• “Burning foot” syndrome (acute/subacute, predominantly small/large fiber
• sensory)
• Motor-dominant (acute Guillain-Barré Syndrome-like, “dry” beriberi)
• Cranial nerve involvement (weakness of tongue, facial and eye muscles)

B6 deficiency OR excess can cause neuropathy. 

Deficiency is rare; usually due to pregnancy/lactation, general malnutrition (e.g., alcoholism), medications (B6 antagonists, e.g., isoniazid, hydralazine, penicillamine, 4-deoxypyridoxine, oral contraceptive pills), chronic dialysis

Sources: fish, beef liver, organ meats, potatoes, starchy vegetables, fruit (other than citrus), fortified cereals

Diagnosis: blood B6 or pyridoxal phosphate levels

Deficiency can cause:

• Painful burning sensations, numbness in feet
• Skin changes
• Seizures (infants)

Treatment for deficiency: <50 mg/day (U.S. RDA=2 mg). Avoid excess!

Neuropathy due to EXCESS B6

Source: homeopathic cold remedies, excess supplementation, energy drinks. 

Burning sensations and balance issues described in patients taking 2 grams/day

(Schaumburg et al., N Engl J Med, 1983)

Also reported in patients taking minimum of 200 mg/day

(Parry and Bredesen, Neurology, 1985)

All improved after discontinuing B6

Model of isolated sensory neuropathy without systemic disease

Vitamin B12

B12: important for myelin sheath (nerve fiber insulation) formation due to

formation of:

1. methionine, tetrahydrofolate;

2. succinyl coenzyme A.

Source: meat/dairy products, fortified foods, supplements

Complex metabolism

Absorbed in terminal ileum

Up to 40% of older adults have low blood B12 levels. 

Normal blood values=250-1100 pg/mL; target>400 pg/mL

Vitamin B12 Deficiency

Causes of deficiency:

• Pernicious anemia (immune destruction of intrinsic factor, a protein made in the stomach that is required for B12 absorption.  This can cause low red blood cell count with some enlarged red blood cells, which is called megaloblastic anemia.)
• Vegan diet (can take 5 yrs to manifest)
• Medications (proton pump inhibitors, metformin),
• Food-cobalamin malabsorption (due to nitrous oxide exposure [inactivates methyl-cobalamin])

Diagnosis: low B12, elevated methylmalonic acid (MMA) level

Renal disease→false positive MMA elevation

Homocysteine elevation: less specific (also seen with hypothyroidism, folate and vitamin B6 deficiency, advanced age, cigarette smoking)

Additional testing: intrinsic factor and parietal cell antibodies?

Neurologic syndromes associated with B12 deficiency

1. Neuropsychiatric abnormalities

2. Subacute combined degeneration of the spinal cord with involvement of:

• Dorsal columns: loss of sense of position, shown by loss of balance when patient stands with feet together and eyes closed
• Lateral columns: corticospinal weakness (e.g., hip, knee flexors) spastic partial paralysis
• Reflexes: mixed with absent ankle reflexes and brisk knee and ankle reflexes

3. Neuropathy: typically sensory axonal neuropathy +/- damage to spinal cord 

• Acute onset, upper +/- lower extremity involvement=clues to diagnosis 
• Megaloblastic anemia may NOT be present in patients with neuro manifestations

4. Damage to the nerve to the retina of each eye

B12 deficiency treatment                       

1. Oral: 1000 mcg/day (1%, or 10 mcg; RDA=3-6 mcg/day.)  
2. Intramuscular injections: 1000 mcg daily X 3-7 days or 1000 mcg weekly X 4, then maintenance with 1000 mcg monthly.
3. Intranasal (Nascobal): 500 mcg weekly 

Oral as effective as IM?    

(Vidal-Alaball et al., Cochrane Database Syst Rev, 2005)

Muscle injection is preferable in pernicious anemia, or with a history of gut malabsorption

Neurologic improvement expected in first 6 months;

May only prevent further neurologic deterioration. 

B3 (niacin, nicotinic acid)

Classic clinical triad: skin inflammation, dementia, diarrhea.

Absorbed in intestine via simple diffusion

Risk factors: homelessness, anorexia, certain cancers, malabsorption

Neurologic manifestations: apathy, inattention, irritability, depression. 

Not known to be a cause of neuropathy. 

Copper

Component of important enzymes

(e.g., cytochrome C oxidase) for ATP production,

antioxidation, neurotransmitter production,

and cross-linkage of collagen and elastin. 

Sources: seafood, nuts, wheat, grains

Absorbed in stomach and proximal duodenum via active or passive mechanisms (depending on dietary levels). 

Gastric acid required to solubilize dietary copper. 

In liver, copper incorporated into ceruloplasmin for delivery to cells.  (Liver excretes excess copper into bile.)

Zinc→upregulation of metallothionein in enterocytes which binds copper→sloughed off in feces.

Copper deficiency→myelopathy or myeloneuropathy

(Kumar et al., Neurology, 2004)

Also hematologic abnormalities: anemia, occasionally myelodysplastic syndrome. 

Causes: gastric surgery, excess zinc (supplements or older denture creams), poor diet, clioquinol or idiopathic. 

Copper deficiency causing myeloneuropathy (damage to spinal cord as well as peripheral nerves)

Mimics subacute combined degeneration (sensory ataxia due to dorsal column dysfunction, corticospinal tract weakness, lower limb spasticity)

Gait difficulties

Abnormal sensations in skin of lower limb, such as pins and needles, numbness or burning

Dorsal column: loss of position sense, vibration, loss of balance

Lateral column: corticospinal-pattern weakness, spasticity, brisk knee reflexes, extensor plantar responses. 

MRI of the spine shows changes in parts of the spinal cord in the neck or thorax in ~50% of cases

(Jaiser & Winston, J Neurol, 2010)

Copper deficiency

Diagnosis: check blood and urine zinc, copper, blood ceruloplasmin. 

RDA=900 mcg/day.

• Low blood copper
• Low ceruloplasmin
• 24-hr urine: low copper (more sensitive than blood level)
• Zinc level in blood/urine: normal or high (if exogenous source)

Treatment: 2 mg elemental copper three times a day  

Vitamin E

Alpha-tocopherol=biologically active form of vitamin E in humans, fat-soluble.

Sources: animal fat, vegetable oils, nuts, grains

Incorporated into chylomicrons, passively absorbed in intestines.

Vitamin E delivered to tissues via chylomicrons.

Transferred to very VLDL lipoproteins via alpha-tocopherol transfer protein (TTP). 

Deficiency: malabsorption or transport deficiencies (mutations of transfer protein, abetalipoproteinemia), cystic fibrosis. 

Pathogenesis: due to loss of protective effect (antioxidant, free radical scavenger).

Neuro manifestations: ataxia, decreased reflexes, loss of sense of position or vibration, speech difficulty, involuntary eye movements, paralysis of eye muscles, damage to the retina, head shaking, decreased sensation and weaknessof muscles in the upper arms and legs. 

Nerve conduction studies show sensory-predominant, axonal neuropathy.   

Diagnosis: measure blood alpha-tocopherol levels, total blood vitamin E: total blood lipid concentration. 

Case Study

54 y/o woman with diabetes, asthma, high blood pressure, morbid obesity (body mass index=65; weight=377 lbs)
10/2002: gastric bypass.  Post-op had nausea and vomiting with rapid weight loss
5/2003: tingling, numbness in feet, gait imbalance.  B12 deficiency suspected (not tested); started intramuscular injections
9/2003: respiratory distress, nausea/vomiting, abdominal pain. Weight=225 lbs.
10/2003: incoordination of hands, numbness, asymmetric limb weakness
X-ray showed enlarged heart and fluid in lungs, leading to insertion of a breathing tube

www.foundationforpn.org

Fluoroquinolones

Peripheral neuropathy: rare but reported side effect.

Food and Drug Administration (2013) included risk of permanent neuropathy as side effect.

Increased risk reported

(Etiman et al., Neurology, 2014)

Statins

Muscle pain (at onset of use) is more typical

Association with peripheral neuropathy more controversial.

Some reports of small fiber sensory/autonomic neuropathy with mild clinical symptoms.

NO association between statins and neuropathy recently reported

(Svendsen et al., Br J Clin Pharmacol, 2017)

Conclusion

In the developed world:

Nutritional neuropathies in setting of inadequate diet, medications, alcohol, malabsorption (GI disease or bariatric surgery).

Toxic neuropathies due to alcohol, medications (chemo, non-chemo), alcohol, heavy metals (mercury?). 

Alcohol→thiamine deficiency, direct toxic effect

B6 EXCESS→sensory neuronopathy

B12 deficiency→subacute combined degeneration +/- peripheral neuropathy

Copper deficiency→neuropathy involving nerves of the spinal cord and periphery

These neuropathies are typically length-dependent (affecting lower legs and arms), sensory or sensorimotor, axonal. 

Repletion of deficiency or elimination of toxin may arrest progression, but recovery may be limited.