|Year : 2022 | Volume
| Issue : 6 | Page : 1099-1103
Profiling cognitive impairment in mild COVID-19 patients: A case-control study at a secondary healthcare centre in the hilly region of North India
Sanat Kumar Khanna1, Neelu Khanna2, Manoj Kumar Malav3, Himanshu Chhagan Bayad4, Akshay Sood5, Leena Abraham2
1 Department of Surgery, Military Hospital Shimla, Shimla, Himachal Pradesh, India
2 Department of Medicine, Military Hospital Shimla, Shimla, Himachal Pradesh, India
3 Department of Neurology, SN Medical College, Agra, Uttar Pradesh, India
4 Department of Otorhinolaryngology (ENT), Military Hospital Shimla, Shimla, Himachal Pradesh, India
5 Department of Emergency Medicine, Military Hospital Shimla, Shimla, Himachal Pradesh, India
|Date of Submission||20-Jun-2022|
|Date of Decision||21-Jun-2022|
|Date of Acceptance||24-Jul-2022|
|Date of Web Publication||3-Dec-2022|
Himanshu Chhagan Bayad
Department of Otorhinolaryngology (ENT), Military Hospital, Circular Road, Sanjauli, Shimla, Himachal Pradesh
Source of Support: None, Conflict of Interest: None
| Abstract|| |
Context: COVID-19 pandemic continues to be a serious threat to humanity even after the last 2.5 years and multiple reported waves. Post-COVID-19 cognitive impairment has a detrimental effect on the quality of life, education, occupation, psychosocial as well as adaptive functioning and independence. Aims and Objective: Profiling the cognitive impairment in the mild COVID-19 recovered patients. Settings and Design: Interview-based case-control study. Materials and Methods: This study was conducted at a secondary healthcare center in a hilly region of north India. Group A included mild COVID-19 recovered patients and Group B included local non-COVID healthy individuals. Both groups of participants were interviewed using Montreal Cognitive Assessment (MoCA) to identify global and domain-wise cognitive impairment. Statistics Used: Descriptive statistics were used to analyze the demographic and clinical variables. The Chi-square test was used to evaluate these results and statistical analysis was done using the Statistical Package for Social Sciences (version 23) program. Results: A total of 284 individuals were enrolled in our study, equally split into Groups A (cases) and B (controls). No global cognitive decline was found in any participant. However, 40 cases scored low on MoCA. The decrease in domain-wise cognitive function was statistically significant for visuospatial skill/executive function and attention. Conclusion: Our results have demonstrated that there is domain-wise cognitive impairment associated with mild COVID-19 disease. We recommend lowering the threshold of the MoCA to identify the early cognitive impairment and the inclusion of detailed cognitive assessment in post-COVID-19 follow-ups to initiate early cognitive rehabilitation among these patients.
Keywords: Case-control study, cognitive impairment, COVID-19, hilly region, MoCA
|How to cite this article:|
Khanna SK, Khanna N, Malav MK, Bayad HC, Sood A, Abraham L. Profiling cognitive impairment in mild COVID-19 patients: A case-control study at a secondary healthcare centre in the hilly region of North India. Ann Indian Acad Neurol 2022;25:1099-103
|How to cite this URL:|
Khanna SK, Khanna N, Malav MK, Bayad HC, Sood A, Abraham L. Profiling cognitive impairment in mild COVID-19 patients: A case-control study at a secondary healthcare centre in the hilly region of North India. Ann Indian Acad Neurol [serial online] 2022 [cited 2023 Feb 6];25:1099-103. Available from: https://www.annalsofian.org/text.asp?2022/25/6/1099/361563
| Introduction|| |
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2), which causes COVID-19 disease, was first reported in December 2019 in China. COVID-19 pandemic continues to be a serious threat to humanity even after the last 2.5 years and multiple reported waves. COVID-19 disease has serious effects on respiratory, nervous, cardiovascular, immune, digestive, and genitourinary systems. Each day more and more evidence is emerging of the cognitive and neurological manifestations associated with it.,
Neuropathologic findings in COVID-19 patients include lymphoid inflammation, acute hypoxic-ischemic changes, subacute cerebral infarcts, astrogliosis, spontaneous hemorrhage, microthrombi, and occasional infarcts of the anterior pituitary. Complications of COVID-19 also include psychological, psychiatric, and psychosocial sequelae. Several hypotheses of possible pathogenic mechanisms for acute and chronic neurological sequelae have emerged due to the neuroinvasive properties of COVID-19. This neuroimmune interaction is also implicated in systemic inflammation and its effects at the cognitive level. There are four probable mechanisms for the cognitive impairment due to COVID-19 infection:
- Direct neural invasion and neurotropism,
- Cerebral vascular events and coagulopathies,
- Neural damage secondary to the excessive inflammatory response (cytokine storm),
- Hypoxic brain injury.
These hypotheses were primarily derived from the studies on patients who recovered from moderate and severe COVID-19 disease. Limited data is available about the consequences of COVID-19 on the cognitive functions of mild COVID-19 recovered patients.,
Additionally, the hippocampus is sensitive to changes in oxygen concentration. Low oxygen concentration in cerebral blood supply can lead to memory loss. Endothelial lesions described in COVID-19 have been implicated in impaired clearance of brain metabolites such as beta-amyloid peptides, which are also involved in Alzheimer's disease.,
Cognitive impairment has a detrimental effect on the quality of life, education, occupation, psychosocial as well as adaptive functioning and independence.,, Especially, the decline in executive function is strongly associated with decreased quality of life and greater psychosocial distress in patients with COVID-19 infection. Post-COVID-19 syndrome is not limited to severe cases only but is also highly prevalent among mild-to-moderate cases.
A clear understanding of the long-term effects of direct neural invasion by SARS-CoV-2 still eludes us. Considering the majority of COVID-19 patients suffered from mild disease and the lack of data on the cognitive profile of mild COVID-19 recovered patients in the literature, we undertook this study with a focus on assessing and analyzing the cognitive profile of mild COVID-19 recovered patients.
| Materials and Methods|| |
Study Design and Participants
A case-control study was conducted at a secondary care hospital in the hilly terrain of North India from April 2020 to March 2022. The hospital is located at an altitude of 2202 meters (7224 ft). All the consenting RT-PCR positive mild COVID-19 patients, irrespective of gender, between 18 and 60 years of age were included as cases (Group A). Since this study was conducted at a moderate-high altitude, the low environmental oxygen concentration could have been a confounding factor. Therefore, we selected a control group (Group B) of healthy non-COVID (who never contracted COVID-19 infection) individuals from the same locality. To avoid sample bias, the controls were matched for age, gender, and education. Exclusion criteria for both cohorts were a history of neurological or psychiatric disorders before the COVID-19 pandemic, drug abuse or drug dependence, and hearing or visual impairments. Clinical records of all mild COVID-19 patients, containing detailed clinical history, examination, and lab workup were analyzed.
Initially, the cognitive assessment of Group A participants was done using the Montreal Cognitive Assessment (MoCA) and Mini-Mental State Examination (MMSE). The MoCA mainly includes extensive neuropsychological assessment of visuospatial skills/executive functions, attention, memory, and language. MoCA and MMSE for Group A were conducted at least 6 months after recovery from COVID-19 infection. The results of both tests were compared to find a better screening tool. Depending on this comparison, we chose the test which was found to be superior in the assessment of Group B [Figure 1].
Descriptive statistics were used to analyze the demographic and clinical variables. The categorical variables were expressed as absolute values (percentage), while the continuous variables with normal distribution were described as mean ± standard deviation (SD), and those without normal distribution as median and interquartile range (IQR). The results are presented as odds ratio (OR) for each significant domain. The Chi-square test was used to evaluate these results and statistical analysis was done using the Statistical Package for Social Sciences (version 23) program. We hypothesized that there is mild cognitive impairment associated with mild COVID-19 infection. In all cases, the level of significance was set at P value < 0.05 with a confidence limit of 95%.
| Results|| |
A total of 284 individuals were enrolled in this study, equally split into Groups A (cases) and B (controls). The characteristics of participants of Groups A and B were matched for age, gender, and education [Table 1].
The male to female sex ratio was approximately 2.22:1. The overall mean age of mild COVID-19 patients at the assessment was 34.91 ± 8.64 years (interquartile range of 29–41 years). The majority of the patients were in the age range between 31 and 40 years old (38.03%), followed by 32.34% of patients in the age range between 18 and 30 years old [Figure 2]. After applying the Chi-square test, it was noted that there was no significant relationship between age, gender, and education with cognitive impairment.
Montreal Cognitive Assessment Vs Mini-Mental State Examination
Initially, MMSE was used to identify any cognitive impairment among cases, as this test was widely used, time-efficient, and easier to interpret. Only 8 participants of Group A scored low but there was no evidence of global cognitive impairment. On the other hand, 40 participants of Group A scored low on the MoCA with no evidence of global cognitive impairment. Thus, we decided to go ahead with the MoCA for this study as it was more sensitive.
General cognitive performance
MoCA was used to assess the cognitive impairment among the participants. We did not find any global cognitive impairment in both groups as per the given cut-off of the MoCA. However, there was decreased scoring among 40 participants of Group A with an OR of 3.08, a Chi-square score of 6.406, and a P value of 0.0113, which was significant. When these decreased MoCA scores were statistically analyzed and critically examined, the deviation was statistically significant in Cohen's (0.311343), Delta's (0.28658), and Hedge's variations (0.311343). This suggests that the deviation of the parameter that is being measured is statistically significant as well as boosts the results and the desired conclusion of this study.
Domain-wise cognitive impairment
When the results of the MoCA were analyzed on the basis of scoring in individual domains, it was found that the decreased scores among Group A participants for visuospatial skill/executive function and attention were statistically significant with P values of 0.00137 and 0.0279, respectively [Figure 3]. The scores of participants of Group A for abstraction and delayed recall were statistically significant at a confidence level of 90% with P values of 0.0289 and 0.0703, respectively [Table 2].
|Figure 3: Domain-wise distribution of significant MoCA scores among Groups A and B|
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|Table 2: Domain-wise distribution of significant MoCA scores among Groups A and B|
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Isolated single-domain cognitive impairment was seen in 9.85% of Group A participants with visuospatial skill/executive function (7.04%) being the most commonly affected domain. 18.03% of Group A participants had multidomain cognitive impairment.
| Discussion|| |
We described a case-control study of the cognitive impairment in mild COVID-19 patients versus healthy local individuals in the hilly terrain. The study was conducted at a secondary health care center at an altitude of 2202 meters (7224 ft). It was evident from our study that 28.16% of mild COVID-19 patients did have cognitive impairment on the MoCA in the form of decreased visuospatial skill/executive function (9.85%), attention (16.90%), abstraction (12.67%), and memory (delayed recall) (16.90%), however, we could not find any patient with global cognitive impairment.
A systematic review of 22 clinical studies by Tavares et al. cited that COVID-19 associated cognitive impairment varied from 2.6 to 81%. In studies where the assessment was performed 6–12 months after the acute phase, cognitive impairment ranged from 21 to 65%. Del Brutto et al. performed the only study with pre- and post-COVID-19 cognitive assessment in mild COVID-19 disease and found cognitive impairment in 21.6% of patients. Studies by Hosp et al., Miskowiak et al., and Whiteside et al. also demonstrated impairment in cognitive domains of attention and executive functions from 1 to 6 months post-COVID-19 infection.,, Similar to our results, a study by Crivelli et al. identified deficits predominantly in executive functions and attention with minor effects on language and memory among mild COVID-19 patients.
A magnetic resonance imaging-based study by Lu et al. observed cortical microstructural damage with probable disruption in frontal-subcortical pathways irrespective of COVID-19 severities. The disturbance in executive function is a characteristic feature of frontal-subcortical disruption.
The impact of the decrease in cognitive domains such as executive function, attention, or memory adversely impacts the quality of life of the patients. We have realized that there is an acute need to identify the cognitive deficits in mild COVID-19 patients to provide them with cognitive rehabilitation and psychological support as soon as possible. We also found that age, gender, and education did not play any significant role in cognitive impairment among mild COVID-19 patients.
Despite its wide popularity, MMSE should be used cautiously because of its limited ability to detect initial visuospatial and executive function impairments. Therefore, based on our results, MoCA which includes more domains for cognitive assessment represents a more sensitive and superior screening test to detect a wide range of cognitive impairments.
Being a secondary healthcare center in the hilly region, we could not subject the participants to advanced objective modalities such as functional magnetic resonance imaging of the brain and extensive CSF analysis, however, we recommend that these tests should be part of any future research on cognitive effects of mild COVID-19 disease.
| Conclusion|| |
Our results have demonstrated that there is domain-wise cognitive impairment associated with mild COVID-19 disease. We propose the initial cognitive effects of mild COVID-19 must not be overlooked as this impairment may persist for a long time after the recovery from COVID-19 infection, if not identified early. The impaired executive function, attention, and memory take a toll on the quality of life and subject the affected individuals to greater psychological distress. Thus, we recommend the inclusion of detailed cognitive assessment in post-COVID-19 follow-ups to initiate early cognitive rehabilitation among these patients. We also recommend the modification of cognitive assessment tools in the form of a lower threshold to identify the cognitive impairment at the initial stage.
The authors assert that all the procedures contributing to the present work comply with the ethical standards of the relevant national and institutional guidelines on human experimentation and with the Helsinki Declaration of 1975, as revised in 2008.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
Zhu N, Zhang D, Wang W, Li X, Yang B, Song J, et al
. A novel coronavirus from patients with pneumonia in China, 2019. New Eng J Med 2020;382:727-33.
Shen Q, Li J, Zhang Z, Guo S, Wang Q, An X, et al
. COVID-19: Systemic pathology and its implications for therapy. Int J Biol Sci 2022;18:386-408.
Septyaningtrias DE, Susilowati R. Neurological involvement of COVID-19: From neuroinvasion and neuroimmune crosstalk to long-term consequences. Rev Neurosci 2021;32:427-42.
Moro E, Priori A, Beghi E, Helbok R, Campiglio L, Bassetti CL, et al
. EAN core COVID-19 task force. The international European Academy of Neurology survey on neurological symptoms in patients with COVID-19 infection. Eur J Neurol 2020;27:1727-37.
Nagu P, Parashar A, Behl T, Mehta V. CNS implications of COVID-19: A comprehensive review. Rev Neurosci 2021;32:219-34.
Fisicaro F, Di Napoli M, Liberto A, Fanella M, Di Stasio F, Pennisi M, et al
. Neurological sequelae in patients with COVID-19: A histopathological perspective. Int J Environ Res Public Health 2021;18:1415.
Wang SC, Su KP, Pariante CM. The three frontlines against COVID-19: Brain, behavior, and immunity. Brain Behav Immun 2021;93:409-14.
Heneka MT, Golenbock D, Latz E, Morgan D, Brown R. Immediate and long-term consequences of COVID-19 infections for the development of neurological disease. Alzheimers Res Ther 2020;12:69.
Alemanno F, Houdayer E, Parma A, Spina A, Del Forno A, Scatolini A, et al
. COVID-19 cognitive deficits after respiratory assistance in the subacute phase: A COVID-rehabilitation unit experience. PLoS One 2021;16:e0246590.
Sartori AC, Vance DE, Slater LZ, Crowe M. The impact of inflammation on cognitive function in older adults: Implications for health care practice and research. J Neurosci Nurs 2012;44:206.
Varga Z, Flammer AJ, Steiger P, Hebrecker M, Andermatt R, Zinkernagel AS, et al
. Endothelial cell infection and endotheliitis in COVID-19. Lancet 2020;395:1417-8.
Weller RO, Subash M, Preston SD, Mazanti I, Carare RO. Perivascular drainage of amyloid-b peptides from the brain and its failure in cerebral amyloid angiopathy and Alzheimer's disease. Brain Pathol 2008;18:253-66.
Abrahamson K, Clark D, Perkins A, Arling G. Does cognitive impairment influence quality of life among nursing home residents? Gerontologist 2012;52:632-40.
Mayo NE, Brouillette MJ, Scott SC, Harris M, Smaill F, Smith G, et al
. Relationships between cognition, function, and quality of life among HIV+Canadian men. Qual Life Res 2020;29:37-55.
Miskowiak KW, Johnsen S, Sattler SM, Nielsen S, Kunalan K, Rungby J, et al
. Cognitive impairments four months after COVID-19 hospital discharge: Pattern, severity and association with illness variables. EurNeuropsychopharmacol 2021;46:39-48.
Tenforde MW, Kim SS, Lindsell CJ, Rose EB, Shapiro NI, Files DC, et al
. Symptom duration and risk factors for delayed return to usual health among outpatients with COVID-19 in a multistate health care systems network—United States, March–June 2020. Morbid Mortal Week Rep 2020;69:993.
Peacock AJ. Oxygen at high altitude. BMJ 1998;317:1063-6.
Nasreddine ZS, Phillips NA, Bédirian V, Charbonneau S, Whitehead V, Collin I, et al
. The montreal cognitive assessment, MoCA: A brief screening tool for mild cognitive impairment. J Am Geriatr Soc 2005;53:695-9.
Pangman VC, Sloan J, Guse L. An examination of psychometric properties of the mini-mental status examination and the standardized mini-mental status examination: Implications for clinical practice. Appl Nurs Res 2000;13:209-13.
Tavares-Junior JWL, de Souza ACC, Borges JWP, Oliviera DN, Siqueira-Neto JI, Sobreira-Neto MA, et al
. COVID-19 associated cognitive impairment: A systemic review. Cortex 2022;152:77-97.
Del Brutto OH, Wu S, Mera RM, Costa AF, Recalde BY, Issa NP. Cognitive decline among individuals with history of mild symptomatic SARS-CoV-2 infection: A longitudinal prospective study nested to a population cohort. Eur J Neurol 2021;28:3245-53.
Hosp JA, Dressing A, Blazhenets G, Bormann T, Rau A, Schwabenland M, et al
. Cognitive impairment and altered cerebral glucose metabolism in the subacute stage of COVID-19. Brain 2021;144:1263-76.
Whiteside DM, Oleynick V, Holker E, Waldron EJ, Porter J, Kasprzak M. Neurocognitive deficits in severe COVID-19 infection: Case series and proposed model. Clin Neuropsychol 2021;35:799-818.
Crivelli L, Calandri I, Corvalan N, Carello MA, Keller G, Martinez C, et al
. Cognitive consequences of COVID-19: Results of a cohort study from South America. Arq Neuropsiquiatr 2022;80:240-7.
Lu Y, Li X, Geng D, Mei N, Wu PY, Huang CC, et al
. Cerebral micro-structural changes in COVID-19 patients-an MRI-based 3- month follow-up study. Arch Neurol 2020;25:100484.
Cummings JL. Frontal-subcortical circuits and human behavior. Arch Neurol 1993;50:873-80.
Dong Y, Sharma VK, Chan BPL, Venketasubramanian N, Teoh HL, Seet RCS, et al
. The montreal cognitive assessment (MoCA) is superior to the mini-mental state examination (MMSE) for the detection of vascular cognitive impairment after acute stroke. J Neurol Sci 2010;299:15-8.
[Figure 1], [Figure 2], [Figure 3]
[Table 1], [Table 2]