TY - JOUR

T1 - A functional observational battery for evaluation of neurological outcomes in a rat model of acute bacterial meningitis

AU - Fisher, Jane

AU - Pavan, Chiara

AU - Ohlmeier, Luisa S.

AU - Nilson, Bo

AU - Lundgaard, Iben

AU - Linder, Adam

AU - Bentzer, Peter

PY - 2020

Y1 - 2020

N2 - Background: Acute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae.Methods: We developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate ofStreptococcus pneumoniae. Rats were evaluated for 6 days following the infection.Results: Pneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats;p= 0.0003), involuntary motor movements (75% of infected vs 0% of control rats;p= 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats;p= 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 +/- 4.0 vs 4.0 +/- 2.0; 48 h 17.3 +/- 7.1 vs 3.4 +/- 1.8; 6 days 17.8 +/- 7.4 vs 1.7 +/- 2.4; p <0.0001 for all).Conclusions: The functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.

AB - Background: Acute bacterial meningitis is a disease with a high mortality and a high incidence of neurological sequelae in survivors. There is an acute need to develop new adjuvant therapies. To ensure that new therapies evaluated in animal models are translatable to humans, studies must evaluate clinically relevant and patient-important outcomes, including neurological symptoms and sequelae.Methods: We developed and tested a functional observational battery to quantify the severity of a variety of relevant neurological and clinical symptoms in a rat model of bacterial meningitis. The functional observational battery included symptoms relating to general clinical signs, gait and posture abnormalities, involuntary motor movements, focal neurological signs, and neuromotor abnormalities which were scored according to severity and summed to obtain a combined clinical and neurological score. To test the functional observational battery, adult Sprague-Dawley rats were infected by intracisternal injection of a clinical isolate ofStreptococcus pneumoniae. Rats were evaluated for 6 days following the infection.Results: Pneumococcal meningitis was not lethal in this model; however, it induced severe neurological symptoms. Most common symptoms were hearing loss (75% of infected vs 0% of control rats;p= 0.0003), involuntary motor movements (75% of infected vs 0% of control rats;p= 0.0003), and gait and posture abnormality (67% of infected vs 0% of control rats;p= 0.0013). Infected rats had a higher combined score when determined by the functional observational battery than control rats at all time points (24 h 12.7 +/- 4.0 vs 4.0 +/- 2.0; 48 h 17.3 +/- 7.1 vs 3.4 +/- 1.8; 6 days 17.8 +/- 7.4 vs 1.7 +/- 2.4; p <0.0001 for all).Conclusions: The functional observational battery described here detects clinically relevant neurological sequelae of bacterial meningitis and could be a useful tool when testing new therapeutics in rat models of meningitis.

KW - Acute bacterial meningitis

KW - Rat model

KW - Neurological symptoms

KW - Functional observational battery

KW - Streptococcus pneumoniae

KW - Pneumococcal meningitis

KW - EXPERIMENTAL PNEUMOCOCCAL MENINGITIS

KW - HEARING-LOSS

KW - DAMAGE

KW - MOTOR

KW - NERVE

KW - BRAIN

KW - INHIBITION

KW - INJURY

U2 - 10.1186/s40635-020-00331-1

DO - 10.1186/s40635-020-00331-1

M3 - Journal article

C2 - 32770475

VL - 8

JO - Intensive Care Medicine Experimental

JF - Intensive Care Medicine Experimental

SN - 2197-425X

IS - 1

M1 - 40

ER -