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“If there’s one universal truth amongst all the patients I’ve interviewed, it’s that they’re often brushed aside, pigeonholed, or, frankly, abandoned,” says Greg Vanichkachorn, MD, buy generic cipro next day without prescription MPH, a family physician and founder of Mayo Clinic’s COVID-19 Activity Rehabilitation Program (CARP).

Take a nap. Tough it out. Push through it. Vanichkachorn describes the frustration voiced by thousands of patients whose lives continue to be disrupted and thrown into upheaval.

Brain fog. Cognitive dysfunction. Headaches. These are just a few of the manifestations of what the National Institutes of Health (NIH) has termed post-acute sequelae of SARS COVID-2 (PASC), more commonly known as long-COVID.

PASC is loosely defined as symptoms and/or sequelae that persist for several weeks to months after the initial infection has cleared. Data that have accumulated since the COVID-19 outbreak in Wuhan, China, suggest that at least 1 in 3 people who are initially infected may be long-haulers.

As reported by Medscape Medical News, 33.6% (95% CI, 11.17 – 34.07) of patients with COVID-19 experience neurologic sequelae in the first 6 months following resolution of the infection. Almost half of cases (12.8%; 95% CI, 12.36 – 13.33) represented first-time diagnoses.

“Anecdotally, the longer we go into this, and the more people that, in the past, have been infected with COVID-19, the more patients will be seeing neurologists with some of these complaints,” said Ralph Sacco, MD, professor and Olemberg Chair of Neurology at Miller School of Medicine University of Miami, in Miami, Florida, and past president of the American Academy of Neurology.

Neurologic Detritus

Further complicating the epidemiologic picture is the broad array of clinical and functional symptoms.

“What we call long-haul COVID is not a single entity,” explained Michel Toledano, MD, a neurology consultant and a member of the CARP team at the Mayo Clinic in Rochester, Minnesota. Patients present with persistent or emergent polysymptomatic and multisystemic diseases that often include neurologic symptoms, he said. In many circumstances, they had an acute infection with either very mild symptoms or no symptoms at all.

“There’s no doubt that these people are experiencing significant neurologic symptoms, but it remains unclear whether the driving factor is mainly systemic or the nervous system independently of what is happening in the body,” he said.

Like patients with SARS-CoV-1 and Middle Eastern respiratory syndrome (MERS), patients recovering from confirmed or suspected SARS-CoV-2 infections experience a variety of self-reported neurologic symptoms that vary in terms of time frame, duration, and severity.

Take Jacqueline Jolly, for example, a 50-year-old single mother and construction permit contractor living outside of Tampa, Florida. She was diagnosed with COVID-19 in January 2021. Jolly explained that she was never sick enough to be admitted to the hospital and yet is still not close to full recovery.

Lingering, debilitating symptoms include executive function challenges, anosmia, headaches, and paresthesia that frequently bring her to the edge of losing consciousness. She has not returned to work, despite multiple attempts.

Vicky Nunally, a 35-year-old single mother and medical office assistant who lives in the suburbs of Atlanta, Georgia, recounted that she landed in the intensive care unit with a severe SARS-CoV-2 infection in December 2020.

Roughly 6 months later, she continues to experience debilitating headaches, brain fog, and cognitive delays. Her endometriosis has flared up. She says that she is depressed, anxious, and has returned to therapy. “It makes you feel crazy,” she said.

Debilitating, Pervasive Symptoms

Findings from an international survey of 3762 respondents that was published on April 21 in medRXiv underscore that PASC occurs predominantly in middle-aged women (78.9% were women; 31% were aged 40 – 49 years; 25.0% were aged 50 – 59 years).

For the most part, it manifests similarly among people with prior confirmed or suspected SARS-CoV-2 infections. In the study, symptoms were reported in both cohorts well past the initial infection; symptoms persisted past 90 days in 96% of patients and for at least 6 months in 65.2%.

Similarly, a recent study showed that 68% of patients who were enrolled in Mayo Clinic’s CARP as of June 2020 were women, middle aged (mean age, 45 ± 14.2 years), and presented roughly 3 months (94.4 ± 65 days) post diagnosis. Of these patients, 75% had not been previously hospitalized.

In both studies, fatigue and cognitive dysfunction were consistently cited as the most debilitating and pervasive manifestations lasting more than 6 months. Others included postexertional (physical or mental) malaise, sensorimotor symptoms, headaches, and memory problems.

Reports of even more severe neurologic first-time diagnoses are emerging. Findings from The Lancet Psychiatry study showed there was a small but clinically relevant risk for a range of conditions that included intracranial hemorrhage (0.14%; 95% CI, 0.10 – 0.20), ischemic stroke (0.43%; 95% CI, 0.36 – 0.52), parkinsonism (0.07%; 95% CI, 0.05 – 0.12), and nerve root/plexus disorders (2.69%; 95% CI, 2.51 – 2.89).

Toledano noted that he’s also seen patients who developed autonomic/small-fiber dysfunction. Preliminary data from a retrospective chart review suggest that the most likely diagnosis is orthostatic intolerance without tachycardia or hypotension.

In the study, 63% (17) of the 27 participants who met the inclusion criteria had abnormal results on function testing, but Composite Autonomic Severity Score results indicated mostly mild disease (sudomotor range, 0–3 [median, 0]; cardiovagal, 0–3 [median, 0]; cardiovascular adrenergic, 0–4 [median, 0]).

“The pattern that’s emerging is consistent with deconditioning,” Toledano said. “However, a small proportion of patients do have evidence of damage to the nervous system, which is something we’ve seen with other viruses.”

Proliferation of Long-COVID Clinics

A few of these patients with orthostatic intolerance developed postural tachycardia syndrome or experienced exacerbations of preexisting sensory or autonomic small-fiber neuropathies. At present, causality and/or underlying mechanisms are unclear.

Speaking on behalf of the American Academy of Neurology, Sacco acknowledged the challenges that lie ahead.

“Like any neurological symptom that continues to affect a patient’s quality of life, you may need to seek the expertise of a neurologist. The only issue is that some may still not be sure exactly what to do; we don’t have all the data yet,” he said.

On the flip side, he pointed to the lessons of the past year and how quickly healthcare systems were able to pivot to deal with the pandemic and critically ill patients, then pivot again to disseminate vaccines, and how they are pivoting yet again to address PASC.

Across the nation, numerous hospitals and healthcare systems and even small private clinics have launched clinics that focus on long-COVID, including Mayo.

The program has a multidisciplinary, collaborative framework and offers both face-to-face and video telemedicine consultations. The latter are geared toward ensuring that underresourced populations can access needed care and assistance.

“At Mayo, we have a centralized triage system to help target patients’ visits so that appropriate subspecialties and studies can be preordered,” explained Toledano.

During these visits, patients are assessed for underlying conditions and possible signs of decompensation, as well as functional and physical needs and psychosocial challenges.

Thereafter, patients enter either CARP, which offers active rehabilitation for up to 3 months after resolution of the acute infection, or the Post-COVID Care Center, which focuses on patients whose condition is not improving or who are demonstrating signs of central sensitization.

An Uphill Battle

Both programs incorporate individually paced occupational and physical therapy aimed at ameliorating symptoms, restoring function, developing psychosocial coping skills, and, ultimately, facilitating a return to work.

“The idea is, if we can meet with these patients sooner than later and help them recover in an appropriate fashion, they will exit the program faster,” Vanichkachorn said. “We do see a group of patients who tend to get better right around the 4-month period.”

Although telemedicine provides an opportunity for clinicians outside these hospital systems to engage patients, Vanichkachorn pointed out that almost all the initial treatments can be offered in the local community by a provider who has adequate time and knowledge of the condition.

He also acknowledged the potential for an uphill battle, especially among those who cling to the belief that PASC is simply a manifestation of anxiety or depression.

“This is something that we’ve seen previously with SARS and MERS, as well as in conjunction with fibromyalgia and chronic fatigue, only now with greater magnitude,” he said. “This is a real condition that has important and huge ramifications on a person’s ability to function.”

The silver lining is that last December, the NIH announced that it was allocating $1.1 billion for research through its NIH PASC Initiative. Like other institutions, Mayo is waiting to hear what it has been awarded. In the meantime, it has developed a biorepository of patient samples to better understand pathophysiologic mechanisms underlying PASC and to identify possible biomarkers that differentiate these patients.

Despite the challenges, Vanichkachorn is hopeful. “If we can get a concrete understanding of what is occurring on the chemical level and develop diagnostic tests, then the education will follow. Providers won’t be able to ignore it any longer,” he said.

The interviewees have disclosed no relevant financial relationships.

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