Welcome to the Rare Classroom, a new series from Patient Worthy. Rare Classroom is designed for the curious reader who wants to get informed on some of the rarest, most mysterious diseases and conditions. There are thousands of rare diseases out there, but only a very small number of them have viable treatments and regularly make the news. This series is an opportunity to learn the basics about some of the diseases that almost no one hears much about or that we otherwise haven’t been able to report on very often.

Eyes front and ears open. Class is now in session.

The disease that we will be learning about today is:

Stiff-Person Syndrome

Also called stiff-man syndrome.

What is Stiff-Person Syndrome?

• Stiff-person syndrome is a rare disorder of the nervous system which is distinguished by progressive stiffness and rigidity.
  • These symptoms primarily impact the torso and can result in postural abnormalities
• Stiff-person syndrome (SPS) is very rare, occurring in about 1 in a million people.
• Certain variants of the disorder, such as those affecting the limbs and a paraneoplastic form, are also recognized
• The disease was first described in 1956, with additional research occurring in the following decades
• Diagnosis is conducted through an evaluation of the clinical findings and the elimination of other conditions
• Identifying antibodies against GAD in a blood test is a clear-cut way to confirm the diagnosis

How Do You Get It?

• The cause of stiff-person syndrome isn’t entirely clear, but most patients have high levels of glutamic acid decarboxylase (GAD)
  • This sign is found in around 80 percent of cases
  • However, this is not the direct cause, as the majority of people that develop these antibodies do not develop SPS
• GAD is believed to play a critical role in the disease, but it’s unclear how
• Other antibodies are also found in many patients
• In a small number of patients, lung cancer, ovarian cancer, or breast cancer can manifest paraneoplastically, triggering stiffness of nearby muscles
• The disease usually starts in middle age
• Women are affected at three times the rate of men

What Are the Symptoms?

• SPS is split into three different types:
  • Classic SPS, typically positive for GAD antibodies and affiliated with other autoimmune diseases (around 70 percent of cases)
  • Partial forms, which can be further subdivided
  • Progressive encephalomyelitis with rigidity and myoclonus (PERM)
• Symptoms of the classic form include:
  • Tightness and aching of the torso muscles
    • These muscles repeatedly contract randomly, causing them to become rigid and enlarged
  • Reduced range of motion
  • Slowing of voluntary movements
  • Abnormal posture, particularly lumbar hyperlordosis
  • Shortness of breath
  • Spread of stiffness to the limbs
  • Loss of balance due to unusual posture
  • Chronic muscle spasms and pain
  • Sensitivity to touch and sound
• Sleep tends to reduce symptoms, while stress, disease, or cold weather worsens them
• Psychiatric disorders, such as substance abuse, anxiety, phobias, and depression, are common
• In the partial form, the limbs (sometimes just one limb) are affected first
  • This develops into the classic form about 25% of the time
• PERM includes many of the above symptoms along with myoclonus, autonomic problems, and brainstem problems

How Is It Treated?

• There are no evidence-based criteria for treatment and there have been no large-scale controlled trials for SPS
• Therapies include GABAergic treatments and immunotherapies.
  • GABA treatments include diazepam or other benzodiazepines, baclofen, levetiracetam, pregabalin, and propofol
  • Larger doses may be needed as the disease worsens, leading to increased risk of side effects
  • Immunotherapy options include rituximab, IVIG, tacrolimus, and plasmapheresis
• Botulinum toxin has also been used, but lacks long-term impacts and can cause severe side effects
• Opiates, a common treatment for pain, can exacerbate symptoms
• Hematopoietic stem cell transplantation has been used successfully to induce remission in a small number of cases
• Outcomes depend on several factors, such as the type of SPS present, the presence of comorbidities, and early diagnosis.
• Early treatment can limit disease progression, but around 65% of patients are incapable of functioning independently
• Around 10% of patients experience sudden death
• While generally responsive to treatment SPS tends to oscillate between stability and progression episodes

Where Can I Learn More???

• Check out our cornerstone on this disease here.
• Learn more about this illness from the Stiff Person Syndrome Research Foundation.