daily in 3 to 4 divided doses. Maximum 100 mg daily. Monitor sedation, weakness and seizures; withdraw slowly (intrathecal baclofen if oral doses fail). Reduce dose in renal impairment (creatinine clearance under 50 mL/min); avoid in peptic ulcer.
• Gabapentin 300 mg orally at night on day 1, 300 mg twice daily on day 2, then 300 mg three times daily on day 3, increased every 3 to 7 days to 900 to 2400 mg daily. Maximum 3600 mg daily. Monitor sedation, dizziness and oedema. Adjust for renal function: creatinine clearance 50 to 79 mL/min, 600 to 1800 mg daily; 30 to 49 mL/min, 300 to 900 mg daily; 15 to 29 mL/min, 150 to 600 mg daily; under 15 mL/min, 150 to 300 mg daily.
• Immunotherapy for those with inadequate response: intravenous immunoglobulin 2 g/kg in total over 2 to 5 days, repeated every 4 to 8 weeks. Maximum 2 g/kg in any 4 week period. Monitor renal function, thrombosis, hypersensitivity and aseptic meningitis; check IgA before the first dose. Avoid in IgA deficiency with anti-IgA antibodies; use caution in renal impairment and heart failure.
• Rituximab 1000 mg intravenously on days 1 and 15, repeated every 6 months if effective. Maximum 1000 mg for each dose. Give with premedication (paracetamol, an antihistamine and hydrocortisone). Screen for hepatitis B before treatment; monitor infusion reactions, infection, neutrophils and immunoglobulins. Avoid in active infection and pregnancy.
• Plasma exchange for severe or refractory disease: 5 exchanges over 10 days, by a specialist.
• Treat associated diabetes, thyroid disease and cancer; physiotherapy, falls prevention, fracture risk review and psychological support.

Monitoring. Review at 4 to 6 weeks, then every 3 months; track spasm frequency, gait, falls, glucose and sedation.

Referral and escalation. Neurology and neuroimmunology for all; oncology for paraneoplastic disease; intensive care for autonomic crisis or respiratory failure.

Special groups. Pregnancy: diazepam and baclofen need specialist advice; immunoglobulin is preferred. Older adults: sedation and falls risk.