Jieli Li 12/07/05

Overview The most common presentation is distal symmetric sensorimotor dysfunction Developed countries: DM and alcoholism are the most common etiologies Worldwide: Leprosy is the most common treatable cause The underlying cause of axonal neuropathies can frequently be treated Demyelinating neuropathies are generally managed with the assistance of a neurologist

Anatomy Peripheral nerves include – Cranial nerves (except the second) – Spinal nerve roots – Dorsal root ganglia – The peripheral nerve trunks and their terminal branches – Peripheral autonomic nervous system

Types of Axons Large myelinated axons (associated with large-fiber neuropathies) – Motor nerves – Sensory nerves for vibration, proprioception and light touch Small myelinated axons (associated with small-fiber neuropathies) – Autonomic nerves – Sensory nerves for light touch, pain and temperature Small unmyelinated axons (associated with small-fiber neuropathies) – sensory nerves for pain and temperature

Pathophysiology Axonopathies – at the level of the axon – Wallerian degeneration – “Dying-back” Neuronopathies – at the level of the motor neuron or dorsal root ganglion – With subsequent degeneration of their peripheral and central processes – Recover is usually incomplete Myelinopathies – at the level of the myelin sheath – Inflammatory (acquired) – recovery is often rapid and complete – Hereditary – usually diffuse, slowly progressive course

Wallerian Degeneration and “Dying Back” After division of the same single nerve fiber, Wallerian degeneration occurs distal to the division. Degeneration will also occur for a variable distance proximal to the nerve division.

Diagnostic Approach Is there a neuropathy? What is the pattern of nerve involvement? – Focal – Multifocal – Symmetric If the neuropathy is symmetric, is it proximal or distal? What is the fiber type? – Motor – Sensorimotor – Sensory only – Small fiber/autonomic Any cranial nerve involvement?

Is There a Neuropathy? Differential diagnosis include: – Motor neuron disease – Disorders of the neuromuscular junction – myopathy – Myelopathy – Syringomyelia – Dorsal column disorders (e.g., tabes dorsalis) – Hysterical symptoms

Neuropathies by Pattern of Involvement Focal Entrapment – Common sites of compression – Myxedema – RA – Amyloidosis – Acromegaly Compressive neuropathies Trauma Ischemic lesions – DM – Vasculitis Leprosy Sarcoidosis Neoplastic infiltration or compression Multifocal DM Vasculitis – Polyarteritis Nodosa – SLE – Sjögren's syndrome Sarcoidosis Leprosy HIV/AIDS Multifocal variant of CIDP Hereditary predisposition to pressure palsies

If the Neuropathy is Symmetric, is it Proximal or Distal? Most toxic and metabolic neuropathies present as a distal symmetric or dying-back process Proximal sensory neuropathies are rare – Porphyria Predominantly motor neuropathies are often proximal – Guillain-Barré syndrome – Exception: lead neuropathy

Is There Cranial Nerve Involvement? Neuropathies with Cranial Nerve Involvement – DM – Guillain-Barré syndrome – HIV/AIDS – Lyme disease – Sarcoidosis neoplastic invasion of skull base or meninges – Diphtheria

Neuropathies by Fiber Type Small-fiber neuropathies Leprosy DM Alcoholic neuropathy Amyloidosis AIDS Hereditary Autonomic neuropathies DM Amyloidosis Porphyria Paraneoplastic neuropathy Lymphoma Thallium, arsenic, mercury toxicity Thiamine deficiency Vincristine (Oncovin, Vincosar PFS) toxicity Guillain-Barré syndrome Alcoholic neuropathy Acute pandysautonomia HIV/AIDS

Pure Sensory Neuropathies Paraneoplastic Medications Carcinomatous sensory neuronopahty Lymphomatous sensory neuronopathy Sjogren’s syndrome Paraproteinemias Nonsystemic vasculitic neuropathy Idiopathic sensory neuronopathy Styrene-induced peripheral neuropathy Primary biliary cirrhoisis Crohn’s disease Chronic gluten enteropathy Vitamin E deficiency Hereditary sensory neuropathy types I and IV Friedreich’s ataxia

Diabetic Neuropathy Most commonly causes a distal, symmetric axonal sensorimotor neuropathy Second most common: a small-fiber, painful neuropathy Autonomic fiber involvement is common in DM but not Alcoholism or HIV infection Multifocal neuropathies including cranial nerves Asymmetric proximal motor neuropathy (diabetic amyotrophy) Symmetric proximal motor neuropathy

Clues in History Temporal course Symptoms and signs PMH – Systemic diseases such as DM or hypothyroidism Medications SH – Drug and alcohol use FH – Hereditary neuropathy Exposure to heavy metals and solvents HIV risk factors Foreign travel (leprosy) Diet (nutrition) Vitamin use (especially B6) Tick bite (Lyme disease)

Drugs Causing Neuropathies Axonal Vincristine, Paclitaxel Isoniazid, Pyridoxine, Ethambutol, Dapsone Metronidazole Didanosine Alfa interferon Chloroquine Lithium Amitriptyline Phenytoin Hydralazine Nitrous Oxide Colchicine Cimetidine Disulfiram (antabuse) Demyelinating Amiodarone Chloroquine Suramin Gold Neuronopathy Thalidomide Cisplatin Pyridoxine

Physical Examination Vitals – May reveal orthostatic hypotension without a compensatory tachycardia (seen in autonomic involvement) Respiratory rate and vital capacity (in GBS) Evidence of systemic disease – Skin lesions – HSM – LAD Cranial Nerve exam Funduscopic exam – May show optic pallor which can suggest leukodystrophies and Vit B12 deficiency

Physical Exam cont. Motor exam – fasciculations or loss of muscle bulk – Muscle tone – Pattern of weakness Sensory exam – Sensitivity to light touch, pinprick, temp – Vibration and position sense – Romberg sign – Sensory loss in specific nerve distributions (mononeuritis multiplex) DTR Gait – Foot drops Trophic changes – Pes cavus (high arch foot) – Kyphoscoliosis – Loss of hair in affected areas – Ulceration Nerve thickening

EMG/NCS Often the most useful initial diagnostic study in patients with peripheral neuropathy Can confirm the presence of a neuropathy Provide information regarding: – Types of fibers involved Motor vs. sensory vs.both – Pathophysiology Axonal loss vs. demyelination – Patterns of involvement Symmetric vs. asymmetric vs. multifocal

Advantages of EMG/NCS Being able to distinguish between axonal vs. demyelinating disorders – Axon loss Loss of amplitude of nerve action potentials – Myelin loss Slowed nerve conduction velocities Dispersion of evoked compound action potentials Conduction block (decreased amplitude of muscle compound action potentials on proximal compared with distal nerve stimulation) Marked prolongation of distal latencies

Limitations of EMG/NCS There is no reliable means of studying proximal sensory nerves NCS can be normal in pts with small-fiber neuropathies Lower extremity sensory responses can be absent in normal elderly pts

Standard Laboratory Tests? CBC ESR TSH SPEP Fasting blood glucose, Hgb A1c BUN/Cr Vitamin B12 ANA UA

Autonomic Studies Determination of heart rate variation with respiration Orthostatics Blood pressure response to sustained hand grip Measurement of sympathetic skin response

CSF Analysis Useful in evaluation of myelinopathies and polyradiculopathies Albuminocytologic dissociation – Elevated total protein with < 5 WBC – Associated with acquired inflammatory neuropathy (e.g., GBS, CIDP)

Nerve Biopsy Only useful in specific cases – Vasculitis – Leprosy – Amyloid neuropahty – Leukodystrophies – Sarcoidosis – CIDP Sural nerve is the most common site Complications – Infection – Poor wound healing – Painful dysesthesias

References Poncelet, AN. An Algorithm for the Evaluation of Peripheral Neuropathy. American Family Physician 1998/57: 4. Rutkove, SB. Overview of Polyneuropathy. Up to Date 2005.