Stiff Person Syndrome 

  • Author: Nancy Theresa Rodgers-Neame, MD; Chief Editor: Nicholas Lorenzo, MD   more...
 
Updated: Aug 27, 2009
 

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]

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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,[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.

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Epidemiology

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.
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Contributor Information and Disclosures
Author

Nancy Theresa Rodgers-Neame, MD  Assistant Professor, Department of Molecular Pharmacology and Physiology, University of South Florida College of Medicine; Director, Florida Comprehensive Epilepsy and Seizure Disorders Program

Nancy Theresa Rodgers-Neame, MD is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society, American Medical Women's Association, Society for Neuroscience, and Southern Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

Paul E Barkhaus, MD  Professor, Department of Neurology, Medical College of Wisconsin; Director of Neuromuscular Diseases, Milwaukee Veterans Affairs Medical Center

Paul E Barkhaus, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and American Neurological Association

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD  Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment

Glenn Lopate, MD  Associate Professor, Department of Neurology, Division of Neuromuscular Diseases, Washington University School of Medicine; Director of Neurology Clinic, St Louis ConnectCare; Consulting Staff, Department of Neurology, Barnes-Jewish Hospital

Glenn Lopate, MD is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, and Phi Beta Kappa

Disclosure: Baxter Grant/research funds Other; Amgen Grant/research funds None

Selim R Benbadis, MD  Professor, Director of Comprehensive Epilepsy Program, Departments of Neurology and Neurosurgery, Tampa General Hospital, University of South Florida College of Medicine

Selim R Benbadis, MD is a member of the following medical societies: American Academy of Neurology, American Academy of Sleep Medicine, American Clinical Neurophysiology Society, American Epilepsy Society, and American Medical Association

Disclosure: UCB Pharma Honoraria Speaking, consulting; Lundbeck Honoraria Speaking, consulting; Cyberonics Honoraria Speaking, consulting; Glaxo Smith Kline Honoraria Speaking, consulting; Pfizer Honoraria Speaking, consulting; Sleepmed/DigiTrace Honoraria Speaking, consulting

Chief Editor

Nicholas Lorenzo, MD  Consulting Staff, Neurology Specialists and Consultants

Nicholas Lorenzo, MD is a member of the following medical societies: Alpha Omega Alpha, American Academy of Neurology, and American College of Physician Executives

Disclosure: Nothing to disclose.

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