muscular rigidity and trigger-induced painful muscle spasms
Frequency
1 in 1,000,000
Stiff-person syndrome (SPS), also known as stiff-man syndrome,[1] 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.[2][3]
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.
Muscle stiffness and contraction can cause abnormal resting postures.
Around 70% of those with SPS have the "classic" form of the disease.[5] People with classic SPS typically first experience intermittent tightness or aching in the muscles of the trunk.[6] These muscles repeatedly and involuntarily contract, causing them to grow and rigidify.[6] 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).[6] Rigid trunk muscles can also prevent the chest and abdomen from expanding, causing shortness of breath and early satiety.[6] In many people with SPS, muscle rigidity eventually progresses from the trunk to the limbs — first affecting muscles closest to the trunk, then further.[6] 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.[6] Alongside growing stiffness, many with SPS develop bouts of muscle spasms that are triggered by sudden movements and feeling upset or startled.[6] Spasms are sometimes accompanied by elevated blood pressure, heart rate, body temperature, and sweating.[6] Some experience chronic muscle pain.[6]
The muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility.[7] As the disease progresses, patients sometimes become unable to walk or bend.[8] Chronic pain is common and worsens over time, but sometimes acute pain occurs as well.[9] Stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them.[7]
SPS patients experience superimposed spasms and extreme sensitivity to touch and sound.[7] These spasms primarily occur in the proximal limb and axial muscles.[10] 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.[8] In rare cases, facial muscles, hands, feet, and the chest can be affected, and unusual eye movements and vertigo occur.[11][12] Brisk stretch reflexes and clonus occur in patients.[7] Late in the disease's progression, hypnagogic myoclonus can occur.[13]
In addition to their physical symptoms, many with SPS experience neurological and psychiatric disorders.[14] Some with SPS have various neurological disorders that affect physical reflexes and the movement of the eyes.[6] Some also experience anxiety, depression, alcohol use disorders, and phobias — particularly agoraphobia.[6] Most patients are psychologically normal and respond reasonably to their situations.[15]
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.[5] This syndrome develops into full SPS about 25% of the time.[16] The stiffness begins in one limb and remains most prominent there. Sphincter and brainstem issues often occur with stiff-limb syndrome.[17]
Progressive encephalomyelitis with rigidity and myoclonus, another variant of the condition,[9] includes symptoms of SPS, with brainstem issues, autonomic disturbances, and myoclonus.[17] In some cases, the limbic system is affected, too. Most patients have upper motor neuron issues and autonomic disturbances.[18]
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.[5] Paraneoplastic SPS can affect either a single limb, or the trunk and limbs together.[19][20]
Causes
Patients with SPS generally have high glutamic acid decarboxylase (GAD) antibody levels in their blood.[21] About 80% of SPS patients have GAD antibodies, compared with about 1% of the general population.[22] 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.[23] 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.[24] Most SPS patients with high-titer GAD antibodies also have antibodies that inhibit GABA-receptor-associated protein (GABARAP).[7] Autoantibodies against amphiphysin and gephyrin are also sometimes found in SPS patients.[24] The antibodies appear to interact with antigens in the brain neurons and the spinal-cord synapses, causing a functional blockade of the inhibitory neurotransmittergamma-aminobutyric acid (GABA).[7] This leads to GABA impairment, which probably causes the stiffness and spasms that characterize SPS.[21] There are low GABA levels in the motor cortexes of SPS patients.[7]
Why GAD autoimmunity occurs in SPS patients is unknown,[25] and whether SPS qualifies as a neuroautoimmune disorder has been questioned.[26] Also unknown is whether these antibodies are pathogenic.[25] The level of GAD antibody titers found in SPS patients does not correlate with disease severity,[21] indicating that these titer levels do not need to be monitored.[27] 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.[28]
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.[7] The excessive firing of motor neurons may be caused by malfunctions in spinal and suprasegmental inhibitory networks that use GABA.[7] Involuntary actions show up as voluntary on EMG scans;[13] even when the patient tries to relax, agonist and antagonist contractions occur.[22]
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.[7] Passive transfer of SPS by plasma injection has been demonstrated in paraneoplastic SPS, but not in classical SPS.[28]
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.[7] This allele is also associated with type 1 diabetes.[29]
Diagnosis
SPS is diagnosed by evaluating clinical findings and excluding other conditions.[7] No specific laboratory test confirms its presence.[5] Due to the rarity and varied symptoms of SPS, most affected by the disease wait several years before they are correctly diagnosed.[5]
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.[7] It can confirm the SPS diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves.[13] Responsiveness to diazepam helps confirm that the patient has SPS, as this drug decreases stiffness and motor-unit firing.[7]
The same general criteria are used to diagnose paraneoplastic SPS as for the normal form of the condition.[15] Once SPS is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic.[7]CT scans are indicated for SPS patients who respond poorly to therapy to determine if cancer is the cause.[30]
Patients' fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic,[32] and they are sometimes suspected of malingering.[12] An average of six years pass after the onset of symptoms before the disease is diagnosed.[32]
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.[31]
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.[33]
Prognosis
The progression of SPS depends on whether it is a typical or abnormal form of the condition, and the presence of comorbidities.[34] Early recognition and neurological treatment can limit its progression. SPS is generally responsive to treatment,[35] but the condition usually progresses and stabilizes periodically.[36] Even with treatment, quality of life generally declines as stiffness precludes many activities.[9] Some patients require mobility aids due to the risk of falls.[12] About 65% of SPS patients are unable to function independently.[37] About 10% require intensive care at some point;[36] sudden death occurs in about the same percentage of patients.[35] These deaths are usually caused by metabolic acidosis or an autonomic crisis.[36]
Epidemiology
SPS is estimated to have a prevalence of about one or two per million people.[38] It affects women up to three times as frequently as men.[38] In the United Kingdom, 119 cases were identified between 2000 and 2005.[37] It does not predominantly occur in any racial or ethnic group.[21] SPS can start at any age,[5] though it most frequently occurs in people in their 40s.[21] About 35% of SPS patients have type I diabetes.[7]
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.[37] Previously, cases of SPS had been dismissed as psychogenic problems.[39] 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.[37] In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms.[40] The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.[40]
In 1963, diazepam was determined to help alleviate symptoms of SPS.[7]Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year.[24] The first use of intravenous immunoglobulin to treat the condition came in 1994.[24]
In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS.[37] Two years later, Solimena found the antibodies in 20 out of 33 patients examined.[41] In the late 1980s, the serum of SPS patients was also found to bind to GABAergic neurons.[25] In 2006, the role of GABARAP in SPS was discovered.[24] The first case of paraneoplastic SPS was found in 1975.[42] In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS,[24] and seven years later, antigephyrin was also found to be involved in the condition.[24]
Notable cases
In December 2022, 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 "live" performance (using playback and Melodyne pitch-correction)[43] since her diagnosis.[44]
Ataxia is a neurological sign consisting of lack of voluntary coordination of muscle movements that can include gait abnormality, speech changes, and abnormalities in eye movements, that indicates dysfunction of parts of the nervous system that coordinate movement, such as the cerebellum.
Lambert–Eaton myasthenic syndrome (LEMS) is a rare autoimmune disorder characterized by muscle weakness of the limbs. It is also known as myasthenic syndrome, Eaton–Lambert syndrome, and when related to cancer, carcinomatous myopathy.
Myasthenia gravis (MG) is a long-term neuromuscular junction disease that leads to varying degrees of skeletal muscle weakness. The most commonly affected muscles are those of the eyes, face, and swallowing. It can result in double vision, drooping eyelids, and difficulties in talking and walking. Onset can be sudden. Those affected often have a large thymus or develop a thymoma.
Neuromyotonia (NMT) is a form of peripheral nerve hyperexcitability that causes spontaneous muscular activity resulting from repetitive motor unit action potentials of peripheral origin. NMT along with Morvan's syndrome are the most severe types in the Peripheral Nerve Hyperexciteability spectrum. Example of two more common and less severe syndromes in the spectrum are cramp fasciculation syndrome and benign fasciculation syndrome. NMT can have both hereditary and acquired (non-inherited) forms. The prevalence of NMT is unknown.
Transverse myelitis (TM) is a rare neurological condition wherein the spinal cord is inflamed. The adjective transverse implies that the spinal inflammation (myelitis) extends horizontally throughout the cross section of the spinal cord; the terms partial transverse myelitis and partial myelitis are sometimes used to specify inflammation that affects only part of the width of the spinal cord. TM is characterized by weakness and numbness of the limbs, deficits in sensation and motor skills, dysfunctional urethral and anal sphincter activities, and dysfunction of the autonomic nervous system that can lead to episodes of high blood pressure. Signs and symptoms vary according to the affected level of the spinal cord. The underlying cause of TM is unknown. The spinal cord inflammation seen in TM has been associated with various infections, immune system disorders, or damage to nerve fibers, by loss of myelin. As opposed to leukomyelitis which affects only the white matter, it affects the entire cross-section of the spinal cord. Decreased electrical conductivity in the nervous system can result.
Morvan's syndrome is a rare, life-threatening autoimmune disease named after the nineteenth century French physician Augustin Marie Morvan. "La chorée fibrillaire" was first coined by Morvan in 1890 when describing patients with multiple, irregular contractions of the long muscles, cramping, weakness, pruritus, hyperhidrosis, insomnia and delirium. It normally presents with a slow insidious onset over months to years. Approximately 90% of cases spontaneously go into remission, while the other 10% of cases lead to death.
Benign fasciculation syndrome (BFS) is characterized by fasciculation (twitching) of voluntary muscles in the body. The twitching can occur in any voluntary muscle group but is most common in the eyelids, arms, hands, fingers, legs, and feet. The tongue can also be affected. The twitching may be occasional to continuous. BFS must be distinguished from other conditions that include muscle twitches.
Post-polio syndrome is a group of latent symptoms of poliomyelitis (polio), occurring at about a 25–40% rate. They are caused by the damaging effects of the viral infection on the nervous system and typically occur 15 to 30 years after an initial acute paralytic attack. Symptoms include decreasing muscular function or acute weakness with pain and fatigue. The same may also occur years after a nonparalytic polio infection.
Myoclonus is a brief, involuntary, irregular twitching of a muscle, a joint, or a group of muscles, different from clonus, which is rhythmic or regular. Myoclonus describes a medical sign and, generally, is not a diagnosis of a disease. It belongs to the hyperkinetic movement disorders, among tremor and chorea for example. These myoclonic twitches, jerks, or seizures are usually caused by sudden muscle contractions or brief lapses of contraction. The most common circumstance under which they occur is while falling asleep. Myoclonic jerks occur in healthy people and are experienced occasionally by everyone. However, when they appear with more persistence and become more widespread they can be a sign of various neurological disorders. Hiccups are a kind of myoclonic jerk specifically affecting the diaphragm. When a spasm is caused by another person it is known as a provoked spasm. Shuddering attacks in babies fall in this category.
Opsoclonus myoclonus syndrome (OMS), also known as opsoclonus-myoclonus-ataxia (OMA), is a rare neurological disorder of unknown cause which appears to be the result of an autoimmune process involving the nervous system. It is an extremely rare condition, affecting as few as 1 in 10,000,000 people per year. It affects 2 to 3% of children with neuroblastoma and has been reported to occur with celiac disease and diseases of neurologic and autonomic dysfunction.
Paraneoplastic cerebellar degeneration (PCD) is a paraneoplastic syndrome associated with a broad variety of tumors including lung cancer, ovarian cancer, breast cancer, Hodgkin’s lymphoma and others. PCD is a rare condition that occurs in less than 1% of cancer patients.
Satoyoshi syndrome, also known as Komuragaeri syndrome, is a rare progressive disorder of presumed autoimmune cause, characterized by painful muscle spasms, alopecia, diarrhea, endocrinopathy with amenorrhoea, and secondary skeletal abnormalities. The syndrome was first reported in 1967 by Eijiro Satoyoshi and Kaneo Yamada in Tokyo, Japan. To this date, fewer than 50 cases worldwide have been reported for the syndrome.
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Cramp fasciculation syndrome (CFS) is a rare peripheral nerve hyperexcitability disorder. It is more severe than the related disorder known as benign fasciculation syndrome; it causes fasciculations, cramps, pain, fatigue, and muscle stiffness similar to those seen in neuromyotonia. Patients with CFS, like those with neuromyotonia, may also experience paresthesias. Most cases of cramp fasciculation syndrome are idiopathic, although some research points to an autoimmune component that may be partly genetic in etiology. Cramp fasciculation syndrome is diagnosed by clinical examination and electromyography (EMG). Fasciculation is the only abnormality seen with EMG. Cramp fasciculation syndrome is a chronic condition. Treatment options include anti-seizure medications such as carbamazepine, immunosuppressive drugs and plasmapheresis.
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Anti-VGKC-complex encephalitis are caused by antibodies against the voltage gated potassium channel-complex (VGKC-complex) and are implicated in several autoimmune conditions including limbic encephalitis, epilepsy and neuromyotonia.
Anti-Hu associated encephalitis, also known as Anti-ANNA1 associated encephalitis, is an uncommon form of brain inflammation that is associated with an underlying cancer. It can cause psychiatric symptoms such as depression, anxiety, and hallucinations. It can also produce neurological symptoms such as confusion, memory loss, weakness, sensory loss, pain, seizures, and problems coordinating the movement of the body.
References
↑ Darras BT, Jones Jr HR, Ryan MM (2014). Neuromuscular Disorders of Infancy, Childhood, and Adolescence. Elsevier Science. p.188. ISBN978-0-12-417127-5. The stiff-man syndrome (SMS, also known as stiff-person syndrome) is a rare central nervous system autoimmune disease, but is likely underrecognized.
↑ Muranova A, Shanina E (Jul 18, 2022). "Stiff Person Syndrome". StatPearls. Treasure Island, FL: StatPearls Publishing. PMID34424651. Retrieved Jan 18, 2023.
↑ Nasri A, Gharbi A, Ouali U, etal. (August 2022). "Psychiatric Symptoms in Stiff-Person Syndrome: A Systematic Review and a Report of Two Cases". Journal of the Academy of Consultation-Liaison Psychiatry. 22 (2): S2667-2960. doi:10.1016/j.jaclp.2022.07.005. PMID35940576. S2CID251427590.
↑ Caffrey D, Finn CT, Song SM, Burton F, Arsan C (2021). "Stiff-Person Syndrome and Psychiatric Comorbidities: A Systematic Review". Journal of the Academy of Consultation-Liaison Psychiatry. 62 (1): 3–13. doi:10.1016/j.psym.2020.08.005. PMID33183848. S2CID224939261.
Alexopoulos H, Dalakas MC (November 2010). "A critical update on the immunopathogenesis of Stiff Person Syndrome". European Journal of Clinical Investigation. 40 (11): 1018–1025. doi:10.1111/j.1365-2362.2010.02340.x. PMID20636380. S2CID30688501.
Ali F, Rowley M, Jayakrishnan B, Teuber S, Gershwin ME, Mackay IR (September 2011). "Stiff-person syndrome (SPS) and anti-GAD-related CNS degenerations: protean additions to the autoimmune central neuropathies". Journal of Autoimmunity. 37 (2): 79–87. doi:10.1016/j.jaut.2011.05.005. PMID21680149.
Baizabal-Carvallo JF, Jankovic J (August 2015). "Stiff-person syndrome: insights into a complex autoimmune disorder". Journal of Neurology, Neurosurgery, and Psychiatry. 86 (8): 840–848. doi:10.1136/jnnp-2014-309201. PMID25511790. S2CID19981869.
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