Ronald Guberman

Karina Tavakalyan

Daniel Howell

Julien Adicho

Elizabet Peraj

Timur Davydov

Mary Ann Picone

Peripheral neuropathies can affect motor, sensory, or autonomic nerves and cause a variety of symptoms. This chapter will discuss various causes of neuropathy including diabetic neuropathy (DN) and chemotherapy-induced neuropathy and their relationship to foot and ankle pain.


Vitamin deficiency can often present to the physician’s office as a peripheral neuropathy. It is paramount to include appropriate blood testing for all first-time patients presenting with neuropathy to be able to work through your differential diagnosis. A few risk factors for vitamin deficiency neuropathy include eating disorders, alcohol abuse, and older age.1 Diseases affecting absorption of vitamins in the gastrointestinal tract, such as inflammatory bowel, chronic liver or pancreatic disease, and gastritis have been correlated with higher rates of vitamin deficiency-induced neuropathy. Also, patients who have recently undergone gastric bypass surgery or small bowel resections should also be looked at as a higher risk subset of patients.1

Vitamin B1

Vitamin B1 (thiamine or thiamin) is absorbed in the small intestine and is the first vitamin deficiency syndrome clinically described in the human population. Vitamin B1 deficiency is known as beriberi and can manifest either without heart failure (dry beriberi) or with heart failure (wet beriberi).2 Thiamin is essential for ATP production and maintenance of the myelin sheath.3 Recommended daily intake of thiamin ranges from 1.0 mg/d in young healthy adults to 1.5 mg/d in breastfeeding women and patients with higher metabolic demands such as athletes.4

Symptoms of thiamine deficiency are often noted with gradual onset over the course of 2 to 3 weeks. In regard to how deficiency manifests in the lower extremity, patients will often experience numbness, paresthesias, muscle weakness, and a burning sensation beginning in the feet.4 The disease will then often progress more proximally if deficiency is not addressed, involving sensorimotor deficit to the hands, disease of cranial nerves causing facial weakness, and disease of the recurrent laryngeal nerve accounting for change in the pitch of voice.3 About one-quarter of patients with vitamin B1 deficiency also will have Wernicke encephalopathy, which can further present with nystagmus and ataxia.1

Once the diagnosis is made, thiamine replacement therapy should be initiated to prevent further spread of disease. Thiamine can be administered IM or IV at a rate of 100 mg/d.3 It may take up to 3 to 6 months before improvement is seen in sensorimotor deficit. Recovery to a degree is seen in most patients; however, in some patients, there may be permanent dysfunction.

Vitamin B12

Vitamin B12 (cobalamin) deficiency is seen in up to 5% to 20% of adults. The recommended daily allowance for vitamin B12 is 2.4 µg per day. Vitamin B12 plays an integral role as a cofactor in biochemical reactions that result in myelin sheath formation, as well as purine and pyrimidine nucleotide synthesis.5 The active form of vitamin B12 is absorbed in the terminal ileum. Vitamin B12 supply is strictly dependent on dietary intake and is only found in animal products so it must be supplemented in strict vegan diets.

Certain medications, such as metformin and proton pump inhibitors, have been shown to be associated with vitamin B12 deficiency. Other potential causes include malnutrition via dietary restrictions, gastrointestinal operations, chronic exposure to nitrous oxide gas, and pernicious anemia, which is the most common cause of vitamin B12 deficiency.5 Pernicious anemia is an autoimmune disorder associated with the destruction of gastric mucosa lining, as well as impaired vitamin B12 absorption.

Symptoms of vitamin B12 deficiency will usually begin with sensory loss in the lower extremity and may progress to neuropsychiatric symptoms as well as optic neuropathy. Diagnosis of vitamin B12 deficiency is dependent on a high clinical suspicion as well as serum vitamin B12 levels under 200 pg/mL. It is often helpful to measure serum metabolite levels of methylmalonic acid and homocysteine. Elevated values of methylmalonic acid and homocysteine suggest a vitamin B12 deficiency. It is often helpful to test these patients for pernicious anemia as well by screening for anti-intrinsic factor and antiparietal cell antibodies.

Treatment should begin immediately upon diagnosis as residual dysfunction can develop in advanced stages. Treatment should begin with 1000 µg B12 administered IM daily for 1 week, followed by 1000 µg IM monthly. Alternative acceptable regimen is once a week injections for the first 4 weeks, followed by monthly injections. Oral replacement therapy is also available with 1000 mg daily of cobalamin, though can be more expensive than IM therapy. Once a patient is begun on supplemental therapy, physicians should order occasional monitoring of serum B12 levels to determine efficacy of treatment. Residual neurologic deficit can often be present, correlated to the degree and duration of symptoms at initial presentation.

Vitamin E

Alpha-tocopherol, the active form of vitamin E, is recommended at 15 mg/d of dietary intake. Vitamin E is absorbed in the intestines after being packaged into chylomicrons, in a process that requires presence of bile acids, fatty acids, and monoglycerides.3 Deficiency of vitamin E most often occurs in patients with fat malabsorption or transport diseases and is commonly seen in patients with cystic fibrosis. Vitamin E primarily functions as an antioxidant that neutralizes free radicals. Most commonly seen with conditions associated with fat malabsorption, isolated vitamin E deficiency is also found with a mutation in the alpha-tocopherol transfer protein gene on chromosome 8q13, a rare genetic autosomal recessive genetic disorder.

Unique to vitamin E deficiency, symptoms may take from 5 to 10 years to manifest with a slow and progressive onset. Patients will present with ataxia, hyporeflexia, loss of proprioception and vibratory sensation, and muscle weakness.6 Diagnosis is made from measuring serum vitamin E levels; however, false negatives can be common. It is helpful to also measure the ratio of serum vitamin E to total lipid concentration. Nerve conduction velocity studies in these patients will show a sensory axonal neuropathy, and nerve biopsy will be consistent with loss of large myelinated fibers.6 Treatment should begin with oral supplementation of vitamin E of 400 IU BID, with gradual increase in dose until normal serum values are noted.7

Vitamin B6

Of the vitamin deficiency neuropathies, vitamin B6 (pyridoxine) deficiency is rare due to it being readily available in our diet.3 Humans are fully dependent on their dietary intake of vitamin B6 due to the inability to synthesize it, and the recommended daily intake is 1.3 mg. Vitamin B6 deficiency is most often seen in patients who are taking a vitamin B6 antagonist, such as isoniazid, phenelzine, hydralazine, and penicillamine. It is also often noted in patients with chronic kidney disease receiving long-term hemodialysis.7

Vitamin B6 deficiency can manifest in infants as a cause of seizures and in adults as an ascending peripheral neuropathy with numbness, burning pain, and paresthesias beginning in the lower extremity. Unique to vitamin B6, an excessive as well as deficiency of the vitamin can lead to neuropathic manifestations. Vitamin B6 toxicity is associated with a sensory neurologic deficit with burning and paresthesias. Diagnosis is made by measuring serum blood levels of vitamin B6. In patients with vitamin B6 deficiency undergoing hemodialysis, a supplemental dose of 10 to 50 mg/d is recommended. In patients on isoniazid or hydralazine therapeutic regimen with vitamin B6 deficiency, a dose of 50 mg daily is suggested.

Vitamin B3

Vitamin B3 (niacin) deficiency clinically manifests as pellagra with the classic triad of diarrhea, dementia, and dermatitis. Once endemic in the United States and Europe, today it is often seen in patients with malabsorption disease. Primarily functioning in carbohydrate metabolism, niacin is absorbed in the intestine. Daily recommended intake is 14 to 16 mg daily.7

Neurologic manifestations of B3 deficiency are primarily depression, irritability, and apathy. Patients with vitamin B3 deficiency will often have multiple other nutritional deficiencies, and isolated vitamin B3 deficiency will usually not cause peripheral neuropathy on its own. Oral replacement of niacin is recommended with 50 mg BID or TID.7

Lower Extremity Manifestations of Vitamin Deficiency Neuropathy

In order for proper diagnosis to be made and treatment to be initiated in a timely manner, the foot and ankle specialist must be aware of how vitamin deficiency neuropathy may present. Patients will oftentimes complain of numbness, burning, tingling, shooting, or a pin and needle sensation in the feet. On clinical examination, patients may have diminished protective sensation to light touch symmetrically. These patients can also present with abnormal response to deep tendon reflexes, muscle weakness, or atrophy, as well as hyperhidrosis as a result of autonomic neuropathy. Important to consider, digital contractures can develop in these patients as a result of the loss of intrinsic muscular function.


When a patient presents with neuropathic symptomology and no clear obvious underlying etiology, a diagnosis of idiopathic neuropathy is often the case. It is a diagnosis by exclusion, with all likely etiologies of peripheral neuropathy being ruled out before diagnosis is made including traumatic, autoimmune, diabetes, infectious, genetic disorders, tumors, metal/vitamin deficiency or toxicity, alcoholism, and exposure to certain medications.8 It is also important to consider that oftentimes neuropathy is misdiagnosed as being attributed to a secondary cause such as infection, systemic disease, or trauma, when in fact is idiopathic in nature. In practicality, it is difficult to assess accurately if the symptoms the patient presents with is a direct result of a secondary cause or not.

Lower extremity manifestation of idiopathic neuropathy is similar to diabetic polyneuropathy, with the patient presenting with numbness, paresthesias, pain, and/or burning sensation in the hands and feet.9 The disease can then progress to proprioceptive deficit with the patient having difficulty in balance and walking on uneven surfaces. Without a known cause, treatment is often on a case-by-case basis primarily focused on alleviating the symptoms presenting at hand. Medication to control neuropathic pain can be helpful, as well as diabetic orthopedic shoes or ankle-foot orthoses (AFOs) to provide for stability and support in patients with proprioceptive deficit.

The clinician should continue to be open minded and cognizant of potential causes for all cases considered to be idiopathic in nature.


DN is a complicated pathology with its associated problems in the diabetic patient. With nearly 34.2 million people in the United States living with diabetes and with 50% of them
developing neuropathy, this is an ongoing and increasing challenge for the medical community. Nearly 25% of diabetic patients with neuropathy will undergo an amputation sometime in their lifetime.10 There are several forms of diabetic peripheral neuropathy.11 The most common type is distal symmetric polyneuropathy (DSP), which can be classified as primarily small fiber, primarily large fiber, or mixed small and large fiber, and accounts for approximately 75% of all DNs.12,13 Diabetic peripheral neuropathy can also be classified as either sensory, autonomic, or combination neuropathy. The etiology of neuropathic pain is usually from DSP, which accounts for about 10% to 30% of patients with DN. The symptoms can include intense burning, stabbing pain, hyperesthesia, and/or deep aches.14

Most DN consists of sensory nerve damage with very few progressing to motor nerve damage. The sensory neurons, specifically dorsal root ganglion neurons, lie outside the blood-nerve barrier, as do the peripheral sensory receptors, while motor neurons are located within the ventral horn of the spinal cord, under the protection of the blood-brain barrier. This blood-brain barrier protects the motor neurons from systemic metabolic and hypoxic stressors. Due to the unmyelinated nature of the small C fibers, which are considered the foot soldier of the peripheral nervous system, they typically are the first to be damaged. DN is thought to be caused by the excess formation of mitochondrial and reactive oxygen species, which results in the loss of axonal energy and axonal injury. The formation of excess reactive species is due to the dysregulation of metabolic pathways caused by hyperglycemia.15

Currently, there are no treatment options proven to cure or reverse the damage caused by DN. The treatment of DN focuses on 3 aspects: glycemic control, foot care, and pain management. Glycemic control along with weight loss has been shown to slow and sometimes stop the progression of the disease.16 Pain management is important for the quality of life for the patient. Currently, there are only a few medications that have been approved by the FDA for the treatment of DN: pregabalin, gabapentin, and duloxetine. These drugs have been shown to significantly reduce the pain caused by DN.17 Other medications that have shown to be effective in treating DN are tricyclic antidepressants (TCAs), but they have not been approved by FDA for treatment of DN.18 Duloxetine is a serotonin and norepinephrine reuptake inhibitor (SNRI). Side effects are usually mild including nausea, dizziness, fatigue, dry mouth, constipation, and diarrhea. It can be particularly helpful in patients with concomitant mood disorders. The most frequently incurred side effects of the anticonvulsant medications include loss of muscle coordination, nystagmus, dizziness, drowsiness, and lethargy.19 These side effects can be very challenging for the patient and must be discussed in detail with the patient before they are prescribed. Vitamin B complex as well as individual vitamin B supplements and derivatives are also commonly prescribed.

Foot care is vital in the care of DN and in preventing foot ulcers. Patients with DN should have their feet screened at least once a year, and these examinations should include a sensory examination with a monofilament, visual inspection, and assessment of lower extremity pulses. Patient education is of vital importance, and they should be instructed to check their feet daily, avoid walking barefoot, and wear supportive and protective shoe gears at all times. Diabetic patients with DN are at an increased risk in developing ulcers, which can lead to amputation.

The pain associated with DN is challenging to treat, but if treated properly, it can dramatically increase the quality of life of patients with DN. Improving the quality of life will lead to improvement in the patient’s mental and emotional well-being and ultimately in their overall health. All aspects of the patient’s health must be examined and treated properly to insure the best overall outcome for these patients.

Sep 8, 2022 | Posted by in ORTHOPEDIC | Comments Off on Neuropathies
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