|Year : 2021 | Volume
| Issue : 1 | Page : 41-45
Mania with malignant catatonia due to nonpara neoplastic Anti-N-methyl-D-aspartate-Receptor encephalitis in a 29-year-old female – A rare entity
Sunny Garg, Alka Chauhan
Department of Psychiatry, Bhagat Phool Singh Government Medical College for Women, Sonipat, Haryana, India
|Date of Submission||02-Nov-2020|
|Date of Acceptance||13-Dec-2020|
|Date of Web Publication||5-May-2021|
Dr. Sunny Garg
S/O Sh. Suresh Kumar, Garg Machinery Store, Pillu Khera Mandi, Jind - 126 113, Haryana
Source of Support: None, Conflict of Interest: None
Anti-N-methyl-D-aspartate (NMDA) receptor encephalitis is a rare neurological autoimmune encephalitis. Its symptoms may mimic psychosis as this disease is neurological disorder in psychiatric costume. Disparity in clinical symptoms and nonsupportive laboratory investigations except the cerebrospinal fluid (CSF) analysis delays the diagnosis. We presented a case of 29-year-old female with psychiatric symptoms such as suspiciousness, decreased sleep, and boastfulness. Within few days, the patient developed neurological symptoms like seizures, disorientation, while the patient was on antipsychotic and benzodiazepines. Her symptoms worsened and the patient entered into the catatonic phase of the illness along with autonomic instability. We reached a positive diagnosis of Anti-NMDA encephalitis through CSF analysis. The patient recovered completely with the help of immunotherapy and intensive cognitive rehabilitation. This case emphasizes the need of a multidisciplinary approach in the management, early detection, and adequate treatment of this challenging illness for the better outcome of the patient.
Keywords: Anti-N-methyl-D-aspartate encephalitis, cerebrospinal fluid analysis, immunotherapy, malignant catatonia, neuropsychiatric
|How to cite this article:|
Garg S, Chauhan A. Mania with malignant catatonia due to nonpara neoplastic Anti-N-methyl-D-aspartate-Receptor encephalitis in a 29-year-old female – A rare entity. J Sci Soc 2021;48:41-5
|How to cite this URL:|
Garg S, Chauhan A. Mania with malignant catatonia due to nonpara neoplastic Anti-N-methyl-D-aspartate-Receptor encephalitis in a 29-year-old female – A rare entity. J Sci Soc [serial online] 2021 [cited 2022 Aug 15];48:41-5. Available from: https://www.jscisociety.com/text.asp?2021/48/1/41/315444
| Introduction|| |
Anti-N-methyl-D-aspartate receptor (NMDAR) encephalitis is an autoimmune disorder that has been recognized recently in 2005 and can be mistaken for schizophrenia, acute psychosis, catatonia, or substance-induced psychosis. It was first described in 2007 by Dalmau et al. in a women with ovarian teratoma. Anti NMDA antibody formation has been associated with the presence of malignancies such as ovarian teratoma (94%), teratoma of the testis, and small-cell lung carcinoma or in some infections such as mycoplasma, Epstein–Barr virus and varicella-zoster or may be idiopathic, but the initiating event has yet to be identified. Later, some authors described its association with nonpara-neoplastic syndromes. Most of the cases found in children and adolescents and mainly occurring in the female. The exact incidence is unknown as it is a rare diagnosis, with just a few hundred cases reported in the literature.
The clinical presentation of encephalitis has been described in the multi-phasic model, i.e., five stages–prodromal, neurobehavioral, nonresponsive, hyperactive, and gradual recovery stage. The nonspecific prodromal phase is suggestive of viral–flu-like in which fever, malaise, or diarrhea may be prominent. Patients present with neuropsychiatric manifestations within 2 weeks of the prodromal phase. The condition mostly clinically recognized in the psychotic phase, in which agitation, mania, psychosis, anxiety, depression, or disorganized behavior may occur. Following these psychotic symptoms, it may be progressed to neurological symptoms such as complex seizures, catatonia or stupor, dyskinesias, impaired attention or confusion, memory loss or delirium, ataxia along with autonomic instability (fluctuating blood pressure, hypoventilation, tachycardia). However, the overlap of these symptoms in this illness is mostly misdiagnosed as primary psychotic illness and leads to inappropriate treatment. It was observed that Anti NMDAR encephalitis cases did not follow this phasic progression or all symptomatology, thereby complicating the diagnosis. Brain magnetic resonance imaging (MRI) and electroencephalogram (EEG) have been reportedly negative in most of the cases, and diagnosis is based only on cerebrospinal fluid (CSF) analysis.
In the following case report, we discuss a patient who reported to the emergency department with behavioral symptoms and was diagnosed with a case of nonpara-neoplastic Anti NMDAR encephalitis. Only a few publications have published idiopathic or nonpara-neoplastic Anti NMDAR encephalitic cases. There has been growing understanding of the disease process and presentation since its first presentation. Hence, we planned to report this case study.
| Case Report|| |
A 29-year-old married female belonging to urban joint family of middle socioeconomic status without significant past or family history of psychiatric illness and surgical history presented to the emergency department with symptoms of acute onset, characterized by agitation, suspiciousness, talking unusually, boastfulness, over the religiosity, decreased sleep and appetite from the last 4 to 5 days. She was given intramuscular Haloperidol 5 mg and Lorazepam 4 mg to calm her. Then, the patient was admitted in the psychiatry ward. She had fever 10 days before the development of these symptoms, which relieved with some antibiotics and paracetamol at home in 2 days. Initial laboratory studies included complete blood count, liver function test, renal function test with electrolytes, a metabolic panel (blood sugar, thyroid profile, and lipid profile), and viral markers (HIV, anti-HBsAG, and anti-hepatitis B virus) were unremarkable. Her provisional diagnosis was Mania with psychotic symptoms and treated accordingly. Hence, patient was put on tablet olanzapine 5 mg, lorazepam 4 mg, and sodium valproate 1000 mg. On the 4th day of admission, family members reported the worsening of the symptoms in the form of being forgetful, was not making any sense and she was not acting like herself. The patient was so confused in the morning as she was not able to feed her 1-year-old baby. On examination, it was found that the patient was disoriented. Hence, we stopped the treatment and the patient was kept under observation in the psychiatry ward.
Without any further improvement in the confusional state and behavior of the patient, on the 6th day of admission, the patient started having seizures like activity. The patient had multiple episodes in the next 2 days, even after giving repeated injection of lorazepam and institution of antiepileptic (injection phenytoin) in higher doses. On the 8th day, her mental status rapidly worsened, and immediately, medicine consultation was sought. Then, the patient was shifted to the intensive care unit (ICU) for close neurologic monitoring and further workup. Giving concern for viral encephalitis, acyclovir was started empirically along with high dose of antiepileptics. Her vital signs were within the normal limits. Neurological examination was performed and found insignificant. Laboratory studies and urine toxicology were unrevealing of any profound metabolic or toxic disturbances. Imaging like MRI/magnetic resonance angiography of the brain revealed no intracranial or neurovascular lesions. A lumbar puncture was performed for CSF examination, which revealed no abnormality. EEG showed some focal epileptiform discharges which were nonspecific. Viral markers were nonreactive. Hence, acyclovir was stopped. Over the course of the ensuing week, the patient continued to exhibit disorganized behavior and confusional state, but her seizures subsided. After 1 week in ICU i.e., on the 14th day, the patient condition deteriorated further. Within 2–3 days, she became immobile, verbally mute, started staring, refusal to eat or drink orally with some autonomic disturbances (increased blood pressure, heart rate, respiratory rate, and sweating). On the 18th day, psychiatric consultation was solicited. On examination, the patient was found to have posturing, rigidity, waxy flexibility, and negativism. A trial of lorazepam challenge test was done and the patient shown some improvement in these symptoms, which confirmed the malignant catatonia. A nasogastric tube was placed, and parenteral nutrition was started because of poor oral intake.
Due to the absence of previous psychiatric history, the persistence of psychotic and neurological symptoms, and autonomic disturbances, a medical cause of the symptoms was contemplated most likely. At this juncture, the possibility of autoimmune phenomenon was considered. On the 19th day, we were agreed with presumptive Anti-NMDR encephalitis and lumbar puncture was performed. In view of this illness, a 5 days course of intravenous immunoglobulin 0.4 mg/kg was initiated on an empiric basis. On the 24th day, the presence of oligoclonal bands and anti NMDA antibody in CSF confirmed the diagnosis. Meanwhile, a complete oncological screening was done, including the X-ray chest and contrast-enhanced computed tomography abdomen and pelvis, which was insignificant.
On the 25th day, a mild improvement (5%–10%) was experienced in neurological symptoms. Then, a 5 day course of IV methyl-prednisolone 1 g per day followed by 60 mg of oral prednisolone once daily, tablet Quetiapine 100 mg for behavioral symptoms and disturbed sleep through nasogastric tube were given. Injection phenytoin was replaced by tablet Levetiracetam 1000 mg to control the seizures. Over the course of 3 weeks, the patient was seizure-free and showed improvement in behavioral and catatonic symptoms, but she was confused and not following the commands. She attempted simple motor reactions, able to sit with support and started accepting the meals orally. On the 45th day, we noted the first verbal reaction and first emotional reaction in the patient. Then, the patient was shifted to the psychiatry ward from the ICU. On the 60th day, she started recognizing her family members and she stands without any support. After that, intensive psychological treatment like rehabilitation and psychotherapy was started. Then, the patient showed much improvement over a gradual course of 2–3 weeks and doses of methylprednisolone was tapered slowly. Hence on the 80th day, we performed a CSF examination, MRI Brain and EEG, which were within the normal limits and without any anti-NMDA antibody. After 84 days of hospitalization, the patient was discharged in good condition with residual memory deficit. We continued the follow-up of the patient with tablet quetiapine (100 mg), levetiracetam (1000 mg), methylprednisolone (30 mg), and lorazepam (1 mg). On the next follow-up after the 1 month of discharge at the psychiatry outpatient unit, the patient was described as continuing to improve in terms of cognitive and functional areas. Hence, we again decreased the doses of prescribed medications. At her latest psychiatry follow-up, 8 months after her discharge patient presented with a normal neurological and psychological profile and used to take care of her children and doing household work and all medications were successfully withdrawn.
| Discussion|| |
Our case presented initially with psychiatric symptomatology, seizures, fluctuations in mental status, then complicated by malignant catatonia with autonomic instability, which was idiopathic in nature. Herken and Pruss have described that “yellow flag” and “red flag” symptoms that are particularly indicative of autoimmune process. Index case fulfilled these criteria and was diagnosed as Anti NMDAR encephalitis.
Our patient presented with a prodromal period of 10 days. Kayser and Dalmau also described that 70% of the patients present with the prodromal period, averaging 5 days but up to 2 weeks. NMDARs play a central role in synaptic transmission, helping in memory, cognition, and learning modulation. The antibodies in Anti-NMDA encephalitis is directed against an epitope on the NR2A/B subunit of the NMDA receptor in the hippocampus and frontotemporal regions. There is a blockade of NMDA glutamate receptor, which removes the GABAergic inhibition, followed by the release of acetylcholine and glutamate, which causes neurotoxicity and psychosis in the patients. It also results in the development of seizures and deficits in memory and learning. Patients' sequelae may be due to the involvement of frontotemporal and limbic regions and their dysfunctions.
It was presumed that the use of antipsychotics helpful in treating the symptoms of psychosis. With the use of antipsychotics, patients are more vulnerable to side effects like neuroleptic malignant syndrome (NMS). In the case of autoimmune encephalitis, it is very difficult to distinguish that symptoms have occurred is a part of natural disease or due to NMS. In addition, worsening of disease occurred with antipsychotics before the use of immunomodulatory agents, may be the potential feature of the disease process., Same happened in the index case, where we found that in the initial phases of the illness, antipsychotics worsened the symptoms, and the patient started having confusion and seizures, so we stopped the antipsychotic (olanzapine). There were multiple studies suggesting the use of benzodiazepines, mainly lorazepam helpful in treating aggression and agitation with or without catatonic features. Unfortunately, the presence of autonomic instability can complicate the use of benzodiazepines, and benzodiazepines may cause or worsen delirium, inhibition, and cause excessive sedation.
EEGs generally reveal nonspecific abnormalities such as diffuse slowing in 90% of the patients. EEGs may reveal extreme versions of “delta brush pattern” which are transient and appears to be unique to anti NMDAR encephalitis. However, it was only seen in 7 out of 23 patients in a study by Schmitt and colleagues., EEG showed some focal or lateralizing epileptiform discharges which were nonspecific in our patient. So EEG was not a diagnostic entity in our study like other studies in the literature., Brain MRI has been reportedly negative in 50%–70% of the cases. Brain MRI studies are normal or show transient fluid-attenuated inversion recovery or contrast-enhancing abnormalities. In our case, MRI was normal consistent with other studies., Serum anti-NMDAR antibodies assays are not as sensitive as CSF assays (sensitivity 98.8% vs. 85.6%). CSF studies show lymphocytic pleocytosis, increased protein, and oligoclonal bands in 60% of the patients. In our study, serum analysis was negative. We found oligoclonal bands and anti-NMDA antibody during CSF analysis, which was consistent with reported cases in the literature.,
Treatment is challenging in idiopathic cases as full recovery is rather slow (1–18 months). Immunotherapy (immunoglobulins, methylprednisolone, and plasma exchange) is the first-line therapy with or without the tumor. More than 50% of patients improve with immunotherapy (either single or in combination) within 1 month. If the patient shows no or minimal response with first-line therapy then initiate the second line of therapy, which includes the immunosuppression such as rituximab, cyclophosphamide, or azathioprine. These therapies help in preventing hippocampal damage. Dalmau et al. suggested that concurrent use of immunoglobulins and methylprednisolone had better outcomes than plasma exchange like in our case. Second-line therapy was not required in our case as the patient showed good recovery with immunotherapy. Along with immunotherapy we used the antipsychotics (quetiapine) to control the behavior and sleep because side effect profile like NMS is rarely associated with quetiapine.
Electroconvulsive therapy (ECT) has been found to be very effective in treating malignant catatonia and autonomic instability in patients who failed to response with aggressive immunotherapy or benzodiazepines or mainly in idiopathic cases. The combination of other form of treatment with ECT may resolve the life-threatening condition, and their efficacy may be synergistic. In our case, ECT was discussed but postponed due to the predominant signs of acute encephalitis.
Approximately 75% of patients achieve full recovery or continue to have mild deficits and 25% of patients have severe disability with 4%–7% mortality rate. Some studies suggest 12%–24% chance of relapse after many years, mainly in idiopathic cases or in the cases in which immunotherapies were not used during their treatment. A study by Titulaer et al. found that 97% of the patients had better outcomes within 24 months. However, our patient shown a full recovery within 8 months of initial presentation. Despite the aggressive symptomatology and admission to ICU care, our patient had a better outcome within a short period as we diagnosed the illness within 1 month of initial presentation and then started the treatment (immunotherapy) without any delay.
To summarize, Anti NMDAR Encephalitis is a serious and potentially lethal syndrome of psychiatric and neurological dysfunctions. Diagnosis is challenging because it is mostly confused with psychotic disorders. Gradually, its diagnosis or recognition is increasing day by day as psychiatrists and physicians are aware of the condition and its presentation. The antipsychotics should be used with caution. The recommendation is to do the screening for ovarian teratoma for the next 2 years using MRI and ultrasound of the abdomen and pelvis even if the patient has recovered from the encephalitis. The present case demonstrates the appropriate need for psychiatrists, neurologists, and other emergency physicians to become aware of this under-diagnosed disorder and consider it in their differential diagnosis.
Declaration of patient consent
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient has given her consent for her images and other clinical information to be reported in the journal. The patient understands that her name and initial will not be published and due efforts will be made to conceal her identity, but anonymity cannot be guaranteed.
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Conflicts of interest
There are no conflicts of interest.
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