PM R 7 (2015) 326-328
www.pmrjournal.org
Case Presentation
Botulinum Toxin A Injection to Facial and Cervical Paraspinal Muscles in a Patient With Stiff Person Syndrome: A Case Report Praveen N. Pakeerappa, MD, Pravardhan Birthi, MD, Sara Salles, DO
Abstract Stiff person syndrome (SPS) is a rare neurologic disorder of unknown etiology characterized by increased resting muscle tone, progressive rigidity, and stiffness of the axial musculature. We present a case of a 48-year-old male patient with SPS who experienced facial and neck muscle spasms that were uncontrolled with oral medications and the use of an intrathecal baclofen pump. Botulinum toxin A injections into the bilateral masseter and neck paraspinal muscles provided pain relief and spasm control, illustrating the use of botulinum toxin A injections in the small muscles of face and neck in patients with SPS.
Introduction Stiff person syndrome (SPS) was first recognized by Moersch and Woltman in 1956 [1]. Clinically, patients with SPS present with rigidity and concurrent waxing and waning muscle spasms [2]. Patients typically experience excruciating musculoskeletal pain that limits activities of daily living. The axial and truncal musculature usually are involved, and patients present with an exaggerated upright lumbar lordotic posture. The small muscles of the face can be affected, and spasms of the masseter can cause jaw pain and bruxism. Involvement of the neck muscles may present as neck pain and headaches. Other less commonly affected areas include the proximal musculature in the limbs, known as stiff limb syndrome (SLS). Anxiety, fear, or loud noise can aggravate stiffness or spasms in patients with SPS. SPS is associated with conditions such as vitiligo, pernicious anemia, and diabetes mellitus [3]. The presence of oligoclonal and polyclonal immunoglobulin G in the cerebrospinal fluid of patients with SPS suggests a possible autoimmune etiology. These autoimmune antibodies in the cerebrospinal fluid have been found to target gamma amino butyric acid (GABA) neurons and their nerve terminals [4]. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Circulating antibodies are found in 60% of the patients with
SPS, and antibodies against epitope-65 of GAD are highly specific for the diagnosis of SPS and pathophysiologically important in impairing GABA synthesis [4]. The diagnosis of SPS is one of exclusion, and a few of the differential diagnoses include neuromyotonia, congenital myopathies, chronic tetanus, startle disease, cervical myelopathy, metabolic myopathies, multiple sclerosis, paraneoplastic myelitis, and strychnine poisoning [5]. Numerous medications, including baclofen, have been used in the management of SPS. Baclofen is a GABA-modulating agent used as monotherapy or in combination with benzodiazepines. It can be administered orally or by an intrathecal pump. Benzodiazepines act on GABAA receptors, causing increased chloride conductance into the cell and hyperpolarization of the cell membrane, thereby potentiating the action of GABA. Among benzodiazepines, diazepam specifically has been shown to be effective for treatment of SPS because of its muscle-relaxant properties. Other agents with limited benefits include several antiseizure and antispasmodic medications. Methocarbamol, commonly used as an antispasmodic medication, has a nonspecific site of action at the brainstem and has been used intravenously, with improvement in muscle stiffness noted in patients with SPS. Dantrolene, another muscle relaxant, was successfully used as an additional treatment option for SPS in a case described by Schreiber
1934-1482/$ - see front matter ª 2015 by the American Academy of Physical Medicine and Rehabilitation http://dx.doi.org/10.1016/j.pmrj.2014.10.013
P.N. Pakeerappa et al. / PM R 7 (2015) 326-328
et al [6]. Valproate, an antiseizure medication, potentiates GABAergic action through blockade of voltagegated sodium channels with membrane stabilizing-like actions. Vigabatrin, another antiseizure medication, potentiates the GABAergic action by inhibiting the metabolism of GABA. Propofol, used for induction and maintenance of general anesthesia, also has been found effective for remission in patients with SLS. Immunosuppressive therapies such as tacrolimus and intravenous immunoglobulin are considered in patients who do not respond to the aforementioned agents. Glucocorticoids may be used as an immunosuppressive treatment and may be given either orally or intravenously and tapered on the basis of the response of the disease. Finally, plasmapheresis may be considered in lifethreatening cases [7]. Medication alone may work well in the management of SPS; however, a multimodal approach may provide the greatest benefits. A multidisciplinary approach may include physical therapy, occupational therapy, and behavioral therapy in addition to medications to further improve a patient’s quality of life and to help control the symptoms and pain associated with this rare syndrome. Case Presentation A 48-year-old white man with a history of SPS presented to the outpatient rehabilitation clinic with generalized stiffness. This patient was diagnosed with SPS 17 years ago after multiple consultations with a neurologist. A review of the patient’s medical history and physical examination, including extensive laboratory work up, noted negative anti-GAD, and the results of a muscle biopsy revealed nonspecific myositis with no conclusive diagnosis. The diagnosis of SPS was based on clinical presentation of episodic spasms that were partially ameliorated with benzodiazepines. The patient
327
was managed on oral daily doses of valium of 10 mg and baclofen 20 mg, each prescribed 4 times daily. Despite high doses, the patient continued to experience poor control of symptoms. When medical management with oral medication failed to control the patient’s symptoms, an intrathecal baclofen pump was implanted with a catheter tip at C7. After implantation of the intrathecal baclofen pump, the patient experienced relief of symptoms in both the bilateral upper and lower extremities. On follow-up visit, it was noted that the patient’s overall stiffness was reduced in his limbs and axial muscles, and he showed improvement in his activities of daily living. However, he continued to have bruxism and neck stiffness. Following further discussion with and consent from the patient, he underwent botulinum toxin A injections to the facial and neck muscles. Botulinum toxin A (onabotulinumtoxin A), commercially available in 100- and 200-unit vials, was used, and standard storage techniques and safety protocols were followed per the manufacturer’s recommendations. Each vial of 100 units was reconstituted with 1 mL of preservative-free 0.9% sodium chloride before use. Each area was prepped, and under sterile conditions with electromyography guidance, the botulinum toxin A was injected into the identified muscles (Figure 1). Care was taken to avoid injection into blood vessels by gentle aspiration of the needle. The patient received a total of 300 units approximately every 3 months with subjective improvement in spasms and pain in both the facial and neck musculature. Discussion Botulinum toxin is a neuromuscular paralytic toxin produced by the gram-positive anaerobic bacteria, Clostridium botulinum. The toxin is secreted as a single chain that is composed of both heavy and light chains.
Figure 1. Schematic images showing points of injection with Botulinum toxin A. (A) Points of injection into the masseter muscle. A total of 75 units was used on the left and 50 units on the right masseter muscle because of more tone on the left side. (B) Points of injection into the trapezius and neck paraspinal muscle. A total of 75 units was injected into the right paraspinal muscles and 100 units injected into the left paraspinal muscles. Copyright Masterfile.
328
Botulinum Toxin A Injection in a Patient With SPS
The heavy chain is responsible for binding the toxin to the presynaptic receptor, whereas the light chain (w50 kDa) acts as an endopeptidase with proteolytic activity located at the N-terminal end. Botulinum toxin A cleaves synaptosomeeassociated protein (SNAP-25), which is a presynaptic membrane protein necessary for fusion of neurotransmitter-containing vesicles [8]. Through this mechanism, the toxin prevents the release of the neurotransmitters at the neuromuscular junction and subsequently inhibits the action of the muscle. The effects of botulinum toxin A wane in approximately 3-4 months, corresponding with axonal regeneration. The standard treatment for SPS typically includes the use of benzodiazepines and baclofen. For this specific patient, however, standard oral medications and a baclofen pump failed to provide relief of neck stiffness, pain, and bruxism. The patient was found to have relief of these symptoms at the time of his 3-month follow-up visit after injection. The patient continued with injection therapy every 3 months with continued improvements. The use of botulinum toxin A as a localized treatment to the masseter and paraspinal muscles was a successful intervention in managing both the stiffness and the accompanying pain and spasms for this patient with SPS. The success of botulinum toxin A with SPS has been previously observed with injections into large muscle groups. Davis and Jabbari [9] reported a case of a patient with SPS who experienced both pain and increased muscle tone in the paraspinal and thigh muscles. This patient was treated successfully with botulinum toxin A injections directly into the lumbar paraspinal and thigh muscles. Anagnostou and Zambelis [10] documented a case of a patient with SLS, affecting only the right lower limb, and the patient’s spasms and pain decreased with botulinum toxin A injections directly into the affected area. The uniqueness of this specific case lies in the effective use of botulinum toxin A for treatment of bruxism, neck pain and spasms by injecting botulinum toxin A directly into the masseter and cervical paraspinal muscles.
Conclusion The use of botulinum toxin A may be a beneficial treatment option for spasms and pain in localized small muscle groups that do not respond to other medications or treatments in persons with SPS. Acknowledgments We thank Dr. Lumy Sawaki and Dr. Vinod Muniswamy for input during the initial stages of manuscript preparation and Dr. Joe E. Springer and Megan Finnie for input in the final submission. Figure 1 is a royalty-free image obtained with permission from masterfile.com. References 1. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man syndrome”): Report of a case and some observations in 13 other cases. Mayo Clin Proc 1956;31:421-427. 2. Shaw PJ. Stiff-man syndrome and its variants. Lancet 1999;353: 86-87. 3. Solimena M, Folli F, Aparisi R, Pozzo G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiffman syndrome. N Engl J Med 1990;322:1555-1560. 4. Dalakas MC, Li M, Jacobowitz DM. Stiff person syndrome; Quantification, specificity and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780-784. 5. Andreadou E, Kattoulas E, Sfagos C, Vassilopoulos D. Stiff person syndrome. Avoiding misdiagnosis. Neurol Sci 2007;28:35-37. 6. Schreiber AL, Vasudevan JM, Fetouh SK, Ankam NS, Hussain A, Rakocevic G. Atypical clinically diagnosed stiff-person syndrome response to dantroleneda refractory case. Muscle Nerve 2012;45: 454-455. 7. Karlson EW, Sudarsky L, Ruderman E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994;37:915-918. 8. Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 1993; 365:160-163. 9. Davis D, Jabbari B. Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. Mov Disord 1993;8:371-373. 10. Anagnostou E, Zambelis T. Botulinum toxin A in anti-GAD-positive stiff-limb syndrome. Muscle Nerve 2012;46:457-458.
Disclosure P.N.P. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY Disclosure: nothing to disclose P.B. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY Disclosure: nothing to disclose
S.S. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Address correspondence to: S.S.; e-mail: [email protected] Disclosure: nothing to disclose Submitted for publication March 24, 2014; accepted October 19, 2014.
www.pmrjournal.org
Case Presentation
Botulinum Toxin A Injection to Facial and Cervical Paraspinal Muscles in a Patient With Stiff Person Syndrome: A Case Report Praveen N. Pakeerappa, MD, Pravardhan Birthi, MD, Sara Salles, DO
Abstract Stiff person syndrome (SPS) is a rare neurologic disorder of unknown etiology characterized by increased resting muscle tone, progressive rigidity, and stiffness of the axial musculature. We present a case of a 48-year-old male patient with SPS who experienced facial and neck muscle spasms that were uncontrolled with oral medications and the use of an intrathecal baclofen pump. Botulinum toxin A injections into the bilateral masseter and neck paraspinal muscles provided pain relief and spasm control, illustrating the use of botulinum toxin A injections in the small muscles of face and neck in patients with SPS.
Introduction Stiff person syndrome (SPS) was first recognized by Moersch and Woltman in 1956 [1]. Clinically, patients with SPS present with rigidity and concurrent waxing and waning muscle spasms [2]. Patients typically experience excruciating musculoskeletal pain that limits activities of daily living. The axial and truncal musculature usually are involved, and patients present with an exaggerated upright lumbar lordotic posture. The small muscles of the face can be affected, and spasms of the masseter can cause jaw pain and bruxism. Involvement of the neck muscles may present as neck pain and headaches. Other less commonly affected areas include the proximal musculature in the limbs, known as stiff limb syndrome (SLS). Anxiety, fear, or loud noise can aggravate stiffness or spasms in patients with SPS. SPS is associated with conditions such as vitiligo, pernicious anemia, and diabetes mellitus [3]. The presence of oligoclonal and polyclonal immunoglobulin G in the cerebrospinal fluid of patients with SPS suggests a possible autoimmune etiology. These autoimmune antibodies in the cerebrospinal fluid have been found to target gamma amino butyric acid (GABA) neurons and their nerve terminals [4]. The dominant antigen recognized by these antibodies is the GABA-synthesizing enzyme glutamic acid decarboxylase (GAD). Circulating antibodies are found in 60% of the patients with
SPS, and antibodies against epitope-65 of GAD are highly specific for the diagnosis of SPS and pathophysiologically important in impairing GABA synthesis [4]. The diagnosis of SPS is one of exclusion, and a few of the differential diagnoses include neuromyotonia, congenital myopathies, chronic tetanus, startle disease, cervical myelopathy, metabolic myopathies, multiple sclerosis, paraneoplastic myelitis, and strychnine poisoning [5]. Numerous medications, including baclofen, have been used in the management of SPS. Baclofen is a GABA-modulating agent used as monotherapy or in combination with benzodiazepines. It can be administered orally or by an intrathecal pump. Benzodiazepines act on GABAA receptors, causing increased chloride conductance into the cell and hyperpolarization of the cell membrane, thereby potentiating the action of GABA. Among benzodiazepines, diazepam specifically has been shown to be effective for treatment of SPS because of its muscle-relaxant properties. Other agents with limited benefits include several antiseizure and antispasmodic medications. Methocarbamol, commonly used as an antispasmodic medication, has a nonspecific site of action at the brainstem and has been used intravenously, with improvement in muscle stiffness noted in patients with SPS. Dantrolene, another muscle relaxant, was successfully used as an additional treatment option for SPS in a case described by Schreiber
1934-1482/$ - see front matter ª 2015 by the American Academy of Physical Medicine and Rehabilitation http://dx.doi.org/10.1016/j.pmrj.2014.10.013
P.N. Pakeerappa et al. / PM R 7 (2015) 326-328
et al [6]. Valproate, an antiseizure medication, potentiates GABAergic action through blockade of voltagegated sodium channels with membrane stabilizing-like actions. Vigabatrin, another antiseizure medication, potentiates the GABAergic action by inhibiting the metabolism of GABA. Propofol, used for induction and maintenance of general anesthesia, also has been found effective for remission in patients with SLS. Immunosuppressive therapies such as tacrolimus and intravenous immunoglobulin are considered in patients who do not respond to the aforementioned agents. Glucocorticoids may be used as an immunosuppressive treatment and may be given either orally or intravenously and tapered on the basis of the response of the disease. Finally, plasmapheresis may be considered in lifethreatening cases [7]. Medication alone may work well in the management of SPS; however, a multimodal approach may provide the greatest benefits. A multidisciplinary approach may include physical therapy, occupational therapy, and behavioral therapy in addition to medications to further improve a patient’s quality of life and to help control the symptoms and pain associated with this rare syndrome. Case Presentation A 48-year-old white man with a history of SPS presented to the outpatient rehabilitation clinic with generalized stiffness. This patient was diagnosed with SPS 17 years ago after multiple consultations with a neurologist. A review of the patient’s medical history and physical examination, including extensive laboratory work up, noted negative anti-GAD, and the results of a muscle biopsy revealed nonspecific myositis with no conclusive diagnosis. The diagnosis of SPS was based on clinical presentation of episodic spasms that were partially ameliorated with benzodiazepines. The patient
327
was managed on oral daily doses of valium of 10 mg and baclofen 20 mg, each prescribed 4 times daily. Despite high doses, the patient continued to experience poor control of symptoms. When medical management with oral medication failed to control the patient’s symptoms, an intrathecal baclofen pump was implanted with a catheter tip at C7. After implantation of the intrathecal baclofen pump, the patient experienced relief of symptoms in both the bilateral upper and lower extremities. On follow-up visit, it was noted that the patient’s overall stiffness was reduced in his limbs and axial muscles, and he showed improvement in his activities of daily living. However, he continued to have bruxism and neck stiffness. Following further discussion with and consent from the patient, he underwent botulinum toxin A injections to the facial and neck muscles. Botulinum toxin A (onabotulinumtoxin A), commercially available in 100- and 200-unit vials, was used, and standard storage techniques and safety protocols were followed per the manufacturer’s recommendations. Each vial of 100 units was reconstituted with 1 mL of preservative-free 0.9% sodium chloride before use. Each area was prepped, and under sterile conditions with electromyography guidance, the botulinum toxin A was injected into the identified muscles (Figure 1). Care was taken to avoid injection into blood vessels by gentle aspiration of the needle. The patient received a total of 300 units approximately every 3 months with subjective improvement in spasms and pain in both the facial and neck musculature. Discussion Botulinum toxin is a neuromuscular paralytic toxin produced by the gram-positive anaerobic bacteria, Clostridium botulinum. The toxin is secreted as a single chain that is composed of both heavy and light chains.
Figure 1. Schematic images showing points of injection with Botulinum toxin A. (A) Points of injection into the masseter muscle. A total of 75 units was used on the left and 50 units on the right masseter muscle because of more tone on the left side. (B) Points of injection into the trapezius and neck paraspinal muscle. A total of 75 units was injected into the right paraspinal muscles and 100 units injected into the left paraspinal muscles. Copyright Masterfile.
328
Botulinum Toxin A Injection in a Patient With SPS
The heavy chain is responsible for binding the toxin to the presynaptic receptor, whereas the light chain (w50 kDa) acts as an endopeptidase with proteolytic activity located at the N-terminal end. Botulinum toxin A cleaves synaptosomeeassociated protein (SNAP-25), which is a presynaptic membrane protein necessary for fusion of neurotransmitter-containing vesicles [8]. Through this mechanism, the toxin prevents the release of the neurotransmitters at the neuromuscular junction and subsequently inhibits the action of the muscle. The effects of botulinum toxin A wane in approximately 3-4 months, corresponding with axonal regeneration. The standard treatment for SPS typically includes the use of benzodiazepines and baclofen. For this specific patient, however, standard oral medications and a baclofen pump failed to provide relief of neck stiffness, pain, and bruxism. The patient was found to have relief of these symptoms at the time of his 3-month follow-up visit after injection. The patient continued with injection therapy every 3 months with continued improvements. The use of botulinum toxin A as a localized treatment to the masseter and paraspinal muscles was a successful intervention in managing both the stiffness and the accompanying pain and spasms for this patient with SPS. The success of botulinum toxin A with SPS has been previously observed with injections into large muscle groups. Davis and Jabbari [9] reported a case of a patient with SPS who experienced both pain and increased muscle tone in the paraspinal and thigh muscles. This patient was treated successfully with botulinum toxin A injections directly into the lumbar paraspinal and thigh muscles. Anagnostou and Zambelis [10] documented a case of a patient with SLS, affecting only the right lower limb, and the patient’s spasms and pain decreased with botulinum toxin A injections directly into the affected area. The uniqueness of this specific case lies in the effective use of botulinum toxin A for treatment of bruxism, neck pain and spasms by injecting botulinum toxin A directly into the masseter and cervical paraspinal muscles.
Conclusion The use of botulinum toxin A may be a beneficial treatment option for spasms and pain in localized small muscle groups that do not respond to other medications or treatments in persons with SPS. Acknowledgments We thank Dr. Lumy Sawaki and Dr. Vinod Muniswamy for input during the initial stages of manuscript preparation and Dr. Joe E. Springer and Megan Finnie for input in the final submission. Figure 1 is a royalty-free image obtained with permission from masterfile.com. References 1. Moersch FP, Woltman HW. Progressive fluctuating muscular rigidity and spasm (“stiff-man syndrome”): Report of a case and some observations in 13 other cases. Mayo Clin Proc 1956;31:421-427. 2. Shaw PJ. Stiff-man syndrome and its variants. Lancet 1999;353: 86-87. 3. Solimena M, Folli F, Aparisi R, Pozzo G, De Camilli P. Autoantibodies to GABA-ergic neurons and pancreatic beta cells in stiffman syndrome. N Engl J Med 1990;322:1555-1560. 4. Dalakas MC, Li M, Jacobowitz DM. Stiff person syndrome; Quantification, specificity and intrathecal synthesis of GAD65 antibodies. Neurology 2001;57:780-784. 5. Andreadou E, Kattoulas E, Sfagos C, Vassilopoulos D. Stiff person syndrome. Avoiding misdiagnosis. Neurol Sci 2007;28:35-37. 6. Schreiber AL, Vasudevan JM, Fetouh SK, Ankam NS, Hussain A, Rakocevic G. Atypical clinically diagnosed stiff-person syndrome response to dantroleneda refractory case. Muscle Nerve 2012;45: 454-455. 7. Karlson EW, Sudarsky L, Ruderman E, et al. Treatment of stiff-man syndrome with intravenous immune globulin. Arthritis Rheum 1994;37:915-918. 8. Blasi J, Chapman ER, Link E, et al. Botulinum neurotoxin A selectively cleaves the synaptic protein SNAP-25. Nature 1993; 365:160-163. 9. Davis D, Jabbari B. Significant improvement of stiff-person syndrome after paraspinal injection of botulinum toxin A. Mov Disord 1993;8:371-373. 10. Anagnostou E, Zambelis T. Botulinum toxin A in anti-GAD-positive stiff-limb syndrome. Muscle Nerve 2012;46:457-458.
Disclosure P.N.P. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY Disclosure: nothing to disclose P.B. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY Disclosure: nothing to disclose
S.S. Department of Physical Medicine and Rehabilitation, University of Kentucky, Lexington, KY. Address correspondence to: S.S.; e-mail: [email protected] Disclosure: nothing to disclose Submitted for publication March 24, 2014; accepted October 19, 2014.
