Tocilizumab in a Child with Acute Leukoencephalopathy with Restricted Diffusion

Takanashi et al.[1] first described 17 children with prolonged febrile seizures followed by seizure clusters after a brief asymptomatic period as a subset of acute encephalopathy syndromes. It has been termed “acute encephalopathy with biphasic seizures and late reduced diffusion” (AESD) or more simply “acute leukoencephalopathy with restricted diffusion” (ALERD).[2] While an initial MRI brain done within 2 days of illness is normal, repeat imaging in the late first and second week shows distinctive diffusion restriction of the cortical and subcortical white matter in a “bright-tree” appearance.[2] It has been documented in 14–16.7% of children with the acute encephalitic syndrome (AES) from Japan and India.[34] Treatment for ALERD has been largely supportive. However, post-encephalitic epilepsy was seen in 23–43.8%, cognitive deficits in 43.8–54.5%, and mortality in 9% of children with ALERD from Japan and India.[345] Interleukin-6 (IL-6) appears to play a pivotal role in the pathogenesis of ALERD.[6] Hence, tocilizumab, an IL-6 inhibitor, appears to be a logical therapeutic option. Tocilizumab has been used effectively in cytokine release syndrome (CRS), especially during the SARS CoV2 epidemic but only once in a child with ALERD.[7] We present our experience with tocilizumab in a child with ALERD. A 24-month-old boy presented with a fever for 2 days followed by left-sided facio-brachial clonic seizures on day 3. He had an unremarkable perinatal, developmental, and past medical history. He was admitted on day 3 and received intravenous midazolam and levetiracetam. Persisting seizures (day 4) required serial loading with intravenous phenytoin, phenobarbitone, and ultimately mechanical ventilation and intravenous midazolam infusion. He also empirically received intravenous ceftriaxone, vancomycin, and acyclovir. Initial hemogram, blood biochemistry, CSF, EEG, and MRI brain were normal. He was extubated after 5 days of ventilation. Persisting encephalopathy prompted the use of intravenous methylprednisolone (30 mg/kg/day for 3 days) and high-dose intravenous immunoglobulin (2 g/kg) on day 8 in view of suspected autoimmune encephalitis. On day 9 of illness, he had a recurrence of fever and left facio-brachial seizures and was referred to our center. In our hospital (day 9), the patient's seizures subsided on reloading with intravenous phenobarbitone though he remained irritable and encephalopathic. Bedside EEG on day 10 was normal. Repeat CSF microscopy and biochemistry (day 10) were normal. CSF multiplex-PCR for neurotropic viruses (adenovirus, chandipura, chikungunya, cytomegalovirus, dengue, enterovirus, Epstein Barr, HHV6, HSV1, HSV2, JCV, JE, measles, mumps, nipah, parecho, rabies, rubela, varicella, and West Nile) and CSF autoimmune panel for anti-NMDA, anti-AMPA, anti-GABA, and anti-VGKC antibodies were negative. A repeat MRI (day 11) revealed diffusion restriction and T2 prolongation of cortical and subcortical regions, especially bifrontal and biparietal hemispheres with relative central white matter sparing suggestive of ALERD [Figure 1]. The serum IL-6 level was 19.96 pg/ml (normal <6). In view of the poor neurological status with persisting encephalopathy and tremulousness, on day 16 our patient was given intravenous tocilizumab (8 mg/kg) after informed consent. Within 24 hours of tocilizumab, his sensorium improved and irritability reduced. He was started on oral prednisolone 1 mg/kg which was tapered over 3 weeks. He continued to improve neurologically with a reduction in tremulousness, irritability, and alertness over the next 5–7 days. Six days after tocilizumab, he started taking it orally and regained eye contact. A repeat serum IL-6 level after 3 days of tocilizumab was 439.06 pg/ml. However, in view of the improved neurological status tocilizumab was not repeated. He was discharged 9 days after tocilizumab on tapering oral steroids, prophylactic cotrimoxazole, and two anti-seizure medications (phenobarbitone 5 mg/kg/day and oxcarbazepine 10 mg/kg/day). On follow-up after 7 days of discharge (17 days after tocilizumab), he could walk independently and speak a few words. At 1-month post-tocilizumab, his motor and language milestones were back to premorbid status and he could speak short sentences and run well. Institutional ethics committee clearance (ECR/204/Inst/M.P./2013/RR-16) was taken for this study and consent was taken from the parents of the child for publication of the case.Figure 1: MRI brain images: (a)–diffusion-weighted image on day 2 of illness was normal, (b and c)–diffusion-weighted images on day 11 showed restricted diffusion in subcortical and cortical regions, (d)–T2-weighted images on day 11 show cortical and subcortical hyperintensities especially in the parietal regionsThe exact pathogenesis of ALERD is yet to be established. Magnetic resonance spectroscopy studies have documented a rise in the Glutamate (Glu)/Glutamine (Gln) peak in patients with ALERD which is not seen in uncomplicated prolonged febrile seizures.[8] CSF IL-6 levels have been noted to be significantly higher in patients with ALERD as compared to patients with prolonged febrile seizures.[6] Overall, the evidence points to an infection-associated excitotoxic neuronal cell death with an important role of IL-6. Tocilizumab is a humanized monoclonal antibody against IL-6 and is approved in juvenile idiopathic arthritis. In pediatrics, the dose is 8–12 mg/kg. Doses may be repeated after 2–4 weeks.[9] There is emerging evidence for its use in new-onset refractory status epilepticus with 6/7 patients having a termination of status after 1–2 doses.[9] In our patient, tocilizumab resulted in rapid improvement of the sensorium. The secondary rise in IL-6 levels after tocilizumab is probably because interleukin-6 receptor (IL-6R)-mediated consumption of IL-6 is inhibited by the unavailability of tocilizumab-free IL-6R.[9] We administered only one dose of tocilizumab since our patient showed immediate and sustained improvement. High IL-6 levels post-tocilizumab may be associated with neurotoxicity due to the transfer of IL-6 into the brain, while tocilizumab does not cross the blood–brain barrier.[10] This secondary neurotoxicity has been noted after tocilizumab therapy in the CRS noted after chimeric antigen receptor T cell (CAR T-cell) therapy.[10] In summary, we describe our experience with the use of tocilizumab in a single child with ALERD which suggests a potential role of this drug in this difficult disease. However, central sparing ALERD as in our case has historically better outcomes than diffuse ALERD, and data in larger cohorts would be more revealing. Declaration of patient consent The authors certify that they have obtained all appropriate patient consent forms. In the form, the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest. Acknowledgements All residents of the department and hospital management.