|Year : 2023 | Volume
| Issue : 1 | Page : 39-42
Anti-N-methyl-D-aspartate receptor encephalitis: A paraneoplastic syndrome in an Indian adolescent girl
Deepti Malhotra1, Sudhir Sane2, Shivaji Mane1, Omkar Hajirnis3
1 Department of Pediatric Surgery, Jupiter Hospital, Thane, Maharashtra, India
2 Department of Pediatrics, Jupiter Hospital, Thane, Maharashtra, India
3 Department of Pediatric Neurology, Jupiter Hospital, Thane, Maharashtra, India
|Date of Submission||06-Aug-2022|
|Date of Decision||24-Jan-2023|
|Date of Acceptance||27-Jan-2023|
|Date of Web Publication||27-Feb-2023|
268/4, Raja Park, Jaipur - 302 004, Rajasthan
Source of Support: None, Conflict of Interest: None
Background: Anti-N-methyl-D-aspartate receptor (anti-NMDAR) encephalitis is an auto-immune encephalitis with prominent neuropsychiatric manifestations that may be paraneoplastic. Clinical Description: A teenage girl presented with an acute illness of 4 days with symptoms of generalized weakness of all four limbs, behavioral abnormalities, and a generalized convulsion. On examination, the child was hemodynamically stable and disoriented to time, place, or person. There was the loss of recent memory. The remaining neurological and systemic examination was normal. The differential diagnoses considered were toxic or metabolic encephalopathy, neurological Wilson's disease, acute intermittent porphyria, autoimmune encephalitis, and neuropsychiatric systemic lupus erythematosus. Investigations were planned for the causes that could not be excluded by history, examination, and baseline investigations. Salient reports were normal brain magnetic resonance imaging (MRI), nonspecific electroencephalogram abnormalities, and absence of pleocytosis and biochemical abnormalities but positive anti-NMDAR antibodies in the cerebrospinal fluid. A right adnexal cystic solid mass was identified in the abdominal ultrasound with the radiological appearance of an ovarian teratoma or germ cell tumor on MRI. Alpha-fetoprotein levels were raised. Management: The patient underwent right salpingo-oophorectomy. The histopathological diagnosis was an immature ovarian teratoma. The patient received first-line and then second-line immunotherapy (when there was no response), as well as chemotherapy. Signs of improvement appear after 6 weeks, with complete recovery within 6 months. Conclusion: Pediatric ovarian teratoma-associated anti-NMDAR encephalitis is rare, but neuropsychiatric symptoms should prompt the clinician to think of this diagnosis in girls. Early treatment is associated with a good prognosis.
Keywords: Anti-N-Methyl-D-aspartate receptor encephalitis, autoimmune encephalitis, ovarian teratoma
|How to cite this article:|
Malhotra D, Sane S, Mane S, Hajirnis O. Anti-N-methyl-D-aspartate receptor encephalitis: A paraneoplastic syndrome in an Indian adolescent girl. Indian Pediatr Case Rep 2023;3:39-42
|How to cite this URL:|
Malhotra D, Sane S, Mane S, Hajirnis O. Anti-N-methyl-D-aspartate receptor encephalitis: A paraneoplastic syndrome in an Indian adolescent girl. Indian Pediatr Case Rep [serial online] 2023 [cited 2023 Mar 22];3:39-42. Available from: http://www.ipcares.org/text.asp?2023/3/1/39/370527
Autoimmune encephalitis (AIE) is emerging as a common cause of pediatric encephalopathy. Patients usually present with neuropsychiatric manifestations that include acute behavioral changes, psychosis, catatonia, seizures, memory deficit, dyskinesias, speech problems, and even autonomic dysregulation. AIE is an antibody-mediated condition in which a plethora of antibodies against the central nervous system have been described. The most common antibody is against the anti-N-methyl-d-aspartate receptor (NMDAR). Anti-NMDAR receptor encephalitis was first described in 2007. However, a significant proportion of patients with AIE may not exhibit detectable antibodies, thus posing a diagnostic challenge to the treating clinician.
We report a case of an adolescent girl who presented with neuropsychiatric manifestations. She was screened for and identified with an ovarian teratoma, a frequent paraneoplastic cause of AIE in girls that must be actively looked for.
| Clinical Description|| |
A 13-year 9-month-old girl was brought with generalized weakness of arms and legs and increased anxiety for 4 days; a single episode of confusion and vacant staring look on the 3rd day of illness; and a convulsion on the day of presentation. The child's symptoms, as reported by her parents, started with acute-onset generalized weakness of all her limbs that progressed over 4 days but was not associated with pain or severe enough to cause difficulties in mobility. This was concurrently associated with brief episodes of anxiety manifested by unprovoked nervousness and restlessness. She also displayed intermittent impulsive and aggressive behavior in the form of episodes of unprovoked shouting, laughter, and inability to restrain herself. On the 3rd day of illness, a transient event occurred in which she appeared confused and disoriented with a prolonged vacant stare. She was referred to a psychiatrist and started on medication (that was described colloquially by the parents as a probable anxiolytic). The following day (4th day of illness), she had a generalized tonic seizure (uprolling of eyeballs, twitching of face, and tonic posturing of all limbs) lasting for around 5 min, followed by post ictal drowsiness for 10 min, and not associated with bowel or bladder incontinence.
There was no report of headache, projectile vomiting, or sleep disturbances. We were unable to elicit a history of any of the following; preceding febrile illness, rashes, respiratory or gastrointestinal symptoms, ingestion of unknown substances, or trauma. The history was not contributory. There was no significant antenatal, birth, or neonatal history. The acquisition of developmental milestones was normal. She was studying in the 9th standard with good academic performance. She was vaccinated as per the national immunization schedule and received an appropriate diet. She had attained menarche at 11 years of age, and had irregular cycles from the onset, though without dysmenorrhea or menorrhagia. Her last menstrual period was 10 days before admission. She was born out of a nonconsanguineous marriage, and there was no similar or significant illness in any family member.
On admission, vital parameters were stable; afebrile, with a heart rate of 112/min, normal respiratory rate, and blood pressure of 112/74 mm Hg (normotensive). Anthropometry was appropriate for age with a body mass index of 21 kg/m2 (between 0 and + 1 z score). There were no signs of pallor, icterus, cyanosis, or lymphadenopathy. She was not oriented to time, place, and person and also displayed a loss of recent memory (she could not recall events that had occurred in the past 24 h). The pupils were bilaterally normal in size and equally reactive to light. The fundus was normal. There were no cranial nerve or focal neurological deficits. The tone, power, and reflexes were normal. Sensory deficits (tested for pain and touch) were not found. Signs of increased intracranial tension or involvement of the cerebellum and/or meninges were absent. The remaining systemic examination was normal.
Management and outcome
Based on the clinical phenotype of the first episode of acute-onset neuropsychiatric manifestation in an adolescent, we kept the differentials of toxic (concealed drug use) or metabolic encephalopathy (Vitamin B12 deficiency), neurological Wilson's disease (although convulsions are not described in this condition), acute intermittent porphyria, AIE, and neuropsychiatric form of systemic lupus erythematosus (SLE). Routine baseline investigations were normal: blood sugar 92 mg/dl; serum electrolytes (sodium 139, potassium 3.5, chloride 106, and serum calcium 9.2); hemogram (hemoglobin 13.7, total leukocyte count 13,280, and platelet 4.15 lakh); and no evidence of infection.
Since we had to operate in a setting of limited finances and availability of resources, further investigations were planned and directed by high likelihood based on clinical evaluation and available reports. Since there was no history of ingestion of drug or substance in conjunction with the absence of any examination finding that was suggestive of any specific toxidrome and a normal metabolic profile without evidence of organ dysfunction, an unknown poisoning was considered unlikely. Since the ophthalmological examination failed to detect Kayser Fleischer rings, Wilson's disease was considered less likely and we deferred the confirmatory tests for later. Dates were taken for magnetic resonance imaging (MRI) and an electroencephalogram (EEG), and certain specific tests based on our differentials were sent, the results of which would be available in a few days.
The patient had another convulsion of similar semiology on the 2nd day of admission that was aborted by intravenous (IV) midazolam, and following which was started on IV Levetiracetam. The EEG showed bilateral parieto-occipital interictal epileptic discharges. A negative urine porphobilinogen report ruled out porphyria. The results of the panel comprising COVID IgG (for post-COVID sequelae), anti-thyroid peroxidase Ab (TPO) (for TPO-positive AIE), antinuclear antibody, and C3, C4 levels (for SLE) were negative.
On the 3rd day of admission, the patient had another convulsion and worsening of mental state with irrelevant talking and prolonged episodes of screaming and disorientation with reduced intervening normalcy. The MRI brain was normal without evidence of cerebral edema, and we were able to proceed with a lumbar puncture. Cerebrospinal fluid (CSF) cytology revealed four cells (100% lymphocytes), proteins 30 mg/dl, sugar 79 mg/dl (blood sugar – 121 mg/dl), and chloride 124 mmol/L. A CSF AIE panel was sent. Since this condition is known to be associated with ovarian teratoma in females while awaiting for the report, we performed a screening ultrasound abdomen. This showed a right adnexal complex cystic, solid mass of size 12.5 cm × 8.6 cm. An abdominal MRI was ordered for better anatomical and etiological visualization, which revealed a heterogeneous solid cystic lesion involving the right adnexal region and measuring around 18 cm × 18 cm × 6 cm [Figure 1]. The radiological impression was a teratoma or germ cell tumor. Serum beta-human chorionic gonadotrophin levels were normal (1.7 mIU/ml; normal <5 mIU/ml), but the alpha-fetoprotein was raised (588.7 ng/ml; normal 0–40 ng/ml). Since the latter is an oncofetal antigen indicative of an ovarian teratoma, the patient underwent right salpingo-oophorectomy on day 4 of admission.
|Figure 1: MRI abdomen showing a heterogenous solid cystic lesion measuring 18 cm × 18 cm × 6 cm involving right adnexal region and extending into the abdominal cavity crossing the midline. The mural nodule has multiple speckled calcifications (arrow 1) and the cyst wall shows peripheral septal type of enhancement (arrow 2). MRI: Magnetic resonance imaging|
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The gross appearance was that of a mass measuring 14 cm × 10 cm × 4 cm, with a smooth surface. Biopsy samples were sent, the cut section of which denoted tufts of hair with calcification along the friable areas suggestive of a teratoma. Based on this and the fact that the NMDA-R antibody was positive, the diagnosis of anti-NMDAR encephalitis was kept. Postoperatively, the patient was started on IV immunoglobulin (IVIG) at 400 mg/kg/day for 5 days, followed by IV Methyl-prednisolone (30 mg/kg/day) for the subsequent 5 days. However, even after this therapy, there was still a worsening of neuropsychiatric symptoms in the form of increased episodes of aggression with no normalcy in between. Hence, the patient was started on IV rituximab (375 mg/m2/per week) along with the first line medication that was continued for 6 weeks.
We received the histopathology report showing grade 3 immature teratoma, confirming paraneoplastic anti-NMDAR encephalitis associated with an ovarian teratoma. For this, the patient was started on chemotherapy (pegfilgrastim, cisplatin, and etoposide) that was given for four cycles. There was an initial worsening of symptoms (deteriorating sensorium necessitating nasogastric feeding) in the initial 3 weeks, following minimal signs of improvement started to appear after 6 weeks. The recovery was gradual, but within 6 months, there was a complete recovery, and she was able to carry out all her routine activities independently, attend school and participate in extracurricular activities.
| Discussion|| |
NMDAR are located predominantly in the forebrain and hippocampus and plays an important role in learning and memory. In this disease, the NR1 subunit of the NMDA receptors is targeted by antibodies resulting in the internalization of NMDAR and progressive decline of NMDAR-associated synaptic functions resulting in neuropsychiatric manifestations. The average age of onset of symptoms is 21 years, although cases have been described in patients ranging from 8 months to 85 years., Brain MRI studies are abnormal in 35% of patients, usually showing nonspecific cortical and subcortical T2-fluid-attenuated inversion recovery signal abnormalities. CSF analysis reveals nonspecific changes. EEG often reveals diffuse delta slowing extreme delta brush-beta-delta complexes without paroxysmal discharges, despite frequent bouts of seizures. The disorder can be considered paraneoplastic due to its association with tumors. However, there are a proportion of cases that have been reported without any detectable tumor. In 30%–60% of women of childbearing age, anti-NMDAR encephalitis has been associated with ovarian teratoma. Out of these, the histopathology in most cases is that of a mature teratoma, but in around 10% (like this case), it may be immature.
Ovarian teratoma-associated anti-NMDAR encephalitis tends to cause more severe symptoms than those without. However, full recovery occurs more frequently in the former if early tumor resection and immunotherapy are performed. The usual first-line options for immunotherapy are corticosteroids, IVIG, or plasmapheresis (not easily performed on pediatric patients). Cyclophosphamide can be used as an effective second-line drug when there is no response to initial treatment. Some authorities recommend a combination of rituximab (2nd line agent), steroids, and IVIG.,, There is a lower likelihood of neurological relapses with earlier initiation of treatment, as well as increasing use of second-line immunotherapy. Recovery is usually slow and can take as long as 2 years after symptom onset. In our patient, the ovarian teratoma was excised on 4th day of admission, therapy was started the next day, and she showed complete recovery within 6 months.
We would like to thank Dr. Chetana Bakshi for her contribution to patient care.
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 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.
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