This document provides a comprehensive overview of peripheral nerve anatomy, pathologies, clinical examinations, and diagnostic evaluations associated with neuropathies. It details symptoms, laboratory assessments, and common causes including metabolic, infectious, autoimmune, and hereditary conditions. Treatment options and the role of rehabilitation strategies are also discussed, highlighting the complex interplay of factors affecting peripheral nerve health.

1. Margarita Correa MD, FAAPMR Physical Medicine and Rehabilitation Physical Medicine Institute Clermont, FL www.physmedi.com

2. Anatomy The peripheral nerves include: cranial nerves (with the exception of the second) spinal nerve roots dorsal root ganglia peripheral nerve trunks and their terminal branches peripheral autonomic nervous system

3. Anatomy Nerves are composed of different types of axons: Large, myelinated axons include motor axons and the sensory axons responsible for vibration sense, proprioception and light touch Small myelinated axons are composed of autonomic fibers and sensory axons and are responsible for light touch, pain and temperature Small, unmyelinated axons are also sensory and subserve pain and temperature

4. History Symptoms Numbness, tingling (feeling of pins and needles) of hands and/or feet Burning pain of hands and/or feet Numbness around mouth Loss of sensation to touch Loss of positional sense Weakness and leg cramping Difficulty picking things up or buttoning clothes Constipation

5. Physical Examination A cranial nerve examination can provide evidence of mononeuropathies or proximal involvement A fundoscopic examination may show abnormalities such as optic pallor, which can be present in leukodystrophies and vitamin B 12 deficiency Direct strength testing of muscles innervated by cranial nerves V, VII, IX/X, XI and XII is important, as mild bilateral weakness can be missed by observation only

6. Physical Examination The motor examination includes a search for fasciculations or loss of muscle bulk (atrophy) Muscle tone is normal or reduced The pattern of weakness helps narrow the diagnosis: symmetric or asymmetric, distal or proximal, and confined to a particular nerve, plexus or root level

7. Physical Examination In a patient with a distal symmetric sensorimotor neuropathy, the sensory examination shows reduced sensitivity to light touch, pinprick and temperature in a stocking-and-glove distribution Vibration and position sense are reduced in the distal legs prior to involvement of the arms In patients with severe loss of position sense, there may be athetoid movement of the fingers or arms when the eyes are closed (pseudoathetosis) or a Romberg sign Patients with mononeuritis multiplex may have sensory loss in specific nerve distributions

8. Physical Examination Deep tendon reflexes are reduced or absent A bilateral foot drop may result in a steppage gait in which the patient must lift the knees very high in order to clear the toes Proximal weakness results in an inability to squat or to rise unassisted from a chair Severe, longstanding neuropathy can result in trophic changes including kyphoscoliosis, pes cavus, loss of hair in affected areas or ulceration

9. Physical Examination Affected autonomic fibers: orthostatic hypotension without a compensatory rise in heart rate Respiratory rate and vital capacity should be evaluated in Guillain-Barré syndrome to assess for respiratory compromise The presence of lymphadenopathy, hepatomegaly or splenomegaly, and skin lesions may provide evidence of systemic disease Pale transverse bands in the nail beds, parallel to the lunula (Mees' lines) suggest arsenic poisoning

10. Laboratories The most common presentation is distal symmetric sensorimotor neuropathy, i.e. diabetes mellitus Initial evaluation should include: fasting serum glucose (FBS) glycosylated hemoglobin (A1C) blood urea nitrogen (BUN) creatinine (Cr) complete blood cell count (CBC) erythrocyte sedimentation rate (ESR) urinalysis vitamin B 12, folate TSH levels

11. Autoantibodies to Peripheral Nerves Antigens Anti-Asialo-GM1 ganglioside neuropathy Anti-GD1a ganglioside neuropathy Anti-GD1b ganglioside neuropathy Anti-GM1 ganglioside neuropathy Anti-GM2 ganglioside neuropathy Anti-GQ1b ganglioside neuropathy Anti-MAG/SGPG neuropathy Anti-sulfatide neuropathy Asialo GM1 antibody GD1a antibody GD1b antibody GM1 antibody GM2 antibody GQ1b antibody MAG/SGPG antibody Sulfatide antibody

12. Rheumatologic, Autoimmune, and Vasculitic Disease Disease Laboratories Polyarteritis SLE Rheumatoid arthritis Wegener’s granulomatosis Sjögren’s syndrome Celiac disease Cryoglobulins, immune complexes, CH50, hepatitis B and C serology, parvovirus serology, HIV-1 serology ANA, dsDNA antibodies Cyclic citrullinated peptide antibody, rheumatoid factor Anti-neutrophil cytoplasmic antibody (ANCA) SS-A/Ro antibody, SS-B/La antibody Gliadin, transglutaminase, and endomysial antibodies

13. Paraneoplastic Disease Neoplasm Laboratory Lung cancer Monoclonal gammopathy Myeloma Macroglobulinemia Chronic lymphocytic leukemia Hu antibodies Immunoglobulin profile, IFE, serum & urine Immunoglobulin profile, IFE, serum & urine, VEGF level Immunoglobulin profile, IFE, serum & urine Immunoglobulin profile, IFE, serum & urine IFE = immunofixation electrophoresis VEGF = vascular endothelial growth factor

14. Primary Amyloidosis Heavy Metal Toxicity: Lead, Arsenic, Mercury Laboratory Immunoglobulin profile, IFE, serum & urine Kappa/lambda light chains, free with ratio, serum Lichen Amyloidosis Laboratory Urine heavy metals Lead Intoxication

15. Nutritional Diseases Vitamin Deficiency Laboratories Vitamin B 12 deficiency Vitamin B 6 deficiency Vitamin B 6 toxicity Vitamin B 1 deficiency Vitamin E deficiency Folate deficiency CBC, serum B 12 Serum B 6 Serum B 6 Serum B 1 Serum vitamin E Serum folate

16. Infectious and Inflammatory Disease Infectious Agent Laboratories AIDS Lyme disease Herpes zoster Cytomegalovirus Hepatitis B Hepatitis C Parvovirus Sarcoidosis HIV-1 antibody Borrelia burgdorferi antibodies (total, IgG, IgM) Varicella zoster antigen and antibodies (IgG, IgM) CMV antigen and antibodies (IgG, IgM) HBs antigen, HBc antibodies (IgG, IgM) Hepatitis C antibody Parvovirus antibody Angiotensin converting enzyme

17. Diagnosis Autonomic studies include determination of: heart rate variation with respiration heart rate response and blood pressure to standing/tilting blood pressure response to sustained hand grip measure of sympathetic skin response

18. Diagnosis The cerebrospinal fluid (CSF) is useful in evaluation of myelinopathies and polyradiculopathies An elevated total protein level with less than 5 white blood cells (albuminocytologic dissociation) is present in acquired inflammatory neuropathy (e.g., Guillain-Barré syndrome, CIDP) Cytology (lymphoma) Special studies such as: Lyme polymerase chain reaction Cytomegalovirus branched chain DNA (polyradiculopathy or mononeuritis multiplex in AIDS)

19. Diagnosis Nerve biopsy is only helpful in very specific cases to diagnose vasculitis, leprosy, amyloid neuropathy, leukodystrophies, sarcoidosis and, occasionally, CIDP The sural nerve is the one most commonly selected for biopsy

20. EMG & NCS EMG and nerve conduction studies are often the most useful initial laboratory studies in the evaluation of patients with peripheral neuropathy

21. Electrodiagnosis Sensory NCS: sural, superficial peroneal, median, ulnar (at least in one side), if abnormal study on the contralateral side Motor NCS: peroneal and tibial nerve, median and ulnar (at least in one side), if abnormal study on the contralateral side, *F-waves/H-reflexes Cranial nerves: if affected, perform direct facial nerve stimulation, blink reflex, spinal accessory Needle EMG: one upper and lower limb muscle, distal & proximal including paraspinal regions, document on the contralateral side in the more affected muscles

22. Classification Hereditary Acquired Focal Idiopathic

23. Facts Diabetes and alcoholism are the most common causes of peripheral neuropathy in the United States The most common presentation of peripheral neuropathy is distal symmetric sensorimotor dysfunction

24. Hereditary Charcot-Marie-Tooth Disease and Related Neuropathies Type I – most common (~1:400) ~ 50% of hereditary neuropathy, autosomal dominant, demyelination and onion bulb Type 2 – axonal atrophy and degeneration Type 3 – Dejerine-Sottas disease, congenital hypomyelination, classic onion bulbs, severe form relatively rare, autosomal dominant sporadic or recessive Type 4 – all forms have hypomyelination

25. Hereditary X-Linked Charcot-Marie-Tooth Disease Hereditary Neuropathy with Liability to Pressure Palsies: HNPP = tomaculous neuropathy Hereditary Sensory and Autonomic Neuropathies (types 1, 2, 3, 4, 5) Familial Amyloid Polyneuropathies (types I, II, III, IV)

26. Hereditary Disorders of Lipid Metabolism Metachromatic Leukodystrophy - widespread myelin degeneration of central & peripheral nervous systems and abdominal organ dysfunction, deficiency of arylsulfatase A results in the accumulation of sulfatides in various tissues Krabbe’s Disease (Globoid Cell Leukodystrophy) widespread degeneration of the CNS white matter with collection of globoid cells = macrophages

27. Hereditary Disorders of Lipid Metabolism Adrenoleukodystrophy - progressive dementia, optic atrophy, cortical blindness, seizures and spasticity Refsum’s Disease - increased phytanic acid, retinitis pigmentosa, cerebellar dysfunction, increased protein in CSF Tangier Disease - rare autosomal recessive disorder, deficiency of HDL

28. Hereditary Disorders of Lipid Metabolism Cerebrotendinous Xanthomatosis (Cholestanolosis) - progressive dementia, spasticity, ataxia, cataracts, deposition of xanthomas on tendons, increased cholestanol -derivative from cholesterol

29. Hereditary Ataxia Friedreich’s Ataxia Vitamin E deficiency Abetalipoproteinemia (Bassen-Kornzweig Disease) Ataxia-Telangiectasia Spinocerebellar Ataxias Marinesco-Sjögren-Garland Syndrome

30. Hereditary Neuropathies Cockayne’s Syndrome Giant Axonal Neuropathy Infantile Neuroaxonal Dystrophy Porphyria : inherited disorders caused by defects in heme biosynthesis, acute abdominal pain, agitation, hallucinations, seizures; later manifestation of motor weakness in the upper or lower limbs, may be asymmetric, cranial nerves and autonomic system can be involved

31. Acquired Neuropathies Immune-Mediated Polyneuropathies Neuropathies Associated with Infections Neuropathies Associated with Endocrinopathies Neuropathies Associated with Systemic Diseases Neuropathies Associated with Malignancies Toxic Neuropathies Neuropathies Related to Nutritional Deficiencies Chronic Idiopathic Sensory or Sensorimotor Polyneuropathy

32. Immune-Mediated Acute Inflammatory Demyelinating Polyradiculo-neuropathy (AIDP) – Guillain Barre Syndrome The most common cause of acute generalized weakness Usually a preceding infectious process: viral, bacterial Ascending paralysis CSF: elevated protein in 80% of patient (+) anti-GM1 antibodies EMG & NCS: conduction block, prolongation or absence of F-waves, reduced conduction velocity, prolonged motor latencies Treatment IVIg Plasmapheresis Rehabilitation

33. CIDP Chronic Acquired Demyelinating Polyneuropathies Chronic Inflammatory Demyelinating Polyneuropathies (CIDP) Distal Acquired Demyelinating Symmetric (DADS) Multifocal Acquired Demyelination Sensory and Motor Neuropathy (MADSAM) Multifocal Motor Neuropathy (MMN)

34. CIDP May be associated with preceding drug use, vaccination, infections, other autoimmune or collagen vascular disease or monoclonal gammopathies Peak incidence: 40-60 years Progressive weakness, usually symmetric, relapsing with sensory changes, absent reflexes Variants: 80% - both motor and sensory involvement, 10% - pure motor, 5-10% - pure sensory

35. CIDP Laboratory Features: Electrodiagnostic (EMG & NCS) abnormality similar to GBS Increased CSF protein concentration is the most frequently abnormal finding (>45mg/dl) Nerve biopsy exhibits demyelination Rx: Prednisone IVIg: 66% - 95% of patients respond to initial IVIg Plasmapheresis Cytotoxic agents - Cyclophosphamide or Cyclosporin Rehabilitation Only 1/3 of the patients achieve complete remission off medications

36. Immune-Mediated: Vasculitis Primary Vasculitis Large Vessel: Giant cell (temporal) arteritis Medium and small vessel vasculitis (Polyarteritis nodosa, Churg-Strauss syndrome, Wegener’s granulomatosis, Microscopic polyangiitis, Isolated angiitis of the nervous system) Secondary Vasculitis associated with Connective tissue disorders: RA, SLE Malignancies: small cell CA lung, lymphoma Infections: herpes varicella zoster, CMV, HIV, hepatitis Cryoglobulinemia

37. Autoimmune Connective Tissue Diseases Sjögren’s Syndrome Rheumatoid Arthritis Systemic Lupus Erythematosus Polyarteritis Nodosa Scleroderma Mixed Connective Tissue Disease

38. Immune-Mediated Sarcoidosis : multisystem granulomatous disorder affecting several organs, central & peripheral nervous system - involved in ±5% of patients Idiopathic Perineuritis Hypereosinophilia Syndrome Isaac’s Syndrome - neuromyotonia, continuous muscle fiber activity syndrome

39. Infectious Leprosy (Hansen’s Disease) : 10 10 million cases, mycobacterium leprae Lyme’s Disease : spirochete transmitted by ticks, Borrelia burgdorferi, erythema migrans Diptheria : neuropathy occurs in ±20% of cases associated with circulatory and myocardial failure; bacterial toxin causes demyelination may cause cranial neuropathies HIV: can be associated to the viral infection, nutritional deficiencies and medications – Nucleoside reverse transcriptase inhibitors (NRTIs), or "d-drugs", are most frequently associated with peripheral neuropathy

40. Infectious Human T-Lymphotropic Virus-I (HTLV-I) CMV Epstein-Barr virus Herpes Varicella Zoster virus Hepatitis B and C

41. Endocrinopathies Diabetes Mellitus: 70% of the patients demonstrate the distal symmetric form, sensory or mixed Hypoglycemia Acromegaly Hypothyroidism – myxedema deposition

42. Systemic Diseases Uremic Neuropathy Gastrointestinal Diseases: Crohn’s disease, gluten-induced enteropathy Liver Diseases: primary biliary cirrhosis COPD Gout Critical Illness Polyneuropathy

43. Malignancies Paraneoplastic Neuropathies : anti-Hu syndrome Cryptogenic Sensory or Sensorimotor Polyneuropathy : 29% related to Gastric malignancy Neuropathies Related to Tumor Infiltration : neurofibromatosis, local infiltration by tumor tissue Noninfiltrative Neuropathies Associated with Lymphoproliferative Disorders and Monoclonal Gammopathies

44. Malignancies Acquired Amyloidosis Monoclonal Gammopathy of Uncertain Significance : IgM is the most common in patients with neuropathy, accounts for >90% Neuropathies Associated with Bone Marrow Transplantation and Graft-vs-Host Disease

45. Toxic Neuropathies Chemotherapy : anti-nucleosides, vincristine, cisplatin, paclitaxel and the podophyllotoxins Other medications : amiodarone, chloroquine, sulfa medications, vitamin B6 intoxication Industrial and Environmental Agents : hexacarbon inhalation Heavy Metal Intoxication : arsenic, lead, mercury Ethanol : alcoholism - 30% of all cases of generalized polyneuropathy

46. Nutritional Deficiencies Thiamine (Vitamin B1) Pyridoxine (Vitamin B6) Cobalamin (Vitamin B12) Folic Acid Vitamin E Postgastrectomy Syndromes Hypophosphatemia Jamaican Neuropathy Alcoholic Neuropathy

47. Focal Peripheral Neuropathies Median Nerve – carpal tunnel syndrome, AIN Ulnar nerve – cubital tunnel syndrome Radial Nerve – radial tunnel syndrome, PIN Peroneal Nerve – fibular head, drop foot Tibial Nerve – tarsal tunnel syndrome Cranial neuropathies: trigeminal, facial, recurrent and superior laryngeal – vagus, phrenic, spinal accessory, hypoglossal

48. Treatment Acquired : treat the cause Medications : Anti-seizures medications: Lyrica, Neurontin Anti-depressant medications: Cymbalta (SNRI) TCA’s: Amitriptyline, Nortriptyline Lidoderm Patch 5%: post-herpetic neuralgia Topical: Capsaicin

49. Treatment Rehabilitation physical therapy occupational therapy therapeutic exercises to strengthen muscles, improve balance, coordination and propioception, desensitization techniques TENS - pain control

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51. Thanks ! www.ninds.nih.gov/disorders/peripheralneuropathy www.neuropathy.org www.diabetes.org www.foundationforpn.org