Pathogenesis and Pathophysiology. Stiff-person syndrome (SPS) is believed to be an idiopathic disorder in some patients and an autoimmune disorder with functional impairment of spinal neurons due to antibodies directed against the enzyme glutamic acid decarboxylase (GAD) in others. y This enzyme is essential for the conversion of glutamic acid to GABA, an inhibitory neurotransmitter found throughout the central nervous system. y In a paraneoplastic form of SPS, amphiphysin, a protein associated with synaptic vesicles, has been implicated, and this product's gene has been mapped to 7p13-14. y Neurophysiological studies show continuous excessive firing of the motor unit, suggesting that the disorder is due to disinhibition of the descending pathways to the Renshaw cells or gamma motor system.y Autopsy information, albeit limited, has failed to demonstrate any abnormalities in the brain stem, spinal cord, peripheral nerve, or muscle.
Epidemiology and Risk Factors. The disorder is more common in women and is frequently associated with other
Clinical Features and Associated Disorders. Typically, SPS patients present with painful muscle cramps and severe lordosis secondary to chronic spasm of the paraspinal muscles. Although predominantly a disease of the axial muscles, cranial involvement has been reported in 25 percent of patients, and spread to the proximal limbs occurs. Examination reveals marked lumbar and thoracic muscle spasms. Stress or exertional activity may provoke painful spasms that may last for hours. Because of hypertonicity, the gait may resemble that of a "tin soldier."
Differential Diagnosis. Among the primary differential diagnoses are dystonia and orthostatic tremor. In both instances, patients may complain of tight cramping muscles and pain, especially when standing. Other rare conditions resembling SPS include tetanus, progressive encephalomyelitis with rigidity, and Isaac's syndrome. Tetanus secondary to infection with Clostridium tetanii is usually associated with a laceration injury and progresses from focal muscle spasm at the site of inoculation to bulbar and generalized spasms. Progressive encephalomyelitis usually begins with pain and sensory changes, and in these patients, a paraneoplastic disorder is possible. Isaac's syndrome is often familial and is associated with peripheral neuropathy, but most important, it usually causes more symptoms in the appendicular muscles than in the axial ones.
Evaluation. Electromyographic demonstration of continuous motor unit activity is essential to confirm the diagnosis of SPS. The presence of reduced motor activity after benzodiazepine administration is also important. Diagnostically, spinal fluid analysis may reveal increased immunoglobulin or oligoclonal bands, and the presence of GAD antibodies is helpful in confirming the autoimmune form of this diagnosis.
Management. Treatment is based on controlling rigidity; currently, diazepam (20 to 300 mg/day) is the most effective medication for this purpose. Baclofen, clonazepam, valproic acid, and clonidine have been reported to improve symptoms. The role of treatment for autoimmune conditions, such as plasmapheresis, corticosteroids, or azathioprine, has yet to be defined. y Intrathecal baclofen and botulinum toxin may also be beneficial, but because of the rarity of this syndrome, controlled clinical trials of these drugs for this purpose have not been undertaken. Although these patients may be in pain, extreme caution must be used in mixing narcotic medications with benzodiazipine derivatives, especially if the patient's spasms induce respiratory acidosis because of the rigidity of the diaphragmatic muscles.
Prognosis and Future Perspectives. Without treatment, SPS progresses to total disability related to generalized rigidity and secondary musculoskeletal deformities. The pathogenetic autoimmune mechanisms remain to be elucidated.
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