Practice Essentials
Stiff person syndrome is a rare disease characterized by muscle rigidity that waxes and wanes with concurrent spasms. [3, 4] 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). [5, 6, 7, 8, 9, 4]
Signs and symptoms
Stiff person syndrome usually begins insidiously in the axial muscles. 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] Later in the disease, proximal limb muscles also begin to be involved, particularly when the patient is stimulated, surprised, angered, upset, or frightened. In the end stages of the disease, few muscles in the body are spared.
Diagnosis
Electromyography (EMG) can be used to show characteristic continuous motor unit activity with normal morphology, which is especially prominent in the paraspinal muscles. Myotonic potentials are absent. Activity resolves with sleep and abates with benzodiazepines (diazepam). Simultaneous continuous motor activity is noted in opposing muscles.
Management
Initial medical treatment may involve either baclofen or a benzodiazepine, such as diazepam. [3] The oral dosage of baclofen is 10-30 mg every 8 hours, while the intrathecal dosage is in the range of micrograms per day. Small dosages of diazepam can be used (2 mg q8h) in milder cases, but resistant severe cases can require very large doses (ie, 15-20 mg q8h; do not administer initially to benzodiazepine-naïve patients).
Some patients may be candidates for intrathecal baclofen therapy for long-term treatment. Because symptoms may be variable, an externally programmable pump may be the best option.
Background
Stiff person syndrome is rather unique among neurologic diagnoses because of its lack of significant similarity to any other neurologic diseases. Although rare, once observed it is quite unforgettable. Possibly the closest related disease is tetanus because both conditions affect peripheral inhibition via central mechanisms and both conditions inhibit central gamma-aminobutyric acid (GABA) systems. [1]
In 1956, Moersch and Woltmann, who also coined the term stiff man syndrome, first clearly described stiff person syndrome as a neurologic clinical entity at the Mayo Clinic. [2] The eponym for this syndrome, Moersch-Woltmann syndrome, is one of the few instances in which the eponym may be the most inclusive and at the same time the most appropriately limiting name for the disease. [2] The term stiff person may be seen to exclude infants, and stiff man is inappropriate for children and women; perhaps stiff individual most perfectly describes the affected patient.
Clinically, stiff person syndrome is characterized by muscle rigidity that waxes and wanes with concurrent spasms. [3, 4] 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). [5, 6, 7, 8, 9, 4] 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. [10, 11, 12, 13, 14, 15, 16]
The pathophysiology of the disease is autoimmune. [17, 18, 19, 20, 21, 9, 3, 22] The most common pathologic correlate, anti–glutamic acid decarboxylase (GAD) antibodies, has been associated with a wide range of neurologic diseases. It is also associated with a number of non-neurologic diseases, including diabetes mellitus and thyroiditis. [23]
Pathophysiology
Endocrinologists were excited by a discovery in the 1980s of an antibody to a 65-kd protein that was strongly associated with adult-onset diabetes mellitus and stiff person syndrome. It is found in a particularly large subset of patients with diabetes, and endocrinologists hoped that it would be the major breakthrough needed to cure this disease in millions of patients worldwide. They were disappointed to find that the 65-kd protein was GAD, an enzyme largely found in the central nervous system (CNS), and, unfortunately, the pathophysiologic link between diabetes and glutamic acid decarboxylase remains unclear.
Since that time, the antibody has been found in patients with a number of neurologic diseases, a scenario that is easier to understand because the pathophysiologic link to neurologic disease is easier to explain. The range of diseases encountered includes seizures, cerebellar dysfunction, cortical dysfunction, and myelopathy, but the association between function of the enzyme and the consequence of the disease is most clear in patients with stiff person syndrome.
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 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, [24] gephyrin, [25] 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, [3] and GAD antibodies are associated with a broad spectrum of disease; consequently, GAD clearly forms only part of the pathophysiology of stiff person syndrome. [26] Possibly, postsynaptic GABA-ergic mechanisms, such as the synaptobrevins involved in tetanus, are involved. Research continues to progress on this interesting subject. [5, 17, 21, 27, 7, 28] Some patients clearly have GAD antibody-negative disease and may also be negative for anti-amphiphysin but otherwise fit the clinical picture.
Epidemiology
Frequency
Stiff person syndrome is rare. Between 2000 and 2005, only 119 cases were identified in the United Kingdom. [29] Age of onset varies (30 to 60 years) and most frequently affects people in their 40s. [29] Stiff person syndrome does not predominantly occur in any racial or ethnic group. [30]
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.
