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.