An Approach to Peripheral Neuropathy

Numb and Number: An Approach to Peripheral Neuropathy

October 4, 2018

Zach London, MD, FAAN Dept. of Neurology University of Michigan Disclosures • None

I will be discussing off-label use of drugs. Objectives

Common Annoying • Distal symmetric polyneuropathy (DSP) • Small fiber polyneuropathy

• Mononeuritis multiplex • Demyelinating neuropathy • Sensory neuronopathy Rare Dangerous Treatable? Objectives

• Subtypes of polyneuropathy • Signs and symptoms of distal symmetric polyneuropathy • Red flags – when is it a good idea to ask for help? • Diagnostic workup of neuropathy • Treatment of neuropathic pain Symptoms of Distal Symmetric Polyneuropathy (DSP) • Distal. Symmetric. Polyneuropathy. • Numbness and tingling • Bunched up sock or standing on a pebble • Creepy/crawly, pins and needles, or foot fell asleep • Poor balance, worse in the dark • Pain • Burning, shooting, stabbing, electric shocks Symptoms of DSP

• Weakness • Tripping over toes or foot is flopping • Dropping things or difficulty opening jars • Autonomic symptoms • Orthostatic lightheadedness • Gastroparesis • Erectile dysfunction • Sweating abnormalities Examination in DSP

• Sensory loss • Pain, temperature, vibration, position sense

Position sense is usually affected last in neuropathy. If it is impaired, and other modalities are relatively spared, consider a spinal cord lesion. Examination in DSP

• Reflexes – absent ankle jerks • Motor – • Weak toe extension or ankle dorsiflexion • Difficulty heel walking • Atrophy of the extensor digitorum brevis Small fiber neuropathy

Distal symmetric Small fiber polyneuropathy polyneuropathy Numbness and Yes Yes pain Autonomic Yes Yes symptoms Sensory loss All modalities Pain/temperature only Weakness Maybe No Reflexes Absent ankle jerks Normal EMG Abnormal Normal Objectives

Mononeuritis multiplex

Not symmetrical Motor predominant Demyelinating neuropathy Rapid onset Young patient Family history Sensory neuronopathy Proximal sensory loss (i.e. trunk and face)

Hereditary neuropathy Objectives

Chemo meds Hereditary Heavy metals Celiac Infectious Other Nutri- meds Rheum Paraproteinemia tional Cancer disease Kidney or liver Diabetes or disease Idiopathic impaired glucose Alcohol tolerance What diagnostic tests can I order?

TSH, free T4, triglycerides, hemoglobin A1c, ESR, ANA, ENA, rheumatoid factor, CRP, ANCA, cryoglobulins, vitamin B1, vitamin B6, vitamin B12, vitamin E, methylmalonic acid, homocysteine, folate, urinalysis, SPEP, immunofixation, UPEP, Bence Jones Screen, bone marrow biopsy, Lyme titer, fasting glucose, glucose tolerance test, HIV, hepatitis B, hepatitis C, ACE, RPR, FTA, Anti-GM1 antibodies, anti-sulfatide antibodies, anti-MAG antibodies, transglutaminase antibodies, endomysial antibodies, gliadin antibodies, paraneoplastic panel, urine heavy metals, serum heavy metals, porphyrin screen, CMT genetic testing, EMG and nerve conduction studies, MRI of the brain and total spine, skin biopsy, nerve biopsy, lumbar puncture, autonomic tests. What diagnostic tests should I order?

• Glucose tolerance test, fasting glucose, hemoglobin A1c • Serum protein electrophoresis and immunofixation • Serum B12

• Maybe: CBC, basic metabolic panel What diagnostic tests should I order?

• Glucose tolerance • Impaired fasting test, fasting glucose, glucose ≥ 100 hemoglobin A1c • Impaired glucose • Serum protein tolerance ≥ 140 electrophoresis and • A1c ≥ 5.7 immunofixation • Serum B12 What diagnostic tests should I order?

• Glucose tolerance • All monoclonal test, fasting glucose, gammopathies are hemoglobin A1c associated with neuropathy • Serum protein • IgM is most likely to be electrophoresis and demyelinating immunofixation • IgA has the highest risk • Serum B12 of malignant transformation • Lambda light chains are most associated with POEMS syndrome and amyloidosis What diagnostic tests should I order?

• Glucose tolerance • If B12 is between test, fasting glucose, 200-500, order a hemoglobin A1c methylmalonic acid. • Serum protein electrophoresis and immunofixation • Serum B12 • Ordering too many labs (i.e. TSH, folate, RPR) • Checking SPEP but not immunofixation • Not checking methylmalonic acid for B12 < 500 • Giving B12 supplementation when B12 is normal • Ordering an MRI of the L-spine for distal symmetric polyneuropathy Objectives

• Challenges • Nothing works that well (even glycemic control in diabetics) • Side effects are common • Impact on improving physical function is limited • Costs may be high, especially for novel agents • Treatments help pain, not numbness or weakness

• Problems with trials: • Almost exclusively for diabetic neuropathy • Placebo effect is significant in all studies (up to 50%) • Most trials have durations of 2-20 weeks • Most are industry-funded Treating neuropathic pain AAN 2011 Guideline

Level A Evidence Level B Evidence

• Pregabalin* • Gabapentin • Valproic acid • Amitriptyline • Venlafaxine • Duloxetine* • Dextromethorphan • Morphine, oxycodone • Tramadol • Capsaicin (cream*) • Isosorbide dinitrate spray • Lidoderm patch • Percutaneous electrical nerve stimulation * FDA approved for treatment of painful diabetic neuropathy. Better Than Placebo Not effective

• Duloxetine • Gabapentin • Venlafaxine • Valproic acid • Pregabalin • Capsaicin • Tricyclic antidepressants • Typical opioids (Imipramine) • Dextromethorphan • Oxcarbazepine • Mexiletine • Tramadol • Lacosamide • Tapentadol • Lamotrigine • Botulinum toxin • Topiramate

Waldfogel 2017 Treatments – What do I use Cost* Dosing Side effects Nortriptyline $4 QHS ++ Venlafaxine $16 BID ++ Gabapentin $11 TID ++ Duloxetine $16 QD ++ Pregabalin $438 BID-TID ++ Oxcarbazepine $20 BID + Amitriptyline $4 QHS +++ Tramadol $10 TID ++ Lidocaine patch $100 BID + Capsaicin cream $10 TID-QID +++ Tapentadol $345 Q4-6h ++ Methadone $11 BID ++ * Lowest price on www.goodrx.com accessed 9/21/18 In conclusion

• Indications for EMG/neuro consult: • Asymmetry • Rapid onset • Motor predominance • Family history • Very proximal numbness • For acquired neuropathy without red flags, you can limit your workup to glucose tolerance test, B12, SPEP/IFIX • Treatments are largely disappointing • A rational approach to treatment considers cost, convenience, and side effects. Key References

• Bril et al, “Evidence-based guideline: Treatment of painful diabetic neuropathy” Neurology. 2011 May 17;76(20):1758-65. Epub 2011 Apr 11. • England et al, “Practice Parameter: evaluation of distal symmetric polyneuropathy: role of laboratory and genetic testing (an evidence-based review)." Neurology. 2009 Jan 13;72(2):185-92. Epub 2008 Dec 3. • Fagius J, “Chronic cryptogenic polyneuropathy. The search for a cause.” Acta Neurol Scand. 1983 Mar;67(3):173-80. • Griebler ML et al, “Pharmacologic interventions for painful diabetic neuroapthy: an umbrela systematic review and comparative effectiveness network meta-analysis.” Ann Intern Med 2014; 161: 639-649. • Singleton JR et al, ”Painful sensory polyneuropathy associated with impaired glucose tolerance.” Muscle Nerve. 2001 Sep;24(9):1225-8. • Novella SP et al, “The frequency of undiagnosed diabetes and impaired glucose tolerance in patients with idiopathic sensory neuropathy.” Muscle Nerve. 2001 Sep;24(9):1229-31. • Saperstein DS et al, “Challenges in the identification of cobalamin-deficiency polyneuropathy.” Arch Neurol. 2003 Sep;60(9):1296-301. • Lubec D et al, “Diagnostic work-up in peripheral neuropathy: an analysis of 171 cases.” Postgrad Med J. 1999 Dec;75(890):723-7. • Waldfogel J et al, “Pharmacotherapy for diabetic peripheral neuropathy pain and quality of life. A systematic review.” Neurology. March 24, 2017 • Zilliox L, “Neuropathic Pain.” Continuum Lifelong Learning in Neurology. 23(2), Apr 2017, 512-532.