Nutritional Peripheral Neuropathies

Peripheral neuropathy, often in conjunction with optic neuropathy, is a common clinical feature in micronutrient deficiencies. The B vitamins are the most important. This article doesn't cover the rare and very complicated genetic causes of deficiencies.
==Micronutrients==
The human body is not able to endogenously synthesise to adequate levels 13 vitamins. These are made up of four fat soluble vitamins (Vitamins D, E, K, A), and 9 water soluble vitamins (Vitamin C; Vitamins B1, B2, B3, B5, B6, B7, B9, and B12). There is also a dietary requirement of trace minerals, with copper being important for nerve function.
Deficiency in a variety of vitamins and minerals have been linked to peripheral neuropathy 
*B Vitamins - B1 (thiamine), B2 (riboflavin), B6 (pyridoxine), B9 (folic acid), B12 (cobalamin). Deficiencies in all of these have been associated with peripheral neuropathy, commonly in conjunction with an optic neuropathy
*Copper. Deficiency can cause peripheral neuropathy and even subacute combined degeneration similar to B12.
* Vitamin E. This is rare from poor dietary intake, but can occur in chronic pancreatitis, IBD, liver disease, cystic fibrosis.
Daily allowances and dietary sources
Micronutrient 	Recommended daily allowances	Dietary sources
Thiamine (B1) 	1.5 mg 	Whole grains, Enriched grain products (cereal, bread, pasta, rice), Pork, Red meat, Fish, Eggs, Beans and peas, Nuts and sunflower seeds
Pyridoxine (B6) 	2 mg 	Grains, Potatoes, Meats, Non-citrus fruits, Salmon and tuna, Beans, Vegetables
Cobalamin (B12) 	6 mcg 	Fortified cereals, Meats, Poultry, Seafood, Eggs, Dairy products
Folate/Folic Acid (B9)	400 mcg 	Enriched grain products (cereal, bread, pasta, rice), Beans and peas, Green leafy vegetables, Asparagus, Avocado, Orange Juice
Vitamin E 	30 IU/15 mg 	Fortified cereals, Fortified juices, Green vegetables, Nuts, seeds, peanuts, Vegetable oils, Dairy products, Meat, Fish
Copper 	2 mg 	Whole grains, Organ meats (liver), Shellfish, Nuts and seeds, Vegetables, Mushrooms, Legumes, Chocolate, Milk
==Risk Factors==
Risk factors for various micronutrient deficiencies (relevant to peripheral neuropathy)
Risk factor 	Deficiencies 	Notes
Bariatric Surgery history (both sleeve gastrectomy and bypass)	B1, B2, B6, B9, B12, copper, others. 	There is a lifetime increased risk. Occurs either through malabsorption or secondary restrictive food intake, and many patients are not compliant long term with supplementation.
ASD and ARFID 	Multiple 	May be "malnourished obese."
Anorexia Nervosa 	Multiple 	
Alcohol Use Disorder 	B1 and B6 most implicated 	Alcohol inhibits B1 absorption by 50% even with an otherwise good diet, reduces conversion to the bioactive form thiamine pyrophosphate. But malnutrition is not the only factor, alcohol also probably has direct neural toxic effects. Neuropathy on NCS is present in ~45%, and pain in ~42% of those with alcoholic neuropathy.
B6 and zinc supplements 	B6 supplements can cause toxicity, zinc can cause copper deficiency	B6 intake probably needs to be extremely high to cause a problem (over 500mg daily). Doses less than 500mg may cause neuropathy over a much longer time frame. Too much B6 actually causes a functional deficiency by competing with the active form causing an identical presentation to B6 deficiency.
Vegans and culturally restrictive diets 	B2 and B12 	e.g. Hinduism, Jainism, Rastafarianism. Vegans can be low in vitamin D, calcium, iron, iodine, zinc, selenium. Vegetarians can get B12 deficiency but it is less likely.
Recreational users of "nangs" (NO cannisters) 	Subacute combined degeneration due to effects on B12. 	Particularly in students who may not be eating a healthy diet. Causes a functional B12 deficiency by rendering methylcobalamin inactive. Symptoms can occur within days.
Pregnancy (particularly hyperemesis) and breastfeeding 	B2, B6 	
Elderly 	B6, B9, B12 	B12 deficiency is extremely common.
Metformin and Omeprazole 	B12 	Particularly in combination and over the long term
Heart failure 	B1 for both 	Loop diuretics reduce absorption, avoiding sodium rich foods that contain B1, impaired intestinal absorption.
Dialysis 	B1 and B6 	Loop diuretic and dialysis effects.
Parkinson Disease 	B6, B9, B12 	High dose oral levodopa/carbidopa has been implicated in causing peripheral neuropathy - metabolism of the drugs consume B6, B9, and B12.
Celiac disease 	B9 	
==Clinical Features==
Other than risk factors, a major clue to the diagnosis is if the patient presents with both a painful sensory polyneuropathy plus an optic neuropathy.
The strands of evidence for each of the implicated deficiencies have included animal studies, unethical human studies in the past, and human studies such as people with specific loss of function pathogenic variants of vitamin dependent pathways. 
Most nutritional deficiencies are length-dependent sensory axonopathies, except for B12 which can also cause non-length dependent sensory neuropathy. Restriction of a single B vitamin doesn't seem to produce a clear phenotype such that one can diagnose the deficiency of a specific vitamin based on the clinical features. There is also often the co-existence of multiple deficiencies. The link to some vitamins has been known for a long time, while B2 and B9 have only been more recently linked to peripheral neuropathy from studying people with loss of function mutations.
 Important deficiencies and their clinical presentations.
Vitamin/nutrient	Other Names	Neurological complications of deficiency 	Time to depletion of stores
Vitamin A 	 	Night blindness, optic neuropathy, (xerophthalmia) 	
Vitamin B1 	Thiamine 	Wernicke-Korsakoff syndrome, peripheral neuropathy - predominantly motor axonal neuropathy in pure B1 deficiency (dry beriberi), painful sensory neuropathy in alcoholics, optic neuropathy, cardiomyopathy (wet beriberi). 	Liver storage is 18 days.
Vitamin B2 	Riboflavin 	Peripheral neuropathy with demyelination, optic and auditory neuropathies, myopathy, oropharyngeal effects. 	Several months
Vitamin B6 	Pyridoxine 	Peripheral neuropathy, neuronopathy / dorsal root ganglionopathy, optic neuropathy, myelopathy / spinal cord posterior column degeneration, skin changes, microcytic anaemia, seizures. 	
Vitamin B9 	Folate 	Peripheral neuropathy (causal evidence not as strong as B12, probably only a factor among other deficiencies in most cases), optic neuropathy, restless leg syndrome 	
Vitamin B12 	Cobalamin 	Ascending sensory myeloneuropathy (subacute combined degeneration), peripheral neuropathy (can be isolated - sensory most common but can also get sensorimotor, pure motor, and small fibre. May be non-length dependent), optic neuropathy, megaloblastic anaemia.	Received wisdom is 5-10 years in typical populations (due to efficient reabsorption). Can occur within 2 months after bariatric surgery,
Vitamin D 	 	Myopathy, peripheral neuropathy risk factor in diabetics. 	
Vitamin E 	 	Myelopathy / posterior column degeneration, peripheral neuropathy, necrotising myopathy, spinocerebellar syndrome. 	
Copper 	 	Myeloneuropathy (subacute combined degeneration), peripheral neuropathy, optic neuropathy, myopathy, 	
==Testing==
===Laboratory Tests===
Most tests require supplying the clinical details to the lab and vetting by a pathologist. Testing is not straight forward. Relying on simple measurements of B1, B2, B6, B9, and B12 can miss many cases of nutritional neuropathies. It is also important to remember that many individuals have multiple simultaneous deficiencies.
B1 (Thiamine)
There are two main tests - thiamine pyrophosphate in whole blood and erythrocyte transketolase assay (functional measure in red blood cells). The latter is no longer available in NZ. The former requires vetting by a pathologist (supply reasons on the form, it may be declined). They recommend using risk factors and treating empirically. 
Serum thiamine levels do not accurately represent tissue concentrations, e.g. it is often normal in even Wernicke's encephalopathy. A test of the biologically active form thiamine diphosphate has been developed but doesn't seem to be available in New Zealand.
An anion gap metabolic acidosis can occur.
B2 (Riboflavin) 
There is apparently no established method of measurement. Erythrocyte glutathione reductase activity is mentioned in UpToDate but doesn't seem to be available in New Zealand. Direct B2 can be measured by the Auckland lab ideally after a period of fasting, it's not clear how accurate this is.
One circuitous method of evaluation is by measuring plasma acyl carnitines and urine organic acids after a period of fasting. These are measures of the fatty acid oxidation pathway but require riboflavin. Elevated levels can indicate a riboflavin deficiency, but so can various genetic conditions unrelated to B2 such as MADD. Homocysteine levels are also raised.
B6 (Pyridoxine)
The active form pyridoxal-5'-phosphate (PLP) is the generally recommended test in review articles. The lab in NZ simply calls the test "B6" and doesn't stipulate if its the active or total form. Total serum B6 measurement has been described and so presumably in NZ it is the total form that is measured. 
Also leads to elevated homocysteine levels as it is a cofactor in homocysteine metabolism. Need to provide clinical information. 
B9 (Folate)
Testing folate is a very standard lab test. Plasma folate measurement generally reflects the recent intake rather than body stores and so it is best measured fasting. 
Red cell folate has been described as a measure not affected by recent folate intake, but is not available in NZ. The labs states "A large increase is seen in serum folate levels 1-3 hours after folate supplementation. However, a "normal" diet contains far less folate and the increase in serum folate after food intake is much smaller. Serum folate levels take 8 - 9 weeks to stabilise after changing dietary intake, thereby reflecting long term folate status. Serum folate shows closer correlation with markers of folate deficiency (such as homocysteine), and a more direct relationship with haemoglobin response to supplementation."
Homocysteine may be elevated in folate deficiency.
Also note that B12 deficiency can cause a functional folate deficiency. 
B12 (Cobalamin)
There are four tests for B12. Two are measurements of B12 - total serum B12 and holotranscobalamin ("active B12"). The other two are functional tests - homocysteine and MMA (methylmalonic acid) which are elevated in deficiencies because B12 is needed for processing in the relevant pathways. Measuring only total B12 can result in false positive and false negative rates as high as 50%. Measuring two of the four biomarkers allows for improved sensitivity and specificity.
Serum B12 is a very common blood test but it has disappointing sensitivity and specificity for B12 deficiency. It measures the circulating B12 that is bound to haptocorrin (transcobalamin I) and transcobalamin II. The former accounts for the majority of bound B12 but isn't available. "Active B12" measures B12 bound to transcobalamin II and is a more reliable screening test for deficiency. The active B12 test is available in NZ.
Homocysteine and MMA are downstream metabolites of B12 metabolism, and are functional biomarkers of deficiency. Folate deficiency can affect homocysteine and so needs to be measured in conjunction. Homocysteine is also higher in men. MMA is increased in CKD and hypothyroidism..
In "nang" users, be aware that serum B12 concentrations may be normal. NO renders methylcobalamin inactive leading to a functional deficiency. Homocysteine needs to be measured to pick up the funtional deficiency. MMA may also be normal because of how NO interacts with the B12 pathways.
If a deficiency is identified, consider antibody testing for pernicious anaemia (parietal cell and intrinsic factor antibodies)
===Other Tests===
The optic neuropathy may be subclinical so refer for ophthalmology assessment if high index of suspicion and no clear cause on laboratory testing. 
Sural nerve biopsy is another test described. Note that you can get inflammatory findings on biopsy in nutritional causes.
Electrophysiology testing is often useful.
MRI is useful for Wernicke encephalopathy and Subacute Combined Degeneration.
==Treatment==
These are treatment doses, not prophylactic doses.
B1 - for Wernicke-Korsakoff the patient is admitted for IV thiamine. Long term 50 to 100mg daily is used. In alcoholics with peripheral neuropathy unfortunately replacing thiamine often doesn't work well, there may be a clinical effect for prescribing B complex supplementation but it isn't clear.
B6 - 50 to 100mg daily.
B9 - 15mg per day or 10mg three times per day.
B12 - intramuscular (1mg stat with different dosing intervals published depending on cause and level of deficiency) or oral (1-2mg daily). Note that oral may be sufficient for most cases of deficiency because passive absorption (1.2%) occurs even in pernicious anaemia and gastric resection.
==Resources==
==References==
Category:Polyneuropathies