Old Woman With Disabling Peripheral Neuropathy Treatment.

Old Woman With Disabling Peripheral Neuropathy Treatment.

Ms Q is a 52-year-old woman who has had progressive polyneuropathy in the setting of diabetes for the past 8 years. Ms Q’s major disability is that of increasingly severe neuropathic pain and cramps that have been poorly responsive to a variety of therapies, including gabapentin and topiramate. The diagnosis of and differential diagnosis for diabetic polyneuropathy are reviewed herein. In general, treatment options for diabetic polyneuropathy remain primarily symptomatic. Improving the metabolic profile through weight loss, exercise, and if necessary, medications may help slow neuropathy progression. Many medications are effective in reducing pain, and newly developed ones, such as pregabalin and duloxetine, while specifically marketed for diabetic neuropathy, are likely to be no better and are considerably more expensive than older ones. {alpha}-Lipoic acid appears to be effective as well.

DR SHIP: Ms Q is a 52-year-old registered nurse with lower extremity neuropathy diagnosed 6 years ago. She lives in the greater Boston area and has managed care health insurance.

Ms Q’s symptoms began about 8 years ago with pain at the base of her left foot. She was seen by a podiatrist, initially diagnosed with plantar fasciitis, and underwent serial cortisone injections. The injections minimized symptoms initially, but her pain persisted. Her pain spread to her right foot, and, given the lack of improvement, she was referred for nerve conduction studies and electromyography (EMG). The studies showed mild reduction in the sural sensory response amplitudes bilaterally with normal conduction velocities; these findings were consistent with a mild distal axonal sensorimotor polyneuropathy.

Ms Q was diagnosed with diabetes about a year before her EMG findings. Her hemoglobin A1C was 7.6% at the time of diagnosis.

Ms Q says that her neuropathic symptoms, which include numbness, tingling, pain, and burning bilaterally, have worsened over the years. Her symptoms seem to worsen when her diabetes is less well controlled. She has had difficulty keeping her diabetes under tight control, however, and her hemoglobin A1C is currently 8.8%.

She has tried a range of medications with only moderate relief. Amitriptyline caused intolerable mouth dryness. Topiramate and gabapentin were ineffective. To treat her pain, she currently uses lidocaine patches, takes 60 mg of duloxetine daily, and uses alternative treatments including arnica cream. Her other medications include atenolol, 100 mg once a day; atorvastatin, 80 mg once a day; fluticasone, 50 µg spray, 1 to 2 sprays daily; glyburide, 10 mg twice daily; hydrochlorothiazide, 25 mg once a day; lisinopril, 40 mg 4 times a day; metformin, 1000 mg twice daily; oxycodone/acetaminophen (5 mg/325 mg), 1 to 2 tablets every 4 hours as needed for pain; trazodone, 100 mg before bed; and ranitidine, 150 mg twice daily.

Ms Q’s other medical problems include obesity, hypercholesterolemia, depression, hypertension, and back pain which persists after a left L5 to S1 hemilaminectomy, medial facetectomy, and microdiskectomy for disk disease in 2000.

Her vitamin B12 and thyrotropin levels were normal. On examination, her blood pressure was 146/74 mm Hg; pulse, 68/min; weight, 237 lb (106.6 kg); and height, 5 ft, 4 in (162.5 cm). Distal strength in the legs and feet was normal. Reflexes were 2+ at the knees and trace at both ankles; no Babinski signs were present. There was a graded reduction in sensation to pinprick and cold in both feet, normalizing at the midshins bilaterally. Vibration was reduced to 2 to 3 seconds in the great toes but was normal proximally. Joint position sense was intact in both feet. Gait was narrow-based, and a Romberg sign was absent.

DR RUTKOVE: This 52-year-old woman with a history of lumbosacral disk disease presents with diabetic polyneuropathy. Her symptoms were initially attributed to plantar fasciitis, likely because the foot pain was initially unilateral. The spreading of the pain to the other side alerted a physician to the possibility of neuropathy, and she was sent for electrophysiologic testing that revealed a mild axonal polyneuropathy. Because she had been diagnosed with diabetes a year earlier, a diagnosis of diabetic polyneuropathy was made. She has had progression of symptoms since then and is currently treated with lidocaine patches and 60 mg of duloxetine. She also takes 100 mg of trazodone at bedtime and 5 mg/325 mg oxycodone/acetaminophen as needed. In addition to neuropathic pain, she notes painful cramping in both feet. Her physicians are trying to improve her pain control while forestalling the progression of the neuropathy.

Nomenclature of Diabetic Neuropathy

Diabetic neuropathies can be grouped into 2 major categories: focal and diffuse. The focal neuropathies include a variety of conditions that have an increased incidence in diabetes compared with the general population, including focal appendicular mononeuropathies, such as median neuropathy at the wrist, and ulnar neuropathy at the elbow, cranial mononeuropathies (such as Bells palsy) or lumbosacral radiculoplexoneuropathy (diabetic amyotrophy).1-2 Of the diffuse diabetic neuropathies, diabetic polyneuropathy—the disorder producing generalized, distally predominant, relatively symmetric dysfunction with sensory function affected more than motor function—is the most common and is the focus of this review. Diabetes has also been associated with a form of generalized polyneuropathy known as chronic inflammatory demyelinating polyradiculoneuropathy; however, recent evidence suggests that the incidence of this disorder in patients with diabetes is no more common than that of the general population.3

The American Diabetic Association defines diabetes as a fasting glucose level of 126 mg/dL or greater (to convert to millimoles per liter, multiply by 0.0555) or a glucose level of 200 mg/dL or greater with an oral glucose tolerance test.4 Impaired glucose tolerance is defined as a plasma glucose level of 140 to 199 mg/dL 2 hours after an oral glucose tolerance test, whereas impaired fasting glucose is defined as a fasting plasma glucose level of 100 to 125 mg/dL. Metabolic syndrome refers to the state of insulin resistance in the setting of increased waist circumference, elevated blood pressure, and fasting glucose level greater than 100 mg/dL. Because polyneuropathy appears to be associated with these prediabetic states,5 for the purposes of this review, I will refer to the condition as forms of diabetic polyneuropathy without regard to category or type of diabetes, except where noted. Ms Q has been previously diagnosed with diabetes, which is poorly controlled with a hemoglobin A1c of 8.8%.

Epidemiology

Diabetes is the most common cause of polyneuropathy in Western countries; however, the proportion of patients with polyneuropathy is unknown. In patients with diabetes, the prevalence of polyneuropathy ranges from 28% to 55%. In one set of studies, 4400 patients with diabetes were followed up for more than 25 years and clinically defined polyneuropathy affected 50% of individuals by the 25th year of study.6-8 The Europe and Diabetes Study (EURODIAB) found a prevalence of polyneuropathy of about 28% in 3250 randomly selected patients with insulin-dependent diabetes from across Europe.9 Among individuals with diabetes in Olmstead County, Minnesota, 55% of those insulin dependent vs 54% of those noninsulin dependent had polyneuropathy, but of those only 15% of the insulin-dependent group and 13% of the noninsulin-dependent group were symptomatic.10 Finally, patients with type 2 diabetes but no polyneuropathy developed polyneuropathy at the rate of 6.1 per 100 person-years.11

Clinical Symptoms and Examination

Diabetic polyneuropathy can present in a variety of ways. As noted in the Olmstead County study, it is often asymptomatic, and evidence for the disorder is only found on examination. However, in many patients, symptoms will goad individuals to seek medical help. Generally, small fiber neuropathy develops before large fiber,12 so many patients will present with complaints of burning, uncomfortable feet. However, for unknown reasons, a large proportion of individuals with diabetic polyneuropathy do not develop pain and only present with large fiber symptoms of numbness, weakness, or gait disturbance.

The most readily identifiable feature of diabetic polyneuropathy is the reduction of pinprick sensation distally with normalization proximally. To identify this, the physician should “march” the pin up from the toes looking for a point at which the pinprick sensation becomes fully sharp. Occasionally during this procedure, patients will complain of hypersensitivity distally. Temperature sensation should be similarly evaluated, most conveniently by sliding the cool round end of a 128-Hz tuning fork up the leg. Sensation to light touch should be tested in a similar manner. Joint position sense should be assessed by making small excursions of the interphalangeal joint of the great toe and determining the patient’s ability to accurately identify the direction of movement. Finally, the physician should apply the tip of a 128-Hz tuning fork to the great toe after striking it firmly nearby, while counting out seconds. Feeling the vibration for at least 12 seconds is generally considered normal. Although the reliability of other types of sensory testing have not been reported, timed vibration testing has an interrater correlation coefficient as high as 0.93 at the great toe.13 Ms Q has reduced sensation to pin prick, cold, and vibration, but other findings were absent.

After completing the sensory examination, the strength of toe extensors and flexors and foot dorsiflexion should be assessed, followed by examination of the deep tendon reflexes. In patients with diabetic polyneuropathy, these are usually normal in the arms and knees and reduced or absent in the ankles. Absence of the Achilles reflex and reduced vibration perception and position sense at the great toe has been found to have a 92.8% positive predictive value for the presence of polyneuropathy.14 Gait often becomes impaired in the presence of diabetic polyneuropathy, with slower walking speeds, longer stance phases, and reduced flexion of the ankle.15

Differential Diagnosis

When evaluating the constellation of symptoms and signs with which patients with presumed diabetic polyneuropathy present, other neurological diagnoses should be considered. First, polyradiculopathy (lumbosacral stenosis) should be considered. For example, one study showed that 14% of 162 patients referred to an EMG laboratory for a diagnosis of possible polyneuropathy were found to have radiculopathy or polyradiculopathy as the likely cause of their symptoms.16 Asymmetries in sensation and reflex testing indicated a radicular etiology over polyneuropathy. Spinal cord disorders, especially cervical spondylotic myelopathy, also can present with predominantly distal complaints and should be excluded.17 Another diagnosis sometimes considered is tarsal tunnel syndrome; however, this syndrome is very rare.18 Other nonneurological diagnoses should also be considered, including plantar fasciitis, which was Ms Q’s initial diagnosis. Planter fasciitis usually produces localized pain just anterior to the heel.