1. Nervoussystemmanifestationsof CKDDr Manish Singla28-02-2012

2. Introduction Neurological complications occur inalmost all patients with severeCKD, potentially affecting all levels of thenervous system, from the CNS throughto the PNS. Patients on dialysis tend to be weakerand less active, and to have reducedexercise capacity, when compared withhealthy individuals Cognitive impairment, peripheral andautonomic neuropathy 3. Objectives Neuropathy Cognitive dysfunction Uremic encephalopathy Dialysis disequilibrium syndrome Stroke Myopathy 4. Neuropathy Peripheral neuropathy Carpal tunnel syndrome Autonomic neuropathy Pruritis 5. Peripheral neuropathy About 50 per cent of patients startingtreatment had clinical evidence of aperipheral neuropathy in early days ofdialysis Because of earlier initiation of dialysisthese days, neuropathy is usuallyasymptomatic Nerve conduction abnormalities havebeen reported in up to 60% of patientsreceiving dialysis Abnormalities in motor nerve conductionvelocity parallel the decline in GFR 6. Peripheral neuropathy Uremic neuropathy is adistal, symmetric, mixed sensorimotorpolyneuropathy. Loss of ankle vibration sensation andthe ankle jerk are often the firstmanifestations, progressing to aburning sensation in the feet, followedby motor deficit, such as weakness ofankle dorsiflexion 7. Peripheral neuropathy It typically involves the lowerextremities more often than the upperextremities, and sensory symptomsprecede motor symptoms. Motor involvement usually indicatesadvanced disease Progress to a stocking neuropathywith weakness and wasting of thedistal leg muscles 8. Wasting of intrinsic hand muscles, with prominentbilateral atrophy of thenar muscles, in a patient withsevere neuropathy resulting from chronic kidneydisease 9. Pathophysiology of uraemicneuropathy Typically the large diameter axons inthe distal nerve trunks supplying thelegs are affected, with relative sparingof the unmyelinated and the smallmyelinated afferent neurons. Predominant defect is one of axonalloss with secondary demyelination Repeated episodes of demyelinationfollowed by remyelination - onion likestructures on nerve biopsies 10. Pathophysiology of uraemicneuropathy Biochemical pathogenesis of uraemic neuropathy ismultifactorial Ouabain sensitive calcium ATPase pump activity hasbeen shown to be decreased in uraemia, therebyaffecting the sodium-calcium exchanger, andhence, reducing the normal calcium gradient Various uraemic toxins (middle molecules) have beenproposed, including guanidine compounds, particularlymethylguanidine which can inhibit the sodium ATPasepump, PTH Polyamines, phenol metabolites, myoinositol, and 3-carboxy-4-methyl-5-propyl-2-fluranpropanoicacid, (which inhibits organic acid transport) toxin induced inhibition of transketolase, and pyridoxalphosphate kinase 11. Transketolase Transketolase is a thiamine-dependent enzyme of pentosephosphate pathway. Found mainly in myelinatedneurons. it maintains axon-cylindermyelin sheaths. Guanidinosuccinic acid caninhibit transketolase resultingdemylination. It also inhibit excitatorysynaptic transmission in CA1region ofhippocampus, contributing tocognitive syndrome in UE. 12. Pathophysiology of uraemicneuropathy Clinical symptoms and nerveconduction parameters improverapidly following renaltransplantation, often within days ofsurgery Rapidity of these changes suggeststhat toxin-mediated blockade of neuraltransmission has an important role inthe neurological dysfunctionassociated with CKD. 13. Diagnosis of uremicneuropathy First step in the diagnosis of uremicneuropathy is to exclude other causes ofneuropathy Serological testing should be undertaken toexclude vas-culitic neuropathy in thoserapidly evolving weakness Nerve conduction studies (NCS) remain thegold standard in the diagnosis of uremicneuropathy. NCS demonstrate generalized neuropathy ofthe axonal type, with reductions in sensoryamplitudes > motor amplitudes Sural sensory amplitude is the most sensitiveindicator of uremic neuropathy 14. Systemic diseases that contribute toESRD and also affect nerve function- Diabetes mellitus Amyloidosis SLE 15. Treatment Renal transplantation remains the onlycure for uremic neuropathy and must beconsidered in any patient withprogressive neuropathy. Rapidly progressive neuropathy is anaccepted indication for patients to betriaged to urgent, nonmatchedtransplantation lists. Following transplantation, clinicalrecovery typically occurs over a period of3-6 months 16. Carpal tunnel syndrome Carpal tunnel syndrome (CTS) is dueto compression of the median nerveas it passes deep to the flexorretinaculum at the wrist, causingnumbness, tingling, and burningsensations in the hand and fingers Attributable to dialysis-associatedamyloidosis or ischemicmononeuropathy associated with anarteriovenous fistula. Prevalence of 26% in patients whohave been on dialysis for more than 4 17. Carpal tunnel syndrome Pain is typically worse at night andduring haemodialysis. Eventually weakness of thumbabduction occurs with wasting of thethenar eminence. CTS is more common in middle aged and older women diabetics patients with hypothyroidism patients on dialysis > 7 years 18. Carpal tunnel syndrome Diagnosis of CTS can be confirmed bymeasuring a delay in median nerveconduction across the wrist, and alsoby ultrasound of the wristdemonstrating bone cysts anddistortion of the flexor tendons Haemodialysis with a high fluxpolyacrylonitrile, orhaemodiafiltration, have been reportedto reduce the deposition of 2-microglobulin 19. Carpal tunnel syndrome Splinting or local corticosteroidinjections for mild disease Surgical decompression in caseswhere symptoms are either refractoryto conservative treatments or whereNCS have demonstrated changesindicative of axonal loss Extended carpal tunnel releaseprocedure 20. Autonomic neuropathy Autonomic dysfunction is a commonand potentially life-threateningcomplication of CKD, and can occur inthe absence of length-dependenturemic neuropathy. More common in diabetics and elderlypatients Cardiovascular autonomic dysfunctionin CKD is associated with anincreased risk of cardiac arrhythmiaand sudden cardiac death 21. Impotence remains the most commonsymptom of autonomic dysfunction inCKD Other common clinical features includebladder and bowel dysfunction, impairedsweating, and orthostatic intolerance Intradialytic hypotension Renal transplantation leads toconsiderable improvement in autonomicfunction Sildenafil , midodrine 22. Objectives Neuropathy Cognitive dysfunction Uremic encephalopathy Dialysis disequilibrium syndrome Stroke Myopathy 23. Cognitive dysfunction Cognitive dysfunction increases inprevalence with CKD severity,potentially affecting up to 80% ofpatients Cognitive impairment in CKD not onlyincreases the risk of mortality, but alsohas major implications for informedconsent in relation to dialysis initiationand maintenance, and, ultimately,renal transplantation 24. Acute Cognitive Impairment In addition to chronic cognitivedysfunction and dementia, acutedisturbances of cognition areprevalent in CKD. In the early days of dialysis, theseacute disturbances frequently took theform of the dialysis disequilibriumsyndrome 25. Acute Cognitive Impairment Acute disturbances in cognitive functiontypically relate to metabolic abnormalitiesthat complicate the uremic state, includingelectrolyte disturbances (forexample, hypercalcemia, hypophosphatemia and hyponatremia), acute fluid shiftsduring dialysis, which lead to cerebralhypoperfusion, and malignant hypertension 26. EFFECT OF HD Rapid variations in cognitive functionwas emphasized by a study of patientswith CKD who underwent cognitivetesting at multiple time points before andafter a single dialysis session In these patients, global cognitivefunction varied markedly, with thegreatest impairments being noted duringthe dialysis session, particularly withregard to memory, executive functioningand verbal fluency. 27. Chronic Cognitive Impairmentand Dementia mild cognitive impairment, subclinical dementia, residual syndrome, and chronic dialysis-dependent encephalopathy 28. Chronic Cognitive Impairmentand Dementia Moderate renal impairment that doesnot require dialysis is also associatedwith a significantly increased risk ofdementia Cognitive tests demonstrate objectiveevidence of moderate to severecognitive impairment in 70% ofpatients with CKD, with dysfunctionmost commonly noted in the domainsof memory and executive function. 29. Dialysis dementia Dialysis dementia is a term reservedto describe a syndrome of progressivedementia related to aluminumintoxication and first described severaldecades ago when aluminumcontamination of dialysate fluid andthe use of aluminum-containingbinders were more prevalent;however, this disorder is now rare. 30. Treatment :- DFO therapy 31. Pathophysiology of CognitiveImpairment vascular dementia high incidence of clinically silentcerebrovascular disease MRI studies have shown that clinicallysilent white matter disease is presentin 50% of patients withCKD, compared with 10% in thegeneral population Traditional and non traditionalvascular risk factors (inflammatorymediators) 32. Pathophysiology of CognitiveImpairment Modern techniques of waterpurification and the use of non-aluminum phosphorus bindershave, however, made aluminumintoxication a rare complication ofCKD Potential roles of secondaryhyperparathyroidism and anemia asrisk factors for cognitive impairment PTH neurotoxic 33. Clinical evaluation ofdementia The Mini-Mental State Exam is the bestknown cognitive test for dementia screeningand requires 7 to 10 minutes to administer. A score below 24 (out of a maximum score of30) has a sensitivity and specificity of greaterthan 80% for dementia detection in thegeneral population. Other cognitive tests that can beadministered in 5 minutes or less, such asthe clock drawing task, the Minicog(consisting of the clock drawing task plusuncued recall of three words), and the ShortPortable Mental Status Questionnaire, havesimilar performance characteristics in thegeneral population 34. Effects of RenalTransplantation Improvements in cognition in relationto baseline values were demonstrated6 months after transplantation Improvements in bothneuropsychological tests, such as theMini-Mental State Examination, andneurophysiological markers ofcognitive function, as measured usingevoked potential latencies and EEGrhythms 35. Treatment Although kidney transplantation isoptimal therapy for most patients withESRD, many patients with chroniccognitive impairment may not beeligible for transplantation Intensification of the dialysis regimenremains a potential managementstrategy 36. EEG from a patient with uraemic encephalopathy.The recording is predominantly (4-8 Hz) and (4 Hz)wave activity, with no normal (>8-13 Hz) or (>13 Hz)waves 37. Uremic encephalopathy Uremic encephalopathy is an acute orsubacute organic brain syndrome thatregularly occurs in patients with acute orchronic renal failure when glomerularfiltration rate declines to less than 10% ofnormal Seen in untreated or inadequatelytreated ESRD Characterized by lethargy and confusionin early stages and can progress toseizures or coma May be accompanied by otherneurologic signs, such astremor, myoclonus, or asterixis 38. Pathophysiology A large number of solutes are retained in uremiaand several may have direct neurotoxicity orcontribute indirectly to the pathogenesis ofuremic encephalopathy by altering the bloodbrain barrier. guanidine compounds, includingguanidinosuccinic acid, methylguanidine, andhomoarginine induce seizures, possibly throughtheir effects on N-methyl-D-aspartic acid (NMDA)receptors or by modulating calcium channels ADMA, is a potent endogenous inhibitor of nitricoxide synthesis and causes cerebralvasoconstriction by impairing endothelialrelaxation Anemia and hyperparathyroidism 39. A 50 year old male , known case of DM /ESRD on intermittent acute PD, getting HDsessions in between as well, past h/osmoking, receiving diuretics for edema, poordietry intake, received one HD session fromregional centre and brought in altered state (history : duration?? ) On probing attendants gave h/o low gradefever for last 3-4 days Medication review aluminium basedphosphate binders, OHA tablets Residents notices some weakness on leftside of body but not sure Diagnosis : .. 40. Treatment After other causes of delirium have beenruled out, prompt treatment of uremicencephalopathy with initiation orintensification of renal replacementtherapy is indicated. Resolution of symptoms typically occurswithin days. Correction of anemia (i.e., hemoglobin