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NORD gratefully acknowledges Scott D. Newsome, DO, MSCS, FAAN, FANA, 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 that most often causes 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 can be triggered by a variety of different events or circumstances including a sudden noise, light physical contact or when exposed to cold. 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 thought to be an autoimmune disorder and sometimes occurs along with other autoimmune disorders (e.g., thyroid disease, diabetes, pernicious anemia [b12 deficiency], and vitiligo).
SPS 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, race, ethnicity and gender. Like other autoimmune disorders, the majority of individuals with the condition are females. SPS is considered by many clinicians and researchers to be a spectrum of diseases ranging from the involvement of just one area of the body to a widespread, rapidly progressive form that also includes involvement of the brain, brain stem and spinal cord.
The characteristic symptoms 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 to years and may remain stable for many years or slowly worsen. In some people, symptoms can be stabilized or improved through medication and non-medication interventions. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall treatment plan.
Affected individuals may initially experience aching discomfort, stiffness, or pain, especially in the lower back, hips, and/or legs (predominantly in the classic type). Early on, stiffness may come and go, but it can gradually become fixed. The shoulders, arms, and/or neck may also be affected and less commonly the face. As the disease progresses, stiffness of the leg muscles (and other body regions) develops and can be 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 an increasingly arched lower back due to inward curving of the lower spine (hyperlordosis).
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 body region. The legs are often involved, which may lead to falls. Spasms of abdominal muscles may lead to individuals feeling bloated and constricted around their torso. Spasms involving the chest and respiratory muscles can be serious, potentially requiring emergency medical treatment with ventilatory support. However, this is uncommon as most people who have respiratory symptoms with spasms just feel short of breath without respiratory compromise.
In general, muscle spasms last seconds to several minutes, but occasionally can 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 spasms.
In some people, SPS becomes severe enough to affect an individual’s ability to perform daily activities and routines. Some individuals may need to use a device such as a cane, walker or wheelchair. Some affected individuals experience intense 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 and result in secondary complications from immobility.
Expanding Clinical Spectrum of SPS
Several sets of characteristics (phenotypes) of SPS have been reported in the medical literature. This suggests that SPS represents a spectrum of diseases ranging from the involvement of one specific, localized body region to widespread involvement. These phenotypes include classic SPS, partial (or focal) SPS, SPS-plus, progressive encephalomyelitis with rigidity and myoclonus (PERM) and overlapping syndromes.
Classic SPS is characterized by muscle stiffness and painful spasms involving the torso and legs (more than arms). This phenotype is the most common type and often presents with asymmetrical limb involvement. The onset of symptoms is typically gradual and slow. Not all individuals will have an excessive curvature of the lower spine (hyperlordosis) and early on people with SPS may have normal exams.
Partial or focal SPS is characterized by the localized involvement of one limb, usually a leg (stiff limb syndrome) or the torso (stiff torso [trunk] syndrome). The stiffness and muscle spasms are similar to those found in classic SPS. Partial SPS may progress to classic SPS (affecting both legs and torso) leading to increased difficulty walking and subsequent falls.
SPS-plus is characterized by having classic SPS features (limb and back stiffness and spasms) plus brainstem and/or cerebellar involvement. Affected individuals can experience double vision, nystagmus, vertigo, incoordination (ataxia), speech issues (dysarthria) and/or swallowing problems (dysphagia) along with musculoskeletal symptoms. Onset of symptoms vary and often slowly worsen over time. Many individuals with SPS-plus will require help with walking and are at high risk of falling.
Progressive encephalomyelitis with rigidity and myoclonus (PERM) is characterized by stiffness and painful muscles that are similar to those seen in individuals with classic SPS. PERM is thought to have a more rapid onset of symptoms (days to several weeks) and progress quicker than other forms of SPS. However, some individuals will develop symptoms over months to years. 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), difficulty speaking (dysarthria) and confusion/seizures. In many patients, paralysis of certain eye movements (ophthalmoplegia), nystagmus, difficulty swallowing (dysphagia) and autonomic dysfunction (labile blood pressure and heart rate) occur. Myoclonus also occurs in individuals with PERM. 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. PERM is considered a distinct disorder from classic SPS and SPS-plus and some think it is a distinct condition all together. There is no evidence that other phenotypes of SPS will inevitably evolve into PERM.
There are overlapping syndromes that do not fit perfectly within the other phenotypes. Affected individuals can have a variety of features that are commonly seen in the previously described phenotypes along with other features including predominantly cerebellar symptoms, epilepsy, encephalitis, amongst others.
The exact cause of SPS is not known. Some studies in the medical literature indicate that it is likely an autoimmune disorder. Autoimmune disorders occur 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 with SPS 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 prevents hyperexcitability within the nervous system. 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. Nonetheless, the exact role that deficiency of GAD plays in the development of SPS is not fully understood.
Less commonly, individuals with SPS 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. Another less common antibody is the glycine receptor antibody. This antibody appears to have a very close association with PERM and may be directly pathogenic in this phenotype. Other antibodies have been noted within the medical literature, but it is unclear whether they are truly associated with SPS.
In some individuals with SPS, no antibodies are detectable. More research is necessary to determine the exact, underlying mechanisms that ultimately cause SPS and the exact role that anti-GAD-65 and other antibodies play in the development and progression of the disorder.
Rarely, affected individuals may have an underlying cancer that is associated with their SPS (paraneoplastic SPS). The most common cancers seen are breast and lung cancer. Less commonly associated cancers seen include lymphoma, thymoma, etc. The symptoms and signs of paraneoplastic SPS typically begin weeks to months, and sometimes years before the cancer is found. However, the majority if not all cancers associated with paraneoplastic SPS are found within the first 5 years from SPS symptom onset. (For more information on this disorder, choose “paraneoplastic neurologic syndromes” as your search term in the Rare Disease Database.)
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. However, this estimate likely does not account for the expanding clinical spectrum. The distribution of SPS between males and females 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 (>60 years old) as well. It appears that SPS can also affect any race and ethnicity.
A diagnosis of SPS is made based upon identification of characteristic symptoms, a detailed patient history, and a thorough clinical examination. Diagnostic tests are used to help support a clinical diagnosis and very importantly, to help rule out other conditions. Such tests include lab work (blood and spinal fluid) to detect the presence of antibodies against GAD-65, amphiphysin (which is most often associated with paraneoplastic SPS) and glycine receptor. Electromyography (EMG) can be helpful in individuals who have musculoskeletal involvement. This test records electrical activity in skeletal (voluntary) muscles at rest and during muscle contraction. An EMG can demonstrate continuous muscle activity in stiff muscles along with co-contraction of agonist and antagonist muscles. Muscle relaxers like diazepam will suppress the characteristic findings on EMG.
Magnetic resonance imaging (MRI) is useful to rule out the presence of other conditions including spinal stenosis, demyelinating disorders and neurosarcoidosis, amongst others. Body computerized tomography (CT) scan and breast imaging are typically used to evaluate for paraneoplastic SPS. Positron emission tomography (PET) with CT scan is sometimes used to also evaluate for cancer and systemic diseases.
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, balance training, behavioral therapy, etc.). Medications 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 and/or tizanidine, usually given in addition to benzodiazepines. Other medications reported to have benefit include methocarbamol, botulinum toxin and anti-seizure (anticonvulsant) medications (vigabatrin, pregabalin and gabapentin). There are additional symptomatic medications that can be found in the medical literature.
Peer-reviewed clinical studies have shown that the most commonly used first-line immune based treatment, intravenous immunoglobulin (IVIG), can be effective in treating symptoms and functions commonly associated with SPS. IVIG, under certain conditions, has been associated with increased risks for blood clots, kidney injury and meningitis. Most common side effects include infusion reactions and headaches. In individuals that are unable to tolerate IVIG, subcutaneous IG (SCIG) has been used. Treatment should be prescribed only after a thorough discussion of the possible 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 and/or alcohol can lead to severe CNS and respiratory depression followed by death.
Several different immune therapies have been used to treat individuals with SPS beyond IVIG including plasmapheresis, SCIG, rituximab, cyclophosphamide and oral immunosuppressive drugs. Corticosteroids have been used but are not preferred due to the increased incidence of diabetes in SPS. Other therapies are being evaluated including non-myeloablative and myeloablative stem cell therapies. There are clinical studies, case series and review articles that might be of interest to readers and can be found on PubMed and below.
Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.
For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:
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Some current clinical trials also are posted on the following page on the NORD website:
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For information about clinical trials conducted in Europe, contact:
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