Psychiatric-Medical ComorbidityManagement of psychiatric symptoms in anti-NMDAR encephalitis: a case series, literature review and future directions
Introduction
Anti-NMDA receptor (NMDAR) encephalitis, formally recognized in 2007, has been increasingly identified as a significant cause of autoimmune and paraneoplastic encephalitis [2]. The exact incidence is unknown. Approximately 80% of the patients are females [3]. The characteristic syndrome evolves in several stages, with approximately 70% of the patients presenting with a prodromal phase with fever, headache and malaise; typically, within 2 weeks, patients develop psychiatric symptoms. Catatonic symptoms, seizures, abnormal movements, memory deficits, speech abnormalities, autonomic instability, central hypoventilation, cerebellar ataxia and hemiparesis may also develop during the course of the disease [5]. Abnormal magnetic resonance imaging (MRI), electroencephalography (EEG) and cerebrospinal fluid (CSF) findings were noted in 33%, 90% and 79% of the patients with anti-NMDAR encephalitis, respectively [5]. Presences of antibodies against the GluN1 subunit of the NMDAR in the CSF and/or serum confirm the diagnosis of NMDAR encephalitis, which also should prompt a thorough search for an underlying tumor [2], [3], [4]. Age, gender and ethnicity may all play a role, as Asian and African American females older than 18 years of age have an increased likelihood of an underlying tumor, most commonly teratoma [2], [3], [5], [32]. Treatment is focused on tumor resection and first-line immunotherapy (corticosteroids, plasma exchange and intravenous immunoglobulin). In nonresponders, second-line immunotherapy (rituximab or cyclophosphamide or combined) is required [3]. More than 75% of the patients recover completely or have mild sequelae, while the remaining patients demonstrate persistent severe disability or death [3]. There is a paucity of literature on the management of psychiatric symptoms in this population. We describe two patients diagnosed with NMDAR encephalitis presenting with different psychiatric manifestations. The first patient presented with psychotic mania and catatonic symptoms sensitive to some antipsychotics, while the second suffered from depression with psychotic and catatonic features refractory to psychotropic medications. We review of the use of psychotropic medications and electroconvulsive therapy (ECT) to address insomnia, agitation, psychosis, mood dysregulation and catatonia in NMDAR encephalitis.
A 35-year-old Caucasian male with no psychiatric history presented with prodromal symptoms of fever and night sweats followed by a two week course of confusion, bizarre behavior, depression and suicidal ideation. He exhibited illogical speech, tangential thoughts, emotional lability and grandiosity. He demonstrated catatonic symptoms of mutism, impulsivity, posturing, hypoactivity, staring and poor eye contact. Computed tomography of the head, lumbar puncture, MRI of the brain, MR venogram of the brain, electroencephalography (EEG), paraneoplastic panel, urine and blood cultures, HIV, West Nile virus, rapid plasma reagin, erythrocyte sedimentation rate, complete blood count, heavy metals, thyroid-stimulating hormone, electrolyte panel and urine tox screens were all within normal limits. Subsequently, he received a 6-day trial of olanzapine. He then developed muscle stiffness, slurred speech, drooling, catatonic posturing and vomiting. Cessation of olanzapine and a trial of lorazepam 1–2 mg q2h prn led to clinical improvement.
Upon admission to our facility, he continued to display behavioral disinhibition, hypersexuality, poor sleep and appetite. He demonstrated mutism, stared, displayed ambitendency and had periods of impulsivity but was largely hypoactive. He was provided lorazepam 1 mg three times per day to treat his catatonic symptoms, and his speech improved.
An extensive medical workup revealed unremarkable results. Following confirmation of NMDA antibodies positive in both serum and CSF fluid, he received a 5-day course of iv methylprednisolone with mild clinical improvement. The patient then underwent a course of plasma exchange (PLEX) and transitioned to oral prednisone and azathioprine. Secondary to erotomania and behavioral dyscontrol, he was initiated on quetiapine 25 mg bid. He improved in terms of both behavior and mentation. He was discharged on quetiapine 25 mg twice a day and lorazepam 1 mg three times a day as needed. Four months later, he reported resolution of symptoms and a return to his prior functioning.
A 30-year-old woman was admitted to an outside facility for depression with suicide attempt, abdominal pain, nausea, vomiting, intermittent fevers and an unintentional 20-lb weight loss in 2 months. She was recently initiated on desvenlafaxine 50 mg XR po daily for depression and lorazepam 1 mg prn for anxiety. Despite multiple medication trials including sertraline, ziprasidone, quetiapine, olanzapine and valproic, she continued to deteriorate, displayed disinhibition, engaged in self-injurious behaviors, and had hallucinations and delusions. She displayed catatonic symptoms such as mutism, rigidity, posturing, stupor, staring, negativism, withdrawal, autonomic abnormality and combativeness. She was transferred to the Mayo Clinic for further management. All laboratory investigations and imaging were negative. CSF paraneoplastic antibody panel was positive for NMDA Ab.
She received methylprednisolone 1 g for 5 days and initiated on lorazepam 1 mg tid with minimal clinical improvement. She proceeded to have seizure-like activity and was loaded with levetiracetam. EEG monitoring revealed clinical seizures which were managed with levetiracetam 1500 mg bid and valproic acid 500 mg bid.
She was transitioned to oral prednisone 60 mg daily, received seven sessions of PLEX and had minimal improvement. She was started on iv immunoglobulin (IVIG) 0.4 mg/kg for 3 days and was discharged home with plans to continue prednisone 60 mg daily, weekly IVIG infusion × 8 weeks and weekly rituximab infusion × 4 weeks. Agitation was treated with olanzapine 5 mg bid prn.
Following discharge, she missed a dose of IVIG and rituximab, refused therapy and assaulted a staff member during an outpatient visit. She was rehospitalized and started on a 3-day course of IVIG with plan to continue the infusion weekly for 7 more weeks along with rituximab with plan to continue the weekly infusion × 3 weeks, as outpatient EEG revealed some mild diffuse nonspecific slowing of the background but no potentially epileptogenic activity. We recommended scheduled olanzapine 2.5 mg daily, 5 bid as needed. In 4 days, she returned to her baseline.
Section snippets
Discussion
Glutamate is the major excitatory neurotransmitter distributed throughout the brain, and glutamate receptors are of two types: inotropic receptors (NMDA, AMPA, kainate), which are ligand-gated cation channels, and metabotropic receptors, which are G-protein-coupled receptors [25]. Of these receptors, NMDA receptors have been studied more extensively given its significant role in normal central nervous system development, neuroplasticity, learning, memory and human behavior. NMDA receptors are
Psychotic symptoms and agitation
The psychotic symptoms often include delusions, hallucinations and aggression. Both typical and atypical antipsychotics have been used either alone or in combination to manage these symptoms [7]. Typical antipsychotics, especially highly potent dopamine antagonists like haloperidol, can cause extrapyramidal symptoms (EPS) including akathisia, dystonia and tremors, which can worsen agitation [14]. Extrapyramidal symptoms can also confound the picture and mimic the dyskinesias resulting from the
Mood symptoms
Mood lability and mania have been reported more frequently than depression. Mood stabilizers like lithium [1], [12] and valproic acid [1] have been used to treat manic symptoms; the latter confers the additional benefit of increased sedation, sleep and seizure prophylaxis/ treatment and can be administered intravenously if needed. Augmentation with benzodiazepines can also be considered. Sleep disturbances, especially insomnia, are usually managed with benzodiazepines, trazodone, melatonin and
Catatonic symptoms
Catatonic symptoms including mutism, withdrawal, staring, posturing and negativism associated with both affective and psychotic symptomatology have been reported. While benzodiazepines remain the first line of choice to treat the catatonic symptoms [18] it would also help with sleep and aid in prophylactic treatment of seizures. Antipsychotic use in catatonia is controversial because it could precipitate NMS.
In several case reports, the use of ECT has demonstrated improvement in psychotic and
Future directions
While psychotropic medications have been used for management of psychiatric symptoms associated with NMDAR encephalitis, response may be limited, and their role in increasing glutamate and GABA neurotransmission as an adjunct to immunotherapy has not been explored. The NMDA hypofunction in schizophrenia is slightly different from that in anti-NMDAR encephalitis in that there is a reversible loss of surface NMDAR in the latter. Small clinical trials using direct glycine receptors agonists like
References (44)
- et al.
Anti-NMDA-receptor encephalitis: case series and analysis of the effects of antibodies
Lancet Neurol
(2008) - et al.
Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis
Lancet Neurol
(2011) - et al.
Anti-NMDA receptor encephalitis. The disorder, the diagnosis and the immunobiology
Autoimmun Rev
(2012) - et al.
Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study
Lancet Neurol
(2013) - et al.
Paraneoplastic encephalitis presenting as postpartum psychosis
Psychosomatics
(2011) - et al.
Psychiatric manifestations of anti-NMDA receptor encephalitis in a man without tumor
Psychosomatics
(2011) - et al.
Differential effects of electroconvulsive shock on the glutamate receptor mRNAs for NR2A, NR2B and mGluR5b
Brain Res Mol Brain Res
(1998) - et al.
Positive modulation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors reverses sub-chronic PCP-induced deficits in the novel object recognition task in rats
Behav Brain Res
(2010) - et al.
Alpha 2 adrenergic agonists prevent MK-801 neurotoxicity
Neuropsychopharmacology
(1995) - et al.
Olanzapine and fluperlapine mimic clozapine in preventing MK-801 neurotoxicity
Schizophr Res
(1996)
Differential effects of clozapine and haloperidol on ketamine-induced brain metabolic activation
Brain Res
NMDA receptor hypofunction model of schizophrenia
J Psychiatr Res
Anti-NMDA receptor encephalitis: diagnosis, psychiatric presentation, and treatment
Am J Psychiatry
Anti-NMDA receptor encephalitis: an important differential diagnosis in psychosis
Br J Psychiatry
Abnormal glutamate receptor expression in the medial temporal lobe in schizophrenia and mood disorders
Neuropsychopharmacology
From revolution to evolution: the glutamate hypothesis of schizophrenia and its implication for treatment
Neuropsychopharmacology
Electroconvulsive therapy can improve psychotic symptoms in anti-NMDA-receptor encephalitis
Psychiatry Clin Neurosci
Glutamate involvement in schizophrenia: focus on N-methyl-d-aspartate receptors
Primary Psychiatry
Anti-N-methyl-d-aspartate receptor encephalitis presenting with acute psychosis in a preteenage girl: a case report
J Med Case Rep
Anti-NMDA receptor encephalitis with associated catatonia during pregnancy
J Neurol
Activation of glutamatergic neurotransmission by ketamine: a novel step in the pathway from NMDA receptor blockade to dopaminergic and cognitive disruptions associated with the prefrontal cortex
J Neurosci
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