THE 1ST ADMISSION
A boy had a history of febrile seizures when he was 1 year old, but his family did not go to hospital because his temperature dropped to normal and seizure relieved. Three years later, on December 15, 2016, when the boy was 4 years and 5 months old, he was admitted to hospital for "two intermittent convulsions in one day". One day ago, the child complained of abdominal pain and cough at the beginning of the disease. Then, he suffered from two convulsions, showing sudden disturbance of consciousness, gaze, cyanosis around the lips and the four limbs ankylosis, which lasted for 1-2 minutes and relieved spontaneously. Vital signs were stable except respiratory rate up to 28bpm. Physical examination were normal except poor spirit and hyperemia in pharynx and occasional slight phlegm sounds in both lungs.
Examination: after admission, the child had a brain computed tomography (CT) (Figure 2, A) in the emergency department showing low density lesions in bilateral temporal lobes hippocampus. Due to the abnormal results of CT, further examination of magnetic resonance imaging (MRI) was recommended after 3 days. MRI showed lesions in bilateral temporal lobe hippocampus, insular lobes, ventrolateral thalamus and pons (Figure2, B~H). The child also had a gastrointestinal ultrasonography, electroencephalogram (EEG) and electrocardiogram (ECG). The results were as follows: 1. No abnormality was found in gastrointestinal ultrasonography and ECG. 2. EEG: A large amount of delta slow waves showed in bilateral occipital area and there was no obvious dominant rhythm. In addition, routine examination of blood, urine, stool, blood biochemical (including liver function, renal function, blood glucose and blood ammonia et al) and cerebrospinal fluid (CSF) examination were executed and part of results were listed in Table 2. Blood: c-reactive protein (CRP), creatinine and total bilirubin were lower than normal. AST/ALT, CK-MB and α-HD were higher than normal. CSF: intracranial pressure (ICP), white blood cell count, protein and ammonia were higher than normal, glucose lower than normal and pan test(±).
Table 2
Laboratory evaluation of the patient of two episodes.
Variable
|
Project
|
1st admission
|
State
|
2nd admission
|
State
|
Normal Range
|
Age
|
-
|
4y6mo
|
-
|
7y
|
-
|
-
|
Routine blood examination
|
Neutrophils
|
2.12
|
N
|
8.25
|
↑
|
1.8–6.3×109/L
|
Lymphocyte
|
1.58
|
N
|
2.28
|
N
|
1.1–3.2×109/L
|
Hemoglobin
|
120
|
N
|
133
|
N
|
120-140g/L
|
Platelets
|
160
|
N
|
203
|
N
|
100–300×109/L
|
Blood biochemical examination
|
Lactate
|
3.43
|
N
|
3.87
|
↑
|
1.06-2.09mmol/L
|
Ammonia
|
22.9
|
N
|
34.4
|
N
|
18–72 umol/L
|
CRP
|
0.62
|
↓
|
1.00
|
N
|
0.068-8.2mg/L
|
Homocysteine
|
9.25
|
N
|
NC
|
N
|
<15umol/L
|
CK-MB
|
37
|
↑
|
24
|
N
|
0-24U/L
|
Creatine kinase
|
101
|
N
|
222
|
↑
|
38–174 U/L
|
Crt
|
31
|
↓
|
38
|
↓
|
41–109 umol/L
|
Total bilirubin
|
2.5
|
↓
|
3.8
|
↓
|
5–21 umol/L
|
Glu
|
13
|
N
|
13
|
N
|
10–60 U/L
|
ALT
|
17
|
N
|
14
|
N
|
9–50 U/L
|
AST
|
40
|
N
|
34
|
N
|
15–40 U/L
|
α-HD
|
208
|
↑
|
145
|
N
|
90–180 U/L
|
AST/ALT
|
2.35
|
↑
|
2.43
|
↑
|
0.80–1.50
|
Glucose
|
4.68
|
N
|
13.85
|
↑
|
3.9-6.1mmol/L
|
CSF
|
Aspect
|
transparent
|
N
|
transparent
|
N
|
transparent
|
Pan test
|
weak positive
|
(±)
|
positive
|
( + + )
|
negative(-)
|
White blood cell count
|
20
|
↑
|
6
|
↑
|
0–15×106/L
|
Protein
|
903
|
↑
|
4378
|
↑
|
200-400mg/L
|
Glucose
|
2.16
|
↓
|
3.94
|
N
|
2.5-4.4mmol/L
|
Ammonia
|
124.5
|
↑
|
121.7
|
N
|
111–123 mmol/L
|
Hospital stay
|
-
|
9d
|
-
|
7d
|
-
|
-
|
Outcome
|
-
|
fully recovered
|
-
|
lameness in the right lower limb
|
-
|
-
|
y, year; m, month; NC, not clear; ALT, Alanine aminotransferase; AST, Aspartate aminotransferase; α-HD, α-hydroxybutyrate dehydrogenase; |
Crt, Creatine; CRP, C-reactive protein; CK-MB, creatine kinase MB; Glu, Glutamyltransferase |
THE 2ND ADMISSION
On December 31, 2019, when the child was 7 years old, the patient was readmitted to hospital because of "fever for 2 days and intermittent convulsions for half a day". Two days ago, he had no obvious trigger of fever, the highest temperature was 40℃. The boy complained of abdominal pain as same as the first admission. After 2 days, he deteriorated and developed 6 convulsions within half a day on the day of admission. During attack, he showed gaze, unresponsive, cyanosis around the lips, four limbs ankylosis, and urinary incontinence. Each convulsion lasted 1 minute and relieved spontaneously. After convulsions, he vomited. Vital signs: temperature: 37.0℃, pulse rate: 120bpm, respiratory rate: 18bpm, blood pressure: 135/84mmHg, Glasgow coma score (GCS) 7. Nervous system physical examination: coma, response to stimulation, stiff-neck three transverse fingers, positive in Knig's sign and Brudzinski's sign.
Examination: after admission, the child underwent imaging examinations: brain CT was normal (Figure 3, A). MRI showed multiple lesions in bilateral thalamus, left hippocampus and brainstem (Figure 3, B~F). Laboratory tests was the same as the first admission and results were listed in Table 2. Blood: neutrophils, lactate, creatine kinase, AST/ALT and glucose were higher than normal. Creatinine and total bilirubin were lower than normal. CSF: ICP, white blood cell count, protein and ammonia were higher than normal.
The clinical process can be divided into three stages: prodromal stage, acute encephalopathy stage and convalescent stage. The first stage lasted about 3 days and children had respiratory, gastrointestinal symptoms such as fever, cough and vomit [8]. After a short prodromal period, rapid alteration of consciousness and convulsions occurred. About 30% children may die in acute encephalopathy stage. Among patients who were lucky enough to get through the second period, less than 10% of them recovered completely in the third period [3]. This child admitted to hospital twice for seizures, the first time his prodromal period was so short that the boundary between prodromal and acute encephalopathy stage was not clear. The child showed abdominal pain without any other common prodromal symptoms. At the 2nd admission, he fevered for 2 days and the highest temperature up to 41℃. In acute encephalopathy stage, the child showed 6 seizures and alteration of consciousness.
Most ANE cases are sporadic and will not recur. But the neurological function of a few ANE patients with recurrent encephalopathy deteriorated [9, 10]. For this little boy, he left the right lower limb slightly lameness at the 2nd discharge even though the treatment was similar to the first admission which leaded to fully recovery. A study in Japan, it was pointed out that the independent factors related to the death of ANE included AST > 500U/L, blood glucose > 150U/dl, hematuria/ albuminuria. For this boy, he was not satisfied with any of the independent factors.
In radiological research, the identification of ANE is the most important factor in determining the outcome [11]. Imaging shows multiple and symmetrical lesions located mostly in bilateral thalamus, brain stem, periventricular white matter, cerebellar medulla etc[12]. Thalamus is the most frequently involved area, which can be seen in most ANE patients. The typical signs are “concentric/laminar structure” or “tricolor pattern” in appearance. At the first of admission, the child had a brain CT showing low density lesions in bilateral temporal lobe hippocampus. After 3 days, MRI showed bilateral and symmetrical long T1 signal and long T2 signal in bilateral thalami, insular lobes. Axial fluid attenuated inversion recovery (FLAIR) showed abnormal, high signal of the bilateral thalami, insular lobes, temporal lobes hippocampus and the pons. Apparent diffusion coefficient (ADC) map showed “concentric/laminar structure” in bilateral insular lobes, large areas of restriction of diffusion in bilateral insular lobes and temporal lobes hippocampus. Diffusion-weighted imaging (DWI) showed high signal in the bilateral thalami, insular lobes. The 2st time, brain CT showed normal. But MRI showed long T1 and long T2 signal in bilateral thalamus, left hippocampus and brain stem. FLAIR, ADC, DWI showed high signal. According to the literature, hemorrhagic transformation may occur in the focus. Compared with MRI on the first admission, lesions on the second time were reduced and absorbed. Therefore, the performance was consistent with literature.
Laboratory examination showed that thrombocytopenia, liver enzyme increased but blood ammonia decreased in hematological and increased protein without pleocytosis in CSF [13]. Due to cytokine storms, cytokines may cause damage to multiple organs and lead to the above abnormality. It may show platelets reduced or liver enzymes increased in blood examinations. However, the results of platelet count and liver function were unremarkable during two hospitalizations. CSF protein increased obviously while no pleocytosis is one of the characteristics of ANE. Although the mechanism is unclear, it can help distinguish ANE from other encephalitis such as acute diffuse encephalomyelitis (ADE). CSF showed no pleocytosis and protein results of two admission were 903mg/L, 4378mg/L respectively, which distinguished ANE from ADE. In addition, CSF protein is one of the indexes to predict the prognosis of ANE. Higher CSF protein is associated with worse prognosis. 94% of the seriously ill patients had CSF protein > 0.45g/l [9]. For this boy, CSF protein was much higher than the first one. And he recovered completely the first time but left a sequelae the second time the second time.
We believe that it is necessary to test RANBP2 gene in ANE patients because one of the risk factors of ANE is RANBP2 gene mutation. It is associated with familial ANE and recurrent ANE. In addition, 40% of children carrying RANBP2 mutations are likely to develop ANE and there is a 50% chance of recurring ANE [6]. Moreover, infection-induced acute encephalopathy (IIAE) is a group of neurological diseases caused by infection. IIAE has many subtypes. ANE is one of the subtypes which is known as IIAE3 [9]. As for this family, the boy presented with IIAE3. His grandfather had “viral encephalitis”. His three siblings also showed acute encephalopathy although the cause was unknown. It was a pity that even though we highly suspected that his families carried RANBP2 gene mutation, the little boy and his families did not test RANBP2 gene. Nevertheless, we still believe that it is very important to establish a diagnosis of gene-related ANE [9, 10]. Because genetic test of ANE patient may be a benefit to family members. It provides opportunities for preventive vaccination, early intervention and prenatal detection of ANE. Some experts suggest that children more than 6 months old could be vaccinated against influenza every year, which is meaningful for ANE survivors and caregivers.