The missing link:

Small gut bacterial overgrowth as a cause of thiamine deficiency

I mentioned in an earlier blog that I had symptoms similar to long Covid, only these happened 10 years ago, long before Covid-19.

The most frustrating symptoms were extreme post-exertional fatigue, brain fog, also worse after activity, and insomnia, associated with unrefreshing sleep. I would fall into a deep sleep in the early evening and then suddenly wake up, often with palpitations and feeling agitated or anxious, as though panicking, but I wasn’t stressed, I wanted to sleep. I just wanted to feel better.

All the tests I had were normal. Except for a very low vitamin D level.

Interestingly, my symptoms, particularly the tremor, were relieved by sugar. I craved sugar to give me energy. I snacked on chocolate bars to get me through my shift in the hospital. I would add sugar to my tea. I also ate nuts (not just with chocolate) and seeds, so I had some healthy thiamine-rich foods, too.

As I deteriorated I felt as though I was developing dementia. I certainly had all the cardinal symptoms: I was struggling to remember recent events, I was having problems following conversations, I was forgetting the names of close friends and familiar objects, I was repeating myself, I was repeating myself, I was having problems thinking and reasoning, I had difficulty recognising my surroundings (visual-spatial coordination, a key marker of dementia).

I also had muscle twitches, pains in my hands and feet, and digestive problems.

I initially thought I must be unique. Then I realised that lots of people had crossover symptoms with mine. My illness resembled so many of the common, present-day, non-communicable illnesses with unknown causes: irritable bowel syndrome, chronic fatigue syndrome, restless legs, the Parkinsonian tremor, the complications of type-2 diabetes, as well as dementia.

As a physician I tried to heal myself, I experimented with various treatments. I scribbled my discoveries and daily diatribes initially in diaries, which I subsequently typed out and eventually published last year.

The main discovery — the ‘missing link’ — was that I had developed bacterial overgrowth in the small gut, and that these bacteria were making me thiamine deficient.

There was a paper by a researcher called Lakhani. He found that patients who had bacterial stasis induced by gastric bypass surgery for obesity were thiamine deficient. Antibiotic treatment corrected the thiamine deficiency. Simply treating these patients with thiamine did not correct the thiamine deficiency. The patients in this trial had high folate. Bacteria make folate.

 These bacteria in my small gut were also making me vitamin D deficient; bacterial overgrowth is a recognised cause of vitamin D deficiency. My folate was high, too. Taking a course of antibiotics resolved my symptoms. Unfortunately this was only a short-term fix.

My small gut was abnormal due to a congenital anomaly — something I was born with, which had caused adhesions. The adhesions caused partial obstruction. I am sure that thiamine deficiency led to autonomic nerve dysfunction, affecting reflex functions such as blood pressure and pulse, and making my gut movement even more sluggish, worsening the obstruction and consequently the bacterial overgrowth.

I was certain that I had developed a condition called beriberi — thiamine deficiency presenting with very variable symptoms.

I phoned a friend, asking a colleague to help me. He had suggested before that I was thiamine deficient, having recognised the symptoms from working with alcoholic patients and drug addicts. At the time, I was insulted. I had a healthy diet and didn’t drink any alcohol (anymore). How could I possibly be thiamine deficient?

Here is an extract from my book:

“[…] I telephoned Frazer the next morning.’

          ‘Hou’s it gaun?’ he asked, sounding non-committal.

          ‘You were right!’ I exclaimed, unable to keen the excitement out of my voice. I was so keen to tell him my discovery that I had forgotten he would be in the middle of a ward round.

          ‘Richt ‘bout whit?’ he enquired, sounding unusually polite. It was not often I told him he was right about something.

          ‘Thiamine, I must be thiamine deficient. It’s what is causing the pains. It’s neuralgia, not arthralgia!’ I blurted it all out, eager for him to understand in my desperation.

          ‘Can a gie ye Pabrinex?’

He was offering to treat me with a solution of high-dose intravenous vitamins, which contain thiamine […]”

I was given the treatment in Frazer’s office:

“[…] I sat and waited, expecting to be able to report back on the success or otherwise of the experiment after a few days. I felt the coldness of the fluid track up my arm and then started to feel a little flushed […]”

The flush was due to niacin — vitamin B3, which is in the infusion Pabrinex, and interestingly has been suggested as a possible treatment for long Covid.

“ […] After 20 minutes, the bright amber liquid had almost completely run through the line and the infusion bag was empty. I felt a wave of calm pass over me. My entire body felt relaxed and it was as though every cell was smiling. The relief was dramatic. I actually felt human again. The fog in my brain had lifted and I felt like a totally different person from the one who had staggered into the unit just 30 minutes earlier. After approximately another half an hour, my hands gradually improved and an hour later even the pains in my feet had disappeared.

It was bizarre — I was cured! […] ”

I relapsed 48 hours later. I subsequently discovered that bacteria produce thiaminases — enzymes that breakdown thiamine. This renders the thiamine useless for humans, because, unlike bacteria, we don’t produce the right enzymes needed to re-make thiamine. Thiaminases have been found in human stool, indicating evidence of this process in the gut.

I also discovered that benfotiamine is not broken down by thiaminases, and that it worked as well as Pabrinex, whereas oral thiamine had had no effect on my symptoms.

Interestingly, another scientist called Yudkin, author of Pure, White and Deadly: how sugar is killing us and what we can do to stop it, found that thiamine-deficient rats were able to thrive provided that their diet was free from sucrose — sugar. Thiamine-deficient rats were unable to process sugar. Instead they produced toxins, which Yudkin termed “perverted metabolism”. Decades ago, back in the 1950s, he was essentially describing the metabolic syndrome, as we know it today. Perhaps thiamine-deficient humans, like myself, were unable to process sugar. The sugar was killing me.

Sugar (glucose) is broken down by an enzyme — pyruvate dehydrogenase, which requires thiamine to function. Not only that, sugar in the gut feeds bacteria directly, worsening any bacterial overgrowth.

My hypothesis is as follows:

I had become thiamine deficient. My risk factors were numerous: 4 pregnancies in 6 years, intentional weight loss then unintentional as I deteriorated, exercise to get fit, alcohol — until I realised it made me feel worse, recurrent infections mostly due to aspiration from the partial bowel obstruction.

I craved sugar, I had an abnormal gut with adhesions, and I had had regular courses of antibiotics for chest infections. All these factors exacerbated the bacterial growth in my small gut. Thiamine deficiency caused autonomic neuropathy, worsening my gut movements, exacerbating the bacterial overgrowth. Bacterial overgrowth exacerbated the thiamine deficiency

Recently, I have been wondering whether there are similarities in patients with long Covid, with the virus precipitating thiamine deficiency. I have read about a lot of cases related to risk factors for thiamine deficiency such as pregnancy, breastfeeding, exercise, dietary factors, etc.

To summarise: Thiamine deficiency and/or direct nerve damage from the virus causes autonomic nerve dysfunction, leading to bacterial overgrowth, which worsens thiamine deficiency. Exercise, sugar, alcohol, and further infections all exacerbate thiamine deficiency.

I remedied my illness with a strict regime of:

• No alcohol
• No sugar
• High protein, low carbohydrate diet
• Periods of fasting, once my weight allowed
• Minimal exercise
• Pabrinex  and subsequently benfotiamine
• Courses of antibiotics — rifaximin worked best
• Surgical correction of malrotation and excision of adhesions

It took months, but I gradually recovered.

References

Lakhani SV, Shah HN, Alexander K, Finelli FC, Kirkpatrick JR and Koch TR. Small intestinal bacterial overgrowth and thiamine deficiency after Roux-en-Y gastric bypass surgery in obese patients. Nutr. Res. 2008; 28(5): 293-8.

Dixon J. The missing link in dementia. A memoir. Wrate’s Publishing. 2020. ISBN 978-1-9996089-8-9. https://www.amazon.co.uk/Missing-Link-Dementia-memoir-Dixon/dp/1999608984

Yudkin J. The vitamin B1 sparing action of fat and protein. 4. The effect of carbohydrate in diets deficient in vitamin B1 upon the survival and vitamin B1 content of the rat. Biochem. J. 1951; 48(5): 608-11.

Yudkin J. Pure, White and Deadly: How sugar is killing us and what we can do to stop it. London: Penguin.

Vaccines

I’m back. The scheduled break was in cautious anticipation of a bad reaction to my second Covid vaccine, which ensued as expected—but I guess that just means I have developed a good immune response.

Vaccination programmes appeared again in the news this week, not just the obvious global Covid vaccination updates, but the chicken pox vaccine, too.  

Some historical perspective is necessary to really appreciate the incredible advances made through vaccination. So, the first question I’d like to address, how did immunisation come about? In the Western World Edward Jenner was credited with using the fluid from cowpox pustules to protect against small pox. It was recognised that milkmaids had good complexions not marked by pox scars. This was in 1796. Small pox has now been eradicated.

Louis Pasteur developed the rabies vaccine in 1885. He is also one of the scientists who recognised that by pasteurising milk—heating it to less than 100°C—would make it last longer by destroying bacteria and other pathogens.

In the last century many more vaccines were developed: measles, mumps, rubella, diphtheria, polio etc. Advancing technology enabled scientists to trial vaccines against major diseases such as malaria, TB and HIV. These vaccines are still being tested.

There has been a chickenpox vaccine available since 1984, yet it is not part of our immunisation regime. The reasons given being that it is considered a mild childhood disease (only occasionally causing death), and (unfounded) concerns that vaccination will mean that infections will shift to older people, who are more susceptible to developing severe disease. Another assumed benefit is that chickenpox in children might provide a booster for older people, giving increased protection against shingles—an approach which is not only unfounded but also completely unregulated.

WHO recommend that the chickenpox vaccination should be introduced when chickenpox becomes a significant burden to public health. It has been included in the national immunisation programmes of many countries, including Germany, Italy, Spain and United States, which have consequently benefitted from a much lower burden of disease.

Studies have shown that 25% of parents have to take time off work to care for children with chickenpox who are excluded from educational establishments. Given that it is largely women who shoulder the responsibility of unpaid work such as childcare, this burden primarily falls on the mother. Three of my children were sick for two weeks each, resulting in six weeks of chickenpox illness in the household.

In countries with low uptake of the vaccination the hospitalisation and death rate has remained as high. In order for the national chickenpox vaccination schedule to be successful over 80% of the population have to be vaccinated.

The varicella zoster virus (VZV) that causes chickenpox and shingles is a type of herpes virus (also known as human alphaherpesvirus 3—HHV3). After contracting chickenpox the virus remains latent—alive, but not active, until it reactivates to produce shingles.

There is a relatively new Shingrix vaccine, consisting of a protein—glycoprotein e, the most abundant protein on the surface of the VZV-infected cells. Vaccination with Shingrix has been shown to treat patients with recurrent shingles, who have repeated bouts of shingles, due to reactivation of the virus.

The coronavirus is an RNA virus. Like all viruses it takes over cells and instructs the cells to make the proteins and genetic material it needs to make new virus particles. Viruses cannot live independently of the cells of other organisms. In this way, they are not strictly living beings.

Recent vaccine production has relied on massive innovation, due to the urgent need for rapid development of massive amounts of vaccine. The conventional method of growing viruses is inside chicken eggs. The virus produced is then weakened so that it doesn’t cause the illness. Subsequently a large amount is required for the vaccination to work.

The body produces an immune response (antibodies) against parts of the virus (antigens). In this case, the antigen is the spike glycoprotein, which protrudes from the surface of the virus particle giving it its spiky shape, and accordingly, its name—‘corona’ meaning ‘crown-like’.

There are two types of Covid vaccines: those consisting of part of the RNA virus—mRNA (‘M’ standing for messenger—a template for protein production), and those made of another virus (adenovirus) carrying the genetic information, which then enters the hosts’ cells and tells them which viral proteins to make—in this case it instructs the hosts’ cells to make the spike protein.

The Pfizer and Moderna vaccines are both mRNA vaccines. The problem with RNA is that it is unstable and that RNases—enzymes that break down RNA— are abundant. This is why the vaccine has to be kept at such low temperatures, making distribution more difficult.

The other type of vaccine—known as a viral vector vaccine—uses DNA, which is much more robust than RNA. The DNA for the spike protein is inserted into the DNA of another respiratory virus—an adenovirus. After injection the adenovirus releases its DNA, along with the inserted spike protein DNA, into the hosts’ cells. The hosts’ cells make spike protein—antigen, using the DNA as a template. The body then develops an immune responses—antibodies, as before.

Adenovirus-based vaccines are not new. They are being used to make vaccines against tuberculosis—TB, HIV and malaria—but these vaccines are still in development. There is an adenovirus vector Ebola vaccine produced by Johnson and Johnson that has been approved.

In the last few weeks exciting news has surfaced with the Oxford Group announcing that their malaria vaccine is 77% effective against malaria. Until now there have been no vaccines against parasitic diseases, such as malaria. Even though it is clear that resistance to these diseases occurs in people living in countries with a lot of malaria it has been tricky to determine which part of the parasite to use for immunisation. It looks like the new vaccine utilises part of a protein from the malaria bug—one that is important for uptake in the liver, which is where the parasite reproduces. It also contains part of a hepatitis B protein and then Matrix-M is a chemical known to induce a potent immune response. This has been a major break-though.

The adenovirus vector technology isn’t new, but the vaccine programmes do not exist yet, or rather, did not exist, not until Covid.

There is a vaccine for TB— so called BCG, Bacillus Calmette-Guérin. It was developed from a similar bacterium that causes TB in cows—Mycobacterium bovis. Unfortunately the vaccine is only 20% effective against infection, although it does reduce the severity of illness in those who develop TB. It is no longer part of a national vaccination programme in most of Europe. 

The adenovirus-based TB vaccine (AdAg85A)was tested in mice and found to be effective. Interestingly, it was more effective when given via the nose. This bodes well for future vaccines if all we need is a nasal spray.

There has clearly been a lot of work that has gone into developing these adenovirus vector (carrying DNA from the bacteria and viruses) vaccines. One of the issues raised has been that we are all exposed to many human adenoviruses and so there is a certain amount of immunity already to human adenovirus vaccines (AdHu) and that would potentially make the vaccine less effective.

The solution has been to develop non-replicating adenoviruses and non-human ones. The same group synthesised a chimpanzee-adenovirus (AdCh68) TB vaccine, which also worked well with nasal delivery giving good lung protection.

The Oxford-AstraZeneca vaccine is a chimpanzee adenovirus (ChAdOx1) vectored vaccine. The Johnson and Johnson vaccine is a non-replicating human adenovirus (Ad26).

There are several correlations between coronavirus and chickenpox: a mild disease in many, a protein on the surface useful for immunisation, 80% of the population needs to be vaccinated for effectiveness. And then possible similarities: latent virus in nerves causing chronic, lasting health problems. The obvious difference is that the Covid vaccine has had to be rolled out rapidly in order to stay one step ahead of the inevitable mutations.

My only wish was that there were a better way to feed back any issues. Well, it turns out that there is. The MHRA (Medicines and Healthcare products Regulatory Agency) —a government organisation in UK—has had a yellow card system for reporting adverse reactions to drugs since 1964 following the thalidomide tragedy.

Anyone can report through the yellow card scheme. It is much simpler now that it is conducted electronically rather than a using page that had to be ripped out of the back of the BNF (British National Formulary). Reports are encouraged, especially for new drugs and those administered for children and during pregnancy.

There is an excellent website: https://yellowcard.mhra.gov.uk. This site even has a specific COVID-19 button to report ‘suspected side effects to medicines and vaccines or medical device and diagnostic adverse incidents used in coronavirus treatment’. I searched the leaflet that I had been given after my vaccination. The information was there, but it’s unfortunate that it appeared like so in print:

Summary: We all need to get vaccinated. Any of the rare adverse events should be reported through the Yellow Card system, particularly as these vaccines are still new, and the adenovirus vaccine method is new, too.

Next blog in two weeks.

References

Wutzler P, Bonanni P, Burgess M, Gershon A, Sáfadi MA and Casabona G. Varicella vaccination – the global experience. Expert Rev Vaccine. 2017: 16(8): 833-43.

Office for National Statistics. Women shoulder the responsibility of ‘unpaid work’. https://www.ons.gov.uk/employmentandlabourmarket/peopleinwork/earningsandworkinghours/articles/womenshouldertheresponsibilityofunpaidwork/2016-11-10

Wang J, Thorson L, Stokes RW, Santosuosso M, Huygen K, Zganiacz, Hitt M and Xing Z. Single mucosal, but not parenteral immunization with recombinant adenoviral-based vaccine provides potent protection from pulmonary tuberculosis. J Immunol. 2004 173: 6357-6365.

Jeyanathan M, Thanthrige-Don N, Afkhami S, Lai R, Damjanovic D, Zganiacz A, Feng X, Yao X-D, Rosenthal KL, Medina MF, Gauldie J, Ertl HC and Xing Z. Novel chimpanzee adenovirus-vectored respiratory mucosal tuberculosis vaccine: overcoming local antihuman adenovirus immunity for potent TB protection. Mucosal Immunity. 2015: 8; 1373-1387.

How does Covid lead to long-Covid? Part I

One suggestion, by someone who has also likened long-Covid to beriberi, is that this is a slightly more virulent virus than usual, one that we have not had any experience of before, and that the high morbidity and mortality is due to the generally poor nutritional state of sufferers.¹

The influenza pandemic ‘Spanish Flu’ from 1918 onwards was thought to be particularly deadly as it happened at the end of World War I when there was a significant amount of malnutrition.

Another explanation was that the Spanish Flu triggered a cytokine storm—an over-reactive immune response.

These two things—exaggerated immune response and poor nutritional status are not mutually exclusive. One study in patients having surgery for colorectal cancer showed that malnourished patients had a higher interleukin 6 (IL-6) level.² Interestingly, IL-6 is one of the key drivers of inflammation and the cytokine storm in Covid.

Another well-known cytokine is IL-17, produced by Th17 cells. The Th stands for helper T cells. These cells are very important in infections. They help activate the B cells—the ones that produce antibodies. Th17 or helper T cells also help to activate the cytotoxic T cells that can kill cells that are infected to clear the virus.

The cytokine IL-17 protects individuals from bacterial infections, but in excess it can cause the inflammation in the lungs—ARDS or adult respiratory distress syndrome—seen in Covid. IL-17 promotes the downstream production of other pro-inflammatory molecules, such as IL-6 and TNF-α (tumour necrosis factor).

Wernicke’s encephalopathy is a well-established model of thiamine deficiency. Patients with this disorder develop instability walking, eye muscle abnormalities and mental changes, and it occurs in a proportion of alcoholics, as well as patients with very poor nutrition, such as gut disorders, severe sickness in pregnancy, malignancy and AIDS.

Thiamine deficiency is associated with increased pro-inflammatory cytokines; IL-6, TNF-α and IL-17. Increased IL-6 and TNF-α were found in post-mortem brains of patients who had died of a thiamine deficient, non-alcohol-associated state called Wernicke’s encephalopathy.³ Another recently reported study showed that treatment with thiamine in patients with Wernicke’s Encephalopathy significantly lowered IL-17.⁴

In critically ill patients thiamine deficiency has been found to be present in as many as 71% of patients.⁵ Certain medical conditions, such as alcoholism, diabetes, gut resection, predispose patients to thiamine deficiency.   

In summary: Covid is associated with an exaggerated immune response. Critical illness, of any cause, can lead to thiamine deficiency and certain conditions, such as diabetes are associated with thiamine deficiency, and also with increased risk of mortality from Covid. Thiamine deficiency is associated with an increased immune response as seen in patients with Covid. Hence long-Covid could be caused by an overactive immune system in addition to thiamine deficiency resulting from a severe infection or underlying condition or nutritional state.

Next week: how does Covid lead to long-Covid? Part II. Does Covid damage nerves?

References

1. Olney RW. Long covid: How to define it and how to manage it. BMJ 2020; 370: m3489.

2. Hatada T and Miki C. Nutritional status and postoperative cytokine response in colorectal cancer patients. Cytokine. 2000; 12(9): 1331-6.

3. Neri M, Cantatore S, Pomara C, Riezzo I, Bello S, Turillazzi E and Fineschi V. Immunohistochemical expression of proinflammatory cytokines IL-1β, IL-6, TNF-α and involvement of COX-2, quantitatively confirmed by Western blot analysis, in Wernicke’s encephalopathy.  Pathol Res Pract. 2011; 207(10): 652-8

4. Vatsalya V, Li F, Frimodig J, Gala KS, Srivastava S, Kong M, Ramchandani VJ, Feng W, Zhang X and McClain CJ. Repurposing treatment of Wernicke-Korsakoff syndrome for Th-17 cell immune storm syndrome and neurological symptoms in Covid-19: thiamine efficacy and safety, in-vitro evidence and pharmacokinetic profile. Front Pharmacol. 2020; 11: 598128.

5. Costa NA, Gut AL, de Souza Dorna M, Pimentel JAC, Cozzolino SMF, Azevedo PS, Fernandes AAH, Zornoff LAM, de Paiva SAR and Minicucci MF. Serum thiamine concentration and oxidative stress as predictors of mortality in patients with septic shock. J Crit Care. 2014; 29(2): 249-52.

Who is at risk for long-Covid and how come thiamine is involved?

Vitamin is short for vital amine. Vital meaning essential, amine indicating that it is a nitrogen-containing compound. Vitamins are essential because humans cannot synthesise them, so these substances have to be taken in as part of the diet. Thiamine is essential for all living things, to release the energy stored in food. When energy cannot be released, fatigue occurs.

Food basically consists of three major types of substances: protein, fat and carbohydrate. These large compounds are broken down into chains of smaller constituents: amino acids, fatty acids and glucose respectively. 

Glucose is metabolised—broken down—by a process called glycolysis, forming a substance called pyruvate. This reaction releases energy, but it only releases a small amount of energy. 

To fully metabolise glucose and release all the potential energy pyruvate has to be broken down by an enzyme called pyruvate dehydrogenase. This enzyme requires thiamine otherwise it doesn’t work. Pyruvate dehydrogenase converts pyruvate into acetyl CoA.

Acetyl CoA can then enter the next metabolic pathway—a series of reactions—called the Tricyclic Acid Cycle. This pathway then releases a lot more energy.

Without thiamine, entry to this second cycle is reduced and the result is a low energy production—fatigue, crashing, feeling as though the blood sugar is low. 

The brain and nerves only metabolise glucose; they function on glucose alone. Although they contribute a relatively small amount of the total body’s weight, they use up 20% of the energy in the body. The brain and nerves are energy hungry. Energy is key in the body. Without energy the essential maintenance and repair work can’t be carried out.

The nervous system and the brain are therefore particularly vulnerable to low energy levels and low thiamine levels.

The autonomic nervous system controls bodily functions that we are not really aware of until they go awry, such as heart rate, blood pressure, gut motility. These nerves are also much thinner and, unlike the other types of nerves, they don’t have a myelin sheath—a protective covering which acts rather like the plastic coating on a wire. The autonomic nerves are even more vulnerable to thiamine deficiency. 

An autonomic neuropathy leads to symptoms such as palpitations, an overwhelming sense of doom, panic attacks, dizziness on standing due to a low blood pressure—called orthostatic hypotension, or POTS, and irregular guts—either overactive, with diarrhoea, or just plain stubborn with nausea due to the stomach not emptying, bloating, abdominal discomfort and constipation.

These symptoms have all been described in patients with long-Covid.

Who is at risk of thiamine deficiency? Thiamine is necessary whenever the body needs to produce energy. Energy is required for growth, pregnancy, exercise, fighting infections and recovering from severe infections.

Children are growing and are often active. Slightly more girls than boys are affected by long-Covid, whereas, in adults it is predominantly women that are affected. A pattern is emerging—women in mid 20s to mid 50s, high achievers, leading an active lifestyle, and many have children. Reading through patients’ stories most people report having been extremely fit and active prior to Covid.

There are other factors that might be important: alcohol reduces thiamine uptake. It is also a direct neurotoxin. A high carbohydrate diet increases thiamine usage and depletes reserves, particularly a diet high in white rice or white flour. Raw fish contains enzymes that break down thiamine—thiaminase—so that it can no longer be used. I used to enjoy sushi and roll mop herrings, sadly no more. There are also drugs that reduce thiamine—metformin, proton pump inhibitors and frusemide. Estrogen is interesting; while it may protect against thiamine deficiency, probably by increasing glucose uptake in the brain, women do seem more at risk of long-Covid, and the reason for this is not clear. It appears that postmenopausal women are also more likely to be affected but that HRT reduces the likelihood of developing long-Covid.

There is a design flaw. Yes, all humans have a glitch. Thiamine is terribly important and yet we are not able to absorb much of it or produce it. I suspect many of us have a subclinical thiamine deficiency, without realising it. By subclinical I mean low levels, just about adequate, not causing noticeable symptoms. We know that 10-20% of hospital patients have thiamine deficiency. When Covid hits, thiamine reserves are not sufficient to cope with infection on top of all the other demands.

That’s what happened to me—not Covid, but four pregnancies in six years, a full time medical career, exercising to keep fit, keen to lose excess weight after pregnancies and careful with my diet, taking on extra responsibilities at work, as well as keeping the status quo at home, drinking alcohol most evenings to unwind. I thought I was invincible.

I regularly drank a glass of wine in the evenings, usually only one glass, until I realised it made me feel worse. Alcohol actually makes it very difficult to absorb thiamine as it messes with the absorption route—specially adapted receptors on the lining of the gut that pull thiamine out of the ingested food and into the blood stream. With alcohol also being a direct neurotoxic, it’s a double whammy! It is therefore worth avoiding alcohol to recover from any nerve or brain injury.

Summary: Thiamine is essential for the release of energy from food. Low thiamine leads to fatigue, a feeling of crashing and a sense that blood sugar is low. Thiamine is crucial for nerve and brain health to maintain function and repair damage. The autonomic nerves are most vulnerable and symptoms such as palpitations, a sense of doom, panic attacks, dizziness, and GI symptoms can all be explained as an autonomic neuropathy. Thiamine is poorly absorbed and used up by growth, pregnancy, exercise and infections.

Next week’s blog: how Covid leads to long-Covid.

What causes peripheral neuropathy and how can it be treated?

Last week I explored how, by examining the symptoms described by patients, a number of cases of long-Covid could be due to a peripheral neuropathy. There are multiple causes of peripheral neuropathy, therefore a handy mnemonic (with a silent m) always helped me to remember: V-I-T-A-M-I-N-C:

• Vitamin deficiencies—more on this below.
• Inherited—unlikely to be simple inheritance in long-Covid. Extremely unlikely to lead to treatment options in the short term.
• Trauma—often a problem post-ITU, but usually affects one or two specific nerves, such as a brachial plexus injury from prone positioning (on the front to improve ventilation), as seen in post-ITU long-Covid
• Alcohol & toxins—including certain drugs. More on alcohol later.
• Metabolic— predominantly diabetes mellitus
• Infiltrative—disease processes like amyloid—unlikely to be relevant here.
• Neoplasia—cancers
• Connective tissue diseases—such as lupus, associated with autoantibodies, potentially an issue as autoantibodies have been found after Covid and infections can be a trigger for autoimmune disease. It may explain a few cases, especially where there is ongoing fever. However, I think it is an unlikely explanation for the majority of cases.

The main vitamin deficiencies that cause neuropathy are B1 (thiamine), B6 (pyridoxine) and B12 (cobalamin), but all the B vitamins are important.

Vitamin B12 levels are frequently tested and stores last several months. I have not seen any reports on B12 deficiency in association with Covid.

Vitamin B6 is necessary for the production of many proteins in the body, and is important for the release of glucose from stores.  Vitamin B6 deficiency is unusual, however, its metabolism is disrupted in inflammation and with the use certain drugs such as the oral contraceptive. I read about one case of a post-Covid peripheral neuropathy associated with vitamin B6 deficiency, however, replacing the vitamin B6, along with treatments such as steroids, didn’t lead to a full recovery.¹ Supplements have been tried for a variety of conditions, such as cognitive impairment and nerve injury, but long term, high dose supplementation causing toxicity has been associated with nerve damage.

Vitamin B1 or thiamine deficiency is a concern. It is rarely tested, poorly absorbed, thiamine stores last only days and deficiency is far more common than recognised.

Vitamin B1 deficiency is well known as the cause of beriberi. It can be classified as dry beriberi—essentially neuropathy, or wet beriberi—cardiac failure. Beriberi was a major problem in the 19^th century in Asia. Interestingly, no two people had the same symptoms; the presentation was very variable; everyone with beriberi had a slightly different experience. It’s curious that everyone with long-Covid experiences slightly different symptoms.

There are seldom tests for thiamine now as oral replacement therapy is thought to be adequate to prevent thiamine deficiency. Unfortunately, thiamine is not well absorbed, so tablets don’t always work. In hospital it is possible to administer thiamine through the vein (intravenously—IV) or muscle (intramuscularly—IM).

Thiamine was the first vitamin to be discovered. It was initially called anti-neuritic factor. It was first found to be important when scientists observed chickens fed different diets. By feeding chickens white rice, with the husk removed, leg paralysis developed, whereas feeding chickens red rice, with the husk intact, resulted in healthy chickens. Thiamine was later found to be in the rice husk.  

We recently rescued ex-commercial chickens— meet Donna, Rosie and Tanya.

Our fourth hen, Cher, was poorly. She was shaky and wasn’t eating. Cher was fed chicken porridge and brewers yeast, as the yeast is also an excellent source of thiamine. Cher’s appetite has improved and she is no longer shaky. Unfortunately, as the weakling, she has been bullied by the other hens and has had to be separated until her feathers have grown back. But life in the courtyard isn’t too bad.

There is no evidence for effective treatment in long-Covid. It is difficult to undertake trials when it is clearly a group of conditions that have been lumped together by a common factor—persisting symptoms occurring after Covid infection. There is unlikely to be a single medicine that fixes all—a panacea. However, there is a wealth of scientific evidence for treatments that help patients suffering with peripheral neuropathy. There are also plenty of online forums on this topic.

Most of the evidence comes from patients with diabetic neuropathy. This condition causes burning hands and feet, and eventual loss of sensation. For many years patients have found that a tablet called benfotiamine can be remarkably helpful.² Benfotiamine has also been shown to improve the heart rate variability—a marker of cardiac autonomic function—in diabetics.³ Another group of patients who suffer with peripheral neuropathy are alcoholics and there is evidence that benfotiamine leads to improvement in nerve function in this situation.⁴

Benfotiamine isn’t a drug—it is not prescribed in UK. Classed as a food supplement, it is a synthetic thiamine-derived compound, which is soluble in fat. This chemical alteration dramatically increases its absorption from the gut and thiamine is released into the blood in much larger amounts than by taking regular thiamine tablets. Large doses over a prolonged period are required as nerve recovery is generally slow. Overdose hasn’t been a problem because the thiamine is readily excreted in the urine.

Summary: What causes peripheral neuropathy and (more importantly) how can peripheral neuropathy be treated?

There are many causes of peripheral neuropathy, but high dose thiamine seems to help nerve recovery. The regular thiamine tablets don’t seem to work. Thiamine has to be given intravenously or using benfotiamine to achieve the levels required for nerve recovery.

More again next week: who is at risk for long-Covid and how come thiamine is involved?

References

1. Bureau BL, Obeidat A, Dhariwal MS and Jha P. Peripheral neuropathy as a complication of SARS-Cov-2. Cureus 2020; 12(11): e11452.
2. Winkler G, Pál B, Nagybéganyi E, Ory I, Porochnavec M and Kempler P. Effectiveness of different benfotiamine dosage regimens in the treatment of painful diabetic neuropathy. Arzneimittelforschung. 1999; 49(3): 220-4
3. Serhiyenko VA, Ajmi S and Serhiyenko AA. Benfotiamine in the treatment of diabetic cardiovascular autonomic neuropathy. European Association for the Study of Diabetes. 2017; 985.
4. Woelk H, Lehrl S, Bitsch R and Köpcke W. Benfotiamine in treatment of alcoholic polyneuropathy: an 8-week randomized controlled study (BAP I Study) Alcohol Alcohol 1998; 33(6): 631-8.

Swimming in Circles

I am very excited to announce the release of my new novel: Swimming in Circles.

This is the blurb:

IT’S IN THE WATER, IN WATER EVERYWHERE

It happens to the animals first.

Cats dancing, fish floating to the surface, birds falling out of the sky, elephants collapsing, sea stars wasting away, salmon fry swimming in circles…

Michael is a scientist investigating mysterious deaths in young salmon.

When his father is diagnosed with Parkinson’s disease, Michael is determined to find the cause of this devastating illness. He becomes obsessed with water pollution, his father having lived and worked by the river in the Midwest America all his life.

Michael moves to England to be with his partner, Luke, and they work together to solve the puzzle. As he discovers a chilling parallel between the animal mortalities and his father’s ill health, Michael realises the problem runs deeper than anyone could have imagined.

It always affects the animals first. Then it affects us…

A modern ecofiction novel shaped by real-lifescience.

The book has just been published with Wrate’s Publishing. I promise there will be no spoilers!

My personal interest in mysterious illnesses has led me to investigate environmental causes for many of our modern day ailments.

It is strange that in the Blue Zones, the places where people are found to live the longest—remote areas far from industrialization—there are few neurodegenerative diseases; there is also apparently very little ‘functional disability.’ I presume ‘functional disability’ means the conditions for which there is no obvious cause, such as chronic fatigue syndrome, myalgic encephalitis, irritable bowel syndrome, maybe even to an extent long Covid…

I researched real-science stories. The ‘cats dancing’ is a reference to the strange affliction in the cats by the harbour in Minamata, Japan. Vital for the fishing trade, the cats protected the nets from rodents; they also ate fish. Whatever pollutant was ‘in the water’, caused the fish to float and also affected the cats.

In the Baltic, gulls, feeding on herring had suffered large mortalities. In Southwest America songbirds fell out of the sky. Eagles and turkey vultures flew as though drunk in Ontario, Canada, after the river was poisoned by the local mill.

Hundreds of elephants died in Botswana’s Okavango Delta, with no identifiable cause. The elephants were emaciated and appeared to have collapsed suddenly. Locals reported that there were fewer vultures around the corpses.

There were mass deaths of purple sea urchins and baby sea lions off the coast of California. Sea stars (starfish) also died, having been degraded to mush, some had detached limbs, others seemed to melt. This occurred over a few days along an extensive area of the west coast of America. There were a few theories about this mass mortality event, but no proof or certainty.

The alligators in Florida had mysteriously died. The young salmon had been dying for decades from a disease called Early Mortality Syndrome. It affected the fry in the Great Lakes of America as well as those in the Baltic Sea. Scientists had made progress with these two conditions, but still there were unanswered questions.

These reports about the animals dying are all true. I wondered what these events had in common. I had my suspicions; each time there was an obvious theme. Wherever I looked there were the same issues occurring.

I was already concerned that neurodegenerative diseases were related to water pollution. When I looked into this in more detail, I wasn’t the only one concerned.

The story starts with Michael’s father, Joe, a fictionalized character who has developed Parkinson’s disease. In my medical practice I have seen patients with Lewy body dementia related to Parkinson’s disease, and they have presented with visual hallucinations, like Joe.

Michael, likewise, is a fictional character, although he shares my suspicions about water quality. Luke, Michael’s partner, is a neurologist. They piece together the science, medicine, and environmental studies, trying to understand and explain the changes that occur in Parkinson’s disease, and to work out why it happens.

In this extract from the book Luke is interested in alpha-synuclein, the protein that accumulates in Parkinson’s disease, and he is explaining to Michael how and why it happens:

Luke carried on, ignoring Michael’s sniggers. ‘Alpha-synuclein belongs to a family of proteins that are called “disordered proteins.”’ Luke knew Michael would like this, because of his intolerance of anything disordered, including a theory that kept changing. ‘In fact, alpha-synuclein is one of the most disordered. It’s also known as a “natively unfolded protein.”’

            ‘Well, why didn’t you say? That’s just asking for trouble,’ Michael joked, beginning to feel more confident and paying attention.

‘The alpha-synuclein proteins form well-defined, highly ordered structures. Once the initial binding has occurred, the fibril surface locks the protein in place. The binding acts like a seed for the propagation of folding, making the other adjacent proteins fold in such a way as to bind on. In this way it behaves like a prion protein, as it is capable of spreading.’

            ‘Holy cow! It’s like uncontrollable, contagious origami!’ Michael feigned being shocked.

            ‘These fibrils seem to disrupt the nerve cells, but the oligomers are definitely bad news, as they harm the nerve cells — they are cytotoxic.’

            ‘I got it. These proteins and their sidekicks . . .’

            ‘Groups. Their side groups,’ Luke corrected. He could tell Michael was having a bit of fun, entering lecture mode, and he played along.

            ‘They’re little devils,’ added Michael.

            ‘Well, no, they are useful. We don’t quite know what they do, but they are important.’ Luke put Michael right again.

            ‘They go around . . .’

            ‘In nerves,’ Luke added.

            ‘Yeah, and they persuade other likely proteins, more of a kind . . .’

            ‘More of the same kind—other alpha-synuclein.’

            ‘To radicalise . . .’

            ‘Er, not quite. They alter the naive synuclein, so they . . .’

            ‘Yeah, I got it, clump together.’ Michael was on a roll now. ‘But you needn’t worry so much about the bigger groups, as they’re more stable and less dangerous. It’s the little guys you gotta watch out for. They’re dangerous!’

In the next excerpt Michael has challenged Luke about a new theory. I don’t want to give away the plot, so I have replaced the key words with “marshmallows,”

‘I read the papers from China last night. How can you be so sure it’s marshmallows?’

            Luke laughed. ‘I’m not, but it’s quite convincing—a globally-polluting, toxic marshmallow causes Parkinsonian symptoms, while the levels of marshmallows are increasing, as are the number of cases of Parkinson’s, and the countries with the highest prevalence also have the worst pollution?’

            Michael had to admit it was suspicious. He didn’t want to offend his friend, but he also wondered why no one else had made the link. He wanted to know about other countries, and whether this information meant Parkinson’s was treatable. There were so many questions.’

It wasn’t just Parkinson’s disease, there was epidemiological data on Alzheimer’s disease that Michael and Luke found intriguing. In this excerpt Luke is quizzing Michael on the states in America with the highest rates:

‘Guess which is the state with the highest death rate, and presumably the most severe disease burden?’ Luke asked.

            ‘Pub quiz time,’ Michael replied, raising his eyebrows, but actually enjoying the banter. He shrugged, ‘I really don’t know. Florida?’ he guessed.

            ‘Mississippi,’ Luke replied, studious for a few minutes. ‘The prevalence doesn’t change that much between states.’ He explained that although the prevalence was between ten and fourteen per cent, the age-adjusted death rate, which gave an easier comparison between states with different age populations, was significantly different. Luke was reordering the states according to the age-adjusted death rate. ‘Mississippi, then Tennessee, Georgia, Alabama, South Carolina, Louisiana, Arkansas . . .’

            ‘Tennessee, Arkansas, Mississippi and Louisiana – these states are all downstream of Chicago along the Mississippi River…’

The more I read about this the more concerned I was. I found out about specific cases of Parkinson’s disease where patients had been exposed to the risk factors I had discovered, such as swimming in polluted water and regularly eating fish. People didn’t seem to be aware of the issues.

Luke opened the paper on global Parkinson’s disease prevalence on his laptop, and then clicked on another chart. He started writing down the countries in two columns: China, the US, India, Russia, Japan, Germany, South Africa, South Korea, Indonesia and Poland. Then a second list: China, the US, India, Japan, Russia, Germany, Indonesia, Italy, Brazil and France.

            ‘What are these?’ Michael asked, noting the similarities in the two lists.

            ‘The first list is the top ten marshmallows in order of size.’

            ‘The second list?’ Michael suspected he knew already, and there were remarkable similarities that couldn’t just be coincidence.

            ‘That’s Parkinson’s disease prevalence in order, starting with China. It uses one million megawatts of marshmallows, over forty-nine per cent of the global consumption of marshmallows is in China alone and one point four million people in the country are living with Parkinson’s disease. That was in 2016 and the numbers are still going up. I read in one article that by 2030, China will have fifty per cent of the cases of Parkinson’s disease in the world.’

I had been looking at the evidence all over the world: Hubei, Mexico, India, Philippines, Brazil, Midwest America, London, the Mersey…

Then the pandemic struck, and I found that the countries in the news with the highest number of cases of Covid-19 and the worst mortality rate were in the same places that I had been studying—the place with the most pollution. There seemed to be a link between Covid-19 and air pollution. I thought there might also be a link with water pollution in these places. Air pollution and water pollution are extrinsically linked.

The question I had that hasn’t been answered is whether there is an increased prevalence of long-Covid in areas with higher pollution. I suspect there might be and I can think of an explanation as to why this might be…

…but no spoilers, you’ll have to read the book 😉

For more information about me and my books please check out my new website: http://www.drjodixon.co.uk

Antiviral Effects of Lysine

My daughter, Catherine, has several autoimmune conditions, and has been treated with biologics—specific antibody treatment—which have knocked off her immune system. She is now extremely vulnerable to infections. One of the infections is recurrent shingles.

Shingles is due to reactivation of the human herpes virus (HHV), more commonly known as the chicken pox virus or varicella zoster, or simply zoster.

The first time Catherine developed shingles she had an itchy, painful rash. She thought she had been bitten by a mosquito, but then the pain developed, and it became obvious that it wasn’t an insect bite after all. Shingles affects an area of skin served by a single nerve. This area is called a dermatome and there are online maps showing the distribution of dermatomes.

She started acyclovir and, as with most cases of shingles, managing the pain was the most difficult thing.

We figured that the reason she had developed shingles was that she was stressed – it was the end of her first year at university, she had exams, she had been sent home from university urgently as there were cases of coronavirus in the residences and she was deemed high risk, or extremely clinically vulnerable, as we have now learnt to call it.

She told me she had recently started drinking coffee again, and could this have anything to do with the shingles and I laughed, dismissing the notion as, quite frankly, ridiculous. How can coffee cause shingles!

Skip forward a year. Catherine has had shingles recurrently requiring higher than usual maintenance doses of acyclovir. I read that increased doses are sometimes required to prevent recurrence in immunosuppressed and immunocompromised patients, such as those with HIV. Interestingly, the shingles is now atypical. The prodromal sore throat, headache, fever, fatigue (which Catherine describes as feeling ‘hit by a bus’) is the worst part, the rash may be a single lesion, with a change in the skin sensation on that dermatome.

Each time the shingles recurs she has to increase her dose of steroids for her body to cope with the stress of an infection—something the endocrinologists call ‘sick day rules’. Unfortunately it often takes longer that the 2 days of sick day rules to control the symptoms and for the fever to resolve, and hence this leads to higher steroid requirement, when she is desperate to reduce the dose have already suffered the consequences of long term steroids.

She joined various groups to connect with other sufferers. One such forum suggested lysine supplementation. She read up on it, ordered it online, told me it was probably nonsense, but unlikely harmful and that she might as well give it a go.

She took the lysine, stopped drinking coffee, and managed to reduce her dose of steroids and even felt confident about reducing the maintenance dose of acyclovir.

Catherine is committed to reducing her impact on the planet wherever possible. Acyclovir packaging is not planet-friendly, another motivation for reducing the dose. Many of the drug packets involve wasteful packaging. She also takes dispersible aspirin. Boots recently changed their packaging from a small plastic bottle to blister packs. She has been collecting blister packs ready to recycle when the facilities are available. Catherine chooses to be vegan as she recognizes that this is the best way she can reduce her impact on our planet.

For the past few weeks Catherine has felt unwell. She had a chest infection, non-Covid related, requiring a course of antibiotics, which helped with the productive cough, but the fever and exhaustion persisted. A couple of days ago she found a small flat blister-like lesion on her arm with abnormal sensation and, it became obvious, she had developed shingles again. She had run out of lysine a month ago, and had been drinking coffee regularly.

I found this curious and wondered whether there was any scientific support for lysine to suppress viral reactivation.

Lysine is an amino acid—one of the basic building blocks for protein. Lysine is in fact ‘essential’, meaning that humans cannot make it so they have to take it in their diet. Lysine is found in highest quantities in dairy produce and meat.

Arginine, another amino acid, structurally similar to lysine, promotes viral growth. Arginine is essential for viruses enabling them to replicate. Arginine is found in nuts, seeds and many fruits and vegetables—a vegan diet.

Arginine can be synthesised by humans but synthesis is limited for example, during severe infections. When the body is deficient in arginine it starts making more from another amino acid called citrulline, which is found in squash and chickpeas—the vegan diet again.

When there is ample lysine in the diet lysine is taken up from the diet instead of arginine. It is the same transporter that controls the uptake of both amino acids.

Studies in tissue culture (in vitro—using petri dishes to grow the viruses in the lab) have shown that arginine deficiency can suppress replication of herpes simplex virus—the caus e of cold sores when it reactivates. Lysine slows down the viral growth-promoting effects of arginine.¹ Arginine is necessary for the virus to produce protein to make virus particles.²

Hence there is some scientific proof to support reducing foods high in arginine (nuts and seeds) and taking lysine supplements.

A similar experiment was carried out with another herpes virus—cytomegalovirus. Removing arginine in the feed slowed the virus production, the virus became inactive—dormant, but then could be activated by adding arginine again.³ This is like activation of a latent virus, as seemed to be happening with Catherine.

It seems that lysine-rich foods or lysine supplements mean that lysine is absorbed in preference to arginine and this results is arginine depletion in the body.

Not all viruses are sensitive to arginine depletion, but it is possible that SARS-CoV2 is suppressed by lysine, particularly as MERS-CoV (another coronavirus) activity was reduced in a petri dish using a lysine-aspirin drug.⁴ There are studies underway to investigate whether taking an enzyme that destroys arginine could be beneficial in acute Covid.⁵

Another study showed that 80% of sufferers had a 70% reduction in symptoms of acute Covid whilst taking lysine.⁶ This article by Kagan actually gives very helpful advice on how to take lysine (not with food) and the dose (usually 2g per day, up to 3g), avoiding zinc and calcium supplements at the same time, and starting on a low dose (500mg) if you have medical conditions. There are also cautions against taking single amino acid supplements long term, particularly in children, although I wonder whether it may be beneficial in vegan diets.

There was an explanation for how coffee might make Catherine more prone to shingles. Coffee or caffeine causes an increase in arginine; it somehow displaces lysine, which presumably means that the lysine is excreted faster resulting in lower levels.

Another interesting comment seems to refer to long-Covid. It stated that ‘coffee/high caffeine consumption was the most common behavior of long-term symptomatic sufferers’, presumably referring to long-Covid sufferers. The other common traits were being a vegetarian. If lysine has a part to play here, then a vegan diet might cause further problems given that dairy provides a good source of lysine. Exercise was also linked to the development of long-term symptoms.

Could this help people with long-Covid? Would they benefit from Lysine supplementation, or avoiding coffee and arginine-rich foods? However vegans and pescatarians are reportedly less likely to get severely ill from coronavirus.⁷ Are they more likely to get long-Covid though?

I suspect long-Covid is, like many syndromes, due to a diverse combination of causes. Even though the original trigger is acute Covid infection, the body’s response is extremely varied and the subsequent long-Covid syndrome is likely to be different in each individual. I couldn’t find any specific reports on using lysine to recover from long-Covid.

Finally, scientists have reported that Covid-19 virus particles have been found in the brainstem and the vagus nerve.⁸ Disruption of the vagus nerve function might explain some of the dysautonomic symptoms experienced after Covid infections. Brainstem involvement affecting the breathing centre could be the reason acute Covid sufferers aren’t aware when the blood oxygen level is dangerously low—rather tragically called ‘happy hypoxia.’

I was more concerned that the virus might lie dormant in the nerves in some individuals, just like zoster virus, able to reactivate when conditions are right. 

If this is the case lysine might help individuals with persistent, dormant coronavirus, patients who are experiencing flares, as though they are getting recurring infections.

Sensible advice would then be to stop coffee and caffeinated drinks, reduce high arginine-containing foods and consider trying lysine supplements.

References

1. Griffith RS, DeLong DC and Nelson JD. Relation of arginine-lysine antagonism to herpes simplex growth in tissue culture. Chemotherapy. 1981; 27: 209-213.
2. Becker Y. Olshevsky U and Levitt J. The role of arginine in the replication of herpes simplex virus. J Gen Virol. 1967; 1(4): 471-8.
3. Garnett HM. The effect of arginine deprivation on the cytopathic effect and replication of human cytomegalovirus. Arch Virol. 1975; 48(2): 131-45.
4. Müller C, Karl N, Ziebuhr J and Pleschka S. D, L-lysine acetylsalicylate + glycine impairs coronavirus replication. J Antivir Antiretrovir. 2016: 8;4.
5. Grimes JM, Khan S, Badeaux M, Rao RM, Rowlinson SW and Carvajal RD. Arginine depletion as a therapeutic approach for patients with COVID-19. Int J Infect Dis. 2021; 102: 566-70.
6. Kagan C, Chaihorsky A, Tal R and Karlicki B. Lysine therapy for SARS-Cov-2. https://www.researchgate.net/publication/344210822
7. COVID-19: Vegans and pescatarians less likely to get severely ill from coronavirus, study suggests. Sky News. 08/06/21
8. Bulfamante G, Bocci T, Falleni M, Campiglio L, Coppola S, Tosi D, Chiumello D and PrioriA. Brainstem neuropathology in two cases of Covid-19: SARS-CoV-2 traficking between brain and lung. J Neurol. 2021. https://doi.org/10.1007/s00415-021-10604-8.

Nine lessons for long Covid

I learnt a new expression last week—an ‘earworm’. It immediately conjured up images of the chickens pecking at earthworms wriggling in the damp soil. Two or three pecks then whoosh, or rather gloop (not Goop), down the hatch. This is a picture of our rescue hen, now fully feathered and happily pecking at earthworms—and my plants!

Cher annd Bjorn caught in the act!

I wasn’t at all sure what an earworm was initially, especially as I heard it on the radio and it seemed out of context, particularly when the presenter was talking about how one might go about curing it. Was it a parasite?

Earlier, because of my interest in long Covid, I had been forwarded an article ‘How to live with long Covid.’ The article detailed the ‘best treatments available’. It stated that long Covid was ‘a quandary of our time’—a fitting description, I thought.

The article started by explaining that there are no trials, and so no evidence for any of the treatments, save a few anecdotal reports for antihistamines. I made a mental note to look into this later. The author claimed that the treatments would do no harm, except to your wallet—they were right there! The article rubbished Gwyneth Paltrow’s suggestion of ‘intuitive fasting’. It also suggested that long Covid sufferers should pace themselves—which is rather ambiguous.

I could not believe it when I read through the ‘treatments’ available. Starting at £275 for an appointment at a combined sports medicine/ physio clinic, to Q&A sessions for a fee with sporty medics, to pricy probiotics, expensive nutritionists, food trackers and meditation through to five grand on a clinic in Spain, ten grand for a sleep clinic or 78 grand on a full immersive clinic in Europe.

This seemed such a scam. People jumping on the bandwagon to offer anything for a fee. I remembered part of a song with appropriate lyrics: ‘The best things in life are free.’ It has a catchy tune, repeated over and over in my mind. It suddenly all made sense. An earworm is a tune that goes on and on in your head.

Not wanting to quibble, I wanted to know whether there was a feasible mechanism for diet or fasting to help recovery in long Covid sufferers. I started with what we know:

• Gastrointestinal symptoms are common in acute Covid, and often precede fever.
• There is viral shedding in the stool long after the respiratory symptoms have passed—a good reason to wash hands, as faecal-oral spread seems quite likely.
• The amount of virus in the stool increases with the symptoms of diarrhea.
• The calprotectin is increased in these patients. Calprotectin is a protein that is produced by white blood cells, the ones that fight off infections and are present in inflammation. It is therefore a useful marker of inflammation in the gut.
• There are anecdotal reports of diet helping patients to recover.
• Diet is known to help patients with the inflammatory bowel disease, for example Crohn’s.
• In Crohn’s disease patients have inflammation, diarrhea, an environmental trigger (possibly an infection).
• There is a change in the type of bacteria that occurs in the gut in both Covid sufferers and in Crohn’s.
• Diet can be used to change the type and variety of bacteria in the gut. In particular sugary foods, non-sugary sweeteners, food additives in processed foods, and restrictive diets reduce the type of bacteria, in a potentially harmful way.
• Patients with persisting gastrointestinal symptoms were more likely to have had proton pump inhibitors—which alter the bacteria in the gut, and steroids—which suppress the immune system.

So there is plenty of reason to suggest that diet helps. The best diet is probably a low-sugar, low-fat (poorly absorbed in inflammation), low-fibre (can worsen diarrhea), low-processed-food diet. Gwyneth Paltrow may be right after all.

I listened to an inspirational speech by Tim Minchin for the University of Western Australia graduation ceremony. He gave the new graduates nine lessons for life. It was highly entertaining, inspiring, relevant, and packed with truth, and it made me realise that these nine lessons can be adapted for use anywhere, any difficult situation, even long Covid. So here are the nine lessons for long Covid (sadly, I wont be recorded delivering this, posted on YouTube, with thousands of followers, but do have a listen to the original, its worth it):

1. Set small, easily achievable goals—‘Micro-ambitions’—make a list. Mine would start with 1. Get up 2. Have breakfast 3. Bath 4. Get dressed. After the first hour of the morning I had already achieved more than 50% of my goals for the day.

2. Keep busy—doing as little as possible. I used to sit quietly doing jigsaws. These generally required little effort, minimal brainpower, but gave me a sense of achievement.

3. Recognise that you are lucky. Appreciate that there are so many people worse off. Focus on what you can do and not that which you cannot. You are alive!

4. Limit exercise. Imagine you have a rechargeable battery inside and the battery sign takes 48 hours to show the amount of charge left. If you have a busy day one day, the next day should be a quiet day to complete jigsaws or catch up with series on TV. If after 48 hours of chilling you do not feel about to collapse, then you can assume the battery has been recharged and be active again, slowly increasing the amount that you do.

5. Think for yourself. There is no magic bullet. There is no evidence base for treatment. The doctors are baffled and don’t have the answers even if they set up clinics—these may not offer effective treatments. Work out for yourself what makes you feel better and what causes a deterioration; do more of the former and stop doing the things that hinder recovery. For me I felt worse after excess activity, alcohol and sugar. I felt better after rest, eating fruit, and feeling I had achieved something. I wrote a diary, to keep a record.

6. Share your ideas— Connect with and learn from others on Twitter, Facebook, blogs, Instagram, online forums. I used these, as well as medical papers, when I was ill. I have since shared my ideas in my book.

7. Have a routine to cope with insomnia. Insomnia was for me the worst thing. I disagree with the ‘sleep hygiene’ recommendations—advocating falling asleep and waking up at the same time every day. These people have clearly never had pathological insomnia. I would crash into a deep sleep early evening every night and then wake with a start unable to get back to sleep.

Now, when I wake up I have a routine: I get something small to eat—nothing worse than finally feeling sleepy and realising you’re hungry; I take vitamin C, benfotiamine, and usually take paracetamol if I have any aches or pains; I make a chamomile tea; I brush my teeth; I return to bed and look at the list of things I was going to read up about (Ah yes! What was I going to look up? Antihistamine use in long Covid or chronic fatigue etc.) It then becomes exciting to be awake. It is an opportunity rather than a nuisance. Other methods I found useful were to make a list of whatever is on my mind stopping me sleeping. Finally I make sure I am warm enough. A hot water bottle helps. I read an interesting article on the sleep-inducing properties of an electromagnetic field, and that an electric blanket creates an electromagnetic field. I have been researching this on cold nights, but feel that there is enough already to cover in this blog, so will return to this fascinating subject another time.

8. Respect everyone—especially healthcare workers. Even the doctors who are too arrogant to admit that they do not know how to treat you. Work out what you need from a consultation prior to the appointment. Be realistic about this. If you are not happy with the outcome, don’t take it as a personal affront, seek a second opinion, or think for yourself—you are your own boss—be autonomous, self-ruling.

9. Be positive—keep telling yourself you will get better, because you might, and hope is vital to recovery.

I looked up the exact words to the earlier earworm:

The best things in life are free

But you can give them to the birds and bees

I want money

That’s what I want…

And the cure for an earworm…

Ooh, ooh, ooh, ooh, ooh, ooh, (Whistling)

Don’t worry,

Be happy…

…it’s another earworm!

In every life we have some trouble,

But when you worry you make it double…

Further reading

R Newman. How to live with long Covid. Financial Times. 05/05/21

Zhong P, Xu J, Yang D et al. Covid-19-associated gastrointestinal and liver injury: clinical features and potential mechanisms. Sig Transduct Target Ther. 2020; 5: 256.

Guo M, Tao W, Flavell RA and Zhu S. Potential intestinal infection and faecal-oral transmission of SARS-CoV-2. Nature Reviews Gastroenterology and Hepatology. 2021; 18: 269-83.

Hindson J. Covid-19: faecal –oral transmission? Nature Reviews Gastroenterology and Hepatology. 2020; 17: 259.

Chen Y, Chen L, Deng Q et al. The presence of SARS-CoV-2 RNA in the feces of Covid-19 patients. J Med Virol. 2020; 92(7): 833-40.

Weng J, Li Y, Li J et al. Gastrointestinal sequelae 90 days after discharge for Covid-19. The Lancet. 2021; 6(5): 344-6.

Hunter J. Elemental diet and the nutritional treatment of Crohn’s disease. Gatroenterol Hepatol Bed Bench. 2015; 8(1): 4-5.

Valdes AM, Walter J, Segal E and Spector TD. Role of the gut microbiota in nutrition and health. BMJ. 2018; 361: k2179.

Tim Minchin. Occasional address.

Occasional Address

Berry Gordy and Janie Bradford. Money (That’s what I want). 1959Bobby McFerrin. Don’t worry, be happy. 1988

How does Covid cause long-Covid — Part 2

There are anecdotal reports that vaccination may improve long-Covid symptoms. This could be explained if the virus directly attacked nerves and remained in the nerve. So does Covid attack nerves?

Viruses usually affect the outer parts of the body initially, the nose, mouth, or respiratory mucosa, like coronavirus. Some viruses can then invade nerves in the periphery, and can spread to the central nervous system—the brain and spinal cord. The brain is protected from many types of viruses by the immune system and certain barriers, but some viruses are specialists at attacking nerves, notably rabies and certain herpes viruses.

There are many viruses that can invade the central nervous system and cause infection in the brain—encephalitis. Others remain latent—inactive—in nerves or the brain and can reactivate later.

Shingles is caused by reactivation of varicella zoster, more commonly know as the causative agent in chickenpox. It has developed to enter the nervous system. During the primary infection as chickenpox it is not usually obvious that the nerves have been affected.

Another virus, the polyoma JC virus, reactivates and leads to areas of demyelination—removal of the protective coating around nerves. HIV causes neuro-degeneration, which can then result in peripheral neuropathy and cognitive impairment. These two viruses affect the nervous system when the immune system is weak.

Coronaviruses cause infections in many different animals. They are known to cause acute and chronic diseases. Some coronaviruses, such as the mouse hepatitis virus, have been studied extensively. This mouse coronavirus is known to cause acute brain infection—encephalitis, as well as chronic demyelination. It is also capable of infecting all the different types of cells in the brain.

Following infection with mouse coronavirus there is a peak load of virus in the brain at 5 days. After clearance by the immune system the virus is still present in the brain. An overactive immune system then causes demyelination following infection and this usually peaks at about a month post-infection.

SARS-CoV was previously studied following the outbreak in China in 2002. The original SARS-CoV is in the same family as the mouse hepatitis virus. It would not be surprising if there were brain infection and demyelination in a significant proportion of people following infection with Covid.

Infection and spread of the strain of mouse coronavirus that is particularly capable of invading nerves and is toxic to depend on the structure of the spike protein.¹ Certain mutations make it more dangerous. The spike protein is being used in all the Covid vaccines.

In 2011 a review on how coronavirus causes disease questioned whether there would be another human coronavirus infection.² It concluded that it seemed likely as the same virus, SARS-CoV, had been found in bats and civet and that it had only taken a few mutations in the spike protein to adapt to humans.

Covid does seem to cause neuropathy. It seems plausible that it would cause nerve damage. Curiously it hasn’t been found in human brain tissue, and it doesn’t seem to infect the nerve cells. It’s not clear if this is the same in long-Covid. It’s still possible that it only takes a few mutations in the spike protein to increase the likelihood of nerve infection resulting in long-Covid.

Back to the original question, does Covid attack nerves? Do we actually know yet? Whilst there is still ongoing research perhaps vaccinating those with long-Covid early and boosting the immune system and nerve repair mechanisms with multivitamins, and particularly thiamine, will aid recovery.

I’m taking a break next week, but will return shortly with more information on the vaccine.

References:

1. Miura TA, Travanty EA, Oko L, Bielefeldt-Ohmann H, Weiss SR, Beauchemin N and Holmes K. The spike glycoprotein of murine coronavirus MHV-JHM mediates receptor-independent infection and spread in the central nervous systems of ceacam1a-/- mice. J Virol. 2008: 82(2); 755-63. https://doi.org/10.1128/JVI.01851-07

2. Weiss SR and Leibowitz JL. Coronavirus pathogenesis. Adv Virus Res. 2001; 81:85-164.

What is long-Covid?

I have an idea that may help anyone suffering from long-Covid. I am a retired doctor, but that is not my reason for writing. This is not something I learnt at medical school or even from being a doctor. I’m writing because I had similar symptoms and recovered with treatment that I discovered for myself, reading up about cases and symptoms on the Internet. 

Patients with long-Covid, according to the NHS website, have extreme tiredness, chest pains, problems with memory or concentration (brain fog), difficulty sleeping (insomnia), heart palpitations, dizziness, pins and needles, joint pain, depression and anxiety, feeling sick, diarrhoea, stomach aches and loss of appetite, among other symptoms.

Long-Covid is a syndrome. It’s a constellation of symptoms—what people experience, and a few signs—what doctors and others can see. There are more symptoms than signs, which means that it is even more important to listen carefully to the patient. Syndromes do not have specific diagnostic tests and different cases probably have different underlying causes, making any trials of treatment tricky, and evidence for successful treatment nigh on impossible. Hence there is no evidence for effective treatment in long-Covid, but do not despair.

In addition to the list of symptoms above, many patients have on-going lung problems. There are detectable changes in the lungs on scans, which may account for the persistent symptoms of breathlessness. There is also an increased risk of blood clots with Covid. Patients with breathlessness should be seen by a medical team. Other patients have on-going fever or rashes. It seems that Covid induces autoantibodies in certain patients and this is something that should be assessed formally. Patients with these problems may also suffer with the other aforementioned symptoms of fatigue, brain fog, pins and needles etc..

Many of these symptoms, which are baffling the medical profession, resonate with my own experience of a mystery illness. It was a mystery, because all my tests were normal, and yet I felt dreadful. I was never diagnosed. I felt as though no one was listening to me, but in truth, they just didn’t recognise the combination of symptoms that I was describing and so didn’t know how to help me. I kept a diary of how I felt. Reading stories about people suffering from long-Covid, I noticed a number of parallels with my own symptoms and experiences.

I often woke with a start, my whole body jolting as though I had fallen off a pavement in my sleep. My heart was trying to batter itself out of my chest. I felt hyper-alert. It was as if I was experiencing a panic attack or acute anxiety, only I wasn’t anxious, worried or scared. I just wanted to sleep. I had dreadful insomnia, and felt wired much of the time. I had palpitations, which were eased by applying gentle pressure to the side of my neck. I seemed to be suffering with episodes that mimicked low blood sugar. I had terribly sharp pains in my feet when I put my feet on the floor. It was as though I was treading on shards of glass. I was falling over regularly. I lost sensation in my hands and feet. I lost my sense of smell. My brain felt as though it was covered in a fleece. I became obsessive about my belongings, having misplaced so many things. The frustration resulted in multiple outbursts of anger. I would become extremely shaky. Bending the wrist joint provoked an excruciating sharp, lancinating pain shooting up my arm. I developed muscle twitches. I had pains in calf muscles.  My legs felt like two lead weights. The list seems endless, but thankfully I have completely recovered.

Reading from the media and blog site accounts, patients have described their symptoms extremely well:

• Frequent, all-consuming tiredness, lack of energy
• Sudden brain fog, difficulty with decision making, feeling as though brain smothered in cotton wool, poor concentration
• Brain wired, unrefreshing sleep
• Awareness of heart beating strongly or faster, as though blood sugar levels were low
• Pins and needles, uncomfortable burning and tingling in hands, often worse at night
• Agonising pains in both hands, like jolts of electric shocks
• Fluctuating or volatile moods, obsessive compulsive disorder
• Anxiety, sudden onset panic attacks, with an overwhelming feeling of terror, which tend to be short-lived, but leave patients feeling shaken, trembling and exhausted afterwards
• Uncontrollable shakes after only slight exertion
• Nausea, irritable bowel syndrome.

Like me, these people are describing the symptoms of neuropathy. Neuropathy is a sickness (‘-pathy’) of the nerves (‘neuro-‘). Patients also suffer from a slowness of the nerves in the brain.

There are three main types of nerves: sensory nerves, which mostly transmit information from the skin; autonomic nerves, which are the ones supplying the guts, heart, heart vessels and lungs, keeping everything running along smoothly, without us having to think about it; and motor or movement nerves, which supply the muscles.

Below are the typical symptoms from a sensory neuropathy. As you can see the list is remarkably similar to the accounts given so far:

• Numbness, tingling or burning starting in the feet and/or hands, spreading upwards into legs and arms
• Sharp, sudden stabbing pains when stretching the nerves, bending joints or putting feet on the ground
• Extremely sensitive skin, for example when a duvet rests on feet
• Glove and stocking numbness.

If there are fewer impulses from the peripheral nerves telling you the position of your feet then you may lack coordination, stumble, trip or even fall over.

When the autonomic nerves are involved the following symptoms are typical:

• Intolerance of heat
• Heavy sweating or no sweating
• Lack of gut movement leading to nausea, bloating, diarrhoea or constipation
• Low blood pressure, particularly on standing, causing dizziness.

Motor nerve dysfunction, usually a later symptom, causes muscle weakness or paralysis.

Patients with long-Covid have described muscle twitches, arm weakness, and heaviness and unresponsiveness in the legs, almost as if commands from the brain to move would be ‘held up somewhere in my nervous system in a lag of a few microseconds’. In fact, this is exactly what is happening.

Summary: What is long-Covid?
In a significant number of cases, the symptoms of long-Covid may be caused by neuropathy.

Next week’s blog: Why are long-Covid sufferers developing neuropathy and how it can be treated?

References

E Rooksby. Nine months in the long limbo of long covid. (2021) (available at https://edrooksby.wordpress.com)

M Smith. ‘Coronavirus has left me with devastating after effects.’ Wales online. (2020) (available at https://www.walesonline.co.uk/news/health/doctor-believes-hes-suffering-long-19022875)