- Email: [email protected]
Acute disseminated encephalomyelitis presenting as a brainstem encephalitis
Clinical Neurology and Neurosurgery 143 (2016) 76–79
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Acute disseminated encephalomyelitis presenting as a brainstem encephalitis Daniel S. Atherton a,∗ , Sarah R. Perez b , Nathan D. Gundacker c , Ricardo Franco c , Xiaosi Han b a
Department of Pathology, HSB 175J, 619 19th St. South, University of Alabama, Birmingham, AL 35249, United States Department of Neurology, SC 350, 1720 2nd Ave. South, University of Alabama, Birmingham, AL 35294, United States c Division of Infectious Diseases, 1201 11th Ave. South, University of Alabama, Birmingham, AL 35205, United States b
a r t i c l e
i n f o
Article history: Received 1 May 2015 Received in revised form 5 February 2016 Accepted 10 February 2016 Available online 15 February 2016 Keywords: Acute disseminated encephalomyelitis Hemorrhagic leukoencephalopathy Demyelination Rhomboencephalitis
a b s t r a c t Acute disseminated encephalomyelitis (ADEM) is a disease characterized by inflammation and destruction of myelin. Acute hemorrhagic leukoencephalitis (AHLE) is a severe form of ADEM known for its particularly poor outcome. We present a case of a young Caucasian female who presented with drowsiness and slurred speech followed by rapid brainstem involvement resembling rhomboencephalitis. Despite multiple diagnostic tests and empiric therapy with immunosuppressants, immunoglobulins, and antimicrobials, she lost most brainstem reflexes within a few weeks and ultimately passed away. Magnetic resonance imaging (MRI) showed progression of lesions from the brainstem to eventually involve bilateral cerebral hemispheres. Autopsy and microscopic examination of the brain revealed several hemorrhagic lesions throughout the brain and rendered a diagnosis of AHLE. AHLE was initially described in 1941 and is thought to be autoimmune related, possibly related to cross reactivity between the immune system and CNS tissues like myelin. While a definitive inciting pathogen was not discovered, this case emphasizes the importance of considering AHLE in the differential diagnosis of patients with rapid loss of neurologic function and highlights an atypical presentation of ADEM/AHLE. © 2016 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
Acute disseminated encephalomyelitis (ADEM) is a rare disease characterized by severe inflammation of the central nervous system (CNS) with resultant destruction of myelin and white matter [1]. It is thought to be autoimmune related and possibly triggered by viral infection or even recent immunization [2]. Acute hemorrhagic leukoencephalitis (AHLE), also known as Weston-Hurst syndrome, is a hyperacute and frequently fatal form of ADEM and comprises only about 2% of cases of ADEM. While most forms of ADEM are generally self-limiting with disease progression occurring only in the first few days of onset, AHLE has a more aggressive and prolonged clinical course. Herein, we present the case of a 34 year old woman who died of autopsy-proven AHLE. The disease had atypical features of severe brainstem involvement that simulated other causes of rhomboencephalitis.
A 34 year old Caucasian woman presented to an outside hospital complaining of 3–4 weeks of fatigue, drowsiness, slurred speech, extremity numbness, and a metal taste in her mouth. On the morning of admission, she appeared intoxicated and was dismissed from work, prompting admission to the hospital. In the hospital, she became unresponsive and was transferred to the Intensive Care Unit (ICU), where she was intubated for airway protection. Magnetic resonance imaging (MRI) of the brain demonstrated an abnormal signal in the midbrain of unclear etiology, and the patient was transferred to our hospital. Upon arrival at our hospital, the patient was admitted to the ICU with a heart rate of 78 beats per minute, blood pressure of 109/73 mm Hg, respiratory rate of 12 breaths per minute, and body temperature of 95.0 ◦ F. Neurological examination demonstrated the patient to be nonresponsive with a Glascow Coma Scale (GCS) of 7/15 (E2V1tM4) [opened eyes in response to painful stimuli (E2); verbal response unevaluable due to tracheal intubation (V1t); withdrawal from pain (M4)]. Motor exam showed withdrawal to pain on the right side and grimace to pain with trace movement on the left side. Deep tendon reflexes were symmetric 2+ throughout. Ini-
∗ Corresponding author. E-mail address: [email protected] (D.S. Atherton). http://dx.doi.org/10.1016/j.clineuro.2016.02.014 0303-8467/© 2016 Elsevier B.V. All rights reserved.
D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
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Fig. 1. Progression of lesions in brainstem and cerebral hemispheres on MRI. Top row: contrast-enhanced images; (A) hospital day 0; (B) hospital day 6; (C and D) hospital day 14. Bottom row: T2/FLAIR images: (E) hospital day 0; (F) hospital day 6; (G,H) hospital day 14.
tial labs were significant for a negative human immunodeficiency virus (HIV) antibody test, negative comprehensive rheumatologic panel, elevated white blood cell count (WBC) of 15,000/L (normal: 4500–10,000/L), and urinalysis suggestive of urinary tract infection. On hospital day 2, she developed fever and lost all spontaneous extremity movement, but was still able to nod her head in response to questions. The patient’s fiancé indicated that 6 weeks prior to this presentation there had been an outbreak of hand-foot-andmouth disease (HFMD) at the daycare where the patient worked as a teacher. She fell ill at the time with self-limited upper respiratory symptoms. Initial MRI of the brain showed scattered T2/FLAIR (Fluid Attenuated Inversion Recovery) hyperintense lesions with the largest lesion at the midbrain/pons showing heterogeneous enhancement and focal hemorrhage (Fig. 1). A right cerebellar lesion appeared similarly. Lumbar puncture taken shortly after admission demonstrated a mildly elevated protein of 48 mg/dL (normal: <45 mg/dL), glucose of 50 mg/dL (normal: 50–80 mg/dL), and WBC of 0 cells/L (normal: 0–5 cells/L). Other CSF tests were within normal range.
She was then started on high dose intravenous methylprednisolone for a suspected inflammatory condition. She remained persistently febrile for 2 days which prompted empiric coverage with acyclovir, ampicillin, vancomycin, and piperacillintazobactam. Her neurologic status continued to decline, and she lost all ability to respond to questions. A repeat MRI (hospital day 6) showed new lesions in the frontal lobes and medulla and marked progression of disease in bilateral hippocampi (Fig. 1). The GCS score on hospital day 6 was 6/15 (E1V1tM4) [no eye opening (E1); verbal response unevaluable due to tracheal intubation (V1t); withdrawal from pain (M4)]. After completing 5 days of high dosed steroids, she was switched to intravenous immunoglobulin (IVIG) for possible viral or inflammatory rhomboencephalitis. A serological test for coxsackievirus eventually returned a titer of 1:16 for coxsackievirus B6. Biopsy was considered, but thought to be low-yield given the amount of hemorrhage that was seen on imaging. Instead, it was decided to biopsy an enlarged paratracheal lymph node, which would later return as non-diagnostic. Given the absence of a confirmatory diagnosis and the severity of CNS involvement, the patient was broadly treated for potential infectious
Fig. 2. Cross section of pons shows irregular, hemorrhagic, and destructive lesion.
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D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
Fig. 3. Hemotoxylin & eosin-stained sections of tissue from pons. (A) Solid arrow shows vessel with severe mixed inflammation. Arrow outlines show fibrin vascular thrombi with perivascular hemorrhage. (B) Two vessels with occlusive fibrin thrombi, abundant mixed inflammation, vascular necrosis, and perivascular hemorrhage.
pathogens known to cause brainstem and/or temporal encephalitis. During the ICU stay, amphotericin B (due to concerns for Aspergillus), RIPE (rifampin, isoniazid, pyrazinamide, ethambutol), and toxoplasmosis treatment (sulfadiazine and pyrimethamine) were added in a stepwise fashion in an attempt to broadly address rare infectious causes of rhombencephalitis. Extensive, non-invasive work-up searching for fungal, viral, and mycobacterial pathogens remained negative. She continued to decline neurologically, losing most of her brainstem reflexes by hospital day 12. Her bedside electroencephalogram (EEG) showed mixed theta and delta waves without signs of seizure. Repeat MRI of the head obtained 14 days after admission showed innumerable foci of diffusion restriction with enlargement of previously identified brainstem, cerebral, and cerebellar lesions (Fig. 1). Given the worsening MRI and poor neurologic exam, the family decided to withdraw care. On hospital day 16, the patient passed away. Autopsy was performed. Coronal sections of the cerebral hemispheres revealed multiple, widely scattered hemorrhagic lesions involving the cerebral cortical areas and underlying peripheral white matter, basal ganglia, thalamus, right hippocampus, and bilateral mesial temporal lobes (Fig. 2). Brainstem sections showed similar appearing lesions involving the midbrain, pons, and medulla. Microscopic examination of the lesions showed subacute infarcts characterized by tissue necrosis, red neurons, perivascular inflammation, parenchymal hemorrhage, microvasculature occluded with fibrin thrombi, and vacuolization of the neuropil (Fig. 3). A diagnosis of AHLE was rendered. At the time of autopsy, brain tissue, body fluids, and stool were sent to the Centers for Disease Control (CDC) for polymerase chain reaction (PCR) viral analyses, and these returned negative for detection of Enteroviruses. 3. Discussion ADEM is a rare disease that usually affects children. The mechanism of destruction is thought to be autoimmune with multiple viruses, bacteria, and certain types of immunization implicated in initiating the cascade of events that leads to widespread CNS destruction. AHLE is a rare form of ADEM, and death is common in the first week of its onset. AHLE is different from most forms of ADEM in that it is more likely to be characterized by cerebral edema, diffuse white matter changes on imaging, histologic evidence of hemorrhage involving the white matter, and a more rapidly fatal clinical course [3]. Unlike ADEM, AHLE is more common in adults than children. AHLE was first described in 1941 by E. Weston Hurst who described two adult patients that developed acute encephalopathy and neurologic deficits after a respiratory illness [4]. He described hemorrhagic lesions of the white matter characterized by perivas-
cular polymorphonuclear inflammation, demyelination, necrosis, and vascular fibrin deposition. Indeed, these are still the major histologic characteristics used to render the diagnosis today. One autoimmune mechanism by which ADEM and AHLE develop is thought to be related to activation of myelin autoantigens like myelin basic protein or proteolipid protein, which could potentially share similar epitopes with an infecting pathogen. An immune response directed at that pathogen could potentially cross-react with CNS proteins, precipitating an autoimmune attack against one’s own CNS tissues. Another autoimmune mechanism thought to be potentially related to ADEM and AHLE is increased vascular permeability and subsequent perivascular damage and inflammation, possibly related to circulating immune complexes developed in response to a pathogen or immunization. Treatment for ADEM and AHLE is targeted toward identification and eradication of an inciting pathogen, if present, and immune suppression with glucocorticoids. If glucocorticoids are ineffective, IVIG and plasma exchange should be considered. Many patients with ADEM will improve with such an approach, though those that fall under the AHLE spectrum tend to have more fatal outcomes, as in our case. The patient was a teacher at a daycare where there was reported to be a recent outbreak of HFMD. HFMD is classically associated with coxsackievirus A16 and Enterovirus 71 but has also been linked to other coxsackievirus strains like B2 and B5. Serologic complement fixation testing of our patient for coxsackievirus did not detect antibodies to coxsackievirus A but did detect antibodies to coxsackievirus B6 at a titer of 1:16, which may be indicative of past or recent infection. More definitive clinical interpretation of the complement fixation test result requires comparison of an acute serum sample to a convalescent serum sample, which was not available in our case. The specific etiology for AHLE in our patient is unclear, despite our attempts to confirm exposure to coxsackievirus by testing tissue, stool, and body fluids in a reference laboratory. Thus, no definitive evidence was found that would necessarily implicate typical viruses associated with HFMD as the etiology of AHLE in this case. Initially, MRI revealed severe brainstem involvement with hemorrhagic foci, along with bilateral hippocampi lesions. This primary imaging pattern was eventually followed by other supra-tentorial and medullary white matter lesions. This is a unique presentation of a rare disease with detailed MRI characteristics resembling other causes of infectious and inflammatory rhomboencephalitis. A similar presentation of AHLE has been reported once [5]. 4. Conclusion This case presents a patient with acute onset of neurological symptoms and rapidly progressive destructive white matter
D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
lesions who died from AHLE. This case emphasizes the importance of considering AHLE in the differential diagnosis of acute rhomboencephalitis and also emphasizes the lethality of such a rapid demyelinating process. Finally, this case emphasizes the importance of aggressive attempts to identify any potential pathogen and aggressive medical management in patients suspected to have AHLE. References [1] S. Pillai, Y. Hacohen, E. Tantsis, K. Prelog, V. Merheb, A. Kesson, et al., Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome, Pediatrics 135 (April (4)) (2015) 974–984.
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[2] K. O’Conner, K. McLaughlin, P. De Jager, T. Chitnis, E. Bettelli, C. Xu, et al., Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein, Nat. Med. 13 (February (2)) (2007) 211–217. [3] N. Rosman, S. Gottlieb, C. Bernstein, Acute hemorrhagic leukoencephalitis: recovery and reversal of magnetic resonance imaging findings in a child, J. Child Neurol. 12 (October (7)) (1997) 448–454. [4] A. Hurst, Acute hemorrhagic leukoencephalitis: a previously undefined entity, Med. J. Aust. 1 (1941) 1–6. [5] P. Pinto, R. Taipa, B. Moreira, C. Correia, M. Melo-Pires, Acute hemorrhagic leukoencephalitis with severe brainstem and spinal cord involvement, J. Magn. Reson. Imaging 33 (April (4)) (2011) 957–961.
Contents lists available at ScienceDirect
Clinical Neurology and Neurosurgery journal homepage: www.elsevier.com/locate/clineuro
Case report
Acute disseminated encephalomyelitis presenting as a brainstem encephalitis Daniel S. Atherton a,∗ , Sarah R. Perez b , Nathan D. Gundacker c , Ricardo Franco c , Xiaosi Han b a
Department of Pathology, HSB 175J, 619 19th St. South, University of Alabama, Birmingham, AL 35249, United States Department of Neurology, SC 350, 1720 2nd Ave. South, University of Alabama, Birmingham, AL 35294, United States c Division of Infectious Diseases, 1201 11th Ave. South, University of Alabama, Birmingham, AL 35205, United States b
a r t i c l e
i n f o
Article history: Received 1 May 2015 Received in revised form 5 February 2016 Accepted 10 February 2016 Available online 15 February 2016 Keywords: Acute disseminated encephalomyelitis Hemorrhagic leukoencephalopathy Demyelination Rhomboencephalitis
a b s t r a c t Acute disseminated encephalomyelitis (ADEM) is a disease characterized by inflammation and destruction of myelin. Acute hemorrhagic leukoencephalitis (AHLE) is a severe form of ADEM known for its particularly poor outcome. We present a case of a young Caucasian female who presented with drowsiness and slurred speech followed by rapid brainstem involvement resembling rhomboencephalitis. Despite multiple diagnostic tests and empiric therapy with immunosuppressants, immunoglobulins, and antimicrobials, she lost most brainstem reflexes within a few weeks and ultimately passed away. Magnetic resonance imaging (MRI) showed progression of lesions from the brainstem to eventually involve bilateral cerebral hemispheres. Autopsy and microscopic examination of the brain revealed several hemorrhagic lesions throughout the brain and rendered a diagnosis of AHLE. AHLE was initially described in 1941 and is thought to be autoimmune related, possibly related to cross reactivity between the immune system and CNS tissues like myelin. While a definitive inciting pathogen was not discovered, this case emphasizes the importance of considering AHLE in the differential diagnosis of patients with rapid loss of neurologic function and highlights an atypical presentation of ADEM/AHLE. © 2016 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
Acute disseminated encephalomyelitis (ADEM) is a rare disease characterized by severe inflammation of the central nervous system (CNS) with resultant destruction of myelin and white matter [1]. It is thought to be autoimmune related and possibly triggered by viral infection or even recent immunization [2]. Acute hemorrhagic leukoencephalitis (AHLE), also known as Weston-Hurst syndrome, is a hyperacute and frequently fatal form of ADEM and comprises only about 2% of cases of ADEM. While most forms of ADEM are generally self-limiting with disease progression occurring only in the first few days of onset, AHLE has a more aggressive and prolonged clinical course. Herein, we present the case of a 34 year old woman who died of autopsy-proven AHLE. The disease had atypical features of severe brainstem involvement that simulated other causes of rhomboencephalitis.
A 34 year old Caucasian woman presented to an outside hospital complaining of 3–4 weeks of fatigue, drowsiness, slurred speech, extremity numbness, and a metal taste in her mouth. On the morning of admission, she appeared intoxicated and was dismissed from work, prompting admission to the hospital. In the hospital, she became unresponsive and was transferred to the Intensive Care Unit (ICU), where she was intubated for airway protection. Magnetic resonance imaging (MRI) of the brain demonstrated an abnormal signal in the midbrain of unclear etiology, and the patient was transferred to our hospital. Upon arrival at our hospital, the patient was admitted to the ICU with a heart rate of 78 beats per minute, blood pressure of 109/73 mm Hg, respiratory rate of 12 breaths per minute, and body temperature of 95.0 ◦ F. Neurological examination demonstrated the patient to be nonresponsive with a Glascow Coma Scale (GCS) of 7/15 (E2V1tM4) [opened eyes in response to painful stimuli (E2); verbal response unevaluable due to tracheal intubation (V1t); withdrawal from pain (M4)]. Motor exam showed withdrawal to pain on the right side and grimace to pain with trace movement on the left side. Deep tendon reflexes were symmetric 2+ throughout. Ini-
∗ Corresponding author. E-mail address: [email protected] (D.S. Atherton). http://dx.doi.org/10.1016/j.clineuro.2016.02.014 0303-8467/© 2016 Elsevier B.V. All rights reserved.
D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
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Fig. 1. Progression of lesions in brainstem and cerebral hemispheres on MRI. Top row: contrast-enhanced images; (A) hospital day 0; (B) hospital day 6; (C and D) hospital day 14. Bottom row: T2/FLAIR images: (E) hospital day 0; (F) hospital day 6; (G,H) hospital day 14.
tial labs were significant for a negative human immunodeficiency virus (HIV) antibody test, negative comprehensive rheumatologic panel, elevated white blood cell count (WBC) of 15,000/L (normal: 4500–10,000/L), and urinalysis suggestive of urinary tract infection. On hospital day 2, she developed fever and lost all spontaneous extremity movement, but was still able to nod her head in response to questions. The patient’s fiancé indicated that 6 weeks prior to this presentation there had been an outbreak of hand-foot-andmouth disease (HFMD) at the daycare where the patient worked as a teacher. She fell ill at the time with self-limited upper respiratory symptoms. Initial MRI of the brain showed scattered T2/FLAIR (Fluid Attenuated Inversion Recovery) hyperintense lesions with the largest lesion at the midbrain/pons showing heterogeneous enhancement and focal hemorrhage (Fig. 1). A right cerebellar lesion appeared similarly. Lumbar puncture taken shortly after admission demonstrated a mildly elevated protein of 48 mg/dL (normal: <45 mg/dL), glucose of 50 mg/dL (normal: 50–80 mg/dL), and WBC of 0 cells/L (normal: 0–5 cells/L). Other CSF tests were within normal range.
She was then started on high dose intravenous methylprednisolone for a suspected inflammatory condition. She remained persistently febrile for 2 days which prompted empiric coverage with acyclovir, ampicillin, vancomycin, and piperacillintazobactam. Her neurologic status continued to decline, and she lost all ability to respond to questions. A repeat MRI (hospital day 6) showed new lesions in the frontal lobes and medulla and marked progression of disease in bilateral hippocampi (Fig. 1). The GCS score on hospital day 6 was 6/15 (E1V1tM4) [no eye opening (E1); verbal response unevaluable due to tracheal intubation (V1t); withdrawal from pain (M4)]. After completing 5 days of high dosed steroids, she was switched to intravenous immunoglobulin (IVIG) for possible viral or inflammatory rhomboencephalitis. A serological test for coxsackievirus eventually returned a titer of 1:16 for coxsackievirus B6. Biopsy was considered, but thought to be low-yield given the amount of hemorrhage that was seen on imaging. Instead, it was decided to biopsy an enlarged paratracheal lymph node, which would later return as non-diagnostic. Given the absence of a confirmatory diagnosis and the severity of CNS involvement, the patient was broadly treated for potential infectious
Fig. 2. Cross section of pons shows irregular, hemorrhagic, and destructive lesion.
78
D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
Fig. 3. Hemotoxylin & eosin-stained sections of tissue from pons. (A) Solid arrow shows vessel with severe mixed inflammation. Arrow outlines show fibrin vascular thrombi with perivascular hemorrhage. (B) Two vessels with occlusive fibrin thrombi, abundant mixed inflammation, vascular necrosis, and perivascular hemorrhage.
pathogens known to cause brainstem and/or temporal encephalitis. During the ICU stay, amphotericin B (due to concerns for Aspergillus), RIPE (rifampin, isoniazid, pyrazinamide, ethambutol), and toxoplasmosis treatment (sulfadiazine and pyrimethamine) were added in a stepwise fashion in an attempt to broadly address rare infectious causes of rhombencephalitis. Extensive, non-invasive work-up searching for fungal, viral, and mycobacterial pathogens remained negative. She continued to decline neurologically, losing most of her brainstem reflexes by hospital day 12. Her bedside electroencephalogram (EEG) showed mixed theta and delta waves without signs of seizure. Repeat MRI of the head obtained 14 days after admission showed innumerable foci of diffusion restriction with enlargement of previously identified brainstem, cerebral, and cerebellar lesions (Fig. 1). Given the worsening MRI and poor neurologic exam, the family decided to withdraw care. On hospital day 16, the patient passed away. Autopsy was performed. Coronal sections of the cerebral hemispheres revealed multiple, widely scattered hemorrhagic lesions involving the cerebral cortical areas and underlying peripheral white matter, basal ganglia, thalamus, right hippocampus, and bilateral mesial temporal lobes (Fig. 2). Brainstem sections showed similar appearing lesions involving the midbrain, pons, and medulla. Microscopic examination of the lesions showed subacute infarcts characterized by tissue necrosis, red neurons, perivascular inflammation, parenchymal hemorrhage, microvasculature occluded with fibrin thrombi, and vacuolization of the neuropil (Fig. 3). A diagnosis of AHLE was rendered. At the time of autopsy, brain tissue, body fluids, and stool were sent to the Centers for Disease Control (CDC) for polymerase chain reaction (PCR) viral analyses, and these returned negative for detection of Enteroviruses. 3. Discussion ADEM is a rare disease that usually affects children. The mechanism of destruction is thought to be autoimmune with multiple viruses, bacteria, and certain types of immunization implicated in initiating the cascade of events that leads to widespread CNS destruction. AHLE is a rare form of ADEM, and death is common in the first week of its onset. AHLE is different from most forms of ADEM in that it is more likely to be characterized by cerebral edema, diffuse white matter changes on imaging, histologic evidence of hemorrhage involving the white matter, and a more rapidly fatal clinical course [3]. Unlike ADEM, AHLE is more common in adults than children. AHLE was first described in 1941 by E. Weston Hurst who described two adult patients that developed acute encephalopathy and neurologic deficits after a respiratory illness [4]. He described hemorrhagic lesions of the white matter characterized by perivas-
cular polymorphonuclear inflammation, demyelination, necrosis, and vascular fibrin deposition. Indeed, these are still the major histologic characteristics used to render the diagnosis today. One autoimmune mechanism by which ADEM and AHLE develop is thought to be related to activation of myelin autoantigens like myelin basic protein or proteolipid protein, which could potentially share similar epitopes with an infecting pathogen. An immune response directed at that pathogen could potentially cross-react with CNS proteins, precipitating an autoimmune attack against one’s own CNS tissues. Another autoimmune mechanism thought to be potentially related to ADEM and AHLE is increased vascular permeability and subsequent perivascular damage and inflammation, possibly related to circulating immune complexes developed in response to a pathogen or immunization. Treatment for ADEM and AHLE is targeted toward identification and eradication of an inciting pathogen, if present, and immune suppression with glucocorticoids. If glucocorticoids are ineffective, IVIG and plasma exchange should be considered. Many patients with ADEM will improve with such an approach, though those that fall under the AHLE spectrum tend to have more fatal outcomes, as in our case. The patient was a teacher at a daycare where there was reported to be a recent outbreak of HFMD. HFMD is classically associated with coxsackievirus A16 and Enterovirus 71 but has also been linked to other coxsackievirus strains like B2 and B5. Serologic complement fixation testing of our patient for coxsackievirus did not detect antibodies to coxsackievirus A but did detect antibodies to coxsackievirus B6 at a titer of 1:16, which may be indicative of past or recent infection. More definitive clinical interpretation of the complement fixation test result requires comparison of an acute serum sample to a convalescent serum sample, which was not available in our case. The specific etiology for AHLE in our patient is unclear, despite our attempts to confirm exposure to coxsackievirus by testing tissue, stool, and body fluids in a reference laboratory. Thus, no definitive evidence was found that would necessarily implicate typical viruses associated with HFMD as the etiology of AHLE in this case. Initially, MRI revealed severe brainstem involvement with hemorrhagic foci, along with bilateral hippocampi lesions. This primary imaging pattern was eventually followed by other supra-tentorial and medullary white matter lesions. This is a unique presentation of a rare disease with detailed MRI characteristics resembling other causes of infectious and inflammatory rhomboencephalitis. A similar presentation of AHLE has been reported once [5]. 4. Conclusion This case presents a patient with acute onset of neurological symptoms and rapidly progressive destructive white matter
D.S. Atherton et al. / Clinical Neurology and Neurosurgery 143 (2016) 76–79
lesions who died from AHLE. This case emphasizes the importance of considering AHLE in the differential diagnosis of acute rhomboencephalitis and also emphasizes the lethality of such a rapid demyelinating process. Finally, this case emphasizes the importance of aggressive attempts to identify any potential pathogen and aggressive medical management in patients suspected to have AHLE. References [1] S. Pillai, Y. Hacohen, E. Tantsis, K. Prelog, V. Merheb, A. Kesson, et al., Infectious and autoantibody-associated encephalitis: clinical features and long-term outcome, Pediatrics 135 (April (4)) (2015) 974–984.
79
[2] K. O’Conner, K. McLaughlin, P. De Jager, T. Chitnis, E. Bettelli, C. Xu, et al., Self-antigen tetramers discriminate between myelin autoantibodies to native or denatured protein, Nat. Med. 13 (February (2)) (2007) 211–217. [3] N. Rosman, S. Gottlieb, C. Bernstein, Acute hemorrhagic leukoencephalitis: recovery and reversal of magnetic resonance imaging findings in a child, J. Child Neurol. 12 (October (7)) (1997) 448–454. [4] A. Hurst, Acute hemorrhagic leukoencephalitis: a previously undefined entity, Med. J. Aust. 1 (1941) 1–6. [5] P. Pinto, R. Taipa, B. Moreira, C. Correia, M. Melo-Pires, Acute hemorrhagic leukoencephalitis with severe brainstem and spinal cord involvement, J. Magn. Reson. Imaging 33 (April (4)) (2011) 957–961.