Complaints from a neurological point of view

The most common complaints after COVID-19 infection are postexertional malaise, fatigue, memory problems, and persistent anosmia. Interdisciplinary care with somatic and mental health expertise is required. Treatment is with individualized physical stress program and cognitive behavioral therapy.

When clinical symptoms and pathologic examination findings occur during or after COVID-19 disease and persist for at least 12 weeks after acute infection and cannot be explained by other diagnoses, the term post-COVID-19 syndrome is often used. Because the criteria for a circumscribed syndrome are not met, the term postacute sequelae of SARS-CoV-2 infection (PASC) is now preferred, defined as persistent, recurrent, or new-onset symptoms or complaints after Sars-CoV-2 infection [1].

The most common complaints are shortness of breath and neurological complaints such as fatigue, exercise intolerance and cognitive impairment. More specific neurological symptoms include olfactory and gustatory disturbances.

• Fatigue is a subjectively severely limiting, disproportionate in relation to previous stresses, and not sufficiently improving by recovery, on a somatic, cognitive, or psychological level.
• In particular, a stress intolerance, postexertional malaise (PEM), is typical. This is a worsening of symptoms after physical, mental or emotional exertion, which sometimes has a delayed onset and lasts for hours, occasionally even days.
• Cognitive deficits according to COVID-19 involve planning thinking, concentration, memory or language skills. This is often accompanied by a subjective inhibition or slowing of the thought process (brain fog).

Especially after hospitalization for covid-19 infection, central or peripheral neurologic symptoms may also persist after stroke, delirium, polyneuropathy, or myopathy.

Risk factors for post-COVID complaints.

As shown in a systematic review with meta-analysis of 41 studies and 860 783 patients, female gender, older age, high BMI, smoking, and previous hospitalization (especially ICU) are risk factors for persistent post-COVID symptoms [2]. Allergies, autoimmune diseases, and pre-existing mental health conditions such as depression or anxiety disorder also increase the risk.

Pathogenesis of post-COVID complaints.

A clinically relevant problem is the observation that symptoms subjectively attributed to a SARS-CoV-2 infection that has occurred do not correlate with serologic detection of infection by PCR testing. Both Sars-CoV-2 infection and vaccination against the pathogen have a significant nocebo effect. Personality traits such as neuroticism, increased body consciousness, and excessive rumination, as well as low physical activity and loneliness, are associated with the occurrence of PASC [3].

On the other hand, data from the UK biobank started in the pre-pandemic era with cMRI findings before and after COVID-19 in the same individuals after intervening SARS-CoV-2 infection demonstrate a decrease in gray matter in the orbitofrontal cortex and parahippocampal gyrus, tissue changes in brain regions functionally associated with the primary olfactory cortex [4] (Fig. 1). Cognitive impairment was more common with delayed SARS-CoV-2 RNA clearance [5] and was associated in part with the detection of antineuronal antibodies in CSF [6]. (Table 1). Data from the national health database of the US Department of Veterans Affairs show that in the first year after COVID-19, there is an increased risk of cardiovascular disease patterns such as thrombosis or stroke, regardless of age, ethnicity, gender, and risk factors such as hypertension, obesity, or diabetes mellitus [7]. Postinfectious persisting coagulopathy could be an explanation for this.

Clarification of post-COVID complaints

The first step in the workup in the primary care physician’s office should be an internal medicine status with basic laboratory tests for inflammatory activity, increased tendency to thrombosis, and exclusion of metabolic causes. If pathologic cardiac or pulmonary status is present, appropriate internal medicine therapy must be provided.

In addition, an affective status to question mental disorder and a neuro status to exclude focal symptoms are required. This is followed by the recording of subjective complaints with fatigue scales and basic neuropsychological diagnostics. In the absence of evidence of internal or neurological symptom complexes, general practitioner psychotherapeutic treatment can be provided depending on severity and participation status, supplemented by psychosomatic rehabilitation if necessary.

For cognitive problems, if the Montreal Cognitive Assessment (MoCA) test is abnormal, anosmia or focal neurologic symptoms are present, referral to a specialist is required. Extended workup is then performed using cMRI, neurophysiology, and cerebrospinal fluid. Neurorehabilitation may be indicated.

Treatment of post-COVID complaints

A dual treatment concept taking somatic and psychological aspects into account is always required. The basis is an individually adapted physical stress program and neurocognitive training. For fatigue, the effect of cognitive behavioral therapy was demonstrated in a randomized controlled trial [8]. Immunomodulatory therapy with steroids, immunoglobulins, or apheresis procedures should be performed only in the context of controlled trials when there is laboratory evidence of autoimmune pathogenesis. Low-dose anticoagulation may be useful if there is evidence of coagulopathy.

Since there are no proven drug therapy options, prevention is of great importance. The Sars-CoV-2 vaccines not only protect against severe acute courses, but also against post-COVID symptoms [9].

Take-Home-Messages

• The most common complaints after Covid-19 infection are postexertional malaise, fatigue, memory problems, and persistent anosmia.
• Targeted questions should be asked about social factors, anxiety disorder, depression, post-traumatic stress disorder.
• Pathophysiologically, autoimmune mechanisms, coagulopathy, and psychological factors should be evaluated.
• Interdisciplinary care with somatic and mental health expertise is required.
• Treatment with individually adapted physical stress program and cognitive behavioral therapy.

Literature:

1. Thaweethai T, Jolley SE, Karlson EW, et al.: Development of a Definition of Postacute Sequelae of SARS-CoV-2 Infection. JAMA 2023; doi: 10.1001/jama.2023.8823.
2. Tsampasian V, Elghazaly H, Chattopadhyay R, et al.: Risk Factors Associated with Post−COVID-19 Condition: A Systematic Review and Meta-analysis. JAMA Intern Med 2023; doi: 10.1001/jamainternmed.2023.0750.
3. Selvakumar J, Havdal LB, Drevvatne M, et al.: Prevalence and Characteristics Associated With Post-COVID-19 Condition Among Nonhospitalized Adolescents and Young Adults. JAMA Netw Open 2023; 6(3): e235763; doi: 10.1001/jamanetworkopen.2023.5763.
4. Douaud G, Lee S, Alfaro-Almagro F, et al.: SARS-CoV-2 is associated with changes in brain structure in UK Biobank. Nature 2022; 604: 697–707; doi: 10.1038/s41586-022-04569-5.
5. Antar ARR, et al.: Long COVID brain fog and muscle pain are associated with longer time to clearance of SARS-CoV-2 RNA from the upper respiratory tract during acute infection. Front Immunol 2023; doi: 10.3389/fimmu.2023.1147549.
6. Franke C, et al.: Association of cerebrospinal fluid brain-binding autoantibodies with cognitive impairment in Post-COVID-19 syndrome. Brain Behavior and Immunity 2023; doi: 10.1016/j.bbi.2023.01.006.
7. Xie Y, Xu E, Bowe B, et al.: Long-term cardiovascular outcomes of COVID-19. Nat Med 2022; doi: 10.1038/s41591-022-01689-3.
8. Kuut TA, Müller F, Csorba I, et al.: Efficacy of cognitive behavioral therapy targeting severe fatigue following COVID-19: results of a randomized controlled trial. Clin Infect Dis 2023; doi: 10.1093/cid/ciad257.
9. Azzolini E, Levi R, Sarti R, et al.: Association Between BNT162b2 Vaccination and Long COVID After Infections Not Requiring Hospitalization in Health Care Workers. JAMA 2022; doi: 10.1001/jama.2022.11691.

InFo PNEUMOLOGIE ALLERGOLOGIE 2024; 6(3): 22–24