Stiff person syndrome: how to recognize this ultra-rare disease

Stiff Person Syndrome (SPS) is an extremely rare disease.

A condition is defined as rare when its prevalence does not exceed 5 cases per 10,000 people. With an estimated prevalence of about 1 case per million individuals, SPS falls into the category of ultra-rare diseases. It mainly affects women (with a ratio of about 3:1) and typically develops between the ages of 20 and 50.

From an etiological perspective, Stiff Person Syndrome is an autoimmune disease, meaning that the immune system, whose normal function is to protect the body from pathogens such as harmful viruses and bacteria, mistakenly attacks the body’s own tissues. Only a small percentage of cases are paraneoplastic, meaning they are associated with the presence of a tumor.

Biologically, SPS is characterized by the production of antibodies against the enzyme GAD (glutamic acid decarboxylase), a key protein involved in the production of GABA, a neurotransmitter responsible for inhibiting nervous system activity and regulating muscle contraction.

When anti-GAD antibodies reduce GABA levels, the nervous system loses part of its ability to control muscle activity. As a result, muscles tend to contract excessively and have difficulty relaxing, causing stiffness and spasms.

“The result of this biological mechanism is a marked muscle hyperexcitability: muscles become excessively reactive and may contract rigidly or involuntarily,” explains Dr. Falzone.

“In its classic form, Stiff Person Syndrome presents with muscle stiffness, mainly affecting:

• the axial muscles, meaning the muscles of the trunk that support and move the spine, particularly the paravertebral muscles along the spine;
• the proximal muscles of the limbs.

This stiffness can become so severe that it causes:

• pain
• very painful muscle spasms
• loss of muscle control
• sudden falls
• trauma," adds the doctor.

There are also some less frequent clinical variants of Stiff Person Syndrome:

• Stiff Limb Syndrome (SLS), often paraneoplastic (associated with tumors), in which symptoms affect only one limb.
• Progressive encephalomyelitis with rigidity and myoclonus (PERM), characterized by widespread stiffness, sudden muscle contractions, and focal neurological signs affecting specific areas of the nervous system.

Due to its rarity and complexity, Stiff Person Syndrome is often diagnosed years after the onset of symptoms.

Initial suspicion arises from the patient’s clinical symptoms and is confirmed through:

• the presence of specific antibodies, particularly anti-GAD antibodies.
• neurophysiological testing with electromyography (EMG), an exam that measures the electrical activity of muscles using a small needle inserted into the muscle. In SPS, the test typically shows continuous and simultaneous activation of agonist and antagonist muscles, responsible for the characteristic spasms.

Currently, there is no definitive cure for Stiff Person Syndrome. Treatment approaches focus on improving the patient’s quality of life and slowing disease progression. As Dr. Falzone explains:

“Treatment involves two main approaches:

• symptomatic treatment, aimed at relieving the most evident symptoms, such as painful spasms, using medications like benzodiazepines and muscle relaxants.
• etiological treatment, which targets the autoimmune cause of the disease using therapies such as corticosteroids, immunoglobulins, and plasmapheresis to modulate immune system activity, as well as immunosuppressive drugs like rituximab to reduce the immune system’s attack on the muscles.

Unfortunately, a definitive cure is still not available. However, research, despite being limited by the rarity of the disease, is also exploring drugs already approved for other autoimmune conditions in the hope of identifying targeted therapies.”

Although Stiff Person Syndrome does not typically cause direct cognitive impairment, its psychological impact on patients can be profound.

“Living with a chronic condition characterized by painful spasms and traumatic events such as falls, dislocations, and fractures exposes many patients to high levels of anxiety and depression, often fueled by the constant fear that these episodes may recur,” explains Dr. Falzone.

In this complex context, consultation with experienced specialists plays a crucial role.

“The rarity of the disease makes it essential for patients to rely on reference centers and multidisciplinary expertise. An open approach to collaboration and referral allows physicians not only to explore all available treatment options but also to reduce the risk of diagnostic delays, ensuring patients receive care that fully reflects the complexity of the disease.”