Stiff-Person Syndrome

Description

The stiff-person syndrome (SPS) is most often an adult-onset sporadic acquired disorder characterized by progressive muscle stiffness with superimposed painful muscle spasms accompanied by electromyographic evidence of continuous motor activity at rest. SPS has been associated with autoimmune disorders, diabetes mellitus, thyrotoxicosis, and hypopituitarism with adrenal insufficiency (George et al., 1984).

Approximately 60% of patients with SPS have antibodies to glutamic acid decarboxylase (GAD2, or GAD65; 138275), the rate-limiting enzyme in the synthesis of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA), suggesting an immune-mediated pathogenesis (Folli et al., 1993). Approximately 10% of patients develop SPS as a paraneoplastic neurologic disorder associated with antibodies to amphiphysin (AMPH; 600418), an intracellular protein associated with neuronal synaptic vesicle endocytosis (Burns, 2005).

See also congenital stiff-man syndrome, or hereditary hyperexplexia (149400), which is caused by mutations in subunits of the glycine receptor gene (GLRA1, 138491; GLRB, 138492).

Meinck and Thompson (2002) provided a detailed review of stiff-person syndrome. They also discussed 2 possibly related conditions, progressive encephalomyelitis with rigidity (PERM), a more severe disorder with other neurologic features, and stiff-limb or stiff-leg syndrome, a focal disorder.

Clinical Features

Moersch and Woltman (1956) reported stiff-man syndrome in patients with progressive fluctuating muscular rigidity and spasms.

Solimena et al. (1988) reported a patient with stiff-man syndrome characterized by fluctuating muscle rigidity with painful spasms. He also had type I diabetes mellitus (222100) and epilepsy. Elevated levels of IgG were found in serum and cerebrospinal fluid, which stained gray matter regions of brain sections in patterns identical to those produced by antibodies to glutamic acid decarboxylase. Both CSF and serum antibodies reacted with a band comigrating with GAD2 in sodium dodecyl sulfate-polyacrylamide gels, suggesting the possibility of an autoimmune pathogenesis.

Meinck et al. (1994) reported 8 patients with stiff-man syndrome. All had adult onset of severe muscle stiffness and superimposed painful violent spasms or jerks including opisthotonos, stiffening of the arms and/or legs, and inversion of extended feet. Jerks and spasms were elicited by somatosensory stimuli to almost all parts of the body, even those uninvolved in the spasms. Five patients experienced by an aura-like feeling of an imminent attack, associated in some with fear and restlessness, beforehand. Seven patients had autonomic symptoms during attacks, including profuse sweating, tachycardia, hypertension, or pupillary dilation. All patients had been diagnosed earlier with hysterical anxiety neuroses. Two patients had additional features, such as nystagmus, vertigo, or paresthesias, consistent with 'progressive encephalomyelitis with rigidity and myoclonus.' EMG in all patients showed steady, low-frequency firing of normal motor units that abruptly increased in response to somatosensory or acoustic stimulation; these findings disappeared during natural or drug-induced sleep. Treatment with benzodiazepines or immunosuppression was effective. Four patients, including 1 with features of PERM, had anti-GAD antibodies; there was no difference in symptoms between those with and those without antibodies. Electrophysiologic studies by Meinck et al. (1995) identified a characteristic spasmodic reflex myoclonus in the trunk muscles induced from a wide peripheral receptive field.

Dalakas et al. (2000) evaluated the clinical spectrum of 20 patients with anti-GAD antibodies and stiff-man syndrome. Average age at onset was 41.2 years. The characteristic clinical findings were muscle stiffness with superimposed episodic spasms and contractures of the abdominal and thoracic paraspinal muscles, as well as stiff gait with frequent falls. Thirteen patients had facial involvement. Autoimmune diseases or autoantibodies were noted in 80% of patients. Dalakas et al. (2000) noted that many patients were misdiagnosed due to multifaceted presentations.

Burns et al. (2003) reported a father and daughter with SPS associated with anti-GAD65 antibodies. At age 53 years, the father developed rigidity of the extremities, which the authors termed the 'stiff-limb variant.' He had a personal history of pernicious anemia and thyroiditis and a family history of diabetes mellitus. His daughter developed recurrent, episodic extension of the head and neck at age 31 years. Her symptoms progressed over time, and she developed an opisthotonic response to tapping of the patellar tendon. Serum analysis showed anti-thyroperoxidase (TPO; 606765) antibodies in the absence of clinical thyroid disease. During this period, she gave birth to a healthy infant who did not exhibit clinical symptoms of SPS despite transient transplacental acquisition of maternal GAD65 antibodies. Low levels of anti-GAD65 antibodies were detected in the serum of 4 other family members without SPS.

Rakocevic et al. (2004) found that many patients with stiff-person syndrome have comorbid neuropsychiatric disorders, including anxiety and depression. In a study of 16 patients, they found no correlation between GAD antibody titers and clinical severity as measured by a 'stiffness index.' The authors concluded that anti-GAD antibodies are a good marker for the disorder, but are not useful in monitoring progression.

Nemni et al. (2004) reported the presence of high titer anti-GAD65 antibodies until age 24 months in 2 asymptomatic newborns of a woman with stiff-person syndrome. As the children were not breastfed, the antibodies were presumably acquired by passive transplacental transfer to the bloodstream of the infants. The authors suggested that the antibodies did not pass the blood-brain barrier in the infants, and thus were unable to attack the putative antigen, GABAergic neurons in the CNS. The children remained symptom-free at ages 6 and 8 years. Nemni et al. (2004) noted that up to 40% of patients with SPS do not have anti-GAD65 antibodies, and concluded that other cofactors are required for the development of the disorder.

Using transcranial magnetic stimulation, Koerner et al. (2004) demonstrated that untreated patients with SPS or PER had significantly enhanced motor cortex excitability compared to treated patients or controls. Motor cortex excitability was more enhanced in patients with anti-GAD antibodies and correlated with antibody levels in CSF. The findings supported a disturbance of intrinsic cortical GABAergic neurotransmission in SPS and PER.

In a neuropsychologic assessment of 10 patients with SPS, Ameli et al. (2005) concluded that fear, anxiety, and phobic symptoms were realistic and secondary to the symptoms of SPS rather than due to inherent primary phobic neuroses.

Economides and Horton (2005) reported a 38-year-old woman with SPS and anti-GAD65 antibodies who had eye movement abnormalities in addition to muscle stiffness and ataxia. Oculomotor findings included gaze-holding nystagmus, limited abduction, ocular misalignment, deficient smooth pursuit, and impaired saccadic initiation. There was no evidence of myasthenia gravis (MG; 254200). Economides and Horton (2005) suggested that the oculomotor abnormalities were a primary manifestation of SPS, perhaps related to GABA depletion.

Hutchinson et al. (2008) reported a 54-year-old man with clinical features of PERM associated with serum autoantibodies to the glycine receptor alpha-1 subunit (GLRA1; 138491). There was no evidence of malignancy. The clinical course was progressive, beginning with tingling sensation and spontaneous violent jerks of the limbs and trunk. He later developed ptosis, horizontal gaze palsies, facial weakness, spinal rigidity, and difficulty walking. Aggressive immunosuppressive therapy resulted in significant improvement. The authors noted that mutations in the GLRA1 gene result in hereditary hyperekplexia (149400), which is characterized by excessive startle response. Hutchinson et al. (2008) postulated that anti-GLRA1 antibodies may disrupt glycinergic inhibition in the brainstem and spinal cord.

Stiff-Person Syndrome as a Paraneoplastic Syndrome

Folli et al. (1993) reported 3 unrelated women with SPS and ductal breast cancer who had plasma and CSF autoantibodies to a 128-kD cytosolic protein concentrated at synapses in the central nervous system. None of the women had anti-GAD65 antibodies measured by different methods. Autoantibodies against the 128-kD protein were not detected in control patients with SPS without breast cancer or in patients with cancer who did not have SPS. Two of the patients presented clinically with SPS involving the proximal limb musculature and absence of truncal rigidity; symptoms resolved after cancer treatment in 1 patient, whereas the other patient showed deterioration with involvement of the trunk. The third patient had leg involvement and opisthotonos, with improvement after cancer treatment.

Wessig et al. (2003) reported a 71-year-old woman with invasive ductal carcinoma and a paraneoplastic stiff-person syndrome characterized by stiffness in the right arm, stiff and unsteady gait, and increased sweating. Autoantibodies to amphiphysin (600418), a 128-kD protein, were detected in the patient's serum and CSF, and the patient temporarily responded to plasmapheresis. Postmortem studies detected anti-amphiphysin antibodies in the CNS parenchyma, suggesting a pathogenic role.

Butler et al. (2000) identified high-titer autoantibodies directed against gephyrin (GPH; 603930) in a patient with mediastinal cancer and clinical features of stiff-man syndrome. Their findings provided evidence for a link between autoimmunity directed against components of inhibitory synapses and neurologic conditions characterized by chronic rigidity and spasms.

Murinson and Guarnaccia (2008) evaluated 11 patients with SPS and amphiphysin autoantibodies. All were women, 10 of 11 had breast cancer, and none had diabetes. The patients had a later age at onset and tended to have a higher frequency of cervical and arm involvement with a broader distribution pattern of stiffness compared to 112 SPS patients with anti-GAD antibodies. Four patients showed a favorable response to steroid treatment, and 3 of 5 showed marked improvement after tumor excision and chemotherapy. The findings suggested that amphiphysin antibody-associated SPS is distinct from GAD antibody-associated SPS.

Clinical Management

Amato et al. (1994) used intravenous immunoglobulin to treat 3 patients with sporadic stiff-man syndrome and detectable serum antibodies to GAD. All 3 patients showed subjective and objective improvement. Dalakas et al. (2001) did a control study of 16 patients who had stiff-person syndrome and anti-GAD65 antibodies. The patients received intravenous immunoglobulin, which was well tolerated and effective.

In a woman with stiff-person syndrome, Ruegg et al. (2004) reported successful treatment using levetiracetam, an antiepileptic drug that facilitates GABAergic transmission in the central nervous system. The treatment primarily resolved increasing and painful paroxysmal spasms and was effective during 2 years of follow-up.

Hattan et al. (2008) reported successful treatment of SPS with low doses of intravenous propofol in a 70-year-old female patient.

Pathogenesis

Using MR spectroscopy, Levy et al. (2005) found that 8 patients with SPS had decreased levels of GABA in the sensorimotor cortex compared to 16 controls. Two patients with severe SPS who were wheelchair-bound or bedridden had more significant reductions in GABA (32 and 52% less than controls) than the other patients. None of the patients had structural abnormalities on brain imaging. The findings were consistent with decreased GABAergic function resulting in impaired inhibitory neurotransmission.

Sommer et al. (2005) demonstrated that intraperitoneal injection of purified plasma anti-amphiphysin IgG antibodies from a patient with paraneoplastic SPS (Wessig et al., 2003) into female rats resulted in dose-dependent stiffness with spasms resembling human SPS. Analysis of the brain and spinal cord demonstrated that human IgG antibodies had crossed that blood-brain barrier in symptomatic animals. The findings showed that passive transfer of IgG antibodies were sufficient to cause the disorder in animals, suggesting that anti-amphiphysin antibodies are pathogenic in paraneoplastic SPS.

Animal Model

Gilbert et al. (2006) proposed that the 'hypertonic' mutant mouse (hyrt) is a model for stiff-man syndrome. They showed that the gene responsible for the hyrt phenotype is that encoding trafficking protein, kinesin-binding 1 (TRAK1; 608112). Hyrt mutant mice have much lower levels of GABA(A) receptors in the CNS, particularly the lower motor neurons, than do wildtype mice, indicating that the hypertonicity of the mutants is likely to be caused by deficits in GABA-mediated motor neuron inhibition.