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Stiff Person Syndrome

What Is It, Causes, Diagnosis, and More

Author: Lahav Constantini

Editors: Alyssa Haag, Ian Mannarino, MD, MBA, Kelsey LaFayette, DNP

Illustrator: Abbey Richard

Modified: 25 Apr 2024


What is stiff person syndrome?

Stiff person syndrome (SPS), also known as Moersch-Woltman syndrome, and formerly known as “stiff man syndrome,” is a rare, immune-mediated neurological movement disorder characterized by rigidity, stiffness, and sudden painful spasms, particularly in the axial and proximal appendicular muscles (e.g., spinal and abdominal, as well as muscles of the thigh and upper arm, respectively), leading to severely-impaired ambulation. It typically presents gradually and if left untreated, SPS can lead to severe disability

An infographic detailing the background, risk factors, symptoms, diagnosis, and treatments of stiff person syndrome; including lateral view of a person with stiffness at the arms, lower back, and legs.

How is stiff person syndrome classified?

Stiff person syndrome can be classified into different forms based on the clinical presentation: classic SPS; partial SPS variants (e.g., stiff limb syndrome, jerky SPS, SPS with epilepsy, cerebellar variant, and dystonia); and rarer forms, including progressive encephalomyelitis with rigidity and myoclonus (PERM) and paraneoplastic SPS

Classic SPS is the most common form of SPS, and it refers to general truncal and appendicular stiffness, frequent spasm episodes, and a stiff, wide-based gait. It may also coexist with autoimmune disorders. Partial SPS is the second most common and is characterized by similar symptoms affecting a single limb, which is usually the leg, thereby causing reduced mobility and pronounced difficulty walking. The other SPS forms are extremely rare, yet identification of paraneoplastic SPS is essential, as it may be recognized before the neoplasm is identified. This form occurs in the context of paraneoplastic syndrome, which is a complex set of clinical manifestations, resulting from the immune system’s response to an underlying malignancy. Paraneoplastic SPS is primarily related to breast cancer, but may also occur in cases of lung cancer, Hodgkin lymphoma, and other malignancies. 

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What causes stiff person syndrome?

The etiopathogenesis of SPS is thought to be autoimmune-related, due to the syndrome’s association with certain autoimmune diseases, such as type 1 diabetes mellitus, thyroiditis, pernicious anemia, myasthenia gravis, and vitiligo. Additionally, SPS is characterized by high titers of autoantibodies often found in affected individuals' blood. These are mainly antibodies against glutamic acid decarboxylase (GAD), a rate-limiting enzyme involved in the production of gamma-aminobutyric acid (GABA), the main inhibitory neurotransmitter in the brain. These antibodies affect the GABAergic pathways in the brain, ultimately causing a continuous motor unit firing, and thus may cause constant or repetitive muscle contraction. Anti-GAD autoantibodies are commonly identified, and confer an effective diagnostic marker, but have an uncertain role in the pathogenesis. In addition, the titer of anti-GAD antibodies does not always correlate with the disease activity, and some people with SPS have a negative antibody profile. Other antibodies that may be associated with low GABA levels in the brain and cerebrospinal fluid are associated with the postsynaptic gamma-aminobutyric acid type A (GABAA) receptor. 

In paraneoplastic SPS, antibodies against gephyrin or amphiphysin have been found in some cases. Amphiphysin is a presynaptic protein involved in endocytosis of GABA-containing vesicles. Antibodies against amphiphysin can lead to a reduced amount of GABA receptors, which reduces the presynaptic GABA vesicle pool, and consequently impairs the GABA transmission.  

Furthermore, inheritance of specific human leukocyte antigen (HLA) alleles (e.g., some DQB1 and DRB1 MHC-II alleles), which are associated with an increased risk of type 1 diabetes mellitus, also confer a genetic predisposition for idiopathic and paraneoplastic variants of SPS. Additionally, those assigned female at birth are twice to thrice more likely to be affected by stiff person syndrome, compared to those assigned male at birth.

What are the signs and symptoms of stiff person syndrome?

Signs and symptoms of stiff person syndrome are mainly related to involuntary muscle contractions, causing stiffness and rigidity, typically of the trunk and lumbar areas. The proximal limb muscles may also be affected. Over time, these symptoms may increase the risk of an exaggerated lumbar or cervical lordosis; a slow ambulation; a stiff, unsteady, and wide-based gait; and falls. Additionally, SPS is marked by sudden episodes of intense and painful spasms that are provoked by certain triggers, such as sudden movement, noise, or emotional upset. Sometimes, these spasms, which can be clearly visible and palpable, can also create enough force to cause bone fractures

Due to the extreme nature of the symptoms, people with stiff person syndrome often develop intense fear, anxiety, depression, panic attacks, avoidance behavior, and agoraphobia (i.e., avoidance of public places, related to fear or anxiety from being in settings from which a potential escape or readily help may not be available). These may further exacerbate or precipitate rigidity and spasms, leading to a vicious loop of clinical deterioration. Moreover, people with SPS may deal with chronic pain and severe limitations on activities of daily living. Accordingly, when SPS is left untreated, one’s clinical manifestations considerably worsen. 

More rarely, SPS is associated with certain eye deficits, such as acute bilateral ophthalmoplegia (i.e., sudden weakness or paralysis of eye muscles in both eyes), abduction deficits, vertical diplopia (i.e., a double vision where images seem to stack vertically), and esotropia (i.e., a form of strabismus where one's eye turns inward). When the muscles associated with swallowing and esophageal motility are affected, aspiration can occur. Another extremely rare manifestation is paroxysmal autonomic dysfunction which is characterized by transient hyperpyrexia, diaphoresis, tachypnea, tachycardia, pupillary dilatation, and arterial hypertension

How is stiff person syndrome diagnosed?

The most accepted criteria for the diagnosis of stiff person syndrome are based upon an evaluation of the person’s medical history, physical examination, blood tests, electromyography (EMG), the clinical response to therapy with benzodiazepines, and the absence of other neurological disorders that may explain the clinical manifestations. 

Additionally, blood tests can be conducted upon suspicion to assess for the presence of anti-GAD antibodies, which are positive in most cases of stiff person syndrome. Higher titers correlate to a higher likelihood of having SPS, yet anti-GAD antibodies are not necessary for the diagnosis, as they may also be negative in some individuals with SPS. If cerebrospinal fluid (CSF) is evaluated, anti-GAD antibodies or antibodies against GABAergic neurons may be positive.

Blood tests may also be utilized to rule out other conditions that present similarly, such as ankylosing spondylitis that presents with increased inflammatory markers like erythrocyte sedimentation rate (ESR) and c-reactive protein (CRP). Additionally, after a diagnosis of SPS, blood tests may be utilized to check for concomitant autoimmune disorders, such as autoimmune thyroid disease and type 1 diabetes mellitus. Therefore, the laboratory tests standardly performed include a complete blood count (CBC); chemistry profile, including liver and kidney function tests; thyroid function tests, including thyroid peroxidase antibodies; hemoglobin A1C (i.e., glycosylated hemoglobin); creatine kinase; ESR; and CRP. 

Electromyography testing may be performed and typically shows continuous firing of motor units simultaneously in both agonist and antagonist muscles at rest. Another possible assessment is the evaluation of the therapeutic response to diazepam, a long-acting benzodiazepine and the most commonly used medication for treating SPS. Typically, those with SPS will have a clinical response to oral diazepam, including a reduction in pain and stiffness; an improvement in physical function; or an elimination of the EMG motor unit activity upon administration of intravenous diazepam. 

Lastly, routine screening tests for cancer according to age, are also included in the post-diagnostic evaluation in order to identify the presence of cancer and paraneoplastic SPS. 

How is stiff person syndrome treated?

The management of stiff person syndrome mainly focuses on improving one’s function and mobility. Routine practice recommends therapy with benzodiazepines, which are muscle relaxants and anti-anxiety medications that work by enhancing the effects of GABA in the brain. Low-dose oral benzodiazepines, such as diazepam or clonazepam, which are slowly titrated up until reaching optimal stiffness control and mobility improvement, are usually given as a first-line treatment. The dosage is split to be given a few times a day for better symptom control and response to the therapy should be seen within several weeks. 

If there’s a lack of or unsatisfactory response to treatment, baclofen, which is a GABA-receptor agonist, is usually attempted next, either as monotherapy or in cautious combination with benzodiazepines, if there has been some response to the benzodiazepine. Lastly, for symptoms that are severe or resistant to the aforementioned treatment options, immune-modulating therapy, such as intravenous immunoglobulins (IVIG) therapy, plasma exchange, or rituximab (i.e., an anti-CD20 monoclonal antibody given to achieve B-cell depletion and reduction of the autoantibody levels), may be offered. These last medications appear to be effective due to the proposed underlying immune mechanisms, and the suppression of GABA and GABAergic neurons. 

Several other therapies (e.g., methocarbamol, botulinum toxin A, vigabatrin, sodium valproate, and propofol) have been attempted in isolated cases and small patient groups, but their effectiveness remains uncertain.

What are the most important facts to know about stiff person syndrome?

Stiff person syndrome is a rare neurological movement disorder characterized by sudden and painful proximal and axial muscle stiffness and spasms. These muscle contractions can lead to difficulty walking, increased risk of falls and fractures, and other consequences that impair the mental stability and quality of life of people with SPS. The etiopathogenesis of SPS is thought to be autoimmune-related, as individuals often have concomitant autoimmune disorders, such as type 1 diabetes mellitus. Individuals with stiff person syndrome typically also have high levels of autoantibodies, particularly anti-GAD autoantibodies, which affect GABA neurotransmitters and lead to uninhibited muscle contractions. SPS diagnosis is mainly based on the clinical manifestations, however, additional tests, such as blood tests, electromyography, and clinical analysis of the response to medical therapy can confirm diagnosis. Treatment is mainly symptomatic and based on pharmacological treatment with benzodiazepines, baclofen, or in more severe cases, IVIG therapy, plasma exchange, or rituximab.

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Related links

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Resources for research and reference

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Dalakas MC. Stiff person syndrome: Advances in pathogenesis and therapeutic interventions. Curr Treat Options Neurol. 2009;11(2):102-110. doi:10.1007/s11940-009-0013-9

Daroff RB, Jankovic J, Mazziotta JC, Scott Loren Pomeroy, Bradley WG. Bradley’s Neurology in Clinical Practice. Elsevier; 2016.

Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med. 1993;328(8):546-551. doi:10.1056/NEJM199302253280805

McKeon A, Robinson MT, McEvoy KM, et al. Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol. 2012;69(2):230-238. doi:10.1001/archneurol.2011.991

Mitsumoto H, Schwartzman MJ, Estes ML, et al. Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol. 1991;238(2):91-96. doi:10.1007/BF00315688

Stiff Person Syndrome. NORD (National Organization for Rare Disorders). https://rarediseases.org/rare-diseases/stiff-person-syndrome/](https://rarediseases.org/rare-diseases/stiff-person-syndrome/

Vasconcelos OM, Dalakas MC. Stiff-person syndrome. Curr Treat Options Neurol. 2003;5(1):79-90. doi:10.1007/s11940-003-0024-x