Movement Disorders Vol. 8, No. 3, 1993, pp. 371-373 0 1993 Movement Disorder Society

Brief Report

Significant Improvement of Stiff-Person Syndrome After Paraspinal Injection of Botulinum Toxin A

Dave Davis and ""rahman Jabbari

Departments of *Physical Medicine and Rehabilitation and fNeurology, Walter Reed Army Medical Center, Washington, DC, and ?Department of Neurology, Uniformed Services University of the Health Sciences,

Bethesda, Maryland, U.S.A.

Summary: Following several months of low back pain, a 36-year-old man developed progressive stiffness of the abdominal, low back, and thigh muscles. On examination, these muscles demonstrated marked hypertonia consistent with the clinical diagnosis of stiff-person syndrome. The patient demonstrated increased lumbar lordosis and had focal hyperhidrosis at different sites. Electromyography showed continuous activity of the paraspinal and thigh muscles, and serum and cerebrospinal fluid antibodies to glu- tamic acid decarboxylase (GAD) were markedly elevated. Diazepam and Lioresal of- fered partial pain relief. Paraspinal muscle administration of botulinum toxin A reduced the tone of paraspinal and thigh muscles significantly and resulted in marked improve- ment of ambulation and cessation of pain. Key Words: Stiff-person syndrome- Botulinum toxin A.

Stiff-person syndrome is an unusual disorder of neuro- muscular function originally described by Moersch and Woltman in 1956 (1). To date approximately 100 cases have been described in the medical literature (2). Lorish and associates (3) recently proposed the following diag- nostic criteria: (a) progressive stiffness and rigidity of the axial muscles; (b) slow progression of stiffness to include proximal limb musculature; (c) hyperlordosis; (d) super- imposed episodic spasms precipitated by movement, noise, or emotional stress; (e) normal intellect; ( f ) normal motor and sensory examinations; (g) typical electromyo- gram (EMG) findings; and (h) positive response to ben- zodiazepines. Recently, high levels of antibodies to glu- tamic acid decarboxylase (GAD) have been found in the majority of the patients with stiff-person syndrome.

Hyperactivity of the y motor neuron system seems to play an important role in the pathophysiology of this con- dition, resulting from either suprasegmental hyperactivity of the catecholaminergic pathways (4) or a defect in the inhibitory system y aminobutyric acid (GABA)-ergic (5,6). The second hypothesis draws support from the

Address correspondence and reprint requests to Dr. Bahman Jabbari, Neurology Service, Walter Reed Army Medical Center, Washington, DC 20307, U.S.A.

The statements and assertions in this article are the private views of the authors and should not be construed as the views of the U.S. Army, Department of Defense, or Uniformed Services University of the Health Sciences.

finding of autoantibodies to the enzyme GAD in the se- rum and cerebrospinal fluid (CSF) of the patients with stiff-person syndrome (7,8). This enzyme promotes the conversion of L-glutamic acid into GABA, an inhibitory neurotransmitter found in spinal Renshaw cell interneu- rons.

Stiff-person syndrome is probably an autoimmune dis- order. It often coexists with autoimmune diseases (2), and affected patients show antibodies to pancreatic GABA, gastric parietal cells and thyroglobulin (9-12), increased levels of CSF immunoglobulins (13), and improvement after plasmapheresis and immunomodulating medications (14-16). Stiff-person-like syndromes have been described in association with encephalomyelitis, paraneoplastic syndromes, and endocrinopathies (17,18). High doses of benzodiazepines (diazepam, 20 mg or more daily) offer symptomatic relief, but such doses often cause undesir- able sedation.

We now report a patient with clinical, EMG, and au- toimmune features of stiff-person syndrome in whom in- jection of botulinum toxin type A in the lumbar paraspinal musculature resulted in remarkable relief from pain and stiffness and significant improvement of ambulation.

CASE REPORT

The patient was a 36-year-old right-handed black man who had been in his usual state of good health until 18 months earlier when he began having episodic pain and

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stiffness of his lumbar musculature. He was initially di- agnosed as having degenerative arthritis. and he was treated with nonsteroidal anti-inflammatory medications without relief. His symptoms gradually progressed into marked stiffness of the lower back and abdominal mus- cles as well as the proximal muscles of the lower extrem- ities. More recently, severe episodic spasms had devel- oped, especially in his lumbar area. The spasms were primarily triggered by physical activity. He reported a 20-lb weight gain as well as progressive curvature of his lumbar spine over the previous year. The patient had an unremarkable past medical history; however, his family history was pertinent for a sister with both insulin- dependent diabetes and hypothyroidism. A review of sys- tems was notable for hyperhidrosis.

Physical examination showed a well-developed man in moderate discomfort. His intellect was normal. Examina- tion of the cranial nerves and cerebellar and sensory sys- tems disclosed no abnormalities. On motor examination he appeared to be muscular, with hypertrophied lumbar, thigh, and calf musculature. No involuntary movements were noted. There was hyperlordosis of the lumbar spine. The tone was markedly increased in all muscles below the rib cage, most notably in the paraspinal and abdominal regions where they felt “wooden” on palpation. In the lower limbs, the proximal muscles were more severely involved. The patient was unable to proceed unassisted from the supine to the standing position due to muscle pain and stiffness. His gait was awkward, hesitant, and antalgic. Deep tendon reflexes were normal and symmet- ric with flexor plantar responses. There was markedly decreased range of motion in the lumbar spine and hip joints.

Laboratory studies included a hemogram, electrolytes, liver enzymes, urinalysis, thyroid function panel, coagu- lation studies, glucose tolerance test, ANA, adrenocorti- cotropic hormone (ACTH) stimulation test, and erythro- cyte sedimentation tests; all were normal. CSF analysis demonstrated a protein of 25 mg/dl, glucose of 76 mg/dl, cell count of 2 WBC and no RBC, and a differential of 100% mononuclear cells. Tests for HLA-B27, VDRL, hu- man immunodeficiency virus (HIV) and Lyme titer were negative. Pulmonary function tests showed FVC of 3.93 L (86%), FEVl of 3.12 L (83%), and a ratio of 79%.

Electrocardiogram and electroencephalogram (EEG) were normal. A concurrent EEG and surface EMG using the method of Armon et al. (19) showed continuous motor unit activity in agonist and antagonist thigh muscles, which diminished during stage I sleep and returned with awakening. Needle EMG of the lumbar paraspinal mus- cles showed continuous muscle activity in the awake state. Nerve conduction velocities were normal in both upper and lower extremities. Spine roentgenograms, bone scan, and magnetic resonance imaging of the head and spine were normal except for the finding of increased lumbar lordosis. Biopsy of the right rectus femoris muscle including histochemistry evaluation was normal. The pa- tient serum and CSF were assayed for GAD in the Mayo Clinic using immunoperoxidase staining of baboon’s pan- creas. The end-point dilution for GAD antibody in serum was 11122,000 (normal, <1/120) and in CSF was 11128 (normal < 1/2), both very high values.

A combination of diazepam and Lioresal, at a dosage of 15 mg of each daily, produced some symptomatic pain relief. We then injected a total of 560 U of botulinum toxin type A into the lumbar paraspinal muscles over a period of 3 weeks at three different injecting sessions (160, 200, and 200 U). Five sites were injected on each side at the L1-5 paraspinal regions using 16-20 U/site. A week after the last injection, the patient reported almost total relief from exertional pain and complete cessation of spontaneous painful spasms. On examination, he demon- strated markedly decreased tone in paraspinal, abdominal wall, and thigh musculature and ambulated much more comfortably. There was clinical and radiological evidence of improved lumbar lordosis.

A repeat EMG showed decreased firing of all muscles. The patient sustained this degree of clinical improvement over a month of follow-up and then moved to Europe. Four months later he reported gradual return of muscle stiffness and painful spasms; at the fifth month be re- quired diazepam in excess of 30 mg daily. He was read- mitted to us 6 months after the last injection of botulinum toxin, following 2 weeks of slow diazepam taper to 10 mg daily. He demonstrated difficult ambulation and com- plained of much pain. Abdominal and lumbar paraspinal muscle tone was markedly increased but less than the first time. We injected a total of 200 U of botulinum toxin in the lumbar paraspinal region (100 U on each side). Within a few days, he reported significant pain relief and showed improvement of ambulation. He was happy with the results and did not wish more injections at this time.

DISCUSSION

Patients with stiff-person syndrome are treated with multiple systemic medications with varying success. Physical modalities such as heat, ice, massage, and range- of-motion exercises can suppress local spasm and prevent contractures. Gait training and the use of assistance de- vices maintain ambulation in some individuals. Pharma- cologically, benzodiazepines such as diazepam and clo- nazepam (20,21), baclofen (22,23), and valproic acid (24) are effective, probably due to augmentation of GABA- ergic transmission, whereas clonidine may work via inhi- bition of the motor catecholinergic pathways (5 ) . Plasma- pheresis has produced mixed results (14-16). Steroids caused partial relief from pain and discomfort in two fe- male patients (25).

Botulinum toxin is now considered the treatment of choice for blepharospasm, hemifacial spasm, spasmodic dysphonia, and torticollis (26). Recently, it has shown promise in treatment of spasticity (27). Botulinum toxin prevents exostosis of acetylcholine from presynaptic ves- icles and thereby chemically denervates the muscle. We used botulinum toxin in our patient because of the effec- tiveness of this agent against dystonic states, spasticity, and hypertonia. A total dose of 560 U (injected into the lumbar paraspinal muscles at three different sessions) re- sulted in cessation of pain, significant improvement of stiffness and function, and a decrease in lumbar lordosis documented by examination and serial spinal radio- graphs. The effect wore off in approximately 4 months. and repeat injection of a smaller dose at 6 months pro-

Movement Disorders, Vol. 8, No. 3 , 1993

STIFF-PERSON SYNDROME AND BOTULINUM 3 73

duced similar results. It should be noted that our initial dose of 560 U exceeds the total dose recommended for dystonia (400450’U for torticollis), and repeated injec- tion of such a dose may produce antibodies to botulinum toxin.

The decreased tone of uninjected thigh muscles after injection at a paraspinal region was an intriguing finding. This might have resulted from reduced proprioceptive in- put from paraspinal muscle spindles and Ia fibers to the y motor neurons of a shared pool with thigh muscles or from diffusion of the toxin via nerve roots to these shared segments. In rat and cat, radiolabeled botulinum toxin reaches the corresponding half of the spinal cord after injections into one gastrocnemius muscle (28). In addi- tion, intramuscularly injected botulinum toxin reduces re- current inhibition mediated by the Renshaw cells, pre- sumably by an action of the toxin between these cells and alpha motor neurons (29). This observation may have an important clinical implication in that injection of large thigh muscle groups may not be necessary in patients with stiff-person syndrome.

In conclusion, lumbar paraspinal administration of bot- ulinum toxin type A resulted in marked functional im- provement of a patient with typical stiff-person syndrome and reduced the need for systemic agents. The role of botulinum toxin type A as a sole agent in the treatment of stiff-person syndrome and the overall prognosis of this syndrome after early administration remain to be inves- tigated.

Acknowledgment: We thank Vanda A. Lennon, M.D., Ph.D., at Mayo Clinic Foundation for assaying antibodies to glutamic acid decarboxylase in the serum and CSF of the patient dis- cussed in this article.

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Movement Disorders, Vol. 8 , No. 3, 1993