Download Mechanisms of meningitis-associated labyrinthitis and hearing

Mechanisms of meningitis-associated labyrinthitis and hearing impairment
M. Klein, U. Koedel, and H.W. Pfister
Ludwig-Maximilians University, Munich, Germany
Background:
Characteristics of hearing loss.
Long term sequelae are a burden for
of hearing impairment in bacterial meningitis can range from very
these, hearing loss is the most common, affecting 26% after
mild to severe and even complete deafness. Almost always,
pneumococcal meningitis and 10% after meningococcal meningitis.
hearing loss develops in a very early stage of the disease and it
This makes bacterial meningitis one of the leading causes of
can be transient or lead to permanent hearing impairment. This
acquired hearing impairment in children. Its consequences are
indicates that some alterations are reversible, whereas others
alarming. Even mild changes in a child’s hearing ability can lead to
lead to permanent destruction. The main site of the lesion is the
auditory
and
linguistic
disabilities
and
therefore
Animal model of
meningitis-associated labyrinthitis
The severity
approximately 50% of survivors from bacterial meningitis. Among
impaired
cochlea. This was shown by histology and by auditory brainstem
communication skills. Quite often, social problems and difficulties at
responses in patients and animals with meningitis-associated
school are the result. Therefore, a better understanding of the
hearing loss. Thus, meningitis-associated hearing loss is usually
pathophysiology of meningitis-associated hearing loss and more
sensorineural.
S. pneumoniae tpye 3
6h – 2 weeks
Abx treatment and
adjunctive therapy
Adult rats / mice
Hearing assessment: Auditory brainstem response (click, tone)
24h after infection
before infection
10 5dB
90 dB
11 5dB
80 dB
11 0dB
70 dB
60 dB
50 dB
40 dB
35 dB
30 dB
10 5dB
time after stimulus (ms)
B
acute stage
• Bacterial proliferation in perilymphatic space
- cochlear is an immunoprivilidged space with reduced antibody
concentrations and limited patroulling immunocompetent cells
Routes of infection:
• most likely: arrival of bacteria through perilymphatic duct
(direct connection of middle cranial fossa and cochlea)
acute stage
Activation of immune response
Inflammation is triggered through MyD88-dependent pathways
• Bacterial autolysis
Æ liberation of bacterial toxins such as pneumolysin
supportive arguments:
- aggravation of inflammation at opening of perilymphatic duct
- aggravation of inflammation in basal cochlear turn, S. tympani
- high frequency hearing loss first
time after stimulus (ms)
C
acute stage
Bacterial proliferation and toxicity
Route of bacterial invasion
Morphology
Blood-labyrinth barrier disruption
Spiral ganglion neuronal density
Cochlear occlusion
Pathophysiologic data has been obtained using animal models
of pneumococcal meningitis and hearing loss.
Course of cochlear alterations in pneumococcal meningitis
A
Histology
4 µ V/div
4 µV/div
effective treatment options are needed.
TLR
MyD88
Il1R
MyD88
NF-kappaB
activation
Inflammation
• Direct toxic effects of pneumolysin
damage of Organ of Corti, esp. cochlear hair cells
- pneumolysin-deficient pneumococci leads to diminished
damage to the Organ of Corti
- perfusion of cochlea with pneumolysin leads to significant
hearing loss
(e.g., Klein et al. Brain Pathol 2003, Merchant et al. Am J Otol 1999))
Rat with pneumococcal meningitis, 24h after
infection. Note the opening of the cochlear
aqueduct (arrow) which is filled with leukocytes.
• MyD88-deficient mice with pneumococcal meningitis develop
less hearing loss and cochlear inflammation than WT mice.
• Bacterial killing is impaired
MyD88-/-
WT
(Winter et al. Infect Immun 1997, Skinner et al. Acta Otolaryngol 2004)
µ
40 m
µ
40 m
Staining: H&E. Basal turn of cochlea
24h after intracisternal infection of mice with S. pneumoniae
(Klein et al. JID 2007)
ROS/RNS
D
acute stage
E1
Damage through oxidative stress
• Inflammation of the cochlea is replaced by fibrocytes
• Activation of inducible NO synthase (iNOS)
• Next, the cochlea ossifies over time
• Production of NO and O2Æ formation of reactive peroxynitrite (ONOO-)
Staining of cochlea
for Nitrotyrosin, a marker
for ONOO-.
uninfected control
infected
**
100
60
+ *+
40
20
Infiziert
+Ceftriaxon
+ NAC
Infiziert
+Ceftriaxon
+ MnTBAP
0
Kontrollen
Hörverlust (dB)
80
- in gerbils with meningitis, osteoid deposits were seen as early
as 3 days after infection
- also in gerbils, ossification progressed for at least 12 months
Tinling et al., Laryngoscope 2004 and Nabili et al., Laryngoscope 1999
Kastenbauer and
Klein et al. Brain Res 2001
oxidative damage of the cochlea
Infiziert
+Ceftriaxon
•
infected
residual stage
Ossification of the cochlea
Treatment of infected rats with antibiotics and
antioxidants
(N-Acetyl-L-Cysteine
(NAC),
MnTBAP)leads to a reduction of hearing loss (left)
and ist morphologic correlates (cochlear occlusion
(E), neuronal loss (F), and blood-labyrinth barrier
damage (not shown) .
Klein et al. Ann Neurol 2003
E2
residual stage
Spiral ganglion neuronal loss
• Hallmark of cochlear alterations after survival of meningitis
• Significantly correlates with degree of hearing loss
Left: Neuronal loss in spiral ganglionof
a rat, 2 weeks after meningitis
Right: Time course of neuronal loss in a
mouse model of pneumococcal meningitis.
(Klein et al. Ann Neurol 2003 and JID 2007)
Cochlea of a rat 2 weeks after pneumococcal
meningitis. Dense fibrocytic occlusion can be
noted in the perillymphatic space (S. tympani
and S. vestibuli). Staining HE. Insert: uninfected
control.
Klein et al. Ann Neurol 2003
Possible mechanisms of neuronal damage
• Acute stage: oxidative stress and direct toxicity, e.g. through
pneumolysin (please see B and D)
• Degeneration through long lasting inactivity due to hair cell
damage and missing neurotrophins
(Li et al. J Child Neurol 2005)
Acknowledgement: The current funding of our work on meningitis-associated hearing loss by the Else-Kroner Fresenius
Foundation (cochlear immune activation during meningitis) and the Meningitis Research Foundation (Meningitis-associated hearing
loss: protection against cochlear neuronal damage by adjunctive therapy with neurotrophins) is greatly appreciated.