Unusual presentation of acute encephalopathy with biphasic seizures and late reduced diffusion in Miller–Dieker syndrome

Abstract

Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is a unique subtype of acute encephalopathy that occurs in children. A girl aged 2 years and 8 months with Miller-Dieker syndrome (MDS) was admitted for status epilepticus and high fever. Brain MRI performed on the third day postadmission showed abnormally high intensities in the subcortical white matter on diffusion-weighted images. Acute encephalitis/encephalopathy was diagnosed based on the electroencephalography (EEG) findings of diffuse high-voltage delta waves. Six days postadmission, frequent apnoeic episodes were observed, with oxygen desaturation due to cluster seizures. Subclinical seizures were found on amplitude-integrated EEG (aEEG). The disturbance of consciousness was difficult to recognise because of severe developmental disabilities due to MDS. EEG aids in the evaluation of consciousness, and aEEG can be helpful in monitoring and controlling subclinical seizures in the biphasic phase of AESD, especially in patients with underlying neurological disorders.

Background

Miller–Dieker syndrome (MDS) is a contiguous gene deletion syndrome of chromosome 17p13.3, characterised by classical type I lissencephaly, severe developmental delay, seizures, cardiac defects and dysmorphic facial features including bitemporal hollowing, prominent forehead, furrowed brow, short nose with anteverted nares, prominent upper lip and small jaw.^1–3 Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) is an established encephalopathy syndrome that is diagnosed based on its clinical manifestations and imaging findings.^{4 5} Acute encephalopathy/encephalitis, including AESD, has not been reported in patients with MDS, although symptoms associated with the central nervous system, including those of different epilepsy phenotypes,⁶ are common. Here, we describe the neurophysiological and neuroimaging findings of a young patient with MDS who developed AESD, which is a unique subtype of acute encephalopathy in children.

Case presentation

A girl aged 2 years and 8 months, born at 37 weeks of pregnancy with birth weight of 1844 g, was admitted to the neonatal intensive care unit for low birth weight and respiratory distress. MDS was diagnosed by brain magnetic resonance imaging (MRI) (figure 1) and fluorescence in situ hybridisation (FISH) after noting microcephaly, a narrow forehead, small nose and chin, and cardiac malformations. Her family history was unremarkable.

Figure 1.

MRI at 28 days after birth. T1-weighted imaging (A) and T2-weighted imaging (B) shows lissencephaly.

At the age of 5 months, she presented with repeated afebrile seizures, which led to a diagnosis of epilepsy. Before the onset of acute encephalopathy, generalised seizures occurred a few times each week; these were treated with zonisamide and levetiracetam. An awake EEG showed background theta activity (50–150 µV) with superimposed 18–20 Hz fast activity (figure 2). She could pursue objects and ingest food orally but could not hold her head up and exhibited severe motor and intellectual disabilities. At the age of 2 years and 8 months, she was admitted to the hospital for status epilepticus with a fever of 40°C.

Figure 2.

Awake electroencephalography at the age of 1 year and 7 months. Electroencephalography shows background theta activity (50–150 µV) with superimposed 18–20 Hz fast activity.

Investigations

The seizures continued for more than 1 hour until intravenous diazepam and phenobarbital were administered. Three days postadmission, MRI was performed because she had not opened her eyes and was minimally responsive to stimulation, despite the disappearance of the seizures. Her Glasgow coma scale score was 5/15 (E1V1M4), indicating severe injury. Diffusion-weighted imaging (DWI) MRI revealed abnormally high intensities in the frontal subcortical white matter, and an apparent diffusion coefficient (ADC) map indicated reduced ADC values for the lesion (figure 3). Acute encephalitis/encephalopathy was diagnosed based on the EEG findings of diffuse high-voltage delta waves without seizure activity (figure 4), which have been reported as the EEG findings in acute encephalopathy cases previously.⁷ Her cerebrospinal fluid (CSF) contained 5 cells/mm³, 10 mg/dL of protein and 66 mg/dL of glucose.

Figure 3.

MRIon the third day postadmission, diffusion-weighted imaging (DWI) (repetition time, (TR)/echo time (TE) 2800/88; B value=1000) (A) and the apparent diffusion coefficient (ADC) MAP (B) shows abnormally high intensities in the frontal subcortical white matter. on the sixth day postadmission, DWI (TR/TE 2800/88; B value=1000) (C) and the ADC MAP (D) shows abnormally diffuse high intensities in the subcortical white matter, predominantly in the frontal areas.

Figure 4.

Electroencephalography and amplitude-integrated electroencephalography. (A) Electroencephalography on the third day postadmission shows diffuse high-voltage delta waves with no seizure activity. (B) On the sixth day postadmission, amplitude-integrated electroencephalography shows a ‘saw-tooth’ (arrows) pattern, indicating seizures. The seizures were suppressed by treatment with intravenous midazolam administration.

Treatment

The patient was treated with methylprednisolone pulse therapy (30 mg/kg/day for 3 days), immunoglobulin (1 g/kg, one dose) and acyclovir infusion. She opened her eyes slightly 3–4 days after admission but remained minimally responsive to stimulation. Six days postadmission, frequent apnoea episodes were observed, with oxygen desaturation for approximately 30 s, which were sometimes accompanied by jerking of the eyelids. Amplitude-integrated EEG (aEEG) monitoring indicated that the apnoea episodes were caused by seizures, and AESD was diagnosed based on the clinical course. The apnoea episodes were suppressed by continuous intravenous midazolam administration (0.18 mg/kg/hour); subclinical seizures were then detected via aEEG monitoring. These were controlled by increasing the dose of continuous intravenous midazolam administration (0.27 mg/kg/hour) (figure 4). DWI MRI revealed diffuse abnormally high intensities in the subcortical white matter. Rapid antigen tests for influenza and respiratory syncytial virus and antibody tests for herpes simplex virus and Epstein-Barr virus were negative. CSF and blood samples tested negative for herpes simplex virus in the PCR analyses. No apnoea episodes were noted after continuous intravenous midazolam administration and so it was discontinued 11 days postadmission.

Outcome and follow-up

Twenty-nine days postadmission, MRI revealed brain atrophy and diffuse abnormally high intensities in the subcortical white matter. The patient was discharged from our hospital 35 days after admission. One year postadmission, she could no longer pursue objects and required tube feeding. She had generalised brief tonic seizures more than 10 times a day despite treatment with anticonvulsant agents (valproate, levetiracetam, topiramate and perampanel).

Discussion

AESD is an established encephalopathy syndrome that is diagnosed based on its clinical manifestations and imaging findings. The initial presentation includes prolonged febrile seizures, followed by clustered seizures after several days (biphasic seizures). When consciousness deteriorates 3–7 days after the onset of AESD, MRI shows restricted diffusion that most frequently involves the frontal or frontoparietal subcortical white matter, while sparing the perirolandic cortex, also called the ‘bright tree’ appearance.^{4 5} In our case, subsequent clustered seizures with high DWI signals in the subcortical white matter were recognised 5 days after the patient had presented status epilepticus with high fever. This clinical course was consistent with AESD diagnosis. The imaging findings were considered unique due to the presence of lissencephaly in a case of MDS. Delayed neuronal cell death due to excitotoxicity is assumed to be the pathomechanism of AESD, based on MR spectroscopy, showing increased glutamate followed by increased glutamine.⁸ DWI findings in the subcortical white matter may reflect excitotoxicity rather than the direct result of secondary seizures.

Patients with underlying neurological disorders accounted for 25.4% of the acute encephalopathy cases (14/55). Moreover, they had a propensity for augmented neuronal hyperexcitability in acute encephalopathy, such as AESD and hemiconvulsion–hemiplegia syndrome.⁹ In our case, the disturbance of consciousness was not discovered until 3 days postadmission, because of the patient’s severe motor and intellectual disabilities attributable to MDS. Although consciousness can be evaluated easily in patients with normal development, it may be difficult to evaluate the deterioration of consciousness in those exhibiting extremely severe developmental delay. EEG might be useful in diagnosing acute encephalopathy when episodes involve suspected deterioration of consciousness (eg, when reduced responsiveness after status epilepticus is recognised in a patient with severe motor and intellectual disabilities).

In this case, the cause of apnoea episodes was not determined until aEEG monitoring revealed that the episodes were related to the seizures. A previous report described a case of clustered seizures with apnoea accompanied by staring and bradycardia in a patient with clinical signs compatible with those of biphasic seizures, who was equivocally diagnosed with AESD.¹⁰ Komatsu et al reported that aEEG was useful in monitoring children with AESD. Moreover, it might reveal subsequent cluster seizures and facilitate objective evaluation of the efficacy of antiepileptic drugs.¹¹ In this patient, aEEG monitoring was also useful for determining the appropriate treatment for seizures, as the subclinical seizures remained even after continuous intravenous midazolam administration had eliminated the apnoea episodes. Furthermore, aEEG monitoring was useful for recognising frequent apnoea as a symptom of partial seizures.

In conclusion, we reported the case of a patient with MDS who developed AESD. There have been no further reports of concurrent MDS and AESD in the patient. Because disturbances of consciousness might be difficult to recognise in patients with severe motor and intellectual disabilities, such as those with MDS, EEG may be useful for evaluating consciousness. Furthermore, aEEG enables continuous monitoring of patients with AESD, thereby aiding the appropriate evaluation of the treatment efficacy.

Learning points.

• Consciousness evaluation might be difficult to recognise in children with severe motor and intellectual disabilities (eg, Miller–Dieker syndrome).

• Electroencephalography is useful for evaluating consciousness and diagnosing acute encephalopathy.

• Amplitude-integrated electroencephalography can be helpful in monitoring and controlling subclinical seizures.

Ethics statements

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Consent obtained from parent(s)/guardian(s).