SEARCH

SEARCH BY CITATION

The National Encephalitis Guidelines Development and Stakeholder Groups have recently published guidelines for the management of suspected viral encephalitis in children.1 The guideline review and grade the available evidence with an algorithm (Fig. 1), emphasizing the emergency clinical evaluation at initial presentation in patients without underlying immunosuppression. As the evidence for the benefit of early treatment with aciclovir is unequivocal, encephalopathy secondary to herpes simplex encephalitis (which involves direct brain invasion) is highlighted. There is a lot of information about diagnosis and differential diagnosis in the algorithm, as well as in the tables. This makes it easy to check crucial facts quickly for the benefit of patients who may have herpes simplex encephalitis, e.g. criteria making viral encephalitis more or less likely than tuberculous meningitis once cerebrospinal fluid has been obtained. The algorithm also spells out the recommended dose and duration of treatment for aciclovir in relation to host factors, e.g. immunosuppression and renal failure, and the requirement to repeat cerebrospinal fluid polymerase chain reaction and continue to treat if positive (Fig. 1). Contraindications to lumbar puncture before neuroimaging are included but the authors emphasize that it is essential to undertake this procedure as early as possible in order to establish or exclude a diagnosis of herpes simplex encephalitis, or related herpes encephalitides responsive to aciclovir (such as that due to herpes zoster), so that an optimal treatment strategy can be mapped out.

image

Figure 1.  Algorithm for the management of patients with suspected encephalitis. Reproduced with permission from Kneen et al.1

Download figure to PowerPoint

The guideline arose from a problem previously identified by this group during an audit of the use of aciclovir.2 Of 51 children identified as having received aciclovir over a 6-month period, only 2 (4%) had proven herpes simplex encephalitis and there was no rational basis for treatment in 14. As a result of the emphasis placed on treatable causes in training schedules, aciclovir is commonly the first-line strategy for acute neurological presentations, such as seizures, coma, and focal signs. It is used even in children with underlying conditions, such as renal or cardiac disease, where alternative causes of encephalopathy such as posterior reversible encephalopathy syndrome (Fig. 2[c2,3]) or venous sinus thrombosis (Fig. 2[a2; d2,3]) are more likely but may not be appropriately managed unless a paediatric neurologist or intensivist is consulted. The triage and appropriate management of children presenting with acutely reduced level of consciousness, seizures, or behavioural problems remains a complex and controversial issue. The new guideline emphasizes the importance of neuroimaging in establishing a diagnosis and points out that very rapid computed tomography (CT) is now routine for hospitals with an adult stroke unit. However, CT may miss the diagnosis of herpes simplex encephalitis early on, while magnetic resonance imaging (MRI) is much more specific and sensitive for other conditions as well. Emergency transfer to a regional centre with facilities for urgent out-of-hours MRI under anaesthesia is often essential, especially when diagnosis of other conditions requiring specific treatments may reduce morbidity and mortality, such as aspirin for post-varicella vasculopathy and stroke3,4 (Fig. 2[b3]. Although there have been no randomized trials of aspirin or of the aciclovir or steroids recommended in the guidelines), thrombolysis for basilar occlusion4 (Fig. 2[f2,3]), or anticoagulation for venous sinus thrombosis (Fig. 2[a2; d2,3]).4,5

image

Figure 2.  Imaging for diagnosis and differential diagnosis of acute encephalopathy: Columns (a-f) are distributions seen in encephalitis. Examples of patients diagnosed as Encephalitis are shown in Row 1 while differential diagnosis and additional imaging required to make the diagnosis are shown in rows 2 and 3 T2-weighted magnetic resonance imaging (MRI) unless stated. (a) Widespread focal cortical involvement in (1) herpes simplex encephalitis in a neonate, (2) sagittal venous sinus thrombosis in iron deficiency anaemia, and (3) diffusion-weighted images (DWI) consistent with ischaemia in an unconscious child with unilateral slowing and a family history of hemiplegic migraine. (b) Small focal lesions: (1) focus of high signal density in the left frontal white matter in a child with anti-NMDA receptor antibody encephalitis who recovered after steroids, plasma exchange, and cyclophosphamide, (2) high signal on fluid-attenuated inversion recovery (FLAIR) imaging in a child presenting with hemichorea and a raised antistreptolysin O titre who recovered after 2 weeks of penicillin and prednisolone, and (3) basal ganglia infarct in a child who had three transient ischaemic attacks (TIAs) 4-months post-chickenpox and focal cerebral arteriopathy on magnetic resonance angiography; the TIAs ceased on aspirin. (c) Posterior involvement: (1) splenial abnormality on DWI (MERRS) in a child who recovered rapidly from acute coma, (2) posterior abnormality consistent with posterior reversible encephalopathy syndrome in an immunosuppressed boy with juvenile chronic arthritis and hypertension in whom (3) bilateral borderzone ischaemia was demonstrated on DWI the following day after a period of hypotension. (d) Thalamic involvement in (1) acute disseminated encephalomyelitis after acute otitis media (DWI), (2) bilateral thalamic ischaemia in a child with (3) venous sinus thrombosis (T1) and severe iron deficiency anaemia (haemoglobin 4g/dL) who recovered fully after anticoagulation. (e) Widespread symmetrical abnormality. FLAIR MRI showing (1) symmetrical basal ganglia, thalamic, white matter and (2) cerebellar involvement in acute necrotizing encephalopathy in a child with acute sepsis for which the differential diagnosis includes (3) symmetrical basal ganglia involvement on computed tomography in Leigh’s disease. (f) Cerebellar involvement in (1) cerebellitis with descent of the cerebellar tonsils in the context of rising titres to Epstein–Barr virus (2) infarction (T1) in a child with (3) basilar occlusion which was thrombolyzed 11 hours after presentation with good outcome.

Download figure to PowerPoint

The distinction between encephalitis and encephalopathy in association with other infection is much less clear and the mechanisms of brain injury are so poorly understood that it is not currently possible to produce evidence-based guidelines. Host factors, such as abnormal fluid balance with hyponatraemia,6 acute anaemia with hypoxia,7,8 raised intracranial pressure and the position of the cerebellar tonsils (Fig. 2[e1]), and blood pressure fluctuations (Fig. 2[c2,3]), may determine the clinical and neuroradiological presentation of infectious encephalopathies. In addition to demyelination, e.g. acute disseminating encephalomyelitis (Fig. 2[d1]), antibody mediated disorders (Fig. 2[b1]), and more specific MRI phenotypes such as mild encephalopathy with a reversible splenial lesion triggered by infection (Fig. 2[c1]) and acute necrotizing encephalomyelitis (Fig. 2[e1,2])1,6,8,9 there may be imaging abnormalities in children with acute febrile seizures.10 Viral ribonucleic acid is not consistently detected in the cerebrospinal fluid of patients with influenza-associated encephalopathy/encephalitis and cerebrospinal fluid pleocytosis is uncommon,11 although many patients with neurological symptoms were treated with antivirals during the recent H1N1 pandemic. Influenza infection may expose specific metabolic disorders, for example disorders of mitochondrial β–oxidation associated with inactivated carnitine palmitoyltransferease II.12 A wide variety of para- and post-infectious neurological symptoms in the context of common infections such as influenza, Lyme disease,12 and mycoplasma pneumoniae may have a vascular4,13 or autoimmune14 basis requiring adjunctive therapy, as well as by directly infecting the central nervous system. Direct viral invasion (encephalitis) and additional mechanisms for encephalopathy are not mutually exclusive.15

The guidelines give a sensible stepwise approach to exclusion of other infectious diseases and strongly recommend consultation with microbiology and/or infectious diseases units. The approach to clinical diagnosis and further research must include an appropriate neuroimaging protocol and good working relationships with neuroradiologists experienced in encephalopathies as well as immunologists so that treatable causes are identified as quickly as possible. Excluding autoimmune conditions requiring specific treatment, such as anti-NMDA receptor antibody encephalitis, is likely to be more cost-effective than an extensive search for viruses, which are less common16 and for which non-specific supportive management is appropriate currently. As networks between peripheral hospitals and tertiary centres with paediatric neurology and intensive care units develop, rapid central triage and emergency management in the acute phase9,13,16,17 followed by longer-term management and rehabilitation locally, perhaps guided from centres with experienced therapists using virtual techniques via Skype, FaceTime, or mobile phones, is likely to improve outcomes. More high quality population-based data on risk factors and outcomes18 are urgently needed so that randomized controlled trials of treatment can be organized.

Acknowledgements

  1. Top of page
  2. Acknowledgements
  3. References

The author thanks Oliver Morris and Rhea Bhadresha for assistance with the literature review.

References

  1. Top of page
  2. Acknowledgements
  3. References
  • 1
    Kneen R, Michael BD, Menson E, et al.Management of suspected viral encephalitis in children – Association of British Neurologists and British Paediatric Allergy, Immunology and Infection Group National Guidelines. J Infect2012; 64: 44977.
  • 2
    Kneen R, Jakka S, Mithyantha R, Riordan A, Solomon T. The management of infants and children treated with aciclovir for suspected viral encephalitis. Arch Dis Child2010; 95: 1006.
  • 3
    Touré A, Chabrier S, Plagne MD, Presles E, des Portes V, Rousselle C. Neurological outcome and risk of recurrence depending on the anterior vs. posterior arterial distribution in children with stroke. Neuropediatrics2009; 40: 1268.
  • 4
    Ganesan V, Kirkham FJ, editors. Stroke and Cerebrovascular Disease in Childhood. International Review of Child Neurology Series. London: Mac Keith Press, 2011.
  • 5
    Lebas A, Chabrier S, Fluss J, et al.EPNS/SFNP guideline on the anticoagulant treatment of cerebral sinovenous thrombosis in children and neonates. Eur J Paediatr Neurol2012; 16: 21928.
  • 6
    Takanashi J, Tada H, Maeda M, Suzuki M, Terada H, Barkovich AJ. Encephalopathy with a reversible splenial lesion is associated with hyponatremia. Brain Dev2009; 31: 21720.
  • 7
    Wierenga KJ, Serjeant BE, Serjeant GR. Cerebrovascular complications and parvovirus infection in homozygous sickle cell disease. J Pediatr2001; 139: 43842.
  • 8
    Lee KH, McKie VC, Sekul EA, Adams RJ, Nichols FT. Unusual encephalopathy after acute chest syndrome in sickle cell disease: acute necrotizing encephalitis. J Pediatr Hematol Oncol2002; 24: 5858.
  • 9
    Vargas WS, Merchant S, Solomon G. Favorable outcomes in acute necrotizing encephalopathy in a child treated with hypothermia. Pediatr Neurol2012; 46: 3879.
  • 10
    Hesdorffer DC, Chan S, Tian H, et al.Are MRI-detected brain abnormalities associated with febrile seizure type?Epilepsia2008; 49: 76571.
  • 11
    Glaser CA, Winter K, Dubray K, et al.A population-based study of neurologic manifestations of severe influenza A(H1N1)pdm09 in California. Clin Infect Dis2012; 55: 51420.
  • 12
    Chen Y, Mizuguchi H, Yao D, et al.Thermolabile phenotype of carnitine palmitoyltransferase II variations as a predisposing factor for influenza-associated encephalopathy. FEBS Lett2005; 579: 20404.
  • 13
    Binalsheikh IM, Griesemer D, Wang S, Alvarez-Altalef R. Lyme neuroborreliosis presenting as Alice in Wonderland syndrome. Pediatr Neurol2012; 46: 1856.
  • 14
    Takanashi J, Takahashi Y, Imamura A, et al.Late delirious behavior with 2009 H1N1 influenza: mild autoimmune-mediated encephalitis?Pediatrics2012; 129: e106871.
  • 15
    Jia M, Xiong N, Huang J, et al.Japanese encephalitis accompanied by cerebral venous sinus thrombosis: a case report. BMC Neurol2012; doi: 10.1186/1471-2377-12-43.
  • 16
    Gable MS, Sheriff H, Dalmau J, Tilley DH, Glaser CA. The frequency of autoimmune N-methyl-D-aspartate receptor encephalitis surpasses that of individual viral etiologies in young individuals enrolled in the California Encephalitis Project. Clin Infect Dis2012; 54: 899904.
  • 17
    Ahmed AI, Eynon CA, Kinton L, Nicoll JA, Belli A. Decompressive craniectomy for acute disseminated encephalomyelitis. Neurocrit Care2010; 13: 3935.
  • 18
    Hoshino A, Saitoh M, Oka A, et al.Epidemiology of acute encephalopathy in Japan, with emphasis on the association of viruses and syndromes. Brain Dev2012; 34: 33743.