eMedicine Specialties > Neurology > Neuromuscular Diseases

Stiff Person Syndrome

Author: Nancy Theresa Rodgers-Neame, MD, Assistant Professor, Department of Molecular Pharmacology and Physiology, University of South Florida; Director, Florida Comprehensive Epilepsy and Seizure Disorders Program
Contributor Information and Disclosures

Updated: Aug 27, 2009

Introduction

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.¹ 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.¹ 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.^2,3 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).^4,5,6,7,8,3 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.^{9,10,11,12,13,14,15}

The pathophysiology of the disease is autoimmune.^{16,17,18,19,20,8,2} 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.²¹

Pathophysiology

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,²² gephyrin,²³ 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,² and GAD antibodies are associated with a broad spectrum of disease; consequently, GAD clearly forms only part of the pathophysiology of stiff person syndrome.²⁴ Possibly, postsynaptic GABA-ergic mechanisms, such as the synaptobrevins involved in tetanus, are involved. Research continues to progress on this interesting subject.^{4,16,20,25,6,26} Some patients clearly have GAD antibody-negative disease and may also be negative for anti-amphiphysin but otherwise fit the clinical picture.

Frequency

International

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 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.

• 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.

Clinical

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.
• 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.
  • 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:

• 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.²³

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