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, auto- nomic testing, nerve biopsy, confocal corneal microscopy, and laser Doppler imager flare. Continuum Lifelong Learning Neurol 2012;18(1):13–38. 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, vibra- tion, 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. Continuum Lifelong Learning Neurol 2012;18(1):13–38 www.aan.com/continuum 13 Copyright @ American Academy of Neurology. Unauthorized reproduction of this article is prohibited. Clinical Approach 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, 14 www.aan.com/continuum February 2012 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