Transcript Acute and Chronic Infections of the CNS

Alexander Saveriano
PGY-4 Neurology
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General Principles
Acute Meningitis
◦ Bacterial
◦ Viral
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Clinical presentation
Causative organisms
Treatment
Complications
Acute Encephalitis
◦ Common
◦ “Weird & Wonderful”
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Important to recognize the clinical syndromes
of meningitis & encephalitis
Remember the differential diagnosis
◦ NMS, SAH, stroke/CVST, PRES, toxic/metabolic
encephalopathy, immune-mediated encephalitis
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Clinical severity ranges from benign to
devastating
Both host and pathogen factors influence
clinical presentation and outcome
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Inflammation of the meninges
“Pachy-” vs. “lepto-”
Acute vs. subacute vs. chronic (>4 weeks)
◦ Time course depends on etiology
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Infectious categories:
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Account for most
Bacterial
acute meningitides
Viral
Fungal
Mycobacterial
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Affects all ages, though incidence has
declined (HIB vaccination)
Mortality rate remains high
◦ 9.4% in children
◦ 20% or higher in adults
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Pathogen depends on age group and patient
characteristics
◦ Knowledge of common pathogens guides treatment
◦ S. Pneumoniae responsible for majority of cases in
all age groups except infants younger than 2
months
◦ Gram negatives responsible for 1/3rd of nosocomial
cases
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“Triad” of fever, nuchal rigidity and altered
mental status in 44%
95% have at least 2/4 classic signs/symptoms
of headache, neck stiffness, fever and altered
mental status
Altered level of consciousness present in
2/3rds
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Presentation typically acute to hyper-acute
(hours-1 day)
Caveats:
◦ Headache may improve after LP
◦ Absence of nuchal rigidity, Kernig’s sign or
Brudzinksi’s sign should never be used to exclude
bacterial meningitis
◦ Children more likely to have a clear syndrome of
otitis or URI before meningitis
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Rapid
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Succinct history:
◦ Time course
◦ Recent trauma/surgeries
◦ PMHx/meds (?immuno-compromised)
 Don’t forget antipsychotics
◦ Any suggestion of seizure?
◦ Behaviour changes?
◦ Recent infectious prodrome
◦ Travel, sick contacts, animal contacts
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Physical Examination
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Vitals
Assess level of consciousness
Assess for nuchal rigidity
Assess for any lateralizing signs
Dermatologic exam
Cardio-resp exam
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Medical emergency
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Guiding principles:
◦ Rapid diagnosis (Hx, PE, LP)
◦ Administration of appropriate antibiotics as soon as
possible
◦ Excluding structural brain lesions
◦ Identifying pathogen
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Delays in administration of antibiotics worsen
outcomes, increase mortality
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Need urgent lumbar puncture – confirms
diagnosis, identifies pathogen
What about timing of scan?
◦ Abnormal CT in 24% (associated with age >60,
immuno-compromise, seizure, focal deficits,
inability to follow 2 consecutive commands)
◦ Absence of any of these findings has NPV of 97% considered safe to proceed with LP
◦ In practice in tertiary care centre, CT essentially
always performed prior to LP
◦ Do not delay antibiotics for scan – start them, then
send patient to scan
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What antibiotics to start? Why?
Broad coverage – No margin for error here
Ceftriaxone – Neisseria, most strep, H. Flu
Vancomycin – Beta-lactam resistant strep
Ampicillin – Listeria
+/- Acyclovir – HSV coverage (Ddx)
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Practical dosing:
Ceftriaxone 2 g IV q12h
Vancomycin 30-45 mg/kg/day divided q812h (e.g. 1 g IV q12h), monitor levels
◦ Goal trough levels 15-20 mcg/ml
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Ampicillin 2 g IV q4h
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Yield of LP decreases within “hours” of
antibiotic administration, not so with other
CSF parameters
Obtain blood cultures immediately before
antibiotics
◦ Positive in 50%
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Don’t forget antibiotic prophylaxis for
meningococcus (as early as possible!)
◦ Close contacts
◦ Family members/roommates
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Regimens include (adult dosing):
◦ Rifampin 600 mg po bid x 2 days
◦ Cipro 500 mg po x 1
◦ Ceftriaxone 250 mg IM x 1
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European trial of 301 patients randomly assigned
to Abx alone or Abx + Dexamethasone 10 mg IV
q6h x 4 days
Primary endpoint death or neurological disability
at 8 weeks
Dexamethasone reduced mortality (7 vs. 15%)
and disability (15 vs. 25%)
◦ All benefit seen in group with pneumococcal meningitis
◦ Should be given immediately before or with first dose of
antibiotics
◦ Only to be continued if cultures confirms S. Pneumoniae
Complications of bacterial
meningitis
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45F admitted to Medicine for confirmed
bacterial meningitis. Received appropriate
Abx with initial good clinical response.
Several days later, Medicine senior calls
because patient having worsening
headache…asks to “please reassess”…
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Neurological complications in 28%
Raised ICP/herniation
Hydrocephalus
Abscess formation
Seizures (20%, negative prognostic indicator)
Cranial nerve palsies
Cerebrovascular disorders (stroke, venous
thrombosis, arteritis, aneurysm formation)
◦ Hearing loss
◦ Cognitive impairment
◦ SIADH/Hyponatremia
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MRI/MRV performed:
◦ No abscess
◦ Transverse sinus thrombosis
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Most common cause of meningitis
~ “Aseptic meningitis”
Symptoms of meningeal irritation
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Fever
Headache
Neck stiffness
Photophobia
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Normal brain function
◦ Distinguishing feature from encephalitis
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Patients may be uncomfortable or distracted
by headache, but they should not be
encephalopathic per se
Don’t forget
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Travel history
HIV risk factors
Animal/insect contact
Dermatological exam
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Enterovirus family (esp. Late summer-Fall)
HSV
◦ HSV2 an important cause of meningitis (30% of females
with primary genital herpes infection)
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VZV
HIV
◦ Inquire about HIV risk factors
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WNV
Non-viral agents
◦ Lyme
◦ Syphillis
◦ Rocky mountain spotted fever
“The classics”
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Inflammation of brain parenchyma
Infectious vs. Post-infectious/immunemediated
May be concurrent with meningeal irritation
(“meningo-encephalitis”)
Symptoms and signs of disturbed cerebral
function, in addition to infectious “clues”
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Altered mental status/behavioural changes
Seizures
Fever
Headache
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Extensive list of viral etiologies
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HSV
VZV
Eastern Equine Encephalitis
St. Louis Encephalitis
WNV
CMV (esp. HIV patients)
Enterovirus (esp. Rituxan patients or IgG def.)
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Treponema
Mycoplasma
Listeria
Rickettsia
Non-viral agents:
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21-year-old woman on her way to college
reports smelling an unusual, unpleasant odor
that was unapparent to everyone else in her
family. Upon arriving at college, she went to
bed. Her roommate was unable to waken her
the next morning, and she was brought to
the emergency department.
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Neurologic examination:
Deeply somnolent, no response to voice,
some reaction to pain
No neck stiffness and optic discs flat
Left-sided hyperreflexia and left Babinski
sign
CSF: 41 RBC, 327 WBC (87% lymphs), Ptn 1.8,
glucose WNL
Encephalitis and Postinfectious
Encephalitis
Greenlee, John E.
CONTINUUM: Lifelong Learning in
Neurology. 18(6, Infectious
Disease):1271-1289, December
2012.
doi:
10.1212/01.CON.0000423847.401
47.06
Copyright © 2013 American Academy of Neurology . Published by Lippincott Williams & Wilkins.
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HSV
Neurosyphillis
WNV
VZV
EBV
HHV6
Congenital CMV
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10-15% of viral encephalitides
Male=Female
No seasonal variation
May occur at any age
HSV1 implicated in 90% of cases
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Predilection for orbitofrontal and temporal
lobes
Cingulate gyrus commonly involved as well
Unilateral or bilateral
Involvement of other areas of cortex or
brainstem without temporal lobe involvement
does not exclude HSV
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Diagnosis confirmed with HSV PCR in CSF
98% diagnostic accuracy
Yield falls to 21% after 2 weeks of therapy
Possible to be falsely negative very early in
disease
◦ Repeat in 4-7 days
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Acyclovir – Inhibits HSV synthesis by causing
DNA chain termination
Shown to reduce mortality
◦ 70% -> 28%
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10 mg/kg IV q8h for 21 days
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Start early!
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Many have lasting complications of disease
◦ Epilepsy
◦ Cognitive/behavioural disorders
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73F known DM2, renal impairment presents
with 2-day history of headache, followed by
increasing somnolence. On arrival to ER, she
is drowsy and is febrile at 38.4. She is started
on antibiotic and antiviral therapy.
LP done-> 140 WBC (60% PMN), Ptn 1.1,
glucose WNL
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In the ensuing hours, she becomes
increasingly obtunded, requiring intubation
Admitted to ICU
Exam reveals comatose woman with intact
brainstem exam, up-going plantars and
cogwheel rigidity in the upper extremities
MRI
FLAIR sequence depicting
basal ganglia hyperintensities
MRI
FLAIR sequence depicting
hyperintensities in the midbrain
and right mesial temporal lobe
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HSV PCR negative
CSF bacterial cultures negative
West Nile serology positive 10-14 days later
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Season runs from June – November
Peak in late August
Life cycle links mosquitoes, birds and humans
◦ Mosquito vector bites & infects bird...
◦ Bird serves as excellent host for replication of
virus...
◦ Bird infects more mosquitoes...
◦ Which then infect humans
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History of mosquito bite not always present
Travel to endemic areas (?)
5-15 day incubation
About 20% become symptomatic
◦ Fever, headache, malaise, myalgias, rash, vomiting,
back or limb pain
◦ Lasting 3-6 days
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Neurological complications typically arise
days after systemic symptoms
3 syndromes of neuro-invasive disease
◦ Aseptic Meningitis
◦ Meningoencephalitis
◦ Acute flaccid paralysis
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Affects 1/150 of those infected
Elderly & immune-compromised at highest
risk
◦ Median age 70
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Symptomatology:
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Confusion
Disorientation
Fever
Behavioural changes
Movement disorders/Parkinsonism
Weakness
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“Classic” CSF profile:
◦ Pleocytosis (neutrophilic predominance in 37-45%)
◦ Elevated protein
◦ Normal glucose
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West Nile Serology (IgM/IgG)
◦ Serum or CSF
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Ferritin levels (?)
◦ Elevated in cases of WNV encephalitis, but not other
encephalitides
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Study of 16 cases of WNV
meningoencephalomyelitis with MR imaging
◦ 5 normal
◦ 11 abnormal
 3 with “ischemic” changes on DWI
 8 with “lesions in the basal ganglia, mesial temporal
lobe, thalami, midbrain, pons, cerebellum, and
hemispheric white matter”
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Supportive care
◦ Intubation
◦ Prevention of secondary infection
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No specific medication shown to be of benefit
Acyclovir to cover possibility of HSV
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Development of limb weakness with dramatic
progression over 48 hours
Asymmetric
Hypo/Areflexia
Absence of sensory symptoms
Bladder dysfunction common
May occur in isolation or in combination with
other neurological manifestations
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76F seen 3 weeks ago for vesicular rash
around L. Eye along with corneal involvement.
She now presents with new-onset R.
hemibody weakness and confusion
On exam, she is mildly febrile (38.1) with a
mild expressive aphasia and R. hemiparesis
and hyperreflexia
CT head shows multifocal L. hemispheric
infarcts with hemorrhagic component
Ideas?
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Occurs more often than previously recognized
◦ 15% of encephalitis where cause identified (Mailles et al.,
2007)
◦ Most common cause after HSV in immunocompetent
◦ Even more common in immunocompromised
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Infects endothelial cells of small and large
vessels (vasculopathy)
Can lead to focal/multifocal ischemia or even
aneurysm formation and hemorrhage
“Classic” case is that of herpes zoster
ophthalmicus, followed days-weeks later by a
stroke with contralateral hemiparesis
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May occur without rash
Immunocompromised state is a risk-factor
Diagnosis by detection of VZV IgG in CSF
PCR also available, but –ve test does not
exclude VZV encephalitis
Treatment with Acyclovir
The Weird and [not so]
Wonderful
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42 year-old male presents to ER with “confusion”
and bizarre behaviour. He was seen and
discharged about 1 week ago for symptoms of
myalgias, headache and malaise.
For the past 2 days he has been increasingly
aggressive and incoherent. His wife reports that
he did not sleep all night.
On exam, he is agitated, combative, and drooling
He periodically grabs his throat and appears to
be in severe discomfort
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There is no focal weakness, though he is
diffusely hyperreflexic and plantar responses
are extensor.
Anything else you would like to know on
history/exam?
◦ Travel to Africa 1-2 months ago, travelled through
rural villages
◦ Bitten by dog, sought local medical care
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Lyssavirus
Predilection for neural spread
Animal reservoir (dogs, bats, cats, skunks,
foxes, etc.)
30,000-70,000 deaths per year worldwide
◦ Mostly developing countries
◦ 2 cases/year in USA
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Transmission:
◦ Exposure to saliva of infected animal
◦ Non-saliva exposure (aerosolized virus in bat caves)
◦ Transplanted tissue from infected patients
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Incubation 1-3 months (range from days to 1
year)
2 clinical stages of disease
◦ Prodromal
◦ Clinical rabies
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Prodromal symptoms are non-specific, viral
◦ Paresthesiae radiating proximally from wound
would be suggestive
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May see percussion myoedema
◦ Mounding of muscle around percussion site
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2 variants of “clinical rabies”
◦ Encephalitic (“Furious”) rabies – 80%
◦ Paralytic (“Dumb”) rabies – 20%
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Hydrophobia (33-50%)
“After some preliminary feeling of discomfort in the throat or
dysphagia, the patient suddenly develops an overwhelming
terror of water based on involuntary pharyngeal muscle
spasms during attempts to drink. Later in the disease, even
the sight or mention of water may trigger these involuntary
spasms.”
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Aerophobia – Also pathognomonic, less
common (9%)
Opisthotonus
ANS instability
Combativeness/aggression
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Ascending paralysis (GBS mimic)
Flaccid paralysis, usually most apparent in
bitten limb
Absent DTRs, may see fasciculations
Hydrophobia unusual
Late cerebral involvement
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Diagnosis usually requires multiple tests
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Serum and CSF antibodies
Isolation of virus from saliva
Skin biopsy
Pathologic hallmark – Negri Body
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Traditionally uniformly fatal disease
“Best treatment is prevention”
Pre-exposure vaccination
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Post-exposure prophylaxis
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◦ High-risk groups (vets, travelers to endemic areas where
contact with wildlife likely)
◦ Vaccine
◦ Rabies immunoglobulin
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52M 3 ½ weeks post HSCT
Neurology team called to assess for
“confusion” for several days
Pt reports some headache
On exam, he is afebrile, has a supple neck,
and is awake. He is disoriented and
anterograde amnesia is evident.
Remainder of exam non-focal
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Routine blood work relatively unremarkable
Team asks for CT head -> “Normal”
What next?
◦ LP: WBC 4 (lymphs), RBC 2, Ptn and glucose WNL
◦ HSV PCR sent
◦ Started empirically on Acyclovir
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Ubiquitous neurotropic virus
Usually acquired early in life
No clear adverse effects in immunocompetent
adults
Recently identified as an important cause of
encephalitis in the immunocompromised host
◦ Specifically allogenic stem cell transplant patients
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Onset of anterograde amnesia, headache,
confusion 2-6 weeks after SCT
Seizures common as well (40-70%)
CSF profile normal or only mildly abnormal
◦ Median cell count = 5
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MRI
◦ T2/FLAIR hyperintensities in mesial temporal lobes
◦ Diffusion restriction may be seen as well
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Diagnosis established by viral CSF PCR
Treatment with ganciclovir or foscarnet
appears to be beneficial
◦ Optimal duration of therapy not known
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Little information regarding natural history
Seems to be associated with worse prognosis
after SCT (Bhanushali et al., Neurology, 2013)
◦ Not necessarily as direct result of encephalitis
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Do not delay antibiotics when considering
bacterial meningitis (do not wait for CT/LP)
Multiple neurological complications of
bacterial meningitis
Not all viral meningitis is enterovirus
◦ Remember travel history, animal/insect contacts,
HIV risk factors
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Treat HSV encephalitis promptly with
acyclovir
Not all mesial temporal lesions are HSV, and
not all HSV is in the mesial temporal lobe
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VZV may be an under-recognized cause of
meningitis or encephalitis
Rabies is an important cause of encephalitis
in the developing world
Remember WNV during Summer & Fall
HHV-6 is an important cause of encephalitis
in the immunocompromised patient, with its
own treatment
◦ Don’t be fooled by “normal” CSF