Stiff-person syndrome

Template:Short description Template:Infobox medical condition (new) Stiff-person syndrome (SPS), also known as stiff-man syndrome, is a rare neurological disorder of unclear cause characterized by progressive muscular rigidity and stiffness. The stiffness primarily affects the truncal muscles and is characterised by spasms, resulting in postural deformities. Chronic pain, impaired mobility, and lumbar hyperlordosis are common symptoms.

SPS occurs in about one in a million people and is most commonly found in middle-aged people. A small minority of patients have the paraneoplastic variety of the condition. Variants of the condition, such as stiff-limb syndrome, which primarily affects a specific limb, are often seen.

SPS was first described in 1956. Diagnostic criteria were proposed in the 1960s and refined two decades later. In the 1990s and 2000s, the role of antibodies in the condition became clearer. SPS patients generally have glutamic acid decarboxylase (GAD) antibodies, which seldom occur in the general population. In addition to blood tests for GAD, electromyography tests can help confirm the condition's presence.

Benzodiazepine-class drugs are the most common treatment; they are used for symptom relief from stiffness. Other common treatments include baclofen, intravenous immunoglobin, and rituximab. Limited but encouraging therapeutic experience of haematopoietic stem cell transplantation exists for SPS.

Signs and symptoms

Stiff-person syndrome (SPS) is often separated into several subtypes, based on the cause and progression of the disease.

There are three clinical classifications of SPS:

• Classic SPS, associated with other autoimmune conditions and usually GAD-positive
• Partial SPS variants
• Progressive encephalomyelitis with rigidity and myoclonus (PERM)

Forearm showing the hand formed into a fist shape, wrist bend inwards due to muscle contraction

Muscle stiffness and contraction can cause abnormal resting postures.

Around 70% of those with SPS have the "classic" form of the disease.Template:Sfn People with classic SPS typically first experience intermittent tightness or aching in the muscles of the trunk.Template:Sfn These muscles repeatedly and involuntarily contract, causing them to grow and rigidify.Template:Sfn Eventually, rigidified muscles reduce the affected person's range of motion, slow their voluntary movements, and may cause them to have abnormal posture, particularly lumbar hyperlordosis (a distinctive curve in the lower back).Template:Sfn Rigid trunk muscles can also prevent the chest and abdomen from expanding, causing shortness of breath and early satiety.Template:Sfn In many people with SPS, muscle rigidity eventually progresses from the trunk to the limbs — first affecting muscles closest to the trunk, then further.Template:Sfn Stiffened limbs can affect a person's balance and gait, causing awkward 'statue-like' falls, where the affected person cannot put out their arms to soften the impact.Template:Sfn Alongside growing stiffness, many with SPS develop bouts of muscle spasms that are triggered by sudden movements and feeling upset or startled.Template:Sfn Spasms are sometimes accompanied by elevated blood pressure, heart rate, body temperature, and sweating.Template:Sfn Some experience chronic muscle pain.Template:Sfn

The muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility.Template:Sfn As the disease progresses, patients sometimes become unable to walk or bend.Template:Sfn Chronic pain is common and worsens over time, but sometimes acute pain occurs as well.Template:Sfn Stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them.Template:Sfn

SPS patients experience superimposed spasms and extreme sensitivity to touch and sound.Template:Sfn These spasms primarily occur in the proximal limb and axial muscles.Template:Sfn Spasms usually last for minutes and can recur over hours. Attacks of spasms are unpredictable and are often caused by fast movements, emotional distress, or sudden sounds or touches.Template:Sfn In rare cases, facial muscles, hands, feet, and the chest can be affected, and unusual eye movements and vertigo occur.Template:SfnTemplate:Sfn Brisk stretch reflexes and clonus occur in patients.Template:Sfn Late in the disease's progression, hypnagogic myoclonus can occur.Template:Sfn

In addition to their physical symptoms, many with SPS experience neurological and psychiatric disorders. Some with SPS have various neurological disorders that affect physical reflexes and the movement of the eyes.Template:Sfn Some also experience anxiety, depression, alcohol use disorders, and phobias — particularly agoraphobia.Template:Sfn Most patients are psychologically normal and respond reasonably to their situations.Template:Sfn

A minority of people with SPS experience "partial" SPS, also called "stiff-limb syndrome", where the muscle contractions and stiffness are limited to the limbs, or sometimes a single limb.Template:Sfn This syndrome develops into full SPS about 25% of the time.Template:Sfn The stiffness begins in one limb and remains most prominent there. Sphincter and brainstem issues often occur with stiff-limb syndrome.Template:Sfn

Progressive encephalomyelitis with rigidity and myoclonus, another variant of the condition,Template:Sfn includes symptoms of SPS, with brainstem issues, autonomic disturbances, and myoclonus.Template:Sfn In some cases, the limbic system is affected, too. Most patients have upper motor neuron issues and autonomic disturbances.Template:Sfn

Around 5% of those with SPS experience the symptoms as a paraneoplastic syndrome — a result of a tumor elsewhere in the body releasing bioactive molecules.Template:Sfn Paraneoplastic SPS can affect either a single limb, or the trunk and limbs together.Template:Sfn

Causes

Patients with SPS generally have high glutamic acid decarboxylase (GAD) antibody levels in their blood.Template:Sfn About 80% of SPS patients have GAD antibodies, compared with about 1% of the general population.Template:Sfn The overwhelming majority of people who have GAD antibodies do not develop SPS, indicating that systemic synthesis of the antibody is not the sole cause of SPS.Template:Sfn GAD, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way autoantibodies affect SPS patients are not known.Template:Sfn Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP).Template:Sfn Autoantibodies against amphiphysin and gephyrin are also sometimes found in SPS patients.Template:Sfn The antibodies appear to interact with antigens in the brain neurons and the spinal-cord synapses, causing a functional blockade of the inhibitory neurotransmitter gamma-aminobutyric acid (GABA).Template:Sfn This leads to GABA impairment, which probably causes the stiffness and spasms that characterize SPS.Template:Sfn There are low GABA levels in the motor cortexes of SPS patients.Template:Sfn

Why GAD autoimmunity occurs in SPS patients is unknown,Template:Sfn and whether SPS qualifies as a neuroautoimmune disorder has been questioned.Template:Sfn Also unknown is whether these antibodies are pathogenic.Template:Sfn The level of GAD antibody titers found in SPS patients does not correlate with disease severity,Template:Sfn indicating that these titer levels do not need to be monitored.Template:Sfn GAD antibodies have not been proven to be the sole cause of SPS, but possibly they are a marker or an epiphenomenon of the condition's cause.Template:Sfn

In SPS patients, motor-unit neurons fire involuntarily in a way that resembles a normal contraction. Motor-unit potentials fire while the patient is at rest, particularly in the muscles that are stiff.Template:Sfn The excessive firing of motor neurons may be caused by malfunctions in spinal and suprasegmental inhibitory networks that use GABA.Template:Sfn Involuntary actions show up as voluntary on EMG scans;Template:Sfn even when the patient tries to relax, agonist and antagonist contractions occur.Template:Sfn

In a minority of patients with SPS, breast, ovarian, or lung cancer manifests paraneoplastically as proximal muscle stiffness. These cancers are associated with the synaptic proteins amphiphysin and gephyrin. Paraneoplastic SPS with amphiphysin antibodies and breast adenocarcinoma tend to occur together. These patients tend not to have GAD antibodies.Template:Sfn Passive transfer of SPS by plasma injection has been demonstrated in paraneoplastic SPS, but not in classical SPS.Template:Sfn

Evidence exists of genetic influence on SPS risk. The HLA class II locus makes patients susceptible to the condition. Most SPS patients have the DQB1* 0201 allele.Template:Sfn This allele is also associated with type 1 diabetes.Template:Sfn

Diagnosis

SPS is diagnosed by evaluating clinical findings and excluding other conditions.Template:Sfn No specific laboratory test confirms its presence.Template:Sfn Due to the rarity and varied symptoms of SPS, most affected by the disease wait several years before they are correctly diagnosed.Template:Sfn

The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and cerebrospinal fluid (CSF) testing. Anti-GAD65 is found in about 80% of SPS patients. Antithyroid, antiintrinsic factor, antinuclear, anti-RNP, and antigliadin antibodies are also often found in blood tests. Electromyography demonstrates involuntary motor unit firing in SPS patients.Template:Sfn It can confirm the SPS diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves.Template:Sfn Responsiveness to diazepam helps confirm that the patient has SPS, as this drug decreases stiffness and motor-unit firing.Template:Sfn

The same general criteria are used to diagnose paraneoplastic SPS as for the normal form of the condition.Template:Sfn Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic.Template:Sfn CT scans are indicated for SPS patients who respond poorly to therapy to determine if cancer is the cause.Template:Sfn

A variety of conditions have similar symptoms to SPS, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders.Template:Sfn Tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome,Template:Sfn multiple sclerosis, and Parkinson's disease should also be excluded.Template:Sfn

Patients' fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic,Template:Sfn and they are sometimes suspected of malingering.Template:Sfn An average of six years pass after the onset of symptoms before the disease is diagnosed.Template:Sfn

Treatment

No evidence-based treatment has been found for SPS, nor have large, controlled trials of treatments for the condition been conducted. The rarity of the disease complicates efforts to establish guidelines.Template:Sfn

Nonetheless, first line treatment strategies include managing the symptoms with GABA-ergic drugs, such as diazepam and baclofen. Immunotherapies, such as IVIG and rituxamab, can also be used in individuals who have inadequate response to symptomatic management. Physical therapy may also help.

Prognosis

The progression of SPS depends on whether it is a typical or abnormal form of the condition, and the presence of comorbidities. Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment,Template:Sfn but the condition usually progresses and stabilizes periodically.Template:Sfn Even with treatment, quality of life generally declines as stiffness precludes many activities.Template:Sfn Some patients require mobility aids due to the risk of falls.Template:Sfn About 65% of SPS patients are unable to function independently.Template:Sfn About 10% require intensive care at some point;Template:Sfn sudden death occurs in about the same percentage of patients.Template:Sfn These deaths are usually caused by metabolic acidosis or an autonomic crisis.Template:Sfn

Epidemiology

SPS is estimated to have a prevalence of about one or two per million people. It affects women up to three times as frequently as men. In the United Kingdom, 119 cases were identified between 2000 and 2005.Template:Sfn It does not predominantly occur in any racial or ethnic group.Template:Sfn SPS can start at any age,Template:Sfn though it most frequently occurs in people in their 40s.Template:Sfn About 35% of SPS patients have type I diabetes.Template:Sfn

History

SPS was first described by Frederick Moersch and Henry Woltman in 1956, who named it "stiff-man syndrome". Their description of the disease was based on 14 cases that they had observed over 32 years. Using electromyography, they noted that motor-unit firing suggested that contractions of voluntary muscle were occurring in their patients.Template:Sfn Previously, cases of SPS had been dismissed as psychogenic problems.Template:Sfn Clinical diagnostic criteria were developed by Gordon et al. in 1967. They observed "persistent tonic contraction reflected in constant firing, even at rest" after providing patients with muscle relaxants and examining them with electromyography.Template:Sfn In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms.Template:Sfn The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.Template:Sfn

In 1963, diazepam was determined to help alleviate symptoms of SPS.Template:Sfn Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year.Template:Sfn The first use of intravenous immunoglobulin to treat the condition came in 1994.Template:Sfn

In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS.Template:Sfn Two years later, Solimena found the antibodies in 20 out of 33 patients examined.Template:Sfn In the late 1980s, the serum of SPS patients was also found to bind to GABAergic neurons.Template:Sfn In 2006, the role of GABARAP in SPS was discovered.Template:Sfn The first case of paraneoplastic SPS was found in 1975.Template:Sfn In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS,Template:Sfn and seven years later, antigephyrin was also found to be involved in the condition.Template:Sfn

Notable cases

In October 2023, singer Céline Dion announced that she is suffering from this syndrome, resulting in cancelled performances. In July 2024, Dion performed "Hymne à l'amour" at the opening ceremony of the Paris Olympic Games, her first public performance since her diagnosis.

See also

• Hyperekplexia
• Satoyoshi syndrome

External links

• Stiff-Person Syndrome Information Page at NINDS