Excitotoxicity in Acute Encephalopathy with Biphasic Seizures and Late Reduced Diffusion

Abstract

SUMMARY:Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a recently described clinicoradiologic syndrome. MR spectroscopy in 3 patients with AESD revealed decreased N-acetylaspartate (NAA) and elevated glutamine/glutamate complex (Glx) during the week of presentation. Afterward, Glx normalized, whereas NAA remained low in 2 patients with neurologic sequelae but nearly normalized in the third patient without neurologic sequelae. These findings support the hypothesis that excitotoxic neuronal damage plays an important role in the pathogenesis of AESD and suggest that MR spectroscopy might be predictive of outcome.A n acute encephalopathy syndrome characterized by biphasic seizures and late reduced diffusion (AESD) was recently reported in 17 Asian children. The syndrome is characterized by a prolonged (Ͼ30 minutes) febrile seizure as the initial neurologic symptom on day 1, followed by secondary seizures (most often in a cluster of complex partial seizures) at days 4 -6; affected children display variable levels of neurologic sequelae.1,2 MR imaging shows no acute abnormality during the first 2 days; reduced diffusion appears in the frontal or frontoparietal subcortical white matter, with sparing of perirolandic region, during days 3-9, then disappears between days 9 and 25. Ultimately, patients develop cerebral atrophy. Other reports have described patients with closely related entities, such as acute encephalopathy with febrile convulsive status epilepticus (AEFCSE).3 Recently, a mild form of AESD with a brief initial febrile seizure (non-status epilepticus) and the absence of permanent neurologic sequelae has also been reported, 2 suggesting that AESD has a wider spectrum than AEFCSE.The exact pathogenesis of AESD is uncertain; excitotoxic injury with delayed (or apoptotic) neuronal death is hypothesized as a possible mechanism.3 Elevated glutamine (Gln)/ glutamate (Glu) complex (Glx, at 2.1-2.5 and 3.8 ppm on MR spectroscopy) was reported in 1 patient with AESD.1 We performed MR spectroscopy in 3 additional patients with AESD to evaluate metabolites in vivo and to test the hypothesis that excitotoxicity is the mechanism of pathogenesis. Case Reports Patient 1A previously healthy 2-year-old Japanese girl presented with a generalized tonic-clonic seizure, lasting an hour, following a 7-hour prodromal illness consisting of a high fever, cough, and rhinorrhea. Blood and CSF examinations findings were normal. Electroencephalography (EEG) showed diffuse high-voltage slow waves. A rapid antigen-detection assay from a nasopharyngeal swab revealed influenza A. She became comatose after cessation of the initial seizure. On day 5, she manifested a cluster of partial seizures, each lasting a few minutes. MR imaging on day 6 revealed reduced diffusion (Fig 1A, B) and T2 and T1 prolongation diffusely in the subcortical white matter with sparing of the perirolandic region; follow-up MR imaging on day 20 showed mild cortical T2 prolongation with mild cerebral atrophy (Fig 1D). On the basis of t...

Differences of Clinical Manifestations According to the Patterns of Brain Lesions in Acute Encephalopathy with Reduced Diffusion in the Bilateral Hemispheres

“…MR spectroscopy has shown increased glutamate concentrations and decreased N-acetylaspartate levels in patients with AESD. 16 However, a prolonged seizure at onset was rare in our patients. Further studies are necessary to clarify the pathogenesis of acute encephalopathy with central-sparing lesions.…”

Prediction of acute encephalopathy with biphasic seizures and late reduced diffusion in patients with febrile status epilepticus

“…The pathogenesis of AESD has been suggested to be related to excitotoxic injury because AESD does not show hypercytokinemia, the IL-6 levels in the cerebrospinal fluid are elevated to protect the brain against the ischemic and excitotoxic damage, and the Glx (glutamate/glutamine complex) on proton MR spectroscopy (MRS) is elevated as an excitatory neurotransmitter [6][7][8]. Many cases of AESD have been reported in Japan.…”

ADORA2A polymorphism predisposes children to encephalopathy with febrile status epilepticus

“…[22][23][24][25] An increase of extracellular glutamate in the brain lesion of AESD has recently been demonstrated by magnetic resonance spectrometry. 5 Involvement of ADORA2A in the pathogenesis of AESD may have therapeutic implications. Experimental studies have previously shown that an ADORA2A antagonist, but not an ADORA1 agonist, can terminate or suppress seizures.…”

“…Cranial MRI reveals high signal intensity lesions in the cerebral subcortical white matter on diffusion-weighted images, which appear around the occurrence of late seizure (figure 1). 5,6 Excitotoxicity is considered to be the main pathologic mechanism of AESD. 2,4 The genetic background of AESD remains to be elucidated.…”