Neurological Manifestations of Uremic Encephalopathy

Neurological Manifestations of Uremic Encephalopathy

No Results

No Results

processing….

Uremia describes the final stage of progressive renal insufficiency and the resultant multiorgan failure. It results from accumulating metabolites of proteins and amino acids and concomitant failure of renal catabolic, metabolic, and endocrinologic processes. No single metabolite has been identified as the sole cause of uremia. Uremic encephalopathy (UE) is one of many manifestations of renal failure (RF).

The exact cause of UE is unknown. Accumulating metabolites of proteins and amino acids affect the entire neuraxis. Several organic substances accumulate, including urea, guanidine compounds, uric acid, hippuric acid, various amino acids, polypeptides, polyamines, phenols and conjugates of phenols, phenolic and indolic acids, acetoin, glucuronic acid, carnitine, myoinositol, sulfates, phosphates, and middle molecules. Levels of some of the guanidine compounds, including guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, increase in patients with uremia who are or who are not receiving dialysis. Endogenous guanidino compounds have been identified to be neurotoxic. [1]

Patients with terminal RF have >100-fold increases in levels of guanidinosuccinic acid and guanidine, 20-fold increases in levels of methylguanidine, and 5-fold increase in levels of creatinine in various regions of the brain. Disturbance in the kynurenic pathway, by which tryptophan is converted to neuroactive kynurenines, has also been implicated. Levels of 2 kynurenines, 3-hydroxykynurenine and kynurenine, are elevated in rats with chronic renal insufficiency; these changes lead to alterations in cellular metabolism, cellular damage, and eventual cell death. Kynurenine can induce convulsions. Middle-molecules, a series of small protein-bound and nonprotein-bound molecules, such as β2-microglobulin, have been identified as uremic toxins. [2]

Abnormalities that may be associated with UE include acidosis, hyponatremia, hyperkalemia, hypocalcemia, hypermagnesemia, overhydration, and dehydration. Acute renal injury has been found in mice with increased neuronal pyknosis and microgliosis in the brain. Acute renal injury also led to increased levels of the proinflammatory chemokines keratinocyte-derived chemoattractant and G-CSF in the cerebral cortex and hippocampus, as well as increased expression of glial fibrillary acidic protein in astrocytes. Acute renal injury led to both soluble and cellular inflammation in the brain, affecting the CA1 region of the hippocampus foremost. Acute renal injury leads to increase in brain microvascular leakage. [3, 4]

No single abnormality is precisely correlated with the clinical features of UE. Increased levels of glycine, organic acids (from phenylalanine), and free tryptophan and decreased levels of gamma-aminobutyric acid (GABA) in the CSF may be responsible for early phases of the disorder. In rats with RF, brain levels of creatine phosphate, adenosine triphosphate (ATP), and glucose are increased, whereas levels of adenosine monophosphate (AMP), adenosine diphosphate (ADP), and lactate are decreased. This finding suggests that the uremic brain uses less ATP and produces less ADP, AMP, and lactate than healthy brains, consistent with a generalized decrease in metabolic function.

Transketolase, found mainly in myelinated neurons, is a thiamine-dependent enzyme of the pentose phosphate pathway; it maintains axon-cylinder myelin sheaths. Plasma, CSF, and low-molecular-weight (< 500 Da) dialysate fractions from patients with uremia substantially inhibit this enzyme. Erythrocyte transketolase activity is lower in nondialyzed patients than in dialyzed patients. Guanidinosuccinic acid can inhibit transketolase.

Synaptosome studies of uremic rats have shown altered function of the sodium ATP and other metabolic pumps. Methylguanidine can induce a condition similar to UE that includes seizures and uremic twitch-convulsive syndrome. Guanidinosuccinic acid can also inhibit excitatory synaptic transmission in the CA1 region of the rat hippocampus, an effect that may contribute to cognitive symptoms in UE.

Guanidinosuccinic acid, methylguanidine, guanidine, and creatinine inhibited responses to GABA and glycine (inhibitory amino acids) in cultured mouse neurons. Guanidino compounds (GCs) inhibit nitric oxide synthase (NOS) modulators in vivo and in vitro. Accumulation of asymmetric dimethylarginine (ADMA), a NOS inhibitor, has been observed in patients with uremia; this accumulation induces hypertension and possibly increases ischemic vulnerability to the uremic brain.

UE involves many hormones, levels of several of which are elevated. Such hormones include parathyroid hormone (PTH), insulin, growth hormone, glucagon, thyrotropin, prolactin, luteinizing hormone, and gastrin. In healthy dogs, high levels of PTH produce CNS changes like those seen in uremia. PTH is thought to promote the entry of calcium into neurons, which leads to the changes observed.

A combination of factors, including increased calcium and decreased GABA and glycine activity, leads to a distorted balance of excitatory and inhibitory effects that contributes to systemic changes associated with UE.

United States

The prevalence of UE is difficult to determine. UE may manifest in any patient with end-stage renal disease (ESRD), and directly depends on the number of such patients. In the 1990s, more than 165,000 people were treated for ESRD, compared with 158,000 a decade earlier. In the 1970s, the number was 40,000. As the number of patients with ESRD increased, presumably so did the number of cases of UE. On a yearly basis, 1.3 per 10,000 patients develop ESRD.

For related information, see Medscape’s End-Stage Renal Disease Resource Center.

International

The worldwide prevalence is unknown. In western Europe and in Japan (ie, countries with healthcare systems similar to that of the United States), statistics parallel to those of United States are expected. In general, the care of patients with UE depends on costly intensive care and dialysis that is not available in developing nations.

RF is fatal if untreated.

UE reflects worsening renal function, with symptoms worsening as RF progresses. If untreated, UE progresses to coma and death.

Patients need aggressive care to prevent complications and maintain homeostasis. They depend on intensive care and dialysis. In the United States, more than 200,000 patients are currently receiving hemodialysis.

RF is more common in African Americans than in other races. Of all patients in the Medicare ESRD treatment program in 1990, 32% were African American, though African Americans account for only 12% of the US population. The overall incidence of ESRD is 4 times greater in African Americans than in whites.

Incidences are equal in men and woman.

People of all ages can be affected, but the fastest growing group with ESRD is the elderly, ie, persons older than 65 years. RF has a proportionally increased prevalence in this group compared with any other age group.

De Deyn PP, D’Hooge R, Van Bogaert PP, Marescau B. Endogenous guanidino compounds as uremic neurotoxins. Kidney Int Suppl. 2001 Feb. 78:S77-83. [Medline].

Meyer TW, Hostetter TH. Uremia. N Engl J Med. 2007. 357:1316-1325.

Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol. 2008 Jul. 19(7):1360-70. [Medline]. [Full Text].

Lacerda G, Krummel T, Hirsch E. Neurologic presentations of renal diseases. Neurol Clin. 2010 Feb. 28(1):45-59. [Medline].

Mahale RR, Buddaraju K, Gireesh MS, Acharya P, Srinivasa R. Acute Generalized Chorea as Presenting Manifestation of Uremic Encephalopathy. J Neurosci Rural Pract. 2017 Aug. 8 (Suppl 1):S156-S158. [Medline].

Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. 2004 Dec. 107(1):1-16. [Medline].

Bansal VK, Bansal S. Nervous system disorders in dialysis patients. Handbook of Clinical Neurology. 2014. Vol 119 (3rd series):395-404.

Jia LJ, Qu ZZ, Zhang XQ, Tian YJ, Wang Y. Uremic encephalopathy with isolated brainstem involvement revealed by magnetic resonance image: a case report. BMC Neurol. 2017 Aug 8. 17 (1):154. [Medline].

Camara-Lemarroy CR, Flores-Cantu H, Gonzalez-Velazquez CD, Calderon-Hernandez HJ, Mendoza-Garcia AG, Villareal-Velazquez HJ. Bilateral cytotoxic edema of the centrum semiovale in uremic encephalopathy. J Neurol Sci. 2014 Oct 15. 345 (1-2):260-1. [Medline].

Choi EK, Oh LK, C YA. Brain SPECT and MRI findings in a Uremic Patient with Parkinsonism. Clinical Nuclear Medicine. 2015. 40:e453-e454.

Röhl JE, Harms L, Pommer W. Quantitative EEG findings in patients with chronic renal failure. Eur J Med Res. 2007 Apr 26. 12(4):173-8. [Medline].

Singh NP, Sahni V, Wadhwa A, Garg S, Bajaj SK, Kohli R. Effect of improvement in anemia on electroneurophysiological markers (P300) of cognitive dysfunction in chronic kidney disease. Hemodial Int. 2006 Jul. 10(3):267-73. [Medline].

Cheng BC, Chang WN, Lu CH, Chen JB, Chang CS, Lee CH. Bacterial meningitis in hemodialyzed patients. J Nephrol. 2004 Mar-Apr. 17(2):236-41. [Medline].

Yoon CH, Seok JI, Lee DK, An GS. Bilateral basal ganglia and unilateral cortical involvement in a diabetic uremic patient. Clin Neurol Neurosurg. 2009 Jun. 111(5):477-9. [Medline].

Arieff AI, Mahoney CA. Pathogenesis of dialysis encephalopathy. Neurobehav Toxicol Teratol. 1983 Nov-Dec. 5(6):641-4. [Medline].

Balzer S, Kuttner K. [Early auditory evoked potential. A diagnostic parameter in uremic encephalopathy]. HNO. 1996 Oct. 44(10):559-66. [Medline].

Biasioli S, D’Andrea G, Chiaramonte S, Fabris A, Feriani M, Ronco C, et al. The role of neurotransmitters in the genesis of uremic encephalopathy. Int J Artif Organs. 1984 Mar. 7(2):101-6. [Medline].

Biasioli S, D’Andrea G, Fabris A, Feriani M, La Greca G. The pathogenesis of uremic encephalopathy (UE). Int J Artif Organs. 1985 Jan. 8(1):59-60. [Medline].

Bolton CF, Young GB. Uremic encephalopathy. Neurological Complications of Renal Disease. Boston, MA: Butterworths; 1990. 43-74.

Bourne JR, Teschan PE. Computer methods, uremic encephalopathy, and adequacy of dialysis. Kidney Int. 1983 Oct. 24(4):496-506. [Medline].

Brouns R, De Deyn PP. Neurological complications in renal failure: a review. Clin Neurol Neurosurg. 2004 Dec. 107(1):1-16. [Medline].

Chiappa KH, Hill RA. Evoked Potentials in Clinical Medicine. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1997.

Chow KM, Wang AY, Hui AC, Wong TY, Szeto CC, Li PK. Nonconvulsive status epilepticus in peritoneal dialysis patients. Am J Kidney Dis. 2001 Aug. 38(2):400-5. [Medline].

De Deyn PP, Saxena VK, Abts H, et al. Clinical and pathophysiological aspects of neurologic complications in renal failure. Acta Neurol Belg. 1992. 92:191-206. [Medline].

De Deyn PP, Vanholder R, D’Hooge R. Nitric oxide in uremia: effects of several potentially toxic guanidino compounds. Kidney Int Suppl. 2003 May. S25-8. [Medline].

Ganesh SK, Hulbert-Shearon T, Port FK, Eagle K, Stack AG. Mortality differences by dialysis modality among incident ESRD patients with and without coronary artery disease. J Am Soc Nephrol. 2003 Feb. 14(2):415-24. [Medline].

Habach G, Bloembergen WE, Mauger EA, Wolfe RA, Port FK. Hospitalization among United States dialysis patients: hemodialysis versus peritoneal dialysis. J Am Soc Nephrol. 1995 May. 5(11):1940-8. [Medline].

Hung SC, Hung SH, Tarng DC, Yang WC, Chen TW, Huang TP. Thiamine deficiency and unexplained encephalopathy in hemodialysis and peritoneal dialysis patients. Am J Kidney Dis. 2001 Nov. 38(5):941-7. [Medline].

Jagadha V, Deck JH, Halliday WC, Smyth HS. Wernicke’s encephalopathy in patients on peritoneal dialysis or hemodialysis. Ann Neurol. 1987 Jan. 21(1):78-84. [Medline].

Jeppsson B, Freund HR, Gimmon Z, et al. Blood-brain barrier derangement in uremic encephalopathy. Surgery. 1982 Jul. 92(1):30-5. [Medline].

Kiley JE, Pratt KL, Gisser DG, Schaffer CA. Techniques of EEG frequency analysis for evaluation of uremic encephalopathy. Clin Nephrol. 1976 Jun. 5(6):279-85. [Medline].

Liu M, Liang Y, Chigurupati S, Lathia JD, Pletnikov M, Sun Z, et al. Acute kidney injury leads to inflammation and functional changes in the brain. J Am Soc Nephrol. 2008 Jul. 19(7):1360-70. [Medline].

Lockwood AH. Neurologic complications of renal disease. Neurol Clin. 1989 Aug. 7(3):617-27. [Medline].

Mahoney CA, Arieff AI. Uremic encephalopathies: clinical, biochemical, and experimental features. Am J Kidney Dis. 1982 Nov. 2(3):324-36. [Medline].

Moe SM, Sprague SM. Uremic encephalopathy. Clin Nephrol. 1994 Oct. 42(4):251-6. [Medline].

Murphy SW, Foley RN, Barrett BJ, Kent GM, Morgan J, Barré P, et al. Comparative hospitalization of hemodialysis and peritoneal dialysis patients in Canada. Kidney Int. 2000 Jun. 57(6):2557-63. [Medline].

Niedermeyer E. Metabolic central nervous system disorders. Basic Principles, Clinical Applications, and Related Fields. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1993. 405-18.

Norenberg MD, Bruce-Gregorios J. Renal disease. Textbook of Neuropathology. 3rd ed. Philadelphia, PA: Lippincott Williams & Wilkins; 1997. 575-9.

Ropper AH, Brown RH. Uremic encephalopathy. Adams and Victor’s Principles of Neurology. 8th ed. New York, NY: McGraw-Hill Professional; 2005. 969-71.

Schmidt M, Sitter T, Lederer SR, et al. Reversible MRI changes in a patient with uremic encephalopathy. J Nephrol. 2001 Sep-Oct. 14(5):424-7. [Medline].

Souheaver GT, Ryan JJ, DeWolfe AS. Neuropsychological patterns in uremia. J Clin Psychol. 1982 Jul. 38(3):490-6. [Medline].

Topczewska-Bruns J, Pawlak D, Chabielska E, et al. Increased levels of 3-hydroxykynurenine in different brain regions of rats with chronic renal insufficiency. Brain Res Bull. 2002 Aug 15. 58(4):423-8. [Medline].

Wu AW, Fink NE, Marsh-Manzi JV, Meyer KB, Finkelstein FO, Chapman MM, et al. Changes in quality of life during hemodialysis and peritoneal dialysis treatment: generic and disease specific measures. J Am Soc Nephrol. 2004 Mar. 15(3):743-53. [Medline].

Zucker I, Yosipovitch G, David M, et al. Prevalence and characterization of uremic pruritus in patients undergoing hemodialysis: uremic pruritus is still a major problem for patients with end-stage renal disease. J Am Acad Dermatol. 2003 Nov. 49(5):842-6. [Medline].

Gabriel Bucurescu, MD, MS Attending Neurologist, Neurology Service, Corporal Michael J Crescenz Veterans Affairs Medical Center

Gabriel Bucurescu, MD, MS is a member of the following medical societies: American Academy of Neurology, American Clinical Neurophysiology Society, American Epilepsy Society

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Received salary from Medscape for employment. for: Medscape.

Jasvinder Chawla, MD, MBA Chief of Neurology, Hines Veterans Affairs Hospital; Professor of Neurology, Loyola University Medical Center

Jasvinder Chawla, MD, MBA is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Clinical Neurophysiology Society, American Medical Association

Disclosure: Nothing to disclose.

J Stephen Huff, MD, FACEP Professor of Emergency Medicine and Neurology, Department of Emergency Medicine, University of Virginia School of Medicine

J Stephen Huff, MD, FACEP is a member of the following medical societies: American Academy of Neurology, American College of Emergency Physicians, Society for Academic Emergency Medicine

Disclosure: Nothing to disclose.

Neurological Manifestations of Uremic Encephalopathy

Research & References of Neurological Manifestations of Uremic Encephalopathy|A&C Accounting And Tax Services
Source