Category: Diet

B12

In the fall 2016 MPDN article on dietary supplements, I noted that there are studies indicating Parkinson disease (PD) patients may be deficient in vitamins B6, B12, and D.   I find that when people learn this they often assume it would be a good idea to pick up some vitamins at the grocery store as a preventive measure.  That is not the right move, and is probably a result of years of advertising by industry, to create the false image that vitamins are always safe, and more is better.  Vitamins are not benign, and one should not blindly take them.

Instead, just as I advised in the supplement article, if a qualified doctor has found a low level, that doctor can advise you on whether or not you should take a vitamin.  If that is the case, stick to the dose directed by your doctor.  Don’t improvise, don’t listen to unqualified, however well-meaning people, and don’t believe the majority of what you read on the internet about the topic of vitamins.  With vitamins, too little or too much may lead to serious health problems. 

Having said that, let’s discuss B12 (cyanocobalamin).  Several studies have shown an association with low B12, the total amount of levodopa someone has taken, and peripheral neuropathy (nerve damage in the hands and feet).  In other words, the more levodopa someone has taken, the greater the risk might be of that person running low on B12.  Low B12 is a common cause of nerve damage.  People with PD treated with oral levodopa have a higher prevalence of a mild, chronic sensory neuropathy, though rare cases of severe, subacute neuropathy similar to Guillain-Barré syndrome have been reported (1).  The great majority of both types of cases were associated with low B12 levels.  The association became more obvious after the dopamine pump was introduced in Europe (2, 3).   Continuous infusion of carbidopa/levodopa intestinal gel (LCIG) was associated with a peripheral neuropathy and vitamin B12 and/or B6 deficiency.   Cases of LCIG-associated neuropathy often responded to vitamin supplementation without the need for stopping the pump.  Investigators advocated for monitoring of vitamin B12 and B6 status before and after patients start LCIG, and vigilance for signs of neuropathy, such as numbness in the feet, tingling, or even burning sensations.

In addition, neuropathy is not the only problem low B12 can cause.  Every nerve in the body uses B12, and without it, disease occurs.  It might make sense then, to know that B12 deficiency can also cause blindness, memory loss, dementia, and spinal cord damage, which may become permanent.  Some patients have told me they know about these issues, and have learned that B12 deficiency can also cause anemia.  The logic goes that since they are not anemic, they have nothing to worry about.   They are unfortunately wrong.  The neurologic damage associated with B12 deficiency is usually established before a person develops anemia.  You can’t rely on the presence or absence of anemia to screen for low B12.

Though it is stored in the liver, doctors check B12 with a blood test (with an at least four hour fast prior to drawing blood).  It is advisable not to take vitamins before the test, as these will falsely elevate the level, rendering the test useless.  Most of the time a level over 300 pg/mL is considered normal. The tricky part is that “normal” levels of this vitamin vary from person to person, and for some a level somewhat under 300 pg/mL may be fine.  Fortunately, there is a way to sort this out.   Because B12 is necessary for certain enzymes to work, low B12 can cause a buildup in the blood of substances that would have otherwise been broken down, such as methylmalonic acid (MMA) and homocysteine (HC).  Think about it like a scale is tipped.  When a borderline low B12 level is present and MMA and HC are high, one has a deficiency.   In fact, because the B12 blood test may be falsely elevated, MMA is actually a more sensitive test for the state of a person’s B12 storage.  In the above-referenced LCIG patients, all of these lab tests verified deficiency.

If B12 is low, it can be replaced by high-dose shots, or sometimes by high-dose tablets, which should again be directed by a doctor.   The orally absorbed B12 goes directly into the bloodstream and may be better absorbed than swallowed pills, though some of these are also very effective.

Under normal circumstances, we get B12 from dietary sources, and the minimum daily requirement is about 2.5 mcg, with a recommended daily intake of 6 mcg (six millionths of a gram).  A person’s liver will store about 3 mg of B12.  A typical American diet contains about 20 mcg of B12 daily, almost all coming from meat or dairy products.  Vegan diets can lead to deficiency, and no vegetable product is known to contain a reliable source of biologically active B12.   There is some data that the mori, or purple laver of edible seaweed used to wrap sushi might contain sufficient biologically active B12 (4).  If a healthy person were to stop ingesting B12 suddenly, deficiency might take up to five years to develop because of those high liver stores.

There are a multitude of other ways one might develop B12 deficiency.  These include, but are not limited to: bariatric surgery, taking certain other medications such as proton pump inhibitors or metformin, inhalation of laughing gas (nitrous oxide) and some other inhaled anesthetics, allergic gastritis, and Helicobactor pylori infection.   In my neurology group practice B12 deficiency is diagnosed daily.

In the U.S., there is no guideline to check B12 among PD patients.  It sounds like a good idea to me, though.

REFERENCES

  1. Uncini et al. J Neurol Neurosurg Psychiatry. 2014 Aug 28.  Polyneuropathy associated with duodenal infusion of levodopa in Parkinson’s disease: features, pathogenesis and management.
  2. Müller et al. Parkinsonism Relat Disord. 2013;19(5):501-7. Peripheral neuropathy in Parkinson’s disease: levodopa exposure and implications for duodenal delivery.
  3. Santos-García et al.  J Neurol. 2012;259(8):1668-72. Polyneuropathy while on duodenal levodopa infusion in Parkinson’s disease patients: we must be alert.
  4. Watanabe, et al. Biosci Biotechnol Biochem 2000;64(12):2712-05.  Characterization of a vitamin B12 compound in the edible purple laver, Porphyra yezoensis.

 

Vitamin D

Levels of vitamin D are lower in PD patients worldwide (1).  Several neurologic disorders are associated with vitamin D deficiency, including MS, stroke, and other neurodegenerative disorders.   We are not sure yet what this means, or what all of the functions of vitamin D are (though what is known is extensive).   It seems clear, however, that keeping a normal level is a good idea.

Doctors measure vitamin D with a blood test.  The test checks levels of 25-hydroxy D total, a combination of D2 and D3.  We get vitamin D2 from diet, and some conversion is made when we are exposed to sunlight and UVB enters the skin, helping us produce the active vitamin D3 form.  According to Mayo Medical Laboratories New England, 10-24 ng/mL = mild to moderate deficiency, and optimum levels in the normal population are 25-80 ng/mL.

Interestingly, vitamin D receptors are found all over the brain.  One location that is relevant here is the receptors on large neurons of the substantia nigra, the darkly pigmented structure of our upper brainstem, which produces dopamine.   These cells are unfortunately lost throughout disease in PD.  The progressive depletion of these neurons over several years ultimately results in enough of a dopamine deficiency for the first motor signs of PD to show (tremor, stiffness, slowness).   As disease progresses, one has fewer of the cells, and therefore, less dopamine.

I am going to get a little technical here.  One thing that vitamin D does in these cells is to increase an enzyme called tyrosine hydroxylase.  This enzyme converts the amino acid tyrosine into dopa, a precursor of dopamine.  Therefore, we may need vitamin D to make dopamine efficiently.

Researchers have shown in mice that knocking out the vitamin D receptor on these neurons will result in a PD-like motor impairment (2).  This led the same investigators to question whether low vitamin D might predispose people to neurodegenerative disease.  Further, they wanted to know if keeping levels in the high normal range would make a difference.   In a 12-month study with 114 PD patients who averaged a vitamin D level of 22.5 ng/dL, 56 were given 1200 IU of vitamin D daily and 58 were given placebo.  At the end of the study, the treatment group had a higher vitamin D level, with an average of 42 ng/dL.  The very simple Hoehn and Yahr stage was stable, but not the more detailed UPDRSIII motor score.  This is not an impressive result, but it was a limited study.

The jury is still out on vitamin D levels in PD.  A normal level is probably a good idea for many reasons, but it is not clear if it will have an effect on disease progression.  There is no data on high levels, except to say that taking too much can cause toxicity.  Acute vitamin D toxicity may cause confusion, excess urination and thirst, loss of appetite, vomiting, and muscle weakness.  Chronically high levels of vitamin D may result in kidney stones, loss of bone mineralization, and pain.  So, as with any vitamin, work with your doctor to make sure your level is normal.

REFERENCES

  1. Lv, et al.  Vitamin D Status and Parkinson’s disease” as systematic review and meta-analysis. Neurol Sci 2014;35:1723-30.
  2. Suzuki et al. Does vitamin D arrest the progress of PD?   American Journal of Clinical Nutrition. 2013;97:1004-13.

 

What is the Gut-Brain Axis?

We have long known that constipation is a common non-motor feature of Parkinson disease (PD) (1). One study of 7000 men over a period of 24 years showed that those with initial constipation (less than one bowel movement per day) had a three-fold risk of PD after an average of 10 years (2).  Thus, unexplained and persistent constipation in adults is associated with an increased risk of PD: 1/3 will have constipation a year prior to PD diagnosis, and 2/3 will have constipation after diagnosis (3,4).  Ultimately, greater than 80% of PD patients will have GI dysfunction of some type early in disease.  Investigators have tried to explain this for many years.  In the 1970s, one idea was the “slow transit hypothesis,” the idea that slowing down of the gut allowed the absorption of toxins which might trigger PD (5).  Though this fell out of mainstream discussion, and may have seemed an oversimplification, the idea is not so far from current thought.

To understand what we now call the gut-brain axis, it helps first to know that your gut, or your digestive tract, contains a lot of bacteria, tens of trillions of them. Largely because of the population in the gut, there are more bacteria than human cells in our bodies.   One way they get away with this is that they tend to be much smaller than our cells.  Bacteria tend to be about 0.1-5 micrometers in size (millionths of a meter).  Human cells range from about 10 to 100 micrometers, so our cells tend to be many times bigger than bacteria.  And, as long as they stay in specific locations, bacteria work with, not against us; but when they go to the wrong place, illness occurs: think diarrhea, nausea, vomiting, etc.  Under ideal circumstances, among several jobs, many gut bacteria help us to digest food and collect certain nutrients we otherwise would not be able to extract or produce.  In exchange for this, they are given food, shelter, and a chance to move along to some other environment – a great reason why we should all wash our hands when leaving a restroom.  Half of the dry weight of our stool is bacteria, and if it winds up travelling the fecal-oral route, e.g., hand to doorknob to someone else’s hand to mouth, the consequences can be bad.  A few minutes spent in a busy public restroom will alert you that hand washing is not a universal practice.

A healthy gut requires a healthy population of bacteria.  To understand this a little better, let’s define a few terms.  A single bacterial cell is a microbe.  The terms microbiome and microbiota are used a lot when discussing this topic, and for our purposes, they are the collection of bacteria in the gut.  There is a group of over a thousand different species of microbes in the gut.  Their library of unique genes is over 100 times larger than the number of genes in a person’s DNA library.  That is a considerable genetic power. The balance among types of organisms present in the gut is important as well.  When there is too much or too little of one type or another, this is imbalance, which we call dysbiosis.  Dysbiosis has been linked to inflammation, metabolic disease, certain cancers, and neurologic disease.

Dysbiosis can cause disease because one of the roles of a healthy microbiome is to regulate gut and bodily inflammation.  They do this by the release of tiny chemical messengers.  In PD, delayed gastric emptying and slow transit of stool may increase the over-production of some types of bacteria, which not only upsets the local balance, but creates the symptoms of gas, colic, and inflammation (6,7).  This makes it even easier to get their messengers into the bloodstream.  Further, as if pretending to be nerve cells, bacteria can produce neurotransmitters and neuromodulators such as GABA, serotonin, dopamine, or short-chain fatty acids (8).  This may allow bacteria to communicate with our nervous system (9).

It also goes the other way.  The drugs PD patients take may influence the microbiome (10).  One study evaluated 197 PD patients and 130 controls without PD.  They were able to identify the types and numbers of microbes taken from stool of each person.  Investigators took into account 39 potential confounders such as medications, diet, GI symptoms, and demographics.  The gut microbiome was different in PD, and multiple families of bacteria were much more robust.  In the PD patients there were also different balances corresponding to different drugs, such as COMTs and anticholinergics.  In the study, the effect of L-dopa could not be separated out as 90% of PD patients were taking the drug.

Another reason dysbiosis may be a risk factor for disease is that our gut bacteria protect us by breaking down xenobiotics (herbicides, flame retardants, insect repellents we encounter in the environment).  Living in agricultural settings is a known risk factor for PD and this may explain why.  In the lab we know that xenobiotics can cause the death of dopamine-producing cells and motor abnormalities in animal models of PD.  Therefore, dysbiosis might expose humans to toxins which would otherwise have been broken down.  The toxins may trigger disease.  The evidence that this may be happening is supported by the observation that the pathologic hallmark of PD, the Lewy body, may be seen in neurons of the gut years prior to the development of motor symptoms of PD, and may be seen in the gut of lab animals given xenobiotics.   These observations helped lead to the hypothesis that PD starts in the gut (11).

The most common protein in Lewy bodies is called alpha-synuclein (aSyn). This little protein is found at the point of communication between neurons called the synapse.  The job of aSyn is to stabilize little bags of dopamine (vesicles), and to help control synaptic plasticity (the formation of new neural pathways in the brain involved with learning).  This protein, like all others, has a very specific three-dimensional shape which it must maintain in order to work.  This is similar to a key, which must be shaped a certain way to fit into a lock and turn the tumblers.  If the key is bent, it will not work.  If aSyn is misfolded, it does not work, dopamine is not released, and new pathways are not made.  It may be that exposure to certain toxins triggers the misfolding of aSyn, or there may be other factors such as gene mutations.  Whatever the cause, misfolded aSyn may behave very much like a prion, where one bad protein warps others of the same class (think one bad apple spoils the whole bunch).

Testing this idea, researchers exposed lab mice to the pesticide rotenone, which has long been associated with risk of PD in humans (12).  The mice developed misfolded aSyn in the gut.  Abnormal aSyn in the gut activates immune cells in the brain known as microglia (13).  These microglia are then primed to destroy neurons containing abnormal aSyn.  This is one of the ways PD patients lose neurons.  If present long enough, misfolded aSyn will also travel up the long vagus nerve to the brainstem, where it will spread upwards in the same way the protein spreads in humans with PD.  Of note, mice and men with a severed vagus nerve have a lower risk of PD.

In order to test the effects of microbes and molecules on animals, researchers relied on the first gene abnormality identified in PD, the PARK1 gene (14).  The PARK1 gene causes the overproduction of aSyn.  When the gene is present in mice, they manifest a form of parkinsonism very early in life.  However, if the mice are treated with antibiotics to kill the microbiome, motor symptoms of disease become minimal, and there is reduced activation of microglia (15).   This led the investigators to raise PARK1 mice in a sterile environment with no microbiome.  These mice too, had minimal motor issues. When colonized with a microbiome (transplanted feces) from humans without PD, the mice were unchanged.  When given the microbiome from PD patients, the mice developed impaired motor function.  This supports the “two-hit” hypothesis, that PD is likely caused by genes and environment.  In other words, if someone is predisposed to develop PD because of genes, they may not do so until exposed to some trigger such as a toxin.   Researchers were also able to normalize the affected mice by adding normal chemical messages such as short chain fatty acids that a normal microbiome would produce.

Thus, the gut-brain axis raises several interesting questions:

  • Would a simple stool test reveal risk to PD and other diseases?
  • Would understanding the microbiome help physicians in selecting the appropriate drugs for people with PD, or lead to the formation of new treatments?
  • Would changing the microbiome improve disease for people with PD?

If you know, tell me.  Otherwise, stay tuned.  This is a big topic in PD.

 

Stylistic and copy editing of this article, as well as helpful insights, by Sarah Savard, RN, and Liz Stamey, RN.

 

REFERENCES

  1. https://mainepdnews.org/2016/06/12/constipation-in-pd/
  2. Abbott.  Neurology 2001; 57: 456–62
  3. Pfeiffer RF.  Gastrointestinal dysfunction in Parkinson’s disease. Parkinsonism Relat Disord 2011; 17: 10-15.
  4. Mulak A, Bonaz B.  Brain-gut-microbiota axis in Parkinson’s disease. World Journal of Gastroenterology.  2015;21(37): 10609-10620.
  5. Singharam.  Lancet 1995; 346: 861–64.
  6. Hasegawa, et al.  Intestinal dysbiosis and lowered serum lipopolysaccharide-binding protein in Parkinson’s disease.   PLoS ONE 2015;10, e0142164.
  7. Keshavarzian, et al.  Colonic bacterial composition in  Parkinson’s disease.  Mov. Disord. 2015; 30: 1351–1360.
  8. Lyte M.  Microbial endocrinology: Host-microbiota neuroendocrine interactions influencing brain and behavior.  Gut Microbes 2014; 5:381-389.
  9. Mayer , et al.  Gut/brain axis and the microbiota.  J Clin Invest 2015; 125: 926-938.
  10. Hill-Burns et al.  Parkinson’s Disease and Parkinson’s Disease Medications have Distinct Signatures of the Gut Microbiome.  Movement Disorders. 2017:00: (00)epub online Feb, 2017.
  11. Braak H.  Staging of brain pathology related to sporadic Parkinson’s disease. Neurobiology of Aging, 2003 24: 197.
  12. Pan-Montojo, et al.  Progression of Parkinson’s disease pathology is reproduced by intragastric administration of rotenone in mice.  PloS One  2010;5:e8762.
  13. Erny, et al.  Host microbiota constantly control maturation and function of microglia in theNS. Nat. Neurosci. 2015; 18: 965–977.
  14. Polymeropoulus, et al.  Mutation in the α-Synuclein Gene Identified in Families with Parkinson’s Disease.  Science 1997: 276 (5321);2045-2047.
  15. Sampson et al.  Gut Microbiota Regulate Motor  Deficits and Neuroinflammation in a Model of Parkinson’s Disease.  Cell 167, 1469–1480, December 1, 2016.

 

Protein Redistribution Diet

by Alison Fernald RD, LD, CDE

Editor’s note: This is a companion to the PD and diet article, presented as a way for patients concerned about the effect of eating proteins while taking carbidopa/levodopa (Sinemet).  As mentioned in the article, the two may compete for absorption and therefore reduce the effect of the drug.  The general approach is to take levodopa one hour before, or two hours after meals containing protein.  

-WS

 

Protein needs vary depending on height, weight, gender and age, but generally, 1.2 grams of protein per kilogram (2.2 pounds) of weight is adequate to preserve lean muscle mass.  The diet below provides approximately 85 grams of protein, enough for a person weighing about 160 pounds.

7:00 a.m.   Take medication – coffee or tea if desired, which have no protein unless milk is added

7:45 a.m.   Breakfast of 2 eggs or ½ c. cottage cheese, or nuts if tolerated; a piece of fruit; a slice or two of whole grain toast with 2 tsp. butter or vegetable oil spread; and 6 ounces milk (cow, almond or soy). (22 g protein)

11:00 a.m. Take medication

12:00 p.m. Lunch with 1 cup of vegetables of choice, including beans if desired; 2 oz. tuna or other protein of choice; 2/3 c. brown rice, stone ground bread or quinoa (a whole grain that has extra calcium, is less refined, and has more fiber than white bread).  Don’t forget to add some fat to the meal – mix tuna with olive oil mayo, or drizzle oil and vinegar on vegetables – 1/2 to 1 tablespoon is fine.  (about 20 g protein)

4:00 p.m.   Take medication

5:00 p.m.   Meal with up to 4-5 ounces of protein:  chicken, fish, beef, pork (lean) or a bean dish like chili with lots of chopped vegetables (at least 1 c.), and a salad, or sautéed onions with the protein (or any vegetable you like), and ~1 c. of whole grain/starch of choice – ex:  pasta, peas and corn, brown rice, whole grain bread or roasted red skin potatoes, or a baked potato.  Add a little healthy fat – cold pressed oils like grape seed, walnut and extra virgin olive oil have potential to be slightly better than the mass produced vegetable oils (we all need some fat in our diets, just avoid deep fried choices, or pre-deep fried items like tater tots and chicken nuggets).  (about 35 g protein)

8:00 p.m.   Snack on 1 ounce sharp cheese and/or nuts and fruit, some non-starchy vegetables – marinated cucumbers, celery and carrot sticks, or some whole grain crackers like “Hint of Salt” Triscuits or other fiber-rich cracker. (about 10 g protein)

It generally takes 3 to 4 hours for a meal, including its protein, to be completely digested.  If you take a fourth dose of medication at night, you will need to time the snack accordingly, i.e. have the snack at 2:00 p.m., or put it off until 10:00 p.m., after you have taken your nighttime dose at 9:00 p.m.

PD and diet

Recently, at a talk regarding PD in Brunswick, a common question came up as to whether diet influences the disease.  I gave sort of a stock answer, in that no dietary intervention has been proven to treat the condition, but that there are several points to consider about diet (see, for example, the article in MPDN about constipation).  Here, I will review some other issues.

Not surprisingly, the data seems to favor eating a healthy diet.  Many ask, “What is a healthy diet?”  That is a complex question.  Most studies seem to point to something akin to the Mediterranean diet, which contains significant olive oil, grains, vegetables, fruits, potatoes, seeds, nuts, legumes, and fish; and generally lower intake of red meats, poultry, dairy, and alcohol (though small amounts of red wine can be beneficial).  Numerous observations have been made regarding longevity and the reduction of cardiovascular or metabolic diseases among those who eat this way.

These observations have led investigators to study diet for improving health and preventing disease.  The DASH diet (Dietary Approach to Stop Hypertension) is based on the Mediterranean diet, though using relatively more low-fat dairy and less fish.  The MIND diet (Mediterranean–DASH Intervention for Neurodegenerative Delay) takes elements from both diets and increases consumption of berries, nuts, and beans. A meta-analysis, which is an in-depth review of multiple similar studies, looked at 14 prospective trials totaling thousands of participants in the U.S., Greece, Europe, and Australia (1).  In these trials, people were followed from 3.7 to 18 years and had lower rates of Alzheimer disease.  One of the studies, conducted by the World Health Organization Study Group, followed more than 130,000 health care professionals for 16 years, and showed that those who ate a Mediterranean diet had lower rates of PD (2).  Studies of older people who followed the MIND diet showed less cognitive decline at a 4.7-year follow-up (3, 4).

The PREDIMED study included 522 people aged 55-80 who were at high risk for cardiovascular disease (5). These people were randomly assigned to one of three diets: a Mediterranean diet with supplemental extra-virgin olive oil (EVOO), a Mediterranean diet with supplemental mixed nuts, or a regular diet with reduced dietary fat.  Heart attack, stroke, and death from cardiovascular causes were all reduced in those eating the diet with EVOO, and those people scored higher on the Mini-Mental State Examination (MMSE) and the clock-drawing test at 6.5 years.

In a four-month study, 124 participants with high blood pressure started either a DASH diet, or aerobic exercise and a DASH diet (6).  Those with the combined approach had better psychomotor speed (basically, a measure of the time for the connection between thought and movement).  Though none of these patients were noted to have PD, the finding is interesting because one of the problems with PD is a decrease in psychomotor speed.

In a large population study of 1,260 people with cardiovascular risk factors for dementia, the Finnish Geriatric Intervention Study to Prevent Cognitive Impairment and Disability (FINGER) (7), participants were chosen who had average, or slightly lower than average, cognitive performance for age, and were randomly assigned to a combination of diet, exercise, cognitive training, and vascular risk monitoring, or to a health advice control group.  The diet included fruit, vegetables, whole-grain cereals, low-fat milk, low-fat meat, low sugar, margarine instead of butter, and two or more portions of fish per week.  Participants underwent a group of 14 neuropsychological tests. During the 24-month follow-up period, composite scores were 25% higher in the intervention group than those who received advice alone.  Executive functioning, which includes problem solving, critical analysis, and processing speed, were better in the intervention group.

There is some data that caffeine consumption may decrease risk of PD.  Over 8,000 men were followed for 30 years in the Honolulu Heart Program (8). Incidence of PD decreased with amount of coffee intake:  the more coffee consumed, the lower the risk of PD.  Similar data was found among those that consumed caffeine from sources other than coffee, such as tea. The National Institutes of Health-AARP Diet and Health Study prospectively examined whether caffeine intake was associated with lower risk of PD among over 300,000 men and women (9).  The effect was equal, with no gender difference.  Again, the more caffeine consumed, the less likely one was to develop PD.  Multiple other studies have shown similar results. Caffeine is hypothesized to protect dopaminergic neurons by antagonizing a neuronal receptor known as adenosine A2A (10).  Animal models have shown that chemicals which inhibit A2A can protect dopamine-containing neurons, and caffeine has been shown to improve some motor function in PD (11).  The effect on A2A receptors has led to a new class of investigational drugs, such as istradefylline.  Of note, caffeine is also a CNS stimulant which may help with daytime sleepiness, alertness, and cognitive function.

Curcumin is an active ingredient of turmeric. In volumes used in cooking it is non-toxic. It is able to cross the blood-brain barrier.  Curcumin binds to mutant α-synuclein (see the article in MPDN about alpha-synuclein), and thus may prevent aggregation and formation of Lewy bodies (12, 13).

Mucuna pruriens, the velvet bean, aka cowhage, has long been used in traditional Ayurvedic medicine for Parkinsonism.  In 1937, researchers isolated levodopa from the beans (14), though this was prior to a scientific understanding of the link between levodopa and Parkinson disease.  From 1978 to 2000 there were at least three open label studies (in which patients knew they were taking the study drug instead of taking a blinded pill, which might be treatment or placebo) (15, 16, 17).  These studies reported significant improvements in Parkinsonism for up to 20 weeks.  In 2004, London researchers demonstrated with eight PD patients that single doses of immediate release 50/200 mg carbidopa/levodopa were not as fast in onset of effect as a 30 g mucuna preparation (34.6 v 68.5 min), and this was consistent with time to peak blood concentration (18).  Average ON time was 37 minutes longer with 30 g mucuna than carbidopa/levodopa, and plasma concentrations 110% higher, implying the amount of levodopa was much higher in the mucuna preparation, essentially double the dose of the carbidopa/levodopa.  Each of the eight patients were trialed with mucuna, and two complained of mild nausea, whereas one dropped out of the study due to “short lasting vomiting.”  Acute side effects of levodopa are known to include nausea and vomiting.  This is the reason carbidopa is combined with the drug in tablets.  The authors suggested that domperidone might be combined with mucuna to prevent these side effects, and that larger randomized trials should be undertaken to evaluate mucuna.  Mucuna is unfortunately still not endorsed by such trials, and no standard measurement of levodopa derived from the bean is as yet available.

Fava beans, Vicia fava, aka the broad bean, have been known to contain levodopa since 1913 (19).  One open-label study comparing 250 g of cooked fava with 100 mg synthetic carbidopa/levodopa showed lower peak plasma concentrations after eating the beans, though the effect was similar to synthetic levodopa (20). Unlike mucuna, however, the concentration of levodopa in fava beans is very low, and therefore would require a large number of beans to reach a benefit.  Likewise, there is no standard for the amount of levodopa in fava beans, making dosing unpredictable.  In addition, some people with a genetic deficiency of glucose 6-phosphate dehydrogenase may react to eating fava beans with favism, a form of hemolytic anemia.

Finally, because levodopa, the active ingredient in carbidopa/levodopa (Sinemet), Duopa, and entacapone/carbidopa/levodopa (Stalevo) competes with amino acids for absorption in the GI tract, it should be taken one hour before, or two hours after, meals containing protein.   This creates certain problems with timing of medications and foods.  It is better to stick with a consistent time to dose meds, and plan meals around this.  Often, patients report they have stopped eating proteins, or moved all protein to the nighttime.  There are problems with this approach as well, because we need proteins, but the all at once approach may not be the right path.

I discussed this issue with Alison Fernald, RD, LD, CDE, of Mid Coast Center for Diabetes & Endocrinology, in Brunswick, Maine.  She notes that “an average person can only digest 25-30 grams of protein at a time, and a 140 pound person needs at least 50 grams of protein a day.   So, they have to break it up, and not eat it all at once.”  For those who need detailed instructions, Alison suggested a way to tackle this might be the protein redistribution diet, which will be included in this edition of MPDN.

 

REFERENCES

  1. Sofi, et al., Adherence to Mediterranean diet and health status: meta-analysis. BMJ. 2008;337:a1344.
  2. Gao, et al. Prospective study of dietary pattern and risk of Parkinson Disease. Am J Clin Nutr. 2007;86(5):1486–94.
  3. Morris, et al. MIND diet slows cognitive decline with aging. Alzheimers Dement. 2015;11:1015-1022.
  4. Morris, et al. MIND diet associated with reduced incidence of Alzheimer’s disease. Alzheimers Dement. 2015;11:1007-1014.
  5. Martinez-Lapiscina, et al. Mediterranean diet improves cognition: the PREDIMED-NAVARRA randomised trial. J Neurol Neurosurg Psychiatry. 2013;84:1318-1325.
  6. Smith, et al. Effects of the dietary approaches to stop hypertension diet, exercise, and caloric restriction on neurocognition in overweight adults with high blood pressure. Hypertension. 2010;55:1331-1338.
  7. Ngandu, et al., A 2 year multidomain intervention of diet, exercise, cognitive training, and vascular risk monitoring versus control to prevent cognitive decline in at-risk elderly people (FINGER): a randomised controlled trial. Lancet. 2015;385(9984):2255-6
  8. Ross, et al. Association of caffeine and coffee intake with risk of Parkinson disease.  Jama.2000;283:2674-79.
  9. Lui, et al. Caffeine Intake, Smoking, and Risk of Parkinson Disease in Men and Women.  Am J Epidemiol. 2012;175(11):1200–07.
  10. Schwarzschild, et al. Caffeinated clues and the promise of adenosine A(2A) antagonists in PD. Neurology. 2002;58(8):1154–1160.
  11. Cieślak, et al. Adenosine A(2A) receptors in Parkinson’s disease treatment. Purinergic Signal. 2008 Dec; 4(4):305-12.
  12. Ahsan, et al. Curcumin Pyrazole and its derivative (N-(3-Nitrophenylpyrazole) Curcumin inhibit aggregation, disrupt fibrils and modulate toxicity of Wild type and Mutant α-Synuclein. Sci. Rep. 2015;5:9862.
  13. Ahmad B., Lapidus L.J. Curcumin prevents aggregation in α-synuclein by increasing reconfiguration rate. J. Biol. Chem. 2012;287(12):9193–9199.
  14. Damodaran M, Ramaswamy R. Isolation of L-dopa from the seeds of Mucuna pruriens. Biochem J 1937;31:2149–451.
  15. Vayda, et al. Treatment of Parkinson’s disease with the cowhage plant – Mucuna pruriens (Bak). Neurol India 1978;36:171–6.
  16. HP-200 in Parkinson’s Disease Study Group. An alternative medicine treatment for Parkinson’s disease: results of a multicenter clinical trial. J Altern Complement Med1995; 1:249–55.
  17. Nagashayana, et al. Association of L-dopa with recovery following ayurveda medication in Parkinson’s disease.  J Neurol Sci2000;176:124–7.
  18. Katznschlager, et al. Mucuna pruriens in Parkinson’s disease: a double blind clinical and pharmacological study. J Neurol Neurosurg Psychiatry.2004; 75(12):1672–1677
  19. Guggenheim M. Dioxyphenylalanin, eine neue Aminosaeure aus Vicia fava.Z Physiol Chem 1912;88:276–84.
  20. Rabey, et al. Improvement of parkinsonian features correlate with high plasma levodopa values after broad bean (Vicia fava) consumption. J Neurol Neurosurg Psychiatry1992;55:725–7.

 

Dietary Supplements

It is estimated that over 50% of U.S. citizens use a daily supplement, whether an herbal, plant-based, amino acid, or a vitamin.  Many PD patients take one or more of these compounds.  My experience is that there is often an assumption that these products are natural, and therefore good for you, and the supply in stores is safe because the FDA will protect us from harmful substances.  These points should be taken separately.

 Are supplements good for you?

The issue is complex.  Some might be, and some are not.  Consider vitamins, for example. Vitamins are by definition required for health, but for the vast majority of us vitamin supplements are not necessary because we get the very small amounts we need from foods in a healthy diet.  Most of the time, if a person does not have a documented vitamin deficiency, taking over the counter vitamins does not improve health at all.  In fact, many well-designed studies involving hundreds of thousands of people have found no evidence that vitamins prevent heart disease, dementia, or cancers (1-3).  Experts in medicine have called for patients to stop taking unnecessary vitamins (4).  Thus, taking a vitamin to “make sure” you have enough in your system is not recommended.  Complicating matters, there are studies indicating PD patients may be deficient of vitamins B6, B12, and D.  And, there is marketing all around telling consumers to take vitamins.   The best approach is, if indicated, for a qualified doctor to check a level and advise you on whether or not you should take a vitamin.  If taking a vitamin for a specific medical reason, stick to the dose directed by the doctor.  There are certain medical conditions that may call for a period of taking a higher than normal dose of a vitamin. However, in general, taking a “more is better” approach may lead to serious health problems, especially when one takes megadoses (doses many times larger than usual or recommended).  Some vitamins may actually be toxic in high doses commonly available in stores. Vitamin B6 toxicity can cause neuropathy or dermatitis.   Acute vitamin D toxicity may cause confusion, excess urination, excess thirst, loss of appetite, vomiting, and muscle weakness. Chronically high levels of vitamin D may result in kidney stones, loss of bone mineralization, and pain. Vitamin E supplementation was found to be unhelpful for PD in the DATATOP trial of the 1990s, and is also known to be associated with health risks.  A meta-analysis (a review of multiple studies) including nearly 136,000 people showed that use of vitamin E in doses at or above 400IU daily may increase all causes of death (5). The bottom line: take vitamins only if directed by a doctor familiar with the guidelines.

And vitamins are not the only supplements.    The use of CoQ10 is widespread, though in a large, multi-center trial by the Parkinson Study Group, the supplement showed no clinical benefit (6).  In other words, it did not help symptoms or improve scores on PD rating scales. CoQ10 also did not slow down disease, as had been hoped. Similar negative results have been shown in trials of CoQ10 for several other neurologic diseases.

Plants hold a vast potential for medicine. Plant-based supplements however, are not always effective, and some may interact with or block the effect of prescription medications.  Some plant or herb supplements may cause harm. Nature is potent, and produces trees that can be used to make chemotherapy, bark that can be made into aspirin, and clover that is used to make the blood thinner warfarin, to name just a few.  Doctors know that these products are potentially as dangerous as they are helpful.  For example, the molecules used to make warfarin are also used as a poison found in pesticides.  When used as a medicine warfarin has to be adjusted very carefully.  The same care should be taken with any ingested compound, especially if there is the potential for danger. Simply designating a supplement safe because it comes from a plant is a dangerous and irrational position.   For example, the supplement kava (extracted from the pepper plant Piper methysticum), may actually worsen PD symptoms, and if combined with the drug alprazolam, may result in a coma-like state (7). There are many other examples.   Plants have had millions of years to evolve defenses against animals, some of which are very complex.  Plants are potent for good and bad, and that is about as natural as you can get.   This is one very important reason why it is important to make sure the compounds you take are safe.

Does the FDA protect us from harmful substances getting into supplements?

The FDA does not necessarily protect us from the potential dangers of supplements.  By federal law, they are actually quite limited in this regard.  To be clear, it was Congress which defined vitamins and other supplements as “dietary supplements” in 1994 (8), restricted the FDA, and created a law in which the supplement industry was to police itself.   To quote the FDA (9):

“The U.S. Food and Drug Administration (FDA) does not have the authority to review dietary supplement products for safety and effectiveness before they are marketed.  The manufacturers and distributors of dietary supplements are responsible for making sure their products are safe before they go to market.”

Why is there a law preventing the FDA from regulating supplements?

In 1993, Dr. David Kessler, then commissioner of the FDA, attempted to regulate supplements.  He was quoted in the June 15, 1993 edition of the New York Times to say, “The dietary supplement industry is pushing hard for deregulation of their products…There are no assurances that these products are appropriately manufactured, that what’s on the label is actually in the bottle, that they bear adequate directions for use to insure safety or that basic safety data has been collected and reviewed” (10).  This was in the face of numerous cases of injury or death resulting from the use of supplements.  However, according to Dr. Kessler on the program Frontline, January 2016 (11), “What happened was the dietary supplement industry recognized that the standard that we set — significant scientific agreement — would require it, before it could make a claim, to have a scientific basis.  And they just couldn’t make any claim.  And they saw, literally, billions of dollars at stake, and they unleashed a lobbying campaign that was second to none.”  This included a national television commercial (12) presenting the FDA in a fictitious middle-of-the-night, special ops-style raid on the home of actor Mel Gibson because he had a bottle of vitamin C.  The commercial included dark lighting, ominous sound effects, and a voice over with Mel urging, “If you don’t want to lose your vitamins, make the FDA stop.  Call the U.S. Senate and tell them you want to take your vitamins in peace.” The commercial ended with a written instruction to “Protect your right to use vitamins and other supplements. Write Congress Now.”  Several other actors spoke out publically, making similar straw man arguments, and Americans seemed to side with them, rather than the federal agency staffed with scientists and doctors, which had been established to protect them.   The call to action by those with no medical or scientific training, along with organized efforts in health food stores around the country, resulted in massive letter writing.  Per Frontline, Congress received over two million letters on this topic. In 1994, Congress passed the Dietary Supplements Health and Education Act (DSHEA), which limited then, and continues to limit now, the FDA as above.  The key author was Senator Orin Hatch of Utah.  According to author Dan Hurley in his 2006 book Natural Causes (13), supplements were the focus of Utah’s third leading industry, Hatch owned over 35,000 shares of stock in a company that manufactured supplements, and Hatch’s son was a lobbyist for the supplement industry.  Hatch was further noted to be the recipient of large campaign contributions from the supplement industry dating back to the 1980s.

 Is anyone evaluating supplements?

Federal laws restricting the FDA have not stopped independent investigators from analyzing supplements to see if they truly contain what their labels state.   Multiple studies have shown outright substitution of herbal supplements in which the product contains something other than the stated substance (14,15), and whatever is actually in the supplement is not listed. Other studies have demonstrated that traditional supplements manufactured overseas may contain contaminants including toxic heavy metals such as lead, mercury, and arsenic (16-22).  The U.S. manufacture of supplements containing these toxins has also been demonstrated (23).  Per the World Health Organization (24) “It is well known that there are many contaminants and residues that may cause harm to the consumers of herbal medicines.”  There are many reports in which prescription drugs have been added to supplements without reporting this on the label.  Thus, it is of the utmost importance to make sure that the product one is using is safe.  How that will happen is unclear.   Experts call for reform and proper oversight of the supplement industry (25).  Writers in lay press point to the lack of oversight and the politics behind the DSHEA law in less flattering terms (26, 27).   Consumer Reports (CR) dedicated its September 16, 2016 issue to supplements and safety.  The article “Supplements, a complete guide to safety,” notes, “Pills and capsules make promises they can’t keep in a marketplace with a profound lack of oversight.”  The article notes that since DSHEA became law, supplement products have grown in number from about 4,000 in 1994 to over 90,000 today.  CR cites an industry currently generating $40 billion a year.

But this is a safe supplement, right?

Finally, many patients tell me that they believe some supplement is superior because a healthcare provider sold it to them directly in the office.   The American Medical Association (AMA) Code of Physician Conduct (28) notes that the sale of health-related products by physicians raises ethical concerns about financial conflict of interest, undue pressure on the patient, erosion of trust, undermining of the primary obligation of physicians to serve the interests of their patients before their own, and such sales “demean the profession of medicine.”  The Maine Board of Licensure in Medicine also reflects this language.

References   (URLS accessed in August and early September, 2016)

  1. Fortmann, et al. Vitamin and mineral supplements in the primary prevention of cardiovascular disease and cancer: an updated systematic evidence review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013; 159:824-34.
  2.  Grodstein, et al. Long-term multivitamin supplementation and cognitive function in men. A randomized trial. Ann Intern Med. 2013; 159:806-14.
  3.  Lin, et al. Screening for cognitive impairment in older adults: a systematic review for the U.S. Preventive Services Task Force. Ann Intern Med. 2013; 159:601-12.
  4. Guallar, et al. Enough Is Enough: Stop Wasting Money on Vitamin and Mineral Supplements. Ann Intern Med. 2013;159:850-851   http://annals.org/article.aspx?articleid=1789253 .
  5. Miller, et al.  Meta-analysis: high-dosage vitamin E supplementation may increase all-cause mortality. Ann Intern Med.  2005;142(1):37-46.
  6. Beal, et al. A randomized clinical trial of high-dosage coenzyme Q10 in early Parkinson disease: no evidence of benefit. JAMA Neurol. 2014;71(5):543-52.
  7. Izzo A, Ernst E.  Interactions between herbal medicines and prescribed drugs: a systematic review.  Drugs. 2001;61(15):2163-75.
  8. http://www.fda.gov/food/dietarysupplements/usingdietarysupplements/ucm480069.htm#
  9.  http://www.fda.gov/Food/DietarySupplements/UsingDietarySupplements/ucm109760.htm
  10. http://www.nytimes.com/1993/06/15/us/fda-is-again-proposing-to-regulate-vitamins-and-supplements.html
  11. http://www.pbs.org/wgbh/frontline/film/supplements-and-safety/transcript/       The segment Supplements and Safety may be watched at  http://www.pbs.org/wgbh/frontline/film/supplements-and-safety/
  12. https://www.youtube.com/watch?v=IV2olDA0w8U
  13. Hurley, Dan. p76.  Natural Causes.  2006, Broadway Books, New York, New York.   A thorough and well-referenced history of the history of the interaction between the FDA and the supplement industry, including the passage of the DSHEA law.
  14. de Boer, et al. DNA Barcoding and Pharmacovigilance of Herbal Medicines.  Drug Saf. 2015;38(7):611-20.
  15. Parvathy, et al.  Detection of plant-based adulterants in turmeric powder using DNA barcoding.  Pharm Biol. 2015;53(12):1774-9.
  16. Saper, et al.  Heavy Metal Content of Ayurvedic Herbal Medicine Products. Jama 2004;292(23):2868-2873.
  17. Gair. Heavy Metal Poisoning  from Ayurvedic Medicines. BCMJ. 2008;50(2):105
  18. Gogtay, et al. The use and safety of non-allopathic Indian medicines. Drug Safety 2002;25:1005-1019.
  19. Lynch, et al. A review of the clinical and toxicological aspects of ‘traditional’ (herbal) medicines adulterated with heavy metals. Expert Opin Drug Saf 2005;4:769-778.
  20.  Kumar, et al. Unique Ayurvedic metallic-herbal preparations, chemical characterization. Biol Trace Elem Res 2006;109:231-254.
  21. Centers for Disease Control and Prevention (CDC). Lead poisoning associated with Ayurvedic medications—five states, 2000–2003. MMWR. 2004;53:582-584.
  22.  Breeher et al. A cluster of lead poisoning among consumers of Ayurvedic medicine International Journal of Occupational 304 and Environmental Health2015;21(4):304-7.
  23. Saper et al.  Lead, Mercury, and Arsenic in US- and Indian-Manufactured Ayurvedic Medicines Sold via the Internet JAMA. 2008;300(8): 915–923.
  24. WHO Guidelines for assessing quality of herbal medicines with reference to contaminants and residues.  2007  http://apps.who.int/medicinedocs/documents/s14878e/s14878e.pdf
  25. Starr R. Should states and local governments regulate dietary supplements? Drug Test Anal. 2016;8(3-4):402-6.
  26.  http://www.nytimes.com/2015/02/06/opinion/the-politics-of-fraudulent-dietary-supplements.html?_r=0
  27. http://www.nytimes.com/2013/11/05/science/herbal-supplements-are-often-not-what-they-seem.html?pagewanted=all&_r=0
  28. AMA Code of Medical Ethics

B6, friend or foe?

Pyridoxine, also known as vitamin B6, is a supplement that many people take, either by itself or in a multivitamin.  It is available over the counter, no prescription required.  Most of the patients taking B6 with whom I have spoken, however, have very little idea what B6 does, and other than a general recommendation they have been given at some point, are not very clear about whether they should take it at all.

It is true that B6 deficiency can lead to illness.  It is also true that taking too much B6 can be dangerous.   Here, I am going to briefly explain the basics of B6 and take apart the common issues PD patients may face with this vitamin.

B6 is classified as a coenzyme.  Coenzymes are small molecules that assist enzymes in chemical reactions.  There are thousands upon thousands of these reactions going on all the time in your body.   B6 is involved in over 100 enzyme reactions with proteins, amino acids, carbohydrates, and lipids.  B6 helps to maintain homocysteine levels in the blood; is a participant in immune function; and is involved the development of cognition through the formation of neurotransmitters – those chemicals like dopamine that allow one nerve to communicate with another.   Deficiency of B6 is therefore associated with many different conditions such as anemia, dermatitis, cheilosis (scaling of lips, and cracks at the corners of the mouth), immune dysfunction, glossitis (swollen tongue), confusion, irritability, seizures, neuropathy, and depression.  In short, it is important to have normal B6 levels.

We get B6 by eating a healthy diet.  It is found in fruits, grains, fish, poultry, beef liver and other organ meats, potatoes, and some other starchy vegetables.  Absorbing nutrients from foods is not always easy, however, and this leads some to think that they should supplement B6 and other vitamins to “make sure” they are getting enough.  This should not be done blindly.

It is true that some vitamins and minerals are absorbed by a special process, which may take several steps in the body.  A failure of any one of the multiple biochemical steps required may cause poor absorption of the vitamin, and thus a deficiency.  This is the case with B12, for example, but it is not the case for B6.   B6 is absorbed passively in the jejunum, a part of the small bowel.  When a vitamin is absorbed passively, absorption is not an energy-requiring process, and when one has good health, there is usually no obstacle to B6 moving freely into the blood stream.  It would therefore seem easy to maintain a normal level of B6 in the body.

However, a small percentage of people will have B6 deficiency for a variety of reasons, such as kidney disease; celiac disease, Crohn’s disease, ulcerative colitis, and other malabsorption syndromes; autoimmune disease such as rheumatoid arthritis; alcohol dependence; and exposure to certain medications such as antiepileptic drugs.   There is some data, also, that PD patients who take large amounts of levodopa may have low B6 levels (1, 2).  Most of that data comes from European case reports of patients receiving continuous carbidopa/levodopa infusion via the Duodopa pump (not to be confused with Duopa in the United States), but it is also known that PD patients taking high doses of oral carbidopa/levodopa have a higher prevalence of chronic, sensory, axonal polyneuropathy (3), in other words, nerve damage.  It should be noted that some studies point to a deficiency of B12 in these patients, and apparently B6 was not always measured.   There is mounting evidence for both. It is not entirely clear how a B6 deficiency is happening in these patients.  One possible mechanism involves carbidopa, which is meant to block an enzyme in the body called dopamine decarboxylase, so that levodopa makes it to the brain.  However, carbidopa also inhibits the action of B6.  It may also be that absorption of B6 is somehow blocked by carbidopa/levodopa, or that downstream biochemical reactions deplete B6 and B12.  According to the prescribing information of carbidopa/levodopa (Sinemet), B6 and carbidopa/levodopa may be given safely together (4).  Though there is no formal guideline recommending testing, it has been suggested by some authors that it might be worthwhile to check one’s blood level, especially if one is taking moderate to high doses of levodopa, or suffering from any of the above-mentioned disease states (1).  Anecdotally, in my clinic I have diagnosed multiple PD patients taking carbidopa/levodopa with B6 deficiencies, where no other clear cause is evident.

The good news is that measuring a B6 level is done with a simple blood test, and replacement may be given with over-the-counter tablets.  However, as with any supplement or medication, care should be taken in replacing B6, and to be clear, I re-emphasize that I am not recommending anyone take a B6 supplement without knowing one’s own blood level first.  Ideally, a qualified physician should interpret the test and tell you whether you need B6 supplementation, and if so, how much you should take.  The United States Recommended Daily Allowance (USRDA) daily dose for men over 50 is 1.7mg, and for women of the same age 1.5mg (5).   In most individuals, this amount is readily obtainable with consumption of a healthy diet. Higher doses are sometimes recommended for short periods, for specific conditions.  You should know that many over the counter vitamin supplements carry amounts of B6 that are far higher than this, sometimes into or over the 500% or “megadose” range.  The Food Intake Board of the Institute of Medicine has established that for men or women over 50, the tolerable daily upper intake level of B6 is 100 mg (6), a dose commonly found in grocery stores.  B6 at this dose is 59 times higher than USRDA for women and 67 times higher than USRDA for men.

Overdosing B6 can be dangerous for several reasons.  Merck Pharmaceuticals has stated that B6 in doses of 10 mg to 25 mg may actually reverse the effects of levodopa by increasing the rate of the enzyme activity that carbidopa is meant to inhibit (4).  In other words, levodopa is depleted in the body before it can get to the brain, where it is needed to work against PD.   There is no mention of the effect on the same enzyme when B6 is given at 100, 500, even 1000mg (all doses which are available in some health food, drug, and grocery stores), though one would suspect it is even more potent in driving down levodopa, and thus worsening the symptoms of PD.  In addition, much like the case when B6 levels in the body are too low, excess B6 is well documented to cause neuropathy, or nerve damage, as well as a disfiguring skin condition ( 7, 8,9). The Weill Cornell Neuropathy Center evaluated all new neuropathy consultations from July 2014 until June 2015 and found that 7% had elevated B6 levels; whereas only 1.5% combined had either B6, or B12 deficiencies (10). Among the total group studied abnormal levels of nutritional factors were implicated in 24%. Likewise, the Peripheral Neuropathy Center at Columbia University evaluated patients over a 10 year period ending in 2012 (11). These were new referrals with an existing diagnosis of idiopathic neuropathy, meaning another physician, typically a neurologist, had not yet determined the cause of the neuropathy. Among these patients, B6 toxicity accounted for 2.5%; whereas B6 deficiency was 0.3%, and B12 deficiency 1.4%.

In summary, some PD patients may have a high or low B6 level, and either may be harmful. There is some concern that carbidopa/levodopa may indirectly drive B6 levels down.  B6 supplements may contain doses that are far too strong for daily use, and toxicity has been linked to neuropathy, and possible negative impact on PD symptoms. If you have concerns about your B6 level, have a qualified doctor check your level and advise you about how and whether to take B6.

REFERENCES (online sources as of mid September, 2016)

1.  Müller et al. Peripheral neuropathy in Parkinson’s disease: levodopa exposure and implications for duodenal delivery.  Parkinsonism Relat Disord. 2013;19(5):501-7.

2.  Urban et al.  Subacute axonal neuropathy in Parkinson’s disease with cobalamin and vitamin B6 deficiency under duodopa therapy. Mov Disord. 2010;25(11):1748-52.

3. Uncini et al. Polyneuropathy associated with duodenal infusion of levodopa in Parkinson’s disease: features, pathogenesis and management.  J Neurol Neurosurg Psychiatry. 2015;86(5):490-5.

4. https://www.merck.com/product/usa/pi_circulars/s/sinemet/sinemet_pi.pdf

5.https://ods.od.nih.gov/factsheets/VitaminB6-HealthProfessional/

6.  http://www.nationalacademies.org/hmd/~/media/Files/Activity-Files/Nutrition/DRIs/New%20Material/4_%20UL%20Values_Vitamins%20and%20Elements.pdf

7. Schaumburg et al.  Sensory neuropathy from pyridoxine abuse: a new megavitamin syndrome.  N Engl J Med. 1983;309(8):445-448.

8. Barak N, Huminer D, Stahl B. Vitamin B6 (Pyridoxine) — excessive dosage in food supplements and OTC medications. Harefuah 2004;143(12):887-90, 910, 909.

9. de Kruijk JR, Notermans NC.  Sensory disturbances caused by multivitamin preparations. Ned Tijdschr Geneeskd. 2005;149(46):2541-2544.

10. Latov et al.  Abnormal nutritional factors in patients evaluated at a neuropathy center.  J Clin Neuromuscul Dis. 2016;17(4):212-214.

11. Farhad et al., Causes of Neuropathy In Patients Referred As “Idiopathic Neuropathy” Muscle Nerve 2016;53:856-861