#1013 Approaching Neuropathies January 18 to 21 Steven M. Nash, MD Assistant Professor of Clinical Neurology Department of Neurology The Ohio University Medical Center Isabelle Periquet, MD Assistant Professor of Neurology Department of Neurology The Ohio University Medical Center

1 Steven M. Nash, MD Assistant Professor of Clinical Neurology Department of Neurology The Ohio University Medical Center

Profile Mr. Winkleman 67 year old male Symptoms Falling down frequently Unexplained weight loss Low back, hip, and leg pain Tingling in right side of trunk Right foot drop Mr. Winkleman 67 year old male Symptoms Falling down frequently Unexplained weight loss Low back, hip, and leg pain Tingling in right side of trunk Right foot drop 2

Profile Mr. Winkleman Evaluation Weakness in multiple muscle groups - Asymmetrical from side to side Less severe sensory loss EMG showed active, asymmetrical sensory motor polyneuropathy Sural nerve biopsy revealed vasculitic neuropathy Diagnosis: Vasculitic neuropathy Mr. Winkleman Evaluation Weakness in multiple muscle groups - Asymmetrical from side to side Less severe sensory loss EMG showed active, asymmetrical sensory motor polyneuropathy Sural nerve biopsy revealed vasculitic neuropathy Diagnosis: Vasculitic neuropathy 2A

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Key Points Neuropathies may present in many different ways Neuropathy is a result of some other pathology Treatment requires identification and removal of the underlying cause Work-up includes a careful history and physical exam, blood work, and EMG Neuropathies may present in many different ways Neuropathy is a result of some other pathology Treatment requires identification and removal of the underlying cause Work-up includes a careful history and physical exam, blood work, and EMG 4

Neuropathies Mononeuropathy (including radiculopathy, plexopathy) Multiple mononeuropathies Neuronopathy Axonal polyneuropathy Demyelinating polyneuropathy Mononeuropathy (including radiculopathy, plexopathy) Multiple mononeuropathies Neuronopathy Axonal polyneuropathy Demyelinating polyneuropathy 5

Peripheral Motor Neurons Cell bodies located in anterior horn of spinal cord or in brainstem nuclei Axons myelinated Axons terminate on skeletal muscle fibers Cell bodies located in anterior horn of spinal cord or in brainstem nuclei Axons myelinated Axons terminate on skeletal muscle fibers 6

Peripheral Motor Neurons Cell bodies in dorsal root ganglia (pseudounipolar) Both myelinated (proprioception) and unmyelinated (pain/temperature) axons Terminate in sensory receptors Cell bodies in dorsal root ganglia (pseudounipolar) Both myelinated (proprioception) and unmyelinated (pain/temperature) axons Terminate in sensory receptors 7

Peripheral Autonomic Neurons Cell bodies (second order neurons) in spinal cord nuclei. Axons terminate on third order neurons in autonomic ganglia Axons are unmyelinated (slow) Axons of third order neurons terminate in glands and smooth muscle Cell bodies (second order neurons) in spinal cord nuclei. Axons terminate on third order neurons in autonomic ganglia Axons are unmyelinated (slow) Axons of third order neurons terminate in glands and smooth muscle 8

Symptoms of Neuropathy Numbness Imbalance Burning, stinging pain dysesthesia) Insomnia Depression Weakness Numbness Imbalance Burning, stinging pain dysesthesia) Insomnia Depression Weakness 9

Signs of Neuropathy Loss of position and vibration sensitivity Pain and temperature loss Romberg sign Weakness and loss of reflexes Trophic changes of skin, hair loss, d ecrease / increase of sweating Loss of position and vibration sensitivity Pain and temperature loss Romberg sign Weakness and loss of reflexes Trophic changes of skin, hair loss, d ecrease / increase of sweating 10

Common Causes of Neuropathy Diabetes Alcohol abuse Diabetes Alcohol abuse 11

Presentations of Diabetic Neuropathy Mononeuropathy (including cranial nerves, lumbosacral plexus) Multiple mononeuropathies Distal sensorimotor polyneuropathy Mononeuropathy (including cranial nerves, lumbosacral plexus) Multiple mononeuropathies Distal sensorimotor polyneuropathy 12

Alcoholic Neuropathies Direct toxic effect Secondary nutritional effects (vitamin deficiencies) Direct toxic effect Secondary nutritional effects (vitamin deficiencies) 13

Uncommon Causes of Neuropathy Nutritional (vitamin deficiencies) Guillain-Barre syndrome Toxic (drugs, hexacarbons, heavy metals) Hereditary Rheumatologic disease Amyloid Nutritional (vitamin deficiencies) Guillain-Barre syndrome Toxic (drugs, hexacarbons, heavy metals) Hereditary Rheumatologic disease Amyloid 14

Other Uncommon Causes Paraneoplastic (Anti-Hu) Infection Systemic disease (uremia, hypothyroid, etc) Tumors (Especially in neurofibromatosis, type1) Paraneoplastic (Anti-Hu) Infection Systemic disease (uremia, hypothyroid, etc) Tumors (Especially in neurofibromatosis, type1) 15

Guillain-Barre Syndrome “Ascending paralysis”, loss of reflexes Elevated CSF protein, normal cell count Slowing on nerve conduction studies Diagnosis often requires high index of suspicion Most recover with prompt care Plasmapheresis / IVIg both speed recovery “Ascending paralysis”, loss of reflexes Elevated CSF protein, normal cell count Slowing on nerve conduction studies Diagnosis often requires high index of suspicion Most recover with prompt care Plasmapheresis / IVIg both speed recovery 16

Neuropathy Due to Vasculitis May be isolated to peripheral nerves Sometimes associated with rheumatologic diseases Multiple mononeuropathies Requires nerve biopsy for definite diagnosis Treated with corticosteroids; cyclophosphamide often required May be isolated to peripheral nerves Sometimes associated with rheumatologic diseases Multiple mononeuropathies Requires nerve biopsy for definite diagnosis Treated with corticosteroids; cyclophosphamide often required 17

Blood Work in Work-up of Neuropathy Patients Glucose, BUN, creatinine, liver enzymes, TSH, ESR, hemoglobin A1C, serum protein electrophoresis ANA, RF, ANCA in selected patients Gene testing in selected patients Antibody testing in selected patients Glucose, BUN, creatinine, liver enzymes, TSH, ESR, hemoglobin A1C, serum protein electrophoresis ANA, RF, ANCA in selected patients Gene testing in selected patients Antibody testing in selected patients 18

Antibody Testing in Polyneuropathies Anti-Hu useful in sensory neuronopathies Anti-GM1 only for motor neuropathies in the absence of conduction block on NCS Anti-MAG, anti-sulfatide not helpful for diagnosis or treatment Anti-Hu useful in sensory neuronopathies Anti-GM1 only for motor neuropathies in the absence of conduction block on NCS Anti-MAG, anti-sulfatide not helpful for diagnosis or treatment 19

Electromyography / Nerve Conduction Studies Used to evaluate function of the large, myelinated peripheral nerve fibers All patients with clinical evidence of polyneuropathy should be studied to determine distribution, type (axonal vs. demyelinating), severity, and activity Used to evaluate function of the large, myelinated peripheral nerve fibers All patients with clinical evidence of polyneuropathy should be studied to determine distribution, type (axonal vs. demyelinating), severity, and activity 20

Conclusions Neuropathies may present in many different ways Neuropathy is a result of some other pathology Treatment requires identification and removal of underlying cause Work-up includes a careful history and physical exam, blood work, and EMG Neuropathies may present in many different ways Neuropathy is a result of some other pathology Treatment requires identification and removal of underlying cause Work-up includes a careful history and physical exam, blood work, and EMG 21

Summary Mr. Winkleman Treatment IV corticosteroids Tapering dose of oral Prednisone Six months of oral Cytoxan Physical therapy Not back to baseline, but improving Re-gained some weight Prognosis: Good Mr. Winkleman Treatment IV corticosteroids Tapering dose of oral Prednisone Six months of oral Cytoxan Physical therapy Not back to baseline, but improving Re-gained some weight Prognosis: Good 22

Isabelle Periquet, MD Director, Peripheral Neuropathy Center Assistant Professor of Neurology Department of Neurology The Ohio University Medical Center 23

Profile Mrs. Blanton 57 year old female Symptoms 8 year history of burning foot pain Tingling sensations Mrs. Blanton 57 year old female Symptoms 8 year history of burning foot pain Tingling sensations 24

Profile Mrs. Blanton Evaluation Strength preserved Reflexes preserved Sensory testing: - Normal vibration, position and light touch sensation - Diminished pin sensation Normal EMG Diagnosis: ? Mrs. Blanton Evaluation Strength preserved Reflexes preserved Sensory testing: - Normal vibration, position and light touch sensation - Diminished pin sensation Normal EMG Diagnosis: ? 24 A

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Evaluation Is this a neuropathy or is it something else? How can I confirm a diagnosis of neuropathy? What laboratory tests are needed to evaluate for a cause? How do I treat this patient? Is this a neuropathy or is it something else? How can I confirm a diagnosis of neuropathy? What laboratory tests are needed to evaluate for a cause? How do I treat this patient? 26

Painful Sensory Neuropathy Prospective Evaluation Using Skin Biopsy 140 consecutively referred patients Inclusion criteria - Pain in the extremities as a primary complaint - No significant weakness - No identified cause 140 consecutively referred patients Inclusion criteria - Pain in the extremities as a primary complaint - No significant weakness - No identified cause 27

Evaluation: EMG / NCS 114 Patients EMG / NCS Abnormal Normal 60/114 (53%) 54/114 (47%) QST AUTO Skin Biopsy 114 Patients EMG / NCS Abnormal Normal 60/114 (53%) 54/114 (47%) QST AUTO Skin Biopsy 28

Evaluation: QST Computerized method of determining vibration threshold (large fiber function) and temperature threshold (small fiber function) QST was abnormal in 72% of patients with normal EMGs Computerized method of determining vibration threshold (large fiber function) and temperature threshold (small fiber function) QST was abnormal in 72% of patients with normal EMGs 29

Evaluation: Autonomic Testing Battery of tests evaluating sweat function (QSART), heart rate and blood pressure responses to deep breathing, valsalva and tilt QSART was abnormal in 59% of patients with normal EMG’s Battery of tests evaluating sweat function (QSART), heart rate and blood pressure responses to deep breathing, valsalva and tilt QSART was abnormal in 59% of patients with normal EMG’s 30

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Evaluation: Blood Studies Routine blood studies - CBC, lytes, ESR, BUN, Cr, Ca++, LFTs, TSH, HgbA1C, B12 (MMA, HC), chol, TG Immune / infectious blood studies - HIV, FTA, ANA, ENA, RF, IEP with IF - Nerve antibodies (GM1, MAG, SGPG, Hu, sulfatide) DNA - PMP22 mutations, FAP (met 30) Routine blood studies - CBC, lytes, ESR, BUN, Cr, Ca++, LFTs, TSH, HgbA1C, B12 (MMA, HC), chol, TG Immune / infectious blood studies - HIV, FTA, ANA, ENA, RF, IEP with IF - Nerve antibodies (GM1, MAG, SGPG, Hu, sulfatide) DNA - PMP22 mutations, FAP (met 30) 32

Differential Diagnosis Large Fiber Sensory Neuropathy - Hereditary 5 - Connective tissue disease 3 (Sjogren’s, MCTD) - Monoclonal gammopathy 2 - Amyloidosis 2 - Cancer (CML) 1 - Vasculitis (non-systemic) 1 - Ganglionitis 1 - Old GBS 1 - Drug-induced (Taxol) 1 - Creutzfeld-Jacob disease 1 - Idiopathic 42 Large Fiber Sensory Neuropathy - Hereditary 5 - Connective tissue disease 3 (Sjogren’s, MCTD) - Monoclonal gammopathy 2 - Amyloidosis 2 - Cancer (CML) 1 - Vasculitis (non-systemic) 1 - Ganglionitis 1 - Old GBS 1 - Drug-induced (Taxol) 1 - Creutzfeld-Jacob disease 1 - Idiopathic 42 33

Differential Diagnosis Small Fiber Sensory Neuropathy - Hereditary 1 - Monoclonal gammopathy 1 - PROMM 1 - Idiopathic 41 Need also to consider - diabetes, AIDS, uremia, porphyria, Tangier Fabry Small Fiber Sensory Neuropathy - Hereditary 1 - Monoclonal gammopathy 1 - PROMM 1 - Idiopathic 41 Need also to consider - diabetes, AIDS, uremia, porphyria, Tangier Fabry 34

Treatment Non-Pharmacologic Measures - TENS - Immersion in cold / warm water - Application of creams (Lidocaine cream) - Massage - Dorsal column stimulation Non-Pharmacologic Measures - TENS - Immersion in cold / warm water - Application of creams (Lidocaine cream) - Massage - Dorsal column stimulation 35

Treatment Tricylic antidepressants (amitriptyline, nortriptyline, desipramine) Anticonvulsants (carbamazepine, phenytoin, gabapentin, clonazepam, lamotrigine, topiramate) Antiarrythmics (mexiletine, lidocaine drip) SRIs (fluoxetine, paroxetine, ventrafaxine) Opiates Others (tramadol, baclofen, transdermal / intrathecal clonidine) Tricylic antidepressants (amitriptyline, nortriptyline, desipramine) Anticonvulsants (carbamazepine, phenytoin, gabapentin, clonazepam, lamotrigine, topiramate) Antiarrythmics (mexiletine, lidocaine drip) SRIs (fluoxetine, paroxetine, ventrafaxine) Opiates Others (tramadol, baclofen, transdermal / intrathecal clonidine) 36

Press: # (pound) + 71 on your phone keypad to speak with Dr. Periquet, and Dr. Nash Visit OMEN OnLine Visit OMEN OnLine Questions on this subject? 37

#1014 Ulcer Disease Update January 25 to 28 Hagop S. Mekhjian, MD Professor of Internal Medicine Division of Digestive Diseases Medical Director, OSU Hospitals The Ohio University Medical Center E. Christopher Ellison, MD Zollinger Professor of Surgery and Interim Chair, Department of Surgery The Ohio University Medical Center NEXT WEEK