T.T., a 26-year-old woman with type 1 diabetes diagnosed at the age of 14, presented with persistent burning pain in her lower extremities and upper extremity digital paresthesias that made her work as a dental hygienist difficult. Recently, her family had noted that she seemed to be stumbling at times. She reported that neither increased doses of a selective serotonin reuptake inhibitor (SSRI) nor trials of tricyclic antidepressants (phenytoin [Dilantin], carbamazepine [Epitol, Tegretol], or gabapentin [Neurontin]) had relieved her symptoms.

T.T. had no known history of diabetic retinopathy or nephropathy. She also denied resting tachycardia, orthostatic lightheadedness, early satiety, early morning nausea, changes in bowel habits, or postprandial sweating. She did note a history of depression, which was treated with counseling and medication. She also noted menstrual irregularity, dysmenorrhea, and premenstrual emotional lability. She had been treated with oral contraceptives in the past, but had discontinued these 6–8 months ago.

Her glycemic control had never been optimal despite a multiple-dose insulin program. Her hemoglobin A1c (A1C) levels had typically been in the 8–9% range.

Exam revealed a moderately overweight (BMI 27 kg/m2) woman with a blood pressure of 138/85 mmHg with no orthostatic change and a resting pulse of 72 with no change with Valsalva maneuver. Lower extremity exam showed normal skin pigmentation, easily palpable dorsalis pedis pulses, but decreased position sense as well as decreased sensation to 10-g monofilament testing.

Laboratory testing revealed an A1C of 8.2% (normal <6.5%); an albumin-to-creatinine ratio of 25 μg/mg (normal <30 μg/mg); and normal serum creatinine, complete blood count, total protein, sedimentation rate, and thyroid stimulating hormone.

When asked to bring in all over-the-counter and prescribed medications previously and currently used, the patient acknowledged taking pyridoxine (vitamin B6), a medication that she had started after reading on the Internet that it could help in the treatment of both pre-menstrual syndrome and carpal tunnel syndrome. She reported taking pyridoxine at a dosage of 200–500 mg daily for the past 6 months.

  1. What is the differential diagnosis of peripheral neuropathy in people with diabetes?

  2. What commonly used medications can be associated with peripheral neuropathy?

  3. Are there any known benefits to the use of pyridoxine in a person with diabetes?

Peripheral neuropathy has many potential etiologies yet is often quickly attributed to diabetes in diabetic patients, particularly in those with poorly controlled diabetes. The differential diagnosis includes metabolic etiologies, such as uremia, myxedema, amyloidosis, and deficiency of vitamin B12, B6, or thiamine; toxic etiologies, such as ethanol or heavy metal exposure; and as a side effect of prescribed medications, including allopurinol (sold under various brand names), isoniazid (INH, Lanizid, Nydrazid), and nitrofurantoin (Macrodantin, Macrobid).

Peripheral neuropathy may also be associated with malignancy, such as lymphoma or bronchogenic or gastric carcinoma, and with infectious/inflammatory processes, such as monoclonal paraproteinemias, HIV, lyme disease, borreliosis, or leprosy. In addition, it may also be associated with a variety of familial syndromes, such as Charcoat-Marie-Tooth syndrome.1 

Providers must also recognize that over-the-counter remedies can have side effects including, in this instance, peripheral neuropathy. High-dose pyridoxine (B6) has been reported to cause sensory dysfunction and ataxia that improves after the vitamin is discontinued. Although initially believed to be related to mega-dose ingestion,2 these symptoms have been reported in lower-dose users including those taking as little as 200 mg/day.3 Most patients note improvement or complete resolution of symptoms with discontinuation of pyridoxine. T.T. had substantial improvement within just 2–3 weeks of discontinuing pyridoxine.

Although neuropathy is a common complication of diabetes, it is important to be aware of other potential etiologies of neuropathy in diabetic patients to avoid missing an important diagnostic clue for a treatable condition. A careful history should be obtained including use of both over-the-counter and prescription medications because commonly used agents can be associated with neuropathy.46 

Treatment of specific problems, such as carpal tunnel syndrome, with pyridoxine has been thought at times to be beneficial,7 but not all data have supported this.8 

Strongly encouraging patients to bring in all their medications can be a simple but helpful tool in making a more accurate diagnosis and effective therapeutic intervention.

  1. The differential diagnosis of peripheral neuropathy in diabetic patients is not limited to diabetes, but rather may have a variety of metabolic, toxic, inflammatory, malignant, infectious, and familial causes.

  2. A thorough history and appropriate laboratory testing are needed to ensure completeness of the search for these etiologies. This should include a review of all over-the-counter medications being used about which patients may not initially volunteer information.

  3. Several medications commonly used by people with diabetes may be associated with neuropathy.

  4. Evidence of a beneficial role for pyridoxine in the treatment of neuropathy is inconclusive.

Dace L. Trence, MD, FACE, is associate director of the Diabetes Care Center and an assistant professor in the Division of Nutrition, Endocrinology, and Metabolism at the University of Washington School of Medicine in Seattle.

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