1. An Emerging Culprit for Conversion or Factitious Disorders: Anti–N-Methyl-D-Aspartate Receptor Encephalitis Nadine Schwartz MD, Shivani U Mehta MD Dept. of Psychiatry, Drexel University College of Medicine, Philadelphia, PA
Drs. Schwartz and Mehta have no conflicts or disclosures
ABSTRACT
CASE SUMMARY
RESULTS
A 14-year-old female with no prior seizure history had 3 episodes of witnessed tonic-clonic seizures with tongue bite, including one in the Emergency Department (E.D.) of a tertiary care Pediatrics hospital. She was then admitted to the Neurology service for routine EEG which was normal. 
One week later the patient returned to the E.D. with shaking of her right arm, leaning to right side, drooling, and a reported brief loss of consciousness. Her physical exam was within normal limits except for a healing tongue laceration.  While in the E.D., she had a tonic-clonic seizure lasting 4 seconds, was given Lorazepam and admitted to the Neurology service. Initial laboratory results including urine drug screen were all within normal limits. A 24hour EEG showed no significant events. In that first 24 hours of admission, the patient was at times paranoid, anxious and overly clingy with her mother. She also had an episode of unprovoked agitation with screaming and perseveration on the deaths of her grandparents by stroke and fears that she was now also dying of stroke. 
The Psychiatry service was consulted on hospital day #2 to “rule out Conversion Disorder”.  The patient was initially uncooperative but eventually reported that for the 3 weeks prior to admission she had experienced transient episodes of word finding difficulties (anomia) and trouble recognizing faces (prosopagnosia).  She also stated that on the day of presentation to the E.D. she "suddenly felt that her mother was dying, tried to scream out but couldn’t get the words out", collapsed, and later woke up in the E.D.. 
The patient's social history was unremarkable.  She lived with her biological mother, was in 9th grade with excellent grades, was reportedly social with many friends, denied any other stressors aside from the deaths of her grandparents.  No history of physical, sexual or psychological abuse was elicited.  Patient denied substance abuse of any kind. 
Pertinent Mental Status Examination findings (hospital day 2): The patient had fluctuating concentration, was paranoid, guarded and clinging to her mother.  She began cursing when the nurses tried to re-connect her to the EEG monitor, seeming to fear it would harm her.  She was initially uncooperative with the interview but as she watched her mother answer questions, the patient became more involved.  She kept interrupting to correct her mother's reports of her symptoms, but repeatedly needed to re-explain herself and stated she felt her words were not being understood.  As the interview progressed, she stated the word “noise” repeatedly and then became tired and frustrated and refused to try to speak further.
During the admission, the patient had Echocardiogram, EKG, LP, MRI, MRA & various blood chemistries all of which were within normal limits. Over a few days the patient gradually developed ataxia, anomia, and ultimately was essentially mute. At that point she made attempts to write, and could produce single letters but not words, not even her own name.  We attempted to have her utilize a facilitated communication board that uses simple pictures and single words; however, she was seemingly unable to recognize the words or images and pushed it away in frustration.  The Psychiatry team continued to follow the patient for anxiety which was increasing as the medical work-up continued without resolution and her symptoms worsened. Dr. Mehta, the Child Psychiatry Fellow, suggested testing for anti-NMDA receptor encephalitis as she had seen a patient with a similar presentation several months earlier while on Neurology rotation at this same hospital.   NMDA receptor antibody titers were sent on hospital day 7 and were positive.  The patient was thus diagnosed with anti-NMDAR encephalitis.  Further work-up was then completed but did not reveal a tumor.
Objectives: Our aim is to increase awareness among Child Psychiatrists of the relatively new diagnosis Anti–N-methyl-D-aspartate receptor encephalitis (Anti-NMDAR encephalitis). 
Methods: We conducted a literature review on Anti-NMDAR encephalitis.  We present a case report of a patient seen by us as a Psychiatry consult in a tertiary care Pediatrics hospital.
Results: In our review of the literature, we found that almost all of the publications on this disorder were in Neurology journals1,2,3,4,5 and very few in Psychiatry or Child Psychiatry journals.  The first reports of this disorder were published within the past 10 years.1,3 We also found that despite being so recently described, this disorder is being diagnosed with increasing frequency.1  Approximately 85% of cases initially present with change in mental status or acute psychosis.1 Thus, many patients are first seen by a Psychiatrist or within a Psychiatric facility1 and may be initially diagnosed with Conversion, Factitious, or another Psychiatric disorder.  Eventually, neurologic symptoms present, but in atypical fashion.1  Only 55%  of patients had brain MRI findings in initial case series,3 and although this process is often paraneoplastic, no tumor is detected in 41% of patients.3,1 As occurred with our patient, this combination of factors increases the risk of a presumptive yet incorrect Psychiatric diagnosis.  The prognosis for Anti-NMDAR encephalitis is significantly improved with early recognition and initiation of appropriate medical treatment. Increased awareness of the existence of the disorder should decrease incidence of missed or late diagnosis and ultimately improve prognosis for affected patients.
Conclusions: Anti-NMDAR encephalitis is an emerging culprit for the mis-diagnosis of Conversion or Factitious Disorder due to its typical pattern of initial presentation and lack of early findings on standard medical evaluation.
The first large anti-NMDA-receptor encephalitis case series and analysis of the effects of antibodies was published in 2007 by a team from the University of  Pennsylvania.3,1  Several prior reports of single cases or smaller series were published, but our search did not reveal any prior to 2000.  Since those early descriptions of the disease, patients with unexplained neurological symptoms and/or signs with psychiatric manifestations have been increasingly diagnosed with anti-NMDA receptor encephalitis. Most often these patients had first presented to Psychiatrists or Child Psychiatrists.1  Despite this, in our review of the literature, we found that almost all of the publications about this diagnosis were in the Neurology literature with very few publications in Psychiatry and Child Psychiatry journals.  
The disorder often (but not exclusively) affects young women, 1 the same group most likely to be diagnosed with Conversion Disorder. Most patients who ultimately receive this diagnosis are first hospitalized for psychiatric care with diagnoses such as acute schizophrenia, catatonia, drug abuse, conversion disorder, factitious disorder or malingering1,5 It is not until these patients develop seizures, autonomic instability, dyskinesias or a decreased level of consciousness that an organic illness is considered.1 Less frequently, patients present with severe short-term memory deficits resembling limbic encephalopathy.5   Anti-NMDA-receptor encephalitis is paraneoplastic in about 59% of patients, most commonly associated with teratoma of the ovary3,1.  Despite the severity of the disorder, patients often improve with immunotherapy and removal of the teratoma if one is present.3,1 
At this point, the macroanatomical location of the disease process within the CNS has not been determined. MRI findings are present only in 55% and are extremely variable5,3,2. The disturbances in function in affected patients are usually not suggestive of particular CNS anatomical involvement, and very limited neuropathological data are available5,3,2.  Some investigators have obtained brain biopsy of affected patients, but the abnormalities found were non-specific.  The main target of the antibodies is in the extracellular N-terminal domain of the NR1 subunit of the NMDA receptor which decreases the numbers of cell-surface NMDA receptors as well as NMDA-receptor clusters in postsynaptic dendrites3,1.  A main goal of therapy is antibody removal to reverse that process3,1,5,4. Early detection and decrease in antibody titers is associated with greater likelihood of clinical improvement.3,1,4,5 Antibody titer decrease has successfully been achieved using immunotherapy such as corticosteroids, IVIG, and/or plasma exchange3,1,5,4.  Other therapies that have been tried with less success include rituximab, cyclophosphamide, and azathioprine3,1. 
Utility of selected medical tests in diagnosis of anti-NMDAR encephalitis
Test
Utility
Most Common Result
in Anti-NMDAR encephalitis1,3,5,2
EEG
High Yield
Generalized slowing
MRI
Low to Medium Yield
Highly variable
CSF
Leukocyte Pleocytosis
Radiology for tumor detection (U/S, CT, etc.)
Medium Yield
Ovarian Teratoma
Analysis of NMDA receptor antibodies
Highest Yield
Positive for antibodies
METHODS
We conducted a review of the literature on Anti-NMDAR encephalitis and present a case report of a patient who was seen by us on the Child and Adolescent Psychiatry Consultation Service of a tertiary care Pediatrics hospital.
CONCLUSIONS
REFERENCES:
Anti–N-Methyl-D-Aspartate Receptor (NMDAR) Encephalitis in Children and Adolescents. N Florance et al. Ann Neurol July 2009; 66 (1):
Anti-NMDA-receptor encephalitis: a cause of psychiatric, seizure, and movement disorders in young adults. A Vincent, C Bien. The Lancet Neurol Dec 2008; 7(12):
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies. J Dalmau et al.The Lancet Neurol Dec 2008; 7(12):1091–1098.
Reversible limbic encephalitis with antibodies against the membranes of neurons of the hippocampus. H Shimazaki et al. J Neurol Neurosurg Psychiatry Mar 2007;78(3):324-5.
A patient with encephalitis associated with NMDA receptor antibodies. L Sansing et al. Nature Clinical Practice Neurology 2007; 3:
Anti-NMDAR encephalitis initially presents with change in mental status and/or acute psychosis so patients most often present to a Psychiatrist and may be initially diagnosed with Conversion or Factitious Disorder or some other Psychiatric disorder1,2,3,5. 
Neurologic symptoms eventually present but in a fashion not typical of other neurologic illnesses.1   As occurred with our patient, the lack of findings on a thorough medical work-up is a risk for missed or late diagnosis of the actual disorder and incorrect initial diagnosis with a Psychiatric diagnosis such as Conversion Disorder.
While anti-NMDAR encephalitis is newly described, it is highly unlikely that it is a newly existing disease.  As such, we raise the question, just like Multiple Sclerosis prior to the development of MRI technology, could anti-NMDAR encephalitis represent a newly emergent culprit for some indeterminate number of past cases of Conversion or Factitious Disorder?