History
Stiff person syndrome
Stiff person syndrome usually begins insidiously in the axial muscles, and, if the patient is referred at an early stage, little objective findings may be found at the initial presentation.
In the initial stage of the disease, the patient has an exaggerated upright posture and may report back discomfort or stiffness or pain in the entire back, which is worse with tension or stress. [31]
Patients may report disturbed sleep because, although the stiffness is relieved with sleep, when the patient transitions from rapid eye movement (REM) to stage 1 or 2 sleep they may lose the relief from the spasms, which may awaken them.
In some patients in the early stages, brief episodes of rather dramatic severe worsening that resolve spontaneously within hours or days may occur. Unfortunately, because of the subtle findings and apparent strong psychological components in the early stages, the patients are labeled as psychogenic, and effective treatment is often delayed.
Later in the disease, proximal limb muscles also begin to be involved, particularly when the patient is stimulated, surprised, angered, upset, or frightened. This sort of stimulus may evoke painful severe spasms in the proximal arm and leg muscles that resolve slowly. The patient begins to move very slowly because rapid movement induces severe spasms. Even the distal extremities may become involved when moved rapidly. Exaggerated lumbar lordosis is present combined with contraction of abdominal muscles. [32]
Not surprisingly, depression has been noted as a comorbidity during the late stage of the disease. The patient's quality of life is affected severely at this point, making it difficult or impossible to drive, work, or have a satisfying social life. About 65 percent of SPS patients are unable to function independently. [29]
In the end stages of the disease, few muscles in the body are spared. Trismus is absent. However, facial and pharyngeal muscles may be affected markedly. Joint deformities may occur. Skeletal fractures and muscle ruptures may occur during spasms. Postsurgically, abdominal incisions are at risk of spontaneous rupture. Eating, simple movement, and other simple activities of daily living (ADLs) may be problematic.
Stiff baby syndrome
The clinical presentation of stiff baby syndrome is somewhat different. Babies and young children are less rigid between attacks. Involvement of the distal muscles is often more evident, particularly during paroxysms. Opisthotonic posturing is more prominent. Startle or stress is a frequent and prominent precipitant of the attacks.
Its clinical characteristics are within a broader descriptive category known as hyperekplexia. Differentiation of a particular case as stiff baby syndrome sometimes is considered dependent upon the presence of anti-GAD antibodies. In addition, stiff baby syndrome may be more persistent or more frequently recurrent, although this is not invariable.
Diagnosis can also be more complex because other etiologies (eg, other neuromuscular disorders, seizures, withdrawal or intoxication from maternal drug abuse) need to be excluded.
Associated diseases
Diabetes mellitus: Although different epitopes for the GAD antibodies in diabetes have been identified, stiff person syndrome and diabetes have demonstrated comorbidity. This comorbidity occurs in association with a finding of positive GAD antibodies. Early distal involvement and involvement of a single limb is more frequent in patients with diabetes mellitus. Stiff person syndrome has also been associated with diabetes mellitus and ICA 105 pancreatic autoantigen with and without the presence of anti-GAD antibodies. About 35 percent of SPS patients have type 1 diabetes. [33]
Thyroiditis: An association with thyroiditis has been described. This may be due to comorbidity of multiple autoimmune entities or may be a more direct association. At least one group has suggested a link due to neuromuscular hyperactivity.
Breast cancer: A variant of stiff person syndrome occurs rarely in patients with breast cancer. The antibodies involved are to a synaptic protein, amphiphysin. Anti-GAD antibodies are absent.
Epilepsy: Anti-GAD antibodies have been described in patients with medication-resistant focal epilepsies. In one series, 4 of 19 patients with anti-GAD–positive stiff person syndrome were also found to have localization-related epilepsy.
Cerebellar ataxia: A number of case studies report the presence of cerebellar ataxia (with or without stiff person syndrome) associated with anti-GAD antibodies.
A form of familial spastic cerebral palsy has been described with a missense mutation in the GAD-67 gene. This is a different isoform of glutamic decarboxylase; however, it demonstrates that the pathophysiology of stiff person syndrome is likely due to abnormalities in the function of glutamic acid decarboxylase.
Physical
In general, increased muscle tension, which may be more marked proximally than distally, is present. Frequently, lower extremities are most severely affected. Rarely, upper and lower extremities are affected. One limb may be affected, sparing other muscle groups. In most if not all patients, opposing muscle groups are noted to be tense, and tonic contraction with long relaxation times (myotonia) may be noted following percussion of the muscle. In most patients, the neurologic examination findings are otherwise normal. Anxiety is common.
Variations and stages are as follows:
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Early in the disease, patients may report stiffness of the back and sometimes the neck; very little objective findings are revealed. Patients may walk and sit with an exaggerated upright posture (classic "tin-soldier" appearance).
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Later in the disease, response to stimuli becomes marked. Startle may lead to very uncomfortable and prolonged spasms. The symptoms worsen significantly with stress or anxiety, and the worsening of symptoms causes anxiety, often causing a disturbing self-perpetuating cycle.
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Late stages and acute exacerbations of the disease are accompanied by crippling involvement of the extremities. Skeletal fractures and muscular rupture have been observed in late stages of disease
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One variation of the disease known as stiff limb syndrome is observed more frequently in patients with diabetes mellitus. In this variation, the axial involvement is less marked, and one or (rarely) more extremities are affected.
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In stiff baby syndrome, distal findings may be more pronounced than in adults. Smaller babies may have increased tonic extension of the leg at the hip. Younger patients frequently have a more pronounced response to startle than adults, and hyperekplexia must be considered in the differential.
Causes
Three autoantibodies associated with stiff person syndrome have been identified. The idiopathic form is most often associated with glutamic acid decarboxylase antibodies. The paraneoplastic form is most often associated with amphiphysin antibodies. One case report identifies gephyrin antibodies associated with stiff person syndrome. [25]
Complications
The earliest and most common complications of stiff person syndrome are anxiety and depression. Unfortunately, the nature of the disease and the reaction of physicians and family to the problems may act in concert to produce this comorbidity.
The function of GAD is to convert glutamate to GABA. Although this is not the only source of GABA for the CNS, it is a significant source; depending on the situation, GABA can be depleted rapidly. GABA serves as a natural antianxiety compound. The most potent antianxiety medications are based on augmentation of the GABA-A receptor. Because a significant portion of patients with stiff person syndrome have antibodies to GAD, not surprisingly patients also have anxiety. Tragically, anxiety worsens the spasms.
In the early stages, signs of the disease are often subtle to physicians and other health care workers. The patient feels uncomfortable and is aware of the stiffness, but his or her daily life is not disrupted significantly. Unfortunately, the failure of physicians and family to respond to the problem may result in increased anxiety and lead to dysphoria on the part of the patient. Ironically, the anxiety and dysphoria may become more disruptive to the patient's quality of life than the disease, and the patient may be diagnosed with a somatization disorder.
In the late stages of the disease, patients may experience spasm of the pharyngeal muscles, making swallowing difficult and necessitating alternative methods of feeding. Severe paroxysms of spasms may result in skeletal fractures, particularly of the vertebral elements. They also have been reported in long bones. Muscle rupture has been reported in severe cases during spasms.
