Background
Clinically, stiff person syndrome (SPS) is characterized by muscle rigidity that waxes and wanes with concurrent spasms. [1, 2] Usually, it begins in the axial muscles and extends to the proximal limb muscles, but the severity of the limb muscle involvement may overwhelm the axial muscle involvement (stiff limb syndrome). [3, 4, 5, 6] 7 Some confusion has occurred as a result of cases that include other neurologic findings, such as encephalomyelitis, epilepsy, cerebral palsy, or cerebellar deficits, sometimes in addition to the classic clinical syndrome. [7, 8, 9, 10, 11, 12, 13]
Stiff person syndrome is clinically classified into three main subtypes:
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Classic stiff person syndrome (SPS):
Characterized by progressive muscle stiffness and spasms, primarily affecting the axial muscles (trunk and proximal limbs).
Symptoms worsen over time, leading to postural deformities such as hyperlordosis.
Often associated with glutamic acid decarboxylase (GAD) antibodies.
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Stiff limb syndrome (SLS):
A variant that predominantly affects one or both limbs (typically the legs), leading to severe stiffness, spasms, and impaired mobility.
Unlike classic SPS, the axial muscles are less involved.
May later progress to involve additional muscle groups.
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Progressive encephalomyelitis with rigidity and myoclonus (PERM):
Etiology
Three autoantibodies associated with stiff person syndrome have been identified. The idiopathic form is most often associated with glutamic acid decarboxylase (GAD) antibodies. The paraneoplastic form is most often associated with amphiphysin antibodies. One case report identified gephyrin antibodies associated with stiff person syndrome. [16]
Pathophysiology
In stiff person syndrome, spinal interneurons function to inhibit spontaneous discharges from spinal motor neurons, primarily through the action of glycine. However, this is only one inhibitory input for the motor pathway that includes GABA-mediated inhibition from the cortex, brain stem, and cerebellum. If glutamic acid decarboxylase (GAD) function is inhibited significantly, then GABA available for these functions is decreased and muscles become continuously stimulated by the motor neurons. Additional possible pathophysiologic etiologies in patients negative for GAD antibody include postsynaptic elements such as synaptophysin, amphiphysin, [17] gephyrin, [16] and GABA-transaminase.
Glutamate is an excitatory amino acid synthesized from glucose via the Krebs cycle. It has several fates within the cell. Glutamate can be packaged for release from synaptic clefts, and it can be acted on by several transaminases to transform it to either glutamine or GABA. Following release from the synapse, glutamate is absorbed either by reuptake mechanisms by the neurons or, more commonly, by astrocytes. GAD is nearly ubiquitous in the CNS and is located in or near the synaptic button. It is rate limited primarily by the availability of free glutamate. However, GAD is not the only source of GABA. The Krebs cycle also serves to synthesize GABA via GABA-transaminase.
However, GAD antibodies alone appear to be insufficient to cause stiff person syndrome, [1] and GAD antibodies are associated with a broad spectrum of disease; consequently, GAD clearly forms only part of the pathophysiology of stiff person syndrome. [18] Possibly, postsynaptic GABA-ergic mechanisms, such as the synaptobrevins involved in tetanus, are involved. Some patients clearly have GAD antibody-negative disease and may also be negative for anti-amphiphysin but otherwise fit the clinical picture.
Epidemiology
Prevalence
Stiff person syndrome is rare. Prevalence estimates range from one to two cases per 100,000 to one per million individuals. [19] Age of onset varies (30 to 60 years) and most frequently affects people in their 40s, with a higher incidence in females. [20, 19] Stiff person syndrome does not predominantly occur in any racial or ethnic group. [21]
Mortality/Morbidity
Complications of this disease are multifaceted and may occur at any stage of the disease. In general, complications are responsible for the mortality and morbidity and are discussed in more detail in Complications.
Infants with stiff baby syndrome are at particularly high risk of sudden infant death and require monitoring.
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Complications of baclofen pump failure can occur. Cataclysmic exacerbations of the disease have been reported due to baclofen pump failure. At least one death has been reported. In addition, rare malfunctions of the baclofen pump have been associated with excessive release of baclofen intrathecally also resulting in death or permanent disability.
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Psychiatric morbidity from this disease is common. The unpredictability of symptoms and the linkage to stressful events only serve to exacerbate the situation. In addition, GABA mechanisms subserve many of the brain's emotional centers, which may contribute significantly to the psychiatric symptomatology.
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Musculoskeletal complications are common, particularly in later stages of the disease. Joint deformity, joint dislocation, joint contracture, skeletal fracture, and muscle rupture have been reported.
Prognosis
Prognosis in stiff person syndrome is variable. Many patients have an indolent course that is primarily asymptomatic and is punctuated by occasional episodes of stiffness. Other patients may have a much more aggressive course, rapidly progressing to the late stages of disease.
Other forms of the disease have been described that are accompanied by cerebellar findings, encephalopathy, and other CNS abnormalities, but whether they are separate diseases or different manifestations of the same disease is unclear.
Prognosis for stiff baby syndrome is perhaps better. It is generally believed to be self-limiting and resolves with maturation of the CNS. Unfortunately, long-term follow-up studies are lacking.
