Cognitive dysfunction after covid-19
BMJ 2024; 384 doi: https://doi.org/10.1136/bmj-2023-075387 (Published 01 February 2024) Cite this as: BMJ 2024;384:e075387
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Dear Editor,
The article 'Cognitive Dysfunction after Covid-19' by Ladd et al [1] provides a good picture of the background of neurocognitive complaints post-Covid and the possible options for GPs to help their patients. Unfortunately, the contribution of some important neuroimmunological mechanisms and the possible medicinal intervention that results from them is missing.
In our paper Treatment of 95 post-Covid patients with SSRIs [2], which appeared a month after the publishing process of Ladd’s paper, we mention seven possible neurobiological mechanisms explaining neurocognitive symptoms. They all have to do with serotonin (a neurotransmitter transmitting chemical messages between nerve cells).
The positive results of treatment with selective serotonin reuptake inhibitors (SSRIs) in our explorative study supported our hypotheses: 63,5% (n=93) of these patients reported a fairly good to strong effect. [2] Brainfog and sensory overload decreased the most (3.8 and 3.6 pts out of 10, respectively), muscle pain and weakness responded the least (2.1 and 1.9 pts, respectively). Treatment with an SSRI also gave an average increase on the Bell Functionality Score from 23,5 to 47.2: from lying on the couch all day to full self-care, shopping, walking, and (partial) return to work.[2]
Our explaining hypotheses have now been supported by some recent papers. Klein et al reported in 2023 in Nature [3] that cortisol (stress hormone) levels in post Covid patients were significant lower than in control groups. The HPA axis (in the brains) signals the adrenal glands to release cortisol, while an SSRI modulates the HPA axis. Shortly after our publication in 2023 Wong et al showed in Cell that in post-Covid on average the serotonin level has been halved [4]. The authors recommend further research into SSRIs in preventing and treatment of post Covid. A recent study by Sydky et al [5] showed that in the case of a Covid-19 infection, the Sigma1 receptor agonists among the SSRIs (such as citalopram, fluvoxamine, fluoxetine) may prevent post-Covid better than the Sigma1 receptor antagonists, such as sertraline. And as far as the selective serotonin-norepinephrine reuptake inhibitors (SNRIs) are concerned, venlafaxine and duloxetine are Sigma1 receptor antagonists as well. This supported our experience when treating post-Covid patients with SSRIs. Another recent article mentions serotonin as possibly a key mechanistic biomarker for long covid. [6]
From the upcoming of post Covid until now we have advised more than 1,500 post-Covid patients and their GPs an SSRI-treatment including the 95 patients in our study. An SSRI is a cheap and accessible drug that can often be used by GPs. We experienced that titrating the SSRI needs special attention, more than in the traditional indications of depression and anxiety disorder. Important is very slow titration because of the side effects, and stopping with further titration in time. Sometimes you need to switch to a different SSRI.
Based on our hypothesis we identified some other options for medications and supplements. [2] So nowadays, in addition to SSRIs, we also use NAC (N-acetylcysteine): 3 dd 600 mg and resveratrol (an AHR antagonist): 2 dd 200 mg.
Competing interests: No competing interests
References
1 Ladds E, Darbyshire JL, Bakerly ND, et al. Cognitive dysfunction after covid-19. BMJ. 2024;e075387.
2 Rus CP, de Vries BEK, de Vries IEJ, et al. Treatment of 95 post-Covid patients with SSRIs. Sci Rep. 2023;13:18599.
3 Klein J, Wood J, Jaycox JR, et al. Distinguishing features of long COVID identified through immune profiling. Nature. 2023;623:139–48.
4 Wong AC, Devason AS, Umana IC, et al. Serotonin reduction in post-acute sequelae of viral infection. Cell. 2023;186:4851-4867.e20.
5 Sidky H, Sahner DK, Girvin AT, et al. Assessing the Effect of Selective Serotonin Reuptake Inhibitors in the Prevention of Post-Acute Sequelae of COVID-19. medRxiv. 2023;2022.11.09.22282142.
6 Butzin-Dozier Z, Ji Y, Sarang, et al. SSRI Use During Acute COVID-19 Infection Associated with Lower Risk of Long COVID Among Patients with Depression. medRxiv. Published Online First: 6 February 2024. doi: 10.1101/2024.02.05.24302352
Competing interests: No competing interests
Dear Editor
It is refreshing to see work being done to explore the complexities of post-viral cognitive symptoms and provide guidance on management strategies. As an ME/CFS specialist, I would like to point out that there has been no mention of ME/CFS in the article other than on the list of other potential contributors to cognitive impairment (which is potentially confusing). In addition to the cognitive dysfunction, the article covers fatigue and post-exertional malaise (PEM) symptom patterns. Given that debilitating fatigue, PEM and cognitive issues are the core symptoms of ME/CFS it would be prudent to describe the clear overlaps between Long Covid and ME/CFS.
ME/CFS is a defined illness and specialist ME/CFS services existed long before the SARS-CoV2 virus evolved, and the condition has been a much overlooked, misunderstood and underfunded area of medicine. The ME/CFS community have felt hopeful that the new clinical interest and research funding that has come out of the devastating pandemic would also serve to improve the care and treatment options for people with ME/CFS. In some parts of the UK, it was the existing ME/CFS services that stepped up and provided a Long Covid service during the pandemc. In some other regions the Long Covid services have expanded to provide an ME/CFS service where none existed before. It is clear there is a lot of shared pathophysiology between the 2 conditions (ref 1) and the 2 diagnostic labels are not mutually exclusive. Staff who have experience of supporting people with these complex multisystem conditions have acquired advanced skills that could be utilised for both patient groups.
Very few ME/CFS services can conduct clinical research due to insufficient medical input, lack of research experience and difficulty in accessing investigations or prescribing (Ref 2). Some Long Covid services have been able to secure much better financial support which has helped them make valuable progress in understanding the pathophysiology of Long Covid, but there is still a lot of work to do in this area of post-viral syndromes. The current waning of interest in Long Covid and potential threat of reduction in funding for services appears to be driven by a short-sighted view that Long Covid might be a short-term problem but as this article shows there are significant numbers of people still significantly impacted by life changing symptoms. It is estimated there are currently at least 750,000 individuals in the UK with persistent symptoms for more than 2 years (and hence become a long-term condition) (ref 3). Many ME/CFS services are also reporting steady increases in referral numbers and also increased clinical complexity which demonstrates the need for service expansion (ref 2).
The British Association of Clinicians in ME/CFS (BACME) has welcomed involvement from clinicians working in Long Covid services. The development of a Clinical Post COVID Society hosted by the British Society of Physical & Rehabilitation Medicine (ref 4) has the potential to be a positive step forward and we look forward to seeing more collaborative service development that could expand and improve the care for people with ME/CFS, Long Covid and other associated conditions.
Our power will be much greater if we work together.
1. Komaroff AL, Lipkin WI. ME/CFS and Long COVID share similar symptoms and biological abnormalities: road map to the literature. Frontiers in Medicine. 2023 Jun 2;10:1187163.
2. BACME National Services Survey October 2023 Accessed 20th February 2024 https://bacme.info/wp-content/uploads/2023/10/BACME-National-Services-Su...
3. ONS. Prevalence of ongoing symptoms following coronavirus (COVID-19) infection in the UK: 2 February 2023: Office for National Statistics; 2023 [Available from: https://www.ons.gov.uk/peoplepopulationandcommunity/healthandsocialcare/...
4. Sivan M, Heightman M. A new professional society for post-COVID condition and other post-viral conditions. Adv Rehabil Sci Pract. 2024 Feb 9;13:27536351241231351.
Competing interests: No competing interests
Could Physical exercise and caloric restriction benefit cognitive problems after acute SARS-CoV-2 infection?
Dear Editor,
Recent studies address the issue of cognitive problems after acute SARS-CoV-2 infection, also illustrating the therapeutic measures that may be useful to counteract the decline in efficiency of certain brain functions [1].
I take this opportunity to evaluate whether caloric restriction could be useful (the extent of which, with the relative details of foods, would be evaluated for each individual), even if there is not already a metabolic alteration, such as Diabetes II.
Starting from the assumption that Mitochondrial dysfunctions are the prime source of neurodegenerative diseases and neurodevelopmental disorders, the maintenance of mitochondrial homeostasis is crucial for neuronal development , mitochondria functionality depends on the equilibrium between mitochondrial biogenesis and mitophagy [2].
The hippocampus and temporal lobe structures are critical relays for learning and memory: physical exercise and caloric restriction (CR) would benefit global metabolic efficiency and neuroplasticity in the hippocampus [3].
In addition, the fundamental role of Astrocytes is highlighted by some Authors.
Astrocytes are strategically positioned to mediate the positive influence of physical activity and diet on neuronal function.
Studies of cellular mechanisms of brain longevity suggest that astrocyte-neuron communications have a vital role in the beneficial effects of CR, physical exercise and their pharmacological mimetics on synaptic homeostasis and cognitive function [4]
Finally, other authors hypothesize a synergism between CR and dietary nitrate which could provide a feasible and more effective nutritional strategy (than either intervention alone) to improve cardio-metabolic and brain health [5].
REFERENCES:
[1] Ladds E, Darbyshire JL, Bakerly ND, Falope Z, Tucker-Bell I. Cognitive dysfunction after covid-19. BMJ. 2024 Feb 1;384:e075387. doi: 10.1136/bmj-2023-075387. PMID: 38302141.
[2] Uittenbogaard M, Chiaramello A. Mitochondrial biogenesis: a therapeutic target for neurodevelopmental disorders and neurodegenerative diseases. Curr Pharm Des. 2014;20(35):5574-93. doi: 10.2174/1381612820666140305224906. PMID: 24606804; PMCID: PMC4823001.
[3] Stranahan AM, Mattson MP. Impact of energy intake and expenditure on neuronal plasticity. Neuromolecular Med. 2008;10(4):209-18. doi: 10.1007/s12017-008-8043-0. Epub 2008 Jun 10. PMID: 18543119; PMCID: PMC2635925..
[4] Lalo U, Pankratov Y. Astrocytes as Perspective Targets of Exercise- and Caloric Restriction-Mimetics. Neurochem Res. 2021 Oct;46(10):2746-2759. doi: 10.1007/s11064-021-03277-2. Epub 2021 Mar 7. PMID: 33677759; PMCID: PMC8437875.
[5] Alharbi M, Stephan BC, Shannon OM, Siervo M. Does dietary nitrate boost the effects of caloric restriction on brain health? Potential physiological mechanisms and implications for future research. Nutr Metab (Lond). 2023 Oct 25;20(1):45. doi: 10.1186/s12986-023-00766-9. PMID: 37880786; PMCID: PMC10599060
Competing interests: No competing interests