April 27, 2022
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NORD gratefully acknowledges Scott D. Newsome, DO, FAAN, Associate Professor of Neurology, Director of Stiff Person Syndrome Center, Johns Hopkins School of Medicine, for assistance in the preparation of this report.
Stiff-person syndrome (SPS) is a rare acquired neurological disorder characterized by progressive muscle stiffness (rigidity) and repeated episodes of painful muscle spasms. Muscular rigidity often fluctuates (i.e., grows worse and then improves) and usually occurs along with the muscle spasms. Spasms may occur randomly or be triggered by a variety of different events including a sudden noise or light physical contact. In most cases, other neurological signs or symptoms do not occur. The severity and progression of SPS varies from one person to another. If left untreated, SPS can potentially progress to cause difficulty walking and significantly impact a person’s ability to perform routine, daily tasks. Although the exact cause of SPS is unknown, it is believed to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders.
Stiff-person syndrome has been described in the medical literature under many different, confusing names. Originally described as stiff-man syndrome, the name was changed to reflect that the disorder can affect individuals of any age and of either gender. In fact, most individuals with the condition are women. Stiff-person syndrome is considered by many researchers to be a spectrum of disease ranging from the involvement of just one area of the body to a widespread, rapidly progressive form that also includes involvement of the brain stem and spinal cord (PERM).
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 may remain stable for many years or slowly worsen. In some people, 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 legs (predominantly classic type). Early on, stiffness may come and go, but it gradually becomes fixed. The shoulders, neck, 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 upper spine (kyphosis) or an arched back due to inward curving of the lower spine (hyperlordosis). In some individuals, stiffness may progress to involve the arms or face.
In addition to muscular rigidity/stiffness, 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, cold environments, stress or situations that cause a heightened emotional response. 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) leading to 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 an assist device such as a cane, walker or wheelchair. Some affected individuals experience uncontrollable anxiety when they need to cross large, open 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, progressive encephalomyelitis with rigidity and myoclonus, and paraneoplastic-related SPS. These variants are sometimes collectively referred to as “stiff-person 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 variant SPS. When SPS affects only one specific area of the body, it may also be referred to as focal or partial 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. PERM is considered a distinct disorder from classic SPS and some feel that it is a distinct condition all together. There is no evidence that SPS will inevitably evolve into PERM.
Paraneoplastic-related stiff-person syndrome is a rare disorder that affects the nervous system in some individuals with cancer, especially individuals with cancer of the lungs or breast. The disorder is characterized by stiffness and rigidity, along with painful spasms. Symptoms usually begin in the muscles of the lower back and legs, although some individuals experience neck and upper torso symptoms first. The disorder may grow progressively worse eventually affecting the arms and other parts of the body. Painful muscle spasms can be worsened or triggered by a variety of events including anxiety, loud or unexpected noises or light physical contact. Paraneoplastic stiff-person syndrome is thought to be immune-mediated and is typically associated with a different auto-antibody (called anti-amphiphysin) than is found in individuals with classic stiff-person syndrome. This antibody is usually found in the blood and spinal fluid of affected individuals. (For more information on this disorder, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)
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 that is involved in the creation (synthesis) of the main inhibitory neurotransmitter called gamma-aminobutyric acid (GABA). GABA helps control muscle movement and prevent hyperexcitibility within the brain and spine. The symptoms of SPS may develop when the immune system mistakenly attacks certain nerve cells (neurons) that produce GAD leading to a deficiency of GABA 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 anti-GAD antibodies play in the development and progression of the disorder.
SPS is an extremely 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 which often requires a multifaceted approach including non-medication interventions (stretching, heat therapy, aqua therapy, massage therapy, acupuncture, etc). Drugs that are considered GABA-ergic agonists therapies such as benzodiazepines, specifically 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, pregabalin, and gabapentin.
Peer-reviewed clinical studies have shown that intravenous immunoglobulin (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 and can rarely cause kidney injury and meningitis. 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.
There are classes of medications that should be avoided in SPS, including serotonin-norepinephrine reuptake inhibitors (SNRIs; i.e, tricyclic antidepressants and duloxetine) and opioids. SNRIs have previously been shown to worsen the EMG activity and clinical symptoms in SPS. Opioids are not recommended for pain control because most individuals with SPS are on benzodiazepines. Mixing these two classes of medications can lead to severe respiratory depression and death.
Several different immune therapies have been used to treat individuals with SPS beyond IVIG including plasmapheresis, corticosteroids, rituximab, and oral immunosuppressive drugs. Other therapies are being evaluated including non-myeloablative and myeloablative stem cell therapies.
Plasmapheresis may be of benefit in individuals with SPS. This procedure is a method for removing unwanted substances (toxins, bad antibodies, 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 or albumin.
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.
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