* Correspondence to last author at Departments of Neurology and Pediatrics, University of Virginia Health System, PO Box 800394, Charlottesville, VA 22908, USA. E-mail: firstname.lastname@example.org
We report an 18-month-old Japanese female living in the USA whose clinical course and radiographic findings were consistent with acute encephalopathy with biphasic seizures and late reduced diffusion (AESD). She was initially diagnosed with complex febrile seizures. However, on day 3 of admission, she had a cluster of complex partial seizures and the onset of a global developmental regression. In contrast to the normal magnetic resonance image of the brain obtained on admission, subsequent imaging demonstrated transient subcortical diffusion-weighted abnormalities in the white matter of the bilateral posterosuperior frontal, parietal, temporal, and occipital regions, with sparing of the perirolandic area. One year later, her developmental delay, although improved, persisted and she continued to experience sporadic seizures while being treated with topiramate monotherapy. Repeat imaging showed diffuse, poorly defined, increased T2 signals in the white matter of the posterosuperior frontal, parietal, temporal and occipital regions and diffuse cerebral volume loss. Previous reports of AESD have been limited to children aged under 4 years living in Japan. With the identification of this case, it is important that all physicians, not only those in Japan, who care for children with febrile seizures be aware of AESD and its associated neurological morbidity.
Even when prolonged, the short-term outcome after a febrile seizure is usually excellent.1,2 However, occasionally febrile seizures herald Dravet’s syndrome or, in a few cases, the later development of mesial temporal lobe epilepsy. Recently, an acute encephalopathy syndrome presenting as a febrile seizure followed within several days by a cluster of secondary seizures and late diffusion-weighted magnetic resonance image (MRI) abnormalities (AESD) has been described in a cohort of Japanese children.3–5 Most of these children had new-onset neurological sequelae that included mental retardation*, hemiparesis, and epilepsy.
We report an additional Japanese child living in the USA presenting with a prolonged febrile seizure whose subsequent clinical course and radiographic findings were consistent with those of AESD.
Informed consent was obtained from the father for the publication of his child’s case history.
An 18-month-old, previously healthy, Japanese female was transferred to our facility for additional management of a complex febrile seizure. She had been living in the USA for approximately 4 months and had a history of a single, simple febrile seizure at 11 months of age.
The day before presentation she received the diphtheria, tetanus and acellular pertussis immunization. On the day of admission, she had a self-limited secondarily generalized seizure of 5 to 10 minutes that started with clonic movements of the left upper extremity. She was taken by private car to an emergency department where a second seizure occurred, resulting in prompt treatment with diazepam and subsequent intubation. While being transported to our facility, a third event began. Upon arrival at our facility’s emergency department, there was clonic jerking of the upper and lower extremities, with deviation of the eyes up and to the right. The estimated duration of this third event was approximately 30 minutes. It was refractory to typical doses of benzodiazepines and subsequently controlled with boluses of intravenous propofol. Her lowest recorded blood pressure during the administration of the propofol was 63/36. Her temperature at the time of transfer was 40.1°C. Additional details about the onset of the second and third seizures were not present in the medical record, and parents did not observe the onset of these events.
Evaluation of blood, urine, and cerebrospinal fluid were negative for an infectious etiology. Specific titers and polymerase chain reaction for human herpes viruses 6 and 7 were not performed. Serum chemistry, complete blood count, and liver enzymes were unremarkable. An initial electroencephalogram (EEG) obtained approximately 12 hours after the termination of the third, prolonged seizure displayed bilateral hemispheric slowing. Brain MRI on day 1 of admission was normal (diffusion-weighted imaging not done).
Initially, she was observed in the University of Virgina Children’s Hospital Pediatric Intensive Care Unit. Clinically, she was deemed well enough to be transferred to the hospital ward on the second day of admission. Although she had not returned to her baseline mental status, it was improving and she was beginning to interact with her family.
Late on the third day, the infant had two complex partial seizures of less than 5 minutes each, characterized by clonic movements of the right upper extremity and alteration of consciousness which terminated with the administration of diazepam intravenously. Between the seizures, which were separated by 4 hours, and after the second seizure, she was documented as lethargic.
A second EEG displayed frequent bilateral parieto-occiptal spikes and generalized slowing of the background. On repeat brain MRI (day 4), there were diffusion-weighted abnormalities with corresponding T2 hyperintensities in the white matter of the bilateral parietal and temporal lobes and lesser involvement of the posterosuperior frontal and occipital regions (Fig. 1a–c). The perirolandic regions were spared and there was no abnormal contrast enhancement.
After these seizures, she displayed severe motor regression of the right upper extremity with associated hypotonia and ataxia, verbal regression, reversed sleep-wake cycle, and she was unable to fixate visually on objects. Flash-visual evoked potentials were normal.
On brain MRI obtained upon transfer to a rehabilitation facility (day 15), the previous white-matter diffusion-weighted image abnormalities had become isointense and the cortex in the posterosuperior frontal, parietal, temporal, and occipital regions now displayed mildly high signal on both diffusion-weighted image and T2 sequences. Diffuse volume loss and cerebral atrophy were also noted.
One year later, she continued to have sporadic, complex partial seizures with rare secondary generalization controlled with topiramate. She displayed global developmental delay; however, she was regaining use of her right arm, using one- to two-word verbal phrases, showing improved visual acuity, and was able to walk up steps. Repeat brain MRI showed diffuse, poorly defined, increased T2 signal in the white matter of the posterosuperior frontal, parietal, temporal, and occipital regions, and mild, diffuse cerebral volume loss (Fig. 1d). Diffusion-weighted images were normal.
This child had an initial diagnosis of complex febrile seizures based on the description of focal onset with the first event, recurrent seizures within 24 hours, and the duration of the third event. Her initial evaluation and early clinical course were consistent with this diagnosis. However, the occurrence of a cluster of complex partial seizures late on the third day of admission, the presence of new diffusion-weighted signal abnormalities on repeat MRI of the brain, and her subsequent course were most consistent with AESD.3,4
AESD is an encephalopathy syndrome characterized both by its clinical manifestations and by imaging findings. The initial presentation, with exception,4 is a prolonged febrile seizure followed by a cluster of secondary seizures several days later (biphasic seizures). Neurological outcome has ranged from normal to new onset severe mental retardation, hemiparesis, spastic quadriplegia, and epilepsy. So far, children with AESD have all been under 4 years of age and of east Asian descent. A source of infection, including influenza A and human herpes virus 6, has been identified in over half of the cases.
MRI obtained soon after initial presentation and before the cluster of secondary seizures was normal. After the secondary seizures, the MRI was abnormal with reduced diffusion that has most frequently, but not exclusively, been observed in the frontal or frontoparietal subcortical white matter with sparing of the perirolandic region. It has been posited that these diffusion abnormalities were the result of glutamate-induced astrocytic swelling and edema.3 Later, imaging demonstrates resolution of the diffusion-weighted abnormalities and the presence of generalized atrophy.
As the clinical presentation and imaging findings of AESD overlap with other acute encephalopathy syndromes, such as acute infantile encephalopathy predominantly affecting the frontal lobes,6 acute encephalopathy of obscure origin,7 and hemiconvulsion-hemiplegia-epilepsy syndrome,8 it is likely that it is part of a spectrum of disorders that share a common final pathophysiological process resulting in cerebral injury with resultant atrophy. In our patient, the initial prolonged seizure occurred after vaccination for diphtheria, tetanus, and acellular pertussis. A source of infection was not isolated and she presented outside the usual period for influenza in this country. This suggests that the pathophysiological mechanism of AESD does not require direct infection of the central nervous system. In addition, this patient’s east Asian descent supports the previous hypothesis of an underlying genetic predisposition for the development of AESD.3
An unusual component of the clinical history in this patient was the inability to fixate on objects. The normal flash-visual evoked potentials suggest that the primary visual pathway was intact and that this symptom resulted from dysfunction of visual cortex or secondary visual areas. In addition, in this patient, a potential alternative explanation for the late MRI findings is hypoxic–ischemic injury resulting from hypotension associated with the intravenous bolus of propofol used to terminate the initial prolonged seizure. However, this mechanism is not completely consistent with the extent of the diffusion-weighted abnormalities, with the relative sparing of the watershed regions, and the severity and duration of the hypotension.
To our knowledge, this report is the first to describe a patient diagnosed with AESD in the USA. Therefore, all physicians, not only those in Japan, should be familiar with this syndrome and its associated neurological morbidity. The identification of additional patients with AESD is required to define the pathophysiological mechanism better.
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HPG receives funding from the National Institutes of Health (NS-048413).