Semmes-Weinstein monofilament examination. The 5.07 monofilament can detect the presence or loss of protective sensation. This photo demonstrates the correct usage of the Semmes-Weinstein monofilament to detect neuropathy and to determine if protective sensation is lost. The patient should be comfortable and have his eyes closed. The monofilament buckles when the 10 g of linear force are applied by the examiner for about 10 seconds. Note that this patient has early claw toe deformities. He was insensate to the 5.07 and even the 6.65 monofilament. (Adapted with permission from Tanenberg RJ, Donofrio PD. Neuropathic problems of the lower extremities in diabetic patients. In: Bowker JH, Pfeifer MA, editors. Levin and O’Neal’s the diabetic foot, 7th ed. St. Louis: Mosby; 2008:51.) 

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... of myoinositol and protein ki- nase C3 leading to neuronal demyelination have also been described in DPN. Figure 1 shows the proposed pathogenic mechanisms and their interaction leading to clinical diabetic neuropathy. Why this disorder often leads to a clinical scenario of painful feet in the minor- ity of cases and a painless neuropathy in the majority of cases is not understood. Diabetic neuropathy may present as either a focal or diffuse type. Focal neuropathies, including en- trapment neuropathy (eg, carpal tunnel syndrome), mononeuropathy multiplex, cranial neuropathies, plexopathies, and rarely polyradiculopathy, will not be addressed in this review. 7 Diffuse neuropathy, or gener- alized polyneuropathy, is typically characterized by the predominant fiber type(s) involved: small-fiber sensory, large-fiber sensory, large- and small-fiber sensory, or sensorimotor polyneuropathy. DPN often presents with neuropathic pain but can also present with decreased balance or a change in gait. The International Association for the Study of Pain has described neuropathic pain as “pain initiated or caused by a primary lesion or dysfunction in the nervous system.” 9 However, a recent review proposed redefining neuropathic pain as “pain arising as a direct conse- quence of a lesion or disease of the somatosensory system.” 10 Neuropathic pain is different in quality and onset from nociceptive pain, which patients can often link to a specific musculoskeletal or soft tissue injury. The neuropathic pain from DPN usually has a gradual and insidious onset and appears to arise de novo. Three distinct types of pain have been described in patients with DPN. Dysesthesic pain is an unpleasant abnormal sensation, whether spontaneous or evoked, and often presents as severe burning or itching sensations. Paresthetic pain presents as a “pins and nee- dles” sensation or an electric or knife-like shooting pain. Muscular pain presents as a deep, dull, aching or cramping pain that may be described as “night cramps.” Each of these types of pain may have a different pathogenesis and anatomical distribution. 8 Although most patients have a mixed or “pansensory” neuropathy, occasionally patients present with selective involvement. Involvement of small sensory fibers often causes severe superficial burning pain, whereas involvement of large sensory fibers is more often associated with paresthesias, loss of ankles jerks, and decreased balance ( Table 1 ). In general, pain from DPN is worse at rest and in the evenings, possibly because the nervous system is not “distracted” in the evening by a multiplicity of other inputs (eg, visual, locomotory, or thinking) that it is constantly processing during the day. Patients with diabetes whose pain is worse with walking or standing need to be evaluated for a concomitant disorder. It is classically symmetrical and distal. Since DPN is felt to be a “dying back” of the nerves, it affects the most distal extremities first, resulting in the “stocking and glove” distribution ( Figure 2 ). Patients with DPN may experience allodynia, which is pain due to a stimulus that does not normally provoke pain (eg, severe pain caused by a bed sheet touching bare toes), or hyper- algesia, which is an increased response to a stimulus that is not normally painful (eg, pain occurring with light touch). 11 Patients may also complain of other abnormal sensations, such as “my shoes feel too tight,” or describe a feeling of “walking on pebbles” or like their “feet are in ice water.” The physical examination in a patient with sus- pected DPN begins with inspection of the lower extremities. Observation may reveal dry and cracked skin and/or cold skin (despite good pulses) in patients with DPN. These abnormalities result from autonomic components of DPN, including loss of sweat glands and shunting of blood away from the skin. A character- istic finding on neurologic examination is loss of deep tendon reflexes. Ankle jerks are initially decreased and then lost. Knee jerks may be preserved until more advanced stages of the disease when the hands become affected. The 128 Hz tuning fork is the instrument of choice to check for the presence or absence of vibratory sensation in the feet. Initially, patients show deficits in vibration perception of the great toes, but over time the deficits move proximally to the metatarsal- phalangeal joints, dorsum of the foot, ankle, and the mid-tibial region. Use of the Semmes-Weinstein monofilament has helped define degrees of sensory loss in the feet and hands of patients with DPN. To use the device proper- ly, the examiner should place the tip of the monofilament perpendicular to the plantar surface of the great toe. Examiners should not allow the filament to slide across the skin or make repetitive contact to the site. Areas of callus must be avoided for an accurate exam. With their eyes closed, patients should be able to sense the monofilament by the time the monofilament buckles ( Figure 3 ). The thicker (higher number) the monofilament, the more force is required to cause the buckle. Patients without neuropathy should be able to sense the 3.61 monofilament (equivalent to 0.4 g of linear pressure). The inability to sense monofilaments of 4.17 (equivalent to 1 g of linear pressure) or higher is considered consistent with neuropathy (large-fiber modality). The inability to sense a monofilament of 5.07 (equivalent to 10 g of linear force) is consistent with severe neuropathy and loss of protective sensation. Unfortunately, most physicians are only familiar with or have access to the 5.07 monofilament, and there is a widespread misconception that DPN may be ruled out when a patient can feel this size device. Small fiber nerve loss can be detected with pinprick, although a cold perception gradient loss (using hot and cold water-filled test tubes or the flat side of a tuning fork) may be easier to define than loss of pinprick perception. The last sensory modality to become abnormal in this distal gradient loss neuropathy is loss of joint position sense (proprioception). Unfortunately, this is an all too common finding in many patients with long-standing DPN. Foot deformities are common findings in advanced cases of DPN. Although primarily a sensory disorder, DPN often includes an accompanying motor disorder that leads to the “hammer toe” or “claw foot” deformities ( Figure 4 ). The loss of foot flexor strength allows the unopposed foot extensors to contract and pull the toes into a hammer or claw position. This deformity re- distributes the weight on the often insensate metatarsal heads, greatly predisposing the neuropathic individual to ulceration. Other foot findings seen in patients with diabetic neuropathy include Charcot arthropathy, limited joint mobility, abnormal toe position, calluses, and partial foot amputations. When DPN involves the hands, it typically occurs several years after affecting the lower extremities. Often patients have become completely insensate to the mid- tibia when their hands begin to lose feeling. Initially, most patients complain of paresthesias in the hands. Later, as the hands become weaker, patients may complain about dropping objects and deteriorating hand- writing. Loss of muscle mass in the hands (wasting of the intrinsic hand muscles) becomes apparent. The consensus definition of DPN requires ruling out other disorders that cause peripheral neuropathy before attributing the neurologic findings to diabetes ( Table 2 ). Evaluation of the patient should include basic laboratory tests, such as a thyroid-stimulating hormone, serum protein electrophoresis, and vitamin B 12 level, to look for other causes of polyneuropathy. Patients with diabetes mellitus also commonly develop other diseases such hypothyroidism, B 12 deficiency, celiac disease, and uremia, all of which may cause or contribute to peripheral neuropathy. It should also be noted that prediabetes (previously called impaired glucose tolerance or impaired fasting glucose) may also present with DPN. In fact, neurologists will frequently order a glucose tolerance test when a patient presents with an idiopathic peripheral neuropathy. A good history and physical examination as described above are required to confirm sensory loss and to look for coexisting motor involvement. However, since DPN is a diagnosis of exclusion the clinician must consider non-neuropathic disorders as well as other causes of peripheral neuropathy (Table 2). If the patient’s neurologic findings are primarily in the upper extremities, more motor than sensory, or predominantly unilateral, DPN (if present) is most likely not the major diagnosis. In these cases, referral to a neurologist for electromyog- raphy and nerve conduction studies can exclude focal nerve entrapments, lumbar radiculopathy, chronic inflammatory demyelinating polyradiculoneuropathy, and other disorders. However, even these studies have limita- tions since they only assess large nerve fibers. A patient may have neuropathic pain and normal studies, or have abnormal studies with no pain. In these cases, additional sophisticated studies may be required to establish the diagnosis and recommend a treatment strategy. 12 Pain is primarily carried by unmyelinated C-fibers within the peripheral sensory nerves, which enter the dorsal horn of the spinal cord. Peripheral nerve injury causes the release of various neurotransmitters at the dorsal horn region, which in turn leads to an increased calcium influx into cells in a process known as central sensitization. Eventually the spinal cord becomes hypersensitive to afferent fibers. Although a detailed explanation of this phenomenon is beyond the scope of this article, an understanding of the central and peripheral mechanism for neuropathic pain helps to explain why different classes of drugs can be beneficial for treating neuropathic pain. 13,14 Pharmacologic treatment of painful DPN is limited, since no drug will ...