Stiff person syndrome
Stiff person syndrome (SPS) (or stiff-man syndrome; also known as Moersch-Woltman Condition) is a rare neurologic disorder of unclear etiology characterized by progressive rigidity and stiffness, primarily of the axial musculature, that is superimposed by spasms, resulting in postural deformities. There are also sub-variants: stiff baby syndrome and stiff limb syndrome. Other forms or types of the disease include focal SPS, jerking SPS, and progressive encephalomyelitis with rigidity and myoclonus.
Signs and symptoms
Individuals with stiff person syndrome tend to present in 3 different stages: early, late and end stage. In the early stages, there are few objective findings indicating SPS during the initial assessment. SPS will begin insidiously in the axial muscles. Patients will present with an exaggerated upright posture and have stiffness and pain in the whole back. Sleep disturbances are also common due to muscle spasms waking them. In the late stages, proximal limb muscle become involved and the patient tends to move slower as fast movements will cause the severe spasms. Emotions such as anger have been shown to have a link to causing the spasms, which begin in this stage. Exaggerated lumbar lordosis becomes more evident in the patients. Depression can be comorbid with SPS at this stage due to the patient’s quality of life decreasing. In the end stage, activities of daily living such as eating and simple movements become hard to perform. Skeletal fractures and muscle ruptures occur quite often along with joint deformities.
Those with the illness experience progressive, fluctuating tonic muscle contractions, particularly the axial musculature. These spasms occur in response to environmental stimuli such as voluntary or passive movements, and unexpected somatosensory or auditory stimulation. Often changes in emotion or stress can trigger spasms as well. Common signs of SPS found during assessment are hypertonia, hyperreflexia and rigidity of muscles.
Reflexive integrity in individuals with stiff person syndrome can be assessed via deep tendon reflexes as well as resistance to passive stretch. Deep tendon reflexes are graded using a 0 to 4+ scale. 0 indicates absent reflexes, 1+ indicates hypoactive (decreased) reflexes, 2+ indicates normal reflexes, 3+ indicates hyperactive (increased) reflexes without clonus and 4+ indicates hyperactive reflexes with clonus. During the examination, individuals with stiff person’s syndrome are likely to have deep tendon reflexes which are graded at 2+ (normal) or 3+ (increased reflexes). Furthermore, they are likely to exhibit increased startle reflex as well as an increased head retraction reflex (HRR).
Symptoms begin in the region of the trunk and the lower extremities before moving proximally in the upper limbs, and eventually affecting facial and laryngeal muscles used for swallowing and speech. Depression and anxiety are often noted although this may be a result of discomfort due to stiffness, rather than underlying neurochemical abnormalities. MRI detection of GABA in the brain have demonstrated reduced levels in stiff-person syndrome.
In the variant Stiff-limb syndrome, symptoms present focally affecting one or more limbs. Motor symptoms occur predominantly in distal limb muscles rather than axial muscles. However, when patients experience severe spasms, motor symptoms can be seen in the trunk, upper extremities and face. Increased distal limb stiffness in ankles and feet leads to feet being in constant plantar flexion. This in turn affects posture during gait and increases fall risks for the patient.
Because many patients with SPS have circulating antibodies to the enzyme glutamic acid decarboxylase (GAD), an autoimmune cause of the disease has been postulated. However, GAD antibodies cannot be the sole cause, as most Type I diabetics possess anti-GAD antibodies, yet the frequency of SPS among Type I diabetics is 1 in 10,000. Approximately 60% of patients diagnosed with SPS have anti-GAD antibodies present, while 40% do not and therefore rely on clinical testing for diagnosis. The GAD protein regions (epitopes) recognized by these antibodies may differ in each disease(GAD65ab). A mutation in GLRA1 (glycine receptor) is responsible for some cases of stiff person syndrome. Apart from antibodies to GAD65 seen in the serum, these antibodies are also found in the cerebrospinal fluid of stiff-person syndrome patients. Rarely, SPS is associated with breast cancer and Hodgkin's lymphoma.
SPS is diagnosed by evaluating clinical findings and excluding other conditions. There is no specific laboratory test that confirms its presence. Underdiagnosis and misdiagnosis are common.
The presence of antibodies against GAD is the best indication of the condition that can be detected by blood and CSF testing. Anti-GAD65 is found in SPS patients in about 80% of cases. Anti-thyroid, anti-intrinsic factor, anti-nuclear, anti-RNP, and anti-gliadin are also often present in blood tests. Electromyography (EMG) demonstrates involuntary motor unit firing in SPS patients. EMG can confirm the diagnosis by noting spasms in distant muscles as a result of subnoxious stimulation of cutaneous or mixed nerves. Responsiveness to diazapam often confirms that the patient is suffering from SPS, as this decreases stiffness and motor unit potential firing.
The same general criteria are used to diagnose paraneoplastic SPS as the normal variant. 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 this is the case.
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. They are sometimes suspected of malingering. It takes an average of six years after the onset of symptoms before the disease is diagnosed.
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. The typical form of SPS is generally responsive to treatment, but the condition usually progresses and stabilizes periodically. Even with treatment, qualify of life generally declines as stiffness precludes many normal activities. Some patients require mobility aids due to the risk of falls. About 65 percent of SPS patients are unable to function independently. About ten percent of SPS patients require intensive care at some point; sudden death occurs in about the same amount of patients. These deaths are usually caused by metabolic acidosis or an autonomic crisis.
There is no evidence-based criteria 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.
GABAA agonists, usually diazapam but sometimes other benzodiazepines, are the primary initial 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 a muscle relaxant and anticonvulsant effect, often providing symptom relief. Because the condition worsens over time, patients generally require higher doses over time, leading to more side effects. For this reason, gradual increase in dosage of benzodiazepines is indicated. 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.
Treatments that target the autoimmune response are also used. Intravenous immunoglobin is the best second-line treatment for SPS. It often decreases stiffness and improves quality of life and startle reflex. It is generally safe, but there are possible serious side effects and it is expensive. The European Federation of Neurological Sciences suggests it be used when disabled patients do not respond well to diazapam and baclofen. Steroids, rituximab, and plasma exchange have been used to suppress the immune system in SPS patients. The efficacy of these treatments is unclear. Botulinum toxin has been used to treat SPS, but it does not appear to have long-term benefits and has potential serious side effects. In paraneoplastic cases, the tumor must be managed for the condition to be contained. Opiates are are sometimes used to treat severe pain, but in some cases they exacerbate symptoms.
SPS is estimated to have a prevalence of about one per million. Underdiagnosis and misdiagnosis hinder epidemiological information about the condition and may have led to its prevalence being underestimated. In the United Kingdom, 119 cases were identified between 2000 and 2005. It does not predominantly occur in any racial or ethnic group. The age of onset varies from about 30 to 60, and it most frequently occurs in people in their 40s. Five to ten percent of patients with SPS have the paraneoplastic variant of the condition. In one group of 127 patients, only 11 of them had paraneoplatic symptoms. About 35 percent of SPS patients have type I diabetes.
SPS was first described by Moersch and Woltman in 1956. 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 voluntary muscle contractions were occurring in their patients. Previously, cases of SPS had been dismissed as psychogenic problems. Moersch and Woltman initially called the condition "stiff-man syndrome", but the first female patient was confirmed in 1958 and a young boy was confirmed to have it in 1960. 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. In 1989, criteria for an SPS diagnosis were adopted that included episodic axial stiffness, progression of stiffness, lordosis, and triggered spasms. The name of the disease was shifted from "stiff-man syndrome" to the gender-neutral "stiff-person syndrome" in 1991.
In 1988, Solimena et al. discovered that autoantibodies against GAD played a key role in SPS. Two years later, Solimena found the antibodies in 20 out of 33 patients examined. In the late 1980s, it was also demonstrated that the serum of SPS patients would bind to GABAergic neurons. In 2006, the role of GABARAP in SPS was discovered. The first case of paraneoplastic SPS was found in 1975. In 1993, antiamphiphysin was shown to play a role in paraneoplastic SPS, and seven years later antigephyrin was also found to be involved in that variant of the condition.
In 1963, it was determined that diazapam helped alleviate symptoms of SPS. Corticosteroids were first used to treat the condition in 1988, and plasma exchange was first applied the following year. Intravenous immunoglobulin was first used to treat the condition in 1994.
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