What are the differential diagnoses and management options for Acute Necrotizing Encephalopathy (ANE) of childhood?

Acute Necrotizing Encephalopathy of Childhood: Differential Diagnoses and Management

Acute Necrotizing Encephalopathy of Childhood (ANEC) requires immediate aggressive treatment with intravenous immunoglobulin and methylprednisolone to improve outcomes in this potentially fatal condition. 1

Clinical Presentation and Characteristics

ANEC is a rare, fulminant neurological disorder characterized by:

• High fever, convulsions, and coma in children aged 1-5 years 2
• Rapid onset typically 2-4 days after respiratory symptoms 2
• Altered level of consciousness and seizures (67%) as common presenting symptoms 3
• Bilateral thalamic involvement on neuroimaging, which is characteristic 2
• Symmetrical multifocal brain lesions affecting thalami, brainstem tegmentum, cerebral white matter, or cerebellar medulla 4

Differential Diagnoses

1. Viral Encephalitis

   • Particularly HSV encephalitis, which presents with fever, headache, altered consciousness, ataxia, and seizures 2
   • CSF may show pleocytosis, unlike ANEC which often has normal CSF 2

2. Reye's Syndrome

   • Characterized by protracted vomiting and encephalopathy in afebrile patients 2
   • Elevated ammonia levels 24-48 hours after mental status changes 2
   • Hepatic dysfunction with fatty metamorphosis or elevated liver enzymes 2
   • Associated with aspirin use during viral illnesses 2

3. Acute Disseminated Encephalomyelitis (ADEM)

   • Immune-mediated process affecting predominantly subcortical white matter 2, 5
   • Often post-infectious with multifocal lesions at different stages 5
   • May have periventricular white matter and corpus callosum involvement 5

4. Metabolic Encephalopathies

   • May present with altered consciousness and seizures 5
   • Often have associated metabolic abnormalities (acidosis or alkalosis) 5

5. Autoimmune Encephalitis

   • May have positive autoimmune or paraneoplastic antibodies 5
   • Often subacute presentation compared to ANEC's rapid onset 5

6. Influenza-Associated Encephalopathy Spectrum

   • Includes mild encephalopathy with seizures, ADEM, posterior reversible encephalopathy syndrome, and malignant brain edema syndrome 2

Diagnostic Approach

1. Clinical Assessment

   • Evaluate for preceding febrile illness (especially influenza) 3
   • Assess neurological status, focusing on level of consciousness and seizures 3

2. Laboratory Investigations

   • Complete blood count and liver function tests (elevated transaminases common in ANEC) 3, 6
   • Normal ammonia levels (to differentiate from Reye's syndrome) 3

3. CSF Analysis

   • Often shows increased protein without pleocytosis in ANEC 3
   • Rule out infectious causes with viral PCRs 5
   • Check for oligoclonal bands and CNS demyelinating disease antibodies 5

4. Neuroimaging

   • MRI is essential and diagnostic, showing:
     • Bilateral thalamic involvement (hallmark finding) 2, 3
     • Additional lesions in brainstem, cerebral white matter, or cerebellum in 67% of cases 3
     • Edema, hemorrhage, and necrosis may be present 6

Management

1. Initial Management

   • Empirical treatment with antibiotics and antiviral agents (acyclovir) pending diagnosis 1
   • Seizure control with appropriate anticonvulsants 2
   • Airway management and ventilatory support as needed 7

2. Specific Treatment

   • Intravenous immunoglobulin (IVIG) at 2g/kg over 5 days (0.4g/kg/day) 5, 1
   • High-dose intravenous methylprednisolone (1g daily for 3-5 days) 5, 1
   • Consider plasmapheresis if no response to IVIG and steroids 5

3. Supportive Care

   • Management of increased intracranial pressure 2
   • Correction of metabolic imbalances 2
   • Consultation with specialists in metabolic medicine 2

4. Follow-up

   • Taper steroids over at least 4-6 weeks 5
   • Monitor for rebound symptoms during steroid taper 5
   • Follow-up MRI at 4-6 weeks to evaluate lesion evolution 5
   • Regular neurological examinations to assess treatment response 5

Prognosis

The prognosis of ANEC is generally poor:

• Mortality rate is very high, with fewer than 10% of patients recovering completely 2, 4
• In more recent studies with aggressive immunomodulatory treatment, mortality was reported at 25% 1
• Survivors often have significant neurological sequelae 4, 7
• Early intervention with IVIG and IV methylprednisolone may improve outcomes 1

Common Pitfalls

• Delayed diagnosis due to failure to recognize characteristic neuroimaging findings 6
• Misdiagnosis as viral encephalitis without appropriate neuroimaging 2
• Failure to consider ANEC in children with influenza-like illness who develop neurological symptoms 7
• Delayed initiation of immunomodulatory therapy 1
• Inadequate follow-up during steroid taper, risking rebound symptoms 5