- Email: [email protected]
A Confused Child
Abstract: Children presenting to the emergency department with an acutely altered mental state require a thoughtful systematic approach to accurately identify the underlying disease process. We present a case of anti–N-methyl-Daspartate receptor encephalitis that initially presented to our emergency department with acute confusion. With increasing recognition of this form of encephalitis, emergency physicians will benefit from understanding the salient neuropsychiatric features, disease progression, diagnostic options, management, and prognostic outcome of these patients.
Keywords: Anti–N-methyl-D-aspartate receptor antibody encephalitis; anti-NMDAR encephalitis; encephalitis; altered mental state; confusion; psychosis
Pediatric Emergency Medicine, SUNY Downstate Medical Center/Kings County Hospital Center, Brooklyn, NY. Reprint requests and correspondence: Sathyaseelan Subramaniam, MD, Pediatric Emergency Medicine, SUNY Downstate Medical Center/Kings County Hospital Center, 450 Clarkson Ave, Brooklyn, NY 11203. [email protected] This case was selected for presentation as part of the American Academy of Pediatrics Section on Emergency Medicine Emergi-Quiz Case Competition held during the 2014 National Convention and Exhibition in San Diego, CA. 1522-8401 © 2015 Elsevier Inc. All rights reserved.
EMERGI-QUIZ CLINICAL PUZZLER
A Confused Child Sathyaseelan Subramaniam, MD
A
12-year-old girl was brought to the emergency department (ED) in June for evaluation of sexual assault. The girl had arrived home late that evening and, upon questioning by her parents, stated that she was taken off the school bus and raped in a subway station by the bus driver. Upon hearing this, the parents immediately called the police and emergency medical services. In the ED, upon further police questioning, she recanted her story. She admitted fabricating her story to avoid punishment for returning home late. During evaluation by the pediatric ED physician and social worker, it became clear that the patient's behavior was not normal. She had intermittent bouts of loud laughter between periods of barely audible monosyllable answers. Despite her odd behavior, it was ascertained that she had been feeling helpless, fatigued, and depressed in mood with anhedonia for the past 3 weeks. Even more concerning, however, was her admission that for the past 2 weeks she had been hearing voices instructing her to commit suicide. The parents denied their daughter had any recent illness, fever, headache, or other complaints. She was known to have simple headaches in the past and had a history of cutting her wrists, but neither of these had occurred recently. She had not seen any mental health provider previously, was not on any medication, and had no allergies. She had a normal term birth, reached all her milestones as expected, and was doing well in seventh grade. She achieved menarche at age 11, and her last menstrual period was 4 days before presentation. Her immunizations were up to date. She lived with both her parents and 2 older brothers. Everyone in the family was healthy with no family history of psychiatric or neurologic disorders. She denied any form of abuse. Her vital signs included a heart rate of 80 beats per minute, respiratory rate of 20 breaths per minute, blood pressure of 123/76 mm Hg, a temperature of 37.4°C, and she had an oxygen saturation of 100% in room air. On physical examination, she was a well appearing, well-nourished child. She had no evidence of trauma to her head; a supple neck; and a normal eye, ear, nose, and throat examination. She had good pulses and perfusion, and her heart and lung examinations were normal. Her abdomen was soft and A CONFUSED CHILD / SUBRAMANIAM • VOL. 16, NO. 1 69
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nontender, with normal bowel sounds, and no masses were appreciated. The external genitourinary examination was normal, with no signs of trauma, and a pelvic examination was deferred. Her neurologic examination revealed an alert and oriented individual, with a Glasgow Coma Score of 15, with normal-sized, equal and reactive pupils, normal muscle tone, strength, reflexes, sensation, and coordination in upper and lower limbs. She had a normal cranial nerve examination and was compliant enough to stand and walk with a normal gait. Her mental status examination was significant for avoidant eye contact and seeming indifferent to her surroundings. Her speech was slow and halting. Her mood appeared depressed with a blunt affect, but, at times, she burst out in bouts of laughter. She could not identify a reason for feeling sad but acknowledged auditory hallucinations that were telling her to kill herself. On laboratory evaluation, she had a normal complete blood count (white blood cell count, 7.5; hemoglobin level, 13.7; hematocrit, 42.6, and platelets, 259) and a normal comprehensive metabolic panel (sodium, 143; potassium, 4.3; chloride, 106; carbon dioxide, 22; serum urea nitrogen, 9; creatinine, 0.46; glucose, 93; calcium, 9.7; aspartate aminotransferase, 27; alanine transaminase, 16; alkaline phosphatase, 187; albumin, 4.7; and total bilirubin, 0.2). In addition, her blood ethanol, salicylate, and acetaminophen levels and her urine toxicology screen were all negative. She also had a normal urinalysis, normal thyroid stimulating hormone level, and a negative urine pregnancy test. Given the current lack of an organic cause for her altered behavior, history of depressed mood, and auditory hallucinations, the psychiatry service was consulted. On their assessment, she was deemed to be a danger to herself and was unable to engage in a contract for safety. She was admitted to the inpatient psychiatric unit with a 1:1 nursing sitter to ensure her safety. Upon admission to the psychiatry unit, she was started on the antipsychotic, olanzapine. During the first 3 days of her inpatient stay, she displayed increasingly bizarre activity including use of profanity, frequent touching of her genitalia and mouth, and constant rubbing of her buttock on the unit floor. She also had new onset hypertension with blood pressures ranging from 130/80 up to 160/90 mm Hg. During episodes of agitation, she was given lorazepam and haloperidol to calm her down. On her fourth day on the unit, her mental status was noted to be waxing and waning; and she experienced an observed, selflimited, 2-minute, tonic-clonic seizure. She also started to drool and exhibit frequent orofacial movements resembling grimacing and pouting. She
remained afebrile. The pediatric neurology service was consulted. On their examination, she was found to have a Glasgow Coma Score of 9 (E1, V3, and M5). She had normal-sized equal and reactive pupils, new onset increased tone of her right upper extremity, normal reflexes, and the rest of the examination was deferred given her mental status. They recommended transfer to the pediatric intensive care unit (PICU) and further investigations that led to the definitive diagnosis in this acutely encephalopathic 12-year-old girl.
DIFFERENTIAL DIAGNOSIS Children who present with an acutely altered mental state are a diagnostic challenge given the extensive number of potential diagnoses. Infections, intracranial lesions, drugs, psychiatric conditions, epileptic syndromes, and autoimmune diseases are broad differential groups that warrant consideration. Emergency physicians need to obtain a detailed history of symptoms to narrow the differential. The presence of fevers, prodromal illness, neurologic impairments, use of recreational drugs, medical history of an autoimmune, epileptic or headache syndrome, or a family history of any of these is a potential lead to a diagnosis. The examination needs to be systematic and thorough, observing the patient's vital signs, mental status, and stigmata of autoimmune or malignant diseases and eliciting any focal neurologic deficits. The use of appropriate investigative imaging and laboratory data is crucial in aiding the clinician to make a diagnosis and plan management. Immediate life-threatening conditions need to be screened for initially. Glucose and thyroid function tests are easily obtained to detect hypoglycemia and thyroid storm. A child with a fever and an altered mental state needs to be investigated expeditiously for infectious encephalitis or meningitis, and these should be high on the ED clinician's differential. Bacterial or viral pathogens like mycoplasma, herpes simplex virus (HSV) 1 or 2, enteroviruses, and arboviruses are conceivable causative agents. With infections, a lumbar puncture generally shows cerebrospinal fluid (CSF) pleocytosis and may reveal a deranged CSF glucose and protein value. Intracranial pathology, including mass lesions and strokes, can present with psychosis and altered behavior, albeit rarely. More commonly, there is a depressed mental state associated with other signs of increasing intracranial pressure, such as headache, nausea, and vomiting. Imaging is the most sensitive method to diagnose these conditions. Ingested drugs, such as anticholinergics, hallucinogens, and sympathomimetics need to be investigated for in a previously well child that develops a
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rapid change in mental status. Vital signs, pupil size, agitated or sedated mental state, and skin changes (sweating or dry) can help define toxidromes and differentiate between the classes of ingested toxins or related signs of withdrawal. Urine toxicology studies obtained in the ED can help identify common drugs of abuse, though not all. Direct questioning of caregivers and friends regarding the patient's access to medications and recreational drugs may provide clues to possible ingestion/ intoxication. Furthermore, neuroleptic malignant syndrome is a concern in any patient receiving typical or atypical neuroleptic drugs. Nonconvulsive status epilepticus, Lenox-Gestaut syndrome, and Landau-Kleffner syndrome are epileptic syndromes that can present with a change in behavior including deafness and psychosis with or without seizure activity. If suspected, the ED physician can consult with a pediatric neurologist to determine the utility of monitoring for typical electrical activity with an electroencephalogram (EEG) in the ED, as findings can be diagnostic. Primary psychiatric illnesses are very likely in any patient who presents with psychotic symptoms. However, these diagnoses should be considered only after excluding potential organic causes of a change in behavior. Schizophrenia, major depressive disorder, and bipolar disorder can be screened for in the ED; and a psychiatry consult can aid in the diagnosis. Finally, a variety of autoimmune conditions can result in children presenting in a state of acute delirium. Conditions ranging from post-infectious acute demyelinating encephalitis, systemic lupus erythematosus, Hashimoto encephalopathy, and neuronal autoimmune syndromes like anti–N-methyl-Daspartate receptor (NMDAR) encephalitis are all
feasible culprits. Anti-NMDAR encephalitis requires a high index of suspicion. Although this particular diagnosis is not usually entertained in an ED setting, ED physicians should consider involving pediatric neurology services early on in the assessment, especially when psychotic symptoms are accompanied with classic neurologic signs. Table 1 lists the broad disease groups, with specific examples, that can be considered in the differential diagnosis in a pediatric patient presenting with an acutely altered mental state.
CASE PROGRESSION At the time of the neurology consult, the differential diagnosis was broad. It included infectious diseases, toxins, metabolic disorders, seizures, and autoimmune-related encephalopathy. Initially, investigations were aimed at ruling out the more common and potentially life-threatening possibilities. Once in the PICU, a computed tomography study of the head was performed, which was interpreted as being normal. Laboratory studies, including a complete blood count, comprehensive metabolic panel, serum lead, cortisol, erythrocyte sedimentation rate, C-reactive protein, and complement proteins, were all normal. Because of ongoing orofacial movements, a trial of intravenous (IV) diphenhydramine was given for possible dystonia. This intervention had no effect on her dyskinesia. An EEG showed diffuse slowing indicative of cerebral dysfunction but no ongoing epileptiform activity. Magnetic resonance imaging (MRI) of the brain was remarkable only for mild white matter changes in the left frontal lobe. Lumbar puncture demonstrated normal opening pressure with
TABLE 1. Disease groups, with examples, for consideration in the differential diagnosis of a child with an acutely altered mental state. Disease group
Specific example
Infectious encephalitis/meningitis Acute toxic-metabolic encephalopathy Primary psychiatric disorders Childhood epileptic encephalopathy Demyelinating disorders Autoimmune-associated encephalitides Neuroleptic malignant syndrome Migraine variants
Mycoplasma, HSV type 1, HHV 6, enterovirus Phencyclidine, ketamine, lead Brief reactive psychosis, major depressive disorder with psychotic episode Lennox-Gestaut syndrome, Landau-Kleffner syndrome Acute disseminated encephalomyelitis Rasmussen encephalitis, other neuronal antibodies to GABA, AMPA, LGI1, NMDA receptors With quetiapine use, complicating psychotic presentation Confusional migraine
Abbreviations: HHV; human herpes virus; HSV, herpes simplex virus; GABA, γ-aminobutyric acid; AMPA, α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid; LGI1, leucine-rich glioma inactivated 1; NMDA, N-methyl-D-aspartate. Data and modified from Jones et al. 9
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leukocytosis and lymphocytic predominance but normal glucose and protein. Acyclovir was started but discontinued once all CSF cultures and viral CSF polymerase chain reaction (enterovirus/HSV) tests were negative. All routine autoimmune antibody laboratory tests (antinuclear antibody, anti-dsDNA, anti-Jo, anti-La, anti-Ro, anti-Smith (Sm), anti-ribonucleoprotein (RNP), anti-Scl, anticentromere, and antihistone) were negative. With negative cultures, drug, and autoimmune panels; nonspecific brain findings on MRI and EEG; the likelihood of infectious, toxin, seizure, and demyelinating disorders as a cause for her encephalopathy was becoming increasingly unlikely. However, the autoimmune synaptic receptor encephalitis, anti-NMDAR encephalitis, was emerging as a possible diagnosis. Her constellation of neuropsychiatric clinical features, specifically her personality change and display of hypersexual behavior, movement disorders, seizures, and autonomic instability were hallmarks of the disease. The various teams involved in her care converged on this diagnosis and serum and CSF anti-NMDAR titers were obtained. On day 3 of her PICU admission, she was started on a 5-day course of pulsed steroids and IV immunoglobulin (Ig) as empirical first-line therapy for this condition. Despite completion of the medication course, there was no improvement in her clinical status. She remained disorientated and awoke intermittently only to vocalize unintelligibly. On day 9 of PICU admission, her CSF and serum anti-NMDAR antibody titers returned positive. With a confirmed diagnosis of anti-NMDAR encephalitis, she was started on second-line therapy with rituximab and cyclophosphamide. As some anti-NMDAR encephalitis cases are associated with a paraneoplastic process, efforts to locate a tumor as a precipitant were made. Subsequent imaging of her chest, abdomen, and pelvis were negative. During her 6-week stay in the PICU, she continued to deteriorate and required placement of a gastrostomy tube and a tracheostomy. She was also started on antiepileptics and antihypertensives for seizure and blood pressure control. She was eventually placed at a long-term care facility with monthly scheduled readmissions to the PICU for chemotherapy. At the time of discharge, she was nonverbal and nonmobile with only choreoathetoid movements of her extremities. Encouragingly, at her last readmission for a routine chemotherapy session, there were significant strides in her recovery. She was vocalizing single words specifically and accurately and walking independently and purposefully.
CASE DISCUSSION In recent years, there has been abundant literature detailing this increasingly diagnosed autoimmune encephalitis. Initially described as a paraneoplastic neurologic disease in young women, it is now understood to affect both sexes with ages ranging from 8 months to 85 years. 1,2 Indeed, many cases of idiopathic encephalitis and encephalitis lethargica have been proven to be due to anti-NMDAR antibodies, and data from the California Encephalitis Project indicate that anti-NMDAR encephalitis is relatively frequent, rivaling the prevalence of viral causes. 3-5
Pathophysiology Anti-NMDAR antibodies are IgG antibodies that bind to the subunit NR1 on the NMDA receptor found within the brain. 6 In animal models, antibody-receptor binding causes internalization of the receptor that leads to a reversible decrease in these receptors. Resultant NMDA receptor dysfunction is thought to be responsible for the symptom complex of anti-NMDAR encephalitis. Not surprisingly, similar symptoms are seen with a variety of neuropsychiatric disorders including schizophrenia, epilepsy, dementia, ketamine and phencyclidine overdoses, and Huntington's and Parkinson's disease, where a reduction in NMDAR activity has been linked. 7 The reason for autoantibody production remains unclear at this time. Theories include tumor or infections triggering the immune system to produce autoantibodies. 7 Around 58% of patients who have the disease demonstrate a tumor, either ovarian or extraovarian teratomas, thymomas, lung, breast, and pancreatic cancer. 8 Similarly HSV, H1N1, mycoplasma infections, and relapsing post-HSV encephalitis have been linked to production of anti-NMDAR antibodies. However, a large majority of patients have no tumor or evidence of infection preceding their presentation. A combination of genetics and an inciting factor (infection or tumor) most likely acts as an adjuvant for the development of anti-NMDAR encephalitis.
Clinical Features Although anti-NMDAR encephalitis in adults has a female to male ratio of 4:1, the pediatric population does not have as much of a sex bias. There is usually a prodrome of nonspecific symptoms like headache, nausea, rhinitis, and vomiting, similar to a viral illness. Within 2 weeks of illness, a constellation of disease specific features described below emerges: 7 1. Psychiatric and behavioral problems Anxiety, paranoia, mania, and hallucinations
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can be observed in afflicted patients. In younger children, psychosis is not as easily identified; and behavioral or personality changes like hypersexuality, aggression, and irritability are seen. Given these symptoms, psychiatrists are often the first specialty clinicians to be consulted. The clinical course can become complicated with the use of antipsychotics, as disease progression frequently overlaps symptoms of neuroleptic malignant syndrome. 9 2. Seizures and cognitive problems In a case series of 32 children, seizures were seen in 77%. Seizures were either partial or generalized with 2 patients experiencing status epilepticus. 10 Most children from this series (19 patients) had partial or complex seizures. Cognitive problems include confusion, amnesia, reduced speech, echolalia, frank mutism, and deterioration to catatonia. 3. Movement disorders Movement disorders are a very common feature in children with anti-NMDAR encephalitis. A variety of dyskinesias are described including orofacial movement disorders (chewing, tongue thrusting, lip smacking, and facial grimacing), choreoathetosis, and catatonia. In addition, patients may exhibit sterotypies like pelvic thrusting and pseudopiano playing. 9 4. Autonomic instability Brady and tachycardia, hypertension, hypoventilation, and temperature dysregulation can occur. In rare cases, seen more commonly in adults, instability can be severe, requiring intervention with mechanical ventilation and pacing. Fevers can compound the clinical picture, often prompting clinicians to investigate for infectious processes. The features detailed above can be classified as either early or late phase symptoms. Psychiatric, behavioral, and cognitive problems, along with seizures are more common in the early phase of the disease (within 2 weeks of prodrome illness onset), whereas movement disorders and autonomic instability are late phase symptoms. 6
Diagnostic Tests Diagnosis of anti-NMDAR encephalitis requires the detection of anti-NMDAR antibodies in either serum or CSF. Initial testing for anti-NMDAR antibodies was qualitative, but diagnostic assays have now been developed to allow quantitative reporting of anti-
NMDAR antibody titers. 7 Quantitative testing has prognostic value, as high titers are associated with teratoma and poorer neurologic outcome. 11 Titers fall with the initiation of therapy and can be used as a method for monitoring disease response. 12 Other CSF changes can include pleocytosis, presence of CSF specific oligoclonal bands, and abnormalities of the IgG index. Brain imaging with computed tomography has poor sensitivity, whereas MRI imaging can be normal or show abnormalities in fluid-attenuated inversion recovery (FLAIR) signaling, nonspecific changes that cast a wide net over radiologic differentials. Electroencephalography is useful when movement disorders and seizures are hard to distinguish clinically. Patients not actively seizing may have a nonspecific slowing and disorganized background activity seen on the EEG. Immunotherapeutic agents are the mainstay of treatment for children with anti-NMDAR encephalitis. First-line medications include methylprednisolone and IV Ig given simultaneously over 5 days. 6 Plasmapheresis has been suggested but is not convenient given the need for central line placement in a child who is likely to be uncooperative. Dalmau et al 13 suggests moving to second-line therapy in cases of poor response after 10 days of initial therapy. Second-line agents consist of rituximab and cyclophosphamide. Given the lack of controlled clinical trials, support from pediatric oncologists, neurooncologists, or rheumatologists is essential for dosing and planning long-term therapy. As substantial numbers of patients have an underlying neoplasm, carefully planned imaging to locate a tumor should be conducted. Identification and removal of a tumor can be curative. Those without identifiable tumors have a tendency to experience relapses; therefore, continued immunosuppressive therapy with azathioprine or mycophenolate can be considered. Surveillance imaging should be performed at 6 monthly intervals for 4 consecutive years in females above the age of 12. 6 A case series by DeSena et al 14 has suggested classification of symptoms and severity into 3 phenotypes. Depending on phenotype classification, patient recovery times may be roughly estimated. In general, given the low incidence of tumor identification in the pediatric population, recovery is protracted, and relapses are more likely. Prognostic factors that indicate a favorable outcome are tumor association, early institution of immunotherapy, and no intensive care admission. At 2 years, 80% of patients have a good outcome (0-2 on the 5-point modified Rankin scale), whereas 7% experience mortality. 2
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SUMMARY This case demonstrates how children presenting with altered mental status in the ED can have a very broad differential requiring thoughtful approach for precise diagnosis. Patients afflicted with antiNMDAR encephalitis benefit from early recognition and management. Understanding that psychiatric, behavioral and cognitive problems, seizures, movement disorders, and autonomic instability are all characteristic features of the disease will aid in early diagnosis and can impact the prognosis in affected patients. Acknowledgment Thank you to Dr. Jennifer Chao and Dr. Konstantinos Agoritsas for the mentoring of this case.
REFERENCES 1. Vitaliani R, Mason W, Ances B, et al. Paraneoplastic encephalitis, psychiatric symptoms, and hypoventilation in ovarian teratoma. Ann Neurol 2005;58:594–604. 2. Titulaer MJ, McCracken L, Gabilondo I, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157–65. 3. Gable MS, Gavali S, Radner A, et al. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. Eur J Clin Microbiol Infect Dis 2009;28: 1421–9.
4. Dale RC, Irani SR, Brilot F, et al. N-methyl-D-aspartate receptor antibodies in pediatric dyskinetic encephalitis lethargica. Ann Neurol 2009;66:704–9. 5. Gable MS, Sheriff H, Dalmau J, et al. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis 2012;54:899–904. 6. Mann AP, Grebenciucova E, Lukas RV. Anti-N-methyl-Daspartate-receptor encephalitis: diagnosis, optimal management, and challenges. Ther Clin Risk Manag 2014;10:517–25. 7. Lazar-Molnar E, Tebbo AE. Autoimmune NMDA receptor encephalitis. Clin Chim Acta 2014;438:90–7. 8. Florance-Ryan N, Dalmau J. Update on anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and adolescents. Curr Opin Pediatr 2010;22:739–44. 9. Jones KC, Benseler SM, Moharir M. Anti-NMDA receptor encephalitis. Neuroimaging Clin N Am 2013;23:157–65. 10. Florance NR, Davis RL, Lam C, et al. Anti-N-methyl-Daspartate receptor (NMDAR) encephalitis in children and adolescents. Ann Neurol 2009;66:11–8. 11. Gresa-Arribas N, Titulaer MJ, Torrents A, et al. Antibody titres at diagnosis and during follow-up of anti-NMDA receptor encephalitis: a retrospective study. Lancet Neurol 2014;13:167–77. 12. Irani SR, Bera K, Waters P, et al. N-methyl-D-aspartate antibody encephalitis: temporal progression of clinical and paraclinical observations in a predominantly non-paraneoplastic disorder of both sexes. Brain 2010;133:1655–67. 13. Dalmau J, Lancaster E, Martinez-Hernandez E, et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63–74. 14. DeSena AD, Greenberg BM, Graves D. Three phenotypes of anti-N-methyl-D-aspartate receptor antibody encephalitis in children: prevalence of symptoms and prognosis. Pediatr Neurol 2014;51:542–9.
Keywords: Anti–N-methyl-D-aspartate receptor antibody encephalitis; anti-NMDAR encephalitis; encephalitis; altered mental state; confusion; psychosis
Pediatric Emergency Medicine, SUNY Downstate Medical Center/Kings County Hospital Center, Brooklyn, NY. Reprint requests and correspondence: Sathyaseelan Subramaniam, MD, Pediatric Emergency Medicine, SUNY Downstate Medical Center/Kings County Hospital Center, 450 Clarkson Ave, Brooklyn, NY 11203. [email protected] This case was selected for presentation as part of the American Academy of Pediatrics Section on Emergency Medicine Emergi-Quiz Case Competition held during the 2014 National Convention and Exhibition in San Diego, CA. 1522-8401 © 2015 Elsevier Inc. All rights reserved.
EMERGI-QUIZ CLINICAL PUZZLER
A Confused Child Sathyaseelan Subramaniam, MD
A
12-year-old girl was brought to the emergency department (ED) in June for evaluation of sexual assault. The girl had arrived home late that evening and, upon questioning by her parents, stated that she was taken off the school bus and raped in a subway station by the bus driver. Upon hearing this, the parents immediately called the police and emergency medical services. In the ED, upon further police questioning, she recanted her story. She admitted fabricating her story to avoid punishment for returning home late. During evaluation by the pediatric ED physician and social worker, it became clear that the patient's behavior was not normal. She had intermittent bouts of loud laughter between periods of barely audible monosyllable answers. Despite her odd behavior, it was ascertained that she had been feeling helpless, fatigued, and depressed in mood with anhedonia for the past 3 weeks. Even more concerning, however, was her admission that for the past 2 weeks she had been hearing voices instructing her to commit suicide. The parents denied their daughter had any recent illness, fever, headache, or other complaints. She was known to have simple headaches in the past and had a history of cutting her wrists, but neither of these had occurred recently. She had not seen any mental health provider previously, was not on any medication, and had no allergies. She had a normal term birth, reached all her milestones as expected, and was doing well in seventh grade. She achieved menarche at age 11, and her last menstrual period was 4 days before presentation. Her immunizations were up to date. She lived with both her parents and 2 older brothers. Everyone in the family was healthy with no family history of psychiatric or neurologic disorders. She denied any form of abuse. Her vital signs included a heart rate of 80 beats per minute, respiratory rate of 20 breaths per minute, blood pressure of 123/76 mm Hg, a temperature of 37.4°C, and she had an oxygen saturation of 100% in room air. On physical examination, she was a well appearing, well-nourished child. She had no evidence of trauma to her head; a supple neck; and a normal eye, ear, nose, and throat examination. She had good pulses and perfusion, and her heart and lung examinations were normal. Her abdomen was soft and A CONFUSED CHILD / SUBRAMANIAM • VOL. 16, NO. 1 69
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nontender, with normal bowel sounds, and no masses were appreciated. The external genitourinary examination was normal, with no signs of trauma, and a pelvic examination was deferred. Her neurologic examination revealed an alert and oriented individual, with a Glasgow Coma Score of 15, with normal-sized, equal and reactive pupils, normal muscle tone, strength, reflexes, sensation, and coordination in upper and lower limbs. She had a normal cranial nerve examination and was compliant enough to stand and walk with a normal gait. Her mental status examination was significant for avoidant eye contact and seeming indifferent to her surroundings. Her speech was slow and halting. Her mood appeared depressed with a blunt affect, but, at times, she burst out in bouts of laughter. She could not identify a reason for feeling sad but acknowledged auditory hallucinations that were telling her to kill herself. On laboratory evaluation, she had a normal complete blood count (white blood cell count, 7.5; hemoglobin level, 13.7; hematocrit, 42.6, and platelets, 259) and a normal comprehensive metabolic panel (sodium, 143; potassium, 4.3; chloride, 106; carbon dioxide, 22; serum urea nitrogen, 9; creatinine, 0.46; glucose, 93; calcium, 9.7; aspartate aminotransferase, 27; alanine transaminase, 16; alkaline phosphatase, 187; albumin, 4.7; and total bilirubin, 0.2). In addition, her blood ethanol, salicylate, and acetaminophen levels and her urine toxicology screen were all negative. She also had a normal urinalysis, normal thyroid stimulating hormone level, and a negative urine pregnancy test. Given the current lack of an organic cause for her altered behavior, history of depressed mood, and auditory hallucinations, the psychiatry service was consulted. On their assessment, she was deemed to be a danger to herself and was unable to engage in a contract for safety. She was admitted to the inpatient psychiatric unit with a 1:1 nursing sitter to ensure her safety. Upon admission to the psychiatry unit, she was started on the antipsychotic, olanzapine. During the first 3 days of her inpatient stay, she displayed increasingly bizarre activity including use of profanity, frequent touching of her genitalia and mouth, and constant rubbing of her buttock on the unit floor. She also had new onset hypertension with blood pressures ranging from 130/80 up to 160/90 mm Hg. During episodes of agitation, she was given lorazepam and haloperidol to calm her down. On her fourth day on the unit, her mental status was noted to be waxing and waning; and she experienced an observed, selflimited, 2-minute, tonic-clonic seizure. She also started to drool and exhibit frequent orofacial movements resembling grimacing and pouting. She
remained afebrile. The pediatric neurology service was consulted. On their examination, she was found to have a Glasgow Coma Score of 9 (E1, V3, and M5). She had normal-sized equal and reactive pupils, new onset increased tone of her right upper extremity, normal reflexes, and the rest of the examination was deferred given her mental status. They recommended transfer to the pediatric intensive care unit (PICU) and further investigations that led to the definitive diagnosis in this acutely encephalopathic 12-year-old girl.
DIFFERENTIAL DIAGNOSIS Children who present with an acutely altered mental state are a diagnostic challenge given the extensive number of potential diagnoses. Infections, intracranial lesions, drugs, psychiatric conditions, epileptic syndromes, and autoimmune diseases are broad differential groups that warrant consideration. Emergency physicians need to obtain a detailed history of symptoms to narrow the differential. The presence of fevers, prodromal illness, neurologic impairments, use of recreational drugs, medical history of an autoimmune, epileptic or headache syndrome, or a family history of any of these is a potential lead to a diagnosis. The examination needs to be systematic and thorough, observing the patient's vital signs, mental status, and stigmata of autoimmune or malignant diseases and eliciting any focal neurologic deficits. The use of appropriate investigative imaging and laboratory data is crucial in aiding the clinician to make a diagnosis and plan management. Immediate life-threatening conditions need to be screened for initially. Glucose and thyroid function tests are easily obtained to detect hypoglycemia and thyroid storm. A child with a fever and an altered mental state needs to be investigated expeditiously for infectious encephalitis or meningitis, and these should be high on the ED clinician's differential. Bacterial or viral pathogens like mycoplasma, herpes simplex virus (HSV) 1 or 2, enteroviruses, and arboviruses are conceivable causative agents. With infections, a lumbar puncture generally shows cerebrospinal fluid (CSF) pleocytosis and may reveal a deranged CSF glucose and protein value. Intracranial pathology, including mass lesions and strokes, can present with psychosis and altered behavior, albeit rarely. More commonly, there is a depressed mental state associated with other signs of increasing intracranial pressure, such as headache, nausea, and vomiting. Imaging is the most sensitive method to diagnose these conditions. Ingested drugs, such as anticholinergics, hallucinogens, and sympathomimetics need to be investigated for in a previously well child that develops a
A CONFUSED CHILD / SUBRAMANIAM • VOL. 16, NO. 1 71
rapid change in mental status. Vital signs, pupil size, agitated or sedated mental state, and skin changes (sweating or dry) can help define toxidromes and differentiate between the classes of ingested toxins or related signs of withdrawal. Urine toxicology studies obtained in the ED can help identify common drugs of abuse, though not all. Direct questioning of caregivers and friends regarding the patient's access to medications and recreational drugs may provide clues to possible ingestion/ intoxication. Furthermore, neuroleptic malignant syndrome is a concern in any patient receiving typical or atypical neuroleptic drugs. Nonconvulsive status epilepticus, Lenox-Gestaut syndrome, and Landau-Kleffner syndrome are epileptic syndromes that can present with a change in behavior including deafness and psychosis with or without seizure activity. If suspected, the ED physician can consult with a pediatric neurologist to determine the utility of monitoring for typical electrical activity with an electroencephalogram (EEG) in the ED, as findings can be diagnostic. Primary psychiatric illnesses are very likely in any patient who presents with psychotic symptoms. However, these diagnoses should be considered only after excluding potential organic causes of a change in behavior. Schizophrenia, major depressive disorder, and bipolar disorder can be screened for in the ED; and a psychiatry consult can aid in the diagnosis. Finally, a variety of autoimmune conditions can result in children presenting in a state of acute delirium. Conditions ranging from post-infectious acute demyelinating encephalitis, systemic lupus erythematosus, Hashimoto encephalopathy, and neuronal autoimmune syndromes like anti–N-methyl-Daspartate receptor (NMDAR) encephalitis are all
feasible culprits. Anti-NMDAR encephalitis requires a high index of suspicion. Although this particular diagnosis is not usually entertained in an ED setting, ED physicians should consider involving pediatric neurology services early on in the assessment, especially when psychotic symptoms are accompanied with classic neurologic signs. Table 1 lists the broad disease groups, with specific examples, that can be considered in the differential diagnosis in a pediatric patient presenting with an acutely altered mental state.
CASE PROGRESSION At the time of the neurology consult, the differential diagnosis was broad. It included infectious diseases, toxins, metabolic disorders, seizures, and autoimmune-related encephalopathy. Initially, investigations were aimed at ruling out the more common and potentially life-threatening possibilities. Once in the PICU, a computed tomography study of the head was performed, which was interpreted as being normal. Laboratory studies, including a complete blood count, comprehensive metabolic panel, serum lead, cortisol, erythrocyte sedimentation rate, C-reactive protein, and complement proteins, were all normal. Because of ongoing orofacial movements, a trial of intravenous (IV) diphenhydramine was given for possible dystonia. This intervention had no effect on her dyskinesia. An EEG showed diffuse slowing indicative of cerebral dysfunction but no ongoing epileptiform activity. Magnetic resonance imaging (MRI) of the brain was remarkable only for mild white matter changes in the left frontal lobe. Lumbar puncture demonstrated normal opening pressure with
TABLE 1. Disease groups, with examples, for consideration in the differential diagnosis of a child with an acutely altered mental state. Disease group
Specific example
Infectious encephalitis/meningitis Acute toxic-metabolic encephalopathy Primary psychiatric disorders Childhood epileptic encephalopathy Demyelinating disorders Autoimmune-associated encephalitides Neuroleptic malignant syndrome Migraine variants
Mycoplasma, HSV type 1, HHV 6, enterovirus Phencyclidine, ketamine, lead Brief reactive psychosis, major depressive disorder with psychotic episode Lennox-Gestaut syndrome, Landau-Kleffner syndrome Acute disseminated encephalomyelitis Rasmussen encephalitis, other neuronal antibodies to GABA, AMPA, LGI1, NMDA receptors With quetiapine use, complicating psychotic presentation Confusional migraine
Abbreviations: HHV; human herpes virus; HSV, herpes simplex virus; GABA, γ-aminobutyric acid; AMPA, α-amino-3-hydroxy5-methyl-4-isoxazolepropionic acid; LGI1, leucine-rich glioma inactivated 1; NMDA, N-methyl-D-aspartate. Data and modified from Jones et al. 9
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leukocytosis and lymphocytic predominance but normal glucose and protein. Acyclovir was started but discontinued once all CSF cultures and viral CSF polymerase chain reaction (enterovirus/HSV) tests were negative. All routine autoimmune antibody laboratory tests (antinuclear antibody, anti-dsDNA, anti-Jo, anti-La, anti-Ro, anti-Smith (Sm), anti-ribonucleoprotein (RNP), anti-Scl, anticentromere, and antihistone) were negative. With negative cultures, drug, and autoimmune panels; nonspecific brain findings on MRI and EEG; the likelihood of infectious, toxin, seizure, and demyelinating disorders as a cause for her encephalopathy was becoming increasingly unlikely. However, the autoimmune synaptic receptor encephalitis, anti-NMDAR encephalitis, was emerging as a possible diagnosis. Her constellation of neuropsychiatric clinical features, specifically her personality change and display of hypersexual behavior, movement disorders, seizures, and autonomic instability were hallmarks of the disease. The various teams involved in her care converged on this diagnosis and serum and CSF anti-NMDAR titers were obtained. On day 3 of her PICU admission, she was started on a 5-day course of pulsed steroids and IV immunoglobulin (Ig) as empirical first-line therapy for this condition. Despite completion of the medication course, there was no improvement in her clinical status. She remained disorientated and awoke intermittently only to vocalize unintelligibly. On day 9 of PICU admission, her CSF and serum anti-NMDAR antibody titers returned positive. With a confirmed diagnosis of anti-NMDAR encephalitis, she was started on second-line therapy with rituximab and cyclophosphamide. As some anti-NMDAR encephalitis cases are associated with a paraneoplastic process, efforts to locate a tumor as a precipitant were made. Subsequent imaging of her chest, abdomen, and pelvis were negative. During her 6-week stay in the PICU, she continued to deteriorate and required placement of a gastrostomy tube and a tracheostomy. She was also started on antiepileptics and antihypertensives for seizure and blood pressure control. She was eventually placed at a long-term care facility with monthly scheduled readmissions to the PICU for chemotherapy. At the time of discharge, she was nonverbal and nonmobile with only choreoathetoid movements of her extremities. Encouragingly, at her last readmission for a routine chemotherapy session, there were significant strides in her recovery. She was vocalizing single words specifically and accurately and walking independently and purposefully.
CASE DISCUSSION In recent years, there has been abundant literature detailing this increasingly diagnosed autoimmune encephalitis. Initially described as a paraneoplastic neurologic disease in young women, it is now understood to affect both sexes with ages ranging from 8 months to 85 years. 1,2 Indeed, many cases of idiopathic encephalitis and encephalitis lethargica have been proven to be due to anti-NMDAR antibodies, and data from the California Encephalitis Project indicate that anti-NMDAR encephalitis is relatively frequent, rivaling the prevalence of viral causes. 3-5
Pathophysiology Anti-NMDAR antibodies are IgG antibodies that bind to the subunit NR1 on the NMDA receptor found within the brain. 6 In animal models, antibody-receptor binding causes internalization of the receptor that leads to a reversible decrease in these receptors. Resultant NMDA receptor dysfunction is thought to be responsible for the symptom complex of anti-NMDAR encephalitis. Not surprisingly, similar symptoms are seen with a variety of neuropsychiatric disorders including schizophrenia, epilepsy, dementia, ketamine and phencyclidine overdoses, and Huntington's and Parkinson's disease, where a reduction in NMDAR activity has been linked. 7 The reason for autoantibody production remains unclear at this time. Theories include tumor or infections triggering the immune system to produce autoantibodies. 7 Around 58% of patients who have the disease demonstrate a tumor, either ovarian or extraovarian teratomas, thymomas, lung, breast, and pancreatic cancer. 8 Similarly HSV, H1N1, mycoplasma infections, and relapsing post-HSV encephalitis have been linked to production of anti-NMDAR antibodies. However, a large majority of patients have no tumor or evidence of infection preceding their presentation. A combination of genetics and an inciting factor (infection or tumor) most likely acts as an adjuvant for the development of anti-NMDAR encephalitis.
Clinical Features Although anti-NMDAR encephalitis in adults has a female to male ratio of 4:1, the pediatric population does not have as much of a sex bias. There is usually a prodrome of nonspecific symptoms like headache, nausea, rhinitis, and vomiting, similar to a viral illness. Within 2 weeks of illness, a constellation of disease specific features described below emerges: 7 1. Psychiatric and behavioral problems Anxiety, paranoia, mania, and hallucinations
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can be observed in afflicted patients. In younger children, psychosis is not as easily identified; and behavioral or personality changes like hypersexuality, aggression, and irritability are seen. Given these symptoms, psychiatrists are often the first specialty clinicians to be consulted. The clinical course can become complicated with the use of antipsychotics, as disease progression frequently overlaps symptoms of neuroleptic malignant syndrome. 9 2. Seizures and cognitive problems In a case series of 32 children, seizures were seen in 77%. Seizures were either partial or generalized with 2 patients experiencing status epilepticus. 10 Most children from this series (19 patients) had partial or complex seizures. Cognitive problems include confusion, amnesia, reduced speech, echolalia, frank mutism, and deterioration to catatonia. 3. Movement disorders Movement disorders are a very common feature in children with anti-NMDAR encephalitis. A variety of dyskinesias are described including orofacial movement disorders (chewing, tongue thrusting, lip smacking, and facial grimacing), choreoathetosis, and catatonia. In addition, patients may exhibit sterotypies like pelvic thrusting and pseudopiano playing. 9 4. Autonomic instability Brady and tachycardia, hypertension, hypoventilation, and temperature dysregulation can occur. In rare cases, seen more commonly in adults, instability can be severe, requiring intervention with mechanical ventilation and pacing. Fevers can compound the clinical picture, often prompting clinicians to investigate for infectious processes. The features detailed above can be classified as either early or late phase symptoms. Psychiatric, behavioral, and cognitive problems, along with seizures are more common in the early phase of the disease (within 2 weeks of prodrome illness onset), whereas movement disorders and autonomic instability are late phase symptoms. 6
Diagnostic Tests Diagnosis of anti-NMDAR encephalitis requires the detection of anti-NMDAR antibodies in either serum or CSF. Initial testing for anti-NMDAR antibodies was qualitative, but diagnostic assays have now been developed to allow quantitative reporting of anti-
NMDAR antibody titers. 7 Quantitative testing has prognostic value, as high titers are associated with teratoma and poorer neurologic outcome. 11 Titers fall with the initiation of therapy and can be used as a method for monitoring disease response. 12 Other CSF changes can include pleocytosis, presence of CSF specific oligoclonal bands, and abnormalities of the IgG index. Brain imaging with computed tomography has poor sensitivity, whereas MRI imaging can be normal or show abnormalities in fluid-attenuated inversion recovery (FLAIR) signaling, nonspecific changes that cast a wide net over radiologic differentials. Electroencephalography is useful when movement disorders and seizures are hard to distinguish clinically. Patients not actively seizing may have a nonspecific slowing and disorganized background activity seen on the EEG. Immunotherapeutic agents are the mainstay of treatment for children with anti-NMDAR encephalitis. First-line medications include methylprednisolone and IV Ig given simultaneously over 5 days. 6 Plasmapheresis has been suggested but is not convenient given the need for central line placement in a child who is likely to be uncooperative. Dalmau et al 13 suggests moving to second-line therapy in cases of poor response after 10 days of initial therapy. Second-line agents consist of rituximab and cyclophosphamide. Given the lack of controlled clinical trials, support from pediatric oncologists, neurooncologists, or rheumatologists is essential for dosing and planning long-term therapy. As substantial numbers of patients have an underlying neoplasm, carefully planned imaging to locate a tumor should be conducted. Identification and removal of a tumor can be curative. Those without identifiable tumors have a tendency to experience relapses; therefore, continued immunosuppressive therapy with azathioprine or mycophenolate can be considered. Surveillance imaging should be performed at 6 monthly intervals for 4 consecutive years in females above the age of 12. 6 A case series by DeSena et al 14 has suggested classification of symptoms and severity into 3 phenotypes. Depending on phenotype classification, patient recovery times may be roughly estimated. In general, given the low incidence of tumor identification in the pediatric population, recovery is protracted, and relapses are more likely. Prognostic factors that indicate a favorable outcome are tumor association, early institution of immunotherapy, and no intensive care admission. At 2 years, 80% of patients have a good outcome (0-2 on the 5-point modified Rankin scale), whereas 7% experience mortality. 2
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SUMMARY This case demonstrates how children presenting with altered mental status in the ED can have a very broad differential requiring thoughtful approach for precise diagnosis. Patients afflicted with antiNMDAR encephalitis benefit from early recognition and management. Understanding that psychiatric, behavioral and cognitive problems, seizures, movement disorders, and autonomic instability are all characteristic features of the disease will aid in early diagnosis and can impact the prognosis in affected patients. Acknowledgment Thank you to Dr. Jennifer Chao and Dr. Konstantinos Agoritsas for the mentoring of this case.
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