Published on May 20, 2010
Journal club : Journal club Ranjith kumar, Postgraduate in Neurology, Gandhi medical College. Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review) : Practice Parameter: Evaluation of distal symmetric polyneuropathy: Role of laboratory, genetic, and autonomic testing; nerve biopsy; and skin biopsy (an evidence-based review) Report of the Quality Standards Subcommittee of the American Academy of Neurology, the American Association of Neuromuscular and Electrodiagnostic Medicine, and the American Academy of Physical Medicine and Rehabilitation J.D. England, MD; G.S. Gronseth, MD, FAAN; G. Franklin, MD; G.T. Carter, MD; L.J. Kinsella, MD; J.A. Cohen, MD; A.K. Asbury, MD; K. Szigeti, MD, PhD; J.R. Lupski, MD, PhD; N. Latov, MD; R.A. Lewis, MD; P.A. Low, MD; M.A. Fisher, MD; D.N. Herrmann, MD; J.F. Howard Jr, MD; G. Lauria, MD; R.G. Miller, MD; M. Polydefkis, MD, MHS; and A.J. Sumner, MD AAN Guideline Process : AAN Guideline Process Clinical Question Evidence Conclusions Recommendations AAN Classification of Evidence : AAN Classification of Evidence All studies rated Class I, II, III, or IV Five different classification systems: Therapeutic Randomization, control, blinding Diagnostic Comparison to gold standard Prognostic Screening Causation AAN Classification of Evidencefor Diagnosis : Class I: A cohort study with prospective data collection of a broad spectrum of persons with the suspected condition, using an acceptable reference standard for case definition. The diagnostic test is objective or performed and interpreted without knowledge of the patient’s clinical status. Study results allow calculation of measures of diagnostic accuracy. AAN Classification of Evidencefor Diagnosis AAN Classification of Evidencefor Diagnosis : AAN Classification of Evidencefor Diagnosis Class II: A case control study of a broad spectrum of persons with the condition established by an acceptable reference standard compared to a broad spectrum of controls or a cohort study where a broad spectrum of persons with the suspected condition where the data was collected retrospectively. The diagnostic test is objective or performed and interpreted without knowledge of disease status. Study results allow calculation of measures of diagnostic accuracy. AAN Classification of Evidencefor Diagnosis : AAN Classification of Evidencefor Diagnosis Class III: A case control study or cohort study where either persons with the condition or controls are of a narrow spectrum. The condition is established by an acceptable reference standard. The reference standard and diagnostic test are objective or performed and interpreted by different observers. Study results allow calculation of measures of diagnostic accuracy. Class IV: Studies not meeting Class I, II or III criteria including consensus, expert opinion or a case report. AAN Level of Recommendations : AAN Level of Recommendations A = Established as effective, ineffective or harmful (or established as useful/predictive or not useful/predictive) for the given condition in the specified population. B = Probably effective, ineffective or harmful (or probably useful/predictive or not useful/predictive) for the given condition in the specified population. C = Possibly effective, ineffective, or harmful (or possibly useful/predictive or not useful/predictive) for the given condition in the specified population. U = Data inadequate or conflicting; given current knowledge, treatment (test, predictor) is unproven. Note that recommendations can be positive or negative. Translating Class to Recommendations : Translating Class to Recommendations A = Requires at least two consistent Class I studies.* B = Requires at least one Class I study or two consistent Class II studies. C = Requires at least one Class II study or two consistent Class III studies. U = Studies not meeting criteria for Class I through Class III. Presentation Objectives : Presentation Objectives To review the evidence for the role of the following in assessing DSP: Laboratory, genetic, and autonomic testing Nerve biopsy Skin biopsy To present evidence-based recommendations Methods : Methods OVID MEDLINE, OVID Excerpta Medica (EMBASE), OVID Current Contents Database creation to March 2007 Relevant, fully published, peer-reviewed articles Supplemented through manual searches by panel members Search terms Peripheral neuropathy, polyneuropathy, and distal symmetric polyneuropathy Methods : Methods Cross-referenced with diagnosis, electrophysiology, autonomic testing, nerve biopsy, and skin biopsy At least two panelists reviewed each article for inclusion. A third panelist was added for arbitrating disagreements. Risk of bias was determined using the classification of evidence for each study (Classes I–IV). Literature Review : Literature Review Laboratory and genetic testing Inclusion criteria: - Relevant to the clinical questions Limited to human subjects Bibliographies, articles identified by panel members Exclusion criteria: - Articles not relevant to evaluation of polyneuropathy Literature Review : Literature Review Autonomic testing, nerve biopsy, and skin biopsy Inclusion criteria: - Relevant to the clinical questions Limited to human subjects Bibliographies, articles identified by panel members Exclusion criteria: - Articles not relevant to evaluation of polyneuropathy Back groundClassification of Neuropathies : Back groundClassification of Neuropathies Clinical Course (Onset to Peak) Acute Within 4 Wks Sub-acute Between 4 to 8 Wks Chronic Over 8 Wks Remitting / Relapsing …… Neuropathies with Abrupt / Rapid Onset : Neuropathies with Abrupt / Rapid Onset Guillain Barre Syndrome & Allied Disorders Ischaemic Neuropathies Connective Tissue Diseases Diabetes Mellitus Nerve Compression Hemorrhage Swelling in a Restricted Anatomic Compartment (Anterior Tibial Syndrome) Direct External Compression Penetrating Wounds Thermal Injury Iatrogenic ( Injection into Nerves) Subacute Polyneuropathies : Subacute Polyneuropathies Vasculitis Paraneoplastic Sub-acute Inflammatory Demyelinating Polyneuropathy with or without a Gammopathy Toxins Drugs Chronic Polyneuropathies : Chronic Polyneuropathies Chronic Inflammatory Demyelinating Neuropathy Metabolic Diabetes Mellitus Chronic Renal Failure Chronic Liver Failure Thyroid Disease Nutritional B12 Deficiency Infections HIV Leprosy Inherited Relapsing : Relapsing CIDP AIDP Toxic HIV Vasculitis Diabetes Porphyria HNPP Neuropathies with Cranial Nerve Involvement : Neuropathies with Cranial Nerve Involvement Diabetes mellitus Guillain-Barré syndrome HIV/AIDS Lyme disease Sarcoidosis Diphtheria Melkersson-Rosenthal Syndrome Neoplastic Invasion of Skull Base & Meningeal Diseases Polyneuropathies Predominant Upper Limbs Involvement : Polyneuropathies Predominant Upper Limbs Involvement Guillain-Barré Syndrome Diabetes Mellitus Porphyria Hereditary Motor Sensory Neuropathy Hereditary Amyloid Neuropathy Type II Lead Neuropathy Proximal Symmetric Motor Polyneuropathies : Proximal Symmetric Motor Polyneuropathies Guillain- Barré Syndrome Chronic Inflammatory Demyelinating Neuropathy Diabetes Mellitus Porphyria Osteosclerotic Myeloma & Para Proteinemias Acute Arsenic Polyneuropathy Lymphoma Diphtheria HIV/AIDS Lyme Disease Neuropathies by Pattern of Involvement : Neuropathies by Pattern of Involvement Focal Compressive Neuropathies / Entrapment Common Sites of Compression Myxedema Rheumatoid Arthritis Amyloidosis Acromegaly Trauma Ischemic Lesions Diabetes Mellitus Vasculitis Leprosy Sarcoidosis Neoplastic Infiltration or Compression Neuropathies by Pattern of Involvement : Neuropathies by Pattern of Involvement Multifocal Diabetes Mellitus Vasculitis Polyarteritis Nodosa Systemic Lupus Erythematosus Sjögren's Syndrome Sarcoidosis Leprosy HIV/AIDS Multifocal Variant of CIDP Hereditary Predisposition to Pressure Palsies Classification of Polyneuropathies By Fiber Type : Classification of Polyneuropathies By Fiber Type Motor Sensory Large Well Myelinated Small Poorly Myelinated or Unmyelinated Autonomic Predominantly Motor Neuropathy : Predominantly Motor Neuropathy Guillain-Barre’ Syndrome Diphtheria Toxin Acute Intermittent Porphyria Lead Poisoning Dapsone Toxicity Hypertrophic Neuropathy Hypoglycemia Pure Sensory Neuropathies & Neuronopathies : Pure Sensory Neuropathies & Neuronopathies Paraneoplastic Carcinomatous / Lymphomatous Sjögren's Syndrome Paraproteinemias Non-systemic Vasculitic Neuropathy Idiopathic Sensory Neuronopathy Primary Biliary Cirrhosis Crohn's Disease Chronic Gluten Enteropathy Vitamin E Deficiency Hereditary Sensory Neuropathy Predominantly Sensory Neuropathy : Predominantly Sensory Neuropathy Diabetes Mellitus Leprosy Alcoholic, Vitamin Deficiency Pernicious Anemia, Malabsorption Arsenic Intoxication Paraproteinemia, Multiple Myeloma Cryoglobulinemia, Amyloidosis Carcinomatous (Ganglioradiculitis) Fabry’s Disease Neuropathies with Autonomic Involvement : Neuropathies with Autonomic Involvement Diabetic Neuropathy Amyloidosis Porphyria Paraneoplastic Neuropathy Lymphoma Thallium, Arsenic, Mercury Toxicity Thiamine Deficiency Vincristine Toxicity Guillain-Barré Syndrome Alcoholic Neuropathy Acute Pandysautonomia HIV/AIDS Small-fiber NeuropathiesSensory - Autonomic : Small-fiber NeuropathiesSensory - Autonomic Leprosy Diabetes Mellitus Alcoholic Neuropathy Amyloidosis AIDS Hereditary Distal Symmetric Sensorimotor Polyneuropathies : Distal Symmetric Sensorimotor Polyneuropathies Endocrine diseases Diabetes mellitus Hypothyroidism Acromegaly Nutritional diseases Alcoholism, Thiamine deficiency Vitamin B12 deficiency , Folate deficiency Whipple's disease,Postgastrectomy syndrome Gastric restriction surgery for obesity Critical illness polyneuropathy Connective tissue diseases Rheumatoid arthritis Polyarteritis nodosa Systemic lupus erythematosus Churg-Strauss vasculitis Distal Symmetric Sensorimotor Polyneuropathies : Distal Symmetric Sensorimotor Polyneuropathies Infectious diseases Acquired immunodeficiency syndrome Lyme disease Sarcoidosis Toxic neuropathy Acrylamide, Carbon disulfide, Dichlorophenoxyacetic acid, Ethylene oxide Hexacarbons,Organophosphorus esters,Glue sniffing Metal neuropathy Chronic arsenic intoxication Mercury Gold Thallium Lead Amyloidosis Gouty neuropathy Carcinomatous axonal sensorimotor polyneuropathy Lymphomatous axonal sensorimotor polyneuropathy Background : Background DSP is the most common type of neuropathy. Prevalence is approximately 2,400 (2.4%) per 100,000 population but rises to approximately 8,000 (8%) per 100,000 in individuals older than 55 years.1,2 Simple screening laboratory tests, along with medical history, neurological examination, and EDX studies, reveal the cause of DSP in 74 to 82% of patients with polyneuropathy.3–12 Analysis of Evidence : Analysis of Evidence Question 1: What is the yield of screening laboratory tests in the evaluation of DSP, and which tests should be performed? Conclusion/Recommendation : Conclusion/Recommendation Conclusion: Screening laboratory tests are probably useful in determining the cause of DSP, but the yield varies depending upon the particular test (Class III). Recommendation: Screening laboratory tests may be considered for all patients with DSP (Level C). Conclusion/Recommendation : Conclusion/Recommendation Conclusion: 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). Recommendation: Although routine screening with a panel of basic tests is often performed, 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). Conclusion/Recommendation : Conclusion/Recommendation Conclusion: Patients with distal symmetric sensory polyneuropathy have a relatively high prevalence of diabetes or pre-diabetes (impaired glucose tolerance), which can be documented by blood glucose, or GTT (Class III). Recommendation: When routine blood glucose testing is not clearly abnormal, other tests for pre-diabetes (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). Recommendation : Recommendation Recommendation: 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 . Analysis of Evidence : Analysis of Evidence Question 4: What is the usefulness of clinical autonomic testing in the evaluation of polyneuropathy, and which tests have the highest sensitivity and specificity? Standard Protocol of Autonomic Testing : Standard Protocol of Autonomic Testing Tests for Sudomotor Function Tests for Cardiovagal Functions Tests of Adrenergic Function Low PA, Seminars in Neurology, 2003 Sudomotor FunctionLaboratory Evaluation : Sudomotor FunctionLaboratory Evaluation Quantitative Sudomotor Axon Reflex Test (QSART) Thermoregulatory Sweating Sympathetic Skin Response (SSR) QSART : QSART Assesses the postganglionic sudomotor nerve fibers and the sweat glands in localized areas of the skin Quantitative Sudomotor Axon Reflex TestTechnique : Quantitative Sudomotor Axon Reflex TestTechnique Stimulus : Acetyl Choline by Iantophoresis Through Constant Current Generator. Neural Pathway : Axon Reflex Mediated by Post- ganglionic Sudomotor Axons. Recording Sites : Proximal Foot, Proximal Leg, Medial Forearm & Optional Site. Measurement : Multi compartmental Sweat Cell & Sudorometer Quantitative Sudomotor Axon Reflex TestMeasurements : Quantitative Sudomotor Axon Reflex TestMeasurements Normal : Latency (1 to 2 Minutes) Duration (Less than 5 Minutes) Configuration (Rapid Rise and Slow Fall ) Symmetry Distal - Proximal Gradient Abnormal : Reduced Absent Excessive Persistent Normal Response Suggests Integrity of Postganglionic Sudomotor Axon, Provided Iantophoresis is Successful and Eccrine Sweat Glands are Present Slide 45: QSART: Patterns Thermoregulatory test (TST) : Thermoregulatory test (TST) Directly maps the topography of sudomotor function Thermoregulatory Sweating :Procedure : Thermoregulatory Sweating :Procedure “Unclothed” Subject on a Movable Cart in Heating Cabinet with infrared heaters and a Feedback System Parameters: Ambient Temperature- 45-50 Degree c. Relative Humility - 35% to 40% Skin Temperature- 38. 5 to 39. 5 Degree c. Oral Temperature-rise by 1 Degree or Reach 38 Degree c. Approximate Period – 45 to 50 Minutes Indicator Powder (Alizarin:Starch:Sodium Carbonate::1:2:1) Digital Photograph Computation Reporting Slide 48: Thermo Regulatory Sweating - Sweat Cabinet Thermo Regulatory Sweating : Thermo Regulatory Sweating Normal: symmetrical with variable involvement of the proximal limbs and legs Abnormal patterns: distal anhidrosis, segmental or regional anhidrosis and focal anhidrosis, global anhidrosis, mixed pattern Slide 50: Thermoregulatory Sweating Sympathetic Skin Response (SSR) : Sympathetic Skin Response (SSR) Analogous to Galvanic Skin Response. A Measure of Change(s) in Skin Conductance Levels in Response to Various Internal or External Stimuli. Has Long Been Used to Assess the Integrity of the Sympathetic Sudomotor Function. Can Be Easily Carried-out in Electrophysiology Laboratory With EMG System Sympathetic Skin ResponsePutative Pathways : Sympathetic Skin ResponsePutative Pathways Afferent - Sound, Cough, Gasp, Electrical or Magnetic Stimulation, LASER (Large Diameter Myelinated fibers). Efferent - Spinal Cord - Pre Ganglionic and Post Ganglionic Sympathetic Unmyelinated ‘C’ Fibers. Centre - Posterior Hypothalamus +????. Effectors - Sweat Gland. Sympathetic Skin Response : Sympathetic Skin Response Stimulation Fore head (Supra Orbital) Wrist (Median) Ankle (Posterior Tibial) Recording Hand Foot Elbow Knee Genitalia Sympathetic Skin Response Electrical Stimulation : Normal Parameters : Sympathetic Skin Response Electrical Stimulation : Normal Parameters Latency (sec) Upper Limb 1.47 0.64 Lower Limb 1.93 0.63 Amplitude Variable Duration Variable Wave form Bi / Triphasic Sympathetic Skin ResponseWhat is Abnormal ? : Sympathetic Skin ResponseWhat is Abnormal ? Absent Response Prolonged Latency Asymmetry Between Sides Slide 56: Sympathetic Skin Response Tests of Cardiovascular Autonomic Functions : Tests of Cardiovascular Autonomic Functions Tests of Cardiovagal Functions Heart rate variability with deep respiration Heart rate response to Valsalva maneuver Heart rate response to postural change Tests of sympathetic adrenergic function BP response to active standing and passive tilting BP response to a Valsalva maneuver Isometric exercise Cold pressor and mental stress test Prolonged tilt table test for neurally mediated syncope Carotid sinus massage Tests of Cardiovagal Functions Heart rate variability with deep respiration : Tests of Cardiovagal Functions Heart rate variability with deep respiration Most widely used index of cardiac parasympathetic function Parameters assessed Beat to beat amplitude variation Standard deviation of R-R interval Mean square successive difference Expiratory : Inspiratory ratio Usually done in supine position where vagal tone is maximum Key Influencing Factor Frequency and depth of respiration Slide 59: Normal Abnormal Tests of Cardiovagal Functions Heart rate variability with deep respiration Useful and Simple Bedside Tests of Cardiovascular Autonomic Function : Useful and Simple Bedside Tests of Cardiovascular Autonomic Function Composite Autonomic Severity Score : Composite Autonomic Severity Score 10 point Composite Autonomic Severity score Adrenergic : 4 points Sudomotor : 3 points Cardiovagal : 3 points Scoring Mild Autonomic dysfunction : 1-2 points Moderate Autonomic Dysfunction : 4-6 points Severe Autonomic Dysfunction : >7 points Indications for Autonomic Function Tests : Indications for Autonomic Function Tests When Generalized Autonomic Failure Suspected To Diagnose Limited Autonomic Neuropathy When Distal Small fiber Neuropathy is Suspected To Diagnose Orthostatic Intolerance To Detect Neuropathic basis in Neurocardiogenic syncope To Monitor Course of Neuropathy To Evaluate Response to Therapy To Evaluate Autonomic Involvement in Peripheral Neuropathies To Detect Sympathetic Dysfunction in Sympathetically Maintained Pain Clinical Treatment Trials Conclusions : Conclusions Conclusions: Autonomic testing is probably useful in documenting autonomic nervous system involvement in polyneuropathy (Class II and III). The sensitivity and specificity vary with the particular test. The utilization of the combination of autonomic reflex screening tests in the CASS provides the highest sensitivity and specificity for documenting autonomic dysfunction (Class II). Recommendations : Recommendations Recommendations: Autonomic testing should be considered in the evaluation of patients with polyneuropathy to document autonomic nervous system involvement (Level B). Autonomic testing should be considered in the evaluation of patients with suspected autonomic neuropathies (Level B) and may be considered in the evaluation of patients with suspected distal SFSN (Level C). The combination of autonomic screening tests in the CASS should be considered to achieve the highest diagnostic accuracy (Level B). Analysis of Evidence : Analysis of Evidence Question 2: How accurate is genetic testing for identifying patients with genetically determined neuropathies? Question 3: Which patients with polyneuropathy should be screened for hereditary neuropathies? Inherited neuropathies : Inherited neuropathies Hereditary sensory motor neuropathies : Hereditary sensory motor neuropathies Conclusions : Conclusions 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 classical 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. Recommendation : Recommendation Recommendation: Genetic testing may be considered in patients with a cryptogenic polyneuropathy and classical hereditary neuropathy phenotype (Level C). Clinical Context : 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 versus axonal). Figure 1 : Figure 1 Conclusion/Recommendation : Conclusion/Recommendation Conclusion: There is insufficient evidence to determine the usefulness of routine genetic screening in cryptogenic polyneuropathy patients without a classical hereditary neuropathy phenotype. Recommendation: There is insufficient evidence to support or refute the usefulness of routine genetic testing in cryptogenic polyneuropathy patients without a classical hereditary phenotype (Level U). Nerve biopsy : Nerve biopsy Procedure, handling, technique Most common-sural nerve, well characterised in health and disease. Superficial peroneal nerve, intermediate cutaneous nerve of thigh, superficial radial,ante brachial. Invasive,15%complication rate Wound infection, wound dehiscence, stump neuroma, unpleasant sensory symptoms. Single teased fibers, morphometry,semithin sections. Specific Diagnoses : Specific Diagnoses I. Inflammatory/Infections CIDP, GBS Vasculitis Leprosy Sarcoidosis CMV neuritis II. Neoplasm/paraprotein associated Non amyloid paraprotein associated - IgM anti MAG (widely spaced myelin) - POEMS (uncompacte myelin) - Ig Deposit disease Primary amyloidosis Neoplastic infiltrative Lymphomatoid granulomatosis EM III. Genetically determined HMSN HNPP GAN/INAD HSAN Polygluosan body dis Storage (MLD, Fabry’s, Tangier) IV. Matabolic/Toxic Amiodarone Hexacarbon STAINS : STAINS Hematoxylin & Eosin, Masson’s Trichrome stain Myelin Kulchitsky Pal stain Loyez (paraffin embedded sections Luxol fast blue (stains collagen) Axon Silver stains (Bodian, Bielchowsky, Palmgreen) Immunohistochemistry for neurofilament Storage material Cresyl violet (sulfatide) Congo red (Amyloid) Oil red O (Fat) PAS (glycogen) Slide 76: Hematoxylin & Eosin H&E Masson’s Trichrome stain MAT Longitudinal sections Slide 77: NORMAL MILD SEVERE MODERATE Pathological Changes : Pathological Changes Axonal changes Wallerian Degeneration Acute: Watery axoplasm, granular disintegration Myelin collapses – “ovoids” Chronic: Schwann cells proliferate – Bands of Bungner Axonal sprouting – within the bands Regenerating cluster ( 3 or more closely apposed myelinated axons that occupies the space of the parent fibre) Distal axonopathy (Dying back: distal portion of axon dies) - Axonal atrophy - secondary de/remyelination Myelin Changes : Myelin Changes Active myelin breakdown (ovoids) Denuded axons (semi thin sections)/ Thinly Myelinated fibres (De/Remyelination) : Teased fibre Onion bulb : recurrent episodes of de/remyelination – axon gets enveloped by concentric schwann cell lamellae Inflammatory demyelinating neuropathies (IDP) : Inflammatory demyelinating neuropathies (IDP) Pathological hallmarks: - Inflammatory infiltrate (mononuclear) Macrophage, lymphocytes, plasma cells (neutrophils – absent) - Segmental de/remyelination – Teased fibre Role Of Nerve biopsies : Role Of Nerve biopsies Vasculitis Sarcoidosis Hansen’s disease Amyloid Analysis of Evidence : Analysis of Evidence Question 5: What is the usefulness of nerve biopsy in determining the etiology of distal symmetric polyneuropathy? Conclusion/Recommendation : Conclusion/Recommendation Conclusion: There is no evidence to support or refute a conclusion regarding the role of nerve biopsy in the evaluation of DSP (Class IV). Recommendation: No recommendations can be made regarding the role of nerve biopsy in determining the etiology of DSP (Level U). Analysis of Evidence : Analysis of Evidence Question 6: What is the usefulness and diagnostic accuracy of skin biopsy in the evaluation of polyneuropathy? Skin biopsy : Skin biopsy Cutaneous innnervation in sensory neuropathy Un myelinated intra epidermal nerve fibers Con-focal, immuno staining marker 9.5 Limitations:standardisation 13-20% of normal age, gender, different parts of body does not provide specific diagnosis Conclusion/Recommendation : Conclusion/Recommendation Conclusion: IENF density assessment using PGP 9.5 immunohistochemistry is a validated, reproducible marker of small fiber sensory pathology. Skin biopsy with IENF density assessment is possibly useful to identify DSP which includes SFSN in symptomatic patients with suspected polyneuropathy (Class III). Recommendation: For symptomatic patients with suspected polyneuropathy, skin biopsy may be considered to diagnose the presence of a polyneuropathy, particularly SFSN (Level C). Future Research : Future Research Laboratory testing. - The finding of a laboratory abnormality does not necessarily mean that the abnormality is etiologically significant. need for more research into the basic pathobiology of the peripheral nervous system. a need to determine whether aggressive treatment or reversal of specific laboratory abnormalities improves or alters the course of polyneuropathy Future Research : Future Research Genetic testing Genetically determined neuropathies are more common and clinically diverse than previously appreciated. - to identify genotype-phenotype correlation is needed to improve the evaluation process for patients with suspected hereditary neuropathies. -The issue of cost/benefit ratio of genetic testing is important . -potential for the understanding of basic pathophysiology and treatment of neuropathies. Future Research : Future Research Autonomic testing. Autonomic testing can with a high degree of accuracy document autonomic system dysfunction . Research is necessary to determine whether the documentation of autonomic abnormalities is important in modifying the evaluation and treatment of polyneuropathy. Specific tests such as QSART can document small fiber (i.e., sudomotor axon) loss with a high degree of sensitivity, making the test useful to confirm the diagnosis of small fiber polyneuropathy. Since skin biopsy with determination of IENF density can also document small fiber loss, there is a need for studies that compare and correlate the two techniques Future Research : Future Research . Nerve biopsy. There are no studies of nerve biopsy in the evaluation of DSP. useful to know the outcome of well-designed prospective studies in this area. Skin biopsy. IENF density is a technique for the objective documentation of small fiber loss. Future Research : Future Research Skin biopsy - - distinguishing patients with suspected polyneuropathy, particularly SFSN, from patients with sensory complaints or pain unrelated to peripheral neuropathy. -reference standard for the diagnosis of SFSN should be specifically stated . -regenerative capacity are being studied and used as outcome measures in therapeutic trials. -Role in immunemediated neuropathies, Charcot-Marie-Tooth (CMT), detection or monitoring of leprosy, hereditary amyloidosis, vasculitic neuropathy, and Fabry’s disease.1 References : References Martyn CN, Hughes RAC. Epidemiology of peripheral neuropathy. J Neurol Neurosurg Psychiatry 1997;62:310–318. England JD, Asbury AK. Peripheral neuropathy. Lancet 2004;363:2151–2161. Barohn RJ. Approach to peripheral neuropathy and myopathy. Seminars Neurology 1998;18:7–18. (Class III) Jann S, Beretta S, Bramerio M, Defanti CA. Prospective follow-up study of chronic polyneuropathy of undetermined cause. 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