Prevalence and prognostic value of neurological affections in … – Nature.com

Participants

Hospitalized patients with COVID-19 were recruited between May 2020 and March 2022 at the University Hospital Duesseldorf, Germany, to participate in the PROGNOSE study. Inclusion criterion was an ongoing infection with SARS-CoV-2, confirmed by real-time reverse-transcription polymerase chain reaction. Here, we only focus on patients with symptoms of COVID-19. Exclusion criteria were: (1) pregnancy, (2) previous or ongoing neurological conditions with possible influence on the study readouts, and (3) age<18years.

Patients with neurological preconditions that only affected some assessments (e.g., dementia) were excluded only for confounded investigations (e.g., neuropsychology). Study participation did not influence the clinical treatment, which was performed according to the best medical care available at the time of examination.

The study was approved by the ethical committee of the medical faculty of the Heinrich-Heine-University Dsseldorf (Study-Number 2020-979) and carried out in accordance with the declaration of Helsinki. Informed written consent was provided prior to participation by the patient or, in case of inability to consent, by relatives and post-hoc by the patient.

Since there is no COVID-19 specific score for classification of neurological symptoms and disability yet, the following established disability scores were adjusted to the COVID-19 pathology and determined by neurological examination: (1) Expanded Disability Status Scale (EDSS) based on the following Functional Systems (FS): brainstem, pyramidal, cerebral, cerebellar, sensory14, (2) Modified Rankin Scale15, (3) INCAT disability score16, (4) Barthel Index17. All scores are described in detail in the Supplementary Methods. The clinical status of the patient at the time of examination was assessed by the WHO clinical progression scale (WHO score), documenting disease severity from 0 (uninfected) to 10 (dead)18.

Blood samples were collected as part of the clinical routine during or shortly after admission, and the following laboratory markers were analyzed: C-reactive protein, urea, lymphocytes, procalcitonin, troponin, ferritin, lactate dehydrogenase, and D-dimers. At admission, the level of consciousness was assessed by the Glasgow Coma Scale19.

The neuropsychological assessment consisted of the Montreal Cognitive Assessment (MoCA, version 7)20 as a screening battery for mild cognitive impairment and the Symbol Digit Modalities Test (SDMT)21 as a measure of information processing speed (IPS). Delirium was assessed using the 4 As Test22 and Confusion Assessment Method for use in intensive care unit (ICU) patients23. MoCA and SDMT scores were transformed into demographically adjusted z-scores (see Supplementary Methods)24,25. In case of language barriers, neuropsychological assessment was limited to the SDMT or cancelled.

The EA included NCS of the right tibial, sural and ulnar nerves, BR of the bilateral ocular orbicular muscle, SSR, and motor and somatosensory evoked potentials (MEP/SSEP) to/from all extremities. If the right side could not be assessed in the NCS (e.g., due to an intravenous line) or patients specifically reported symptoms on the left side requiring clinical examination, the left side was measured instead. MEP were recorded from bilateral tibialis anterior and 1st dorsal interosseus muscles. Supramaximal stimuli of bilateral medial and tibial nerves with at least 200 averages were used for SSEP, recording responses at the poplitea/Erbs point, C5/T12 and Cp/Cz, respectively.

All measurements were carried out with a Nihon Kohden Neuropack X1 (Nihon Kohden Corporation, Tokyo, Japan) and AgAgCl surface electrodes (2820mm [MEP, SSR, and NCS]/ 2015mm [BR], Ambu, Ballerup, Denmark) and subdermal needle electrodes (SSEP/120.4mm, Ambu, Ballerup, Denmark) were used for recordings. MEP were evoked by single pulse transcranial magnetic stimulation via a standard circular coil (90mm outer diameter, The Magstim Company Ltd., Whitland, UK) connected to a Magstim 200 (The Magstim Company Ltd., Whitland, UK).

All EA were evaluated based on the clinical norms of the University Hospital Dsseldorf (Supplementary Tables S1S5) and affections were classified into PNS, CNS, and ANS (multiple selection possible).

PNS affection was defined as any abnormality in the NCS (distal motor latency [DML], F-wave latency, compound muscle action potential [CMAP], sensory nerve action potential [SNAP], motor/sensory conduction velocity [mCV/sCV]) or the following abnormalities in the BR: (1) R1, iR2 and cR2 exclusively delayed on one side, or (2) R1 and iR2 delayed on one side and cR2 delayed on the other side. Axonal pathology was defined as a reduction in CMAP/SNAP amplitude, whereas demyelinating pathology was defined as a reduction in mCV/sCV or prolongation of DML or F-wave latency.

CNS affection was defined as (1) reduced N20 and/or P40 in the SSEP and normal peripheral response (defined as normal N10 in the SSEP, if available, or as normal latency measured in the NCS), (2) increased central motor conduction time (CMCT) in the MEP, (3) increased cortical latency in the MEP and normal peripheral response (measured in the NCS), (4) delayed R1 exclusively on one side in the BR, (5) delayed R2 exclusively on one side in the BR, 6) delayed R2 on both sides in the BR.

ANS affection was defined as pathological latencies in the SSR. Please refer to Supplementary Tables S1S5 for applied cut-offs for each assessment.

Since the primary goal of the study was to investigate the unknown prevalence of (sub)clinical neurological affections, sample size was based on the number of patients willing to participate rather than statistical power calculation.

Clinical and demographic differences between surviving and deceased patients were assessed by Fishers exact test for categorical data and MannWhitney-U-test for continuous variables with non-normal distribution. P-values<0.05 were considered significant. Prevalence rates were calculated using crosstabulations (1) considering all patients, including those with missing data, and (2) including only patients who underwent the respective assessments. Exploratively, statistical analyses were repeated excluding patients with diabetes mellitus (DM) as the most prevalent potential confounding factor.

The relationship between abnormalities in the EA and death was assessed by Firth logistic regression models. Firth logistic regression models were also calculated for all predictive parameters for the patients outcome of the 4C Deterioration Model and 4C Mortality Score26,27, as well as for the WHO score18, sedation, and the Modified Rankin Scale15. Due to the exploratory nature of the study, we did not correct for multiple testing.

To avoid confounding influences of sedation, regression analyses were repeated excluding sedated patients. Further, age and sex were included as potentially confounding factors. All analyses were repeated using the raw data of the EA as independent factor.

Probabilities of mortality were estimated using KaplanMeier analysis and Cox proportional hazard models were used to compare the probability of death between patients with and without pathological findings in the EA. Again, analyses were conducted separately for the whole sample and, subsequently, only for non-sedated patients.

All analyses were conducted using R Studio (version 2021.09.1+372), except for KaplanMeier analysis and Cox proportional hazard models which were conducted using IBM SPSS Statistics (version 26).

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Prevalence and prognostic value of neurological affections in ... - Nature.com