20042004

With many thanks to With many thanks to

P. Parizel, (neuro)radiology, UA, UZAP. Parizel, (neuro)radiology, UA, UZA

Philippe G JorensPhilippe G JorensDepartment of Intensive Care Department of Intensive Care

MedicineMedicineUniversity of Antwerp, UZA, BelgiumUniversity of Antwerp, UZA, Belgium

Meningitis-Meningitis-encephalitisencephalitis

CASE REPORT…CASE REPORT…

viral prodrome several days: fever, viral prodrome several days: fever, headache, nausea, lethargy, headache, nausea, lethargy, myalgiasmyalgias

diffuse or focal syndromes: diffuse or focal syndromes: personality changes, decreased personality changes, decreased consciousness, stiff neck, consciousness, stiff neck, confusion, convulsions, deafness, confusion, convulsions, deafness, facial palsyfacial palsy

Meningitis-encephalitisMeningitis-encephalitis

Meningitis encephalitisMeningitis encephalitis– Viral vs bacteriallViral vs bacteriall

MeningoencephalitisMeningoencephalitis ADEM, encephalomyelitis ADEM, encephalomyelitis Myelitis, TMMyelitis, TM cerebritis ...cerebritis ...

Meningitis-encephalitisMeningitis-encephalitis

Meningitis: leptomeningeal Meningitis: leptomeningeal (photophobia, headache, stiff (photophobia, headache, stiff neck)neck)

Only 50 % over 16 of age: triadeOnly 50 % over 16 of age: triade

EncephalitisEncephalitis

(diffuse ) inflammation of the brain (diffuse ) inflammation of the brain parenchymaparenchyma– presents as diffuse and/or focal presents as diffuse and/or focal

neuropsychological dysfunction, neuropsychological dysfunction, consciousnessconsciousness

– Hemiplegia, hyperthermia, seizures Hemiplegia, hyperthermia, seizures distinct from meningitis, although distinct from meningitis, although

symptoms of meningeal symptoms of meningeal inflammation may coexist inflammation may coexist

Intracranial infectionsIntracranial infectionsAnatomic locationAnatomic location

Lepto-Lepto-meningeameningea

llMixedMixed

Cerebral Cerebral parenchyparenchy

mama

ViralViral

BacterialBacterial

OtherOtherEti

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al ag

ent

Eti

olo

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al ag

ent

Meningitis-encephalitis: Meningitis-encephalitis: etiology etiology

reactivation of the virus ( herpes reactivation of the virus ( herpes simplex), sporadicallysimplex), sporadically

mosquitos or ticks (arbovirus)mosquitos or ticks (arbovirus) animal bite (rabies)animal bite (rabies) immunocompromised ( varicella-immunocompromised ( varicella-

zoster, CMV)zoster, CMV) HIV HIV

Encephalitis: etiologyEncephalitis: etiology

hematogenous or spread along hematogenous or spread along neural (rabies, HSV, VZV) and neural (rabies, HSV, VZV) and olfactory (herpes simplex) olfactory (herpes simplex) pathways) after entrance by the pathways) after entrance by the resp. tract ( influenza), resp. tract ( influenza), gastronitestinal tract (poliovirus) or gastronitestinal tract (poliovirus) or subcutaneous tissue (Rickettsia)subcutaneous tissue (Rickettsia)

EtiologyEtiology

Over 100 viruses nervous system Over 100 viruses nervous system infectionsinfections

Epidemic and largely seasonal Epidemic and largely seasonal (Arbo and entero)(Arbo and entero)– Summer, fallSummer, fall

Endemic (Herpes, Rabies)Endemic (Herpes, Rabies)

Etiology- DNAEtiology- DNA

Poxviridae: variola, vacciniaPoxviridae: variola, vaccinia Herpesviridae: Simplex 1, 2, Herpesviridae: Simplex 1, 2,

Varicella-zoster, CMV, EBV, Herpes Varicella-zoster, CMV, EBV, Herpes 6,7 and 86,7 and 8

Adenoviridae : AdenovirusAdenoviridae : Adenovirus Papoviridae : Simian virus 40, JCPapoviridae : Simian virus 40, JC Hepadnaviridae: Hep BHepadnaviridae: Hep B Parvoviridae: Parvovirus B19Parvoviridae: Parvovirus B19

Etiology-RNAEtiology-RNA Paramyxoviridae: parainfluenza, mumps, Paramyxoviridae: parainfluenza, mumps,

measles, RSVmeasles, RSV Orthomyxoviridae: influenzaOrthomyxoviridae: influenza Rhabdoviridae: RabiesRhabdoviridae: Rabies Filoviridae: Ebola, Marburg, Bunyaviridae: Filoviridae: Ebola, Marburg, Bunyaviridae:

California encephalitis, HantavirusCalifornia encephalitis, Hantavirus Arenaviridae: lymphocytic Arenaviridae: lymphocytic

choriomenigitis viruschoriomenigitis virus Retroviridae: HTLV I and II, HIV I and IIRetroviridae: HTLV I and II, HIV I and II

Etiology: RNA (2)Etiology: RNA (2)

Coronaviridae: coronavirusCoronaviridae: coronavirus Reoviridae: ReovirusesReoviridae: Reoviruses Togaviridae: RubellaTogaviridae: Rubella Flaviviridae: St. Louis, Japanese Flaviviridae: St. Louis, Japanese

encephalitis, Hep Cencephalitis, Hep C Picornaviridae: Polio, Coxsackie, Picornaviridae: Polio, Coxsackie,

Echo, entero, Hep AEcho, entero, Hep A

New…New…

West Nile virus (New York)West Nile virus (New York) Nipah virus (Malaysia)Nipah virus (Malaysia) Asia (enterovirus 71)Asia (enterovirus 71)

Encephalitis : incidenceEncephalitis : incidence

8-30/100000 year children, 5 adults8-30/100000 year children, 5 adults Herpes simplex : 0.2/100000 Herpes simplex : 0.2/100000

(neonatal: 2-3/10000)(neonatal: 2-3/10000) arbovirus: only 10 % encephalitisarbovirus: only 10 % encephalitis measles: - post-infectious (1/1000 measles: - post-infectious (1/1000

persons): SSPE (1/100000 persons)persons): SSPE (1/100000 persons) Japanese encephalitis: most Japanese encephalitis: most

common type outside US common type outside US

PrognosisPrognosis

462 children, death 2.8 % , 462 children, death 2.8 % , severely damaged 6.7 % severely damaged 6.7 % (Rautonen et al, 1991)(Rautonen et al, 1991)

HSV poor outcome (11.7 increased HSV poor outcome (11.7 increased risk) risk)

Viral meningitisViral meningitis

10-year-old boy10-year-old boy Laboratory tests Laboratory tests

revealed CNS revealed CNS enterovirus infection, enterovirus infection, with clinical symptoms with clinical symptoms of meningitis. of meningitis.

CT -/+ C was normal.CT -/+ C was normal. There was no There was no abnormal meningeal abnormal meningeal thickening or thickening or enhancement. enhancement.

Varicella meningo-Varicella meningo-encephalitisencephalitis

29-year-old man29-year-old man Symmetric distribution of edema (subinsular, frontal Symmetric distribution of edema (subinsular, frontal

and temporal opercular regions); hyperintensity in and temporal opercular regions); hyperintensity in the lentiform and caudate nucleus on the rightthe lentiform and caudate nucleus on the right

Subtle meningeal enhancement is notedSubtle meningeal enhancement is noted

VaricellaVaricella

1-3/10000 1-3/10000 Cases immunocompromised Cases immunocompromised

patient patient

CMV encephalitis CMV encephalitis abscessabscess

Immunocompromised 49-y-o woman (renal transplant)Immunocompromised 49-y-o woman (renal transplant) Early stage: Early stage:

– edema edema – serpiginous and micronodular enhancementserpiginous and micronodular enhancement

Late stage (4 months later): abscessLate stage (4 months later): abscess

RabiesRabies Encephalitis: 30000-70000 deaths/yearEncephalitis: 30000-70000 deaths/year RNA RhabdoviridaeRNA Rhabdoviridae Saliva, but also aerosolSaliva, but also aerosol Uniformely fatal disease, nervous tissueUniformely fatal disease, nervous tissue Only 6 cases of survival after onset of Only 6 cases of survival after onset of

clinical rabiesclinical rabies– Prrexposure prophylaxis, expidious postexposurePrrexposure prophylaxis, expidious postexposure– Wild animalsWild animals

Fluorescent material skin biopsy, serology Fluorescent material skin biopsy, serology ……

Herpes Herpes simplex virus simplex virus

(type 1) (type 1) encephalitisencephalitis

Herpes simplexHerpes simplex

Fatality : 30 -70 %Fatality : 30 -70 % Type 1 (neonate: type II)Type 1 (neonate: type II) Prediliction inferior and medial Prediliction inferior and medial

temporal lobestemporal lobes EEGEEG

Intra-Intra-uterine uterine

CMV CMV infectioninfectionTORCHTORCH

EnterovirusesEnteroviruses

Coxsackie A and B, polio, echo, Coxsackie A and B, polio, echo, entero 68 and 71entero 68 and 71

Good prognosis, except enterovirus Good prognosis, except enterovirus 71: 1998 Taiwan outbreak71: 1998 Taiwan outbreak– 129106 cases hand, fouth and mouth 129106 cases hand, fouth and mouth

diseasedisease– 405 severe cases ( encephalitis, 405 severe cases ( encephalitis,

aseptic meningitis)aseptic meningitis)

West Nile virusWest Nile virus

1999: New York City1999: New York City– 2002: 4156 human cases, 284 fatal2002: 4156 human cases, 284 fatal

1937: Uganda1937: Uganda Birds (New York zoo …)Birds (New York zoo …)

– Enzootic cycle: birds, mosquitosEnzootic cycle: birds, mosquitos 2000: found in 14 mosquito species2000: found in 14 mosquito species Organ transplantation, blood Organ transplantation, blood

transfusiontransfusion

West Nile virusWest Nile virus

Arbovirus: St Louis , JapaneseArbovirus: St Louis , Japanese Incubation: 3-14 daysIncubation: 3-14 days Flu like , Africa Middle east: rarely Flu like , Africa Middle east: rarely

neurological neurological 1/150 infected: severe, meningitis, 1/150 infected: severe, meningitis,

encephaltis, meningoencephalitisencephaltis, meningoencephalitis Brain stemBrain stem

Japanese encephalitisJapanese encephalitis

15000 deaths annually 15000 deaths annually Children, young adultsChildren, young adults 1/3 die, 50 % survivors severe 1/3 die, 50 % survivors severe

neurological deficit neurological deficit Vaccination (97.5 % effective)Vaccination (97.5 % effective)

HIVHIV

HIV: dementiaHIV: dementia CMV, Varicella …CMV, Varicella … Progressive multifocal Progressive multifocal

leukoencephalopathyleukoencephalopathy– JC virus, human polyomavirusJC virus, human polyomavirus– Destruction oligodendrocytesDestruction oligodendrocytes– Middle cerebellar peduncle, HIVMiddle cerebellar peduncle, HIV

MeaslesMeasles

Progressive postinfectious Progressive postinfectious encephalitisencephalitis

SSPE (subacute sclerosing SSPE (subacute sclerosing panencephalitis)panencephalitis)– Progressive dissemination of Progressive dissemination of

defective (noninfectious) viral defective (noninfectious) viral replication replication

Encephalitis: morbidityEncephalitis: morbidity

untreated herpes: mortality 50-75 untreated herpes: mortality 50-75 %, treatment 20 %%, treatment 20 %

varicella untreated: 15 %, 100 % varicella untreated: 15 %, 100 % immunosuppressedimmunosuppressed

sex: prediliction SSPE male (2-4)sex: prediliction SSPE male (2-4)

BACTERIAL INFECTIONSBACTERIAL INFECTIONS

Pyogenic bacterial infections of the Pyogenic bacterial infections of the CNS most commonly cause: CNS most commonly cause: – focal cerebritis focal cerebritis – abscess abscess – meningitismeningitis– empyema (subdural or epidural). empyema (subdural or epidural).

Tuberculous meningitis (1)Tuberculous meningitis (1)

CT+C in a 1-year-old girl with proven tuberculous meningitisCT+C in a 1-year-old girl with proven tuberculous meningitis Hydrocephalus (communicating hydrocephalus)Hydrocephalus (communicating hydrocephalus) Cisternal enhancement (thick gelatinous exudate) Cisternal enhancement (thick gelatinous exudate) Arterial involvement can result in thrombosis and infarction Arterial involvement can result in thrombosis and infarction

(MCA most commonly involved).(MCA most commonly involved).

Subdural empyema with Subdural empyema with abscessabscess

Thickening and enhancement of the falx cerebriThickening and enhancement of the falx cerebri Incipient abscess formationIncipient abscess formation Mass effect and edema in the left cerebral Mass effect and edema in the left cerebral

hemispherehemisphere

CerebritisCerebritis Axial TSE T2Axial TSE T2 Axial FLAIRAxial FLAIR Axial SE T1 + Axial SE T1 +

GdGd Coronal SE T1 Coronal SE T1

+ Gd+ Gd

TuberculomaTuberculoma

HIV-positive 46-year-old man.HIV-positive 46-year-old man. Axial FLAIR (left) and T2-weighted (right) Axial FLAIR (left) and T2-weighted (right)

images show a hypointense nodular mass in images show a hypointense nodular mass in the pons. There is perilesional edema. the pons. There is perilesional edema.

TuberculomaTuberculoma

HIV-positive 46-year-old man.HIV-positive 46-year-old man. Gd-enhanced axial (left) and coronal (right) T1-Gd-enhanced axial (left) and coronal (right) T1-

weighted images reveal circumferential weighted images reveal circumferential peripheral enhancement of the tuberculoma. peripheral enhancement of the tuberculoma.

Cryptococcal-meningitisCryptococcal-meningitis

38-year-old-HIV-positive-woman38-year-old-HIV-positive-woman Diffuse meningeal enhancement (e.g. at the Diffuse meningeal enhancement (e.g. at the

superior meningeal covering of the vermis. superior meningeal covering of the vermis. No evidence of parenchymal disease in this patient. No evidence of parenchymal disease in this patient.

Toxoplasma encephalitisToxoplasma encephalitis

Proven toxoplasma encephalitis in a 28-year-old HIV+ man.Proven toxoplasma encephalitis in a 28-year-old HIV+ man. Bright nodules with ringlike enhancement in the left Bright nodules with ringlike enhancement in the left

lentiform nucleus and in the head of the caudate nucleus. lentiform nucleus and in the head of the caudate nucleus. Bifrontally on there is cortical and subcortical thickening and Bifrontally on there is cortical and subcortical thickening and

edema and meningeal enhancement.edema and meningeal enhancement.

NeurocysticercosisNeurocysticercosis

25-year-old-woman 25-year-old-woman Multiple nodular lesions with intensely enhancing peripheral Multiple nodular lesions with intensely enhancing peripheral

rim and prominent perilesional edemarim and prominent perilesional edema Several lesions demonstrate a hypointense center on both T1- Several lesions demonstrate a hypointense center on both T1-

and T2-weighted images due to calcificationand T2-weighted images due to calcification

II. Meningo-encephalitisII. Meningo-encephalitis

Case reportCase report 34-year-old woman34-year-old woman Previous medical history is Previous medical history is

unremarkableunremarkable CC:CC:

– Progressive lethargy and somnolenceProgressive lethargy and somnolence– Evolution to deep coma over a 3-day time Evolution to deep coma over a 3-day time

intervalinterval– Lumbar puncture: pneumococcal meningitisLumbar puncture: pneumococcal meningitis

MRI is requested to rule out MRI is requested to rule out parenchymal involvementparenchymal involvement

Meningo-encephalitisMeningo-encephalitis

MeningitisMeningitis EncephalitisEncephalitis

– convulsionsconvulsions– focal neurological deficitfocal neurological deficit

Necrotising vasculitisNecrotising vasculitis

Addendum ... Addendum ... physiopathogenesisphysiopathogenesis

Eenheid normaal Patiënt 1 Patiënt 2

MBP ug/l < 0.6 2.2 7.5

S100 ug/l < 3.3 2.9 22.6

NSE Ug/l < 17.5 6.4 51.8

ADEM/ Demyelinating ADEM/ Demyelinating diseasesdiseases

MyelinMyelin– CNS: produced by CNS: produced by oligodendrocytes oligodendrocytes (glial cells)(glial cells)

– Peripheral: Schwann Peripheral: Schwann cellscells

MyelinMyelin

Demyelinating: destruction of existing myelinDysmyelinating: abormal myelin (leukodystrofies)

Demyelinating diseasesDemyelinating diseases

Central nervous systemCentral nervous system– Multiple sclerosisMultiple sclerosis– ADEMADEM– Central pontine myelolysisCentral pontine myelolysis– LeukoencephalopathyLeukoencephalopathy– EncephalitisEncephalitis

ADEMADEM

Acute inflammatory and Acute inflammatory and demyelinating multifocal disease demyelinating multifocal disease of the brain and spinal cordof the brain and spinal cord

Days or weeks after infection Days or weeks after infection (viral, streptococcal, vaccination)(viral, streptococcal, vaccination)

Difficult to differentiate from MSDifficult to differentiate from MS

ADEM- Encephalomyelitis ADEM- Encephalomyelitis (1)(1)

follows infection or vaccination, DD MSfollows infection or vaccination, DD MS infection: infection: Adenovirus, mumps, CMV, EBV, HIV 1 Adenovirus, mumps, CMV, EBV, HIV 1

and II, herpes simplex, influenza A and and II, herpes simplex, influenza A and B, measles, parainfluenza 1,2,3, RSV, B, measles, parainfluenza 1,2,3, RSV, Rubella, varicella, herpes 6, polio, hantaRubella, varicella, herpes 6, polio, hanta

vaccination: smallpox, rabiesvaccination: smallpox, rabies mortality 5-30 % mortality 5-30 % (Nasr et al, 2000)(Nasr et al, 2000)

ADEMADEM

CASE HISTORY (1)CASE HISTORY (1)

3-year-old-child3-year-old-child no vaccinationno vaccination

CASE REPORT (2) CASE REPORT (2)

– lethargy, vomiting, meningeal lethargy, vomiting, meningeal syndromesyndrome

– otitis media en externaotitis media en externa– cyanotic, hypotonic, anisocoria, cyanotic, hypotonic, anisocoria,

intubatedintubated– CT-scan: right temporal lesionCT-scan: right temporal lesion– transfer UZAtransfer UZA

CASE REPORT (3)CASE REPORT (3)

tetraplegic, anisocoria, purulent tetraplegic, anisocoria, purulent discharge from the eardischarge from the ear

L.P (2): 10, 13 WBC, total protein L.P (2): 10, 13 WBC, total protein 81 mg/dl (nl 15-45), increased 81 mg/dl (nl 15-45), increased no no malignant cellsmalignant cells

CASE REPORT (4)CASE REPORT (4)

cultures of blood, nasopharynx, cultures of blood, nasopharynx, endotracheal asp., urine ...: negativeendotracheal asp., urine ...: negative

middle ears: Streptococcus pyogenes, middle ears: Streptococcus pyogenes, type M6type M6

CSF:negative, including viral (herpes, CSF:negative, including viral (herpes, entero, RSV, (para)influenza, CMV, entero, RSV, (para)influenza, CMV, adeno and mumps). PCR: Herpes adeno and mumps). PCR: Herpes simplex and type 6, toxoplasma, simplex and type 6, toxoplasma, Mycoplasma and CMVMycoplasma and CMV

CASE REPORT (5)CASE REPORT (5)

na raised antibody titers na raised antibody titers (admission and after 3 (admission and after 3 weeks) :“28” from adeno to weeks) :“28” from adeno to toxoplasmatoxoplasma

ADEM after infectionADEM after infection

Adenovirus, mumps, CMV, EBV, HIV Adenovirus, mumps, CMV, EBV, HIV 1 and II, herpes simplex, influenza 1 and II, herpes simplex, influenza A and B, measles, parainfluenza A and B, measles, parainfluenza 1,2,3, RSV, Rubella, varicella, 1,2,3, RSV, Rubella, varicella, herpes 6, polio, hantaherpes 6, polio, hanta

Boreelia, Brucella, Chlamydia, Boreelia, Brucella, Chlamydia, Mycoplasm, Toxoplasma, Mycoplasm, Toxoplasma, Trerponema pallidum, Leptospira …Trerponema pallidum, Leptospira …

MRI : day 1 and 8 after MRI : day 1 and 8 after admissionadmission

T2-weighted images multiple scattered T2-weighted images multiple scattered and confluent areas subcortical and and confluent areas subcortical and deep white matter, assymetric, ranging deep white matter, assymetric, ranging 2-20 mm2-20 mm

large lesion lower medulla oblongata, large lesion lower medulla oblongata, cervical spinal cord up to C4cervical spinal cord up to C4

confluent areas of demyelination?confluent areas of demyelination? after 8 days: breakdown blood-brain after 8 days: breakdown blood-brain

barrierbarrier

MRI: day 8 after admissionMRI: day 8 after admission

CASE REPORT (6)CASE REPORT (6)

EMG: normal; evoked potentials: EMG: normal; evoked potentials: delayed latenciesdelayed latencies

CASE REPORT (7)CASE REPORT (7)

therapy acyclovir (Herpes?) , therapy acyclovir (Herpes?) , erythromycin (Mycoplasma?) and erythromycin (Mycoplasma?) and ceftriaxone, 10 daysceftriaxone, 10 days

corticosteroids (30 mg/kg 3 days, corticosteroids (30 mg/kg 3 days, tapered) and 0.4 g/kg/d IVIG 5 tapered) and 0.4 g/kg/d IVIG 5 days, five monthly coursesdays, five monthly courses

periods arythmiaperiods arythmia

MRI: 35 days after MRI: 35 days after admissionadmission

MRI: 5 months after MRI: 5 months after admissionadmission

CASE REPORT (8)CASE REPORT (8)

6 months after admission: high 6 months after admission: high titers of antibodies against SPEA titers of antibodies against SPEA and SPEBand SPEB

CASE REPORT (9)CASE REPORT (9)

tetraplegic, ventilator-dependenttetraplegic, ventilator-dependent tracheostomy, port-a-cath, tracheostomy, port-a-cath,

suprapubic urinary catheter, suprapubic urinary catheter, enterogastrostomyenterogastrostomy

only the expression of its facial only the expression of its facial musculature has been improving, musculature has been improving, learned to speak and eatlearned to speak and eat

CASE REPORT (10)CASE REPORT (10)

returned home after 30 months of returned home after 30 months of hospitalisationhospitalisation

died 6 months later: hyperthermia, died 6 months later: hyperthermia, new lesions on MRI, status new lesions on MRI, status epilepticus, cerebral edemaepilepticus, cerebral edema

CONCLUSION CONCLUSION

the expansion might have been the expansion might have been caused by an interaction with caused by an interaction with toxins produced by the isolated S. toxins produced by the isolated S. pyogenes strainpyogenes strain

human T cells showing in vitro human T cells showing in vitro reactivity to myelin antigens may reactivity to myelin antigens may be pathogenic in vivo be pathogenic in vivo (Jorens et al, (Jorens et al, Neurology, 2000)Neurology, 2000)

SUPERANTIGEN IN VIVO- SUPERANTIGEN IN VIVO- DEMYELINATIONDEMYELINATION

Idiopathic Transverse Idiopathic Transverse myelitis-myelopathymyelitis-myelopathy

Sensory, motory or autonomic Sensory, motory or autonomic dysfunction attributable to the spinal dysfunction attributable to the spinal cordcord

Inflammation (pleocytosis)Inflammation (pleocytosis) Clearly defined sensory levelClearly defined sensory level Bilateral signsBilateral signs Progression to nadir between 4h and Progression to nadir between 4h and

21 days (longer progressive form of 21 days (longer progressive form of MS)MS)

Exclusion criteria: non-Exclusion criteria: non-compressive compressive

myelopathy/secondary myelopathy/secondary Transverse myelitisTransverse myelitis

RadiationRadiation Thrombosis arterial circulationThrombosis arterial circulation AVM, Connective tissue disorderAVM, Connective tissue disorder

Infection Infection

Mycoplasma, parasites … Mycoplasma, parasites … – (Herpes Simplex 1,2, HHV-6, CMV, EBV, (Herpes Simplex 1,2, HHV-6, CMV, EBV,

enteroviruses, HIV, , VZV, HTLV-1, Hep A,B enteroviruses, HIV, , VZV, HTLV-1, Hep A,B and C …)and C …)

– Vaccination Vaccination

Transverse myelitis-Transverse myelitis-myelopathymyelopathy

DiagnosisDiagnosis

Encephalitis: without identified Encephalitis: without identified causative agent 24-74 %causative agent 24-74 %

Diagnosis: signsDiagnosis: signs

Alterations consciousnessAlterations consciousness FeverFever HeadacheHeadache Personality changesPersonality changes SeizuresSeizures HemiparesisHemiparesis Cranial nerve defects …Cranial nerve defects …

Encephalitis: work upEncephalitis: work up

laboratory: SIADH, viral serology, laboratory: SIADH, viral serology, leukocytosis (relative leukocytosis (relative lymphocytosis), amylaselymphocytosis), amylase

Systemic signsSystemic signs

Rash ( Lyme, varicella, enterovirus Rash ( Lyme, varicella, enterovirus …)…)

Neonatal: vesicular erythemaNeonatal: vesicular erythema History of tick bite (Lyme)History of tick bite (Lyme)

LPLP

Deteriorating GCS ?Deteriorating GCS ? Intracranial pressure ?Intracranial pressure ? Bleeding disorder?Bleeding disorder? 2 exceptions2 exceptions

Intracranial pressure, bleeding Intracranial pressure, bleeding disorderdisorder

Exception LPException LP

DiagnosisDiagnosis

Gram stainGram stain CultureCulture Protein, WBC, differential count Protein, WBC, differential count PCR , viral culture, CSF serology PCR , viral culture, CSF serology

ratio …ratio …

LPLP Mononuclear pleocytosis with normal glucose Mononuclear pleocytosis with normal glucose

and (elevated ?) protein and (elevated ?) protein High CSF lymphocytosis: TBC, mumps, High CSF lymphocytosis: TBC, mumps,

uncommon viruses (California encephalitis …)uncommon viruses (California encephalitis …) Atypical lymphocytes: EBV, CMV, HerpesAtypical lymphocytes: EBV, CMV, Herpes Bacterial: decreased glucose ? Low glucose and Bacterial: decreased glucose ? Low glucose and

lymphocytes: TBClymphocytes: TBC 3000 LPs children less than 3 years3000 LPs children less than 3 years

– > 6 wbc/mm3:> 6 wbc/mm3: Sensitivity 98.4 %, specificity 75.2 % bacterial Sensitivity 98.4 %, specificity 75.2 % bacterial

meninigitismeninigitis > 6 lymphocytes: > 95% viral> 6 lymphocytes: > 95% viral

LPLP

repeat examination repeat examination ( Feigin et al, ( Feigin et al, 1973)1973)

Concurrent viral cultures Concurrent viral cultures (nasopharynx, mucous membranes (nasopharynx, mucous membranes …)…)

CT scan : edema, hydrocephalus, CT scan : edema, hydrocephalus, petechial hemorhage (herpes); ring-petechial hemorhage (herpes); ring-enhancing lesions (Toxoplasm)enhancing lesions (Toxoplasm)

Encephalitis: work up (2)Encephalitis: work up (2)

MRI: T2 signal medial temporal lobes and MRI: T2 signal medial temporal lobes and inferior frontal gray matter (Herpes)inferior frontal gray matter (Herpes)

MRI: Eastern equine encephalitis/ basal MRI: Eastern equine encephalitis/ basal ganglia, thalamiganglia, thalami

EEG: paroxysmal epileptiform (herpes): high EEG: paroxysmal epileptiform (herpes): high voltage spike wave activity temporal voltage spike wave activity temporal regions, slow wave complexesregions, slow wave complexes

brain biopsy (96 % sensitivity): eosinophilic brain biopsy (96 % sensitivity): eosinophilic intranuclear inclusion bodies (Cowdry type intranuclear inclusion bodies (Cowdry type A, herpes)A, herpes)

ConclusionsConclusions Intracranial infections, viral iIntracranial infections, viral infectionsnfections are best are best

depicted by MRI scans.depicted by MRI scans. CT has a low sensitivity for leptomeningeal CT has a low sensitivity for leptomeningeal

infections; CT is useful in detecting infections; CT is useful in detecting calcifications (chronic stage).calcifications (chronic stage).

TThe pattern of involvement is not specific for he pattern of involvement is not specific for a particular infectious agent. a particular infectious agent.

There are no reliable distinguishing features There are no reliable distinguishing features among lesions, with the possible exception of among lesions, with the possible exception of cryptococcal lesions.cryptococcal lesions.

Keep up with current literature …Keep up with current literature …

Tools for diagnosis of Tools for diagnosis of demyelination?demyelination?

DDDD MRIMRI Myelin basic protein (like Myelin basic protein (like

material) :material) :– CSF, dominant epitope decapeptideCSF, dominant epitope decapeptide– Acute phase: ng/ml ( related to mass Acute phase: ng/ml ( related to mass

of myelin damage and how recently it of myelin damage and how recently it occurred)occurred)

– Not validated in serumNot validated in serum

TREATMENT (1)TREATMENT (1)

prehospital: treat shock or prehospital: treat shock or hypotensionhypotension

airway protection in patients with airway protection in patients with altered mental statusaltered mental status

seizure precautionsseizure precautions oxygen, IV access, rapid transitoxygen, IV access, rapid transit

TREATMENT: EMERGENCY TREATMENT: EMERGENCY ROOM (encephalitis)ROOM (encephalitis)

acyclovir and antibiotics, after acyclovir and antibiotics, after collecting labs and culturescollecting labs and cultures

treat systemic complications treat systemic complications ( shock, hypoxemia, SIADH and the ( shock, hypoxemia, SIADH and the exacerbation of chronic diseases)exacerbation of chronic diseases)

TREATMENT : DRUGS (2)TREATMENT : DRUGS (2)

viral (herpes, varicella)viral (herpes, varicella)– acyclovir, 10 mg/kg ( infuse over 1 h), acyclovir, 10 mg/kg ( infuse over 1 h),

q8h, 10-21 dq8h, 10-21 d interactions: nephrotoxic drugsinteractions: nephrotoxic drugs adjust creatinine clearanceadjust creatinine clearance causes phlebitis, nausea, hypotension, causes phlebitis, nausea, hypotension,

encephalopathyencephalopathy Mortality 28-33 %Mortality 28-33 %

Acyclovir resistanceAcyclovir resistance

Immunocompromised: 3-6 %Immunocompromised: 3-6 % Bone marrow transplant: 14-30 %Bone marrow transplant: 14-30 %

– Recurrent genital HerpesRecurrent genital Herpes

TREATMENT : DRUGS (3)TREATMENT : DRUGS (3)

foscarnet ( acyclovir resistance, HIV foscarnet ( acyclovir resistance, HIV patients)patients)

40 mg/kg q8h 14-26 d or continuous after 40 mg/kg q8h 14-26 d or continuous after bolusbolus

develop impaired renal function, seizures develop impaired renal function, seizures ( fluoroquinolones)( fluoroquinolones)

arabinoside ( alternative)arabinoside ( alternative) Vidarabine (15 mg/kg)…Vidarabine (15 mg/kg)… HIV: JC virus: HAART ?HIV: JC virus: HAART ?

TREATMENT : DRUGS (4)TREATMENT : DRUGS (4)

Interferon ? Interferon ? CMV ( combined ganciclovir and CMV ( combined ganciclovir and

foscarnet?) foscarnet?) ( Zaknun et al, 1997)( Zaknun et al, 1997) Mycoplasma (macrolide antibiotics)Mycoplasma (macrolide antibiotics) Toxoplasma (pyrimethamine with Toxoplasma (pyrimethamine with

sulfadiazine/clindamycin)sulfadiazine/clindamycin) Listeria (no third generation Listeria (no third generation

cephalosporins)cephalosporins)

Corticosteroids?Corticosteroids?De Gans De Gans et al, 2002et al, 2002

European dexamethasone trialEuropean dexamethasone trial– dexamethasone 10 mg or placebo 15-dexamethasone 10 mg or placebo 15-

20 min before AB20 min before AB– 4 days4 days– 35-37 % 35-37 % Streptococcus pneumoniaeStreptococcus pneumoniae

Corticosteroids ?Corticosteroids ?

?? Animal models – viral load ?Animal models – viral load ?

TREATMENT : metabolic TREATMENT : metabolic consequencesconsequences

monitoring blood glucose : monitoring blood glucose : envolvment hypothalamic regionenvolvment hypothalamic region

TREATMENT: intracranial TREATMENT: intracranial pressure pressure

8 patients with biopsy proven herpes 8 patients with biopsy proven herpes encephalitis, started 7 days after onset encephalitis, started 7 days after onset of symptoms: 5 survivors initial ICP of symptoms: 5 survivors initial ICP below 12 mm Hg, 5 of 6 patients with below 12 mm Hg, 5 of 6 patients with mean daily ICP higher than 20 mm Hg mean daily ICP higher than 20 mm Hg died died ( Barnett et al, 1988)( Barnett et al, 1988)

peak ICP at day 12; GCS at insertion of peak ICP at day 12; GCS at insertion of ICP monitor did not correlate with ICP monitor did not correlate with outcome outcome (Barnett et al, 1988)(Barnett et al, 1988)

INTRACRANIAL PRESSURE: INTRACRANIAL PRESSURE: INCIDENCEINCIDENCE

intracranial hypertension: in 13 intracranial hypertension: in 13 patients with encephalitis, only in patients with encephalitis, only in 3/7 patients with ADEM 3/7 patients with ADEM (Rebaud et (Rebaud et al, 1988)al, 1988)

TREATMENT TREATMENT INTRACRANIAL PRESSUREINTRACRANIAL PRESSURE

hydrocephalus and increased hydrocephalus and increased intracranial pressureintracranial pressure– Herpes: early involvment of the limbic Herpes: early involvment of the limbic

system and temporal lobes (edema, system and temporal lobes (edema, gyral enhancement)gyral enhancement)

– manage fever and painmanage fever and pain– head elevationhead elevation– drug therapy (osmodiuretics, drug therapy (osmodiuretics,

thiopental, TRIS ...)thiopental, TRIS ...)

TREATMENT: TREATMENT: INTRACRANIAL PRESSUREINTRACRANIAL PRESSURE

intraventricular ICP monitoring: intraventricular ICP monitoring: – dangerous focal edema with a pressure dangerous focal edema with a pressure

gradient between temporal lobe and gradient between temporal lobe and subtentorial space not detectedsubtentorial space not detected

– monitor placement may aggravate a monitor placement may aggravate a pressure gradientpressure gradient

large series in children (303, 30 large series in children (303, 30 encephalitis); complications low encephalitis); complications low ( infection 0.3 %) ( infection 0.3 %) ( Pople et al, 1995)( Pople et al, 1995)

TREATMENT: TREATMENT: INTRACRANIAL PRESSUREINTRACRANIAL PRESSURE

decompression hemicraniectomy decompression hemicraniectomy ( ( Jourdan et al, 1993)Jourdan et al, 1993)

TREATMENT: partim TREATMENT: partim myelinmyelin

Remyelination following damage Remyelination following damage may occur in a few weeks may occur in a few weeks

Uncontrolled autoimmune Uncontrolled autoimmune response response

Therapeutic strategiesTherapeutic strategies

antibiotics ? once acute antibiotics ? once acute manifestations are triggered, manifestations are triggered, ineffectiveineffective

anticytokine therapies?anticytokine therapies? vaccination? synergyzing with other vaccination? synergyzing with other

virulence factors, not effective? virulence factors, not effective? interferons ?interferons ? immunosuppressive drugs?immunosuppressive drugs?

Thee possible Thee possible interventionsinterventions

immunoglobulinsimmunoglobulins plasma exchangeplasma exchange glucocorticoidsglucocorticoids

IMMUNOGLOBULINS ...IMMUNOGLOBULINS ...

IVIG from plasma of more than IVIG from plasma of more than 1000 healthy donors1000 healthy donors

igG molecules with a distribution of igG molecules with a distribution of igG subclasses res.serumigG subclasses res.serum

half-life : 3 weeks iG1,2 and 4, 1 half-life : 3 weeks iG1,2 and 4, 1 week igG3week igG3

Immunoglobulins: Why Immunoglobulins: Why should it work?should it work?

modulation of T and B modulation of T and B lymphocyte functionlymphocyte function: : – inhibits proliferation of B and T inhibits proliferation of B and T

lymphocytes, reduction of bone lymphocytes, reduction of bone marrow B-cells marrow B-cells ( Sunblad et al, ( Sunblad et al, 1991)1991)

– inhibits antibody production by B-cells inhibits antibody production by B-cells , dependent on Fc, dependent on Fc

IMMUNOGLOBULINS: why IMMUNOGLOBULINS: why should it work?should it work?

ComplementComplement– complement deactivation complement deactivation – divert the production of lytic divert the production of lytic

complement components in the fluid complement components in the fluid phase ; dermatomyositis, phase ; dermatomyositis, disappearance of complement from disappearance of complement from musclemuscle)( Basta et al, 1994))( Basta et al, 1994)

Viral transmission?Viral transmission?

Hep A, B, C …HIV, HTLV, herpes, Hep A, B, C …HIV, HTLV, herpes, Parvovirus B-19, …Parvovirus B-19, …

Plasmapheresis: GoalPlasmapheresis: Goal Cornerstone of the treatment of diseases Cornerstone of the treatment of diseases

– the removal of suspected toxic substances the removal of suspected toxic substances from the body from the body

– Hemodialysis uremiaHemodialysis uremia Abnormal presence of endogenous or Abnormal presence of endogenous or

exogenous substances, whose biophysical exogenous substances, whose biophysical properties do not allow their removal with properties do not allow their removal with hemodialysis or hemofiltrationhemodialysis or hemofiltration

Hemoperfusion: blood purificationHemoperfusion: blood purification Therapeutic apheresis Therapeutic apheresis

PlasmapheresisPlasmapheresis

Plasmapheresis: removal of a limited Plasmapheresis: removal of a limited amount of plasmaamount of plasma

Plasma exchange: the removal and Plasma exchange: the removal and substitution of the whole plasma substitution of the whole plasma volumevolume

RemoveRemove– Toxins of all size including protein-and lipid Toxins of all size including protein-and lipid

boundbound– substances with low volume of distributionsubstances with low volume of distribution

TREATMENT : ADEM? TREATMENT : ADEM? ENCEPHALOMYELITIS (1)ENCEPHALOMYELITIS (1)

no reliable documented therapies no reliable documented therapies glucocortiocoids, ACTH glucocortiocoids, ACTH (Straub, (Straub,

1997),1997), no decrease in long term no decrease in long term sequelae in 14 patients sequelae in 14 patients ( Karelitz, ( Karelitz, 1966 ), Nasr et al1966 ), Nasr et al

intravenous immunoglobulinintravenous immunoglobulin hypothermia hypothermia (Takata et al, 1999)(Takata et al, 1999)

TREATMENT: TREATMENT: ENCEPHALOMYELITIS (2)ENCEPHALOMYELITIS (2)

plasmapheresis, 2 patients plasmapheresis, 2 patients ( Kanter et ( Kanter et al, 1995al, 1995))

glatimar acetate, 3 patients ; triggering glatimar acetate, 3 patients ; triggering myelin-activated suppressor cells myelin-activated suppressor cells (Abramsky et al, 1977)(Abramsky et al, 1977)

polylysine ,1 patient, inducer interferon polylysine ,1 patient, inducer interferon (Salazar et al, 1981)(Salazar et al, 1981)

cyclosporin, 1 patient, cyclosporin, 1 patient, ( Belendiuk et al, ( Belendiuk et al, 1988)1988)

PreventionPrevention

Vaccines (mumps, measles, rubella)Vaccines (mumps, measles, rubella) Rabies, Japanese encephalitisRabies, Japanese encephalitis Arthropod-borne viruses, local Arthropod-borne viruses, local

vectorvector– DEET spray, lotionDEET spray, lotion– Protective clothingProtective clothing– Minimizing outside exposure during Minimizing outside exposure during

Encephalitis …Encephalitis … EE ncephalomyelitis/ADEM ncephalomyelitis/ADEM NN ipah virus (100)ipah virus (100) CC erebritiserebritis EE osinophilic inclusion bodiesosinophilic inclusion bodies PP CRCR HH erpeserpes AA cyclovir, antibioticscyclovir, antibiotics LL eukencephalopathyeukencephalopathy II CP-monitoringCP-monitoring TT ransverse myelitisransverse myelitis II mmunoglobulin, plasmapheresis mmunoglobulin, plasmapheresis SS ugar ugar

ConclusionConclusion

Meningitis … more than pain in the Meningitis … more than pain in the backback