Painful Diabetic Polyneuropathy || Diagnosis of Painful Diabetic Neuropathy

27E. Lawson and M. “Misha” Backonja (eds.), Painful Diabetic Polyneuropathy: A Comprehensive Guide for Clinicians, DOI 10.1007/978-1-4614-6299-6_3, © Springer Science+Business Media New York 2013

Introduction

Painful diabetic neuropathy (PDN) is found in about 16% of diabetes patients and is not optimally managed in that 40% of individuals with PDN are untreated [ 1 ] . Such gaps in care produce patient dissatisfaction and negatively impact quality of life [ 2 ] . Since ef fi cacious, evidence-based treatments are available for PDN [ 3 ] , it becomes important to understand why treatment is not offered to patients. In part, this lack of treatment may arise from failure to make the diagnosis of PDN. This chapter aims to present a discussion concerning the diagnosis of PDN that may allow better treat-ment of patients.

Clinical Presentation of PDN

Neuropathy is the most common complication of diabetes, and can take several forms as outlined in Table 3.1 . The most common type is diabetic polyneuropathy, a length-dependent, sensorimotor axonal polyneuropathy, most commonly referred to as diabetic neuropathy (DN). This form of neuropathy presents in a “dying-back”

V. Bril , B.Sc., M.D., F.R.C.P.C. (*) Division of Neurology, Department of Medicine , University Health Network , 5EC-309, TGH, 200 Elizabeth Street , Toronto , ON , Canada M5G 2C4 e-mail: [email protected]

B. A. Perkins , M.D., M.P.H. Division of Metabolism and Endocrinology, Department of Medicine , University Health Network , Toronto , ON , Canada M5G 2C4 e-mail: [email protected]

Chapter 3 Diagnosis of Painful Diabetic Neuropathy

Vera Bril and Bruce A. Perkins

28 V. Bril and B.A. Perkins

fashion affecting the distal segments of the longest axons fi rst and then progressing in a centripetal fashion producing a “glove-and-stocking” pattern of neurological de fi cits.

The symptoms of DN are numbness, paresthesia (tingling), sensitivity to touch, pain, unsteadiness, and weakness. These symptoms are common to other polyneu-ropathies, but sensory symptoms are features of early DN. Painful symptoms occur commonly and include lancinating (electric shock-like, shooting), burning, freezing, cramping, and squeezing pain as typical descriptors. These symptoms affect the feet fi rst, starting in the toes and soles of the feet, and then migrate proximally as the neu-ropathy progresses. The symptoms can be intermittent or persistent and are often most troublesome in the evenings when the patient is resting, or at night producing sleep disturbances. The only symptom of DN may be pain, or pain may accompany other symptoms of neuropathy. The painful symptoms range from mild to intolerable and can be accompanied by other features such as insomnia, impaired quality of life, inability to work, and low productivity in the home and at work [ 2 ] . The symptoms are most often chronic, lasting longer than 3 months and in many cases lasting for years. In treating patients, it is important to consider comorbidities that may be present (e.g.: depression) and tailor the treatment for the speci fi c patient pro fi le [ 4 ] .

The physical examination may be normal despite the presence of characteristic painful symptoms indicating peripheral nerve injury. Other patients have sensory loss of the primary modalities of pinprick, temperature, light touch, vibration, and position sense, observed distally in the toes initially, and then more proximally in the lower limbs as the severity of neuropathy and degree of fi ber loss increases. Finally, sensory loss will be evident in the upper limbs and also along the anterior chest as nerves of shorter length become affected. Early loss of pinprick, cold sensation, light touch, and vibration is often observed, but loss of position sense is a fi nding of late DN. Atrophy of small foot muscles, weakness, and loss of re fl exes are similarly late signs. These physical fi ndings are typical of both painful and painless DN.

These are common presentations of PDN. Some authorities have formulated scales to encompass the symptoms, such as the DN4 or Douleur neuropathique en 4 questions [ 5, 6 ] . These scales present simple tools for screening for the presence of PDN and may be useful. Bouhassira compared fi ve simple screening tools for neuropathic pain [ 5 ] and found universal symptom descriptors across the scales

Table 3.1 Types of diabetic neuropathy

Mononeuropathy Cranial (3, 6, 7) Truncal (thoracic) Peripheral nerve entrapment: CTS, ulnar, peroneal Lumbosacral plexoradiculoneuropathy (“femoral neuropathy”) Polyneuropathy Sensorimotor polyneuropathy (DN) Autonomic neuropathy Diabetic cachexia “Small fi ber neuropathy”

293 Diagnosis of Painful Diabetic Neuropathy

for the presence of neuropathic pain, namely: burning pain, electric shock-like pain and pain evoked by touch, and tingling and numbness. In PDN, the symptoms of pain such as burning, electric shock-like, and aching coldness in the lower limbs occurring mainly at rest and at night, associated with tingling or numbness support the diagnosis [ 7 ] . Different scales that score the severity of pain have been devel-oped including the Brief Pain Inventory (BPI) [ 8 ] and the Neuropathic Pain Questionnaire (NPQ) [ 9 ] . The NPQ provides a general assessment of neuropathic pain and aids in the discrimination of neuropathic from non-neuropathic pain states. This is a 12-item scale with 74.7% sensitivity and 77.6% speci fi city. A brief version consisting of three items can also indicate the presence of neuropathic pain [ 10 ] . The three items are tingling pain, numbness, and increased pain due to touch. The development of these scales is aimed at improving our ability to diagnose NP and can be used for the diagnosis of DPN. The severity of pain can be followed using the NPQ or the Neuropathic Pain Symptom Inventory (NPSI), a self-administered pain symptom questionnaire [ 11 ] . This pain questionnaire was developed initially to monitor the effects of therapy on neuropathic pain [ 12 ] .

Despite this universal consensus, symptoms that are suggestive of neuropathic pain can be present in non-neuropathic pain disorders as shown in Table 3.2 , so they are not speci fi c and cannot be assumed to indicate the presence of DN when present [ 13 ] . Simple screening for the presence of DN can be accomplished by the use of the mono fi lament examination [ 14 ] , although a normal test does not exclude a diag-nosis of neuropathy. Other summary tools for DN include the Toronto Clinical Neuropathy Score that provides an assessment of severity, but not detailed informa-tion on painful symptoms [ 15 ] .

Role of Con fi rmatory Tests for Neuropathy: Mono fi lament, NCS, VPT, QST, LDI, CCM (Table 3.3 )

Some authorities take the position that the symptoms of neuropathic pain, with or without abnormal signs on physical examination, in a patient with diabetes are suf fi cient to formulate the diagnosis of PDN. This position may lead to inaccuracies and less precision than optimal as the symptoms of burning, electric shocks, tingling,

Table 3.2 Prevalence of symptoms in neuropathic pain and non-neuropathic pain disorders [ 13 ]

Symptom Neuropathic pain Non-neuropathic pain p -Value

Burning 68.3 30.4 <0.001 Squeezing 48.8 37.7 0.171 Cold 25.6 10.1 0.015 Electric shock 64.6 17.4 <0.001 Lancinating 75.6 65.2 0.162 Tingling 59.8 15.9 <0.001 Pins and needles 65.9 17.4 <0.001 Numbness 65.9 30.4 <0.001


pins and needles, and numbness are not speci fi c for PDN, and can be observed in other types of neuropathy so that a differential diagnosis for PDN should be consid-ered. Further, although symptoms are suggestive of neuropathic pain, they can be observed in non-neuropathic pain states [ 13 ] .

Most practitioners favor obtaining an objective test result to con fi rm the diagno-sis of PDN. The absence of any objective measures raises the probability that the population under consideration is not homogeneous and that other diagnoses are being overlooked. The objective tests for DN include large fi ber tests of nerve con-duction studies (NCS), and vibration perception thresholds (VPT), but these can be normal in PDN if small fi bers are primarily affected early in the course of the disor-der. For small fi ber neuropathy, different objective tests that assess small fi bers, such as quantitative thermal thresholds (QTT), axon-re fl ex-mediated cutaneous fl are response area (LDI fl are), and others, are used.

Although the large fi ber tests may be normal in PDN, if they are abnormal, then an objective measure con fi rms the presence of peripheral nerve disease. The most objec-tive and speci fi c measure are NCS as they measure directly peripheral nerve abnor-mality, whereas VPT measure the entire somatosensory pathway and can be abnormal in myelopathy as well as peripheral neuropathy. Despite that NCS measure large fi ber function, the strongest correlations of “small fi ber symptoms” (such as pain) can be found with NCS parameters rather than presumptive small fi ber tests, perhaps due to the reliability of the NCS compared with that for small fi ber tests [ 16 ] . VPT may be used more often than NCS in the clinic due to wider availability of VPT devices, their ease of use, and lack of need for referral to specialized testing centers [ 17 ] .

The small nerve fi ber tests that may be useful to indicate the presence of periph-eral nerve dysfunction include QTT and LDI fl are. QTT have been used in clinical trials for 25 years [ 18– 20 ] , but they are not widely available in the diabetes clinic yet due to issues with reliability, expense of obtaining suitable equipment, and time con-sidered necessary to obtain QTT [ 16 ] . The main drawback is the reliability issue that shows differences in QTT as high as 100% on repeat testing, not infrequently [ 20 ] . Despite these considerations, if PDN is suspected on clinical grounds and QTT are abnormal, then there is supportive evidence that small nerve fi bers are not functioning properly. Unfortunately, no good relationship between QTT and painful symptoms can be found, so the implications of abnormal QTT are uncertain [ 16 ] . LDI fl are is

Table 3.3 Objective tests for PDN

Test Neuropathy PDN

Nerve conduction studies + +/− Vibration perception thresholds + +/− Quantitative thermal thresholds +/− +/− Laser Doppler fl are ? ? Cornal confocal microscopy ? ? IENFD +/− +

+ useful, − not useful, +/− may be useful, ? role is uncertain, IENFD intra-epidermal nerve fi ber density


mainly an investigative measure of small cutaneous nerve fi bers and its role in the identi fi cation of PDN is uncertain at this time [ 21– 23 ] .

The most reliable small fi ber test currently is considered to be the intra-epidermal nerve fi ber density (IENFD) at the ankle [ 24 ] , although there is disagreement on how strongly IENFD testing is recommended for diagnosis of small fi ber neuropathy [ 25 ] . If a skin punch biopsy shows reduced IENFD, then a diagnosis of small fi ber neuropathy is established even in the absence of abnormality on clinical examination or other objective tests (NCS, VPT, QTT). This relatively recent method [ 26 ] for the examination of peripheral nerves is invasive, although minimally, not available in most clinics, and expensive. Further, as more is being learned about the limits of IENFD, different ways of assessing intra-epidermal nerve fi bers beyond fi ber den-sity are being suggested. For example, ratio of IENFD at thigh to ankle may reveal a relative reduction distally in the presence of a value of IENFD at the ankle within the normal range [ 27, 28 ] . Structural characteristics of the nerve fi bers (abnormal dilata-tions) may suggest abnormality even if IENFD is normal [ 27, 29 ] . The changing landscape of intra-epidermal nerve fi ber assessment indicates that this pathological method of small fi ber testing is still being explored and that any particular assess-ment cannot be recommended universally for the diagnosis currently. Also, detailed morphological assessments of skin fi bers are not as available as routine IENFD and are limited to research laboratories. For routine clinical diagnoses of PDN, the use of IENFD is not recommended highly.

Novel measures, such as corneal confocal microscopy (CCM), as objective methods to evaluate small nerve fi bers are being investigated [ 30, 31 ] . CCM pro-vides direct visualization of corneal nerve fi bers and parameters of fi ber density, fi ber length, fi ber branching, and others can be derived from the CCM. These parameters relate to DN and may be a noninvasive method of assessing small nerve fi bers directly. Such an examination could be part of an annual ocular/retinal exam-ination in patients with diabetes, and provide an objective measure of peripheral nerves. This methodology is still under investigation, but shows promise for the objective evaluation of PDN.

A summary of the objective tests for neuropathy and their role in PDN is shown in Table 3.3 .

Differential Diagnosis

Diabetic neuropathy is a diagnosis of exclusion and, by extension, PDN is also a diagnosis of exclusion. The pain expert might argue that the treatment for all forms of neuropathic pain is similar and therefore, it is not essential to formulate the diag-nosis of PDN accurately. However, some forms of neuropathic pain respond differently to different medications [ 32 ] . For example, carbamazepine is not effective for PDN [ 3 ] , but is effective for trigeminal neuralgia [ 33 ] . HIV neuropathy fails to respond to amitriptyline [ 34 ] in contrast to demonstrated ef fi cacy in PDN [ 3 ] . Furthermore, patients with diabetes can have disorders other than PDN producing similar symptoms


and these problems would require different treatments. For example, vitamin B12 de fi ciency states would produce similar clinical phenotypes, but the patients need to be treated with vitamin B12 replacement and not simply medications to control painful symptoms. So, it is necessary to consider the differential diagnosis in patients suspected of having PDN. Table 3.4 outlines the differential diagnosis in patients with suspected PDN. In the case of a speci fi c form of neuropathy, other than, or coexistent with PDN, it is necessary to address the underlying etiology, as well as treat the neuropathic pain. The most common coexistent neuropathic disorders that cause similar pain symptoms are vitamin B12 de fi ciency, monoclonal gammopathy, and ethanol abuse. However, attention must be paid to other potential diagnostic confounders that can mimic PDN. For example, the patient may have osteoarthritis or plantar fasciitis that can produce symptoms that mimic PDN. So a full evaluation of diabetes patients is required to ensure that alternative diagnoses are not being overlooked.

When counseling patients about their diagnosis and treatment, it is necessary to be reasonably sure that the correct diagnosis has been made.

Summary on Diagnosis of PDN

Patients with diabetes often have PDN. If symptoms of pain are present in a patient with diabetes, then different scales such as the short form NPQ can assist with the diagnosis of PDN. Clinical symptoms suggestive of a painful neuropathy may be

Table 3.4 Differential diagnosis of PDN

Other neuropathies a Vitamin B12 de fi ciency Alcohol abuse Uremic MGUS CIDP, sensory variant Familial Toxic, drug (chemotherapy, others) Paraneoplastic Morton’s neuroma Peripheral vascular disease Central disorders Polyradiculopathies Demyelinating disease Others Rheumatological disease Osteoarthritis Plantar fasciitis

a These neuropathies may be coexistent with PDN or independent causes of neuropathic pain symptoms in a patient with diabetes


accompanied by abnormal fi ndings on examination but the examination may be normal. Con fi rmatory evidence of neuropathy can be obtained with objective tests of NCS, VPT, QTT, and IENFD. The differential diagnosis of PDN should be con-sidered to exclude confounding diagnoses and to direct therapy appropriately. Response to therapy in PDN can be monitored with tools such as the NPSI.

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Painful Diabetic Polyneuropathy || Diagnosis of Painful Diabetic Neuropathy