ACUTE ENCEPHALITIS SYNDROME by DR.LIKITHA

PRATHIMA INSTITUTE OF MEDICAL COLLEGE
2nd YEAR MD. PEDIATRICS

1. DR A LIKHITHA MENTOR: DR.G.V. HARISH PROFESSOR DEPT.OF PEDIATRICS PIMS ACUTE ENCEPHALITIS SYNDROME

2. Encephalitis in children is a neurological syndrome caused either by an infectious agent or a non-infectious cause. Various terms including acute febrile encephalopathy, acute encephalitis syndrome and infectious encephalitis have been commonly used INTRODUCTION : Acute encephalitis syndrome term was coined in 2008 by WHO for surveillance and research in India.

3. TERMINOLOGIES : ENCEPHALITIS : Encephalitis refers to the inflammation of brain parenchyma Encephalitis is characterized by an acute onset of fever and encephalopathy (altered sensorium ranging from irritability to coma) with/without seizures or other neurologic signs due to CNS inflammation.( CSF pleocytosis present) ENCEPHALOPATHY: Encephalopathy refers to disruption of brain function in the absence of a direct inflammatory process in brain parenchyma., , hence cerebrospinal fluid (CSF) shows no pleocytosis The causative factors include metabolic disturbances, hypoxia, ischemia, drugs, toxins, organ dysfunction or systemic infection.

4. ACUTE ENCEPHALITIS SYNDROME : World Health Organization defines acute encephalitis syndrome as : “acute onset of fever and a change in mental status and/or new onset of seizures in a person of any age at any time of the year”. This definition excludes febrile seizures . Acute encephalitis syndrome is a medical emergency. Though the causes of acute encephalitis are many, initial presentation may be similar. Focused clinical evaluation and initial stabilization are the Corner stone of management

5. ETIOLOGY : INFECTIVE : Viral : HSV ,JE , EBV,VZV,CMV,polio virus,west nile virus Bacterial :My. pneumoniae, M.tuberculosis , Listeria monocytogenes, Bartonella , Coxiella burnetti , Rickettsia , Treponema pallidum Fungal : Cryptococcus neoformans, Histoplasma capsulatum, Coccidioides spp , Candida spp Parasitic : Toxoplasma gondii, Plasmodium falciparum, Naegleria fowleri , Acanthamoeba spp NON INFECTIVE : Immune mediated ADEM Auto immune encephalitis-anti NMDAR Hashimotos encephalopathy Bickerstaff brain stem encephalitis Acute necrotizing encephalitis FIRES: Febrile infection related epilepsy syndrome IEM NCSE : non convulsive status epilepticus

6. Acute disseminated encephalomyelitis (ADEM ) is an inflammatory disorder frequently involving white matter of brain and spinal cord . ADEM can also be triggered by immunization with DPT , MMR , rabies, Japanese B encephalitis, hepatitis B, influenza or meningococcal vaccines. Viruses have been mainly attributed to be the cause of AES in India Immune-mediated encephalitis includes autoimmune encephalitis without cancer association , paraneoplastic encephalitis and systemic vasculitis . Neuronal receptors which are targeted by these autoantibodies are N-methyl D aspartate receptor (NMDAR), voltage gated potassium channel (VGKC), α- amino 3-hydroxy 5-methyl 4-isoxazole propionic acid (AMPAR), γ- amino butyric acid receptor (GABABR)

7. Etiologic clues : Travel /Recent vaccination (acute disseminated encephalomyelitis (ADEM)) Contact with animals (rabies), Consumption of raw milk (brucellosis) Contact with unchlorinated fresh water (amoeba) Water contaminated with animal urine (leptospirosis) Exposure to mosquito/tick bites (arboviruses, lyme disease, tick borne encephalitis) Known risk factors for HIV/immunocompromised. Siblings with similar illness/multiple episodes of encephalopathy: IEM HISTORY EVELUATION :

8. Clinical presentation includes flu-like syndrome, altered sensorium, seizures, pyramidal signs, cerebellar, extrapyramidal involvement In children with encephalitis, up to 80% had fever, seizures (79% focal ), focal neurological signs and up to 50% had low GCS CLINICAL PRESENTATION :

9. Clinical presentation in encephalitis of varying etiology : HERPES VIRUS : Fever ,seizures ,altered sensorium , behavioural changes JAPANESE B VIRUS : fever, meningeal signs , dystonias ANTI NMDAR ENCEPHALITIS : Orofacial dyskinesias and psychiatric features such as delusions, hallucinations and catatonia EPSTEIN BARR VIRUS Encephalitis , ADEM , encephalopathy , cerebellar ataxia

10. INVESTIGATIONS : This includes : Complete blood count, RFT S electrolytes, S calcium, Blood glucose, Liver function tests, Prothrombin time, activated partial thromboplastin time, C-reactive protein, Urine ketones, Arterial blood gases, l actate, ammonia, Peripheral smear for malarial parasite, Chest X-ray, Blood culture, Screening for HIV. Lumbar puncture

11. Lumbar puncture is mandatory in all children with acute encephalitis, unless there are absolute contraindications. Cerebrospinal spinal fluid should be analyzed for cell count, protein, sugar. Electroencephalography (EEG) is mandatory in all children with unexplained encephalopathy and in children with altered sensorium after a convulsive status to rule out an ongoing non-convulsive status. Presence of periodic lateralized epileptiform discharges (PLEDs) in EEG suggests the possibility of herpes encephalitis .

12. Neuroimaging is essential in all children with acute encephalitis. MRI brain with diffusion weighted images and gadolinium contrast is preferred over CT brain Brain biopsy should be considered in children who succumb during an outbreak of encephalitis, If no pathogen is identified Other tests : Thyroid antibodies, vasculitis markers , anti-NMDA receptor antibodies, anti-VGKC antibodies and other onconeural antibodies Basic metabolic profile such as blood TMS , urine gas chromatography mass spectrometry, ammonia , ABG , lactate levels

13. Neuro imaging clues HERPES SIMPLEX ENCEPHALITIS T2 or FLAIR signal hyperintensity in temporal lobe, and cingulate gyrus; Non-temporal location maybe present in HIV infected children ADEM asymmetric, multifocal, subcortical white matter and bilateral thalamic hyperintensities

14. JAPANESE B ENCEPHALITIS : Bilateral thalamic, substantia nigra hyperintensities 50 % - normal, remaining have hyper intensity in hippocampus,cerebral /cerebellar cortex +/- sc ANTI NMDAR

15. TREATMENT : Managing airway, breathing and circulation must be the priority in all children with acute encephalitis. Maintain euthermia and euglycemia. Correct acid-base abnormalities and dys electrolytemia Children with raised intracranial pressure: 30º elevation of head end; ventilation targeting low normal PCO2; adequate analgesics and sedation; therapy with 3% normal saline and mannitol Anticonvulsants (phenytoin) should be given if : child is having seizures, or has history of seizures, even in the absence of seizures in children with GCS < 8, and features of raised intracranial pressure

16. INFECTiOUS ETIOLOGY : A broad spectrum antibiotic such as ceftriaxone must be started Empirical therapy with acyclovir should be initiated and continued in all children with acute encephalitis till diagnostic test reports are availab le NON INFECTIOUS ENCEPHALITIS : 1 ) ADEM - Intravenous pulse methyl prednisolone 30mg/kg for 5 days. If no improvement, repeat pulsing steroids or IV IG 2gm/kg. If residual deficit, oral steroids 1 mg/kg for 3 weeks 2)Anti NMDAR ENCEPHALITIS - Concurrent IV IG and methyl prednisolone infusion or plasma exchange. Tumor removal if present If no improvement, rituximab ± cyclophosphamide If improvement occurs, chronic immunosuppression with mycophenolate mofetil or azathioprine yearly tumor surveillance

17. Artesunate 2.4 mg/kg IV 1 st dose FOR PLASMODIUM FALCIPARUM Anti-tubercular treatment (ATT) for 10–12 months is recommended for CNS tuberculosis by RNTCP Then at 12 and 24 hours Then OD for a total of 7 days Change to oral preparation once the child is able to swallow.

18. PREVENTION : Public health measures such as sanitation, avoidance of man vector contact and vector control play vital role in preventing outbreaks of encephalitis Universal precautions must be followed by all health care workers. Adequate immunization coverage for measles, mumps, rubella, varicella, influenza and post exposure prophylaxis for rabies is essential. In geographic areas endemic for Japanese encephalitis, mass vaccination strategies against JE virus Reported mortality in HSV encephalitis was upto 10% and in Japanese encephalitis was upto 40%. Most children with immune-mediated encephalitis make a near complete recovery and reported mortality in anti NMDAR encephalitis was less than 5%

19. A 7 yr old male with – fever since 6 days convulsions since 1 day Fever : high grade ,a/w chills and rigors no h/o rash ,catarrh ,headache ,burning micturition Convulsion : sudden in onset with LOC, uprolling of eyeballs tonic clonic type involving left side no h/o fall no h/o recent vaccination On admission – GCS – E2V1M3 afebrile pallor + Cns exmn – cranial nerves normal fundus normal pupils mid dilated and sluggishly reacting no meningeal signs tone increased in all 4 limbs DTR exaggerated sens – abnormal flexion response to pain CASE SCENARIO :

20. Diag - AES TREATMENT - 1) inj ceftriaxone 2) inj vancomycin 3) inj acyclovir 4)o2 5)anti epileptics – phenytoin,valproate 6)3 % ns Inv : hb – 8.5 abg – normal lft – normal mp,mf,widal – neg csf : pressure - normal clear cell count – 10/ cmm mononuclear cells sugar – 75 prot – 14 gram stain – neg ZN stain – neg Indian ink – neg Je serology,hsv serology,csf cbnaat - neg culture – no growth

21. So now consider auto immune encephalitis and send for anti nmdar , thyroid abs start methy pred MRI – NORMAL EEG – DIIFUSE ENCEPHALOPATHY

22. CASE SCENARIO 2 A 9 year old female child presented with URT illness – fever,dry cough, Neck lymphnodes Prescribed amoxicillin Developed maculo popular rash on face trunk limbs after 2 days All synptoms resolved then started headache,vomitings,fever Confusion,seizures

23. Child was admitted Supportive care, Vancomycin, ceftriaxone, acyclovir started Meanwhile- past hist,family hist,vaccination hist was Not significant Ct – normal Csf – normal On examn – signs of meningeal irritation + hypertonia + Then mri showed – multifocal asymmetric whitematter lesions

24. Diagnosis : ADEM post EBV infection

25. DR LIKHITHA PREVENTION OF NEONATAL BRAIN INJURY

26. INTRODUCTION : The most common causes of neonatal brain injury are extreme prematurity, neonatal stroke, and hypoxic-ischemic encephalopathy (HIE) The preoligodendrocytes, mature between 24 and 32 weeks of development, are particularly susceptible to injury such as intracranial hemorrhage, periventricular leukomalacia The most important acquired brain injuries preterm infants born are periventricular-intraventricular hemorrhages (PIVH) and diffuse white matter injury dWMI . This brain injury may lead to cerebral palsy and learning difficulties, and can have major impact on the quality of life

27. Oxidative stress (OS) plays a fundamental role in early injury, along with excitotoxicity. OS is a degenerative process due to overproduction of free radicals (FRs) These FRs include superoxide anion (O2 −), hydroxyl radical (OH), and hydrogen peroxide (H2O2) FRs cause damage to lipids, protein, and DNA, initiating a cascade that results in cell death Tissue damage is possible when there are low levels of antioxidants or increased FR activity Brain cells death at any age is primarily due to hypoxia and energy depletion, followed by reperfusion and FR overproduction. Excitotoxicity and nitric oxide (NO) production are responsible of secondary energy failure and delayed death

28. HYPOXIC ISCHAEMIA ANAEROBIC GLYCOLYSIS Decreased ATP Impair Na,K pumps , release of neurotransmitters ( glutamate ) Influx of Na, calcium Cytotoxic odema Activates proteases, lipases, NO synthases Free radical damage , apoptotic cell death PRIMARY ENERGY FAILURE :

29. When cerebral circulation is re established after resuscitation ,cellular metabolism is restored , ATP levels return to baseline , glutamate is cleared and Lactate levels improve. The initial perfusion phase is f/b a latent phase. The secondary energy failure phase occurs 6-15 hours after the initial phase, reaches its Nadir by 24-48 hours and may continue for days to weeks . During this phase , a secondary cascade of brain injury occurs as a result of accumulation of excitatory neurotransmitters , oxidative injury , apoptosis and activation of inflammation. The latent resolution phase corresponds to a therapeutic window of approximately 6hours . Initiaiton of therapies in a therapeutic window has been successful in reducing brain damage SECONDARY ENERGY FAILURE :

30. Hypoxia – ischemia Anaerobic glycolysis Adenosine dec atp inc lactate Hypoxanthine inc glutamate xanthine oxidase xanthine NMDA RECEPTOR Free radicals inc IC Ca++ activates activates NOS lipases inc FFA NO free radicals POTENTIAL PATHWAYS FOR BRAIN INJURY AFTER HYPOXIC ISCHEMIA

31. STRATEGIES TO DECREASE BRAIN INJURY : ANTENATAL : Prevent preterm delivery Antenatal steroids reduces IVH by 46% Antenatal mgso4 reduces risk of severe CP Antibiotics for PPROM POSTNATAL : Delayed cord clamping Caffeine for apnea of prematurity Indomethacin prophylaxis-we don’t use it Early surfactant administration Prevent NEC , late onset sepsis

32. THERAPEUTIC HYPOTHERMIA : It reduces the severity of secondary reperfusion brain injury by acting at various levels of the cascade of neuronal Injury It reduces cerebral metabolism , energy utilization and attenuates excitotoxic injury ,inhibits apoptosis ,suppresses free radical protection NEUROPROTECTIVE STRATEGIES : Cooling should be initiated within the therapeutic window period of 6 hours. The earlier the cooling is commenced the better is the outcome The core temp should be maintained at 33.5 degree C ( 33-34 ) for 72 hours The baby shoud be rewarmed slowly at a rate of 0.2-0.5 degree Celsius per hour. Rapid rewarming may cause hypotension , hypoglycemia ,and hypokalemia Each step in the oxidative injury cascade has become a potential target for neuroprotective intervention

33. PRESENCE OF LETHAL CHR ABNORMALITY(TRI 13/18) PRESENCE OF CONG ANOMALIES-CHD MAJOR ICH SIGNIFICANT BLEEDING DIATHESIS SYMPTOMATIC SYST CONG BACT INFECTION SYMPTOMATIC SYST CONG VIRAL INFECTION A . BOTH >/= 36 weeks or >/= 1800 gms < 6 hours of age B. ANYONE : APGAR @ 10 MIN < 5 ABG (cord / 1 hr postnatal ph < 7,base deficit>16 Need for prolonged IPPV for > / =10 min C .MODERATE TO SEV ENCEPHALOPATHY INCLUSION CRITERIA EXCLUSION CRITERIA

34. ANTENATAL CORTICO STEROIDS : GIVE FIRST DOSE OF CS TO - all women at risk of preterm birth from 24+0 to 33+6 weeks when all the 3 conditions are met 1 ) GA assessment can be accurately undertaken 2 ) PT birth is imminent as evidenced by true labour pains 3 ) No clinical evidence of maternal infection INDICATIONS FOR REAPEAT COURSE OF CS : GA < 34 weeks at risk of preterm delivery with in next 7 days + prior dose completed before > 14 days DRUG AND DOASGE - dexamethasone : 6 mg/4 doses betamethasone : 12 mg/2 doses every 24 hours

35. OTHER NEURO PROTECTIVE STRATEGIES : 1 ) XENON : noble gas used in anesthesia It is a potent NMDA receptor antagonist, inhibits AMPA and kainite receptors under trial dis adv – very expensive 2 )ERYTHROPOEITIN : Epo is hematopoeitic growth factor produced locally in the brain it is neuroprotective against HI neuronal injury anti inflammatory and anti apoptotic high dose – 5000 U / kg reduces the infarct size in neoanatal stroke in mod HIE ,low dose -300/500 U /Kg improved neurological outcome at 18m needs further research for use 3) N ACETYL CYSTEINE : NAC is free radical scavenger ,decreases NO production clinical trials showed decrease in incidence of PVL by 39% in preterms human trials are awaited

36. 4 )MELATONIN : potent free radical scavenger and indirect anti oxidant human trials are awaited 5) ANTI CONVULSANTS : PROPHYLACTIC PHENOBARBITONE – before cooling has been shown to be ineffective TOPIRAMATE – modulates AMPA/kainite and GABA –A channels reduces excitotoxic NTs ,and cal overload under trial LEVETIRACETAM – regulates AMPA and NMDA receptor mediated excitatory NT , reduces glutamate release limited study 6)ALLOPURINOL: it inhibits xanthine oxidase, also scavenges other oxygen free radicals shown to decrease reperfusion injury in animal models

37. 7)MGSO4 –MAGNESIUM SULPHATE : it is a naturally occurring NMDA receptor antagonist it decreases inf cytokines, decreases platelet aggregation 8)DRUGS – indomethacin ,bumetanide ,memantine ,sodium cromoglycate 9) GROWTH FACTORS – ILG -1 ,nerve growth factor ,brain derived neuro trophic factor 10 )CORD BLOOD STEM CELL THERAPY 11)PROSTAGLANDIN INHIBOTORS – INDOMETHACIN – to prevent PV/ IVH

38. Q 1) ADEM is characterized by all except ? Age of onset < 10 years Post vaccinal encephalitis u/l optic neuritis Pleocytosis in CSF

39. u/l optic neuritis

40. Q 2) M/C cause of acute encephalitis syndrome ? Viral Bacterial Fungal parasitic

41. VIRUSES ARE THE M/C CAUSATIVE AGENTS

42. Q3) EEG finding in HSV encephalitis is ?

43. PERIODIC LATERALIZED EPILEPTIFORM DISCHARGES (PLED )

44. Q4 ) Avoid ACS In which of the following scenarios ? Mother who is already on oral steroids Mother with GDM Evidence of maternal infection

45. ABSOLUTE CONTRA INDICATION FOR ACS IS CHORIO AMNIONITIS

46. Q 5)True regarding HSV 1 encephalitis is ? a)Focal findings in MRI b)Negative CSF cultures C) Most sensitive inv – csf hsv pcr d) All the above

47. ALL THE ABOVE

48. Q) Atypical lymphocytes in CSF of viral encephalitis are Commonly seen with a)EBV b)CMV c)HSV d)enterovirus

49. EBV

50. Q) In MRI of HSV encephalitis which lobe of brian is most affected? Frontal Temporal Parietal occipital

51. TEMPORAL LOBE

52. Q) In therapeutic hypothermia Core temperature of 33.5 must be Maintained for duration of ? a)24 hrs b)48 hrs c)72 hrs

53. 72 HOURS