Laura Mayans, MD; David Mayans, MD Department of Family and Causes of : Community Medicine (Dr. L. Mayans), Department of Internal Medicine (Dr. Diabetes and beyond D. Mayans), University of Kansas School of Medicine– Wichita; Leg paresthesias can be challenging to evaluate because Consultants of Kansas, Wichita (Dr. D. Mayans) of the varied causes and clinical presentations. This

[email protected] diagnostic guide with at-a-glance tables can help.

The authors reported no potential conflict of interest relevant to this article.

CASE 1 u Sally G, age 46, has been experiencing paresthesias PRACTICE RECOMMENDATIONS for the past 3 months. She says that when she is cycling, the air on her legs feels much cooler than normal, with a similar feel- ❯ When evaluating a patient ing in her hands. Whenever her hands or legs are in cool water, with lower extremity numb- ness and tingling, order she says it feels as if she’s dipped them into an ice bucket. Sum- fasting blood glucose, vitamin mer heat makes her skin feel as if it's on fire, and she’s noticed B12 level with methylmalonic increased sweating on her lower legs. She complains of itching acid, and either serum protein (although she has no rash) and she’s had intermittent tingling electrophoresis (SPEP) or im- and burning in her toes. On neurologic exam, she demonstrates munofixation electrophoresis normal strength, sensation, reflexes, coordination, and cranial (IFE) because these test have nerve function. a high diagnostic yield. C ❯ Obtain SPEP or IFE when CASE 2 u Jessica T, age 25, comes in to see her family physician evaluating all patients because she’s been experiencing numbness in her right leg. It over age 60 with lower had begun with numbness of the right great toe about a year extremity paresthesias. C ago. Subsequently, the numbness extended up her foot to the ❯ Consider prescribing lateral aspect of the lower leg with an accompanying burning pregabalin for treating sensation. Three months prior to this visit, she developed weak- painful paresthesias because ness in her right foot and toes. She denies any symptoms in her strong evidence supports its left leg, upper extremities, or face. use; the evidence for A neurologic exam of the upper extremities is normal. gabapentin, sodium Ms. T also has normal cranial nerve function, and normal valproate, amitriptyline, strength, sensation, and reflexes in the left leg. A motor exam venlafaxine, and of the right leg reveals normal strength in the hip flexors, duloxetine is moderate. A hip adductors, hip abductors, and quadriceps. On the Medical Strength of recommendation (SOR) Research Council scale, she has 4/5 strength in the hamstrings, A Good-quality patient-oriented 0/5 in the ankle dorsiflexors, 1/5 in the posterior tibialis, and evidence 3/5 in the gastrocnemius. She has a normal right patellar re- B Inconsistent or limited-quality patient-oriented evidence flex, and an ankle jerk reflex and Babinski sign are absent. She  C Consensus, usual practice, has reduced sensation on the posterior and lateral portions opinion, disease-oriented evidence, case series of the right leg and the entire foot. Sensation is preserved on the medial side of the right lower leg and anterior thigh. She has right-sided steppage gait. If these 2 women were your patients, how would you pro- ceed with their care?

774 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2015 | VOL 64, NO 12 Look for positive neuropathic symptoms such as cramping and tingling, negative symptoms such as numbness and weakness, and autonomic symptoms such as constipation, diarrhea, and sweating.

aresthesias such as numbness and neuropathy, multiple mononeuropathy, or tingling in the lower extremities are : Pcommon complaints in family medi- • Mononeuropathy is focal involve- cine. These symptoms can be challenging ment of a single nerve resulting from to evaluate because they have multiple po- a localized process such as compres- tential etiologies with varied clinical pre- sion or entrapment, as in carpal tunnel sentations.1 syndrome.1 A well-honed understanding of lower • Multiple mononeuropathy (mono- extremity anatomy and the location and multiplex) results from dam- characteristics of common complaints is age to multiple noncontiguous nerves essential to making an accurate diagnosis that can occur simultaneously or se- and treatment plan. This article discusses quentially, as in vasculitic causes of the tests to use when evaluating a patient neuropathy.1 who presents with lower extremity numb- • Polyneuropathy involves 2 or more ness and . It also describes the typical contiguous nerves, usually symmet- presentation and findings of several types ric and length-dependent, creating of peripheral neuropathy, and how to man- a “stocking-glove” pattern of pares- age them. thesias.1 Polyneuropathy affects lon- ger nerves first, and thus, patients will initially complain of symptoms Paresthesias are often the result in their feet and legs, and later their of peripheral neuropathy hands. Polyneuropathy is most com- IMAGE © JOE GORMAN While paresthesias can arise from disorders monly seen in diabetes. of the central or peripheral nervous system, Possible causes of peripheral neu- this article focuses on paresthesias that are ropathy include numerous anatomic, sys- the result of peripheral neuropathy. Periph- temic, metabolic, and toxic conditions eral neuropathy can be classified as mono- (TABLE 1).1,2 CONTINUED

JFPONLINE.COM VOL 64, NO 12 | DECEMBER 2015 | THE JOURNAL OF FAMILY PRACTICE 775 TABLE 1 early satiety, constipation or diarrhea, im- Consider these causes potence, sweating abnormalities, and ortho- 3 1,2 stasis. The timing of onset, progression, and of peripheral neuropathy duration of such symptoms can give impor- Anatomic tant diagnostic clues. For example, an acute • /sciatic compression onset of painful foot drop may indicate an in- flammatory cause such as vasculitis, whereas • Fibular nerve compression/entrapment slowly progressive numbness in both feet • Nerve dissection from surgery or accidental points toward a distal sensorimotor poly- injury neuropathy, likely from a metabolic cause. Systemic Symmetry or asymmetry at presentation, as • HIV infection well as speed of progression of symptoms, can also significantly narrow the differential • Carcinoma/paraneoplastic syndrome (TABLE 2). • Monoclonal gammopathy Determining the exact location of symp- • Amyloidosis toms is important and usually requires • Sarcoidosis prompting. For example, when a patient re- fers to “the legs,” he could mean anywhere • Sjögren’s syndrome from the foot to the hip. The presence of ra- An acute onset • Tick bite diating pain can also help localize the lesion, of painful Metabolic generally pointing to a (dis- foot drop may • Diabetes mellitus ease at the root of a nerve). Bowel or bladder involvement could suggest involvement of indicate an • Thyroid disease inflammatory the spinal cord or autonomic nervous system. cause of • Renal disease A thorough social history can help identi- neuropathic • Chronic liver disease fy potentially treatable causes of neuropathy. symptoms, such Toxic The probability of a toxic, infectious, or vita- min deficiency etiology can be ascertained by as vasculitis. • Vitamin deficiency (B1, B6, B12) inquiring about a patient’s occupation, sexu- • Vitamin B6 excess al history, dietary habits, and drug, alcohol, • Heavy metal poisoning (arsenic, lead, and tobacco history.3 Personal and family mercury) medical history can suggest possible genetic • Drug-induced (amiodarone, digoxin, or endocrine causes of neuropathy. A per- isoniazid, lithium, metronidazole, statins) sonal or family history of childhood “clumsi- • Organophosphate exposure ness” (suggestive of a hereditary neuropathy, such as Charcot-Marie-Tooth disease), dia- • Alcohol use betes mellitus, or thyroid, renal, hepatic, or HIV, human immunodeficiency virus. autoimmune diseases would be significant. A personal or family history of cancer is also an important diagnostic clue.3 What’s causing the neuropathy? The search for telltale clues While obtaining the history, ask the patient These tests help narrow about the presence of positive, negative, or the diagnostic possibilities autonomic neuropathic symptoms. Positive Motor and sensory testing are essential, as is symptoms, which usually present first, are testing of coordination and reflexes. Motor due to excess or inappropriate nerve activity examination involves manual muscle test- and include cramping, twitching, burning, ing. In many patients, pain can limit effort, and tingling.3 Negative symptoms are due to so encourage patients to try hard during test- reduced nerve activity and include numb- ing so you can determine the true severity of ness, weakness, decreased balance, and poor weakness. Sensory testing should include pin- sensation. Autonomic symptoms include prick, temperature differentiation, vibration,

776 THE JOURNAL OF FAMILY PRACTICE | DECEMBER 2015 | VOL 64, NO 12 PERIPHERAL NEUROPATHY

TABLE 2 Getting to the root of peripheral neuropathy: Onset of symptoms and symmetry provide clues

Acute Subacute Chronic

Symmetric Guillain-Barré syndrome Monoclonal gammopathy Diabetes mellitus Organophosphate exposure Paraneoplastic syndromes Thyroid disease Paraneoplastic syndromes Liver or kidney disease Autoimmune disorders Inherited disorders Tick bite Vitamin B12 deficiency Autoimmune disorders Drug-induced CIDP (rare) Inherited disorders Asymmetric Tick bite Amyloidosis CIDP Nerve compression Paraneoplastic syndromes Inherited disorders Guillain-Barré syndrome (rare) Sarcoidosis Vasculitis HIV infection Vitamin deficiency/excess Heavy metal poisoning Drug-induced nerve compression

CIDP, chronic inflammatory demyelinating polyneuropathy; HIV, human immunodeficiency virus.

and proprioception. Also examine the cranial “How best to use EDX and lab testing to evalu- nerves and upper extremities because abnor- ate peripheral neuropathy”1-3 on page 778.) mal findings could suggest a central nervous system (CNS) lesion or proximal progression of disease, with the patient unaware of subtle So what type of neuropathy symptom worsening or spreading. The pattern are you dealing with? of deficits as well as predominance of motor vs The details of your patient’s history and find- sensory nerve involvement can further narrow ings from the exam and testing will point the differential. For example, unilateral symp- you toward any one of a number of different toms typically suggest either a structural lesion types of neuropathies. The list below covers a or inflammatory lesion as the cause, while range—from the common (distal sensorimo- unilateral weakness without numbness could tor polyneuropathy) to the more rare (para- be significant for the onset of amyotrophic neoplastic neuropathies). lateral sclerosis.1 A careful skin, hair, and mu- cous membrane exam is useful because many Distal sensorimotor polyneuropathy (DSP) infectious, toxic, autoimmune, and genetic DSP is the most common type of neuropathy.4 causes of peripheral neuropathy also cause The typical presentation of DSP is chronic, dis- changes in these areas. High arches, hammer tal, symmetric, and predominantly sensory.5 toes, and inverted champagne bottle legs sug- Any variation on this suggests an atypical neu- gest a hereditary neuropathy.3 ropathy.5 Patients with DSP present with loss In addition to the history and examina- of function (loss of sensation to pinprick, tem- tion, electrodiagnostic testing (EDX) is often perature, vibration, proprioception) and/or helpful, and judicious laboratory testing can tingling, burning, and pain starting symmetri- further narrow diagnostic possibilities. (See cally in the lower extremities. Over the course

JFPONLINE.COM VOL 64, NO 12 | DECEMBER 2015 | THE JOURNAL OF FAMILY PRACTICE 777 common causes are vitamin deficiencies How best to use EDX (vitamin B1, B6, B12), folate deficiency, para- and lab testing to evaluate proteinemia, and hypo/hyperthyroidism. Also consider alcohol abuse, human immu- peripheral neuropathy nodeficiency virus (HIV) infection, gastric After taking a detailed history and performing a physical exam bypass, chemotherapy, chronic kidney dis- on a patient with lower extremity numbness and tingling, electro- ease, and autoimmune conditions such as diagnostic testing (EDX) and laboratory testing can help further Sjögren’s syndrome, lupus, and rheumatoid elucidate the diagnosis. arthritis.1 EDX can be considered an extension of the physical exam. It can ❚ Testing. EDX can help confirm a di- assess and characterize the proportion of motor vs sensory involve- agnosis of DSP. A 2009 American Academy ment, the severity of symptoms, and distribution of deficits and of Neurology review of lab testing for DSP 3 dysfunction. EDX studies consist of both (EMG) found the tests with the highest diagnostic and nerve conduction studies (NCS). These tests are complementary yield were fasting blood glucose, vitamin B12 and should be performed together. They have essentially no con- level with methylmalonic acid, and serum traindications, although they are usually not performed on patients protein electrophoresis and immunofixation who have open sores or cellulitis. EMG is avoided in certain muscles 4 in anticoagulated patients, primarily the paraspinal muscles and electrophoresis (IFE). If the initial screen tibialis anterior, to avoid either an epidural hematoma or compart- with a fasting blood sugar or hemoglobin A1c ment syndrome. (HbA1c) is negative, further testing with a glucose tolerance test is recommended. A systematic evaluation of sequential muscles and nerves can ❚ identify polyneuropathy, entrapment neuropathy, , or Treatment of DSP depends on the radiculopathy. Even a normal study can be informative. For example, underlying etiology. Vitamin deficiencies EDX can provide information only on large fiber nerves; small nerve should be corrected and metabolic or auto- fibers cannot be tested. Therefore, a normal EDX in certain clinical immune etiologies addressed as appropriate. scenarios suggests a small fiber neuropathy, which can be confirmed There are multiple pharmacologic options by skin biopsy. for treating persistent pain or discomfort. 6 Laboratory testing is a useful adjunct because the possible Best evidence (Level A) exists for pregabalin. causes of peripheral neuropathy are vast. According to expert Moderate evidence of effectiveness (Level B) opinion, lab work that should be ordered routinely when evaluating exists for gabapentin, sodium valproate, ami- lower extremity peripheral neuropathy includes a complete blood triptyline, venlafaxine, and duloxetine.6 cell count, erythrocyte sedimentation rate, fasting blood glucose (and possibly hemoglobin A1c), thyroid studies, renal function stud- Small fiber neuropathy 1-3 ies, and vitamin B12 level. If a patient’s B12 level is <400 pg/mL, Small fiber neuropathy can present similarly also test methylmalonic acid and homocysteine levels due to their to DSP, with distal painful paresthesias, but greater diagnostic yield.3 can spread to the upper extremities within a Serum protein electrophoresis or serum immunofixation electropho- few weeks or months from onset, while DSP resis are also recommended in patients over age 60, because mono- spreads to the hands years after onset. Small clonal gammopathy is a common cause of peripheral neuropathy in fiber neuropathy is also associated with early 1,3 this age group. If the history and physical warrant, laboratory tests autonomic dysfunction. Examination usually for paraneoplastic, autoimmune, infectious, or toxic etiologies can reveals decreased sensation distally, but re- be performed. flexes and strength are normal. Common causes of small fiber neu- of years, paresthesias move up the legs to the ropathy are diabetes, glucose intolerance, knees before symptoms begin in the arms. metabolic syndrome, hypo/hyperthyroidism, While the disorder can be quite pain- monoclonal gammopathy, alcohol abuse, vi- ful, it is not usually functionally limiting un- tamin B12 deficiency, and hypertriglyceride- less the loss of sensation is severe enough to mia.7 Less common causes include Sjögren’s cause falls from sensory ataxia. Weakness is syndrome, HIV, Lyme disease, sarcoidosis, rare. When it occurs, it is usually a mild weak- heavy metal toxicity, amyloidosis, and celiac ness of the distal leg with foot atrophy. disease.7 The most common cause of DSP is dia- ❚ Testing and treatment. Skin biopsy betes or impaired glucose tolerance. Other is used to confirm the diagnosis of small fi-

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PERIPHERAL NEUROPATHY ZECUITY® (sumatriptan iontophoretic transdermal system) Table 1: Adverse Reactions Reported by at least 2% of Patients in Study 1 Percent of Subjects Reporting ZECUITY Control ber neuropathy.7 (EDX results are normal.7) = = Adverse Reaction (n 234) (n 235) Persistent pain can be treated with the same Application site pain 26% 17% Application site paresthesia 9% 16% agents discussed above for treating DSP. Application site pruritus 8% 7% Application site warmth 6% 3% Application site discomfort 6% 6% Acquired demyelinating neuropathy Application site irritation 4% 2% Acquired demyelinating neuropathy is a rare Application site discoloration 3% 1% condition, but one in which prompt recogni- The incidence of “atypical sensations” adverse events (paresthesia, sensation warm/cold) and “pain and other pressure sensations” (chest pain/tightness/pressure/ tion and treatment can prevent significant heaviness or neck/throat/jaw pain, tightness, pressure or heaviness) was 2% each in neurologic decline. There are both acute ZECUITY-treated patients, vs. 0% in the control group. Application site bruising was reported in 2 ZECUITY-treated patients (0.9%) vs. no patient in the control group. and chronic types of acquired demyelinating Subgroup analyses of age (≤41 years, >41 years), race (Caucasian, non-Caucasian) neuropathies. and body mass index (BMI) (≤25.7 mg/kg2, >25.7 mg/kg2) showed no difference between subgroups for adverse events. ❚ Guillain-Barré syndrome (GBS) is an Skin Irritation Examination acute inflammatory demyelinating polyra- In Study 1, patients performed their own examination of the TDS application site at 4, 12, and 24 hours post TDS activation, and daily thereafter until resolution. The diculoneuropathy. Nearly two-thirds of pa- median time to “no redness” was 2.6 days for ZECUITY compared with 0.3 day in the control group. tients with GBS report a previous respiratory Application site reactions across clinical studies (Controlled single dose acute or gastrointestinal illness; cytomegalovirus migraine study and long term safety studies) In the controlled and uncontrolled clinical studies combined (n = 796 unique and Campylobacter jejuni are the most fre- ZECUITY-treated subjects), the frequency of application site reactions of clinical quently associated infections.8 interest was: discoloration (5%), contact dermatitis (4%), irritation (4%), vesicles (3%), bruising (2%), and erosion (0.4%). The onset of GBS often involves pain in DRUG INTERACTIONS the back or limbs, followed by a rapid pro- Ergot-Containing Drugs gression of sensory loss and weakness (over Ergot-containing drugs have been reported to cause prolonged vasospastic reactions. Because these effects may be additive, use of ergotamine-containing or days to a few weeks) that typically starts in ergot-type medications (like dihydroergotamine or methysergide) and ZECUITY the feet and moves upward.8 Though the within 24 hours of each other is contraindicated [see Contraindications]. B:11.375” T:10.5” Monoamine Oxidase-A Inhibitors typical presentation of GBS is “ascending,” S:9.75” MAO-A inhibitors increase systemic exposure by 2-fold. Therefore, the use of there are frequent exceptions to this pattern.8 ZECUITY in patients receiving MAO-A inhibitors is contraindicated [see Contrain- dications]. Physical exam shows weakness, sensory loss, Other 5-HT1 Agonists and absent reflexes. Severe cases can result Because their vasospastic effects may be additive, coadministration of ZECUITY and other 5-HT1 agonists (e.g., triptans) within 24 hours of each other is contraindicated. in complete paralysis, even of extraocu- Selective Serotonin Reuptake Inhibitors/Serotonin Norepinephrine Reuptake lar movements. Autonomic dysfunction is Inhibitors and Serotonin Syndrome Cases of serotonin syndrome have been reported during coadministration of trip- common. tans and SSRIs or SNRIs, SNRIs, TCAs, and MAO inhibitors [see Warnings and ❚ Testing. EDX and lumbar puncture are Precautions]. needed to accurately diagnose GBS.8 EDX USE IN SPECIFIC POPULATIONS Pregnancy initially may be unremarkable, but over time, Pregnancy Category C: There are no adequate and well-controlled studies in preg- areas of demyelination become apparent. nant women. ZECUITY should be used during pregnancy only if the potential benefit justifies the potential risk to the fetus. Lumbar puncture shows albuminocytologic Nursing Mothers dissociation (no white cells, elevated protein). It is not known whether sumatriptan is excreted in human milk following transder- mal administration. Because many drugs are excreted in human milk, and because ❚ Treatment. Patients with GBS are ini- of the potential for serious adverse reactions in nursing infants from ZECUITY, a decision should be made whether to discontinue nursing or to discontinue the drug, tially managed as inpatients because 33% of taking into account the importance of the drug to the mother. cases lead to respiratory failure.9 Treatments Pediatric Use Safety and effectiveness in pediatric patients have not been established. include intravenous immunoglobulin (IVIg) Since clinical data to determine the frequency of serious adverse reactions in pedi- or plasmapheresis; both have similar out- atric patients who might receive subcutaneous, oral, or intranasal sumatriptan are not presently available, the use of ZECUITY in patients under 18 years of age is not comes, speeding neurologic recovery time recommended. but not affecting overall long-term prog- Geriatric Use 10 Clinical trials of ZECUITY did not include sufficient numbers of subjects aged 65 nosis. Response to treatment is often not and over to determine whether they respond differently from younger subjects. In immediate, and some patients continue to general, dose selection for an elderly patient should be cautious, usually starting 8 at the low end of the dosing range, reflecting the greater frequency of decreased worsen after treatment. Still, long-term prog- hepatic, renal, or cardiac function and of concomitant disease or other drug therapy. nosis is good, even for severely affected pa- A cardiovascular evaluation is recommended for geriatric patients who have other cardiovascular risk factors prior to using ZECUITY [see Warnings and Precautions]. tients, as long as they receive good supportive 8 NuPathe, Inc., is a wholly-owned subsidiary of Teva Pharmaceuticals USA, Inc. care. The relapse rate is between 2% and 6%. ©2014 Teva Pharmaceuticals USA, Inc. ❚ In chronic inflammatory demyelinat- All rights reserved. ing polyneuropathy (CIDP), patients de- Brief Summary of ZECUITY Prescribing Information ZEC-001 velop stepwise nerve dysfunction over many ZEC-40059 September 2014

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4C Zecuity HCP Launch Journal Ad weeks to months. One nerve is affected, then if needed. Conservative treatments aimed at another, usually in a different limb. There is modifying or correcting the underlying eti- generally no antecedent illness, and pain is ology, such as removing a tight-fitting cast infrequent.8 Progressive limb weakness is or brace or instructing a patient to stop leg by far the most common presentation, and crossing, can be effective. Occasionally, sur- manifests as a foot drop or . Patients gery is required. may report difficulty getting up from a chair, ❚ Anterior syndrome is walking up stairs, or opening jars.8 Facial or compression of the deep fibular nerve as it extraocular nerve involvement is uncom- passes through the inferior extensor retinac- mon, as is respiratory involvement.8 Neuro- ulum of the distal lower leg. Characteristic logic exam shows absent reflexes, weakness, symptoms include pain and burning over the and loss of sensation in the distribution of a dorsum of the foot.11 Paresthesias in the first particular nerve or nerves. dorsal web space are also common.11 This can ❚ Testing and treatment. Diagnosis of be seen in athletes who perform repetitive CIDP is made by a combination of EDX that ankle plantar flexion, such as ballet dancers, shows demyelination and lumbar puncture soccer players, and runners.12 It can also be that demonstrates albuminocytologic dis- caused by recurrent ankle sprains, ganglion sociation. Treatments include long-term im- cysts, and tight-fitting shoes or boots.11,12 munosuppression with oral prednisone, IVIg, Chronic cases can result in toe extensor Small fiber plasmapheresis, and rarely, agents such as weakness or atrophy of the extensor digito- neuropathy can mycophenolate mofetil, azathioprine, cyclo- rum brevis muscle. look like distal sporine, and rituximab.9 ❚ Testing and treatment. Again, EDX sensorimotor is very useful in identifying the exact area of polyneuropathy, Entrapment neuropathy compression and involved nerve segments. but can spread This is the result of compression or entrap- Management requires correcting the under- to the upper ment of a nerve by another anatomic struc- lying etiology, which can usually be done extremities ture. It can be caused by internal or external conservatively. Surgical decompression may quicker and can factors, including fluid retention.11 Dam- be needed. cause autonomic age from compression or entrapment pro- dysfunction. gresses in stages and, over time, can result Paraneoplastic neuropathies in demyelination and distal degeneration of Paraneoplastic neuropathies are exception- the nerve.11 More interior nerve fibers, such ally rare but often develop before cancer is as pain nerve fibers, are often the last to be diagnosed. Therefore, early suspicion and affected.11 Therefore, patients often first -ex recognition can greatly affect cancer progno- perience loss of motor function or loss of sen- sis.13 Certain characteristics should increase sation to light touch. suspicion of a paraneoplastic process. For ❚ Common fibular nerve (formerly example, symptoms with a subacute progres- known as common peroneal nerve) entrap- sive onset that involve the upper extremities ment at the fibular head is the most common early in the disease are characteristic of a entrapment neuropathy in the lower extremi- paraneoplastic process.13 ties. It’s usually the result of direct trauma, Coexisting CNS symptoms and/or such as prolonged positioning in debilitated constitutional symptoms of malignancy patients or surgical patients, habitual leg- should also increase suspicion.13 Consider a crossing, tight boots, or tight casts.11,12 Unco- paraneo­plastic process in patients who have ordinated gait due to poor dorsiflexion of the a past history of cancer or significant cancer foot at the ankle (foot drop) is common while risk factors, such as smoking. plantar flexion is preserved. Pain and sensory ❚ Testing. When you suspect a paraneo- loss depend on the degree of compression plastic process, the work-up should include and the exact location of compression. antibody testing for the most common or ❚ Testing and treatment. EDX is useful likely cancers according to patient character- for identifying the location of compression or istics. Panels of the most common paraneo- entrapment and can guide further imaging, plastic antibodies are available from many

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commercial labs. Obtain imaging to identify FIGURE a possible underlying malignancy. MRI identifies the source That said, it’s also important to perform a basic work-up for the more common causes of of neuropathic symptoms neuropathy in patients you suspect may have cancer. The reason: Paraneoplastic neuropa- thies are rare, and not all neuropathies in pa- tients with cancer are paraneoplastic.13

CASE 1 u Ms. G describes diffuse paresthesias that are worse in her lower extremities, but she has a normal neurologic exam. Her physi- cian suspects a neuropathic cause, and a normal exam makes small fiber neuropathy more likely. EDX is normal. The initial work-up includes an HbA1c, thyroid-stimulating hormone, vitamin

B12 level, antinuclear antibody, erythrocyte sed- MD MAYANS, OF: DAVID PHOTO COURTESY Magnetic resonance imaging of Ms. T’s hip and upper imentation rate, IFE, and free light chain assay. leg showed a heterogeneously enhancing mass in the Testing reveals that Ms. G has a high free right . Biopsy revealed a high grade, poorly light chain ratio, which suggests a monoclonal differentiated synovial sarcoma. Suspect a gammopathy is the most likely etiology. Skin bi- paraneoplastic opsy demonstrates decreased nerve fiber densi- proximal sciatic lesion, but not the underlying process if a ty consistent with a small fiber neuropathy. Her etiology. Since the lesion had been precisely patient presents physician refers her to Hematology for bone localized, her physician orders imaging. with subacute marrow biopsy, and also prescribes gabapentin Magnetic resonance imaging of Ms. T’s hip progressive 300 mg/d at bedtime for symptomatic relief. and upper leg shows a 10.7 cm x 7.8 cm x 13 cm onset of Ms. G is currently being closely monitored for heterogeneously enhancing mass in the expect- neuropathic conversion to multiple myeloma. ed location of the right sciatic nerve (FIGURE). symptoms Biopsy reveals a high grade, poorly differenti- in the upper CASE 2 u In Ms. T’s case, the exam helps local- ated synovial sarcoma. Her physician refers her extremities. ize the lesion. Areas supplied by the common to an oncologist for initiation of chemotherapy, fibular nerve, , and sural nerve are radiation, and debulking surgery. JFP affected, while the area innervated by the femoral nerve and saphenous nerve and the CORRESPONDENCE proximal hip muscles are spared. This localizes Laura C. Mayans, MD, Department of Family and Community Medicine, University of Kansas School of Medicine-Wichita, a lesion to the sciatic nerve. EDX confirms a 1010 N. Kansas, Wichita, KS 67214; [email protected].

References 1. Katirji B, Koontz D. Disorders of peripheral nerves. In: Daroff R, neuropathy. Continuum (Minneap Minn). 2012;18:192-198. ed. Bradley’s Neurology in Clinical Practice. 6th ed. Philadelphia, 7. Gibbons CH. Small fiber neuropathies. Continuum (Minneap PA: Elsevier; 2012:1915-1983. Minn). 2014;20:1398-1412. 2. Azhary H, Farooq MU, Bhanushali M, et al. Peripheral neuropa- 8. So YT. Immune-mediated neuropathies. Continuum (Minneap thy: differential diagnosis and management. Am Fam Physician. Minn). 2012;18:85-105. 2010;81:887-892. 9. Dimachkie MM, Saperstein DS. Acquired immune demyelinating 3. Alport AR, Sander HW. Clinical approach to peripheral neuropa- neuropathies. Continuum (Minneap Minn). 2014;20:1241-1260. thy: anatomic localization and diagnostic testing. Continuum 10. Patwa HS, Chaudhry V, Katzberg H, et al. Evidence-based guide- (Minneap Minn). 2012;18:13-38. line: intravenous immunogloblin in the treatment of neuromus- 4. England JD, Gronseth GS, Franklin G, et al. Practice parameter: cular disorders. Neurology. 2012;78:1009-1015. evaluation of distal symmetric polyneuropathy: role of labora- 11. Flanigan RM, DiGiovanni BF. Peripheral nerve entrapments of tory and genetic testing (an evidence-based review). Neurology. the lower leg, ankle and foot. Foot Ankle Clin. 2011;16:255-274. 2009;72:185-192. 12. Meadows JR, Finnoff JT. Lower extremity nerve entrapments in 5. Smith AG, Singleton JR. Diabetic neuropathy. Continuum (Min- athletes. Curr Sports Med Rep. 2014;13:299-306. neap Minn). 2012;18:60-84. 13. Muppidi A, Vernino S. Paraneoplastic neuropathies. Continuum 6. Shenoy AM. Guidelines in practice: treatment of painful diabetic (Minneap Minn). 2014;20:1359-1372.

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