Stiff Person Syndrome

General

SPS was described by Moersch and Woltman in 1956. It is characterized by a centrally mediated, insidiously progressive spasticity and rigidity of the proximal limb and axial musculature. Lorish and colleagues^[1] subsequently proposed 7 clinical criteria required for the diagnosis of SPS:

Stiffness and rigidity in axial muscles
Progression to involve proximal limb muscles
Abnormal axial posture, increased lumbar lordosis
Superimposed spasms
Absence of brainstem, pyramidal, extrapyramidal, and lower motor neuron signs; sphincter and sensory disturbance; or cognitive involvement
EMG showing continuous motor unit activity in at least 1 axial muscle
Response to diazepam

The differential diagnosis for someone who presents with spasticity and rigidity is listed in Table 1. Most of these entities can be excluded based on careful imaging and electrodiagnostic testing. The "classic" SPS is an autoimmune neurologic syndrome with other systemic autoimmune manifestations, such as diabetes mellitus.

It is now known that this syndrome can also occur as a paraneoplastic syndrome. Although first described in women with breast cancer,^[2] it has now been reported in patients with small cell lung cancer, Hodgkin's disease, and colon cancer.^[3-6] The classic and paraneoplastic SPS have clinically distinct presentations, autoantibody findings, and disease associations. These 2 distinct clinical presentations of the same disease will be discussed separately; Table 2 highlights the major differences.

Clinical Features

Classic SPS. SPS is an uncommon disease, frequently of autoimmune origin, characterized by progressive muscle stiffness of the paraspinal and limb musculature with superimposed painful spasms of the affected muscles. Classic SPS is thought of as an autoimmune disease because of the high incidence of autoantibodies and its association with other autoimmune diseases. Diabetes is seen in 40% to 70% of patients; autoimmune thyroid disease and vitiligo are also associated with SPS. Autoantibodies (microsomal, thyroglobulin, islet cell, parietal cell) are found in 86% of patients with high titer anti-GAD antibodies.

The hallmark of the disease is the association with anti-GAD antibodies, seen in 60% of patients. The anti-GAD titers in SPS may be 50 times higher than those associated with type 1 diabetes mellitus. Other laboratory studies including CSF analysis are normal, although elevated IgG and oligoclonal bands can be seen in 60% of patients. EMG and NCS demonstrate continuous motor-unit activity in antagonist muscle groups at rest. The muscle spasms are brought out by emotion, light touch, or other tactile stimuli, and have been demonstrated both clinically and electrographically to disappear after administration of IV or oral diazepam. Prognosis for these patients is fair. Withdrawal of benzodiazepines may be life-threatening and physical therapy must be tailored to the needs of the patient.

Paraneoplastic SPS. The paraneoplastic SPS was first described in a woman with breast cancer who had the triad of the SPS, breast adenocarcinoma, and anti-amphiphysin autoimmunity.^[2] Since this original description, cases have been described in patients with other cancers including small-cell lung cancer, Hodgkin's disease, and colon cancer.^[3-6] In contrast to classic SPS, the paraneoplastic syndrome usually presents with a distinctly different pattern of musculature involvement. Most patients have rigidity and spasms of the limbs, both the distal lower extremity and the upper extremity are described. In paraneoplastic SPS the musculature of the trunk is typically spared; increased lumbar lordosis may be absent in this variant.

EMG and NCS show continuous motor unit activity at rest and may also show hypersynchronous segmented discharges termed spasmodic reflex myoclonus. CSF studies may show antiamphiphysin antibodies. In contrast to those with classic SPS, these patients do not typically produce anti-GAD antibodies, although at least 2 patients with the paraneoplastic syndrome have been described with both anti-GAD and antiamphiphysin antibodies. Overall prognosis is determined by the underlying malignancy, and treatment of the underlying tumor plays an important role in the reversal of clinical symptoms.

Treatment

The mainstay of treatment for spasticity and rigidity are centrally acting medications such as diazepam, clonazepam, and baclofen. The proposed biologic mechanism for efficacy of the medications is through increased GABA-mediated central inhibition. Intrathecal baclofen may be useful, but patients are sensitive to withdrawal of baclofen and pump replenishment can be rife with peril.

For the patient with classic SPS, benzodiazepine withdrawal may be life-threatening. Other gamma-aminobutyric acid (GABA)-ergic therapies have been reported as effective; vigabatrin is not preferred because of visual field effects. Many case reports have described responses to immunomodulatory therapies and although controlled clinical trials are yet to be reported, there are reasons to believe that treatments such as intravenous immune globulin will be useful.

Table 1. Differential Diagnosis of Stiff-Person Syndrome

Peripheral

Isaac's syndrome

Central

Stiff-person syndrome
Focal lesions of spinal cord

Intrinsic neoplasm
Syringomyelia
Traumatic
Vascular
Paraneoplastic segmental myelitis

Infectious/toxic causes

Acute poliomyelitis
Borreliosis
Encephalomyelitis lethargica
Acute or chronic tetanus
Strychnine
Tetanus

Table 2. Clinical Syndromes

	Classic SPS	Paraneoplastic SPS
Patient population	Sporadic	Occult or diagnosed cancer
Autoantibody	GAD, Other*	Amphiphysin, Hu^Ü, Gephyrin
Disease association	Type 1 diabetes mellitus, intractable epilepsy	Breast cancer and SCLC
Disease association	Type 1 diabetes mellitus, intractable epilepsy	Colon cancer, Hodgkin's disease
Clinical presentation	Increased lumbar lordosis, proximal limb stiffness	Upper or lower limb stiffness
EMG	Continuous motor unit activity (CMUA)	Continuous motor unit activity
NCS	Normal	Normal

Antimicrosomal, antithyroglobulin, anti-islet cell, and anti-parietal cell antibodies.

Ü Anti-Hu antibodies can be seen in a majority of patients with antiampiphysin antibodies and small cell lung cancer (SCLC).

References

1. Lorish TR, Thorsteinsson G, Howard FM. Stiff-man syndrome updated. Mayo Clin Proc 1989;64:629-636.

2. Folli F, Solimena M, Cofiell R, et al. Autoantibodies to a 128-kd synaptic protein in three women with the stiff-man syndrome and breast cancer. N Engl J Med. 1993;328:546-551.

3. Rosin L, DeCamilli P, Butler M, et al. Stiff-man syndrome in a woman with breast cancer: an uncommon central nervous system paraneoplastic syndrome. Neurology. 1998;50:94-98.

4. Aimard G, Boisson D, Kopp N, et al. Neuropathy with contractures evoking the stiff-man syndrome. Latent solitary plasmacytoma. Rev Neurol. 1984;140:510-512.

Ferrari P, Federico M, Grimaldi LM, et al. Stiff-man syndrome in a patient with Hodgkin's disease. An unusual paraneoplastic syndrome. Haematologica. 1990;75:570-572.
Saiz A, Dalmau J, Butler MH, et al. Anti-amphiphysin I antibodies in patients with paraneoplastic neurological disorders associated with small cell lung carcinoma. J Neurol Neurosurg Psychiatry. 1999;66:214-217.