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Devic Syndrome: A Diagnostic Dilemma
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Devic Syndrome: A Diagnostic Dilemma Muhammad K. Perwaiz, MD; Fadi Hammoudeh, MD; Francis Schmidt, MD
Neuromyelitis optica (NMO, also known as Devic syndrome or Devic disease) is a rare clinical entity. Early recognition and prompt treatment can save patients from long-term disability, especially in themonophasic variant of disease. A 24-year-old African American female presented with highgrade fever for 1 day associated with frontal headache, photophobia, and 2 episodes of nonbloody vomiting. She had a history of nonitchy vesicular rash with sudden diminution of vision in the left eye 2 weeks ago. Over the next 24 hours, she developed progressively worsening weakness and numbness in her left arm and left leg, which later involved all limbs. Left eye vision was reduced to light perception with light and accommodation reflexes intact. Lumbar puncture showed lymphocytic pleocytosis with elevated protein. On day 2, neurological examination exhibited quadriparises with hypereflexia and clonus. Magnetic resonance imaging showed diffuse hyperintense signals in the spinal cord in cervical and lumbar regions. An assessment of neuromyelitis optica was made. Anti-NMO antibodies were negative. On day 3, she was intubated because of progressive dyspnea. Plasmapheresis resulted in rapid improvement in respiratory and neurological status. She was extubated on the second day and transferred to floor on day 4. Later, the patient was discharged. Keywords: Devic syndrome n ophthalmic J Natl Med Assoc. 2011;103:176-178 Author Affiliations: Departments of Medicine (Dr Perwaiz) and Pulmonology (Drs Hammoudeh and Schmidt), Interfaith Medical Center, Brooklyn, New York. Correspondence: Muhammad Perwaiz MD, Department of Medicine, Interfaith Medical Center, 1545 Atlantic Ave, Brooklyn, NY 11213 ([email protected]).
Case Presentation
A
24-year-old African American female with past medical history of tuberculous lymphadenitis in childhood was in a state of usual health when she developed a nonitchy vesicular rash over her upper trunk and shoulders. This was followed by sudden loss of vision in left eye (vision reduced to light perception only) with mild retro orbital pain on ocular movement. Patient visited her primary doctor, who diagnosed her with a viral rash and recommended she see an ophthalmologist. 176 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Ten days later, she developed high-grade fever with chills and rigors associated with mild headache with photophobia. This was accompanied by 2 episodes of projectile nonbloody vomiting. Over the next 24 hours, she developed weakness and numbness in the left arm and left leg, which progressively worsened to involve all 4 limbs. She denied chest pain, shortness of breath, gastrointestinal or genitourinary symptoms. There was no history of unsafe sexual contact or intravenous drug abuse. The patient was oriented to time, place, and person. Left eye vision was reduced to light perception. Light and accommodation reflexes were intact. Fundoscopic examination was negative. Cranial nerve and sensory system examinations were normal. Motor examination revealed lower motor neuron weakness in all limbs. Power Upper limb Lower limb
Left 3/5 2/5
Right 3+/5 4/5
Reflexes Upper limb Lower limb
Left 1+ Absent
Right 1+ 1+
Complete blood count and serum chemistry were grossly normal. Computed tomography scan of the brain did not reveal any evidence of infarct, hemorrhage, or midline shift. Lumbar puncture was done in the emergency department and showed the following results: • Opening pressure: 150 cm water • Fluid was clear and watery in appearance • Cerebrospinal fluid: red blood cells, 82 µ/L; white blood cells, 223 µ/L (neutrophils, 18%; lymphocytes, 85%); glucose, 44 mg/dL; protein, 199 mg/dL • Differential diagnosis was: (1) viral meningitis/ encephalitis-likely secondary to herpes simplex virus; (2) acute attack of multiple sclerosis?; (3) acute retroviral syndrome The patient was admitted to the intensive care unit. Acyclovir and dexamethasone were started. Cerebrospinal fluid was sent for polymerase chain reaction and culture (for herpes and mycobacterium). Human immunodeficiency virus (HIV) test (enzyme-linked immunosorbent VOL. 103, NO. 2, FEBRUARY 2011
A diagnostic dilemma
assay) was negative. On day 2, neurological examination exhibited weakness in all 4 limbs with hypereflexia and clonus in left leg. Magnetic resonance imaging of the brain showed normal brain imaging with diffuse hyperintense signals in cervical, thoracic, and conus medularis regions of the spinal cord (Figure). Cerebrospinal fluid polymerase chain reaction was negative for herpes, mycobacterium, and oligoclonal bands. Assessment of neuromyelitis optica (NMO, also known as Devic syndrome) or postinfectious demyelination was made. A test for anti-NMO antibodies was ordered, which was negative. The patient was started on a high-dose steroid. Acyclovir was discontinued. The patient observed some improvement in her vision over the next few days, but her motor strength worsened. On day 3, she developed tachypnea and shortness of breath and was intubated. Plasmapheresis was started, which resulted in rapid improvement in respiratory and Figure. Hyperintense Signals in the Spinal Cord
neurological status. She was extubated on the second day and transferred to floor on day 4. Later, the patient was discharged home, with a follow-up appointment in the neurology clinic. Now, she has some residual weakness in left leg. Her vision is good and she has been in remission since that time.
Review of Literature
NMO is an inflammatory disorder that predominantly involves the optic nerves and spinal cord.1 It affects young adults. Mean age of onset is 29 years (range, 1-54 y) for monophasic patients and 39 years (range, 6-72 y) for relapsing patients. The incidence and prevalence of NMO are unknown. In Western nations, it has generally been considered a rare disorder.
Clinical Course A viral prodrome precedes the onset of the disease in 30% to 50% of cases. The prodrome most often consists of headache, pyrexia, fatigue, myalgia, and respiratory or gastrointestinal complaints. There are 2 major types of Devic disease—monophasic and relapsing. In the relapsing form, repeated episodes of optic neuritis and myelitis occur that are separated by months or years. Optic neuritis is usually bilateral. It is almost always acute, usually severe, and may or may not be associated with retro-orbital pain. During the first episode of optic neuritis in NMO, nearly 40% of affected eyes become completely blind (no light perception) at the nadir of the event; however, some cases involve only minor visual deficits.1 Acute transverse myelitis, defined as severe, bilateral inflammatory spinal cord injury with neurological dysfunction worsening over several hours to days and involving motor, sensory, and sphincter function, is a typical presentation of NMO.5 The acute lesion usually traverses at least 3 contiguous vertebral segments of the spinal cord and may result in “spinal shock” with flaccid weakness, absent deep-tendon reflexes, and mute plantar responses. Partial recovery is common following the initial myelitis event in 78% to 88% of patients.
Pathophysiology
The cause of NMO is not known. Its clinical and pathological features have led most to consider it an autoimmune variant of multiple sclerosis. A high prevalence of serum autoantibodies, NMO-IgG, suggests that NMO may be driven primarily by B-cell dysfunction. These antibodies target a protein called aquaporin 4 in the cell membranes of astrocytes, which acts as a channel for the transport of water across the cell membrane.2-4 In 20% cases of NMO, this antibody is negative. So this makes the above-described case a diagnostic dilemma. The inflammatory differ from multiple sclerosis pattern II lesions in their prominent perivascular distribution.2,6 Devic disease has been associated with many systemic diseases, based on anecdotal evidence of some Devic
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
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A diagnostic dilemma
disease patients with a comorbid condition. Such conditions include: collagen vascular diseases, autoantibody syndromes, infections with varicella-zoster virus, Epstein-Barr virus, and HIV, and exposure to clioquinol and antituberculosis drugs.8
Diagnostic Criteria The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic disease in 2006. The new guidelines for diagnosis require 2 absolute criteria plus at least 2 of 3 supportive criteria.7 Absolute criteria. The absolute criteria are: (1) optic neuritis and (2) acute myelitis. Supportive Criteria. Supportive criteria include: (1) a brain MRI not meeting criteria for multiple sclerosis at disease onset. (The diagnosis of NMO is strongly supported by the absence of brain parenchymal lesions or the presence of nonspecific white-matter lesions that do not meet radiological criteria for multiple sclerosis; (2) a spinal cord MRI with contiguous T2-weighted signal abnormality extending over 3 or more vertebral segments, indicating a relatively large lesion in the spinal cord; (3) NMO-IgG seropositive status. The NMO-IgG test checks the existence of antibodies. Serological tests. One or more auto antibodies, including antinuclear antibody, anti-DsNA, extractable nuclear antigen, and antithyroid antibodies, are commonly present at the time of diagnosis. The true incidence is not known, but may approach 50%. Cerebrospinal fluid. Cerebrospinal fluid analysis may support the diagnosis of NMO. Occasionally, patients have a pleocytosis of more than 50 white blood cells/mm3 around the time of an acute myelitis exacerbation; this degree of cerebrospinal fluid cellularity is very rare in typical multiple sclerosis.
178 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Treatment NMO typically lacks secondary progression and therapy is designed to address acute attacks and limit destruction thereof.8 For acute attacks, an initial course of solumedrol is standard, consisting of 5 to 7 days of treatment. Refractory cases are often highly responsive to plasma exchange. Rituximab is an anti-CD20 monoclonal antibody that eliminates pre B and mature B cells can be used as weekly infusions.10 It increases relapse-free interval and Expanded Disability Status Scale improvement. Mitoxantrone is also an option.9
References
1. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expressions. Arch Neurol. 2006;63(7):964-968. 2. Wingerchuk DM. Neuromyelitis optica. Int MS J. 2006;13:42-50. 3. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112. 4. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477. 5. Mayo Clinic. Devic’s Disease Symptoms. www.mayoclinic.org/devicsdisease/symptoms.html. Accessed April 14, 2010. 6. Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125(7):1450-1461. 7. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489. 8. Poser CM, Brinar VV. Disseminated encephalomyelitis and multiple sclerosis: two different diseases—a critical review. Acta Neurol Scand. 2007;116(4):201-206. 9. Weinstock-Guttman B, Ramanathan M, Lincoff N, et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol. 2006;63(7):957-963. 10. Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Opin Neurol. 2007;20(3):255-260. n
VOL. 103, NO. 2, FEBRUARY 2011
a
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Devic Syndrome: A Diagnostic Dilemma Muhammad K. Perwaiz, MD; Fadi Hammoudeh, MD; Francis Schmidt, MD
Neuromyelitis optica (NMO, also known as Devic syndrome or Devic disease) is a rare clinical entity. Early recognition and prompt treatment can save patients from long-term disability, especially in themonophasic variant of disease. A 24-year-old African American female presented with highgrade fever for 1 day associated with frontal headache, photophobia, and 2 episodes of nonbloody vomiting. She had a history of nonitchy vesicular rash with sudden diminution of vision in the left eye 2 weeks ago. Over the next 24 hours, she developed progressively worsening weakness and numbness in her left arm and left leg, which later involved all limbs. Left eye vision was reduced to light perception with light and accommodation reflexes intact. Lumbar puncture showed lymphocytic pleocytosis with elevated protein. On day 2, neurological examination exhibited quadriparises with hypereflexia and clonus. Magnetic resonance imaging showed diffuse hyperintense signals in the spinal cord in cervical and lumbar regions. An assessment of neuromyelitis optica was made. Anti-NMO antibodies were negative. On day 3, she was intubated because of progressive dyspnea. Plasmapheresis resulted in rapid improvement in respiratory and neurological status. She was extubated on the second day and transferred to floor on day 4. Later, the patient was discharged. Keywords: Devic syndrome n ophthalmic J Natl Med Assoc. 2011;103:176-178 Author Affiliations: Departments of Medicine (Dr Perwaiz) and Pulmonology (Drs Hammoudeh and Schmidt), Interfaith Medical Center, Brooklyn, New York. Correspondence: Muhammad Perwaiz MD, Department of Medicine, Interfaith Medical Center, 1545 Atlantic Ave, Brooklyn, NY 11213 ([email protected]).
Case Presentation
A
24-year-old African American female with past medical history of tuberculous lymphadenitis in childhood was in a state of usual health when she developed a nonitchy vesicular rash over her upper trunk and shoulders. This was followed by sudden loss of vision in left eye (vision reduced to light perception only) with mild retro orbital pain on ocular movement. Patient visited her primary doctor, who diagnosed her with a viral rash and recommended she see an ophthalmologist. 176 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Ten days later, she developed high-grade fever with chills and rigors associated with mild headache with photophobia. This was accompanied by 2 episodes of projectile nonbloody vomiting. Over the next 24 hours, she developed weakness and numbness in the left arm and left leg, which progressively worsened to involve all 4 limbs. She denied chest pain, shortness of breath, gastrointestinal or genitourinary symptoms. There was no history of unsafe sexual contact or intravenous drug abuse. The patient was oriented to time, place, and person. Left eye vision was reduced to light perception. Light and accommodation reflexes were intact. Fundoscopic examination was negative. Cranial nerve and sensory system examinations were normal. Motor examination revealed lower motor neuron weakness in all limbs. Power Upper limb Lower limb
Left 3/5 2/5
Right 3+/5 4/5
Reflexes Upper limb Lower limb
Left 1+ Absent
Right 1+ 1+
Complete blood count and serum chemistry were grossly normal. Computed tomography scan of the brain did not reveal any evidence of infarct, hemorrhage, or midline shift. Lumbar puncture was done in the emergency department and showed the following results: • Opening pressure: 150 cm water • Fluid was clear and watery in appearance • Cerebrospinal fluid: red blood cells, 82 µ/L; white blood cells, 223 µ/L (neutrophils, 18%; lymphocytes, 85%); glucose, 44 mg/dL; protein, 199 mg/dL • Differential diagnosis was: (1) viral meningitis/ encephalitis-likely secondary to herpes simplex virus; (2) acute attack of multiple sclerosis?; (3) acute retroviral syndrome The patient was admitted to the intensive care unit. Acyclovir and dexamethasone were started. Cerebrospinal fluid was sent for polymerase chain reaction and culture (for herpes and mycobacterium). Human immunodeficiency virus (HIV) test (enzyme-linked immunosorbent VOL. 103, NO. 2, FEBRUARY 2011
A diagnostic dilemma
assay) was negative. On day 2, neurological examination exhibited weakness in all 4 limbs with hypereflexia and clonus in left leg. Magnetic resonance imaging of the brain showed normal brain imaging with diffuse hyperintense signals in cervical, thoracic, and conus medularis regions of the spinal cord (Figure). Cerebrospinal fluid polymerase chain reaction was negative for herpes, mycobacterium, and oligoclonal bands. Assessment of neuromyelitis optica (NMO, also known as Devic syndrome) or postinfectious demyelination was made. A test for anti-NMO antibodies was ordered, which was negative. The patient was started on a high-dose steroid. Acyclovir was discontinued. The patient observed some improvement in her vision over the next few days, but her motor strength worsened. On day 3, she developed tachypnea and shortness of breath and was intubated. Plasmapheresis was started, which resulted in rapid improvement in respiratory and Figure. Hyperintense Signals in the Spinal Cord
neurological status. She was extubated on the second day and transferred to floor on day 4. Later, the patient was discharged home, with a follow-up appointment in the neurology clinic. Now, she has some residual weakness in left leg. Her vision is good and she has been in remission since that time.
Review of Literature
NMO is an inflammatory disorder that predominantly involves the optic nerves and spinal cord.1 It affects young adults. Mean age of onset is 29 years (range, 1-54 y) for monophasic patients and 39 years (range, 6-72 y) for relapsing patients. The incidence and prevalence of NMO are unknown. In Western nations, it has generally been considered a rare disorder.
Clinical Course A viral prodrome precedes the onset of the disease in 30% to 50% of cases. The prodrome most often consists of headache, pyrexia, fatigue, myalgia, and respiratory or gastrointestinal complaints. There are 2 major types of Devic disease—monophasic and relapsing. In the relapsing form, repeated episodes of optic neuritis and myelitis occur that are separated by months or years. Optic neuritis is usually bilateral. It is almost always acute, usually severe, and may or may not be associated with retro-orbital pain. During the first episode of optic neuritis in NMO, nearly 40% of affected eyes become completely blind (no light perception) at the nadir of the event; however, some cases involve only minor visual deficits.1 Acute transverse myelitis, defined as severe, bilateral inflammatory spinal cord injury with neurological dysfunction worsening over several hours to days and involving motor, sensory, and sphincter function, is a typical presentation of NMO.5 The acute lesion usually traverses at least 3 contiguous vertebral segments of the spinal cord and may result in “spinal shock” with flaccid weakness, absent deep-tendon reflexes, and mute plantar responses. Partial recovery is common following the initial myelitis event in 78% to 88% of patients.
Pathophysiology
The cause of NMO is not known. Its clinical and pathological features have led most to consider it an autoimmune variant of multiple sclerosis. A high prevalence of serum autoantibodies, NMO-IgG, suggests that NMO may be driven primarily by B-cell dysfunction. These antibodies target a protein called aquaporin 4 in the cell membranes of astrocytes, which acts as a channel for the transport of water across the cell membrane.2-4 In 20% cases of NMO, this antibody is negative. So this makes the above-described case a diagnostic dilemma. The inflammatory differ from multiple sclerosis pattern II lesions in their prominent perivascular distribution.2,6 Devic disease has been associated with many systemic diseases, based on anecdotal evidence of some Devic
JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
VOL. 103, NO. 2, FEBRUARY 2011 177
A diagnostic dilemma
disease patients with a comorbid condition. Such conditions include: collagen vascular diseases, autoantibody syndromes, infections with varicella-zoster virus, Epstein-Barr virus, and HIV, and exposure to clioquinol and antituberculosis drugs.8
Diagnostic Criteria The Mayo Clinic proposed a revised set of criteria for diagnosis of Devic disease in 2006. The new guidelines for diagnosis require 2 absolute criteria plus at least 2 of 3 supportive criteria.7 Absolute criteria. The absolute criteria are: (1) optic neuritis and (2) acute myelitis. Supportive Criteria. Supportive criteria include: (1) a brain MRI not meeting criteria for multiple sclerosis at disease onset. (The diagnosis of NMO is strongly supported by the absence of brain parenchymal lesions or the presence of nonspecific white-matter lesions that do not meet radiological criteria for multiple sclerosis; (2) a spinal cord MRI with contiguous T2-weighted signal abnormality extending over 3 or more vertebral segments, indicating a relatively large lesion in the spinal cord; (3) NMO-IgG seropositive status. The NMO-IgG test checks the existence of antibodies. Serological tests. One or more auto antibodies, including antinuclear antibody, anti-DsNA, extractable nuclear antigen, and antithyroid antibodies, are commonly present at the time of diagnosis. The true incidence is not known, but may approach 50%. Cerebrospinal fluid. Cerebrospinal fluid analysis may support the diagnosis of NMO. Occasionally, patients have a pleocytosis of more than 50 white blood cells/mm3 around the time of an acute myelitis exacerbation; this degree of cerebrospinal fluid cellularity is very rare in typical multiple sclerosis.
178 JOURNAL OF THE NATIONAL MEDICAL ASSOCIATION
Treatment NMO typically lacks secondary progression and therapy is designed to address acute attacks and limit destruction thereof.8 For acute attacks, an initial course of solumedrol is standard, consisting of 5 to 7 days of treatment. Refractory cases are often highly responsive to plasma exchange. Rituximab is an anti-CD20 monoclonal antibody that eliminates pre B and mature B cells can be used as weekly infusions.10 It increases relapse-free interval and Expanded Disability Status Scale improvement. Mitoxantrone is also an option.9
References
1. Pittock SJ, Weinshenker BG, Lucchinetti CF, Wingerchuk DM, Corboy JR, Lennon VA. Neuromyelitis optica brain lesions localized at sites of high aquaporin 4 expressions. Arch Neurol. 2006;63(7):964-968. 2. Wingerchuk DM. Neuromyelitis optica. Int MS J. 2006;13:42-50. 3. Lennon VA, Wingerchuk DM, Kryzer TJ, et al. A serum autoantibody marker of neuromyelitis optica: distinction from multiple sclerosis. Lancet. 2004;364(9451):2106-2112. 4. Lennon VA, Kryzer TJ, Pittock SJ, Verkman AS, Hinson SR. IgG marker of optic-spinal multiple sclerosis binds to the aquaporin-4 water channel. J Exp Med. 2005;202(4):473-477. 5. Mayo Clinic. Devic’s Disease Symptoms. www.mayoclinic.org/devicsdisease/symptoms.html. Accessed April 14, 2010. 6. Lucchinetti CF, Mandler RN, McGavern D, et al. A role for humoral mechanisms in the pathogenesis of Devic’s neuromyelitis optica. Brain. 2002;125(7):1450-1461. 7. Wingerchuk DM, Lennon VA, Pittock SJ, Lucchinetti CF, Weinshenker BG. Revised diagnostic criteria for neuromyelitis optica. Neurology. 2006;66(10):1485-1489. 8. Poser CM, Brinar VV. Disseminated encephalomyelitis and multiple sclerosis: two different diseases—a critical review. Acta Neurol Scand. 2007;116(4):201-206. 9. Weinstock-Guttman B, Ramanathan M, Lincoff N, et al. Study of mitoxantrone for the treatment of recurrent neuromyelitis optica (Devic disease). Arch Neurol. 2006;63(7):957-963. 10. Matiello M, Jacob A, Wingerchuk DM, Weinshenker BG. Neuromyelitis optica. Curr Opin Neurol. 2007;20(3):255-260. n
VOL. 103, NO. 2, FEBRUARY 2011