Influenza-associated Encephalopathy H1N1

Influenza Associated Encephalopathy/EncephalitisPotential Role of High Dose N-Acetylcysteine Anti-oxidant Therapy : 

Influenza Associated Encephalopathy/EncephalitisPotential Role of High Dose N-Acetylcysteine Anti-oxidant Therapy Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Spectrum of CNS Complications of Influenza Virus Infection : 

Spectrum of CNS Complications of Influenza Virus Infection Encephalitis lethargica Reye’s syndrome Acute necrotizing encephalopathy (ANE) Influenza encephalopathy and encephalitis Sudden onset of high fever, early development of unconsciousness, recurrent convulsions and death within 2 or 3 days. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) Febrile convulsion (most common) Acute disseminated encephalomyelitis (ADEM) In Queen Elizabeth Hospital, we have two documented cases of ADEM after H1N1 2009 pneumonia Seasonal influenza H3N2 is the most common etiology of influenza associated encephalopathy / encephalitis Seasonal H3N2 infections cause almost 14 times the number of influenza related deaths than seasonal H1N1 infections and are associated with a higher epidemic severity index due to the presence of a truncated PB1-F2 protein in seasonal H1N1 Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, et al. (1997) The impact of influenza epidemics on mortality: Introducing a severity index. Am J Public Health 87: 1944–1950 Simonsen L, Fukuda K, Schonberger LB, Cox NJ (2000) The impact of influenza epidemics on hospitalizations. J Infect Dis 181: 831–837. Zell R, Krumbholz A, Eitner A, Krieg R, Halbhuber KJ, et al. (2007) Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 88: 536–546.

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Direct viral invasion is uncommon except for H5 and H7 because the presence of polybasic amino acids at the cleavage site of HA0 in H5 and H7 allow the breakdown of HA0 by nonspecific protease  easy breakdown of organ barrier and invasion of central nervous system Spectrum of CNS Complication of Influenza Virus Infection (AESD = Acute encephalopathy with biphasic seizures and late reduced diffusion) Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy[Hideo Aiba, MD, Mika Mochizuki, MD, Mitsuaki Kimura, MD and Hiroatsu Hojo, MD Neurology 2001;57:295-299] Obsolete Cx after discontinuation of aspirin in Rx of childhood fever Role of High Dose N-acetylcysteine

Reye’s Syndrome : 

Reye’s Syndrome Reye's syndrome, a severe neurologic disease that causes death or long-term neurologic sequelae in about one third of patients, was uncommon after withdrawal of aspirin as analgesic and antipyretic agent for childhood febrile illness. Reye's syndrome in the United States from 1981 through 1997. Belay ED. Bresee JS. Holman RC. Khan AS. Shahriari A. Schonberger LB. New England Journal of Medicine. 340(18):1377-82, 1999 May 6. Microvesicular steatosis

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The dramatic decline in the number of reported cases of Reye's syndrome since 1980. due to reports of the association of Reye's syndrome with the use of aspirin during antecedent varicella and influenza-like illness, the issuance of an advisory by the surgeon general, and the labeling of aspirin-containing medications with a warning about the risk of Reye's syndrome.

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Reye's syndrome in the United States from 1981 through 1997. Belay ED. Bresee JS. Holman RC. Khan AS. Shahriari A. Schonberger LB. New England Journal of Medicine. 340(18):1377-82, 1999 May 6.

Reye’s syndrome: lab tests : 

Reye’s syndrome: lab tests Elevated lipase and amylase levels Decreased serum bicarbonate secondary to vomiting Elevated BUN and creatinine levels Anion gap test for metabolic acidosis Increased urine specific gravity 80% of patients have ketonuria Hypoglycemia – patients < 1 year of age CSF: elevated opening pressure and WBC’s Elevated free fatty acids and amino acids LFT’s: elevated ammonia 1.5 x’s normal 24-48 hours after onset of mental status changes

Reye’s syndrome: treatment : 

Reye’s syndrome: treatment Establish and maintain airway and circulation Check BG levels – patients < 1 yo or with altered mental status Give dextrose for hypoglycemia NO specific treatment Prevention of metabolic abnormalities cerebral edema respiratory failure acute renal failure

Reye’s syndromeCDC diagnostic stages : 

Reye’s syndromeCDC diagnostic stages Stage 0: alert, abnormal history and lab findings Stage 1: vomiting, sleepiness, lethargy Stage 2: restless, irritable, combative, disoriented, tachycardia, hyperreflexia, + Babinski sign Stage 3: obtunded, comatose, inappropriate response to noxious stimuli Stage 4: deep coma Stage 5: seizures, flaccid paralysis, absent DTR, respiratory arrest Stage 6: patients cannot be classified because treated with curare or other meds that alter consciousness

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Reye's syndrome in the United States from 1981 through 1997 Belay ED. Bresee JS. Holman RC. Khan AS. Shahriari A. Schonberger LB. New England Journal of Medicine. 340(18):1377-82, 1999 May 6.

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Impaired mitochondrial function in microvesicular steatosis effects of drugs, ethanol, hormones and cytokinesBernard Fromenty, Dominique Pessayre Journal of hepatology 2007 Vol 26 Supplement 2 Pages 43-53 Mitochondrial Defect Microvesicular Steatosis

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Impaired mitochondrial function in microvesicular steatosis effects of drugs, ethanol, hormones and cytokinesBernard Fromenty, Dominique Pessayre Journal of hepatology 2007 Vol 26 Supplement 2 Pages 43-53

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Impaired mitochondrial function in microvesicular steatosis effects of drugs, ethanol, hormones and cytokinesBernard Fromenty, Dominique Pessayre Journal of hepatology 2007 Vol 26 Supplement 2 Pages 43-53

Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. Trost LC. Lemasters JJ. Toxicology & Applied Pharmacology. 147(2):431-41, 1997 Dec. : 

Role of the mitochondrial permeability transition in salicylate toxicity to cultured rat hepatocytes: implications for the pathogenesis of Reye's syndrome. Trost LC. Lemasters JJ. Toxicology & Applied Pharmacology. 147(2):431-41, 1997 Dec. Salicylate, the active metabolite of aspirin, induces the mitochondrial permeability transition (MPT) in mitochondria by opening of a high conductance, cyclosporin A-sensitive pore in the mitochondrial inner membrane leads to swelling, depolarization, and uncoupling of oxidative phosphorylation. The onset of the MPT may be the common pathophysiologic mechanism causing mitochondrial injury in Reye's syndrome and Reye's-related drug toxicities . The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury. Trost LC. Lemasters JJ.Journal of Pharmacology & Experimental Therapeutics. 278(3):1000-5, 1996 Sep.

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The mitochondrial permeability transition: a new pathophysiological mechanism for Reye's syndrome and toxic liver injury. Trost LC. Lemasters JJ. Journal of Pharmacology & Experimental Therapeutics. 278(3):1000-5, 1996 Sep. Induction of mitochondrial permeability transition by opening of a high conductance, cyclosporin A-sensitive pore 粒線體過渡性通透孔

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Role of mitochondrial membrane permeabilization in apoptosis and cancer Judith Henry-Mowatt, Caroline Dive, Jean-Claude Martinou and Dominic James Oncogene (2004) 23, 2850–2860. doi:10.1038/sj.onc.1207534 Influenza Virus PB1-F2 Protein Induces Cell Death through Mitochondrial ANT and VDAC Dmitriy Zamarin,1 Adolfo García-Sastre,1 Xiaoyao Xiao,2 Rong Wang,2 and Peter Palese1 PLoS Pathog. 2005 September; 1(1): e4. Mitochondrial control of nuclear apoptosis. Zamzami N. Susin SA. Marchetti P. Hirsch T. Gomez-Monterrey I. Castedo M. Kroemer G. Journal of Experimental Medicine. 183(4):1533-44, 1996 Apr 1. VDAC PBR ANT CyD The Mitochondrial Permeability Transition Pore The Ca2+-sensitive permeability transition pore (PTP) consists of the peripheral benzodiazepine receptor (PBR), the voltage-dependent anion channel (VDAC), adenine nucleotide translocator (ANT) and cyclophilin D (CyD). Hexokinase (HK), Cyclosporin A (CsA) and Bongkrekic acid (BKA) can all induce closure of the PTP via interaction with VDAC, CyD and ANT respectively. HK BKA CsA Influenza  ↑ROS CL Cytochrome C ROS induced release of mitochondrial lipid cardiolipin (CL) bounded cytochrome C Influenza Virus PB1-F2 Protein induces Cell Death through interaction with Mitochondrial ANT3 and VDAC1 Potential Role of High Dose N-acetylcystine in influenza induced apoptosis of cells

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Antiviral Response in Pandemic Influenza Viruses Adolfo García-Sastre Emerging Infectious Diseases • www.cdc.gov/eid • Vol. 12, No. 1, January 2006 A novel influenza A virus mitochondrial protein that induces cell death Weisan Chen et al Nature Medicine 7, 1306 - 1312 (2001) A Single Mutation in the PB1-F2 of H5N1 (HK/97) and 1918 Influenza A Viruses Contributes to Increased Virulence published October 18, 2007 Gina M. Conenello, Dmitriy Zamarin, Lucy A. Perrone, Terrence Tumpey, Peter Palese PLOs pathogens INFLUENZA VIRUS INDUCTION OF APOPTOSIS BY INTRINSIC AND EXTRINSIC MECHANISMS R. JOEL LOWY ‌ International Reviews of Immunology 2003, Vol. 22, No. 5-6, Pages 425-449 After comparing viruses from the Hong Kong 1997 H5N1 outbreak, one amino acid change (N66S) was found in the PB1-F2 sequence at position 66 that correlated with pathogenicity. This same amino acid change (N66S) was also found in the PB1-F2 protein of the 1918 pandemic A/Brevig Mission/18 virus. Apoptosis of immune cells lead to ↓Ag presentation and ↓ adaptive immune response PB1 gene has been one of the segments found to reassort to create the pandemic strains of 1957 and 1968, potentially giving these viruses a more pathogenic PB1-F2 and thus a higher virulence PB1-F2 Protein’s Role in Mitochondrial Permeability Transition Pore

Influenza Virus PB1-F2 Protein Induces Cell Death through Mitochondrial ANT3 and VDAC1 Dmitriy Zamarin,1 Adolfo García-Sastre,1 Xiaoyao Xiao,2 Rong Wang,2 and Peter Palese1 PLoS Pathog. 2005 September; 1(1): e4. : 

Influenza Virus PB1-F2 Protein Induces Cell Death through Mitochondrial ANT3 and VDAC1 Dmitriy Zamarin,1 Adolfo García-Sastre,1 Xiaoyao Xiao,2 Rong Wang,2 and Peter Palese1 PLoS Pathog. 2005 September; 1(1): e4. Viral PB1-F2 protein sensitizes cells to apoptotic stimuli such as tumor necrosis factor alpha, as demonstrated by increased cleavage of caspase 3 resulting cleavage of caspase C, cytochrome c release, loss of the mitochondrial membrane potential, and enhancement of tBid-induced mitochondrial permeabilization. The Influenza Virus PB1-F2 Protein uniquely interacts with the inner mitochondrial membrane adenine nucleotide translocator 3 and the outer mitochondrial membrane voltage-dependent anion channel 1, both of which are part of the mitochondrial membrane transition pore involved during apoptosis. These interactions promote the permeabilization of the mitochondrial membrane transition pore and facilitate the release of mitochondrial products that trigger cell death (apoptosis) during influenza infection.

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Influenza Virus PB1-F2 Protein Induces Cell Death through Mitochondrial ANT3 and VDAC1 Dmitriy Zamarin,1 Adolfo García-Sastre,1 Xiaoyao Xiao,2 Rong Wang,2 and Peter Palese1 PLoS Pathog. 2005 September; 1(1): e4.

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Diagnosis and interpretation of steatosis and steatohepatitis. Burt AD. Mutton A. Day CP. Seminars in Diagnostic Pathology. 15(4):246-58, 1998 Nov.

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency : 

Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency 1% American are heterozygous, Homozygous 1:17,000 Microsteatosis Encephalopathy Suddne death Lethargy Hypoglycemia Reye’s like syndrome

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Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency

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Medium-chain acyl-coenzyme A dehydrogenase (MCAD) deficiency

Epidemic Encephalitis Lethargica1917-1927 Associated with H1N1 : 

Epidemic Encephalitis Lethargica1917-1927 Associated with H1N1 Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Encephalitis Lethargica : 

Encephalitis Lethargica

Was encephalitis lethargica a post-influenzal or some other phenomenon? Time to re-examine the problem.Mortimer PP. Epidemiology & Infection. 137(4):449-55, 2009 Apr. : 

Was encephalitis lethargica a post-influenzal or some other phenomenon? Time to re-examine the problem.Mortimer PP. Epidemiology & Infection. 137(4):449-55, 2009 Apr.

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1918 Influenza, encephalitis lethargica, Parkinsonism Ravenholt RT, Foege WH. Lancet 1982; ii : 860–864.

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Encephalitis Lethargica Coincide with Influenza Season (e.g. in U.S.A. Influenza season begins at November and ends at May) Influenza Season Influenza Season

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Children and encephalitis lethargica: a historical review. Vilensky JA. Foley P. Gilman S. Pediatric Neurology. 37(2):79-84, 2007 Aug.

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Age Distribution Curve of 1918 H1N1 Influenza Similar Age Distribution To Encephalitis Lethargica

Encephalitis Lethargica(von Economo’s disease) : 

Encephalitis Lethargica(von Economo’s disease) Epidemic 1916 and 1927 with basal ganglia and midbrain involvement Clinical features (von Economo): Sleep disturbance /reversal (sleep reversal-awake at night and asleep during the day) Lethargy Extrapyramidal movements (Parkinsonism and dyskinesia) Neuropsychiatric disorders catatonia, obsessive±compulsive, disorder and mutism, apathy and conduct disorders). Oculogyric crises Ocular features (ophthalmoplegia and ptosis) Central cardiorespiratory features (particularly hiccough) N.B. Deep grey matter (particularly basal ganglia) may be involved in the control of mood, emotion, behaviour and volition (Cheyette and Cummings, 1995; Ward, 2003) Midbrain and deep grey matter are involved in sleep control (von Economo)

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Clinical Features and Laboratory Findings

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The encephalitis lethargica syndrome is a neuropsychiatric syndrome with a movement disorder—either hypokinetic or hyperkinetic—prominent psychiatric features and a sleep disorder. This constellation of symptoms and signs results from pathological involvement of the diencephalon and mid-brain structures. Cortico–striato–thalamo–cortical circuitry of the brain which controls motor, emotional and cognitive domains.

Encephalitic lethargica: a report of four recent cases. Howard R, Lees A. Brain. 1987;110:19-28. : 

Encephalitic lethargica: a report of four recent cases. Howard R, Lees A. Brain. 1987;110:19-28. Howard and Lees Proposed Clinical Diagnostic Criteria Three of the following major criteria: (1) signs of basal ganglia involvement, (2) oculogyric crises, (3) ophthalmoplegia, (4) obsessive-compulsive behavior, (5) akinetic mutism, (6) central respiratory irregularities (7) somnolence and/or sleep inversion

Encephalitis Lethargica : 

Encephalitis Lethargica 28 types of manifestation of encephalitis lethargica has been described but 3 forms are most common: paralysis agitans-like, abortive, cerebellar, hyperkinetic, hemiplegic, cortical, spinal, polyneuritic, cataleptic, meningeal, progressive, aberrant, monosymptomatic, insomniac, paralytic, myoclonic, thalamic, and juvenile pseudo-psychopathic manifestation types. DDx idiopathic parkinsonism  Occur at younger age group with onset before age 40 years

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Clinical Features and Laboratory Findings

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A drawing of the human brainstem, taken from von Economo’s original work. Lesion (diagonal hatching) at the junction of the brainstem and forebrain that caused prolonged sleepiness. Lesion (horizontal hatching) in the anterior hypothalamus that caused prolonged insomnia The arrow points to a region between the two, including the posterior lateral hypothalamus. Von Economo suggested that narcolepsy was caused by lesions at this site.

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Reticular activaing System – 2 branches Ascending pathway to thalamus (Yellow)  Activates thalamic relay neurons, crucial for transmission of information to cerebral cortex Bypasses the thalamus  Activate neurons in basal forebrain and lateral hypothalamic area

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MRI of brain

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MRI of the brain in a somnolent patient with bradykinesia and rigidity Encephalitis lethargica syndrome: 20 new cases and evidence of basal ganglia autoimmunity Russell C. Dale et al October 21, 2003 Brain (2004), 127, 21-33 Midbrain and periaqueductal grey matter lesion Right putamen lesion Bilateral thalami and midbrain lesion Convalescent imaging showing resolution of the in¯ammatory changes in the thalami and midbrain.

Encephalitis Lethargica: Its Sequelae and Treatment. Von Economo C. Translated by K.O. Newman, Oxford University Press: London, England; 1931. : 

Encephalitis Lethargica: Its Sequelae and Treatment. Von Economo C. Translated by K.O. Newman, Oxford University Press: London, England; 1931.

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Clinical Features and Laboratory Findings

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Of 58 childhood cases of encephalitis lethargica described by Neal, 44 were male, 34 recovered, 14 died, and 10 were “cured.” Gradual onset, marked lethargy and asthenia, headache, low irregular temperature, cranial nerve and other palsies, and often a masked face Other possible features included catatonia, marked tremors, choreiform movements, profuse sweating, insomnia, delirium, and myoclonus. Vomiting was common.

Psychiatric Manifestation in Children : 

Psychiatric Manifestation in Children Whereas 70% of pediatric encephalitis lethargica survivors showed some psychological changes, approximately one third exhibited behavioral disorders. Marked personality changes, always negative. The term “Apache” was used to characterize the most aggressive of these children, a pejorative reference to Apache Indians Excitation crises (usually evening): agitation, screams, or insomnias; Impulsiveness; Infantile or precocious sexuality; Self-mutilation tics; Vandalism; Malicious cruelty coupled with feigned friendliness; and Theft Memory loss, true psychosis, and depression, on the other hand, were regarded as uncommon.

Approximately one third of affected children underwent a rapid transformation from normal behavior to delinquency,often leading to institutionalization ! : 

Approximately one third of affected children underwent a rapid transformation from normal behavior to delinquency,often leading to institutionalization ! Encephalitis lethargica triggered behavioral changes in children that are not duplicated by any other neurologic condition, with the possible exception of traumatic brain injury. These unique behavioral abnormalities may provide the earliest clear indication of new encephalitis lethargica cases, whether alone or in concert with an influenza epidemic. Children and encephalitis lethargica: a historical review. Vilensky JA. Foley P. Gilman S. Pediatric Neurology. 37(2):79-84, 2007 Aug.

Whereas the neurologic lesions are the same for adults and children with encephalitis lethargica, adults do not exhibit the “deterioration of character” unique to encephalitis lethargica in children. [Juvenile Pseudopsychopathia] : 

Whereas the neurologic lesions are the same for adults and children with encephalitis lethargica, adults do not exhibit the “deterioration of character” unique to encephalitis lethargica in children. [Juvenile Pseudopsychopathia] Many of these children with antisocial behavior are being send to a state institution or mental institutions or arrested as a result of their uncontrolled, delinquent behavior. Some has undergone frontal leucotomy. Remarks on the psychopathology of oculogyric crises in epidemic encephalitis. Wexberg E. J Nerv Ment Dis 1937;85:56-69

Institute for Juvenile Research in Chicago : 

Institute for Juvenile Research in Chicago Six behaviors that best distinguished children with encephalitis lethargica from those without encephalitis lethargica (although these control subjects were not “normal” children): Change of personality; Emotional instability, changeable moods, and crying spells; Irritability and temper tantrums, and quarrelsomeness; Nervousness, restlessness, and restlessness in sleep, and irregular sleep habits; Disobedience and defiant attitude; and Listlessness. They do not evade detection. They are indifferent to punishment

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Violent and aggressive behaviour and gesticulation of Hitler may have been due, at least partly to Encephalitis Lethargica ! Lancet Editorial. Anon. 1981; ii : 1396–1397. Was encephalitis lethargica a post-influenzal or some other phenomenon? Time to re-examine the problem P. P. MORTIMER Epidemiology and Infection (2009), 137:449-455

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Direct Viral Invasion in the presence of Mitochondrial Respiratory chain Defect H5N1 infection in mice causes severe loss of dopaminergic neurons 60 days after infection by provoking a destructive autoimmune response Changing Etiology of Encephalitis Lethargica Treatment: Pulse steroid Plasmapheresis IVIG Azathioprine

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection : 

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection Ab to GAS epitope N-acetylglucosamine cross react with Lysoganglioside on neuronal cells leading to induction of calcium calmodulin-dependent protein kinase I and increased tyrosine hydrolase and dopamine release

Both patients respond dramaticially to pulse steroid therapy(a) Methylprednisolone 0.5g IVI daily for 5 days or (b) Methylprednisolone 1g IVI daily for 3 days : 

Steroid treatment should be considered in the acute phase of patients with features suggestive of encephalitis lethargica. Clinical features and management of two cases of encephalitis lethargica. Blunt SB, Lane RJ, Turjanski N, Perkin GD Mov Disord. 1997 May;12(3):354-9. Both patients respond dramaticially to pulse steroid therapy(a) Methylprednisolone 0.5g IVI daily for 5 days or (b) Methylprednisolone 1g IVI daily for 3 days

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Any Questions ?

Influenza Associated Encephalopathy / Encephalitis : 

Influenza Associated Encephalopathy / Encephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Spectrum of CNS Complications of Influenza Virus Infection : 

Spectrum of CNS Complications of Influenza Virus Infection Encephalitis lethargica Reye’s syndrome Acute necrotizing encephalopathy (ANE) Influenza encephalopathy and encephalitis Sudden onset of high fever, early development of unconsciousness, recurrent convulsions and death within 2 or 3 days. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) Febrile convulsion (most common) Acute disseminated encephalomyelitis (ADEM) In Queen Elizabeth Hospital, we have two documented cases of ADEM after H1N1 2009 pneumonia Seasonal influenza H3N2 is the most common etiology of influenza associated encephalopathy / encephalitis Seasonal H3N2 infections cause almost 14 times the number of influenza related deaths than seasonal H1N1 infections and are associated with a higher epidemic severity index due to the presence of a truncated PB1-F2 protein in seasonal H1N1 Simonsen L, Clarke MJ, Williamson GD, Stroup DF, Arden NH, et al. (1997) The impact of influenza epidemics on mortality: Introducing a severity index. Am J Public Health 87: 1944–1950 Simonsen L, Fukuda K, Schonberger LB, Cox NJ (2000) The impact of influenza epidemics on hospitalizations. J Infect Dis 181: 831–837. Zell R, Krumbholz A, Eitner A, Krieg R, Halbhuber KJ, et al. (2007) Prevalence of PB1-F2 of influenza A viruses. J Gen Virol 88: 536–546.

Pathological Finding : 

Pathological Finding

Influenza-associated Encephalopathy/Encephalitis : 

Influenza-associated Encephalopathy/Encephalitis The most serious complication of influenza infection. Occur worldwide, but is most prevalent in East Asia, and every year several hundreds of Japanese children are affected by influenza-associated encephalopathy. Mortality has recently declined, but is still high. Many survivors are left with motor and intellectual disabilities, and some with epilepsy.

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Neurologic complications in children hospitalized with influenza: comparison between USA and Hong Kong. Chung BH, Tsang AM, Wong VC. J Pediatr. 2007 Nov;151(5):e17-8; author reply e18-9. Disease burden of Influenza related neurological complication in U.S.A and Hong Kong

Influenza-associated encephalitis and encephalopathy in children : 

Influenza-associated encephalitis and encephalopathy in children Isolated case reports and small series of encephalitis and encephalopathy from U.S. Largest series from Houston during 2003-04 flu season (Maricich S et al. Neurologic complications associated with influenza A in children during the 2003-2004 influenza season in Houston, Texas. Pediatr 2004; 114:e626-33.) 478 laboratory-confirmed cases of influenza A at Texas Children’s Hospital 8 patients hospitalized with neurologic symptoms Antiviral use after admission – 4 received rimantidine and one received Tamiflu One with significant neurologic sequelae (ANE)

Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factorsNewland JG. Laurich VM. Rosenquist AW. Heydon K. Licht DJ. Keren R. Zaoutis TE. Watson B. Hodinka RL. Coffin SE. Journal of Pediatrics. 150(3):306-10, 2007 Mar. : 

Neurologic complications in children hospitalized with influenza: characteristics, incidence, and risk factorsNewland JG. Laurich VM. Rosenquist AW. Heydon K. Licht DJ. Keren R. Zaoutis TE. Watson B. Hodinka RL. Coffin SE. Journal of Pediatrics. 150(3):306-10, 2007 Mar. The incidence of influenza related neurological complications (INC) was approximately 4 cases per 100,000 child-years. Patients between the ages of 2 and 4 years and patients with a pre-existing neurological or neuromuscular diseases were at greatest risk for developing an INC. Seizures were the most common INC. Influenza encephalopathy occurred in a small proportion of patients hospitalized with laboratory confirmed influenza (LCI) infections.

Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year reviewAmin R, Ford-Jones E, Richardson SE, et al. Pediatr Infect Dis J 2008;27:390–395. : 

Acute childhood encephalitis and encephalopathy associated with influenza: a prospective 11-year reviewAmin R, Ford-Jones E, Richardson SE, et al. Pediatr Infect Dis J 2008;27:390–395. Influenza virus infection was associated with 5% of acute childhood encephalopathy cases in Toronto. (14-22/311) The majority of children were <5 years of age and the prevalence of neuroimaging abnormalities was higher in children <2 years of age suggesting that younger children are predisposed to the neurologic complications of influenza. A respiratory prodrome was documented in 93% of subjects. In 64% neurologic manifestations developed within 5 days of onset of respiratory symptoms.  An acute rather than a postinfectious process Neurologic sequelae occurred in more than one-half of subjects and included acute cognitive and behavioral problems, focal neurologic deficits, and death from neurologic complications

Influenza EncephalopathyA bitter experience from Japan : 

Influenza EncephalopathyA bitter experience from Japan Mandatory mass influenza vaccination program in children was aborted in 1994 because of neurological complications at 10 per million vaccinated children Discontinuation of Vaccination Program results in more death and disability due to influenza encephalopathy, encephalitis and acute necrotizing encephalopathy. The annual mortality rates of influenza-associated acute encephalopathy/encephalitis during 1995-2000 were significantly higher than the expected mortality of influenza associated with central nervous system signs in children aged <14 years (P < 0.05). Mass immunization of school-aged children reduced the mortality rate from influenza-associated acute encephalopathy/encephalitis in children less than 9 years of Age !!! Effect of mass immunization against influenza encephalopathy on mortality rates in children. Ono S, Kudo M, Aoki K, Ezaki F, Misumi J Pediatr Int. 2003 Dec;45(6):680-7.

Influenza-associated encephalitis and encephalopathy in childrenIASR Vol. 28, No. 12 (No. 334) http://idsc.nih.go.jp/iasr/28/334/tpc334.html : 

Influenza-associated encephalitis and encephalopathy in childrenIASR Vol. 28, No. 12 (No. 334) http://idsc.nih.go.jp/iasr/28/334/tpc334.html Increased reports of influenza-associated encephalitis and encephalopathy from Japan beginning in 1990s Prompted nationwide surveillance efforts in Japan with medical community and public education of CNS complications of influenza It become a notifiable disease since Nov 2003 and physicians must notify within 7 days after diagnosis.

Influenza A–Associated Encephalopathywith Bilateral Thalamic Necrosis in JapanMasayoshi Shinjoh Clinical Infectious Diseases 2000;31:611–13 : 

Influenza A–Associated Encephalopathywith Bilateral Thalamic Necrosis in JapanMasayoshi Shinjoh Clinical Infectious Diseases 2000;31:611–13 Typically associated with sudden onset of high grade fever, severe convulsions, rapidly progressive coma, and death within 2 or 3 days Distinguishing features of influenza encephalopathy/encephalitis from Reye’s syndrome: No history of taking aspirin; Hyperammonemia rarely seen Rapid loss of consciousness, with coma ensuing within 24 h; Convulsions occur in almost all patients in the early stage of onset; Neuroimaging often reveals bilateral thalamic lesions, which have not been demonstrated in cases of Reye’s syndrome.

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Acute Necrotizing Encephalopathy Bilateral thalamic hypodensities On admission 10hr after admission (C) Apparent diffusion coefficient mapping approximately 11 hours after original CT. Note bilateral thalamic and periaqueductal involvement. (D) Fluid-attenuated inversion recovery image approximately 11 hours after original CT clearly delineating extent of acute changes. Acute necrotizing encephalopathy of childhood with radiographic progression over 10 hours Alexander G. Bassuk, Delilah M. Burrowes, and Wes McRae Neurology, Vol. 60, Issue 9, 1552-1553, May 13, 2003

Influenza-associated encephalopathy in JapanSugaya N. Sem in Pediatr Infect Dis 2002; 13(2):79-84. : 

Influenza-associated encephalopathy in JapanSugaya N. Sem in Pediatr Infect Dis 2002; 13(2):79-84. 100 cases of fatal influenza encephalopathy in Japan reported annually over past 4 years, most following A/H3N2/Hong Kong: Associated with early sudden onset of high fever, early severe seizures, rapidly progressive coma, death within 2-3 days Acute necrotizing encephalopathy in >90% > 25% of patients with bilateral thalamic necrosis Increasing Incidence of Influenza-encephalopathy reported in Japan after termination of mandatory influenza vaccination program

Encephalitis and encephalopathy associated with an influenza epidemic in Japan.Morishima T et al. Clin Infect Dis 2002; 35:512-7. : 

Encephalitis and encephalopathy associated with an influenza epidemic in Japan.Morishima T et al. Clin Infect Dis 2002; 35:512-7. Retrospective study of 1998-99 flu season, National survey of every local health care center in Japan Definition of encephalitis/encephalopathy clinical (altered consciousness or loss of consciousness), diagnosis of influenza based on positive culture, antigen test, PCR, or increased HAI titers 148 cases met their definition of encephalopathy with documented influenza

Encephalitis and encephalopathy associated with an influenza epidemic in Japan.Morishima T et al. Clin Infect Dis 2002; 35:512-7. : 

Encephalitis and encephalopathy associated with an influenza epidemic in Japan.Morishima T et al. Clin Infect Dis 2002; 35:512-7. Typical course Onset of high fever, seizures, and altered consciousness, rapid progression to comatose state within 1-2 days of flu symptoms Few patients with Reye’s syndrome (4%) Associated with influenza A (88%) CSF findings frequently normal, brain imaging suggestive of cerebral edema and localized areas of low density, some with bilateral symmetric thalamic low densities (acute necrotizing encephalopathy, ANE) Very high mortality (32%) and “disability” (28% total, 9% with severe sequelae)

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Effect of mass immunization against influenza encephalopathy on mortality rates in children. Ono S, Kudo M, Aoki K, Ezaki F, Misumi J Pediatr Int. 2003 Dec;45(6):680-7. Age <4 most affected

Effect of mass immunization against influenza encephalopathy on mortality rates in childrenSHIGETOO ONO, MASANOBU KUDO, KAZUO AOKI, FUSAKO EZAKI AND JUNICHI MISUMI Pediatrics International (2003) 45 , 680–687 : 

Effect of mass immunization against influenza encephalopathy on mortality rates in childrenSHIGETOO ONO, MASANOBU KUDO, KAZUO AOKI, FUSAKO EZAKI AND JUNICHI MISUMI Pediatrics International (2003) 45 , 680–687 Total influenza mortality among children aged <19 years has increased since 1990, with children aged <4 years after 1994 being the worst affected. The mean values of mortality rates of influenza associated with central nervous system signs during 1963–1978 and the estimated mortality of children aged <9 years during 1979–1994 were significantly lower than in some years before 1962, and after 1995 ( P < 0.05). The annual mortality rates of influenza-associated acute encephalopathy/encephalitis during 1995–2000 were significantly higher than the expected mortality of influenza associated with central nervous system signs in children aged <14 years ( P< 0.05). Mass immunization of school-aged children reduced the mortality rate from influenza-associated acute encephalopathy/encephalitis in children less than 9 years of Age !!!

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Details of pathogen in acute encephalitis cases 2004-2007 Japan ~ 80% of influenza-associated encephalopathy cases occur in children aged <5 years Neurologic signs typically develop within 1--2 days of influenza symptom onset Manifestations: Seizures, altered consciousness, incoherence, irritability, and psychotic behaviors

Influenza encephalopathy in Japan 2004 – 2007 (after Nov. 2003) : 

Influenza encephalopathy in Japan 2004 – 2007 (after Nov. 2003) It is estimated that annually 100-300 cases of acute encephalopathy accompanying influenza occur according to the study group of MHLW on influenza encephalopathy headed by Dr. T. Morishima.   According to NESID, 53 cases (type A 19 cases, type B 29 cases, types A+B 3 cases, and type unknown 2 cases) in 2004/05 season, 53 cases (type A 48 cases, type B 4 cases, and type A+rotavirus 1 case) in 2005/06 season, and, 42 cases (type A 30 cases, type B 7 cases and type unknown 5 cases) in 2006/07season were reported, reflecting the prevalent type of each season.

Influenza-associated encephalitis and encephalopathy in children in Japan : 

Influenza-associated encephalitis and encephalopathy in children in Japan No accepted explanation for difference in rate/pattern of CNS complications in Japan compared to other countries Japanese report continued high rates of influenza-related encephalitis and encephalopathy in subsequent flu seasons but mortality rates have decreased Some suggest decreased mortality due to increased awareness and rapid diagnosis and treatment of influenza among children

Radiological Features of Influenza Associated Encephalopathy and Encephalitis : 

Radiological Features of Influenza Associated Encephalopathy and Encephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Clinical and radiological variability ofinfluenza-related encephalopathy or encephalitis. Kimura S, Ohtuki N, Nezu A, et al. Acta Paediatr Jpn 1998;40:264–70 : 

Clinical and radiological variability ofinfluenza-related encephalopathy or encephalitis. Kimura S, Ohtuki N, Nezu A, et al. Acta Paediatr Jpn 1998;40:264–70 Influenza-related brain changes based on the MR imaging and CT findings: Category 1: Normal Category 2: Diffuse involvement of the cerebral cortex Category 3: Diffuse brain edema Category 4: Symmetric involvement of the thalamus Category 5: Postinfectious focal encephalitis

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(a) Normal CT scan on admission (b) Severe brain edema developed within 12 hour of the first CT scan Clinical and radiological variability ofinfluenza-related encephalopathy or encephalitis. Kimura S, Ohtuki N, Nezu A, et al. Acta Paediatr Jpn 1998;40:264–70 Category 3: Diffuse brain edema

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Selective and symmetrical involvement of the thalami and pons bilaterally: (a) low signal intesity lesions on TIweighted images, and (b) high signal intensity lesions on T2-weighted images. (c,d) These lesions appear markedly reduced in size on the follow-up MRI performed 2 months later. The thalamic lesions have almost completely resolved, but small, low-intensity lesions have persisted in the brain stem (c.d). Category 4: Symmetric involvement of the thalamus

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(a) MRI on admission showing selective and symmetrical low signal intensity lesions in the thalamus and putamina on TI-weighted images (b) Severe brain edema and tonsillar and uncal herniations are apparent on MRI performed the next day Category 4 Category 3

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Bilateral thalamic low density on admission Influenza A–Associated Encephalopathy with Bilateral Thalamic Necrosis in Japan Masayoshi Shinjoh at alClinical Infectious Diseases 2000;31:611–13

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Bilateral thalamic hemorrhage and peripheral low density D3 after admission Influenza A–Associated Encephalopathy with Bilateral Thalamic Necrosis in Japan Masayoshi Shinjoh at alClinical Infectious Diseases 2000;31:611–13

MRI of Influenza Encephalopathy in Children: Value of Diffusion-Weighted ImagingTsuchiya, Kazuhiro; Katase, Shichiro; Yoshino, Ayako; Hachiya, Junichi Volume 24(2), March/April 2000, pp 303-307 : 

MRI of Influenza Encephalopathy in Children: Value of Diffusion-Weighted ImagingTsuchiya, Kazuhiro; Katase, Shichiro; Yoshino, Ayako; Hachiya, Junichi Volume 24(2), March/April 2000, pp 303-307 Influenza encephalopathy is visualized on MRI as areas of elongated T2, and sometimes T1, in the cerebral cortex and adjacent white matter. The lesion distribution is rather nonspecific. Diffusion-weighted MRI appears to depict the lesions as areas of restricted diffusion more sensitively than conventional imaging techniques.

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MRI of Influenza Encephalopathy in Children: Value of Diffusion-Weighted ImagingTsuchiya, Kazuhiro; Katase, Shichiro; Yoshino, Ayako; Hachiya, Junichi Volume 24(2), March/April 2000, pp 303-307

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T2-weighted spin echo showed slight swelling and hyperintensity in the parietal gyri bilaterally. FLAIR image shows equivocal hyperintensity in the parietal gyri bilaterally T1-weighted image is unremarkable Postcontrast T1-weighted image shows enhancement within sulci, probably representing venous congestion, but no lesion enhancement E and F: Single shot echo planar diffusion-weighted image shows clear hyperintensity in the frontoparietal cortex and adjacent subcortical white matter bilaterally (arrows). The apparent diffusion coefficient map shows hypointensity of the lesions representing restricted diffusion (arrows).

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A 1.6-year-old girl examined 12 days after the onset of symptoms. A: FLAIR image shows mild hyperintensity in the left cerebral hemisphere. B: Postcontrast T1-weighted image shows no lesion enhancement but enhancement within sulci probably due to venous congestion. C: Single shot echo planar diffusion-weighted image shows hyperintensity of the lesion in similar extent to the FLAIR image. However, the lesions are more conspicuously demonstrated on this image. D: The apparent diffusion coefficient map shows hypointensity of the lesion due to restricted diffusion.

Prognostic Factors and Sequelae of Influenza Associated Encephalopathy and Encephalitis : 

Prognostic Factors and Sequelae of Influenza Associated Encephalopathy and Encephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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Prognostic Factors in Influenza-Associated Encephalopathy Takashi Nagao, MD; Tsuneo Morishima, MD, PhD; Hiroshi Kimura, MD, PhD; Syumpei Yokota, MD, PhD; Nobuko Yamashita, MD, PhD* Takashi Ichiyama, MD, PhD; Mana Kurihara, MD, PhD; Chiaki Miyazaki, MD, PhD; Nobuhiko Okabe, MD, PhD Pediatr Infect Dis J. 2008;27(5):384-389 In the univariate analyses, 14 variables had statistical significance (P < 0.05): peak body temperature of 40-41°C and ≥41°C; diarrhea; AST level of 100-500 IU/L and ≥500 IU/L; creatinine phosphokinase level of 200-1000 IU/L and ≥1000 IU/L; platelet count of <10 × 104/μL; blood glucose level of <50 and ≥150 mg/dL; hematuria or proteinuria; CT showing edema, low-density areas, or hemorrhage; and use of diclofenac sodium and mefenamic acid for fever during influenza virus infection. Influenza-associated encephalopathy 100 annual death for children <6yr 30% mortality rate without Rx Influenza A: B ratio = 84.2%: 9.5%

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Differences in clinical manifestations of influenza-associated encephalopathy by age. Wada T, Morishima T, Okumura A, et al. Microbiol Immunol 2009;53:83--8. Neurologic sequelae occurred in more than one-half of subjects and included acute cognitive and behavioral problems, focal neurologic deficits, and death from neurologic complications (Toronto) (Amin R Pediatr Infect Dis J 2008;27:390–39) 2/8 had neurological sequelae (1 mild and 1 severe). Houston, Texas. Maricich SM Pediatrics. 2004 Nov;114(5):e626-33. 182 patients had neurological complications: 5 encephalopathy, 1 encephalitis and 1 aseptic meningitis  2 died and 1 neurological sequale

Acute encephalopathy with biphasic seizures and late reduced diffusion : 

Acute encephalopathy with biphasic seizures and late reduced diffusion Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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Spectrum of CNS Complication of Influenza Virus Infection (AESD = Acute encephalopathy with biphasic seizures and late reduced diffusion) Important to differentiate from febrile convulsion which occur in 6-40% children because of significant associated mortality and morbidity

Febrile convulsion Vs AESD : 

Febrile convulsion Vs AESD Influenza A is associated with a high incidence (6 to 40%) of febrile convilsion, especially in older children and. Most of these persist for less than 15 min (45/47, 95.7%), and neurological prognosis is good. Therefore, no clinical follow-up is generally recommended for patients with a brief FS associated with influenza A infections. However, the parents should be informed about the possible secondary progression around day 5. This may herald the condition acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) that is associated with significant mortality and morbidity.

Severe form of acute influenza encephalopathy with biphasic seizures and late reduced diffusion.Tada H. Takanashi JI. Terada H. Tajima K. Neuropediatrics. 39(2):134-6, 2008 Apr.Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15. : 

Severe form of acute influenza encephalopathy with biphasic seizures and late reduced diffusion.Tada H. Takanashi JI. Terada H. Tajima K. Neuropediatrics. 39(2):134-6, 2008 Apr.Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15. Acute encephalopathy with biphasic seizures and late reduced diffusion (AESD) Biphasic seizures on days 1, and 4 to 6; Radiologically by no acute abnormality is visible during the first two days, while reduced diffusion in the subcortical white matter is seen during days 3 to 9, finally resulting in cerebral atrophy. The subcortical abnormalities do not result from the initial seizure as patient with status epilepticus has no subcortical abnormalities.

Acute encephalopathy with biphasic seizures and late reduced diffusion : 

Acute encephalopathy with biphasic seizures and late reduced diffusion MR spectroscopy study revealed transient increased glutamate/glutamine complex along with imaging findings of reduced subcortical diffusion. Glutamate, an excitatory neurotransmitter, is taken up by surrounding astrocytes and metabolized into a relatively harmless compound, glutamine. Excess of glutamine in astrocytes creates an osmotic gradient, resulting in astrocytic swelling or edema, which may play a part in the reduced diffusion seen in AESD. In patients with influenza associated encephalopathy, CSF studies have shown increased glutamine and nitrite/nitrate (NOx) levels together with decreased glutamate levels, suggesting increased activity of the glutamate uptake transporter and glutamine synthetase in astrocytes. Some authors have speculated that the astrocytes may be activated by high NOx, some (unknown) viral factors and cytokines in CSF Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15.

EEG on day 5 shows high voltage slow waves in the frontal region. : 

EEG on day 5 shows high voltage slow waves in the frontal region. Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15

Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15. : 

Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15. Diffusion weighted image (A, spin-echo EPI: TE = 103; b = 1000; MPG with y axis) on day 6 reveals symmetric high signal lesion in the frontal subcortical white matter. T2-weighted image (B, FSE: TR/TE = 4000/100) shows no signal abnormality. These observations suggest reduced subcortical diffusion. Follow-up MRI after 6 months showed disappearance of the signal abnormalities and mild cerebral atrophy Reduced diffusion in the subcortical white matter

Reduced Subcortical Diffusion : 

Reduced Subcortical Diffusion Diffusion weighted image (A, spin-echo EPI: TR, 4000; TE = 100; b = 1000) on day 5 reveals asymmetric high signal lesion in the fronto-parietal subcortical and deep white matter with sparing of peri-Rolandic region. T2-weighted image (B, FSE: TR/TE = 3400/90) shows subtle T2 abnormality in the cortex and blurring of the cortical-white matter junction in the same area that shows the diffusion abnormality. These observations suggest reduced subcortical diffusion. Follow-up MRI at day 40 shows mild cerebral atrophy with no signal abnormalities (C, D). Mild influenza encephalopathy with biphasic seizures and late reduced diffusion.Takanashi J. Tsuji M. Amemiya K. Tada H. Barkovich AJ Journal of the Neurological Sciences. 256(1-2):86-9, 2007 May 15

Pathogenesis of Influenza Associated Encephalopathy and Encephalitis : 

Pathogenesis of Influenza Associated Encephalopathy and Encephalitis DR. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

Possible Role of Direct Viral Invasion ? Role of Mitochondrial Respiratory Chain Defect : 

Possible Role of Direct Viral Invasion ? Role of Mitochondrial Respiratory Chain Defect In rare incidence, influenza virus can be detected in CSF or brain of patient suffering from influenza encephalopathy or encephalitis Detection of influenza virus RNA by reverse transcription-PCR and proinflammatory cytokines in influenza-virus-associated encephalopathy. Ito Y, Ichiyama T, Kimura H, et al. J Med Virol 1999;58:420--5. (1/11 in CSF of patient) Maricich SM, Neul JL, Lotze TE, et al. Neurologic complications associated with influenza A in children during the 2003--2004 influenza season in Houston, Texas. Pediatrics 2004;114:e626--33. (1/8 patient has influenza A virus isolated in CSF) Direct viral invasion is uncommon for influenza infection except for H5 and H7 serotype because the presence of polybasic amino acids at the cleavage site of HA0 in H5 and H7 allow the breakdown of HA0 by nonspecific protease  easy breakdown of organ barrier and invasion of central nervous system.

An adult autopsy case of acute encephalopathy associated with influenza A virus.Ishigami A. Kubo S. Ikematsu K. Kitamura O. Tokunaga I. Gotohda T. Nakasono I. Legal Medicine. 6(4):252-5, 2004 Oct. : 

An adult autopsy case of acute encephalopathy associated with influenza A virus.Ishigami A. Kubo S. Ikematsu K. Kitamura O. Tokunaga I. Gotohda T. Nakasono I. Legal Medicine. 6(4):252-5, 2004 Oct. 35 year old male die of pneumonia and cerebral edema. Influenza A virus antigen was detected in both the lungs and brain. Brain edema was also observed, and proliferation of lymphocytes was observed around the capillary vessels of the hippocampus.

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Accumulation of mini-plasmin in the cerebral capillaries causes vascular invasion of the murine brain by a pneumotropic influenza A virus: implications for influenza-associated encephalopathy. Yao D. Chen Y. Kuwajima M. Shiota M. Kido H. Biological Chemistry. 385(6):487-92, 2004 Jun.

MRI Finding in Mitochondrial Respiratory Chain Defect : 

MRI Finding in Mitochondrial Respiratory Chain Defect Magnetic resonance imaging (MRI) showed diffuse cortical atrophy in 34 cases (70.8%), basal ganglia signal changes in 18 cases (37.5%) and thalamus signal changes in 12 cases (25.0%). Mitochondrial respiratory chain defects: Underlying etiology in various epileptic conditions *Young Mock Lee, †Hoon Chul Kang, *Joon Soo Lee, ‡Se Hoon Kim, §Eung Yeop Kim, §Seung Koo Lee, ¶Abdelhamid Slama, and *Heung Dong Kim Epilepsia Volume 49 Issue 4, Pages 685 - 690

Role of Cytokines in Influenza Associated Encephalopathy and Encephalitis : 

Role of Cytokines in Influenza Associated Encephalopathy and Encephalitis Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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MPTP = The Mitochondrial Permeability Transition Pore

Cytokines and Influenza Encephalopathy : 

Cytokines and Influenza Encephalopathy NFκβ activation hold a pivotal role in cytokine production in influenza infection. The activation of NFκβ is induced by reactive oxygen species during influenza infection by a process called endoplasmic recticulum overload induced by haemaglutinin. Cytokines are considered to play an important role in the pathogenesis of influenza encephalopathy. The levels of IL-6, IL10, TNF-α and soluble TNF receptors 1 (sTNFR1) were significantly increased in both serum and CSF in influenza encephalopathy. The IL-6 serum level could be used as a predictive value in the prognosis of influenza encephalopathy and IL6 level directly correlated with mortality CSF TNF-α and sTNFR1 levels are potentially important for predicting neurological sequelae, however they were not elevated in several severe cases. Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathy

Cytokine regulation of interleukin-6 gene expression in astrocytes involves activation of an NF-κB-like nuclear proteinSPARACIO S. M. ; YIHONG ZHANG (1) ; VILCEK J. ; BENVENISTE E. N. Journal of neuroimmunology 1992, vol. 39, no3, pp. 231-242 (1 p.) : 

Cytokine regulation of interleukin-6 gene expression in astrocytes involves activation of an NF-κB-like nuclear proteinSPARACIO S. M. ; YIHONG ZHANG (1) ; VILCEK J. ; BENVENISTE E. N. Journal of neuroimmunology 1992, vol. 39, no3, pp. 231-242 (1 p.) The cytokines interleukin-1 beta (IL-1β) and tumor necrosis factor-alpha (TNF-α) induce interleukin-6 (IL-6) gene expression in astrocytes. The molecular mechanism(s) by which these cytokines activate IL-6 expression was examined by transient transfection of the human IL-6 promoter linked to the reporter gene CAT (IL-6-CAT) in primary rat astrocytes. Both IL-1β and TNF-α exert their effects through the IL-6 promoter to increase CAT activity, indicating that the cytokines act at the transcriptional level. Use of deletion mutants revealed that the NF-KB-like binding site is required for cytokine induction of IL-6 promoter activity.

Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy[Hideo Aiba, MD, Mika Mochizuki, MD, Mitsuaki Kimura, MD and Hiroatsu Hojo, MD Neurology 2001;57:295-299] : 

Predictive value of serum interleukin-6 level in influenza virus–associated encephalopathy[Hideo Aiba, MD, Mika Mochizuki, MD, Mitsuaki Kimura, MD and Hiroatsu Hojo, MD Neurology 2001;57:295-299] The serum IL-6 levels were >6,000 pg/mL in children with brain stem dysfunction, about 150 pg/mL in children without brain stem dysfunction, and <80 pg/mL in controls. The time course of the serum IL-6 level also reflected the clinical condition. Once the serum IL-6 level was increased to >15,000 pg/mL, none of the children survived. The lower the maximal serum IL-6 level, the milder the CNS sequelae.

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathyT. Ichiyama, H. Isumi, H. Ozawa, T. Matsubara, T. Morishima and S. Furukawa,, Scand J Infect Dis 35 (2003), pp. 59–61 : 

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathyT. Ichiyama, H. Isumi, H. Ozawa, T. Matsubara, T. Morishima and S. Furukawa,, Scand J Infect Dis 35 (2003), pp. 59–61

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathyT. Ichiyama, H. Isumi, H. Ozawa, T. Matsubara, T. Morishima and S. Furukawa,, Scand J Infect Dis 35 (2003), pp. 59–61 : 

Cerebrospinal fluid and serum levels of cytokines and soluble tumor necrosis factor receptor in influenza virus-associated encephalopathyT. Ichiyama, H. Isumi, H. Ozawa, T. Matsubara, T. Morishima and S. Furukawa,, Scand J Infect Dis 35 (2003), pp. 59–61 The present study revealed elevated cytokine levels not only in serum but also in CSF of children with influenza virus-associated encephalopathy. The children with a poor outcome tended to have highly elevated levels of IL-6, TNF- α and sTNFR1 in serum and/or CSF. In particular, the 4 children with elevated TNF- α and sTNFR1 levels in CSF had neurological sequelae. A high level or overexpression of IL-6 may be neurotoxic under pathological conditions. TNF- α increases blood–brain vascular permeability, injures vascular endothelial cells, and induces necrosis of myelin and oligodendrocytes. Previous studies showed that sTNFR is the natural homeostatic regulator of the action of TNF- α, and that its level, rather than that ofTNF-α, reflects the true biological activity of TNF- α.

Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathyH. Nunoi, M.R. Mercado, T. Mizukami, K. Okajima, T. Morishima and H. Sakata et al., Pediatr Int 47 (2005), pp. 175–179. : 

Apoptosis under hypercytokinemia is a possible pathogenesis in influenza-associated encephalopathyH. Nunoi, M.R. Mercado, T. Mizukami, K. Okajima, T. Morishima and H. Sakata et al., Pediatr Int 47 (2005), pp. 175–179.

There is an increase of microglia and apoptosis of neurons and glial cells in fatal cases of influenza encephalopathy and encephalitis. In particular activated microglia and apoptosis may play an important role in their pathogenesis.Activation of caspase 3 is involved in the apoptotic pathway in the brains of influenza encephalopathy cases : 

There is an increase of microglia and apoptosis of neurons and glial cells in fatal cases of influenza encephalopathy and encephalitis. In particular activated microglia and apoptosis may play an important role in their pathogenesis.Activation of caspase 3 is involved in the apoptotic pathway in the brains of influenza encephalopathy cases Apoptosis and microglial activation in influenza encephalopathy Nakai Y, Itoh M, Mizuguchi M, Ozawa H, Okazaki E, Kobayashi Y, Takahashi M, Ohtani K, Ogawa A, Narita M, Togashi T, Takashima S. Acta Neuropathol. 2003 Mar;105(3):233-9. Epub 2002 Dec 20.

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Apoptosis can occur via cell-surface-death-receptor- or mitochondrial-dependent pathways. SIV-mediated apoptosis might be regulated by both receptor- and mitochondrial-mediated cell death. Activation of the intrinsic mitochondrial apoptotic pathway in swine influenza virus-mediated cell death Young Ki Choi EXPERIMENTAL and MOLECULAR MEDICINE, Vol. 38, No. 1, 11-17, February 2006

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FAS and TNFR induced mitochondrial apoptosis pathway

? LDH can serve as a marker of influenza virus induced apoptotic cell degradation : 

? LDH can serve as a marker of influenza virus induced apoptotic cell degradation Lactate Dehydrogenase Leakage as a Marker for Apoptotic Cell Degradation Induced by Influenza Virus Infection in Human Fetal Membrane CellsNoboru Uchide, Kunio Ohyama, Toshio Bessho, Hiroo Toyoda Intervirology 2009;52:164-173

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Blocked by NAC Hypothesis Increases blood–brain vascular permeability, injures vascular endothelial cells, and induces necrosis / apoptosis of myelin and oligodendrocytes. Potential Role of High Dose N-acetylcysteine Anti-oxidant Therapy for Influenza Associated Encephalopathy / Encephalitis

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Any Questions ?

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Historical Perspective — Emergence of Influenza A (H1N1) VirusesShanta M. Zimmer, M.D., and Donald S. Burke, M.D. Volume 361:279-285 July 16, 2009 Number 3 Sporadic cases of Post-encephalitis Parkinsonism and Post encephalitis lethargica have been reported recently after H1N1 was reintroduced in 1977 although no viral etiology has been documented. (Rail et al., 1981; Clough et al., 1983; Howard and Lees, 1987; Geddes et al., 1993; Barletta et al., 1995).

Slide 125: 

W.H.O. has raised pandemic alert from phase 5 to phase 6 on 11/6/2009

Slide 126: 

? Protected by Immunization Program with major reduction in mortality 1918 Influenza U.S.A. CDC Volume 12, Number 1, January 2006 1918 Influenza: the Mother of All Pandemics Jeffery K. Taubenberger* and David M. Morens Very similar Mortality Rate

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Neurologic Complications Associated with Novel Influenza A (H1N1) Virus Infection in Children --- Dallas, Texas, May 2009 MMWR July 24, 2009 / 58(28);773-778  All four patients recovered fully and had no neurologic sequelae at discharge

H1H1 2009 Pandemic Japan (up to 13 Nov 2009)Infectious Diseases Weekly Report Japan, 45th week, Infectious Disease Surveillance Center, pages 16-20 : 

H1H1 2009 Pandemic Japan (up to 13 Nov 2009)Infectious Diseases Weekly Report Japan, 45th week, Infectious Disease Surveillance Center, pages 16-20 60 cases of influenza encephlopathy as a result of pandemic H1N1 Median age: 8 years M:F 35:25 All 60 cases had disturbance of consciousness Period of disturbance of consciousness: Unidentified - 2 cases Over 48 hours - 19 cases 24-48 hours - 15 cases Under 24 hours - 15 cases Other features Cramps - 31 cases of 60 (52 percent) Abnormal behaviors - 45 cases of 60 (75 percent) Abnormal electroencephalogram - 35/47 (74 percent) Brain CT - 23/56 (41 percent) Brain MRI - 14/47 (30 percent) No signals from electroencephalogram, CT and MRI - 8 cases Outcome: Death - 3/59 (5 percent) (4.5.7 years) After effects - 7/59 (12 percent) Healing - 49/59 (83 percent) Bed days in 50 cases - 2-39 days (median 9 days) http://idsc.nih.go.jp/idwr/kanja/idwr/idwr2009/idwr2009-45.pdf http://www.promedmail.org/pls/otn/f?p=2400:1001:19224::NO::F2400_P1001_BACK_PAGE,F2400_P1001_PUB_MAIL_ID:1010,80287

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ADEM Diffusion restriction

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Contrast-enhanced transverse T1-weighted images show diffuse meningeal enhancement in both cerebral hemispheres, which is more pronounced in the right perirolandic area. MR Imaging in Novel Influenza A(H1N1)-Associated Meningoencephalitis A. Haktanir American Journal of Neuroradiology 31:394-395, March 2010 Novel Influenza A(H1N1)-Associated Meningoencephalitis

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MR Imaging in Novel Influenza A(H1N1)-Associated Meningoencephalitis A. Haktanir American Journal of Neuroradiology 31:394-395, March 2010 T2-weighted transverse MR images demonstrate bilateral thalamic (upper left) and perirolandic (upper right) hyperintensities with restricted diffusion in the isotropic b 1000 image (lower right) and the ADC map (lower left).

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MRI. a Axial DWI showing restricted diffusion in the thalami bilaterally. b Accompanying ADC map Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

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Acute necrotizing encephalopathy in a child with H1N1 influenza infection Jane B. Lyon & Cheryl Remigio & Thomas Milligan & Carol Deline Pediatr Radiol (2010) 40:200–205 Acute necrotizing encephalopathy

Influenza Associated Encephalopathy and EncephalitisPotential Role of High Dose N-acetylcysteine Anti-oxidant Therapy : 

Influenza Associated Encephalopathy and EncephalitisPotential Role of High Dose N-acetylcysteine Anti-oxidant Therapy Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

CRP Response to High Dose N-acetylcysteine (100mg/Kg infusion Daily) (An experience in 9 patients) : 

CRP Response to High Dose N-acetylcysteine (100mg/Kg infusion Daily) (An experience in 9 patients) Responders have a rapid drop in CRP Death

Theory Behind High Dose N-acetylcysteine Therapy for Influenza Associated Encephalopathy and Encephalitis : 

Theory Behind High Dose N-acetylcysteine Therapy for Influenza Associated Encephalopathy and Encephalitis H1N1 Pneumonia kills by cytokine storm and co-infection NFκβ hold a pivotal role in cytokine activation in influenza infection We can selectively block NFκβ and hence its cytokine activity without affecting the B cell and T cell immunity of influenza virus infection. The activation of NFκβ is induced by reactive oxygen species during influenza infection N-acetylcysteine in doses used for the treatment of acetaminophen (Paracetamol) poisoning can achieve high enough anti-oxidant activity to block reactive oxygen species induced by influenza infection. (hypothesis) "Attenuation of influenza-like symptomatology and improvement of cell-mediated immunity with long-term N-acetylcysteine treatment". S. De Flora, C. Grassi, L. Carati (1997).Eur Respir J: 1535–1541 Falk Nimmerjahn Journal of General Virology (2004), 85, 2347–2356 Active NF-kB signalling is a prerequisite for influenza virus infection Role of oxidants in influenza virus-induced gene expression Katharine Knobil et al Am J Physiol Lung Cell Mol Physiol vol 274: issue 1, L134-L142, 1998 van Klaveren, RJ, Demedts, M, Nemery, B Cellular glutathione turnover in vitro, with emphasis on type II pneumocytes. Eur Respir J 1997;10,1392-1400 Wendl, A, Cikryt, P The level and half life of glutathione in human plasma. FEBS Lett 1980;120,209-211 Effect of N-acetyl cysteine on the concentrations of thiols in plasma, bronchoalveolar lavage fluid, and lung tissue. M M Bridgeman. Thorax 1994;49:670-675 Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B HL Pahl and PA Baeuerle J. Virol., Mar 1995, 1480-1484, Vol 69, No. 3

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Cutting Edge: Influenza A Virus Activates TLR3-Dependent Inflammatory and RIG-I-Dependent Antiviral Responses in Human Lung Epithelial Cells Ronan Le Goffic The Journal of Immunology, 2007, 178: 3368-3372. Cytokine storm can be blocked without affecting anti-viral activity.

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Cytokine Storm TNF-alpha, IL-1beta, IL-6, and IL-8. Expression of influenza virus hemagglutinin activates transcription factor NF-kappa B HL Pahl and PA Baeuerle J. Virol., Mar 1995, 1480-1484, Vol 69, No. 3 The cytokines storm of influenza virus is through the activation of NF-ķB by reactive oxygen species

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Haemagglutinin Activation of NF-kappa B is caused by the accumulation of proteins in the endoplasmic recticulum membrane, a condition we have called ER overload. Both the release of Ca2+ from the ER and the subsequent production of reactive oxygen intermediates are required for ER-overload-mediated NF-kappa B activation. The ER-overload response: activation of NF-kappa B. Pahl HL. Baeuerle PA. Trends in Biochemical Sciences. 22(2):63-7, 1997 Feb. Signal Transduction From the Endoplasmic Reticulum to the Cell Nucleus Heike L. Pahl Physiological Reviews, Vol. 79, No. 3, July 1999, pp. 683-701 Role of NAC

Theory Behind High Dose N-acetylcysteine Therapy for Influenza Associated Encephalopathy and Encephalitis : 

Theory Behind High Dose N-acetylcysteine Therapy for Influenza Associated Encephalopathy and Encephalitis IL6 was one of the major cytokine produced during influenza infection. Symptoms and fever in natural acute influenza correlate with the release of IL-6. IL6 can lead to the production of CRP, fibrinogen and factor VIII:C. CRP can serve as marker of IL6 level and influenza cytokine activities. There is close correlation in the severity of influenza encephalopathy and the interleukin 6 level. Currently there is no medication that can suppress IL-6 production without major immunosuppression. In our patients, high dose N-acetylcysteine at 100mg/Kg/day infusion can cause a rapid and drastic decrease in CRP, a biomarker of IL-6 level. High dose N-acetylcysteine has a potential role in rapid control of CRP or perhaps IL6 level during influenza associated encephalopathy or encephalitis. Prospective randomized trial should be conducted to confirm this hypothesis. Symptom pathogenesis during acute influenza: interleukin-6 and other cytokine responses. Kaiser L. Fritz RS. Straus SE. Gubareva L. Hayden FG. Journal of Medical Virology. 64(3):262-8, 2001 Jul. Pathways by which IL-6 contributes towards haemostasis – an overview Kerr: Br J Haematol, Volume 115(1).October 2001.3-12 Factor VII and fibrinogen levels as risk factors for venous thrombosis: A case-control study of plasma levels and DNA polymorphisms: the Leiden Thrombophilia Study (LETS). Koster T, Rosendaal FR, Reitsma PH, van der Valden PA, Briet E, Vandenbroucke JP. Thromb Haemost. 1994;71:719–722 Excess factor VIII: a common cause of hypercoagulability. Bobrow RS. Journal of the American Board of Family Practice. 18(2):147-9, 2005 Mar-Apr.

Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria[Maria Luisa Colamussi Blood, Vol. 93 No. 7 (April 1), 1999: pp. 2395-2403] : 

Influenza A Virus Accelerates Neutrophil Apoptosis and Markedly Potentiates Apoptotic Effects of Bacteria[Maria Luisa Colamussi Blood, Vol. 93 No. 7 (April 1), 1999: pp. 2395-2403] Defective neutrophil and monocyte chemotactic, oxidative, and bacterial killing functions Cytokine Storm TNF-alpha, IL-1beta, IL-6, and IL-8.

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Bacterial and Fungal Sepsis Block by High Dose NAC

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Blocked by NAC Hypothesis Increases blood–brain vascular permeability, injures vascular endothelial cells, and induces necrosis / apoptosis of myelin and oligodendrocytes. Potential Role of High Dose N-acetylcysteine Anti-oxidant Therapy for Influenza Associated Encephalopathy / Encephalitis

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Thank you for your attention