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Stiff-Person Syndrome: A Case Report and Review of the Literature
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Stiff-Person Syndrome: A Case Report and Review of the Literature Steve Egwuonwu, MD; Fernando Chedebeau, MD
We report a case of stiff-person syndrome associated with several autoimmune diseases. A 49-year-old male with type 1 diabetes presented with a 6-month history of muscle rigidity and spasms of his upper and lower extremities. Anti–glutamic acid decarboxylase 65 antibody was elevated at 609 nmol/L. Electromyography revealed continuous motor unit activity in agonist and antagonist muscles. He responded favorably to diazepam, baclofen, and intravenous immunoglobulin infusions. This case report describes stiff-person syndrome in association with pernicious anemia and diabetes mellitus. A review of the literature discusses the diagnosis and treatment of this rare entity. Keywords: stiff-person syndrome n anemia n diabetes mellitus J Natl Med Assoc. 2010;102:1261-1263 Author Affiliations: Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas. Correspondence: Steve Egwuonwu, MD, Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine,4800 Alberta Ave, El Paso, TX 79905 ([email protected]).
Introduction
S
tiff-person syndrome (SPS) was first described in 1956 by Moersch and Woltman after a review of 14 patients over 27 years. It is an extremely rare neuroimmunologic disorder characterized by progressive muscle rigidity and stiffness with concurrent painful spasms of the axial muscles.1,2 SPS may be associated with autoimmune diseases such as type 1 diabetes mellitus, thyroiditis, and pernicious anemia. Paraneoplastic manifestation of SPS may occur with neoplasms in 5% of cases. Very specific anti–glutamic acid decarboxylase antibodies are detected in 60% of patients with this syndrome.3 In some cases of SPS associated with neoplasms such as breast cancer; antiamphiphysin antibodies are detected.4 We present a case of SPS with review of the literature emphasizing associations, diagnosis, and treatment.
Case Report
A 49-year-old male presented with progressively worsening muscle rigidity and spasms of his upper and
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
lower extremities of 6 months’ duration. He experienced constant hip pain and frequent falls, necessitating the use of a walker. Past medical history was significant for previous hospitalization for diabetic ketoacidosis and humeral fracture sustained from a fall. Physical examination revealed generalized rigidity in both upper and lower extremities. Motor and sensory functions were intact. Findings from a cranial nerve examination were normal. Gait was hobbled, and the patient could only take stiff, rigid steps with a walker. He had normal reflexes with negative Hoffmann and Babinski signs. Laboratory analysis revealed anemia with hemoglobin of 10 g/dL and a mean corpuscular volume of 88. Serum vitamin B12 was low at 72 pg/mL. Antibody to intrinsic factor was positive, consistent with a diagnosis of pernicious anemia. Findings from computerized tomographies of the head, chest, and abdomen were normal. Anti–glutamic acid decarboxylase 65 antibody was elevated at 609 nmol/L. Electromyography showed continuous motor unit activity in agonist and antagonist muscles. He was diagnosed with SPS, and treatment was initiated with 10 mg twice daily oral diazepam, oral baclofen at 10 mg thrice daily, and intravenous immunoglobulin at 2 g/kg for 2 days. He also received vitamin B12 therapy. The patient did well, with gradual improvement in functional status and diminished pain in his lower extremities. He has required repeated intravenous infusions of immunoglobulin over the years, and his clinical course has remained stable.
Discussion
The exact prevalence of SPS is unknown; it is a rare condition. It affects more females than males, and the age of onset is in the third to sixth decade of life. g-Aminobutyric acid (GABA) is an inhibitory neutronsmitter in brain and spinal interneurons. GABAergic pathways serve as one of the types of inhibitory pathways by which spinal interneurons coordinate motor function by inhibiting spontaneous discharges from spinal motor neurons. Impairment of the GABAergic pathways with deficiencies in brain GABA leads to continuous firing of the spinal motor neurons, with resultant stiffness and spasms, which are the hallmark of SPS.5 It has been demonstrated that antibodies to GABAA receptor–associated protein VOL. 102, NO. 12, DECEMBER 2010 1261
Stiff-person syndrome
(GABARAP) inhibit GABAA receptor expression, leading to GABA receptor instability. This may play a role in SPS pathogenesis.6 Anti–glutamic acid decarboxylase antibodies are associated with several autoimmune diseases and are excellent diagnostic markers in SPS. Their role in the pathophysiology of SPS, however, is uncertain.5 SPS begins insidiously, as rigidity and stiffness in the axial muscles manifesting as achiness of the back in early stages. Over time, rigidity and stiffness progress to involve the proximal limbs. Additionally, concurrent episodic painful spasms are a feature of SPS. These spasms are precipitated by noise, touch, sudden movement, or emotional upset. Hypertonia and superimposed spasms lead to loss of postural reflexes, resulting in falls, with increased risk of fractures. Lumbar or cervical lordosis is a prominent finding in these patients. As SPS progresses and activities of daily living become difficult, there is the need for use of assist devices for ambulation. Paroxysmal autonomic dysfunction, including diaphoresis, papillary dilatation, tachypnea, tachycardia, hypertension, and hyperpyrexia, has been reported in SPS and may result in sudden death.7 Dysphagia from esophageal dysmotility may occur, leading to aspiration. Anxiety, phobias, and depression are prevalent in SPS patients. Seizures have also been reported.8 SPS may be associated with autoimmune diseases such as type 1 diabetes mellitus (60% of cases),3 thyroiditis, and myasthenia with or without thymoma, vitiligo, adrenal insufficiency, and pernicious anemia. Evaluation by Dalakas et al of 20 SPS patients positive for anti–glutamic acid decarboxylase revealed 80% association with autoimmune diseases. Three of the patients had pernicious anemia, 8 had insulin dependent diabetes mellitus, and 8 others had thyroid disease.3 The coexistence of diabetes mellitus and pernicious anemia may be part of the autoimmune polyglandular syndrome spectrum. The association of SPS and these autoimmune diseases underlies the reason for previous postulations that SPS has an autoimmune pathogenesis. Paraneoplastic manifestations of SPS, from breast cancer4 and small cell lung cancer, have been reported. The diagnostic criteria8 for SPS were proposed in 1989 and include:
5. normal findings on motor and sensory nerve examinations; 6. normal intellect; 7. electromyographic findings typical of continuous motor activity that can be abolished by intravenous or orally administered diazepam.
1. initial stiffness and rigidity in the axial muscles; 2. slow progression of stiffness to include proximal limb muscles, making volitional movements and ambulation difficult; 3. a fixed deformity of the spine, as in lordosis, and with some patients, a restriction of hip movement 4. the presence of superimposed episodic spasms; precipitated by sudden movements, jarring noise, and emotional upset;
In this report, we describe a patient with SPS in association with type 1 diabetes mellitus and pernicious anemia. Treatment with diazepam, baclofen, and intravenous immunoglobulin resulted in significant clinical improvement in his functional status. Increased awareness of this disease entity is necessary to prevent delay in diagnosis. Early recognition and prompt institution of treatment is paramount to prevent long-term disability. Physicians should be cognizant of the association of SPS with autoimmune diseases and or malignancy.
1262 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Workup for SPS includes basic laboratory studies, including complete blood count for anemia, complete metabolic panel, thyrotropin, and computed tomography of the chest to exclude a thymoma. Antibody testing is very useful in the diagnosis of SPS. Anti–glutamic acid decarboxylase antibodies are detected in 60% of patients and are strongly supportive of SPS. Absence of anti–glutamic acid decarboxylase antibodies does not rule out a diagnosis of SPS. Antiamphiphysin antibodies are detected when SPS is associated with malignancy.4 Electromyography is a very important diagnostic tool and reveals continuous motor unit activity simultaneously in agonist and antagonist muscles. This motor activity is abolished by diazepam, sleep, or general anesthesia. Benzodiazepines are generally considered an effective initial therapy for SPS.8 Diazepam is the benzodiazepine commonly used. Intrathecal or oral baclofen has been used in SPS unresponsive to diazepam. Corticosteroids are used in patients refractory or intolerant to benzodiazepines and or baclofen. Repeated intravenous immunoglobulin is used as a disease-modifying therapy in SPS.2 The efficacy of intravenous immunoglobulin was reported in a study comparing placebo to intravenous immunoglobulin therapy where 11 of 16 patients showed improvement of functional status after intravenous immunoglobulin therapy.9 Rituximab (antiCD20 monoclonal antibody) was used to induce clinical remission in a single case report of SPS refractory to conventional therapy, including intravenous immunoglobulin.10 Other forms of therapy have been reported in the literature, including intravenous methocarbamol, vigabatrin, sodium valproate, azathioprine, botulinum toxin A, propofol, plasmapharesis, and thymectomy for thymoma-associated SPS. The role of these agents in SPS treatment is unclear.
Conclusion
VOL. 102, NO. 12, DECEMBER 2010
Stiff-person syndrome
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. Duddy ME, Baker MR. Stiff person syndrome. Front Neurol Neurosci. 2009;26:147-165. 3. Dalakas MC, Fujii M, Li M, et al. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000;55:15311535. 4. De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. J Exp Med. 1993;178:2219-2223.
5. Dalakas MC. Stiff person syndrome: Advances in pathogenesis and Therapeutic Interventions. Curr Treat Options Neurol. 2009;11:102-110. 6. Raju R. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain. 2006;129:3270-3276. 7. Mitsumoto H, Schwartzman MJ, Estes ML, et al. Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol. 1991;238:91-96. 8. Lorish TR, Thorsteinsson G, Howard FM. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64:629-636. 9. Dalakas MC, Fuji M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001;345:1870-1876. 10. Baker MR, Das M, Isaacs J, et al. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005;76:999-1001. n
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JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
VOL. 102, NO. 12, DECEMBER 2010 1263
a
s
e
r
e
p
o
r
t
Stiff-Person Syndrome: A Case Report and Review of the Literature Steve Egwuonwu, MD; Fernando Chedebeau, MD
We report a case of stiff-person syndrome associated with several autoimmune diseases. A 49-year-old male with type 1 diabetes presented with a 6-month history of muscle rigidity and spasms of his upper and lower extremities. Anti–glutamic acid decarboxylase 65 antibody was elevated at 609 nmol/L. Electromyography revealed continuous motor unit activity in agonist and antagonist muscles. He responded favorably to diazepam, baclofen, and intravenous immunoglobulin infusions. This case report describes stiff-person syndrome in association with pernicious anemia and diabetes mellitus. A review of the literature discusses the diagnosis and treatment of this rare entity. Keywords: stiff-person syndrome n anemia n diabetes mellitus J Natl Med Assoc. 2010;102:1261-1263 Author Affiliations: Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine, El Paso, Texas. Correspondence: Steve Egwuonwu, MD, Department of Internal Medicine, Texas Tech University Health Sciences Center, Paul L. Foster School of Medicine,4800 Alberta Ave, El Paso, TX 79905 ([email protected]).
Introduction
S
tiff-person syndrome (SPS) was first described in 1956 by Moersch and Woltman after a review of 14 patients over 27 years. It is an extremely rare neuroimmunologic disorder characterized by progressive muscle rigidity and stiffness with concurrent painful spasms of the axial muscles.1,2 SPS may be associated with autoimmune diseases such as type 1 diabetes mellitus, thyroiditis, and pernicious anemia. Paraneoplastic manifestation of SPS may occur with neoplasms in 5% of cases. Very specific anti–glutamic acid decarboxylase antibodies are detected in 60% of patients with this syndrome.3 In some cases of SPS associated with neoplasms such as breast cancer; antiamphiphysin antibodies are detected.4 We present a case of SPS with review of the literature emphasizing associations, diagnosis, and treatment.
Case Report
A 49-year-old male presented with progressively worsening muscle rigidity and spasms of his upper and
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
lower extremities of 6 months’ duration. He experienced constant hip pain and frequent falls, necessitating the use of a walker. Past medical history was significant for previous hospitalization for diabetic ketoacidosis and humeral fracture sustained from a fall. Physical examination revealed generalized rigidity in both upper and lower extremities. Motor and sensory functions were intact. Findings from a cranial nerve examination were normal. Gait was hobbled, and the patient could only take stiff, rigid steps with a walker. He had normal reflexes with negative Hoffmann and Babinski signs. Laboratory analysis revealed anemia with hemoglobin of 10 g/dL and a mean corpuscular volume of 88. Serum vitamin B12 was low at 72 pg/mL. Antibody to intrinsic factor was positive, consistent with a diagnosis of pernicious anemia. Findings from computerized tomographies of the head, chest, and abdomen were normal. Anti–glutamic acid decarboxylase 65 antibody was elevated at 609 nmol/L. Electromyography showed continuous motor unit activity in agonist and antagonist muscles. He was diagnosed with SPS, and treatment was initiated with 10 mg twice daily oral diazepam, oral baclofen at 10 mg thrice daily, and intravenous immunoglobulin at 2 g/kg for 2 days. He also received vitamin B12 therapy. The patient did well, with gradual improvement in functional status and diminished pain in his lower extremities. He has required repeated intravenous infusions of immunoglobulin over the years, and his clinical course has remained stable.
Discussion
The exact prevalence of SPS is unknown; it is a rare condition. It affects more females than males, and the age of onset is in the third to sixth decade of life. g-Aminobutyric acid (GABA) is an inhibitory neutronsmitter in brain and spinal interneurons. GABAergic pathways serve as one of the types of inhibitory pathways by which spinal interneurons coordinate motor function by inhibiting spontaneous discharges from spinal motor neurons. Impairment of the GABAergic pathways with deficiencies in brain GABA leads to continuous firing of the spinal motor neurons, with resultant stiffness and spasms, which are the hallmark of SPS.5 It has been demonstrated that antibodies to GABAA receptor–associated protein VOL. 102, NO. 12, DECEMBER 2010 1261
Stiff-person syndrome
(GABARAP) inhibit GABAA receptor expression, leading to GABA receptor instability. This may play a role in SPS pathogenesis.6 Anti–glutamic acid decarboxylase antibodies are associated with several autoimmune diseases and are excellent diagnostic markers in SPS. Their role in the pathophysiology of SPS, however, is uncertain.5 SPS begins insidiously, as rigidity and stiffness in the axial muscles manifesting as achiness of the back in early stages. Over time, rigidity and stiffness progress to involve the proximal limbs. Additionally, concurrent episodic painful spasms are a feature of SPS. These spasms are precipitated by noise, touch, sudden movement, or emotional upset. Hypertonia and superimposed spasms lead to loss of postural reflexes, resulting in falls, with increased risk of fractures. Lumbar or cervical lordosis is a prominent finding in these patients. As SPS progresses and activities of daily living become difficult, there is the need for use of assist devices for ambulation. Paroxysmal autonomic dysfunction, including diaphoresis, papillary dilatation, tachypnea, tachycardia, hypertension, and hyperpyrexia, has been reported in SPS and may result in sudden death.7 Dysphagia from esophageal dysmotility may occur, leading to aspiration. Anxiety, phobias, and depression are prevalent in SPS patients. Seizures have also been reported.8 SPS may be associated with autoimmune diseases such as type 1 diabetes mellitus (60% of cases),3 thyroiditis, and myasthenia with or without thymoma, vitiligo, adrenal insufficiency, and pernicious anemia. Evaluation by Dalakas et al of 20 SPS patients positive for anti–glutamic acid decarboxylase revealed 80% association with autoimmune diseases. Three of the patients had pernicious anemia, 8 had insulin dependent diabetes mellitus, and 8 others had thyroid disease.3 The coexistence of diabetes mellitus and pernicious anemia may be part of the autoimmune polyglandular syndrome spectrum. The association of SPS and these autoimmune diseases underlies the reason for previous postulations that SPS has an autoimmune pathogenesis. Paraneoplastic manifestations of SPS, from breast cancer4 and small cell lung cancer, have been reported. The diagnostic criteria8 for SPS were proposed in 1989 and include:
5. normal findings on motor and sensory nerve examinations; 6. normal intellect; 7. electromyographic findings typical of continuous motor activity that can be abolished by intravenous or orally administered diazepam.
1. initial stiffness and rigidity in the axial muscles; 2. slow progression of stiffness to include proximal limb muscles, making volitional movements and ambulation difficult; 3. a fixed deformity of the spine, as in lordosis, and with some patients, a restriction of hip movement 4. the presence of superimposed episodic spasms; precipitated by sudden movements, jarring noise, and emotional upset;
In this report, we describe a patient with SPS in association with type 1 diabetes mellitus and pernicious anemia. Treatment with diazepam, baclofen, and intravenous immunoglobulin resulted in significant clinical improvement in his functional status. Increased awareness of this disease entity is necessary to prevent delay in diagnosis. Early recognition and prompt institution of treatment is paramount to prevent long-term disability. Physicians should be cognizant of the association of SPS with autoimmune diseases and or malignancy.
1262 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Workup for SPS includes basic laboratory studies, including complete blood count for anemia, complete metabolic panel, thyrotropin, and computed tomography of the chest to exclude a thymoma. Antibody testing is very useful in the diagnosis of SPS. Anti–glutamic acid decarboxylase antibodies are detected in 60% of patients and are strongly supportive of SPS. Absence of anti–glutamic acid decarboxylase antibodies does not rule out a diagnosis of SPS. Antiamphiphysin antibodies are detected when SPS is associated with malignancy.4 Electromyography is a very important diagnostic tool and reveals continuous motor unit activity simultaneously in agonist and antagonist muscles. This motor activity is abolished by diazepam, sleep, or general anesthesia. Benzodiazepines are generally considered an effective initial therapy for SPS.8 Diazepam is the benzodiazepine commonly used. Intrathecal or oral baclofen has been used in SPS unresponsive to diazepam. Corticosteroids are used in patients refractory or intolerant to benzodiazepines and or baclofen. Repeated intravenous immunoglobulin is used as a disease-modifying therapy in SPS.2 The efficacy of intravenous immunoglobulin was reported in a study comparing placebo to intravenous immunoglobulin therapy where 11 of 16 patients showed improvement of functional status after intravenous immunoglobulin therapy.9 Rituximab (antiCD20 monoclonal antibody) was used to induce clinical remission in a single case report of SPS refractory to conventional therapy, including intravenous immunoglobulin.10 Other forms of therapy have been reported in the literature, including intravenous methocarbamol, vigabatrin, sodium valproate, azathioprine, botulinum toxin A, propofol, plasmapharesis, and thymectomy for thymoma-associated SPS. The role of these agents in SPS treatment is unclear.
Conclusion
VOL. 102, NO. 12, DECEMBER 2010
Stiff-person syndrome
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. Duddy ME, Baker MR. Stiff person syndrome. Front Neurol Neurosci. 2009;26:147-165. 3. Dalakas MC, Fujii M, Li M, et al. The clinical spectrum of anti-GAD antibody-positive patients with stiff-person syndrome. Neurology. 2000;55:15311535. 4. De Camilli P, Thomas A, Cofiell R, et al. The synaptic vesicle-associated protein amphiphysin is the 128-kD autoantigen of Stiff-Man syndrome with breast cancer. J Exp Med. 1993;178:2219-2223.
5. Dalakas MC. Stiff person syndrome: Advances in pathogenesis and Therapeutic Interventions. Curr Treat Options Neurol. 2009;11:102-110. 6. Raju R. Autoimmunity to GABAA-receptor-associated protein in stiff-person syndrome. Brain. 2006;129:3270-3276. 7. Mitsumoto H, Schwartzman MJ, Estes ML, et al. Sudden death and paroxysmal autonomic dysfunction in stiff-man syndrome. J Neurol. 1991;238:91-96. 8. Lorish TR, Thorsteinsson G, Howard FM. Stiff-man syndrome updated. Mayo Clin Proc. 1989;64:629-636. 9. Dalakas MC, Fuji M, Li M, et al. High-dose intravenous immune globulin for stiff-person syndrome. N Engl J Med. 2001;345:1870-1876. 10. Baker MR, Das M, Isaacs J, et al. Treatment of stiff person syndrome with rituximab. J Neurol Neurosurg Psychiatry. 2005;76:999-1001. n
To photocopy, e-mail, post on Internet or distribute this or any part of JNMA, please visit www.copyright.com.
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
VOL. 102, NO. 12, DECEMBER 2010 1263