The Mystery of Long COVID and the Brain

Theoharides TC, Cholevas C, Polyzoidis K, Politis A. Long-COVID syndrome-associated brain fog and chemofog: Luteolin to the rescue. Biofactors. 2021 Mar;47(2):232-241. doi: 10.1002/biof.1726. Epub 2021 Apr 12. PMID: 33847020; PMCID: PMC8250989.

Since early in the COVID-19 pandemic, patients have described lingering symptoms following acute infection, now called Long Covid, post-COVID-19 syndrome, or post-acute sequelae of SARS-CoV-2 infection (PASC). PASC is defined by the persistence of clinical signs and symptoms that arise during or after COVID-19, persist for more than 12 weeks, and are not explained by an alternative diagnosis.

Although the estimate of those experiencing PASC is commonly estimated at 10-30% one study showed that between 10-65% of survivors who suffered mild/moderate COVID-19 had symptoms of post-COVID-19 syndrome at 12 weeks or more. PMID: 34042167

And at least 30% may have symptoms of anxiety and/or depression after recovery from the acute phase of the infection. PMID: 34042167

An online survey of 3762 patients (87% between 30-59 y.o., 79% women, 76% were from the U.S. or U.K. and 18% were healthcare workers) experiencing continued symptoms from COVID-19 was conducted between December 2019 and May 2020. For the majority of respondents (>91%), the time to recovery exceeded 35 weeks. PMID: 34308300

Seven months after the onset of COVID-19, 78% reported persistent fatigue, 73% had post-exertional malaise, 56% had sensorimotor symptoms, and 58% had cognitive dysfunction. Many were unable to work or required a reduced work schedule compared with prior to infection.

Symptoms were clustered based on their temporal changes and the symptom group that increased over the 7 month period (see Figure below) included: palpitations , bradycardia, skin rashes, GI symptoms (constipation, reflux), hearing and vision symptoms, new allergies and anaphylaxis, joint and muscle pain, and neuropsych symptoms- brain fog, memory issues, neuralgia, speech and language issues, tremors, and vibrating sensations as well as post-exertional malaise. Menstrual issues and bladder control issues also increased.

Cognitive dysfunction, and memory impairment at work were highest in the 18-39 year old groups and were healthy and active prior to infection. The majority were never hospitalized during their acute COVID-19 illness, reflecting mild initial disease.

Other studies have agreed that post-infection symptoms are varied but the most common symptoms are fatigue, dyspnea, impaired attention, concentration, memory and sleep, anxiety and depression.

Fifteen clinical studies and 47,910 patients (age range: 18-87 years) analyzed the frequency of 55 symptoms or long-term complications after suffering from COVID-19. The follow-up time was between 14 and 110 days after infection. 80% had suffered from one or more symptoms and the five most prevalent symptoms were fatigue (58%), headache (44%), attention deficit (27%), alopecia (25%) and dyspnea (24%). Other prevalent neurological and psychiatric symptoms were ageusia (23%), anosmia (21%), memory problems (16%), tinnitus (15%), anxiety (13%), and depression (12%). Less common symptoms of chills, flushing, ear pain, and visual impairments were also documented. PMID: 33175566

Similar post-viral syndromes have been observed with prior human coronavirus diseases- fatigue, myalgia, and psychiatric impairments have inflicted survivors of Middle East respiratory syndrome (MERS) and severe acute respiratory syndrome (SARS) for up to four years post-infection. Even at 7-year and 15-year follow-ups, pulmonary and bone radiological complications were still evident among a proportion of SARS survivors who were mostly younger than 40 years of age. PMID: 32128276/PMID: 30605995/ PMID: 20008700

Many other viruses also cause post-viral syndromes: Epstein-Barr, herpes type 6, cytomegalovirus, dengue, West Nile, chikungunya, Ebola, influenza, Coxsackie, retroviruses as well as bacterial, fungal and protozoal infections (Borrelia, Mycoplasma, Chlamydia, etc.). Common examples are Lyme disease post-treatment syndrome, chronic fatigue syndrome/myalgic encephalitis, post-viral cerebellar ataxia or post-polio syndrome. PMID: 31394725

The cause of this direct or indirect invasion of the virus into the brain and it’sconsequent immune dysregulation is unclear but could include hormonal disturbances (sub-acute thyroiditis, thyroid dysfunction and new-onset diabetes are seen post-COVID), elevated cytokine levels leading to chronic inflammation, direct tissue damage to other organs, and/or persistent low-grade infection. PMID: 34181102

Despite the lack of understanding of the mechanisms, brain structural changes are real. A study of 60 “recovered” COVID-19 patients and 39 controls at three months post-discharge found brain MRI abnormalities in the thalamus and thalamic radiations and impairment in executive and visuospatial areas in the COVID-19 survivors that correlated with their memory loss, anosmia, and fatigue. PMID: 3283824

Strategies to address neurologic damage with PASC will need to be able to reverse neuroinflammation and address potential hormonal dysregulation. They will also have to address the changes in circulation in the blood-brain and blood-cerebrospinal fluid barriers that may induce neuronal, glial and brain vessel inflammation. PMID: 33753937