New Onset Focal Seizure Clusters in Children: Expanding the Spectrum of Anti NMDAR Encephalitis
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.304087
Source of Support: None, Conflict of Interest: None
Keywords: AntiNMDAR encephalits, monosymptomatic presentation, seizure cluster
Anti-N-methyl-d-aspartate receptor (Anti-NMDAR) encephalitis was first described in 2007 by Dalmau as paraneoplastic syndrome in a patient with ovarian teratoma. Since then several large cohorts have been published regarding the clinical features . The disease onset in children may be different from that of adults and incidence of tumor is less in children compared to adults. However, the usual clinical presentation is polysymptomatic with behavioral or cognitive change, seizures, and focal deficits. Here we are reporting 6 cases of antiNMDAR encephalitis with a monosymptomatic presentation of new onset seizures.
This is a retrospective series of 6 cases of anti NMDAR encephalitis treated in our institute, which is a tertiary referral center, between 2010 and 2014. All the patients with NMDA encephalitis were initially included. We are describing the baseline demographics, clinical presentations, investigations (CSF, MRI and EEG), course in the hospital and details of treatment. Short and long-term outcomes were documented from the available medical records. Children presenting with monosymptomatic seizure clusters were only included in the final analysis.
Twenty Eight children were diagnosed with anti NMDAR encephalitis during the study period. Twenty two children had classical polysymptomatic presentations and were not included in this analysis. The remaining 6 children (5 girls and one boy), who presented with only acute seizure clusters without any major behavior changes were grouped separately and analyzed .There were one male and five females in the series. All patients were in the age group > 12 years. There was no history of any preceding illness. There is no history of fever, headache or vomiting. The average duration of seizures prior to admission was 5 days.
All children presented with acute cluster of focal seizures. Four out of six had focal status epilepticus while two out of six had recurrent focal seizures. Commonest semiology was clonic seizure in four out of six and one child had dystonic seizure and one had tonic seizure. Clonic seizures were mainly distal involving the hand. Three out of six with clonic seizure had involvement of upper limb alone, two had upper limb and lower face clonic seizure and one had hemiclonic seizure. All 4 children with focal motor status epilepticus had recurrent focal seizure which evolved over a mean of two days into status epilepticus. Right side involvement was seen in five and one had left side involvement. None of patient had impairment of cognitive function, behavior issues, or focal deficits.
CSF cells, protein and sugar were normal in all children. CSF and serum NMDA were positive in all patients. MRI was normal in all children. EEG showed focal epileptiform activity in left side in five and right side in one patient. Interictal discharge was seen in the frontocentral region in four, parietotemporal in two. Ictal onset was documented in all children in the corresponding area of Interictal discharges (IED).
All patients were managed in ICU. Mean of three antiepileptics were required to control seizure. None of the patients required anesthetic agents to control seizures. All patients were started on IV methylprednisolone 30mg per kg per day for 5 days followed by 2mg per kg per day of oral steroid which was tapered over two months. No other immunomodulators or immunosuppressants were used. None of patient required intubation.
Screening for underlying teratoma and malignancy were negative. On discharge all patients had seizure control with no focal deficits. On two-year follow up one out of six of patient had recurrence while 5 were normal and antiepileptic drug (AED) was tapered and stopped in all children.
Relapsing focal encephalitis
A 12 yr old girl first born, with normal antenatal, natal and post -natal history with normal development presented with multiple episodes of seizures since 1 week. She was well till 1 week back, when she developed tonic posturing of right upper limbs. She was evaluated outside and was started on Phenytoin. The child continued to get recurrent seizures all of same semiology with preserved consciousness. Events were preceded by upper limb numbness and in between the seizures the child was normal. There was no history of preceding illness, prodromal symptoms or encephalopathy or behavioral issues. On examination child was fully conscious with vitals stable and no focal deficits.
Blood investigations, MRI and CSF were normal. EEG showed focal slowing over left centroparietal regions. Recorded several electro clinical events with left parietotemporal onset. Serum and CSF NMDA were positive. She was started on IV methylprednisolone and seizure control was attained with three antiepileptic drugs. She was discharged after 2 weeks with no deficits and on oral steroids and antiepileptic drugs. She was tapered off steroids over a period of six weeks and one AED was stopped.
One month after stopping steroids, she presented with recurrent focal seizure of same semiology. She had fever and coryza 5 days prior to onset of illness. EEG recording showed generalized non specific disturbance of electrical function more over left hemisphere. Serum NMDA was positive and MRI was normal. She was managed with IV Methyl prednisolone for 5 days followed by oral steroids and AED were titrated. She was started on mycophenolate mofetil and NMDA was repeated every 3months. Child was on regular follow up and became NMDA negative after 1 year and mycophenolate mofetil was stopped. She is 2 years into follow up and now asymptomatic and off antiepileptic drugs.
This case series of acute focal seizure clusters in children adds to the burgeoning literature on Anti NMDA encephalitis expanding the clinical spectrum. Polysymptomatic presentation is classically described in this syndrome, the commonest being seizures and psychosis. Here we are reporting 6 cases of anti NMDAR encephalitis presenting only with focal seizures. There was no preceding history of epilepsy in any of the children.Titulaer et al. in his series of 577 patients of all ages showed that 87% had at least four of the eight groups of symptoms and only 1% continued to have a monosymptomatic illness. We have so far 28 cases of NMDA encephalitis in children during the study period of which 78.5% had polysymptomatic presentation. Compared to Titulaer in our series the incidence of monosymptomatic presentation was high 21.4%. In our series all children were older than 12 years of age, previous reports have shown children more than 12 years of age tend to present more often with psychiatric symptoms (45%) than seizures.
About 70% of patients have prodomal symptoms consisting of headache, fever, nausea, vomiting, diarrhoea, or upper respiratory-tract symptoms. In our series none of the patients had prodromal symptoms. Motor seizures develop at early stages of the disease. The frequency and intensity of the seizures decrease as the disease evolves. Status epilepticus and recurrence of seizure can occur at any stage of disease. In our series seizures were the first and only symptom. Seizures are reported in approximately 76% of anti NMDAR encephalitis which can be generalized or focal. Viaccoz et al. suggested that partial seizure is more common presenting symptom in men compared to females. In our series in children seizure as the presenting symptom was seen more in females. In our series all children had partial seizures and focal motor status epilepticus was seen in four. None of the patients developed other symptoms, they remained monosymptomatic through out the course.
EEG findings described in literature in this syndrome are: generalized slowing or generalized rhythmic slowing  and focal abnormalities are reportedly rare. We noticed focal abnormalities in our series which included focal IED, focal onset of ictal discharges and focal slowing. Extreme delta brush a novel finding in Anti NMDAR encephalitis was not seen in our series. Extreme delta brush is usually seen in severe form of disease, its absence in our series could be due to less disease severity.
The cerebrospinal fluid (CSF) is initially abnormal in 80% of patients and becomes abnormal later in the disease in most other patients. CSF findings include moderate lymphocytic pleocytosis, normal or mildly increased protein concentration and normal sugar. In our series all had normal CSF study this could be due to focal pathology or since CSF is done early in patients suspected with encephalitis and repeat CSF is not usually done. MRI findings in anti NMDAR encephalis include increased FLAIR signal, faint enhancement of cortex or meninges or basal ganglia or MRI can be normal. In our series MRI was normal in all patients.
All children were managed in ICU. Mean of three AED were required to control seizure, none of the patients required IV anesthetic agents for seizure control. Besides AEDs, all children were started on IV methylprednisolone. In the literature, good responses have been described with combination therapy of steroid and IVIG, and more severely affected patients have been treated with rituximab, cyclophosphamide or plasmapheresis . Since our patients had only monosymptomatic presentation we started with methylprednisolone alone. After starting steroids in mean of 3 days seizures were controlled. There have been adult cases reported in literature where clinical recovery occurred without specific treatment. None of the patient had any underlying tumor in this cohort.
Dalmau J et al. re ported increased relapse rates in patients with underlying tumor. Only one child in this cohort had clinical relapse during 2 year follow up and repeat evaluations did not find any underlying tumor
This is first report of Anti NMDAR encephalitis presenting as new onset seizure clusters in children. Unlike the existing literature these children did not develop any other symptoms and remained monosymptomatic through out the course [Table 1]. We propose that focal encephalitis could be the reason for this monosymptomatic presentation, hence in children with new onset clusters of focal seizures, Anti NMDAR encephalitis should also be considered.
Conflicts of interest
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