Pearls and Oy-sters: Evaluation of peripheral neuropathies
Michelle L. Mauermann, MD and
Ted M. Burns, MD
From the Mayo Clinic (M.L.M.), Rochester, MN; and University of Virginia (T.M.B.), Charlottesville.
Address correspondence and reprint requests to Dr. Michelle L. Mauermann, Mayo Clinic, 200 First Street SW., Rochester, MN 55902 mauermann.michelle{at}mayo.edu
Peripheral neuropathy is common, with an estimated prevalenceof 2% in the general population and prevalence as high as 8%in those over the age of 55 years.1 Residents and fellows willundoubtedly evaluate many patients with various types of peripheralneuropathies during their careers. The evaluation for the etiologyof a patient’s peripheral neuropathy can be challenginggiven the vast number of potential etiologies2,3 and the factthat despite an appropriate evaluation, a high percentage ofcases will remain idiopathic.4,5 In this article, we providea simple, easy-to-remember algorithm that can simplify the evaluationof peripheral neuropathy.
The evaluation of peripheral neuropathy should begin with thegathering of clinical data including the history of presentillness, past medical history, family history, and physicalexamination. The determination of what of that clinical datais relevant requires knowledge of various diseases and the riskfactors for those diseases. The information then needs to besynthesized in order to characterize the complaints and findingsand determine an appropriate workup. The appropriate characterizationof the complaints and findings is essential in order to performan efficient, cost-effective, and successful evaluation. Werecommend characterizing the neuropathy by answering four basicquestions about the neuropathy: What? Where? When? What setting?(figure).6 This simple algorithm should facilitate the earlystep in clinical reasoning of creating a mental abstraction—thatis, a problem representation or one-sentence summary of thedefining and discriminating characteristics of the case.7 Thecreation of an accurate problem representation will allow theevaluating physician to focus on a small list of potential etiologies.This critical step in diagnostic reasoning will usually guidethe physician down the correct diagnostic path, but it mustbe kept in mind that our algorithm is not absolute and therewill always be cases that prove to be exceptions. The creationand utilization of problem representations will also serve asanchor points in memory that should allow the physician to moreefficiently evaluate future cases and particularly to identifysubtle but meaningful variations in similar cases.7
Figure Pearls for classification of peripheral neuropathies
A suggested construct for the approach to neuropathy, using the "what, where, when, and what setting" approach to characterizing the neuropathy and placing the neuropathy into a presumed etiologic category. PNSS = positive neuropathic sensory symptoms; CMT = Charcot-Marie-Tooth; HMSN = hereditary motor and sensory neuropathies; HNPP = hereditary neuropathy with liability to pressure palsy; GBS = Guillain-Barré syndrome; CIDP = chronic inflammatory demyelinating polyradiculoneuropathy; MMN = multifocal motor neuropathy; PAN = polyarteritis nodosa; SLE = systemic lupus erythematosus; RA = rheumatoid arthritis. Modified and reprinted with permission from Mauermann ML, Burns TM. The evaluation of acquired neuropathies. Semin Neurol 2008;28:133–151.6
What?
Determine what nerve fiber modalities—motor, sensory,or autonomic—are involved. If sensory fibers are involved,sensory symptoms should be characterized into those with a positivesensation, such as prickling, tingling, or buzzing, vs thosewith a negative sensation, such as loss of sensation or imbalance.This differentiation is helpful because these positive sensorysymptoms often suggest a neuropathy is acquired rather thaninherited.4 Acquired neuropathies with large fiber dysfunction(either motor or sensory with loss of vibration, proprioception,or light touch) due to demyelination often have symptoms ofweakness with or without ataxia with positive sensory symptomssuch as tingling. Those with small fiber dysfunction (loss ofpain or temperature) often have symptoms such as burning withoutweakness or ataxia. Small fiber neuropathies can have positivesensory symptoms such as burning, regardless of whether theyare acquired or inherited. However, most types of inheritedneuropathies tend to have more signs (examination abnormalities)than symptoms. The identification of sensory nerve fiber involvementin almost all instances excludes disorders of the anterior horncell, neuromuscular junction, and muscle. Deciding whether weaknessor sensory symptoms are more prominent can also be helpful becausethe inflammatory demyelinating neuropathies often manifest withweakness overshadowing sensory nerve fiber disturbance. Autonomicnerve involvement can be an important clue because only a smallnumber of neuropathic processes affect both autonomic and somaticnerves such as diabetes, amyloidosis, acquired inflammatorydemyelinating polyneuropathies, paraneoplastic syndromes, Sjögrensyndrome, porphyria, HIV, and hereditary sensory and autonomicneuropathies.
Where?
Next decide if the distribution is length-dependent and symmetricor not. Length-dependent neuropathies manifest first in thefeet and are symmetric. Non-length-dependent neuropathies maybe asymmetric, focal, or multifocal. The etiology of length-dependentneuropathies is usually inherited, metabolic/toxic, or idiopathic,whereas a neuropathy that is not length-dependent is often causedby an immune-mediated or infectious process. Some examples ofnon-length-dependent neuropathies are polyradiculoneuropathies(e.g., acquired inflammatory demyelinating polyneuropathies),plexopathies (often inflammatory), sensory polyganglionopathies(e.g., paraneoplastic subacute sensory neuronopathy caused bysmall cell lung cancer), and mononeuritis multiplex (causedby vasculitis). At times it may be difficult to determine whetherthe neuropathy is symmetric or asymmetric due to clinical progression,so it is best to ask the patient to describe the location ofonset of symptoms followed by the distribution of subsequentprogression.
When?
The onset of the neuropathy should be classified. The neuropathiesthat are acute or subacute in onset are more typical of an immune-mediatedor infectious etiology. As patients have difficulty recallingthe course, it is helpful to determine whether the symptomshad a definite date of onset. A less-exact date of onset suggestsa gradual or insidious onset, indicative of inherited, idiopathic,or toxic/metabolic etiologies. The tempo following symptom onsetis also an important consideration. Symptom onset and tempooften correlate in a predictable manner, owing largely to theunderlying mechanism.6
What setting?
The neuropathy has to be considered within the context of thepatient’s unique clinical circumstances. This is aidedby determining what is relevant in the patient’s medicalhistory, medication list, social history, family history, andthe review of systems. An understanding of the significanceof these clinical factors requires knowledge of the risk factorsof neuropathy and knowledge of the clinical features of thediseases that may be risk factors for neuropathy. For example,unexplained weight loss raises concern for immune or neoplasticcauses such as vasculitis, lymphoma, diabetic and nondiabeticlumbosacral radiculoplexus neuropathy, or a paraneoplastic autoimmuneprocess. The clinician should always consider the most commoncauses of neuropathy such as diabetes, alcohol use, or inheritedetiologies. Family members should be examined whenever possible.It is important for the neurologist to obtain an accurate alcoholconsumption history and smoking history in a nonthreatening,nonjudgmental manner. Alcoholism is a very common problem andneuropathies due to alcohol use or secondary nutritional deficienciescan occur, so appropriate effort must be spent during the clinicvisit investigating this possibility.6,8
Clinical neurophysiologic assessment.
Characterization using electrodiagnostic testing (EDX) is usuallyhelpful in confirming the presence of a neuropathy and to furtherdefine motor and sensory involvement. EDX testing can be normalin small fiber neuropathies, very distal length-dependent neuropathies,and early neuropathic processes, particularly within the firstfew days. Normal EDX testing can also point to another etiologyfor the patient’s complaints, for example a myelopathy.EDX aids in determining if the neuropathy is primarily axonalor demyelinating. EDX can also help with defining symmetry,length-dependence, and subclinical involvement and provide baselineparameters in case future EDX in needed to monitor the patient’scourse. Autonomic function may be assessed through autonomicreflex testing or other provocative testing, such as a thermoregulatorysweat test, which specifically assess the autonomic nervoussystem.
There are three important tips to keep in mind when evaluatingperipheral neuropathies.
1. Do not let your sensory examination mislead you.
First, your patient almost certainly has sensory involvementif he or she complains of sensory symptoms, regardless of whatyou find on examination. It is well known that symptoms of sensoryinvolvement are more sensitive for detecting sensory nerve dysfunctionthan signs on examination. For example, 75% of patients withacute inflammatory neuropathies (i.e., Guillain-Barrésyndrome) will complain of sensory symptoms at hospital admissionbut only 40% will have confirmatory findings on examination.9Do not let that dissuade you from timely diagnosis and treatment.The second point about the sensory examination is that it isfrequently misgraded as abnormal in the unaffected elderly patientand conversely misgraded as normal in the affected young patient.Age (and to a lesser extent height and other anthropomorphicfeatures) must be factored into the judgment of whether sensorytesting is normal or abnormal. Also remember that myelopathiescan mimic peripheral neuropathy, particularly acute-onset neuropathiessuch as acute inflammatory neuropathies. Myelopathies oftenhave more profound proprioceptive loss compared to vibrationbut this is not absolute and the physician should have a lowthreshold for obtaining imaging of the spinal cord in casesof possible myelopathy. The presence of bowel and bladder impairmentcan be a helpful differentiator as it strongly favors a myelopathyas the cause.
2. Not all asymmetric neuropathies are acquired.
While most inherited neuropathies cause symmetric symptoms andimpairments, hereditary neuropathy with liability to pressurepalsies (HNPP) often presents with multiple compressive mononeuropathies(e.g., ulnar, median, and peroneal nerves). Thus, HNPP is arelatively common neuropathy that does not conform well to ourparadigm. However, family history, foot deformity, subtle detailsabout the history, and the specific EDX characteristics of HNPPusually provide enough clues to prompt consideration and eventualdiagnosis. Electrodiagnostic studies demonstrate multiple mononeuropathieswith focal conduction blocks as well as generalized prolongationof distal latencies.
3. If it does not fit, acquit.
If the characterization of a particular neuropathy does notfit well with the clinical context, for example the medicalhistory or an associated laboratory abnormality, one needs tolook elsewhere. Conditions such as diabetes mellitus, hypothyroidism,and renal insufficiency are common in the general populationand are most often associated with a length-dependent sensorimotorneuropathy without other systemic features. However, just becausethese conditions are common does not mean they are always thecause of the neuropathy. Furthermore, these patients are notimmune to the development of other acquired neuropathies suchas Guillain-Barré syndrome, chronic inflammatory demyelinatingpolyneuropathy, amyloidosis, or B12 deficiency. For example,approximately 2% of patients with type 1 diabetes and approximately6% of patients with type 2 diabetes have other causes of neuropathy.10
Martyn CN, Hughes RA. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 1997;62:310–318.[Free Full Text]
England JD, Asbury AK. Peripheral neuropathy. Lancet 2004;363:2151–2161.[Medline]
Dyck PJ, Dyck PJ, Grant IA, Fealey RD. Ten steps in characterizing and diagnosing patients with peripheral neuropathy. Neurology 1996;47:10–17.[Abstract/Free Full Text]
Dyck PJ, Oviatt KF, Lambert EH. Intensive evaluation of referred unclassified neuropathies yields improved diagnosis. Ann Neurol 1981;10:222–226.[Medline]
Lubec D, Mullbacher W, Finsterer J, Mamoli B. Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases. Postgrad Med J 1999;75:723–727.[Abstract/Free Full Text]
Mauermann ML, Burns TM. The evaluation of chronic axonal polyneuropathies. Semin Neurol 2008;28:133–151.[Medline]
Bowen JL. Educational strategies to promote clinical diagnostic reasoning. N Engl J Med 2006;355:2217–2225.[Free Full Text]
Monforte R, Estruch R, Valls-Sole J, Nicolas J, Villalta J, Urbano-Marquez A. Autonomic and peripheral neuropathies in patients with chronic alcoholism: a dose-related toxic effect of alcohol. Arch Neurol 1995;52:45–51.[Abstract/Free Full Text]
Ropper AH. The Guillain-Barré syndrome. N Engl J Med 1992;326:1130–1136.[Medline]
Dyck P. In: Horizons in Mayo Neurology and Neurosurgery: Perspectives on
2% in the general population and prevalence as high as 8% in those over the age of 55 years.1 Residents and fellows will undoubtedly evaluate many patients with various types of peripheral neuropathies during their careers. The evaluation for the etiology of a patient’s peripheral neuropathy can be challenging given the vast number of potential etiologies2,3 and the fact that despite an appropriate evaluation, a high percentage of cases will remain idiopathic.4,5 In this article, we provide a simple, easy-to-remember algorithm that can simplify the evaluation of peripheral neuropathy. 
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PERIPHERAL NEUROPATHY ALGORITHM
PEARLS FOR EVALUATING PERIPHERAL...
