stiff-person syndrome stiff-person syndrome stiff-person syndrome (sps), also known as stiff-man syndrome (sms), is a rare neurologic disorder of unclear cause characterized by progressive rigidity and stiffness. the stiffness primarily affects the truncal muscles and is superimposed by spasms, resulting in postural deformities. chronic pain, impaired mobility, and lumbar hyperlordosis are common symptoms. stiff-person diseasespecialtyneurology 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 roles 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. there is a limited but encouraging therapeutic experience of haematopoietic stem cell transplantation 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). around 70% of those with sps have the "classic" form of the disease. people with classic sps typically first experience intermittent tightness or aching in the muscles of the trunk. these muscles repeatedly and involuntarily contract, causing them to grow and rigidify. 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). rigid trunk muscles can also prevent the chest and abdomen from expanding, causing shortness of breath and early satiety. in many people with sps, muscle rigidity eventually progresses from the trunk to the limbs – first affecting muscles closest to the trunk, then further. 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. alongside growing stiffness, many with sps develop bouts of muscle spasms that are triggered by sudden movements as well as feeling upset or startled. spasms are sometimes accompanied by elevated blood pressure, heart rate, body temperature, and sweating. some experience chronic muscle pain. the muscle stiffness initially fluctuates, sometimes for days or weeks, but eventually begins to consistently impair mobility. as the disease progresses, patients sometimes become unable to walk or bend. chronic pain is common and worsens over time, but sometimes acute pain occurs as well. stress, cold weather, and infections lead to an increase in symptoms, and sleep decreases them. sps patients experience superimposed spasms and extreme sensitivity to touch and sound. these spasms primarily occur in the proximal limb and axial muscles. 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. in rare cases, facial muscles, hands, feet, and the chest can be affected and unusual eye movements and vertigo occur. there are brisk stretch reflexes and clonus occurs in patients. late in the disease's progression, hypnagogic myoclonus can occur. 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. some also experience anxiety, depression, alcohol use disorders, and phobias – particularly agoraphobia. most patients are psychologically normal and respond reasonably to their situations. 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. this syndrome develops into full sps about 25% of the time. the stiffness begins in one limb and remains most prominent there. sphincter and brainstem issues often occur with stiff-limb syndrome. progressive encephalomyelitis with rigidity and myoclonus, another variant of the condition, includes symptoms of sps with brainstem issues, autonomic disturbances, and myoclonus. in some cases, the limbic system is affected as well. most patients have upper motor neuron issues and autonomic disturbances. 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. paraneoplastic sps can affect either a single limb, or the trunk and limbs together. causes patients with sps generally have high glutamic acid decarboxylase (gad) antibody levels in their blood. about 80 percent of sps patients have gad antibodies, compared with about one percent of the general population. 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. gad, a presynaptic autoantigen, is generally thought to play a key role in the condition, but exact details of the way that autoantibodies affect sps patients are not known. most sps patients with high-titer gad antibodies also have antibodies that inhibit gaba-receptor-associated protein (gabarap). autoantibodies against amphiphysin and gephyrin are also sometimes found in sps patients. 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). this leads to gaba impairment, which probably causes the stiffness and spasms that characterize sps. there are low gaba levels in the motor cortexes of sps patients. it is not known why gad autoimmunity occurs in sps patients, and whether sps qualifies as a neuro-autoimmune disorder has been questioned. it is also unknown whether these antibodies are pathogenic. the level of gad antibody titers found in sps patients does not correlate with disease severity, indicating that these titer levels do not need to be monitored. it has not been proven that gad antibodies are the sole cause of sps, and the possibility exists that they are a marker or an epiphenomenon of the condition's cause. 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 which are stiff. the excessive firing of motor neurons may be caused by malfunctions in spinal and supra-segmental inhibitory networks that utilize gaba. involuntary actions show up as voluntary on emg scans: even when the patient tries to relax, there are agonist and antagonist contractions. 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. passive transfer of sps by plasma injection has been demonstrated in paraneoplastic sps but not in classical sps. there is evidence 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. this allele is also associated with type 1 diabetes. diagnosis sps is diagnosed by evaluating clinical findings and excluding other conditions. there is no specific laboratory test that confirms its presence. due to the rarity and varied symptoms of sps, most affected by the disease wait several years before they are correctly diagnosed. 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 percent of sps patients. anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-rnp, and anti-gliadin are also often found in blood tests. electromyography (emg) demonstrates involuntary motor unit firing in sps patients. emg can confirm the sps diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves. responsiveness to diazepam helps confirm that the patient has sps, as this drug will decrease stiffness and motor unit firing. the same general criteria are used to diagnose paraneoplastic sps as for the normal form of the condition. once sps is diagnosed, poor response to conventional therapies and the presence of cancer indicate that it may be paraneoplastic. ct scans are indicated for sps patients who respond poorly to therapy to determine if cancer is the cause. a variety of conditions have similar symptoms to sps, including myelopathies, dystonias, spinocerebellar degenerations, primary lateral sclerosis, neuromyotonia, and some psychogenic disorders. tetanus, neuroleptic malignant syndrome, malignant hyperpyrexia, chronic spinal interneuronitis, serotonin syndrome, multiple sclerosis, parkinson's disease, and isaacs syndrome should also be excluded. patients' fears and phobias often incorrectly lead doctors to think their symptoms are psychogenic, and they are sometimes suspected of malingering. it takes an average of six years after the onset of symptoms before the disease is diagnosed. treatment there is no evidence-based criterion for treating sps, and there have been no large, controlled trials of treatments for the condition. the rarity of the disease complicates efforts to establish guidelines. however, treatments can either be categorized as gabaergic or immuno-therapy. gabaergic therapy gabaa agonists, usually diazepam but sometimes other benzodiazepines, are the primary treatment for sps. drugs that increase gaba activity alleviate muscle stiffness caused by a lack of gabaergic tone. they increase pathways that are dependent upon gaba and have muscle relaxant and anticonvulsant effects, often providing symptom relief. because the condition worsens over time, patients generally require increased dosages, leading to more side effects. benzodiazepines benzodiazepines (such as diazepam and clonazepam) are psychoactive drugs that enhance a gaba neurotransmitter's effect at the gaba receptor in enhancing inhibitory circuits. the drug has been used as sedative, muscle relaxant, and anticonvulsant. patients with classic or partial sms and gad-65-positive antibody have shown improvement in stiffness and spasm symptoms with long-term benzodiazepine treatment. however, this change cannot solely be attributed to monotherapy of benzodiazepine as adjunct medications were also commonly administered. currently, diazepam is the mainstay of therapy. most patients respond well to diazepam. oral and intrathecal baclofen baclofen, a gabab agonist, is generally used when individuals taking high doses of benzodiazepines have high side effects. in some cases, it has shown improvements in electrophysiological and muscle stiffness when administered intravenously. intrathecal baclofen administration may not have long-term benefits though, and there are potential serious side effects. levetiracetam (lev) a 2008 small (n=3) single-blind, placebo-controlled study where participating patients were treated with oral lev of 500 mg twice daily. the study noted that showed that the patients had improvement in axial rigidity and disappearance of the paroxysmal respiratory arrests within three days after starting therapy. a similar improvement was noted in the other two patients with a marked reduction in legs' stiffness and difficulty walking. on lev treatment, all patients improved as assessed by all outcome measures. in particular, at emg recordings, patients relaxed their musculature better. however, no long-term studies on lev on patients with sps have been done. pregabalin pregabalin works by inhibiting calcium influx and subsequent release of excitatory neurotransmitters, including glutamate and norepinephrine. as a possible mechanism of action in sps, pregabalin might have compensated for the imbalance between inhibitory and excitatory intracortical circuits. the prolongation of the gaba-b supports this hypothesis-mediated cortical silent period (csp) after pregabalin introduction. propofol a 2020 review article by ortiz, ghani, cox, and tambo, noted a case report, where a sps patient reporting persistent, severe symptoms and taking high-dose benzodiazepines, baclofen, corticosteroids, lev, ivig, and iv ethanol. after that, the patient received a small dose of propofol, which improved the patient's reported symptoms. additionally, the authors documented a patient with stiff-limb syndrome (a variant of sps) with refractory therapy who also responded well to propofol. the mechanism by which propofol interacts in the nervous system is not entirely understood. nevertheless, it is suggested that it might be related to increased gabaergic activity in the brain. as it is unrealistic to have a patient with a long-term therapy to propofol, the authors suggest that propofol could be used as a bridge therapy to a more permanent intervention in patients with