functional neurological recovery after spinal cord injury is - brain

BRAINA JOURNAL OF NEUROLOGY

Functional neurological recovery after spinal cordinjury is impaired in patients with infectionsVieri Failli,1,* Marcel A. Kopp,1,* Christine Gericke,2,* Peter Martus,2,3 Susann Klingbeil,1,4

Benedikt Brommer,1 Ines Laginha,1 Yuying Chen,5 Michael J. DeVivo,5 Ulrich Dirnagl6 andJan M. Schwab1

1 Department of Neurology and Experimental Neurology, Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology), Charite—

Universitatsmedizin Berlin, D-10117 Berlin, Germany

2 Institute of Biostatistics and Clinical Epidemiology, Charite—Universitatsmedizin Berlin, D-12203 Berlin, Germany

3 Department of Clinical Epidemiology and Applied Biostatistics, Eberhard Karls Universitat Tubingen, D-72070 Tubingen, Germany

4 Department of Neurology, University Hospital of Cologne, D-50937 Cologne, Germany

5 National Spinal Cord Injury Statistical Center, Department of Physical Medicine and Rehabilitation, University of Alabama at Birmingham,

Birmingham, AL 35233, USA

6 Department of Neurology and Experimental Neurology, Centre for Stroke Research Berlin, Charite—Universitatsmedizin Berlin, D-10117 Berlin,

Germany

*These authors contributed equally to this work.

Correspondence to: Prof. Jan M. Schwab, MD, PhD,

Department of Neurology and Experimental Neurology,

Clinical and Experimental Spinal Cord Injury Research (Neuroparaplegiology),

Charite—Universitatsmedizin Berlin,

Chariteplatz 1,

D-10117 Berlin, Germany

E-mail: [email protected]

Infections are a common threat to patients after spinal cord injury. Furthermore, infections might propagate neuronal death, and

consequently contribute to the restriction of neurological recovery. We investigated the association of infections (i.e. pneumonia

and/or postoperative wound infections) with functional neurological outcome after acute severe traumatic spinal cord injury. We

screened data sets of 24 762 patients enrolled in a prospective cohort study (National Spinal Cord Injury Database, Birmingham,

AL, USA). Patients were assessed according to the ASIA classification. ASIA impairment scale–classified A and B patients

recruited within 24 h post-trauma (n = 1436) were selected as being a major recruitment population for interventional trials.

Patients with documented pneumonia and/or postoperative wound infections (n = 581) were compared with control subjects

(non-documented infections, n = 855). The functional neurological outcome parameters (i) upward ASIA impairment scale con-

versions; (ii) gain of ASIA motor scores; and (iii) gain of motor and sensory levels were consecutively analysed over time up to 1

year after spinal cord injury. The group with pneumonia and/or postoperative wound infections revealed less ASIA impairment

scale upward conversions after 1 year than the control group (ASIA impairment scale A: 17.2 versus 23.9%, P = 0.03; ASIA

impairment scale B: 57.1 versus 74.7%, P = 0.009). ASIA motor score gain [median (interquartile range)] was lower in patients

with infections [ASIA impairment scale A: 8 (4–12) versus 10 (5–17), P = 0.01; ASIA impairment scale B: 19.5 (8–53.5) versus 42

(20.5–64), P = 0.03)]. Analysis of acquired motor/sensory levels supported these findings. In ASIA impairment scale A patients,

doi:10.1093/brain/aws267 Brain 2012: 135; 3238–3250 | 3238

Received February 27, 2012. Revised July 23, 2012. Accepted August 10, 2012

� The Author (2012). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved.

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the gain in motor levels (21.7 versus 33.3%, P = 0.04) and sensory levels (24.4 versus 38 of 102, 37.3%, P = 0.03) was

significantly lower in the group with pneumonia and/or postoperative wound infections than in the control group. Multiple

regression analysis identified pneumonia and/or postoperative wound infections as independent risk factors for impaired ASIA

impairment scale upward conversion (odds ratio: 1.89, 95% confidence interval: 1.36–2.63, P50.0005) or lower gain in ASIA

motor score (regression coefficient: �8.21, 95% confidence interval: �12.29 to �4.14, P50.0005). Infections associated with

spinal cord injury, such as pneumonia and/or postoperative wound infections, qualify as independent risk factors for poor

neurological outcome after motor complete spinal cord injury. Infections constitute a clinically relevant target for protecting

the limited endogenous functional regeneration capacity. Upcoming interventional trials might gain in efficacy with improved

patient stratification and might benefit from complementary protection of the intrinsic recovery potential after spinal cord injury.

Keywords: intrinsic/endogenous recovery potential; poor outcome; neurological recovery

Abbreviations: ASIA = American Spinal Injury Association; AIS = ASIA impairment scale; NSCID = National Spinal Cord InjuryDatabase; SCI = spinal cord injury

IntroductionThis study investigates the hypothesis that infections restrict re-

covery of neurological function after spinal cord injury (SCI).

Infections are the leading cause of morbidity and mortality in pa-

tients after SCI. Infection rates range from 28 to 38%, leading to

a mortality rate between 4.4 and 16.7% (DeVivo et al., 1999;

Sekhon and Fehlings, 2001; Meisel et al., 2005). Several risk fac-

tors contribute to increased susceptibility of these patients to in-

fections (e.g. for pneumonia: aspiration due to drowsiness,

impaired bulbar reflexes, dysphagia and hypostasis in bedridden

patients and invasive procedures). Immobility and reduced reflex

status increase the risk of aspiration itself, but do not sufficiently

explain the increased risk of developing infections. The search for

additional underlying reasons led to the discovery of the SCI-

induced immune depression syndrome, which may pave the way

for infections. SCI-induced immune depression syndrome is a neu-

rogenically triggered secondary immune deficiency syndrome

(immune paralysis) (Riegger et al., 2003, 2007, 2009; Vega

et al., 2003; Furlan et al., 2006; Lucin et al., 2007; Held et al.,

2010; Oropallo et al., 2012). It occurs within 24 h after SCI, af-

fects the innate and adaptive immune systems irrespective of the

administration of iatrogenic methylprednisolone and shares similar

characteristics in experimental models and post-SCI patients

(monocytopenia, lymphopenia) (Riegger et al., 2003, 2009;

Vega et al., 2004; Furlan et al., 2006; Lucin et al., 2007).

Infections may pose an independent risk factor for poor out-

come, impeding an intrinsic functional neurological recovery after

ischaemic injury to the CNS (Meisel et al., 2005; Vermeij et al.,

2009). Specifically, the induction of pneumonia, a frequent infec-

tion after both stroke and SCI, has been shown to promote sec-

ondary damage in experimental ischaemic CNS injury (Meisel

et al., 2004). To date, there are no systematic data available

that evaluate the effect of infections on the clinical neurological

outcome after SCI. We analysed data from a large prospective

multicentre cohort study (Marino et al., 1999; Fawcett et al.,

2007) to learn more about the impact of paradigmatic infections

such as pneumonia and postoperative wound infections and report

the first systematic investigation of their effects on the neuro-

logical recovery of post-SCI patients.

Patients and methods

Database informationThe data sets were obtained from the National Spinal Cord Injury

Database (NSCID) at the National Spinal Cord Injury Statistical

Center, Birmingham, AL, USA. Data were collected prospectively in

25 specialized SCI care centres (Model Spinal Cord Injury Systems)

from patients whose injuries were of acute traumatic aetiology

(Richards et al., 1995; Stover et al., 1999). The procedures taken to

ensure the quality of data have been previously described (Richards

et al., 1995; Stover et al., 1999; DeVivo et al., 2002). At the SCI

centre level, a defined set of procedures and responsibilities are estab-

lished to ensure that the required data are collected prospectively by

qualified staff familiar with the definitions and guidelines as stipulated

in the NSCID data collection syllabus. The National Spinal Cord Injury

Statistical Center performs two types of periodic analysis on all data-

base variables to identify data collection problems. The first analysis

determines the number and percentage of unknown responses for

each variable from each SCI centre. The second analysis reveals the

variability in responses across the SCI centres. Extensive quality control

checks are built into the National Spinal Cord Injury Statistical Center’s

data management software (checking routines) used at each SCI

centre. Checks are performed on each record entered by an SCI

centre, and each record must pass all quality control checks before it

is merged into the NSCID. Finally, twice during a 5-year period, all SCI

centre data collectors received refresher training to ensure standar-

dized data procurement.

Data qualifying the longitudinal course of neurological recovery after

traumatic SCI have been previously reported (Marino et al., 1999) and

have been consistent with data from other databases such as the

European Multicentre Study on Spinal Cord Injury with regards to

the main end-points used for this study (Fawcett et al., 2007; Furlan

et al., 2008). The institutional review board of each model system

approved the database, and enrolment was in accordance with the

Declaration of Helsinki. All subjects were informed about the database

and its aim and gave their written informed consent.

Neurological assessmentThe neurological assessments were performed in compliance with the

International Standards for Neurological Classification of Spinal Cord

Injury/American Spinal Injury Association (ASIA) classification of SCI

Infections and recovery after SCI Brain 2012: 135; 3238–3250 | 3239

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(Marino, 2003), the validated instrument for the identification and lon-

gitudinal evaluation of SCI patients (Furlan et al., 2008). The (i) ASIA

impairment scale (AIS); (ii) ASIA motor score; and (iii) neurological

motor and sensory levels were assessed (Supplementary material).

Baseline data were obtained at admission to a model system for

acute care. The assessment points for follow-up were admission to

in-patient rehabilitation (start of rehabilitation), discharge from in-pa-

tient rehabilitation (end of rehabilitation) and first annual examination

(1 year) after SCI.

Study populationThe NSCID was screened according to the data collection syllabus

terms. The data sets of patients suffering from SCI of acute traumatic

aetiology and recruited within 24 h after injury were selected at the

database level for detailed follow-up data collection (Fig. 1). Patients

admitted later than 24 h were not assigned to follow-up documenta-

tion, and for this reason, not accessible for longitudinal outcome

evaluation. Patients were not analysed in this study if they had been

assessed with the outdated Frankel scale, which was replaced by the

AIS in 1992. Predefined eligibility criteria were applied (Fig. 1).

Exclusion criteria were as follows: (i) age 515 and 470 years;

(ii) non-infectious pulmonary complications such as pulmonary embol-

ism; (iii) complications that might be related to pulmonary embolism,

such as deep vein thrombosis; (iv) rehospitalization for unspecified

infectious and parasitic diseases during trial course; (v) missing a

neurological level for each side of the body; and (vi) missing AIS at

baseline. The AIS was also encoded as ‘missing’ if an associated injury

or cognitive impairment interfered with the performance of a complete

neurological examination. For example, patients with severe concomi-

tant traumatic brain injury or psychological disorders were excluded.

Consequently, the reliability of the early baseline assessment was

improved (Burns et al., 2003). The exclusion criteria also included

patients unavailable at the NSCID at 1 year because of death or loss

to follow-up (Fig. 1). To describe potential sources of selection bias,

differences between the selected patient population and excluded

patients were assessed (Supplementary Table 1).

For the selected patient population (AIS A–D), the rate of pneumo-

nia/postoperative wound infections during the first year after SCI was

calculated stratified for AIS. Pneumonia was defined as a state of lung

tissue inflammation of infectious aetiology with radiographic demon-

stration of parenchymal disease. Postoperative wound infections were

defined as postoperative wound infection at the site of spinal surgery

that was performed during the reporting period. Patients with AIS C

and D were excluded from outcome analysis (i) owing to the low

overall incidence of pneumonia/postoperative wound infections

(Table 1); and (ii) because potential ceiling effects on AIS conversion

and ASIA motor score apply for motor-incomplete SCI (Fawcett et al.

2007; Steeves et al. 2007). For the final ‘analysis-in population’ (AIS A

and B), the timing of the neurological assessments, as well as the

frequency and timing of pneumonia/postoperative wound infections

episode occurrence during acute care, during in-patient rehabilitation

and after discharge, was calculated. Furthermore, baseline character-

istics and clinical characteristics during follow-up were assessed.

Analysis strategyAs reported previously, it is acceptable to pool examination data when

evaluating recovery at the group level (Marino et al., 1999; Curt et al.,

2007; Fawcett et al., 2007). We compared patients with pneumonia/

postoperative wound infections and patients without documented

pneumonia/postoperative wound infections (control patients) stratified

for AIS at baseline (Fawcett et al., 2007). We grouped pneumonia and

postoperative wound infection data together because the number of

patients with postoperative wound infections was too low for statistical

evaluation as a separate group. AIS conversions were evaluated in

patients with neurological levels from C1 to S1. Conversion rates

from AIS at baseline into the different AIS grades at 1 year were

calculated and subsequently categorized into patients gaining or plat-

eauing/worsening over the first year after SCI.

In analysing ASIA motor score gain, we selected patients with motor

levels C1–C8 documented on both body sides at baseline. Patients

with cervical injury are of particular interest because most thoracic

and sacral segments are not represented in ASIA motor scoring

(Supplementary material), and thereby cannot be monitored. In add-

ition, cervical patients comprise the relevant patient population for

upcoming interventional trials focusing on the primary end-point ‘im-

proved motor recovery’ (Fawcett et al., 2007; Steeves et al., 2007).

The ASIA motor score was analysed over time at each assessment

point up to 1 year. Patients with at least one available follow-up as-

sessment were included. The differences in the total motor score from

baseline were calculated for each group at each assessment point. The

patients were differentially assigned to the groups (with or without

pneumonia/postoperative wound infections) with regards to the oc-

currence of pneumonia/postoperative wound infections before the re-

spective assessment point.

For the analysis of acquired motor or sensory levels, we selected

patients with motor or sensory levels C1–C8 at baseline. Only patients

with documented levels on both body sides were included. Motor and

sensory levels were evaluated individually. The difference between

levels at baseline and levels at 1 year was calculated for each side

of the body. Then, the mean of the side-specific level differences

was calculated for each patient. The proportion of patients gaining

more than one level at 1 year was calculated for each group and

defined as relevant improvement.

Multiple logistic or linear regression analyses were performed to

determine factors independently associated with impaired AIS conver-

sion or ASIA motor score recovery, respectively. To address the prob-

lem of missing data in the ‘analysis-in population’, ‘missing value’

analysis of baseline parameters and multiple imputation was

performed.

Finally, to evaluate an influence of the frequency, the timing and

the type of infection episodes on changes in the AIS and the ASIA

motor score, we performed subgroup analyses. To achieve sufficient

group sizes for subgroup analyses, AIS A and B patients were taken

together. Control patients were compared with patients with one epi-

sode and patients with two or more episodes of pneumonia/post-

operative wound infections. In addition, control patients were

compared with patients who first presented with a pneumonia/post-

operative wound infection episode during acute care and with patients

who first presented with pneumonia/postoperative wound infections

during rehabilitation or after discharge up to 1 year after SCI.

Furthermore, control patients were compared with patients presenting

with pneumonia, patients presenting with postoperative wound infec-

tions and patients with both types of infection (pneumonia and post-

operative wound infections).

Statistical analysisThe distribution of continuous variables was described as median and

quartiles or means and 95% limits of confidence (CI). The Mann–

Whitney test was used to compare between the groups. The

Kruskal–Wallis test was applied for multiple comparison, followed by

post tests. The �2 test was used for categorical variables. Missing value

3240 | Brain 2012: 135; 3238–3250 V. Failli et al.

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http://brain.oxfordjournals.org/cgi/content/full/aws267/DC1



Figure 1 Patient enrolment chart. A stepwise data set selection was performed from the NSCID. In the ‘analysis-in population’ (pool of

patients for outcome analysis), groups for statistical analysis were determined with respect to characteristics of the particular outcome

parameter and the availability of data at each follow-up assessment point. We controlled for missing data–related attrition bias, applying

multiple regression models after multiple imputation. Besides applying linear and logistic regression models, we tested for interactions.

Note that total numbers differ from subgroup numbers because, for some patients, items apply several times. Pn/Wi = pneumonia and/or

postoperative wound infection.


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analysis was performed for AIS and ASIA motor score in the

‘analysis-in population’. Logistic regression analysis was performed

using impaired AIS conversion at 1 year as a dependent variable.

Linear regression analysis was performed using ASIA motor score re-

covery at 1 year as a dependent variable. In both multiple regression

analyses, forward variable selection was applied (inclusion criterion:

P = 0.05, exclusion criterion: P = 0.10). Furthermore, interactions be-

tween AIS and pneumonia/postoperative wound infections were ana-

lysed. Goodness of fit was assessed using the Hosmer–Lemeshow test.

Multiple imputation was performed as follows: the first imputation

used the conversion or motor score differences on the first two time

points and motor score differences or conversion on the three time

points as independent variables without imputation of themselves.

Only one variable (conversion or motor score difference on third

time point) was imputed at this stage. In the second imputation, all

independent variables from the analysis were used as independent

variable and were imputed. Then the merged data set was used for

the imputation repeated five times. The final algorithm averaged the

five imputations.

With 396 versus 540 patients and an overall rate of AIS conversion

of 32% 1 year after SCI, differences of 9% could be detected with

80% power in this study. With 163 versus 173 patients and standard

deviations of 24.7 and 17.6, respectively, differences in overall motor

score recovery of 6.7 points (mean) 1 year after SCI could be detected

with 80% power.

All tests were two sided, and the level of significance was 0.05. The

power analysis was calculated with nQueryAdvisor version 6.0. All

other statistical analyses were performed with SPSS for Windows ver-

sion 19.0.

Results

Baseline characteristics and clinical dataSCI patients (n = 24 762) were incorporated in the NSCID at the

time point of the analysis (Fig. 1). Within 24 h, 10 859 patients

were admitted and assigned to complete the longitudinal

follow-up documentation. The 6339 patient data sets assessed

with the outdated Frankel scale were not considered for the

study. The study monitored for attrition bias (‘missing data’,

‘loss to follow-up’) and selection bias due to ‘exclusion criteria’.

After application of the exclusion criteria, 2089 data sets from

AIS A–D patients were selected. These patients were recruited

between 1992 and 2005 and followed up to 1 year after injury,

until 2006. The 2089 individuals included (AIS A–D) were evalu-

ated for baseline differences compared with the 2431 individuals

who were excluded (Supplementary Table 1). Descriptive data

from the selected patients were comparable with the excluded

patients in terms of gender, ethnic group and ASIA motor score

at baseline, but revealed differences in age, AIS and neurological

level. The group of excluded patients showed a higher mean age,

and rates of AIS A and cervical neurological level were slightly

higher than those in the selected patients. These differences

might be attributable to the exclusion of patients older than 70

years and to the number of patients lost from the NSCID because

of death, as severely injured patients are more likely to develop

fatal complications.

The AIS grades of included data sets were compared to assess

whether the occurrence of a documented pneumonia/postopera-

tive wound infection was dependent on the completeness of injury

(Table 1). High rates of pneumonia/postoperative wound infection

were observed in severely impaired, complete AIS A and motor

complete AIS B patients. The rate of pneumonia/postoperative

wound infections was low in the motor incomplete AIS C and D

patients.

The neurological function was evaluated in the final ‘analysis-in

population’ of 1436 AIS A and B patients (pool of patients with or

without pneumonia/postoperative wound infections, Fig. 1). From

the ‘analysis-in population’, 581 (40.5%) patients had a total of

687 documented episodes of pneumonia/postoperative wound in-

fection. Some patients developed more than one episode or type

of infection. Of those patients, 550 (94.7%) had at least one

episode of pneumonia and 45 (7.7%) had at least one episode

of postoperative wound infection. Pneumonia/postoperative

wound infection episodes were documented in 407 cases

(70.1%) during stay in acute care, in 211 cases (36.3%) during

in-patient rehabilitation and in 69 cases (11.9%) after discharge

up to 1 year post-trauma. The first presentation of infection during

in-patient rehabilitation occurred in 148 cases (25.5%), whereas

the first presentation of pneumonia/postoperative wound infection

after discharge up to 1 year occurred only in 26 cases (4.5%).

Thus, 495% of pneumonia/postoperative wound infections

occurred first during acute care and in-patient rehabilitation. The

neurological baseline assessment at admission to an SCI centre

was performed during acute care at Day 1 (0–2) after SCI

[median (interquartile range)]; the first follow-up assessment was

performed at admission to in-patient rehabilitation at Day 15

(8–25), and the second follow-up assessment was performed at

discharge from in-patient rehabilitation at Day 62 (42–98). The

final 1-year outcome was obtained at the first annual examination

365 (304–408) days after SCI (Table 2).

Next, we investigated the groups (with or without pneumonia/

postoperative wound infection) for their congruency with regards

to outcome-relevant factors (Table 3). The groups revealed similar

baseline characteristics such as age, gender and race. The rate of

penetrating injury also revealed no statistical difference between

the groups. The groups were distinct in AIS and neurological level,

or in mechanical ventilation and rehospitalization during follow-up.

In addition, there was a significant difference in enrolment period

between the groups with regards to the likelihood of developing

pneumonia/postoperative wound infection. To provide an estima-

tion of access to rehabilitation, we compared the length of stay in

in-patient rehabilitation between the groups. Patients with pneu-

monia/postoperative wound infection had a longer access to in-

Table 1 Rates of pneumonia/postoperative wound infec-tions stratified for AIS at baseline

AIS at baseline Total n Pn/Win (%)

AIS A 1098 470 (42.8)

AIS B 338 111 (32.8)

AIS C 378 83 (22.0)

AIS D 275 36 (13.1)

Pn/Wi = pneumonia and/or postoperative wound infection (up to 1 year after SCI).


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patient rehabilitation of 57 (35–88) days compared with control

patients with an access time of 47 (30–78) days (P5 0.0005).

The ‘missing value’ analysis revealed no significant baseline dif-

ferences between the groups with regards to the primary outcome

parameter ‘neurological outcome’, which encompasses (i) AIS

(P = 0.51) and (ii) ASIA motor score (P = 0.21) within the

‘analysis-in population’.

Association of pneumonia/postopera-tive wound infections with impairedneurological recoveryWe first investigated AIS conversion rates at 1 year (n = 936,

Fig. 2). Significantly lower AIS upward conversions were observed

for patients with documented pneumonia/postoperative wound

infections compared with the control group. Among AIS A pa-

tients, 56 of 326 patients (17.2%) from the pneumonia/post-

operative wound infections group converted upwards compared

with 94 of 394 (23.9%) in the control group (P = 0.03). The AIS B

pneumonia/postoperative wound infections group demonstrated

lower upward conversion rates in 40 of 70 patients (57.1%),

versus 109 of 146 (74.7%) in the control group (P = 0.009).

Consequently, AIS A and B patients in the pneumonia/postopera-

tive wound infections group are significantly more likely to plateau

as non-converters.

To determine whether pneumonia/postoperative wound infec-

tions is an independent risk factor that affects AIS conversion

(dependent variable) during 1-year follow-up, we controlled for

baseline and clinical differences between the groups using multiple

regression models. The results of the multiple logistic regression

analysis identified pneumonia/postoperative wound infections as

an independent risk factor associated with lower AIS upward con-

version, as represented by an odds ratio (OR) of 1.89 (95% CI:

1.36–2.63, P5 0.0005) in the multiple analysis (n = 931, Table 4).

Subsequently, we performed multiple imputations to calculate for

missing data. Calculation of the logistic regression analysis after

multiple imputation (n = 1428) revealed an OR of 1.47 (95% CI:

1.06–2.04, P = 0.02, Supplementary Table 2). Subgroup analysis

of the frequency of pneumonia/postoperative wound infections

revealed no statistically significant differences in the AIS conver-

sion rates between patients with a single episode and patients with

several episodes of pneumonia/postoperative wound infection

(Supplementary Fig. 1A). Evaluation of the timing of pneumo-

nia/postoperative wound infections, in particular, early occurrence

during acute care versus later onset during rehabilitation or after

discharge (Supplementary Fig. 1B), did not demonstrate a differ-

ential impact for the timing of infections on AIS conversion within

the group of patients with pneumonia/postoperative wound infec-

tions. Differential evaluation of pneumonia and postoperative

wound infections was limited to a descriptive analysis in patients

Table 3 Baseline characteristics and clinical data in the ‘analysis-in population’

Baseline characteristics Control Pn/Wi P-value

Age [median (IQR)] n = 855 [28 (21–39)] n = 581 [29 (21–40)] 0.39

Gender: [male (%)] n = 855 [688 (80.5)] n = 581 [475 (81.8)] 0.54

Ethnic group: [Caucasian (%)] n = 791 [508 (64.2)] n = 555 [370 (66.7)] 0.35

AIS A (%) 628 (73.5) 470 (80.9) 0.001

AIS B (%) 227 (26.5) 111 (19.1)

Neurological level: C1–C4 (%) 107 (12.6) 171 (29.7)

Neurological level: C5–C8 (%) 220 (25.8) 146 (25.3)

Neurological level: T1–T6 (%) 163 (19.1) 127 (22.0) 50.0005

Neurological level: T7–T12 (%) 275 (32.3) 110 (19.1)

Neurological level: L1–S1 (%) 87 (10.2) 22 (3.8)

Enrolment period: 1992–98 (%) 430 (50.3) 395 (68.0) 50.0005

Enrolment period: 1999–2005 (%) 425 (49.7) 186 (32.0)

Penetrating injury (%) n = 854 [206 (24.1)] n = 581 [128 (22.0)] 0.36

Clinical data

Spinal surgery (%) n = 855 [581 (68.0)] n = 580 [407 (70.2)] 0.37

Mechanical ventilation (%) n = 853 [123 (14.4)] n = 581 [292 (50.3)] 50.0005

Rehospitalization (%) n = 834 [216 (25.9)] n = 563 [240 (42.6)] 50.0005

Distribution of baseline characteristics and clinical characteristics as occurring during the trial course up to 1 year in the ‘analysis-in population’ is shown. For statistical

comparison between the groups (�pneumonia/postoperative wound infections), the Mann–Whitney test was used for age, and the �2 test was applied for all othervariables. Differences in patient numbers within the groups result from missing data for the respective variables. Correction of ‘baseline differences’ and ‘missing data’ wasconducted by plugging into multiple regression models and missing value analysis (Tables 4 and 5).

Table 2 Assessment points after SCI

Assessment point Days, median(IQR)

Acute care within 24 h—‘baseline’ 1 (0–2)

Admission to rehabilitation 15 (8–25)

Discharge from in-patient rehabilitation 62 (42–98)

Annual examination after SCI—‘1 year’ 365 (304–408)

Assessment points are calculated for the ‘analysis-in population’ AIS A and B(n = 1436). IQR = interquartile range.


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with postoperative wound infection because the number of pa-

tients with postoperative wound infection was low. However, the

group of patients with pneumonia was significantly different from

control patients in terms of an impaired AIS conversion rate

(Supplementary Fig. 1C).

Next, we investigated the effect of pneumonia/postoperative

wound infections on motor recovery over time (Fig. 3). This was

done in patients with cervical lesions through a longitudinal com-

parison of differences in the total motor score from baseline at

each assessment point. A longitudinal set-up was chosen to moni-

tor (i) ‘when’ a putative alteration appeared over time; and

(ii) whether it became possible to distinguish early from late effects

on neurological outcome to track different underlying patho-

physiological mechanisms. The group with pneumonia/postopera-

tive wound infections and the control group were comparable

with regards to early outcome at the start of rehabilitation. At

the end of rehabilitation, a lower gain in motor score in the

group with pneumonia/postoperative wound infections did not

yield a statistical significance in the AIS A group. The motor re-

covery in AIS B was more compromised in the group with pneu-

monia/postoperative wound infections already at the end of

rehabilitation and resulted in a significantly lower gain in motor

score points [median (interquartile range), 8 (1.5–27.5) versus 22

(9.5–45), P = 0.001] constituting a 64% difference at that time

point. One year after SCI served as our final assessment point

for determining whether the observations were persistent and

not restricted to episodes of rehabilitation. Here, the gain in

ASIA motor score in AIS A patients with pneumonia/postoperative

wound infections was significantly lower [AIS A: 8 (4–12) versus

10 (5–17), P = 0.01], demonstrating a 20% difference. In AIS B,

the group with pneumonia/postoperative wound infections

showed a persisting impairment of motor recovery [19.5 (8–

53.5) versus 42 (20.5–64), P = 0.03], constituting a 55%

Table 4 Logistic regression analysis using AIS conversion at 1 year as dependent variable

Variable Univariate analysis Multiple analysis

OR (95% CI) P-value OR (95% CI) P-value

Age (per 10 years increase) 0.88 (0.79–0.98) 0.02

Gender (male = 1; female = 2) 0.87 (0.61–1.23) 0.43

Ethnic group (Caucasian = 0; others = 1) 1.16 (0.86–1.56) 0.33

AIS (AIS B = 0; AIS A = 1) 8.45 (6.02–11.87) 50.0005 7.72 (5.41–11.00) 50.0005

Neurological level (L1–S1 = 0; C1–C4 = 1; C5–C8 = 2;T1–T6 = 3; T7–T12 = 4)

1.53 (1.37–1.72) 50.0005 1.53 (1.35–1.74) 50.0005

Penetrating injury (no = 0; yes = 1) 2.02 (1.44–2.85) 50.0005

Pn/Wi (no = 0; yes = 1) 1.88 (1.41–2.51) 50.0005 1.89 (1.36–2.63) 50.0005

Mechanical ventilation (no = 0; yes = 1) 1.18 (0.87–1.60) 0.30

Spinal surgery (no = 0; yes = 1) 0.76 (0.56–1.02) 0.07

Rehospitalization (no = 0; yes = 1) 1.74 (1.27–2.38) 0.001

Enrolment period (1999–2005 = 0; 1992–1998 = 1) 1.25 (0.95–1.66) 0.12

Univariate and multiple logistic regression analysis in patients AIS A and B score (n = 931). The coding of the variable categories is indicated in the table. The neurologicallevel L1–S1 was encoded as 0 because patients with L1–S1 demonstrated the highest rate of AIS upward conversion, followed by high cervical (C1–C4), low cervical (C5–C8) and thoracic levels (T1–T6 and T7–T12). The analysis of interactions between the AIS and pneumonia/postoperative wound infections revealed no significance withregards to AIS conversion (P = 0.29). The multiple analysis was performed after forward variable selection (Nagelkerke’s R2 = 0.30; Hosmer–Lemeshow test, P = 0.34).Correction of confounders and baseline differences was conducted by plugging in univariate followed by multiple regression models. After univariate analysis, the cohort

was controlled for ‘neurological level’, ‘lesion severity’ (AIS), ‘age’, ‘penetrating injury’ and ‘rehospitalization’. Only AIS, neurological level and pneumonia/postoperativewound infections were approved as being independently associated with impaired AIS conversion rates, yielding statistical significance in the multiple model. Pn/Wi =pneumonia and/or postoperative wound infection.

Pn/W

i

Pn/W

i

Contro

l

Contro

l

n = 724

n = 216

AIS A

AIS BA

IS g

rade

impr

ovin

gA

IS g

rade

sta

ble

or w

orse

ning

50%

0%

50%

10%

20%

30%

40%

40%

30%

20%

10%

60%

70%

80%

80%

70%

60%

Figure 2 Pneumonia/postoperative wound infections are

associated with rates of impaired upward conversion. Motor

complete injury AIS A and AIS B patients with documented

pneumonia/postoperative wound infections had a significantly

reduced rate of upward conversions in the AIS compared with

control patients. �2 test, *P = 0.03, **P = 0.009.


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reduction of the intrinsic recovery potential (Fig. 3). Thus, if

the reduced gain in motor function occurs during in-patient re-

habilitation, it persists up to 1 year and is not compensated for

later on. To determine whether pneumonia/postoperative wound

infections have an independent effect on ASIA motor-score

changes at 1 year (dependent variable), a linear regression

model was applied. The multiple linear regression analysis identi-

fied pneumonia/postoperative wound infections as an independ-

ent prognostic factor associated with a lower gain of motor score

points 1 year after SCI [regression coefficient: �8.21 (95% CI:

�12.29 to �4.14), P50.0005, Table 5]. Again, the linear regres-

sion model after multiple imputation (n = 603) confirmed this

result [regression coefficient: �4.96 (95% CI: �8.85 to �1.07),

P = 0.01, Supplementary Table 3]. Of note, in contrast to pneu-

monia/postoperative wound infections, ‘mechanical ventilation’

did not reach significance levels as a risk factor for either AIS

conversion or ASIA motor score gain (Tables 4 and 5). The sub-

group analysis of frequency, type and timing of infections was

consistent with the results of the AIS conversion analysis

(Supplementary Fig. 2A–C).

Finally, we evaluated the gain in motor and sensory levels as

secondary outcome parameters, focusing on cervical injury pa-

tients. Groups were compared for improvement of more than

one motor or sensory level (Figs 4 and 5). The most pronounced

effect was observed in AIS A patients. In the group with pneu-

monia/postoperative wound infection, the gain in motor levels

was significantly lower compared with control group [31 of 143

(21.7%) versus 39 of 117 (33.3%)]. In AIS B patients, no statis-

tically significant difference was detected. AIS A patients in the

pneumonia/postoperative wound infection group were character-

ized by significantly lower sensory level gains [33 of 135 (24.4%)

versus 38 of 102 (37.3%), P = 0.03]. AIS B patients demonstrated

no statistically significant association. The clearly smaller group

sizes compared with the AIS A group may explain the observed

discrepancy between the results of the AIS conversion or motor

score analysis. Furthermore, reaching robust significance levels in

Figure 3 Pneumonia/postoperative wound infections are associated with lower gain in ASIA motor score points. Differences from

baseline (median 1 day post-SCI) in the ASIA motor score were analysed at each assessment point during 1-year follow-up in patients with

cervical lesions stratified for AIS at baseline. At start of rehabilitation (median 15 days post-SCI), no significant differences in motor

recovery were observed between patients with documented pneumonia/postoperative wound infections and control patients (AIS A and

B). AIS A patients with pneumonia/postoperative wound infections revealed a statistically significant lower recovery in the ASIA motor

score compared with control patients at 1 year. In AIS B patients, a significant impairment of motor recovery was detectable in the group

with pneumonia/postoperative wound infections at end of rehabilitation (median 62 days post-SCI) and was persistent up to 1 year.

Number of AIS A patients (control patients, pneumonia/postoperative wound infection): start of rehabilitation n = 240, n = 152; end of

rehabilitation n = 197, n = 203; and 1 year n = 113, n = 137. Number of AIS B patients (control patients, pneumonia/postoperative wound

infection): start of rehabilitation n = 101, n = 41; end of rehabilitation n = 90, n = 53; and 1 year n = 50, n = 36. Boxes are plotted as

median and interquartile range; whiskers are defined according to Tukey and outliers are indicated by dots. Mann–Whitney test,

*P = 0.03, **P = 0.01, ***P = 0.001.


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the primary outcome parameter AIS conversions and gain of

ASIA motor scores and less pronounced in the secondary outcome

(gain of motor/sensory level) point to differences in sensitivity to

detect changes due to the immanent characteristics of the ASIA

assessments.

DiscussionTo address the impact of prevalent infections (pneumonia/post-

operative wound infection) on neurological recovery after SCI

(Marino et al., 1999), we investigated parameters of neurological

Table 5 Linear regression analysis using ASIA motor score difference from baseline at 1 year as dependent variable

Variable Univariate analysis Multiple analysis

b (95% CI) P-value b (95% CI) P-value

Age (per 10 years increase) 2.24 (0.48 to 4.00) 0.01 2.23 (0.70 to 3.75) 0.004

Gender (male = 1; female = 2) 1.09 (�4.69 to 6.86) 0.71

Ethnic group (Caucasian = 0; others = 1) �0.66 (�5.87 to 4.55) 0.80

AIS (AIS B = 0; AIS A = 1) �23.29 (�28.07 to �18.50) 50.0005 �22.21 (�26.88 to �17.54) 50.0005

Neurological level (C1–C4 = 1; C5–C8 = 2) 2.42 (�2.33 to 7.16) 0.32

Penetrating injury (no = 0; yes = 1) �7.71 (�14.58 to �0.83) 0.03

Pn/Wi (no = 0; yes = 1) �10.39 (�14.98 to �5.81) 50.0005 �8.21 (�12.29 to �4.14) 50.0005

Mechanical ventilation (no = 0; yes = 1) �9.91 (�14.56 to �5.26) 50.0005

Spinal surgery (no = 0; yes = 1) 0.96 (�4.07 to 6.62) 0.74

Rehospitalization (no = 0; yes = 1) �5.44 (�10.32 to �0.56) 0.03

Enrolment period (1999–2005 = 0;1992–1998 = 1)

�1.65 (�6.43 to 3.14) 0.50

Univariate and multiple linear regression analysis in cervical injury patients AIS A and B score (n = 336). The coding of the variable categories is indicated in the table.Interactions between AIS and pneumonia/postoperative wound infections were not significant with regards to the motor score (P = 0.39). The multiple analysis wasperformed after forward variable selection (R2 = 0.26). With the exceptions of AIS, pneumonia/postoperative wound infections and age, none of the variables that yieldedstatistical significance in the univariate model was confirmed by reaching statistical significance in the multiple model.b = unstandardized regression coefficient.

Pn/W

i

Pn/W

i

Contro

lCon

trol

AIS A

n = 260

Gai

n of

mor

e th

an o

ne m

otor

leve

l G

ain

of o

ne m

otor

leve

l or

less

50%

0%

50%

10%

20%

30%

40%

40%

30%

20%

10%

60%

70%

80%

80%

70%

60%

AIS Bn.s.

n = 87

Figure 4 Effect of pneumonia/postoperative wound infection

on motor levels gained 1 year after SCI. A significantly lower

number of AIS A patients gained more than one motor level in


compared with control patients. In incomplete AIS B patients, no

significant differences were observed. �2 test, *P = 0.04.

Pn/W

i Pn/W

i

Contro

l Contro

l

n = 237

AIS AAIS B

n.s.n = 83

Gai

n of

mor

e th

an o

ne s

enso

ry le

vel

Gai

n of

one

sen

sory

leve

l or

less

50%

0%

50%

10%

20%

30%

40%

40%

30%

20%

10%

60%

70%

80%

80%

70%

60%

Figure 5 Effect of pneumonia/postoperative wound infections

on sensory levels gained 1 year after SCI. A significantly lower

number of AIS A patients gained more than one motor level in


compared with control patients. In AIS B patients, no significant

differences were observed. �2 test, *P = 0.03.


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motor and sensory function (Steeves et al., 2007) in a longitudinal,

multicentre cohort study assessing data from a large prospective

database (Richards et al., 1995; Marino et al., 1999; Stover et al.,

1999; DeVivo et al., 2002). At 1 year after SCI, there were sig-

nificantly fewer upward AIS conversions, lower gains in ASIA

motor score (up to 450%) and lower sensory and motor level

gains in the group with pneumonia/postoperative wound infec-

tion. Pneumonia/postoperative wound infections were evaluated

in logistic regression or linear regression models and identified as

independent risk factors associated with AIS conversion or ASIA

motor score gain. These evaluations were confirmed after multiple

imputation for both models.

The findings for AIS conversion and ASIA motor score evalu-

ation in AIS A were consistent with those in AIS B patients. In the

motor or sensory level analysis, AIS A patients demonstrated a

significant association of pneumonia/postoperative wound infec-

tion with lower sensory or motor level gain. However, this was not

detectable and thus not significant in AIS B patients, a finding that

in a general sense is due to their clearly smaller group sizes com-

pared with AIS A. Further explanation is found in the characteris-

tics of the ASIA assessments and differences in the intrinsic

recovery pattern between AIS A and B patients. In particular,

most AIS B patients reveal partial recovery in several segments

beyond the lesion, whereas for most AIS A patients, the recovery

is restricted to few segments directly adjacent to the lesion level.

In this context, partial sensory or motor recovery might lead to AIS

conversion without necessarily influencing sensory or motor levels,

as for gain of more than one level, full recovery of function is

needed in at least one dermatome or key muscle. In parallel, par-

tial motor recovery in numerous key muscles might lead to sub-

stantial motor score improvement in AIS B patients without

necessarily influencing motor levels.

The group with pneumonia/postoperative wound infection and

the control group did not differ in the longitudinal ASIA motor

score analysis during early observation. This supports the hypoth-

esis that the difference in the observed outcome is attributable to

the pneumonia/postoperative wound infection status, and weak-

ens the alternative hypothesis that pneumonia/postoperative

wound infections just passively accumulate as ‘epiphenomena’ in

patients with more severe types of injury, who are anyhow prone

to have inferior outcomes. Another more general argument is sup-

ported by recent epidemiological studies, which report a higher

upward conversion rate in complete (AIS A) cervical injury

(33%) compared with patients with thoracic injury (18%)

(Steeves et al., 2011; Zariffa et al., 2011). This fundamentally

challenges the assumption that inferior neurological outcome is

just a passive coincidence of a higher degree of organ dysfunction

(e.g. cervical versus thoracic), and implies the relevance of ‘disease

modifying’ factors for the prognosis and evolution of functional

recovery. In conclusion, infections do not appear to be unspecific

markers for patients with SCI with poor prognosis but rather one

of the causes of inferior outcome. Infections appear as early

effectors defining the path of neurological recovery and are char-

acterized by their ability to trigger several specific pathophysio-

logical sequelae as demonstrated in experimental CNS injury

models (Schnell et al., 1997; Meisel et al., 2004; McColl et al.,

2007, 2008; Moreno et al., 2011). The underlying mechanisms by

which infections impair functional neurological recovery are likely

to be multiple.

The induction of pneumonia promotes secondary damage in

experimental ischaemic CNS injury (Meisel et al., 2004; McColl

et al., 2007). Stroke-associated infection might be an independent

risk factor for poor clinical outcome (Vermeij et al., 2009),

although there is consensus that singular interventional trials test-

ing preventive antibiotics have so far been restricted by patient

numbers too low to unequivocally prove improved outcome

(Westendorp et al., 2011). A recent meta-analysis comprising

data from 137 817 patients after acute stroke stresses the need

to prevent infections in acute stroke (Westendorp et al., 2011).

Infections, in particular, pneumonia, appear to be among the main

modifiable factors leading to early death and poor outcome in

patients treated in stroke units (Finlayson et al., 2011;

Koennecke et al., 2011).

Experimental stroke models have provided evidence that sys-

temic inflammation exacerbates the neurological deficit by trigger-

ing a chemokine and acute-phase response (McColl et al., 2007)

with induced vascular tight junction disruption and sustained

blood–brain barrier disturbance (McColl et al., 2008). These mech-

anisms are likewise relevant to SCI because ischaemia is a feature

of traumatic CNS injury. Peripheral infections also aggravate neu-

rodegeneration in experimental models and human neuropathol-

ogy as reviewed by Perry et al. (2003). For example, systemic

inflammation led to axonal damage during inflammatory CNS

disease (Moreno et al., 2011). Sustained degeneration of oligo-

dendrocytes and neurons can be observed even in the late chronic

phase after SCI, as reviewed by Bramlett and Dietrich (2007).

Consequently, the substrate for neuronal plasticity, which is con-

sidered the major effector mechanism for neurological recovery, is

reduced (Reinetenau and Schwab, 2001; Curt et al., 2008).

Preventive antibacterial treatment reduced secondary damage

and improved neurological outcome after experimental stroke

(Meisel et al., 2004). The lesional CNS inflammatory response is

exacerbated and sustained when accompanied by infection,

whether of viral (Schnell et al., 1997) or bacterial (McColl et al.,

2007, 2008) origin. Lesional inflammation can perpetuate neuro-

degeneration through multiple effector mechanisms involving cells

of innate and acquired immunity, as reviewed elsewhere

(Wyss-Coray and Mucke, 2002; Glass et al., 2010). Furthermore,

given that systemic immunological responses are triggered by in-

fections, they are likely to interfere directly or indirectly with the

capacity of the lesioned CNS for adaptive reorganization on many

levels via soluble factors (Reinetenau and Schwab, 2001; Moreno

et al., 2011) by triggering acute-phase responses (Popovich et al.,

2009).

In this study, the group with pneumonia/postoperative wound

infection and the control group did not differ in terms of known

outcome-relevant parameters associated with poor neurological

recovery, with the exception of AIS at baseline, for which the

direct comparison was stratified, and the neurological level,

which was included in the regression models. Noteworthy, pneu-

monia/postoperative wound infection is verified to be independent

of the lesion severity parameter (AIS) and lesion level. In addition,

the rates of penetrating injury and the performance of spinal sur-

gery were comparable in both groups, and patients with


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interfering concomitant injuries or cognitive impairment were

excluded from the analysis. This suggests that the alternative hy-

pothesis according to which inferior outcome is due to (i) more

severe; (ii) higher lesions; or (iii) more generalized impairment

accompanied by infections seems less likely. Nevertheless, in the

group with pneumonia/postoperative wound infection, a higher

rate of mechanical ventilation was observed. Consequently, a

more frequent ventilation might already appear to be a predispos-

ing reason for higher infection rates that then lead to impaired

neurofunctional outcome. This explanation can be ruled out by

multiple logistic regression analysis, which yields an OR of 1.89

for impaired upward conversions for patients with pneumonia/

postoperative wound infection, whereas mechanical ventilation

itself does not impact AIS upward conversion. Furthermore, with

regards to lower ASIA motor score gain, the multiple linear regres-

sion analysis does not reveal a statistically significant relationship

for mechanical ventilation or any other established outcome-

predictive parameter such as penetrating injury, except for AIS at

admission and age, which was expected. The AIS was included as

an independent variable in both regression models because the

interactions between pneumonia/postoperative wound infections

and AIS were not significant with regards to the dependent vari-

ables. We propose that infection should be considered a novel in-

dependent factor causally linked to poor neurofunctional recovery.

This study has the limitations of a retrospectively performed

evaluation of data from a prospective database. We apply this

setting to generate new hypotheses, with the perspective of opti-

mizing clinical care in the future. We limit our analysis to pneu-

monia and wound infections. Other types of infection frequently

occurring after SCI, such as urinary tract infections, are not

encoded in the NSCID. Thus, the ‘control group’ with no docu-

mented pneumonia/postoperative wound infections might also

contain patients with other infectious complications. However,

the fact that not all infections in the control group are identified

might imply that the effects of infection are even more pro-

nounced and that the control group is thus already impaired in

terms of recovery potential. With regards to the amount of re-

habilitation received, a possible factor influencing the neurological

outcome, our analysis is restricted to the length of stay in rehabili-

tation, as data on the exact amount of rehabilitation were not

accessible for the majority of the study subjects. Nevertheless,

patients with pneumonia/postoperative wound infection had

access over a longer period to in-patient rehabilitation compared

with the control group. Infections might impede functional recov-

ery by limiting the efficacy of rehabilitation. The strengths and

limitations of the NSCID have been described previously (Stover

et al., 1999). Its main limitation is that it is not population based.

Another limitation is that the data of patients who were lost to

follow-up are missing; this might lead to bias in favour of those

patients who were successfully followed relative to the entire data-

base. Loss to follow-up as a source of attrition bias is a common

problem with any longitudinal database. The problem of missing

data within the ‘analysis-in population’ was addressed by multiple

imputation for both regression models. In our imputation analyses,

only �21 or 25% of the variability was explained by covariates,

whereas the complete case analysis explained �26 or 30% of the

variability. Thus, the observed shrinkage of differences after

imputation as compared with complete case analysis is conserva-

tive and probably not due to systematic differences between pa-

tients with complete and patients with missing data.

In conclusion, prospective trials are needed to determine pos-

sible detrimental effects on functional neurological recovery that

could result from infections that are not yet encoded by the

NSCID. Our findings might trigger the incorporation of more de-

tailed information on infectious complications in the relevant SCI

registries such as the NSCID or the European Multicentre Study on

Spinal Cord Injury. It is essential to decipher infections caused by

neurogenic syndromes such as SCI-induced immune depression

syndrome through epidemiological cohort studies to determine

their relevance to outcome and formulate new research hypoth-

eses to improve clinical neurological outcome.

The conclusion of this study identifying SCI-associated infec-

tions as an independent risk factor for poor neurological outcome

provides ‘best evidence’ available and is an essential prerequisite for

regulatory authorities to approve prospective interventional trial

protocols. Based on the reported data, the establishment of early

infection-predictive parameters identifying patients prone to infec-

tion constitutes a consequent, preventive, specific strategy verified

by a feasible time frame of opportunity. The development of

predictive diagnostic parameters (‘immunological fingerprinting’)

(e.g. Urra et al., 2009) would enable a selective preventive interven-

tional approach to protect the limited intrinsic recovery capacity after

SCI and thus improve neurological function. At present, the findings

are of particular relevance for current interventional trials to improve

outcome prediction (e.g. improved patient group stratification)

aiming at cervical lesions (Fawcett et al., 2007; Zorner et al.,

2010). Here, incident postinjury infections (pneumonia/postopera-

tive wound infections) can be confined as a ‘disease modifying’ and

possible confounding factor for effective rehabilitation in interven-

tional trials (Dobkin 2007a, b, 2009; Fouad et al., 2011).

AcknowledgementsWe would like to thank Dr. Lisa Schnell and Prof. Dr. Andreas

Meisel for valuable suggestions for the interpretation of the re-

sults. The Department of Clinical and Experimental Spinal Cord

Injury Research (Neuroparaplegiology), Department of

Experimental Neurology, Charite Universtatsmedizin Berlin, is an

Associated Member of the European Multicentre Study about

Spinal Cord Injury.

FundingThis work was supported by the German Research Council (DFG,

Research Training School, Neuroinflammation, Grant number

1258); the Berlin-Brandenburg Centre for Regenerative Therapies

(BCRT, Grant number 81717034); the International Foundation for

Research in Paraplegia, Switzerland (IFP, Grant number P102); and

Wings for Life Spinal Cord Research Foundation, Austria (Grant

Number WfL-DE-006/12). The NSCID is funded by the National

Institute on Disability and Rehabilitation Research (NIDRR, Grant

number H133A060039), U.S. Department of Education, USA.


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Supplementary materialSupplementary material is available at Brain online.

ReferencesBramlett HM, Dietrich WD. Progressive damage after brain and spinal

cord injury: pathomechanisms and treatment strategies. Prog Brain Res

2007; 161: 125–41.

Burns AS, Lee BS, Ditunno JF Jr, Tessler A. Patient selection for clinical

trials: the reliability of the early spinal cord injury examination.

J Neurotrauma 2003; 20: 477–82.Curt A, Van Hedel HJ, Klaus D, Dietz V, EM-SCI Study Group. Recovery

from a spinal cord injury: significance of compensation, neural plasti-

city, and repair. J Neurotrauma 2008; 25: 677–85.

DeVivo MJ, Krause JS, Lammertse DP. Recent trends in mortality and

causes of death among persons with spinal cord injury. Arch Phys Med

Rehabil 1999; 80: 1411–19.

DeVivo MJ, Go BK, Jackson AB. Overview of the national spinal

cord injury statistical center database. J Spinal Cord Med 2002; 25:

335–8.

Dobkin BH. Confounders in rehabilitation trials of task-oriented training:

lessons from the designs of the EXCITE and SCILT multicenter trials.

Neurorehabil Neural Repair 2007a; 21: 3–13.

Dobkin BH. Curiosity and cure: translational research strategies for

neural repair-mediated rehabilitation. Dev Neurobiol 2007b; 67:

1133–47.Dobkin BH. Motor rehabilitation after stroke, traumatic brain, and spinal

cord injury: common denominators within recent clinical trials. Curr

Opin Neurol 2009; 22: 563–9.

Fawcett JW, Curt A, Steeves JD, Coleman WP, Tuszynski MH,

Lammertse D, et al. Guidelines for the conduct of clinical trials for

spinal cord injury as developed by the ICCP panel: spontaneous re-

covery after spinal cord injury and statistical power needed for thera-

peutic clinical trials. Spinal Cord 2007; 45: 190–205.

Finlayson O, Kapral M, Hall R, Asllani E, Selchen D, Saposnik G, et al.

Risk factors, inpatient care, and outcomes of pneumonia after ischemic

stroke. Neurology 2011; 77: 1338–45.

Fouad K, Krajacic A, Tetzlaff W. Spinal cord injury and plasticity: oppor-

tunities and challenges. Brain Res Bull 2011; 84: 337–42.

Furlan JC, Krassioukov AV, Fehlings MG. Hematologic abnormalities

within the first week after acute isolated traumatic cervical spinal

cord injury: a case-control cohort study. Spine 2006; 31: 2674–83.

Furlan JC, Fehlings MG, Tator CH, Davis AM. Motor and sensory as-

sessment of patients in clinical trials for pharmacological therapy of

acute spinal cord injury: psychometric properties of the ASIA

Standards. J Neurotrauma 2008; 25: 1273–301.Glass CK, Saijo K, Winner B, Marchetto MC, Gage FH. Mechanisms

underlying inflammation in neurodegeneration. Cell 2010; 140:

918–34.

Held KS, Steward O, Blanc C, Lane TE. Impaired immune responses

following spinal cord injury lead to reduced ability to control viral in-

fection. Exp Neurol 2010; 226: 242–53.

Koennecke HC, Belz W, Berfelde D, Endres M, Fitzek S, Hamilton F,

et al. Factors influencing in-hospital mortality and morbidity in patients

treated on a stroke unit. Neurology 2011; 77: 965–72.Lucin KM, Sanders VM, Jones TB, Malarkey WB, Popovich PG. Impaired

antibody synthesis after spinal cord injury is level dependent and is due

to sympathetic nervous system dysregulation. Exp Neurol 2007; 207:

75–84.

Marino RJ, Ditunno JF Jr, Donovan WH, Maynard F Jr. Neurologic re-

covery after traumatic spinal cord injury: data from the Model Spinal

Cord Injury Systems. Arch Phys Med Rehabil 1999; 80: 1391–6.

Marino RJ. International standards for neurological classification of spinal

cord injury. J Spinal Cord Med 2003; 26 (Suppl 1): S50–6.

McColl BW, Rothwell NJ, Allan SM. Systemic inflammatory stimulus po-

tentiates the acute phase and CXC chemokine responses to experi-

mental stroke and exacerbates brain damage via interleukin-1- and

neutrophil-dependent mechanisms. J Neurosci 2007; 27: 4403–12.

McColl BW, Rothwell NJ, Allan SM. Systemic inflammation alters the

kinetics of cerebrovascular tight junction disruption after experimental

stroke in mice. J Neurosci 2008; 28: 9451–62.Meisel C, Prass K, Braun J, Victorov I, Wolf T, Megow D, et al.

Preventive antibacterial treatment improves the general medical and

neurological outcome in a mouse model of stroke. Stroke 2004; 35:

2–6.

Meisel C, Schwab JM, Prass K, Meisel A, Dirnagl U. Central nervous

system injury-induced immune deficiency syndrome. Nat Rev

Neurosci 2005; 6: 775–86.

Moreno B, Jukes JP, Vergara-Irigaray N, Errea O, Villoslada P, Perry VH,

et al. Systemic inflammation induces axon injury during brain inflam-

mation. Ann Neurol 2011; 70: 932–42.

Oropallo MA, Held KS, Goenka R, Ahmad SA, O’Neill PJ, Steward O,

et al. Chronic spinal cord injury impairs primary antibody responses but

spares existing humoral immunity in mice. J Immunol 2012; 188:

5257–66.Perry VH, Newman TA, Cunningham C. The impact of systemic infection

on the progression of neurodegenerative disease. Nat Rev Neurosci

2003; 4: 103–12.

Popovich P, McTigue D. Damage control in the nervous system: be-

ware the immune system in spinal cord injury. Nat Med 2009; 15:

736–7.

Raineteau O, Schwab ME. Plasticity of motor systems after incomplete

spinal cord injury. Nat Rev Neurosci 2001; 2: 263–73.

Richards JS, Go BK, Rutt RD, Lazarus PB. The national spinal cord injury

collaborative database. In: Stover SL, DeLisa JA, Whiteneck GG, edi-

tors. Spinal cord injury: clinical outcomes from the model systems.

Gaithersburg, MD: Aspen Publishers; 1995. p. 10–20.

Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, et al.

Hematologic cellular inFammatory response following human spinal

cord injury [abstract]. Acta Neuropathol 2003; 106: 392.Riegger T, Conrad S, Liu K, Schluesener HJ, Adibzahdeh M, Schwab JM.

Spinal cord injury-induced immune depression syndrome (SCI-IDS). Eur

J Neurosci 2007; 25: 1743–7.

Riegger T, Conrad S, Schluesener HJ, Kaps HP, Badke A, Baron C, et al.

Immune depression syndrome following human spinal cord injury

(SCI): a pilot study. Neuroscience 2009; 158: 1194–9.

Schnell L, Schneider R, Berman MA, Perry VH, Schwab ME. Lymphocyte

recruitment following spinal cord injury in mice is altered by prior viral

exposure. Eur J Neurosci 1997; 9: 1000–7.

Sekhon LH, Fehlings MG. Epidemiology, demographics, and patho-

physiology of acute spinal cord injury. Spine 2001; 26 (Suppl 24):

S2–12.

Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH,

Ditunno JF, et al. International Campaign for Cures of Spinal Cord

Injury Paralysis. Guidelines for the conduct of clinical trials for spinal

cord injury (SCI) as developed by the ICCP panel: clinical trial outcome

measures. Spinal Cord 2007; 45: 206–21.

Steeves JD, Lammertse D, Curt A, Fawcett JW, Tuszynski MH,

Ditunno JF, et al. Extent of spontaneous motor recovery after trau-

matic cervical sensorimotor complete spinal cord injury. Spinal Cord

2011; 49: 257–65.

Stover SL, DeVivo MJ, Go BK. History, implementation, and current

status of the National Spinal Cord Injury Database. Arch Phys Med

Rehabil 1999; 80: 1365–71.Urra X, Villamor N, Amaro S, Gomez-Choco M, Obach V, Oleaga L,

et al. Monocyte subtypes predict clinical course and prognosis in

human stroke. J Cereb Blood Flow Metab 2009; 29: 994–1002.

Vega JL, Ganea D, Jonakait GM. Acute down-regulation of antibody

production following spinal cord injury: role of systemic catechol-

amines. J Neuropathol Exp Neurol 2003; 62: 848–54.

Vermeij FH, Scholte op Reimer WJ, de Man P, van Oostenbrugge RJ,

Franke CL, de Jong G, et al. Stroke-associated infection is an


Dow



ecember 2021


independent risk factor for poor outcome after acute ischemic stroke:data from the Netherlands Stroke Survey. Cerebrovasc Dis 2009; 27:

465–71.

Westendorp WF, Nederkoorn PJ, Vermeij JD, Dijkgraaf MG, van de

Beek D. Post-stroke infection: a systematic review and meta-analysis.BMC Neurol 2011; 11: 110.

Wyss-Coray T, Mucke L. Inflammation in neurodegenerative disease—a

double-edged sword. Neuron 2002; 35: 419–32.

Zariffa J, Kramer JL, Fawcett JW, Lammertse DP, Blight AR, Guest J,et al. Characterization of neurological recovery following traumatic

sensorimotor complete thoracic spinal cord injury. Spinal Cord 2011;

49: 463–71.

Zorner B, Blanckenhorn WU, Dietz V, EM-SCI Study Group, Curt A.Clinical algorithm for improved prediction of ambulation and patient

stratification after incomplete spinal cord injury. J Neurotrauma 2010;

27: 241–52.


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ecember 2021

functional neurological recovery after spinal cord injury is - brain

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