General Approach to Peripheral Nerve Disorders

Home , POEMS syndrome, Polyneuropathy

1241 . 2017 American Academy Supplemental digital content: Direct URL citationsthe printed appear text and are in in included theversions HTML, of this PDF, article. and app Relationship Disclosure: Dr Russell has servedconsultant as for a W2O Group, receives publishing royalties from McGraw-Hill Education, and has received personal compensation for medicolegal record review. Unlabeled Use of Products/Investigational Use Disclosure: Dr Russell reports no disclosure. * of Neurology. Address correspondence to Dr James A. Russell, Lahey Hospital and Medical Center, Department of Neurology, 41 Mall Rd, Burlington, MA 01805, [email protected] 8 However, it 6,9 The commonly used 3 6 Review Article The prevalence of probable or 1,3 Lack of consensus in diagnostic is generally accepted thatstandards the minimal for diagnosinginclude neuropathy ating least features: two distal symmetricsymptoms, of sensory distal thesory symmetric follow- loss, sen- andankle diminished reflexes. or absent and variable opinionsthe exist role regarding ofropathy determination. electrodiagnosis in neu- incidence and prevalence of neuropathy in general, and chronic idiopathicneuropathy axonal in particular,age. increase with criteria and variableto terminology uncertainty add miology regarding of the peripheral epide- neuropathy, definite polyneuropathy inare those older who estimated than to 80 exceedpopulation years 30% study. in of one age large was 1 6 Y 1 The 1,7 This article provides a conceptual framework for the Although these strategies are largely time-honored, recent Sensory loss in the 3 Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Copyright © American Academy of Neurology. Unauthorized reproduction of this article is The strategies suggested in this article are intended to facilitate accurate

James A. Russell, DO, FAAN

ABSTRACT Continuum (Minneap Minn) 2017;23(5):1241–1262. Purpose of Review: evaluation of patientsability with to suspected localize polyneuropathypossible, identify and to an etiologic confirm enhance diagnosistesting the peripheral through strategies. use clinician’s nervous of rationalRecent system clinical and pathology judicious Findings: and,insights when pertaining tothies the pathophysiology and of tocauses certain evolving of immune-mediated neuropathy genetic neuropa- are testingSummary: conceptualized, strategies evaluated, and may managed. bedside modify diagnosis the in wayand patients that judicious with use select suspectedwhen of polyneuropathy indicated. supplementary and testing allow and efficient application of rational treatment feet often goeslarly unrecognized, in those particu- who with diabetes are mellitus elderly;patients or with only diabetes 10% mellitusto reported to be aware 15% of of their neuropathy. Continuum (Minneap Minn) 2017;23(5):1241–1262 ContinuumJournal.com Also in the Netherlands,of the definite prevalence neuropathy5.5%, is and estimated theand at prevalence definite ofestimated neuropathy probable at combined 13.1%, butunderestimated. is these are likely In the Netherlands,dence neuropathy in inci- anmates adult 77 population per approxi- 100,000 person-years. INTRODUCTION Peripheral neuropathy ismon a problem veryEstimates in com- of neurology itslence practice. incidence are variable, andon undoubtedly preva- the based populationtion studied, the of defini- intensity neuropathy of the evaluation used, employed. and the Disorders Peripheral Nerve General Approach to

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KEY POINTS h Peripheral neuropathy is designations of distal symmetric inflammatory demyelinating poly- a common neurologic polyneuropathy, chronic axonal polyradiculoneuropathy [CIDP], the neu- problem, affecting neuropathy, or chronic idiopathic ropathy of monoclonal gammopathy 12 approximately 5% of axonal polyneuropathy, which have of undetermined significance). adults and as many as subtle conceptual differences, are gen- Patients should be informed that 30% of patients who erally used synonymously. good treatment options do not neces- are elderly. The etiologies of peripheral neu- sarily follow from a diagnosis, such as h Although they have ropathy are legion, exceeding 200 hereditary neuropathy, estimated to 2 minor conceptual depending on the classification system include as many as one-third of cases. differences, used.2,5,9 Identification and assign- However, informed diagnostic pursuit distal symmetric ment of an etiology are influenced by provides the opportunity for diag- polyneuropathy, chronic variables that include the population nostic closure, education regarding axonal polyneuropathy, studied, the nature and intensity of the disorder’s natural history, and and chronic idiopathic the evaluation, and the willingness to counseling germane to the preven- axonal polyneuropathy assign causation to a laboratory abnor- tion and management of potential may be considered Y mality that may be coincidental.1 3,7,10 future morbidity. In the case of distal as essentially synonymous terms. One study reporting a 58% prevalence sensory polyneuropathy, the patient of test abnormalities in patients with can be reassured that progression h Although the primary peripheral neuropathy considered only to nonambulation or amputation is goal in the evaluation 9% of these abnormalities to be diag- uncommon.7,13 of a patient with 11 peripheral neuropathy nostically significant. To be confi- ANATOMIC, PHYSIOLOGIC, is to identify the cause dent of a causal relationship between whenever possible, a a test abnormality and peripheral AND PATHOPHYSIOLOGIC common category of neuropathy, the clinician should con- CONSIDERATIONS IN polyneuropathy is sider the neuropathy pattern and the PERIPHERAL NEUROPATHY chronic idiopathic contextual features in each case, Understanding peripheral nerve anat- axonal polyneuropathy, allowing generation of a relevant dif- omy and physiology is required for which may represent ferential diagnosis aligned with these adequate clinical assessment and close to a half of features. Judicious testing in the proper electrodiagnostic study design. Under- patients with neuropathy clinical context reduces the risk of false- standing the pathophysiology of the in some populations. positive testing. disorder allows for rational therapeu- h Accurate diagnosis of As with any diagnostic assessment, tic strategy and prognostication. In polyneuropathy directs the patient should be advised of the view of their unique anatomic and treatment in a limited risks and benefits involved in the physiologic properties, peripheral number of cases but diagnostic workup. Ideally, a treatable nerves are vulnerable to multiple also provides the benefit disorder is identified; however, diag- potential insults.14 of diagnostic closure, opportunities for nosis may be elusive. Following eval- Axonal Polyneuropathies education regarding the uation, 20% to 50% of patients are natural history of the designated as chronic idiopathic axo- The viability of peripheral nerves disease, and a means nal polyneuropathy or chronic axonal depends on the metabolic capabilities 1,3,4,7,11 by which to prevent polyneuropathy. Although a of anterior horn cells and dorsal root and address potential 2016 study reported that a diagnosis ganglia and effective axon transport. future morbidities. could be achieved in two-thirds of The latter is bidirectional and essential 284 patients with chronic idiopathic for axonal nutrition and support for axonal neuropathy when reevaluated, the normal turnover of organelles over half of these individuals were (particularly mitochondria) and pro- assigned a diagnosis that should have teins (such as microtubules and been apparent on initial evaluation neurofilaments).15 Anterograde trans- (eg, diabetic neuropathy, chronic port from cell body to neuromuscular

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT junction along axons is dependent on myelin sheath. Peripheral nerve myelin h Disordered axonal the kinesin family of molecular mo- of Schwann cell origin is compacted transport is thought tors; retrograde transport depends on along the internode, noncompacted at to be the mechanism the dynein/dynactin complex. Animal the paranode (allowing for increased underlying the models using nerve toxins have surface area of potential pathogenic pathophysiology of shown disruption of critical axon significance), and absent at the nodes most toxic and transport proteins resulting in distal of Ranvier (where ion channels are metabolic neuropathies axonal degeneration. This can be read- concentrated). Predominantly demye- and some hereditary ily extrapolated to the pathophysio- linating peripheral neuropathies neuropathies. logic basis for toxic or metabolic affecting myelin or Schwann cells length-dependent neuropathies in may be either acquired or heritable humans.1,16Y20 The same neuropathy (Table 1-1).19,22,23 Demyelinating neu- pattern can be also be attributable to ropathies impair nerve conduction gene mutations involved in cell migra- by allowing current leakage through tion, anterograde and retrograde trans- exposed axons where a paucity of ion port, folding of cytoskeletal proteins, channels exists, thus impeding action and neurofilament organization.19,21 potential propagation.24 Acquired demyelinating neuropa- Demyelinating thies are thought to be immune Polyneuropathies mediated through either cellular or Optimal peripheral nerve function is humoral mechanisms. Antigenic targets also dependent on the integrity of the are located in the paranodal or

TABLE 1-1 Predominantly Demyelinating Polyneuropathies/ Polyradiculoneuropathies

b Charcot-Marie-Tooth disease type 1 b Charcot-Marie-Tooth disease type 3 b Charcot-Marie-Tooth disease type 4 b Hereditary neuropathy with liability to pressure palsies (HNPP) b Krabbe disease b Metachromatic leukodystrophy b Refsum disease b Cockayne syndrome b Acute inflammatory demyelinating polyradiculoneuropathy (AIDP) b Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) b Polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes (POEMS) syndrome b Multifocal motor neuropathy (MMN) b Multifocal acquired demyelinating sensory and motor neuropathy (MADSAM) b Distal acquired demyelinating symmetric neuropathy (DADS) b Toxins (diphtheria, buckthorn, amiodarone, n-hexane, arsenic)

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KEY POINT h juxtaparanodal regions of the internode autoantibodies, found in the vast In some cases, good 24,25 correlation appears to (Figure 1-1). Identifiable auto- majority of patients with Miller Fisher exist between the antibodies in some of these disorders syndrome, are concentrated in the anatomic location of have diagnostic or, in some cases, paranodal regions of cranial nerves III, 26Y33 peripheral nerve probable pathogenic relevance. IV, and VI. They have been demon- antigenic targets, Their presence serves to justify immu- strated to block nerve conduction and autoantibodies against nomodulating treatment in certain represent the most convincing example these targets, and syndromes.31Y34 Some peripheral nerve of peripheral nerve disease linking an specific peripheral antigens associated with well-defined autoantibody with a specific neuropathy neuropathy syndromes. peripheral nerve syndromes are found syndrome.29Y33 exclusively in peripheral nerves (eg, The concept that autoantibodies sulfoglucuronyl glycosphingolipid and might cause neuropathy is also rein- the distal acquired demyelinating forced by the observation that the symmetric [DADS] neuropathy associ- blood-nerve barrier is less well estab- ated with IgM monoclonal proteins). lished at the nerve roots, dorsal root Other autoantibodies demonstrate ganglia, and terminal nerve twigs. This strong correlations between the pre- correlates with the pathologic observa- dominant location of their target anti- tion that these regions are often pref- gens and the clinical neuropathy erentially involved in the inflammatory/ pattern they are associated with.24,25,29 immune polyradiculoneuropathies.24,33 For example, the ceramide content of Additional support for immune-mediated gangliosides differs between motor and nerve injury comes from the observa- sensory nerves. Autoantibodies directed tion that the sera of patients with cer- against GM1, GD1a, and GT1b ganglio- tain immune-mediated neuropathies sides preferentially affect motor nerves (eg, multifocal motor neuropathy) is and are most commonly found in high disruptive to the blood-nerve barrier.35 titer in motor-predominant neuropa- Little or no overlap appears to exist thies. Conversely, GD1b autoantibodies in the molecular targets of autoimmune preferentially target sensory nerves and and hereditary neuropathy.33 In general, are most commonly associated with hereditary neuropathies are associated ataxic neuropathy syndromes. GQ1b with genes coding for structural myelin

FIGURE 1-1 Diagram of a myelinated axon, showing subdivision into sections with different diameters.

Modified with permission from Franssen H, Straver DC, Muscle Nerve.24 B 2013 Wiley Periodicals, Inc. onlinelibrary.wiley.com/doi/10.1002/mus.24068/full.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT proteins, whereas the autoantibodies for the rapidly reversible conduction h Recently, in addition to associated with acquired immune- failure seen in this disorder. This axons and myelin, mediated neuropathies, with the excep- hypothesis is also consistent with the antigenic targets tion of myelin-associated glycoprotein recognition that AMAN is frequently including ion channels 19,33 (MAG), typically target gangliosides. associated with autoantibodies directed located at or near the against GM1 and GD1a gangliosides, nodes of Ranvier have Nodopathies localized on the nodal axolemma, been considered as a The anatomic classification of neuropa- particularly in the terminal nerve twigs third anatomic category thies has been historically divided into where the blood-nerve barrier is less of peripheral nerve disorders of axons or myelin. Now it is well established.24,26Y36 disease susceptible recognized that some toxic, immune- Like demyelination, nodopathies to autoimmune or toxic injury. mediated, and hereditary disorders tar- are not necessarily limited to disrupted get proteins and ion channels in the conduction and may be associated nodal region.19,36 These disorders have with subsequent axon loss. Impairment been referred to as nodopathies or of sodium-calcium pump function is channelopathies.26,30,36 The best exam- hypothesized to lead to intracellular ple is the acute motor axonal neuropa- calcium accumulation contributing to thy (AMAN) variant of the Guillain-Barre´ eventual axonal degeneration.24Y36 syndrome. This disorder is character- Other neuropathies in which nodal ized by rapid decline of compound dysfunction is hypothesized to play a muscle action potential (CMAP) ampli- role in disease pathogenesis are listed tudes, suggesting motor axon loss. The in Table 1-2.36 rapid resolution of clinical and nerve conduction study changes, however, is CLASSIFICATION AND CAUSES not compatible with expected recovery OF POLYNEUROPATHIES from that mechanism of injury. Con- Classification of peripheral neuropa- duction block produced by impaired thies is commonly based on the initial ion channel function unassociated location of pathology derived from with anatomic myelin or axonal injury phenotypic and electrodiagnostic pat- provides a more likely explanation tern recognition.2,37 Figure 1-2 shows

TABLE 1-2 Nodopathies

b Acute motor axonal variant of Guillain-Barre´ syndrome b Guillain-Barre´ syndrome with autoantibodies associated with nodal antigens b Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP) associated with autoantibodies to nodal antigens b Miller Fisher syndrome b Multifocal motor neuropathy (MMN) b Marine toxins (saxitoxin, ciguatoxin, tetrodotoxin) b Drugs with ion channel blocking properties (phenytoin) (more electrophysiologic than clinical) b Possibly critical illness polyneuropathy b Possibly ischemic monomelic neuropathy b Possibly thiamine deficiency

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KEY POINT h The primary benefit of neuropathy classification is to limit differential diagnostic considerations in order to generate a rational and targeted diagnostic strategy.

FIGURE 1-2 Estimated prevalence of common polyneuropathy categories. Modified with permission from Visser NA, et al, Neurology.1 B 2014 American Academy of Neurology. neurology.org/content/84/3/259.full.

the prevalence of common categories based on the primary anatomic target of neuropathy. Neuropathies that (axon or myelin), neuropathy pattern appear to originate in motor or sen- (length dependent or non-length sory cell bodies are referred to as dependent), or size of peripheral neuronopathies. These disorders have nerve fibers preferentially affected clinical and electrodiagnostic features (ie, small or large). These subclassifi- that suggest axonal degeneration. cations are not mutually exclusive. It is Sensory neuronopathies are pre- common, for example, to describe a sumed to result from selective damage neuropathy as a small fiber length- to dorsal root ganglia. A significant dependent axonopathy. The purpose percentage are considered idiopathic. of subclassification is to limit the Recognized etiologies include para- differential diagnostic considerations. neoplastic, immune-mediated, infec- The majority of neuropathies have tious, toxic, and hereditary causes predominantly axonal, symmetric, and (Table 1-338).37 It has been speculated length-dependent patterns. Length- that the fenestrated nature of dorsal dependent peripheral neuropathy is root ganglia capillaries diminishes attributed to disordered axonal trans- the blood-nerve barrier, rendering port leading to dying back, or centrip- these cells more susceptible to etal degeneration of the longest axons. immune-mediated causes.38 Motor The apparent sensory predominance of neuronopathies (motor neuron dis- most length-dependent peripheral neu- eases) preferentially target anterior horn ropathies has led to their designation as cells as a result of a select group of distal sensory polyneuropathy. In fact, infectious, hereditary, and degenerative distal motor involvement of intrinsic conditions (Table 1-4).21,39 foot muscles is often present but diffi- Neuropathies, more so than neuro- cult to clinically detect. nopathies, lend themselves to sub- Small fiber neuropathies are typi- classification. Classification can be cally considered a subcategory of

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% of Patients With the % of Sensory Disease Who Neuropathy Have Sensory Categories Notable Examples Patients Neuropathy Idiopathic NA 50 NA Inflammatory/ Sjo¨ gren syndrome 5 39 immune Paraneoplastic sensory neuronopathy Unknown 74 mediated (anti-Hu positive) Autoimmune hepatitis Unknown Unknown Toxic Pyridoxine toxicity Unknown Unknown Platin chemotherapy Unknown Unknown Infectious Herpes zoster Unknown Unknown Epstein-Barr virus Unknown Unknown Human T-cell lymphotropic virus type 1 (HTLV-1) Unknown Unknown Human immunodeficiency virus (HIV) Unknown Unknown Hereditary/ Mitochondrial: polymerase + (POLG), sensory Unknown Unknown degenerative ataxic neuropathy, dysarthria, and ophthalmoplegia (SANDO) Cerebellar ataxia, neuronopathy, vestibular Unknown Unknown ataxia syndrome (CANVAS) Spinocerebellar degeneration Unknown Unknown Facial-onset sensory and motor neuropathy Unknown Unknown (FOSMN) NA = not applicable. a Data from Gwathney KG, Muscle Nerve.38 onlinelibrary.wiley.com/doi/10.1002/mus.24943/full. painful length-dependent neuropa- ropathy is the ataxic sensory neurop- KEY POINT h thies, but one-fourth to a one-third athy associated with IgM monoclonal Although the majority may be non-length dependent based proteins related, in many cases, with of length-dependent polyneuropathies fall upon distribution of symptoms and MAG autoantibodies.24,29 Hereditary into the chronic intraepidermal nerve fiber density length-dependent neuropathies include 40Y42 idiopathic axonal assessment. Despite their charac- Charcot-Marie-Tooth disease (CMT) and polyneuropathy teristic length-dependent clinical pat- the hereditary motor neuropathies (also category, acquired tern, it has been postulated that small referred to as distal forms of spinal demyelinating 2,19,22,23 fiber neuropathies may represent dor- muscular atrophy). neuropathies and Y sal root ganglionopathies.40 44 NonYlength-dependent polyneu- motor-predominant Length-dependent presentations may ropathies include neuronopathies, heritable neuropathies also occur with demyelinating neuropa- multifocal neuropathies, polyradiculo- may occur in this thies, both acquired and inherited.24,29 pathies, and polyradiculoneurop- pattern is well. A notable example of an acquired athies.2,45 Multifocal neuropathies demyelinating length-dependent neu- commonly result from disorders that

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KEY POINTS h Multifocal neuropathies TABLE 1-4 Motor Neuropathies/Neuronopathies typically result from disorders that infarct, Pattern Notable Examples inflame, or infiltrate Length-dependent Hereditary motor neuropathy, hereditary spastic nerves or render pure motor paraparesis (some genotypes) them more susceptible to compression. Length-dependent Charcot-Marie-Tooth disease, toxins motor predominant (arsenic, lead) h The recommended approach to peripheral Monomelic Benign focal amyotrophy/monomelic amyotrophy neuropathy begins with Monomelic Amyotrophic lateral sclerosis/progressive muscular pattern recognition progressing atrophy, infectious (polio/postpolio/West Nile followed by to generalized virus/enterovirus D68), paraneoplastic (rare) consideration of Proximal symmetric/ Spinal muscular atrophy, acute motor axonal contextual features, generalized neuropathy (Guillain-Barre´ variant), such as the chronologic hexosaminidase deficiency course, risk factors, and potential Multifocal Multifocal motor neuropathy (MMN) involvement of other organ systems. Testing is then applied to confirm or refute the infarct, inflame, or infiltrate nerves or ating. Guillain-Barre´ syndrome (or potential causes render them more susceptible to acute inflammatory demyelinating generated from compression (Table 1-5). Diabetes polyradiculoneuropathy [AIDP]) and this strategy. mellitus and vasculitides are common CIDP are the most common forms of h The intensity of both causes.45,46 Most are associated with this neuropathy syndrome (Table 1-7). diagnostic evaluation axon loss and have both motor and and treatment should sensory characteristics, dependent, in CLINICAL APPROACH be influenced by the part, on the fiber types within the Polyneuropathy is initially suspected impact of the affected nerve(s). Those with demyelin- based on characteristic symptoms neuropathy on the ating characteristics include multifocal occurring in characteristic patterns. patient’s lifestyle, motor neuropathy (MMN), multifocal The clinical strategy employed begins including considerations of both comfort acquired demyelinating sensory and with identification of the pattern of and function. motor neuropathy (MADSAM), heredi- involvement, with subsequent consid- tary neuropathy with liability to pres- eration of contextual features such as sure palsies (HNPP), and CMT type X thetimecourseandriskfactors, in some cases.2,23,45 including any indication of other end Polyradiculopathies are disorders organ involvement. A differential diag- that affect multiple nerve roots. Lum- nosis is then generated in consider- bosacral spinal stenosis is the most ation of these features and knowledge common cause, resulting in mechanical of the causes of neuropathy known to compression of lumbosacral nerve roots behave in this manner. Ancillary testing within an anatomically compromised is then applied to confirm or refute spinal canal. Polyradiculopathies may these suspicions. The clinical approach also result from disorders that inflame to neuropathy should include an assess- or infiltrate meninges and the nerve ment of how the neuropathy impacts roots and cranial nerves that traverse the patient’s lifestyle, considering both them (Table 1-6). comfort and function. Appreciation of Polyradiculoneuropathies are typi- these factors allows rational testing and cally acquired and axonal or demyelin- treatment determination.

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Category Examples Electrophysiology Hereditary Hereditary neuropathy with liability Demyelinating to pressure palsies (HNPP) Ischemic Systemic vasculitic neuropathy Axonal Nonsystemic vasculitic neuropathy Axonal Ischemic monomelic neuropathy Axonal Diabetes mellitus Axonal Cryoglobulinemia Axonal Inflammatory Multifocal motor neuropathy (MMN) Demyelinating Multifocal acquired demyelinating Demyelinating sensory and motor neuropathy (MADSAM) Acute brachial plexopathy (monomelic) Axonal Infiltrative Sarcoidosis Axonal Amyloidosis Axonal Neurolymphomatosis Axonal Leprosy Axonal Neurofibromatous Axonal

Length-dependent one-third of these patients are esti- Neuropathies matedtohaveneuropathicpain, Patients with length-dependent neurop- suggesting that certain neuropathies 5 athy patterns with large fiber sensory have large and small fiber overlap. involvement commonly describe numb- Motor involvement in length-dependent ness or loss of sensation and liken it polyneuropathies may be implicated by to a sense of swelling or feeling as intrinsic foot muscle atrophy as clinical though their socks are balled up under detection of intrinsic foot muscle their feet (Case 1-1). Table 1-8 lists weakness is difficult. In the common common causes of length-dependent axonal forms of length-dependent polyneuropathy. Mild loss of balance neuropathy, the ankle muscle stretch may be described. In very slowly pro- reflexes may be diminished or absent gressive disorders such as hereditary depending on severity, but other neuropathies, the patient may not be reflexes are typically initially pre- aware of the sensory loss. The greatest served. A multifocal neuropathy may proportion of patients with acquired be mistaken for a length-dependent length-dependent polyneuropathy will polyneuropathy if care is not taken to be characterized as having a distal identify the initial focal nature of symp- symmetric polyneuropathy, a near- toms before their confluence. synonym for chronic idiopathic axonal polyneuropathy, as the former may Small Fiber Polyneuropathy have identifiable secondary as well as Patients with small fiber neuropathy idiopathic etiologies. Approximately commonly describe painful dysesthetic

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at the ankle or an abnormal thermal TABLE 1-6 Some Causes of Polyradiculopathy response to quantitative sensory testing at the foot.40 A pure small fiber b Structural neuropathy should have normal large fiber sensation, strength, and Spondyloarthropathy muscle stretch reflexes and normal Spinal stenosis routine nerve conduction studies. b Radiation Operationally, patients diagnosed with small fiber neuropathy may have b Neoplastic concomitant large fiber involvement; Non-Hodgkin lymphoma examples include diabetes mellitus Acute leukemia and amyloidosis. Not all patients with length- Melanoma dependent neuropathy have chronic Carcinoma idiopathic axonal neuropathy or b Infectious Lyme disease TABLE 1-7 Causes of Poly- radiculoneuropathy Cytomegalovirus Human immunodeficiency b Hereditary virus (HIV) Porphyria Tuberculosis b Inflammatory Herpes zoster Guillain-Barre´ syndrome Schistosomiasis Chronic inflammatory b Inflammatory demyelinating polyradiculoneuropathy Sarcoidosis (CIDP) Polyneuropathy, organomegaly, sensations, such as burning or local- endocrinopathy, ized shooting pains, and may experi- monoclonal plasma cell disorder, and skin ence signs and symptoms referable to changes (POEMS) dysautonomia. Diagnostic criteria have syndrome been published for small fiber neurop- b Toxic athy, which may be conceptualized as a type of distal symmetric poly- Arsenic 40,44 neuropathy. Possible small fiber n-Hexane neuropathy is defined by a length- Amiodarone dependent pattern of abnormal painful sensations that occur spontaneously Diphtheria or are provoked by tactile stimuli. b Metabolic/Ischemic Probable small fiber neuropathy Diabetic radiculoplexus requires two additional features: signs neuropathy attributable to small fiber loss and b Idiopathic a normal sural sensory nerve action potential (SNAP). Definite small fiber Idiopathic radiculoplexus neuropathy requires either an abnor- neuropathy mal intraepidermal nerve fiber density

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 1-1 h Newly acquired global areflexia in peripheral A 72-year-old woman was evaluated for 2 years of foot numbness. She neuropathy is described this as a sensation of cotton stuffed between her toes that frequently associated began insidiously and symmetrically with gradual ascent to midfoot level. with a predominantly She denied pain and disability. Her body mass index was 34, and she demyelinating had mild hypertension, hypercholesterolemia, hypothyroidism, and a neuropathy. recently detected hemoglobin A1c of 5.9. Her medications included low doses of lisinopril, atorvastatin, and levothyroxine. Examination showed normal strength, including toe flexion and extension. Ankle jerks were present but less active than the knee jerks. She had transient perception of vibration with a 128-Hz tuning fork applied to the great toes; ability to distinguish a pin from a monofilament was diminished distal to the ankles bilaterally. She could balance on one foot momentarily but could not sustain it for 5 seconds. Her electrodiagnostic testing showed absent mixed plantar responses, reduced amplitudes of the sural and superficial fibular (peroneal) sensory nerve action potentials (SNAPs), and normal motor conduction studies. Needle examination showed fibrillation potentials only in intrinsic foot muscles. Comment. This patient appears to have a length-dependent pattern consistent with chronic idiopathic axonal polyneuropathy. Even with more extensive evaluation, it is unlikely that a cause will be found. Her comorbidities are common and are of uncertain relevance. American Academy of Neurology guidelines suggest judicious testing, counseling the patient regarding the probable benign natural history of this disorder, and recommending strategies she can use to limit risk of future morbidity.11,46 These strategies include safety precautions to minimize risk of infection, such as daily inspection of the soles of the feet and avoidance of walking on bare feet to minimize risk of contact with foreign bodies. Night lights, durable medical equipment, and, in bathrooms, nonskid surfaces and grab bars can help to reduce the risk of falls. small fiber neuropathy. Patients with NonYlength-dependent this pattern and prominent sensory Neuropathies ataxia may have DADS neuropathy or NonYlength-dependent neuropathies a sensory neuronopathy. Patients with (Case 1-2) may be subcategorized DADS are likely to be globally are- as neuronopathies, multifocal neu- flexic, a characteristic of most acquired ropathies, polyradiculopathies, and predominantly demyelinating neuropa- polyradiculoneuropathies. thies or polyradiculoneuropathies. In Neuronopathies. Motor neuro- patients with a length-dependent pat- nopathies typically present as painless tern with motor predominance, CMT, progressive weakness and atrophy, hereditary motor neuropathies, and often associated with muscle cramping distal myopathies should be consid- and fasciculations. Both the pattern of ered, particularly if symptoms are weakness and chronologic course are slowly progressive. Preservation of toe dependent on cause. Hereditary causes extension relative to foot dorsiflexion is commonly result in symmetric patterns one clue suggesting myopathy as a of weakness that may be proximally cause of symmetric footdrop. predominant or generalized (as in the

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TABLE 1-8 Common Causes of Length-dependent Polyneuropathy

Estimated Prevalence of Category Notable Examples All Types Diabetes Large fiber sensory predominant 33% mellitus Small fiber 10Y25% of above Impaired glucose tolerance Unknown Chronic Idiopathic 25Y55% idiopathic axonal polyneuropathy Small fiber Idiopathic 2% neuropathy Hereditary Charcot-Marie-Tooth disease 5Y33% (hereditary motor sensory neuropathy), hereditary sensory and autonomic neuropathy, hereditary motor neuropathy

Metabolic Vitamin B12/other nutritional 12% deficiency, end organ failure/critical illness polyneuropathy Toxic Chemotherapy, industrial/ 14% environmental toxins Inflammatory Distal acquired demyelinating 9% symmetric neuropathy associated with IgM monoclonal protein IgM = immunoglobulin M.

spinal muscular atrophies) or distally atypical of a length-dependent axonal predominant (as in the hereditary neuropathy and suggest a sensory motor neuropathies).21,45 Infectious neuronopathy, demyelinating neuro- and degenerative motor neuronopa- pathy, or, in some cases, multifocal thies begin focally in most cases. In neuropathy.5,7,8,38 Patches of numbness the latter case, identifying concomitant on the arms, trunk, or scalp superim- upper motor neuron findings raises posed on an otherwise length-dependent concern for the diagnosis of amyo- pattern of sensory signs and symp- trophic lateral sclerosis. toms should also suggest sensory Sensory neuronopathies may man- neuronopathy. ifest in a length-dependent pattern, In patients whose sensory symptoms but clues suggesting nonYlength- begin in the hands, the differential dependent features may be identified. diagnosis should include compressive Sensory ataxia is a common feature. cervical myelopathy, deficiency of Sensory symptoms in the hands devel- vitamin B12 or copper, and carpal oping before lower extremity sensory tunnel syndrome superimposed on symptoms reach the knee would be polyneuropathy.

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 1-2 h A detailed history identifying an initial A 65-year-old woman with a history of bladder cancer was evaluated asymmetric symptom for 2 years of pain and numbness in her hands, unexplained abdominal onset before symptom pain, diarrhea, and weight loss. Her hand pain was debilitating and confluence may aid associated with allodynia, necessitating the use of gloves. The pain in the identification had not responded to carpal tunnel release. Within the past year, of a multifocal she had developed numbness in her feet as well as orthostatic neuropathy pattern. intolerance. Her examination revealed a cachectic woman whose systolic blood pressure dropped by 50 mm Hg upon standing. Strength was difficult to assess because of pain and deconditioning. She was areflexic. She had reduced perception of vibration in the hands more than the feet and a stocking distribution of diminished pinprick below the knees. Her electrodiagnostic studies showed reduced compound muscle action potential (CMAP) and sensory nerve action potential (SNAP) amplitudes in a nonYlength-dependent pattern, affecting the upper extremities to a greater extent than the lower extremities. She had no demyelinating features. Comment. This case includes features that would justify a more aggressive diagnostic evaluation than is applied for the typical patient with distal sensory polyneuropathy.7,47 Although the nature of the patient’s symptoms suggested small fiber involvement, the nonYlength-dependent pattern of sensory symptoms, dysautonomia, and history of systemic disease suggested a more serious systemic condition.7 Eventually, a peripheral nerve biopsy of the superficial radial nerve led to identification of amyloid deposition secondary to a pathogenic mutation in the transthyretin gene.

Multifocal neuropathies. The multi- sory findings evolving from initial focal neuropathy pattern is characterized asymmetry with limited discomfort by the asymmetric, often stepwise, may be occasionally seen. Although development of motor disturbances, the majority of the inflammatory sensory disturbances, or both. Multi- demyelinating polyradiculoneurop- focal neuropathies are often suspected athies are characterized by symmetric by detailed history taking and may be patterns of greater motor deficits more easily identified by EMG than by than sensory deficits, MADSAM is a clinical examination. The differen- notable exception. tial diagnosis of multifocal neuropathy includes polyradiculopathy and DIAGNOSTIC TESTING asymmetric forms of polyradiculo- STRATEGIES neuropathy. Polyradiculopathy may be Testing practices in peripheral neu- recognizable because of the segmental ropathyvaryconsiderablyandare nerve pattern of deficits and the higher undoubtedly influenced by a number probability of cranial nerve involve- of factors.2,7,48 Electrodiagnostic test- ment than in multifocal neuropathies. ing; blood, genetic, and CSF analyses; Polyradiculopathy resulting from lum- imaging; and nerve biopsy should be bosacral spinal stenosis is typically used judiciously as targeted tools.49,50 associated with back and leg pain with In general, nonYlength-independent neurogenic claudication, but a length- phenotypes, particularly those with the dependent pattern of motor and sen- characteristics identified in Table 1-9,

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KEY POINTS h mal individuals. Proponents point out Patients with an TABLE 1-9 Neuropathy indolent neuropathy Characteristics that denervation potentials in normal and a chronic idiopathic Suggesting the individuals are rare, foot muscles are axonal polyneuropathy Need for a More Intensive the most likely place to find early a pattern may require Evaluation abnormalities, denervation potentials limited testing as indicate motor involvement, and recommended by b Acute to subacute onset examination of foot muscles facilitates American Academy of b Rapid progression definition of length dependency and Neurology guidelines. symmetry. b Motor predominance h Although the routine use of electrodiagnosis b Non-length dependence Blood and Cerebrospinal in peripheral neuropathy b Associated dysautonomia Fluid Testing evaluation has been b AAN guidelines suggest that routine challenged, it remains Associated systemic disease laboratory work include vitamin B12, a a valuable diagnostic Modified with permission from methylmalonic acid, and glucose levels tool in the confirmation Watson JC, Dyck PJB, Mayo Clin 7 B and serum protein immunofixation in and characterization Proc. 2015 Mayo Foundation for Medical Education and Research. patients with distal symmetric poly- of large fiber neuropathy mayoclinicproceedings.org/article/ and other conditions S0025-6196(15)00378-X/pdf. neuropathy patterns (Supplemental Y that might mimic it. Digital Content 1 1; links.lww.com/ CONT/A224).11,46 However, the guide- h Acute to subacute warrant consideration of more exten- lines also recognize the need for onset, significant 2,45,47 asymmetry, motor sive testing. physician judgment in the evaluation predominance, of patients with neuropathy based dysautonomia, and Electrodiagnostic Testing upon the clinical situation, which may 11 evidence of other end An American Academy of Neurology justify additional testing. Additional organ development (AAN) practice parameter endorses testing should be considered when a are justifications for the use of electrodiagnostic testing patient does not conform to a distal a more intensive in patients with suspected neuropa- symmetric polyneuropathy or chronic evaluation in a patient thy.8,11,46 Patients with long-standing idiopathic axonal polyneuropathy with neuropathy. symptoms and minimal morbidity pattern and has clinical or electro- do not need electrodiagnostic test- diagnostic features suggesting an alter- ing unless results are likely to influ- native cause (Table 1-9). CSF analysis ence diagnosis and treatment. The is not routinely recommended in the routine use of electrodiagnostic test- evaluation of distal symmetric poly- ing in the evaluation of patients with neuropathy but should be considered suspected neuropathy has recently with a polyradiculopathy or poly- been both challenged and sup- radiculoneuropathy pattern.11 ported.6,9 For more information on Diabetes mellitus is estimated to be electrodiagnostic testing, refer to the the cause of neuropathy in one-third article ‘‘Neurophysiologic Studies in or more of cases in population-based the Evaluation of Polyneuropathy’’ by studies and is widely recognized as the John C. Kincaid, MD, FAAN,51 in this most common cause in developed issue of Continuum. countries.1,3,5,6 The prevalence of The role of needle examination of neuropathy is estimated at 8% at the intrinsic foot muscles in the evaluation time of diagnosis with diabetes of suspected peripheral neuropathy mellitus, increasing with disease dura- has been debated. Detractors point tion to eventually affect as many as to discomfort and the possibility of two-thirds of individuals with long- finding denervation potentials in nor- standing disease.5 Of these, 10% to

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Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited. 7,10 KEY POINTS 25% will have a painful variant. lism, identified in approximately half h 20 The potential However, caution is required, as 10% of cases. relationship between of patients with diabetes mellitus are prediabetes and estimated to have an alternative or Antibody Testing peripheral neuropathy, additional etiology for their neurop- The role of autoantibody testing in the particularly small athy.7 Fasting blood sugar and hemo- evaluation of a patient with peripheral fiber neuropathy, globin A1c level are considered neuropathy remains unclear. As inci- remains unsettled. sufficient as screening tools. A 2-hour dental identification of autoantibodies h Small fiber neuropathies glucose tolerance test is considered in low titer is fairly common in clinical may be conceptualized a more sensitive means of detecting practice, the risk of false-positive as a painful subcategory glucose intolerance at its earliest results is significant.50 Therefore, it is of distal symmetric stage, potentially relevant in the generally recommended that the use polyneuropathy, which evaluation of patients with small fi- of autoantibody panels be avoided, may be idiopathic in up ber neuropathy.4,7,11 particularly those that test for dispa- to 90% of cases. The relationship between the pre- rate clinical patterns simultaneously. h Professional neurologic diabetic state and neuropathy remains Autoantibody testing should target associations recognize unsettled.12 Early in this century, a disorders based on relevant clinical the value of genetic relationship between neuropathy and patterns (Table 1-10). testing in the evaluation impaired glucose tolerance was pro- of neuropathy when used in a judicious and moted by multiple observations that Genetic Testing targeted fashion. the prevalence of neuropathy in indi- Hereditary neuropathies constitute a viduals with impaired glucose toler- significant proportion of peripheral ance was essentially double that of neuropathy, although prevalence control populations, particularly in estimates vary widely. In studies of patients with a small fiber poly- middle-aged to elderly patients with neuropathy pattern.11 More recently, neuropathy, hereditary causes have these observations were refuted by a been estimated to represent as little population study that failed to dem- as 0.3% to 3% of the neuropathy onstrate an increased prevalence of cohort. In other studies, the preva- neuropathy (painful or painless), as lence has been estimated to be as assessed by both clinical and electro- high as 30% to 42%.2,3,53 diagnostic means, in patients with The majority of hereditary neurop- abnormal glucose metabolism.52 Of athies fall into the CMT category. note, determination of neuropathy in Currently, in excess of 80 recognized this study was based on electro- hereditary neuropathy genotypes are diagnostic and clinical assessment known, with dominant, recessive, through the Neuropathy Impairment and X-linked inheritance patterns Score, which may lack sensitivity in the (Table 1-11).19,23 Opinions differ re- detection of small fiber neuropathy. garding the role of genetic testing Investigations in patients with small in the evaluation of patients, although fiber polyneuropathy are influenced judicious testing is endorsed by neu- by the recognition that diagnostic rologic and neuromuscular professional yield is lower than with the large fiber organizations.11,23,54 Potential benefits distal sensory polyneuropathy pattern. include diagnostic closure, with both Up to 90% of small fiber polyneurop- psychological and cost benefits, and athy is considered idiopathic.12 The optimal genetic counseling for family most common definable potential members.54,55 Genetic diagnosis can association with small fiber polyneu- clarify prognosis and direct monitor- ropathy is abnormal glucose metabo- ing and treatment of end organ

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TABLE 1-10 Serologic Markers With Clinical Utility in Peripheral Neuropathy Evaluation

Phenotype Autoantibodies Sensitivity Acute motor axonal neuropathy GM1, GD1a, GD3 50% (5Y10% of Guillain-Barre´ syndrome cases) Miller Fisher syndrome GQ1a, GT1a 85% Ataxic neuropathies (CANOMAD, GD1b 46% acute sensory ataxic neuropathy) Distal acquired demyelinating IgM monoclonal Approximately symmetric neuropathy (DADS) protein 100% MAG 50% POEMS syndrome Lambda light chain 85% Multifocal motor neuropathy IgM GM1 48% (MMN) IgM GM1:GalC 75% Paraneoplastic sensory neuronopathy ANNA-1 (Hu) Approximately 60% CRMP-5 (CV-2) Unknown Sensory neuronopathy associated SSA (Ro), SSB (La) Approximately with Sjo¨ gren syndrome 50% Vasculitic neuropathy associated with: Microscopic polyangiitis ANCA 60Y80% Eosinophilic granulomatosis ANCA 30Y40% with polyangitiis Granulomatosis with polyangiitis ANCA 90%

ANCA = antineutrophil cytoplasmic antibody; ANNA-1 = antineuronal nuclear antibody type 1; CANOMAD = chronic ataxic neuropathy, ophthalmoplegia, IgM paraprotein, cold agglutinins, and disialosyl antibodies; CRMP-5 = collapsin response mediator protein-5; IgM = immunoglobulin M; MAG = myelin-associated glycoprotein; POEMS = polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disorder, and skin changes; SSA = SjPgren syndrome A; SSB = Sjo¨ gren syndrome B.

involvement. This includes potential which single-gene testing is opti- avoidance of neurotoxic drugs used mally used. With single-gene testing, for treatment of other disorders. In a positive result is likely to be a true rare cases (eg, Fabry disease), genetic positive. diagnosis can lead to disease-specific With genetically heterogeneous dis- therapeutic intervention. orders such as CMT, the diagnostic Sanger genotype sequencing pro- strategy is more complex. Commer- vides single-gene mutational analysis, cially available panels of bundled beneficial when a limited number of single-gene tests are diagnostically genes are known to produce a sin- tempting but, in many cases, cost- gle phenotype. Hereditary neuralgic prohibitive.56 Expert opinion suggests amyotrophy represents a disorder in that the majority of patients with a

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b Peripheral Nervous System Predominant Disorders Charcot-Marie-Tooth disease (hereditary motor and sensory neuropathy) Hereditary sensory and autonomic neuropathy Hereditary motor neuropathy (distal spinal muscular atrophy) b Peripheral Neuropathies Associated With Central Nervous System or Other End Organ Involvement Familial amyloid polyneuropathy Mitochondrial disorders (MNGIE, NARP, SANDO) Hereditary disorders of lipid metabolism (eg, Fabry disease, metachromatic leukodystrophy) Porphyria Neurofibromatosis Neuropathies associated with predominant central nervous system phenotypes (eg, spinocerebellar degeneration, hereditary spastic paraparesis, ataxia telangiectasia) Miscellaneous (eg, giant axonal neuropathy)

MNGIE = mitochondrial neurogastrointestinal encephalomyopathy; NARP = neuropathy, ataxia, retinitis pigmentosa; SANDO = sensory ataxic neuropathy, dysarthria, and ophthalmoplegia.

CMT phenotype have one of four sequencing techniques were both mutations.57 Accordingly, the strategy commonplace and confounding, and historically recommended by experts identification of unrelated patho- is a targeted strategy of discriminant logic mutations may pose ethical chal- single-gene testing limited to these lenges. Whole-exome sequencing or four genes and refined by consider- whole-genome sequencing may also ations of onset age and nerve conduc- not be as comprehensive as their names tion velocity.57 imply.54 In one report, only one-third of Next-generation sequencing pro- kindreds previously undiagnosed by vides both promise and challenges in targeted-candidate gene testing were genetic testing, particularly for genet- successfully genotyped.58 Even more ically heterogeneous disorders such as recently, target-enrichment sequencing CMT. It uses high-throughput tech- was used to supplement targeted whole- nology to provide a far more cost- exome sequencing; when assessing effective means of multigene testing 197 neuropathy-related genes in 93 by simultaneously assessing the whole genetically unresolved cases of chronic exome or whole genome.56,58 Next- length-dependent neuropathy, 87 of generation sequencing also provides which had a hereditary neuropathy the opportunity to identify new muta- phenotype, only 21% were successfully tions previously unassociated with a genotyped.59 Recognition of neuropathy patient’s phenotype.54,56,58Y60 Limita- before the age of 40 coupled with a tions remain. Variants of unclear sig- positive family history increased the nificance with initial next-generation diagnostic yield to 33%, whereas later

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KEY POINTS h onset and absence of family history neuropathy pattern and clinical con- Current recommendations 55 for genetic evaluation of reduced the yield to 5%. text. In consideration of invasiveness, chronic neuropathies is A proposed algorithm has been cost, low yield, and sacrifice of sensory to initially test for the recently offered in consideration of nerve fibers, nerve biopsy is con- PMP22 deletion/ these refined next-generation sequenc- sidered a diagnostic procedure of duplication in an ing capabilities.55 This algorithm con- last resort. It may be performed as a individual with siders nerve conduction velocity, age at research tool on motor nerve branches demyelinating which the neuropathy is recognized, but is almost always clinically per- conduction velocities. and family history to direct the genetic formed on sensory nerves, such as Targeted evaluation of a patient with a chronic the sural, superficial fibular (peroneal), next-generation length-dependent neuropathy pattern. or superficial radial.61,62 In general, sequencing is In an individual with demyelinating nerve biopsies are always performed recommended in those individuals with conduction velocities, PMP22 deletion/ on nerves whose SNAP is reduced or negative PMP22 duplication testing is recommended as absent. Nerve biopsy is rarely clinically analysis or in patients the initial test performed following used in patients with a distal sensory with chronic axonal electrodiagnostic studies. Targeted polyneuropathy, hereditary neuropa- neuropathies who are next-generation sequencing with copy thy, or inflammatory demyelinating younger than 40 years number evaluation (if possible) is polyradiculopathy pattern. Biopsy in of age, have a motor recommended in patients with a nega- patients with diabetes mellitus should predominant pattern, tive PMP22 analysis with demyelinating be avoided unless a serious concern or have other similarly conduction velocities or in patients with exists for a secondary (nondiabetic) affected family unexplained chronic neuropathy who cause because of its limited value and members. are younger than 40 years of age, have risk of poor wound healing. h Peripheral nerve biopsy a motor-predominant pattern, or have Skin biopsy is primarily performed remains a valuable tool other family members with the same to assess the density of intraepidermal in a very select group disorder.55 A& or C nerve fibers.44 The specimen of individuals whose As with all algorithms, exceptions can be obtained by different tech- pattern suggests a exist. Testing for an IgM monoclonal niques and from different locations, cause for which biopsy is likely to provide a protein should be considered before but the standard is 10 cm proximal to diagnosis that cannot genetic testing in an individual with a the lateral malleolus. The biopsy is be confirmed with less chronic demyelinating length-dependent considered diagnostic of small fiber invasive means. neuropathy that is sensory predominant neuropathy if the intraepidermal nerve h Assessment of without other affected family members. fiber density is less than 5% of age- epidermal nerve fiber Conversely, testing for hereditary neu- and gender-matched controls. Other density through skin ropathyshouldbeconsideredinolder morphologic changes, such as axonal biopsy is useful in individuals without a family history or swelling, are considered less accurate. support of a diagnosis demyelinating electrophysiology if the In general, skin biopsy is performed of small fiber phenotype is characteristic of a hered- with the goal of identifying the exis- neuropathy but rarely itary neuropathy. CMT type 1B is one tence, but not the cause, of small fiber identifies the genotype recognized to present at an neuropathy. Intraepidermal nerve fiber underlying cause. older age without demyelinating elec- density has been reported to have a trophysiologic features.58 sensitivity of 90%, a specificity and positive predictive value of 95%, and a Histologic Testing negative predictive value of 91% in the Peripheral nerve biopsy is a valuable detection of small fiber neuropathy.44 tool for the evaluation of select pa- As these numbers have been acquired tients with peripheral neuropathy.7,61,62 in the absence of an ideal gold stan- Table 1-12 lists the disorders for which dard, their accuracy is not universally biopsy can be useful as suggested by accepted.20,44 A normal study effectively

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b Disorders for which nerve biopsy can be diagnostic where nerve biopsy is endorsed if not readily achieved by less invasive means Vasculitic neuropathy (systemic or nonsystemic) Amyloidosis (primary systemic) b Disorders for which nerve biopsy has characteristic or diagnostic features where diagnosis is preferably achieved by less invasive means Amyloidosis (hereditary) Leprosy Sarcoidosis Neurofibromatous neuropathy Neurolymphomatosis Hereditary metabolic/multisystem diseases Fabry disease, metachromatic leukodystrophy, Krabbe disease, adrenomyeloneuropathy, polyglucosan body disease, giant axonal neuropathy, Tangier disease Chronic inflammatory demyelinating polyradiculoneuropathy (CIDP), Guillain-Barre´ syndrome Distal acquired demyelinating symmetric (DADS) neuropathy Hereditary neuropathy with liability to pressure palsies (HNPP) Hexacarbon toxicity b Rare conditions for which nerve biopsy has been diagnostic in isolated reports Silver toxicity Hereditary disorders of uric acid metabolism excludes small fiber neuropathy, but suspected seronegative SjPgren syn- the specificity and ability to prove the drome, lymph node biopsy in sus- existence of a small fiber neuropathy is pected sarcoidosis, or small bowel less convincing.46 biopsy in suspected celiac disease. Muscle biopsy has a limited role in the diagnostic evaluation of patients CONCLUSION with peripheral neuropathy. When As with all neurologic problem-solving performed, it is usually in conjunction strategies, the approach to a patient with a nerve biopsy (eg, superficial with suspected peripheral neuropathy fibular [peroneal] nerve/peroneus should be both individualized and brevis muscle) to increase the diagnos- rational, with the goal of identifying the tic yield in disorders such as vasculitis underlying cause whenever possible. As or amyloidosis, in which the character- always, a patient is best served when his istic histologic findings may be identi- or her physician applies both knowl- fied in muscle as well as nerve. Biopsy edge and judgment, allowing for diag- of other tissues may be useful, such as nostic and therapeutic intervention when minor salivary gland (lip) biopsy in called for and providing education and

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reassurance without intervention when 11. England JD, MD Gronseth GS, Franklin G, et al. Practice parameter: evaluation of it is not. Despite advances in our under- distal symmetric polyneuropathy: role of standing of these disorders, this pro- laboratory and genetic testing (an cess still begins at the bedside with evidence-based review). Neurology Y a physician who is skilled in pattern 2009;72(2):185 192. doi:10.1212/ 01.wnl.0000336370.51010.a1. recognition, knowledgeable about as- 12. Farhad K, Traub R, Ruzhansky KM, sociated causes, and capable of evalua- Brannagan TH. Causes of neuropathy in tion and management. patients referred as ‘‘idiopathic neuropathy’’. Muscle Nerve 2016;53(6):856Y861. REFERENCES doi:10.1002/mus.24969. 1. Visser NA, Notermans NC, Linssen RSN, 13. Callaghan B, Kerber K, Langa KM, et al. et al. Incidence of polyneuropathy in Longitudinal patient-oriented outcomes in Utrecht, the Netherlands. Neurology neuropathy: importance of early detection 2015;84(3):259Y264. doi:10.1212/ and falls. Neurology 2015;85(1):71Y79. WNL.0000000000001160. doi:10.1212/WNL.0000000000001714. 2. Burns TM, Mauermann ME. The evaluation 14. Cavanagh JB. The problems of neurons with Y of polyneuropathies. Neurology 2011; long axons. Lancet 1984;1(8389):1284 1287. Y Y 76(7 suppl 2):S6Y13. doi:10.1212/ doi:10.1016/S0140 6736(84)92457 7. WNL.0b013e31820c3622. 15. Lloyd TE. Axonal transport disruption in 3. Hanewinckel R, Drenthen J, van Oijen M, peripheral nerve disease. J Peripher Nerv Y et al. Prevalence of polyneuropathy in the Syst 2012(suppl 3):46 51. doi:10.1111/ j.1529Y8027.2012.00431.x. general middle-aged and elderly population. Neurology 2016;87(18):1892Y1898. 16. Smith JA, Slusher BS, Wozniak KM, et al. doi:10.1212/WNL.0000000000003293. Structural basis for induction of peripheral neuropathy by microtubule-targeting cancer 4. Callaghan B, McCammon R, Kerber K, et al. drugs. Cancer Res 2016;76(17);5115Y5123. Tests and expenditures in the initial doi:10.1158/0008Y5472.CAN-15Y3116. evaluation of peripheral neuropathy. Arch Intern Med 2012;172(2):127Y132. 17. Tourtellotte WG. Axon transport and doi:10.1001/archinternmed.2011.1032. neuropathy relevant perspectives on the etiopathogenesis of familial dysautonomia. 5. Callaghan BC, Price RS, Feldman EL. Am J Pathol 2016;186(3):489Y499. Distal symmetric polyneuropathy: a review. doi:10.1016/j.ajpath.2015.10.022. JAMA 2015;314(20):2172Y2181. doi:10.1001/jama.2015.13611. 18. Pareyson D, Saveri P, Sagnelli A, Piscosquito G. Mitochondrial dynamics and inherited 6. Callaghan BC, Kerber KA, Lisabeth LL, et al. peripheral nerve diseases. Neurosci Lett Role of neurologists and diagnostic tests on 2015;596:66Y77. doi:10.1016/ the management of distal symmetric j.neulet.2015.04.001. polyneuropathy. JAMA Neurol 2014; 71(9):1143Y1149. doi:10.1001/ 19. Klein CJ, Duan X, Shy ME. Inherited jamaneurol.2014.1279. neuropathies: clinical overview and update. Muscle Nerve 2013;48(4):604Y622. 7. Watson JC, Dyck PJB. Peripheral neuropathy: doi:10.1002/mus.23775. a practical approach to diagnosis and 20. Kissel JT, Smith AG. Understanding small symptom management. Mayo Clin Proc 2015;90(7):940Y951. doi:10.1016/ fiber neuropathy: the long and the short Y j.mayocp.2015.05.004. of it. JAMA Neurol 2016;73(6):635 637. doi:10.1001/jamaneurol.2016.0256. 8. England JD, Gronseth GS, Franklin G, et al. Distal symmetric polyneuropathy: a 21. Drew AP, Blair IP, Nicholson GA. Molecular definition for clinical research. Neurology genetics and mechanisms of disease in distal 2005;64(2):199Y207. hereditary motor neuropathies: insights directing future genetic studies. Curr Mol 9. Bodofsky EB, Carter GT, England JD. Is Med 2011;11(8):650Y665. doi:10.2174/ electrodiagnostic testing for polyneuropathy 156652411797536714. overutilized? Muscle Nerve 2017;55(3): 22. Saperstein DS, Katz JS, Amato AA, 301Y304. doi:10.1002/mus.25464. Barohn RJ. Clinical spectrum of chronic 10. Vinik AI. Clinical practice. Diabetic sensory acquired demyelinating polyneuropathies. and motor neuropathy. N Engl J Med Muscle Nerve 2001;24(3):311Y324. 2016;374(15):1455Y1464. doi:10.1056/ doi:10.1002/1097Y4598(200103)24:3G311:: NEJMcp1503948. AID-MUS100193.0.CO;2-A.

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