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AUTHORS’ AFFILIATIONS
From the Louisiana State University Health Sciences Center (J.D.E., A.J.S.), New Orleans; University of Kansas (G.S.G.), Kansas City; University of Washington (G.F.), Seattle; Providence Health System (G.T.C.), Southwest Washington; St. Louis University School of Medicine (L.J.K.), St. Louis, MO; Dartmouth Hitchcock Medical Center (J.A.C.), Lebanon, NH; University of Pennsylvania School of Medicine (A.K.A.), Philadelphia; Baylor College of Medicine (K.S., J.R.L.), Houston, TX; Weill Medical College of Cornell (N.L.), New York, NY; Wayne State University School of Medicine (R.A.L.), Detroit, MI; Mayo Clinic (P.A.L.), Rochester, MN; Loyola University Chicago Stritch School of Medicine and the Hines VAH (M.A.F.), IL; University of Rochester Medical Center (D.H.), NY; University of North Carolina (J.F.H.), Chapel Hill; Fondazione IRCCS National Neurological Institute "Carlo Besta" (G.L.), Milan, Italy; California Pacific Medical Center (R.G.M.), San Francisco; and Johns Hopkins Medical Institutions (M.P.), Baltimore, MD.
Address correspondence and reprint requests to the American Academy of Neurology, 1080 Montreal Avenue, St. Paul, MN 55116 guidelines{at}aan.com
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Abstract. |
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 Top. Abstract. FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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Methods: A literature review using MEDLINE, EMBASE, and Current Contents was performed to identify the best evidence regarding the evaluation of polyneuropathy published between 1980 and March 2007. Articles were classified according to a four-tiered level of evidence scheme and recommendations were based upon the level of evidence.
Results and Recommendations: 1) Screening laboratory tests may be considered for all patients with polyneuropathy (Level C). Those tests that provide the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). If there is no definite evidence of diabetes mellitus by routine testing of blood glucose, testing for impaired glucose tolerance may be considered in distal symmetric sensory polyneuropathy (Level C). 2) Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with cryptogenic polyneuropathy who exhibit a hereditary neuropathy phenotype (Level C). Initial genetic testing should be guided by the clinical phenotype, inheritance pattern, and electrodiagnostic features and should focus on the most common abnormalities which are CMT1A duplication/HNPP deletion, Cx32 (GJB1), and MFN2 mutation screening. There is insufficient evidence to determine the usefulness of routine genetic testing in patients with cryptogenic polyneuropathy who do not exhibit a hereditary neuropathy phenotype (Level U).
AAN = American Academy of Neurology; AANEM = American Academy of Neuromuscular and Electrodiagnostic Medicine; AAPM&R = American Academy of Physical Medicine and Rehabilitation; CMT = Charcot-Marie-Tooth; DSP = distal symmetric polyneuropathy; EDX = electrodiagnostic; GTT = glucose tolerance testing; IFE = immunofixation electrophoresis; QSS = Quality Standards Subcommittee; SPEP = serum protein electrophoresis.
This practice parameter provides recommendations for the role of laboratory and genetic tests in the evaluation of distal symmetric polyneuropathy (DSP) based upon a prescribed review and analysis of the peer-reviewed literature. The parameter was developed to provide physicians with evidence-based guidelines regarding the role of laboratory and genetic tests for the assessment of polyneuropathy.
The diagnosis of DSP should be based upon a combination of clinical symptoms, signs, and electrodiagnostic criteria as outlined in the previous case definition.1 See Mission statement (appendix e-1 on the Neurology® Web site at www.neurology.org) for details.
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FORMATION OF EXPERT PANEL |
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Top.Abstract.FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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DESCRIPTION OF THE ANALYTIC PROCESS |
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Top.Abstract.FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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Panel experts were asked to identify additional articles missed by the initial search strategy. Further, the bibliographies of the selected articles were reviewed for potentially relevant articles.
Subgroups of committee members reviewed the titles and abstracts of citations identified from the original searches and selected those that were potentially relevant to the evaluation of polyneuropathy. Articles deemed potentially relevant by any panel member were also obtained.
Each potentially relevant article was subsequently reviewed in entirety by at least three panel members. Each reviewer graded the risk of bias in each article by using the diagnostic test classification-of-evidence scheme (appendix e-2). In this scheme, articles attaining a grade of Class I are judged to have the lowest risk of bias, and articles attaining a grade of Class IV are judged to have the highest risk of bias. Disagreements among reviewers regarding an article’s grade were resolved through discussion. Final approval was determined by the entire panel. The AAN’s method for determining the strength of recommendation was used (appendix e-3).
The QSS (AAN; appendix 1), the Practice Issues Review Panel (AANEM; appendix 2), and the Practice Guidelines Committee (AAPM&R; appendix 3) reviewed and approved a draft of the article. The draft was next sent to members of the AAN, AANEM, and AAPM&R for further review and then to Neurology®for peer review. Boards of the AAN, AANEM, and AAPM&R reviewed and approved the final version of the article. At each step of the review process, external reviewers’ suggestions were explicitly considered. When appropriate, the expert panel made changes to the document.
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ANALYSIS OF EVIDENCE |
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Role of laboratory testing in the evaluation of polyneuropathy. With the exception of electrodiagnostic (EDX) studies, laboratory tests are not utilized to diagnose polyneuropathy; however, laboratory tests are routinely utilized in patients with a diagnosis of polyneuropathy as a screening test for specific etiologies. Several questions regarding the use of laboratory testing as a screening tool in the evaluation of polyneuropathy were assessed.
What is the yield of screening laboratory tests in the evaluation of DSP, and which tests should be performed? The cause of most polyneuropathies is evident when the information obtained from the medical history, neurologic examination, and EDX studies are combined with simple screening laboratory tests. Such a comprehensive investigation yields an etiologic diagnosis in 74 to 82% of patients with polyneuropathy.4-13 Laboratory test results must be interpreted in the context of other clinical information since the etiologic yield of laboratory testing alone is limited by the low specificity of many of the tests. For example, one study of idiopathic polyneuropathy found that laboratory tests alone had only a 37% diagnostic yield (Class III).6 In another study, laboratory abnormalities were documented in 58% of 91 patients with chronic cryptogenic polyneuropathy, but only 9% were etiologically diagnostic (Class III).10 The majority of studies indicated that screening laboratory tests comprised of a complete blood count, erythrocyte sedimentation rate, comprehensive metabolic panel (blood glucose, renal function, liver function), thyroid function tests, serum B12, and serum protein immunofixation electrophoresis are indicated for most patients with polyneuropathy.4-13 Five Class III studies indicated that the highest yield of abnormality was seen with screening for blood glucose, serum B12, and serum protein immunofixation electrophoresis.4,6,10,13,14 The test with the highest yield was the blood glucose, consistent with the well-known fact that diabetes mellitus is the most common cause of DSP. In patients with DSP, blood glucose was elevated in approximately 11%, serum protein electrophoresis or immunofixation was abnormal in 9%, and serum B12 was low in approximately 3.6%. Two Class III studies showed that routine CSF analysis had a low diagnostic yield except in demyelinating polyneuropathies, which usually showed an increased CSF protein level.5,8
Vitamin B12 deficiency was relatively frequent in patients with polyneuropathy, and the yield was greater when the metabolites of cobalamin (methylmalonic acid and homocysteine) were tested (Class II and III).4,14-17 Serum methylmalonic acid and homocysteine were elevated in 5–10% of patients whose serum B12 levels were in the low normal range of 200–500 pg/dL.16,17 In large series of patients with polyneuropathy, between 2.2 and 8% of patients had evidence of B12 deficiency as indicated by elevations of these metabolites.4,14 In one Class III study involving 27 patients with polyneuropathy and B12 deficiency, 12 (44%) had B12 deficiency based upon the finding of abnormal metabolites alone.14 Thus, serum B12 assays with metabolites (methylmalonic acid and homocysteine) are useful in documenting B12 deficiency.
Although both methylmalonic acid and homocysteine are sensitive for B12 deficiency, methylmalonic acid is more specific. In a large Class III study involving 434 patients with vitamin B12 deficiency, serum methylmalonic acid was elevated in 98.4% and serum homocysteine was elevated in 95.9%.17 In the same study, serum methylmalonic acid was elevated in 12.2%, but serum homocysteine was elevated in 91% of 123 patients with isolated folate deficiency.17 Homocysteine may also be elevated in pyridoxine deficiency and heterozygous homocystinemia. Both homocysteine and methylmalonic acid may be elevated in hypothyroidism, renal insufficiency, and hypovolemia.
Several studies highlight the relatively high prevalence of prediabetes (impaired glucose tolerance) in patients with DSP who do not fulfill the criteria for definite diabetes mellitus (Class III).18-20 In these studies, glucose tolerance testing (GTT) was performed in patients with idiopathic DSP. Impaired glucose tolerance was documented in 25–36% of patients compared to approximately 15% of controls. Additionally, patients with painful sensory polyneuropathies were more likely to have impaired glucose tolerance than those with painless sensory polyneuropathies. Only one major study has not found an increased prevalence of impaired glucose tolerance in chronic idiopathic axonal polyneuropathy (Class III).21
Monoclonal gammopathies are more common in patients with polyneuropathy than in the normal population. IgM monoclonal gammopathies may be associated with autoantibody activity, type I or II cryoglobulinemia, macroglobulinemia, or chronic lymphocytic leukemia. IgG or IgA monoclonal gammopathies may be associated with myeloma, POEMS syndrome, primary amyloidosis, or chronic inflammatory conditions. In one Class III study of 279 consecutive patients with polyneuropathy of otherwise unknown etiology seen at a referral center, 10% had monoclonal gammopathy, a significant increase over that reported in community studies.22 Serum protein immunofixation electrophoresis (IFE) is more sensitive than serum protein electrophoresis (SPEP), especially for detecting small or nonmalignant monoclonal gammopathies. Ten of 58 (17%) monoclonal gammopathies, including 10 of 36 (30%) with IgM <5 g/L, were identified by IFE but not by SPEP.23
Conclusions. Screening laboratory tests are possibly useful in determining the cause of DSP, but the yield varies depending upon the particular test (Class III). The tests with the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Class III). Patients with distal symmetric sensory polyneuropathy have a relatively high prevalence of diabetes or prediabetes (impaired glucose tolerance), which can be documented by blood glucose or GTT (Class III).
Recommendations. Screening laboratory tests may be considered for all patients with DSP (Level C). Although routine screening with a panel of basic tests is often performed (table e-1), those tests with the highest yield of abnormality are blood glucose, serum B12 with metabolites (methylmalonic acid with or without homocysteine), and serum protein immunofixation electrophoresis (Level C). When routine blood glucose testing is not clearly abnormal, other tests for prediabetes (impaired glucose tolerance) such as a GTT may be considered in patients with distal symmetric sensory polyneuropathy, especially if it is accompanied by pain (Level C).
Although there are no control studies (Level U) regarding when to recommend the use of other specific laboratory tests, clinical judgment correlated with the clinical picture will determine which additional laboratory investigations (table e-2) are necessary.
Role of genetic testing in the evaluation of polyneuropathy. Hereditary neuropathies are an important subtype of polyneuropathy with a prevalence of approximately 1:2,500 people. DSP is the predominant phenotype, but phenotypic heterogeneity may be present even within the same family; therefore, when genetic testing is contemplated all neuropathy phenotypes need to be considered. In the evaluation of polyneuropathy, a comprehensive family history should always be elicited. A high index of suspicion for a hereditary neuropathy phenotype is essential. Since molecular diagnostic techniques are available, guidelines for their usefulness in the evaluation of polyneuropathy are needed.
The majority of genetically determined polyneuropathies are variants of Charcot-Marie-Tooth (CMT) disease, and genetic testing is available for an increasing number of these neuropathies. The clinical phenotype of CMT is extremely variable, ranging from a severe polyneuropathy with respiratory failure through the classic picture with pes cavus and "stork legs" to minimal neurologic findings.24,25 Since a substantial proportion of CMT patients have de novo mutations, a family history of neuropathy may be lacking.24-26 Additionally, different genetic mutations can cause a similar phenotype (genetic heterogeneity) and different phenotypes can result from the same genotype (phenotypic heterogeneity).
How accurate is genetic testing for identifying patients with genetically determined neuropathies? The CMT phenotype has been linked to 36 loci and mutations have been identified in 28 different genes, several of which can be identified by commercially available genetic testing. Previous segregation studies followed by several prospective cohort studies have documented that the results of currently available genetic testing are unequivocal for diagnosis of established pathogenic mutations, providing a specificity of 100% (i.e., no false positives) and high sensitivity (Class I and II).27-36 The interpretation of novel mutations may require further characterization available in specialized centers. Data from six Class I, six Class II, and one Class III study indicate that genetic testing is useful for the accurate classification of hereditary polyneuropathies.24,26-37 See table 1 for details.
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Which patients with polyneuropathy should be screened for hereditary neuropathies? Genetic studies of hereditary neuropathies have tested the prevalence of various mutations in selected patients with the classic CMT phenotype with and without a family history of polyneuropathy27,31-36 (Class III evidence for screening). For these patients, the yield of genetic tests has been relatively high.
Data from seven studies indicate that the demyelinating form of Charcot-Marie-Tooth (CMT1) is the most prevalent, and about 70% of these patients have a duplication of PMP22 gene (CMT1A).27,31-36 CMT1A is also the most common variety of sporadic CMT1, accounting for 76–90% of cases.26,32 Six studies showed that when the test for CMT1A duplication is restricted to patients with clinically probable CMT1 (i.e., autosomal dominant, primary demyelinating polyneuropathy), the yield is 54–80% as compared to testing a cohort of patients suspected of having any variety of hereditary peripheral neuropathy where the yield is only 25–59% (average of 43%).27,29,30,32,34,36
Axonal forms of Charcot-Marie-Tooth (CMT2) are most commonly caused by MFN2 mutations, which account for approximately 33% of the cases.37 MFN2 mutations have not occurred in the CMT1 group.
Data from eight studies indicate that Cx32(GJB1) mutations cause an X-linked neuropathy (CMTX), which may present with either a predominantly demyelinating or axonal phenotype and account for approximately 12% of all cases of CMT.27-30,33-36 If the pedigree is uninformative as to whether the inheritance is autosomal dominant or X-linked (lack of father to son transmission), Cx32(GJB1) mutation is in the differential diagnosis for both predominantly demyelinating and axonal neuropathies.
Data from seven studies have established average mutation frequencies of 2.5% for PMP22 point mutations, and 5% for MPZ mutations in the CMT population.27-29,34-36 CMT caused by other genes is much less frequent (figure).
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Given the relationships between pattern of inheritance, EDX results, and specific mutations, the efficiency of genetic testing can be improved by following a stepwise evaluation of patients with possible hereditary neuropathy. First, a clinical classification that includes EDX studies should be performed to determine whether the neuropathy is primarily demyelinating or primarily axonal in type. Since EDX studies are sometimes problematic in children, some physicians may opt to proceed directly to genetic testing of symptomatic children suspected of having CMT. Secondly, the inheritance pattern (autosomal dominant, autosomal recessive, or X-linked) should be ascertained. Based upon this information, the most appropriate genetic profile testing can then be performed.
The figure indicates an evidence-based, tiered approach for the evaluation of suspected hereditary neuropathies, and table 2 shows the relative frequency of the most common genetic abnormalities accounting for the CMT phenotype from population studies.
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The previous discussion applies to patients with polyneuropathy and a classic hereditary neuropathy phenotype with or without a family history. The authors were not able to find studies of the yield of genetic screening in polyneuropathy patients without a classic hereditary neuropathy phenotype. Some patients with CMT genetic mutations have minimal neurologic findings and do not have the classic CMT phenotype.24,25 Thus, some patients with cryptogenic polyneuropathies without the classic CMT phenotype may also have hereditary neuropathies. The prevalence of mutations in this population is unknown.
Conclusions. Genetic testing is established as useful for the accurate diagnosis and classification of hereditary polyneuropathies (Class I). For patients with a cryptogenic polyneuropathy who exhibit a classic hereditary neuropathy phenotype, routine genetic screening may be useful for CMT1A duplication/deletion and Cx32 mutations in the appropriate phenotype (Class III). Further genetic testing may be considered guided by the clinical question. There is insufficient evidence to determine the usefulness of routine genetic screening in cryptogenic polyneuropathy patients without a classic hereditary neuropathy phenotype.
Recommendations. Genetic testing should be conducted for the accurate diagnosis and classification of hereditary neuropathies (Level A). Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classic hereditary neuropathy phenotype (Level C). There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classic hereditary phenotype (Level U).
Clinical context. To achieve the highest yield, the genetic testing profile should be guided by the clinical phenotype, inheritance pattern (if available), and EDX features (demyelinating vs axonal). See the figure for guidance.
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RECOMMENDATIONS FOR FUTURE RESEARCH |
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DISCLOSURE |
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Top.Abstract.FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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DISCLAIMER |
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Top.Abstract.FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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This statement is provided as an educational service of the AAN, AANEM, and AAPM&R. It is based upon an assessment of current scientific and clinical information. It is not intended to include all possible proper methods of care for a particular neurologic problem or all legitimate criteria for choosing to use a specific test or procedure. Neither is it intended to exclude any reasonable alternative methodologies. The AAN, AANEM, and AAPM&R recognize that specific care decisions are the prerogative of the patient and physician caring for the patient, based on all of the circumstances involved. The clinical context section is made available in order to place the evidence-based guideline into perspective with current practice habits and challenges. No formal practice recommendations should be inferred.
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Appendix 1 |
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Top.Abstract.FORMATION OF EXPERT PANELDESCRIPTION OF THE ANALYTIC...ANALYSIS OF EVIDENCERECOMMENDATIONS FOR FUTURE...DISCLOSUREDISCLAIMERAppendix 1REFERENCES |
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Practice Issues Review Panel (AANEM): Yuen T. So, MD, PhD (chair); Michael T. Andary, MD; Atul Patel, MD; Carmel Armon, MD; David del Toro, MD; Earl J. Craig, MD; James F. Howard, Jr, MD; Joseph V. Campellone Jr., MD; Kenneth James Gaines, MD; Robert Werner, MD; and Richard Dubinsky, MD.
Clinical Quality Improvement Committee (AAPM&R): Dexanne B. Clohan, MD (chair); William L. Bockenek, MD; Lynn Gerber, MD; Edwin Hanada, MD; Ariz R. Mehta, MD; Frank J. Salvi, MD, MS; and Richard D. Zorowitz, MD.
Supplemental data at www.neurology.org
See page 177
e-Pub ahead of print on December 3, 2008, at www.neurology.org.
Published simultaneously in PM&R and Muscle & Nerve.
Authors’ affiliations are listed at the end of the article.
The AAN Mission Statement, Classification of evidence, Classification of recommendations, and Conflict of Interest Statement (appendices e-1 through e-4), as well as tables e-1, e-2, and e-3, are available as supplemental data on the Neurology® Web site at www.neurology.org.
Approved by the AAN Quality Standards Subcommittee on November 10, 2007; by the AAN Practice Committee on January 20, 2008; by the Neuromuscular Guidelines Steering Committee on April 22, 2008; by the AAN Board of Directors on August 20, 2008; by the AANEM Board of Directors on May 1, 2008; and by the AAPM&R Board of Governors on April 7, 2008.
Disclosure: Author disclosures are provided at the end of the article.
Received April 24, 2008. Accepted in final form August 29, 2008.
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REFERENCES |
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; RAB7 small guanosine triphosphatase late endosomal protein; GARS glycyl-transfer RNA synthetase; NEFL neurofilament light chain; HSPB1 heat shock protein beta-1.