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Neurological outcome and quality of life 3 months after COVID‐19: A prospective observational cohort study

Abstract Background and purpose To assess neurological manifestations and health‐related quality of life (QoL) 3 months after COVID‐19. Methods In this prospective, multicenter, observational cohort study we systematically evaluated neurological signs and diseases by detailed neurological examination and a predefined test battery assessing smelling disorders (16‐item Sniffin Sticks test), cognitive deficits (Montreal Cognitive Assessment), QoL (36‐item Short Form), and mental health (Hospital Anxiety and Depression Scale, Posttraumatic Stress Disorder Checklist–5) 3 months after disease onset. Results Of 135 consecutive COVID‐19 patients, 31 (23%) required intensive care unit (ICU) care (severe), 72 (53%) were admitted to the regular ward (moderate), and 32 (24%) underwent outpatient care (mild) during acute disease. At the 3‐month follow‐up, 20 patients (15%) presented with one or more neurological syndromes that were not evident before COVID‐19. These included polyneuro/myopathy (n = 17, 13%) with one patient presenting with Guillain‐Barré syndrome, mild encephalopathy (n = 2, 2%), parkinsonism (n = 1, 1%), orthostatic hypotension (n = 1, 1%), and ischemic stroke (n = 1, 1%). Objective testing revealed hyposmia/anosmia in 57/127 (45%) patients at the 3‐month follow‐up. Self‐reported hyposmia/anosmia was lower (17%) at 3 months, however, improved when compared to the acute disease phase (44%; p < 0.001). At follow‐up, cognitive deficits were apparent in 23%, and QoL was impaired in 31%. Assessment of mental health revealed symptoms of depression, anxiety, and posttraumatic stress disorders in 11%, 25%, and 11%, respectively. Conclusions Despite recovery from the acute infection, neurological symptoms were prevalent at the 3‐month follow‐up. Above all, smelling disorders were persistent in a large proportion of patients.

that neurological manifestations are prevalent at follow-up. In addition, we aimed to quantify the impact of COVID-19 on mental health and health-related quality of life (QoL) 3 months after disease onset.

Study design, setting, and participants
For this multicenter observational cohort study, consecutive COVID-19 patients were prospectively enrolled during the acute phase of the disease. They were managed at three participating clinical trial sites, namely at the Department of Internal Medicine II, Medical University of Innsbruck, Zams, and Muenster (all Tyrol, Austria). Innsbruck is a tertiary care center and Zams a secondary care center. Muenster is an acute rehabilitation facility but was refunctioned to a secondary care center during the pandemic. The diagnosis of COVID-19 was based on a typical clinical presentation together with a positive reverse transcriptase-polymerase chain reaction severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) test from a nasopharyngeal or oropharyngeal swab. General inclusion criteria consisted of (i) confirmed SARS-CoV-2 infection, (ii) hospitalization or outpatient management, and (iii) age ≥18 years.
Out of 190 patients screened during the acute phase, 145 were included in the CovILD study. Reasons for nonparticipation were mainly logistic (e.g., tourists who left the country and individuals who lived too far away from the study center to attend regular follow-up, n = 27) or refusal of consent (n = 18) [17]. A total of 135/145 patients agreed to participate in the neurological follow-up 3 months after disease onset and were evaluated using a structured neurological assessment between April 2020 and September 2020. Patients who died during the acute phase were not included in this study, and the ICU mortality rate was 19% as reported elsewhere [18]. Importantly, the Tyrolean healthcare system was never overloaded, and all patients received full medical support [18].

Standard protocol approvals, registrations, and patient consents
The conduct of the study was approved by the local ethics committee (Medical University of Innsbruck, EK Nr: 1103/2020) and was registered at ClinicalTrials.gov (NCT04416100). Written informed consent was obtained from all patients according to local regulations.

Clinical evaluation
Baseline was defined as the day of diagnosis by a positive SARS-CoV-2 test result. Six weeks and 3 months after laboratory-confirmed diagnosis, all patients underwent a structured cardiopulmonary follow-up [17]. Medical history, admission characteristics, hospital complications, and applied treatments were assessed in all patients.
Selected patients were evaluated for neurological symptoms by neurological consultancy during the acute phase of the disease. All patients diagnosed with critical illness polyneuropathy/critical illness myopathy (CIP/CIM) were seen by neurologists during the acute care. A detailed neurological evaluation was performed by neurological consultants or junior neurologists under the supervision of consultants and was carried out at the 3-month follow-up. The neurological assessment consisted of a structured interview and standardized neurological examination. The   the following cognitive domains: visuospatial-executive, naming, memory, attention, language, abstraction, and orientation [20].
Impairment was classified in patients scoring below 26/30 points.
The MoCA was not performed in patients with language barrier or visual impairment (n = 11).

Outcome instruments
Multidimensional outcomes were assessed using five instruments measuring health-related QoL, mental health, and functional outcome.
Health-related QoL was evaluated with the 36-item Short Form (SF-36v2), a self-report questionnaire rating the subjective health condition encompassing mental, physical, and social functioning [21]. The questionnaire provides scores of eight health domains. The

Statistical analysis
Categorical variables are given in counts and percentages, con- Data are given as median (interquartile range), mean ± standard deviation, and count (%). Abbreviation: ICU, intensive care unit.
*χ 2 or Kruskal-Wallis tests were used to assess for differences across severity grades (severe, moderate, mild). A p value <0.05 signifies significantly different data distribution across severity groups.

TA B L E 1 (Continued)
distribution (Kolmogorov-Smirnov test and Shapiro-Wilk test), parametric or nonparametric tests were applied. We used the χ 2 or Kruskal-Wallis test to assess for differences across severity grades. In the setting of a p value <0.05 indicating significantly different data distribution across severity groups, we performed Bonferroni-corrected post hoc pairwise analyses using univariate generalized linear models (Table S1). To test for changes in symptoms between the acute disease course and at 3 months, the McNemar test was used. Missing data were excluded from analysis and indicated appropriately. We built a multivariate generalized linear model to assess factors associated with fatigue 3 months after COVID-19. We included preselected variables with a p < 0.

Data
The data that support the findings of this study are available from the corresponding author, upon reasonable request and by fulfilling data sharing regulations approved by the local ethics committee.

DISCUSS ION
In this prospective observational study of 135 COVID-19 patients, we found neurological diseases unknown before COVID-19 in every sixth patient at the 3-month follow-up with a predominance in ICU patients, including polyneuro/myopathy, mild encephalopathy,  Abbreviations: CIP/CIM, critical illness polyneuropathy/critical illness myopathy; ICU, intensive care unit; PNP, polyneuropathy.
*The χ 2 test was used to assess for differences across severity grades (severe, moderate, mild). A p value <0.05 signifies significantly different data distribution across severity groups.  Little is known about reversibility or persistence of neurological and neuropsychological manifestations after COVID-19. The main neurological features at the 3-month follow-up were hyposmia/anosmia as well as (critical illness) polyneuro/myopathy in our cohort.

TA B L E 3 Neurological signs and symptoms 3 months after COVID-19
The observed prevalence rate of self-reported hyposmia/anosmia is comparable to previous reports during the acute disease and at a 2-month follow-up [13]. Despite significant improvement over time in our cohort, we observed a high discrepancy between objective testing (45%) and self-reported hyposmia/anosmia (17%). This observation has been previously reported [25,26]. Of interest is that none of the severe COVID-19 patients admitted to the ICU reported hyposmia/anosmia at follow-up, although objective assessment was abnormal in every second patient. To date, it is still unclear whether olfactory dysfunction following COVID-19 is a consequence of angiotensin-converting enzyme (ACE) receptor downregulation of the olfactory epithelium or results due to structural abnormalities of the olfactory bulb, primary olfactory cortex (gyrus piriformis), or secondary projection areas including the limbic lobe, thalamus, and anterior cingulum [27]. Advanced neuroimaging studies suggested a decreased volume of the gray matter in patients with persistent hyposmia 3 months after disease compared to COVID-19 patients without anosmia [14]. Another study found an association between transient edema of the olfactory bulb and smelling disorders [28]. In addition, fluid-attenuated recovery images on cerebral MRI revealed *The chi-square test was used to assess for differences across severity grades (severe, moderate, mild). A P value < 0.05 signifies significantly different data distribution across severity groups. *χ 2 or Kruskal-Wallis tests were used to assess for differences across severity grades (severe, moderate, mild). A p value <0.05 signifies significantly different data distribution across severity groups.

TA B L E 3 (Continued)
signal hyperintensities in the olfactory bulb and frontobasal cortical areas in a patient suffering from hyposmia [29]. After recovery, signal alterations of cortical grey matter regions completely disappeared, and the olfactory bulbs appeared thinner. Although careful evaluation for publication bias is warranted, these findings may support a direct virus-associated pathology of neuronal tissue in humans. Besides the retrograde neuronal spread, the sensory organs of smell may also be affected by excessive or uncontrolled production of immune cells and cytokines, a breakdown of the blood-brain barrier, or microvascular damage [27].
Encephalopathy was reported in one third of ICU patients during acute disease stages, with only one of those patients having persistent features 3 months after disease onset. Frontal release signs were positive in 15% of our patients at follow-up, which are unspecific but commonly found in patients with encephalopathy.
Encephalopathy and frontal signs were highly prevalent in another cohort of 58 severe COVID-19 patients admitted to the hospital because of ARDS [2]. In all patients of this study who underwent cerebral MRI because of unexplained encephalopathic features, bilateral frontotemporal hypoperfusion was noted [2]. Limited evidence suggests a direct virus-associated etiology of encephalopathy in COVID-19 patients, and therefore, it is more likely that encephalopathy occurs secondary due to inflammation or other systemic effects including organ failure [30,31].
Cognitive deficits as assessed with the MoCA were frequent 3 months after COVID-19 diagnosis, predominantly affecting hospitalized patients. Every second patient diagnosed with encephalopathy during their ICU stay had cognitive deficits as compared to 23% in the overall cohort. We cannot exclude that non-overt cognitive deficits were undiagnosed before COVID-19 in these patients.
Interestingly, self-reported cognitive deficits (e.g., forgetfulness, trouble in concentrating, difficulty in thinking) were equally reported independent of severity groups (24%-26%), even in patients with mild disease (24%). Other groups recently reported that the estimated prevalence for dementia after COVID-19 is higher during a 6-month follow-up period compared with patients after influenza or other respiratory tract infections [32]. Further longitudinal studies with detailed neuropsychological testing are necessary to evaluate whether cognitive deficits improve over time.
Although several studies indicate the involvement of the CNS  [13]. Postulated underlying mechanisms include a virus-triggered inflammatory response or direct muscle toxicity [35]. The virus may infiltrate the muscle via the ACE-2 receptor, which is expressed on skeletal muscles [36]. In turn, immunemediated mechanisms include muscle damage through T-cell expansion or proinflammatory cytokine and macrophage-mediated muscle fiber injury [37]. Immune-mediated toxicity of the virus has been described in the setting of para-and postinfectious immunemediated diseases such as acute disseminated encephalomyelitis [38] or myelitis [39]. Similarly, the peripheral nervous system is affected by immune-mediated disease with Guillain-Barré syndrome or variants reported in patients after COVID-19 [40,41]. We report 1 COVID-19 patient who developed Guillain-Barré syndrome and showed good recovery 3 months after disease onset [42].
Impairment of QoL, anxiety and depressed mood, sleep disorders, and PTSD were found in a considerable number of patients.
These manifestations have a substantial socioeconomic burden on mental health. Close surveillance to ensure early detection of potentially treatable conditions and the provision of targeted treatment strategies including psychological support seems important in recovered patients. It is worth mentioning that some neuropsychiatric findings may be not associated with the disease itself but with the overall social consequences related to the pandemic. Accordingly, also non-COVID-19 patients developed depression, anxiety, and PTSD symptoms during the pandemic [43]. The number of people affected by these symptoms was found to have increased since onset of the pandemic, predominantly affecting young female patients with low incomes [44].
Fatigue was reported in 50% of ICU patients and in every fourth patient with mild disease in our cohort. This is in line with previous studies reporting fatigue in 53% of hospitalized COVID-19 patients 2 months after symptom onset [13] and in another study reporting fatigue or muscle weakness in 63% (1038/1655) of survivors 6 months after COVID-19 [45]. We found an association between disturbed sleep and the diagnosis of a new-onset neurological disease not diagnosed before COVID 19 and fatigue. Based on our data and previous publications, fatigue does not seem to be limited to severe cases.
There are limitations to this study that should be discussed.
Firstly, our study design does not allow us to conclude causality between COVID-19 and the reported neurological symptoms and diseases, and there is the possibility of a chance association. To minimize this bias, we carefully evaluated preexisting neurological disorders and found that every third patient had neurologic consultancy before COVID-19 onset. Similarly, we did not assess baseline MoCA to quantify preexisting cognitive impairment. We only recorded relevant clinical findings that were diagnosed by a neurological consultancy during the acute disease or by physicians prior to disease onset. This is also important for parkinsonism, which may have been diagnosed by a proper neurological examination before COVID-19. Secondly, neurological assessment 3 months after disease onset may not sufficiently represent longterm consequences of this disease. Therefore, several initiatives call for a minimum 12-month follow-up [46]. Thirdly, underrepresentation of COVID-19 patients with mild disease may have led to a substantial bias in reported prevalence rates. Still, the strength of our study lies in the inclusion of all severity grades ranging from mild disease to severe manifestations requiring ICU admission.
Our data should be interpreted in the context of a healthcare system that never collapsed during the pandemic.

CON CLUS ION
In summary, despite recovery from acute infection, neurological abnormalities were common at the 3-month follow-up. Although neurological diseases were diagnosed in every sixth patient, smelling disorders were more prevalent (45%), even in COVID-19 patients recovering from mild disease. Every third patient reported poor QoL at the 3-month follow-up. Importantly, 3-month functional outcome was good, and nearly all patients regained functional independence. Early identification of patients at high risk for persistent neurologic features is important to evaluate these patients for further neuro-rehabilitative support and to develop strategies for secondary prevention. Further studies investigating socioeconomic and neurological long-term consequences of COVID-19 beyond 3 months are needed.