Stiff Person Syndrome

What Causes Stiff Person Syndrome?

Scientists don’t know precisely what causes SPS, but they suspect it is an autoimmune disorder in which the body’s immune system mistakenly attacks healthy cells. In many cases, the autoimmune reaction seems to disrupt the production of a biochemical that helps control muscle movements.

SPS is sometimes associated with other conditions and disorders. Some of these associated conditions are autoimmune disorders, including:

• Diabetes
• Autoimmune thyroiditis
• Vitiligo
• Pernicious anemia

SPS is also sometimes associated with certain cancers, including:

• Breast cancer
• Lung cancer
• Thyroid cancer
• Colon cancer
• Hodgkin’s lymphoma

Is Stiff Person Syndrome Hereditary?

Scientists have not identified any genes or genetic mutations associated with SPS, and the disorder does not seem to have an inherited component.

How Is Stiff Person Syndrome Detected?

The symptoms, progression, and early signs of SPS vary widely from case to case. However, it commonly begins gradually, with symptoms that come and go before eventually becoming persistent.

Potential early signs of SPS include:

• Aches, pain, or stiffness in the lower back or legs
• Muscle stiffness that comes and goes
• Painful muscle spasms
• Stiffness that spreads to the legs, sometimes only on one side

How Is Stiff Person Syndrome Diagnosed?

Doctors may take several different diagnostic steps when suspecting a patient may have SPS. Part of the diagnostic procedure is usually ruling out other neurological conditions, such as multiple sclerosis and muscular dystrophy, that could be causing the symptoms.

Possible diagnostic steps include:

• Blood tests. Lab tests can spot the presence of specific antibodies that are present in the majority of SPS cases. The tests can also be used to rule out other conditions.
• Lumbar puncture (spinal tap). Examination of the cerebrospinal fluid may also detect the antibodies associated with SPS.
• Electromyography. This exam measures electrical activity in the muscles. It may be able to detect the abnormal, continuous activity characteristic of SPS.

How Is Stiff Person Syndrome Treated?

SPS has no cure. Treatment options aim to reduce the severity of symptoms and improve the patient’s quality of life. Because the disorder’s symptoms vary so much from person to person, the best course of treatment will vary from case to case.

Common SPS treatment options include:

• Benzodiazepine sedatives (diazepam and clonazepam) to control excessive msucle activity
• Baclofen, a muscle relaxant
• Anti-seizure drugs (vigabatrin, valproate, pregabalin, and gabapentin)
• Immune-suppressant therapies, including intravenous immunoglobulin (IVIG), plasmapheresis, rituximab, and autologous stem cell transplants
• Physical therapy
• Heat therapy
• Aqua therapy
• Massage
• Acupuncture

How Does Stiff Person Syndrome Progress?

SPS is progressive, so symptoms typically worsen over a period of months or years. In some people, symptoms eventually stabilize and cause relatively minor impairments. However, symptoms are more severe in other cases and can lead to significant impairments. Rarely, complications of the disorder can be life-threatening.

Possible long-term effects of SPS include:

• Difficulty walking or loss of the ability to walk
• Hunched posture caused by curvature of the spine
• Falls and injuries caused by muscle spasms of the legs
• Broken bones or dislocations caused by severe muscle contractions
• Weight loss
• Breathing difficulties (sometimes life-threatening) caused by muscle contractions in the chest
• Mental health-related issues

How Is Stiff Person Syndrome Prevented?

There is no known way to prevent SPS.

Stiff Person Syndrome Caregiver Tips

Some people with SPS also suffer from other brain and mental health-related issues, a condition called co-morbidity. Here are a few of the disorders that may be associated with SPS:

• Anxiety is common in people with SPS.
• Many people with SPS also have agoraphobia, a fear of public places and/or crowds.
• People with SPS are at increased risk of depression.

Stiff Person Syndrome Brain Science

Research has suggested that SPS is associated with problems related to a brain chemical called gamma-aminobutyric acid (GABA). GABA is a neurotransmitter, a chemical that allows nerve cells to communicate with each other and other types of cells.

GABA is the primary inhibitory neurotransmitter in the brain and other parts of the central nervous system. One of its jobs is to counter the action of glutamate, an excitatory neurotransmitter. Glutamate allows the transmission of electrical signals from one nerve cell to another, and GABA helps inhibit signals when their transmission is inappropriate. Glutamate and GABA work together to keep the central nervous system functioning correctly.

The majority of people with SPS have antibodies in their blood that are known to break down an enzyme called glutamic acid decarboxylase (GAD). GAD is one of the building blocks of GABA, and when these antibodies attack and destroy GAD, nerve cells cannot produce enough GABA. Typically, the action of GABA in nerve cells inhibits the transmission of unwanted signals from the brain to the muscles. When there isn’t enough GABA to do the job adequately, the unwanted signals are passed along. The result can be uncontrolled muscle contractions, spasms, and exaggerated responses to stimuli such as noises, touch, or stress.

Stiff Person Syndrome Research

Title: Autologous Peripheral Blood Stem Cell Transplant for Neurologic Autoimmune Diseases

Stage: Recruiting

Principal investigator: George Georges

Fred Hutch/University of Washington Cancer Consortium

Seattle, WA

This phase II trial studies the side effects and how well carmustine, etoposide, cytarabine, and melphalan together with antithymocyte globulin before a peripheral blood stem cell transplant works in treating patients with autoimmune neurologic disease that did not respond to previous therapy. In autoimmune neurological diseases, the patient’s immune system ‘attacks’ the nervous system, including the brain/spinal cord and/or the peripheral nerves. Giving high-dose chemotherapy, including carmustine, etoposide, cytarabine, melphalan, and antithymocyte globulin, before a peripheral blood stem cell transplant weakens the immune system and may help stop the immune system from ‘attacking’ a patient’s nervous system. When the patient’s (autologous) stem cells are infused into the patient, they help the bone marrow make red blood cells, white blood cells, and platelets so the blood counts can improve.

Title: Cause, Development, and Progression of Stiff-Person Syndrome

Stage: Completed

National Institute of Neurological Disorders and Stroke

Bethesda, MD

Stiff-person syndrome (SPS) is a progressive neurological disorder characterized by stiffness of the trunk or limb muscles and frequent muscle spasms induced by unexpected visual, auditory, or somatosensory stimuli. It is an incapacitating disorder that leads to recurrent falls and impaired ambulation. The cause of the disease is unknown, but an autoimmune pathogenesis is implicated based on its association with other autoimmune diseases and auto-antibodies, specific HLA haplotypes, and high titer antibodies against GAD, the rate-limiting enzyme for the synthesis of GABA. Understanding the autoimmune mechanisms of SPS is fundamental to refining the diagnostic criteria and developing specific therapies. The goals of this study are: a) define the natural history of SPS in a homogeneous cohort of patients, b) explore a pathogenetic link between SPS and viral infections based on the known peptide homology between GAD and certain viruses, and c) establish GAD-specific T-cell clones and search for candidate antigenic epitopes using synthetic peptide libraries. Collected clinical data will be used to delineate the rate of disease progression and the frequency of association with other autoimmune illnesses, auto-antibodies, or malignancies. It is anticipated that the knowledge acquired from the study will help us understand the mechanism of the disease and design antigen-specific therapeutic strategies. This is an investigative study intended to define the natural history and pathogenesis of SPS. No new therapy will be provided except for standard of care.

Title: Rituximab to Treat Stiff Person Syndrome

Stage: Completed

National Institute of Neurological Disorders and Stroke (NINDS)

Bethesda, MD

This study will examine the safety, tolerability, and efficacy of the humanized monoclonal antibody Rituximab to induce clinical and serological remission in patients with Stiff Person Syndrome (SPS) associated with high anti-GAD antibodies. Rituximab is a monoclonal antibody specific for the common B cell antigen CD20. Its administration depletes pre-B and mature B lymphocytes without altering neutrophils or hematopoietic stem cells. In humans with indolent B cell lymphomas, Rituximab can be safely administered, is well tolerated, promotes selective B cell depletion, and lowers the serum IgG and IgM levels. Preliminary experience in some non-malignant antibody-mediated disorders has shown that Rituximab was beneficial in improving the patients’ symptoms and reducing antibody levels.

SPS is an antibody-mediated autoimmune disease affecting GABA-ergic transmission resulting in incapacitating stiffness and spasms. The anti-GAD antibodies are also produced intrathecally; it is believed to be responsible for the reduction of GABA level in serum and CSF. Although removal or modulation of serum antibodies by plasmapheresis or IVIg results in clinical improvement, a number of patients do not respond, or their response is modest and short-lived, and remain with significant disability. The need for more effective therapy prompted us to conduct the present study to examine in a randomized trial if Rituximab is effective in patients with GAD-antibody-positive SPS.

Twenty-four patients will be randomized, in a double-blind fashion, to receive a placebo or Rituximab given at a fixed dose of 1 GM on Day 1and 1 GM on day 15 (plus or minus two days). The primary outcome will be based on measurements of stiffness using the Distribution of Stiffness Index. Secondary outcomes will be measured by the Heightened-Sensitivity Scales. The serum and CSF anti-GAD antibody titers, including intrathecal GAD-specific IgG synthesis, will be monitored before and after treatment. Clearance of GAD-reactive T cells will also be examined in the serum and CSF using T cell clones established from PBL and CSF. The study has these anticipated outcomes: a) provide a new, immune-based, and target-oriented therapy for patients with Stiff Person Syndrome and b) examine the pathogenetic role of anti-GAD antibodies in the cause of the disease.