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Nonprofit Organization U.S. Postage PAID Twin Cities, MN VOLUME 23, NUMBER 4 200 University Ave. E. Permit No. 5388 St. Paul, MN 55101 651-291-2848 ADDRESSwww.gillettechildrens.org SERVICE REQUESTED VOLUME 23, NUMBER 4 2014

A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA encephalitis

Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have and other neurological conditions. as one of the most common identifiable causes of encephalitis in children and She received an M.D. from the University of Iowa’s Carver ■ Time-to-diagnosis and treatment of young adults. College of Medicine in Iowa City, Iowa, and completed a NEWS & NOTES anti-NMDA receptor encephalitis pediatric residency and a child neurology residency at have a significant impact on patient The Children’s Hospital Colorado in Denver. Her profes- In the California Encephalitis Project, only 79 of 761 cases of encephalitis in recovery and final outcome. individuals under age 30 had an identifiable etiology. Anti-NMDA receptor sional interests include anti-NMDA receptor encephalitis, New Physician Joins Gillette neuroimmunology, leukodystrophies and other metabolic Visit www.gillettechildrens.org/ encephalitis accounted for 32 of those cases, and 65 percent of those patients Joy Taber, M.D., is board-certified in physical medicine and rehabilitation. She cares for and genetic neurological disorders. OurCareTeam to learn more about were younger than 19. Additionally, the study showed that anti-NMDA receptor Gillette’s specialists. adult patients who have cerebral palsy, spina bifida and other childhood-onset conditions. She received a medical degree and completed her residency in physical medicine and encephalitis may be more common than any single infectious cause of encephalitis, Clinical Education rehabilitation at the University of Minnesota School of Medicine in Minneapolis. In other than enterovirus.1 Visit our website to find videos and addition, she served as a U.S. Air Force flight surgeon. She is a member of the American professional presentations. Academy of Physical Medicine and Rehabilitation, American Medical Association and www.gillettechildrens.org Minnesota Medical Association. She sees patients at Gillette Lifetime Specialty Healthcare. Frequency of Identifiable Causes of Encephalitis in the California Encephalitis Project Back Issues of A Pediatric Perspective www.gillettechildrens.org/for-medical- professionals/publications

Anti-NMDA receptor encephalitis Gillette Children’s Specialty Healthcare Enterovirus is named in honor of orthopedic surgeon Herpes Simplex Virus (HSV-1) Arthur Gillette, M.D., who helped found West Nile Virus the nation’s first publicly funded hospital for children who have disabilities. We are Varicella Zoster Virus an independent, not-for-profit children’s hospital, and our organization has no affiliation with the Gillette Company or the Gillette brand of personal care products.

www.gillettechildrens.org

Clinical Presentation Autonomic Dysfunction • Occasionally, brain MRIs will show white matter lesions with • Other medications are often needed to treat specific Patients with anti-NMDA receptor encephalitis have a constel- • The most frequent autonomic manifestations include associated enhancement after contrast that is consistent with symptoms, such as seizures, abnormal movements lation of symptoms that are recognizable to providers familiar fever, tachycardia, hypertension, bradycardia and demyelination. Patients with demyelinating lesions and confirmed or psychosis. with the condition. However, comparisons of presentations hypersalivation. anti-NMDA receptor encephalitis should be tested for anti-NMO • Rehabilitation programs, with intensive physical, among patients with this condition show significant variability. • A small percentage of patients develop hypoventi- antibodies, which have been found in this subset of patients. occupational and speech therapy, are important to lation, even when consciousness is preserved, and help patients regain function, and an inpatient Most patients will exhibit multiple, but not all, possible symptoms Young Child With Anti-NMDA Receptor of the condition. The order in which symptoms develop can vary require respiratory support. Electroencephalogram (EEG) admission to a specialized rehabilitation unit is • Close monitoring of vital signs is recommended for • EEGs are used to assess the background activity and to evaluate often required. Encephalitis from patient to patient, and not all symptoms may be present all patients. for seizures. during the initial evaluation. Additionally, presentation varies History: The mother of a 4-year-old girl brought her daughter • Most patients with anti-NMDA receptor encephalitis will have by age group. Very young children present with symptoms that Outcomes to the emergency room because of a change in behavior. are distinct from those seen in teens and adults. Differential Diagnosis an abnormal EEG at some point in their disease course. At least 75 percent of patients will have substantial She reported that the girl had seemed sad and unlike herself The differential diagnosis of anti-NMDA receptor • 90 percent of patients will have slowing of background frequencies. recovery. The rate and degree of recovery appear to be for one week. She first noticed her daughter having frequent Psychiatric Symptoms encephalitis is broad and includes infectious causes • 25 to 50 percent will have epileptic features, such as spike and related to how quickly a diagnosis is made and treat- episodes of crying for no apparent reason. During the preceding week, the girl also seemed more tired than normal, and she • The most common presenting symptoms in teenagers and of encephalitis, such as herpes simplex virus; acute wave discharges or captured seizures. ment is begun using appropriate immunomodulating had low grade fevers to 100.1 F. Four days earlier, her mother adults include anxiety, insomnia, delusions, mania and paranoia. disseminated encephalomyelitis (ADEM); inborn errors agents. There is limited information about cognitive Infectious Disease Evaluation observed that her daughter seemed to be constantly playing • Young children tend to present with behavior changes, temper of metabolism, including urea cycle disorders; environ- and psychological outcomes in these patients; how- with her tongue, chewing on it and running it over her teeth. • The evaluation for viral encephalitis is individualized, tantrums, hyperactivity and irritability, instead of overt mental toxins and medication overdoses; rheumatologic ever, my experience suggests that these problems are She also noticed that the girl seemed to be fidgeting with her and depends on time of year and geographic location. psychotic symptoms. conditions, such as neuropsychiatric lupus; and primary under-recognized in patients with otherwise excellent hands more, “like she was anxious and couldn’t keep them • Every patient should be tested for herpes simplex virus (HSV). • This initial phase is often followed by a stage with periods of psychiatric conditions, such as . Due to neurologic recovery. still.” The patient was seen by her pediatrician and a psych- • The infectious disease team is often consulted to co-evaluate alternating agitation and catatonia. the extensive differential diagnosis, the diagnostic work- ologist and they felt she was depressed. Over the next two the patient. days, she stopped speaking, began sleeping very little and • Often the first provider to see the patient is a psychologist up of each patient must be individualized based on the Conclusion developed an unsteady gait. Shortly after admission to the or psychiatrist. presentation, and consultation with a child neurologist Anti-NMDA receptor encephalitis is a relatively Tumor Evaluation hospital, she had a new spell that consisted of stiffening her is recommended. common and treatable cause of encephalitis in right arm and staring. • The first cases of anti-NMDA receptor encephalitis were Language Changes pediatric patients. Any child presenting with • A reduction in spontaneous speech occurs in all age groups described in young women with ovarian . In these Diagnostic Tests personality change or psychiatric symptoms should Evaluation: On neurologic examination, the child had patients, the body’s immune response to this benign tumor continuous oro-lingual dyskinesias, chorea of her upper ex- and may be a presenting symptom in pediatric patients. be evaluated for co-existing neurological symptoms Cerebrospinal Fluid (CSF) Evaluation resulted in production of the antibodies which cross-reacted tremities and was unable to walk. She was mute but attentive. • A progression to mutism is very common in pediatric patients such as abnormal movements or new seizures. • CSF will be abnormal in up to 90 percent of patients. with the patient’s brain. She underwent blood work and a spinal tap. Her spinal fluid and may also be seen in adults. If these symptoms are present, an urgent child • More than 80 percent of patients will have positive • Tumors, specifically teratoma, are found in less than half of adults showed nine white blood cells. An extensive infectious workup neurology evaluation is indicated and an evaluation oligoclonal bands, which are antibodies in the CSF with this condition and become increasingly rare in younger was negative. MRI of the brain with and without Movement Disorders for anti-NMDA receptor encephalitis should be initi- contrast was normal. Her serum was positive for anti-NMDA that are not found in the serum. patients. • Almost all patients will develop abnormal movements during • Up to 75 percent of patients will have elevated CSF ated. Time-to-diagnosis and treatment of anti-NMDA receptor antibodies. An EEG was done to evaluate the • Every patient with anti-NMDA receptor encephalitis should episodes of staring and arm stiffening and confirmed that the course of the disease. white blood cell counts, usually with lymphocytic receptor encephalitis have a significant impact on undergo a tumor evaluation. these events were seizures. • Oro-lingual-facial dyskinesias, such as chewing movements predominance, but neutrophilic predominance can patient recovery and final outcome. We welcome your and tongue rolling, are the most characteristic movements. also be seen. questions and referrals. Treatment: She had the classic clinical presentation for • Abnormal movements of the trunk and extremities, including Treatment • Approximately 10 to 15 percent of patients will have • Medications are used to decrease the circulating disease-causing a young child with anti-NMDA receptor encephalitis. chorea, dystonia and rigidity, are also frequently seen. References Specifically, she was a young child whose change in mood/ elevated protein concentrations. anti-NMDA receptor antibodies and the body’s overactive • Young children may have ataxia or difficulty walking and may 1 Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency personality was accompanied by multiple neurologic symp- • Anti-NMDA receptor antibodies can be found in the immune response. of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses even lose the ability to walk. that of individual viral etiologies in young individuals enrolled in the toms including a movement disorder, mutism and seizures. CSF as well as the serum. • Methylprednisolone is an IV steroid that can be given at high California Encephalitis Project. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2012;54:899- Due to the clinical picture, treatment with IV methylpred- doses and is often used with IV immunoglobulins (IVIG) as 904. nisolone and IV immunoglobulins (IVIG) was initiated after Seizures MRI of the Brain first-line therapy. CSF cultures were negative for 24 hours. She was started on • New onset seizures are common and occur in 50 to 75 percent • For 50 percent of cases, MRIs will appear normal. • IVIG are pooled antibodies, given by IV, that result in the body Additional Resources oxcarbazepine for control. of patients. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice- • The most common abnormal finding is nonspecific T2 degrading circulating antibodies, including the anti-NMDA Gordon R. Clinical experience and laboratory investigations in patients • Common seizure types include focal seizures, motor seizures, with anti-NMDAR encephalitis. The Lancet Neurology 2011;10:63-74. Outcome: She required a 10-day admission to the inpatient hyperintense lesions involving the gray and/or white receptor antibodies that are disease-causing. complex partial seizures and generalized convulsions. rehabilitation unit. At discharge, she walked independently matter of the cortex, or brainstem; spine • Rituximab is a monoclonal antibody, given by IV, that targets Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate recep- • Patients are at risk for status epilepticus—prolonged seizures tor (NMDAR) encephalitis in children and adolescents. Annals of and was able to say a few words with prompting. One month lesions are rare. the body’s antibody producing cells and stops ongoing produc- Neurology 2009;66:11-18. after discharge, her mother reported that the girl is still less lasting longer than 30 minutes. • The changes are usually mild and transient, but can tion of anti-NMDA receptor antibodies. It is often used as a Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic talkative than before her illness, but this is the only remaining factors for long-term outcome in patients with anti-NMDA receptor occasionally be extensive. second-line therapy for those patients whose recovery after encephalitis: an observational cohort study. The Lancet Neurology symptom. 2013;12:157-165. receiving first-line treatments is inadequate. 2 3

Clinical Presentation Autonomic Dysfunction • Occasionally, brain MRIs will show white matter lesions with • Other medications are often needed to treat specific Patients with anti-NMDA receptor encephalitis have a constel- • The most frequent autonomic manifestations include associated enhancement after contrast that is consistent with symptoms, such as seizures, abnormal movements lation of symptoms that are recognizable to providers familiar fever, tachycardia, hypertension, bradycardia and demyelination. Patients with demyelinating lesions and confirmed or psychosis. with the condition. However, comparisons of presentations hypersalivation. anti-NMDA receptor encephalitis should be tested for anti-NMO • Rehabilitation programs, with intensive physical, among patients with this condition show significant variability. • A small percentage of patients develop hypoventi- antibodies, which have been found in this subset of patients. occupational and speech therapy, are important to lation, even when consciousness is preserved, and help patients regain function, and an inpatient Most patients will exhibit multiple, but not all, possible symptoms Young Child With Anti-NMDA Receptor of the condition. The order in which symptoms develop can vary require respiratory support. Electroencephalogram (EEG) admission to a specialized rehabilitation unit is • Close monitoring of vital signs is recommended for • EEGs are used to assess the background activity and to evaluate often required. Encephalitis from patient to patient, and not all symptoms may be present all patients. for seizures. during the initial evaluation. Additionally, presentation varies History: The mother of a 4-year-old girl brought her daughter • Most patients with anti-NMDA receptor encephalitis will have by age group. Very young children present with symptoms that Outcomes to the emergency room because of a change in behavior. are distinct from those seen in teens and adults. Differential Diagnosis an abnormal EEG at some point in their disease course. At least 75 percent of patients will have substantial She reported that the girl had seemed sad and unlike herself The differential diagnosis of anti-NMDA receptor • 90 percent of patients will have slowing of background frequencies. recovery. The rate and degree of recovery appear to be for one week. She first noticed her daughter having frequent Psychiatric Symptoms encephalitis is broad and includes infectious causes • 25 to 50 percent will have epileptic features, such as spike and related to how quickly a diagnosis is made and treat- episodes of crying for no apparent reason. During the preceding week, the girl also seemed more tired than normal, and she • The most common presenting symptoms in teenagers and of encephalitis, such as herpes simplex virus; acute wave discharges or captured seizures. ment is begun using appropriate immunomodulating had low grade fevers to 100.1 F. Four days earlier, her mother adults include anxiety, insomnia, delusions, mania and paranoia. disseminated encephalomyelitis (ADEM); inborn errors agents. There is limited information about cognitive Infectious Disease Evaluation observed that her daughter seemed to be constantly playing • Young children tend to present with behavior changes, temper of metabolism, including urea cycle disorders; environ- and psychological outcomes in these patients; how- with her tongue, chewing on it and running it over her teeth. • The evaluation for viral encephalitis is individualized, tantrums, hyperactivity and irritability, instead of overt mental toxins and medication overdoses; rheumatologic ever, my experience suggests that these problems are She also noticed that the girl seemed to be fidgeting with her and depends on time of year and geographic location. psychotic symptoms. conditions, such as neuropsychiatric lupus; and primary under-recognized in patients with otherwise excellent hands more, “like she was anxious and couldn’t keep them • Every patient should be tested for herpes simplex virus (HSV). • This initial phase is often followed by a stage with periods of psychiatric conditions, such as schizophrenia. Due to neurologic recovery. still.” The patient was seen by her pediatrician and a psych- • The infectious disease team is often consulted to co-evaluate alternating agitation and catatonia. the extensive differential diagnosis, the diagnostic work- ologist and they felt she was depressed. Over the next two the patient. days, she stopped speaking, began sleeping very little and • Often the first provider to see the patient is a psychologist up of each patient must be individualized based on the Conclusion developed an unsteady gait. Shortly after admission to the or psychiatrist. presentation, and consultation with a child neurologist Anti-NMDA receptor encephalitis is a relatively Tumor Evaluation hospital, she had a new spell that consisted of stiffening her is recommended. common and treatable cause of encephalitis in right arm and staring. • The first cases of anti-NMDA receptor encephalitis were Language Changes pediatric patients. Any child presenting with • A reduction in spontaneous speech occurs in all age groups described in young women with ovarian teratoma. In these Diagnostic Tests personality change or psychiatric symptoms should Evaluation: On neurologic examination, the child had patients, the body’s immune response to this benign tumor continuous oro-lingual dyskinesias, chorea of her upper ex- and may be a presenting symptom in pediatric patients. be evaluated for co-existing neurological symptoms Cerebrospinal Fluid (CSF) Evaluation resulted in production of the antibodies which cross-reacted tremities and was unable to walk. She was mute but attentive. • A progression to mutism is very common in pediatric patients such as abnormal movements or new seizures. • CSF will be abnormal in up to 90 percent of patients. with the patient’s brain. She underwent blood work and a spinal tap. Her spinal fluid and may also be seen in adults. If these symptoms are present, an urgent child • More than 80 percent of patients will have positive • Tumors, specifically teratoma, are found in less than half of adults showed nine white blood cells. An extensive infectious workup neurology evaluation is indicated and an evaluation oligoclonal bands, which are antibodies in the CSF with this condition and become increasingly rare in younger was negative. MRI of the brain with and without Movement Disorders for anti-NMDA receptor encephalitis should be initi- contrast was normal. Her serum was positive for anti-NMDA that are not found in the serum. patients. • Almost all patients will develop abnormal movements during • Up to 75 percent of patients will have elevated CSF ated. Time-to-diagnosis and treatment of anti-NMDA receptor antibodies. An EEG was done to evaluate the • Every patient with anti-NMDA receptor encephalitis should episodes of staring and arm stiffening and confirmed that the course of the disease. white blood cell counts, usually with lymphocytic receptor encephalitis have a significant impact on undergo a tumor evaluation. these events were seizures. • Oro-lingual-facial dyskinesias, such as chewing movements predominance, but neutrophilic predominance can patient recovery and final outcome. We welcome your and tongue rolling, are the most characteristic movements. also be seen. questions and referrals. Treatment: She had the classic clinical presentation for • Abnormal movements of the trunk and extremities, including Treatment • Approximately 10 to 15 percent of patients will have • Medications are used to decrease the circulating disease-causing a young child with anti-NMDA receptor encephalitis. chorea, dystonia and rigidity, are also frequently seen. References Specifically, she was a young child whose change in mood/ elevated protein concentrations. anti-NMDA receptor antibodies and the body’s overactive • Young children may have ataxia or difficulty walking and may 1 Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency personality was accompanied by multiple neurologic symp- • Anti-NMDA receptor antibodies can be found in the immune response. of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses even lose the ability to walk. that of individual viral etiologies in young individuals enrolled in the toms including a movement disorder, mutism and seizures. CSF as well as the serum. • Methylprednisolone is an IV steroid that can be given at high California Encephalitis Project. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2012;54:899- Due to the clinical picture, treatment with IV methylpred- doses and is often used with IV immunoglobulins (IVIG) as 904. nisolone and IV immunoglobulins (IVIG) was initiated after Seizures MRI of the Brain first-line therapy. CSF cultures were negative for 24 hours. She was started on • New onset seizures are common and occur in 50 to 75 percent • For 50 percent of cases, MRIs will appear normal. • IVIG are pooled antibodies, given by IV, that result in the body Additional Resources oxcarbazepine for seizure control. of patients. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice- • The most common abnormal finding is nonspecific T2 degrading circulating antibodies, including the anti-NMDA Gordon R. Clinical experience and laboratory investigations in patients • Common seizure types include focal seizures, motor seizures, with anti-NMDAR encephalitis. The Lancet Neurology 2011;10:63-74. Outcome: She required a 10-day admission to the inpatient hyperintense lesions involving the gray and/or white receptor antibodies that are disease-causing. complex partial seizures and generalized convulsions. rehabilitation unit. At discharge, she walked independently matter of the cortex, basal ganglia or brainstem; spine • Rituximab is a monoclonal antibody, given by IV, that targets Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate recep- • Patients are at risk for status epilepticus—prolonged seizures tor (NMDAR) encephalitis in children and adolescents. Annals of and was able to say a few words with prompting. One month lesions are rare. the body’s antibody producing cells and stops ongoing produc- Neurology 2009;66:11-18. after discharge, her mother reported that the girl is still less lasting longer than 30 minutes. • The changes are usually mild and transient, but can tion of anti-NMDA receptor antibodies. It is often used as a Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic talkative than before her illness, but this is the only remaining factors for long-term outcome in patients with anti-NMDA receptor occasionally be extensive. second-line therapy for those patients whose recovery after encephalitis: an observational cohort study. The Lancet Neurology symptom. 2013;12:157-165. receiving first-line treatments is inadequate. 2 3

Nonprofit Organization U.S. Postage PAID Twin Cities, MN VOLUME 23, NUMBER 4 200 University Ave. E. Permit No. 5388 St. Paul, MN 55101 651-291-2848 ADDRESSwww.gillettechildrens.org SERVICE REQUESTED VOLUME 23, NUMBER 4 2014

A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA receptor encephalitis

Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune seizures and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have epilepsy and other neurological conditions. as one of the most common identifiable causes of encephalitis in children and She received an M.D. from the University of Iowa’s Carver ■ Time-to-diagnosis and treatment of young adults. College of Medicine in Iowa City, Iowa, and completed a NEWS & NOTES anti-NMDA receptor encephalitis pediatric residency and a child neurology residency at have a significant impact on patient The Children’s Hospital Colorado in Denver. Her profes- In the California Encephalitis Project, only 79 of 761 cases of encephalitis in recovery and final outcome. individuals under age 30 had an identifiable etiology. Anti-NMDA receptor sional interests include anti-NMDA receptor encephalitis, New Physician Joins Gillette neuroimmunology, leukodystrophies and other metabolic Visit www.gillettechildrens.org/ encephalitis accounted for 32 of those cases, and 65 percent of those patients Joy Taber, M.D., is board-certified in physical medicine and rehabilitation. She cares for and genetic neurological disorders. OurCareTeam to learn more about were younger than 19. Additionally, the study showed that anti-NMDA receptor Gillette’s specialists. adult patients who have cerebral palsy, spina bifida and other childhood-onset conditions. She received a medical degree and completed her residency in physical medicine and encephalitis may be more common than any single infectious cause of encephalitis, Clinical Education rehabilitation at the University of Minnesota School of Medicine in Minneapolis. In other than enterovirus.1 Visit our website to find videos and addition, she served as a U.S. Air Force flight surgeon. She is a member of the American professional presentations. Academy of Physical Medicine and Rehabilitation, American Medical Association and www.gillettechildrens.org Minnesota Medical Association. She sees patients at Gillette Lifetime Specialty Healthcare. Frequency of Identifiable Causes of Encephalitis in the California Encephalitis Project Back Issues of A Pediatric Perspective www.gillettechildrens.org/for-medical- professionals/publications

Anti-NMDA receptor encephalitis Gillette Children’s Specialty Healthcare Enterovirus is named in honor of orthopedic surgeon Herpes Simplex Virus (HSV-1) Arthur Gillette, M.D., who helped found West Nile Virus the nation’s first publicly funded hospital for children who have disabilities. We are Varicella Zoster Virus an independent, not-for-profit children’s hospital, and our organization has no affiliation with the Gillette Company or the Gillette brand of personal care products.

www.gillettechildrens.org

Clinical Presentation Autonomic Dysfunction • Occasionally, brain MRIs will show white matter lesions with • Other medications are often needed to treat specific Patients with anti-NMDA receptor encephalitis have a constel- • The most frequent autonomic manifestations include associated enhancement after contrast that is consistent with symptoms, such as seizures, abnormal movements lation of symptoms that are recognizable to providers familiar fever, tachycardia, hypertension, bradycardia and demyelination. Patients with demyelinating lesions and confirmed or psychosis. with the condition. However, comparisons of presentations hypersalivation. anti-NMDA receptor encephalitis should be tested for anti-NMO • Rehabilitation programs, with intensive physical, among patients with this condition show significant variability. • A small percentage of patients develop hypoventi- antibodies, which have been found in this subset of patients. occupational and speech therapy, are important to lation, even when consciousness is preserved, and help patients regain function, and an inpatient Most patients will exhibit multiple, but not all, possible symptoms Young Child With Anti-NMDA Receptor of the condition. The order in which symptoms develop can vary require respiratory support. Electroencephalogram (EEG) admission to a specialized rehabilitation unit is • Close monitoring of vital signs is recommended for • EEGs are used to assess the background activity and to evaluate often required. Encephalitis from patient to patient, and not all symptoms may be present all patients. for seizures. during the initial evaluation. Additionally, presentation varies History: The mother of a 4-year-old girl brought her daughter • Most patients with anti-NMDA receptor encephalitis will have by age group. Very young children present with symptoms that Outcomes to the emergency room because of a change in behavior. are distinct from those seen in teens and adults. Differential Diagnosis an abnormal EEG at some point in their disease course. At least 75 percent of patients will have substantial She reported that the girl had seemed sad and unlike herself The differential diagnosis of anti-NMDA receptor • 90 percent of patients will have slowing of background frequencies. recovery. The rate and degree of recovery appear to be for one week. She first noticed her daughter having frequent Psychiatric Symptoms encephalitis is broad and includes infectious causes • 25 to 50 percent will have epileptic features, such as spike and related to how quickly a diagnosis is made and treat- episodes of crying for no apparent reason. During the preceding week, the girl also seemed more tired than normal, and she • The most common presenting symptoms in teenagers and of encephalitis, such as herpes simplex virus; acute wave discharges or captured seizures. ment is begun using appropriate immunomodulating had low grade fevers to 100.1 F. Four days earlier, her mother adults include anxiety, insomnia, delusions, mania and paranoia. disseminated encephalomyelitis (ADEM); inborn errors agents. There is limited information about cognitive Infectious Disease Evaluation observed that her daughter seemed to be constantly playing • Young children tend to present with behavior changes, temper of metabolism, including urea cycle disorders; environ- and psychological outcomes in these patients; how- with her tongue, chewing on it and running it over her teeth. • The evaluation for viral encephalitis is individualized, tantrums, hyperactivity and irritability, instead of overt mental toxins and medication overdoses; rheumatologic ever, my experience suggests that these problems are She also noticed that the girl seemed to be fidgeting with her and depends on time of year and geographic location. psychotic symptoms. conditions, such as neuropsychiatric lupus; and primary under-recognized in patients with otherwise excellent hands more, “like she was anxious and couldn’t keep them • Every patient should be tested for herpes simplex virus (HSV). • This initial phase is often followed by a stage with periods of psychiatric conditions, such as schizophrenia. Due to neurologic recovery. still.” The patient was seen by her pediatrician and a psych- • The infectious disease team is often consulted to co-evaluate alternating agitation and catatonia. the extensive differential diagnosis, the diagnostic work- ologist and they felt she was depressed. Over the next two the patient. days, she stopped speaking, began sleeping very little and • Often the first provider to see the patient is a psychologist up of each patient must be individualized based on the Conclusion developed an unsteady gait. Shortly after admission to the or psychiatrist. presentation, and consultation with a child neurologist Anti-NMDA receptor encephalitis is a relatively Tumor Evaluation hospital, she had a new spell that consisted of stiffening her is recommended. common and treatable cause of encephalitis in right arm and staring. • The first cases of anti-NMDA receptor encephalitis were Language Changes pediatric patients. Any child presenting with • A reduction in spontaneous speech occurs in all age groups described in young women with ovarian teratoma. In these Diagnostic Tests personality change or psychiatric symptoms should Evaluation: On neurologic examination, the child had patients, the body’s immune response to this benign tumor continuous oro-lingual dyskinesias, chorea of her upper ex- and may be a presenting symptom in pediatric patients. be evaluated for co-existing neurological symptoms Cerebrospinal Fluid (CSF) Evaluation resulted in production of the antibodies which cross-reacted tremities and was unable to walk. She was mute but attentive. • A progression to mutism is very common in pediatric patients such as abnormal movements or new seizures. • CSF will be abnormal in up to 90 percent of patients. with the patient’s brain. She underwent blood work and a spinal tap. Her spinal fluid and may also be seen in adults. If these symptoms are present, an urgent child • More than 80 percent of patients will have positive • Tumors, specifically teratoma, are found in less than half of adults showed nine white blood cells. An extensive infectious workup neurology evaluation is indicated and an evaluation oligoclonal bands, which are antibodies in the CSF with this condition and become increasingly rare in younger was negative. MRI of the brain with and without Movement Disorders for anti-NMDA receptor encephalitis should be initi- contrast was normal. Her serum was positive for anti-NMDA that are not found in the serum. patients. • Almost all patients will develop abnormal movements during • Up to 75 percent of patients will have elevated CSF ated. Time-to-diagnosis and treatment of anti-NMDA receptor antibodies. An EEG was done to evaluate the • Every patient with anti-NMDA receptor encephalitis should episodes of staring and arm stiffening and confirmed that the course of the disease. white blood cell counts, usually with lymphocytic receptor encephalitis have a significant impact on undergo a tumor evaluation. these events were seizures. • Oro-lingual-facial dyskinesias, such as chewing movements predominance, but neutrophilic predominance can patient recovery and final outcome. We welcome your and tongue rolling, are the most characteristic movements. also be seen. questions and referrals. Treatment: She had the classic clinical presentation for • Abnormal movements of the trunk and extremities, including Treatment • Approximately 10 to 15 percent of patients will have • Medications are used to decrease the circulating disease-causing a young child with anti-NMDA receptor encephalitis. chorea, dystonia and rigidity, are also frequently seen. References Specifically, she was a young child whose change in mood/ elevated protein concentrations. anti-NMDA receptor antibodies and the body’s overactive • Young children may have ataxia or difficulty walking and may 1 Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency personality was accompanied by multiple neurologic symp- • Anti-NMDA receptor antibodies can be found in the immune response. of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses even lose the ability to walk. that of individual viral etiologies in young individuals enrolled in the toms including a movement disorder, mutism and seizures. CSF as well as the serum. • Methylprednisolone is an IV steroid that can be given at high California Encephalitis Project. Clinical infectious diseases: an official publication of the Infectious Diseases Society of America 2012;54:899- Due to the clinical picture, treatment with IV methylpred- doses and is often used with IV immunoglobulins (IVIG) as 904. nisolone and IV immunoglobulins (IVIG) was initiated after Seizures MRI of the Brain first-line therapy. CSF cultures were negative for 24 hours. She was started on • New onset seizures are common and occur in 50 to 75 percent • For 50 percent of cases, MRIs will appear normal. • IVIG are pooled antibodies, given by IV, that result in the body Additional Resources oxcarbazepine for seizure control. of patients. Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice- • The most common abnormal finding is nonspecific T2 degrading circulating antibodies, including the anti-NMDA Gordon R. Clinical experience and laboratory investigations in patients • Common seizure types include focal seizures, motor seizures, with anti-NMDAR encephalitis. The Lancet Neurology 2011;10:63-74. Outcome: She required a 10-day admission to the inpatient hyperintense lesions involving the gray and/or white receptor antibodies that are disease-causing. complex partial seizures and generalized convulsions. rehabilitation unit. At discharge, she walked independently matter of the cortex, basal ganglia or brainstem; spine • Rituximab is a monoclonal antibody, given by IV, that targets Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-D-aspartate recep- • Patients are at risk for status epilepticus—prolonged seizures tor (NMDAR) encephalitis in children and adolescents. Annals of and was able to say a few words with prompting. One month lesions are rare. the body’s antibody producing cells and stops ongoing produc- Neurology 2009;66:11-18. after discharge, her mother reported that the girl is still less lasting longer than 30 minutes. • The changes are usually mild and transient, but can tion of anti-NMDA receptor antibodies. It is often used as a Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic talkative than before her illness, but this is the only remaining factors for long-term outcome in patients with anti-NMDA receptor occasionally be extensive. second-line therapy for those patients whose recovery after encephalitis: an observational cohort study. The Lancet Neurology symptom. 2013;12:157-165. receiving first-line treatments is inadequate. 2 3

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A Pediatric Perspective focuses on specialized topics in pediatrics, orthopedics, neurology, neurosurgery and rehabilitation medicine. Diagnosing and Treating Anti- KEY INSIGHTS To subscribe to or unsubscribe from A Pediatric Perspective, please send an email to [email protected]. N-Methyl-D-Aspartate (NMDA) ■ Anti-NMDA receptor encephalitis

Editor-in-Chief – Steven Koop, M.D. is a relatively common and treatable Editor – Ellen Shriner Receptor Encephalitis cause of encephalitis in pediatric Designers – Becky Wright, Kim Goodness patients. Photographers – Anna Bittner, Amanda Moen, M.D., pediatric neurologist Paul DeMarchi ■ Common symptoms include person- Copyright 2014. Gillette Children’s Specialty ality change, abnormal movements, Amanda Moen, M.D. Healthcare. All rights reserved. Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is an autoimmune seizures and autonomic dysfunction. condition in which the body produces antibodies that act against receptors in ■ If these symptoms are present, an the brain, resulting in both neurologic and psychiatric symptoms. Common urgent child neurology evaluation is symptoms include personality change, psychosis, abnormal movements, indicated and an evaluation for anti- To make a referral, call 651-325-2200 or seizures and autonomic dysfunction. The antibodies associated with this NMDA receptor encephalitis should Pediatric neurologist Amanda Moen, M.D., treats children 855-325-2200 (toll-free). condition were first identified in 2005, and since then it has become recognized be initiated. who have epilepsy and other neurological conditions. as one of the most common identifiable causes of encephalitis in children and She received an M.D. from the University of Iowa’s Carver ■ Time-to-diagnosis and treatment of young adults. College of Medicine in Iowa City, Iowa, and completed a NEWS & NOTES anti-NMDA receptor encephalitis pediatric residency and a child neurology residency at have a significant impact on patient The Children’s Hospital Colorado in Denver. Her profes- In the California Encephalitis Project, only 79 of 761 cases of encephalitis in recovery and final outcome. individuals under age 30 had an identifiable etiology. Anti-NMDA receptor sional interests include anti-NMDA receptor encephalitis, New Physician Joins Gillette neuroimmunology, leukodystrophies and other metabolic Visit www.gillettechildrens.org/ encephalitis accounted for 32 of those cases, and 65 percent of those patients Joy Taber, M.D., is board-certified in physical medicine and rehabilitation. She cares for and genetic neurological disorders. OurCareTeam to learn more about were younger than 19. Additionally, the study showed that anti-NMDA receptor Gillette’s specialists. adult patients who have cerebral palsy, spina bifida and other childhood-onset conditions. She received a medical degree and completed her residency in physical medicine and encephalitis may be more common than any single infectious cause of encephalitis, Clinical Education rehabilitation at the University of Minnesota School of Medicine in Minneapolis. In other than enterovirus.1 Visit our website to find videos and addition, she served as a U.S. Air Force flight surgeon. She is a member of the American professional presentations. Academy of Physical Medicine and Rehabilitation, American Medical Association and www.gillettechildrens.org Minnesota Medical Association. She sees patients at Gillette Lifetime Specialty Healthcare. Frequency of Identifiable Causes of Encephalitis in the California Encephalitis Project Back Issues of A Pediatric Perspective www.gillettechildrens.org/for-medical- professionals/publications

Anti-NMDA receptor encephalitis Gillette Children’s Specialty Healthcare Enterovirus is named in honor of orthopedic surgeon Herpes Simplex Virus (HSV-1) Arthur Gillette, M.D., who helped found West Nile Virus the nation’s first publicly funded hospital for children who have disabilities. We are Varicella Zoster Virus an independent, not-for-profit children’s hospital, and our organization has no affiliation with the Gillette Company or the Gillette brand of personal care products.

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