Journal of Pediatric Critical Care P - ISSN: E - ISSN: Year: 2017 Volume: 4 Issue: 3 DOI /

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1 Journal of Pediatric Critical Care P - ISSN: E - ISSN: Year: 2017 Volume: 4 Issue: 3 DOI / Symposium Article Intensive care issues in Acute Encephalitis in Children Mounika Reddy*, Arun Bansal** *Senior Resident, **Professor, Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh,India Received: 12-Jun-17/Accepted: 30-Jul-17/Published online: 20-Jul-17 Correspondence: Prof Arun Bansal, Pediatric Critical Care Unit, Advanced Pediatrics Centre, PGIMER, Chandigarh , Phone: , drarunbansal@gmail.com ABSTRACT Encephalitis is a major cause of acute neurological dysfunction among children and constitutes a medical emergency. Acute infectious encephalitis is usually viral in etiology. However, immune-mediated encephalitis, which are eminently treatable also forms asignificant proportion. The evaluation and management have evolved with the advances in diagnostic studies, neuromonitoring techniques and antimicrobials. Early recognition, systematic approach and institution of timely appropriate symptomatic and specific therapy are essential to improve outcomes. Cerebrospinal fluid examination and neuroimaging may point to a specific diagnosis. With few exceptions, no specific therapy is available for most forms of viral encephalitis. Morbidity and mortality can be significantly reduced in HSV encephalitis by adequate treatment with acyclovir while delays in treatment can be devastating. Long term sequelae are common among survivors. Key words: Encephalitis, children, intensive care, viral, Herpes Introduction Encephalitis is an important cause of morbidity and mortality in children. While on one hand, the changing epidemiology and spread of arboviral encephalitis presents new challenges to the pediatricians, the availability of newer imaging and viral diagnostic techniques, advances in neurocritical care and availability of better antiviral and immunomodulatory therapies is changing the management of children with suspected encephalitis. 1 Definitions Encephalitis: Encephalitis is defined as inflammation of the brain parenchyma with clinical evidence of neurological dysfunction. Though, strictly speaking, it is a pathological diagnosis requiring tissue confirmation on brain biopsy or autopsy, there may be surrogate markers of neuronal inflammation in cerebrospinal fluid (CSF) or on neuroimaging. 2,3

2 Acute or sub-acute onset global cerebral dysfunction with fever may be due to an infective encephalitis, non-infective encephalitis or encephalopathy. Non-infective encephalitis may be immune mediated, as in, acute demyelinating encephalomyelitis (ADEM) which usually follows infections and vaccinations. It is important to differentiate this entity from infective encephalitis as the management differs. Often, encephalitis may coexist with concomitant inflammation of meninges (meningoencephalitis), spinal cord (encephalomyelitis) or nerve roots (encephalomyeloradiculitis). Encephalopathy: Encephalopathy is non-inflammatory diffuse brain dysfunction. It may or may not be associated with fever and can occur secondary to various conditions like systemic infections, metabolic disturbances, hypoxia, ischemia, critical illness, organ dysfunction, trauma, vasculitis, drugs and intoxications. Non-infective causes of encephalopathy are usually characterized by absence of fever, gradual onset, absence of CSF pleocytosis and lack of focal changes on neuroimaging. 4 Etiology Encephalitis is usually caused by viruses and some small intracellular bacteria and parasites which infect the brain parenchyma directly. A wide range of viruses cause viral encephalitis in children in tropical countries, most common being herpes viruses, enteroviruses and arboviruses (Table1). 3 The various infectious and non-infectious conditions that may mimic viral encephalitis are presented in table 2. 2 Table 1: Causes of acute viral encephalitis Sporadic (not geographically restricted): Herpes viruses: Herpes simplex virus (HSV) 1 and 2, Varicella Zoster virus (VZV), Epstein Barr virus (EBV), Cytomegalovirus (CMV), Human herpes virus (HHV) 6 and 7 Enteroviruses: Enterovirus 70 and 71, Coxsackie virus, Poliovirus, Echovirus, Parechovirus Paramyxoviruses: Measles virus, Mumps virus Rabies virus Others (rare): Influenza virus, Adenovirus, Parvovirus B19, Rubella virus Endemic and epidemic(geographically restricted): Arboviruses: Japanese encephalitis (JE) virus, Dengue virus, Chikungunya virus, West Nile virus, Tick-borne encephalitis Epidemiology The epidemiology of viral encephalitis is changing due to spread of arboviruses to new areas (e.g. Japanese encephalitis virus, West Nile virus across North America and Europe), increasing number of immunocompromised patients who are at risk of encephalitis due to various pathogens, and reduction in encephalitis due to vaccine preventable diseases like measles, mumps, varicella, and rubella. The incidence of encephalitis in children is not known exactly due to under-reporting, lack of large prospective studies and use of different case definitions or diagnostic studies. The annual incidence is 5-10/100,000 as per most studies with higher incidence in younger children.the cause of encephalitis is diagnosed in less than one-third cases. Herpes simplex virus (HSV) encephalitis remains the most commonly diagnosed sporadic viral encephalitis the world over, though in Asia, Japanese encephalitis (JE) is the most common cause of epidemic encephalitis. 1,5

3 Table 2: Diseases that may mimic viral encephalitis CNS infections: Bacterial meningitis Tuberculosis Brain abscess Mycoplasma pneumonia infection Enteric fever Leptospirosis Listeriosis Brucellosis Lyme disease Rickettsiae: Scrub typhus, Rocky mountain spotted fever (RMSF), Q fever, Ehrlichiosis, Cat-scratch fever Parasites: Cerebral malaria, Cysticercosis, Toxoplasmosis, Amoebiasis Fungi: Candidiasis, Cryptococcosis, Histoplasmosis, Coccidiomycosis Para/post-infectious causes: Guillian Barre syndrome (GBS) Acute demyelinating encephalomyelitis (ADEM) Non-infectious causes: Vasculitis Intracranial bleed Ischemic stroke Primary brain tumour or metastasis Metabolic encephalopathy: Hypoglycemia, diabetic ketoacidosis, uremia, hepatic failure, Reye syndrome, mitochondrial diseases,toxins or drugs Epilepsy Pathogenesis Several mechanisms have been proposed in the pathogenesis of encephalitis. It may be due to direct viral cytopathology (destruction of cells by viruses) or it may be a para/postinfectious inflammatory or immune mediated response (e.g. Measles). Other mechanisms which may be operating include diffuse cerebral edema (e.g. influenza), vasculitis (e.g. Varicella zoster virus) and demyelination. 3 With a particular virus, a single mechanism may predominate or multiple mechanisms may be involved. Pathogens must cross the blood brain barrier to cause encephalitis. It may be through the re-activation of latent infection in the neural pathways (e.g. herpes viruses) or through viremia and subsequent spread across the blood brainbarrier (e.g. enteroviruses, arboviruses). Some viruses may exhibit tropism for certain areas of the brain. HSV primarily targets the parenchymal cells in temporal lobes, though it may also involve the frontal and parietal areas. Japanese encephalitis virus has a predilection to involve the thalami and the basal ganglia. Presentation The clinical syndrome of acute infectious encephalitis is considered in any acutely febrile child with altered consciousness and signs of diffuse cerebral dysfunction. Viral encephalitis usually begins with an acute flu-like prodrome followed by high grade fever, nausea, vomiting, headache, acute cognitive dysfunction and behavior changes, often associated with new onset seizures and focal neurological signs. The irritability, somnolence or abnormal behavior is greater than that usually seen in children with any febrile illness.

4 Meningeal signs may be present as encephalitis is invariably associated with some degree of leptomeningeal inflammation. 6,7 Table 3: Salient points on history and examination History: Symptoms: onset, progression, severity (in chronology) History of similar illness in family/community Travel history Vaccination history Contact with insects or animals Occupation history and history of recreational activities Presence of an immunocompromised state: malnutrition, retroviral infection, primary immunodeficiency, cancer chemotherapy, post-transplant patients etc. General examination: Pallor, icterus, edema Rash: maculopapular, petechial, purpuric, vesicular Lymphadenopathy, hepatosplenomegaly Respiratory: crepitations Neurological examination: Higher mental functions Cranial nerve involvement Tone abnormalities Focal neurological signs Abnormal/extrapyramidal movements Meningeal signs Signs of raised intracranial pressure (ICP) altered pupillary responses, raised blood pressure, bradycardia, altered respiratory pattern, abnormal posture (decorticate or decerebrate), papilledema Approach A child with suspected acute infectious encephalitis constitutes a medical emergency. Systematic approach with early recognition of the clinical syndrome, initial stabilization, prompt empirical therapy and meticulous supportive care followed by appropriate diagnostic evaluation and rapid institution of specific therapy when available is essential to prevent ongoing brain damage and improve outcomes. Assessment and treatment have to proceed simultaneously as it is associated with high mortality and morbidity with long-term sequelae among survivors. The salient points to note on history and examination are given in table 3. Certain clues may point to a specific etiology (table 4). One should also search for other possible explanations of coma. 6 Investigations Evaluating a child with suspected viral encephalitis includes investigating for the specific etiology, and presence and severity of organ dysfunction. Complete blood picture may reveal anemia, leukocytosis or leucopenia, and/or thrombocytopenia. Atypical lymphocytes may be seen in Epstein Barr virus (EBV) infection. Serum electrolytes, coagulation studies, renal and hepatic function tests should be obtained. Elevated amylase and lipase levels may be noted in mumps encephalitis. Blood cultures are important to identify any bacterial or fungal etiology, though positive cultures may only point to encephalopathy due to systemic infection rather than primary encephalitis.

5 Table 4: Epidemiological and clinical pointers to specific etiology Season Late summer, early fall: enteroviral, arboviral Winter: influenza Geography Sporadic: HSV Endemic to tropical areas: arboviral infections Insect/animal contact Birds: JE, Cryptococcus neoformans Dogs: Rabies Swine: JE Mosquitoes: malaria, dengue Ticks: RMSF Lymphadenopathy HIV, EBV, CMV, Measles, rubella, Mycobacterium tuberculosis Parotitis, orchitis Mumps Rash VZV, HHV6, Parvovirus, Rubella, enterovirus, mycoplasma, measles, mumps Respiratory symptoms Influenza, adenovirus, mycoplasma, Mycobacterium tuberculosis Cerebellar ataxia VZV, EBV, Mumps Cranial nerve HSV, EBV, Listeria, tuberculosis, cryptococcosis abnormalities Rhombencephalitis/basal HSV, Enterovirus, Listeria, tuberculosis meningoencephalitis Table 5: CSF characteristics in various CNS infections 1 CSF characteristic Opening pressure Gross appearance Normal Viral meningoencephalitis Acute bacterial meningitis Tuberculous meningitis Fungal meningitis 7-15 cm Normal-high High High High-very high Clear Clear or Cloudy Clear/cloudy hemorrhagic WBC/mm3 <5 Slightly increased-high (5-5000) Differential All Mostly cell count lymphocytes lymphocytes CSF/plasma High very high (100-50,000) Mostly Neutrophils Cloudy/ straw coloured with cobweb formation Slightly increased (25-500) Mostly lymphocytes 66% Normal Low Low-very low (<30%) High (>1) High-very high glucose ratio Protein (g/l) <0.45 Normal-high (0.5-1) Normal-high Mostly lymphocytes Normal-low Normal-very high Specific diagnostic investigations include cerebrospinal fluid (CSF) analysis, neuroimaging, and viral studies guided by epidemiological and clinical clues. Identification of etiological agent is essential for definitive treatment, potential prophylaxis, prognostication and public health interventions. However, despite extensive testing, etiological diagnosis often remains elusive.5 Lumbar puncture (LP) to obtain CSF is essential in patients of encephalitis to identify the cause for tailored therapy and must be performed as early as possible. However, delay in doing LP should not delay the administration of empirical antimicrobials. Contraindications

6 to performing a LP include presence of new onset seizures (focal/generalized), focal neurological signs, deep coma, features of raised intracranial pressure (ICP). In such cases, neuroimaging is warranted prior to doing a LP and findings of intracranial space occupying lesion, cerebral edema or brain shift (herniation across midline or tentorium or foramen magnum) on neuroimaging contraindicate LP. Findings on CSF analysis in various central nervous system (CNS) infections are presented in table 5. In viral encephalitis, CSF is usually clear with mildly raised opening pressure. There is mild to moderate CSF pleocytosis, predominantly lymphocytic; however, early in the course, it may be normal or neutrophilic. CSF red cell count is usually normal or slightly raised, but it may be markedly raised in HSV encephalitis or acute necrotizing hemorrhagic leukoencephalitis. CSF:blood glucose ratio is often normal but may be reduced in mumps or enteroviral infections and CSF protein is usually slightly raised. 6 Table 6: Characteristic neuroimaging patterns in viral encephalitis Etiology HSV encephalitis Japanese B encephalitis Enterovirus 71 encephalitis VZV encephalitis Dengue encephalitis Rabies encephalitis Influenza encephalitis Characteristic neuroimaging pattern Temporal lobe edema and hemorrhage Bilateral temporal lobe involvement is nearly pathognomonic but is a late finding Thalamus, basal ganglia Mid brain, pons, medulla (brainstem encephalitis) Cerebral cortex, basal ganglia, cortical white matter junction, cerebellum Basal ganglia, thalami, temporal lobe. May present as acute hemorrhagic or necrotizing encephalitis Basal ganglia, thalami, brainstem, limbic system, spinal cord as well as frontal and parietal lobes Cortex and white matter The definitive etiological diagnosis of encephalitis is through demonstration of the pathogen in the CNSbyculture or polymerase chain reaction (PCR) of brain tissue/csf or by demonstrating specific antibody response in CSF. Detecting the pathogen elsewhere in the body doesn t necessarily indicate CNS infection. CSF viral culture is rarely done these days as newer more sensitive PCR techniques are now available like real time and quantitative PCR for many organisms with improved yield. The most commonly available CSF viral PCR is for HSV encephalitis. CSF HSV PCR is >95% sensitive and specificand remains positive in 80% even a week after starting antiviral therapy. However, it may be negative in first few days of illness. In case of strong clinical suspicion of HSV encephalitis, it should be repeated after a couple of days. If two PCRs are negative, then it is unlikely to be HSV infection. Further investigations may be guided by the clinical picture and initial CSF or neuroimaging findings. Newer enzyme immunoassays can detect specific IgM and IgG antibodies in serum and CSF for most viruses and mycoplasma pneumonia though negative result in the acute phase doesn t rule out infection. Four-fold rise in antibody titers between the paired acute and convalescent sera collected 2-4 weeks apart to document seroconversion doesn t help in immediate management but may be useful for retrospective etiological diagnosis. Presence of virus specific IgM antibodies in higher titers in CSF as compared to serum implies CNS infection, as IgM usually doesn t cross blood brain barrier (BBB) unless inflamed. 7 PCR or culture or antigen testing of a throat swab or nasopharyngeal aspirate may help in identification of mycoplasma, chlamydia, adenovirus, influenza virus, mumps and measles.

7 Enterovirus may be identified in a throat swab or a rectal swab. Fluid from a vesicular lesion can be sent for electron microscopy, immunofluorescence, antigen detection, PCR or culture to identify herpes viruses or enterovirus. Brain biopsy for culture, electron microscopy, PCR and immunohistochemistry has a very limited role and may be done in deteriorating undiagnosed patients. Neuroimaging plays an important role in the evaluation of a child with viral encephalitis. In emergency settings, to identify focal lesions or cerebral edema, computed tomography (CT) scan is preferred to magnetic resonance imaging (MRI) scan as it is cheaper, more widely available and technically less difficultto acquire. However, MRI is has better sensitivityto detect brain parenchymal changes and is important for prognostication (Table 6). In the early stages, conventional MRI may be normal and special sequences like diffusion-weighted imaging (DWI) may be useful in such conditionsto detect early changes Fig 1: MRI in Japanese encephalitis Fig 2: MRI in HSV encephalitis Electroencephalogram (EEG) has a supportive role in the intensive management of encephalitis. It helps in detecting non-convulsive status epilepticus (NCSE) and in demonstrating burst suppression during treatment of refractory status epilepticus. EEG also has a diagnostic role. In most cases of encephalitis, it may show non-specific diffuse high amplitude slow waves of encephalopathy. Periodic lateralized epileptiform discharges are usually seen in HSV encephalitis though they are not highly specific. Treatment In a child with suspected viral encephalitis, evaluation and treatment should proceed together. The treatment includes initial stabilization, definitive therapy, management of complications and supportive care. Initial stabilization: The priorities during management in emergency include: Assessment of airway and stabilization Hemodynamic assessment and resuscitation if needed Assessment of level of consciousness using a quantitative scale like GCS Management of complications like seizures and raised intracranial pressure (ICP)

8 Definitive therapy: After initial stabilization, the treatment of viral encephalitis involves definitive antiviral or immunomodulatory therapy to halt or reverse the disease progression. Presumptive treatment pending neuroimaging and/or lumbar puncture includes administering antimicrobials to cover for organisms causing both bacterial meningitis and viral encephalitis. As HSV is the most common cause for sporadic encephalitis and currently one of the very few potentially treatable causes of viral encephalitis, there should be a high index of suspicion and acyclovir should be empirically started as early as possible. In proven cases of HSV encephalitis, acyclovir is given for a total of 3 weeks duration because of the risk of relapse with shorter therapies. CSF examination may be repeated at the end of treatment and acyclovir should be continued if fever persists or CSF HSV-PCR is still positive. 11 Other treatable causes of viral encephalitis are varicella zoster encephalitis (acyclovir), cytomegalovirus (CMV) encephalitis (ganciclovir, valaciclovir). 12,13 Management of complications: The most important neurological complications of encephalitis are raised ICP and status epilepticus. Ideally, such children should be managed in an intensive care setting with continuous neurocritical care monitoring. 14 Presence of raised ICP should be anticipated in children with encephalitis and proactively managed. When it is clinically suspected, an ICP monitoring catheter should be inserted for objective measurement. First tier anti-raised ICP measures include head end elevation to , keeping head in midline, minimal stimulation, control of fever and seizures. Osmotherapy may be used to reduce the cerebral edema. Hypertonic saline is preferred over mannitol for osmotherapy because of lesser side effects like hypotension or renal failure and presence of additional rheological benefits. For raised ICP refractory to these measures, barbiturate coma or Decompressive craniectomy may be considered. Seizures are a common presentation in encephalitis and time-based protocolized management of status epilepticus improves outcomes. First line anti-epileptics include benzodiazepines, phenytoin, valproate and levetiracetam while barbiturate coma, ketamine, lignocaine and general anesthesia may be tried in refractory status epilepticus. Nonconvulsive status epilepticus (NCSE) should be considered in all children with unexplained persistent encephalopathy and continuous EEG monitoring should be done. Supportive care: Supportive care is paramount in management of children with encephalitis. Patient positioning and prevention of bed sores, nutrition and physiotherapy should be meticulously taken care off. Tracheostomy should be considered in those anticipated to require prolonged airway or respiratory support. Prognosis Withthe recent advances in diagnosis and management, mortality due to encephalitis in children has come down significantly, however, neurological sequelae are still common in long term survivors. They include motor, sensory and cognitive impairments, epilepsy, behavioral problems and psychiatric disorders. Long term follow-up and neurorehabilitation are important to improve outcomes. Conclusion Encephalitis is a common problem in pediatrics, mostly caused by viruses. Early diagnosis and meticulous management is critical for better outcomes. CSF examination and neuroimaging are critical for diagnosis and management. Supportive care is the mainstay of therapy and acyclovir is the drug of choice in those with clinical suspicion of herpes encephalitis. Inspite of the best treatment, mortality is still significant and long-term sequelae are common in those who survive.

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