, Introduction
Anti-N-methyl-ᴅ-aspartate receptor (NMDAR) encephalitis is a rare disease with an estimated incidence of 1.5 per million people per year and was described only 15 years ago in 2007 by Dalmau et al. [1]. The understanding of this disease started a new era in neurology and psychiatry. The proposed pathophysiology of anti-NMDAR encephalitis is thought to involve antibodies against the NR1 subunit of the NMDAR, which causes reversible internalization of the receptor in neurons [2]. Tumors and viral infection are two potential immunologic triggers of anti-NMDAR encephalitis [3]. However, in about half of the patients with anti-NMDAR encephalitis, the immunologic triggers are still unknown. It is hypothesized that the antigen (NMDAR), which may be expressed in ovarian teratomas or released by viral-induced neuronal disruption, is directly transported to the local lymph nodes in soluble form or taken up by antigen-presenting cells. This results in the generation of memory B cells that cross the blood-brain barrier (BBB) and finally differentiate into anti-NMDAR antibody-producing plasma cells [4]. However, there have been reports in the literature that stress can induce anti-NMDAR encephalitis [5-8].
Case Report
Informed consent was taken from the patients for publishing the cases and lab reports.
Case 1
A 16-year-old female sitting her high school exit examination presented with abnormal behavior in the form of agitation and other psychiatric symptoms like anxiety, panic attacks, delusions, and disorganized thinking. This was followed by abnormal movements. She was seen by a psychiatrist and a neurologist; her brain magnetic resonance imaging (MRI) was normal (Figure 1), and the electroencephalography (EEG) done before admission was reported as normal. Her sensorium started to worsen at home, and she reported to emergency. She was having recurrent abnormal movements of the mouth and limbs with encephalopathy. The patient was admitted into the intensive care unit and was intubated. Investigations revealed normal cerebrospinal fluid (CSF); polymerase chain reaction (PCR) was negative for herpes simplex virus. Repeat EEG was normal, though continuous EEG monitoring was not done. In view of the abrupt onset of psychiatric symptoms associated with abnormal limb movements and encephalopathy, a differential diagnosis of anti-NMDAR encephalitis was kept, and anti-NMDAR antibodies in CSF were positive. The assay used for detection was a cell-based assay (indirect immunofluorescence test). She received high-dose intravenous methylprednisolone, intravenous immunoglobulin (IVIG), and multiple antiseizure drugs, and she slowly improved. Ultrasound and computed tomography of the abdomen and pelvis were performed to look for any ovarian teratoma and were normal.
She was put on mycophenolate mofetil and remained in remission for 2 years. At this point, mycophenolate mofetil was stopped. The patient subsequently had a relapse after 6 months, which was precipitated by stress regarding the higher secondary exit examination and was admitted while she was in the midst of examination days. This time she had mania, agitation, hallucination, and sleep disturbances in the form of insomnia. There were no seizures or any movement disorders associated. The patient was conscious, and all of the symptoms were purely psychiatric. Repeat contrast MRI of the brain and CSF were normal. EEG revealed intermittent delta slowing more on the right side. Anti-NMDAR encephalitis antibody was present. She was given intravenous immunoglobulin and went into remission. Subsequently she was started on rituximab and has been in remission since then. Each time she needed management from the psychiatric department and medications for her psychiatric symptoms in the form of atypical antipsychotics and benzodiazepines. A summary of the case is shown in Figure 2.
Case 2
An 18-year-old female with no relevant history presented with a 2-week history of behavioral abnormalities in the form of agitation and abusiveness. There were also other psychiatric features like mania and grandiosity. The patient had sleep disturbances, abnormal body movements of the face and arms, biting of lips, and one episode of loss of consciousness with incontinence. This all started while she was to appear for a pre-entrance examination for a professional course. On clinical examination, there were no localizing or meningeal signs. Contrast brain MRI was normal, and EEG revealed delta slowing in the frontotemporal left more than the right side (Figure 3). Routine CSF was normal, and CSF was negative for herpes simplex virus PCR. An autoimmune encephalitis panel of the CSF revealed anti-NMDAR antibodies. Ultrasound of the abdomen and pelvis and MRI of the pelvis were performed to look for any ovarian teratoma and were normal. The patient received high-dose intravenous methylprednisolone for 5 days but after no recovery received IVIG and later was put on injection rituximab for maintenance. On follow-up, the patient was tapered off from antiseizure medications and antipsychotics. Follow-up brain MRI and EEG were normal. A summary of the case is shown in Figure 4.
Discussion
Neither case had teratoma or herpes simplex virus, the known immunologic triggers for NMDAR encephalitis, while both had emotional stress preceding the illness. These cases along with others previously reported in the literature (described briefly in Table 1) highlight the importance of identifying stress as a trigger for anti-NMDAR encephalitis [5-8]. The clinical presentation of these cases, especially the psychiatric features, is not different from those well described for this disease [9]. These patients had psychiatric features in the form of behavioral change, psychosis, mood disorder, and sleep disturbances, along with seizures and encephalopathy. They did not have other psychiatric features like catatonia, suicidal behavior, eating disorders, or obsessive-compulsive disorder, which are of lesser incidence.
There are two issues which need attention in the backdrop of these cases and similar other cases alluded to above (Table 1) [5-8]. Firstly, as the initial clinical presentation of most anti-NMDAR encephalitis is psychiatric, if a patient presents with a history that symptoms have come during exam stress or any other stress, it is tempting for a physician to make a diagnosis of conversion reaction/functional neurological disorder, especially if the patient is a “young female” with a “normal preliminary workup.” Secondly, it raises the question whether stress is just a bystander in these cases or there is a causal relationship between stress and encephalitis. It is rational to ponder as to what could be the role of stress in triggering encephalitis in such cases.
In both cases, we found that there was a definite reluctance in labeling the constellation of symptoms as organic on the part of the practitioners with whom they had come in contact, and the preceding history of emotional stress seemed to have pushed the clinicians in these instances not to consider organicity and rather consider the symptoms to be of pure psychiatric origin. One of the reasons could possibly be that the link between stress and organic diseases, though it has been discussed, has never been established in a robust way [10].
Coming to the second aspect, humans are at some point during their lives exposed to trauma or significant life stressors. Persons with stress may have alterations in the hypothalamic-pituitary-adrenal (HPA) axis and autonomic nervous system. These disruptions might in turn affect various bodily functions, such as immune function, and thereby result in susceptibility to various diseases [11]. In a Swedish cohort, exposure to a stress-related disorder was significantly associated with increased risk of subsequent autoimmune disease, compared with matched unexposed individuals and with full siblings [12].
Stress has been reported in a high proportion of autoimmune disorders [13]. Various mechanisms have been hypothesized for stress leading to autoimmune diseases, such as stress-induced intestinal barrier disruption at the onset and/or during the course of autoimmune diseases [14]. There are anecdotal reports and studies that reported the association between stress and anti-NMDAR encephalitis, though the mechanism was still not well defined [6-10]. Increased seroprevalence of anti-NMDAR antibodies has been shown in human migrants having chronic stress [15].
Thus, emotional stress has been proposed to trigger immune dysregulation, which ultimately results in anti-NMDAR encephalitis [10]. One of the postulated pathways is based on the altered levels of regulatory T cells (Tregs) in anti-NMDAR encephalitis patients as well as in those with stress [16,17]. The other suggested mechanism is that the preexisting anti-NMDAR antibody in the peripheral blood passes the BBB, the integrity of which gets disrupted under stress [18]. This alteration in permeability of the BBB has been demonstrated in animal models where restraint stress mediates time-dependent alterations in the permeability of the BBB [19]. Furthermore, acute psychosocial stress also has proinflammatory effects mediated by activation of mast cells and is associated with opening of the BBB [20].
Evidence for the crucial role for the microbiota in regulating stress-related changes in physiology, behavior, and brain function has emerged primarily from animal studies. Results from subsequent studies have continued to support a connection between gut microbiota and stress responsiveness, including reports that stress exposure early in life or in adulthood can change the organism’s microbiota composition, and that microbial populations can shape an organism’s stress responsiveness [21]. In a case-control study that looked for gut microbiome changes in anti-NMDAR encephalitis patients, the results showed that abundance and evenness of bacterial distribution was significantly lower and compromised in patients with anti-NMDAR encephalitis than in healthy controls. Hence, their findings were suggestive of an association between gut microbiome composition changes and anti-NMDAR encephalitis, though they could not prove cause and effect [22].
There can therefore be many plausible explanations for stress to trigger NMDAR encephalitis. Stress may lead to change in gut microbiota, which in turn leads to alterations in the HPA axis and immune dysregulation, triggering anti-NMDAR encephalitis in susceptible individuals. Appropriately designed studies can help to establish a link between stress and anti-NMDAR encephalitis. Stress management strategies can be offered to prevent relapses in diagnosed cases of anti-NMDAR encephalitis.
In conclusion, anti-NMDAR encephalitis is a rare disorder caused by immune dysregulation. Apart from known triggers such as tumors and viral infections, stress can be considered as a trigger. Possible mechanisms for stress triggering immune dysregulation are wide-ranging, from alterations in the HPA axis, autonomic nervous system, alteration of permeability of BBB and involvement of Treg cells. Changes in microbiota because of stress, in turn leading to immune dysregulation, is also a cogent mechanism. Furthermore, neuropsychiatric symptoms in the backdrop of a stressful event in life should not be written off as hysterical; anti-NMDAR encephalitis might be a differential diagnosis in appropriate settings. Stress management strategies should be offered to prevent relapses in diagnosed cases of anti-NMDAR encephalitis.
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