With many thanks to

1
Philippe G JorensDepartment of Intensive Care
MedicineUniversity of Antwerp, UZA, Belgium
Meningitis-encephalitis

• 2004
• With many thanks to
• P. Parizel, (neuro)radiology, UA, UZA

2
CASE REPORT

• viral prodrome several days fever, headache,
  nausea, lethargy, myalgias
• diffuse or focal syndromes personality changes,
  decreased consciousness, stiff neck, confusion,
  convulsions, deafness, facial palsy

3
Meningitis-encephalitis

• Meningitis encephalitis
• Viral vs bacteriall
• Meningoencephalitis
• ADEM, encephalomyelitis
• Myelitis, TM
• cerebritis ...

4
Meningitis-encephalitis

• Meningitis leptomeningeal (photophobia,
  headache, stiff neck)
• Only 50 over 16 of age triade

5
Encephalitis

• (diffuse ) inflammation of the brain parenchyma
• presents as diffuse and/or focal
  neuropsychological dysfunction, consciousness
• Hemiplegia, hyperthermia, seizures
• distinct from meningitis, although symptoms of
  meningeal inflammation may coexist

6
Intracranial infections
Anatomic location Anatomic location Anatomic location
Lepto-meningeal Mixed Cerebral parenchyma
Viral
Bacterial
Other
Etiological agent
7
Meningitis-encephalitis etiology

• reactivation of the virus ( herpes simplex),
  sporadically
• mosquitos or ticks (arbovirus)
• animal bite (rabies)
• immunocompromised ( varicella-zoster, CMV)
• HIV

8
Encephalitis etiology

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

9
Etiology

• Over 100 viruses nervous system infections
• Epidemic and largely seasonal (Arbo and entero)
• Summer, fall
• Endemic (Herpes, Rabies)

10
Etiology- DNA

• Poxviridae variola, vaccinia
• Herpesviridae Simplex 1, 2, Varicella-zoster,
  CMV, EBV, Herpes 6,7 and 8
• Adenoviridae Adenovirus
• Papoviridae Simian virus 40, JC
• Hepadnaviridae Hep B
• Parvoviridae Parvovirus B19

11
Etiology-RNA

• Paramyxoviridae parainfluenza, mumps, measles,
  RSV
• Orthomyxoviridae influenza
• Rhabdoviridae Rabies
• Filoviridae Ebola, Marburg, Bunyaviridae
  California encephalitis, Hantavirus
• Arenaviridae lymphocytic choriomenigitis virus
• Retroviridae HTLV I and II, HIV I and II

12
Etiology RNA (2)

• Coronaviridae coronavirus
• Reoviridae Reoviruses
• Togaviridae Rubella
• Flaviviridae St. Louis, Japanese encephalitis,
  Hep C
• Picornaviridae Polio, Coxsackie, Echo, entero,
  Hep A

13
New

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

14
Encephalitis incidence

• 8-30/100000 year children, 5 adults
• Herpes simplex 0.2/100000 (neonatal 2-3/10000)
• arbovirus only 10 encephalitis
• measles - post-infectious (1/1000 persons) SSPE
  (1/100000 persons)
• Japanese encephalitis most common type outside
  US

15
Prognosis

• 462 children, death 2.8 , severely damaged 6.7
  (Rautonen et al, 1991)
• HSV poor outcome (11.7 increased risk)

16
Viral meningitis

• 10-year-old boy
• Laboratory tests revealed CNS enterovirus
  infection, with clinical symptoms of meningitis.
• CT -/ C was normal. There was no abnormal
  meningeal thickening or enhancement.

17
Varicella meningo-encephalitis

• 29-year-old man
• Symmetric distribution of edema (subinsular,
  frontal and temporal opercular regions)
  hyperintensity in the lentiform and caudate
  nucleus on the right
• Subtle meningeal enhancement is noted

18
Varicella

• 1-3/10000
• Cases immunocompromised patient

19
CMV encephalitis ? abscess

• Immunocompromised 49-y-o woman (renal transplant)
• Early stage
• edema
• serpiginous and micronodular enhancement
• Late stage (4 months later) abscess

20
Rabies

• Encephalitis 30000-70000 deaths/year
• RNA Rhabdoviridae
• Saliva, but also aerosol
• Uniformely fatal disease, nervous tissue
• Only 6 cases of survival after onset of clinical
  rabies
• Prrexposure prophylaxis, expidious postexposure
• Wild animals
• Fluorescent material skin biopsy, serology

21
Herpes simplex virus (type 1) encephalitis
22
Herpes simplex

• Fatality 30 -70
• Type 1 (neonate type II)
• Prediliction inferior and medial temporal lobes
• EEG

23
Intra-uterine CMV infectionTORCH
24
Enteroviruses

• Coxsackie A and B, polio, echo, entero 68 and 71
• Good prognosis, except enterovirus 71 1998
  Taiwan outbreak
• 129106 cases hand, fouth and mouth disease
• 405 severe cases ( encephalitis, aseptic
  meningitis)

25
West Nile virus

• 1999 New York City
• 2002 4156 human cases, 284 fatal
• 1937 Uganda
• Birds (New York zoo )
• Enzootic cycle birds, mosquitos
• 2000 found in 14 mosquito species
• Organ transplantation, blood transfusion

26
West Nile virus

• Arbovirus St Louis , Japanese
• Incubation 3-14 days
• Flu like , Africa Middle east rarely
  neurological
• 1/150 infected severe, meningitis, encephaltis,
  meningoencephalitis
• Brain stem

27
Japanese encephalitis

• 15000 deaths annually
• Children, young adults
• 1/3 die, 50 survivors severe neurological
  deficit
• Vaccination (97.5 effective)

28
HIV

• HIV dementia
• CMV, Varicella
• Progressive multifocal leukoencephalopathy
• JC virus, human polyomavirus
• Destruction oligodendrocytes
• Middle cerebellar peduncle, HIV

29
Measles

• Progressive postinfectious encephalitis
• SSPE (subacute sclerosing panencephalitis)
• Progressive dissemination of defective
  (noninfectious) viral replication

30
Encephalitis morbidity

• untreated herpes mortality 50-75 , treatment 20
  
• varicella untreated 15 , 100 immunosuppressed
• sex prediliction SSPE male (2-4)

31
BACTERIAL INFECTIONS

• Pyogenic bacterial infections of the CNS most
  commonly cause
• focal cerebritis
• abscess
• meningitis
• empyema (subdural or epidural).

32
Tuberculous meningitis (1)

• CTC in a 1-year-old girl with proven tuberculous
  meningitis
• Hydrocephalus (communicating hydrocephalus)
• Cisternal enhancement (thick gelatinous exudate)
• Arterial involvement can result in thrombosis and
  infarction (MCA most commonly involved).

33
Subdural empyema with abscess

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

34

• Cerebritis
• Axial TSE T2
• Axial FLAIR
• Axial SE T1 Gd
• Coronal SE T1 Gd

35
Tuberculoma

• HIV-positive 46-year-old man.
• Axial FLAIR (left) and T2-weighted (right) images
  show a hypointense nodular mass in the pons.
  There is perilesional edema.

36
Tuberculoma

• HIV-positive 46-year-old man.
• Gd-enhanced axial (left) and coronal (right)
  T1-weighted images reveal circumferential
  peripheral enhancement of the tuberculoma.

37
Cryptococcal-meningitis

• 38-year-old-HIV-positive-woman
• Diffuse meningeal enhancement (e.g. at the
  superior meningeal covering of the vermis.
• No evidence of parenchymal disease in this
  patient.

38
Toxoplasma encephalitis

• Proven toxoplasma encephalitis in a 28-year-old
  HIV man.
• Bright nodules with ringlike enhancement in the
  left lentiform nucleus and in the head of the
  caudate nucleus.
• Bifrontally on there is cortical and subcortical
  thickening and edema and meningeal enhancement.

39
Neurocysticercosis

• 25-year-old-woman
• Multiple nodular lesions with intensely enhancing
  peripheral rim and prominent perilesional edema
• Several lesions demonstrate a hypointense center
  on both T1- and T2-weighted images due to
  calcification

40
II. Meningo-encephalitis
41
Case report

• 34-year-old woman
• Previous medical history is unremarkable
• CC
• Progressive lethargy and somnolence
• Evolution to deep coma over a 3-day time interval
• Lumbar puncture pneumococcal meningitis
• MRI is requested to rule out parenchymal
  involvement

42
Meningo-encephalitis

• Meningitis
• Encephalitis
• convulsions
• focal neurological deficit
• Necrotising vasculitis

43
Addendum ... physiopathogenesis
44
ADEM/ Demyelinating diseases

• Myelin
• CNS produced by
• oligodendrocytes
• (glial cells)
• Peripheral Schwann
• cells

45
Myelin
Demyelinating destruction of existing
myelin Dysmyelinating abormal myelin
(leukodystrofies)
46
Demyelinating diseases

• Central nervous system
• Multiple sclerosis
• ADEM
• Central pontine myelolysis
• Leukoencephalopathy
• Encephalitis

47
ADEM

• Acute inflammatory and demyelinating multifocal
  disease of the brain and spinal cord
• Days or weeks after infection (viral,
  streptococcal, vaccination)
• Difficult to differentiate from MS

48
ADEM- Encephalomyelitis (1)

• follows infection or vaccination, DD MS
• infection
• Adenovirus, mumps, CMV, EBV, HIV 1 and II, herpes
  simplex, influenza A and B, measles,
  parainfluenza 1,2,3, RSV, Rubella, varicella,
  herpes 6, polio, hanta
• vaccination smallpox, rabies
• mortality 5-30 (Nasr et al, 2000)

49
ADEM
50
CASE HISTORY (1)

• 3-year-old-child
• no vaccination

51
CASE REPORT (2)

• lethargy, vomiting, meningeal syndrome
• otitis media en externa
• cyanotic, hypotonic, anisocoria, intubated
• CT-scan right temporal lesion
• transfer UZA

52
CASE REPORT (3)

• tetraplegic, anisocoria, purulent discharge from
  the ear
• L.P (2) 10, 13 WBC, total protein 81 mg/dl (nl
  15-45), increased g, no malignant cells

53
CASE REPORT (4)

• cultures of blood, nasopharynx, endotracheal
  asp., urine ... negative
• middle ears Streptococcus pyogenes, type M6
• CSFnegative, including viral (herpes, entero,
  RSV, (para)influenza, CMV, adeno and mumps). PCR
  Herpes simplex and type 6, toxoplasma, Mycoplasma
  and CMV

54
CASE REPORT (5)

• na raised antibody titers (admission and after 3
  weeks) 28 from adeno to toxoplasma

55
ADEM after infection

• Adenovirus, mumps, CMV, EBV, HIV 1 and II, herpes
  simplex, influenza A and B, measles,
  parainfluenza 1,2,3, RSV, Rubella, varicella,
  herpes 6, polio, hanta
• Boreelia, Brucella, Chlamydia, Mycoplasm,
  Toxoplasma, Trerponema pallidum, Leptospira

56
MRI day 1 and 8 after admission

• T2-weighted images multiple scattered and
  confluent areas subcortical and deep white
  matter, assymetric, ranging 2-20 mm
• large lesion lower medulla oblongata, cervical
  spinal cord up to C4
• confluent areas of demyelination?
• after 8 days breakdown blood-brain barrier

57
MRI day 8 after admission
58
CASE REPORT (6)

• EMG normal evoked potentials delayed latencies

59
CASE REPORT (7)

• therapy acyclovir (Herpes?) , erythromycin
  (Mycoplasma?) and ceftriaxone, 10 days
• corticosteroids (30 mg/kg 3 days, tapered) and
  0.4 g/kg/d IVIG 5 days, five monthly courses
• periods arythmia

60
MRI 35 days after admission
61
MRI 5 months after admission
62
CASE REPORT (8)

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

63
CASE REPORT (9)

• tetraplegic, ventilator-dependent
• tracheostomy, port-a-cath, suprapubic urinary
  catheter, enterogastrostomy
• only the expression of its facial musculature has
  been improving, learned to speak and eat

64
CASE REPORT (10)

• returned home after 30 months of hospitalisation
• died 6 months later hyperthermia, new lesions on
  MRI, status epilepticus, cerebral edema

65
CONCLUSION

• the expansion might have been caused by an
  interaction with toxins produced by the isolated
  S. pyogenes strain
• human T cells showing in vitro reactivity to
  myelin antigens may be pathogenic in vivo (Jorens
  et al, Neurology, 2000)

66
SUPERANTIGEN IN VIVO- DEMYELINATION
67
Idiopathic Transverse myelitis-myelopathy

• Sensory, motory or autonomic dysfunction
  attributable to the spinal cord
• Inflammation (pleocytosis)
• Clearly defined sensory level
• Bilateral signs
• Progression to nadir between 4h and 21 days
  (longer progressive form of MS)

68
Exclusion criteria non-compressive
myelopathy/secondary Transverse myelitis

• Radiation
• Thrombosis arterial circulation
• AVM, Connective tissue disorder
• Infection
• Mycoplasma, parasites
• (Herpes Simplex 1,2, HHV-6, CMV, EBV,
  enteroviruses, HIV, , VZV, HTLV-1, Hep A,B and C
  )
• Vaccination

69
Transverse myelitis-myelopathy
70
Diagnosis

• Encephalitis without identified causative agent
  24-74

71
Diagnosis signs

• Alterations consciousness
• Fever
• Headache
• Personality changes
• Seizures
• Hemiparesis
• Cranial nerve defects

72
Encephalitis work up

• laboratory SIADH, viral serology, leukocytosis
  (relative lymphocytosis), amylase

73
Systemic signs

• Rash ( Lyme, varicella, enterovirus )
• Neonatal vesicular erythema
• History of tick bite (Lyme)

74
LP

• Deteriorating GCS ?
• Intracranial pressure ?
• Bleeding disorder?
• 2 exceptions
• Intracranial pressure, bleeding disorder

75
Exception LP
76
Diagnosis

• Gram stain
• Culture
• Protein, WBC, differential count
• PCR , viral culture, CSF serology ratio

77
LP

• Mononuclear pleocytosis with normal glucose and
  (elevated ?) protein
• High CSF lymphocytosis TBC, mumps, uncommon
  viruses (California encephalitis )
• Atypical lymphocytes EBV, CMV, Herpes
• Bacterial decreased glucose ? Low glucose and
  lymphocytes TBC
• 3000 LPs children less than 3 years
• gt 6 wbc/mm3
• Sensitivity 98.4 , specificity 75.2 bacterial
  meninigitis
• gt 6 lymphocytes gt 95 viral

78
LP

• repeat examination ( Feigin et al, 1973)
• Concurrent viral cultures (nasopharynx, mucous
  membranes )
• CT scan edema, hydrocephalus, petechial
  hemorhage (herpes) ring-enhancing lesions
  (Toxoplasm)

79
Encephalitis work up (2)

• MRI T2 signal medial temporal lobes and inferior
  frontal gray matter (Herpes)
• MRI Eastern equine encephalitis/ basal ganglia,
  thalami
• EEG paroxysmal epileptiform (herpes) high
  voltage spike wave activity temporal regions,
  slow wave complexes
• brain biopsy (96 sensitivity) eosinophilic
  intranuclear inclusion bodies (Cowdry type A,
  herpes)

80
Conclusions

• Intracranial infections, viral infections are
  best depicted by MRI scans.
• CT has a low sensitivity for leptomeningeal
  infections CT is useful in detecting
  calcifications (chronic stage).
• The pattern of involvement is not specific for a
  particular infectious agent.
• There are no reliable distinguishing features
  among lesions, with the possible exception of
  cryptococcal lesions.
• Keep up with current literature

81
Tools for diagnosis of demyelination?

• DD
• MRI
• Myelin basic protein (like material)
• CSF, dominant epitope decapeptide
• Acute phase ng/ml ( related to mass of myelin
  damage and how recently it occurred)
• Not validated in serum

82
TREATMENT (1)

• prehospital treat shock or hypotension
• airway protection in patients with altered mental
  status
• seizure precautions
• oxygen, IV access, rapid transit

83
TREATMENT EMERGENCY ROOM (encephalitis)

• acyclovir and antibiotics, after collecting labs
  and cultures
• treat systemic complications ( shock, hypoxemia,
  SIADH and the exacerbation of chronic diseases)

84
TREATMENT DRUGS (2)

• viral (herpes, varicella)
• acyclovir, 10 mg/kg ( infuse over 1 h), q8h,
  10-21 d
• interactions nephrotoxic drugs
• adjust creatinine clearance
• causes phlebitis, nausea, hypotension,
  encephalopathy
• Mortality 28-33

85
Acyclovir resistance

• Immunocompromised 3-6
• Bone marrow transplant 14-30
• Recurrent genital Herpes

86
TREATMENT DRUGS (3)

• foscarnet ( acyclovir resistance, HIV patients)
• 40 mg/kg q8h 14-26 d or continuous after bolus
• develop impaired renal function, seizures (
  fluoroquinolones)
• arabinoside ( alternative)
• Vidarabine (15 mg/kg)
• HIV JC virus HAART ?

87
TREATMENT DRUGS (4)

• Interferon ?
• CMV ( combined ganciclovir and foscarnet?) (
  Zaknun et al, 1997)
• Mycoplasma (macrolide antibiotics)
• Toxoplasma (pyrimethamine with sulfadiazine/clinda
  mycin)
• Listeria (no third generation cephalosporins)

88
Corticosteroids?De Gans et al, 2002

• European dexamethasone trial
• dexamethasone 10 mg or placebo 15-20 min before
  AB
• 4 days
• 35-37 Streptococcus pneumoniae

89
Corticosteroids ?

• ?
• Animal models viral load ?

90
TREATMENT metabolic consequences

• monitoring blood glucose envolvment
  hypothalamic region

91
TREATMENT intracranial pressure

• 8 patients with biopsy proven herpes
  encephalitis, started 7 days after onset of
  symptoms 5 survivors initial ICP below 12 mm Hg,
  5 of 6 patients with mean daily ICP higher than
  20 mm Hg died ( Barnett et al, 1988)
• peak ICP at day 12 GCS at insertion of ICP
  monitor did not correlate with outcome (Barnett
  et al, 1988)

92
INTRACRANIAL PRESSURE INCIDENCE

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

93
TREATMENT INTRACRANIAL PRESSURE

• hydrocephalus and increased intracranial pressure
• Herpes early involvment of the limbic system and
  temporal lobes (edema, gyral enhancement)
• manage fever and pain
• head elevation
• drug therapy (osmodiuretics, thiopental, TRIS ...)

94
TREATMENT INTRACRANIAL PRESSURE

• intraventricular ICP monitoring
• dangerous focal edema with a pressure gradient
  between temporal lobe and subtentorial space not
  detected
• monitor placement may aggravate a pressure
  gradient
• large series in children (303, 30 encephalitis)
  complications low ( infection 0.3 ) ( Pople et
  al, 1995)

95
TREATMENT INTRACRANIAL PRESSURE

• decompression hemicraniectomy ( Jourdan et al,
  1993)

96
TREATMENT partim myelin

• Remyelination following damage may occur in a few
  weeks
• Uncontrolled autoimmune response

97
Therapeutic strategies

• antibiotics ? once acute manifestations are
  triggered, ineffective
• anticytokine therapies?
• vaccination? synergyzing with other virulence
  factors, not effective?
• interferons ?
• immunosuppressive drugs?

98
Thee possible interventions

• immunoglobulins
• plasma exchange
• glucocorticoids

99
IMMUNOGLOBULINS ...

• IVIG from plasma of more than 1000 healthy donors
• igG molecules with a distribution of igG
  subclasses res.serum
• half-life 3 weeks iG1,2 and 4, 1 week igG3

100
Immunoglobulins Why should it work?

• modulation of T and B lymphocyte function
• inhibits proliferation of B and T lymphocytes,
  reduction of bone marrow B-cells ( Sunblad et
  al, 1991)
• inhibits antibody production by B-cells ,
  dependent on Fc

101
IMMUNOGLOBULINS why should it work?

• Complement
• complement deactivation
• divert the production of lytic complement
  components in the fluid phase dermatomyositis,
  disappearance of complement from muscle)( Basta
  et al, 1994)

102
Viral transmission?

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

103
Plasmapheresis Goal

• Cornerstone of the treatment of diseases
• the removal of suspected toxic substances from
  the body
• Hemodialysis uremia
• Abnormal presence of endogenous or exogenous
  substances, whose biophysical properties do not
  allow their removal with hemodialysis or
  hemofiltration
• Hemoperfusion blood purification
• Therapeutic apheresis

104
Plasmapheresis

• Plasmapheresis removal of a limited amount of
  plasma
• Plasma exchange the removal and substitution of
  the whole plasma volume
• Remove
• Toxins of all size including protein-and lipid
  bound
• substances with low volume of distribution

105
TREATMENT ADEM? ENCEPHALOMYELITIS (1)

• no reliable documented therapies
• glucocortiocoids, ACTH (Straub, 1997), no
  decrease in long term sequelae in 14 patients (
  Karelitz, 1966 ), Nasr et al
• intravenous immunoglobulin
• hypothermia (Takata et al, 1999)

106
TREATMENT ENCEPHALOMYELITIS (2)

• plasmapheresis, 2 patients ( Kanter et al, 1995)
• glatimar acetate, 3 patients triggering
  myelin-activated suppressor cells (Abramsky et
  al, 1977)
• polylysine ,1 patient, inducer interferon
  (Salazar et al, 1981)
• cyclosporin, 1 patient, ( Belendiuk et al, 1988)

107
Prevention

• Vaccines (mumps, measles, rubella)
• Rabies, Japanese encephalitis
• Arthropod-borne viruses, local vector
• DEET spray, lotion
• Protective clothing
• Minimizing outside exposure during

108
Encephalitis

• E ncephalomyelitis/ADEM
• N ipah virus (100)
• C erebritis
• E osinophilic inclusion bodies
• P CR
• H erpes
• A cyclovir, antibiotics
• L eukencephalopathy
• I CP-monitoring
• T ransverse myelitis
• I mmunoglobulin, plasmapheresis
• S ugar

109
Conclusion

• Meningitis more than pain in the back