Stiff-person syndrome
Contributors
Kathleen M Shannon MD, author. Dr. Shannon of Rush-Presbyterian St. Luke's Medical Center receives research support from Schering and Titan.
Joseph Jankovic MD, editor. Dr. Jankovic, Director of the Parkinson's Disease Center and Movement Disorders Clinic, Baylor College of Medicine, has received research support from Advanced Neuromodulation Systems, Allergan, Boehringer Ingelheim, Ceregene, Chitern International, EMD Serono, Impax Pharmaceuticals, Ipsen Limited, Medtronic, Merz Pharmaceuticals, Neurogen, Novartis, Ortho-McNeil, and Teva. He has served as a consultant for Allergan, EMD Serono, Lundbeck, Merz Pharmaceuticals, and Teva.
Publication dates
Originally released September 2, 1994; last updated February 13, 2009; expires February 13, 2012
Synonyms
Stiff-man syndrome
In 1956, Moersch and Woltman described 14 patients who had a progressive syndrome comprised of fluctuating muscle rigidity and spasm. They named this symptom complex "stiff-man syndrome" (Moersch and Woltman 1956). Gordon later summarized additional cases from the literature, adding a case of his own, and suggested diagnostic criteria that, with minimal revision, remain valid to this day (Gordon et al 1967). In 1991, McEvoy summarized clinical, immunologic, and presumed pathogenesis of the disorder in 98 cases seen at the Mayo Clinic, or reported in other literature between 1956 and 1991 (McEvoy 1991a). Although the name "stiff-person syndrome" is more accurate in both the epidemiologic and political senses, the moniker "stiff-man syndrome" is sometimes used.
Stiff-person syndrome is an acquired disorder of adult life, typically beginning in the third through sixth decades (Gordon et al 1967). Symptoms begin insidiously with aching and stiffness of the axial muscles, particularly in the neck and lower back (Stayer and Meinck 1998). Although prior trauma (Brashear and Phillips 1991) or systemic illness (Howard 1963) has been reported by some patients, in most cases no such history is elicited (Gordon et al 1967). Stiffness gradually spreads from axial to proximal appendicular muscles. Spasm of paraspinal muscles results in a characteristic extreme lordosis, and occasionally, more prominent upper back or shoulder spasm produces a kyphotic posture with shoulder elevation and inability to move the head (McEvoy 1991b). Stiffness of chest wall muscles may restrict respiration, causing poor exercise tolerance or inability to swim underwater (Howard 1963). Abdominal muscle spasm may cause early satiety (Olafson et al 1964). Although distal extremities and facial muscles tend to be spared by the process, cranial muscles have been involved in up to 80% of patients in some series (Gordon et al 1967; Dalakas et al 2001b), and foot spasm with dystonic posture has been reported (Jog et al 1992). Stiffness and spasm are relieved by sleep, general anesthesia, and neuromuscular blocking agents (Gordon et al 1967; Meinck et al 1984; Lorish et al 1989). However, even sleep may not relieve the spinal abnormality, which is profound.
Paroxysms of intense spasm of involved muscles intensify the chronic tightness and stiffness. Often triggered by emotional upset, sudden movement, or external stimuli, such as noise or manipulation of affected body parts, the spasms last seconds to more than 1 hour (Olafson et al 1964; Gordon et al 1967; Miller and Korsvik 1981; Jog et al 1992). They are accompanied by profuse diaphoresis, hypertension, tachycardia, and extreme dysphoria (Miller and Korsvik 1981), and may be severe enough to cause hip fracture or joint dislocation (Olafson et al 1964). Spasms that occur during walking cause patients to fall (Gordon et al 1967). There have been anecdotal reports of dysphagia with disordered esophageal and gastric motility (Soykan and McCallum 1997). Total esophageal obstruction due to spasm of the cricopharyngeus muscle has also been reported (Sulway et al 1970). Autonomic symptoms include diaphoresis, papillary dilation, increased heart and respiratory rate, hyperthermia, and hypertension. Sudden death due to autonomic failure has been reported (Mitsumoto et al 1991). Seizures have been noted in 10% of cases in some series (Lorish et al 1989). Derangements of extraocular movement (including gaze-holding nystagmus, ocular misalignment, impaired pursuit, and delays and fatigue in saccade initiation) have also been reported (Economides and Horton 2005; Oskarsson et al 2008). A series of cases has been reported in which stiff-person syndrome was associated with subacute cerebellar changes including ataxia, oculomotor abnormalities, and dysarthria (Rakocevic et al 2006). Depression is seen in more than half of patients and contributes to impairments in quality of life (Gerschlager et al 2002a). Anxiety, phobias, and alcoholism have also been reported (Black et al 1998; Henningsen and Meinck 2003).
Examination between extreme spasms reveals rock hard back, abdominal muscles, and proximal limb muscles (Lorish et al 1989). The paraspinal muscles are grossly hypertrophied, and it is often possible for the examiner to bury a hand in the furrow between the paraspinal columns. Extreme lumbar lordosis is typical. The patient may be unable to bend at the waist to touch the toes or to sit in a chair. Co-contraction of agonist and antagonist muscles is obvious to the examiner and underlies complaints of rigidity. Voluntary movements are restricted in range and slowed. The gait is slow and deliberate, resembling that of "a tin soldier" (Ornsteen 1935).
The examiner may be able to trigger an extreme spasm with noise or sudden extremity movement. Motor and sensory examinations are within normal limits. Other signs including dementia (Drake 1983), hyperreflexia, spastic gait, fasciculations, and brainstem signs have been reported but are atypical (McEvoy 1991a).
Barker and colleagues have suggested a division on clinical grounds into 3 separate illnesses. Stiff trunk syndrome is usually associated with the presence of antiglutamic acid decarboxylase (anti-GAD) antibodies and evidence of other autoimmune disease; it responds to pharmacotherapy with baclofen or diazepam and has a prolonged course. Stiff limb syndrome is more rarely associated with anti-GAD antibodies and other autoimmune dysfunction; it runs a protracted course and responds poorly to pharmacotherapy (Bartsch et al 2003). Progressive encephalomyelitis with rigidity and myoclonus progresses to death within months and may be associated with grossly abnormal cerebrospinal fluid (Barker et al 1998). The latter syndrome is often a paraneoplastic syndrome and may be associated with antibodies to glutamic acid decarboxylase, amphiphysin I, geophysin, or Ri antibodies (Butler et al 2000; Dalakas et al 2000; Wessig et al 2003; McCabe et al 2004).
Currently accepted clinical criteria for the diagnosis of stiff-person syndrome include: (1) insidious onset of muscular rigidity with difficulty turning or bending, with rigidity most prominent in the limbs and axial muscles, especially abdominal and thoracolumbar; (2) co-contraction of agonist and antagonist muscles, confirmed clinically and electrophysiologically; (3) episodic spasms superimposed on the underlying rigidity, precipitated by noise, tactile stimuli, or emotional upset; and (4) absence of other neurologic or other diseases that could explain the symptoms (Dalakas 1999).
Early studies noted a relationship between stiff-person syndrome and type I diabetes mellitus in as many as 60% of patients (Dalakas et al 2000). Other autoimmune disorders, including thyroiditis (Gorin et al 1990), myasthenia gravis with or without thymoma (Aso et al 1997; Nicholas et al 1997), adrenal and ovarian failure (McEvoy 1991a), pernicious anemia, vitiligo (Brashear and Phillips 1991), and autoimmune retinopathy have been described (Steffen et al 1999). Antibodies to GAD can be detected in up to 80% of patients with stiff-person syndrome using immunocytochemistry or radioimmunoassay. GAD antibodies are not specific for the diagnosis of stiff-person syndrome, but titers are higher than in other patients with GAD antibodies, including those with type I diabetes mellitus (Daw et al 1996). Among stiff-person syndrome patients with GAD antibodies, other organ-specific antibodies (such as those directed against islet cells, parietal cells, thyroid microsomal fraction, and thyroglobulin) are more commonly seen. Non-organ-specific antibodies, such as antinuclear, antimitochondrial, and antismooth muscle antibodies are also common in stiff-person syndrome (Grimaldi et al 1993). These patients are also more likely to have a personal or family history of organ-specific autoimmune disease (Solimena et al 1990).
Because antibody-positive patients may represent a homogeneous subgroup of stiff-person syndrome patients, Dalakas and colleagues looked at a series of such patients. In this series of 20 patients with stiff-person syndrome and positive anti-GAD antibodies, the average age at the onset of symptoms was 41 years. Diagnosis was made an average of 6 years after symptom onset. The predominant symptoms were muscular rigidity and episodic superimposed spasms. Most had asymmetric onset, and rigidity began as an intermittent phenomenon, but later became fixed. Falls occurred commonly, and chest restriction caused respiratory symptoms in 50% of the patients. On examination, all patients had increased paraspinal tone with hyperlordosis. Stiffness in facial and neck muscles was common. Nearly half the patients had hyperreflexia, and 2 patients intermittently had Babinski signs. Assistive devices were required by all the patients for ambulation. Spasms were common and were provoked by unexpected tactile or auditory stimuli or by psychological factors. Diabetes mellitus and thyroid disease were present in 8 patients. Three patients had pernicious anemia, 1 had celiac disease, and 1 had notalgia paresthetica. Family members with diabetes or thyroid disease were common. Also seen in family members were systemic lupus erythematosus, rheumatoid arthritis, myasthenia gravis, and vitiligo. Other autoantibodies were common (Dalakas et al 2000).
Jerking stiff-man syndrome resembles stiff-person syndrome; in addition to the chronic muscle spasm, though, there are rapid, violent, nocturnal, or diurnal myoclonic jerks in the axial and proximal appendicular muscles (Martinelli et al 1978; Leigh et al 1980; Alberca et al 1982). Usually, the myoclonic jerks first appear many years into the course of the illness and respond well to diazepam. These patients sometimes present with stimulus-sensitive myoclonus, even when the symptoms are otherwise well controlled by diazepam. This should be considered a rare variant of stiff-person syndrome.
A dominantly-inherited syndrome resembling stiff-man syndrome has been reported in 2 families (Klein et al 1972; Sander et al 1980). Onset of rigidity occurred at birth, and remained severe for the first 2 to 3 weeks of life. Symptoms then waned, only to recur in a milder form during adolescence or adulthood. Characteristic spasms were provoked when the patient was startled. No antibody studies were performed in these patients; the relationship of this disorder to stiff-person syndrome remains unknown. In another family, the affected father and daughter both had titers of antibody to GAD65, but they had different clinical involvement with predominantly appendicular involvement in the father and axial involvement in the daughter (Burns et al 2003).
Several members of a family with spinocerebellar ataxia type 3 with ataxia, myokymia, and pyramidal signs showed progressive trunk and abdominal muscle stiffness with painful spasms and electromyographic signs of continuous motor unit activity (Berciano et al 2006).
There is one report of stiff-person syndrome with GAD-antibodies following West Nile fever (Hassin-Baer et al 2004).
A 49-year-old woman of Haitian origin developed left leg stiffness and spasms, along with lumbar spasm and pain associated with exaggerated lumbar lordosis. Superimposed on chronic pain and stiffness in the left leg and back were intermittent episodes of painful extension of the knee and dorsiflexion of the foot that lasted for minutes. The patient had long-standing vitiligo, but no history of diabetes mellitus or other autoimmune disease. A family history of systemic lupus erythematosus existed in both her sister and niece. Physical examination demonstrated extreme hypertrophy and spasm of the paraspinal muscle columns and proximal greater than distal left leg. There were also intermittent slow extensor spasms of the left leg. An EMG demonstrated continuous firing of paraspinal and leg muscles.
Although earlier studies suggested no neuropathological changes in postmortem tissue from stiff-person syndrome patients, later studies suggested loss of anterior horn cells and spinal interneurons associated with perivascular inflammatory changes and gliosis.
Stiff-person syndrome may not reflect a single pathophysiologic process. However, the association of symptoms with disorders of organ-specific and non-organ-specific autoimmunity as well as the demonstration of autoantibodies in a majority of cases suggests that the syndrome relates to an autoimmune process. Antibodies to glutamic acid decarboxylase were detected in persons with stiff-person syndrome in 1988. Anti-GAD antibodies can be detected in serum or CSF using immunocytochemistry or radioimmunoassay in as many as 80% of persons with clinically diagnosed stiff-person syndrome (Murinson et al 2004), and there is evidence of intrathecal antibody synthesis (Dalakas et al 2001b). Intrathecal synthesis of CAD65 antibodies persists for years (Skorstad et al 2009). Radioimmunoassay is 96% sensitive and 95% specific compared with immunocytochemistry for the detection of GAD antibodies (Chang and Lang 2004; Murinson et al 2004). Anti-GAD antibodies are not specific for the diagnosis of stiff-person syndrome. They can be seen in 22% of patients with type 1 diabetes and in 3% of patients with neurodegenerative diseases. However, in these disorders, antibody titers are usually low, and there is no immunoreactivity to recombinant GAD65 (Levy et al 1999). On Western blot, serum and CSF from persons with stiff-person syndrome recognize a 65-kDa protein corresponding to GAD65 (Levy et al 1999). Recently, luciferase immunoprecipitation analysis of anti-GAD antibodies has demonstrated dramatic titer differences between persons with stiff-person syndrome and other disorders associated with these antibodies, with 100% sensitivity and specificity. Anti-GAD antibodies in persons with stiff-person syndrome showed high immunoreactivity, particularly with the central region containing decarboxylase catalytic domain (Burbelo et al 2008). Autoantibodies to the GABA-A receptor-associated protein were demonstrated in 70% of persons with stiff-person syndrome (Raju et al 2006).
In a subgroup of patients, stiff-person syndrome is a paraneoplastic disorder. These patients have a different distribution of stiffness with more prominent upper body involvement and less frequent lumbar hyperlordosis and abdominal muscle involvement (McCabe et al 2004; Murinson and Murinson 2008). In a recent series of 11 patients with stiff-person syndrome and amphiphysin antibodies, all patients were women, most had breast cancer, and none had diabetes (Murinson and Murinson 2008). Underlying malignancies include breast, small cell lung, thymoma, and ovarian cancer. The paraneoplastic type of stiff-person syndrome may be associated with high titers of GAD, amphiphysin I, gephyrin, or Ri antibodies (Butler et al 2000; Dalakas et al 2000; Wessig et al 2003; Murinson and Murinson 2008).
Studies of motor cortex excitability using transcranial magnetic stimulation suggest that there is an imbalance between inhibitory and excitatory intracortical circuitry, and that motor cortex hyperexcitability correlates with GAD antibody titers in CSF (Sandbrink et al 2000; Koerner et al 2004). Increased brainstem excitability is suggested by an abnormal recovery cycle of the R2 component of the blink reflex and abnormalities of masseter and glabellar reflexes similar to those seen in hyperekplexia (Molloy et al 2002; Khasani et al 2004). Electromyography suggests that the motor unit is excessively active in stiff-person syndrome; its activity does not decrease when the subject attempts to relax the muscle or to activate its antagonist and increases when the skin overlying the muscle is stimulated (Martinelli et al 1978). Meinck and colleagues have described a phenomenon called "spasmodic reflex myoclonus." Following stimulation of a peripheral nerve, they were able to record 1 to 3 myoclonic bursts in the trunk muscles occurring during the ensuing 60 to 70 ms. The recruitment order of the muscles suggested that the activity was organized in the spinal cord (Meinck et al 1995), perhaps involving Renshaw cells (Howard 1963) or the gamma motor system (Gordon et al 1967).
Levy and colleagues have suggested that impaired intracortical inhibition causes excessive discharge of motor cortex neurons to the alpha motor neurons, which is enhanced by the loss of spinal inhibitory circuits, resulting in excessive ambient muscle activity. Superimposed spasms in response to sudden stimuli may relate to excessive responses to afferent stimuli from muscle spindles and skin receptors caused by impairments in spinal inhibitory interneurons (Levy et al 1999).
A preliminary PET study that imaged GABA-A receptors with 11C-flumazenil demonstrated an extensive decrease in ligand binding in the premotor cortex bilaterally and less so in the motor cortex and right supplementary cortex in 2 patients with stiff-person syndrome. Binding was increased in cerebellar nuclei (Perani et al 2007).
The association of stiff-person syndrome GAD antibodies prompted a search for evidence that an autoimmune process causes these changes in motor excitability. The target of GAD65 antibodies, glutamic acid decarboxylase, catalyzes the conversion of glutamic acid to GABA and is specific for GABA-ergic neurons in the CNS. Immunologically identical GAD is found in the pancreatic beta islet cell, fallopian tube epithelium, and spermatozoa (Solimena and DeCamilli 1991). GAD is localized at the cytoplasmic surface of synaptic vesicles in GABA-ergic nerve terminals and in pancreatic beta islet cells (Solimena et al 1990; Solimena and DeCamilli 1991). Glutamic acid decarboxylase exists in 2 isoforms, 65-kd and 67-kd, which are the products of 2 different genes. Analysis of the binding specificity of GAD65 antibodies in stiff-person syndrome suggests differences in epitope specificity of plasma and CSF GAD65 antibodies, supporting intrathecal synthesis of the antibody. The antibodies inhibit GAD65 activity, preventing GABA synthesis (Raju et al 2005). Detailed immunologic study has shown that T-cells of persons with stiff-person syndrome target epitopes in the middle of GAD65, whereas T-cells of persons with type 1 diabetes target different epitopes in the middle and at the C-terminal end of GAD65 (Lohmann 2003; Burbelo et al 2008). The patients show differences in GAD antibodies as well, with IgG4 and IgE antibodies in stiff-person syndrome compared to IgG1 antibodies in type 1 diabetes. These findings suggest that different antibody and cellular responses to the same antigen cause different disorders (Lohmann 2003), although others have suggested the differences are more related to the higher titers of anti-GAD antibodies in patients with stiff-person syndrome (Piquer et al 2005). In a recent study, clinical records were reviewed for all subjects who were screened for GAD antibody for neurologic or endocrinologic reasons at a large screening laboratory and whose GAD-antibody titers by radioimmunoassay were greater than or equal to 2000 U/ml. Eighty-two percent had a neurologic disorder; of these, 36% had stiff-person syndrome and 28% had cerebellar ataxia. Other associated neurologic syndromes included epilepsy, non-paraneoplastic limbic encephalitis, and paraneoplastic syndromes (Saiz et al 2008).
The origin of GAD antibodies in stiff-person syndrome is unknown. Antigen-antibody interactions do not occur with intracellular antigen, so a humoral immune process seems unlikely. Antibodies may be seen as an epiphenomenon when cellular damage exposes intracellular antigen to the immune system, but the immune response is rarely as robust or as specific for a single antigen as would be suggested by data in stiff-person syndrome. T-cell mediated autoimmune processes have been implicated in type 1 diabetes mellitus and might play a role in the pathogenesis of stiff-person syndrome as well (Solimena and DeCamilli 1991; Costa et al 2002). T-cells may recognize peptide fragments of intracellular antigens that are presented at the cell surface by major histocompatibility complex molecules (Solimena and DeCamilli 1991). However, although pancreatic beta islet cells express major histocompatibility complex molecules at the cell surface, neurons are not generally believed to undergo this process (Dumon and Docherty 1992). It has been demonstrated that cultured GABA-ergic neurons may express major histocompatibility complex class 1 molecules after experimental manipulations, such as treatment with lymphokines or insulin (Dumon and Docherty 1992). Further work in this area will be necessary before the mechanism of the disorder is understood. Any theory that both type 1 diabetes and stiff-person syndrome are T-cell-mediated autoimmune disorders must also take into account the fact that documented cell destruction in type 1 diabetes exists, whereas no such cell destruction has been consistently demonstrated in stiff-person syndrome.
Passive transfer of amphiphysin IgG to rats induces a characteristic syndrome of muscle stiffness with spasms, supporting a direct role of amphiphysin antibodies in paraneoplastic stiff-person syndrome (Sommer et al 2005). Purified IgG from patients with stiff-person syndrome and anti-GAD antibodies infused directly into the rat cerebellum blocked the enhancement of the corticomotor response caused by repetitive stimulation of the sciatic nerve. Paraspinal administration of the purified IgG induced continuous motor activity in the gastrocnemius muscle (Manto et al 2007).
Neuropharmacologic studies have shown that the muscle spasm of stiff-person syndrome decreases following the administration of diazepam, baclofen, valproic acid, levetiracetam, and propofol, all of which enhance GABA neurotransmission (Howard 1963; Whelan 1980; Spehlmann et al 1981; Meinck et al 1984; Riegg et al 2004; Hattan et al 2008; Vernino and McEvoy 2008). Muscle activity is increased in response to clomipramine and levodopa and decreased by clonidine, which decreases catecholaminergic activity. A report of increases in 3-methoxy-4-hydroxyphenylglycol, a metabolic product of norepinephrine in the urine of an affected patient, suggests that excessive catecholamine activity plays a role in the production of muscle spasm (Schmidt et al 1975). Magnetic resonance spectroscopy studies in stiff-person syndrome suggest lower levels of GABA in the motor and posterior occipital cortices (Levy et al 1999). Brain magnetic resonance spectroscopy studies show reduced GABA levels in the sensorimotor and posterior occipital cortices (Levy et al 2005). It is now believed that dysfunction of a brainstem system that uses GABA (inhibitory) and catecholamine (excitatory) neurotransmitters is responsible for the loss of descending inhibition that underlies the abnormal muscle activity.
Necropsy studies have shown loss of GABA-ergic cells in the cerebellar cortex, decreased size of Renshaw cells in the spinal cord, and neurogenic atrophy in skeletal muscle (Warich-Kirches et al 1997). Perivascular lymphocytic cuffing has been described in the brainstem and spinal cord (Mitsumoto et al 1991). Changes in muscle do not suggest a primary muscle disorder (Gordon et al 1967).
There is no available information on the incidence and prevalence of stiff-person syndrome.
There are no known risk factors or preventive strategies for stiff-person syndrome.
The differential diagnosis of stiff-person syndrome includes peripheral neuromuscular disorders, as well as disorders of central motor control. It most closely resembles Isaac syndrome, the disorder characterized by continuous muscle fiber activity. This is a heterogeneous group of disorders characterized by involuntary muscle contraction, often with myokymia. EMG shows continuous motor unit activity, and may show fibrillations and fasciculations. Persistence of the muscle contraction during sleep and general anesthesia as well as proximal nerve block distinguish these disorders from stiff-person syndrome, as does the response of these symptoms to anticonvulsant medications (Auger 1991). Spasticity differs from stiff-person syndrome in distribution of the increased tone, absence of typical intense spasm, and associated weakness and pathologic reflexes. Extrapyramidal disorders may present with rigidity. In early progressive supranuclear palsy the rigidity may be predominantly axial, but other extrapyramidal signs, as well as more common parkinsonian syndromes, distinguish this disorder from stiff-person syndrome. Involuntary posturing accompanies the stiffness seen in dystonia. Chronic tetanus may superficially resemble stiff-person syndrome. However, trismus is common, the spasms are abrupt in onset and resolution, and the clinical syndrome lasts weeks to months, rather than years (Roos 1991). Motor unit abnormalities and lack of continuous motor unit activity distinguish neuropathic and myopathic disorders from stiff-person syndrome (Olafson et al 1964).
The cornerstone of the diagnostic workup is the electromyographic demonstration of continuous motor unit activity. The motor unit activity should subside with the administration of intravenous diazepam or with chronic oral diazepam therapy (Gordon et al 1967). Electromyography also helps differentiate stiff-person syndrome from other etiologies of muscle stiffness such as myopathy, muscular dystrophy, and Isaac syndrome. Neuroimaging studies may help to diagnose progressive encephalomyelitis with rigidity and structural lesions of the nervous system. CSF studies may demonstrate increased immunoglobulin or oligoclonal bands, but these findings are not specific for etiology and may not increase diagnostic yield. The increased incidence of diabetes and other autoimmune disorders in patients with stiff-person syndrome warrants a search for non-organ-specific autoantibodies, such as smooth muscle, mitochondrial, and nuclear antibodies, as well as organ specific autoantibodies including thyroid-microsomal, thyroglobulin, and parietal cell antibodies (Gorin et al 1990; Darnell et al 1993; Grimaldi et al 1993). Although not needed for diagnosis, in settings where assays for CSF and serum glutamic acid decarboxylase antibodies are available, these may be useful in the confirmation of diagnosis. An evaluation for underlying malignancy is important, particularly in patients with predominant upper body stiffness and sparing of the lumbar and abdominal musculature, or when other neurologic deficits such as encephalopathy, opsoclonus, or ataxia are present.
Untreated stiff-person syndrome may progress to total disability. Complications of the bedridden state (eg, pneumonia) may represent underreported case fatalities (Kasperek and Zebrowski 1971). Sudden death, presumably due to autonomic dysfunction, has been reported in some cases (Mitsumoto et al 1991). Although treatment with diazepam and other agents provides effective symptom relief, the course of the disease is not altered. Sufficient information does not exist to judge the effects of aggressive therapy directed at the autoimmune process on prognosis or disease course.
Treatment of stiff-person syndrome has focused on symptomatic control of rigidity and spasm. Diazepam is clearly the most effective medication (Howard 1963; Lorish et al 1989; McEvoy 1991a; 1991b; Jog et al 1992). The recommended initial dose is 20 mg daily, in divided doses. Dose escalation occurs as tolerated; some patients require doses as high as 400 mg daily (McEvoy 1991a; Jog et al 1992). Baclofen has also been reported effective at a daily dose of 60 to 90 mg (Whelan 1980; Miller and Korsvik 1981; McEvoy 1991a). Other medications considered effective include clonazepam, valproic acid, clonidine, vigabatrin, tiagabine, and levetiracetam (Spehlmann et al 1981; Lorish et al 1989; McEvoy 1991a; Prevett et al 1997; Murinson and Rizzo 2001; Riegg et al 2004). The rarity of stiff-person syndrome has precluded any controlled trials of either symptomatic treatments or strategies to treat the presumed autoimmune basis of the condition.
Anecdotal reports of the effectiveness of plasmapheresis and immunosuppression vary (Piccolo et al 1988; Harding et al 1989; Vicari et al 1989; Brashear and Phillips 1991). High-dose steroid therapy may be contraindicated in the face of diabetes. However, when no contraindication is present and the patient is responding poorly to therapy, immunosuppressive treatment with high dose steroids, azathioprine, or plasmapheresis may be attempted (Shariatmadar and Noto 2001). Intravenous immune globulin has been reported to have benefited 6 patients in open trials at 2 centers (Amato et al 1994; Karlson et al 1994) and in anecdotal cases (Khanlou and Eiger 1999; Souza-Lima et al 2000). Dalakas and colleagues conducted a randomized, double-blind, placebo-controlled crossover study of intravenous immune globulin (2 g/kg per month administered as sequential doses of 1 g/km over successive days) in 16 patients with stiff-person syndrome. Each treatment was given over 3 months. There were significant improvements in the intravenous immune globulin treatment group in stiffness score and in the heightened-sensitivity scale. Anti-GAD65 antibody titers declined during the active treatment phase (Dalakas et al 2001a). Intravenous immune globulin treatment improves quality of life in stiff-person syndrome (Gerschlager and Brown 2002b). An evidence-based review suggested intravenous immunoglobulin was useful as second-line therapy in stiff-person syndrome (Dalakas 2004).
There is an anecdotal report of response to rituximab in a patient refractory to conventional treatment and cytotoxic agents (Baker et al 2005). There is an ongoing clinical trial of rituximab for stiff-person syndrome (see www.clinicaltrials.gov).
Intrathecal baclofen (Penn and Mangieri 1993; Seitz et al 1995) and intramuscular injections of botulinum toxin A (Davis and Jabbari 1993) are believed to have been helpful in isolated cases. In a double-blind, placebo-controlled study of intrathecal baclofen in 3 patients, all showed improvement in EMG activity, but only 1 patient had significant clinical improvements (Silbert et al 1995).
In isolated cases, stiff-person syndrome symptoms in women have begun during pregnancy or in the peripartum period (Trethowan et al 1960; George et al 1984). Pregnancy in a woman with established stiff-person syndrome has been described. The pregnancy itself was unremarkable. Indeed, stiffness and spasm improved, allowing reductions in the patient's requirement for diazepam and baclofen. The delivery was complicated by fetal distress, requiring the use of forceps, and generalized spasms in the mother precipitated by the episiotomy despite epidural analgesia. Following delivery, the baby did well, though the mother was required to once again increase her medication doses (Weatherby et al 2004). In another woman who had 2 successful pregnancies, GAD antibodies were detected in amniotic fluid and blood of the infants, but there were no signs of stiff-person syndrome in the infants (Nemni et al 2004). GAD65 antibodies may be seen in the serum of infants of mothers with stiff-person syndrome, but the infants do not themselves necessarily show evidence of the disorder.
A syndrome resembling stiff-person syndrome has been reported with the use of sufentanil during cardiac, abdominal, or vascular surgery. There was no confirmation of continuous muscle firing by electromyography in these 3 cases, in which symptoms resolved within 12 hours (Gust and Bohrer 1995). Prolonged weakness following general anesthesia, including the use of nondepolarizing muscle relaxants, has also been reported in stiff-person syndrome (Johnson and Miller 1995; Bouw et al 2003).
ICD-9:
Other and unspecified extrapyramidal diseases and abnormal movement disorders: 333.91
ICD-10:
Other specified extrapyramidal and movement disorders: G25.8
Ataxia
Depression
Dysarthria
Graves disease
Hashimoto thyroiditis
Myasthenia gravis
Pernicious anemia
Type 1 diabetes mellitus
Vitiligo
Autoantibodies
Baclofen
Botulinum toxin treatment of neurologic disorders
Diazepam
Endocrine neuroimmunology
Paraneoplastic syndromes
Periodic limb movements
peripheral neuromuscular disorders
central motor control disorders
Isaac syndrome
spasticity
extrapyramidal disorders
early progressive supranuclear palsy
parkinsonian syndromes
dystonia
chronic tetanus
neuropathic disorders
myopathic disorders
For more specific demographic information, see the Epidemiology, Etiology, and Pathogenesis and pathophysiology sections of this clinical summary.
Age
13-18 years
19-44 years
45-64 years
65+ years
Population
None selectively affected.
Occupation
None selectively affected.
Sex
male=female
Family history
None
Heredity
None
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**References especially recommended by the author or editor for general reading.