Handbook of Clinical Neurology, Vol. 119 (3rd series) Neurologic Aspects of Systemic Disease Part I Jose Biller and Jose M. Ferro, Editors © 2014 Elsevier B.V. All rights reserved

Chapter 25

Nervous system disorders in dialysis patients 1

VINOD K. BANSAL1* AND SEEMA BANSAL2 Division of Nephrology and Hypertension, Loyola University Medical Center, Maywood, IL, USA 2

Pediatric Neurology, National Children’s Medical Center, Washington, DC, USA

INTRODUCTION End-stage renal disease (ESRD) patients require lifelong dialysis unless they receive a kidney transplant. Various neurologic disorders have been reported in such a population, whether receiving hemodialysis or peritoneal dialysis. Currently there are approximately 500 000 patients on dialysis in the US (U.S. Renal Data System, 2010). The neurologic manifestations may be seen in patients with advanced chronic kidney disease who have not yet been started on dialysis or in patients who have been started on dialysis. These disorders, which may be of either the central nervous system (CNS) or the peripheral nervous system (PNS), are given a simple classification in Table 25.1.

CENTRAL NERVOUS SYSTEM COMPLICATIONS Uremic encephalopathy The syndrome of uremic encephalopathy is the cerebral manifestation of the uremia and varies from subtle neuropsychiatric changes such as mild cognitive impairment to coma (Brouns and De Deyn, 2004; Seifter and Samuels, 2011). Severe uremic encephalopathy in early childhood may affect the brain development in children (Gipson et al., 2004). Earliest symptoms include lack of attention, concentration, emotional changes, subtle or advanced cognitive changes, memory deficit, delirium, psychosis, seizures, and coma. Motor symptoms, although less common, include generalized weakness, myoclonus, and asterixis. Seizures are generalized, with partial seizures less common. Depression, anxiety, and action tremors are often seen (Brouns and De Deyn, 2004). Neurologic impairment may develop in about

20% of the patients with acute renal injury (Mehta et al., 2004). In chronic kidney disease the uremic syndrome is more subtle and does not correlate with severity of uremia. Uremia is used in the setting of either acute or chronic kidney failure where generally both serum blood urea nitrogen or serum creatinine are elevated. But the symptom complex of uremic encephalopathy may not correlate to the severity kidney failure or the levels of blood urea nitrogen and creatinine (Tyler, 1970; Brouns and De Deyn, 2004). Uremic encephalopathy is much less commonly seen today because of earlier dialysis intervention and occurs only in circumstance where either the patient refuses to accept dialysis until symptomatic or a decision has been made not to initiate dialysis (Seifter and Samuels, 2011). The circumstances where it occurs are generally in acute renal failure, where there are many other concurrent diseases that may produce similar symptoms. A careful search should be made for any other causes before a decision is reached to initiate dialysis because of neurologic status. Upper motor neuron signs as well as speech and gait disturbances may also be present in late stages of uremic encephalopathy (Burn and Bates, 1998; Smogorzewski, 2001). The diagnosis of uremic encephalopathy is made based on clinical signs and symptoms. The level of blood urea or blood urea nitrogen or serum creatinine is not related to the onset or severity of uremic encephalopathy. Lumbar puncture, EEG, or imaging procedures are nonspecific and are used to exclude other conditions. Cerebrospinal fluid (CSF) in uremic encephalopathy may show pleocytosis (usually less than 25 cells/mm3) and increased protein (usually less than 100 mg/m). The electroencephalogram (EEG) is abnormal with generalized slowing and excess of d and y waves (Balzar et al., 1986). Brain imaging may show cerebral atrophy and

*Correspondence to: Vinod K. Bansal, M.D., Professor of Medicine, Division of Nephrology and Hypertension, Loyola University Medical Center, 2160 S. First Avenue, Maywood, IL 60153, USA. Tel: þ1-708-216-3306, Fax: þ1-708-216-4060, E-mail: [email protected]

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V.K. BANSAL AND S. BANSAL

Table 25.1 Simple classification of central and peripheral nervous system complications observed in dialysis patients Central nervous system complications

Peripheral nervous system complications

Uremic encephalopathy Dialysis disequilibrium syndrome Dialysis dementia Wernicke’s encephalopathy Posterior reversible leukoencephalopathy Intracranial hypertension Movement disorders, restless legs syndrome Sleep disorders Cognitive abnormalities

Mononeuropathy Polyneuropathy Myopathy

enlargement of the ventricles. The differential diagnosis of uremic encephalopathy includes hypertensive encephalopathy, ischemic stroke, electrolyte abnormalities, metabolic acidosis, and sepsis. In some ways, it remains a diagnosis of exclusion. The pathogenesis of uremic encephalopathy is not precisely known but it is fairly clear that the level of urea or blood urea nitrogen or serum creatinine do not have significant relationship to the symptoms. Many so-called neurotoxins are hypothesized but no single neurotoxin has been identified that might be linearly related and dialyzable, whose removal would result in improvement, and that experimentally could reproduce symptoms complex of uremia. The many compounds incriminated in uremic pathogenesis are those which accumulate in serum in renal failure. The balance of excitatory and inhibitory neurotransmitters may be disrupted by various organic substances Among the most reported are the various guanidino compounds which are increased in cerebral spinal fluids (De Deyn et al., 2001; Smogorzewski, 2001; Vandolder et al., 2003). These compounds antagonize g-aminobutyric acid (GABA) which leads to cortical excitability (De Deyn et al., 2003). There are disturbances in monoamine metabolism such as depletion of norepinephrine, and suppression of central dopamine has also been described. A number of metabolites, such as myoinositol, carnitine, indoxyl sulfate, and polyamines, may also play some role. One other consideration should be the drugs which are being administered to such patients since in acute renal failure the excretion of various medications is impaired and could lead to cumulative effects. Treatment of uremic encephalopathy is initiation of dialysis. Although either hemodialysis or peritoneal dialysis may be used, in general, hemodialysis is the

preferred modality. The decision to initiate dialysis is made on several factors, such as neurologic status, and metabolic and electrolyte abnormalities. Most nephrologists consider neurologic symptoms to be an indication for dialysis initiation. Dialysis should gradually improve the neurologic status fairly rapidly; if, after dialysis has been started, there is no neurologic improvement, other conditions should be pursued vigorously.

Dialysis disequilibrium syndrome Dialysis disequilibrium syndrome (DDS) is an infrequent complication due to rapid metabolic changes occurring at the initiation of hemodialysis (Arieff, 1994). Patients exhibit signs and symptoms suggestive of cerebral edema. These include acute onset of headache, fatigue, nausea, vomiting, tremors, blurred vision, muscle cramps, disturbed consciousness, convulsions, and coma (Benna et al., 1981; Arieff, 1994). The term disequilibrium is used because, whereas blood biochemistries such as blood urea nitrogen and serum creatinine levels improve, clinical neurologic signs and symptoms deteriorate. DDS usually results from acute changes in osmolality when there is rapid decrease in urea in extracellular fluid but the decrease in brain cells lags, thus favoring water movement into brain cells. Other intracellular osmolytes within brain cells may also be present (Arieff, 1994). The condition spontaneously reverses after a period of dialysis. The osmotic gradient occurs because of delay in urea being removed from brain as compared to plasma. In bilateral nephrectomized rats, hemodialysis reduced brain urea concentration less than plasma, thus setting up a high osmotic gradient and increased brain water (Silver et al., 1992). It was proposed that because urea is so highly diffusible and a small molecule, that the blood–brain barrier is due to development of organic osmolytes or idiogenic osmoles (Arieff, 1994). Subsequent experimental studies convincingly established that DDS was due to reverse urea gradient (Silver, 1995). The presence of cerebral edema is confirmed by either computerized brain scan or by diffusion-weighted magnetic resonance imaging (MRI) (Chen et al., 2007). The reverse urea effect is the result of slow removal of urea from the brain compared to large decreases in plasma concentration. Recent studies have shed light on the molecular mechanism of dialysis disequilibrium syndrome. Water and urea movements across cell membranes are facilitated by water channels, called aquaporin (AQP) and urea transporters (UTs). In brain, among the APQ and UTs cloned so far, AQP1, AQP4 AQP9 and UT-B1 are expressed (TrinhTrang-Tan et al., 2005). AQP4, AQP9 and UT-B1 are believed to facilitate rapid equilibrium of water and urea throughout the brain parenchyma. Trinh-Trang-Tan et al., in an experimental model of chronic kidney disease, showed that in brain, in such a model, there is a decrease

NERVOUS SYSTEM DISORDERS IN DIALYSIS PATIENTS in UT-B1 expression and rise in AQPs. This leads to impaired transport of urea out of the brain cells and facilitates water movement inside the cells, resulting in brain edema (Trinh-Trang-Tan et al., 2005). The mechanism for marked reduction of UT-B1 in chronic renal failure is unclear. The other hypothesis is that there is disparity in CSF pH and blood pH due to rapid dialysis. The systemic metabolic acidosis is quickly corrected by rapid hemodialysis while the CSF acidosis lags. This may lead to secondary hypoventilation and rise of plasma PCO2 which diffuses into CSF, elevating CSF PCO2. The resulting fall in CSF pH may contribute to development of brain edema by unknown mechanisms. (Arieff, 1994). In current practice, DDS has largely disappeared. The initial dialysis is started slowly, with low blood flow of around 150–200 mL/min and a less efficient dialyzer and short duration, all in an effort to slow down the disparity between plasma and brain urea concentration. The dialysis is then gradually increased in time and efficiency. With the use of bicarbonate bath and the slow dialysis, there should be minimal or no rapid changes in CSF and plasma pH.

Dialysis dementia Dialysis encephalopathy or dialysis dementia is a subacute, progressive, and often fatal disease. It is typically observed in prevalent dialysis patients who have been on hemodialysis for a while. Symptoms include personality changes, directional disorientation, seizures, visual and auditory hallucinations, dysarthria, dysphagia, apraxia asterixis, myoclonic jerks, seizures, and dementia (Brouns and De Deyn, 2004). The disease is progressive and may eventually lead to death. EEG findings showed a relatively normal background with very frequent frontal intermittent bursts of d activity, triphasic waves, and paroxysmal bursts of spike and wave activity (Chokroverty and Gandhi, 1982). The etiology of dialysis dementia was determined to be aluminum neurotoxicity. This was demonstrated by markedly increased levels of total body aluminum in patients who died of dialysis dementia as compared to nonuremic patients or uremic patients dying of some other cause. The evidence for aluminum toxicity came from epidemiologic studies. The places where dialysis dementia was seen had a higher water concentration of aluminum as compared to areas where no such cases were being reported. Another source of aluminum was the use of aluminum hydroxide phosphate binders. The resulting absorbed aluminum increased serum levels. The mechanism by which aluminum leads to neurodegenerative changes in the brain is unknown (Bolton and Young, 1990). With water treatment that removes aluminum from water and discontinuation of oral Al(OH)3 the incidence has fallen and the disorder is now rarely seen (Dunea, 2001). Aluminum toxicity also leads to

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osteomalacia and anemia in dialysis patients and, along with neurologic symptoms, helps diagnose this condition. Treatment is the avoidance of aluminum-containing phosphate binders and the maintenance of proper water treatment. In established patients, treatment is use of the chelating agent desferrioxamine (DFO), and has been shown to reverse the symptoms of dementia (Milne et al., 1983). Although this entity is now rarely seen, if suspected, the diagnosis should be made on the blood level of aluminum (normally

Nervous system disorders in dialysis patients.

Neurologic complications are frequently encountered in dialysis patients. These may be due to the uremic state or to dialysis therapy, and require car...
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