Cardinal Hill Rehabilitation Hospital

1. Botulinum Toxin A Injection to the Facial Muscles in a Patient with Stiff PersonSyndrome Implanted with an Intrathecal Baclofen Pump: A Case Report Praveen N Pakeerappa,MD.PravardhanBirthi, MD. Sara Salles, DO. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY Cardinal Hill Rehabilitation Hospital

2. CASE STUDY Settings: Outpatient rehabilitation clinic. Patient: 48 year old Caucasian male with history of Stiff Person Syndrome (SPS). Case Description: Apatient with a 17 year history of SPS presented with prominent stiffness bilaterally in both the upper and lower extremities. Medical management with oral benzodiazepines failed to control the patient’s symptoms and the patient experienced side effects with high doses of oral baclofen. Subsequently, an intrathecal baclofen pump was implanted and the patient experienced relief of symptoms in the bilateral upper and lower extremities. On a follow-up visit to the outpatient clinic, it was noticed that his overall stiffness was reduced and he had improvement in his activities of daily living, yet he continued to have bruxism and neck stiffness. Following consent and discussion with the patient, the decision was made to undergo botulinum toxin-A injections to the bilateral masseter muscles and cervical paraspinal muscles.

3. STIFF PERSON SYNDROME (SPS) INTRODUCTION Stiff person syndrome (SPS) is a rare neurological disorder of unknown etiologythat is characterized by progressive rigidity and stiffness of the axial musculature (1,2,11). It was first described by Moersch and Woltmann in 1956.

4. EPIDEMIOLOGY • Stiff person syndrome is a very rare disease. • Prevalence has not been reported, however it may be as rare as 1 per 1,000,000(million) person. • Patients with SPS often have associated autoimmune disease. • There is no racial or ethnic predisposition. • The disease is more common in women than in men. • Most frequent age of onset is between third and fifth decade of life.

5. HEAD AND NECK CLINICAL SYMPTOMS • Small muscles of the face can be affected. • Spams of the masseter can cause jaw pain and bruxism. • Difficulty in mastication and dysarthria are noted. • Neck muscles may present as neck pain and headaches.

6. THORACIC AND LUMBAR REGION CLINICAL SYMPTOMS • Waxing and waning of muscle spasms. • Axial rigidity and spasm of the musculature of upper and lower extremities. • Thoracic musculature may cause chest wall restriction. • Present with an exaggerated upright lumbar lordotic posture. • Experience limitation in activities of daily living. • Stiff limb syndrome. • Anxiety, fear or loud noise can aggravate stiffness or spasms.

7. Electromyography reveals continuous firing of normal appearing voluntary units simultaneously in agonist and antagonist muscles. (Data from Dalakas MC. The role of IVIg in the treatment of patients with stiff person syndrome and other neurological diseases associated with anti-GAD antibodies. J Neurol 2005;252(Suppl 1):I19-I25).

8. PATHOPHYSIOLOGY • Oligoclonal and polyclonal IgG against GAD in the CSF of SPS provided insight into the autoimmune etiology(3)

9. PATHOPHYSIOLOGY • Circulating antibodies are found in 60% of the patients (8) with SPS. • These autoimmune antibodies in the cerebrospinal fluid have been found to target GABAergic (gamma amino butyric acid) neurons and their nerve terminals. • The presence of anti-GAD autoantibodies strongly supports the diagnosis (99% specific by immunocytochemistry). • Immunoreactive studies (cytochemistry, western blot, ELISA and RIA) are used in the detection of the antibodies.

10. DIFFERENTIAL DIAGNOSIS • SPS is a diagnosis of exclusion. Before the diagnosis of SPS can be made, other diagnoses that must be considered are: • Hereditary spastic paraplegia. • Progressive multiple sclerosis. • Neuromyotonia. • Congenital myopathies. • Tetanus. • Startle disease. • Cervical myelopathy. • Metabolic myopathies. • Paraneoplastic myelitis. • Strychnine poisoning.

11. TREATMENT OF STIFF PERSON SYNDROME • Several medications are used in the management of SPS. • Benzodiazepines; specifically diazepam, has been shown to be an effective treatment (6) . • Baclofen; used as monotherapy or in combination with benzodiazepines. Used orally or by intrathecal route. • Other agents; tizanidine, valproate, vigabatrin and propofol. • Immunosuppressive therapy and IVIG. • Glucocorticoids. • Plasmapheresis. • A multimodality approach includes PT, OT and behavioral therapy, which can be used adjunctively to improve quality of life.

12. A B Figures showing points of Injection of Botulinium toxin A . Figure A shows the points of injection with 25 Units of Botulinium toxin A into the masseter muscle. A total of 100 Units were used in each side. Figure B shows the points of injection with 25 Units of Botulinium toxin A into the trapezius muscle. A total of 100 Units were used in each side.

13. ASSESSMENT / RESULTS The patient experienced dramatic improvements in his neck stiffness and bruxism after the initial Botox injections. Patient was seen on routine follow up in 3-4 months and continued to receive Botox injections into bilateral masseter and neck paraspinal muscles, for maintenance of the beneficial results.

14. CONCLUSION: Botulinumtoxin A can be considered as mode of management for bruxism and neck stiffness in addition to the Baclofen pump for symptomatic relief in patients with stiff person syndrome.

15. REFERENCES • Syndrome: from bedside to the bench. Arthritis Rheum 1999; 2:1312 • Shaw PJ. Stiff-man syndrome and its variants. Lancet 1999; 353:86. • Werk EE Jr,SholitonLJ.The “stiff-man” syndrome and hyperthyroidism.Am J Med 1961; 31:647. • Christian Geis, Andreas Weishaupt, Benedikt Grunewald, et al; Human stiff-person syndrome and IgG induces anxious behaviour in rats.( Plosone Feb 2011, vol 6,e16775). • Marinos C. Dalakas., Mavis fuji, M.D., Mian Li M.D., et al; High dose intravenous immunoglobulin for stiff-person syndrome. (N Engl J Med 2001;345:1870-6). • Lorish TR. Thorsteinsson G Howard FM Jr; Stiff man syndrome updated, Mayo clinic Proc 1989;64;629 • Jarius S, Stich O, Speck,J, et al. Quanlitative and quantitative evedence of anti-glutamic acid Decarboxylase-specific intrathecal antibody synthesis in patients with stiff person syndrome. J Neuroimmunology 2010;229:219 • Solimena M, Folli F, Aparisi R, et al.Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiff-mann syndrome. N Engl J Med 1990; 322 :1555. • Helfgott SM. Stiff-man syndrome: from bedside to the bench. Arthritis Rheum 1999; 42:1312 • DalakasMC,Li M, JacobowitzDM.Stiff person symdrome; uantification,specificity and intrathecal synthesis of GAF65 antibodies. Neurology 2001; 57;780. • Lorish, TM, Thorsteinsson G, Howard FM. Stiff-man syndrome updated. Mayo Clin Proc. 1989;69;629-636. • Mata S, Muscas,GC, Cincotta, M, et al.GAD antibodies associated neurological disorders: incidence and phenotype distribution among neurological inflammatory diseaases. J Neuroimmunol 2010; 227:175. • Brashear HR, Philips LH 2nd. Autoantibodies to GABAergic neurons and response to plasmapheresis in stiff-man syndrome. Neurology 1991:41:1588.