NORD gratefully acknowledges Beth B. Murinson, MD, PhD, Associate Professor of Neurology, Director of Pain Education, Johns Hopkins School of Medicine, for assistance in the preparation of this report.
The characteristic findings associated with SPS are progressive, fluctuating muscular rigidity that occurs along with muscle spasms. The severity and progression of SPS can vary from one person to another. The symptoms usually develop over a period of months and then remain stable for many years or slowly worsen. In some cases, symptoms can be stabilized through medication. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
In many cases, SPS begins slowly over several months or a few years. Affected individuals may initially experience aching discomfort, stiffness, or pain, especially in the lower back or neck. Early on, stiffness may come and go, but it gradually becomes fixed. The shoulders and hips may also be affected. As the disease progresses, stiffness of the leg muscles develops, and is often more pronounced on one side than the other (asymmetrical). This leads to a slow, stiff manner of walking. As stiffness increases, affected individuals may develop a hunched or slouched posture due to outward curving of the spine (kyphosis) or an arched back due to inward curving of the spine (lordosis). In some individuals, stiffness may progress to involve the arms or face.
In addition to muscular rigidity, individuals with SPS also develop muscle spasms, which may occur for no apparent reason (spontaneously) or in response to various triggering events (i.e., stimuli). Spasms can be triggered by unexpected or loud noises, minor physical contact, stress or situations that cause a heightened emotional response such anxiety- or fear-producing situations. Muscle spasms are often very painful and usually worsen existing stiffness. The spasms may involve the entire body or only a specific region. The legs are often involved, which may lead to falls. Spasms of abdominal muscles may lead to individuals feeling full faster than normal (early satiety) and unintended weight loss. Spasms involving the chest and respiratory muscles can be serious, potentially requiring emergency medical treatment with ventilatory support. Spasms may last several minutes, but occasionally last for hours. Sudden withdrawal of medication in individuals with SPS may result in a life-threatening situation with overwhelmingly severe muscle spasms. Sleep usually suppresses the frequency of contractions.
In some cases, SPS becomes severe enough to affect an individual’s ability to perform daily activities and routines. Some individuals may need to use a walker or wheelchair. Some affected individuals experience uncontrollable anxiety when they need to cross large areas unassisted (agoraphobia) and become reluctant to go outside. If left untreated, SPS can potentially progress to cause significant disability or life-threatening complications such as respiratory compromise.
SPS may be associated with other autoimmune disorders more frequently than would be regularly expected to occur in the general population. The most common associated condition is diabetes. Less commonly, affected individuals may also develop inflammation of the thyroid (thyroiditis), pernicious anemia and vitiligo. Pernicious anemia is characterized by low levels of red bloods cells due to the body’s inability to absorb vitamin B12 from the gastrointestinal tract. Vitiligo is a skin condition in which loss of color (pigmentation) of areas of skin results in the development of abnormal white patches. Clinical reports indicate that individuals with SPS also have an increased incidence of epilepsy.
Several variants of SPS have been reported in the medical literature suggesting that SPS represents a spectrum of disease ranging from the involvement of one specific, localized area to widespread involvement. These variants include stiff-limb syndrome, jerking stiff-person syndrome, and progressive encephalomyelitis with rigidity and myoclonus. These variants are sometimes collectively referred to as “stiff-man plus syndromes”.
Stiff-limb syndrome is characterized by the localized involvement of one limb, usually a leg. The stiffness and muscle spasms are extremely similar to those found in classic stiff-person syndrome. Stiff-limb syndrome may progress to eventually affect both legs and may cause difficulty walking. Some individuals may eventually develop classic stiff-person syndrome or progressive encephalomyelitis with rigidity and myoclonus. When SPS affects only one specific area of the body, it may be referred to as focal stiff-person syndrome.
Jerking stiff-person syndrome is characterized by muscles stiffness and spasms usually affecting the legs. Affected individuals also develop involvement of the brainstem, which can cause myoclonus. Myoclonus is a general term used to describe the sudden, involuntary jerking of a muscle or group of muscles caused by muscle contractions (positive myoclonus) or muscle relaxation (negative myoclonus). The twitching or jerking of muscles cannot be controlled by the person experiencing it. Only a handful of cases of jerking stiff-person syndrome have been described in the medical literature.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is characterized by stiffness and painful muscles that are similar to those seen in individuals with classic stiff-person syndrome. PERM is more rapidly progressive than other forms of SPS; onset of symptoms usually occurs over several weeks. Stiffness and spasms may occur along with, before or after the development of other symptoms including vertigo, a lack of coordination of voluntary muscles (ataxia), and difficulty speaking (dysarthria). In some cases, the cranial nerves may also become involved causing paralysis of certain eye muscles (ophthalmoplegia), rapid, involuntary eye movements (nystagmus), difficulty swallowing (dysphagia), and hearing loss. It is considered likely that PERM is a distinct disorder from classic SPS. There is no evidence that SPS will inevitably evolve into PERM.
The exact cause of SPS is not known. Some studies in the medical literature indicate that it may be an autoimmune disorder. Autoimmune disorders are caused when the body’s natural defenses (e.g., antibodies) against “foreign” or invading organisms begin to attack healthy tissue for unknown reasons.
Most of those affected have antibodies to glutamic acid decarboxylase (GAD), a protein in inhibitory nerve cells involved in the creation (synthesis) of a substance called gamma-aminobutyric acid (GABA) that helps to control muscle movement. The symptoms of SPS may develop when the immune system mistakenly attacks certain nerve cells (neurons) that produce GAD leading to a deficiency of GAD in the body.
Less commonly, individuals with SPS will have antibodies to amphiphysin, a protein involved in the transmission of signals from one nerve cell to another. In these individuals, breast cancer is quite prevalent.
The exact role that deficiency of GAD plays in the development of SPS is not fully understood. Antibodies to GAD-65 are associated with several other disorders including diabetes. In fact, GAD-65 is the most common antibody produced by people with autoimmune diabetes and many people have these antibodies in that context. In some individuals with SPS no antibodies to GAD are detectable. The cause of SPS in these individuals may ultimately be unknown (idiopathic), but testing for other causes (e.g. amphiphysin antibodies) is usually appropriate. More research is necessary to determine the exact, underlying mechanisms that ultimately cause SPS and the exact role that GAD antibodies play in the development of the disorder.
SPS is a rare disorder. The exact incidence and prevalence of SPS is unknown, although one estimate places the incidence at approximately 1 in 1,000,000 individuals in the general population. The distribution of SPS between men and women indicates a female predominance. SPS usually becomes apparent sometime between 30-60 years of age. However, SPS has been reported to occur in children and older adults as well.
SPS was first described in the medical literature by doctors Moersch and Woltman in 1956 as stiff-man syndrome. The disorder is now known as stiff-person syndrome to reflect that the disorder affects individuals of any age and both genders.
A diagnosis of SPS is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical evaluation. Additional tests can be used to support a diagnosis and to rule out other conditions. Such tests include screening tests to detect the presence of antibodies against GAD-65, antibodies against amphiphysin (which are associated with paraneoplastic SPS) and an electromyography (EMG), a test that records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate continuous muscle motor unit firing in stiff muscles, which is characteristic of SPS. High doses of diazepam will suppress the characteristic EMG results.
The treatment of SPS is directed toward the specific symptoms that are apparent in each individual. Drugs known as benzodiazepines, such as diazepam and clonazepam, are used to treat muscle stiffness and episodic spasms. Affected individuals may also benefit from baclofen, usually given in addition to benzodiazepines. Other medications reported to have benefit in a small number of individuals include anti-seizure (anticonvulsant) drugs including vigabatrin, valproate, and gabapentin.
Peer-reviewed clinical studies have shown that IVIG is effective and well-tolerated in improving the symptoms commonly associated with SPS. IVIG is commonly used as a therapy for immune-mediated disorders as SPS is believed to be. IVIG, under certain conditions, has been associated with increased risks for stroke and heart attacks, treatment should be prescribed only after a discussion of the attendant risks and benefits. More research is necessary to determine the long-term safety and effectiveness of IVIG for the treatment of individuals with SPS.
Several different therapies have been used to treat individuals with SPS including intravenous a monoclonal antibody called rituximab, plasmapheresis, corticosteroids, and other oral immunosuppressive drugs.
Plasmapheresis may be of benefit in individuals with SPS. This procedure is a method for removing unwanted substances (toxins, metabolic substances, plasma parts) from the blood. Blood is removed from an affected individual and blood cells are separated from plasma. The plasma is then replaced with other human plasma and the blood is re-transfused into the affected individual. This therapy remains under investigation to analyze side effects and effectiveness. More research is needed to determine what role plasmapheresis may play in the treatment of individuals with SPS.
Researchers are studying the monoclonal antibody, rituximab, for the treatment of individuals with SPS. Monoclonal antibodies are antibodies that are artificially created in a laboratory. Rituximab is an immunotherapy, which is a therapy that enhances the body’s immune system to help fight disease. Initial reports in the medical literature detail that in some individuals symptoms have improved while on rituximab. More research is necessary to determine the long-term safety and effectiveness of rituximab for the treatment of SPS.
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FROM THE INTERNET
Rodgers-Neame NT. Stiff Person Syndrome. Emedicine Journal, Aug 27, 2009. Available at: http://emedicine.medscape.com/article/1172135-overview Accessed on: March 10, 2010.
National Institute of Neurological Disorders and Stroke. Stiff-Person Syndrome Information Page. Oct. 6, 2009. Available at: http://www.ninds.nih.gov/disorders/stiffperson/stiffperson.htm Accessed On: March 10, 2010.
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