Stiff-Person Syndrome
The clinical presentation of this patient is a relatively typical case of stiff-person syndrome. The patient had stiffness and rigidity of muscles, predominantly in the lower limbs, which resulted in slowly progressive impairment of her ability to ambulate. She had frequent superimposed episodes of spasms, precipitated by emotional stress and by sudden movements. Her intellectual functions were normal. She had increased muscle tone and hyperreflexia on examination, consistent with her stated complaints, and occurring in the absence of sensory findings. The electromyographic study showed continuous muscle activity despite relaxation, suggesting excessive activity of otherwise normal motor units. A test for serum antibodies glutamic acid decarboxylase (GAD) was positive, providing additional support for the diagnosis of stiff-person syndrome.
Several of the respondents suggested the possibility of a paraneoplastic association for this patient's diagnosis of stiff-person syndrome, which is occasionally reported (e.g., Folli et al., 1993). Although the patient did have a small (<1 cm) thyroid adenoma, found to be benign on needle aspiration, there was no evidence of any malignant process on mammograms or on chest imaging. To date, we have detected no evidence of occult malignancy on subsequent screening or examinations.
This patient's stiffness and muscle spasms are unlikely to have arisen from a discrete spinal cord lesion, in view of the electromyographic results, absence of a sensory level and rectal tone abnormalities on exam, and negative imaging studies. Isaacs' syndrome, or acquired neuromyotonia, which in some cases is associated with autoantibodies against voltage-gated K+ channels, is also less likely in view of clinical and electromyographic absence of fasciculations, and clinical absence of myokymia or hyperhidrosis. Furthermore, the repetitive afterdischarges, high-frequency doublets or multiplets, or myokymic discharges typical of a neuromyotonic process were not detected on the electromyographic studies. Extrapyramidal syndromes, particularly progressive supranuclear palsy, may present with relatively isolated, axial rigidity early in the clinical course, but should not be confused with this patient's illness, particularly in the absence of eye movement abnormalities and autonomic failure. Chronic tetanus may present with intermittent spasms, lasting a few weeks to months (usually not years) and trismus is common on examination. Frequently, a history or clinical evidence of injury can be elicited in such cases. Likewise, tetany resulting from electrolyte abnormalities, which usually presents in a more generalized distribution, was not evident in this patient.
A syndrome of progressive encephalopathy with rigidity and reflex myoclonus (PERM) may also be considered in patients presenting with acquired axial rigidity and spasms, but the patient's normal mental status and absence of myoclonus make such a consideration unlikely in her case.
Frequently a psychiatric diagnosis, such as an anxiety disorder, may be entertained early in the course of the illness by physicians inexperienced in the recognition and treatment of neuromuscular disorders. In our referral experience, this initial impression may be reinforced by a positive response to benzodiazepines, which may be used in the treatment of anxiety disorders as well as the stiff-person syndrome. A careful history and examination, documenting positive evidence of neurologic dysfunction as well as the lack of evidence for a primary psychiatric disorder, is of critical importance in such cases.
The stiff-person (or stiff-man) syndrome was described by Moersch and Woltman in 1956. Their original description included 14 patients which had a progressive syndrome of fluctuating muscle rigidity and spasm. These patients were described as resembling tin soldiers with titanic muscle spasms. Lorisch et al. (1989) proposed the following diagnostic criteria for the stiff-person syndrome:
The stiff-person syndrome, although described as a rare disorder, is seen frequently enough for many referral centers to compile substantial case series. In a large series from the Mayo Clinic, McEvoy (1990) summarized 98 cases diagnosed between 1956-1991. It is seen more frequently in women than men. Symptoms usually begin between 30-70 years of age. The onset of stiffness is insidious, mainly in the neck and back (axial) muscles, and accompanied by pain. Most patients do not report prior trauma or illness as a possible inciting event, although some patients may relate their onset of symptoms to a possible triggering event. Stiffness typically spreads from axial to appendicular muscles, and it usually involves lower limb muscles predominantly. Spasm involving paraspinal muscles can result in extreme lordosis and spasm of muscles around the shoulder and neck may give rise to kyphosis. Patients may also have spasm of respiratory, abdominal, and facial muscles, and even the cricopharyngeus muscle. Spinal anesthesia as well as sleep and neuromuscular blocking agents can relieve spasms and stiffness. Paroxysms of muscle spasm can be accompanied by profuse diaphoresis, hypertension, tachycardia, and extreme dysphoria. Spasms can occasionally be severe enough to cause bone fractures, or dislocation of the hip or other joints. Frequently the examination reveals hypertrophy of paraspinous muscles in addition to stiffness. The patient is unable to bend and touch the toes, but often cannot flex or extend the spine even minimally, due to the pronounced stiffness. Lower extremity spasticity and hyper-reflexia are often present.
Many authors, including Baker et al. (1997) and Shaw (1999), categorize patients with stiff-person syndrome into multiple subtypes, such as stiff-trunk syndrome, stiff-limb syndrome and progressive encephalomyelitis with rigidity. Other groups emphasize that some "stiff-person" presentations should be considered as separate disorders, with differing causes and prognosis from the "classical" stiff-person syndrome.
Electrical studies typically show normal nerve conduction velocities and distal latencies, together with continuous motor activity in clinically involved muscles, which can be abolished by intravenous diazepam. This excessive motor unit activity does not decrease with patient's attempts to relax a given muscle or to activate its antagonist muscle. Motor unit activity may also increase when skin overlying the muscle is stimulated. This continuous activity is thought to result from a failure of normal inhibitory mechanisms, and abolition of continuous motor unit activity by spinal anesthesia suggests a locus of dysfunction at a spinal or higher level.
Frequently, autoimmune disorders are associated with the stiff-person syndrome, including insulin-dependent diabetes mellitus (up to 1/3 of patients with stiff-person syndrome), thyroiditis, myasthenia gravis, adrenal and ovarian failure, pernicious anemia, and vitiligo. CSF studies occasionally show increased IgG levels and oligoclonal bands, suggestive of a localized immune process. Most prominently described in the stiff-person syndrome, however, are specific autoantibodies thought to be involved in the pathogenesis of the disorder. In this regard, three forms of the stiff-person syndrome are generally recognized:
Antibodies to GAD may be found in CSF as well as serum. There are anti-GAD antibodies detectable in 60% of patients; if criteria are applied rigorously, the percentage of patients with anti-GAD antibodies may reach 90% for typical presentations (Brown and Marsden, 1999). Serum anti-amphiphysin antibodies are found in <5% of patients with stiff-person syndrome.
Although anti-GAD antibodies may be found in patients with autoimmune diabetes mellitus lacking neuromuscular symptoms, increasing evidence suggests that the autoantibodies detected in these two disorders may be functionally distinguishable. Sera from patients with stiff-person syndrome can reduce GABA production in brain extracts, whereas sera from patients with autoimmune diabetes mellitus or polyendocrine dysfunction do not (Dinkel et al., 1998). Patients with stiff-person syndrome have much higher titers of anti-GAD antibodies than those with insulin-dependent diabetes mellitus. Furthermore, disease-specific epitope recognition by autoantibodies has been strongly suggested (e.g., Kim et al., 1994). GABA, an inhibitory neurotransmitter, is synthesized with the assistance of two GAD isoforms, GAD 65 and GAD 67. One or more conformation-dependent epitopes on GAD 65 (particularly an N-terminal epitope, and an epitope located between amino acids 475-585) may be uniquely recognized by sera from patients with stiff-person syndrome. It is not clear at this time whether the subtypes of anti-GAD antibodies found selectively in patients with stiff-person syndrome can directly injure GABAergic neurons, or whether their effects, if actually pathogenic, are largely on neuronal function.
Therapies for patients with stiff-person syndrome are based on three approaches: enhancing spinal cord inhibitory processes, suppression of autoimmune processes, and (if detected) removal of an associated malignancy. Diazepam is highly effective at reducing spasms and stiffness, but oral doses of up to 300 mg per day may be necessary in some patients. Baclofen has been used with excellent responses both orally and intrathecally with typical dosage ranges of 10-100 mg per day orally, and 50-1000 mcg (µg) per day intrathecally. Other agents with reported benefit in some patients are tizanidine, methocarbamol, vigabatrin, and valproate (the latter used mainly for spasms). Botulinum toxin has been used in some occasions for severe muscle spasms with dystonia. Immunosuppressive therapies which may be helpful in patients with stiff-person syndrome are corticosteroids, plasma exchange and intravenous immunoglobulin infusions.
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