<%server.execute "isdev.asp"%> Anti-N-methyl-<sc>d</sc>-aspartate receptor encephalitis: A case series and review of the literature John CM, Mathew DE, Abdelaziz M, Mahmoud AA, AlOtaibi AD, Sohal AP - J Pediatr Neurosci
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REVIEW ARTICLE
Year : 2019  |  Volume : 14  |  Issue : 4  |  Page : 180-185
 

Anti-N-methyl-d-aspartate receptor encephalitis: A case series and review of the literature


1 Angels Speciality Clinic, Chennai, Tamil Nadu, India
2 Apollo Speciality Hospital, Chennai, Tamil Nadu, India
3 St Helens and Knowsley NHS Trust, Prescot, United Kingdom
4 National Neuroscience Institute, King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
5 King Fahad Medical City, Riyadh, Kingdom of Saudi Arabia
6 Neuropedia Children's Neuroscience Center, Dubai, United Arab Emirates

Date of Submission12-Jun-2019
Date of Acceptance04-Sep-2019
Date of Web Publication05-Dec-2019

Correspondence Address:
Dr. Cheri M John
Angels Speciality Clinic, AL-190, 1st Street, 12th Main Road, Anna Nagar, Chennai 600040, Tamil Nadu.
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/jpn.JPN_83_19

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   Abstract 

Anti-NMDAR (N-methyl-d-aspartate receptor) encephalitis is a potentially severe form of encephalitis associated with antibodies against NR1 and NR2 subunits of the NMDAR. Anti-NMDAR encephalitis is a treatable cause of encephalitis. An underlying tumor should be actively looked for as this is also considered to be a paraneoplastic syndrome. We report two children with anti-NMDAR encephalitis with a literature review of current evidence in diagnosing and managing this rare condition. Resection of the tumor, glucocorticoids, intravenous immunoglobulin, and plasma exchange often result in improvement, usually within four weeks. Outcome corresponds with the rapidity of commencing appropriate treatment.


Keywords: Encephalitis, N-methyl-d-aspartate, N-methyl-d-aspartate receptor


How to cite this article:
John CM, Mathew DE, Abdelaziz M, Mahmoud AA, AlOtaibi AD, Sohal AP. Anti-N-methyl-d-aspartate receptor encephalitis: A case series and review of the literature. J Pediatr Neurosci 2019;14:180-5

How to cite this URL:
John CM, Mathew DE, Abdelaziz M, Mahmoud AA, AlOtaibi AD, Sohal AP. Anti-N-methyl-d-aspartate receptor encephalitis: A case series and review of the literature. J Pediatr Neurosci [serial online] 2019 [cited 2020 Apr 3];14:180-5. Available from: http://www.pediatricneurosciences.com/text.asp?2019/14/4/180/272365





   Introduction Top


Anti-NMDAR (N-methyl-d-aspartate receptor) encephalitis is a potentially severe form of encephalitis associated with antibodies against NR1 and NR2 subunits of the NMDAR. It is important to recognize that anti-NMDAR encephalitis is a treatable cause of encephalitis. Patients with anti-NMDAR encephalitis have a constellation of symptoms that are recognizable to doctors familiar with the condition. Although increasingly diagnosed, it is still relatively rare in childhood. Antibodies produced by the body’s own immune system attack NMDARs in the brain. NMDARs are proteins that control electrical impulses in the brain. The underlying reasons why anti-NMDAR antibodies are formed in the first place is yet to be elucidated.

We report two children with anti-NMDAR encephalitis with a literature review of current evidence in diagnosing and managing this rare condition.

Case 1

A previously healthy 13-year-old girl presented to her local Emergency Department (ED) with a history of fever for five days associated with loss of appetite. She was provisionally diagnosed as having an upper respiratory infection and had been prescribed oral antibiotics. She was born at full term to non-consanguineous parents after an uneventful pregnancy by normal delivery. Her growth and development were age appropriate. She had three healthy siblings. A paternal uncle had been diagnosed with Hashimoto’s thyroiditis.

Two days after being sent home from ED, she re-presented with changes in behavior that included anxiety and insomnia. She was admitted for observation and evaluation. She had marked changes in her level of alertness with periods of agitation and appearance of orofacial and lingual dyskinesias following which focal seizures with impairment of level of consciousness ensued. She had presented in another facility where she had been started on phenytoin and carbamazepine before transfer.

Her baseline blood counts and basic metabolic panel and blood cultures were unremarkable. She had positive antithyroid antibodies although thyroid function was within normal limits. Cerebrospinal fluid (CSF) analysis showed glucose level of 3.5 mmol/L (serum glucose level, 5 mmol/L), protein, 0.45g/L, white blood cell (WBC) count, 15 per mm3 (2 mononuclear and 13 lymphocytes), and red blood cell (RBC) count, 2.

Further CSF analysis revealed high NMDAR antibodies with a titer of 1:32 (normal < 1:2). CSF autoimmune panel revealed no antibodies to Voltage Gated Potassium Channel - complex, Leucine - Rich Glioma Inactivated 1, Contactin Associated Protein Receptor 2, Anti Glutamic Acid Decarboxylase 65 antibodies, Gamma – Amino Butyric Acid, α-amino-3-hydroxy-5-methyl-4-isoxazole Propionic Acid Receptor, Anti-Neuronal Nuclear Antibody type 1 (ANNA-1), and Anti-Neuronal Nuclear Antibody type 2 (ANNA-2), Anti-Glial Nuclear Antibody-Purkinje cell Cytoplasmic Antibody type 1 (PCA-1), Purkinje cell Cytoplasmic Antibody type 2 (PCA-2) Neuronal and muscle Cytoplasmic Amphiphysin antibodies, Neuronal and muscle Cytoplasmic Amphiphysin, and striational antibodies Purkinje cell Cytoplasmic Antibody type Tr (PCA-Tr), amphiphysin, and Collapsin Response Mediator Protein-5. Magnetic resonance imaging (MRI) of brain and ultrasound of abdomen were normal.

She was started on intravenous immunoglobulin (IVIG) at 2g/kg over three days. This was followed by 1g of pulsed IV methylprednisolone once daily for five days. Tapering doses of oral prednisolone were maintained at 60mg/day for one week and then tapered over six weeks. She was also commenced on IV acyclovir and ceftriaxone, which were discontinued after her blood and CSF cultures and Polymerase Chain Reaction (PCR) returned negative. Phenytoin was gradually tapered and she was maintained on 15mg/kg of carbamazepine. Owing to excessive agitation, she was started on haloperidol and diazepam. A child psychiatry review was undertaken, and quetiapine was recommended for sleep and behavior disturbances. Electroencephalogram (EEG) revealed slow wave discharges, suggestive of diffuse cerebral dysfunction with no active epileptiform abnormalities.

On discharge 47 days later, she had no seizures, showed normal behavior, and had a satisfactory sleep pattern. On follow-up six months later, her neurological and mental status evaluation were normal.

Case 2

A 4.5-year-old boy was brought to ED with fever, decreased level of consciousness, and abnormal movements. A week earlier, he had developed vomiting, agitation, and had a brief period of unresponsiveness and loss of balance. He developed dyskinetic movements of his extremities and orolingual dyskinesia and subsequently became encephalopathic. He then developed recurrent focal seizures. He was born at full term after an uneventful pregnancy and by normal delivery to non-consanguineous parents. His growth and development were age appropriate. There was no family history of note.

On admission, a computed tomography (CT) of brain was found to be normal. His initial blood tests revealed a slightly elevated WBC count (16 × 109/L, 79% neutrophils). Other investigations including liver function, renal profile, Erythrocyte sedimentation rate, C-reactive protein, anti-streptolysin O titer, lactate, ammonia, tandem mass spectroscopy, urine Gas chromatography-mass spectrometry, thyroid function tests, and thyroid antibodies returned normal. A slightly “blood stained” CSF analysis showed a normal glucose level of 4.5 mmol/L, protein 0.28g/L, and relatively high WBC count of 26 (RBC, 3826, 70% lymph, WBC:RBC, 1:147). His mycoplasma pneumonia titer was normal and PCR for herpes simplex virus, Epstein–Barr virus, and cytomegalovirus were negative.

A provisional diagnosis of autoimmune encephalitis was made, and he was commenced on IV acyclovir and ceftriaxone to cover for infections as a possible etiology. For his seizures, levetiracetam and benzodiazepines were added. Two days after admission, a second CSF analysis showed RBC, 576; WBC, 57; protein, 0.61g/L, and CSF was sent for anti-NMDAR antibodies.

Treatment with IVIG was started (2g/kg over three days), followed by high dose of pulsed IV methylprednisolone for five days. He also underwent an MRI of brain, which was unremarkable. His EEG showed diffuse slowing with no epileptiform activity, suggestive of diffuse cerebral dysfunction.

Three weeks later, CSF result returned positive for anti-glutamate receptor (type NMDA) Immunoglobulin G (IgG) (titers, 1:64). Day 24 into admission, an eight-day course of plasma exchange (PLEX) was performed without improvement, followed by a second dose of IVIG and pulsed IV methylprednisolone. Following this, he was commenced on weekly IV rituximab for four weeks.

His testicular and abdominal ultrasound, whole body MRI, and urine catecholamine metabolites were unremarkable. Repeat CSF and serum anti-NMDAR antibodies showed 1:8+ and 1:320, respectively. He then received additional two PLEXs seven weeks apart and monthly IVIG. Follow-up of brain MRI two months later showed diffuse volume loss atrophic changes. EEG showed diffuse slowing and bilateral epileptiform discharges.

He had swallowing dysfunction, which necessitated gastrostomy tube placement for three months. He developed muscle spasticity, which was treated with baclofen, Botox injection, and intensive occupational and physiotherapy.

He showed recovery after seven months of admission and was transferred to rehab for two months. At 16-month follow-up, EEG was normal and he was seizure free. His anticonvulsant therapy was then discontinued. Eventually, he made a good recovery with normal neurological examination. A year and a half after initial presentation, he became functionally independent in all daily activities. He has retained normal motor activity and has normal cognition and language.


   Discussion Top


Anti-NMDAR encephalitis is a rare form of autoimmune encephalitis seen in children and adults. It is being increasingly diagnosed due to increasing awareness of this condition among pediatricians and health professionals. A large observational study revealed that 65% of cases occurred in patients aged ≤18 years.[1] Females were affected significantly more often than males, at nearly three times the rate (P < 0.01).[1] The etiology may be unclear; however, preceding infections (mycoplasma, varicella zoster, and herpes simplex) have been suspected to play a role in anti-NMDAR encephalitis.[2] In one case series of 44 patients with herpes simplex virus encephalitis (HSVE), 33% were found to have NMDAR antibodies.[3] In all reported patients, relapsing symptoms have presented two to six weeks after the initial viral infection. The role of HSVE as a trigger of NMDAR antibody synthesis was shown in a series of patients with antibody-negative serum and CSF at the time of HSVE infection that seroconverted to positive NMDAR antibodies a few weeks later in the setting of relapsing symptoms.[4] The preceding infection could be directly inducing antibodies (in non-paraneoplastic cases) and circulating cytokines associated with the preceding infection could be causing changes in the blood–brain barrier, allowing existing antibodies to access targets within the brain.[5]

Many patients complain of flu-like symptoms around the time their disease began, and it is likely that this may be acting as a trigger for anti-NMDAR encephalitis.

[Table 1] lists the diagnostic criteria for anti-NMDAR encephalitis. Typically, patients develop a dyskinetic movement disorder (usually of the arms, legs, mouth, and tongue, but may include full body spasms), which often consists of continuous writhing and twitching of face and limbs but can also be a generalized slowing down of movements. They may also develop choreoathetosis, dystonia, rigidity, opisthotonic postures, and very rarely catatonia.
Table 1: Listing diagnostic criteria for anti-NMDA receptor encephalitis[6]

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The children may also need intensive care due to impaired or loss of consciousness, ensuing coma, autonomic dysfunction, including central hypoventilation, hypotension, hyperthermia, heartbeat arrhythmias, and urinary and fecal incontinence. The severity of the clinical symptoms of this disorder correlates with antibody levels.[5]

The differential diagnosis of anti-NMDAR encephalitis is broad and includes infectious causes of encephalitis, such as herpes simplex virus; acute disseminated encephalomyelitis; inborn errors of metabolism, including urea cycle disorders; toxins/poisoning and medication overdoses; rheumatologic conditions, such as neuropsychiatric lupus; and primary psychiatric conditions, such as schizophrenia.

It is important for psychiatrists to be highly aware of this disorder as a psychiatric diagnosis is often one of the initial diagnoses.

A study examining patients with dyskinetic “encephalitis lethargica,” a descriptive term that likely includes several forms of idiopathic encephalitis, showed that 20 of 20 patients had anti-NMDAR encephalitis.[7]

Association with tumors

Once a patient has been diagnosed with NMDAR antibody encephalitis, an underlying tumor should be actively looked for as this is also considered to be a paraneoplastic syndrome. Most tumors associated with anti-NMDAR encephalitis contain neural tissue and NMDARs. It is presumed that antibodies are initially formed against NMDARs found within tumors, and then attack similar-looking receptors in the brain producing the symptoms and signs associated with anti-NMDAR encephalitis.

The detection of an ovarian teratoma is age dependent, approximately 50% of female patients older than 18 years have ovarian teratomas, whereas less than 9% of girls younger than 14 years have a teratoma.[8],[9] Tumor removal is a very important part of treatment. Patients who have a tumor that is removed, recover faster and are less likely to experience a recurrence (or relapse) of their disease than those in whom no tumor is found.

Investigations

The diagnosis of anti-NMDAR encephalitis is confirmed by the detection of IgG antibodies to the GluN1 (also known as NR1) subunit of the NMDAR in serum or CSF.[9] After treatment or in advanced stages of the disease, the CSF antibodies usually remain elevated if there is no clinical improvement, whereas serum antibodies may be substantially decreased by treatments.[10] The titer of CSF antibodies appears to correlate more closely with the clinical outcome.[5],[8]

Tests on the CSF are more accurate than those on the blood. Therefore, if blood tests are negative, the CSF should be tested before concluding that the patient does not have anti-NMDAR encephalitis.

CSF may show lymphocytic pleocytosis or oligoclonal bands (although CSF can be normal initially).

EEG may show infrequent epileptic activity, but may also show frequent slow, disorganized activity that does not correlate with most abnormal movements.

Brain MRI is often normal or shows transient Fluid-attenuated inversion recovery or contrast-enhancing abnormalities in cortical (brain and cerebellum) or subcortical regions (hippocampus, basal ganglia, and white matter).[5],[8] Although not routinely performed, positron emission tomography reportedly shows a characteristic change of increased frontal-to-occipital gradient of cerebral glucose metabolism, which correlates with disease severity.[11]

All patients suspected of having anti-NMDAR encephalitis should be screened for the presence of tumors. This is usually carried out with imaging (CT or MRI) of the chest, abdomen, and pelvis. Women should also receive an ultrasound of the ovaries, and men should receive an ultrasound of the testes. Even after removal, tumors can regrow. Therefore, people with anti-NMDAR encephalitis should be checked periodically for the presence (or recurrence) of tumors.

Treatment

The variation in clinical outcome observed in previously published cases appears to correspond to the rapidity of commencing appropriate treatment. Patients who received early tumor treatment (usually with immunotherapy) had better outcome (P = 0.004) and fewer neurological relapses (P = 0.009) than the rest of the patients.[5]

Resection of the tumor, glucocorticoids, IVIG, and PLEX often result in improvement, usually within four weeks.[5],[8],[12],[13],[14],[15],[16],[17] Patients who do not improve with these first-line therapies (often cases without tumor) may improve with rituximab and/or cyclophosphamide.[5],[8],[16],[17],[18] Progressive neurologic deterioration and death can occur without treatment.

Uptodate.com[19] recommends concurrent immunoglobulin (0.4g/kg daily for five days) and methylprednisolone (1g daily for five days).[20] This is preferred to PLEX, which can be difficult to implement in children and agitated patients as well as patients with autonomic instability. If there is no significant clinical improvement after 10 days, second-line therapy is recommended for adults—rituximab combined with cyclophosphamide. Children are generally treated with just one of these agents, usually rituximab.[2],[21] A definite or probable response to rituximab as second-line therapy was noted in approximately 80% of those with anti-NMDAR encephalitis.

Treatment is continued until substantial recovery occurs, which may take up to 18 months.[16] In one series of 577 patients, 81% of patients had a good outcome (modified Rankin scale 0 to 2) at 24 months.[16] Substantive persistent cognitive impairments are more common and more severe when there is a delay in diagnosis and treatment.[22]

Patients with anti-NMDAR encephalitis are at risk for relapse, and may require longer duration of immunosuppression. Relapse occurs in 15%–24% of the patients, sometimes after several years, and is often associated with occult or relapsing teratoma or with the absence of a tumor.[5],[13] In one series, relapses were more common among those who did not receive immunotherapy on initial presentation.[23] Immunosuppressive therapy (mycophenolate mofetil or azathioprine) can be continued for at least one year after initial immunotherapies are discontinued.[20]

It is vital that central nervous system infections are first excluded. Some patients are now being treated after recognition of the clinical symptoms and signs while the antibody result is awaited, to try to improve recovery. If the antibody result is positive, treatments in the form of immunotherapies are used to dampen down the immune system.

Many other medications may also be required to control blood pressure, stop seizures, ease anxiety, improve sleep, and to treat hallucinations or abnormal behaviors.

Prompt therapies offer a good chance of substantial recovery in the majority of patients. As they improve, there is often a reduction in the amount of NMDAR antibody in the person’s blood when the test is repeated.

Prognosis

Although anti-NMDAR encephalitis can be a serious and life-threatening disease, the majority of patients who receive prompt diagnosis and appropriate treatment make a good recovery.

However, recovery is usually slow (may take months or even years) and many patients spend few months in hospital, including the time in the intensive care unit. Interestingly, both patients showed different periods of recovery, which again shows the diverse nature of this disease.

The recovery process may wax and wane in severity and may be complicated by relapses or emergence of new symptoms, necessitating regular monitoring and including repeat imaging to ensure that no tumor is found. Relapses may occur in up to 14%–25% of patients. Relapses are more likely to occur in patients in whom a tumor has not been identified and in those who were not treated with immunosuppressants during their first attack. The disease is known to be fatal in some cases.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
   References Top

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Dalmau J, Tüzün E, Wu HY, Masjuan J, Rossi JE, Voloschin A, et al. Paraneoplastic anti-N-methyl-d-aspartate receptor encephalitis associated with ovarian teratoma. Ann Neurol 2007;61:25.  Back to cited text no. 12
    
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Seki M, Suzuki S, Iizuka T, Shimizu T, Nihei Y, Suzuki N, et al. Neurological response to early removal of ovarian teratoma in anti-NMDAR encephalitis. J Neurol Neurosurg Psychiatry 2008;79:324.  Back to cited text no. 13
    
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Smith JH, Dhamija R, Moseley BD, Sandroni P, Lucchinetti CF, Lennon VA, et al. N-methyl-d-aspartate receptor autoimmune encephalitis presenting with opsoclonus-myoclonus: treatment response to plasmapheresis. Arch Neurol 2011;68:1069.  Back to cited text no. 15
    
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Titulaer MJ, McCracken L, Gabilondo I, Armangué T, Glaser C, Iizuka T, et al. Treatment and prognostic factors for long-term outcome in patients with anti-NMDA receptor encephalitis: an observational cohort study. Lancet Neurol 2013;12:157.  Back to cited text no. 16
    
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Ishiura H, Matsuda S, Higashihara M, Hasegawa M, Hida A, Hanajima R, et al. Response of anti-NMDA receptor encephalitis without tumor to immunotherapy including rituximab. Neurology 2008;71:1921.  Back to cited text no. 18
    
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20.
Dalmau J, Lancaster E, Martinez-Hernandez E, Rosenfeld MR, Balice-Gordon R. Clinical experience and laboratory investigations in patients with anti-NMDAR encephalitis. Lancet Neurol 2011;10:63.  Back to cited text no. 20
    
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Dale RC, Brilot F, Duffy LV, Twilt M, Waldman AT, Narula S, et al. Utility and safety of rituximab in pediatric autoimmune and inflammatory CNS disease. Neurology 2014; 83:142.  Back to cited text no. 21
    
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Finke C, Kopp UA, Prüss H, Dalmau J, Wandinger KP, Ploner CJ. Cognitive deficits following anti-NMDA receptor encephalitis. J Neurol Neurosurg Psychiatry 2012; 83:195.  Back to cited text no. 22
    
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Gabilondo I, Saiz A, Galán L, González V, Jadraque R, Sabater L, et al. Analysis of relapses in anti-NMDAR encephalitis. Neurology 2011;77:996.  Back to cited text no. 23
    



 
 
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