Practical Neurology: Polyneuropathy for the Non-Neurologist

Steven A. Day, MD Providence Neurological Specialties Definitions

Foundational Principle:

With neurological problems think of LOCALIZATION before SYNDROME Definitions

• Neuronopathy – Motor neuronopathy – Sensory neuronopathy • Radiculopathy • Plexopathy • Neuropathy – Mononeuropathy – Polyneuropathy The Netter Collection of Medical Illustrations, Volume 1, Nervous System, 2002 “ROOTS” C4 TRUNKS C5 Dorsal scapular n. C6 TRUNKS C7 Suprascapular n. T1 DIVISIONS

Musculocut- aneous n. CCF CORDS  2002

Long thoracic n. TERMINAL NERVES

CCF ©2002 Axillary n. Radial n. Median n. Ulnar n. Definitions

‘Neuropathy’ is a diagnosis which specifies the location of pathology, not a symptom Definitions

• Axonal = axon loss pathology

• Demyelinating = myelin loss pathology Topical Diagnosis in Neurology, 3rd ed. 1998 Topical Diagnosis in Neurology, 3rd ed. 1998 Duss’ Topical Diagnosis in Neurology, 4th ed. 2005 Polyneuropathy Polyneuropathy: Typical Presentation

• Insidious onset • Distal (toes, pads of feet) • Gradual progression • Complaints are primarily sensory Polyneuropathy: Key Exam Features

• Sensory – Distal gradient of sensory loss • Pin prick or cold • Monofilament • Cotton wisp • Vibration at toes and ankles • Proprioception: toe movements Polyneuropathy: Key Exam Features

• Motor – Is there intrinsic foot or hand muscle atrophy? – Weakness pattern • Distal • Proximal and distal • Asymmetric – Able to stand/elevate on toes and heels? Polyneuropathy: Key Exam Features

• Reflexes – Distal gradient of loss of reflexes • Ankle jerks – Brachioradialis Polyneuropathy: Key Exam Features

• Gait/Station – Narrow vs wide or variable/stumbling base – Steppage gait – Watching ground – Tandem gait steady? – Romberg: swaying when standing with eyes closed with a narrow base Polyneuropathy: causes

• Endocrinopathies • Idiopathic: 1/3rd to 1/2 • Other systemic disease of all cases • Nutritional deficiencies • Senescent • Infections • Hereditary • Toxins • Autoimmune PN and Endocrinopathy

• Diabetes • Hypothyroidism • Hyperinsulinemia (e.g. insulinoma) Neuropathy and Diabetes

• Most common cause of PN in developed countries • DM1 and DM2 – 15-20% with symptomatic PN – 66% with objective evidence of PN • Treatment-induced • Glucose intolerance • Metabolic syndrome Neuropathy and Diabetes

• Associated neuropathies – Distal symmetric sensory or sensorimotor PN – Mononeuropathy (e.g. CTS) – Autonomic • Orthostasis, arrhythmias • Gastroparesis – Cranial neuropathies – Polyradiculoneuropathies – Small fiber Neuropathy and Diabetes: Distal Symmetric Sensorimotor PN • Most common form of diabetic neuropathy • Slowly progressive • Length dependent (distal to proximal) • Symptoms – Numbness – Paresthesias – Dysesthesias – Allodynia – Autonomic dysfunction Neuropathy and Diabetes: Distal Symmetric Sensorimotor PN • Can be the presenting symptom of DM

• Can be a presenting symptom of glucose intolerance/prediabetes/metabolic syndrome Neuropathy and Diabetes: Distal Symmetric Sensorimotor PN Pathology – Axon loss – Segmental demyelination – loss of intraepidermal nerve fibers – arteriole/capillary endothelial hyperplasia • Pathophysiology: – Metabolic derangement – Microangiopathic ischemia – Inflammation Neuropathy and Diabetes: Distal Symmetric Sensorimotor PN Treatment • Exquisite glucose control • Symptomatic pain control Neuropathy and Hypothyroidism

• Median mononeuropathy at the wrist (Carpal Tunnel Syndrome) – Etiology: edema in tunnel • Generalized sensorimotor polyneuropathy – Etiology: unknown Neuropathy and other Systemic Disease • Renal Failure • Chronic Liver Failure • Cancer (paraneoplastic) • Sjögren syndrome • Rheumatoid arthritis • Systemic lupus erythematosus • Sarcoidosis • Scleroderma (Systemic Sclerosis) • Vasculitis Neuropathy and Nutritional Deficiencies • Overall uncommon in developed countries • Treatable Neuropathy and B12 Deficiency

• Most common nutritional cause of neuropathy in developed countries • Can occur in the absence of macrocytic anemia • At risk – Chronic metformin – Chronic antacids – Chronic alcoholics – Post-bariatric surgery – Vegans – Pernicious anemia – Inflammatory bowel disease at ileum Neuropathy and B12 Deficiency

Dietary B12 Absorption – binds to R proteins in saliva, gastric secretions – Release requires acidic pH – intrinsic factor produced by gastric parietal cells – bound by intrinsic factor at duodenum – B12-intrinsic factor complex absorbed at ileum Neuropathy and B12 Deficiency

Impaired Absorption – Gastrectomy – Gastric bypass – Celiac sprue – Crohn’s disease – Ileal resection – Chronic use/high dose H2 and proton pump inhibitors – Pancreatic insufficiency – Bacterial overgrowth (blind loop syndrome) – Fish tapeworm Neuropathy and B12 Deficiency

1. Sensory predominant polyneuropathy 2. Subacute Combined Degeneration: – Polyneuropathy • Decr light touch • Decr proprioception • Sensory ataxia – Myelopathy • Increased DTRs (except ankles) • spasticity Subacute Combined Degeneration

Duss’ Topical Diagnosis in Neurology, 4th ed. 2005 Neuropathy and B12 Deficiency

• Diagnosis – B12 levels • specific but not sensitive – MMA • > 0.40 umol/L • More sensitive than B12 – Homocysteine • >21 umol/L • More easily confounded by other conditions Nitrous Oxide Abuse

• A very rare cause of Subacute Combined Degeneration • B12 levels may be normal – N2O inactivates (via oxidation) but does not lower B12 level • May not present until become B12 deficient • Dx dependent on high level of suspicion (specifically obtaining hx of NO abuse) Other Nutritional Neuropathies • Folate deficiency: as in B12 • Copper deficiency: resembles SCD – Bariatric surgery/small bowel resection – Zinc toxicity: e.g. zinc supplement, (denture creams) • Thiamine deficiency (esp. alcoholics) • Vitamin E deficiency (malabsorption) • Vitamin B6 deficiency – Chronic alcoholism – Isoniazid, hydralazine • Vitamin B6 toxicity: max 50 mg/day Infectious Neuropathies

• HIV • CMV • Hepatitis C • Lyme • HTLV-1 • Diphtheria: Corynebacterium diphtheriae • Leprosy – Mycobacterium leprae – most common cause of all neuropathies in SE Asia, Africa, S America Toxic Neuropathies

• Alcohol • Phenytoin (Dilantin) • Chemotherapy (platinum-based, taxanes, vinca alkaloids, etc) • Nucleosides for HIV • Metronidazole • Chloroquine and Hydroxychlorquine • Amiodarone • Cholchicine • Lithium • Vitamin B6 (pyridoxine) • Heavy metals (Lead, mercury, thallium, inorganic arsenic, gold, etc) Autoimmune Neuropathies

• Acute Inflammatory Demyelinating Polyradiculoneuropathy (AIDP/GBS) • Chronic Inflammatory Demyelinating Polyradiculoneuropathy (CIDP) • Monoclonal gammopathies • Paraneoplastic • Vasculitis Practical Matters: what your patients need from you • Attempt to identify a directly treatable cause • Symptom mitigation Practical Matters: Laboratory evaluation

• High Yield minimum – Diabetic screen – B12 – MMA – Serum Immunofixation Practical Matters: Laboratory evaluation

• Routine/1st tier labs – CBC – CMP – B12, folate, MMA – ANA – ESR/CRP – TSH – A1c or Fasting glucose [-> 2 hour glucose tolerance test] – Serum immunofixation Practical Matters: EMG

• Purpose – Confirm clinical dx – Assess severity – Prognosis (compressive mononeuropathies) – Differentiate axon loss from demyelination • Implications for possible etiology • What? – Nerve conduction testing – Needle electrode exam The Netter Collection of Medical Illustrations, Volume 1, Nervous System, 2002 Practical Matters: EMG

• Not every patient with neuropathy needs an EMG – e.g. typical DM or ETOH PN • When to perform – Idiopathic – Clarify clinical situation • Central vs. peripheral localization • Symptoms out of proportion to findings – Rapidly progressive (days to months) – Motor predominant – Documentation needed for medical or medicolegal Practical Matters: EMG

EMG limitations • Intolerant/non-cooperative patients • Obese • Elderly • Multiple peripheral lesions – e.g. radiculopathy + neuropathy • Anticoagulation • Does not assess small fibers (isolated small fiber PN) • Operator dependent Practical Matters: Pain Control

Set appropriate expectations • What medications treat – Burning – Pins/needles prickling – Aching – sensitivity • No benefit for lack of sensation numbness • Treatments do not heal nerves/promote growth • Degree of benefit Practical Matters: Pain Control

• Extrapolated from trials on diabetic PN • Clinical experience • Most medications are used off-label • “start low, go slow” • Consider topical approach: – Elderly/sensitive to medications – Very localized, e.g. toes – Intermittent dosing Practical Matters: Pain Control

• Topical Agents – Lidocaine • 5% ointment: BID to TID • Lidoderm 5% patch: up to 3 patches for 12 hrs /day – OTC Menthol/Camphor ointment • Cooling relief for burning dysesthesias – Doxepin 5% BID – Compounded topicals – (Capsaicin 0.75% TID to QID) Practical Matters: Pain Control

• 1st Line – Alpha lipoic acid • 600 mg daily (diabetic PN) – Gabapentin • Start 300 mg TID (100 mg TID in elderly) • Titrate to 1200 mg TID (as tolerated) • Newer Qday, BID agents better tolerated – Tricyclic (e.g. nortriptyline > amitriptyline) • Start 10 mg QHS • Titrate to 100 mg QHS (as tolerated) Practical Matters: Pain Control

• 1st Line (cont) – Pregabalin • Start 50 mg TID (25 mg TID in elderly) • Titrate to 100 mg TID (as tolerated) – Duloxetine • Start 60 mg QHS (30 mg QHS in elderly) • Titrate up to 60 mg BID or 120 mg QHS (as tolerated) – Venlafaxine XR • 37.5-75 mg Qday • Titrate by 75 mg/day to 225 mg/day Practical Matters: Pain Control

• 2nd Line – Oxcarbazepine • Start 150-300 mg BID • Titrate by 300 mg/day up to 1200 mg BID • Follow levels, safety labs (CBC, CMP) – Carbamazepine • Start 200 mg BID • Titrate by 200 mg/day to 400 mg QID • Not as well tolerated as oxcarbazepine • Follow levels, safety labs (CBC, CMP) Practical Matters: Pain Control

– Topiramate • Start 25 mg QHS • Titrate qweek by 25 mg to max 200 mg BID – Divalproex sodium • Start 250 mg BID • Titrate by 250 mg up to 500 mg TID Practical Matters: Pain Control

• Marijuana – Largely an unknown due to lack of research – 2014 American Academy of Neurology (AAN) systemic review of data: • No studies to review on peripheral neuropathic pain Practical Matters: Pain Control

• Other – TENS: may be beneficial (1 study in DM) – Magnetic therapy: no benefit based on current data • Pulsed electromagnetic • Magnetic shoe insoles – Light/LASER therapy: no benefit based on current data – Reiki therapy: no benefit based on current data – Acupuncture: no benefit based on current data Practical Matters: Other

• Physical therapy – Strengthening – Gait safety, fall prevention – Assistive device training • Ankle Foot Orthotics (AFO) – Treat foot drop – Reduce tripping/falls Neuropathy Red Flags

• Acute onset • Rapid progression, esp of weakness – Days to weeks • Asymmetry • Proximal weakness • Cranial and peripheral nerve involvement • Early ataxia • Associated with rash or petechiae