1. Uremic Neuropathy Nephrology R4 박미나

2. Uremic Polyneuropathy Uremic Polyneuropathy

3. Introduction  Dysfunction of pph nevous system induced by uremia - common in pts with ESRD - common in pts with ESRD - generally only in advanced renal failure - generally only in advanced renal failure - indication to initiate dialysis - indication to initiate dialysis  Pts being adequately dialyzed are also at some risk, (subclinical and detectable only by electrophysiologic (subclinical and detectable only by electrophysiologic studies) studies)

4. Clinical manifestations  Uremic pph neuropathy - distal, symmetrical, mixed sensorimotor neuropathy - distal, symmetrical, mixed sensorimotor neuropathy - independent underlying disease - independent underlying disease - longer axons, more prominent in lower extremities - longer axons, more prominent in lower extremities - sensory Sx (burning, pain, paresthesia) -> motor Sx - sensory Sx (burning, pain, paresthesia) -> motor Sx - Initial finding : loss of position, vibration sense in toes - Initial finding : loss of position, vibration sense in toes DTR↓ (Achilles reflex) DTR↓ (Achilles reflex) - sensory defects move to knee, hand… - sensory defects move to knee, hand…

5.  Restless leg syndrome - persistent, extremely uncomfortable sensation in - persistent, extremely uncomfortable sensation in lower extremities lower extremities - only relieved by movement of legs - only relieved by movement of legs - more prominent at night and may interfere with sleep - more prominent at night and may interfere with sleep - common among dialysis pts (6-60%) - common among dialysis pts (6-60%) - survival and quality of life ↓ - survival and quality of life ↓

6.  Burning foot syndrome - severe pain, burning sensation in distal lower extremity - severe pain, burning sensation in distal lower extremity - common in early days of dialysis - common in early days of dialysis : thiamine deficiency (d/t water solube, well dialyzed) : thiamine deficiency (d/t water solube, well dialyzed) - routine administration of thiamine and other water - routine administration of thiamine and other water soluble vitamin : eliminate this disorder soluble vitamin : eliminate this disorder  Paradoxical heat sensation - low temperature stimuli evokes sensation of high - low temperature stimuli evokes sensation of high temperature in this condition temperature in this condition

7.  Usually reflects advanced disease  Loss of motor function -> muscle atrophy, myoclonus, eventual paralysis -> muscle atrophy, myoclonus, eventual paralysis  Progression : do not complete recovery with dialysis

8. Diagnosis  Distinguish from DM, SLE, MM,amyloidosis – difficult  Physical Exam - sensation↓ to pin prick, touch, vibration, proprioception - sensation↓ to pin prick, touch, vibration, proprioception - wasting of intrinsic muscle of feet or lower leg - wasting of intrinsic muscle of feet or lower leg - hypoactive or abscent reflex : usually ankle - hypoactive or abscent reflex : usually ankle  Electrophysiologic studies - most sensitive way to detect uremic neuropathy - most sensitive way to detect uremic neuropathy - early diagnosis, used to monitor - early diagnosis, used to monitor

9.  Electromyography/nerve conduction studies (EMG.NCS) - myopathy ? neuropathy ?, axonal ? demyelinating ? - myopathy ? neuropathy ?, axonal ? demyelinating ?  Motor nerve conduction velocity - often measured in peroneal nerve - often measured in peroneal nerve - slowing of nerve conduction velocity - slowing of nerve conduction velocity : parallel decline in CrCL : >50% of pts are abNL when CrCL 50% of pts are abNL when CrCL <10mL/min  Sensory nerve conduction velocity - sural nerve, moresensitive in detecting early dysfunction - sural nerve, moresensitive in detecting early dysfunction

10. Pathology and pathogenesis  Pathologic features of uremic polyneuropathy - axonal degeneration -> segmental demyelination - axonal degeneration -> segmental demyelination - most severe distally - most severe distally  Metabolic and chemical basis - elusive - elusive - thiamine deficiency, decreased transketolase activity, - thiamine deficiency, decreased transketolase activity, decreased biotin and zinc, hyperparathyroidism decreased biotin and zinc, hyperparathyroidism increased phenols and myoinocitol increased phenols and myoinocitol

11.  Accumulation of uremic toxins - uremic toxin of medium molecular wt.(500-2000 daltons) - uremic toxin of medium molecular wt.(500-2000 daltons) - pts on PD had lower incidence of polyneuropathy than - pts on PD had lower incidence of polyneuropathy than those on HD those on HD => efficient middle molecule clearence : polyneuropathy ↓ => efficient middle molecule clearence : polyneuropathy ↓  This hypothesis has been criticized… - failure to consider residual renal function - failure to consider residual renal function - more recent studies comparing HD and PD - more recent studies comparing HD and PD : greater decline in motor nerve conduction and vibration : greater decline in motor nerve conduction and vibration sensation with CAPD sensation with CAPD

12. Treatment  Institution of HD - stabilize or improve Sx - stabilize or improve Sx - extent of recovery - extent of recovery : directly related to degree and extent of dysfunction : directly related to degree and extent of dysfunction prior to initiation of dialysis prior to initiation of dialysis : complete resolution may occur when there are : complete resolution may occur when there are only mild sensory Sx only mild sensory Sx - HD = CAPD, equally effective - HD = CAPD, equally effective

13.  Many pts with persistent neuropathy - do not dialyze until uremia was far advanced, - do not dialyze until uremia was far advanced, - under dialyzed - under dialyzed  Earlier and more intensive dialysis - decline in incidence of uremic neuropathy - decline in incidence of uremic neuropathy  Restoration of near NL renal function with KTP - more consistently improve neurologic Sx - more consistently improve neurologic Sx - initial rapid improvement (over days or weeks) - initial rapid improvement (over days or weeks) - followed by continued, gradual improvement - followed by continued, gradual improvement (over period of several months) (over period of several months)

14.  Gabapentin > TCA > serotonin reuptake inhibitors  Carbamazepine, phenytoin, baclofen  Initially TCA (desipramine) - second line : gabapentin - second line : gabapentin - third line : carbamazepine, phenytoin - third line : carbamazepine, phenytoin - low dose benzodiazepine may help augment the effect - low dose benzodiazepine may help augment the effect - if necessary, tramadol, nonsteroid - if necessary, tramadol, nonsteroid  Distal polyneuropathy are increased risk for foor ulcers - proper foot and nail care - proper foot and nail care

15. Restless legs syndrome  Common among dialysis pts (6-60%)  Anemia, iron deficiency, low PTH concentration  Diagnostic criteria - desire to move extremity + paresthesia, dysthesia - desire to move extremity + paresthesia, dysthesia - motor restlessness - motor restlessness - worning Sx at rest partial relief during activity - worning Sx at rest partial relief during activity - worsening of Sx in evening or at nignt - worsening of Sx in evening or at nignt

16.  Medical treatment for symptom - dopamine agonists - dopamine agonists : pramipexole, ropinirole, cabergoline : pramipexole, ropinirole, cabergoline - benzodiazepines - benzodiazepines : diazepam, clonazepam, triazolam : diazepam, clonazepam, triazolam - opioid - opioid : codeine, methadone, propoxyphene, oxycodone, : codeine, methadone, propoxyphene, oxycodone, tramadol tramadol - gabapentin - gabapentin

17.  Iron replacement - double blined placebo controlled randomized trial - double blined placebo controlled randomized trial - 25 dialysis pts - 25 dialysis pts - placebo : iron dextran (similar iron stores, Hgb/Hct) - placebo : iron dextran (similar iron stores, Hgb/Hct) - significant improvement in Sx, for 4 weeks in iron group - significant improvement in Sx, for 4 weeks in iron group - iron overload… - iron overload…  Decreasing exposure to agents that may exacerbate - caffeine, nicotine, metoclopramide, alchol - caffeine, nicotine, metoclopramide, alchol

18. Uremic mononeuropathy

19. Overview  Systemic polyneuropathy -> clinically apparent mononeuropathy -> clinically apparent mononeuropathy  Forearm (median, ulnar nerve) - commonly affected - commonly affected - capal tunnel syndrome - capal tunnel syndrome  Seven and eight cranial nerves and peroneal nerve

20. Carpal tunnel syndrome  Numbness, tingling, burning along distribution of median nerve in hand median nerve in hand  Atrophy of px thenar muscle  Tinel’s sign - numbness and tingling sense by percussing median n. - numbness and tingling sense by percussing median n.  Electrophysiologic studies - prolonged conduction for both motor and sensory fibers - prolonged conduction for both motor and sensory fibers

22. <Pathogenesis>  Pathogenetically important factors - Direct compression - Direct compression - Ischemia - Ischemia - Infiltration by amyloid - Infiltration by amyloid

23.  Carpal tunnel is narrowed by factors related to vascular access - increased veous pr. extravasation of fluid, extrinsic - increased veous pr. extravasation of fluid, extrinsic compression of nerve compression of nerve - vascular steal phenomenon can lead to ischemic - vascular steal phenomenon can lead to ischemic neural injury and nerve dysfunction neural injury and nerve dysfunction  One factor in pts on long term dialysis - local deposition of amyloid derived from b-microglobulin - local deposition of amyloid derived from b-microglobulin - suggestive diagnosis - suggestive diagnosis : pain in multiple joints of upper and lower extremity : pain in multiple joints of upper and lower extremity : on X-ray, radiolucencies in carpal bones : on X-ray, radiolucencies in carpal bones

24. Other mononeuropathy  Dysfunction of both vestibular and cochlear divisions of eighth cranial nerve - hearing impairment dramatically improved following - hearing impairment dramatically improved following intensive HD or KTP : role of uremia intensive HD or KTP : role of uremia  Facial nerve dysfunction - subclinical, only electrophysiologic studies - subclinical, only electrophysiologic studies

25.  Compressive neuropathy (ulnar nerve, peroneal nerve) - one study - one study : ½ pts undergoing dialysis have ulnar neuropathy : ½ pts undergoing dialysis have ulnar neuropathy - nerve ischemia, direct compression - nerve ischemia, direct compression  Optic neuropathy - ischemia, recurrent hypotension on dialysis, - ischemia, recurrent hypotension on dialysis, atherosclerosis atherosclerosis