A Young Girl with Acute Encephalopathy Who Presented with Status Epilepticus Following a Flu-Like Illness

Introduction

Acute necrotizing encephalopathy of childhood (ANEC) is a rare type of acute encephalopathy in the pediatric age group, commonly preceded by viral infection. Patients with this disease typically present with altered sensorium levels, seizures, and focal neurological signs [1]. MRI of the brain of a patient with ANEC typically shows bilateral symmetrical involvement of the thalami, with wide spreading to the brainstem in case of fulminant acute necrotizing encephalopathy, which predicts a very poor outcome [2].

Early treatment with high-dose steroid therapy can lead to better outcomes in the absence of brainstem involvement [3,4]. However, extensive involvement of the brainstem region signifies a fulminant and progressive course of ANEC, so early clinical recognition of this condition may lead to a favorable prognosis [5].

We report this case to focus on the early detection and management of such uncommon condition in the pediatric population for a better prognosis.

ANEC mainly occurs in countries like Japan and Taiwan, and it affects newborns and young children [6]. Another study supports that ANEC is common in Japan, where there have been 28 reported cases and 13 patients were treated [7].

Case Report

A previously healthy 5-year-old girl presented to our Emergency Department with a 3-day history of rapid and progressive deterioration in consciousness level. The parents also reported frequent attacks of generalized tonic-clonic convulsion lasting for a few minutes, with up-rolling of the eyes and frothy secretions from the mouth. The family also described a flu-like illness with a mild cough and low-grade fever 1 day prior to her clinical presentation.

Initial physical examination of the patient showed normal vital signs with a normal temperature. Her Glasgow Coma Scale score (GCS) was 12/15 and she had a low sensorium level. Her pupils were equal and reactive to light with occasional horizontal nystagmus, and deep-tendon reflexes were brisk with no clonus and a positive Babinski sign bilaterally.

Tone examination results were normal. Power and gait examination could not be assessed because the patient was encephalopathic. The other results of the systemic examination were unremarkable.

The patient’s initial full blood count showed white blood cells of 3.27×109/L, Hb 12.4 g/L, and platelets of 167×109/L. Her liver function test showed abnormal values with G-glutamyl transferase 430 IU/L (normal range 5–36 IU/L), aspartate aminotransferase 445 IU/L (normal range 0–33 IU/L), and alanine aminotransferase 58 IU/L (normal range 0–33 IU/L). Urea was 6.23 mmol/L, abnormal sodium level was 155.9 mmol/L (normal range 136–145 mmol/L), potassium was 4.06 mmol/L, chloride 100.2 mmol/L, abnormal carbon dioxide was 14.2 mEq/L (normal range 23–29 mEq/L), creatinine was 51.2 umol/L, calcium was 2.35 mmol/L, magnesium was 0.99 mmol/L, phosphate was 1.33 mmol/L, and her abnormal C-reactive protein was 21.3 mg/L (normal range is less than 10.0 mg/L).

A lumbar puncture for cerebrospinal fluid (CSF) study was not done because the patient’s clinical condition was not stable. An urgent brain MRI showed symmetrical bilateral hyper-signal intensities of the thalami with brainstem involvement (Figure 1), while the initial EEG showed an encephalopathic picture (Figure 2).

The patient was started initially on ceftriaxone, vancomycin, and acyclovir, receiving antibiotics and antivirals for 7 days. Based on the patient’s history and brain MRI findings, a diagnosis of acute necrotizing encephalopathy was made. On the first day of admission, she was started immediately on intravenous pulse methylprednisolone 30 mg/kg/d for 3 days within 8 hours of her initial clinical presentation. Based on further clinical deterioration of the patient’s condition as she became more unresponsive and encephalopathic, on the second day of admission, she was given a single dose of intravenous immunoglobulin for 2 g/kg body weight. She was also started on oseltamivir on her first day of admission as well for 5 days, as the respiratory gene Xpert showed she was positive for H1N1.

Unfortunately, the patient’s clinical condition showed further rapid deterioration in her level of consciousness, with a GCS of 8/15, with poor respiratory effort, so she was intubated and connected to a mechanical ventilator. Further examination of her neurological status showed fixed and dilated pupils. Urgent brain computed tomography showed marked brain edema and tonsillar herniation (Figure 3).

On day 5 after admission, the patient’s condition remained critical with no improvement, so she received 5 sessions on alternate days of plasma exchange, with 5% albumin solution on her seventh day of admission. Her repeat brain MRI on day 10 showed a widespread brainstem lesion with hemorrhage and cystic change (Figure 4).

Based on the patient’s clinical condition and the worsening of her brain MRI, a brainstem assessment was done, which showed complete absence of brainstem reflexes. This was confirmed by an EEG showing isoelectric findings (Figure 5).

Discussion

Acute necrotizing encephalopathy of childhood (ANEC) is a devastating disease. Early recognition and providing early treatment help in achieving a better outcome in patients.

Indeed, ANEC is a rare clinical condition of encephalopathy in the pediatric age group in which patients may rapidly progress to a fulminant course of encephalopathy if it is not recognized and diagnosed early. ANEC is usually preceded by viral infection, with human herpes virus-6 being the most common virus associated with ANEC. However, other viruses may be implicated in the pathogenesis of this disease, such as the influenza A virus, coxsackievirus, and herpes simplex virus. Typical clinical presentations of ANEC include rapid deterioration of consciousness, status epilepticus, and focal neurological signs [1]. Our patient presented with rapid-onset deterioration in her sensorium level with status epilepticus, which was proceeded by upper respiratory tract infection and positive confirmation of influenza A virus.

A study in 2015 indicted that acute necrotizing encephalopathy (ANE) has certain diagnostic criteria that physicians can depend on when encountering a patient with this condition. To illustrate, usually a viral illness will be one of the first signs of ANE and it will followed by neurological symptoms like seizures and progressive worsening of their consciousness, high levels of protein in CSF with no pleocytosis, increased aminotransferase level with no hyperammonemia, radiological imaging that shows multifocal, symmetrical brain lesions that include both thalami, involving the internal capsule, cerebral periventricular white matter, upper brainstem tegmentum, putamen and cerebellar medulla, without including the other parts of the central nervous system. Also, it is important to rule out conditions that may give a similar presentation. Differential diagnosis can be divided into clinical and radiological categories. The clinical category includes heat stroke, hemolytic uremic syndrome, toxic shock syndrome, Reye syndrome, encephalopathy syndrome, and hemorrhagic shock. Similarly, radiological (pathological) differentials include Wernicke encephalopathy, Leigh encephalopathy, glutaric acidemia, and acute disseminated encephalomyelitis. Similarly, there are other criteria for acute necrotizing encephalopathy type 1 (ANE1): there should be a positive family history or neurological symptoms occurring at the time of an acute episode of an infection; whenever there is fever, the encephalopathy will reoccur; and MRI changes in these areas show insular cortices, medial temporal lobes, amygdale, external capsule, mammillary, hippocampi, and the spinal cord [8].

Studies have suggested that Asian children were the most affected by this disease, mostly patients in Taiwan and Japan ages 5 months to 11 years old, with the peak age being 6 to 18 months [9,10].

The first case of ANEC in the Bahrain Defense Force Hospital was a healthy 6-year-old girl who had neurological symptoms after an upper viral respiratory tract infection, and neurological imaging showed lesions bilaterally in the thalami, with no brainstem involvement. She was managed with intravenous pulse steroid therapy and fortunately had a full recovery [11]. However, this patient’s brainstem was involved.

Typical MRI findings for patients with ANEC include bilateral symmetrical thalamic lesions with multiple areas of necrosis and edema involving the basal ganglia and the cerebral deep white matter regions. These lesions may include the brainstem in case of fulminant progressive ANEC [2]. Our patient showed typical features of ANEC in her brain MRI, including symmetrical bilateral thalamic lesions and extensive lesions in the brainstem with areas of microhemorrhage and hemorrhagic necrosis.

Early treatment with IV pulse methylprednisolone 30 mg/kg/ day within the first 24 hours of the initial symptoms in patients with ANEC may result in a better outcome in the absence of brainstem lesions [3,4]. However, Gon Lee et al stated that patients with ANE and widespread brainstem involvement are associated with a fulminant progressive course of ANE, the mortality rate for which can reach 40% [5]. Our patient’s brain MRI showed characteristic findings of ANE with extensive brainstem lesions associated with areas of necrosis and hemorrhages, which explained her fulminant, rapidly progressive course with eventual absent brainstem reflexes, despite early and aggressive therapy.

The genetic form of acute necrotizing encephalopathy (ANE1) can result from a missense mutation in the RAN binding protein 2 (RANBP2) gene, which accounts for recurrent acute necrotizing encephalitis in pediatric patients [12]. Levine et al stated that for patients who present with typical clinical and neurological features of ANE, testing for RANBP2 missense mutation is highly recommended [13].

Our patient was tested for possible RANBP2 missense mutation by whole-exome sequence, which showed a negative result. She presented with ANE, which proceeded with status epilepticus, which eventually progressed into a coma, and brain MRI showed symmetrical bilateral thalamic involvement of the brainstem (Figure 1), which is similar to the condition that has been described by Huang et al, who also confirmed that the hallmark of ANEC is brain lesions that are bilateral symmetrical, multifocal, and affect the brainstem and thalami. They reported a healthy 3-year-old girl with ANEC after being infected with influenza virus type B, which resulted in severe neurological outcomes [14].

Conclusions

This case report indicates the important role of the rapid neuroradiological imaging in pediatric patients who present suddenly with neurological symptoms and signs. ANEC is a rare condition, and patient history with a recent viral illness and brain imaging are significant and aid in the diagnosis of this disease. Early initiation of treatment is recommended for better outcomes and to avoid mortality.