New research provides insight into Long COVID and ME

Authors: University of Otago July 12, 2022: Science Daily

Summary: Researchers have uncovered how post-viral fatigue syndromes, including Long COVID, become life-changing diseases and why patients suffer frequent relapses.

Arising commonly from a viral infection, Myalgic Encephalomyelitis/Chronic Fatigue Syndrome (ME/CFS), is known to cause brain-centred symptoms of neuroinflammation, loss of homeostasis, brain fog, lack of refreshing sleep, and poor response to even small stresses.

Long-COVID has similar effects on people and is believed to also be caused by neuroinflammation.

Lead author Emeritus Professor Warren Tate, of the University of Otago’s Department of Biochemistry, says how these debilitating brain effects develop is poorly understood.

In a study published in Frontiers in Neurology, he and colleagues from Otago, Victoria University of Wellington and University of Technology Sydney, developed a unifying model to explain how the brain-centred symptoms of these diseases are sustained through a brain-body connection.

They propose that, following an initial viral infection or stressor event, the subsequent systemic pathology moves to the brain vianeurovascular pathways or through a dysfunctional blood-brain barrier. This results in chronic neuroinflammation, leading to a sustained illness with chronic relapse recovery cycles.

The model proposes healing does not occur because a signal continuously cycles from the brain to the body, causing the patient to relapse.

The creation of this model is not only important for the “huge research effort ahead,” but also to provide recognition for ME/CFS and Long COVID sufferers.

“These diseases are very closely related, and it is clear the biological basis of Long COVID is unequivocally connected to the original COVID infection — so there should no longer be any debate and doubt about the fact that post viral fatigue syndromes like ME/CFS are biologically based and involve much disturbed physiology,” Emeritus Professor Tate says.

This work will enable best evidence-based knowledge of these illnesses, and best management practices, to be developed for medical professionals.

“Patients need appropriate affirmation of their biological-based illness and help to mitigate the distressing symptoms of these very difficult life-changing syndromes which are difficult for the patients to manage by themselves.

“This work highlighted that there is a susceptible subset of people who develop such syndromes when exposed to a severe stress, like infection with COVID-19, or the glandular fever virus Epstein Barr, or in some people with vaccination that is interpreted as a severe stress.

“What should be a transient inflammatory/immune response in the body to clear the infection, develop immunity and manage the physiological stress, becomes chronic, and so the disease persists.”

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Materials provided by University of OtagoNote: Content may be edited for style and length.

Journal Reference:

  1. Warren Tate, Max Walker, Eiren Sweetman, Amber Helliwell, Katie Peppercorn, Christina Edgar, Anna Blair, Aniruddha Chatterjee. Molecular Mechanisms of Neuroinflammation in ME/CFS and Long COVID to Sustain Disease and Promote RelapsesFrontiers in Neurology, 2022; 13 DOI: 10.3389/fneur.2022.877772

Acute disseminated encephalomyelitis in a patient vaccinated against SARS-CoV-2

Authors: Karolina Kania,Wojciech Ambrosius,Elzbieta Tokarz Kupczyk,Wojciech Kozubski 04 September 2021 Annals of Clinical and Translational NeurologyVolume 8, Issue 10 p. 2000-2003


Acute disseminated encephalomyelitis (ADEM) is a demyelinating disease, and there are some data that link this event with various vaccinations. We report a young female admitted to the hospital with headache, fever, back pain, nausea, vomiting, and urinary retention. Two weeks prior, she received the first dose of SARS-CoV-2 mRNA vaccine. Brain and spinal cord magnetic resonance imaging (MRI) showed distinctive for ADEM widespread demyelinating lesions. The patient was successfully treated with methylprednisolone.

Acute disseminated encephalomyelitis is a central nervous system demyelinating disease that usually affects the cerebral hemispheres, brainstem, cerebellum, and spinal cord and thus typically presents with multifocal neurologic symptoms. It is widely considered as a monophasic disease with a very rare recurrent variant (multiphasic disseminated encephalomyelitis, MDEM).1

Viral infections appear to trigger approximately up to three-quarters of ADEM cases, which manifests in a rapid onset of multifocal neurological deficits. On the other hand, for many years, there have been, and still, there are concerns that vaccinations may cause autoimmune demyelination. Articles published several years ago suggested that about 5% of ADEM events are associated with immunization for varicella, rabies, measles, mumps, rubella, influenza, hepatitis B, Japanese B encephalitis, diphtheria, pertussis, and tetanus.2 A quite recent report also claims that 61% of ADEM cases developed symptoms 2–31 days after vaccination.3 However, the results of another decent study in which data almost from 64 million vaccine doses have been explored did not show a significant association between ADEM and prior immunization.4 The evidence for a causal link between specific acute demyelinating events and any vaccine has been deemed inconclusive by the Institute of Medicine in the United States.5 ADEM can be classified as an adverse event following immunization (AEFI), defined as any untoward medical occurrence that follows immunization and does not necessarily have a causal relationship with the usage of the vaccine.6 Vaccinations are crucial for the slowdown of the spread of the COVID-19 pandemic, so AEFI monitoring and reporting is an essential part of the strategy against SARS-CoV-2.

A 19-year-old female was admitted to the hospital with complaints of 3-day severe headache, fever (37.5°C), back and neck pain with nausea and vomiting. She also noticed urinary retention last 2 days. Besides atopic dermatitis and depression, she had no significant medical history, upper respiratory infection, or diarrhea. Neurological examination showed nuchal rigidity, bilateral Babinski signs without other neurological deficit symptoms.

Two weeks prior, she received the first dose of SARS-CoV-2 mRNA vaccine (Moderna COVID-19 Vaccine, ModernaTX, Inc. USA).

Brain magnetic resonance imaging (MRI) showed multiple, poorly demarcated, hyperintense lesions in T2-weighted and fluid-attenuated inversion recovery (FLAIR) images located in both brain hemispheres, pons, the medulla oblongata, and cerebellum. Few of them were contrast-enhanced lesions. Cervical and thoracic MRI revealed a widespread hyperintense area in T2-weighted and FLAIR images extended from medulla oblongata to Th11 segment with overlapping few contrast-enhancing lesions (Fig. 1).

Details are in the caption following the image
Figure 1Open in figure viewerPowerPointHyperintense areas shown on MRI brain (FLAIR and post contrast T1-weighted), cervical and thoracic spine (T2-weighted) images.

Upon hospitalization, the cerebrospinal fluid (CSF) white blood cell (WBC) count was 294 × 106/L (reference range, 0–5 × 106/L): 91% lymphocytes (reference range, 40%–80%), 8% monocytes (reference range 15%–45%), 1% neutrophils (reference range 0%–6%); protein levels were 648 mg/L (reference range, 200–400 mg/L) and red blood cell (RBC) count was 77/µL. CSF was negative for antibodies to major pathogens and cultures of bacteria and fungi; genome sequencing also revealed no pathogens (Neisseria meningitidisStreptococcus pneumoniae, group B streptococcus, Haemophilus influenzaeListeria monocytogenes, HSV1, HSV2, VZV, CMV, EBV, HHV6). The reverse transcription real-time PCR (RT-PCR) and the antigen test were used to detect active SARS-CoV-2 infections.

Oligoclonal bands in blood and CSF were negative, and blood antibodies, including anti-aquaporin-4 and anti-myelin oligodendrocyte glycoprotein, were also negative. Empirical therapy with ceftriaxone and acyclovir was started. After establishing a diagnosis of ADEM, patient was treated with methylprednisolone (MPS). The therapeutic plasma exchange (TPE) was also initiated, but the procedure has been stopped because of allergic reactions. The clinical status improved after MPS. Control lumbar puncture was done 12 days after the first one; CSF WBC count was 61 × 106/L and protein levels were 338 mg/L. She was discharged from the hospital without any symptoms except a mild headache. On follow-up after 40 days, she complained of only mild headache.

We are in a worldwide SARS-CoV-2 pandemic, COVID-19 infection could be complicated by many neurological symptoms and disorders: Guillain-Barre syndrome, encephalopathy, cerebrovascular diseases, meningitis, neuralgia, ataxia, or epileptic crisis.78 In the literature, there are also reports of patients with ADEM associated with confirmed COVID-19 disease.917

Our patient manifested a typical radiological pattern for ADEM with extensive, diffuse demyelinating lesions in the brain and along all cervical and thoracic spinal cord. The CSF examination results were specific for ADEM with pleocytosis and the absence of oligoclonal bands. However, clinical urinary retention without lower limbs motor or sensory deficits is quite rare.

Panicker reported a bigger group of 61 patients with ADEM, where lower urinary tract dysfunction was found in 20 (33%) of them (16 patients had urinary retention), but mostly in patients with lower paraparesis.18

In the literature, we found only two cases of patients with ADEM following SARS-CoV-2 vaccination; two women both received inactivated SARS-CoV-2 vaccine of Sinovac (Vero Cells, Beijing Institute of Biological Products Co., Ltd., Beijing, China).1920

The first woman revealed symptoms 2 weeks after vaccination; she presented somnolence and memory decline and improved after steroids and iv immunoglobulins therapy. The second one was admitted to the hospital after the first tonic-clonic seizure one month after vaccination, she had typical scattered, demyelinating lesions in the brain, but because of lack of encephalopathy, it was called ADEM-like presentation.

The reported cases do not impair the importance of COVID-19 vaccinations with global SARS-CoV-2 pandemic, where the risk of neurologic complications, hospitalization, and even death of infected patients is still prevailing. But the clinicians should be aware of the potential implications of this rare neurological condition.

Long-Haul COVID

 Authors: Avindra Nath

Modern medicine has faced its biggest challenge from the smallest of organisms. It is becoming increasingly apparent that many patients who recovered from the acute phase of the SARS-CoV-2 infection have persistent symptoms. This includes clouding of mentation, sleep disturbances, exercise intolerance and autonomic symptoms (table 1). Some also complain of persistent low grade fever and lymphadenopathy. Although there are no peer reviewed papers at the moment on these patients, many news articles have been written about this phenomenon1,,4 and there are Facebook groups with several thousand patients describing these symptoms. They call the illness, “Long-Haul COVID” or “Long-tail COVID.” Many of these patients are health care workers who had massive exposure to the virus early in the pandemic and describe having symptoms for “100+ days.”5

Most of these patients were in excellent health prior to getting infected with SARS-CoV-2. They all had a myriad of symptoms during the acute phase. However as the fever and respiratory symptoms improved, they are left with persistent systemic symptoms some of which are gradually improving but not all are following that course. Still others feel they had nearly recovered from the acute illness and then a few days later, developed a plethora of symptoms that are now persisting. Some describe a cyclical nature to their symptoms where they improve and then worsen every few days. While some were admitted to the hospital due to pulmonary symptoms, the majority were isolated at home. Access to testing and medical care has been limited and most appointments with physicians are being done via telemedicine which has its limitations. Some patients have had extensive testing by internists, infectious disease specialists, cardiologists and pulmonary medicine experts but nothing has been found to explain the symptoms.5 These patients, some of whom are physicians themselves are concerned that they could be stigmatized as being “functional.” Many of these symptoms overlap with those of patients with myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS).6,7 However one needs to be careful not jump to the conclusion that they have ME/CFS unless other possible causes of their symptoms have been investigated (table 2).

Table 2

The cause of ME/CFS remains unknown despite decades of research on the syndrome. Many patients with ME/CFS similarly report a viral infection as a trigger but since they come to our attention often years after symptom onset, it is impossible to know what may have triggered the symptoms.8 Long-Haul COVID thus represents an excellent opportunity to study the pathophysiology of ME/CFS and in doing so may have broader implications.

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