Current Insights On Diagnosing And Treating Neuropathy
Neuropathy is one of the most common problems podiatrists encounter in practice. Peripheral neuropathy has a prevalence of 2.4 percent in the general population and a prevalence of 30 to 50 percent in individuals with diabetes.1,2 It results from either central or peripheral damage to the somatosensory system.
Diabetic peripheral neuropathy is a length-dependent neuropathy, in which the longest nerve fibers are affected first.3 In this type of neuropathic pattern, the signs and symptoms begin in the toes and feet and are typically symmetrical on both sides. Gradually, the symptoms creep up the limb, affecting the more proximal parts of the lower extremities, and eventually the fingers and hands.2,3 A polyradiculoneuropathy is an example of a length-independent neuropathic pattern, in which symptoms begin in both the proximal and distal limbs.1 These patients may present with a focal neurologic deficit, such as foot drop.
Obtaining The Patient History
Subjectively, the patient’s complaints may be of pain that radiates or shoots up the legs, and/or prickling or tingling sensations. They may state they have a feeling of pins and needles in their feet. Some might experience muscle weakness and describe their feet feeling “dead” or heavy. Patients may also experience hyperalgesia or allodynia, leading to complaints that wearing socks or shoes on their feet is painful.2,4
The first step in understanding the cause of neuropathy is obtaining a comprehensive history from the patient. This should include a detailed past medical history, social history and habits, a family history, and all current medications. A previous history of alcohol dependence or lumbar spine radiculopathy may provide clues to the underlying cause of neuropathy. Likewise, a family history of an inherited neuromuscular disease or diabetes mellitus helps practitioners hone their examination.1
Certain medications can lead to numbness and tingling in the hands and feet. Subsiding numbness with cessation of a drug or a greater degree of numbness with increased dosing of a drug are clues that neuropathy may be a related to a given medication the patient is taking. Some of the more common medications that may cause neuropathy are highlighted in the list below.5
Medications That May Cause Neuropathy
Amiodarone
Hydralazine
Cisplatin
Paclitaxel
Vincristine
Isoniazid
Metronidazole
Nitrofurantoin
Infliximab
Colchicine
Keys To The Physical Examination
Always complete a thorough physical examination, at least annually, in those with known neuropathy. This should include testing of vibratory sensation at the level of the hallux, testing of protective sensation with a 10 g Semmes-Weinstein monofilament, ankle reflex testing, proprioception and sharp/dull discrimination testing.
A study by Armstrong and colleagues evaluated the sensitivity and specificity of vibration perception and the Semmes-Weinstein 10 g monofilament in conjunction with a four-question verbal neuropathy score in the detection of peripheral neuropathy.6 They concluded that combining the vibratory testing with the monofilament provided the most sensitive (90 percent) and specific (85 to 90 percent) outcomes in screening for peripheral neuropathy. In addition to the high sensitivity and specificity of these tests, one can easily implement these testing modalities and perform them quickly in the private practice setting.
What You Should Know About Laboratory And Ancillary Studies
It is well known among practitioners that the most common cause of peripheral neuropathy is diabetes mellitus. Unfortunately, there are an estimated 8 million undiagnosed patients with diabetes in the United States.7 Accordingly, a patient presenting with an initial complaint of bilateral, symmetrical neuropathy in the lower extremities should have a prompt screening for diabetes. Laboratory evaluation including a fasting glucose and hemoglobin A1c can aid in the diagnosis.
Additional laboratory studies to obtain in patients without diabetes are vitamin B12 with methylmalonic acid and thyroid stimulating hormone as B12 deficiency and hypothyroidism are known causes of neuropathy.1 In the event that these tests are negative, a serum protein immunofixation electrophoresis (SPIEP) may be warranted to rule out a dysproteinemia.1 A sudden onset of neurologic and neuropathic symptoms in conjunction with flu-like symptoms and a history of deer tick exposure may indicate Lyme disease, which one can diagnose with an enzyme-linked immunosorbent assay (ELISA) test.8
A peripheral nerve biopsy may be warranted when lab studies do not reveal the underlying cause of neuropathy. However, this may be underutilized as nerve biopsy can lead to a definitive diagnosis. A prospective study by Gabriel and colleagues focused on obtaining a sural nerve biopsy from 50 patients.9 In seven patients (14 percent), the nerve biopsy changed the initial diagnosis. The biopsy confirmed 35 cases and the biopsy was non-contributory to eight cases. The authors concluded that the sural nerve biopsy ultimately affected the management of 60 percent of patients and altered the diagnosis in 14 percent.9 The underutilization of this procedure may be due to its invasive nature and the probability of complications, especially in a neuropathic patient.
One may perform electromyography and nerve conduction studies to further confirm the diagnosis of neuropathy.
Emphasizing Appropriate Referrals And Assessing The Treatment Options
All patients with diagnosed neuropathy should get a referral to their primary care physicians or a neurologist for systemic management following the initial visit. For patients with diabetes suffering from painful peripheral neuropathy, adequate glycemic control should be the first step.2 Patients may require referrals to an endocrinologist and nutritionist for proper education and counseling. In the presence of a nutritional deficiency, one can administer supplements to the patient. When dysproteinemia is present, one should refer the patient to a hematologist for further workup and to rule out underlying cancer.
Pharmacologic treatment of neuropathy consists of two categories. First-line topical medications include lidocaine and capsaicin, and both are available in a patch or gel/cream form. The first-line oral medications include gabapentin (Neurontin, Pfizer), pregabalin (Lyrica, Pfizer), amitriptyline (Elavil) and duloxetine (Cymbalta, Eli Lilly).
A number of studies have attempted to determine which of these drugs is most efficacious. Boyle and coworkers performed a randomized, controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy.10 Patients were randomly assigned to one of the three aforementioned treatment groups. Each of the treatment groups received an eight-day placebo dose, followed by 14 days of a low-dose of amitriptyline, duloxetine, or pergabalin based on the group they were placed in. Following the low-dose, they then received 14 days of a higher-dose of the same medication. Following each of the titration periods, the participants were evaluated on their subjective pain, sleep, and daytime functioning. At the end of the study, they found no significant difference in the analgesic effect of the three treatments as all three modalities reduced subjective pain. This study and others like it have shown that the first-line oral medications can all be effective in pain relief.11,12
Because the efficacy of these first-line oral medications is similar, taking a comprehensive and customized approach to treatment has been recommended.11 The presence of comorbidities, such as sleep insomnia, depression, and/or weight gain, may be affected by neuropathy medications and can help to guide therapy.1,11
In my experience, the two most common drugs I have seen podiatrists prescribe for painful neuropathy are pregabalin and gabapentin. Pregabalin dosage begins as 75 mg twice a day for three to seven days. After seven days, one can increase this, if necessary, to 150 mg twice a day with a maximum dose of 300 mg twice a day. When it comes to pregabalin, it is recommended to taper the dosage over a minimum of one week.11,12 In regard to gabapentin, patients would initially take 300 mg once a day with gradual increases over several days to 300 mg three times a day, with a maximum daily dose of 3,600 mg.1
One should only use second-line oral agents for the treatment of neuropathy after the failure of first-line topical and oral treatments and persistence of pain. These include the use of tramadol (Ultram, Janssen Pharmaceuticals) or opioids for pain control, and one should use them with caution.11
References
1. Watson JC, Dyck PJB. Peripheral neuropathy: a practical approach to diagnosis and symptom management. Mayo Clinic Proc. 2015; 90(7):940-51.
2. Tesfaye S. Neuropathy in diabetes. Medicine. 2014; 43(1):26-32.
3. Said G. Diabetic neuropathy - a review. Nature clinical practice: Neurology. 2007; 3(6):331-40.
4. Khan S, Zhou L. Characterization of non-length-dependent small-fiber sensory neuropathy. Muscle Nerve. 2012; 45(1):86-91.
5. Jasmin L. Neuropathy secondary to drugs. MedlinePlus. Available at https://www.nlm.nih.gov/medlineplus/ency/article/000700.htm .
6. Armstrong DG, Lavery LA, Vela SA, Quebedeaux TL, Fleischli JG. Choosing a practical screening instrument to identify patients at risk for diabetic foot ulceration. Arch Intern Med. 1998; 158(9):289-92.
7. American Diabetes Association. Statistics about diabetes. National diabetes statistics report 2014. Available at https://www.diabetes.org/diabetes-basics/statistics/ .
8. Mayo Clinic. Lyme disease: tests and diagnosis. Available at https://www.mayoclinic.org/diseases-conditions/lyme-disease/basics/tests-diagnosis/con-20019701 .
9. Gabriel CM, Howard R, Kinsella N, Lucas S, McColl I, Saldanha G, Hall SM, Hughes RAC. Prospective study of the usefulness of sural nerve biopsy. J Neurol Neurosurg Psychiatry. 2000; 69(4):442-46.
10. Boyle J, Eriksson MEV, Gouni R, Johnsen S, Coppini DV, Kerr D. Randomized, placebo-controlled comparison of amitriptyline, duloxetine, and pregabalin in patients with chronic diabetic peripheral neuropathic pain. Diabetes Care. 2012; 35(12):2451-58.
11. Devi P, Madhu K, Ganapathy B, Sarma GRK, John L, Kulkarni C. Evaluation of efficacy and safety of gabapentin, duloxetine, and pregabalin in patients with painful diabetic peripheral neuropathy. Indian J Pharmacol. 2012; 44(1): 51-56.
12. Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications. 2015; 29(1):145-56.
13. Ziegler D, Fonseca V. From guideline to patient: a review of recent recommendations for pharmacotherapy of painful diabetic neuropathy. J Diabetes Complications. 2015; 29(1):145-56.
14. Pregabalin for neuropathic pain. NPS MedicineWise. 2013. Available at https://www.nps.org.au/publications/health-professional/nps-radar/2013/april-2013/pregabalin .
