Acute necrotizing encephalopathy in children: A case report and literature review

Ping Yuan; Min Zhong

doi:10.4103/ed.ed_20_18

CASE REPORT

Year : 2018 | Volume : 3 | Issue : 4 | Page : 83-87

Acute necrotizing encephalopathy in children: A case report and literature review

Ping Yuan, Min Zhong
Department of Neurology, Children's Hospital of Chongqing Medical University, Ministry of Education Key Laboratory of Child Development and Disorders, Key Laboratory of Pediatrics in Chongqing, Chongqing International Science and Technology Cooperation Center for Child Development and Disorders, Chongqing, China

Date of Submission	28-Sep-2018
Date of Acceptance	12-Nov-2018
Date of Web Publication	25-Jan-2019

Correspondence Address:
Ping Yuan
136#, Zhongshan Erlu, Yuzhong District, Chongqing 400014
China

Source of Support: None, Conflict of Interest: None

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DOI: 10.4103/ed.ed_20_18

Abstract

Acute necrotizing encephalopathy (ANE) is a rare clinical-imaging syndrome with unknown etiology, characterized by acute fulminant severe encephalopathy and brain damage with multifocal symmetry. ANE has no specific clinical symptoms and signs, similar to common encephalitis or encephalopathy symptoms. The characteristic brain imaging examination is diagnostically significant. To date, no specific treatment for ANE is available and the prognosis is poor. Here, we reported a typical case of ANE in a child, and where a good outcome was achieved through combined therapy with immunoglobulin and glucocorticoids.

Keywords: Acute necrotizing encephalopathy, case, children, outcome

How to cite this article:
Yuan P, Zhong M. Acute necrotizing encephalopathy in children: A case report and literature review. Environ Dis 2018;3:83-7

How to cite this URL:
Yuan P, Zhong M. Acute necrotizing encephalopathy in children: A case report and literature review. Environ Dis [serial online] 2018 [cited 2023 Mar 30];3:83-7. Available from: http://www.environmentmed.org/text.asp?2018/3/4/83/250876

Introduction

Acute necrotizing encephalopathy (ANE) is a rare clinical imaging syndrome with unknown etiology characterized by acute fulminant severe encephalopathy and multifocal symmetrical brain damage. Cases have been reported all over the world, with more cases in Asia since the first case was discovered by the Japanese scholar Mizuguchi in 1995.^[1] It is known that no specific treatment for ANE is available and the prognosis is poor. We reported a typical case of ANE in a child with good outcome after anti-cytokine therapy.

Case Report

An 8-month, 2-day-old male child, was admitted to ER with the chief complaint of fever and diarrhea for 3 days, followed by drowsiness and repeated convulsions for 1 day. The child presented clinically with fever, diarrhea and the parents indicated that the child was vomiting 3 days before admission. Preadmission reports indicated that the boy become drowsy and suffered repeated tonic-clonic movements on the day before presenting at the ER. The child was initially treated with a combination of vancomycin, meropenem, mannitol, glycerol, and fructose in the local hospital on the day before transfer. For further management, he was transferred to the present hospital with continuous intravenous infusion of midazolam. The case history revealed that the child had normal intellectual and motor development before the illness onset. His parents denied family history of dyskinesia or mental retardation. The physical examination on admission showed that stable vital signs and no abnormalities were found in the cardiopulmonary and abdomen systems. The child became lethargic and was irritable, with increased muscle tone in his limbs and right hemiplegia after stimulation and arousal. Both pupils were round, equal (0.3 cm) and sensitive to light. Meningeal irritation signs were negative, while bilateral Babinski's signs were positive. Knee tendon reflexes were positive (++). Serum biochemistry revealed white blood cell count 1.91 × 10⁹/L, neutrophils count 0.59 × 10⁹/L, hemoglobin concentration 101 g/L, platelet count 184 × 10⁹/L, calcitonin 25.41 ng/ml, serum glutathione transaminase 71.8 U/L, serum transglutaminase 45.2 U/L, and lactate dehydrogenase (LDH) 359.9 U/L. Renal function, electrolytes, coagulation, blood glucose, blood ammonia, lactic acid, and C-reactive protein were normal. Serum IgM antibody against Coxsackievirus B was positive, while the antibodies against EBV, HSV, and EV71 virus were negative. Antibodies against RSV, adenovirus, influenza virus, and parainfluenza virus were also negative. Bacterial culture of blood and sputum were negative. The concentration of microalbumin in the cerebrospinal fluid (CSF) was 0.52 g/L. No abnormalities were found in routine CSF parameters, viral antibodies or bacterial culture of CSF; neither were there abnormalities on blood tandem mass spectrometry or organic acids in urine. On electroencephalography, background δ and θ activity (2–4 Hz) was found during wakefulness. Brain magnetic resonance imaging (MRI) on the 4^th day of onset revealed a wide symmetrical abnormal signal in the brain, primarily in the thalamus [Figure 1]a,[Figure 1]b,[Figure 1]c. After admission, the child was treated with combined therapy including g-globulin 1 g/kg daily for 2 days, methylprednisolone 10 mg/kg daily for 5 days followed by oral prednisone acetate 1.5 mg/kg daily. Mannitol and fructose glycerol were given to reduce intracranial pressure with the adjunctive treatment of coenzyme Q10, L-carnitine and Vitamin B. MRI re-examination on the 11^th day after onset showed the wide range of brain abnormalities became more focal than prior, accompanied by hemorrhagic foci in bilateral thalamus and corpus callosum [Figure 1]d,[Figure 1]e,[Figure 1]f. No mutation highly-related to acute necrotizing encephalopathy (ANE) was found on Trio clinical exon sequencing or mitochondrial DNA detection. The state of consciousness as well as the signs of provocation, muscle tone, and hemiplegia of the right limb all improved gradually, and he was discharged 22 days after onset. The follow-up after 2 months suggested a 4-months lag behind his peers in physical ability with mild hemiplegia and tremor of the right upper limb. Nevertheless, his cognitive level was near normal. A repeat electroencephalogram found no epileptic discharges. A repeat MRI also revealed that the lesions had significantly absorbed [Figure 1]g,[Figure 1]h,[Figure 1]i.

Figure 1: (a-c) Magnetic resonance imaging on the fourth day of the patient's course with symmetrical abnormal signals in the bilateral thalamus; (d-f) magnetic resonance imaging on the eleventh day of the patient's course with more localized lesions and hemorrhagic signals in the bilateral thalamus; (g-i) the results of reexamination 2 months after onset revealing that the areas of lesions are significantly reduced. T1WI: T1-weighted imaging, T2WI: T2-weighted imaging, DWI: Diffusion-weighted imaging

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Discussion

ANE occurs primarily secondary to viral infection and occurs throughout the year, especially during flu season. The peak age in infants is 6 to 18 months; however, but it is also observed in adolescents and adults. Associated pathogens may include influenza A and B, new influenza A virus (H1N1), parainfluenza virus, herpes simplex virus, varicella-zoster virus, human herpesvirus 6, coxsackievirus, rotavirus, measles virus, rubella virus, Mycoplasma pneumoniae

nd others, however, influenza virus is the most common.^[2],[3],[4] Some studies reported no differences in clinical course or prognosis of ANE between those subtypes caused by influenza virus and those caused by noninfluenza virus.^[5] Therefore, it is thought that the progression of ANE is not dependent on the type of viral infection.

ANE is not caused by direct infection of virus, and its pathological changes primarily include damage to the blood–brain barrier caused by focal vascular injury, plasma exudation, brain edema, dot hemorrhage, and necrosis of neuronal and glial cells. Gross pathological findings show symmetrical encephalomalacia accompanied by partial dissolution of the brain, primarily found in the thalamus, brainstem tegmentum and deep white matter of the brain and cerebellum.^[6] As mentioned earlier, the pathogenesis of ANE remains unknown and is thought to be consistent with the hypercytokinemia hypothesis, i.e., the hyperimmune response induced by cytokine storms^[7] delete after. Cytokine storms cause brain damage by altering vascular permeability, leading to multiple-organ damage, for example liver damage, acute kidney damage, or diffuse intravascular coagulation. In some cases, hemophagocytic syndrome is part of the clinical presentation. In addition, metabolic disorders or mitochondrial dysfunction may be involved in the pathogenesis explaining why brain injury lesions primarily involve anatomical sites with high energy metabolism, including the thalamus and brain stem.

In most cases, ANE occurs sporadically and a higher proportion has been reported in Asia, especially in Japan. This may be ascribed to the genotypes of human leukocyte antigen in the region.^[8] Mutations of RNABP2, SCN1A, and CPT2 genes may be associated with the pathogenesis of ANE.^{[9],[10],[11]} Familial or recurrent ANE cases (named ANE1) have been reported in recent years, and the gene mutation of RNABP2 was demonstrated to play an important role in ANE1 cases.^[3],[12] As the echogenicity, rate of RNABP2 gene is only 40%,^[12] the occurrence of ANE should be the result of interactions of genetic predisposition and environmental factors. In the present case, the child had no family history of ANE. His illness was likely triggered by a gastrointestinal infection based on positive IgM antibody against Coxsackie B virus. We hypothesized that the morbidity would be linked to the viral infection against a certain genetic background. Nevertheless, no mutation associated with ANE was identified on exon sequencing or mitochondrial DNA detection, thus the case should be regarded as sporadic.

ANE has no specific clinical symptoms or signs, and in this regard, it is similar to common encephalitis or encephalopathy. Some scholars classified evolution of ANE into prodromal stage, acute encephalopathy stage and convalescent/chronic stage.^[1],[13] As many as 90% of the children may have precursor symptoms of viral infection, including upper respiratory tract infection, viral gastroenteritis, infantile rash, or others. The symptoms of acute encephalopathy occur one to 3 days after the prodromal infection. As many as 94% of the cases have early seizure activity, most frequently as persistent tonic-clonic seizures. Almost all (98%) of the patients develop rapid consciousness impairment and possible progressive exacerbation, with Glasgow scoring ranging from 6 to 7. It can be accompanied by frequent vomiting (70%), papillary edema (38%), early onset of cerebrospinal ankylosis (85%), pupil narrowing (73%), positive Babinski's sign (66%) and tendon hyperreflexia (66%). The condition may deteriorate rapidly during this period, manifesting as signs of sustained high fever ranging from two to 5 days, decreased muscle tension, frequent apnea, dilated pupil, hypotension and even some fatal complications of diffuse intravascular coagulation, multiple organ dysfunction and hemophagocytic syndrome. About 30% of patients died during this period. Some patients may also have spinal cord involvement, with signs of transverse myelitis.^[14],[15] The convalescence period, marked by the restoration of consciousness, is achieved after the onset of six to 10 days if the condition does not deteriorate. The recovery of nervous system function requires several months, and fewer than 10% of patients achieve complete recovery. Most patients are left with various degrees of sequelae, from lesser conditions of mild hemiplegia, intentional tremor, athetosis, abductor nerve palsy and strabismus induced by abnormal extraocular muscular activity, to more serious signs, including mental retardation, epilepsy, quadriplegia, and persistent vegetative state. The characteristics of our patient's clinical course were consistent with the progression of ANE. Compared to previously described cases, his fever receded faster and the body temperature returned to normal when encephalopathy developed. The severity of his consciousness disorder was also not severe, only manifesting as lethargy. His recovery was relatively good. It should be borne in mind that the degree of fever and consciousness disorder may be related to the prognosis in addition to therapeutic factors.

The differential diagnosis includes epidemic encephalitis B, fulminant hepatitis, poisoning, hemolytic uremic syndrome, Reye's syndrome, acute disseminated encephalomyelitis, hemorrhagic shock, encephalopathy syndrome, subacute necrotizing encephalopathy, Wernicke's encephalopathy, glutaric academia, other subtypes of encephalitis and vasculitis, and arteriovenous infarction.

Blood tests in ANE show elevated white blood cell counts with a dominant proportion of neutrophils, and concentrations of C-reactive protein and Erythrocyte sedimentation rate are also elevated. Severely affected patients may suffer from disseminated intravascular coagulation, manifesting as a combination of thrombocytopenia, prolonged prothrombin time, decrease of fibrinogen, and increase of fibrinolytic degradation products. The concentrations of serum transaminase, LDH, creatine kinase and urea nitrogen also increase. Hypoproteinemia may develop in some patients, while high blood ammonia, hypoglycemia, and electrolyte disturbances rarely occur.^[16] Tests of CSF show no specific alterations except for the increase of protein concentration. The electroencephalogram in the acute phase shows widespread slow waves, and its background activity could show gradual improvement with recovery of consciousness.

Brain imaging is diagnostically significant.^[17] It is characterized by symmetrical multifocal lesions primarily localized in the thalamus (100%), superior brainstem tegmentum (61%), periventricular white matter (56%), and cerebellar medulla (51%), while the anterior part of the lentiform nucleus, periaqueductal gray matter, optic nerve, substantia nigra, and inferior olivary nucleus are rarely involved. Computed tomography images show symmetrical decreases in density at the lesion sites. MRI reveals an early impairment of gray matter with low signal on T1-weighted images and high signal on T2-weighted images. The T1-weighted images of thalamus show signs of concentric rings 3 days after the onset of encephalopathy that is high signal in the central lesion but low signal in the periphery. Subacute hemorrhage appearing as high-signal rings on T1 image can be detected in thalamic lesions in the 2^nd week after onset. Impairments of white matter are always low signals on T1 but high signals on T2-weighted images. The apparent diffusion coefficient (ADC) of diffusion-weighted imaging better reflects the pathological changes, the typical manifestation of which is the characteristic “trichrome pattern,” i.e., a higher ADC value in the central region of the thalamus (hemorrhagic necrosis) with a surrounding lower ADC value (cytotoxic brain edema) compared to normal brain tissue. The periphery of the lesion has a higher ADC value than does the center that is angiogenic brain edema. The center of the lesion in mild cases is free of hemorrhage or necrosis. Its ADC image shows a relatively low value in the central part (cytotoxic brain edema) but a relatively high value in surrounding area (angiogenic brain edema). The lesions shrink in the chronic and convalescent stages. Severe cases may develop multiple cysts with hemosiderin deposits and brain atrophy.

No specific treatment for ANE is currently available. The conventional treatment is primarily supportive with anti-cytokine therapy, as ANE is thought to be cytokine mediated. The therapeutic objectives in the acute phase are seizure control, lowering intracranial pressure through inhibiting brain edema and maintaining good ventilation and cerebral perfusion. Hypothermia therapy^[18] and immunotherapy with methylprednisolone (30 mg/kg/day), gamma globulin or plasma exchange^[19] may be effective. The combination of gamma globulin (400 mg/kg) given once a month with long-term oral dexamethasone (0.075 mg/kg/day) was shown effective to prevent recurrences in patients with ANE1.^[20] To date, no consensus has been reached regarding timing and length of glucocorticoid treatment. In our case, methylprednisolone was administered at 10 mg/kg/day in the acute phase, followed by oral prednisone at 1.5 mg/kg with gradual taper. The length of oral prednisone therapy lasted about 3 months and a beneficial therapeutic effect was achieved. No long-term oral glucocorticoid therapy was given; however, long-term follow-up is warranted because of the risk of relapse.

The prognosis of ANE is poor with mortality rates as high as 30%. Most survivors have various degrees of sequelae. Fewer than 10% of the patients recover completely and the recovery of cognitive function is generally better than that for physical function. The prognosis may be worse if the patients have significantly elevated concentrations of serum aminotransferase and cerebrospinal protein. Patients with hemorrhagic lesions or brainstem involvement on image also have worse prognoses. The quantity of brain lesions negatively correlate with prognosis. Some researchers have established an ANE severity score (ANE-SS)^[21] as follows: three for stroke, two for brainstem lesions, two for age over 48 months, one for platelet count <100 × 10⁹/L, and one for cerebrospinal protein over 60 mg/dl. The prognosis of ANE-SS 0–1 is quite good, while that of ANE-SS 5–9 is poor. The ANE-SS of our case was zero, thereby suggesting a good prognosis.

Conclusion

ANE is a rare syndrome with unknown etiology; there is no specific clinical presentation or treatment. Brain imaging characterized by symmetrical multifocal lesions is diagnostically significant. Good outcome can be achieved via combined therapy with immunoglobulin and glucocorticoids.

Declaration of patient consent

The authors certify that they have obtained all appropriate patient consent forms. In the form the patient(s) has/have given his/her/their consent for his/her/their images and other clinical information to be reported in the journal. The patients understand that their names and initials will not be published and due efforts will be made to conceal their identity, but anonymity cannot be guaranteed.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.

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