Since the onset of the COVID-19 pandemic, the persistence of neurological symptoms following the clearance of SARS-CoV-2 infection has emerged as a major health challenge for both patients and clinicians. The effects of postacute sequelae of SARS-CoV-2 infection (PASC), commonly referred to as Long COVID, are often debilitating and can persist for months after the initial infection. Symptoms such as fatigue, cognitive impairment (often called "brain fog"), sleep disturbances, neuropsychiatric sequelae, and sensorimotor issues have left many individuals struggling to regain their quality of life. Due to the complexity and variability of these symptoms, Long COVID has proven to be a multifaceted condition that is difficult to diagnose and treat.
Currently, there are no specific tests for diagnosing Long COVID, and biomarkers often fail to correlate directly with the condition. This highlights a significant gap in our understanding of the disease and the need for more targeted diagnostic tools. Experts in the field emphasize that Long COVID can affect anyone, regardless of age or prior health status, underscoring that it is not restricted to specific demographics and can impact even the healthiest individuals. To better understand the challenges and ongoing efforts to address Long COVID, Contagion conducted a roundtable discussion with NeurologyLive featuring three leading experts who run specialized Long COVID clinics at their respective institutions.1
The discussion was led by Ravindra Ganesh, MD, MBBS, FACP, Dip ABOM, Svetlana Blitshteyn, MD, FAAN, and Monica Verduzco-Gutierrez, MD, and delved into the nature of Long COVID, highlighting the difficulties in diagnosis, treatment, and the pressing need for continued research.
The Prevalence and Invisible Nature of Long COVID2
In their discussion, Verduzco-Gutierrez emphasized the often-invisible impact of Long COVID, describing it as a condition that is frequently underestimated. She stated, “Long COVID can be something that we know is very prevalent, but sometimes it is an invisible illness. People might not think that it's that much of an issue, but can be for sure.” Because its symptoms are not always externally visible, the condition often goes unreported and underdiagnosed. Recent studies estimate that 1 in 5 Americans has experienced Long COVID, although the actual number may be higher, especially when considering subclinical cases that go unnoticed.
Ganesh pointed out that many patients report feeling “not quite right” after recovering from COVID-19, but these cases often slip through the cracks. He noted, “That number is probably higher when you consider subclinical Long COVID cases, who’ve had COVID but haven’t been quite as sharp afterwards, or haven’t been quite 100%, and that number of people doesn’t get reported, but you talk to patients, and they'll tell you they just haven’t been quite right after having had COVID.” These undiagnosed cases illustrate the condition’s underappreciation by both patients and healthcare providers.
Diagnosing Long COVID is further complicated by the need for a comprehensive patient history. Blitshteyn explained, “It’s important to establish that there was a COVID infection; some patients don’t even realize their symptoms are linked to a previous infection.” Many patients may not initially connect their symptoms, such as fatigue or cognitive decline, to COVID, especially if their initial infection was mild. This delay in recognizing Long COVID can delay appropriate.
Symptoms
Internal Tremors: A new and troubling symptom of Long COVID, experienced by over one-third of participants in a Yale-based study.
Description: Sensation of twitching or vibrating inside the body, with no outward signs or physical spasms.
Prevalence: 37% of survey respondents (158 out of 423) reported experiencing internal tremors.
Impact: The sensation is described as distracting and bothersome, significantly affecting patients' quality of life.
Associated Issues: Those with internal tremors had worse overall health, more financial strain, and were more likely to face housing instability.
Other Symptoms: Participants with internal tremors were more likely to experience dizziness, heart rate issues, and nervous system-related conditions.
The ME/CFS Overlap and Diagnostic Complexities3
A central theme in the discussion was the overlap between Long COVID and Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS). Verduzco-Gutierrez noted that many Long COVID patients exhibit symptoms that closely mirror ME/CFS, such as post-exertional malaise, unrefreshing sleep, autonomic dysfunction, and cognitive deficits. This overlap presents a diagnostic challenge, as the criteria for both conditions are similar. She said, “Some patients, their manifestation of Long COVID is a picture of ME/CFS as well, because they have the criteria for that, because a lot of the criteria also are some of very similar to Long COVID symptoms, because they have post-exertional malaise, they have unrefreshing sleep, some of them have autonomic dysfunction, cognitive deficits as well.”
Blitshteyn confirmed that studies show at least 50% of Long COVID patients meet the diagnostic criteria for ME/CFS. She stated, “We have a number of studies that showed that at least 50% of patients with Long COVID qualify for the diagnosis of ME/CFS,” reinforcing the complexity of diagnosis and treatment.
Ganesh added that infections beyond SARS-CoV-2, including Epstein-Barr Virus (EBV) and chronic Lyme disease, have long been linked to the development of ME/CFS, suggesting that Long COVID may be another post-infectious syndrome that triggers similar chronic conditions. “Taking care of ME/CFS before Long COVID, we knew even then that about 70% of all cases of ME/CFS were related to an infection of sorts, and we have seen it with different infections, most commonly EBV, chronic Lyme, reported mold exposure, and after Zika,” he said.
The Need for Better Diagnostic Tools and Research Advancements3
One of the most pressing challenges in treating Long COVID is the absence of FDA-approved therapies. Ganesh and Verduzco-Gutierrez agreed that treatment remains largely off-label and based on insights gained from other chronic conditions. As Ganesh noted, "Nothing is FDA-approved, and everything we use is pieced together from our understanding of other chronic illnesses." He went on describing patients exhibiting an ME/CFS phenotype may benefit from low-dose medications like naltrexone, while those with autonomic dysfunction may require beta-blockers or other treatments for conditions such as postural orthostatic tachycardia syndrome (POTS).
Verduzco-Gutierrez emphasized that symptom management is crucial, particularly for patients with autonomic dysfunction, stating, "There isn’t a magic cure or pill yet, but figuring out the phenotype is key because symptom management is possible for many patients." She also highlighted that interventions like physical therapy, adjusting activity levels to avoid overexertion, and the use of nerve stimulators for certain types of dysautonomia can help improve quality of life for many patients. "It's also crucial to screen patients for post-exertional malaise because if they have it, we need to identify their energy envelope and ensure they don’t overdo it, which could lead to a crash," she added.
Both Verduzco-Gutierrez and Blitshteyn stressed the need for better diagnostic tools to bridge the gap between research and clinical practice. Blitshteyn echoed this concern, saying, “There’s always a huge gap between the tests available for researchers and those available for clinicians. We need to find a cost-effective way to bridge this gap.” She also highlighted the importance of validated immunologic tests to identify underlying issues like viral persistence, autoimmunity, and hypercoagulability, explaining, “You can’t exercise or diet your way out of these issues.”4
An important study conducted by the NIH on dysregulated miRNAs in Long COVID underscores the complex role these molecules play in immune responses, inflammation, and tissue repair. miRNAs like miR-146a and miR-155 regulate ACE2 expression and contribute to prolonged immune activation and persistent organ damage, which are central to Long COVID's pathophysiology.5 Yet, as Verduzco-Gutierrez pointed out, “These tests are not yet widely available in clinical settings,” despite their significant potential to improve diagnosis and management.
RECOVER Trials
RECOVER-VITAL: Tests PAXLOVID (nirmatrelvir and ritonavir) for viral replication.
RECOVER-NEURO: Investigates treatments for cognitive dysfunction, including BrainHQ, PASC-CoRE, and Transcranial Direct Current Stimulation (tDCS).
RECOVER-AUTONOMIC: Evaluates Gamunex-C for severe POTS and Ivabradine for moderate POTS.
RECOVER-SLEEP: Assesses Modafinil and solriamfetol for hypersomnia, and melatonin with light therapy for sleep disturbances.
RECOVER-ENERGIZE: Focuses on Personalized Cardiopulmonary Rehabilitation for exercise intolerance and Structured Pacing for post-exertional malaise (PEM).
Ganesh highlighted the importance of functional testing, noting that such tests can reveal physiological issues that standard anatomical scans often miss. He explained, "I think most of our patients look fine on anatomical scans, but when we challenge their physiology, when we stress them, that’s when we start to see the deficits. The changes show up."
He also pointed out that Cardiopulmonary Exercise Testing (CPET) is one of the few reliable methods for assessing the severity of conditions like ME/CFS, but its use remains limited due to the invasive nature of the test. Considering these challenges, Ganesh emphasized the significance of ongoing research initiatives, such as the RECOVER initiative, as well as clinical trials like REVERSE-Long COVID, which are exploring potential treatments for Long COVID, including intravenous immunoglobulin (IVIG) and Paxlovid.
“It’s not fair that patients must go to a territory or quaternary care center just to get diagnosed, or try a treatment. When I send them home, it’s often difficult to maintain their care because many physicians won’t continue the treatments. I've heard doctors say, 'I’ve never used this, it’s not FDA-approved, and I’m not going to use it off-label.' We need better uptake of treatments in primary care across the country,” Ganesh said.
Bridging Gaps in Care4
Blitshteyn continued to emphasize the gap between research and clinical availability of tests, particularly for immunologic markers. She said, "There’s always a huge gap between the tests available for researchers and those available for clinicians. We need to find a cost-effective way to bridge this gap." She also stressed the importance of validated immunologic tests, noting, "Even before the COVID pandemic, there was a shortage of good, accessible, and validated immunologic tests, including antibody tests for autoimmune disorders that don’t show up on standard autoimmune panels."
Experts agreed on the need for advancements in diagnostic technologies, including functional MRIs and tests for hypercoagulability. Blitshteyn emphasized the potential of neuroimaging, saying, "Functional MRI should be cheaper and more widely used. We also need tests that can identify hypercoagulability visible on MRI.
These experts have emphasized the need for robust infection prevention and mitigation strategies, alongside targeted long-term care for those grappling with these lasting effects. To help patients find the right care tailored to their specific needs, we explored their personal leading treatment centers dedicated to addressing the complex nature of Long COVID.
What You Need To Know
Long COVID affects at least 1 in 5 Americans, with many cases going unnoticed due to its invisible symptoms like fatigue and brain fog.
Diagnosing Long COVID requires a comprehensive patient history and an assessment of how symptoms evolved after the initial COVID-19 infection, which many patients fail to link.
Many Long COVID patients exhibit symptoms like ME/CFS, making it difficult to differentiate between the two conditions.
The diverse range of symptoms in Long COVID requires a personalized, multidisciplinary approach to care that addresses neurological, cardiovascular, and psychiatric issues.
With no FDA-approved treatments for Long COVID, management focuses on off-label therapies tailored to individual symptoms.
There is a significant gap between emerging research on Long COVID and its clinical application, with limited availability of advanced diagnostic tools and treatments.
Leading Treatment Centers for Long COVID: Mayo Clinic
Ganesh leads the Mayo Clinic’s Long COVID Clinic, overseeing specialized care for individuals affected by Long COVID. Known for its world-class healthcare, Mayo Clinic offers a variety of services aimed at helping patients recover and regain quality of life after COVID-19.
Post-COVID-19 Care Clinics at Mayo Clinic
Mayo Clinic’s Post-COVID Recovery Program brings together physicians, nurses, and wellness experts to create personalized care plans. The clinic offers services at the following locations:
- Mayo Clinic Rochester (Minnesota): Offers a COVID Activity Rehabilitation Program for those struggling to return to normal life or work after COVID. Virtual and in-person rehabilitation options address symptoms such as fatigue, pain, and shortness of breath.
- Mayo Clinic Jacksonville (Florida): Provides the Post-Acute Sequelae of COVID (PASC) Clinic, focusing on individuals experiencing symptoms lasting four weeks or longer.
For remote care, Mayo Clinic offers a Virtual 12-Week Treatment Program, which includes:
- Two virtual group sessions focusing on COVID-19’s effects and symptom management strategies.
- One-on-one consultations with healthcare providers to track progress and adjust care plans.
Accessing Care:
To access Mayo Clinic’s specialized services, patients must meet certain criteria, such as a positive COVID-19 test and being over 18 years old (in Minnesota). For those outside Minnesota, virtual care and extensive online resources are available.
Additional Support:
- Patients can request appointments through the Post-COVID Care Clinics or virtual programs.
- Mayo Clinic also offers online support groups for emotional and informational resources.
Dysautonomia Clinic: Specialized Care for Autonomic Disorders
Blitshteyn directs the Dysautonomia Clinic in New York, focusing on autonomic disorders that have become more common among Long COVID patients. These conditions include Postural Tachycardia Syndrome (POTS), neurocardiogenic syncope, and orthostatic intolerance, as well as conditions like chronic fatigue syndrome (CFS), fibromyalgia, and autoimmune-related dysautonomia.
Specialized Services:
- Care for conditions such as POTS, chronic fatigue syndrome, fibromyalgia, gastroparesis, and autoimmune-related dysautonomia (e.g., Celiac disease, Lupus, Rheumatoid arthritis).
- Telemedicine consultations are available, making it easier for patients worldwide to access care.
Approach:
Blitshteyn’s comprehensive, patient-tailored treatment includes:
- Phone, video, and in-person consultations.
- Detailed assessments to address overlapping conditions such as CFS, fibromyalgia, and autoimmune diseases.
Patients can schedule consultations by emailing the clinic at admin@amherstneurology.com. Follow-up support and coordination with local doctors ensure continuity of care.
UT Health: Post-COVID-19 Recovery Clinic for Multidisciplinary Care
Verduzco-Gutierrez leads the Post-COVID-19 Recovery Clinic at UT Health Science Center in San Antonio, Texas, offers multidisciplinary care for those dealing with Long COVID. As a provider who has personally experienced Long COVID, Dr. Verduzco-Gutierrez offers a unique understanding of the condition’s complexities.
Clinic Services:
The clinic’s team includes specialists in rehabilitation medicine, neurology, pulmonology, and cardiology. Their goal is to help patients manage the wide range of Long COVID symptoms, such as fatigue, shortness of breath, cognitive issues, and exercise intolerance.
Research and Community Focus:
UT Health is part of the NIH-funded RECOVER initiative, a national effort to better understand and treat Long COVID. The clinic is also committed to serving underserved populations, including minority and rural communities that have been disproportionately affected.
Personalized Treatment Plans:
Patients receive customized plans, which may include:
- Cognitive rehabilitation for brain fog.
- Pain management and physical rehabilitation for muscle weakness and deconditioning.
- Psychological support to address the mental health challenges of Long COVID.
Each of these centers represents a dedicated effort to help individuals struggling with the lasting effects of COVID-19. Whether through Mayo Clinic's comprehensive rehabilitation programs, the Dysautonomia Clinic’s specialized care for autonomic disorders, or UT Health's multidisciplinary approach to Long COVID, patients have access to cutting-edge treatment and a wealth of support. Seeking care from one of these centers can provide hope and a pathway to recovery for those suffering from Long COVID.
References
2. Abene S, Ciccone I, Ganesh R, Verduzco-Gutierrez M, Blitshteyn M. Unmasking Long COVID Through Understanding Prevalence and Diagnosis. Contagion. October 11, 2024. Accessed December 6, 2024. https://www.contagionlive.com/view/unmasking-long-covid-understanding-prevalence-and-diagnosis
4. Abene S, Ciccone I, Ganesh R, Verduzco-Gutierrez M, Blitshteyn M. Addressing the Diagnostic Gap in Long COVID Care. Contagion. November 1, 2024. Accessed December 6, 2024. https://www.contagionlive.com/view/addressing-the-diagnostic-gap-in-long-covid-care
5. Constantinescu-Bercu A, Lobiuc A, Căliman-Sturdza OA, Oiţă RC, Iavorschi M, Pavăl NE, Șoldănescu I, Dimian M, Covasa M. Long COVID: Molecular Mechanisms and Detection Techniques. Int J Mol Sci. 2023 Dec 28;25(1):408. doi: 10.3390/ijms25010408. PMID: 38203577; PMCID: PMC10778767
7. About The Clinic. Welcome To Dysautonomia Clinic. Accessed December 6, 2024. http://www.dysautonomiaclinic.com/
8. Post-COVID-19 Recovery Clinic. UT Health. Accessed December 6, 2024. https://uthscsa.edu/physicians/services/rehabilitation
