A Practical Approach to Neuropathy Robert W. Neel, MD University of Cincinnati

Instructional Objectives Upon completion of this course the participants should be able to: 1.  Describe basic patterns of neuropathy 2.  Evaluate a patient with neuropathy 3.  Construct a basic diagnostic approach to neuropathy 4.  Formulate a basic therapeutic plan for the treatment of neuropathy

What defines neuropathy? Is it one entity? How do we define it? By symptoms? (neuropathy vs neuropathic) By signs? By electrodiagnostic testing? By etiology? Does the definition of neuropathy impact treatment? We take for granted that we all know what we are talking about Really should be a combination of symptoms and signs

Symptoms Positive Negative Motor Sensory Autonomics

Symptoms Motor Sensory Positive Negative Cramps, spasms Weakness burning, prickling paresthesias, dysesthesias, and allodynia Numbness Imbalance Autonomics Orthostatic B/B, Sexual, Cardiac, GI

Peripheral Neuropathy Mononeuropathy Individual nerves (e.g. Radial, Ulnar) Carpal tunnel (median neuropathy at the wrist) Polyneuropathy Distal symmetric polyneuropathy Polyradiculoneuropathy Prevalence: 2,400 per 100,000 Age > 55, prevalence is 8,000 per 100K Definition of Distal Symmetric Polyneuropathy We take for granted that we all know what we are talking about

Chronic Inflammatory Polyradiculoneuropathy (CIDP) Autoimmune process similar to GBS Progress beyond 8 weeks Weakness (proximal=distal), sensory loss without significant pain, areflexia Treatments include IVIG, plasmapheresis, steroids, and other immunosuppressive medications

Peripheral PolyNeuropathy Primarily motor Primarily sensory Mixed Large fiber vs. Small fiber Autonomic involvement Distal> proximal, distal=proximal, distal< proximal Axonal vs demyelinating Prevalence: 2,400 per 100,000 Age > 55, prevalence is 8,000 per 100K Definition of Distal Symmetric Polyneuropathy We take for granted that we all know what we are talking about

Distal Symmetric Polyneuropathy: Evidence Based Recommendations 1. Multiple neuropathic symptoms are more accurate than single symptoms 2. Signs are better predictors of polyneuropathy than symptoms 3. A single abnormality upon examination is less sensitive than multiple abnormalities 4. Relatively simple examinations are as accurate in diagnosing polyneuropathy as complex scoring systems Symptoms: numbness, burning, prickling paresthesias, dysesthesias, and allodynia; motor weakness; sensory more likely to be asymmetric Signs: acral, nondermatomal, non-single nerve distribution, centripetal. Abnormal primary sensory modalities (pain, touch, hot, cold, vibration, and proprioception), motor system (weakness and atrophy), tendon reflexes (especially depressed or absent ankle jerks), or autonomic system EDX: sural, peroneal; contralateral peroneal and sural and ipsilateral tibial if abnormal; median sensory, ulnar sensory, ulnar motor if abnormal. 5. There is too much inconsistency among the studies describing the accuracy of quantitative sensory testing (QST) to incorporate QST in the case definition. (Level U) Diagnostic predictors studied varied Single symptoms: foot numbness, foot pain, and complaints of sensory alteration. complex composite symptom checklists Single examination elements included absent ankle reflexes, decreased distal lower extremity strength, and decreased vibration or cold detection. Composites ≥2 exam elements England JD et al. Distal symmetric polyneuropathy: A definition for clinical research. Neurology 2005;64;199-207.

Evaluating a Patient for Neuropathy Examination Motor Deep Tendon Reflexes Reflex hammer (Tromner, Queens Square) Sensory: Safety pin, 128 C tuning fork Electrodiagnostic (EDX) EMG and Nerve conduction studies Large fiber Axonal Demyelinating What about small fiber?

Signs Positive Negative Motor Sensory Autonomics

Signs Motor Sensory Positive Negative Distal to Proximal: Atrophy Weakness DTR loss (ankle) Sensory acral, nondermatomal, non-single nerve distribution, centripetal. Loss of primary sensory modalities, acral and centripetal (pin, temp, vibration, proprioception) Autonomics

Neurophysiologic studies: EMG/NCS Axonal vs Demyelinating? Axonal (amplitudes) NCV’s and distal latencies typically normal CMAP/SNAP amplitudes low Denervation changes on EMG (fibs) Demyelinating (speeds) NCV’s < 75 % lower limit of normal Conduction block Temporal dispersion of CMAP Prolonged distal latencies, F-wave latencies

Diagnostic Approach to Neuropathy Neuropathy is clinically diagnosed Most diagnostic approaches focus on determining etiology Etiology found 74-82%*** As low as 37%

Etiologies based on Neuropathy Type Motor Neuropathies Sensory Neuropathies AIDP/CIDP Acute motor axonal neuropathy MMN CMT Lead intoxication Porphyric neuropathy Diabetes Paraneoplastic HIV/AIDS B12 deficiency Sjögren’s Celiac sprue Cisplatin, thalidomide, pyridoxine Inherited sensory neuropathies Paraproteinemic Mixed Most Peripheral Neuropathy is mixed variety w/ combo of motor/sensory/autonomic

Small-fiber neuropathies Neuropathies w/ significant autonomic features Idiopathic DM/impaired glucose tolerance Amyloid (early) HIV HSAN Fabry’s Tangier Sjögren’s Idiopathic Diabetes Amyloid AIDP Porphyria HIV HSAN Toxic- ie, vincristine

Etiology? Nutritional/Metabolic Autoimmune Infectious Traumatic Toxic Vitamin: Thiamine, B12, Vit D Nutrients: Copper Systemic disease: Thyroid, Diabetes, Renal Failure/Uremia, Porphyria Autoimmune Infectious HIV, Syphilis, Lyme, Leprosy, HCV, HBV Traumatic Toxic Lead, arsenic, organophosphates Iatrogenic

Drugs Causing Peripheral Neuropathy Allopurinol (prolonged) Almitrine Amiodarone Chloroquine Cisplatin Colchicine Dapsone Didanosine Disulfiram Doxorubicin Ethambutol FK 506 Gold salts Isoniazid Levofloxacin Metronidazole Misonidazole Nitrous oxide Nitrofurantoin Non-depolarizing Neuromuscular Blocking Agents Paclitaxel (taxol) Perhexiline Phenytoin Procainamide Pyridoxine excess Stavuldine Suramin Thalidomide Vinca alkyloids (vinblastine, vincristine, vindesine, vinorelbine) Zalcitabine Mendell, J 2001

Auto-immune Etiologies Paraproteinemic neuropathy Monoclonal Gammopathy (IgM) Connective-tissue disease associated Lupus, Rheumatoid, Sjogrens Vasculitis (Polyarteritis)

Lab Testing Recommended for All Patients Glucose Tolerance Testing 25-36% of neuropathy screens vs 15% controls SPEP with Immunofixation B12 and MMA All Class III studies so only Level C recommendations CSF analysis: Low yield unless demyelinating EDX No mention of HgbA1C 17% of monoclonal gammopathies were detected with IFE rather than SPEP Kahn SN and Bina M. Sensitivity of immunofixation electrophoresis for detecting IgM paraproteins ins erum. Clin Chem 1988; 34:1633-1635. Lindenbaum, J et al. Diagnosis of Cobalamin deficiency: II: relative sensitivities of serum cobalamin, methylmalonic acid, and total homocysteine concentrations. Am J Hematology 1990;34:99-107. (Class II) Savage DG and Lindenbaum, J et al. Sensitivity of serum methylmalonic acid and total homocysteine determinatiosn for diagnosing cobalamin deficiencies. A, J Med 1994;96:239-246. (Class III).

What is a reasonable approach? Clinical History Negative Symptoms Positive Symptoms Medication history! Physical Exam Signs Atrophy DTRs Motor Strength Sensory: Vibration, Pin, Position Sense Electrodiagnostic Studies (EMG/NCS) Sweep the Side: 4 motor, 3-4 sensory Lab Tests B12, Homocysteine, MMA Glucose, 2 hr GTT SPEP, IFE Others: ESR, TFTs If demyelinating, may check SPEP/IFE, UPEP/Urine IFE, and CSF protein

Clinical Case A 45 year old man presents to a primary care doctor for his first adult physical in two decades for new symptoms over the last 4 months with numbness and tingling in his feet and toes. He has noted them just in the tips of the toes of both feet, but the symptoms have been slowly crawling up his toes to his feet. He takes no chronic medications and has no past medical history. His neurologic exam is normal except for increased pin sensation in the distal toes of both feet and mild decreased vibratory sense in the toes. The next best testing for diagnostic purposes is: B12 and MMA SPEP Glucose testing EMG All of the above.

Treatment of Neuropathy Therapeutic: Demyelinating Treat underlying etiology Steroids, IVIG, Pheresis Ie. Monoclonal gammopathy Symptomatic: Pharmacologic Positive Symptoms Negative Symptoms* Non-Pharmacologic

Symptomatic Treatment of Neuropathy Antiepileptic medications Gabapentin (Neurontin) and Pregabilin (Lyrica) Drowsiness largest side effect Adjust for renal failure Others are off label Lamotrigine, Levetiracetam, Carbamazepine, TPM, Vimpat Antidepressants Cymbalta (Duloxetine) 30- 120 mg Hyperhydrosis, GI, HTN Amitryptiline/nortryptiline Low doses (10-50 mg) Anticholinergic High doses Prolonged QT

Other symptomatic treatments Topical Compounding topicals Capsaicin May burn Lidocaine Others NSAIDs Narcotics Use cautiously Avoid escalation Mexilitene Compounding topicals may include gabapentin, lidocaine, cyclobenzeprine, pregabilin, etc.

Special Neuropathies A 56 year old male with type 2 diabetes presents with a one week course of severe pain in the left thigh and groin, followed by some weakness in the left leg and some new numbness in the left foot. He was diagnosed with type two diabetes 2 years ago but recently decided to get more serious about treatment and decided to go on a weight loss regimen. He has lost 25 lbs in the last 2 months and his blood sugar control is slowly getting better. His only medication is metformin. His general examination reveals a heart rate of 84, blood pressure 140/85. His physical examination reveals an absent left quadriceps reflex, numbness on the back of the left calf and left lateral calf, and decreased left hip flexion and left knee extension. The right leg appears normal. Fasting blood glucose is 105 and hemoglobin A1c is 6.3.

Diabetic Amyotrophy Diabetic amyotrophy (also called diabetic lumbosacral radioplexus neuropathy, or diabetic lumbosacral radiculoplexopathy) is an uncommon condition seen in type two diabetics, usually more common in men and patients with better glycemic control. It is often associated with a rapid weight change (weight loss or weight gain). Patients generally present with excruciating pain in the lower back, hip, and proximal leg. Within days to weeks, weakness develops asymmetrically in the proximal thigh and leg. Although asymmetric motor symptoms and pain symptoms are most apparent, usually there is also sensory loss in the proximal and distal leg also. The syndrome is monophasic and patients usually have good recovery, although usually not full recovery to pre-amyotrophy conditions. Treatment is predominantly supportive (pain control and physical therapy) as immunotherapy has shown inconsistent results.