A 7‐YEAR‐OLD BOY DYING OF ACUTE ENCEPHALOPATHY

CASE HISTORY

A 7‐year‐old Chinese boy with a history of bronchial asthma had upper respiratory tract infection for the preceding two weeks treated by a pediatrician. He then presented with confusion and incoherent speech on the day of admission. He was afebrile, with the Glasgow coma scale (GCS) of 14/15 (E4V4M6) and normal physical findings. Investigations showed normal complete blood counts, blood glucose, renal and liver function tests except for mildly elevated ALT at 34 IU/L (5–25 IU/L). His blood ammonia, lactate and pyruvate levels were normal. The CT brain showed no space occupying lesion or cerebral edema. Lumbar puncture showed an opening pressure of 12 cm water, CSF glucose 3.1 mmol/L, protein 1.25 gm/L (0.15–0.45 gm/L), RBC 2/mm³ and WBC 2/mm³. The gram stain showed no organisms. The nasopharyngeal aspirate for rapid antigen test for both influenza A and B were negative. About 12 hr after admission, he developed generalized tonic convulsions progressing to decorticate posturing, GCS 3/15 (E1V1M1) and pupils 2.5 mm, equal and reacting sluggishly to light. Seizures were controlled with anticonvulsants. He was intubated and put on mechanical ventilation. Despite treatment with acyclovir, cefotaxime, anti‐tuberculous medications, dexamethasone, hyperventilation and mannitol infusion, the child remained comatose. MRI of brain was done (see below). His pupils became fixed and dilated 34 hours after hospitalization. He finally succumbed on the fourth day of hospitalization.

Subsequent laboratory reports showed that the nasopharyngeal aspirate and throat swab taken on the second day of hospitalization were positive for Influenza A H1N1 by culture (human strain influenza A H1N1/Brisbane/59/2007). Complement fixing antibody titer against influenza A nucleoprotein showed at least a 8‐fold rise within 3 days but hemagglutinating antibody titer was high only for H3. The serological findings were compatible with a recent Influenza A H3 infection while the culture confirmed a current H1N1 infection. Further testing of the child's serum was done after the autopsy findings were available. Overall, there was no serological evidence of a rheumatic disease, in particular systemic lupus erythematosus. The serum interleukin 6 was elevated to 7.01 pg/mL on admission (reference < 5.9) and progressively raised to 130 pg/mL on the day of death. The serum tumor necrosis factor alpha was also persistently raised in the range of 17.8–15.0 pg/mL (reference < 8.1).

IMAGING

MRI showed severe cerebral edema and inferior herniation of cerebellar tonsils. Bilateral and symmetrical lesions with abnormal T2‐hyperintense signals were present in the deep white matter of the cerebral hemispheres, caudate nuclei, putamen, and globus pallidus, and internal capsule, peripheral and posterior portions of the thalami, corpus callosum and tegmentum of brainstem (Figure 1).

Figure 1.

AUTOPSY FINDINGS

Extra‐cranial organs were remarkable only for slightly heavier lungs and histology consistent with intercurrent viral infection and bronchial asthma. Oil‐red‐O stain of frozen liver showed moderate steatosis but no steatosis was noted in the heart, kidney, skeletal muscle and brain.

The brain was heavy (1,700 gm; reference 1,290 gm), markedly congested and edematous. Cerebellar tonsillar and early bilateral uncal herniations were noted. The dural veins and the Circle of Willis were normal. The lateral ventricles were slit‐like. There was symmetrical hemorrhagic necrosis or softening of the head of caudate nucleus, the corpus callosum, the periventricular white matter, the lateral and posterior part of the thalamus and the internal capsule. 2, 3, 4 show coronal sections of cerebrum at the genu of the corpus callosum, mamillary bodies and splenium of the corpus callosum respectively. There was artifactual disruption of the right temporal lobes as shown in 3, 4. The cortical grey matter, the major part of the centrum semiovale, putamen and globus pallidus showed no gross lesions. The brainstem, cerebellum and spinal cord were pale, edematous and focally congested.

Figure 2.

Figure 3.

Figure 4.

On microscopy, necrosis and vasculopathy were noted. The common vasculopathy was an exudative vasculopathy (EV) characterized by an expanded perivascular space with fibrinous exudate, often with a vacuolated artifact. (Figure 5: arteriole about 250 µm in diameter in right thalamus.) EV involved small vessels and arterioles distributed throughout the brain including the necrotic and non‐necrotic areas. The other forms of vasculopathy were necrotizing vasculopathy (NV) and fibrinous vasculitis (FVL), both restricted to the necrotic areas only. NV resembled EV except for the presence of fibrinous necrosis of the vessel wall. (Figure 6: 110 µm vessel in the left head of caudate.) FVL showed additional lymphocytic and neutrophilic exudate on the vascular wall and perivascular space and karyorrhexis with or without luminal thrombosis. (Figure 7: 90 µm vessel in the left head of caudate, Figure 8: 50 µm vessel in the right head of caudate, Figure 9: 80 µm vessel in right internal capsule.) Fibrin deposits in the vessels were confirmed by Martius‐scarlet‐blue stain (Figure 10: same vessel as Figure 9) and immunohistochemistry for fibrin (Figure 11: same vessel as Figure 9). No perivascular demyelination was evident (Figure 12: Luxol fast blue stain, same vessel as Figure 9). The necrotic areas showed ghost shadow of necrotic cells, pyknotic or karyorrhectic nuclear fragments and extravasated red cells in a background of paucicellular and edematous neuropil. There was neither astrocytic nor microglial proliferation. Many of the neurons in the cerebral cortex, hippocampus, cerebellum and brainstem showed ischemic shrinkage and pericellular edema. Some small vessels in the brainstem also showed thrombosis. The generalized ischemic changes of the neurons, thrombosis in the brainstem and cerebellar coning were considered pathological changes secondary to the cerebral edema. The generalized cerebral edema, vasculopathies and necrosis were considered the primary pathology.

Figure 5.

Figure 6.

Figure 7.

Figure 8.

Figure 9.

Figure 10.

Figure 11.

Figure 12.

RT‐PCR was done on fresh samples of the cerebrum, pons, heart, lung, skeletal muscle, spleen, intestine and kidney for influenza A and B, respiratory syncytial virus, parainfluenza 1, 2, 3 and 4, adenovirus, rhinovirus, human metapneumovirus, enterovirus, herpes simplex virus, Epstein‐Barr virus, cytomegalovirus and varizella‐zoster virus and the results were all negative. Viral cell cultures of these tissues were also negative.

What is the diagnosis?

DIAGNOSIS

Influenza associated acute necrotizing encephalopathy (ANE).

DISCUSSION

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.

A thermolabile phenotype of carnitine palmitoyltransferase II variations may be a predisposing factor (1). For a more complete review of ANE, please see: http://path.upmc.edu/divisions/neuropath/bpath/cases/case192/dx.html.

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, 5, 6, 7, 8.See also the Table of autopsied cases of ANE on line at: http://path.upmc.edu/divisions/neuropath/bpath/cases/case192/images/Table.gif.

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.

ABSTRACT

A 7 year old Chinese boy died of a rapidly progressive encephalopathy after influenza infection. MRI showed bilateral and symmetrical lesions including the thalamus and brainstem tegmentum. The pathology of necrosis and vasculopathy were in keeping with acute necrotizing encephalopathy (ANE). ANE was first described in Japan and carries a high mortality and morbidity. A vasculopathy with breakdown of the blood‐brain‐barrier was incriminated but the pathogenesis remained obscure and autopsy studies have been limited. A review of the literature showed only nine postmortem reports in the acute stage. Symmetrical brain necrosis always involved the thalamus followed by the tegmentum of the pons and other regions. Exudative vasculopathy was commonly observed and often accompanied by endothelial cell necrosis. In the present case there was inflammatory fibrinoid vasculitis which has not been previously described.