DIAGNOSIS Influenza associated acute necrotizing encephalopathy (ANE).
The child had a rapidly fatal acute encephalopathy following influenza infection. The MRI showed characteristic features of ANE with bilateral and symmetrical lesions in the deep white matter and basal ganglia including the thalami and tegmentum of the brainstem. The pathological findings of necrosis and vasculopathy were also in keeping with ANE. The differential diagnoses would include acute disseminated encephalomyelitis (ADEM) and its hyper-acute form acute hemorrhagic leukoencephalopathy (AHLE), primary or secondary forms of cerebral vasculitis and metabolic encephalopathy. ADEM and AHLE typically show asymmetrical involvement of the centrum semiovale with infrequent and asymmetrical involvements of the basal ganglia and thalamus. In the brainstem, they involve both the basal and tegmental area in contrast with the selective tegmental involvement in ANE. The necrosis in AHLE was perivascular with or without necrotizing vasculopathy and perivascular demyelination. In contrast, necrosis in ANE is regional and featureless. Primary small vessel cerebral vasculitis usually shows chronic or sub-acute asymmetrical neurological progression (2). Serologically and clinically, the child showed no evidence of an autoimmune or primary vasculitic disorder. The differentiation from metabolic encephalopathy with non-inflammatory necrosis such as Leigh syndrome would require overall clinical-pathological correlation and metabolic investigation. Leigh syndrome shows capillary, astrocytic and histiocytic proliferations in the early stage which are not seen in the acute phase of ANE.
Acute necrotizing encephalopathy of childhood was first coined by Mizuguchi and colleagues in Japan to describe an acute encephalopathy with clinical features resembling Reye's syndrome but unique features on brain computerized tomography (CT) (6). The encephalopathy affected previously healthy children after respiratory tract infection and presented with coma, convulsion and hyperpyrexia. Neuroimaging showed symmetrical lesions of the cerebral white matter, thalamus, cerebellum and brainstem. Autopsy studies showed extensive non-inflammatory fresh cerebral necrosis and edema. Influenza A was identified as the commonest preceding infection but other viral infections could also occur. The influenza strains belong to the common prevalent human seasonal influenza spread by person-to-person. The mortality rate was 28% and most surviving patients had neurological handicap. Subsequently, ANE was recognized as the severe end of the spectrum of influenza-associated encephalopathy (IAE). Mizuguchi has proposed the diagnostic criteria based on the clinical-radiological features and exclusion of other defined entities such as inflammatory encephalopathies (5). Direct invasion of the brain by influenza or other virus has been excluded. A vasculopathy with breakdown of the blood-brain-barrier was incriminated but the exact pathogenesis remained obscure and autopsy studies have been limited. Cytokines storm and metabolic predisposition of ethic groups in the Far East were considered contributory. A thermolabile phenotype of carnitine palmitoyltransferase II variations was suggested as a predisposing factor for ANE. This enzyme is involved in mitochondrial beta-oxidation and its inactivation in continuous high fever may result in systemic energy crisis (1). Recently, mutation in the nuclear pore protein Ran Binding Protein 2 (RANBP2) was reported in familial cases of ANE (8). Treatment with high dose corticosteroid has been successful. Report of its occurrence outside the Far East was rare but as the disease becomes better aware, cases outside the Far East have been reported. Up-to the year 2005, about 300 cases were reported, mostly commonly in Japan and followed by Taiwan. About 15 cases were reported from the United States, Canada and Europe (4).
Nine case reports of ANE with autopsy examination in the acute stage were retrieved from six publications after a complete search of Ovid Medline (date accessed 1 March 2009) (3, 4, 6, 7, 9, 10). The summary of the pathological features including the present case are tabulated in the Table. Four cases occurred outside Far East involving children of non-Asian ethic groups. Varying degree of cerebral edema, frequently severe, was a constant finding but cerebral herniation was noted only in 2 cases. The pathology was largely symmetrical and consisted of combination of gross findings of hemorrhagic necrosis, softening and dusky discoloration and microscopic findings of non-reactive necrosis, hemorrhage and vasculopathy. The thalamus was always involved followed by the pontine tegmentum. Exudative vasculopathy corresponded to that described in the present case occurred in 7/10 cases. Endothelial necrosis corresponded to the necrotizing vasculopathy described in the present case also occurred in 7/10 cases. Only the present case documented the presence of inflammatory vasculitis. Reactive astrocytic or microglial proliferation, demyelination or significant inflammatory infiltrate in the leptomeninges or brain parenchyma were not described. According to the criteria of ANE by Mizuguchi (5), the present case would be excluded because of the presence of inflammatory vasculitis. We classify the present case as an atypical case of ANE as the clinical, neuroimaging and pathological features were otherwise consistent. As ANE is a relatively new entity with only limited post-mortem studies, the defining criteria may be provisional, pending further studies.
The presence of inflammatory vasculitis in the present case may suggest an immune complex mediated vasculopathy. This would be supported if influenza antigen and immunoglobulin could be demonstrated in the vascular wall. Many infection-associated vasculopathies show specific involvement of vessel types and organs. In the present child, a few factors might contribute to a more severe immune reaction. Firstly, the child had a history of atopy (bronchial asthma). Secondly, he was given a short course of immunomodulating drugs (prednisolone and celestamine) immediately before the neurological presentation. The withdrawal of these drugs might result in an immunological rebound and more florid immune reaction. Thirdly, the child had sequential infections by influenza A H3 and H1 serotypes within two weeks. These combinations of factors might have led to the unusual necrotizing fibrinous vasculitis unique to this child and not seen in previous cases of ANE. More postmortem studies on ANE are needed. Investigation along the line of immune mediated vasculopathy may be warranted. The predilections for children in the Far East and for the thalamus also need to be explained.
Contributed by WAI-FU NG, SIN-CHUEN CHIU, DAVID S-Y LAM, YIU-CHUNG WONG, SIDNEY TAM, NGAI-SHAN KWONG, KA-TAI LOO AND KWOK-YUNG YUEN