Dear Editor

We thank Dr. Josef Finsterer for the letter entitled “Pathophysiological aspects of neuro-COVID. Short title: Pathophysiology of neuro-COVID” and the interest in our publication¹1. Puccioni-Sohler M, Poton AR, Franklin M, Silva SJD, Brindeiro R, Tanuri A. Current evidence of neurological features, diagnosis, and neuropathogenesis associated with COVID-19. Rev Soc Bras Med Trop. 2020;53:e20200477. Available from: https://doi.org/10.1590/0037-8682-0477-2020. PMID: 33027418; PMCID: PMC7534972.
https://doi.org/10.1590/0037-8682-0477-2... . The letter highlights how the neurological complications associated with COVID-19 can be widespread¹1. Puccioni-Sohler M, Poton AR, Franklin M, Silva SJD, Brindeiro R, Tanuri A. Current evidence of neurological features, diagnosis, and neuropathogenesis associated with COVID-19. Rev Soc Bras Med Trop. 2020;53:e20200477. Available from: https://doi.org/10.1590/0037-8682-0477-2020. PMID: 33027418; PMCID: PMC7534972.
https://doi.org/10.1590/0037-8682-0477-2... . Dr. Finsterer cites three other pathophysiological mechanisms that can cause secondary neurological complications such as cardiac involvement, intensive care unit treatment, and neuro- or myotoxicity of anti-COVID-19 drugs²2. Finsterer J, Scorza FA, Scorza CA, Fiorini AC. Peripheral neuropathy in COVID-19 is due to immune-mechanisms, pre-existing risk factors, anti-viral drugs, or bedding in the Intensive Care Unit. Arq Neuropsiquiatr. 2021;79(10):924-8. Available from: https://doi.org/10.1590/0004-282X-ANP-2021-0030. Epub ahead of print. PMID: 34287509.
https://doi.org/10.1590/0004-282X-ANP-20...

3. Carvalho AAS. Side Effects of Chloroquine and Hydroxychloroquine on Skeletal Muscle: a Narrative Review. Curr Pharmacol Rep. 2020:1-9. Available from: https://doi.org/10.1007/s40495-020-00243-4. Epub ahead of print. PMID: 33163329; PMCID: PMC7599118.
https://doi.org/10.1007/s40495-020-00243...

4. Mah Ming JB, Gill MJ. Drug-induced rhabdomyolysis after concomitant use of clarithromycin, atorvastatin, and lopinavir/ritonavir in a patient with HIV. AIDS Patient Care STDS. 2003;17(5):207-10.

5. Pradhan S, Pardasani V, Ramteke K. Azithromycin-induced myasthenic crisis: reversibility with calcium gluconate. Neurol India. 2009;57(3):352-3.

6. Raine C, Hamdulay SS, Khanna M, Boyer L, Kinderlerer A. An unusual complication of tocilizumab therapy: MRI appearances of thenar eminence pyomyositis. Joint Bone Spine. 2013;80(2):222.^-77. Minetto MA, D'Angelo V, Arvat E, Kesari S. Diagnostic work-up in steroid myopathy. Endocrine. 2018;60(2):219-23. Available from: https://doi.org/10.1007/s12020-017-1472-5. Epub 2017 Nov 15. PMID: 29143179.
https://doi.org/10.1007/s12020-017-1472-... . Although most of the references cited by the author were conducted prior to the COVID-19 pandemic and based on case reports, numerous other clinical conditions that can cause secondary damage to the nervous system exist. In addition to the letter, there are reports of acute kidney disease, septic shock, and liver and pancreatic dysfunction, among others⁸8. Chaudhury SS, Sinha K, Majumder R, Biswas A, Mukhopadhyay CD. COVID-19 and central nervous system interplay: A big picture beyond clinical manifestation. J Biosci. 2021;46(2):47. Available from: https://doi.org/10.1007/s12038-021-00165-3. PMID: 34047290; PMCID: PMC8154547.
https://doi.org/10.1007/s12038-021-00165...

9. Chen R, Lan Z, Ye J, Pang L, Liu Y, Wu W, et al. Cytokine Storm: The Primary Determinant for the Pathophysiological Evolution of COVID-19 Deterioration. Front Immunol. 2021;12:589095. Available from: https://doi.org/10.3389/fimmu.2021.589095. PMID: 33995341; PMCID: PMC8115911
https://doi.org/10.3389/fimmu.2021.58909... ^-1010. WHO, 2021. Clinical management of COVID-19: living guidance, 25 January 2021. World Health Organization.. Post-acute COVID-19 syndrome including cognitive decline has also been reported¹¹11. Nalbandian A, Sehgal K, Gupta A, Madhavan MV, McGroder C, Stevens JS, et al. Post-acute COVID-19 syndrome. Nat Med. 2021;27(4):601-15. Available from: https://doi.org/10.1038/s41591-021-01283-z. Epub 2021 Mar 22. PMID: 33753937.
https://doi.org/10.1038/s41591-021-01283... ^,1212. 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(10):3245-53. Available from: https://doi.org/10.1111/ene.14775. Epub ahead of print. PMID: 33576150; PMCID: PMC8014083.
https://doi.org/10.1111/ene.14775... . Neurotoxicity or myotoxicity of drugs used in the treatment of COVID-19 can occur in any other disease treated by any drug. Thus, these are drug reactions and not COVID-19 mechanisms.

Our study aimed to introduce an issue that emerged within 7 months of the COVID-19 pandemic in 2020, the mechanisms of nervous system infection, and the absence of the virus in the cerebrospinal fluid¹1. Puccioni-Sohler M, Poton AR, Franklin M, Silva SJD, Brindeiro R, Tanuri A. Current evidence of neurological features, diagnosis, and neuropathogenesis associated with COVID-19. Rev Soc Bras Med Trop. 2020;53:e20200477. Available from: https://doi.org/10.1590/0037-8682-0477-2020. PMID: 33027418; PMCID: PMC7534972.
https://doi.org/10.1590/0037-8682-0477-2... . These topics have widely been discussed in medical literature. We also highlighted the alarming epidemiological, clinical, and neurological findings reported for COVID-19 and the limitations in the laboratory diagnosis of neuro-COVID-19, considering the frequent negative SARS-CoV-2 real-time reverse transcription polymerase chain reaction test result in the cerebrospinal fluid.

In conclusion, although our study was mainly focused on the emergence of a new neuroinvasive virus and its implications for neurological diagnosis, we agree that a broad study that would generate data on adverse reactions of drugs used in COVID-19 therapy as well as other secondary neurological complications would be of great importance.

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