Case Study: Working Through The Differential Diagnosis Of Diabetic Neuropathy

   Given that neuropathy can have a complex range of manifestations, the diagnosis of the condition is not always as obvious as it initially seems. This author emphasizes the importance of a thorough diagnostic workup and the underappreciated value of communicating with the patient.

   When a 62-year-old minister got a referral to see a podiatric physician for neuropathic pain and dystrophic, “dry” changes to his feet, he noted his frustration with previous physicians. He said he felt like “one of those lab rats that has been given one drug and then another and another, hooked up to wires, run through mazes, given tests and then put through it all over again just to see if it comes out different the next time. Only it just seems to get worse, not better.”

   It was not a role the minister would have picked for himself. He was planning for his retirement in a couple of years when he started noticing the first symptoms — the burning, tingling pain in the toes and hands — especially at night when he was trying to fall asleep. His primary care physician (PCP) had at first linked it to his type 2 diabetes. His blood sugar had always been slightly high as his HgA1C is in the 7 to 7.5 range.

   The usual medicine regimen for diabetic neuropathy did not seem to work well for the minister’s pain and his PCP decided to focus on controlling his blood sugars more closely in addition to the other treatments. In the interim, she consulted the podiatrist for his input as a precaution.

   The patient reported in his past medical history what he had just reported to other specialists as well. There were some new symptoms that were now threatening his last years in the pulpit. The minister was starting to not remember his sermons, or for that matter, remember his parishioners, some of whom he had known for decades. He struggled for common words, even in this appointment.

    “Doctor, I walked up to the, uh, the … well, you know, the place where I stand to give my sermon. You know, that piece of furniture where I stand. The … oh gosh, I tell you I just cannot come up with words anymore.” The patient was obviously completely frustrated that he could not remember a simple word like “lectern,” a word he had used commonly.

   Frankly, he was beginning to panic and he was filled with questions. Could this be related to his diabetes? Could out of control blood sugar cause mental changes and the foot pain?

   The podiatrist decided to take a step back, do a detailed past medical history and leave no stone unturned. The DPM wanted to review all of the lab work, the tests that had been ordered by others and determine if he needed to order any other tests to complete the picture. Then the DPM would do his examination. This would be a long visit.

   The patient was appreciative of the time the physician was taking with him. This was not the average 20-minute in-and-out visit. Sometimes, however, it was necessary to clear the appointment book in order to get to the bottom of a medical mystery. Otherwise, the patient continues to get worse, physicians continue to order unnecessary tests and unneeded referrals continue to be made.

   It was fortunate for the doctor and the patient that this was the last appointment of the day. Realistically, the podiatrist knew that if it had not been the last appointment of the day, he would not normally have the luxury of taking this extra time with this complicated patient.

How The Past Medical And Social History Can Be Illuminating

   The minister had been quite healthy over his 62 years. His diet was largely guided by his religious beliefs. As a Seventh Day Adventist, he was a vegetarian but he was well fed. If it had not been for his love of rich desserts and his wife’s good cooking, he would have been a very fit man.
At 5’8”, the minister carried 210 pounds on his frame but he was not a sedentary man. He and his wife stayed busy and were physically active. They went to the YMCA to exercise together at least three times per week. They enjoyed the social activity as well as the physical activity. They stopped going though when he had started feeling bad.

    “Had the burning pain caused you to stop exercising?” the podiatrist asked him.

    “Well, no,” he answered, rather sheepishly. “It was the diarrhea. I had a hard time controlling it. I did not want to be caught in an uncomfortable position at the gym.”

    “Diarrhea. You had not mentioned that. Did that happen about the same time as the burning pain?” the doctor had asked.

    “Yes it did, come to think of it,” the reverend answered as he stopped to think about it. He noted the diarrhea was happening everyday. He could not remember the last time he had had a firm stool. He thought it happened because he ate a lot of fiber and drank water constantly. The podiatrist explained that that would have just the opposite effect: soft but formed stool and predictable bowel movements.

   The mystery was deepening. All of these things could be due to diabetic neuropathy but a HgA1C of 7.5 seemed unlikely to be causing it. In the podiatrist’s experience, it took a much higher HgA1C for a longer period of time to cause this severity of symptoms. However, every patient was different.

   The doctor quizzed him carefully about the possibility of alcohol, thinking that perhaps he was a secret drinker. Since alcoholism is one of the most common causes of neuropathy, the physician could not rule it out, even for a Seventh Day Adventist minister. After questioning, the physician was convinced that this was not the reason for this patient’s neuropathy.

    “As long as I am sharing these strange symptoms with you, there is another one that I have not mentioned because I thought people would think I was just being a vain old fool. I am losing my hair,” he said, reaching up to run his hands through his still black hair. When his fingers came away, his hands were literally filled with hair loosened from his scalp without any pulling.

   The podiatrist began listing the patient’s symptoms. There was symmetrical pain in the feet that felt like tingling, numbness and burning. The patient had diarrhea, hair loss and blood sugars that run high routinely. The symptom that bothers the patient most is the memory loss.

   The memory loss had convinced the patient that he was developing Alzheimer’s. The podiatrist reassured him that the type of memory loss he described was not consistent with Alzheimer’s. When the patient asked if these symptoms could be due to type 2 diabetes, the podiatrist explained that they could. Possible causes of the symptoms in the patient with diabetes included peripheral neuropathy, autonomic neuropathy, glycosylation of proteins and the stress of the disease. However, there did not seem to be an exact fit with that HgA1C reading, especially with that amount of hair loss.

   There were no other clues in his past medical, surgical, family or social history. Perhaps his chart would yield other clues.

What The Patient’s Chart Reveals

   The patient was on a few medications. He was taking a cholesterol-lowering drug, metformin for his diabetes, a multivitamin, OTC ranitidine (Zantac, GlaxoSmithKline) for occasional gastroesophageal reflux disease (GERD) and a daily low-dose aspirin as a cardiac precaution. He also drank two teaspoons of apple cider vinegar and a tablespoon of honey in a cup of hot water with his meals three times a day. Like many people, the minister believed this helped digestion and health in general.

   The PCP had covered all of the bases when it came to testing and now the podiatrist had the advantage of having everything in front of him for review. The PCP had looked for causes of his undiagnosed neuropathy and other symptoms in the area of thyroid, HIV/AIDS (even though he is a minister, one cannot rule it out and the podiatrist had to applaud her insight for including it), anemia and many others. All of these tests were negative.

   The PCP had also turned to nerve studies for a possible answer. The electromyography (EMG) and nerve conduction velocity (NCV) tests provided the diagnostic roadmap needed. One can determine the fibers involved (motor, sensory or dual), pathophysiology (axonal or demyelination), and whether the presentation is symmetrical or asymmetrical.

   However, as the specialists of the lower extremity, we understand the limitations of the EMG/NCV. These exams are often inadequate for reliable interpretation of proximal sensory nerves and in older patients whose neuropathy may be due to trauma or other non-disease related etiologies.

   In this case, the patient’s EMG/NCV showed no specific abnormalities aside from some vague prolonged distal latency of motor nerves that were non-diagnostic.

   All of the lab results were there. The diagnostic exams were complete as well, short of a nerve biopsy. The answer had been there in front of the other physicians all along, even before they ordered all of those tests. Any of the physicians would have diagnosed the problem by just sitting and talking with the patient.

   The real enemy of diagnosis is the lack of time to spend with patients. This is the reason why most patients who come in with “burning, tingling pain” end up with a diagnosis of diabetic neuropathy.

Putting The Pieces Of The Diagnostic Puzzle Together

   Before making the ultimate decision about the diagnosis, the next step is to look at what the patients are telling you about themselves. What makes the patient an outlier? Each patient has a unique story and this one in particular had a very unusual story that should have told each physician exactly what his neuropathy was all about.

   The patient is on a strict vegetarian diet, drinks highly acidic beverages three times daily, takes frequent acid-lowering medications and daily metformin, and has a low “normal” B12.

   The minister’s neuropathy symptoms are symmetrical and distal in the hands and feet. This points to endocrine disorders, infectious disease, connective tissue disorders and toxic compound exposures. An erythrocyte sedimentation rate (ESR) in his blood work showed no indication of inflammatory problems. Physicians also routinely screen for common endocrine disorders and they were ruled out for this patient. The interview should most likely reveal toxic exposures and infectious diseases through discussions about hobbies, work habits and travel.

   The cause of the other symptoms — memory loss, hair loss and diarrhea — is usually revealed in the patient’s lab work results. However, the particular lab — the vitamin B12 test — that will eventually reveal the problem is actually reported as “normal.”

   The accepted normal range of vitamin B12 varies from lab to lab but a median range is generally 200 to 1,100 pg/mL. There is also controversy about what constitutes the low “normal.” Laboratories have begun to add disclaimers to reports, noting that a significant portion of the population will have neurological and/or neuropsychological symptoms at levels higher than those at the low normal range. Many physicians have begun to treat patients with levels as high as 400 as having vitamin B12 deficiency.

   The reverend, like many Americans, finds himself turning to over-the-counter medications to treat his reflux disease on an all too frequent basis, probably more often than he even realizes. This is compounded by his dietary regimen. First of all, the reverend is a strict vegetarian because of religious reasons. Secondly, he ascribes to the folk remedy of apple cider vinegar and honey drinks, which acerbates his GERD.

   He is unwittingly short-circuiting the vitamin B12–hydrochloric acid cycle needed for digestion and maintenance of nerve and red blood cells. As a strict vegetarian, the reverend is not ingesting the meat foods that provide the largest source of vitamin B12. Fortified grain cereals can provide up to 100 percent of the recommended daily amounts of the vitamin but consumers need to be aware and purchase those particular cereals. Dairy products contain lesser amounts.

   In addition, by taking acid-inhibiting medications, the patient is further reducing his body’s ability to release the Vitamin B12 from the protein in food. Normally, the released B12 would then combine with intrinsic factor that is subsequently absorbed by the intestinal tract.

   There has been some evidence as well that metformin can interfere with calcium metabolism and this is a process that can reduce vitamin B12 absorption, which could be adding to this patient’s problem.1

   What the minister needs now is weekly vitamin B12 injections for a month. This should be followed by monthly injections until his hepatic stores of the essential vitamin are restored. Pernicious anemia is not a common finding anymore but the minister was not far from it when he arrived at the podiatrist’s office that day.

Final Thoughts

   Diabetes and alcoholism are still the most common reasons for neuropathy pain in the United States. Human immunodeficiency virus has made a significant increase in the number of cases over the past decade.

   Tracking down diagnoses for neuropathy symptoms is some of the most elusive and expensive work. One may end up with an indefinite diagnosis, which is an unsatisfying situation for both the patient, the physician and the third-party payer as tests continue to be ordered. The diagnostic difficulty is compounded by the fact that peripheral neuropathy is a common component of many diseases.

   After exhaustive testing, up to 42 percent of previously undiagnosed cases eventually result in the determination being familiar neuropathy.

   Many physicians turn to a handful of commonly found diagnoses — diabetes, alcoholism, AIDS/HIV — for their patients’ diagnoses and fail to consider the many diagnoses that may be the root cause of their patients’ symptoms. As physicians enter an era of potential pay-for-performance, we need to reject this shotgun approach toward diagnosis.

   Judicious use of an algorithm will guide the podiatric physician toward the correct diagnosis of a patient’s peripheral neuropathy without the overuse of expensive testing modalities.

Dr. Satterfield is a Clinical Associate Professor at the University of Texas Health Science Center at San Antonio. She is a Fellow of the American College of Foot and Ankle Orthopedics and Medicine.

References:

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