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 Table of Contents  
Year : 2021  |  Volume : 7  |  Issue : 1  |  Page : 66-69

Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis with subclinical hyperthyroidism associated with thyroid antibodies

1 Department of Psychiatry, Alluri Sitarama Raju Institute of Medical Sciences, West Godavari, Andhra Pradesh, India
2 Department of Neurology, Alluri Sitarama Raju Institute of Medical Sciences, West Godavari, Andhra Pradesh, India

Date of Submission17-Apr-2021
Date of Decision18-May-2021
Date of Acceptance22-May-2021
Date of Web Publication18-Jul-2021

Correspondence Address:
Dr. Sukeerthi Busi
H. NO: 1-3-204, Suneetha Nilayam, Near Indira Market, Sirpur Kagaznagar, Komaram Bheem - 504 296, Telangana
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/tjp.tjp_15_21

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Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an autoimmune disorder with neuropsychiatric symptoms. It is most often misdiagnosed initially as a primary psychiatric disorder. Young women in the background of ovarian teratomas, viral infections are most commonly impacted. Recently, the coexistence of anti-thyroid antibodies with anti-NMDAR antibodies in nonparaneoplastic anti-NMDAR encephalitis has come to light. A 32-year-old married female presented with sudden onset of disruptive and ritualistic behavior, decreased need for sleep, preceded by spikes of high-grade fever, chills, and rigor. Later, she developed episodes of catatonia alternating with spontaneous speech associated with shouting and crying spells. Blood investigations (except for hyperthyroidism and anti-thyroid antibodies), brain imaging, electroencephalogram, and cerebrospinal fluid (CSF) analysis were normal. She was treated with lorazepam (to a maximum of 16 mg), antipsychotics, antidepressants, anticonvulsants, dopaminergic, and steroid drugs with no significant improvement. CSF analysis was repeated for the encephalitis panel and revealed anti-NMDAR encephalitis. The patient was started with intravenous immunoglobulin for 5 days which led to significant clinical improvement. Screening for encephalitis is considered necessary in patients with altered behavior, not responding to symptomatic psychotropic and neurological treatments.

Keywords: Anti-N-Methyl-D-aspartate receptor, catatonia, encephalitis

How to cite this article:
Busi S, Kadiyala PK, Pushparaju N. Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis with subclinical hyperthyroidism associated with thyroid antibodies. Telangana J Psychiatry 2021;7:66-9

How to cite this URL:
Busi S, Kadiyala PK, Pushparaju N. Nonparaneoplastic anti-N-methyl-D-aspartate receptor encephalitis with subclinical hyperthyroidism associated with thyroid antibodies. Telangana J Psychiatry [serial online] 2021 [cited 2021 Dec 2];7:66-9. Available from: http://www.:tjpipstsb.org/text.asp?2021/7/1/66/321765

  Introduction Top

Anti-N-methyl-D-aspartate receptor (Anti-NMDAR) encephalitis is a rare autoimmune encephalitic syndrome with an incidence of 1.5 per million per population per year. It occurs predominantly in younger women with a female-to-male ratio of 8:2. The median age group of presentation is 21 years (ranging from <1 year to 85 years).

We managed a young female who presented with fever and abnormal behavior at onset, followed by catatonia. All relevant investigations, including magnetic resonance imaging (MRI) brain, electroencephalogram (EEG), and cerebrospinal fluid (CSF) analysis at admission were normal, except the thyroid abnormalities. We treated with benzodiazepines, psychotropics, anti-epileptics, and steroids with no improvement. Repeat CSF analysis identified NMDAR encephalitis, and treatment with intravenous immunoglobulins (IVIG) showed a good response. The case report highlights the importance of repeat CSF analysis for autoimmune etiology, especially when not responding to symptomatic treatment.

Dalmau et al., first described Anti-NMDA encephalitis in 2007among women with ovarian teratomas who presented with neuropsychiatric symptoms.[1] Individuals with Anti-NMDAR encephalitis usually have CSF IgG antibodies against NMDARs. These antibodies are directed against an epitope found on the NR1 (NMDA receptor-1) subunit, primarily in the brain regions of frontotemporal and hippocampal areas.[1],[2] NMDARs play a crucial role in synaptic transmission in modulating human memory, cognition, learning, and neuronal plasticity.[1] The activity of the NMDAR is affected not only by several exogenous substances (ketamine, ethanol) but also endogenous brain immune interactions that result in tremendous clinical consequences.[2]

Ovarian teratomas and viral infections can also trigger autoimmune reactions. In literature, ovarian teratomas constitute 94% of all neoplasms responsible for anti-NMDAR encephalitis.[3] However, later studies reported anti-NMDAR encephalitis is not exclusively paraneoplastic. Lately, several case reports and studies from literature search have highlighted the coexistence of anti-thyroid antibodies with anti-NMDAR antibodies in nonparaneoplastic anti-NMDAR encephalitis. Among the case reports positive for thyroid autoantibodies, the clinical picture is mostly hyperthyroidism, with a few cases presenting as hypothyroidism.[4],[5]

The clinical course of anti-NMDAR encephalitis is characterized by five stages constituting prodromal, neuro-behavioral, nonresponsive, hyperactive, and gradual recovery.[6] Early presentation is with flu-like symptoms such as headache, fever, followed by an acute psychotic presentation with abnormal behavior, insomnia, and irritability. In later stages, individuals show decreased verbal output or mutism, fluctuating catatonia, autonomic instability, and seizures. The presentation varies from individual to individual.[7] The typical clinical syndrome is usually neuropsychiatric in nature; however, occasional cases present with primary psychiatric manifestations, typically with catatonia.[8]

Early identification and intervention are paramount in its management. Although MRI brain, EEG, and CSF analysis are abnormal, the changes are not specific to this disease entity. Brain MRI is normal in 50% of all cases, and abnormal MRIs commonly show T2-weighted or FLAIR hyperintensities in cortical or subcortical brain regions, sometimes with mild or transient contrast enhancement.[1],[3],[9],[10] EEG findings are usually abnormal, and in some patients, a specific EEG phenomenon, the so-called “extreme delta brush,” has been observed.[1],[10] CSF findings are abnormal in ~60% of cases, with moderate lymphocytic pleocytosis and elevated protein, as well as oligoclonal bands. Firm diagnosis is made by demonstrating that CSF and/or serum antibodies against NMDA receptors. Paired serum and CSF sample has been found to be more beneficial for detection than either sample alone.[1],[7],[9],[10]

Management is the prompt use of immunotherapy and tumor resection. First-line immunotherapy is with IVIG, corticosteroids, or plasmapheresis. If there is partial or no response, treatment is with second-line therapy of cyclophosphamide or rituximab.[3],[9],[10] After recovery, some recommend continued immunosuppression for at least 1 year in view of relapses and periodic screening for ovarian teratoma for up to 2 years.[3]

  Case Report Top

A 32-year-old married female presented to the emergency department with spikes of high-grade fever for 2 weeks, followed by 1 week of abnormal behavior. The behavior was characterized by abrupt onset of shouting, excessive talking about and praising God, increased energy, decreased need for sleep, and difficulty recognizing her family members. She had no previous history of psychiatry or neurological illness; however, had a family history of suicide in her father. She was admitted to a nearby psychiatric hospital, where lorazepam and haloperidol injections were started. On the 3rd day of her admission, she had high-grade fever with chills and rigor lasting for a day. As the febrile episode subsided, she became drowsy and nonresponsive to a painful stimulus. Then, she was given one session of Electroconvulsive therapy with no response.

She was referred to our institution with signs of mutism, negativism, gegenhalten, and posturing with Bush-Francis Catatonia Rating Scale (BFCRS) score 21. Her Glasgow coma scale score was seven, without any focal neurological deficits. The lorazepam challenge test resulted in disorganized and agitated behavior. Laboratory workup of complete blood picture, random blood sugar, serum electrolytes, renal function test, liver function test creatine kinase, CSF analysis, MRI brain, and EEG were within the normal limits with mild elevation of T4 (15.41 μg/dl). She was provisionally diagnosed with Catatonia/Acute and Transient Psychotic Disorder and was started on lorazepam. She had fluctuating episodes of agitated behavior and catatonia with visual tracking at times and often staring (BFCRS-18). She also developed spontaneous episodes (~5–6 per day) of abnormal flickering movements of eyelids, involuntary movements of the upper limbs and head, each episode lasting for few minutes. The dosage of lorazepam was gradually increased to 16 mg and augmented with escitalopram, aripiprazole, levodopa, trihexyphenidyl, modafinil, and anti-epileptics after liaison with the neurologist.

As there was no improvement in her condition, neuropsychiatric disorder secondary to autoimmune was considered. Steroids were given empirically with no improvement. CSF analysis was repeated for autoimmune encephalitis panel, which revealed elevated protein (47 mg/dl), glucose (87 mg/dl), and showed positive for anti-glutamate receptor against NR1 subunit (NMDA). Repeat thyroid function test showed elevated T4 (19.28 μg/dl), anti-thyroglobulin-42.7 IU/ml, and anti-thyroid peroxidase-53.2 IU/ml. Ultrasonography abdomen and pelvis findings, cancer antigen 125, carcinoembryonic antigen ruled out ovarian teratomas, and other carcinomas. By the 5th day of steroids administration, after obtaining the positive report for anti-NMDAR encephalitis, the patient was given IVIG for 5 days. Carbimazole was added to control hyperthyroidism. Her condition improved after 2 days of IG administration. She responded initially by making eye contact with verbal stimuli and showed a gradual decline of involuntary movements. Gradually the symptoms of catatonia (BFCRS-8) and agitation declined. By the completion of therapy, she started communicating and able to do her daily activities and was then discharged. All psychotropics and carbimazole were tapered on follow-up, on regaining the euthyroid state. She is on a regular follow-up to date with no relapse of symptoms [Figure 1]
Figure 1: Course of illness

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  Discussion Top

Our case report describes a female patient with anti-NMDAR encephalitis with primary psychiatric (catatonia) followed by neurological manifestations, which have not resolved with symptomatic psychotropics and neurological treatment. She has no teratomas; however, has thyroid antibodies with hyperthyroidism. She has responded well to immunoglobulin with symptomatic recovery in the reverse order of presentation.

Many case reports have described an apparently milder and earlier phase of NMDAR encephalitis, misdiagnosed as a primary psychiatric illness, with no response to psychotropic treatment. It is often associated with paraneoplastic syndromes, mostly from ovarian teratomas.[9] However, cases with the nonparaneoplastic origin of anti-NMDAR encephalitis are increasingly spotted in recent times. The association of autoimmune thyroiditis presenting as hyperthyroidism, as a potential etiology of autoimmune encephalitis, has recently been emerging.[4],[5]

Immunotherapy or plasmapheresis is the mainstays of treatment.[5] Recovery is a multistage process that occurs in the reverse order of symptom appearance. Patients should have a prolonged follow-up for at least 1 year. Approximately 50% of patients achieve full recovery, and 46% of patients continue to have mild-to-severe deficits.[10]

  Conclusion Top

Any acute presentation of psychiatric illness with no clinically significant neurological signs and laboratory findings initially has to be reviewed again if there is no remarkable improvement with psychiatric medications. The knowledge of the varying presenting symptoms, course of illness, and epidemiological factors associated with NMDA encephalitis is vital for practice for its accurate management. Thyroid antibodies may be checked before or along with the CSF encephalitis panel as a higher incidence of NMDAR encephalitis in patients with autoimmune thyroid antibodies has been observed.[4],[5]

Informed consent

Informed consent was obtained from the patient and caretakers for educational use and no personal patient information has been disclosed.

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 understand that name and initials will not be published and due efforts will be made to conceal identity, but anonymity cannot be guaranteed.

Financial support and sponsorship


Conflicts of interest

There are no conflicts of interest.

  References Top

Dalmau J, Armangué T, Planagumà J, Radosevic M, Mannara F, Leypoldt F, et al. An update on anti-NMDA receptor encephalitis for neurologists and psychiatrists: Mechanisms and models. Lancet Neurol 2019;18:1045-57.  Back to cited text no. 1
Hughes EG, Peng X, Gleichman AJ, Lai M, Zhou L, Tsou R, et al. Cellular and synaptic mechanisms of anti-NMDA receptor encephalitis. J Neurosci 2010;30:5866-75.  Back to cited text no. 2
Bhat P, Ahmed A, Jolepalem P, Sittambalam C. A case report: Anti-NMDA receptor encephalitis. J Community Hosp Intern Med Perspect 2018;8:158-60.  Back to cited text no. 3
Jung Y, Park S, Son HJ, Jung DS, Sa EH, Lee ST, et al. Thyroid autoantibody positive anti-n-methyl-d-aspartate receptor encephalitis. Dement Neurocogn Disord 2016;15:24-7.  Back to cited text no. 4
Khoodoruth MAS, Chut-Kai Khoodoruth WN, Alshawwaf MKM. Anti-N-methyl-D-aspartate receptor encephalitis in a young female with subclinical hypothyroidism associated with anti-thyroid peroxidase and anti-thyroglobulin antibodies: A case report. SAGE Open Med Case Rep. 2020 Aug 21;8:2050313X20949780. doi: 10.1177/2050313X20949780. PMID: 32913651; PMCID: PMC7443984.  Back to cited text no. 5
Mythri SV, Mathew V. Catatonic syndrome in Anti-NMDA receptor encephalitis. Indian J Psychol Med 2016;38:152-4.  Back to cited text no. 6
  [Full text]  
Maneta E, Garcia G. Psychiatric manifestations of anti-NMDA receptor encephalitis: Neurobiological underpinnings and differential diagnostic implications. Psychosomatics 2014;55:37-44.  Back to cited text no. 7
Endres D, Rauer S, Kern W, Venhoff N, Maier SJ, Runge K, Süß P, Feige B, Nickel K, Heidt T, Domschke K. Psychiatric presentation of anti-NMDA receptor encephalitis. Frontiers Neurol 2019;10:1086.  Back to cited text no. 8
Kayser MS, Dalmau J. The emerging link between autoimmune disorders and neuropsychiatric disease. J Neuropsychiatry Clin Neurosci 2011;23:90-7.  Back to cited text no. 9
Ford B, McDonald A, Srinivasan S. Anti-NMDA receptor encephalitis: a case study and illness overview. Drugs in context. 2019;8.  Back to cited text no. 10


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