A 16 year old boy is brought to the emergency room by his parents for bizarre behavior. His parents report that he has not slept more than an hour in the last 3 days and his behavior has become odder over that time. He has been demonstrating repetitive actions at home, such as turning the lamp next to his bed on and off. He has been intermittently confused when having conversations with the parents, yet at other times he has seems to be normal. Today they found him standing on the kitchen table saying he saw someone in the corner of the room when no one was there. He was recently sick with a fever and cold symptoms approximately one week ago, but these have since resolved. He is a good student with no issues in school. He has no significant past medical history.
After having the parents leave the room, he is able to answer your questions although constant redirection is needed. Throughout the interview he appears distracted and asks repetitive questions. He repetitively puts his hands to his mouth, but does not bite his nails or fingers. He denies tobacco, alcohol, and illicit drug use, and reports trying marijuana only once. He denies stressors at school and home. He is not sexually active. He is active on the soccer team at school and denies recent injury in practice or games. His answers, although appropriate, are rambling and perseverate on the same point.
On exam, his vitals are normal except for an elevated heart rate of 95 beats/min. He is afebrile. Glasgow coma scale is 14/15, with a point off for verbal confusion. Heart, lung, and abdominal exam are all normal. Head is normocephalic with no evidence of trauma. Neurologic exam shows an alert awake boy with mostly normal speech, although there are times of confusion and the need for redirection. Pupils are round, equal, and reactive to light, with EOM with conjugate gaze intact in all directions. Nystagmus is seen at the extremes of lateral gaze; no vertical nystagmus is seen. Facial expression is symmetric. Tongue movements are intact without fasciculations seen. Shoulder shrug symmetric. Strength is 5/5 throughout with good muscle strength and tone. Sensation is intact to light touch and direction sense. Gait is normal with toe, heel, and tandem gait all normal. Romberg is negative. No pronator drift is seen. No tremors noted. Finger to nose and rapidly alternating movements are normal. Deep tendon reflexes are 2+ throughout. There is no clonus.
Labs: Urine toxicology screen is negative. CT of the head is negative. CBC and chemistry panel are normal. Initial cerebrospainl fluid (CSF) studies are normal, with normal cell counts, glucose, and protein.
Anti-N-methyl-aspartate receptor (anti-NMDAR or anti-NMDA receptor) encephalitis (also known as anti-NMDA encephalitis) has been associated with predictable symptoms which make up the characteristic syndrome seen in these children. Most patients will present with prodromal symptoms, including headache, fever, and viral-like illness, followed by progressive symptoms of the encephalitis. Whether prodromal symptoms are part of an early immune activation or lead to an immune response crossing the blood brain barrier due to an infectious response is unknown at this time. However, the immune response typically predominates in the nervous system as is seen by the high frequency of pleocytosis, oligoclonal bands, and intrathecal synthesis of NR1 (NMDA receptor 1) antibodies, which will be discussed later in the chapter (4). Symptoms of anti-NMDAR encephalitis are hallmarked by psychiatric manifestations. These can include anxiety, agitation, bizarre behaviors, hallucinations, delusions, and disorganized thinking. This is paired with insomnia, memory loss, seizures, decreased levels of consciousness, dyskinesias, autonomic instability, and language dysfunction. The decreased level of consciousness can be seen as stupor with catatonic features. Dyskinesia can present in a variety of ways from choreoathetoid movements, dystonia, orofacial twitching, opisthotonic postures, etc. Echolalia is common in the early stages and again in the recovery phase of the illness (1). In one study, 76% of patients had seizures within the first 3 weeks of presentation, 88% had decreased consciousness leading to a catatonic state with periods of akinesis alternating with agitation and diminished or paradoxical response to stimuli (4). Eye contact and visual tracking abilities can be completely absent, but are often found to be brief and inconsistent.
Children as young as 23 months have been reported with anti-NMDAR encephalitis. Even children this young will have the symptoms noted above, similar to adolescents and adults. In younger children, dysautonomia and hypoventilation are less frequent. When these are present they are often less severe. Young children often present with acute behavioral changes, seizures, language dysfunction, dystonia, and dyskinesia (1,2).
When testing these children, the CSF can initially be normal, but will eventually show a lymphocytic pleocytosis or oligoclonal bands. Electroencephalogram will show infrequent epileptic activity, but has frequent, slow, disorganized activity that does correlate with the abnormal movements seen on examination. (1) One study showed 77% of patients showing generalized or predominately frontotemporal slow or disorganized activity, usually delta-theta, without epileptic discharges (4). MRI can be normal, but transient enhancing abnormalities can be seen in cortical and subcortical regions. Location of the abnormalities varies widely with patients and can include, but is not limited to, the basal ganglia, medial temporal lobes, corpus callosum, and brainstem (4). There is poor correlation between the symptoms observed and MRI abnormalities. Brain biopsy was done in 14 patients with anti-NMDA encephalitis with 12 patients showing mild perivascular lymphocytic cuffing, 10 showing microglial activation, and 2 being normal. All 14 were negative for viral assays and neuronophagic nodules. (4)
The diagnosis of anti-NMDAR encephalitis is confirmed by the presence of the NR1 subunit of the NMDAR antibodies in serum or CSF. On initial presentation, most children have a positive finding in serum and CSF, with presence of intrathecal synthesis of antibodies. As treatment progresses, CSF antibodies typically remain elevated if there is no clinical improvement, while serum antibodies can be drastically decreased after treatment is started (1). There is some evidence for correlation between antibody titers in CSF and clinical outcome; however, these studies have been inconsistent.
It is important to know the normal function of NMDA receptors to help relate the disease to normal physiology. NMDA receptors are ligand gated cation channels that play a role in synaptic transmission and plasticity. The NR1 subunits bind glycine, and NR2 subunits bind glutamate. Overactivity of the NMDA receptor causes excitotoxicity. This is a proposed mechanism for many disease states, including epilepsy, stroke, and dementia. Low activity of these receptors can produce symptoms of schizophrenia (4).
The possibility of a tumor causing anti-NMDA antibody encephalitis should be considered to be similar to Lambert-Eaton myasthenic syndrome, with the disorder being antibody mediated. There is a strong correlation between ovarian tumors and anti-NMDAR encephalitis depending on the age of the child. Up to 50% of female anti-NMDA patients over 18 years of age have bilateral or unilateral ovarian teratomas. Less than 9% of girls under the age of 14 years have a teratoma. One study showed higher prevalence of teratomas in African American females than other ethnicities. These teratomas are often found through MRI or CT of the pelvis, along with some found on abdominal or transvaginal ultrasound (1). Serum testing for tumor markers, such as homovanillic acid (HVA) and vanillylmandelic acid (VMA) is an option when considering neuroblastoma as a possible cause. Detection of tumors is very rare in males. There are some associated tumors, such as testicular germ cell tumors or teratomas of the mediastinum to name a few examples. Non-paraneoplastic causes are thought to be due to a preceding infection, such as varicella or mycoplasma, in autoimmune anti-NMDA encephalitis.
Treatment focuses on reducing the number of circulating antibodies and slowing antibody production. In cases caused by tumors, tumor resection is curative and can be paired with non-paraneoplastic treatment, including IVIG (intravenous immune globulin), corticosteroids, and plasma exchange. These are considered first line therapies and if they do not improve the patient’s condition, then rituximab and cyclophosphamide can be used. Spontaneous recovery has been reported and has been described in a few patients after months of severe symptoms. The most recognized approach to treatment is concurrent treatment with immune globulin 0.4 g/kg daily for five days and methylprednisolone 1 g daily for five days (3). This is considered better than plasma exchange, as plasma exchange can be difficult logistically in children, agitated patients, or patients with autonomic instability. If no clinical improvement is seen after 10 days, then second line therapy can be started. The second line therapy consists of rituximab 375 mg per square meter body surface area every week for four weeks and can be combined with cyclophosphamide 750 mg per square meter body surface area (given with the first dose of rituximab) followed by monthly pulse cyclophosphamide. Children are usually only treated with one of these agents second line, most often rituximab (2). Treatment is continued with varying combinations of the previous mentioned therapies in varying orders based on response until recovery occurs. Immunosuppressive therapy is suggested for one year after initially discontinuing immunotherapies, generally using mycophenolate mofetil or azathioprine (3). Other long term strategies include treating with immunosuppression if symptoms return or serum levels of antibodies are found to be elevated on follow up, even if symptoms are absent. There are currently no universally accepted protocols for therapy of anti-NMDAR encephalitis, although some hospitals do have their own protocols. Most treatment centers are using varying treatment strategies on a patient to patient basis.
Median duration of hospitalization for anti-NMDAR encephalitis patients is 2.5 months with the range varying from 1 to 14 months. After discharge, one review showed 85% of patients had mild deficits or signs of frontal lobe dysfunction, including poor attention and planning, impulsivity, or behavioral disinhibition. Twenty seven percent of patients had prominent sleep dysfunction, including inversion of sleep patterns and hypersomnia (4).
Patients with anti-NMDAR antibody encephalitis are at high risk of relapse and for this reason long term immunosuppression may be required. Relapse occurs in up to 24% of patients and can be several years after initial presentation. Patients can also have many relapses with one study noting a patient with 3 episodes of relapse (4). Relapse can be seen with occult or recurrence of teratomas (2). In those with non-paraneoplastic causes, relapses were found to be more common in patients who did not receive immunotherapy with initial presentation (1). Median time to relapse was 18 months with a range from 1 to 84 months (4). Like with all episodes of encephalitis, death is a possible outcome. One case review showed up to a 7% mortality rate, with the diagnosis established by examining archived CSF in all cases (4). Death in this disease is typically due to complications, such as pneumonia.
1. What are the classic symptoms seen in anti-NMDAR antibody encephalitis?
2. How is diagnosis of anti-NMDAR antibody encephalitis confirmed?
3. What are the first and second line therapies for anti-NMDAR antibody encephalitis?
1. Dalamu J. Rosenfeld MR. Paraneoplastic and autoimmune encephalitis. Up-To-Date. 2013.
2. Florance-Ryan N, Dalmau J. Update on anti-N-methyl-aspartate receptor encephalitis in children and adolescents. Current Opinion in Pediatrics. 2010; 22: 739.
3. Dalmau J, Lancaster E, Martinez-Hernandez E et al. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurology. 2008; 70:708.
4. Dalmau J, Gleichman AJ et al. Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. Lancet Neurology. 2008; 7: 1091-1098.
5. Jantzen SU et al. In vitro neuronal network activity in NMDA receptor encephalitis. BioMed Central Neuroscience. 2013; 14:17.
6. Hegarty CP, Mikli JE. Behavioral disturbance requiring medical referral: A case of anti-N-methyl-D-asparate receptor encephalitis in the emergency department. Emergency Medicine Australia. 2013; 25: 87-89.
7. Ryan SA, Costello DJ, Cassidy EM, Brown G, Harrington HJ, Markx S. Anti-NMDA Receptor Encephalitis: A cause of Acute Psychosis and Catatonia. Journal of Psychiatric Practice. 2013. 19: 157-161.
8. Gable MS et al. Anti-NMDA receptor encephalitis: report of ten cases and comparison with viral encephalitis. European Journal of Clinical Microbiology & Infectious Diseases. 2009; 28: 1421-1429.
9. Houtrow AJ et al. The Rehabilitation of Children with Anti-N-methyl-D-aspartate-Receptor Encephalitis: A case series. American Journal of Physical Medicine & Rehabilitation. 2012; 91: 435-441.
Answers to questions
1. Hallmarked by the psychiatric manifestations, including anxiety, agitation, bizarre behavior, hallucinations, delusions, and disorganized thinking. This is seen with insomnia, memory loss, seizures, fluctuating consciousness, movement disorders, and language dysfunction.
2. Presence of antibodies against the NR1 subunit of NMDA receptors in serum or CSF.
3. First line therapies include IVIG, corticosteroids, and plasma exchange in varying orders and combinations. Second line therapy includes rituximab and cyclophosphamide, either alone or concurrent.