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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.

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. 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 most appropriately limiting name for the disease. Stiff person seems to exclude babies, 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. 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).

Some confusion has also ensued as a result of cases that include other neurologic findings, such as encephalomyelitis or cerebellar deficits, in addition to the classic clinical syndrome. To further confuse matters, the most common pathologic correlate, anti–glutamic acid decarboxylase (GAD) antibodies, have been associated with a wide range of human disease, including diabetes mellitus and seizures.

 

Frequency:

Internationally: The frequency of stiff person syndrome worldwide and in the United States is unknown, but the syndrome is rare.

Mortality/Morbidity: Complications of this disease are multifaceted and may occur at any stage of the disease. In general, complications areresponsible for the mortality and morbidity and are discussed in more detail in Complications.

Babies with stiff baby syndrome are at particularly high risk of sudden infant death and require monitoring.

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.

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.

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.

Race: No differentiation among races has been reported to date.

Sex: Frequency and severity are nearly equal in males and females, but some series indicate a greater frequency in females. In general, autoimmune diseases are more frequently seen in females.

Age:

The syndrome occurs in children younger than 3 years, most commonly in infants.

Onset in adults is most frequent in the third to fifth decades of life

History:

Stiff person syndrome

Early stages

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.

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 stages

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.

Not surprisingly, depression has been noted as a comorbidity at this stage. 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.

End stages

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.

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.

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 is more marked proximally than distally, is present. Less frequently, lower extremities are most affected. More rarely, upper and lower extremities are affected. In people with diabetes, 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 may be noted following percussion of the muscle. In most patients, the neurologic examination findings are otherwise normal. Variations and stages are noted below.

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).

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.

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

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.

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: See Pathophysiology.

Currently, 3 autoantibodies associated with stiff person syndrome are 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.

 

Complications:

Early stages

The earliest and most common complication of the disease is 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.

Late stages

Difficulty swallowing: Patients may have spasm of the pharyngeal muscles, making swallowing difficult and necessitating alternative methods of feeding.

Skeletal fractures: Severe paroxysms of spasms may result in skeletal fractures, particularly of the vertebral elements. They also have been reported in long bones.

Muscle rupture: Muscle rupture has been reported in severe cases during spasms.

Prognosis:

Prognosis 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.

Patient Education:

For excellent patient education resources, visit eMedicine’s Infections Center. Also, see eMedicine’s patient education article Tetanus.

Medical/Legal Pitfalls:

The major medicolegal pitfalls involving stiff person syndrome are misdiagnosis and delay in diagnosis, which can result in inappropriate medication adverse effects and/or prolonged morbidity.

However, remember that stiff person syndrome is a rare condition and that patients commonly are not diagnosed with this syndrome until they have been evaluated by one or more neuromuscular specialists.

Because of the nature of the disease, the risk for falling (resulting in possible injury) in patients with stiff person syndrome is increased compared to healthy individuals. The proper precautions at home (especially while ambulatory) should be taken. Consultation with a physical medicine specialist may be appropriate.

The condition is most commonly misdiagnosed as conversion disorder, particularly because stiff person syndrome is often accompanied by increasing anxiety. This anxiety state may be physiologic and due to disruption of the mechanism for synthesis of GABA from glutamate, or it may be due to prolonged inadequate therapy.

Careful assessment by a physician or physical therapist is necessary to determine the patient’s level of motor skills (eg, driving, ADLs, occupational) to ensure they are not a danger to themselves or others.

Because presentation frequently does not follow a classic pattern or because it may be associated with other disorders, a high degree of alertness for the unusual patient reporting stiffness increases the likelihood of early diagnosis.

Baclofen pump failure has been described. Although rare, failure to deliver medication can result in catastrophic exacerbation of disease. Another rare complication is sudden delivery of high doses of baclofen intrathecally resulting in respiratory failure. Either complication can lead to significant morbidity or death.

Special Concerns:

Many of the medications for treatment are relatively contraindicated during pregnancy, which may complicate pregnancy significantly. As in other autoimmune diseases, pregnancy can either exacerbate or temporarily relieve symptoms.

Elderly patients may be at increased risk for falls because of concurrent debility from other causes. They may also demonstrate increased CNS sensitivity to benzodiazepines.

Other useful information can be found on the following sites:

NINDS, Stiff-Person Syndrome Information Page

Medical College of Wisconsin, Stiff-Person Syndrome

Participation in a National Institutes of Health (NIH) study is also a possible option for patients with anti-GAD antibodies. Two research studies are currently being conducted through the NIH. A research study on the monoclonal antibody Rituximab, a drug approved to treat lymphomas, targets certain white blood cells that produce antibodies. The purpose of the study is to investigate whether rituximab can also be effective in patients with stiff person syndrome who have high anti-GAD antibodies. The second study is an observational study but also includes evaluation and treatment at the NIH. Physicians who wish to refer patients can contact the NIH public liaison office at prpl@mail.cc.nih.gov.