Reprinted with the kind permission of Cort Johnson and Health Rising.
By Cort Johnson
It’s always hard to lose a loved one, but the deaths in ME/CFS seem particularly hard. They tend to be quite painful, they often take place in the midst of a non-supportive medical system, and they’re a complete mystery. With no seeming way out it’s no wonder that suicide is not uncommon.
Death, when it comes, can leave a silver lining, if not for the person who died, for those whom she/he left behind – an opportunity to learn what went so wrong for their loved ones.
Autopsies can sometimes provide that. Autopsies are surgical procedures designed to determine the cause of death. Most people who die are not given autopsies. They are usually done in cases of sudden death or in cases where the death was a puzzle. They often produce surprise diagnoses that were not suspected at the time of death.
While autopsies are helpful, they are not the be all and end all. It’s thought autopsies pick up only about a fifth of the missed diagnoses a person might have.
Autopsies and Chronic Fatigue Syndrome (ME/CFS)
The autopsies done in ME/CFS are few and far between. Complete medical histories appended to them are, at least in the public realm, usually lacking.
Because autopsies of ME/CFS patients invariably come from the sickest among us, they may not tell the story of less severely ill patients. Doctors report that most people with ME/CFS/FM get worse at first, then improve and usually plateau. A significant subset of patients, however, decline.
This is that group. Of the ME/CFS patients below whose illness duration is known, none had ME/CFS for much more than 10 years.
A look at the autopsy records (such as they are) suggests that, not surprisingly, when people with chronic fatigue syndrome die, they die in a variety of ways. One theme does, however, stand out and could suggest why some severely ill patients get so ill, why they die, quite frankly, in such horrible ways, and why suicide is not uncommon at all.
A Focus on the Brain and Spinal Cord
The history of documented brain abnormalities in ME/CFS, of course, goes way back – at least three decades – to the reports of white matter abnormalities scattered across the brain. Because the abnormalities were found in different places depending on the patient, and because they’re also sometimes found in healthy people, it wasn’t clear what they meant. Such abnormalities were, however, more common in people with ME/CFS. Something was going on.
Brain studies since then suggest that quite a lot may be going on. The studies are generally small, and the findings have not always been validated, but the number of potential abnormalities is surprisingly large. From white/gray matter losses, to problems connecting one part of the brain to another, to alterations in the brain’s response to stressful exercise, to decreased basal ganglia activity – the list goes on and on.
One of the more striking and immediately understandable (to people with ME/CFS) findings indicate that people with ME/CFS use more brain resources and expend more energy than healthy people when doing cognitive work. Another not so surprising finding – at least to people with ME/CFS – was that exercise took their cognitive faculties for a tumble and altered their brains’ functioning.
Metabolically that made sense. Metabolic studies present a picture of an undercharged, aerobically challenged, free radical-pummeled brain that may be low in oxygen at the microvascular level. Findings of impaired basal ganglia and motor cortex activity suggested that the signal for the muscles to move might just not be getting through. The Japanese and the recent Younger findings of widespread neuroinflammation may be getting at the core problem in ME/CFS.
In short, there’s reason to believe that a peek at ME/CFS patients’ brains after death might very well reveal something. Autopsies of ME/CFS patients’ brains have been rare, but last year an extensive one was done.
It involved a formerly active woman who way back in 1974 began repeating herself and having cognitive problems. Over time, she experienced malaise, headache, joint and muscle pain, swollen lymph nodes and brain fog. Resting did not help and she continued to decline and decline, until in 1987 she was admitted to a hospice with a chillingly imprecise diagnosis – a general decline.
By then, she’d been diagnosed with ME/CFS, fibromyalgia, celiac disease and hypothyroidism – nothing her doctors felt could be causing her slide into death. Except for the fact that she was apparently dying of it, she seemed to be a typical ME/CFS patient.
In her last week she became delusional, but in one respect she was hauntingly accurate, telling her family as she drifted in and out of consciousness that, “There is something wrong in my brain. I am dying.”
After being ill for just 12 years, she died at the age of 74 in 1987. Someone at the time had the presence of mind to collect slides of her brain. Thirty years later, thanks to funding from the National Chronic Fatigue and Immune Dysfunction Syndrome Foundation, her brain was examined by researchers at Temple University.
They couldn’t explain how whatever happened to her happened, but they were able to shed some light on what happened. It was not pretty.
Numerous signs indicated that this woman’s frontal cortex (executive control, organization, planning), basal ganglia (reward, fatigue, movement) and thalamus (motor signals, alertness, sleep) had degenerated. Each of these regions of the brain have been associated with ME/CFS before and it’s striking, at least to me, that areas involved with motor activity (i.e. movement, alertness, consciousness and sleep) were the most affected. Neuronal damage was severe with a marked increase in astrocytes – a common finding in autoimmunity.
Microvascular blood flow was probably impaired as the walls of the small blood vessels in her prefrontal cortex had become thickened and exhibited signs of atherosclerosis. Strange fibrous tangles were found in her basal ganglia, thalamus and frontal cortex. Numerous amyloid plaques similar to those found in Alzheimer’s were found around her blood vessels.
A “tauopathy” – a buildup of tau proteins, also found in neurodegenerative diseases such as frontotemporal dementia (FTD), posttraumatic stress disorders (PTSD), dementia pugilistica, and chronic traumatic encephalopathy (CTE), was present.
The ME Association found a “vast excess” of glassy looking cells called corpora amylacea in one person’s spinal cord and brain. Derived from astrocytes, these cells are common in neurodegenerative diseases and are often associated with aging.
Alison was 19 when she became ill. She experienced severe, fluctuating headaches, dizziness, fever, throat ulcerations, muscle and joint pain, fatigue, seizures, neck rigidity, photophobia, abdominal pains, nausea, diarrhea, bloating and weight loss. A slow recovery from childhood infections had been noted. She died in 1996 after ten years of illness.
An autopsy, however, had revealed little. Hoping that as ME/CFS research proceeded, future investigations would reveal more about what happened to their daughter, her family preserved tissues from her brain, spleen, liver, lymph, heart, lung and other organs. In 2016, tissues from her brain were examined for changes to astrocytes and microglia. Remembering Alison’s trips to farms in Australia, tests for antigens to and DNA from coxiella burnetii – the bacterium that causes Q fever- were made with her tissues.
C.burnetii antigens were found in her brain, and antigens and “substantial” amounts of C. burnetii DNA were found in her heart, lungs, spleen and liver. The authors concluded that the likeliest explanation for Alison Hunter’s decline and eventual death was a severe Q fever attack that infected her organs, causing brain and heart dysfunction; i.e. she had a post-infective fatigue syndrome.
The authors noted that the connection between Q fever and long lasting fatigue was thought to be “psychogenic” until the late 1990’s. Studies by the Q Fever Research Group indicate that Q fever illness can, in fact, proceed atypically with no signs of bacteremia, inflammation, etc. and without eventual elimination of the bacteria. They noted Alison Hunter’s case was particularly severe.
Undiagnosed Seizure Disorder
In 2005, Alan Cocchetto, the Medical Director of the NCF, wrote that a medical examiner concluded that a person with a longtime case of ME/CFS and fibromyalgia died of an undiagnosed seizure disorder (epilepsy) which lead to a fall. The fall appeared to trigger rhabdomyolysis, which led to multisystem organ failure (shock), renal failure and death.
An autopsy indicated insufficient blood supply (ischemia) to the gut – a condition that can produce symptoms like abdominal pain, vomiting and diarrhea – symptoms that have shown up in several ME/CFS autopsy cases. Degenerated astrocytes indicated some nonspecific neurodegeneration had occurred. One defect in the right occipital lobe was found.
A Common Theme? Dorsal Root Ganglionitis
Sophia Mirza had always recovered before. After the two car crashes, the suspected meningitis, and the two malaria infections, she recovered, but it was a flu at the age of 26 that got her. She quickly became homebound and then bedbound.
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First came the chemical sensitivities, then the hypersensitivities to light and sounds and touch. After being forcibly removed to a mental health facility, her symptoms worsened. Upon returning to her apartment, she struggled to improve and seemed to get better until small amounts of food and water began causing her pain. Knowing what lay in store for her, she refused to return to the hospital and died in 2005 at the age of 32.
The inquest determined that she died of acute renal failure as a result of dehydration. A later examination of her spinal cord found “unequivocal’ inflammation in her dorsal root ganglia. The doctors reported that:
“The changes of dorsal root ganglionitis seen in 75% of Sophia‘s spinal cord were very similar to that seen during active infection by herpes viruses (such as shingles).”
In August 2011, 15-year old Merryn came down with hives after a trip to Mallorca, Spain. Tests revealed she had, at some point, contracted glandular fever (Infectious mononucleosis). Over time, her health declined in a familiar spiral: severe migraines, stomach problems, problems swallowing, slurred speech, exhaustion, and an excruciating hypersensitivity to touch, light and sound.
Unable to eat without severe pain and vomiting, she was fitted with an intravenous feeding line, but suffered from intestinal failure and was given a terminal diagnosis. After being withdrawn from supportive nutrition, she died the next year in 2017 at the age of 21. She had been ill just six years. No reasons were ever found for her intestinal failure.
A post-mortem found low-grade inflammation of nerve roots and inflammation of the dorsal root ganglia.
Three Autopsy Cases
The ME Association reported on a pilot study of four autopsy cases, two of whom committed suicide and one who died of poisoning. The forth died of renal failure caused by lack of food and water. Like Sophia, Merryn and Alison were all were relatively young (32, 43, 31) at the time of their deaths.
“Marked” dorsal root ganglionitis was found in one person and two others showed signs of dorsal root ganglia degeneration (nageotte nodules).
Dorsal Root Ganglionitis
Dorsal root ganglionitis (DRG) refers to a disease of dorsal ganglia – nodules found just outside the spinal cord which contain the cell bodies of sensory neurons. Because they rely on sensory signals to the brain and play a key role in pain perception, problems with the DRG could conceivably produce many of the sensory and pain problems in ME/CFS and fibromyalgia. One wonders if Anne Ortegren’s problems with clothes touching her skin could have derived from inflammation in her DRG?
The DRG’s role in autonomic nervous system functioning suggests they could contribute to the dysautonomia often found in ME/CFS and FM.
Dorsal root ganglionitis or sensory gangliopathy has been implicated in the sensory and peripheral neuropathies found in HIV/AIDS, cancer pain, diabetes, and most intriguingly, Sjogren’s Syndrome – a disease that is being increasingly associated with POTS, dysautonomia and probably ME/CFS. Sensory ganglionitis can also be associated with small fiber neuropathy – a condition that is also found in fibromyalgia, POTS and ME/CFS.
According to MedLink, sensory ganglionitis can be triggered by a viral or bacterial infection such as Herpes zoster (Gilden et al 2003), HIV, and Borrelia burgdorferi (Lyme disease). The sensory problems arise from inflammation of the ganglia. Interestingly, abnormal blood supply via the capillaries, leading to the entry of inflammatory cells, proteins and other toxins into the neurons, is believed to play a role. This is because the capillaries that supply blood to the DRG’s tend to be “leaky”, allowing the passage of inflammatory cells, proteins and toxins into them.
Diagnosis is not easy. Typical symptoms of dorsal root ganglionitis do not include fatigue, but do contain some symptoms associated with ME/CFS or FM including allodynia, orthostatic intolerance (hypotension), gut issues, erectile dysfunction, paresthesias (areas of numbness or tingling), memory and gait problems. The sensations of temperature, vibration and touch may be affected.
Nerve conduction studies, neuroimaging, and pathological analyses may aid diagnosis. MRI’s can reveal nerve fiber damage. Biopsies are rarely performed but show nageotte nodules, nerve cell damage and immune cell infiltration.
A Sjogren’s Syndrome Segue
Sjogren’s Syndrome is of interest because of its growing association with POTS in particular. A Johns Hopkins 2014 case series used a high resolution magnetic resonance neurography to diagnose abnormal dorsal root ganglia in ten Sjogren’s Syndrome (SS) patients.
The authors pointed out that the burning sensations found in SS often do not follow the typical “stocking and glove” pattern (found from the feet and hands up) that occurs with most people who have small fiber neuropathy. They called small fiber neuropathy “a surrogate marker of DRG neuronal loss” but noted that the unusual distribution of SFN in SS can complicate getting an SFN diagnosis. Plus, some SS patients with burning or “raking” pain may have dorsal root ganglia problems without having small fiber neuropathy.
Five of the ten SS patients in the study had abnormal DRG’s. The fact that none had evidence of small fiber neuropathy, and that two of the patients improved markedly on IVIG therapy, suggested that dorsal root ganglionitis by itself can cause these burning, painful sensations. It also suggested a new way to search for sensory ganglionitis.
In any case, the finding of sensory ganglionitis in Sjogren’s Syndrome suggests that it may not be long – given the proper studies – before it’s also found in POTS, FM and ME/CFS.
Fibromyalgia and ME/CFS
None of the overviews I saw mentioned sound or light sensitivity. Is it possible, though, that some people with ME/CFS/FM have a heretofore unrecognized form of sensory ganglionitis?
Dr. Martinez-Lavin believes so. He believes that infection and/or trauma trigger the aberrant production of sympathetic nerves within the DRG in fibromyalgia. This sympathetic nerve “sprouting” prompts sensory nerves to fire, causing the pain hypersensitivity in fibromyalgia. (He calls fibromyalgia a “sympathetically maintained neuropathic pain syndrome.”)
The ability of herpesviruses to infiltrate the DRG adds another interesting twist. The intersection of herpes virus infections, sensory disturbances, pain production and the autonomic nervous system in the DRG is potentially exciting.
Treatments for DRG includes drugs that target calcium and transient receptor potential channels and glutamate receptors. Interestingly, Ivabradine, which can be very effective in POTS, is being used as a DRG inhibitor.
Sometimes the damaged nodules are ablated or removed. Neurostimulators are also used to regulate them. One report of a treatment-resistant case of migraine found that pulsed radio frequency stimulation of her C2 DRG completely removed her migraines.
In 2015, after a 34-year old with a history of fibromyalgia, post-traumatic stress disorder and occipital neuralgia (chronic pain in the lower neck, back of the head and behind the eyes) unsuccessfully underwent occipital nerve radio frequency ablation, two of his dorsal root ganglia were removed. His pain completely stopped, and he regained normal functioning.
An examination of the removed ganglia revealed chronic inflammation and evidence of an active, productive, herpes simplex-1 (HSV-1) infection.
It comes as no surprise that death due to chronic fatigue syndrome (ME/CFS) arrives in a variety of ways – unexplained neurodegeneration, undiagnosed seizure disorder, a very severe coxiella burnetii infection, and for several, dorsal root ganglionitis.
The findings of dorsal root ganglionitis in five of the nine ME/CFS patients undergoing autopsy is suggestive. With four of them either choosing not to get more medical treatment or committing suicide, this group, if it is a distinct group, appears to be at high risk. Hypersensitivity to stimuli and eating problems appear to be particularly difficult symptoms. They are not typically found in sensory ganglionitis but if sensory ganglionitis can cause allodynia, one would think it might be able to cause gut issues.
Hypersensitivity to light, sounds and smells may be another issue since the sensory signals may not go through the dorsal ganglia. Dorsal ganglia problems could contribute to or trigger what appears to be a truly horrendous case of central sensitization in many of the severely ill.
(Alison Hunter also had severe gut issues and sensitivity to light. No mention of dorsal root ganglionitis was made, but it was unclear if it had been searched for.)
One wonders if more people with ME/CFS should be assessed for dorsal root ganglionitis, and if it’s present, attempts made to treat it. IVIG is one option.
We clearly need much more data. Complete medical histories and extensive autopsies, particularly of the brain and spinal cord, are needed. Dr. Montoya is now accepting brain and tissue samples, and a brain and blood bank in the U.K. has been proposed. I’m not aware if it’s functioning yet.
- The Montoya Blood and Brain Bank at Stanford University – contact Zoe Kim Kenealy: email@example.com or Tullia C. Lieb – firstname.lastname@example.org (650) 725-4992
We also need more information on those most at risk. It seems that hypersensitivity to stimuli and eating problems are common in the severely ill, but studies are needed to fully characterize this group. The Open Medicine Foundation-sponsored Severe ME/CFS Big Data study being done under Ron Davis’s direction, and the last phase of the CDC’s multi-site study, should give us a much better picture of this terribly afflicted group.
About the Author: Cort Johnson has had ME/CFS for over 30 years. The founder of Phoenix Rising and Health Rising, Cort has contributed hundreds of blogs on myalgic encephalomyelitis, chronic fatigue syndrome, fibromyalgia and their allied disorders over the past 10 years. Find more of Cort’s and other bloggers’ work at Health Rising.