Acute Hemorrhagic Leukoencephalitis Associated with Autoimmune Myopathy Neeta Duggal, MD, University of Missouri at Kansas City Iftekhar Ahmed, MD, Research Medical Center Nikki Duggal, MD, University of Missouri at Kansas City
Abstract Journal of Vascular and Interventional Neurology, Vol. 14
Introduction—Acute hemorrhagic leukoencephalitis is a rare acute inflammatory myelinopathy of central nervous system with high mortality. We report a case of an unusual presentation of acute hemorrhagic leukoencephalitis with autoimmune myopathy and a complete recovery with steroids and plasmapheresis. Methods—A 24-year-old female admitted with generalized seizure, lethargy, but no focal neurological signs. Head scans revealed right frontal hypodensity with loss of basal cisterns, mild transfalcine shift to the left, a mass lesion with abnormal signal and multiple small hemorrhages. Biopsy pathology showed white matter demyelinating lesions with necrotizing destruction of small vessels and acute inflammation. EMG was consistent with demyelinating diffuse polyneuropathy and myopathy. Pathology of muscle showed myopathic changes suggestive of autoimmune myopathy. Results—Patient was initially treated with Dexamethasone, Mannitol, Keppra, Antibiotics and Acyclovir. Later when she developed diffuse polyneuropathy and myopathy, she was given plasmapheresis. The patient responded to the treatment and made a full recovery. Conclusion—Acute hemorrhagic leukoencephalitis is a rare and usually fatal disorder. The etiology of AHLE remains clear; cross-reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an immune process causing demyelination. Usually the autoimmune process targets CNS myelin and spares the peripheral; however, in this case there was diffuse involvement of central and peripheral myelin and muscle.
Background We report a case of an unusual presentation of acute hemorrhagic leukoencephalitis with autoimmune myopathy. This association has not been reported in the literature. This disease has a high mortality rate; however, this case presents a patient with acute hemorrhagic leukoencephalitis who responded well with steroids and plasmapheresis and made a complete recovery.
Introduction Acute hemorrhagic leukoencephalitis (AHLE) is a rare acute inflammatory myelinopathy of central nervous system (CNS) with high mortality. Its association with autoimmune myopathy has not been reported previously. This case report provides strong evidence of CNS and peripheral nervous system (PNS) involvement in autoimmune disorders.
Table 1. Causes of Acute Hemorrhagic Leukencephalitis Viral Infections: Influenza Virus Enterovirus Measles Mumps Rebella Varicella zoster Epstein Barr virus Cytomegalovirus Herpes simplex virus Hepatitis A Bacterial Infections: Mycoplasma pneumonia Borrelia burgdorferi Leptospira Beta-hemolytic Streptococci Other: Rabies Vaccine Measles Vaccine Status-post organ transplant
AHLE is a demyelinating disease of the white matter which rapidly progresses from inflammation in the CNS to confusion and muscle weakness to stupor and coma.
Published November, 2014. All Rights Reserved by JVIN. Unauthorized reproduction of this article is prohibited
20
Journal of Vascular and Interventional Neurology, Vol. 14
Figure 3. Presents a Luxol Fast Blue stain with Hematoxylin and Eosin. the slide should be almost entirely light blue in normal white matter. Around the 3 vessels more pink is visible than normal due to the loss of myelin, i.e. a demyelinative process. the vessels appear most consistent with veins or venules.
Figure 4. Higher power view. Note the loss of blue
around the vessel, the presence of neutrophils and the amount of red staining present demonstrating thickening of the vessel wall in this case secondary to necrosis. Figures 1 and 2.
It is characterized by edema, hemorrhage and necrotizing vasculitis of venules and therefore damages the white matter in the brain. AHLE has an overall high mortality rate and survivors are left with residual neurological deficits. Death is common in the first week of the disease, causing an approximate 70% mortality rate. Numerous infectious agents have been associated with AHLE including EBV, HSV and M. pneumonia and others (Table 1). Cross–reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an autoimmune process causing demyelination. Pathology features of AHLE frequently include cerebral edema, perivascular demyelination, hemorrhage and perivascular infiltrates of neutrophils and mononuclear cells.
Although favorable outcomes in AHLE cases are uncommon, positive results have been described in patients receiving immunosuppressive therapy with corticosteroids, cyclophosphamide and therapeutic plasma exchange, individually or in combination, with vigorous control of intracranial pressure.
Case Description A 24 year old female was admitted with generalized seizures. She was lethargic and somnolent but able to move all her extremities. Reflexes were brisk, +3 to +4 at biceps, triceps, brachioradialis, knees and ankles bilaterally. Clonus was present however plantar flexors. Serum chemistries were normal and creatine phosphokinase was 285. Head CT scan was done initially which revealed right frontal hypodensity with loss of basal cisterns and mild transfalcine shift to the left (Figure 1, Figure 2). Magnetic resonance imaging (MRI) of brain
21
Figure 5. Trichrome stain which is intensely red around
Journal of Vascular and Interventional Neurology, Vol. 14
the small vessel walls consistent with fibrin or fibrinoid necrosis of the vessel wall. Also note the neutrophils within the vessel lumen and around the vessel wall and within the white matter. Neutrophils are an important finding in making the diagnosis of AHLE.
Figure 6. Neurofilament stain. Note the brown stain is
present in areas where there was loss of blue staining on the previous slides. This brown stain indicates that axons are present where myelin has been lost. This is consistent with a demyelinative process as opposed to an infarct which would show loss of both.
demonstrated a mass lesion with abnormal signal and multiple small hemorrhages. Craniotomy and decompression surgery were performed and brain biopsies were obtained (Figure 3, 4, 5, and 6). The patient was intubated and was on ventilation for two days after craniotomy procedure. Pathology showed white matter demyelinating lesions with necrotizing destruction of small vessels and acute inflammation Later on patient developed severe paraplegia. EMG was consistent with demyelinating diffuse polyneuropathy and myopathy. The pathology of the muscles showed myopathic changes suggestive of myopathy.
Results The patient was initially treated with Dexamethasone, Mannitol, Keppra, antibiotics and Acyclovir. With development of diffuse polyneuropathy and myopathy, the patient was treated with volume to volume Plasma-
Figures 7, 8, 9 and 10.
pheresis. The patient also received inpatient physical, occupational and speech therapy. The patient responded to the treatment and after a long course of hospital stay, made a full recovery.
Discussion Other autoimmune diseases include Multiple Sclerosis (MS) affecting CNS and Guillain-Barré Syndrome (GBS) affecting PNS. MS is an inflammatory autoimmune disease which involves the loss of oligodendrocytes and damages the myelin sheath of neurons causing autonomic, sensory and motor dysfunction. MS lesions are usually seen in the white matter in the spinal cord, brain stem and optic nerve (CNS). Just as in AHLE, proposed causes include infections and viruses. Given the immune-mediated nature of MS, treatment of steroids and plasmapheresis generally show improvement of symptoms as it filters out antibodies. Unlike MS, GBS
22
effects of the PNS and generally does not cause damage to the brain or spinal cord but rather sensory and autonomic dysfunction. GBS is an autoimmune disease, likely caused by an infectious agent including Campylobacter jejuni and Cytomegalovirus. Treatment of GBS includes plasmapheresis and intravenous immunoglobins. Unlike MS and GBS, AHLE crosses from the CNS to PNS and affects both nervous systems.
Conclusion
Journal of Vascular and Interventional Neurology, Vol. 14
Acute hemorrhagic leukoencephalitis is a rare and usually fatal disorder characterized clinically by an acute onset of neurologic abnormalities. It may occur in association with viral or bacterial infections or after vaccination. The etiology of AHLE remains unclear, cross reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an immune process causing demyelination. Usually the autoimmune process targets central nervous system myelin and spares the peripheral. But in this case there was diffuse involvement of central and peripheral myelin and muscle. Given the likely immune-mediated nature of the disease, combined treatment of steroids and plasmapheresis may lead to neurologic improvement, as seen in our case.
References: 1. Mauro C, Marcello N, et al. Acute hemorrhagic leukoencephalitis with atypical features. Neurol Sci 2009;30:55–57. 2. Sharmeela K, Peter O, Michael K, et al. Acute hemorrhagic leukoencephalitis vs ADEM :FLAIR MRI and neuropathology. Neurology 2003;60:721. 3. Tuhin V, Ashima A, Eric CK. Clinical reasoning: a young adult presents with focal weakness and hemorrhagic brain lesions. Neurology 2011;76:e 106. 4. Lori J.R, Robert B, Nicole D.Z, et al. Use of therapeutic plasma exchange in the management of acute hemorrhagic leukoencephalitis: a case report and review of the literature. Transfusion 2007;47:981–986. 5. Stone MJ, Hawkins CP. 2007;“a medical overview of encephalitis”. Neuropsychol Rehabil 17(4–5):429–49. 6. Davies NW, Sharief MK, Howard RS. July;2006 “Infection-associated encephalopathies: their investigation, diagnosis, and treatment”. J. Neurol 253(7):833–45. 7. Archer H, Wall R. February;2003 “Acute hemorrhagic leukoencephalopathy: two case reports and review of the literature”. J. Infect 46(2):133–7. 8. Compston A, Coles A. April;2002 “Multiple sclerosis”. Lancet 359(9313):1221–31.
Abstract Journal of Vascular and Interventional Neurology, Vol. 14
Introduction—Acute hemorrhagic leukoencephalitis is a rare acute inflammatory myelinopathy of central nervous system with high mortality. We report a case of an unusual presentation of acute hemorrhagic leukoencephalitis with autoimmune myopathy and a complete recovery with steroids and plasmapheresis. Methods—A 24-year-old female admitted with generalized seizure, lethargy, but no focal neurological signs. Head scans revealed right frontal hypodensity with loss of basal cisterns, mild transfalcine shift to the left, a mass lesion with abnormal signal and multiple small hemorrhages. Biopsy pathology showed white matter demyelinating lesions with necrotizing destruction of small vessels and acute inflammation. EMG was consistent with demyelinating diffuse polyneuropathy and myopathy. Pathology of muscle showed myopathic changes suggestive of autoimmune myopathy. Results—Patient was initially treated with Dexamethasone, Mannitol, Keppra, Antibiotics and Acyclovir. Later when she developed diffuse polyneuropathy and myopathy, she was given plasmapheresis. The patient responded to the treatment and made a full recovery. Conclusion—Acute hemorrhagic leukoencephalitis is a rare and usually fatal disorder. The etiology of AHLE remains clear; cross-reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an immune process causing demyelination. Usually the autoimmune process targets CNS myelin and spares the peripheral; however, in this case there was diffuse involvement of central and peripheral myelin and muscle.
Background We report a case of an unusual presentation of acute hemorrhagic leukoencephalitis with autoimmune myopathy. This association has not been reported in the literature. This disease has a high mortality rate; however, this case presents a patient with acute hemorrhagic leukoencephalitis who responded well with steroids and plasmapheresis and made a complete recovery.
Introduction Acute hemorrhagic leukoencephalitis (AHLE) is a rare acute inflammatory myelinopathy of central nervous system (CNS) with high mortality. Its association with autoimmune myopathy has not been reported previously. This case report provides strong evidence of CNS and peripheral nervous system (PNS) involvement in autoimmune disorders.
Table 1. Causes of Acute Hemorrhagic Leukencephalitis Viral Infections: Influenza Virus Enterovirus Measles Mumps Rebella Varicella zoster Epstein Barr virus Cytomegalovirus Herpes simplex virus Hepatitis A Bacterial Infections: Mycoplasma pneumonia Borrelia burgdorferi Leptospira Beta-hemolytic Streptococci Other: Rabies Vaccine Measles Vaccine Status-post organ transplant
AHLE is a demyelinating disease of the white matter which rapidly progresses from inflammation in the CNS to confusion and muscle weakness to stupor and coma.
Published November, 2014. All Rights Reserved by JVIN. Unauthorized reproduction of this article is prohibited
20
Journal of Vascular and Interventional Neurology, Vol. 14
Figure 3. Presents a Luxol Fast Blue stain with Hematoxylin and Eosin. the slide should be almost entirely light blue in normal white matter. Around the 3 vessels more pink is visible than normal due to the loss of myelin, i.e. a demyelinative process. the vessels appear most consistent with veins or venules.
Figure 4. Higher power view. Note the loss of blue
around the vessel, the presence of neutrophils and the amount of red staining present demonstrating thickening of the vessel wall in this case secondary to necrosis. Figures 1 and 2.
It is characterized by edema, hemorrhage and necrotizing vasculitis of venules and therefore damages the white matter in the brain. AHLE has an overall high mortality rate and survivors are left with residual neurological deficits. Death is common in the first week of the disease, causing an approximate 70% mortality rate. Numerous infectious agents have been associated with AHLE including EBV, HSV and M. pneumonia and others (Table 1). Cross–reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an autoimmune process causing demyelination. Pathology features of AHLE frequently include cerebral edema, perivascular demyelination, hemorrhage and perivascular infiltrates of neutrophils and mononuclear cells.
Although favorable outcomes in AHLE cases are uncommon, positive results have been described in patients receiving immunosuppressive therapy with corticosteroids, cyclophosphamide and therapeutic plasma exchange, individually or in combination, with vigorous control of intracranial pressure.
Case Description A 24 year old female was admitted with generalized seizures. She was lethargic and somnolent but able to move all her extremities. Reflexes were brisk, +3 to +4 at biceps, triceps, brachioradialis, knees and ankles bilaterally. Clonus was present however plantar flexors. Serum chemistries were normal and creatine phosphokinase was 285. Head CT scan was done initially which revealed right frontal hypodensity with loss of basal cisterns and mild transfalcine shift to the left (Figure 1, Figure 2). Magnetic resonance imaging (MRI) of brain
21
Figure 5. Trichrome stain which is intensely red around
Journal of Vascular and Interventional Neurology, Vol. 14
the small vessel walls consistent with fibrin or fibrinoid necrosis of the vessel wall. Also note the neutrophils within the vessel lumen and around the vessel wall and within the white matter. Neutrophils are an important finding in making the diagnosis of AHLE.
Figure 6. Neurofilament stain. Note the brown stain is
present in areas where there was loss of blue staining on the previous slides. This brown stain indicates that axons are present where myelin has been lost. This is consistent with a demyelinative process as opposed to an infarct which would show loss of both.
demonstrated a mass lesion with abnormal signal and multiple small hemorrhages. Craniotomy and decompression surgery were performed and brain biopsies were obtained (Figure 3, 4, 5, and 6). The patient was intubated and was on ventilation for two days after craniotomy procedure. Pathology showed white matter demyelinating lesions with necrotizing destruction of small vessels and acute inflammation Later on patient developed severe paraplegia. EMG was consistent with demyelinating diffuse polyneuropathy and myopathy. The pathology of the muscles showed myopathic changes suggestive of myopathy.
Results The patient was initially treated with Dexamethasone, Mannitol, Keppra, antibiotics and Acyclovir. With development of diffuse polyneuropathy and myopathy, the patient was treated with volume to volume Plasma-
Figures 7, 8, 9 and 10.
pheresis. The patient also received inpatient physical, occupational and speech therapy. The patient responded to the treatment and after a long course of hospital stay, made a full recovery.
Discussion Other autoimmune diseases include Multiple Sclerosis (MS) affecting CNS and Guillain-Barré Syndrome (GBS) affecting PNS. MS is an inflammatory autoimmune disease which involves the loss of oligodendrocytes and damages the myelin sheath of neurons causing autonomic, sensory and motor dysfunction. MS lesions are usually seen in the white matter in the spinal cord, brain stem and optic nerve (CNS). Just as in AHLE, proposed causes include infections and viruses. Given the immune-mediated nature of MS, treatment of steroids and plasmapheresis generally show improvement of symptoms as it filters out antibodies. Unlike MS, GBS
22
effects of the PNS and generally does not cause damage to the brain or spinal cord but rather sensory and autonomic dysfunction. GBS is an autoimmune disease, likely caused by an infectious agent including Campylobacter jejuni and Cytomegalovirus. Treatment of GBS includes plasmapheresis and intravenous immunoglobins. Unlike MS and GBS, AHLE crosses from the CNS to PNS and affects both nervous systems.
Conclusion
Journal of Vascular and Interventional Neurology, Vol. 14
Acute hemorrhagic leukoencephalitis is a rare and usually fatal disorder characterized clinically by an acute onset of neurologic abnormalities. It may occur in association with viral or bacterial infections or after vaccination. The etiology of AHLE remains unclear, cross reactivity between human myelin antigens and viral or bacterial antigens is thought to initiate an immune process causing demyelination. Usually the autoimmune process targets central nervous system myelin and spares the peripheral. But in this case there was diffuse involvement of central and peripheral myelin and muscle. Given the likely immune-mediated nature of the disease, combined treatment of steroids and plasmapheresis may lead to neurologic improvement, as seen in our case.
References: 1. Mauro C, Marcello N, et al. Acute hemorrhagic leukoencephalitis with atypical features. Neurol Sci 2009;30:55–57. 2. Sharmeela K, Peter O, Michael K, et al. Acute hemorrhagic leukoencephalitis vs ADEM :FLAIR MRI and neuropathology. Neurology 2003;60:721. 3. Tuhin V, Ashima A, Eric CK. Clinical reasoning: a young adult presents with focal weakness and hemorrhagic brain lesions. Neurology 2011;76:e 106. 4. Lori J.R, Robert B, Nicole D.Z, et al. Use of therapeutic plasma exchange in the management of acute hemorrhagic leukoencephalitis: a case report and review of the literature. Transfusion 2007;47:981–986. 5. Stone MJ, Hawkins CP. 2007;“a medical overview of encephalitis”. Neuropsychol Rehabil 17(4–5):429–49. 6. Davies NW, Sharief MK, Howard RS. July;2006 “Infection-associated encephalopathies: their investigation, diagnosis, and treatment”. J. Neurol 253(7):833–45. 7. Archer H, Wall R. February;2003 “Acute hemorrhagic leukoencephalopathy: two case reports and review of the literature”. J. Infect 46(2):133–7. 8. Compston A, Coles A. April;2002 “Multiple sclerosis”. Lancet 359(9313):1221–31.
