Two Cases of POLG Mutation-Related Status Epilepticus Mimicking Autoimmune and Viral Encephalitis: A Learning Experience
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Mitochondrial diseases are among the most important inherited metabolic disorders presenting in childhood. Clinical manifestations may include developmental delay, seizures, hypotonia, failure to thrive, sensorineural hearing loss, cardiomyopathy, hepatic dysfunction, and recurrent metabolic decompensation, frequently accompanied by elevated lactate. Super-refractory status epilepticus (SRSE) is a pediatric neurologic emergency with a varied etiology. Mutations in DNA polymerase gamma (POLG) lead to mitochondrial dysfunction, most commonly manifesting as infantile hepatocerebral syndrome and Alpers syndrome [1]. We report two children with distinct presentations of POLG-related epilepsy that mimicked infectious and immune-mediated encephalitis. These cases highlight the diagnostic challenges and the importance of early genetic evaluation in children with cryptogenic refractory seizures.
Case 1: A 13-month-old boy, born to non-consanguineous parents and with normal premorbid development, presented with left focal seizures with impaired consciousness that progressed to bilateral tonic-clonic seizures. The episodes involved jerking of the left arm and leg with facial and eye deviation to the left, followed by jerking of both the upper and lower limbs; they lasted 2 to 3 minutes and were followed by post-event confusion lasting 15 minutes. There was no antecedent febrile illness. Seizures were refractory to multiple anti-seizure medications and progressed to SRSE requiring mechanical ventilation.
There were two prior spontaneous abortions, and there was a family history of developmental delay and seizures in a maternal uncle, who had been treated with levetiracetam and clobazam for epilepsy for the past 5 years. Laboratory investigations revealed elevated liver enzymes (aspartate aminotransferase [AST], 167 U/L; alanine aminotransferase [ALT], 140 U/L) and lactate (3.55 mmol/L). Brain magnetic resonance imaging (MRI) showed bilateral thalamic and dorsal pontine hyperintensities on T2-weighted sequences (Fig. 1). Cerebrospinal fluid (CSF) analysis showed normal cell count, lactate, and biochemistry results, with negative Japanese encephalitis serology, viral and bacterial polymerase chain reaction (PCR) testing, and autoimmune encephalitis panel. Electroencephalography (EEG) showed a burst-suppression pattern following anesthetic infusions (midazolam and ketamine) (Fig. 2).
Brain magnetic resonance imaging of case 1 performed on day 5 of illness, showing a T2-weighted axial sequence with ill-defined areas of hyperintensity in the bilateral thalami (arrow showing right thalamic hyperintensity) (A), and a T2-weighted axial sequence with dorsal pontine hyperintensity as shown with arrow (B).
Continuous electroencephalography tracing of case 1 (high-pass filter 70 Hz, low-pass filter 1 Hz, sensitivity 7 µV/mm, speed 30 mm/sec), showing a burst-suppression pattern.
The child received intravenous immunoglobulin and pulse methylprednisolone without a significant response. Based on the brain MRI findings, which were suggestive of acute necrotizing encephalopathy of childhood with elevated interleukin-6, tocilizumab was administered without a significant response. Valproate was initiated briefly but discontinued because of worsening AST and ALT (550 and 445 U/L). Whole-exome sequencing was performed in view of the atypical disease course and family history of epilepsy and revealed a homozygous pathogenic POLG mutation (c.3287G>T; p.Arg1096Leu). The child was started on mitochondrial supplements and a ketogenic diet, with avoidance of mitochondrial toxins. Gradual clinical improvement was noted, and the child remains in follow-up with seizure control.
Case 2: A 3-year-old boy, second in birth order and born to non-consanguineous parents, presented with right focal seizures with impaired consciousness that progressed to bilateral tonic-clonic seizures. Episodes began with eye deviation to the right, followed by jerking of both the upper and lower limbs, and lasted 5 minutes. He had baseline global developmental delay and a 2-month history of intermittent fever and lethargy. There was no significant family history.
Head circumference was below the 3rd percentile. Investigations showed abnormal liver function tests (AST, 126 U/L; ALT, 102 U/L). EEG showed diffuse background slowing with right parieto-occipital discharges. Brain MRI demonstrated dorsal pontine hyperintensity on T2/fluid-attenuated inversion recovery sequences, with cortical and subcortical diffusion restriction in the right parieto-occipital region on diffusion-weighted imaging/apparent diffusion coefficient maps (Fig. 3). CSF analysis showed elevated protein (1.41 g/L), with normal glucose, cell count, and lactate. Human herpesvirus 6 (HHV-6) was detected by PCR in CSF and was treated with ganciclovir for 14 days. Given the baseline global developmental delay, microcephaly, and transaminitis, an alternative diagnosis was also considered, with the possibility that HHV-6 unmasked an underlying disorder.
Brain magnetic resonance imaging of case 2 performed on day 7 of illness, showing a fluid-attenuated inversion recovery axial sequence with dorsal pontine hyperintensity as indicated by the arrow (A), and an apparent diffusion coefficient axial sequence with diffusion restriction along the right parieto-occipital gyri as shown by the arrow (B).
Metabolic evaluation was unremarkable except for elevated lactate (4.55 mmol/L). Valproate therapy led to worsening AST and ALT and was therefore discontinued. Whole-exome sequencing identified a homozygous pathogenic POLG mutation (c.911T>G; p.Leu304Arg). The child was initiated on mitochondrial supplements and continues to be followed while receiving anti-seizure medications and physiotherapy. Both cases are summarized in Table 1.
Comparative summary of the two cases presented
Mitochondrial diseases in childhood pose considerable diagnostic and therapeutic challenges because of their heterogeneous clinical features. POLG is responsible for mitochondrial DNA replication and repair; dysfunction leads to impaired oxidative phosphorylation and energy failure in high-demand tissues such as the brain and liver [1]. Seizures, particularly status epilepticus (SE), are often a presenting feature and may be precipitated or worsened by valproate, which can lead to acute liver failure in these patients [2,3]. The management of SRSE involves terminating seizures, maintaining hemodynamic stability, and identifying the underlying etiology.
Both children in this series presented with refractory seizures and hepatic dysfunction, although with differing phenotypes. The first child developed SRSE with bilateral thalamic involvement, mimicking immune-mediated encephalopathy, whereas the second child presented with focal epilepsy and cortical diffusion restriction, initially suggestive of viral encephalitis. Bilateral thalamic involvement and cortical diffusion restriction, as seen in these cases, have been described in mitochondrial encephalopathies and may be mistaken for inflammatory or infectious etiologies. Suspicion for POLG-related disease should arise in children with refractory seizures or SE, transaminitis, elevated lactate, and bilateral thalamic or brainstem MRI changes with negative or inconclusive infectious and autoimmune work-up, particularly when valproate worsens liver function or there is a suggestive family history. Even when an etiologic agent is identified in the presence of red-flag signs, an underlying neurometabolic etiology should be considered. As previously reported, an underlying POLG mutation may be unmasked by HHV-6 infection (as in case 2), as viral reactivation has been observed in mitochondrial disorders [4]. Early genetic testing is warranted in this clinical constellation to avoid treatment delays and prevent exposure to mitochondrial toxins.
A review of 372 patients with POLG-related epilepsy reported a median age at onset of 2 years [5]. Seizures were the initial clinical manifestation in 50% of patients, and 37 (10%) had POLG-related SE [5]. In a multinational study of 195 patients with POLG disease, 67% had epilepsy, with SE occurring in 77% of those with epilepsy [6]. SE was the presenting symptom in 43%, and most patients (66%) had refractory or super-refractory SE [6].
Management of POLG-related disorders is largely supportive and includes seizure control, avoidance of mitochondrial toxins, nutritional support, physiotherapy, and mitochondrial supplements such as coenzyme Q10 and levocarnitine, as well as ketogenic diet therapy and L-arginine [7]. Immunotherapy may be attempted when autoimmune encephalitis is suspected, as described herein. The decision to use immunomodulators should be carefully weighed once a genetic etiology is confirmed.
The prognosis of POLG-associated SRSE is generally poor, with refractory seizures and neurodegeneration [7]. However, early identification of the genetic basis allows avoidance of potentially harmful drugs such as valproate, appropriate family counseling, and informed future reproductive decisions.
The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient’s guardian has given consent for the child’s images and other clinical information to be reported in the journal. The patient’s guardian understands that the child’s name and initials will not be published and that due efforts will be made to conceal the child’s identity; however, anonymity cannot be guaranteed.
The authors declare that the research presented in this manuscript adheres to the ethical principles outlined by the Institutional Ethics Committee of Sir Ganga Ram Hospital. All procedures involving human participants were conducted in accordance with the ethical standards of Sir Ganga Ram Hospital, New Delhi, India; Ganga Ram Institute of Postgraduate Medical Education and Research (GRIPMER); and the Declaration of Helsinki (1964), as revised in 2013. Informed consent was obtained from the parents for publication.
Notes
Conflicts of interest
No potential conflict of interest relevant to this article was reported.
Author contribution
Conceptualization: AE and PK. Data curation: RJ and DA. Formal analysis: PK. Methodology: AE. Writing - original draft: RJ and DA. Writing - review & editing: AE and PK.