Neurology News

A Look Inside Stiff Person Syndrome — A Rare Progressive Neurologic Disorder

In early December 2022, singer Celine Dion announced that her 2023 tour would be postponed after she was diagnosed with stiff person syndrome (SPS), an extremely rare, progressive neuromuscular disorder that affects the central nervous system and is characterized by muscle stiffness and spasms, lumbar hyperlordosis, postural instability causing recurrent falls, and chronic pain.1

The prevalence of SPS is 1 to 2 per million persons and it occurs 2 to 3 times more frequently in women than men. Type 1 SPS is associated with other autoimmune conditions and patients are often positive for glutamic acid decarboxylase (GAD); type 2 SPS is paraneoplastic and patients are likely positive for anti-amphiphysin; and type 3 SPS is idiopathic.

To get further insight into SPS etiology, diagnosis, and treatment, we interviewed Marinos Dalakas, MD, a professor of neurology and director of the neuromuscular division at Thomas Jefferson University School of Medicine in Philadelphia.

Dr Dalakas has studied and prolifically published his research on SPS for over 30 years,2-5 beginning in the 1980s when he was chief of the neuromuscular diseases section at the National Institute of Neurological Disorders and Stroke (NINDS) in Bethesda, Maryland. It was there where he first encountered a few patients with unusual neuromuscular presentations that no one had ever seen before.

Neurologists who are involved in the SPS Foundation are very active in discussing the possibility of setting up trials for certain drugs that might be helpful for this patient population.

With his combined interests in neuromuscular disorders and immunology, he did more research into the causes for these uncommon neuromuscular symptoms.

In your practice, how many of your patients present with a high index of suspicion for SPS? 

Dr Dalakas: It is difficult to say how many people with SPS I’ve seen in total over the years. I know I see about 1 to 2 new patients with SPS a week, sometimes just 1 a week, or maybe 3 to 4 a month. It depends.

When we did a study looking at the natural history of the disease and if there is a progression, we had 57 enrolled patients with SPS who we saw sequentially.6

It is important to stress that SPS is a syndrome that is fluctuating. Today, a patient comes in with stiffness and a lot of spasms. Tomorrow, they have less spasms because they are less stressed. When a physician sees the same patient sequentially, the physician can get a real impression about what is going on.

What are some common complaints you’ve heard from patients with SPS? Are there any notable triggers you’ve identified over the years?

Dr Dalakas: Patients with SPS have muscle stiffness and spasms, especially in the back. They get worse when the patient is emotionally upset. This makes it difficult to walk normally and contributes to frequent falling.

There are several triggers. Different people are more sensitive to certain things. Stress and anxiety are triggering factors contributing to muscle spasms, and it changes on a day-to-day basis. Patients with SPS are sensitive to sudden noises, the environment in public places, the anxiety to make a deadline, the stress of speaking or performing in a public place, and the stress of traveling.

Often early on in the diagnostic process, patients with SPS go to see their primary care doctor or neurologist with these issues and are told to see a psychiatrist because it is all stress-related. The psychiatrist gives the patient drugs for anxiety and the patients are getting better because the drugs reduce anxiety and stress that trigger SPS symptoms.

Once the doctor detects the antibodies and sees the muscle spasms that the patients experiences and witnesses the permanent stiffness in the legs and the back, they know it is not a psychiatric disease.

What is the etiology of SPS?

Dr Dalakas: It is a neurologic disease with an autoimmune component. We do not know what triggers the autoimmune component of the disease.

We have observed immunogenetic associations in 2 families with more than 1 person with SPS, while other members of the family have type 1 diabetes. We are currently conducting a study to identify genes associated with SPS. Overall, we still don’t know why some people get it, while others don’t.

Researchers in the 1980s discovered the GAD antibodies in patients with diabetes and also SPS. I found the information about the antibodies in the literature when we were doing research into the possible causes of the disease.

We set up an assay to measure the antibodies in patients with SPS. We used an enzyme-linked immunosorbent assay (ELIZA) assay to measure the titers and the Western blot test where we applied the patient’s serum to detect the GAD antibodies. We found that these GAD antibodies bind to very specific areas of the brain that express GABA, the inhibitor neurotransmitter. These areas include the cerebellum and other areas of the cortex, which are involved in the inhibitory gamma-aminobutyric acid (GABA)ergic pathways.

This lack of GABA inhibition leads to excessive muscle activity. Normally, the nervous system is fixed in such a way that when a person contracts one muscle, such as the biceps, the antagonist muscle, or the triceps, is relaxed. This is because the inhibitory pathways interact.

In SPS, the patient will have co-contractions of both the agonist and the antagonist muscle groups. That is the mechanism of SPS. It explains why the abdomen and the back are stiff at the same time and why movement is so difficult.

What are some diagnostic tools used and laboratory markers evaluated when a patient is suspected to have SPS?

Dr Dalakas: Clinically, you would see the presence of stiffness in both the agonist and antagonist muscle groups. For patients with longer disease duration, they have permanent contracture of the back muscles with an increased curvature of the thoracolumbar spine (hyperlordosis).

An electromyography (EMG) study is an important element in the diagnosis of SPS; however, it must be done properly. This can be difficult because the practitioner performing the EMG study needs to look at both the agonist and antagonist muscle groups while a patient is experiencing the spasms. They would see continuous motor activity in both muscle groups.

Lastly, you have the GAD antibodies which are very important and present in about 80% of patients with SPS. The titers on the ELIZA assay are important because GAD antibodies can be seen at low titers in patients with diabetes (not higher than 2000 units). In neurologic diseases, the GAD antibody titers are very high. In SPS, we see GAD titers of 20,000 and above, even up to a million units. This makes a big difference in the diagnosis.

It is important to note that if a person has received intravenous immunoglobulin (IVIG) treatment for something else, they might have GAD antibodies from that IVIG treatment for a short period of time. This is due to the collection of IVIG materials from many donors, some of whom may have low levels of GAD antibodies. This may lead to a false positive test. Low titers don’t matter, but high titers do.

Around 20% of patients with SPS do not have GAD antibodies and are so-called seronegative patients. They have to fulfill all of the other criteria for diagnosis.

There are 2 other antibodies: the anti-amphiphysin that is seen in 5% of the patients, usually when they have cancer, and the glycine receptor antibody, which is seen in 15% of patients.

There is another pathogenic antibody called the GABA receptor-associated protein (GABARAP) antibody. It is present in about 70% of patients with SPS. We are exploring it to see if it can be helpful with diagnosis and establish its validity, but we see some inconsistencies with it, so it is not used for diagnosis currently in clinical practice.

What are some first- or second-line treatment options to successfully manage SPS? What are some gaps in treatment?

Dr. Dalakas: The first line treatments are medications to reduce the spasms as well as for anxiety that triggers the spasms. Diazepam, baclofen, and gabapentin are 3 drugs that I use first to reduce the spasms and to reduce the factors triggering them.

Often, this improves how patients feel, but not completely, so I go to the second line therapy, which is immune therapy because it is an autoimmune disease. Based on controlled studies that we conducted,3-4 IVIG is helpful because the patients got substantially better statistically. It does not work on every patient.

In a 2022 study published in Neurology: Neuroimmunology & Neuroinflammation,5 we noticed that when IVIG is continued for years (mean period of around 4 years of IVIG), 67% of patients continued to improve with IVIG, but close to 30% of the patients continued to progress slowly.

We need better agents for these patients who continue to progress. We tried rituximab, which was not statistically significant because we saw some placebo effect, but the patients who improved had very impressive improvement.

How can neurologists help raise awareness for this condition? 

Dr Dalakas: I see over the years that there is more awareness of SPS now among younger neurologists. Years ago, I didn’t know about it either. The American Academy of Neurology has to be involved. Lately, the organization has been active in spreading awareness about SPS. They invited me and others who know about SPS to speak at several meetings. The Academy is an important organization needed to spread awareness because all the neurologists are members of this organization and need to take certain courses. We are doing better now than before.

Of course, the story that has been in the press about Celine Dion is very important for people to see it and want to learn about it. The press has also been an important part of spreading this information around.

The Stiff Person Syndrome Foundation will also be helpful in spreading awareness.

Is enough being done to develop effective treatments for this patient population?

Dr Dalakas: I am not aware of any medications or treatments currently in development for SPS. I know that researchers in Europe and Japan are interested in developing more treatments for SPS. Neurologists who are involved in the SPS Foundation are very active in discussing the possibility of setting up trials for certain drugs that might be helpful for this patient population. It is a difficult process in finding sponsors and companies willing to research and develop drugs for so few patients with such a rare disease.

Editor’s note: This Q&A was edited for clarity and length.