Encephalitis Lethargica

Epidemic Encephalitis Lethargica The Potential Implication ofH1N1 2009 Human Swine Influenza Pandemic : 

Epidemic Encephalitis Lethargica The Potential Implication ofH1N1 2009 Human Swine Influenza Pandemic 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

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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)

H1H1 2009 Pandemic Japan (up to 13 Nov 2009) : 

H1H1 2009 Pandemic Japan (up to 13 Nov 2009) 60 cases of influenza encephlopathy Median: 8 years 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)

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H5N1 infection in mice causes severe loss of dopaminergic neurons 60 days after infection by provoking a destructive autoimmune response Hypothesis on Pathogenesis Pulse steroid Plasmapheresis IVIG Azathioprine

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Clinical Features and Laboratory Findings

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MRI and DAT scan. A middle-aged woman with encephalitis lethargica presented with double vision, headache and a behavioural disorder, followed by increasing confusion and reduced level of consciousness due to hypersomnolence. She later developed oculogyric crises and hiccoughing. On recovery she was parkinsonian, with rigidity and bradykinesia, with superimposed tics and dystonic posturing of the right arm. Unfortunately, she was left with chronic obsessive-compulsive behaviour, anxiety, panic attacks and dysthymia. The MRI study during the acute encephalitic crisis showed bilateral swelling of the striatum, with associated signal change on the T2- (left) and proton density-weighted images (centre). These areas were shown to enhance diffusely after the administration of gadolinium (right). The abnormal signal change also extended into the posterior hypothalamus and mid-brain (images not shown). On the far right is an abnormal striatal dopamine transporter (DAT) study, with [123I]beta-CIT ([123I]2beta-carbomethoxy-3beta-(4-iodophenyl)tropane) single photon emission computed tomography (SPECT) showing bilaterally reduced and asymmetrical dopamine transporter density in the striatum. This patient’s serum was positive for ABGAs. Are antibasal ganglia antibodies important, and clinically useful?.Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb.

Spectrum of disorders associated with anti-basal ganglia antibodies : 

Spectrum of disorders associated with anti-basal ganglia antibodies The Role of Group A Streptococcal Infection

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Basal Ganglia and Related Structure of the Brain

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Basal Ganglia and Related Structure of the Brain

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Immuofluorescence microscopy and Western blot of ABGAs. (A) Normal control diluted 1/50 tested against human basal ganglia with no specific staining (magnification ×200). (B) Sample from a patient with Sydenham’s chorea diluted 1/50 and tested against human basal ganglia tissue; IgG staining of axons (arrows) (magnification ×200). (C) Western blots showing serial dilution of strongly positive ABGAs in patients with post-streptococcal movement disorder. Are antibasal ganglia antibodies important, and clinically useful?.Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb.

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Spectrum of disorders associated with antibasal ganglia antibodies

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Antibasal ganglia antibodies and their relevance to movement disorders. Martino D. Giovannoni G. Current Opinion in Neurology. 17(4):425-32, 2004 Aug.

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection : 

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection : 

Anti-Basal Ganglia AntibodyPost-Streptococcal Infection

PANDAS: current status and directions for researchSnider LA. Swedo SE. Molecular Psychiatry. 9(10):900-7, 2004 Oct. : 

PANDAS: current status and directions for researchSnider LA. Swedo SE. Molecular Psychiatry. 9(10):900-7, 2004 Oct.

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Pathogenesis of Post-streptococcal Neurological Disorder Antibasal ganglia antibodies and their relevance to movement disorders. Martino D. Giovannoni G. Current Opinion in Neurology. 17(4):425-32, 2004 Aug.

PANDAS Diagnostic Criteria(Swedo et al. in 1998) : 

PANDAS Diagnostic Criteria(Swedo et al. in 1998) OCD and/or chronic tic disorder (Tourette's, chronic motor, or vocal tic disorder) that meets the DSM-IV diagnostic criteria; age at onset between 3 years and the onset of puberty; Clinical course with an abrupt onset of symptoms and/or a pattern of dramatic recurrent exacerbations and remissions; Temporal relation between GAS infection and onset and/or exacerbations of clinical symptoms; Neurologic abnormalities such as motoric hyperactivity, tics, or choreiform activity during an exacerbation

Are antibasal ganglia antibodies important, and clinically useful? Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb. : 

Are antibasal ganglia antibodies important, and clinically useful? Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb. There is a group of putative autoimmune diseases of the central nervous system characterised by ABGAs associated with recent streptococcal infection. ABGAs are a potentially useful diagnostic marker of immune-mediated basal ganglia disorders triggered by a streptococcal infection. Patients typically present with a neuropsychiatric syndrome with both hyper- and hypokinetic movement disorders; Sydenham’s chorea is the prototypical disorder associated with ABGAs. Apart from Sydenham’s chorea, the association of ABGAs with other clinical phenotypes is not widely accepted.

Are antibasal ganglia antibodies important, and clinically useful? Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb. : 

Are antibasal ganglia antibodies important, and clinically useful? Martino D. Church A. Giovannoni G. Practical Neurology. 7(1):32-41, 2007 Feb. Long-term antibiotic prophylaxis is indicated in patients with Sydenham’s chorea but there is no evidence supporting this policy in other ABGAassociated disorders. Immunotherapy should not be given routinely to patients with ABGAassociated disorders until further controlled trials establish its efficacy. There is a scientific rationale for a therapeutic trial of immunomodulatory therapy in patients who are significantly disabled from their disorder. Our anecdotal experience is that the sooner the patients are treated after the onset of their symptoms, the more likely they are to respond to immunotherapy.

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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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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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.

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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.

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

Somnolent-Ophthalmoplegic : 

Somnolent-Ophthalmoplegic The prodromal phenomena consists of general discomfort, shivering, headache, and slight pharyngitis. The temperature is generally only a little raised to slightly above 98°F.... Von Economo emphasized that the sudden high fever, myalgias, and upper respiratory symptoms characteristic of influenza were absent Within the next few days, somnolence begins to predominate. The patients left to themselves fall asleep in the act of sitting and standing, and even while walking, or during meals with food in the mouth.... If aroused, they wake up quickly and completely, are oriented and fully conscious... but soon drop back to sleep. Sleep in this form may last for weeks or even months but frequently deepens to a state of most intense stupor or even a comatose condition which may terminate fatally after some days or weeks.  Generally, during the first days of the illness (cranial nerve) palsies appear. Ptosis is one of the first and most frequent symptoms. The frequent bilateral occurrence of ocular palsies, incomplete, usually asymmetrical, suggest that it is, in most cases, a nuclear palsy. Rarely observed are supranuclear paralyses, paresis of convergence, nystagmus, optic neuritis, papilledema, pupillary disturbances, and even Argyll Robertson's sign Mortality 50%, but chronic debility and neurologic sequelae were uncommon

Hyperkinetic : 

Hyperkinetic In the winter of 1920, there was observed a very large group of hyperkinetic cases, first in Italy then Austria. Chorea and hemichorea as well as myoclonic twitches which were observed may degenerate into wild jactations.  On the other hand, it may find its mental expression in a general, curious restlessness of an anxious or hypomanic type. In most of these cases, there is a very distinct sleep disturbance and generally the condition is one of troublesome sleeplessness. Mortality 40%, although complete recovery was less common than in the somnolent form.

Amyostatic-Akinetic : 

Amyostatic-Akinetic Third place in order of frequency, the amyostatic-akinetic form, is characterized by a rigidity, without a real palsy and without symptoms arising from the pyramidal tract. This form of encephalitis lethargica is particularly common in the chronic cases, dominating the clinical picture as Parkinsonism. I reserve the name ‘Parkinsonism,' though symptomatically identical with the amyostatic-akinetic form, rather for the chronic cases. To look at these patients one would suppose them to be in a state of profound secondary dementia. Emotions are scarcely noticeable in the face, but they are mentally intact. Mortality in the acute stage of this form of EL was somewhat less than in the other forms, although progression to a chronic form was much more likely.

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Young adult man with encephalitis lethargica with a chronically open mouth and masked face with constant drooling.

OCULOGYRIC CRISES : 

OCULOGYRIC CRISES Oculogyric crisis was the one of the outstanding features of postencephalitic parkinsonism. Of particular interest are the visual fits, described by French authors as ‘crises ocuogyres' (van Bogaert, Bing, and Schwartz, Marinesco and Radovici), in English as "tonic eye-fits" or, more commonly, as oculogyric crises. They consist of tonic visual convulsions, occurring in fits and generally lasting only a few minutes, during which the patients as a rule look upwards and sideways.... Frequently, the convulsive twisting of the eyes is also accompanied by other convulsive movements, such as contortion of the head in the direction of vision, tonic stretching of the neck, even of the trunk and extremities.... 4

Young adult woman with encephalitis lethargica during an oculogyric crisis. Note the typical combination of torticollis with forced lateral and upward eye movements and flexed posture of the right arm. : 

Young adult woman with encephalitis lethargica during an oculogyric crisis. Note the typical combination of torticollis with forced lateral and upward eye movements and flexed posture of the right arm.

Encephalitis Lethargica : 

Encephalitis Lethargica The CSF was abnormal in about 50% of epidemic EL cases, mild elevation of protein and mild lymphocytosis being characteristic (von Economo, 1931; McCall et al., 2001). Recent studies showed all CSF PCR studies were negative, making a neurotropic viral encephalitis unlikely. The presence of intrathecal synthesis of OCB has been proposed to be a useful marker of disease (Williams et al., 1979; Howard and Lees, 1987). 40% showed increased signal in the basal ganglia, substantia nigra and tegmentum. The enhancement resolved after the acute stage in the few patients who had convalescent imaging.

Encephalitis Lethargica : 

Encephalitis Lethargica Brain pathology: Perivascular lymphocytic (plasma cell) cuffing, which predominantly involves the midbrain and basal ganglia.(von Economo, 1931; Rail et al., 1981; Kiley and Esiri, 2001). The lymphocytes were both T and mature B lymphocytes. Other than secondary reactive astrocytes and macrophage activation, there were no other striking pathological features. Brain specimens for 1918 influenza virus RNA was negative. Viral inclusion were negative. Chronic changes included neuronal loss and neurofibrillary degeneration in the midbrain and basal ganglia.

Encephalitis Lethargica : 

Encephalitis Lethargica Histopathology of striatum demonstrates perivenous lymphocytic infiltration. Additional staining with (b) CD3 and (c) CD20 identifies infiltrating cells as T and mature B lymphocytes respectively.

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MRI (FLAIR sequences) findings: case 1 (a), and case 5 (b) had hyperintense thalamic signal abnormalities. C Case 8 had profound hyperintense basal ganglia signal abnormalities. Abnormal signals are demonstrated with white arrows Contemporary Encephalitis Lethargica: phenotype, laboratory findings and treatment outcomes. Lopez-Alberola R. Georgiou M. Sfakianakis GN. Singer C. Papapetropoulos S. Journal of Neurology. 256(3):396-404, 2009 Mar.

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Bilateral substantia nigra lesions on magnetic resonance imaging in a patient with encephalitis lethargica VERSCHUEREN, H; CROLS, R Journal of Neurology, Neurosurgery, & Psychiatry Issue: Volume 71(2), 1 August 2001, p 275 A seroconversion was noted for Coxsackie virus type B3 (titre 0 on day 4, 1/320 on day 25)  indicating similar clinical features can be due to other viral infection.

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Characteristic 18F-FDG PET imaging findings: Variable degrees of suppression of metabolic cortical activity with bilateral basal ganglia hyperactivity

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Marked discrepancy between striatal glucose metabolism and cerebral cortex Anteroposterior gradient absent in PEP FDG- and Dopa-PET in postencephalitic parkinsonism.Ghaemi M. Rudolf J. Schmulling S. Bamborschke S. Heiss WD. Journal of Neural Transmission. 107(11):1289-95, 2000.

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.

Encephalitis Lethargica : 

Encephalitis Lethargica Mortality 20-40% Morbidity: Parkinsonism, dyskinesias or psychiatric disease. The course of disease was monophasic or fluctuating, unlike the progressive course characteristic of the metabolic, biochemical or inherited causes of parkinsonism.

It is unlikely that the 1918 influenza virus was neurotropic and directly responsible for the outbreak of EL because several studies has failed to detected the presence of influenza viral genes from patients suffering from Encephalitis lethargica : 

It is unlikely that the 1918 influenza virus was neurotropic and directly responsible for the outbreak of EL because several studies has failed to detected the presence of influenza viral genes from patients suffering from Encephalitis lethargica Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases Jellinger KA. Journal of Neuropathology & Experimental Neurology. 60(11):1121-2, 2001 Nov. Influenza RNA not detected in archival brain tissues from acute encephalitis lethargica cases or in postencephalitic Parkinson cases McCall S. Henry JM. Reid AH. Taubenberger JK. Journal of Neuropathology & Experimental Neurology. 60(7):696-704, 2001 Jul. Lack of detection of influenza genes in archived formalin-fixed, paraffin wax-embedded brain samples of encephalitis lethargica patients from 1916 to 1920. Lo KC. Geddes JF. Daniels RS. Oxford JS. Virchows Archiv. 442(6):591-6, 2003 Jun.

? Autoimmunity : 

? Autoimmunity Anti-basal ganglia neuronal antibodies in sera Oligoclonal banding in cerebrospinal fluid of EL patients Steroid response Negative virological tests

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

Clinical Aspect of Encephalitis Lethargicain Children : 

Clinical Aspect of Encephalitis Lethargicain Children Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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Clinical Features and Laboratory Findings

Contemporary Encephalitis Lethargica: phenotype, laboratory findings and treatment outcomes. Lopez-Alberola R. Georgiou M. Sfakianakis GN. Singer C. Papapetropoulos S. Journal of Neurology. 256(3):396-404, 2009 Mar. : 

Contemporary Encephalitis Lethargica: phenotype, laboratory findings and treatment outcomes. Lopez-Alberola R. Georgiou M. Sfakianakis GN. Singer C. Papapetropoulos S. Journal of Neurology. 256(3):396-404, 2009 Mar. Sporadic cases of encephalitis lethargica still occur Contemporary EL is more frequent in paediatric (including adolescent) than in adult patients. (M/F: 5/3) ranged from 2–28 years (mean 9.3 ± 9.5). Encephalopathy, sleep disturbances and extrapyramidal symptoms were present in all cases. Laboratory investigations revealed CSF leukocytosis in 5/8 patients and anti-BG Ab in 4/7 patients. MRIs revealed structural abnormalities in 7/8 cases. 18F-FDG PET showed basal ganglionic hypermetabolism in 4/7 patients. Treatment approaches included immunomodulating and symptomatic therapies.

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

Children and encephalitis lethargica: a historical review. Vilensky JA. Foley P. Gilman S. Pediatric Neurology. 37(2):79-84, 2007 Aug. Encephalitis lethargica was at least as devastating for children as for adults, typically causing severe psychiatric as well as motor disorders; The psychiatric effects in children were virtually pathognomonic for encephalitis lethargica, so that a recurrence of encephalitis lethargica might initially be most readily identifiable in children;

Encephalitis lethargica (嗜睡性腦炎) is an acute encephalopathic illness characterised by sleep disturbance, neuropsychiatric and extrapyramidal symptoms. : 

Encephalitis lethargica (嗜睡性腦炎) is an acute encephalopathic illness characterised by sleep disturbance, neuropsychiatric and extrapyramidal symptoms. The diagnosis in children is made by exclusion of infective, biochemical, degenerative, autoimmune, toxic or metabolic causes of acute encephalopathy. Encephalitis Lethargica in a Twelve-year-old Girl: The Response to Levodopa TherapyB Chan, KY Chan, KC Yau HK J Paediatr (New Series) 2009;14:122-125

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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.

Boy with encephalitis lethargica depicting an abnormal posture of flexed body, retracted arms, head leaning forward, and open mouth. : 

Boy with encephalitis lethargica depicting an abnormal posture of flexed body, retracted arms, head leaning forward, and open mouth. JUVENILE PSEUDOPSYCHOPATHIA

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. MORTIMERa1 Health Protection Agency Centre for Infections, London, UK

Novel H1N1 2009 PandemicHuman Swine InfluenzaImplication to Children of China : 

Novel H1N1 2009 PandemicHuman Swine InfluenzaImplication to Children of China Dr. Lai Kang Yiu Intensive Care Unit Queen Elizabeth Hospital

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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).

In Nov. 1977, the Soviet Union reported to W.H.O. the occurrence of widespread outbreaks of influenza due to viruses antigenically related to the H1N1 viruses that has circulated in the human population during the period 1947-1956. : 

In Nov. 1977, the Soviet Union reported to W.H.O. the occurrence of widespread outbreaks of influenza due to viruses antigenically related to the H1N1 viruses that has circulated in the human population during the period 1947-1956. By late Dec 1977, the Soviet Union reported that A/USSR/77(H1N1) virus has caused disease in nearly 2/3 of the cities and has displaced the prevalent H3N2 viruses. Summary of Clinical Trials of Inactivated Influenza Vaccine – 1978 John. R et al. Reviews of infectious dieases Vol 5 No 4 July- August

Since the spring of 1977, two subtypes of influenza A virus (H3N2 and H1N1) have been seasonally infecting the human population. : 

Since the spring of 1977, two subtypes of influenza A virus (H3N2 and H1N1) have been seasonally infecting the human population. Data from 1995 to 2008 has shown that the symptomatic flu due to H1N1 is distributed mainly in a younger population relative to H3N2. (The median age of the H3N2 patients is 23 years while H1N1 patients are 9 years old.) These distinct characteristic spectra of age groups may indicate partial protection possibly carried over from previous pandemics in the older population. Differences in Patient Age Distribution between Influenza A Subtypes Hossein Khiabanian, Gregory M. Farrell, Kirsten St. George, Raul Rabadan PLOS One August 2009 | Volume 4 | Issue 8 | e6832

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

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? 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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http://www.flucount.org/ (10/4/2010)

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Mortality Rate Per Confirmed novel H1N1 Infection 10/4/2010 http://www.flucount.org/

Implication to Hong Kong & China : 

Implication to Hong Kong & China This may partially explained why Mexico is more affected than U.S.A. apart from immunization program. This has strong implication to China. IMR = Infant mortality rate (death per 1000 live birth) 2008 MMR = Maternal mortality rate (death per 100,000 delivery))

La Gloria clinical attack rates : 

La Gloria clinical attack rates H H H H H H P P P P P P Immunization Status of U.S.A. Mexico and China H Haemophilus Influenza B Immunization program P Pneumococcus Immunization program

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Proportion of pediatric pneumococcal disease prevented by PCV There are 90 serotypes of the pneumococcus each of which has a different polysaccharide capsule. Even though there are a total of 90 serotypes, 88% of global disease is caused by 23 serotypes, and only 11 serotypes account for greater than 80% of disease in children under five. Different serotypes of pneumococcus have different global distributions. The 7-valent PCV7 vaccine is in wide use around the world in developed countries because this vaccine contains seven of the most common disease causing serotypes (4, 6B, 9V, 14, 18C, 19F, 23F) in the U.S., Canada, Australia, and Europe

H1H1 2009 Pandemic Japan (up to 13 Nov 2009) : 

H1H1 2009 Pandemic Japan (up to 13 Nov 2009) 60 cases of influenza encephlopathy Median: 8 years 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)

Implication To Children in China (I) : 

Implication To Children in China (I) China and Mexico has similar maternal and neonatal mortality. What happened in Mexico would be repeated in China in the absence of mitigation and influenza vaccination. When there is bacterial co-infection, the mortality rate if children would increase ten times. 30 to 60% of co-infection is due to pneumococcus and Haemophilus influenza. Unlike Mexico, children in China has no Haemophilus influenza b and pneumococcal vaccination. Therefore China would be expected to have higher mortality rate in children then Mexico.. This would be disastrous to affected families because of current one child policy.

Implication To Children in China (II) : 

Implication To Children in China (II) However, the current pneumococcal vaccine PCV7 is not suitable for China because it can only cover 38% of the circulating pneumococcal strains in China. Because of the expected high attack rate among children in China, China should also prepare for two potential complications Influenza encephalopathy/encephalitis Encephalitis lethargica Implication on mortality and morbidity Implication for subsequent personality change with juvenile delinquency

墨西哥的疫情對中國兒童的啟示 : 

墨西哥的疫情對中國兒童的啟示 黎鏡堯醫生 伊利沙伯醫院

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 從基因測試 2009 H1N1 豬流感是綜合病毒，含有四種不同的流感病毒基因，其中包括：北美洲的豬流感、歐亞型的豬流感、北美洲型的禽流感、及人類流感。其中 HA, NS1 and NP 則是於1918年傳入北美豬隻 。因此我們現今第一波時實已處身於1918年的第二波。 15歲以下小童染病率為 61%， 15歲以上為 29% 。但小童死亡率未有預期高。小童流感死亡率多因細菌混合感染併發症。流感的細菌混合感染三成至六成為肺炎鏈球菌及嗜血桿菌。墨西哥早於1999年已為小童提供免費 b型嗜血桿菌疫苗。及後更於2006為兩歲以下小童免費提供肺炎鏈球菌疫苗。因此現時四歲以下小童已為疫苗保障。 吸煙是流感死亡高危因素之一。因吸煙會令血小板活化因數增加，增加肺炎鏈球菌感染的機會。

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 中國的嬰兒死亡率與孕婦死亡率與墨西哥基本相近。墨西哥的疫情可於中國重演。但中國小童並沒b型嗜血桿菌和肺炎鏈球菌疫苗保障及中國成年人煙民數目及比例為世界之冠。因此疫情可能比墨西哥嚴峻。 中國因此應盡速為小童提供免費 b型嗜血桿菌和肺炎鏈球菌疫苗及呼籲成年煙民自行接種肺炎鏈球菌疫苗。

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 但常用的PCV-7 肺炎鏈球菌疫苗並不能為中國小童提供足夠保障, 因為PCV-7只能有效防止38%於中國流行的肺炎鏈球菌。 除肺炎併發症，中國須要防禦豬流感引發的兩類腦部併發症 流感腦炎/腦病(Influenza-associated encephalopathy/encephalitis). 昏睡性腦炎 (encephalitis lethargica) 40% 死亡率 人格變化後的少年犯罪問題。

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 從基因測試 2009 H1N1 豬流感是綜合病毒，含有四種不同的流感病毒基因，其中包括：北美洲的豬流感、歐亞型的豬流感、北美洲型的禽流感、及人類流感。其中 HA, NS1 and NP 則是於1918年傳入北美豬隻 。因此我們現今第一波時實已處身於1918年的第二波。 15歲以下小童染病率為 61%， 15歲以上為 29% 。但小童死亡率未有預期高。小童流感死亡率多因細菌混合感染併發症。流感的細菌混合感染三成至六成為肺炎鏈球菌及嗜血桿菌。墨西哥早於1999年已為小童提供免費 b型嗜血桿菌疫苗。及後更於2006為兩歲以下小童免費提供肺炎鏈球菌疫苗。因此現時四歲以下小童已為疫苗保障。 吸煙是流感死亡高危因素之一。因吸煙會令血小板活化因數增加，增加肺炎鏈球菌感染的機會。

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 中國的嬰兒死亡率與孕婦死亡率與墨西哥基本相近。墨西哥的疫情可於中國重演。但中國小童並沒b型嗜血桿菌和肺炎鏈球菌疫苗保障及中國成年人煙民數目及比例為世界之冠。因此疫情可能比墨西哥嚴峻。 中國因此應盡速為小童提供免費 b型嗜血桿菌和肺炎鏈球菌疫苗及呼籲成年煙民自行接種肺炎鏈球菌疫苗。

墨西哥的疫情對中國的啟示 : 

墨西哥的疫情對中國的啟示 但常用的PCV-7 肺炎鏈球菌疫苗並不能為中國小童提供足夠保障, 因為PCV-7只能有效防止38%於中國流行的肺炎鏈球菌。 除肺炎併發症，中國須要防禦豬流感引發的兩類腦部併發症 流感腦炎/腦病(Influenza-associated encephalopathy/encephalitis). 昏睡性腦炎 (encephalitis lethargica) 40% 死亡率 人格變化後的少年犯罪問題。

Slide 91: 

Thank you for your attention