Overview of Peripheral and Autonomic Neuropathies

Caroline M. Klein, M.D., Ph.D. Department of Neurology UNC-CH School of Medicine

Peripheral Nerve Anatomy

Richardson, EP, Jr and DeGirolami, U., Pathology of the Peripheral Nerve, W.B. Saunders, Vol. 32, Major Problems in Pathology, 1995

Potential pathological responses of peripheral nerve

Richardson, EP, Jr and DeGirolami, U., Pathology of the Peripheral Nerve, W.B. Saunders, Vol. 32, Major Problems in Pathology, 1995

Pathological Processes affecting peripheral nerve

Wallerian degeneration Axonal degeneration Primary neuronal degeneration
Anterior horn cell/lower motor neuron Dorsal root ganglion cell/sensory neuron

Segmental demyelination

Peripheral nerve, Normal anatomy

Dyck,PJ and Thomas, PK. Peripheral Neuropathy, 3rd edition, 1993.

Normal vs. abnormal peripheral nerve

Dyck,PJ and Thomas, PK. Peripheral Neuropathy, 3rd edition, 1993.

Diagnosis of Peripheral Neuropathy

Clinical Features
Symptoms at onset and rate of progression Past medical history Family history Social history Neurological examination

Diagnosis (contd)
Neurophysiological testing to confirm diagnosis and characterize features
EMG and nerve conduction studies Autonomic function testing Quantitative sensory testing

Peripheral neuropathy--History
Characteristics of typical symptoms
Sensory, motor, autonomic

Onset, duration and evolution of symptoms

Course of symptoms (monophasic, progressive, relapsing)

Symptoms of systemic disease

The 10 Ps
Dyck PJ et al., Neurology 1992;42:14-18

Pattern
Temporal Anatomical

Population of neurons Part of neuron Physiology Pathology

Prickling Phenomena Pedigree Plasma Pharmacology

Anatomical pattern of peripheral neuropathy

Mononeuropathy Multiple mononeuropathies Sensorimotor polyneuropathy-length dependent
Pure motor Pure sensory --Mixed

Sensorimotor polyradiculoneuropathy-length independent Small fiber sensory neuropathy Autonomic neuropathy

Diseases of the nerve roots

Ipsilateral, flaccid paresis in distribution of myotome or peripheral nerve Compression of sensory roots leads to tingling paresthesias, pain or numbness in skin area supplied by root or dermatome C6/7 and L4-S1 spinal levels most commonly affected by disc herniation or degenerative disease of the spine

Diseases of the Plexuses

Idiopathic brachial plexitis (Parsonage-Turner syndrome) Lumbosacral plexopathy
Retroperitoneal tumors, hematomas

Radiation-induced plexopathy Metastatic lesions or direct local tumor invasion, lymphoma

Amyotrophic Lateral Sclerosis (ALS)

Also called Lou Gehrigs disease Degenerative disease of anterior horn cells and corticospinal tracts combined upper and lower motor neuron disease Asymmetric muscle weakness Death due to respiratory muscle weakness Rare familial form, may be due to chromosome 21 mutation in gene for superoxide dismutase (SOD1)

Major classification of Peripheral Neuropathy by etiology

Inherited
Charcot-Marie-Tooth (HMSN) Hereditary sensory/autonomic neuropathies Inherited small fiber sensory neuropathy
Burning feet syndrome

Acquired
Toxic, metabolic, infectious, inflammatory

Peripheral Neuropathy--Testing
CBC with diff, lipid panel Vitamin B12/folate RPR, Lyme titer, hepatitis C antibody ESR, ANA, RF, ANCA, ENA, cryoglobulins Liver enzymes, BUN/creat Serum protein electrophoresis with immunofixation Urine 24 hour heavy metal screen Hemoglobin A1C, Glucose tolerance test Paraneoplastic antibodies, Chest X ray

Additional laboratory testing

Cerebrospinal fluid examination
Inflammation, abnormal cytology, infection

Muscle biopsy Peripheral nerve biopsy

Diseases of the Peripheral Nerves

Due to nerve trauma Inherited neuropathies Neuropathies associated with systemic disease Neuropathies associated with infectious disease Toxic neuropathies

Traumatic neuropathies
Carpal tunnel syndrome
Most common entrapment neuropathy Median neuropathy at the wrist

Radial nerve palsy (Saturday night palsy)

Compression of radial nerve at spiral groove of humerus Wrist drop, inability to extend hand at wrist

Ulnar neuropathy at the elbow

Compression at medial epicondyle or cubital tunnel

Traumatic neuropathies, contd

Peroneal nerve palsy
Compression of peroneal nerve at fibular head below the knee Weight loss, excessive leg crossing, brace Foot drop and preserved ankle jerk

Inherited Neuropathies

Inherited Peripheral Neuropathies

High arched feet (pes cavus) Hammertoe deformities Inverted champagne bottle legs
Dyck,PJ and Thomas, PK. Peripheral Neuropathy, 3rd edition, 1993.

HMSN type 1 (CMT 1)

HMSN 1A Chromosome 17p11.2 duplication PMP 22 genecompact peripheral myelin HMSN 1B Chromosome 1 point mutation, P0 gene Adhesion molecule in compact myelin HMSN X X-linked dominant (X1) X-linked recessive (X2) Connexin 32, gap junction protein at nodes of Ranvier

Hereditary Motor and Sensory Neuropathy HMSN 1 (Charcot Marie Tooth Type 1)
CMT 1A (most common) CMT 1B HMSN X1, X2

HMSN 2 (Neuronal type of peroneal muscular atrophy)

HMSN 2A, B, C, D

HMSN 3 (Dejerine-Sottas Syndrome) HMSN 4 (Refsums syndrome) HMSN 5 (Spastic paraplegia) HMSN 6 (With optic atrophy) HMSN 7 (with retinitis pigmentosa)

HMSN 1--Clinical Features

Rarely present with sensory symptoms Pes cavus and hammertoes
Intrinsic foot muscles are weak

Abnormal gait, clumsiness in running Loss of deep tendon reflexes Enlarged palpably firm nerves

HMSN type 1--Electrodiagnosis

Slowed conduction velocities of motor and sensory nerves (slowed to less than half normal values) Demyelination and smaller nerve fiber diameters

Nerve Conduction Studies

Hereditary Neuropathy with Liability to Pressure Palsy (HNPP)

Increased susceptibility to nerve injury from mechanical compression or traction Painless entrapment mononeuropathies or brachial plexopathy Chromosome 17, PMP 22 gene, deletion Abnormal myelin formation, with tomaculae and adjacent segmental demyelination

HNPP
Richardson, EP, Jr and DeGirolami, U., Pathology of the Peripheral Nerve, W.B. .Saunders, Vol. 32, Major Problems in Pathology, 1995

Peripheral Neuropathies associated with Systemic Disease

Diabetic neuropathy
Symmetric diabetic polyneuropathies
Distal sensorimotor polyneuropathy Distal symmetric sensory polyneuropathy Small fiber sensory neuropathy Diabetic autonomic neuropathy

Asymmetric diabetic polyneuropathies

Cranial mononeuropathies (III, IV, VI, VII) Diabetic amyotrophy (lumbosacral radiculoplexus neuropathy)

Diabetic neuropathy, endoneurial vascular changes

Richardson, EP, Jr and DeGirolami, U., Pathology of the Peripheral Nerve, W.B. Saunders, Vol. 32, Major Problems in Pathology, 1995

Lumbosacral radiculoplexus neuropathies

Dyck and Windebank, Muscle and Nerve, 2002;25:477-491

Diabetic and non-diabetic populations at risk Subacute, painful, asymmetric lower limb neuropathy Autonomic and sensory nerve involvement Micro-vasculitis on sural nerve biopsy

Hepatitis C and Cryoglobulinemia with Peripheral Neuropathy

High percentage of patients with mixed cryoglobulinemia have hepatitis C May be associated with multiple mononeuropathies, sensorimotor peripheral neuropathy Sural nerve biopsies demonstrate vasculitis Immune-modulating therapy and treatment of hepatitis C infection

Hepatitis C and cryoglobulinemia Treatment

Interferon alpha 2b +/- ribavirin or peginterferon alpha 2a Combination with other therapies, including IV cyclophosphamide, methylyprednisolone, plasmapheresis Response to therapy around 15-20% Positive predictors: absence of cirrhosis, young age, female, low HCV titers prior to tx, viral genotype Consider rituximab (antiCD20 monoclonal antibody)

Cryoglobulinemic peripheral neuropathy Microvasculitis

Other systemic diseases associated with peripheral neuropathy

Uremia
Slowly progressive, predominantly sensory

Amyloidosis (inherited or acquired)

Sensorimotor axonal polyneuropathy with autonomic involvement

Sarcoidosis
Symmetric sensorimotor polyneuropathy, mononeuropathy multiplex

Vasculitic or inflammatory peripheral neuropathies

Associated with systemic inflammatory disease
Rheumatoid arthritis, systemic lupus erythematosus, Sjogrens syndrome, scleroderma

Gammopathies (MGUS, Waldenstroms macroglobulinemia, multiple myeloma, POEMS syndrome) and cryoglobulinemia

Peripheral neuropathy associated with malignancy

Direct effect
Local tumor invasion or compression of peripheral nerve trunks

Indirect effects
Paraneoplastic neuropathy: Sensory neuronopathy, sensorimotor polyneuropathy Neurotoxicity from chemotherapy Radiation plexopathy Nerve trauma during tumor resection

Peripheral neuropathy and infectious disease

Leprosy: most common cause for peripheral neuropathy worldwide HIV: may occur in 20%, also neurotoxicity from anti-retroviral drugs Diphtheria: primarily motor demyelinating neuropathy Herpes zoster Hepatitis B and C

Acute inflammatory demyelinating polyradiculoneuropathy (AIDP or Guillain-Barre syndrome) Post-viral infection or immunization Progressive ascending paralysis Albuminocytological dissociation in CSF Most common acute paralytic disease in Western countries Majority recover within 1 year Treat acutely with plasmapheresis or intravenous immunoglobulin

Toxic neuropathies
Heavy metal exposure (arsenic,lead, mercury) Drugs (INH, chemotherapy, nitrofurantoin, metronidazole) Alcohol Vitamin deficiency: B1, B6, B12, E Excess vitamin supplementation: B6

Autonomic Neuropathies

Autonomic Nervous System

Duus, P. Topical Diagnosis in Neurology, 2nd ed., Thieme Medical Publishers, 1989

Autonomic Nervous System Peripheral Pathways

Sympathetic
Spinal cord (T1-L2)
Pre- or para-vertebral ganglia Effector organ

Parasympathetic
Cranio-sacral
Brainstem: CN III, VII, IX, X Sacral cord: S2,S3,S4

Clinical History: Autonomic Symptoms

Orthostatic dizziness/lightheadedness Sweating changes Vasomotor/skin color changes Gastrointestinal symptoms Bladder dysfunction Sexual dysfunction Secretomotor changes Sleep disturbance

Autonomic Disorders
Peripheral autonomic neuropathies Central autonomic disorders
Multiple System Atrophy Parkinsons disease

Disorders of orthostatic intolerance

Reflex syncope Neurocardiogenic syncope

Classification of Autonomic Neuropathies

Acute Autonomic Neuropathies
Idiopathic autonomic neuropathy (IAN) Acute paraneoplastic autonomic neuropathy Guillain-Barre syndrome Botulism Acute intermittent porphyria Drug induced (Cisplatin, vincristine, vacor, amiodarone, perhexilitine) Toxic (heavy metals, organic solvents, acrylamide)

Chronic Autonomic Neuropathy

Combined sympathetic/parasympathetic
Amyloidosis Diabetic autonomic neuropathy Pure autonomic failure Familial dysautonomia (Riley-Day syndrome) Hereditary neuropathies (HMSN, HSAN, Fabrys, Friedrichs ataxia) Connective tissue diseases (RA, SLE)

Chronic Peripheral Autonomic Neuropathies

Distal sympathetic
Distal small fiber neuropathy

Pure cholinergic neuropathies

LEMS Chronic idiopathic anhidrosis Adies syndrome Chagas disease

Pure adrenergic failure

Chronic Autonomic Neuropathy

Combined sympathetic/parasympathetic
Infectious (leprosy, AIDS) CIDP Uremia Dysautonomia of the elderly

Disorders of impaired orthostatic tolerance

Postural orthostatic tachycardia syndrome (POTS)

Diagnostic considerations for Autonomic testing

Autonomic neuropathies
Acute Chronic

Syncope/Orthostatic intolerance
GAF
MSA, PD

Neurocardiogenic syncope POTS (Postural Orthostatic Tachycardia Syndrome)

LABORATORY EVALUATION: AIMS

To detect the presence of autonomic failure To quantify its severity and distribution To determine the site of the lesion

AUTONOMIC REFLEX SCREEN

1. SUDOMOTOR
QSART distribution

2. CARDIOVAGAL:
HR response to
Deep Breathing Valsalva maneuver

3. ADRENERGIC
Beat-to-beat BP to the Valsalva maneuver Beat-to-beat BP & HR response to HUT

How do I arrange for Autonomic Function Testing for my patient?

Contact Clinical Neurophysiology Laboratory, UNC Hospital to request an appointment (919) 966-1686 Please review patient medications and provide instructions for holding medications that may affect testing results