- Email: [email protected]
Stiff Person Syndrome Masquerading as Acute Coronary Syndrome
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Stiff Person Syndrome Masquerading as Acute Coronary Syndrome Ashish Sharma, M.D., Myat Han Soe, M.D., Jagdeep Singh, M.D., Scott D. Newsome, D.O.
CASE REPORT Conflicts of interest: None. Acknowledgment: Sameer Shaharyar M.D., Fulvia Banu M.D., Hamid R. Feiz M.D. Abstract: Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by severe progressive muscle stiffness in axial and lower extremity musculature with superimposed painful muscle spasms. Although chest pain is a common reason for SPS patients presenting to the emergency room, this disorder is overlooked and not part of the differential diagnosis of chest pain. Herein, we report on a middle age male presenting with classic symptoms of SPS; however, due to the rarity of this disease, he was initially thought to have acute coronary syndrome. Clinicians should consider the diagnosis of SPS in patients with fluctuating muscle spasms in the torso and/or extremities in the setting of repeated hospitalizations without subsequent symptom relief. Abbreviations: SPS, Stiff Person Syndrome; GABA, Gamma Amino Butyric Acid; ACS, Acute Coronary Syndrome; GAD, Glutamic Acid Decarboxylase; IVIG, Intravenous Immunoglobulins Keywords: Stiff-person syndrome-Glutamic acid decarboxylase antibodyAutoimmune disease
Author affiliations: Ashish Sharma, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA, Aventura Hospital and Medical Center, Aventura, FL, USA; Myat Han Soe, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA; Jagdeep Singh, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA; Scott D. Newsome, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA Correspondence: Scott D. Newsome, D.O., Johns Hopkins Neuroimmunology and Neuroinfectious Diseases, Johns Hopkins Hospital, 600 N. Wolfe St., Pathology 627, Baltimore, MD 21287, USA. Fax: þ1 410 502 8075., email: [email protected] ª 2016 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jnma.2016.06.005
BACKGROUND
S
tiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by severe progressive muscle stiffness in axial and lower extremity musculature with superimposed painful muscle spasms. SPS prevalence is estimated to be one per million and occurs more commonly in women between ages 30 and 50.1,2 Although chest pain is a common reason for SPS patients presenting to the emergency room (ER), this disorder is overlooked and not part of the differential diagnosis of chest pain. Herein, we report on a middle age male presenting with classic symptoms of SPS; however, due to the rarity of this disease, he was initially, thought to have acute coronary syndrome (ACS) with the correct diagnosis uncovered 3 years after initial symptoms onset.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
A 41-year-old African American man with vitamin B12 deficiency and chronic eczema presented to the ER with worsening painful muscle spasms in his chest and back. He was in his usual state of health until 3 years ago when he started having these symptoms. The muscle spasms frequently involved his chest, lower back/legs, were sudden in onset, cramping in nature, and aggravated by voluntary movement, emotional stress and unexpected loud auditory stimuli. The patient had undergone multiple hospitalizations for chest pain and underwent evaluation for suspected ACS. During a previous hospitalization he was found to have a mildly elevated creatinine kinase (CKMB) which prompted a cardiac catheterization; however, that did not demonstrate any coronary obstruction. Subsequently, he began treatment for non-obstructive ACS without improvement of his symptoms. During his most recent admission, the patient had presented with chest pain and diaphoresis. His vital signs were normal and his general examination revealed mild pallor and lower extremity rigidity. His lungs were clear to auscultation and he had no murmurs/gallops or abnormal rhythm. Neurological examination revealed dysarthria, spasticity in all extremities, hyper-reflexia, and impaired ambulation. Initial laboratory testing was significant for a CK of 612 U/L. EKG was normal and chest CTA ruled out pulmonary embolus. Head CT was unremarkable. Due to his progressive neurological decline, he was ultimately transferred to a tertiary care center for subspecialty evaluation. On repeated physical exam, he was noted to have hyperlordosis, paravertebral muscle spasms and torso rigidity. His diagnostic work-up was expanded to include an extensive search for autoimmune disorders, which revealed an anti-Glutamic acid decarboxylase-65 (GAD65) antibody of 53,650 U/mL (normal 1.0 U/ mL). All other serum autoantibody testing were negative including paraneoplastic and rheumatic panel. EMG demonstrated continuous motor unit activity in the vastus medialis and T10 paraspinal muscles. Neuraxial imaging and PET-CT scan ruled out anatomical pathology. Given the clinical presentation and paraclinical findings above,
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STIFF PERSON SYNDROME MASQUERADING AS ACUTE CORONARY SYNDROME
Table 1. Classic and Variants of Stiff Person Syndrome
A. Adapted Dalakas Criteria1 for diagnosis of classic stiff person syndrome 1. Stiffness and rigidity in the axial musculature that can result in hyperlordosis over time 2. Painful spasms in torso and/or extremities that are often provoked by abrupt load noises, tactile stimuli, and exposure to cold or emotional stress 3. Electromyography demonstrating co-contraction of agonist and antagonist muscles and/or continuous involuntary firing of motor units at rest 4. Stiffness not explained by other neurological disease 5. Positive serology for anti-GAD65 (or amphiphysin) antibodies 6. Response to benzodiazepines (most commonly valium)2 B. Variants8 of Stiff Person Syndrome presenting with atypical signs and symptoms 1. Stiff Limb Syndrome: focal onset of stiffness and rigidity in one leg followed by more widespread involvement later on in some patients. The majority of patients are anti-GAD65 Ab negative. 2. Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM): Presents with more rapid neurological decline with features of brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, and dysphagia) and profound autonomic dysfunction. A portion of patients with PERM will have anti-GAD65 antibodies, although in anti-GAD65 negative cases glycine receptor antibodies may be present. 3. Paraneoplastic Stiff Person Syndrome (SPS): Represents approximately 5% of SPS cases. Breast, ovarian and lung cancer are most commonly associated with this variant. Patients will often present stiffness and rigidity in their neck, upper torso, and arms. Some patients will have anti-GAD65 antibodies present, although this variant is also associated with the synaptic proteins amphiphysin and gephyrin antibodies. 4. Other variants of SPS: There can be an admixture of other signs and symptoms superimposed on classic features of SPS including cerebellar dysfunction, gait instability, oculomotor dysfunction, dysarthria, peripheral neuropathy, vertigo, parkinsonism, and seizures. 1
Table adapted with the permission of the author of related manuscript. Not part of Dalakas criteria, but helpful in diagnosis.
2
the patient was diagnosed with SPS. He was started on diazepam, baclofen, and IVIG with notable clinical improvement; decreased spasms/pain/rigidity, resolution of dysarthria, and regained ability to walk. He was ultimately discharged to a rehabilitation facility and currently remains on monthly IVIG and daily GABAergic agonist medications.
DISCUSSION The uniqueness of our case resides in its presentation: an extremely rare disease (SPS) masquerading as a very common disease e ACS. The estimated incidence of SPS is 1 case per million.1 It affects women 2e3 times more often than men, and most patients present between the ages of 20 and 50.1,2 The disease is commonly classified as classic SPS which comprises the majority of cases or variant SPS (Table 1). In patients with variant SPS, stiffness and spasms are usually anatomically limited to one or both lower extremities (stiff limb) while patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), present with rapidly progressive and widespread stiffness and spasms.3,4 The characteristic clinical features of classic SPS are stiffness and rigidity in
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axial and proximal limb muscles with superimposed stimulus-sensitive axial and appendicular spasms that lead to functional impairments with inability to walk and/or care for oneself over time (Table 2). This physical impairment results in excessive falls with increased anxiety/phobia about leaving the home. At onset, the spasms and rigidity may be sporadic, but as the disease progresses symptoms become more persistent, leading to loss of independence and severe disability. The rigidity and continuous motor unit activity disappear during sleep and with anesthesia which indicates a central origin for SPS symptoms. The sporadic stiffening and painful spasms usually result from loss of GABA inhibitory transmission which inhibits spontaneous discharge from spinal motor neurons, resulting in involuntary continuous firing of muscle motor units. Muscle spasms occur spontaneously or by triggered events such as emotional stress, a startle, cold environments and certain movements and involve co-contraction of antagonist muscles.5 The loss or reduced presynaptic synthesis of GABA is thought to be secondary to autoantibodies against GAD-65, which is present in about 60e80% of SPS cases. SPS can also occur as a paraneoplastic syndrome associated with autoantibodies to
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
STIFF PERSON SYNDROME MASQUERADING AS ACUTE CORONARY SYNDROME
Table 2. What to look for during examination: “classic” stiff person syndrome.
Increased tone/rigidity in the axial/truncal muscle groups
Increased tone/spasticity in the legs (symmetric or asymmetric)
Normal power in the upper and lower limbs Possible hyper-reflexia, with or without plantar extension
Normal sensory function and coordination Hyperlordosis of the thoracolumbar spine (results from co-contraction of abdominal and paraspinal muscles)
‘Woody’ feel on palpation of the muscles, due to spasms
Spastic, wide-based and cautious gait Intact cognitive function Normal sphincter function
amphiphysin, synaptophysin and gephysin, which impair GABA release into synaptic cleft.1,2 Diagnosis can be established with appropriate clinical features and paraclinical testing in the absence of other neurological disorders (Table 1). Patients with SPS should be evaluated for other associated autoimmune disorders such as diabetes mellitus, pernicious anemia and thyroiditis. Coexisting autoimmunity is uncommon among anti-GAD65 negative SPS patients and these patients tend to have more limited forms of SPS.4 In a recent observational study of 99 patients with SPS conducted at Mayo Clinic, patients who were anti-GAD65
antibodyeseropositive more often had the classic form of SPS, had coexisting other autoimmune diseases, and were rarely associated with a paraneoplastic process (4%). The most frequent autoimmune disorders associated with SPS in this cohort were DM type I, pernicious anemia, and thyroiditis. Patients who were anti-GAD65 antibody e seronegative more often had variant SPS, and rarely had coexisting other autoimmune diseases, but they frequently were associated with cancer (25%; usually breast or small cell carcinoma). These patients may also have additional neurological findings, including neuropathy, encephalopathy, myelopathy, and cerebellar ataxia.4,6 Patients with SPS require a multidisciplinary approach to their treatment. The initial pharmacological interventions are symptomatic using GABAergic agonists such as benzodiazepines and baclofen. Immunomodulating and/or immunosuppressant therapies such as IVIG, plasmapheresis, azathioprine, mycophenolate mofetil, rituximab, and others should be considered if symptoms cannot be controlled with GABAergic agonists (Table 3). In patients that do not respond to standard immunotherapy, major histocompatibility complex class 1-restricted GAD65 peptide specific cytotoxic CD8þ T lymphocytes are thought to be involved in these cases resulting in early irreversible neuronal damage.4 More aggressive therapies like autologous hematopoietic stem cell transplantation (auto-HSCT) might have a role in treatment resistant cases.7 Non-traditional rehabilitation interventions (i.e., ultrasound, myofascial techniques, aqua therapy, etc.) can be critical in helping increase function in SPS via improving social and occupational functions, and activities of daily living. To our knowledge, this is the first reported case of SPS masquerading as ACS. Although a rare clinical entity, the
Table 3. Potential pharmacological treatment options in stiff person syndrome.
Symptomatic 1. Benzodiazepines (diazepam and clonazepam) 2. Baclofen 3. Tizanidine 4. Gabapentin 5. Pregabalin 6. Vigabatrin 7. Dantrolene 8. Levetiracetam 9. Botulinum toxin injections
Immunomodulating/immunosuppresant 1. 2. 3. 4. 5.
Corticosteroid therapya Intravenous gamma globulin Plasma exchange Rituximab Other immunosuppressive agents, such as mycophenolate, cyclophosphamide, azathioprine, and methotrexate
a
Due to high incidence of diabetes in SPS, steroid treatment is often avoided.
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delay in diagnosis resulted in significant morbidity and cost to our patient. This case illustrates the importance of a thorough review of systems in clinical evaluation and reveals the need for raising awareness about this rare neurologic disease (Table 1A and B) as well as the importance of expert consultation/referral. The rarity of SPS and non-specific complaints of stiffness with common psychiatric symptoms often makes diagnosis of SPS difficult. Usually, SPS remains undiagnosed for a longer period because of its rarity and frequent misdiagnosis. Clinicians should consider the diagnosis of SPS in patients with fluctuating muscle spasms in the torso and/or extremities in the setting of repeated hospitalizations without subsequent symptom relief (Table 2).
REFERENCES
3. Baizabal-Carvallo, J. F., & Jankovic, J. (2015 Aug). Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatr, 86(8), 840e848. 4. McKeon, Andrew, Robinson, Maisha T., McEvoy, Kathleen M., et al. (2012). Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol, 69, 230e238. 5. Ciccotto, Giuseppe, Blaya, Maike, & Kelley, Roger E. (2013). Stiff person syndrome. Neurol Clin, 31, 319e328. 6. McKeon, A., Pittock, S. J., & Lennon, V. A. (2009). Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology, 73, 2132e2133. 7. Sanders, S., Bredeson, C., Pringle, C. E., et al. (2014 Oct). Autologous stem cell transplantation for stiff-person syndrome: two cases from Ottawa blood and marrow transplant program. JAMA Neurol, 71(10), 1296e1299.
1. Hadavi, S., Noyce, A. J., Leslie, R. D., & Giovannoni, G. (Oct 2011). Stiff person syndrome. Pract Neurol, 11, 272e282.
8. Barker, R. A., Revesz, T., Thom, M., et al. (1998). Review of 23
2. Dalakas, Marinos C. (2009). Stiff person syndrome: advances in
into stiff trunk (man) syndrome, stiff limb syndrome, and pro-
pathogenesis and therapeutic interventions. Curr Treat Options
gressive encephalomyelitis with rigidity. J Neurol Neurosurg Psy-
Neurol, 11, 102e110.
chiatr, 65, 633e640.
172
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patients affected by the stiff man syndrome: clinical subdivision
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
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Stiff Person Syndrome Masquerading as Acute Coronary Syndrome Ashish Sharma, M.D., Myat Han Soe, M.D., Jagdeep Singh, M.D., Scott D. Newsome, D.O.
CASE REPORT Conflicts of interest: None. Acknowledgment: Sameer Shaharyar M.D., Fulvia Banu M.D., Hamid R. Feiz M.D. Abstract: Stiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by severe progressive muscle stiffness in axial and lower extremity musculature with superimposed painful muscle spasms. Although chest pain is a common reason for SPS patients presenting to the emergency room, this disorder is overlooked and not part of the differential diagnosis of chest pain. Herein, we report on a middle age male presenting with classic symptoms of SPS; however, due to the rarity of this disease, he was initially thought to have acute coronary syndrome. Clinicians should consider the diagnosis of SPS in patients with fluctuating muscle spasms in the torso and/or extremities in the setting of repeated hospitalizations without subsequent symptom relief. Abbreviations: SPS, Stiff Person Syndrome; GABA, Gamma Amino Butyric Acid; ACS, Acute Coronary Syndrome; GAD, Glutamic Acid Decarboxylase; IVIG, Intravenous Immunoglobulins Keywords: Stiff-person syndrome-Glutamic acid decarboxylase antibodyAutoimmune disease
Author affiliations: Ashish Sharma, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA, Aventura Hospital and Medical Center, Aventura, FL, USA; Myat Han Soe, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA; Jagdeep Singh, Department of Internal Medicine, Prince Georges Hospital Center, Cheverly, USA; Scott D. Newsome, Department of Neurology, Johns Hopkins University, Baltimore, MD, USA Correspondence: Scott D. Newsome, D.O., Johns Hopkins Neuroimmunology and Neuroinfectious Diseases, Johns Hopkins Hospital, 600 N. Wolfe St., Pathology 627, Baltimore, MD 21287, USA. Fax: þ1 410 502 8075., email: [email protected] ª 2016 by the National Medical Association. Published by Elsevier Inc. All rights reserved.
http://dx.doi.org/10.1016/j.jnma.2016.06.005
BACKGROUND
S
tiff person syndrome (SPS) is a rare neuroimmunological disorder characterized by severe progressive muscle stiffness in axial and lower extremity musculature with superimposed painful muscle spasms. SPS prevalence is estimated to be one per million and occurs more commonly in women between ages 30 and 50.1,2 Although chest pain is a common reason for SPS patients presenting to the emergency room (ER), this disorder is overlooked and not part of the differential diagnosis of chest pain. Herein, we report on a middle age male presenting with classic symptoms of SPS; however, due to the rarity of this disease, he was initially, thought to have acute coronary syndrome (ACS) with the correct diagnosis uncovered 3 years after initial symptoms onset.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
A 41-year-old African American man with vitamin B12 deficiency and chronic eczema presented to the ER with worsening painful muscle spasms in his chest and back. He was in his usual state of health until 3 years ago when he started having these symptoms. The muscle spasms frequently involved his chest, lower back/legs, were sudden in onset, cramping in nature, and aggravated by voluntary movement, emotional stress and unexpected loud auditory stimuli. The patient had undergone multiple hospitalizations for chest pain and underwent evaluation for suspected ACS. During a previous hospitalization he was found to have a mildly elevated creatinine kinase (CKMB) which prompted a cardiac catheterization; however, that did not demonstrate any coronary obstruction. Subsequently, he began treatment for non-obstructive ACS without improvement of his symptoms. During his most recent admission, the patient had presented with chest pain and diaphoresis. His vital signs were normal and his general examination revealed mild pallor and lower extremity rigidity. His lungs were clear to auscultation and he had no murmurs/gallops or abnormal rhythm. Neurological examination revealed dysarthria, spasticity in all extremities, hyper-reflexia, and impaired ambulation. Initial laboratory testing was significant for a CK of 612 U/L. EKG was normal and chest CTA ruled out pulmonary embolus. Head CT was unremarkable. Due to his progressive neurological decline, he was ultimately transferred to a tertiary care center for subspecialty evaluation. On repeated physical exam, he was noted to have hyperlordosis, paravertebral muscle spasms and torso rigidity. His diagnostic work-up was expanded to include an extensive search for autoimmune disorders, which revealed an anti-Glutamic acid decarboxylase-65 (GAD65) antibody of 53,650 U/mL (normal 1.0 U/ mL). All other serum autoantibody testing were negative including paraneoplastic and rheumatic panel. EMG demonstrated continuous motor unit activity in the vastus medialis and T10 paraspinal muscles. Neuraxial imaging and PET-CT scan ruled out anatomical pathology. Given the clinical presentation and paraclinical findings above,
VOL 108, NO 3, AUTUMN 2016 169
STIFF PERSON SYNDROME MASQUERADING AS ACUTE CORONARY SYNDROME
Table 1. Classic and Variants of Stiff Person Syndrome
A. Adapted Dalakas Criteria1 for diagnosis of classic stiff person syndrome 1. Stiffness and rigidity in the axial musculature that can result in hyperlordosis over time 2. Painful spasms in torso and/or extremities that are often provoked by abrupt load noises, tactile stimuli, and exposure to cold or emotional stress 3. Electromyography demonstrating co-contraction of agonist and antagonist muscles and/or continuous involuntary firing of motor units at rest 4. Stiffness not explained by other neurological disease 5. Positive serology for anti-GAD65 (or amphiphysin) antibodies 6. Response to benzodiazepines (most commonly valium)2 B. Variants8 of Stiff Person Syndrome presenting with atypical signs and symptoms 1. Stiff Limb Syndrome: focal onset of stiffness and rigidity in one leg followed by more widespread involvement later on in some patients. The majority of patients are anti-GAD65 Ab negative. 2. Progressive Encephalomyelitis with Rigidity and Myoclonus (PERM): Presents with more rapid neurological decline with features of brainstem dysfunction (nystagmus, opsoclonus, ophthalmoparesis, deafness, dysarthria, and dysphagia) and profound autonomic dysfunction. A portion of patients with PERM will have anti-GAD65 antibodies, although in anti-GAD65 negative cases glycine receptor antibodies may be present. 3. Paraneoplastic Stiff Person Syndrome (SPS): Represents approximately 5% of SPS cases. Breast, ovarian and lung cancer are most commonly associated with this variant. Patients will often present stiffness and rigidity in their neck, upper torso, and arms. Some patients will have anti-GAD65 antibodies present, although this variant is also associated with the synaptic proteins amphiphysin and gephyrin antibodies. 4. Other variants of SPS: There can be an admixture of other signs and symptoms superimposed on classic features of SPS including cerebellar dysfunction, gait instability, oculomotor dysfunction, dysarthria, peripheral neuropathy, vertigo, parkinsonism, and seizures. 1
Table adapted with the permission of the author of related manuscript. Not part of Dalakas criteria, but helpful in diagnosis.
2
the patient was diagnosed with SPS. He was started on diazepam, baclofen, and IVIG with notable clinical improvement; decreased spasms/pain/rigidity, resolution of dysarthria, and regained ability to walk. He was ultimately discharged to a rehabilitation facility and currently remains on monthly IVIG and daily GABAergic agonist medications.
DISCUSSION The uniqueness of our case resides in its presentation: an extremely rare disease (SPS) masquerading as a very common disease e ACS. The estimated incidence of SPS is 1 case per million.1 It affects women 2e3 times more often than men, and most patients present between the ages of 20 and 50.1,2 The disease is commonly classified as classic SPS which comprises the majority of cases or variant SPS (Table 1). In patients with variant SPS, stiffness and spasms are usually anatomically limited to one or both lower extremities (stiff limb) while patients with progressive encephalomyelitis with rigidity and myoclonus (PERM), present with rapidly progressive and widespread stiffness and spasms.3,4 The characteristic clinical features of classic SPS are stiffness and rigidity in
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axial and proximal limb muscles with superimposed stimulus-sensitive axial and appendicular spasms that lead to functional impairments with inability to walk and/or care for oneself over time (Table 2). This physical impairment results in excessive falls with increased anxiety/phobia about leaving the home. At onset, the spasms and rigidity may be sporadic, but as the disease progresses symptoms become more persistent, leading to loss of independence and severe disability. The rigidity and continuous motor unit activity disappear during sleep and with anesthesia which indicates a central origin for SPS symptoms. The sporadic stiffening and painful spasms usually result from loss of GABA inhibitory transmission which inhibits spontaneous discharge from spinal motor neurons, resulting in involuntary continuous firing of muscle motor units. Muscle spasms occur spontaneously or by triggered events such as emotional stress, a startle, cold environments and certain movements and involve co-contraction of antagonist muscles.5 The loss or reduced presynaptic synthesis of GABA is thought to be secondary to autoantibodies against GAD-65, which is present in about 60e80% of SPS cases. SPS can also occur as a paraneoplastic syndrome associated with autoantibodies to
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
STIFF PERSON SYNDROME MASQUERADING AS ACUTE CORONARY SYNDROME
Table 2. What to look for during examination: “classic” stiff person syndrome.
Increased tone/rigidity in the axial/truncal muscle groups
Increased tone/spasticity in the legs (symmetric or asymmetric)
Normal power in the upper and lower limbs Possible hyper-reflexia, with or without plantar extension
Normal sensory function and coordination Hyperlordosis of the thoracolumbar spine (results from co-contraction of abdominal and paraspinal muscles)
‘Woody’ feel on palpation of the muscles, due to spasms
Spastic, wide-based and cautious gait Intact cognitive function Normal sphincter function
amphiphysin, synaptophysin and gephysin, which impair GABA release into synaptic cleft.1,2 Diagnosis can be established with appropriate clinical features and paraclinical testing in the absence of other neurological disorders (Table 1). Patients with SPS should be evaluated for other associated autoimmune disorders such as diabetes mellitus, pernicious anemia and thyroiditis. Coexisting autoimmunity is uncommon among anti-GAD65 negative SPS patients and these patients tend to have more limited forms of SPS.4 In a recent observational study of 99 patients with SPS conducted at Mayo Clinic, patients who were anti-GAD65
antibodyeseropositive more often had the classic form of SPS, had coexisting other autoimmune diseases, and were rarely associated with a paraneoplastic process (4%). The most frequent autoimmune disorders associated with SPS in this cohort were DM type I, pernicious anemia, and thyroiditis. Patients who were anti-GAD65 antibody e seronegative more often had variant SPS, and rarely had coexisting other autoimmune diseases, but they frequently were associated with cancer (25%; usually breast or small cell carcinoma). These patients may also have additional neurological findings, including neuropathy, encephalopathy, myelopathy, and cerebellar ataxia.4,6 Patients with SPS require a multidisciplinary approach to their treatment. The initial pharmacological interventions are symptomatic using GABAergic agonists such as benzodiazepines and baclofen. Immunomodulating and/or immunosuppressant therapies such as IVIG, plasmapheresis, azathioprine, mycophenolate mofetil, rituximab, and others should be considered if symptoms cannot be controlled with GABAergic agonists (Table 3). In patients that do not respond to standard immunotherapy, major histocompatibility complex class 1-restricted GAD65 peptide specific cytotoxic CD8þ T lymphocytes are thought to be involved in these cases resulting in early irreversible neuronal damage.4 More aggressive therapies like autologous hematopoietic stem cell transplantation (auto-HSCT) might have a role in treatment resistant cases.7 Non-traditional rehabilitation interventions (i.e., ultrasound, myofascial techniques, aqua therapy, etc.) can be critical in helping increase function in SPS via improving social and occupational functions, and activities of daily living. To our knowledge, this is the first reported case of SPS masquerading as ACS. Although a rare clinical entity, the
Table 3. Potential pharmacological treatment options in stiff person syndrome.
Symptomatic 1. Benzodiazepines (diazepam and clonazepam) 2. Baclofen 3. Tizanidine 4. Gabapentin 5. Pregabalin 6. Vigabatrin 7. Dantrolene 8. Levetiracetam 9. Botulinum toxin injections
Immunomodulating/immunosuppresant 1. 2. 3. 4. 5.
Corticosteroid therapya Intravenous gamma globulin Plasma exchange Rituximab Other immunosuppressive agents, such as mycophenolate, cyclophosphamide, azathioprine, and methotrexate
a
Due to high incidence of diabetes in SPS, steroid treatment is often avoided.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
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STIFF PERSON SYNDROME MASQUERADING AS ACUTE CORONARY SYNDROME
delay in diagnosis resulted in significant morbidity and cost to our patient. This case illustrates the importance of a thorough review of systems in clinical evaluation and reveals the need for raising awareness about this rare neurologic disease (Table 1A and B) as well as the importance of expert consultation/referral. The rarity of SPS and non-specific complaints of stiffness with common psychiatric symptoms often makes diagnosis of SPS difficult. Usually, SPS remains undiagnosed for a longer period because of its rarity and frequent misdiagnosis. Clinicians should consider the diagnosis of SPS in patients with fluctuating muscle spasms in the torso and/or extremities in the setting of repeated hospitalizations without subsequent symptom relief (Table 2).
REFERENCES
3. Baizabal-Carvallo, J. F., & Jankovic, J. (2015 Aug). Stiff-person syndrome: insights into a complex autoimmune disorder. J Neurol Neurosurg Psychiatr, 86(8), 840e848. 4. McKeon, Andrew, Robinson, Maisha T., McEvoy, Kathleen M., et al. (2012). Stiff-man syndrome and variants: clinical course, treatments, and outcomes. Arch Neurol, 69, 230e238. 5. Ciccotto, Giuseppe, Blaya, Maike, & Kelley, Roger E. (2013). Stiff person syndrome. Neurol Clin, 31, 319e328. 6. McKeon, A., Pittock, S. J., & Lennon, V. A. (2009). Stiff-person syndrome with amphiphysin antibodies: distinctive features of a rare disease. Neurology, 73, 2132e2133. 7. Sanders, S., Bredeson, C., Pringle, C. E., et al. (2014 Oct). Autologous stem cell transplantation for stiff-person syndrome: two cases from Ottawa blood and marrow transplant program. JAMA Neurol, 71(10), 1296e1299.
1. Hadavi, S., Noyce, A. J., Leslie, R. D., & Giovannoni, G. (Oct 2011). Stiff person syndrome. Pract Neurol, 11, 272e282.
8. Barker, R. A., Revesz, T., Thom, M., et al. (1998). Review of 23
2. Dalakas, Marinos C. (2009). Stiff person syndrome: advances in
into stiff trunk (man) syndrome, stiff limb syndrome, and pro-
pathogenesis and therapeutic interventions. Curr Treat Options
gressive encephalomyelitis with rigidity. J Neurol Neurosurg Psy-
Neurol, 11, 102e110.
chiatr, 65, 633e640.
172
VOL. 108, NO 3, AUTUMN 2016
patients affected by the stiff man syndrome: clinical subdivision
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION