Stiff Person Syndrome (Stiff-Man Syndrome)

Clinical Features

• Onset: Insidious, typically in middle life (age 30-60), affects women more often than men (roughly 2:1 to 3:1 in most series, though some texts describe equal sex distribution)
• Core presentation: Progressive, fluctuating rigidity and stiffness of axial muscles - the back, abdomen, hips, and shoulders - producing a "board-like" abdomen and exaggerated lumbar lordosis (hyperlordosis)
• Spasms: Superimposed, often painful muscle spasms triggered by emotional upset, unexpected noise, anxiety, or attempted voluntary/passive movement. These can be severe enough to cause falls ("like a wooden person"), bone fractures, or joint dislocations
• Muscles feel rock-hard and immobile on palpation, distinct from spasticity, paratonia, or extrapyramidal rigidity
• Tendon reflexes remain normal (though brisk in some), and there is no trismus (unlike tetanus)
• A hallmark clue: rigidity and spasms disappear during sleep, general anesthesia, or with proximal nerve/spinal block, indicating a central (not peripheral) origin
• Rare severe cases involve respiratory and swallowing muscles, with reported episodes of cyanosis and respiratory arrest during intense spasms
• Related phenotypes (stiff-person spectrum disorders): stiff-limb syndrome (SLS, one or more limbs affected with distal rigidity), and progressive encephalomyelitis with rigidity and myoclonus (PERM, which adds cerebellar, brainstem, or autonomic dysfunction)
• Bradley and Daroff's Neurology in Clinical Practice, p. 1751-1752; Adams and Victor's Principles of Neurology, 12th Ed., p. 1470-1471

Pathophysiology and Antibodies

• About two-thirds of patients have circulating autoantibodies against glutamic acid decarboxylase (GAD65), the enzyme that synthesizes GABA - this impairs inhibitory GABAergic transmission
• A subset has antibodies to the glycine receptor (GlyR), more often associated with the PERM phenotype and generally better treatment response
• Anti-amphiphysin antibodies occur in a smaller subset (often women) and usually signal a paraneoplastic origin, classically linked to breast cancer; GlyR antibodies carry a 10-20% malignancy association (often small cell lung cancer)
• About one-third of patients are seronegative or have other rarer antibodies (GABA-A receptor-associated protein, DPPX)
• SPS is strongly associated with other autoimmune diseases, especially type 1 diabetes mellitus
• Localization in Clinical Neurology, 8e, p. 1149; Harrison's Principles of Internal Medicine 22E, p. 863

Diagnosis

• Serum anti-GAD antibodies are the first-line test (very high titers, often >10,000 IU/mL by ELISA, are typical of SPS vs. the lower titers seen in type 1 diabetes alone)
• If serum antibodies are not markedly elevated, check CSF GAD antibodies or antibodies to other targets (glycine receptor, amphiphysin)
• EMG shows continuous motor unit activity in affected muscles, with normally configured (not myopathic or neurogenic) motor units - distinguishing it from continuous muscle fiber activity syndrome (Isaacs syndrome) or myokymia
• Differential diagnosis includes tetanus, Isaacs syndrome, and subacute myoclonic spinal neuronitis

Treatment

• First-line symptomatic: benzodiazepines (e.g., diazepam) are the mainstay; add levetiracetam, gabapentin, pregabalin, or baclofen if symptoms persist
• Immunotherapy: IVIG has demonstrated efficacy in both paraneoplastic and non-paraneoplastic SPS; corticosteroids and treatment of any underlying tumor help paraneoplastic cases
• Refractory cases: plasma exchange, rituximab, or other second-line immunomodulators have been used
• Patients with GlyR antibodies respond better to immunotherapy than those with GAD or amphiphysin antibodies, or seronegative patients

Recent Evidence Note