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Autopsy findings of a patient with acute encephalitis and refractory, repetitive partial seizures

Open ArchivePublished:January 07, 2016DOI:https://doi.org/10.1016/j.seizure.2016.01.005
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS) is a peculiar form of encephalitis described by Sakuma [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ]. Patients with AERRPS present with sudden onset of repetitive partial seizures after an infection. Seizures are hardly controlled at onset and continue to evolve into post-encephalitic epilepsy without a latent period. Similar conditions have been reported under several different names, such as new-onset refractory status epilepticus (NORSE) [
      • Wilder-Smith E.P.
      • Lim E.C.
      • Teoh H.L.
      • Sharma V.K.
      • Tan J.J.H.
      • Chan B.P.L.
      • et al.
      The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
      ], devastating epilepsy in school-age children, febrile infection-related epilepsy syndrome (FIRES) [
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ] and fever-induced refractory epileptic encephalopathy in school-aged children.
      Although inflammation, neuronal hyperexcitability and epileptic processes have been considered as the mechanisms resulting in AERRPS, the underlying pathogenesis is poorly understood [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ]. We encountered a patient with AERRPS who died from drug-induced multiple-organ failure. The autopsy revealed extensive multifocal cortical lesions along with hippocampal damage. The findings may help to clarify the pathophysiology of the early formation of epileptogenic networks without a latent period.

      1. Case report

      The patient was an 11-year-old boy with no personal or family history of neurological disorders. He was admitted with sudden onset of clustering partial seizures preceded by a 4-day history of fever. Seizures consisted of focal clonic seizures in the upper or lower limbs followed by generalized convulsions lasting 1–5 min. At onset, seizures appeared every few hours, increasing to 1–2 times every hour within 3 days. Although the patient was alert on admission, his level of consciousness gradually decreased with an increasing frequency of seizures. The level of consciousness deteriorated to E1V1M3 on Glasgow Coma Scale on the second day, but the level of consciousness seemed to be affected by the frequent seizures and medication.
      Blood examinations revealed a white blood cell count of 13,300/μl and a serum C-reactive protein level of 1.3 mg/dl, with normal liver and kidney functions. Analysis of cerebrospinal fluid (CSF) showed 5 cells/μl and normal glucose and protein levels. PCR analysis of blood and CSF was carried out for herpes simplex virus, human herpesvirus (HHV)-6, HHV-7, cytomegalovirus, and Epstein–Barr virus, yielding negative results for all. Brain magnetic resonance imaging (MRI) performed on admission showed no abnormalities. Interictal electroencephalogram (EEG) showed continuous frontal-dominant high-voltage slow waves. Ictal EEG revealed left central fast waves with right leg motor seizures or left occipital fast waves without clinical manifestations.
      Intravenous diazepam, midazolam, phenytoin, phenobarbital and steroid pulse therapy failed to control seizures. Continuous intravenous thiamylal was started on day 5 after onset and clinical and electrographic seizures were controlled with induction of a burst-suppression EEG pattern with a 6 mg/kg/h thiamylal. Thiamylal is a barbiturate used for anesthesia and the clinical efficacy is considered equivalent to thiopental. Diffusion-weighted MRI on day 7 showed areas of signal hyperintensity bilaterally in the hippocampus, amygdala and pulvinar of the thalamus (Fig. 1a ). Burst-suppression pattern was kept for 6 days by 2 weeks thiamylal infusion, and we started phenobarbital by nasogastric tube to replace thiamylal. On day 2 after starting phenobarbital, the patient developed systemic skin eruptions. The next day, the patient presented with rhabdomyolysis, hepatic and renal failure, and disseminated intravascular coagulation. Brain MRI at 1 month after onset of multiple-organ failure showed diffuse cerebral atrophy, particularly in bilateral hippocampi. Fluid-attenuated inversion recovery (FLAIR) imaging revealed hyperintensity in the pons (Fig. 1b). Drug lymphocyte stimulation testing, which is an in vitro method for identification of allergy to a specific drug, yielded positive results for thiamylal and negative results for phenobarbital. PCR analysis of blood showed negative results for reactivation of HHV-6. Although continuous hemodiafiltration and plasma exchange were performed, the patient died 2 months after admission.
      Figure thumbnail gr1
      Fig. 1MRI findings on day 7 (a) and at one month after onset (b). (a) Axial diffusion-weighted imaging on day 7 after onset shows signal hyperintensities bilaterally in the hippocampus, amygdala (left) and pulvinar of the thalamus (right). (b) Axial FLAIR imaging at one month after onset of multi-organ failure reveals diffuse cerebral atrophy (right), particularly in bilateral hippocampi and a hyperintense area in the pons (left), suggesting central pontine myelinolysis.

      1.1 Neuropathology

      After obtaining informed consent from the parents of the patient, autopsy was performed. The brain weighed 1320 g, within the normal range for a boy of this age in Japan (average, 1.4 kg). Significant atrophy of the temporal lobes and enlargement of the lateral ventricles was observed. Histologically, CA1 and CA4 of bilateral hippocampi showed severe neuronal loss and gliosis (Fig. 2a ). Neuronal loss and gliosis were also seen bilaterally in the amygdala, thalamus and cerebellum, but milder than in the hippocampi. Multiple foci of neuronal loss, gliosis and microglial proliferation were apparent in the frontal, parietal, temporal and occipital neocortices (Fig. 2b). These multifocal lesions were 1–2 mm in diameter. Although cryptococcus, cytomegalovirus, toxoplasma and multiple micro-abscesses were seen in multiple areas, no findings of meningoencephalitis with these pathogens were seen. Pons showed central pontine myelinolysis.
      Figure thumbnail gr2
      Fig. 2Histological findings with GFAP immunostaining. (a) CA1 of the hippocampus shows severe neuronal loss and gliosis. (b) Frontal cortex shows multiple foci of neuronal loss and gliosis (arrows).

      2. Discussion

      No previous studies have described autopsy findings for AERRPS, although autopsy or biopsy findings have been reported from patients with NORSE or FIRES. Wilder-Smith et al. reported autopsy of two patients with NORSE and showed diffuse patchy neuronal cell loss with reactive gliosis [
      • Wilder-Smith E.P.
      • Lim E.C.
      • Teoh H.L.
      • Sharma V.K.
      • Tan J.J.H.
      • Chan B.P.L.
      • et al.
      The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
      ]. Brain biopsy of 13 patients with FIRES revealed gliosis in 7 patients, although the distribution and severity were not described [
      • Kramer U.
      • Chi C.S.
      • Lin K.L.
      • Specchio N.
      • Sahin M.
      • Olson H.
      • et al.
      Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
      ]. The multifocal cortical lesions in our patient are similar to the patchy lesion reported in NORSE, and suggest the same pathomechanisms among AERRPS, NORSE and FIRES, although gliosis is not a specific finding.
      One of the characteristics of AERRPS is continuous evolution from acute symptomatic seizures to chronic focal epilepsy without a latent period [
      • Sakuma H.
      • Awaya Y.
      • Shiomi M.
      • Yamanouchi H.
      • Takahashi Y.
      • Saito Y.
      • et al.
      Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
      ]. The characteristic evolution to refractory focal epilepsy may be explained by functional neuroimaging studies and our pathological study. Positron emission tomography (PET) in FIRES has revealed multifocal cortical hypometabolism [
      • Mazzuca M.
      • Jambaque I.
      • Hertz-Pannier L.
      • Bouilleret V.
      • Archambaud F.
      • Caviness V.
      • et al.
      18F-FDG PET reveals frontotemporal dysfunction in children with fever-induced refractory epileptic encephalopathy.
      ]. The neuroimaging findings suggest functional abnormality in widespread neuronal networks. From our observation of the pathology, the multifocal hippocampal and neocortical lesions adjacent to preserved neurons may lead to early formation of widespread epileptogenic networks without a latent period in patients with AERRPS. The frequent multifocal onset seizures propagating to adjacent areas during acute stage may be one of the factors causing multifocal epileptogenic lesions. On the other hand, the cause of the super-refractory seizures during acute stage in AERRPS cannot be explained by our pathological observation.
      This report has some limitations. Neither cytokine levels of serum and CSF specimens nor tests for autoantibodies such as anti-NMDA or anti-VGKC antibodies that are detected in limbic encephalitis were performed. However, the super-refractory partial seizures and lack of psychotic symptoms occurred in a healthy school-age child favor AERRPS over limbic encephalitis. Additionally, the findings might represent the results of multiple-organ failure, and these findings only can explain the refractory status epilepticus but don’t explain the initial epileptogenesis in the acute phase.
      In conclusion, these findings of extensive multifocal cortical lesions contribute to our understanding of the pathophysiology of AERRPS. Multifocal cortical lesions explain the early formation of epileptogenic networks without a latent period in AERRPS.

      Acknowledgements

      The authors gratefully acknowledge Dr. Hiroshi Sakuma for providing helpful suggestions.
      Conflict of interest statement
      The authors declare no conflict of interest.

      References

        • Sakuma H.
        • Awaya Y.
        • Shiomi M.
        • Yamanouchi H.
        • Takahashi Y.
        • Saito Y.
        • et al.
        Acute encephalitis with refractory, repetitive partial seizures (AERRPS): a peculiar form of childhood encephalitis.
        Acta Neurol Scand. 2010; 121: 251-256
        • Wilder-Smith E.P.
        • Lim E.C.
        • Teoh H.L.
        • Sharma V.K.
        • Tan J.J.H.
        • Chan B.P.L.
        • et al.
        The NORSE (new-onset refractory status epilepticus) syndrome: defining a disease entity.
        Ann Acad Med Singapore. 2005; 34: 417-420
        • Kramer U.
        • Chi C.S.
        • Lin K.L.
        • Specchio N.
        • Sahin M.
        • Olson H.
        • et al.
        Febrile infection-related epilepsy syndrome (FIRES): pathogenesis, treatment, and outcome: a multicenter study on 77 children.
        Epilepsia. 2011; 52: 1956-1965
        • Mazzuca M.
        • Jambaque I.
        • Hertz-Pannier L.
        • Bouilleret V.
        • Archambaud F.
        • Caviness V.
        • et al.
        18F-FDG PET reveals frontotemporal dysfunction in children with fever-induced refractory epileptic encephalopathy.
        J Nucl Med. 2011; 52: 40-47