“The story is always the same. When a pandemic happens, people always focus on the primary organ, but they forget about the brain.” Avindra Nath, MD
Most researchers, when they focus on post-infectious illnesses, go straight to the body to figure out what’s happening, but Avindra Nath is different – he goes straight to the brain.
“A Crisis in Neurology”
“Undiagnosed neuroinflammatory diseases carry a huge burden with devastating consequences.” Avindra Nath
Nath, the leader of the intramural study on ME/CFS, is a neuroscientist with an interest in neuroinflammation and post-infectious illnesses. Nath’s NIH page suggests he believes that neuroinflammatory diseases may be more prevalent and cause more problems than we know.
Nath was perhaps the first to raise the alarm that something was happening in the brains of COVID-19 patients. In his May “Special Editorial in Neurology, “Neurologic complications of coronavirus infections“, while he asserted that “Fear strikes the minds of the unprepared”, Nath emphasized how just unprepared the medical community is for a virus that affects the central nervous system.
He questioned whether the brainstem was involved, noted that several acute neurologic syndromes have been associated with coronaviruses, and decried the lack of drug development for infection-triggered neurological disorders.
“Although we all recognize the hundreds of viruses that can cause encephalitis and result in devastation to large populations, we have no treatment for any of these organisms except for herpes encephalitis.”
Calling the COVID-19 situation “a crisis in neurology”, he said: “The time to take action is now.”
Parkinson’s (ME/CFS?) Connection?
Next, Nath questioned whether COVID-19 might be a “perfect storm for Parkinson’s disease“. The parts of the brain affected in Parkinson’s (PD) – the midbrain and the basal ganglia – govern movement and reward and can produce severe fatigue.
These parts of the brain appear to be particularly vulnerable to an infectious trigger which induces a kind of chronic immune system sensitization, and likely, neuroinflammation. Nath suggested that the systemic and/or neuroinflammation that COVID-19 causes “might be ‘a perfect storm’ for the development of PD” over time. That’s an interesting idea as studies have implicated the basal ganglia in ME/CFS and fibromyalgia as well. Might a similar process be producing them?
Brain Autopsy Results
It wasn’t surprising to see Nath quickly check out what had happened to the brains of COVID-19 patients who had died. His recent letter, “Microvascular Injury in the Brains of Patients with Covid-19“, described the results of an examination of the olfactory nerve and brainstems of 16 people who had died of COVID-19.
Medical News Today reported that Nath was “completely surprised” at what he found. Instead of damage caused by low oxygen levels, he found “multifocal areas of damage (that are) usually associated with strokes and neuroinflammatory diseases.”
The MRI showed punctate hyperintensities in about half of the autopsies. Punctate hyperintensities refer to lesions that are believed to signal small blood vessel problems in the brain. The walls of these blood vessels were also thinner than normal. A recent review of COVID-19 brain studies (done on live patients) indicated that MRI found white matter (WM) hyperintensities in about the same percentage of patients.
Nath found that these congested blood vessels were leaking fibrinogen, which he interpreted as being microhemorrhages. Activated microglia – a potential sign of neuroinflammation – (as well as macrophage infiltrates, and hypertrophic astrocytes) were found in most patients. Plus one report indicated that T-cells – which should not be found in the brain – were found surrounding these damaged areas. That suggested that immune cells from the body had infiltrated the brain and were likely causing damage.
- In a May editorial, Avindra Nath referred to a “crisis in Neurology” when referring to long COVID’s impact on the central nervous system and the lack of drugs to combat viruses which impact the brain.
- Nath also suggested that the coronavirus’s ability to impact the basal ganglia and midbrain (via the immune system) could set long COVID patients up for Parkinson’s disease down the road. That’s an intriguing idea given that the basal ganglia have also been implicated in ME/CFS and FM.
- In a small autopsy study, Nath found evidence that the COVID patients had suffered from small brain bleeds or strokes across their brains. Nath speculated that the leaky blood vessels he found could have set off a strong immune response and noted that he also commonly found evidence of microglial activation.
- One of the earlier ME/CFS studies done found the same type of lesions (punctate hyperintensities) Nath found increased in ME/CFS. The finding was largely discarded because the lesions appeared to be more or less randomly distributed across the brain. That was the same pattern Nath found. He speculated that lesions in different areas were producing different symptoms in different patients.
- The dead COVID-19 patients appeared to have mild forms of the illness before they apparently suddenly collapsed and died.
- Studies suggest that the microcirculation is impaired in ME/CFS, FM and POTS as well.
- A 1992 ME/CFS study and the 2020 COVID-19 study suggested the same thing was happening in both diseases – an inflammatory attack on the central nervous system.
- A large study involving researchers from 30 countries will be assessing the central nervous system in connection with COVID-19 over time.
Nath only autopsied two parts of the brain – the olfactory lobe and the brainstem – but he may not have needed to go further to determine if the virus itself had made it to the brain. (Both these regions are of prime interest given the loss of taste and smell, and breathing problems found in COVID-19. )
No evidence of the virus was found in either part of the brain. Nath noted that it was possible that virus had been present at some point, or that they had been unable to detect it, but proposed that the immune system was probably largely to blame for the brain damage found. He believes the inflammatory process is the key:
“The inflammatory response is key to the neuropathogenesis of this syndrome, since we were unable to find virus in the brain.”
He believes that the virus triggers an inflammatory response in the nervous system, which damages the blood vessels causing them to leak factors into the brain – which then triggers another immune response. Jennifer A. Frontera, MD, a neuro-critical care doctor also agreed that a secondary (or immune) response involving “inflammation and hypoxia,” was probably key.
The patients Nath had autopsied didn’t spend weeks on a respirator in intensive care before they died. In fact, they only had mild COVID-19 symptoms before they suddenly apparently collapsed and died.
Obviously, nobody reading this will fit that particular pattern, but many of us do, in a way: many of us had “mild” symptoms before becoming coming down with ME/CFS and/or FM. We may have felt wretched, but we didn’t end up in the hospital.
Tony Komaroff showed this back in 1996 when his large study found that people with ME/CFS had significantly worse functioning than people with heart attack, heart failure or multiple sclerosis.
This finding demonstrates that it’s possible to go from mild to debilitated, or even dead, very quickly. It’s another finding that doesn’t really “fit”; it doesn’t seem to make sense to quickly go from a mild COVID infection to death but that weirdness, in a way, makes it perfect for the perennial odd man out – ME/CFS.
ME/CFS, FM and POTS and the Long Haulers
The Long Haulers
“Now we have leads. We know what to look for.” Nath
Nath has begun a long COVID neurological study in which people with ME/CFS will reportedly be used as a control group. One focus will be the microvasculature. Nath has said something similar (“We know what to look for”) regarding his ME/CFS studies.
“In the future, we plan to study how COVID-19 harms the brain’s blood vessels and whether that produces some of the short- and long-term symptoms we see in patients.”
For her part, Frontera is writing up a long-term follow-up of almost 400 COVID-19 patients.
Chronic Fatigue Syndrome (ME/CFS)
In the last blog, we saw quite an overlap in symptoms developing in people with long COVID and people with chronic fatigue syndrome (ME/CFS). Now we see some intriguing similarities developing in the brain and the blood vessels.
Punctate hyperintensities were one of the first findings in ME/CFS. A large percentage (78%) of patients had them compared to healthy controls (21%) but they were discarded, as I remember, because they didn’t fit a pattern: they were spread willy-nilly across the brain.
A similar pattern was found in the COVID-19 autopsies. Nath reported the lesions weren’t evenly distributed: “you would find a small blood vessel here and a small blood vessel there.” He said it was almost as if a series of small strokes had occurred across the brain.
Almost 30 years later, perhaps that 1992 finding may make more sense. The widespread nature of the punctate hyperintensities could reflect the widespread nature of the symptoms in ME/CFS/FM. The symptoms one experiences may reflect the part of the brain with leaky blood vessels. Nath stated that punctate hyperintensities found in the brainstem could produce problems with the heart rate, breathing and blood pressure.
Nath appeared to have hinted at this when he said:
“We hope these results will help doctors understand the full spectrum of problems patients may suffer so that we can come up with better treatments.”
Because they can also be found in healthy people, there’s been some question as to what these hyperintensities mean. They appear to be considered now, though, as “markers of brain frailty“. Increasing levels of punctate hyperintensities have been associated with cognitive problems, including executive functioning and memory, mobility problems, stroke and possibly dementia.
Baraniuk’s 2005 cerebrospinal proteome study suggested that localized bleeding (and the deposition of amyloid-like fragments) was present in ME/CFS patients’ brains as well.
Thus far, Nath’s findings are tracking with some prominent themes in ME/CFS and fibromyalgia. Several studies suggest the basal ganglia may be involved in both diseases. A recent study suggested that the basal ganglia is the center of a fatigue nucleus in multiple sclerosis.
Other studies have highlighted possible microcirculation problems in both diseases as well as postural orthostatic tachycardia syndrome (POTS). Blood vessel problems in the abdomen and lower legs are believed common in POTS. Systrom’s results indicate that a significant subset of people with ME/CFS have microcirculatory problems which are allowing blood to escape into the interstitial spaces, and reducing blood flows to the heart.
- Narrowed Small Blood Vessels Linked to Fatigue in ME/CFS
- Low Energy Production and Pain in Fibromyalgia – Is Your Microcirculation To Blame?
- Could Poor Microcirculation Be Causing Chronic Fatigue Syndrome (ME/CFS)?
Plus, the brainstem is an area of focus in both ME/CFS and fibromyalgia.
Back to the Future?
Compare the conclusion from that 1992 study, “A chronic illness characterized by fatigue, neurologic and immunologic disorders, and active human herpesvirus type 6 infection” (co-authored by Cheney, Peterson, Ablashi, Buchwald, Paul Gallo and Komaroff)
“the patients may have been experiencing a chronic, immunologically mediated inflammatory process of the central nervous system.”
with Nath’s recent statement about the long haulers:
“The inflammatory response is key to the neuropathogenesis of this syndrome.”
While it’s still early yet, and we haven’t gotten the big studies needed to truly validate a pathophysiological link between ME/CFS and long COVID, thus far it seems like we may be coming full circle. Plus, there’s some good news on the brain front in long COVID. It has seemed that in the search for immune issues that the brain was being left out in COVID-19, but the brain research community is stepping up.
The Alzheimer’s Association reported that representatives from more than 30 countries have “formed an international, multidisciplinary consortium to collect and evaluate the short- and long-term consequences of the viral infection on the central nervous system (CNS)”. The study will be evaluating COVID-19 patients for up to 18 months.
Check out a large study which found similar symptoms to ME/CFS in people with long COVID.