Clinical Approach to Peripheral Neuropathy: Anatomic Localization and Diagnostic Testing

Home , Plexopathy, Polyradiculoneuropathy

Review Article

Address correspondence to Dr Howard W. Sander, Clinical Approach to New York University School of Medicine, 400 E. 34th St, RR-311, New York, NY 10016, Peripheral Neuropathy: [email protected]. Relationship Disclosure: Dr Alport reports no Anatomic Localization disclosure. Dr Sander serves on the speakers’ bureau for Grifols and Walgreens and has been an independent peer and Diagnostic Testing reviewer for IPRO and IMEDECS. Dr Sander has also Adina R. Alport, MD; Howard W. Sander, MD served as an expert witness. Unlabeled Use of Products/Investigational Use Disclosure: ABSTRACT Dr Alport reports no disclosure. Purpose of Review: This article provides a clinical approach to peripheral neuropathy Dr Sander discusses the based on anatomic localization and diagnostic testing. unlabeled use of steroids and plasmapheresis for the Recent Findings: Advances have been made in the evaluation of small fiber neu- treatment of chronic ropathy and in the known genetic causes of neuropathy. inflammatory demyelinating Summary: History and physical examination remain the most useful tools for evaluating polyradiculoneuropathy. Copyright * 2012, peripheral neuropathy. Characterization of a neuropathy aids in limiting the differential American Academy diagnosis and includes consideration of temporal profile (tempo of onset and duration), of Neurology. All rights heredity, and anatomic classification. Anatomic classification involves (1) fiber type reserved. (motor versus sensory, large versus small, somatic versus autonomic), (2) portion of fiber affected (axon versus myelin), and (3) gross distribution of nerves affected (eg, length- dependent, length-independent, multifocal). Diagnostic testing may include serologic and CSF evaluation, electrodiagnosis, skin biopsy, quantitative sensory testing, autonomic testing, nerve biopsy, confocal corneal microscopy, and laser Doppler imager flare.

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INTRODUCTION ders, which are termed motor neuron The prevalence of peripheral neurop- disease, and dorsal root ganglion disor- athy is estimated to be between 2% ders, which are termed sensory neuron- and 8%.1 Given the numerous causes of opathy or ganglionopathy. Peripheral polyneuropathy, determining the etiol- neuropathies can be subdivided into ogy can be challenging.2 This article two major categories: primary axonopa- provides a framework for the clinician thies and primary myelinopathies. to approach the diagnosis and testing Neuropathies can be further subdi- of a patient with suspected polyneur- vided on the basis of the diameter of the opathy. The terms neuropathy, polyneu- impaired axon. Large myelinated axons ropathy, and peripheral neuropathy will include motor axons and sensory axons be used synonymously in this article. responsible for proprioception, vibration, and light touch. Thinly myelinated ANATOMY axons include sensory fibers responsible Neuropathic disorders encompass dis- for light touch, pain, temperature, and eases of the neuron cell body (neuron- preganglionic autonomic functions. opathy) and their peripheral processes Small unmyelinated fibers convey pain, (peripheral neuropathy). Neuronopa- temperature, and postganglionic auto- thies include anterior horn cell disor- nomic functions.

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KEY POINTS h The peripheral nervous Peripheral nerve damage can com- associated with orthostasis. Patients with system consists of large prise a focal lesion of a single nerve vasomotor instability may report cold myelinated motor axons (mononeuropathy) or multiple nerves extremities associated with skin color and sensory axons that (polyneuropathy). This article focuses and trophic changes. convey proprioception, on polyneuropathy. Because ‘‘sick It is helpful to ask about impair- vibration, and light touch; nerves are liable to compression,’’ a ment in activities of daily living, such small myelinated axons mononeuropathy may be superimposed as a change in handwriting, problems that convey light touch, on a polyneuropathy (eg, carpal tunnel fastening jewelry or buttons or inserting pain, temperature, and syndrome superimposed on a diabetic and turning keys, tripping on a carpet preganglionic autonomic polyneuropathy). or a curb, falling, and having difficulty function; and small arising from a commode. Details regard- unmyelinated axons HISTORY ing disease onset, duration, and pro- that convey pain, temperature, and Neuropathy may present with a variety gression are quite important for further postganglionic of signs and symptoms that allow the characterization. The patient should be autonomic functions. clinician to narrow the list of diagnostic queried regarding asymmetry at onset, possibilities. Symptoms may be classified location at first onset, involvement of the h Neuropathy symptoms can be motor, sensory, or as either negative or positive. Positive trunk or cranial nerve region, and the autonomic. Questions symptoms reflect inappropriate sponta- specific tempo of progression (mono- regarding impairment in neous nerve activity, whereas negative phasic, steadily progressive, fluctuating, activities of daily living symptoms reflect reduced nerve activ- or stepwise). Other important questions are informative. ity. Negative motor symptoms include regarding the history are similar to those weakness, fatigue, and wasting, and that would be asked of any other patient positive symptoms include cramps, with a suspected neurologic disorder. twitching, and myokymia. Weakness These include questions concerning may not be appreciated until 50% to impairment of consciousness, visual dis- 80% of nerve fibers are lost; positive turbances (eg, diplopia), dysphagia, dys- symptoms may present earlier in the arthria, focal motor weakness, sensory disease process. Negative sensory symp- disturbances, radicular pain, autonomic toms include hypesthesia and gait dysfunction, and bowel and bladder abnormalities such as ataxia. Other dysfunction. Bowel and bladder dysfunc- common symptoms include difficulty tion is uncommon in polyneuropathy differentiating hot from cold and wor- (apart from cauda equina syndrome) sening balance, especially in the dark and should prompt a search for an al- when visual input is less able to com- ternative diagnosis. pensate for proprioceptive loss. Positive The standard history and physical ex- sensory symptoms include burning or amination serve as a general framework lancinating pain, buzzing, and tingling/ for the approach to neuropathy. Social paresthesia. Other symptoms include history can include questions regarding discomfort to sensory stimuli that are occupation (possibility of toxic expo- normally not painful (allodynia) and an sures to solvents, glues, fertilizers, oils, increased sensitivity to painful stimuli and lubricants), sexual history (HIV, (hyperalgesia). Patients with hyperalge- hepatitis C), recreational drug use (vas- sia may describe a sensation of walk- culitis secondary to cocaine), excessive ing on hot coals. Symptoms suggesting alcohol intake, dietary habits (eg, strict autonomic nerve involvement include vegan diet), and smoking (paraneo- early satiety, bloating, constipation, diar- plastic disease). Drugs of abuse con- rhea, impotence, urinary incontinence, fer a severalfold risk: the toxic effects abnormalities of sweating (hyperhidro- of the agent drug or impurities plus sis, anhidrosis), and lightheadedness the behavior-related consequences,

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT including HIV, hepatitis C, and nu- changes [POEMS]), oral ulcers (Behc¸et h History should include tritional deficiency. A childhood his- disease, HIV), salivary gland swelling, dry timeline of disease tory of ‘‘clumsiness’’ or poor athletic eyes or mouth (sarcoidosis, Sjo¨gren syn- progression, social performance suggests a hereditary drome), extremity hair loss (hair follicle history, family history, cause. denervation), and gum ‘‘lead lines’’ (lead medical history (including Medical and family history should exposure). Integumentary changes may underlying conditions focus on illnesses associated with neurop- suggest a specific diagnosis. For exam- associated with athy, such as endocrinopathy (diabetes ple, Mees lines in the nails may suggest neuropathy), surgical mellitus, hypothyroidism), renal insuffi- arsenic or thallium poisoning; alopecia history, and review of ciency, hepatic dysfunction, connective may suggest hypothyroidism, systemic neurotoxic medications. tissue disorders, and cancer. Patients lupus erythematosus (SLE), amyloidosis, with cancer may develop neuropathy or thallium poisoning; curly hair may related to nutritional deficiency, chemo- suggest giant axonal neuropathy; and therapy side effects, or a paraneoplastic distal calf hair loss may suggest distal syndrome. Surgical history should ad- symmetric axonal polyneuropathy. Skel- dress bariatric surgery, multiple orthope- etal deformities such as hammer toes, dic procedures, and multiple surgeries pes cavus, and kyphoscoliosis are sug- for ‘‘entrapped nerves.’’ gestive of an inherited polyneuropathy. The medication list should be re- The feet should be specifically examined viewed to determine a possible tempo- for signs of trauma in an insensate foot ral association between agent use and that could be an early indicator of an neuropathy onset. The ‘‘coasting effect’’ impending Charcot foot deformity. of toxic neuropathy describes symptom Nerve enlargement can suggest demye- progression for months to a year despite linating neuropathy, neoplasia in neuro- agent discontinuation. HIV-related treat- fibromatosis, or possible leprosy. Easy ment and chemotherapeutic agents are locations to palpate nerves are the ulnar the most common causes of toxic neu- nerve in the ulnar groove and the ropathy. Antibiotics such as quinolones superficial radial nerve with a rolling may induce a neuropathy. Nonprescrip- palpation against the radius just prox- tion medications should also be as- imal to the wrist. sessed. Vitamin B6 (pyridoxine) dosing Cranial nerve assessment should exceeding 50 mg to 100 mg daily (and include assessment for anosmia (Refsum possibly even lower doses) may induce disease, vitamin B12 deficiency), optic neuropathy. atrophy (inherited neuropathies with Review of systems should include central and peripheral demyelination), dermatologic changes, arthralgias, dry anisocoria or impaired pupillary light re- eyes and mucous membranes, ortho- flexes (parasympathetic dysautonomia), stasis, gastrointestinal symptoms, and impaired ocular motility (botulism, constitutional symptoms (fever, weight Miller Fisher syndrome), facial weakness loss, night sweats). (Guillain-Barre´ syndrome [GBS]), and tri- geminal sensory loss (Sjo¨gren syndrome). PHYSICAL EXAMINATION A comprehensive motor examination Orthostatic vital signs may identify evi- should assess muscle bulk, including dence of dysautonomia. Skin and mu- observation for intrinsic hand and foot cous membranes may demonstrate muscle atrophy, hyperexcitability, tone, vasculitic rashes (purpura, livedo retic- and strength using the Medical Research ularis), hyperpigmentation (polyneurop- Council scale. Many neuropathies pres- athy, organomegaly, endocrinopathy, ent with a relative symmetry of weak- monoclonal gammopathy, and skin ness. Dynamometry can be used for

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KEY POINTS & V h Weakness of flexion and more precise strength measurement. Polyneuropathy symmetric but extension of the small Because most neuropathies cause distal length-independent V toes and weakness of weakness, the intrinsic foot muscles & Polyneuropathy multifocal great toe extension may may be affected first, resulting in clawed & Radiculopathy (including suspended be an early sign of motor feet and hammer toes. Weakness of sensory level, saddle anesthesia) dysfunction. flexion and extension of the small toes & Plexopathy h The sensory examination and weakness of great toe extension & Central causes (syrinx, heminumbness, should be approached may occur early in the disease. The thoracoabdominal sensory level) with knowledge of angle between the shin and the unsup- During light touch and pin testing, peripheral nerve anatomy ported foot should be approximately ask the patient whether the tested areas and types of disease 130 degrees. A larger angle suggests feel the same or different from other patterns. ankle dorsiflexion weakness. In the areas. Attempt to establish an area of hands, the second and fifth digit ab- relatively normal sensation for com- ductors are often affected first. parison. Compare proximal and distal The sensory examination should be locations; the face, arm, and leg; and the approached with peripheral nerve anat- right and left sides. Most major derma- omy and types of disease patterns in tomes and nerves should be covered. A mind. It can be divided into small and suggested initial screen involves testing large fiber evaluation. Assessment of bilaterally at the forehead, cheek, chin, large fiber function includes vibration, lateral upper arm, palmar surfaces of joint position, and light touch, and digits two and five, lateral thigh, calf (an- small fiber assessment includes pin- teromedial, anterolateral), distal dorsum prick and temperature. Romberg test- of great toe, and lateral sole toward the ing also evaluates large fiber function. plantar aspect. Temperature sensation Light touch evaluates low threshold canbeassessedwithicewater,buta mechanoreception and is mediated by tuning fork may be sufficiently cold and both small and large fibers. Monofilament is readily available. probes can grade severity of loss. Detec- Vibratory perception is best assessed tion of lightest touch or stroking repre- with a 128-Hz tuning fork. The malleo- sents a measure of low-threshold sensory lus, tibial tuberosity, finger, and wrist perception. Impairment of perception to can be assessed. The time interval until 10-g microfilaments is associated with perception of vibration is lost is mea- increased risk of unappreciated trauma. sured. A young adult should appreciate Small fiber evaluation may be per- vibration at the great toe for a minimum formed by examining pain and tem- of 15 seconds; this value may decline by perature using a pin or broken cotton 1 second per decade. Vibratory percep- applicator stick. The goal is to apply tion of less than 10 seconds at the great sharp stimuli without applying signifi- toe is abnormal at any age. A quantita- cant pressure. Difficulty distinguishing tive tuning fork can be more precise. To between sharp and dull stimuli indicates minimize the time needed to perform loss of nociceptive fibers relative to low- the vibratory examination, we suggest threshold mechanoreceptor fibers. an alternative testing method. Initial While performing the sensory exami- testing uses only a very light percussion nation, think anatomically to discern of the tuning fork. If vibration is de- different patterns of numbness, includ- tected, then vibratory perception is ing the following: considered normal in that location. If & Mononeuropathy vibratory perception is not detected, & PolyneuropathyVdistal symmetric then a moderate or a strong percussion

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS can be used. This leads to a rapid and ease) and the spine (cervical spondy- h Ankle jerk hyporeflexia relatively reproducible vibratory percep- lotic myelopathy, multiple sclerosis, or areflexia is common tion assessment with four possible grades. poliomyelitis related to West Nile virus) with length-dependent Joint position testing is less sensitive that may masquerade as neuropathy neuropathy, but ankle than vibratory testing for large fiber should be excluded. Some neuropathies reflexes are normal with function and may only be impaired in may coexist with CNS disease. Alterna- small fiber neuropathy. severe cases. Joint position is tested in tive neuromuscular disorders should h Gait examination can the large toe and second finger at the also be considered, including polyra- reveal weakness not distal interphalangeal joint. The digit diculopathy (multiple compressive radi- identified on manual should be held at the lateral borders culopathies related to spondylosis, muscle testing. The and the movement excursion should be subarachnoid space infection, or ma- patient may be asked to minimal. Proximal joints are tested if lignancy), ALS, neuromuscular junction heel, toe, and tandem distal impairment is present. disease, and myopathy. MRI may aid in walk; squat; and hop. Reflex impairment aids in determi- localization. h Characterization of a nation of a lower motor neuron locali- neuropathy includes zation. Reinforcement can augment consideration of the hypoactive reflexes. Ankle hyporeflexia temporal profile (tempo CHARACTERIZATION OF A or areflexia is common in large fiber of onset and duration), NEUROPATHY heredity, and anatomic neuropathy, but ankle reflexes are typi- classification. Anatomic cally preserved with small fiber neurop- The history and physical examination are classification includes athy (SFN). Reflexes may be preserved often able to confirm a polyneuropathy. However, electrodiagnostic studies, skin (1) fiber type (motor in a mild to moderate large fiber neu- versus sensory, large biopsy, quantitative sensory testing, and ropathy. Reflexes diminish with age; versus small, somatic an absent ankle jerk at age 80 may be other testing may be needed. These versus autonomic), normal. tests are described in the next section. (2) portion of fiber Gait examination can reveal subtle In addition to confirming a polyneurop- affected (axon versus weakness not noted on manual muscle athy, these tests may help with the next myelin), and (3) gross testing, especially with toe, heel, and step of evaluation, characterization of the distribution of nerves tandem walking; squatting; and hop- neuropathy. Characterization of a neu- affected (eg, ping. Footdrop may result in a steppage ropathy includes consideration of the length-dependent, gait that is sometimes audible. In length- temporal profile (tempo of onset and length-independent, multifocal). dependent neuropathy, patients have duration), heredity, and anatomic classi- h more difficulty heel walking than toe fication. Anatomic classification involves Characterization of a walking. A wide-based gait or difficulty (1) fiber type (motor versus sensory, neuropathy helps the with tandem walking may highlight large versus small, somatic versus au- clinician minimize the testingneededto subtle sensory ataxia. tonomic), (2) portion of fiber affected (axon versus myelin), and (3) gross distinguish among the numerous toxic, distribution of nerves affected (eg, hereditary, and CONFIRMATION OF A length-dependent, length-independent, acquired disorders. NEUROPATHY multifocal). On the basis of the history and physical Characterization of the neuropathy examination, the physician should assess helps the clinician minimize the test- whether the signs and symptoms corre- ing needed to determine the etiology of late with a neuropathy. The first step is the neuropathy. Diabetic neuropathy is to confirm that the signs and symptoms the most common cause of neuropathy correspond to a neurologic disease in the United States and has several phe- rather than a primarily psychiatric dis- notypes, which are discussed in detail order.3 Next, diseases of the brain in the article ‘‘Diabetic Neuropathy’’ in (multiple sclerosis, cerebrovascular dis- this issue of .

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KEY POINTS h Most neuropathies are Onset and Duration of clinician. HNPP is an exception, as it of- chronic and progressive Clinical Course ten presents with a relapsing and remit- with an insidious onset; Most neuropathies are chronic and pro- ting course. an acute onset over 1 gressive with an insidious onset. Thus, a Patients with inherited neuropathies month or less suggests neuropathy that has an alternate onset tend to have a relative paucity of symp- Guillain-Barre´ syndrome, or course may direct the clinician to a toms in comparison to their physical vasculitis, porphyria, an limited differential diagnosis. A known examination signs. Genetic neuropa- infectious etiology (eg, precise date of onset is suggestive of thies are covered in more detail in the diphtheria, Lyme disease), an infectious neuropathy. Hyperacute article ‘‘Charcot-Marie-Tooth Disease or toxic/drug exposure lesions presenting over 24 to 72 hours and Related Genetic Neuropathies’’ in (eg, arsenic, thallium, this issue of . chemotherapeutic are rare and may reflect vasculitic lesions agents, dapsone). causing mononeuropathy multiplex. An acute onset with presentation Anatomic Classification h A genetic cause of and progression over 1 month or less There are several different ways to neuropathy should be classify a neuropathy anatomically. The considered in patients suggests GBS, vasculitis, porphyria, an types of classification fall into three main with a family history of infectious etiology (eg, diphtheria, neuropathy, lack of Lyme disease), or toxic/drug exposure groups: nerve fiber type, portion of fiber positive sensory (eg, arsenic, thallium, chemotherapeu- affected, and distribution of nerves af- symptoms, early age tic agents, dapsone). In a critical illness fected in the body. at onset, symmetry, setting, development of weakness over Fiber type. Classification by fiber type associated skeletal days is most likely related to critical includes motor versus sensory, somatic abnormalities, or very illness myopathy with thick filament versus autonomic, and small versus large slowly progressive (myosin) loss, but may be caused by fiber size. Many neuropathies involve a course. critical illness neuropathy. combination of fiber subtypes. Subacute onset of neuropathy over Motor versus sensory.Itisrarefor 6 months or less can suggest toxic neuropathy syndromes to be purely neuropathy, nutritional deficiency, ma- motor or sensory. Although most neu- lignancy, paraneoplastic syndromes ropathies are mixed, they may predomi- (sensory neuronopathy), and some me- nantly reflect dysfunction of one fiber tabolic abnormalities. A neuropathy with type. It is relatively common for pa- a relapsing and remitting course sug- tients to notice only motor or sensory gests demyelination and subsequent symptoms but to have the examination remyelination. Possible etiologies in- or diagnostic testing confirm that both clude chronic inflammatory demyelin- fiber types are involved. During history ating polyneuropathy (CIDP), porphyria, taking, sensory symptoms often over- and hereditary neuropathy with liability shadow motor symptoms. Motor nerve to pressure palsies (HNPP). Repeated symptoms are infrequently the sole pre- toxic exposures should also be consid- sentation. This is related to many fac- ered. Vasculitis may also have this tem- tors, including the exquisite sensitivity poral profile. of the sensory system, the earlier involvement of the sensory system, and the redundancy and reserve built into Heredity the motor system. Intrinsic foot muscle A genetic etiology should be considered weakness often goes unnoticed by the in a generalized polyneuropathy. Family patient. history, lack of positive sensory symp- Neuropathies with predominant motor toms, early age at onset, symmetry, as- involvement include GBS, CIDP, multi- sociated skeletal abnormalities, and very focal motor neuropathy (MMN), por- slowly progressive course may alert the phyria, diphtheria, lead intoxication,

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS botulism, hereditary neuropathies, and ‘‘Painful Small Fiber Neuropathies’’ in h Prominent autonomic toxic exposure related to dapsone, this issue of .Amyloid neuropathy symptoms amiodarone, and vincristine. Pure sen- neuropathy may cause severe pain. suggest diabetes sory neuropathy is rare and can result Isolated SFN may evolve to include mellitus, amyloidosis, or from diabetes mellitus, vitamin B12 large fibers. Guillain-Barre´ syndrome. deficiency, HIV, amyloidosis, leprosy, Axonopathy versus myelinopathy. A h Features suggesting Sjo¨gren syndrome, sarcoidosis, uremia, neuropathy may be classified as pre- demyelinating paraneoplastic syndromes, pyridoxine dominantly or initially involving the neuropathy include (vitamin B6) intoxication, and hereditary Schwann cell, causing demyelination, or weakness without neuropathies. involving the axon itself. This classifica- atrophy, a Somatic versus autonomic. Autonomic tion can be made electrodiagnostically length-independent dysfunction may be seen as a compo- or pathologically. Features suggestive distribution with a nent of a generalized polyneuropathy of a demyelinating neuropathy include proximal predominant or or a distal small fiber sensory neurop- weakness without atrophy, a length- asymmetric/patchy athy or may occur as a result of a independent distribution with a proxi- distribution either clinically or predominantly autonomic neuropathy. mal predominant or asymmetric/patchy electrodiagnostically, Although autonomic nerves outnumber distribution either clinically or electro- early involvement of somatic nerves, autonomic neuropathy diagnostically, early involvement of proxi- proximal reflexes, symptoms are less common than so- mal reflexes, and myokymia. On the and myokymia. matic nerve symptoms. When auto- other hand, distal reflex loss (ankle jerk) nomic symptoms predominate, the with preserved proximal reflexes is most common causes are diabetes mel- common in length-dependent neurop- litus, amyloidosis, and GBS. If the onset athy. The etiology of demyelinating neu- is acute or subacute, the main con- ropathy includes genetic neuropathy siderations are autoimmune autonomic (Charcot-Marie-Tooth disease [CMT] ganglionopathy, paraneoplastic syn- type 1, HNPP, Refsum disease, meta- dromes, GBS, botulism, toxic neurop- chromatic leukodystrophy), CIDP, GBS, athies, and acute porphyria. In chronic MMN, paraproteinemia-related neuropa- predominantly autonomic neuropathies, thy, diphtheria, infectious neuropathy considerations include diabetes, amyloi- (HIV, Lyme disease, leprosy, hepatitis dosis (primary and familial), inherited C, diphtheria), and, less commonly, diseases (eg, hereditary sensory and au- toxin-related neuropathy (eg, n-hexane, tonomic neuropathy [HSAN]), Fabry dis- amiodarone). CIDP may be associated ease, Sjo¨gren syndrome, and toxic and with systemic disease, including infec- infectious neuropathy, including HIV. tions, inflammatory bowel disease, met- Fiber size. In many polyneuropa- abolic conditions, and connective tissue thies, small fibers are predominantly disorders. affected, causing patients to report pain Distribution. Afinalwaytoanatom- as their main symptom. Common causes ically classify neuropathy is based on of SFN include diabetes, glucose intoler- the global distribution of the neurop- ance, toxins (especially alcohol), Fabry athy throughout the body and the disease, Tangier disease, HIV, amyloido- location along the nerve pathway. The sis, connective tissue disease (Sjo¨gren initial question is whether a neuropathy syndrome, SLE), sarcoidosis, HSANs, is symmetric. The next question is idiopathy, and drugs (eg, antiretrovirals). length dependency. Most neuropathies Amoredetailedlistoflesscommon are symmetric and length-dependent. causes can be found in a textbook by They are most commonly attributed Herskovitz and colleagues.4 This topic is to metabolic, idiopathic, inherited, or also discussed in detail in the article toxic conditions.5 Distal dying-back

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KEY POINTS h Most neuropathies are axonopathies have a classic symmetric nerve involvement with infectious, met- symmetric and length-dependent pattern of symptom abolic, and toxic neuropathies or with length-dependent and evolution. Sensory symptoms start in HNPP cause this pattern. The differential are commonly attributed the feet, which are supplied by the diagnosis of length-independent neuro- to metabolic, idiopathic, longest axons. After dysesthesia and pathy includes CIDP (demyelinating inherited, or toxic numbness ascend to the calves, the fin- neuropathyVespecially multifocal ac- conditions. Hand gertips become affected. The legs, fore- quired demyelinating sensory and motor symptoms begin once leg arms, and eventually the anterior chest neuropathy [MADSAM] variant), MMN, symptoms have ascended may be affected. Motor symptomatol- Lyme disease, HIV, sarcoidosis, carci- toward the knees. ogy first affects the intrinsic foot mus- noma, amyloidosis, lymphoma, porphy- h A neuropathy with cles, causing toe flexor weakness and ria, leprosy, and Tangier disease. significant early proximal clawed toes. Anterior tibial compart- A neuropathy with significant early involvement, especially ment muscle weakness then causes proximal involvement raises the pos- hip flexor weakness, ankle dorsiflexion weakness. Plantar sibility of a demyelinating neuropathy. raises the possibility of flexion is relatively preserved, possibly Combined proximal and distal weakness ademyelinating related to the functional redundancy of is the hallmark of CIDP. In particular, neuropathy. Combined proximal and distal the large bulk of posterior compartment hip flexor weakness is suggestive of weakness is the hallmark musculature. The intrinsic hand muscles CIDP, as it is frequently involved and of chronic inflammatory become involved only after the calf mus- cannot be attributed to L4-S1 com- demyelinating cles are involved. Motor weakness is pressive polyradiculopathy. However, polyradiculoneuropathy. usually greater in extensor groups than demyelinating neuropathy may mimic in corresponding flexor groups. Unfortu- a length-dependent pattern, as the nately, despite adequate and thorough longer fibers have a higher probability evaluation, many chronic sensorimotor of being affected. axonopathies remain idiopathic.6 In a predominantly sensory neurop- In contrast, length-independent athy, asymmetric, proximal, or patchy neuropathies or asymmetric neuropa- distribution of dysfunction suggests a thies may begin proximally or have a sensory neuronopathy directly affect- patchy distribution. They are commonly ing the dorsal root ganglia initially. immune mediated or infectious and Sensory involvement of lips and mouth associated with demyelination. Although suggest a length-independent process. demyelinating neuropathy may affect The differential diagnosis of dorsal any nerve segment, the segments tra- root ganglionopathy is limited and in- versing the subarachnoid space and the cludes heavy metals, paraneoplastic most distal segments may be more syndromes, Sjo¨gren syndrome, HIV, susceptible to metabolic and immuno- pyridoxine toxicity, cisplatinum, and logic changes because of a weaker idiopathic. A limited number of neu- blood-nerve barrier. Length-independent ropathies involve the cranial nerves. neuropathies run a spectrum from a Celiac neuropathy may include facial sen- clear mononeuropathy multiplex to a sory symptoms (Case 1-1). Acute facial neuropathy with mild patchiness or diplegia suggests GBS. CIDP and the asymmetry noted on clinical or electro- gelsolin variety of amyloidosis also cause diagnostic examination. The term mono- facial diplegia. The facial palsies associ- neuropathy multiplex traditionally refers ated with Lyme disease and sarcoidosis to individual nerve involvement in a may occur either simultaneously or sepa- stepwise temporal progression. With rated in time. In Melkersson-Rosenthal severe disease, this may result in a con- syndrome recurrent facial paralysis, lip fluent pattern similar to asymmetric and facial swelling, and fissured tongue polyneuropathy. Vasculitis and multiple occur.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 1-1 h Blood testing for the etiology of a neuropathy A 45-year-old teacher presented with a 6-month history of progressive should include fasting bilateral foot, right thigh, and left face paresthesia. She denied loss of blood glucose, vision, diplopia, dysarthria, dysphagia, incontinence, limb weakness, or electrolytes to assess balance difficulty. She was recently diagnosed with hypertension and renal and liver function, started on atenolol. She was married with three children. She drank complete blood count socially and smoked one pack of cigarettes per day. She had a family and differential, vitamin history of diabetes and ovarian cancer. Physical examination was B , erythrocyte remarkable for reduced sensation to pinprick in the V2 distribution of the 12 sedimentation rate, left face and reduced sensation to pinprick in the right thigh and foot. The thyroid-stimulating remainder of the neurologic examination was normal. MRI of the brain hormone or thyroid was normal. Electrodiagnostic testing of the legs, including bilateral sural function tests, and and superficial peroneal responses, was normal. Blink reflex responses serum immunofixation were normal. Skin biopsy revealed normal right distal leg intraepidermal electrophoresis. nerve fiber density and reduced right thigh intraepidermal nerve fiber density. Serum gliadin IgG and transglutaminase antibody levels were elevated. Laboratory testing for the following was normal: complete blood count, metabolic profile, 2-hour glucose tolerance test, hemoglobin A1c, Lyme disease, angiotensin-converting enzyme, anti-Hu antibodies, HIV, antinuclear antibodies, erythrocyte sedimentation rate, C-reactive protein, double-stranded DNA, SS-A, SS-B, and gliadin IgA. Duodenal biopsy revealed severe villous flattening, crypt hyperplasia, and intraepithelial lymphocytosis. Comment. This patient has a length-independent small fiber sensory polyneuropathy, which is confirmed by a decreased intraepidermal nerve fiber density. A diagnosis of celiac disease (gluten-sensitive enteropathy) is suspected based upon the elevated gliadin IgG and transglutaminase antibodies and is confirmed by the duodenal biopsy findings. Celiac neuropathy may occur in patients without gastrointestinal complaints. Multifocal neuropathy affecting the arms more than the legs also raises the possibility of lead toxicity and porphyria. In leprosy, the nerves running closest to the surface of the body are most vulnerable because the cool tissue temperatures favor the mycobacterial growth.

DIAGNOSTIC TESTING serum immunofixation electrophoresis Laboratory and Genetic Testing (IFE). Determining which laboratory tests to The tests with the highest yield of use to evaluate a neuropathy is challeng- abnormality are blood glucose, vitamin ing. Numerous tests are available, and B12 with methylmalonic acid and homo- they can be expensive. The AAN pub- cysteine, and IFE. The 2-hour glucose lished practice parameters to guide labo- tolerance test is more sensitive than ratory and genetic testing in distal hemoglobin A1c and fasting plasma symmetric polyneuropathy.1 The prac- glucose and should be considered if tice parameters recommend the fol- the initial testing is normal. Vitamin B12 lowing tests: fasting blood glucose, deficiency is a common treatable cause electrolytes to assess renal and liver func- of neuropathy. Attention should be paid tion, complete blood count and differ- to the numeric value. When the vitamin ential, serum vitamin B12, erythrocyte B12 level is less than 400 pg/mL, the sedimentation rate, thyroid-stimulating metabolites methylmalonic acid and hormone or thyroid function tests, and homocysteine should be tested to

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KEY POINT 7 h Genetic testing is most increase diagnostic yield. Serum IFE should be considered especially if a con- effective when tailored to is more sensitive than serum protein comitant myelopathy is present or a pre- the clinical presentation, electrophoresis in detecting monoclonal disposing factor such as bariatric surgery inheritance pattern, and gammopathy. When the laboratory or excess zinc intake has occurred. A electrodiagnostic results return, specifically check whether vitaminElevelmayalsobeconsidered, classification. IFE was performed, because phlebot- especially if the history suggests impaired omy laboratories do not always perform fat absorption. Chronic neuropathy may IFE as an independent test in addition be associated with IgM paraproteinemia to the serum protein electrophoresis. A such as myelin-associated glycoprotein negative IFE report will typically include (MAG), sulfatide, and GD1b antibodies. a statement that a monoclonal gam- In demyelinating neuropathy with very mopathy was not detected. Quantitative prolonged distal latencies, consider anti- Igs (IgG, IgA, IgM) may suggest an un- MAG. If MMN is suspected, consider anti- derlying lymphoproliferative disorder. If GM1. In patients with variants of GBS, the initial tests are not revealing, sero- consider testing for anti-GQ1b, anti- logic tests focusing on individual dis- GM1, and anti-GD1a. eases should be considered. In neuropathy with significant auto- Laboratory evaluation of suspected nomic involvement, consider evaluation vasculitis and connective tissue disorders for amyloidosis (fat pad aspirate, rectal (eg, Sjo¨gren syndrome, SLE, rheumatoid biopsy, transthyretin/genetic testing), arthritis, mixed connective tissue disease, urinary porphyrins, paraneoplastic anti- Wegener granulomatosis) may include body panel (including ganglionic acetyl- C-reactive protein, antinuclear antibody, choline receptor antibody, anti-Hu), double-stranded DNA, rheumatoid fac- HSAN syndromes (genetic testing), and tor, proteinase 3, myeloperoxidase, Fabry disease ("-galactosidase assay). complement, angiotensin-converting Genetic testing is most effective enzyme, SS-A and SS-B, hepatitis B and when it is tailored to the clinical pre- C panels, and cryoglobulin. For infec- sentation, inheritance pattern, and elec- tious conditions, consider Lyme disease, trodiagnostic classification. Currently, rapid plasma reagin, and HIV. In a pre- CMT phenotypes have been linked to dominantly sensory neuropathy, espe- 44 loci with mutations in 50 genes. The cially in a patient who smokes, consider efficiency of genetic testing can be im- testing for anti-Hu antibodies, which are proved with a stepwise evaluation. For associated with paraneoplastic neurop- example, hereditary demyelinating neu- athy. Celiac disease was seen in 2.5% ropathy is attributable to duplication of of neuropathy patients at a referral cen- the peripheral myelin protein 22 gene, ter.8 Testing for antigliadin IgG and IgA PMP22, in 70% of cases, so it is rec- and transglutaminase should be con- ommended for initial testing. The most sidered if initial laboratory tests are common mutation associated with axo- nondiagnostic. nal CMT is the mitofusion 2 gene, Serum and urine screening for heavy MFN2. A detailed genetic testing algo- metal analysis is rarely useful unless rithm is available in the AAN practice heavy metal exposure is suspected. If parameters.1 increased urinary arsenic is detected, Additional testing may be warranted fractionation can distinguish between in- if a specific disease is suspected. This nocuous organic arsenic from food (eg, testing may include chest x-ray or CT for shellfish) and toxic inorganic arsenic. sarcoidosis; PET scan or CT of chest, Copper deficiency neuropathy can be as- abdomen, and pelvis for malignancy; sessed with a serum copper level. This skeletal survey and bone marrow biopsy

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT for lymphoproliferative disease; salivary myelinopathy. Demyelination may be h Electrodiagnostic studies gland biopsy for Sjo¨gren syndrome; classified as uniform or patchy. Electro- are helpful in determining endoscopy and duodenal biopsy for diagnostic studies may be repeated to the location of peripheral celiac disease; and colonoscopy for in- monitor disease progression. Although nervous system flammatory bowel disease. the examination may be uncomfortable, involvement, the If an infectious, immune-mediated, risk is minimal. Adequate sampling of population of nerves or neoplastic cause of a neuropathy is nerves is necessary to assess for a mono- affected (motor versus suspected, CSF can be evaluated. Malig- neuropathy multiplex and for asymme- large fiber sensory), the nancy and infection (eg, HIV, cytome- try. In neuropathy, electrodiagnostic severity and distribution galovirus, Lyme disease, West Nile virus) evaluation should include a minimum of involvement, the cause a pleocytosis, whereas a dysim- of two limbs. Additional limbs should be portion of nerve affected (axon versus myelin), mune neuropathy is typically associated evaluated if the initial testing is not suf- and the chronicity and with elevated protein with normal cell ficiently diagnostic, if there is any clini- regeneration status. counts (cytoalbuminologic dissocia- cal or electrophysiologic suggestion of tion). MRI may document nerve root asymmetry or a length-independent pro- enhancement in CIDP, show nerve root cess, or if there is a concern regarding clumping in arachnoiditis, or reveal multiple diagnoses. nerve enlargement in tumors. NCSs involve electrical stimulation of For an extensive list of tests to con- a nerve and recording over a nerve or sider in neuropathy see Herskovitz and muscle, usually using surface electrodes. colleagues.4 Despite an extensive search The size and shape (amplitude, dura- for an etiology, the neuropathy remains tion, area, and phases) of the resultant idiopathic in a substantial number of action potential waveform are assessed. patients, most commonly in elderly pa- Recording from sensory nerves yields tients with mild disease. a SNAP, and recording from muscles yields a compound muscle action Electrodiagnostic Testing potential (CMAP). Reported parameters Electrodiagnostic testing refers to nerve may include latency, amplitude, con- conduction studies (NCSs) and needle duction velocity (CV), and duration. For EMG. These tests are the standard for a CMAP, a distal latency is reported for large fiber polyneuropathy diagnosis the terminal segment, as a pure nerve and are normal in purely SFN. EMG CV cannot be calculated given the in- may help exclude mimics of polyneu- cluded neuromuscular junction trans- ropathy, such as myopathy, neuronop- mission time. Low-amplitude SNAPs athy, plexopathy, or polyradiculopathy. may require averaging to increase the For example, sensory nerve action po- signal to noise ratio. F wave studies re- tentials (SNAPs) are preserved in pre- flect conduction over the entire length ganglionic conditions, single myotomes of a motor nerve. The tibial H reflex is are affected in radiculopathy, multiple the electrophysiologic equivalent of the nerves are affected in plexopathy, and S1 reflex and assesses both sensory and paraspinal abnormalities suggest radi- motor nerve conduction. H reflex mini- culopathy. As an extension of the clinical mal latency prolongation is nonspecific examination, electrodiagnosis augments and may be seen in early neuropathy. the ability to assess the relative motor Erb point, axillary, and cervical or lum- versus sensory involvement, the severity bosacral root stimulation may assess of the neuropathy, and the distribution conduction block and slowing in proxi- of neuropathic dysfunction. Addition- mal nerve segments. ally, electrodiagnosis may determine In axonal neuropathy, reduced the relative extent of axonopathy versus SNAP amplitudes typically develop first,

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followed by reduced CMAP amplitudes. proximal compared to the distal CMAP CVs are usually normal or only mini- with a significant increase in duration mally affected until sufficient loss of [Figure 1-1]); temporal dispersion of large, fast-conducting fibers occurs. In the distal response (multiphasic wave- length-dependent axonal polyneurop- form or prolonged [longer than 9 athy, initially SNAP amplitudes are milliseconds] distal CMAP duration); reduced in distal nerves (sural and markedly prolonged F wave minimal superficial peroneal). Thereafter, CMAP latency; and F wave impersistence, amplitudes of the peroneal nerves are chronodispersion, or absence. These reduced, followed by the tibial and then demyelinating findings are due to an ulnar and median nerves. increased range of nerve fiber conduc- In demyelinating neuropathy, distal tion velocities caused by uneven in- latency prolongation and CV slowing volvement by demyelination or nerve may occur, with reduction of amplitude inexcitability related to demyelination less likely early in the course. Additional (Case 1-2). Severely prolonged motor findings may include conduction block distal latencies raise the possibility of (reduction in amplitude of proximal anti-MAG neuropathy. Blink reflexes compared to the distal CMAP with- may show prolonged R1 latencies in out a significant increase in duration); demyelinating neuropathy. Unfortu- temporal dispersion9 across a nerve nately, the above demyelinating fea- segment (reduction in amplitude of tures may not be detectable in a

FIGURE 1-1 A, Temporal dispersion indicating demyelination. Tibial compound muscle action potentials (CMAPs). Note the multiphasic waveforms and the prolonged CMAP durations (33 and 31 milliseconds). A prolonged distal latency (10.7 milliseconds) and slowed conduction velocity (16.7 m/s) are also present. B, Peroneal CMAPs. Focal demyelination in the ankle-fibular head (FH) segment is indicated by the highly multiphasic waveform with below-FH stimulation along with a 116% increase in total duration (22.7 milliseconds) in comparison to ankle stimulation (10.5 milliseconds). The ankle and popliteal fossa CMAPs are also multiphasic. C, Tibial CMAPs with proximal temporal dispersion. The increased duration of the proximal response, along with relative preservation of the area, indicate the presence of temporal dispersion and not a conduction block.

Modified with permission from Sander HW, Oh SJ. Temporal dispersion terminology: multiphasic and multiturn CMAPs. J Clin Neuromuscul Dis 2006;7(3):173Y174.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINT Case 1-2 h Nerve conduction findings in axonal neuropathy A 69-year-old man with diabetes presented with a 4-year history of tingling include reduced sensory and numbness affecting the feet and hands, difficulty with stair climbing, nerve action potential and and imbalance in the shower when closing his eyes. The symptoms were compound muscle action progressive, although there were a few intervening months in which the potential (CMAP) symptoms seemed to have lessened. He was a retired used car salesman and amplitudes. Findings in lived with his wife. He denied alcohol or tobacco use. Diabetes was demyelinating diagnosed 6 years ago and was controlled by diet and weight loss. His neuropathy include history was significant for hypothyroidism that was treated with conduction velocity levothyroxine and benign prostatic hypertrophy. Neurologic examination slowing, distal latency revealed 4/5 weakness of bilateral iliopsoas and extensor hallucis longus prolongation, conduction muscles and 4+/5 weakness of bilateral abductor digiti minimi and tibialis block, temporal anterior muscles. Sensory examination revealed diminished light touch dispersion, prolonged perception in a bilateral glove distribution to the wrist and in a stocking (greater than distribution to the midfoot. Vibratory perception was diminished in the 9 milliseconds) distal toes. Ankle reflexes were absent. Romberg test was positive. CMAP duration, Hemoglobin A and fasting blood sugar were mildly elevated. The 1C markedly prolonged F antinuclear antibody was borderline positive. The serum thyroid peroxidase wave minimal latency, antibody level was markedly elevated. Laboratory testing for the following and F wave impersistence, was normal: complete blood count, metabolic profile, thyroid-stimulating chronodispersion, or hormone, rheumatoid factor, Lyme disease, angiotensin-converting enzyme, absence. Asymmetry, HIV, C-reactive protein, double-stranded DNA, SS-A, SS-B, GM1, and sural sparing, and antiYmyelin-associated glycoprotein antibody. Motor nerve conduction dissociation between studies revealed moderate conduction slowing and multiphasic responses motor and sensory in bilateral peroneal, right tibial, and right ulnar nerves, with normal to function in the same slightly low compound muscle action potential amplitudes. Bilateral nerve suggest possible peroneal distal compound muscle action potentials had increased duration. acquired demyelinating F wave responses were moderately prolonged. Bilateral tibial H reflexes neuropathy or a were absent. Sensory nerve conduction studies revealed right median and mononeuropathy multiplex. ulnar mild conduction slowing with normal bilateral sural and superficial peroneal responses. Needle EMG revealed only a decreased interference pattern in bilateral tibialis anterior muscles. Comment. This patient clinically has a length-independent sensorimotor large fiber polyneuropathy. Electrodiagnostic studies confirm a length-independent, demyelinating, motor-greater-than-sensory polyneuropathy. A diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP) is established based on the clinical history, physical examination, and electrodiagnostic findings. CIDP responds to immunotherapy and may be treated with IVIg, plasmapheresis, or steroids. It is common for patients with CIDP to have concomitant autoimmune diseases or additional isolated laboratory markers suggesting autoimmunity. CIDP may also occur in association with diabetes. demyelinating neuropathy because of the possibility of acquired demyelinat- either lack of sampling of affected nerves ing neuropathy or a mononeuropathy or secondary axonal loss with low am- multiplex. Various electrodiagnostic cri- plitude or absent responses in severe teria have been established for CIDP.10,11 disease. Asymmetry, sural sparing, and Recent criteria have been created for dissociation between motor and sensory clinical rather than research use and have function in the same nerve should raise greater sensitivity. Uniform demyelinating

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KEY POINTS h Uniform demyelinating features are more commonly associ- to the nerve/plexus/root and evaluate features are more ated with hereditary neuropathies than proximal nerve segments that are inad- commonly associated with acquired neuropathies. Conduc- equately assessed by NCSs. SSEPs may with hereditary tion block and temporal dispersion are be absent or delayed because of root neuropathies than usually seen in acquired conditions. demyelination. SSEPs may be record- acquired neuropathies. Needle EMG assesses electrical ac- able even if SNAPs are absent because of Conduction block and tivity of voluntary muscles. At rest, the central amplification and can document temporal dispersion are presence of fibrillation potentials and CV slowing. Yiannikas and Vucic high- usually seen in acquired positive sharp waves indicates sponta- lighted the use of SSEPs to diagnose conditions. neous discharge of individual muscle different phenotypes of CIDP.13 h Magnetic stimulation and fibers. This finding suggests active somatosensory-evoked denervation of muscle fibers, but it also Quantitative Sensory Testing potentials may assist in occurs in some myopathies, likely due Quantitative sensory testing (QST) in- identifying root, plexus, to muscle fiber splitting. Motor unit po- volves administration of vibration, warm, and proximal nerve (eg, tential (MUP) morphology may suggest cold, and heat pain stimuli to the great femoral) demyelination. a neurogenic lesion with reinnervation toe or index finger to determine the (increased duration, amplitude, and threshold to the sensation. Vibration polyphasia) or a myopathic lesion (brief sensory threshold measures large-diam- duration, low amplitude, and poly- eter sensory fibers. Thermal and heat phasia). A caveat is that MUPs in early pain thresholds evaluate small unmyeli- reinnervation resemble MUPs of myop- nated fibers, which are not assessed with athy. With activation, the recruitment NCSs. QST is noninvasive and can be pattern may be divided into two com- repeated to monitor progression.14 ponents: interference pattern and firing QST instruments use different algo- rate. In neuropathy, there may be an rithms to determine thresholds. Com- increased firing frequency in associa- parisons cannot easily be made between tion with a decreased interference pat- algorithms.15 In the method of limits, tern. In myopathy, there may be an stimulus intensity is gradually increased early recruitment of MUPs with a low- until the patient indicates perception. amplitude envelope of the interference In the method of levels, individual pattern. Needle EMG is useful to local- stimuli are delivered and the patient ize the distribution of dysfunction. It indicates whether the stimulus was per- is also useful in defining the chronicity ceived. This method is reaction time- of an axonopathy based on the dis- independent. Data can be reported in tribution and the amplitude of fibrilla- absolute units of stimulus intensity or tion and sharp waves as well as MUP in steps specified as ‘‘just noticeable morphology. differences.’’ See Figure 1-2 for an example of QST.16 Results are expressed Neurophysiologic Testing as age- and sex-adjusted percentiles. Magnetic stimulation may assess con- QST has been validated to detect and duction in proximal segments such as characterize sensory neuropathy. Stud- the femoral nerve or cauda equina, but ies of patients with diabetes with mini- in general it has limited application in mal or no symptoms have found thermal peripheral neuropathy. Documenta- sensation testing to be more sensitive tion of cauda equina CV slowing can than vibratory testing or NCSs. However, aid in diagnosis of a demyelinating other studies have found NCSs and neuropathy.12 vibratory testing to be more sensitive Somatosensory-evoked potentials than thermal testing. This discrepancy is (SSEPs) may localize sensory symptoms potentially explained by changes in the

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. predominant fiber type involved over the disease course. Thus, combined thermal and vibratory evaluation is beneficial and provides higher sensitivity. HIV neuropathy, Fabry neuropathy, toxic neuropathy, and demyelinating neuropathy have been evaluated using QST. Vibration and cooling thresholds appear most reliable andreproduciblecomparedtowarming and heat pain. QST has limitations. It is time- consuming (takes at least 1 to 2 hours), requires special equipment, and is a psychophysiologic tool requiring patient cooperation. Inattention can lead to inaccuracy. Detecting malingering or other nonorganic abnormalities is challenging. Therefore, QST should not be used in resolving medicolegal matters. QST cannot differentiate between central and peripheral nervous system dysfunction. An AAN QST consensus report FIGURE 1-2 Examples of the 4-2-1 stepping algorithm for cooling thresholds. The broken line at the states: ‘‘Its [QST’s] role is only estab- top is from a patient with painful diabetic lished when used as one of several tools neuropathy, and the solid line is from a normal control. Null stimuli are shown at the bottom (dotted line). Stimuli are started in the evaluation of neurologic disor- at level 13, and the control senses the first two stimuli. In the ders,’’ and ‘‘QST is probably or possibly normal study, after the first turn point at stimulus 5, the patient fails (f ) to note the stimulus, and the step is reduced to two just useful in identifying small and large fiber noticeable differences (JNDs). After the second turn point, the 15 sensory abnormalities.’’ stimuli are refined to 1 JND, and a threshold of 10 JND (80th percentile) is determined. The patient with neuropathy fails to note the first three true stimuli at 13, 17, and 21 JND and two Autonomic Testing null stimuli (not shown). The intervals are refined until an Autonomic testing may complement abnormal threshold of 23 JND (98th percentile) is determined. 17,18 This threshold corresponded to a physical change of j20-C evaluation of polyneuropathy. Sym- (36-F) in skin temperature. pathetic and parasympathetic function Reprinted with permission from Lacomis D. Small-fiber neuropathy. Muscle are assessed using cardiovagal, adren- Nerve 2002;26(2):173Y188. ergic, and sudomotor indices. Sym- pathetic sudomotor testing includes sympathetic skin response (SSR), quan- alized laboratories are needed for the KEY POINT h titative sudomotor axon reflex testing other studies mentioned. Although quantitative (QSART), and thermoregulatory sweat The SSR measures changes in hand sensory testing is useful in identifying both small and testing (TST). Cardiovascular evaluation and foot skin resistance in response to large fiber neuropathy, includes heart rate variability assess- an arousal stimulus, often electrical, it is time-consuming, ment during deep breathing (HRDB), that elicits a startle response. An ab- dependent on patient Valsalva maneuver, and blood pressure sent response is considered abnormal. cooperation, not truly response to standing and tilt. In SFN, Quantitative criteria are not uniformly objective, and unable to sudomotor dysfunction is more likely to established. Some consider a side-to- localize dysfunction. be identified than cardiovagal dysfunc- side amplitude asymmetry of greater tion. Many standard EMG machines can than 50% abnormal. This test is rela- assess SSR and R-R interval. These tests tively insensitive for detection of mild are rapid and easily performed. Speci- dysfunction.

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KEY POINTS h Sympathetic sudomotor TST involves administering con- sweat cells, which are generally placed testing includes trolled heat stimulus and visualizing at four locations. In distal SFN, the sympathetic skin the sweat pattern response using indi- most distal site may have a reduced or response, quantitative cator powders. Areas of reduced sweat- absent response. QSART is the most sudomotor axon ing are computed as a percentage of sensitive physiologic autonomic test in reflex testing, and total anterior body surface. Patients distal SFN, with a sensitivity of 75% to thermoregulatory sweat with neuropathy have hypohidrosis or 90%.20 Intraepidermal nerve fiber loss testing. Cardiovascular anhidrosis. TST sensitivity in SFN is (somatic C fiber involvement) and evaluation includes heart high, especially for detection of distal QSART abnormality (autonomic C fiber rate deep breathing, loss of sweating; however, the test is involvement) are often correlated. Valsalva maneuver, and not routinely available, as it requires a In normal physiology, the heart rate blood pressure response dedicated room and is messy and time- increases with inspiration and decreases to standing and tilt. consuming. SSR and TST are nonlocal- with expiration. HRDB assesses variabil- h In small fiber neuropathy, izing with regard to central versus ity in successive R-R intervals at six sudomotor testing is peripheral sites of dysfunction. breaths/minute. The variation is largely more sensitive than QSART assesses postganglionic sudo- related to parasympathetic/vagal nerve cardiovagal testing. motor nerve fibers with high sensitivity pathways and is reduced in autonomic and specificity (Figure 1-3).19 Axons in dysfunction. HRDB has a sensitivity of skin are activated via acetylcholine approximately 80% in assessment of iontophoresis, resulting in an initial polyneuropathy.20 direct sweat response. Antidromic Valsalva maneuver assesses cardiova- transmission to an axon branch point gal and sympathetic vasomotor func- elicits an orthodromic response leading tion. It involves blowing against airway to a secondary sweat response of sweat resistance at predetermined pressure, glands adjacent to the site of primary causing abrupt elevation of intratho- stimulation. Sweat is measured with racic and intra-abdominal pressures. Technically, the maneuver consists of four phases, with phases II and IV playing the greatest diagnostic role (Figure 1-4).21 Phase I, during the first 2 to 3 seconds of forced expiration, is associated with a brief decrease in heart rate and increase in blood pressure caused by aortic compression from increased intrathoracic and intra- abdominal pressure. During phase II (continued straining), the blood pressure first decreases (reflecting reduced venous return causing diminished stroke FIGURE 1-3 A, Normal quantitative sudomotor volume) and then increases. This is axon reflex testing (QSART) in a secondary to a baroreceptor-mediated healthy control. B, Abnormal QSART in a patient with dysfunction of the increase in sympathetic activity with postganglionic sympathetic sudomotor axon due to resultant increased heart rate and pe- small fiber neuropathy. In contrast to the patient with small fiber neuropathy, sweating increases in ripheral vasoconstriction. In phase III, the healthy control during mental arithmetic (1), the abrupt release of the strain causes during acoustic stimulation (2), and prior to acetylcholine iontophoresis (3). passive blood pressure decline and a resultant increase in heart rate. In phase Reprinted with permission from Hilz MJ, Du¨ tsch M. Quantitative studies of autonomic function. Muscle Nerve 2006;33(1):6Y20. IV (continued relief), the blood pressure overshoots baseline because of

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. FIGURE 1-4 Blood pressure and heart rate response to Valsalva maneuver in a normal participant (A) and a patient with baroreflex-sympathoneural and baroreflex-cardiovagal failure (B). The patient has a progressive fall in blood pressure during the maneuver and slow blood pressure recovery after the maneuver, with absence of a pressure overshoot in phase IV. Concurrent heart rate changes are blunted for given changes in blood pressure.

Reprinted with permission from Goldstein DS, Low PA. Clinical evaluation of the autonomic nervous system. Continuum Lifelong Learning Neurol 2007;13(6):33Y49. Copyright B 2007, American Academy of Neurology. All rights reserved.

persistent peripheral vasoconstriction in gic, sudomotor, and cardiovagal testing KEY POINT h the setting of a normalized venous re- and can be used to increase sensitivity Nerve biopsy evaluation turn and stroke volume. Baroreceptor- and specificity for documenting auto- should not be performed mediated vagal stimulation with reflex nomic dysfunction. before adequate clinical, electrophysiologic, and bradycardia and peripheral vasodilation laboratory assessment. then occurs. In patients with baroreflex Nerve Biopsy failure, the blood pressure falls progres- Historically, nerve biopsy (NB) was used sively in phase II and in phase IV blood to assess the etiology, pathologic local- pressure recovery time is prolonged ization, and severity of nerve damage. In with no pressure overshoot. The Valsalva the last two decades, NB has become less ratio reflects parasympathetic function important because of progress in electro- and is defined as the ratio of the fastest diagnostic, laboratory, and genetic test- heart rate during or after phase II to ing. Currently, the search for an etiology the slowest heart rate in phase IV (after is the main indication for an NB. NB release of strain). A ratio below 1.10 is evaluation should not be performed abnormal. before adequate clinical, electrophysio- Orthostatic hypotension associated logic, and laboratory assessment. The with neuropathy occurs when small mye- yield of an NB depends on a number of linated and unmyelinated baroreflex fibers factors, including patient selection, nerve in splanchnic vasculature are damaged. sampled, laboratory experience, and Tilt-table testing can quantify and provide techniques of evaluation.22 detail regarding orthostatic changes. NB is helpful in only a small subset The composite autonomic scale is a of patients. The yield is best in an acute/ 10-point scale that combines adrener- subacute, asymmetric, multifocal, severe

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KEY POINTS h Nerve biopsy yield is best progressive neuropathy. It is most help- may aid in nerve selection. The surgeon in an acute/subacute, ful in mononeuropathy multiplex or should be familiar with nerve identifi- asymmetric, multifocal, suspected vasculitis. AAN practice pa- cation and specimen handling. Total NB progressive neuropathy. rameters support the usefulness of NB is more informative than fascicular bi- h The AAN practice in the diagnosis of inflammatory dis- opsy. Favored nerves include the sural parameters recommend eases such as vasculitis, sarcoidosis, nerve above the lateral malleolus, the nerve biopsy in the and CIDP; infectious diseases such as superficial peroneal nerve, or, less com- diagnosis of inflammatory leprosy; or infiltrative disorders such monly, the superficial radial nerve at the 20 diseases such as vasculitis, as tumor or amyloidosis. It is also wrist. When vasculitis, amyloidosis, or sarcoidosis, and recommended in progressive diffuse granulomatous disease is suspected, a chronic inflammatory cryptogenic neuropathy. NB is rarely biopsy of adjacent muscle may be per- demyelinating informative in distal symmetric axonal formed. Following a sensory NB, sensory polyradiculoneuropathy; neuropathies associated with toxic and loss in the nerve distribution will occur. infectious diseases such metabolic conditions. Hereditary neu- Dyck reported that 30% of patients ex- as leprosy; or infiltrative ropathies are better diagnosed with perienced subjective and objective sen- disorders such as tumor blood testing, although NB may help sory abnormalities that resolved over or amyloidosis. direct DNA analysis to a particular gene time. Vallat and colleagues reported that h Nerve biopsy is also (Table 1-1). approximately 60% of patients had no recommended in diffuse The current role of NB in CIDP is symptoms after sural NB.25 cryptogenic neuropathy controversial. Patients with CIDP may General pathologic evaluation uses but is rarely informative in distal symmetric erroneously be classified as having an frozen sections, conventional paraffin axonal neuropathy axonal neuropathy on electrodiagnostic sections, epoxy (plastic) sections for light associated with toxic and studies because of sampling error in and electron microscopy, and teased metabolic conditions. patchy disease. NB should be consid- myelinated fibers. Frozen tissue is usu- ered on a case-by-case basis for patients ally not fixed before cutting sections. The with cryptogenic neuropathy with atypi- tissue is fixed in formalin for paraffin cal clinical or electrodiagnostic features sections and in glutaraldehyde for semi- or a rapidly deteriorating course.23 thin plastic sections, electron micro- In axonopathy, NB findings include scopy, and teased fibers.26 fiber loss, evidence of sprouting, and Paraffin sections followed by routine myelin breakdown material. In demyeli- hematoxylin and eosin staining is the nating neuropathy, the axons have inap- most efficient method to screen for propriately thin myelin sheaths relative interstitial lesions such as inflammatory to the diameter of the axons. When cells, neoplastic infiltration, and blood repetitive episodes of demyelination vessel changes. It is particularly helpful involve the same internode, Schwann for detecting vasculitis, amyloidosis, cell proliferation creates concentrically and sarcoidosis. oriented layers termed ‘‘onion bulbs’’ Frozen sectioning allows for immu- (Figure 1-5).24 Tomacula are sausage- nostaining. This may detect immuno- shaped myelin outfoldings observed on logically active cells in vasculitis and teased myelinated fibers and are most deposition of Igs (eg, IgM antibody to commonly observed in hereditary neu- MAG) and complement components. ropathy, especially HNPP. The charac- Light microscopic analysis of resin- teristic lesion of necrotizing vasculitis embedded material assesses for loss of on nerve and muscle biopsy is fibrinoid myelinated fibers, onion bulb forma- necrosis of the endothelium and trans- tion, and size of affected fibers. Quanti- mural inflammatory cell infiltration. fying the number of myelinated fibers Sensory nerves are biopsied under per unit area of endoneurium may be local anesthesia. MRI and ultrasound necessary to determine significant loss.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. TABLE 1-1 Summary of Clinical Situations When Nerve Biopsy May Be Very Useful or Indispensable for the Diagnosis

Disease Groups Condition Comments on Nerve Biopsy Acquired Immune-mediated Vasculitis Diagnostic yield is variable and neuropathies neuropathies may be improved in combination with a muscle biopsy at the same site May be particularly useful when vasculitis is confined to peripheral nerves Chronic inflammatory May be helpful in patients with demyelinating clinically atypical presentations or polyneuropathy (CIDP) when nerve conduction studies are not diagnostic Neuropathy associated with May be extremely helpful to monoclonal gammopathy demonstrate: (1) presence of lymphomatous infiltrates (2) amyloidosis (3) endoneurial deposits (intramyelinic or interstitial) Exception: patients with IgM antiYmyelin-associated glycoprotein neuropathy Toxic neuropathies Various drug-induced May help differentiate a toxic neuropathies, particularly neuropathy from another type of those causing demyelinating neuropathy (eg, amiodarone-induced neuropathies neuropathy with electrophysiologic features suggestive of CIDP) Hereditary Charcot-Marie-Tooth CMT-like presentation in May suggest a hereditary neuropathy neuropathies disease (CMT) sporadic cases in the absence of a family history May direct the search for specific gene mutations in some cases Storage disorders Storage disorders with May reveal accumulation of peripheral nervous system abnormal material in Schwann cells involvement or endothelial cells

Reprinted with permission from Vallat JM, Vital A, Magy L, et al. An update on nerve biopsy. J Neuropathol Exp Neurol 2009;68(8):833Y844.

Electron microscopy is useful in ex- neuropathies, including those that also amining unmyelinated nerve fibers; eval- affect the CNS; and toxic neuropathies. uating ultrastructural features, including Teased myelinated fiber examination cytoplasmic organelles and storage mate- usually involves grading 50 to 100 fibers rials; and evaluating for demyelination. for pathologic abnormalities. Quantita- Diseases assessed by electron micro- tive studies in internodal length and scopy include CIDP; neuropathy due to myelinated fiber diameter are per- a gammopathy (anti-MAG); hereditary formed. Normally there is little variation

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chronic neuropathies, thinly myelinated segments and short internodes can be evidence of remyelination but can also be caused by a chronic axonal disorder. Tomacula may be seen on teased fiber preparation. Myelin ovoids indicate active axonal degeneration, and uniformly shortened internodes are thought to be caused by axonal regeneration.

Skin Biopsy Over the past two decades, understand- ing of cutaneous innervation has dra- matically increased, leading to improved diagnostic and therapeutic techniques.27 Skin biopsy is becoming the standard for assessment of unmyelinated cutaneous nerves. The intraepidermal small nerve fibers convey pain and temperature sensation from the skin and main- tain autonomic function. The neurologic examination may miss subtle sensory abnormalities. Conventional electrodiagnostic studies assess only large nerve fibers. Skin sampling is performed by skin punch or by the less common skin blister technique.28 With a skin punch, a 3 mm diameter, 3 mm to 4 mm thick speci- FIGURE 1-5 Electron micrographs of a sural nerve biopsy in chronic inflammatory demyelinating men is removed using local anesthetic polyradiculoneuropathy specimen ([times]2870). A, shows that the axons have relatively thin myelin without sutures and is fixed in parafor- sheaths (asterisk), a finding suggesting remyelination. Some maldehyde. A small scar may occur. relatively large, unmyelinated axons indicative of demyelination (arrows) are also visible. B, shows a Schwann cell filled with Although biopsy is a simple office pro- myelin debris (asterisk). Stacks of cytoplasmic lamellae (arrows) cedure, pathologic analysis is complex. indicate a loss of unmyelinated axons and myelinated axons. An Intraepidermal nerve fiber density ‘‘onion bulb’’ (arrowhead) surrounds an unmyelinated axon, a finding indicating demyelination. The bars represent 3.48 6m. (IENFD) is quantified and morphologic

Reprinted from Sander HW, Hedley-Whyte ET. Case records of the features are assessed. Complications Massachusetts General Hospital: weekly clinicopathological exercises. (infection, excessive bleeding, and pro- Case 6-2003: a nine-year-old girl with progressive weakness and areflexia. N Engl J Med 2003;348(8):735Y743. Copyright B 2003, with permission from longed healing) occur in fewer than 29 the Massachusetts Medical Society. 0.5% of patients. Immunohistochemi- cal staining is performed, most commonly with protein gene product 9.5, a between internodal lengths in single cytoplasmic neuronal marker. Sections fibers in early adulthood, but gradually 50 Hm thick are cut perpendicular to increasing variation of internodal lengths the epidermis. Using bright field light occurs with age. microscopy, the linear IENFD is calcu- Teased fibers may demonstrate a lated by counting the nerve fibers that demyelinating neuropathy with areas of cross the epidermal basement mem- segmental demyelination. In subacute or brane. The isolated fragments of nerve

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. fibers in the epidermis can also be counted (Figure 1-6A, B). An alternative technique uses fluorescence labeling with or without confocal microscopy. Strict counting rules and intensive train- inghaveledtohighinterraterandin- trarater reliability. The morphology of unmyelinated nerve fibers is assessed. Qualitative changes in neuropathy include attenuation of fibers, large glob- ular and fusiform-shaped swelling, dystrophic change, and tortuous and increasing complex branching. Large axonal swelling is a predegenerative change predictive of nerve fiber degeneration (Figure 1-6C). In several studies, isolated morphologic abnormalities were noted in 20% to 29% of patients with normal IENFD.30 Unfortunately, methods to reliably quantitate qualitative changes in morphology are lacking. In addition to IENFD, staining may also be performed for amyloidosis. IENFD is compared to normative reference data, which are currently available for the bright field immunohis- tochemistry technique for the foot, proximal and distal thigh, distal leg, distal forearm, trunk, and heel. The procedure is most commonly performed in the distal leg calf and in the proximal lateral thigh. IENFD below the fifth percentile is generally considered abnormal. Mean IENFD gradually diminishes with age. Men have a slightly lower IENFD than women. There is no relationship between IENFD and race, height, or weight. Quantitative nerve fiber analysis of the dermis has been limited. Several researchers have developed techniques to quantify the subepidermal nerve plexus. Other researchers are investigating FIGURE 1-6 A, Normal intraepidermal nerve fiber density abnormally short myelin internodes as (IENFD). Small nerve fibers (arrow)inthe a possible diagnostic technique for de- epidermal layer of a skin biopsy with normal IENFD. B, Abnormal IENFD. Skin with abnormally low IENFD, myelinating disorders. consistent with a small fiber neuropathy. C, Axonal bulbing. Sweat gland nerve fiber density Skin with abnormally low IENFD, consistent with a small fiber neuropathy. The arrowheads point to epidermal nerve fibers, (SGNFD) is assessed by skin biopsy with and just below is an axonal swelling. a manual or automated analysis. Sweat Figure courtesy of Therapath, New York, New York. glands have sympathetic sudomotor

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KEY POINT h Skin biopsy is the best innervation; therefore, SGNFD is com- In length-independent neuropathy, re- currently available test for plementary to IENFD, which measures duced IENFD is equal or more promi- 31 small fiber neuropathy. somatic nerves (Figure 1-7). The bi- nent proximally. However, severe length- Intraepidermal nerve fiber opsy requires a thicker specimen (6 mm dependent neuropathy may cause density and nerve fiber to 8 mm) than IENFD to allow for ade- IENFD reduction at all sites. morphology are quate sampling. Reduced SGNFD is In the studies evaluated by the AAN assessed. The most concordant with symptoms of sudo- practice parameter, IENFD diagnostic common biopsy sites are motor dysfunction. In a recent study, sensitivity ranged from 45% to 90% and the distal calf and 20% of skin biopsies found low SGNFD specificity was 95% to 97%. In a study of proximal lateral thigh. as the sole abnormality.32 67 patients with SFN, 88% had reduced Skin biopsies can distinguish neurop- distal leg IENFD while sensory NCSs athy from radiculopathy because radi- were normal.33 The high specificity indi- culopathy does not affect postganglionic cates that IENFD is a good tool to verify fibers. Skin biopsy may help evaluate the a neuropathy, but a normal IENFD does length dependence of a neuropathy by not exclude neuropathy.20 In a large comparing proximal and distal IENFDs. study, 11% of patients with SFN based on clinical examination and QST had normal IENFD.33 IENFD is correlated with objective SFN signs. The rate of false- negative IENFD is higher in patients with symptoms but without signs.29 The literature on the agreement between QST and IENFD is conflicting. IENFD correlates with thermal and nociceptive detection thresholds; however, correlation with other measures is un- certain, possibly because biopsy and QST are performed in different areas. Most studies report that IENFD has a higher sensitivity than QST for SFN.34 IENFD correlation with vibratory threshold is more likely with combined large and small fiber neuropathy. Skin biopsies have proven useful lon- gitudinally. IENFD may reliably predict risk of neuropathy in asymptomatic in- dividuals.InSFN,progressiveIENFD reduction correlates with neuropathy progression. Improved IENFD with regeneration is associated with reduced neuropathic pain and sensory symptoms. It is unknown what IENFD mag- nitude of change is meaningful, and IENFD improvement can serve as a reliable surrogate for evaluation of the FIGURE 1-7 A, Normal skin sweat gland nerve fiber density. B, Abnormal skin sweat gland nerve long-term course of polyneuropathy fiber density. either clinically or in research studies. Figure courtesy of Therapath, New York, New York. Currently, IENFD is used as a secondary outcome in therapeutic trials.30

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. KEY POINTS Recent Advances ganglionopathy (Sjo¨gren disease and h Analysis of sweat gland Two of the latest techniques used to Crohn disease). This noninvasive and nerve fiber density is investigate SFN are corneal confocal repeatable technique is particularly complementary to microscopy and laser Doppler imager promising in length-independent SFN/ intraepidermal nerve fiber flare (LDIF). Additionally, Meissner cor- ganglionopathy because of the proximal density in small fiber nerve puscle (MC) density evaluation (using in location. evaluation, as they assess vivo reflectance confocal microscopy) The major limitation of IVCCM is autonomic and somatic and skin wrinkling evaluation are in the limited availability of equipment and nerves, respectively. early stages of development for clinical trained examiners. Some ophthalmolo- h Skin biopsy may help application. gists have cautioned that the findings differentiate between Corneal confocal microscopy. In are nonspecific and may be seen in length-dependent and vivo laser corneal confocal microscopy amiodarone-induced keratopathy and length-independent (IVCCM)isusedtoimagethesub-basal postphotorefractive keratectomy. Thus, neuropathy. In nerve plexus, which is composed of A more extensive normative data and length-dependent delta and C fibers from the ophthalmic larger confirmatory studies are needed neuropathy, proximal intraepidermal nerve that penetrate Bowman layers to before IVCCM can become a standard nerve fiber density become subjacent to the basal epithelial diagnostic procedure. (IENFD) is relatively cells. Corneal nerve fiber density (CNFD), Laser Doppler imager flare. LDIF preserved, whereas in corneal nerve fiber length (CNFL), corneal evaluates skin C fiber axon reflex re- length-independent nerve branching, and corneal nerve fiber sponse to heating (44-C [111.2-F]), with neuropathy, proximal 35 tortuosity are assessed (Figure 1-8). laser Doppler to measure the area of IENFD may be equal or Reductions in CNFL and CNFD corre- vasodilation in the neurogenic flare. The more affected than distal spond to polyneuropathy severity. Serial flare area is dependent on the receptive IENFD. In radiculopathy, examination has found early nerve regen- field size of the activated axons and is IENFD is normal. eration (an increase in CNFD and CNFL) proportional to nerve fiber density. LDIF h Two of the latest following pancreatic transplantation in is reduced in neuropathy37 and with techniques recommended diabetes. IVCCM has been evaluated in local anesthetics (Figure 1-9).38 Pre- to investigate small fiber impaired glucose tolerance, diabetes,36 liminary data39 found LDIF to be more neuropathy are corneal Fabry disease, chemotherapy-induced sensitive than quantitative thermal thresh- confocal microscopy and neuropathy, anti-MAG neuropathy, and olds to detect SFN. Additionally, studies laser Doppler imager flare. length-independent polyneuropathy/ in patients with diabetes have shown Additionally, Meissner corpuscle density (using in vivo reflectance confocal microscopy) and skin wrinkling evaluation are in the early stages of development.

FIGURE 1-8 Frame from corneal confocal microscopy (original magnification Â 3700). Decreased density of nerve fibers in Bowman layer in a patient with length-independent small fiber sensory neuropathy (as seen in Case 1-1)(A) compared with that in a normal control (B).

Reprinted from Gemignani F, Ferrari G, Vitetta F, et al. Non-length dependent small fibre neuropathy: confocal microscopy study of the corneal innervation. J Neurol Neurosurg Psychiatry 2010;81(7):731Y733. Copyright B 2010, with permission from BMJ Publishing Group Ltd.

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LDIF abnormalities prior to neuropathy detection with currently available methods. Meissner corpuscle density. MCs are skin mechanoreceptors that have one or more myelinated nerves at the base and contain a lobulated network of A beta and unmyelinated fibers. MCs can be assessed using in vivo reflectance confocal microscopy (Figure 1-10).40 Fingertip MC density on skin biopsy paralleled reduction in IENFD in 25 patients with suspected neuropathy. More extensive experience, including normative data, is needed before this noninvasive method is widely used. Stimulated skin wrinkling. Asimple, noninvasive, bedside technique recently described is the use of stimulated skin wrinkling to assess small fiber function. Skin wrinkling is triggered by vasoconstriction that may be induced by immer- FIGURE 1-9 Laser Doppler imager flare technique. The solid sion in water or by administration of circle represents the extent of the skin heater. a eutectic mixture of local anesthetics The eutectic mixture of local anesthetics (lidocaine and prilocaine) blocks the axon reflex. The (EMLA). Water immersionYinduced va- neurogenic (small fiber) component of the hyperemia is soconstriction is mediated by postgan- determined by the ratio of hyperemic area to stimulus area before and after anesthesia. glionic sympathetic fibers. EMLA causes LDIFT = laser Doppler imager flare technique. vasoconstriction possibly by acting on calcium channels in postganglionic neu- Reprinted with permission from Green AQ, Krishnan ST, Rayman G. C-fiber function assessed by the laser Doppler imager flare technique and rons and smooth muscle cells. An ab- acetylcholine iontophoresis. Muscle Nerve 2009;40(6):985Y991. normal result reliably predicts abnormal

FIGURE 1-10 A, Identification of Meissner corpuscles (MCs) with in vivo reflectance confocal microscopy. Glabrous skin from the hand showing a dermal papilla with two MCs (arrows) and an empty papilla (arrowhead). B,Hairyskinof the forearm showing the expected absence of MCs in papillae (arrows). C, A higher magnification in vivo reflectance confocal microscopy image of an MC showing its capsule (arrowhead) and internal lobulated structure (arrow). D, An MC capsule (arrows) and heterogeneous bright signal on in vivo reflectance confocal microscopy of its internal axonal network.

Reprinted from Herrmann DN, Boger NJ, Jansen C, Alessi-Fox C. In vivo confocal microscopy of Meissner’s corpuscles as a measure of sensory neuropathy. Neurology 2007;69(23):2121Y2127. Copyright B 2007, with permission from AAN Enterprises, Inc. All rights reserved.

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Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. IENFD in sensory neuropathy, although diagnosis and treatment of chronic inflammatory demyelinating polyneuropathy. a normal result did not correlate with J Peripher Nerv Syst 2003;8(4):282Y284. normal IENFD.41 12. Maccabee PJ, Eberle LP, Stein IA, et al. Upper leg conduction time distinguishes ACKNOWLEDGMENT demyelinating neuropathies. Muscle Nerve We thank Dr Arthur P. Hays, Dr Daniel 2011;43(4):518Y530. L. Menkes, and Dr Max Hilz for concept 13. Yiannikas C, Vucic S. Utility of somatosensory development and editorial assistance evoked potentials in chronic acquired demyelinating neuropathy. Muscle Nerve and Ms Kathy Harris for administrative 2008;38(5):1447Y1454. assistance. 14. Chong PS, Cros DP. Technology literature review: quantitative sensory testing. Muscle REFERENCES Nerve 2004;29(5):734Y747. 1. England JD, Gronseth GS, Franklin G, et al. 15. Shy ME, Frohman EM, So YT, et al. Practice Parameter: evaluation of distal Quantitative sensory testing: report of the symmetric polyneuropathy: role of laboratory Therapeutics and Technology Assessment and genetic testing (an evidence-based Subcommittee of the American Academy of review). Report of the American Academy Neurology. Neurology 2003;60(6):898Y904. of Neurology, American Association of Neuromuscular and Electrodiagnostic 16. Lacomis D. Small-fiber neuropathy. Muscle Medicine, and American Academy of Physical Nerve 2002;26(2):173Y188. Medicine and Rehabilitation. Neurology 17. Low VA, Sandroni P, Fealey RD, Low PA. 2009;72(2):185Y192. Detection of small-fiber neuropathy by 2. Willison HJ, Winer JB. Clinical evaluation sudomotor testing. Muscle Nerve 2006;34(1): and investigation of neuropathy. J Neurol 57Y61. Neurosurg Psychiatry 2003;74(suppl 2):ii3Yii8. 18. Periquet MI, Novak V, Collins MP, et al. 3. Bromberg MB. An approach to the Painful sensory neuropathy: prospective evaluation of peripheral neuropathies. evaluation using skin biopsy. Neurology Semin Neurol 2005;25(2):153Y159. 1999;53(8):1641Y1647. 4. Herskovitz S, Scelsa S, Schaumberg HH. 19. Hilz MJ, Du¨ tsch M. Quantitative studies of Peripheral neuropathies in clinical practice. autonomic function. Muscle Nerve 2006; New York: Oxford University Press, 2010: 33(1):6Y20. 24Y55. 20. England JD, Gronseth GS, Franklin G, et al. 5. Mauermann ML, Burns TM. The evaluation Practice Parameter: evaluation of distal of chronic axonal polyneuropathies. Semin symmetric polyneuropathy: role of Neurol 2008;28(2):133Y151. autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Report 6. Barohn RJ. Approach to peripheral neuropathy of the American Academy of Neurology, and neuronopathy. Semin Neurol 1998; American Association of Neuromuscular and 18(1):7Y18. Electrodiagnostic Medicine, and American 7. England JD, Asbury AK. Peripheral neuropathy. Academy of Physical Medicine and Lancet 2004;363(9427):2151Y2161. Rehabilitation. Neurology 2009;72(2): 177Y184. 8. Chin RL, Sander HW, Brannagan TH, et al. Celiac neuropathy. Neurology 2003;60(10): 21. Low PA, Goldstein DS. Clinical evaluation of 1581Y1585. the autonomic nervous system. Continuum Lifelong Learning Neurol 2007;13(6):33Y49. 9. Sander HW, Oh SJ. Temporal dispersion terminology: multiphasic and multiturn 22. Sommer CL, Brandner S, Dyck P, et al. CMAPs. J Clin Neuromuscul Dis 2006;7(3): Peripheral Nerve Society Guideline on 173Y174. processing and evaluation of nerve biopsies. J Peripher Nerv Syst 2010;15(3):164Y175. 10. Koski CL, Baumgarten M, Magder LS, et al. Derivation and validation of diagnostic 23. Lacomis D. Clinical utility of peripheral nerve criteria for chronic inflammatory biopsy. Curr Neurol Neurosci Rep 2005; demyelinating polyneuropathy. J Neurol Sci 5(1):41Y47. 2009;277(1Y2):1Y8. 24. Sander HW, Hedley-Whyte ET. Case records of 11. Berger AR, Bradley WG, Brannagan TH, the Massachusetts General Hospital. Weekly et al; Neuropathy Association, Medical clinicopathological exercises. Case 6-2003. A Advisory Committee. Guidelines for the nine-year-old girl with progressive weakness

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