1. Peripheral Neuropathies in Older Adults Annabel K. Wang, MD University of California, Irvine Department of Neurology

2. Peripheral Neuropathies Common disorder Prevalence of non-traumatic peripheral neuropathies 2.4% in general population 15% over the age of 40

3. Peripheral Neuropathies Terms are confusing – polyneuropathy – neuropathy

4. Peripheral Neuropathies Motor neuron disorders Radiculopathies Plexopathies Single and Multiple Mononeuropathies Symmetric Polyneuropathies Motor Neuropathies Sensory Ganglionopathies

5. Goals Early Recognition Early Treatment Prevention of Complications

6. Objectives Review symptoms and signs Identify common causes Discuss treatment options Address co-morbidities

7. Symptoms Positive or negative phenomena Sensory symptoms early Typically symmetric in onset Weakness later Distal symptoms predominant Worse at night

8. Positive Phenomena Tingling Coldness Burning Electrical shocks Stabbing sensations Deep aching

9. Negative phenomena Lack of sensation Hypersensitivity

10. Associated Symptoms Imbalance Fatigue Falls

11. Early Signs Distal sensory loss: Large Fibers loss of vibration before proprioception decreased ankle reflexes Small fibers Loss of pinprick and temperature Stocking-glove distribution

12. Early Signs Distal weakness – Toe extensors – Foot dorsiflexors – Finger extensors

13. Common Causes Diabetes Leprosy Vitamin B12 deficiency

14. Diabetes Prevalence of Diabetes (2011): 8.3% of population 25.8 million children and adults in the US Age 65 years or older – 10.9 million, or 26.9% of this age group have diabetes

15. Diabetes 60-70% will develop neuropathy – polyneuropathy, autonomic neuropathy, CTS Association with amputation – major contributor of amputations – 60% of non-traumatic amputations – 65,700 amputations from 2006

16. Diabetic Polyneuropathy Defined as the presence of symptoms and/or signs of peripheral nerve dysfunction in people with diabetes after the exclusion of other causes An absence of symptoms should never be assumed to indicate an absence of signs

17. Diabetic Polyneuropathy Treatment – Glucose control – Pain management – Management of autonomic symptoms

18. Leprosy Rare in United States Endemic areas Often sensory (ulnar and peroneal nerves) Associated skin lesions Hypertrophic nerves Nerve biopsy Treat underlying infection

19. Vitamin B12 Deficiency Prevalence: 5-20% Malabsorption, insufficient intake, pernicious anemia, gastric bypass surgery, medications Distal sensory and motor loss Combined subacute degeneration Vitamin B12 (<260 pmol/L) and methylmalonic acid (271 nmol/L) levels Supplementation: intramuscular or oral

20. Approach Acute vs. chronic onset – Acute fulminant and live threatening Axonal vs. demyelinating – Demyelinating forms respond well to immunotherapy

21. Acute Polyneuropathies Guillain-Barre Syndrome or Acute Inflammatory Demyelinating Polyradiculoneuropathy Porphyria Toxic (arsenic and thallium)

22. Chronic Polyneuropathies Inherited (CMT, HMSN, HNPP) – Family History – Foot Deformities – Foot Ulcers Acquired – “MINI”

23. Acquired Polyneuropathy “MINI” Metabolic Immune Neoplastic Infectious

24. Metabolic Causes Diabetes Uremia Alcohol abuse Hypothyroid Vitamin B1 or B12 deficiency Vitamin B6 toxicity Medications/chemotherapy

25. Immune Causes Vasculitis Non-vasculitic – CIDP – MMN – Sarcoid – Sjogren’s

26. Neoplastic Causes Paraneoplastic Paraproteinemic

27. MGUS Monoclonal gammopathy of unclear significance Prevalence: – 3% of persons >50 years – 5% >70 years 1% per year risk of progression to multiple myeloma (MM) or a related disorder

28. Infectious Causes Leprosy Hepatitis C Lyme HIV West Nile Syphilis Diptheria

29. Autonomic Symptoms Lightheadedness or “dizziness” Blurred vision Dry eyes, dry mouth Cold feet Early satiety, constipation, diarrhea Urinary retention, incontinence Erectile Dysfunction Hypohidrosis

30. Dysautonomias Diabetes Amyloidosis (acquired and inherited) Paraneoplastic Inherited (HSAN) Sjogren’s Neuropathy Porphyria

31. Differential Diagnosis Small fiber neuropathy Plantar fasciitis Osteoarthritis Vascular insufficiency Cervical myelopathy Lumbosacral radiculopathy

32. Neurophysiology Electromyography Autonomic Testing Quantitative Sensory Studies

33. Electromyography (EMG) Two part test: Nerve conduction studies Needle electromyography Establish diagnosis of polyneuropathy Distinguish demyelinating from axonal Differentiate radiculopathy, plexopathy Normal in small fiber and autonomic neuropathy

34. Autonomic Testing Heart rate response to deep breathing Valsalva Maneuver Tilt Table Quantitative Sudomotor Axon Reflex Test

35. Basic Laboratory Investigation Hematology: – complete blood count – erythrocyte sedimentation rate – C-reactive protein – vitamin B12, folate, – Methylmalonic acid, homocysteine

36. Basic Laboratory Investigation Biochemical and endocrine: – comprehensive metabolic panel (fasting glucose) – thyroid function tests – serum immunofixation. – glucose tolerance test if indicated

37. Basic Laboratory Investigation Urine: – urinalysis – urine immunofixation. Drugs and toxins

38. Specialized Laboratory Investigation Malignancies: – skeletal radiographic survey – mammography – computed tomography or magnetic resonance imaging of chest, abdomen, and pelvis – ultrasound of abdomen and pelvis – positron emission tomography – cerebrospinal fluid analysis including cytology – serum paraneoplastic antibody profile

39. Specialized Laboratory Investigation Connective tissue diseases and vasculitis: – antinuclear antigen profile – rheumatoid factor – anti-Ro/SSA, anti-La/SSB, – antineutrophil cytoplasmic antigen antibody (ANCA) profile – cryoglobulins.

40. Specialized Laboratory Investigation Infectious agents: – Campylobacter jejuni – Cytomegalovirus – hepatitis panel (B and C) – HIV – Lyme disease – herpes viruses – West Nile virus – cerebrospinal fluid analysis.

41. Biopsy Nerve biopsy Sural Superficial peroneal Epidermal skin biopsy

42. Nerve Biopsy Vasculitis Lymphoma Amyloid Sarcoid Leprosy Inflammation

43. Management  Care of feet Inspect feet daily (mirror) Keep feet clean and moisturized Foot care with podiatrist Molded shoes Avoid walking barefoot Checking temperatures of water/sand

44. Treatment Foot care Physical Therapy Gait and balance exercises Ankle supports (orthotics) Occupational Therapy (ADLs)

45. Therapeutic Treatment Importance of diagnosis Recognition of the underlying cause Glucose control Thyroid medication Vitamin supplementation or reduction Antibiotics or antiviral medications Immunotherapy

46. Symptomatic Treatment Only 2 medications are FDA approved for diabetic polyneuropathy – Duloxetine – pregabalin

47. Symptomatic Treatment Pain management limited by side effects – Analgesics – Anti-inflammatories – Antiepileptics – Antidepressants – Narcotics

48. Co-morbidities Depression Decreased mobility Falls Fear of falls Social isolation Osteoporosis

49. Complications Risk of injury due to lack of sensation Charcot joints Foot ulcers Amputations Falls

50. Summary Common disorder – >40 years of age: 15% Routine screening for diabetes, vitamin B12 deficiency, serum immunofixation.

51. Summary Neurophysiological tests distinguish axonal /demyelinating/autonomic/small fiber Demyelinating neuropathies are commonly inflammatory and treatable. Axonal neuropathies have multiple causes

52. Summary Treatment – Therapeutic – Symptomatic – Comorbidities

53. References Diabetes Statistics. http://www.diabetes.org/diabetes-basics/diabetes- statistics/http://www.diabetes.org/diabetes-basics/diabetes- statistics/ Bril V et al. Evidence-based guideline: Treatment of painful diabetic neuropathy. Neurology; Published online before print April 11, 2011; DOI 10.1212/WNL.0b013e3182166ebe Bril V. Treatments for diabetic neuropathy. JPNS 2012:17(s2);22–27. Leishear K et al. Relationship Between Vitamin B12 and Sensory and Motor Peripheral Nerve Function in Older Adults. JAGS 2012:60(6); 1057–1063. England JD et al. Evaluation of distal symmetric polyneuropathy: the role of autonomic testing, nerve biopsy, and skin biopsy (an evidence-based review). Muscle Nerve 2009 ;39: 106–115. England JD et al. Evaluation of distal symmetric polyneuropathy: the role of laboratory and genetic testing (an evidence-based review). Muscle Nerve 2009 ;39: 116–125.

54. References Kyle RA, Rajkumar SV. Monoclonal gammopathy of undetermined significance and smouldering multiple myeloma: emphasis on risk factors for progression. BJH 2007:139(5);730–743. Mauermann ML, Burns TM. The evaluation of chronic axonal polyneuropathies. Semin Neurol. 2008:28(2):133-51. Ramaratnam S. Neurologic Manifestations of Leprosy. http://emedicine.medscape.com/article/1165419- overview#aw2aab6b6 Rutkove SB. Overview of polyneuropathy. http://www.uptodate.com/contents/overview-of-polyneuropathyUpto date