Stiff-Man Syndrome

SMS variants include stiff-limb syndrome, progressive encephalomyelitis with rigidity and myoclonus (PERM), and a paraneoplastic process associated with breast cancer. Idiopathic gait ataxias sometimes accompany SMS. There is one instance of tamilial SMS affecting a father and daughter with transplacental tranfer of antibodies to a granddaughter.

ETIOLOGY

Classic, primary autoimmune SMS is typically associated with rarely a glutamic acid decarboxylase (GAD-65) autoantibody, and rarely a paraneoplastic variant with antiamphiphysin antibodies. Other autoimmune disorders commonly associated with GAD-65 autoimmunity include type-1 diabetes mellitus, thyroiditis, vitiligo, and pernicious anemia. The antibody’s precise pathophysiologic role is unclear. In classic SMS, the autoimmune process may be directed at inhibitory spinal interneurons producing γ-aminobutyric acid (GABA). GAD antibodies from stiff-persons’ serum patients inhibit GAD and GABA synthesis in vitro.

CLINICAL PRESENTATION

Classic generalized SMS is characterized by paraspinal, abdominal, and leg rigidity with lumbar hyperlordosis as a key feature. Leg rigidity impairs walking. Superimposed painful spasms develop, sometimes precipitated by sudden noise, anxiety, or touch. The spasms are sometimes abrupt and powerful, leading to precipitous falls and agoraphobia with fear of falling in public. When the abdominal musculature is involved, the concomitant pain and rigidity can potentially mimic an acute abdomen.

Neurologic examination is often initially normal in patients just experiencing intermittent spasms; however, later with generalized SMS, concomitant paraspinal and abdominal musculature contraction is obvious, with lumbar hyperlordosis and lower limb rigidity. Some patients become extremely frightened of simply moving because that may precipitate severe painful spasms. Sometimes the examiner touching the patient causes a generalized opisthotonic spasm mimicking tetanus. Muscle stretch reflexes are normal to brisk, occasionally associated with Babinski signs.

Primary appendicular SMS variants present focally in a leg with rigidity and spasms; axial involvement is less prominent. Eventually abdominal and truncal muscle involvement develops if the SMS is not diagnosed and treated early.

SMS patients with PERM have associated antiglycine receptor antibodies (GlyR-abs). One SMS syndrome is paraneoplastic, having various manifestations. It is often associated with antiamphiphysin antibodies, requiring search for underlying breast cancer; however, small cell lung cancer, colon cancer, and lymphoma are also associated. Another idiopathic variant, presumed autoimmune, is not associated with an identifiable autoantibody and may be rapidly progressive leading to severe disability and death.

DIFFERENTIAL DIAGNOSIS

SMS patients previously have had multiple nondiagnostic visits to physicians. Normal examination findings early on sometimes lead the unsuspecting physician to label these patients as hysteric or somatoform, leading to psychiatric evaluations. Other diagnostic considerations include lumbosacral disks, dystonia, multiple sclerosis, stroke, arthritis, myelopathy or basal ganglia disorders, Lyme disease, poliomyelitis, spinal myoclonus, tumors, and strychnine poisoning. In acute conditions, tetanus needs consideration because of the severe boardlike, stiffening, abdominal wall muscle spasms. Sparing of the jaw muscles and absence of trismus and risus sardonicus in SMS excludes tetanus. Two channelopathies with muscle rigidity, namely myotonia congenita and Isaac syndrome, are unlikely; these are not painful.

SMS is primarily a clinical diagnosis, and certain features should help alert the clinician to this diagnosis. These include painful muscle stiffness and rigidity, primarily axial but occasionally individual limbs; progressive involvement with abnormal axial posture; marked lumbar hyperlordosis; superimposed muscle spasms; and normal brainstem, extrapyramidal, and lower motor neuron evaluation.

Markedly elevated GAD-65 autoantibody titers in serum support the diagnosis. In classic SMS, 60% to 90% patients have very high serum GAD-65 titers, usually greater than 20 nmol/L. Lower GAD-65 antibody levels may occur with type 1 diabetes mellitus. Elevated amphiphysin antibodies suggest occult cancers, usually of the breast. PERM is associated with elevated anti–GlyR-ab titers.

Although electromyography (EMG) is often normal early in SMS, this must not dissuade the clinician from obtaining antibody studies in an appropriate clinical setting. EMG eventually reveals a characteristic concomitant and continuous firing of motor unit potentials in agonist and antagonist muscles.

TREATMENT

Diazepam is first-line symptomatic therapy. Benzodiazepines are GABA_A receptor agonists inhibiting excessive motor-unit firing and thus painful muscle contraction. Baclofen, a GABA_B receptor agonist, is also effective. Immunotherapy requires high-dose corticosteroid (e.g., prednisone 1 mg/kg/day or intravenous equivalent). Intravenous immunoglobulin (IVIG), plasma exchange and azathioprine are other options.

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