BASIC/CLINICAL SCIENCE
Peripheral Neuropathy for Dermatologists: What If Not Diabetic Neuropathy? Tiffany Kwok, Patricia T. Ting, Eric K. Wong, and Alain Brassard Background: Patients with cutaneous manifestations associated with peripheral neuropathy often present to the dermatologist’s office. Objective/Methods: This article outlines a practical approach for obtaining the history, performing a screening physical examination, and ordering initial diagnostic testing to diagnose the cause of nondiabetic neuropathy. When to refer for neurologic consultation and principles of management of neuropathic pain and neuropathy-related ulcers are also discussed. Results: Cutaneous manifestations of peripheral neuropathy may be secondary to a medical condition predisposing the patient to neuropathy or a manifestation of neuropathy itself. In the latter category, skin affected by neuropathy may show characteristics of xerosis, anhidrosis, rubor, edema, callus, ulceration, muscle wasting, and foot deformity. Most often these findings occur in association with diabetic neuropathy; however, many other infectious, inflammatory, metabolic, paraneoplastic, hereditary, and medication- or toxin-related causes should be considered. The treatment of cutaneous manifestations of neuropathy includes pressure downloading, control of edema, and optimal ulcer and neuropathic pain management. Conclusion: It is important for dermatologists to have a basic approach to neuropathy in patients with related skin disease. Referral to Neurology is warranted when basic workup for reversible causes is negative or for any severe, rapidly progressive symptoms. Contexte: Les manifestations cutane´es associe´es a` la neuropathie pe´riphe´rique donnent souvent lieu a` des consultations en dermatologie. Objectif/Me´thode: Le pre´sent article expose une de´marche pratique d’obtention de l’anamne`se, de re´alisation de l’examen physique de de´pistage, et de prescription d’examens diagnostiques de base permettant de cerner la cause de la neuropathie non diabe´tique. Il sera e´galement question de la pertinence des consultations en neurologie ainsi que des principes de prise en charge de la douleur neuropathique et des ulce`res lie´s a` la neuropathie. Re´sultats: Les manifestations cutane´es de la neuropathie pe´riphe´rique peuvent eˆtre secondaires a` un e´tat sous-jacent, favorable a` la neuropathie ou a` une manifestation de la neuropathie elle-meˆme. Entrent dans cette dernie`re cate´gorie des manifestations cutane´es telles que le xe´rosis, l’anhidrose, la rougeur, l’œde`me, les durillons, les ulce`res, l’amyotrophie, et les de´formations du pied. La plupart du temps, ces manifestations sont lie´es a` la neuropathie diabe´tique; cependant, bon nombre d’autres causes possibles: infectieuses, inflammatoires, me´taboliques, parane´oplasiques, he´re´ditaires, me´dicamenteuses, ou toxiques, devraient eˆtre envisage´es. Le traitement des manifestations cutane´es de la neuropathie comprend la diminution de la pression, la re´duction de l’œde`me, et la prise en charge optimale des ulce`res et de la douleur neuropathique. Conclusions: Il est important que les dermatologues aient une approche de base a` l’e´gard de la neuropathie chez les patients en pre´sentant des manifestations cutane´es. Les consultations en neurologie sont justifie´es dans les cas d’absence de cause re´versible d’apre`s le bilan de base ou d’e´volution rapide et grave des symptoˆmes.
Overview of Neuropathy
From the Division of Dermatology and Cutaneous Sciences and Faculty of Medicine, University of Alberta, Edmonton, AB. Presented at the Canadian Dermatology Association Meeting, Thursday June 28 to Sunday July 1, 2012, Ottawa, ON. Address reprint requests to: Alain Brassard, MD, 2-125 Clinical Sciences Building, Edmonton, AB T6G 2G3; e-mail: [email protected].
DOI 10.2310/7750.2013.WOUND3 # 2013 Canadian Dermatology Association
The four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, multiple mononeuropathy (formerly known as mononeuritis multiplex), and autonomic neuropathy.1,2 Each of these patterns may have motor, sensory, or autonomic deficits or a combination of these neurologic deficits. The time course to symptomatic plateau can be acute (, 4 weeks), subacute (4–8 weeks), or chronic (. 8 weeks).2 The pathophysiology of neuropathy may be axonal, demyelinating, or mixed. However, these distinctions cannot generally be made clinically and require referral to neurology
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for diagnosis by nerve conduction studies. Any given cause of neuropathy may present with multiple cardinal patterns of peripheral neuropathy, although a chronic, symmetrical axonal polyneuropathy is most common overall.1 Cutaneous manifestations of neuropathy may be secondary to a medical condition predisposing the patient to neuropathy or may be a manifestation of neuropathy itself. In the latter category, skin affected by neuropathy may show characteristics of xerosis, anhidrosis, rubor, edema, calluses, ulcers, and foot deformities.1,2 These skin changes may occur in almost any chronic neuropathy, often making the diagnosis of the specific neuropathy very challenging for the dermatologist.
Assessment History and Physical Examination Detailed pertinent information to elicit on the patient history is listed in Table 1. Overall, this includes the patient’s own description of symptoms, past medical history, a complete list of medications, social history, occupational history, and a complete review of systems.3 For a possible hereditary neuropathy, a personal developmental history of any developmental delay, difficulty walking or playing sports, past foot and ankle surgery, Table 1. Important Points on the History of Neuropathy Patient’s description of neuropathy Motor, sensory, or both? Onset, duration of neuropathy Quality of pain Location/distribution/radiation of pain Constant vs intermittent nature Evolutionary course of symptoms Past medical history Diabetes, autoimmune or endocrine disease As a child: developmental delay, difficulty walking, nonathletic/ clumsy Past foot or ankle surgeries Medications Prescription Over the counter Herbal Occupational history Toxin exposures Social history Alcohol use/abuse Family history Neuropathy Foot deformities, difficulty walking
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and family history of neuropathy, foot deformities, or difficulty walking should all be elicited.1,4 Important points on the physical examination are listed in detail in Table 2. The physical examination should start with inspection of the affected extremities for skin changes. Ulcers are often located in areas of increased pressure, such as the heels, plantar aspects of the metatarsal heads, and areas in which foot deformities and immobile joints rub against footwear. Inspecting the pattern of foot deformities, muscle wasting, and footwear should also be done. Palpation includes assessment of neurovascular status. Range of motion involves inspecting for gait and balance, as well as eliciting active and passive range of motion and effusions in the affected and surrounding joints. Finally, a complete neurologic examination would ideally include a Table 2. Important Points on the Physical Examination of Neuropathy Inspection Skin changes Secondary to preexisting skin disease Xerosis Anhidrosis Rubor Edema Calluses, ulcers Evidence of infection (cellulitis, tinea pedis) Foot deformities Muscle wasting Footwear Wear pattern Foreign objects Palpation Vascular status Peripheral pulses Capillary refill Temperature Pallor/rubor on elevation and dependency Nerve thickening or tenderness Range of motion Examine affected and surrounding joints for Active range of motion Passive range of motion Effusions Gait Balance Neurologic Motor function and strength Sensation (may include light touch, pinprick, vibration, proprioception, monofilament) Reflexes Cranial nerves
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Peripheral Neuropathy for Dermatologists: What If It Is Not Diabetic Neuropathy?
complete examination of cranial nerves, motor function, sensation, and reflexes.1,3 However, the most important aspects of the neurologic examination to elicit in the clinic are differentiating between motor and sensory neuropathy and determining the extent of involvement.
with a focus on potential systemic causes of the neuropathy. Suggested initial investigations and the rationale for ordering them are listed in Table 6.1,3,4 The majority of neuropathies, often caused by diabetes or alcohol abuse, have reversible causes that may be managed by the patient’s family physician and do not require referral to Neurology.
Differential Diagnosis The differential diagnosis is extensive for peripheral neuropathy. Any given medical condition can cause multiple patterns of neuropathy, often making the clinical diagnosis challenging. By far, the majority of neuropathies encountered in a nonneurologist’s practice are chronic symmetrical polyneuropathies. The most common causes of these neuropathies are diabetes mellitus and alcohol abuse. A summary of the most common causes of chronic demyelinating and axonal neuropathy is provided in Table 3.1,3 Drug-induced neuropathy may be caused by a multitude of medications, listed in Table 4.1 Hereditary neuropathy is much less common, and common causes of these are provided in Table 5.1,5 Finally, acute neuropathy is rarely encountered in a dermatologist’s practice due to the quick progression of disease and lack of skin findings.
Investigations Laboratory Investigations Given the broad differential diagnosis for a peripheral neuropathy, initial investigations should include bloodwork
Referral to Neurology When no immediately identifiable and reversible cause is found on the initial bloodwork, referral to Neurology is often warranted for expert evaluation and access to more detailed testing, such as nerve conduction studies or nerve biopsy. In addition, referring patients with severe symptoms, rapidly progressing disease, and any motor neuropathy for neurology evaluation is always recommended.1,4 Skin Biopsy Skin biopsy is a safe and reliable technique that may be indicated when investigating a possible peripheral neuropathy, particularly a small-fiber sensory polyneuropathy. Skin biopsies may also be useful for assessing the efficacy of treatment and analyzing the progression of axonal regrowth.6 This procedure most commonly involves a 3 mm punch biopsy of the skin, typically from a proximal and a distal site such as the thigh and calf, in accordance with the symptoms and clinical picture. Specific immunohistochemical techniques, usually involving PGP (protein gene product) 9.5, allow
Table 3. Most Common Causes of Chronic Peripheral Neuropathy (Axonal or Demyelinating) Category Diabetes Alcohol Toxins Medications Thyroid Amyloidosis Connective tissue disease Immune mediated Infectious Other systemic disorders Vitamin deficiency Paraneoplastic Hereditary Spinal cord Idiopathic
Causes Type 1, type 2 diabetes mellitus Alcohol abuse/misuse Lead, mercury, arsenic, acrylamide, thallium, organophosphates, organic solvents See Table 4 Myxedema (hypothyroidism) Plasma cell dyscrasia, myeloma Systemic lupus erythematosus, Sjo¨gren syndrome, systemic sclerosis, vasculitis Sarcoidosis HIV, leprosy, Lyme disease Liver failure (cirrhosis), renal failure (uremia), growth hormone excess (acromegaly) Vitamin B12 (distal sensory deficits), pyroxidine overdose, thiamine (alcoholics, malnourished), malabsorption syndrome Lymphoma, paraproteinemia (associated with POEMS, CANOMAD syndromes) See Table 5 Trauma, tumor, infection Progressive, painful, sensory course predominates; approximately 25% of patients
CANOMAD 5 chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins, disialosyl antibodies; HIV 5 human immunodeficiency virus; POEMS 5 polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.
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Table 4. Most Common Causes of Drug-Induced Neuropathy Class
Medications
Chemotherapy Antibiotics Nucleoside analogue reverse transcriptase inhibitors Antiepileptics Antiarrhythmics Antirheumatics Antialcoholic agents Immunomodulatory Topical cytotoxic agents Vitamins Toxins (may occur in homeopathic medicaions) Other
Quinecin, bortezomib, platinum (carboplatin, cisplatin), suramin, taxol (docetaxel, paclitaxel), vincristine Ethambutol, isoniazid, metronidazole, misonidazole, nitrofurantoin, dapsone Didanosine, stavudine, zalcitabine Phenytoin Amiodarone Chloroquine, gold Disulfuram Thalidomide Podophyllin Pyridoxine (vitamin B6) Lead, mercury, arsenic, acrylamide, thallium, organophosphates, organic solvents Nitrous oxide
for verification and numeration of intraepidermal nerve fibers. Normal reference values are dependent on the location and site of biopsy. A reduction in nerve fiber density significantly raises the likelihood of a polyneuropathy. However, the absence of an abnormal finding does not exclude the diagnosis of a peripheral neuropathy.2 Nerve Conduction Studies Electrodiagnostic testing is useful for supporting the diagnosis of large-fiber neuropathy, assessing disease severity, and differentiating between demyelination and axonal degeneration.1 However, an unremarkable electromyograph is not sufficient to exclude a peripheral neuropathy, especially a small-fiber neuropathy.2 Nerve Biopsy Nerve biopsies are often employed for investigation of neuropathies of inflammatory, infectious, and infiltrative origin.3,7 There is no evidence for the use of nerve biopsies for distal sensory neuropathies as the results are usually disappointing and of little significance.8 When biopsy is performed, the sural and superficial peroneal nerves are the preferred sites.6 Table 5. Common Hereditary Neuropathies Charcot-Marie-Tooth disease Hereditary sensory and autonomic neuropathy (HSAN) Familial amyloid polyneuropathy Distal hereditary motor neuropathy Other multisystem disorders: mitochondrial disorders, leukodystrophy, Refsum disease
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Diagnostic Imaging Initial investigation of a peripheral neuropathy should include chest radiographs, which may aid in diagnosing a paraneoplastic neuropathy.1,3,4 Magnetic resonance imaging (MRI) may serve as an adjunct in evaluation of a suspected etiology of inflammatory origin. Spinal MRI may reveal thickened or enhanced spinal nerve roots or cervical or lumbar plexuses, supporting the diagnosis of entrapment neuropathy. Body MRI may also provide information about other organ involvement.9 Table 6. Initial Investigations for Suspected Neuropathy Test Glucose, hemoglobin A1C CBC ESR AST, ALT, ALP, total bilirubin, GGT Creatinine, BUN TSH SPEP ANA/anti–ds-DNA/ANCA Vitamin B12 Urinalysis Chest radiograph HIV serology (in at-risk patients)
Detects Diabetes mellitus Systemic disease, alcohol misuse Systemic disease Liver dysfunction, alcohol misuse Renal failure Myxedema Paraproteinemia Autoimmune connective tissue disease Vitamin deficiency Diabetes, renal failure Paraneoplastic malignancy, sarcoidosis HIV infection
ALP 5 alkaline phosphatase; ALT 5 alanine transferase; ANA 5 antinuclear antibody; ANCA 5 antineutrophil cytoplasmic antibody; anti–ds-DNA 5 anti–double-stranded deoxyribonucleic acid; AST 5 aspartate aminotransferase; BUN 5 blood urea nitrogen; CBC 5 complete blood count; ESR 5 erythrocyte sedimentation rate; GGT 5 cglutamyltransferase; HIV 5 human immunodeficiency virus; SPEP 5 serum protein electrophoresis; TSH 5 thyroid-stimulating hormone.
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Cerebrospinal Fluid Analysis Cerebrospinal fluid analysis may serve as an adjunct in the diagnosis of an inflammatory or infectious cause. Specific findings of the lumbar puncture may also be present in acquired and immune-mediated polyneuropathies.2,3 Autonomic Testing The most common clinical finding of autonomic dysfunction related to peripheral neuropathy is excessive sweating and circulatory instability of the feet. Patients may also present to the physician’s office with burning pain of the feet along with allodynia and erythromelalgia.8 Specialized autonomic tests such as heart rate variability and response to deep breathing can assess cardiovagal function.
Management Initial management involves identification and treatment of the underlying cause of peripheral neuropathy. For example, reduction or cessation of a neurotoxic drug or treatment of nutritional deficiencies or hypothyroidism can stabilize and even reverse mild neuropathies.2 Early peripheral axonal damage secondary to mild inflammation or compression often improves as Schwann cells can replicate and remyelinate damaged axons, regenerating at up to 1 mm per day. The clinical prognosis is better for distal compared to more proximal nerve damage due to problems with aberrant reinnervation.2,10 Peripheral neuropathy of the lower extremities requires several considerations. Pressure downloading using orthotics, properly fitted shoes, and walking aids will help minimize friction and decrease calluses and ulceration.2 If ulceration occurs, treatment principles of de´bridement, selection of appropriate dressings, and, if not contraindicated, compression are beneficial. Peripheral edema should be managed with leg elevation, compression stockings, and/or diuretics. Patients with decreased sensation and thermal perception should be informed about the importance of preventing complications due to secondary infections, in particular osteomyelitis.2 Neuropathic pain may be treated with medications, including psychotropics such as tricyclic antidepressants and serotonin reuptake inhibitors and antiepileptics such as gabapentin.1,3 The use of statins and fibrates is controversial as they have been found to be neuroprotective in some settings and to induce neuropathy in others.11 Regular exercise and transcutaneous nerve stimulation have also been shown to be helpful for
neuropathic pain. Finally, management of autonomic dysfunction with milidrone can also prevent presyncopal episodes and falls with postural changes.2
Conclusion Skin manifestations secondary to peripheral neuropathy may occur with virtually any chronic neuropathy and include xerosis, anhidrosis, rubor, edema, calluses, and ulcers. Although the differential diagnosis for peripheral neuropathy is broad, many of the most common causes, such as diabetes mellitus and alcohol misuse, are easily diagnosable with basic bloodwork and can be managed by primary care physicians, referring to a neurologist only if no easily reversible cause is found on the workup. Management of neuropathy-related skin disease involves principles of pressure downloading, control of peripheral edema and ulcers, and treatment of neuropathic pain.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Hughes R. Peripheral nerve diseases: the bare essentials. Pract Neurol 2008;8:396–405, doi:10.1136/jnnp.2008.162412. 2. Burns TM, Mauermann M, Srinivasan J, editors. Netter’s neurology. 2nd ed. Philadelphia: Elsevier Saunders; 2011. 3. Azhary H, Farooq MU, Bhanushali M, et al. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician 2010;81:887–92. 4. Hughes R. Investigation of peripheral neuropathy. BMJ 2010;341: 1161–2, doi:10.1136/bmj.c6100. 5. Houlden H, Blake J, Reilly MM, et al. Hereditary sensory neuropathies. Curr Opin Neurol 2004;17:569–77, doi:10.1097/ 00019052-200410000-00007. 6. Lauria G, Lombardi R, Camozzi F, et al. Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology 2009;54:273– 85, doi:10.1111/j.1365-2559.2008.03096.x. 7. Tavee J, Culver D. Sarcoidosis and small-fiber neuropathy. Curr Pain Headache Rep 2011;15:201–6, doi:10.1007/s11916-011-0180-8. 8. England JD, Gronseth GS, Franklin G, et al. Practice parameter: evaluation of distal symmetrical polyneuropathy. Neurology 2009; 72:177–84, doi:10.1212/01.wnl.0000336345.70511.0f. 9. Lunn MP, Willison HJ. Diagnosis and treatment in inflammatory neuropathies. J Neurol Neurosurg Psychiatry 2008;80:249–58. 10. Shields RW Jr, editor. Current clinical medicine. 2nd ed. Philadelphia: Elsevier Saunders; 2010. 11. Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep 2009;9:69–75, doi:10. 1007/s11910-009-0011-z.
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Peripheral Neuropathy for Dermatologists: What If Not Diabetic Neuropathy? Tiffany Kwok, Patricia T. Ting, Eric K. Wong, and Alain Brassard Background: Patients with cutaneous manifestations associated with peripheral neuropathy often present to the dermatologist’s office. Objective/Methods: This article outlines a practical approach for obtaining the history, performing a screening physical examination, and ordering initial diagnostic testing to diagnose the cause of nondiabetic neuropathy. When to refer for neurologic consultation and principles of management of neuropathic pain and neuropathy-related ulcers are also discussed. Results: Cutaneous manifestations of peripheral neuropathy may be secondary to a medical condition predisposing the patient to neuropathy or a manifestation of neuropathy itself. In the latter category, skin affected by neuropathy may show characteristics of xerosis, anhidrosis, rubor, edema, callus, ulceration, muscle wasting, and foot deformity. Most often these findings occur in association with diabetic neuropathy; however, many other infectious, inflammatory, metabolic, paraneoplastic, hereditary, and medication- or toxin-related causes should be considered. The treatment of cutaneous manifestations of neuropathy includes pressure downloading, control of edema, and optimal ulcer and neuropathic pain management. Conclusion: It is important for dermatologists to have a basic approach to neuropathy in patients with related skin disease. Referral to Neurology is warranted when basic workup for reversible causes is negative or for any severe, rapidly progressive symptoms. Contexte: Les manifestations cutane´es associe´es a` la neuropathie pe´riphe´rique donnent souvent lieu a` des consultations en dermatologie. Objectif/Me´thode: Le pre´sent article expose une de´marche pratique d’obtention de l’anamne`se, de re´alisation de l’examen physique de de´pistage, et de prescription d’examens diagnostiques de base permettant de cerner la cause de la neuropathie non diabe´tique. Il sera e´galement question de la pertinence des consultations en neurologie ainsi que des principes de prise en charge de la douleur neuropathique et des ulce`res lie´s a` la neuropathie. Re´sultats: Les manifestations cutane´es de la neuropathie pe´riphe´rique peuvent eˆtre secondaires a` un e´tat sous-jacent, favorable a` la neuropathie ou a` une manifestation de la neuropathie elle-meˆme. Entrent dans cette dernie`re cate´gorie des manifestations cutane´es telles que le xe´rosis, l’anhidrose, la rougeur, l’œde`me, les durillons, les ulce`res, l’amyotrophie, et les de´formations du pied. La plupart du temps, ces manifestations sont lie´es a` la neuropathie diabe´tique; cependant, bon nombre d’autres causes possibles: infectieuses, inflammatoires, me´taboliques, parane´oplasiques, he´re´ditaires, me´dicamenteuses, ou toxiques, devraient eˆtre envisage´es. Le traitement des manifestations cutane´es de la neuropathie comprend la diminution de la pression, la re´duction de l’œde`me, et la prise en charge optimale des ulce`res et de la douleur neuropathique. Conclusions: Il est important que les dermatologues aient une approche de base a` l’e´gard de la neuropathie chez les patients en pre´sentant des manifestations cutane´es. Les consultations en neurologie sont justifie´es dans les cas d’absence de cause re´versible d’apre`s le bilan de base ou d’e´volution rapide et grave des symptoˆmes.
Overview of Neuropathy
From the Division of Dermatology and Cutaneous Sciences and Faculty of Medicine, University of Alberta, Edmonton, AB. Presented at the Canadian Dermatology Association Meeting, Thursday June 28 to Sunday July 1, 2012, Ottawa, ON. Address reprint requests to: Alain Brassard, MD, 2-125 Clinical Sciences Building, Edmonton, AB T6G 2G3; e-mail: [email protected].
DOI 10.2310/7750.2013.WOUND3 # 2013 Canadian Dermatology Association
The four cardinal patterns of peripheral neuropathy are polyneuropathy, mononeuropathy, multiple mononeuropathy (formerly known as mononeuritis multiplex), and autonomic neuropathy.1,2 Each of these patterns may have motor, sensory, or autonomic deficits or a combination of these neurologic deficits. The time course to symptomatic plateau can be acute (, 4 weeks), subacute (4–8 weeks), or chronic (. 8 weeks).2 The pathophysiology of neuropathy may be axonal, demyelinating, or mixed. However, these distinctions cannot generally be made clinically and require referral to neurology
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for diagnosis by nerve conduction studies. Any given cause of neuropathy may present with multiple cardinal patterns of peripheral neuropathy, although a chronic, symmetrical axonal polyneuropathy is most common overall.1 Cutaneous manifestations of neuropathy may be secondary to a medical condition predisposing the patient to neuropathy or may be a manifestation of neuropathy itself. In the latter category, skin affected by neuropathy may show characteristics of xerosis, anhidrosis, rubor, edema, calluses, ulcers, and foot deformities.1,2 These skin changes may occur in almost any chronic neuropathy, often making the diagnosis of the specific neuropathy very challenging for the dermatologist.
Assessment History and Physical Examination Detailed pertinent information to elicit on the patient history is listed in Table 1. Overall, this includes the patient’s own description of symptoms, past medical history, a complete list of medications, social history, occupational history, and a complete review of systems.3 For a possible hereditary neuropathy, a personal developmental history of any developmental delay, difficulty walking or playing sports, past foot and ankle surgery, Table 1. Important Points on the History of Neuropathy Patient’s description of neuropathy Motor, sensory, or both? Onset, duration of neuropathy Quality of pain Location/distribution/radiation of pain Constant vs intermittent nature Evolutionary course of symptoms Past medical history Diabetes, autoimmune or endocrine disease As a child: developmental delay, difficulty walking, nonathletic/ clumsy Past foot or ankle surgeries Medications Prescription Over the counter Herbal Occupational history Toxin exposures Social history Alcohol use/abuse Family history Neuropathy Foot deformities, difficulty walking
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and family history of neuropathy, foot deformities, or difficulty walking should all be elicited.1,4 Important points on the physical examination are listed in detail in Table 2. The physical examination should start with inspection of the affected extremities for skin changes. Ulcers are often located in areas of increased pressure, such as the heels, plantar aspects of the metatarsal heads, and areas in which foot deformities and immobile joints rub against footwear. Inspecting the pattern of foot deformities, muscle wasting, and footwear should also be done. Palpation includes assessment of neurovascular status. Range of motion involves inspecting for gait and balance, as well as eliciting active and passive range of motion and effusions in the affected and surrounding joints. Finally, a complete neurologic examination would ideally include a Table 2. Important Points on the Physical Examination of Neuropathy Inspection Skin changes Secondary to preexisting skin disease Xerosis Anhidrosis Rubor Edema Calluses, ulcers Evidence of infection (cellulitis, tinea pedis) Foot deformities Muscle wasting Footwear Wear pattern Foreign objects Palpation Vascular status Peripheral pulses Capillary refill Temperature Pallor/rubor on elevation and dependency Nerve thickening or tenderness Range of motion Examine affected and surrounding joints for Active range of motion Passive range of motion Effusions Gait Balance Neurologic Motor function and strength Sensation (may include light touch, pinprick, vibration, proprioception, monofilament) Reflexes Cranial nerves
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Peripheral Neuropathy for Dermatologists: What If It Is Not Diabetic Neuropathy?
complete examination of cranial nerves, motor function, sensation, and reflexes.1,3 However, the most important aspects of the neurologic examination to elicit in the clinic are differentiating between motor and sensory neuropathy and determining the extent of involvement.
with a focus on potential systemic causes of the neuropathy. Suggested initial investigations and the rationale for ordering them are listed in Table 6.1,3,4 The majority of neuropathies, often caused by diabetes or alcohol abuse, have reversible causes that may be managed by the patient’s family physician and do not require referral to Neurology.
Differential Diagnosis The differential diagnosis is extensive for peripheral neuropathy. Any given medical condition can cause multiple patterns of neuropathy, often making the clinical diagnosis challenging. By far, the majority of neuropathies encountered in a nonneurologist’s practice are chronic symmetrical polyneuropathies. The most common causes of these neuropathies are diabetes mellitus and alcohol abuse. A summary of the most common causes of chronic demyelinating and axonal neuropathy is provided in Table 3.1,3 Drug-induced neuropathy may be caused by a multitude of medications, listed in Table 4.1 Hereditary neuropathy is much less common, and common causes of these are provided in Table 5.1,5 Finally, acute neuropathy is rarely encountered in a dermatologist’s practice due to the quick progression of disease and lack of skin findings.
Investigations Laboratory Investigations Given the broad differential diagnosis for a peripheral neuropathy, initial investigations should include bloodwork
Referral to Neurology When no immediately identifiable and reversible cause is found on the initial bloodwork, referral to Neurology is often warranted for expert evaluation and access to more detailed testing, such as nerve conduction studies or nerve biopsy. In addition, referring patients with severe symptoms, rapidly progressing disease, and any motor neuropathy for neurology evaluation is always recommended.1,4 Skin Biopsy Skin biopsy is a safe and reliable technique that may be indicated when investigating a possible peripheral neuropathy, particularly a small-fiber sensory polyneuropathy. Skin biopsies may also be useful for assessing the efficacy of treatment and analyzing the progression of axonal regrowth.6 This procedure most commonly involves a 3 mm punch biopsy of the skin, typically from a proximal and a distal site such as the thigh and calf, in accordance with the symptoms and clinical picture. Specific immunohistochemical techniques, usually involving PGP (protein gene product) 9.5, allow
Table 3. Most Common Causes of Chronic Peripheral Neuropathy (Axonal or Demyelinating) Category Diabetes Alcohol Toxins Medications Thyroid Amyloidosis Connective tissue disease Immune mediated Infectious Other systemic disorders Vitamin deficiency Paraneoplastic Hereditary Spinal cord Idiopathic
Causes Type 1, type 2 diabetes mellitus Alcohol abuse/misuse Lead, mercury, arsenic, acrylamide, thallium, organophosphates, organic solvents See Table 4 Myxedema (hypothyroidism) Plasma cell dyscrasia, myeloma Systemic lupus erythematosus, Sjo¨gren syndrome, systemic sclerosis, vasculitis Sarcoidosis HIV, leprosy, Lyme disease Liver failure (cirrhosis), renal failure (uremia), growth hormone excess (acromegaly) Vitamin B12 (distal sensory deficits), pyroxidine overdose, thiamine (alcoholics, malnourished), malabsorption syndrome Lymphoma, paraproteinemia (associated with POEMS, CANOMAD syndromes) See Table 5 Trauma, tumor, infection Progressive, painful, sensory course predominates; approximately 25% of patients
CANOMAD 5 chronic ataxic neuropathy, ophthalmoplegia, monoclonal IgM protein, cold agglutinins, disialosyl antibodies; HIV 5 human immunodeficiency virus; POEMS 5 polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes.
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Table 4. Most Common Causes of Drug-Induced Neuropathy Class
Medications
Chemotherapy Antibiotics Nucleoside analogue reverse transcriptase inhibitors Antiepileptics Antiarrhythmics Antirheumatics Antialcoholic agents Immunomodulatory Topical cytotoxic agents Vitamins Toxins (may occur in homeopathic medicaions) Other
Quinecin, bortezomib, platinum (carboplatin, cisplatin), suramin, taxol (docetaxel, paclitaxel), vincristine Ethambutol, isoniazid, metronidazole, misonidazole, nitrofurantoin, dapsone Didanosine, stavudine, zalcitabine Phenytoin Amiodarone Chloroquine, gold Disulfuram Thalidomide Podophyllin Pyridoxine (vitamin B6) Lead, mercury, arsenic, acrylamide, thallium, organophosphates, organic solvents Nitrous oxide
for verification and numeration of intraepidermal nerve fibers. Normal reference values are dependent on the location and site of biopsy. A reduction in nerve fiber density significantly raises the likelihood of a polyneuropathy. However, the absence of an abnormal finding does not exclude the diagnosis of a peripheral neuropathy.2 Nerve Conduction Studies Electrodiagnostic testing is useful for supporting the diagnosis of large-fiber neuropathy, assessing disease severity, and differentiating between demyelination and axonal degeneration.1 However, an unremarkable electromyograph is not sufficient to exclude a peripheral neuropathy, especially a small-fiber neuropathy.2 Nerve Biopsy Nerve biopsies are often employed for investigation of neuropathies of inflammatory, infectious, and infiltrative origin.3,7 There is no evidence for the use of nerve biopsies for distal sensory neuropathies as the results are usually disappointing and of little significance.8 When biopsy is performed, the sural and superficial peroneal nerves are the preferred sites.6 Table 5. Common Hereditary Neuropathies Charcot-Marie-Tooth disease Hereditary sensory and autonomic neuropathy (HSAN) Familial amyloid polyneuropathy Distal hereditary motor neuropathy Other multisystem disorders: mitochondrial disorders, leukodystrophy, Refsum disease
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Diagnostic Imaging Initial investigation of a peripheral neuropathy should include chest radiographs, which may aid in diagnosing a paraneoplastic neuropathy.1,3,4 Magnetic resonance imaging (MRI) may serve as an adjunct in evaluation of a suspected etiology of inflammatory origin. Spinal MRI may reveal thickened or enhanced spinal nerve roots or cervical or lumbar plexuses, supporting the diagnosis of entrapment neuropathy. Body MRI may also provide information about other organ involvement.9 Table 6. Initial Investigations for Suspected Neuropathy Test Glucose, hemoglobin A1C CBC ESR AST, ALT, ALP, total bilirubin, GGT Creatinine, BUN TSH SPEP ANA/anti–ds-DNA/ANCA Vitamin B12 Urinalysis Chest radiograph HIV serology (in at-risk patients)
Detects Diabetes mellitus Systemic disease, alcohol misuse Systemic disease Liver dysfunction, alcohol misuse Renal failure Myxedema Paraproteinemia Autoimmune connective tissue disease Vitamin deficiency Diabetes, renal failure Paraneoplastic malignancy, sarcoidosis HIV infection
ALP 5 alkaline phosphatase; ALT 5 alanine transferase; ANA 5 antinuclear antibody; ANCA 5 antineutrophil cytoplasmic antibody; anti–ds-DNA 5 anti–double-stranded deoxyribonucleic acid; AST 5 aspartate aminotransferase; BUN 5 blood urea nitrogen; CBC 5 complete blood count; ESR 5 erythrocyte sedimentation rate; GGT 5 cglutamyltransferase; HIV 5 human immunodeficiency virus; SPEP 5 serum protein electrophoresis; TSH 5 thyroid-stimulating hormone.
Canadian Dermatology Association | Journal of Cutaneous Medicine and Surgery, Vol 17, No S1 (July), 2013: pp S1–S5
Peripheral Neuropathy for Dermatologists: What If It Is Not Diabetic Neuropathy?
Cerebrospinal Fluid Analysis Cerebrospinal fluid analysis may serve as an adjunct in the diagnosis of an inflammatory or infectious cause. Specific findings of the lumbar puncture may also be present in acquired and immune-mediated polyneuropathies.2,3 Autonomic Testing The most common clinical finding of autonomic dysfunction related to peripheral neuropathy is excessive sweating and circulatory instability of the feet. Patients may also present to the physician’s office with burning pain of the feet along with allodynia and erythromelalgia.8 Specialized autonomic tests such as heart rate variability and response to deep breathing can assess cardiovagal function.
Management Initial management involves identification and treatment of the underlying cause of peripheral neuropathy. For example, reduction or cessation of a neurotoxic drug or treatment of nutritional deficiencies or hypothyroidism can stabilize and even reverse mild neuropathies.2 Early peripheral axonal damage secondary to mild inflammation or compression often improves as Schwann cells can replicate and remyelinate damaged axons, regenerating at up to 1 mm per day. The clinical prognosis is better for distal compared to more proximal nerve damage due to problems with aberrant reinnervation.2,10 Peripheral neuropathy of the lower extremities requires several considerations. Pressure downloading using orthotics, properly fitted shoes, and walking aids will help minimize friction and decrease calluses and ulceration.2 If ulceration occurs, treatment principles of de´bridement, selection of appropriate dressings, and, if not contraindicated, compression are beneficial. Peripheral edema should be managed with leg elevation, compression stockings, and/or diuretics. Patients with decreased sensation and thermal perception should be informed about the importance of preventing complications due to secondary infections, in particular osteomyelitis.2 Neuropathic pain may be treated with medications, including psychotropics such as tricyclic antidepressants and serotonin reuptake inhibitors and antiepileptics such as gabapentin.1,3 The use of statins and fibrates is controversial as they have been found to be neuroprotective in some settings and to induce neuropathy in others.11 Regular exercise and transcutaneous nerve stimulation have also been shown to be helpful for
neuropathic pain. Finally, management of autonomic dysfunction with milidrone can also prevent presyncopal episodes and falls with postural changes.2
Conclusion Skin manifestations secondary to peripheral neuropathy may occur with virtually any chronic neuropathy and include xerosis, anhidrosis, rubor, edema, calluses, and ulcers. Although the differential diagnosis for peripheral neuropathy is broad, many of the most common causes, such as diabetes mellitus and alcohol misuse, are easily diagnosable with basic bloodwork and can be managed by primary care physicians, referring to a neurologist only if no easily reversible cause is found on the workup. Management of neuropathy-related skin disease involves principles of pressure downloading, control of peripheral edema and ulcers, and treatment of neuropathic pain.
Acknowledgment Financial disclosure of authors and reviewers: None reported.
References 1. Hughes R. Peripheral nerve diseases: the bare essentials. Pract Neurol 2008;8:396–405, doi:10.1136/jnnp.2008.162412. 2. Burns TM, Mauermann M, Srinivasan J, editors. Netter’s neurology. 2nd ed. Philadelphia: Elsevier Saunders; 2011. 3. Azhary H, Farooq MU, Bhanushali M, et al. Peripheral neuropathy: differential diagnosis and management. Am Fam Physician 2010;81:887–92. 4. Hughes R. Investigation of peripheral neuropathy. BMJ 2010;341: 1161–2, doi:10.1136/bmj.c6100. 5. Houlden H, Blake J, Reilly MM, et al. Hereditary sensory neuropathies. Curr Opin Neurol 2004;17:569–77, doi:10.1097/ 00019052-200410000-00007. 6. Lauria G, Lombardi R, Camozzi F, et al. Skin biopsy for the diagnosis of peripheral neuropathy. Histopathology 2009;54:273– 85, doi:10.1111/j.1365-2559.2008.03096.x. 7. Tavee J, Culver D. Sarcoidosis and small-fiber neuropathy. Curr Pain Headache Rep 2011;15:201–6, doi:10.1007/s11916-011-0180-8. 8. England JD, Gronseth GS, Franklin G, et al. Practice parameter: evaluation of distal symmetrical polyneuropathy. Neurology 2009; 72:177–84, doi:10.1212/01.wnl.0000336345.70511.0f. 9. Lunn MP, Willison HJ. Diagnosis and treatment in inflammatory neuropathies. J Neurol Neurosurg Psychiatry 2008;80:249–58. 10. Shields RW Jr, editor. Current clinical medicine. 2nd ed. Philadelphia: Elsevier Saunders; 2010. 11. Weimer LH, Sachdev N. Update on medication-induced peripheral neuropathy. Curr Neurol Neurosci Rep 2009;9:69–75, doi:10. 1007/s11910-009-0011-z.
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