Keywords
uremia, encephalopathy, polyneuropathy, kidney disease, asterixis, metabolic coma, dialysis, restless legs syndrome, carpal tunnel syndrome, myopathy
The neurologic aspects of renal disease and the neurologic complications of dialysis and renal transplantation are discussed in this chapter. The neurologic complications of renal carcinoma are not considered, but paraneoplastic complications of malignancy are considered in Chapter 27 , and the neurologic consequences of radiation and chemotherapy in Chapter 28 . The subject itself is complicated because many of the causes of renal failure lead to neurologic complications that also occur in uremia. Thus, collagen vascular diseases are commonly associated with encephalopathy or seizures, and diabetes with neuropathy or encephalopathy. Attention here is directed primarily to complications that are a direct consequence of the renal failure and its treatment rather than to the underlying cause of the kidney disease. In addition, however, certain hereditary disorders that affect both the nervous system and the kidneys are considered. In order to limit the size of the chapter, the bibliography has largely been restricted to references published since 1990, and particularly to those published in the last 10 to15 years. Earlier references can be found in previous editions of this book.
Uremic Encephalopathy
The neurologic consequences of uremia resemble other metabolic and toxic disorders of the central nervous system (CNS). Thus, the clinical features of the encephalopathy that occurs in uremic patients include an impairment of external awareness that ranges from a mild confusional state, with diminished attention and concentration, to coma. The presence of coma may indicate severe uremia or reflect a complication such as hypertensive encephalopathy, posterior reversible encephalopathy syndrome, fluid and electrolyte disturbances, seizures, or sepsis. Other causes of an encephalopathy in uremic patients include dialysis, thiamine deficiency, drug toxicity, and transplant rejection. Finally, the encephalopathy and renal impairment may both relate independently to the same underlying systemic illness, such as diabetes or connective tissue diseases. All these factors complicate clinical assessment.
In addition to an alteration in external awareness, patients with uremic encephalopathy may have seizures, dysarthria, gait ataxia, asterixis, tremor, and multifocal myoclonus. As with all metabolic encephalopathies, symptoms and signs typically fluctuate in severity over short periods of time, such as over the course of a day or from day to day.
Pathophysiology
In early studies, various pathologic changes were described in the brain of uremic patients, but these probably did not relate directly to the uremia. Thus, neuronal degeneration and necrosis of the granular cell layer of the cerebellar cortex probably related to preterminal hypoxia, and focal demyelination and necrosis to coexisting hypertensive cerebrovascular disease that led to small infarcts. Glycolysis and energy utilization are reduced in the brain, probably as a consequence of a disturbance of synaptic transmission that leads to decreased neuronal interaction and thus to reduced cerebral oxygen consumption.
Uremic encephalopathy almost certainly relates to a variety of metabolic abnormalities, with the accumulation of numerous metabolites, imbalance in excitatory and inhibitory neurotransmitters, and hormonal disturbances leading to cerebral dysfunction. The European Uremic Toxin Work Group has listed 90 compounds considered to be uremic toxins; 68 have a molecular weight less than 500 Da, 12 exceed 12,000 Da, and 10 have a molecular weight between 500 and 12,000 Da. A few merit brief discussion here. Retention of urea occurs; urea clearance, even in well-dialyzed patients, amounts to only one-sixth of physiologic clearance. Accumulation of guanidinosuccinic acid, methylguanidine, guanidine, and creatinine, all of which are guanidine compounds, in the serum and cerebrospinal fluid (CSF) of uremic patients, may play a role in causing uremic seizures and cognitive dysfunction. Activation of N -methyl- d -aspartate (NMDA) receptors and inhibition of γ-aminobutyric acid-A (GABA A ) transmission may be involved, on the basis of studies in animals. Guanidinosuccinic acid may inhibit transketolase, a thiamine-dependent enzyme involved in the pentose phosphate pathway and in the maintenance of myelin. It remains unclear whether low-level aluminum overload in renal failure causes gradual deterioration in cerebral function. Abnormalities of the membrane pumps for both Na + ,K + adenosine triphosphatase and calcium ions have been described in experimental studies in animals and may be of clinical relevance.
Hormonal changes may also be important in the pathogenesis of uremic encephalopathy. Serum concentrations of parathyroid hormone, growth hormone, prolactin, luteinizing hormone, insulin, and glucagon are elevated in uremic patients. Parathyroid hormone levels increase with the severity of the encephalopathy, and alterations in brain calcium could influence neurotransmitter release, the sodium-potassium pump, intracellular enzyme activity, and intracellular metabolic processes, and thereby may affect cerebral function. Experimental studies show that the calcium content of the cerebral cortex is greatly increased in uremia, and this is unrelated to alterations in calcium concentration in the plasma or cerebrospinal fluid. Both clinical and electroencephalographic (EEG) abnormalities, and changes in cerebral calcium concentration, are improved by parathyroidectomy.
In contrast to the process in subjects with normal kidneys, the removal of uremic toxins in dialysis is achieved by a one-step, membrane-based process and is intermittent. The resulting stepwise variation in plasma concentrations of uremic toxins contrasts with the continuous function of normal kidneys.
Clinical Features
The clinical features of uremic encephalopathy do not show a good correlation with any single laboratory abnormality but can sometimes be related to the rate at which renal failure develops. Thus, stupor and coma are relatively common in acute renal failure, whereas symptoms may be less conspicuous and progression more insidious despite more marked laboratory abnormalities in chronic renal failure. Dialysis relieves or prevents some of the more severe features of this encephalopathy.
The most reliable early indicators of uremic encephalopathy are a waxing and waning reduction in alertness and impaired external awareness. The ability to concentrate is impaired, so that patients seem preoccupied and apathetic, with a poor attention span; they become increasingly disoriented with regard to place and time and may exhibit emotional lability and sleep inversion. An impairment of higher cognitive abilities, such as of executive function, becomes evident, and patients become increasingly forgetful and apathetic. With progression, patients become more obtunded so that it may then be necessary to shout or gently shake them to engage their attention and elicit any responses, which are likely to be of variable accuracy and relevance. Delusions, illusions, and hallucinations (typically visual) often develop, and patients may become agitated and excited, with an acute delirium that eventually is replaced by stupor and a preterminal coma.
Tremulousness may be conspicuous and usually occurs before asterixis is found. A coarse postural tremor is seen in the fingers of the outstretched hands, and a kinetic tremor is also common. Asterixis is a nonspecific sign of metabolic cerebral dysfunction. An intermittent loss of postural tone produces the so-called flapping tremor of asterixis after several seconds when the upper limbs are held outstretched with the elbows and wrists hyperextended and fingers spread apart; irregular flexion-extension occurs at the wrist and of the fingers at the metacarpophalangeal joints, with flexion being the more rapid phase. There is complete electrical silence in the wrist flexors and extensors during the downward (flexor) movements, followed by electrical activity in the extensors as they restore the limb’s posture. The axial structures, including the trunk or neck, may also be affected. Asterixis can also be demonstrated in the lower limbs, and flapping may even be elicited in the face by forceful eyelid closure, strong retraction of the corners of the mouth, pursing of the lips, or protrusion of the tongue, provided that some degree of voluntary muscle control persists. In obtunded or comatose patients, or others in whom voluntary effort is limited, asterixis can still be elicited, but at the hip joints. With the patient lying supine, the examiner grasps both ankles of the supine patient and moves the feet upward toward the patient’s body, flexing and abducting the thighs: irregular abduction–adduction movements at the hips indicate asterixis.
Spontaneous and stimulus-sensitive myoclonus is common in uremia and in other metabolic encephalopathies and reflects increased cerebral excitability. The myoclonus is typically multifocal, irregular, and asymmetric; it may be precipitated by voluntary movement (action myoclonus). The myoclonic jerks may be especially conspicuous in the facial and proximal limb muscles. Uremic myoclonus in humans resembles the reticular reflex form of postanoxic action myoclonus. It is usually not associated with EEG spike discharges, although such discharges have sometimes been encountered with the myoclonus. The myoclonus may respond to clonazepam. Multifocal myoclonus is sometimes so intense that muscles appear to be fasciculating ( uremic twitching ) . Tetany may occur.
Seizures are common. They are usually generalized convulsions, may be multiple, and are often multifactorial in etiology. In acute renal failure, convulsions commonly occur several days after onset, during the anuric or oliguric phase. In chronic renal failure, they tend to occur with advanced disease, often developing preterminally; they may relate to the uremia itself or to electrolyte disturbances, medications (such as penicillin, aminophylline, or isoniazid), or an associated reversible posterior leukoencephalopathy syndrome (characterized by vasogenic white-matter edema predominantly localized to the posterior cerebral hemispheres on imaging studies, as shown in Fig. 16-1 ). Their incidence has declined, perhaps because of more effective treatment of renal failure and its complications. Seizures also occur in patients undergoing hemodialysis as part of the dialysis dysequilibrium syndrome (discussed later). Focal seizures sometimes occur. Occasionally patients develop nonconvulsive status epilepticus that may not be recognized unless an EEG is obtained.
During the early stages of uremia, patients may be clumsy or have an unsteady gait. Paratonia ( gegenhalten ), a variable, velocity-dependent resistance to passive movement, especially rapid movement, is common, and grasp and palmomental reflexes may be present, presumably as a result of a depression of frontal lobe function. As uremia advances, extensor muscle tone increases and may be asymmetric; opisthotonos or decorticate posturing of the limbs may eventually occur. Motor deficits may include transient or alternating hemiparesis that shifts sides during the course of the illness, flaccid quadriparesis related to hyperkalemia, or distal weakness from uremic neuropathy. The tendon reflexes are generally brisk unless a significant peripheral neuropathy is present and may be asymmetric; Babinski signs are often present.
Encephalopathy may occur in uremic patients for reasons other than uremia, such as in relation to dialysis, thiamine deficiency, electrolyte imbalance, medication-related toxicity, and graft rejection. These disorders are considered in later sections of this chapter.
Investigations
Laboratory studies provide evidence of impaired renal function but are of limited utility in monitoring the course of the encephalopathy. Furthermore, abnormal renal function tests do not exclude other causes of encephalopathy. An underlying structural lesion must be excluded in uremic patients who have had seizures, especially when focal or multiple seizures have occurred.
The CSF is commonly abnormal, with a pleocytosis that is unrelated to the degree of azotemia and an increased protein content that sometimes exceeds 100 mg/dl. In the older literature, summarized by Raskin, up to 30 percent of uremic patients were found to have neck stiffness and Kernig sign, and in this context the finding of abnormal CSF may lead to the erroneous conclusion that the patient has a meningitic or encephalitic illness.
The EEG is diffusely slowed, with an excess of intermittent or continuous theta and delta waves that may show a frontal emphasis, perhaps reflecting a decreased cerebral metabolic rate. Triphasic waves are often present, with an anterior predominance ( Fig. 16-2 ). Bilateral spike-wave complexes may be present either in the resting EEG or with photic stimulation. The EEG becomes increasingly slowed with progression of the encephalopathy, so that delta activity becomes more continuous; the findings correlate best with the level of retained nitrogenous compounds, although no clear relationship exists between the EEG and a specific laboratory abnormality. Similarly, there are delays of visual, auditory, and somatosensory evoked cerebral potentials. Event-related potentials reveal abnormalities even in asymptomatic patients, with an increase in P3 latency. In a study involving transcranial magnetic stimulation, 36 patients with end-stage renal disease were evaluated at different stages of the disease and under different treatment. Patients on conservative treatment showed a significant reduction of short-interval intracortical inhibition that could be reversed by hemodialysis, peritoneal dialysis, or renal transplantation. After hemodialysis, intracortical facilitation increased, and this was inversely correlated with the decline in plasma osmolarity induced by the dialytic procedure. In other words, patients showed alterations in cortical excitability that were reversed by treatment of the renal disease.
Cerebral imaging studies are of limited help except in excluding other, structural causes of the encephalopathy. They may reveal a reversible, predominantly posterior leukoencephalopathy, with subcortical edema without infarction. There may be multiple areas of symmetric edema in the basal ganglia, brainstem, or cerebellum, with—in severe cases—focal infarcts, sometimes hemorrhagic.
Treatment of Uremic Convulsions
Treatment involves correction of renal failure and related metabolic abnormalities. In patients who have had seizures, anticonvulsant medication may be required, especially when the convulsions are of uncertain cause. If status epilepticus occurs, it is managed as in other circumstances.
Various considerations make anticonvulsant therapy difficult to manage in uremia. As discussed in Chapter 57 and also reviewed elsewhere, plasma protein binding and renal excretion are reduced, and dialysis may remove drugs from the circulation. Phenytoin is often used in this context; reduced protein binding leads to a greater volume of distribution and lower serum concentrations, but the proportion of unbound (active) phenytoin increases and maintains the benefit of a given dose. Free phenytoin rather than total plasma levels are used to monitor treatment; the optimal therapeutic range is 1 to 2 μg/ml. The total daily dose generally need not be changed, but it is probably best taken divided rather than in a single dose. Dialysis does not remove phenytoin from the circulation to any significant extent. Plasma phenobarbital levels are unaffected by renal insufficiency. Lower doses of phenobarbital are used for long-term maintenance therapy, however, because the drug may accumulate; additional doses may be required after dialysis. Primidone and its metabolites may also accumulate, causing toxicity in uremic patients.
Valproic acid is helpful for treating myoclonic seizures and generalized convulsions in uremic patients. Protein binding decreases, but the free fraction remains constant. Dialysis does not necessitate additional doses.
Serum carbamazepine levels are unchanged, and dosing does not need alteration. Impaired renal function leads to decreased clearance of felbamate, gabapentin, topiramate, levetiracetam, vigabatrin, pregabalin, and oxcarbazepine. Gabapentin, pregabalin, and topiramate are excreted mainly by the kidneys, and the daily dose will need to be reduced in uremic patients; dosing of zonisamide may also need reduction. Hemodialysis necessitates additional doses of levetiracetam (typically 250 to 500 mg) and gabapentin (200 to 300 mg); supplemental doses of topiramate and pregabalin after hemodialysis may also be required. Extra doses of zonisamide may not be necessary if this drug is given in a single daily dose after dialysis sessions. Tiagabine and lamotrigine pharmacokinetics show little change even in severe uremia, and dosage adjustment is usually unnecessary.
Uremic Neuropathy
Polyneuropathy
Peripheral nerve function becomes impaired at glomerular filtration rates of less than 12 ml/min, with clinical deficits developing at rates of about 6 ml/min. More than 50 percent of patients with end-stage renal disease have clinical (neuropathic symptoms or signs) or electrophysiologic abnormalities, the exact number depending on the series and diagnostic criteria utilized.
Pathophysiology
Because uremic neuropathy improves with dialysis, uremic neuropathy has been attributed to the accumulation of dialyzable metabolites. Hemodialysis regimes sufficient to control urea or creatinine may nevertheless fail to prevent the development of neuropathy, and this observation led to the “middle molecule” hypothesis. In particular, the lower prevalence of neuropathy in patients on peritoneal dialysis than on hemodialysis suggested that the responsible substance was better dialyzed by the peritoneum, and it was proposed that these substances might be in the middle-molecule range (500 to 12,000 Da), which is poorly cleared by hemodialysis membranes. The adoption of dialysis strategies to improve the clearance of middle molecules reduced the rates of severe neuropathy.
The identity of the responsible neurotoxin has remained elusive. Some evidence exists for the neurotoxicity of parathyroid hormone, as was discussed earlier. Parathyroid hormone prolongs motor conduction velocities in dogs perhaps through accumulation of calcium in peripheral nerves; parathyroidectomy of three dogs with chronic renal failure was associated with reversal of the motor conduction abnormalities and calcium content of nerve despite an additional period of renal failure. Studies in uremic patients of the effect of parathyroid hormone on peripheral nerves, however, have yielded both supporting and conflicting results.
On the basis of the published literature, Bostock and colleagues have emphasized that for a substance to be accepted as a uremic neurotoxin, it must satisfy certain criteria, namely, (1) it must be an identifiable chemical; (2) its concentration in the blood should be increased in patients with uremia; (3) a direct relationship should exist between its blood level and neurologic dysfunction; (4) it should be neurotoxic in animals at appropriate blood levels; (5) its removal from the blood should abolish neurologic dysfunction; and (6) dialysis should remove the substance from the body, but more slowly than it removes urea. If these criteria are accepted, the middle molecule hypothesis cannot be accepted at this time because no identifiable chemical with established neurotoxicity has been demonstrated, with a clear relationship between its blood level and neurologic dysfunction, except for parathyroid hormone, which is not dialyzable. These authors proposed instead that mild hyperkalemia was responsible. It is known that hyperkalemia typically recurs within a few hours of a dialysis session as a result of re-equilibration between intracellular and extracellular fluid compartments. Prolonged hyperkalemia may disrupt normal ionic gradients and activate Ca ++ -mediated processes that are damaging to axons.
Motor and sensory nerve excitability has been studied in relation to changes in serum levels of potential neurotoxins, including calcium and potassium ions, urea, uric acid, and certain middle molecules. Predialysis measures of nerve excitability were abnormal, consistent with axonal depolarization, and correlated strongly with serum potassium levels, suggesting that hyperkalemic depolarization may underlie the development of uremic neuropathy. The severity of symptoms also correlated with excitability abnormalities. Most nerve excitability parameters were normalized by hemodialysis. The findings support the belief that hyperkalemia is primarily responsible for uremic depolarization and probably contributes to the development of neuropathy. There is no evidence of significant Na + /K + pump dysfunction, despite earlier suggestions to the contrary.
If hyperkalemia does indeed have a role in mediating these abnormalities, measures of dialysis adequacy based solely on blood urea or creatinine concentrations may be inadequate for determining whether dialysis will prevent neurotoxicity. Monitoring the serum potassium level and ensuring that it is maintained within normal limits between periods of dialysis may be more relevant in this regard.
Clinical Features
Uremic neuropathy is more common in men than women and in adults than children. It is characterized by a length-dependent, symmetric, mixed sensorimotor polyneuropathy of axonal type that resembles other axonal metabolic-toxic neuropathies. Its clinical manifestations, severity, and rate of progression are variable. As with uremic encephalopathy, its severity correlates poorly with biochemical abnormalities in the blood, but neuropathy is more likely to develop in chronic or severe renal failure.
Initial symptoms commonly consist of dysesthesias distally in the legs; muscle cramps may also be troublesome. The restless legs syndrome often develops before or with the clinical onset of neuropathy, and its occurrence may therefore indicate incipient peripheral nerve involvement. As with many other neuropathies, the earliest clinical signs are of impaired vibration appreciation and depressed or absent tendon reflexes distally in the legs, indicating involvement of large-diameter myelinated fibers. Progression is typically insidious over many months but occasionally is rapid, leading early to severe disability. Thus, a more progressive, predominantly motor subacute neuropathy may occur in uremic patients with diabetes and lead to severe weakness over a few weeks or months; nerve conduction studies typically demonstrate features of an axonal neuropathy but may show demyelination features, and the neuropathy may respond to transplantation or to a switch from conventional to high-flux hemodialysis. The course may be arrested at any time despite continuing or worsening renal failure. It is hard to predict the likely clinical course in individual patients. Most patients are left with distal motor and sensory deficits, but some become severely disabled with a flaccid quadriparesis or paraparesis. Severe neuropathy has become less prevalent with the introduction of dialysis and transplantation techniques but remains common.
Histopathologic examination of nerve biopsy specimens confirms that the neuropathy is a length-dependent axonal degeneration accompanied by secondary demyelination, although in some cases the demyelination seems the predominant finding; damaged endoneural blood capillaries may also be found and support an ischemic theory as one mechanism in the pathogenesis of uremic neuropathy. Nerve conduction studies also support an axonal process, with reduced conduction velocities and response amplitudes; abnormalities are common even in clinically unaffected nerves. The amplitude of the sensory nerve action potential is affected particularly, especially that of the sural nerve. Large fibers are affected more often than small fibers, but in occasional patients a predominantly small-fiber neuropathy occurs. The findings on nerve conduction studies may improve after effective treatment of the underlying renal failure, sometimes very rapidly, but this is not always the case ; sensory nerve conduction velocities in the median, ulnar, and sural nerves may be the most sensitive electrophysiologic indices of the beneficial effect of hemodialysis. Needle electromyography (EMG) may reveal evidence of denervation, particularly in the distal muscles of the legs. Abnormalities of late responses (F waves and H reflexes) are frequent and may be helpful early in the course of renal failure, when standard nerve conduction study results are sometimes normal.
Laaksonen and colleagues examined the clinical severity of uremic neuropathy in 21 patients, using a modified version of the neuropathy symptom score combined with results of electrophysiologic studies. They found that 81 percent of uremic patients were diagnosed with neuropathy: the neuropathy was asymptomatic in 19 percent, associated with nondisabling symptoms in 48 percent, and accompanied by disabling symptoms in 14 percent.
Treatment
Uremic polyneuropathy may stabilize or even show some improvement with dialysis, but mild progression is not uncommon and recovery from severe neuropathy is unlikely. Renal transplantation improves uremic neuropathy, sometimes very rapidly and with a negative correlation between electrophysiologic change and serum creatinine and myo -inositol concentrations, suggesting that metabolic factors may underlie the rapid improvement; in other instances, improvement is more gradual over a number of months, is characterized electrophysiologically by improvement in motor and sensory conduction velocities, and is often incomplete, perhaps because the main reason for improvement is segmental remyelination, with some fibers remaining degenerate in severe neuropathies.
Autonomic Neuropathy
Uremic patients may develop postural hypotension, impaired sweating, impotence, gastrointestinal disturbances, and other dysautonomic symptoms, which progress in some patients—but not all—despite continuing hemodialysis. The dysautonomia correlates with the presence or severity of peripheral neuropathy in many but not all patients and may be corrected by renal transplantation. The mechanism underlying the development of uremic autonomic neuropathy is unknown. In patients with diabetic renal failure, dysautonomia may relate also to the diabetes. Studies of both cardiovagal and sympathetic function (discussed in Chapter 8 ) have revealed objective evidence of dysautonomia that may be subclinical.
Intradialytic hypotension is a frequent complication of hemodialysis and has been shown to relate to impaired autonomic function regardless of whether a peripheral neuropathy is present ; however, there is no agreement on this point, and some investigators have found that hypotension-prone patients are not distinguished by impaired predialytic or intradialytic control of the blood pressure. Midodrine may have a role in the therapy of patients with intradialytic hypotension.
Dialysis may not benefit autonomic neuropathy. However, Vita and colleagues found that when patients were switched from acetate to bicarbonate dialysis, all the patients in a small series eventually showed a reversal of autonomic damage. After renal transplantation, autonomic function may improve or normalize but at a variable rate. Specific treatments, such as sildenafil for impotence, may be helpful.
Restless Legs Syndrome
Development of the restless legs syndrome may indicate incipient peripheral nerve involvement or may occur as an isolated disorder. Patients develop an irresistible urge to move the legs that is worse at night and during periods of inactivity. They complain of curious sensations—often described as creeping, crawling, prickling, or itchy feelings—in the lower limbs, and these tend to be worse in the evening or when the limbs are not in motion. Such sensations are experienced most commonly in the legs but occasionally occur in the thighs or feet; the upper limbs are also sometimes involved. The disorder may occur in nondialyzed patients with chronic renal failure. When it occurs in uremic patients undergoing hemodialysis, it has been related to low hemoglobin levels, high serum phosphorus levels, high anxiety levels, and a great degree of emotion-oriented coping. Treatment of restless legs syndrome is with clonazepam, dopamine agonists, levodopa, certain anticonvulsants, or opioids (propoxyphene or codeine) taken at bedtime. In addition, coexisting anemia and hyperphosphatemia should be corrected. Successful renal transplantation may ameliorate or eliminate symptoms within a few weeks.
Uremic Myopathy
Proximal muscle weakness, atrophy, and muscle fatigue are common in uremic patients, and the progression of the underlying myopathy parallels the decline in renal function. Muscle involvement is more common in patients undergoing chronic hemodialysis. Onset is insidious. The hip girdle is affected more than the shoulder girdle. The primary systemic disease responsible for the renal failure—or its treatment, such as with steroids—may lead to a myopathy. Other causal factors include malnutrition, anemia, accumulation of toxins (including aluminum and iron), endocrine disorders (such as secondary hyperparathyroidism), hypercalcemia, hypophosphatemia, vitamin D deficiency, carnitine deficiency, hyper- and hypokalemia, and physical inactivity. Calciphylaxis in end-stage kidney disease is a rare cause of painful ischemic myopathy; vascular calcification and occlusion of small and medium-sized arteries is responsible. Dialysis-associated systemic fibrosis may cause a myopathy. Myopathy may relate to β 2 -microglobulin–associated amyloidosis.
Treatment is of the underlying cause of the muscle weakness. Hemodialysis patients treated with vitamin D have been found to have greater muscle size and power than those not receiving vitamin supplementation. Renal transplantation is sometimes indicated.
Stroke
Chronic kidney disease is a significant risk factor for stroke and occult cerebrovascular disease. A mildly diminished estimated glomerular filtration rate increases the risk of ischemic stroke, and a severely decreased glomerular filtration rate increases that of hemorrhagic stroke compared to the general population. The control of chronic hypertension is particularly important in reducing stroke risk in patients with chronic kidney disease. In patients with previous atherosclerotic strokes, antiplatelet agents help to reduce secondary stroke risk. Those with atrial fibrillation may benefit from anticoagulation. Statins have a lipid-lowering effect but are probably not useful for stroke-risk reduction in patients on dialysis as they have little or no effect on all-cause mortality or on cardiovascular mortality or events in these circumstances ; they have uncertain effects in kidney transplant recipients. Optimizing diabetic control, cessation of smoking, dietary salt restriction, weight reduction, and correction of coexisting anemia may be important in reducing cardiovascular and stroke risk in individual cases, and carotid endarterectomy is worthwhile in selected patients. The risk of stroke is also high in patients receiving chronic hemodialysis, as is discussed in a later section.
The effect of chronic kidney disease on clinical outcomes after acute ischemic stroke has been studied and found to be an important predictor of poor clinical outcomes. Thus, after adjusting for demographic factors, stroke risk factors, and stroke severity on admission, the estimated glomerular filtration rate was found to be an independent predictor of stroke mortality at 10 years. Proteinuria independently contributes to the increased risks of neurologic deterioration, mortality, and poor functional outcome after acute stroke.
Optic Neuropathy
A progressive unilateral or bilateral optic neuropathy may occur over several days, sometimes as the initial manifestation of end-stage kidney disease ; visual loss is accompanied by reduced pupillary response to light and by papillitis. Prompt hemodialysis and corticosteroid therapy may restore vision in some patients. The optic neuropathy may be neurotoxic, ischemic, related to side effects of medication or intracranial hypertension, or inflammatory in nature.
In ischemic optic neuropathy occurring in patients on hemodialysis, coexisting hypotension and anemia are important risk factors, and treatment may require intravenous saline or blood transfusions in addition to the other measures mentioned earlier. Calcific uremic arteriolopathy may also have an etiologic role. Several cases of nonarteritic ischemic optic neuropathy related to hemodialysis have been reported. The optic neuropathy is produced by compromise of oxygen delivery to the optic nerve, resulting in hypoxic swelling, nerve compression in the optic canal, and ischemia of the optic nerve head. Presentation is with sudden, unilateral, painless inferior visual field defect and a fixed unreactive pupil after relative hypotension. This complication must be considered when examining dialysis options, particularly in patients with other risk factors such as hypotension, anemia, and a past history of anterior ischemic optic neuropathy.
Neurologic Complications of Nephrotic Syndrome
The nephrotic syndrome, which results from glomerular damage, is characterized by excessive proteinuria in the absence of hematuria, and is accompanied by edema, hypoalbuminemia, and hyperlipidemia . There is an increased risk of arterial or venous thromboembolism, and this may involve the cerebral circulation. The causes of the responsible hypercoagulable state are not entirely clear, but alterations occur in various blood coagulation factors, platelet reactivity, and blood viscosity, and in the fibrinolytic system. Cerebral venous thrombosis—particularly involving the major intracranial venous sinuses—is a well-known complication in patients of any age, signaled by the development of headache, seizures, or clinical features of increased intracranial pressure. Arterial thrombosis is less common but may involve a variety of peripheral arteries, including the carotid artery, sometimes as the initial manifestation of the nephrotic syndrome. Presentation is with transient cerebral ischemic attacks or ischemic stroke. By analogy to patients without nephrotic syndrome, treatment of arterial or venous disease involves anticoagulation, typically with heparin followed by oral anticoagulation.
Posterior reversible encephalopathy syndrome (PRES) has also been associated with the nephrotic syndrome or its treatment with immunosuppressive drugs in children or adults. The disorder is characterized by impaired consciousness, seizures, headache, and transient visual disturbances in the setting of hypertension, and is associated with cortical and subcortical edema manifest by high signal intensity on T2 weighted MRI, especially posteriorly. Fluid-attenuated inversion recovery (FLAIR) imaging improves diagnostic confidence and the conspicuousness of the T2 hyperintensities. The prognosis is usually benign, with symptoms settling after several days of adequate treatment. Treatment involves the control of associated hypertension, the management of seizures, and the withdrawal of any medication that is likely to have been responsible for the disorder.
Certain neuromuscular disorders may relate to the nephrotic syndrome. There have been several case reports of the simultaneous development of nephrotic syndrome and Guillain–Barré syndrome. In one such case, plasmapheresis and corticosteroids led to simultaneous recovery of both disorders, suggesting a common pathogenesis of the two conditions. Myasthenia gravis may coexist with nephrotic syndrome, and its temporary improvement may result from antibody elimination during proteinuria in nephrotic syndrome.
Neurologic Complications of Dialysis
Dialysis has been associated with subtle cognitive alterations , possibly reflecting an early manifestation of dialysis dementia at a reversible stage. More commonly, psychologic studies have shown significant improvement in short-term memory both after onset of maintenance dialysis and when comparisons are made between the day before and after an individual dialysis treatment session; attentional functions also seem to improve after dialysis. Subdural hematoma ( Fig. 16-3 ) may occur in patients on maintenance hemodialysis; it has a 20-times higher incidence than in the general population and is associated with high mortality. The symptoms of the subdural hematoma may be attributed erroneously to dysequilibrium syndrome or dialysis dementia. Its occurrence may relate to anticoagulation used to maintain the patency of the conduit for hemodialysis ; platelet function may be impaired in uremia but, in itself, is unlikely to be responsible. A rare case of manganese-induced parkinsonism has been described in a patient on maintenance hemodialysis and was attributed to long-term ingestion of a health supplement; the clinical, laboratory, and magnetic resonance imaging (MRI) findings were abnormal, but the patient improved on edetic acid infusion therapy. The occurrence of hemodialysis-related optic neuropathy was mentioned in an earlier section. These complications will receive no further discussion here.
Muscle cramps are common, tending to occur toward the end of a dialysis session: their etiology is uncertain, but plasma volume contraction and hyponatremia are among the factors that have been incriminated. Headache, nausea, and vomiting may also occur during dialysis, sometimes as the initial manifestations of the dysequilibrium syndrome (discussed later).
The risk of cerebrovascular disease is increased in patients undergoing dialysis and seems related to accelerated cerebrovascular disease and the high incidence of malnutrition, hypertension, diabetes, and hyperlipidemia among these patients. In one study, the high incidence of stroke resulted, at least in part, from inadequately treated hypertension. Presentation may be with hypertensive encephalopathy, transient ischemic attacks, or occlusive or hemorrhagic stroke. Infarcts may show a predilection for the vertebrobasilar arterial territory. Although stroke symptoms are common and are associated with cognitive and functional impairments, clinically significant stroke events are often unrecognized.
The osmotic demyelination syndrome may occur after hemodialysis, leading clinically to convulsions, an alteration in the level of consciousness, and quadriparesis with hyperactive tendon reflexes and bilateral Babinski responses. MRI shows findings of demyelination in pontine and often extrapontine regions. The effects of dialysis on uremic encephalopathy and neuropathy have already been discussed, but dialysis may cause other neurologic disturbances that merit comment.
Sleep disturbances have a high prevalence in patients with end-stage kidney disease undergoing chronic hemodialysis. They include insomnia, obstructive sleep apnea, excessive daytime sleepiness, restless legs syndrome, and various parasomnias.
Entrapment Mononeuropathies
Carpal Tunnel Syndrome
It was originally believed that carpal tunnel syndrome occurred because of increased venous pressure in the distal limb when an arteriovenous shunt had been placed for hemodialysis, the increased extravascular volume within the carpal tunnel or steal being held responsible for the median nerve compression. Recent studies support an etiologic role for arteriovenous fistulas. Thus, in one study, carpal tunnel syndrome was diagnosed significantly less frequently in the contralateral wrist than that ipsilateral to the arteriovenous fistula, and a positive correlation was found between the duration of the fistula and development of carpal tunnel syndrome; in contrast to such clinical assessment, however, electrodiagnostic studies indicate no significant association between the frequency of carpal tunnel syndrome and arteriovenous fistula or its duration.
The occurrence of β 2 -microglobulin amyloidosis is probably more important etiologically in this context, particularly in patients on long-term hemodialysis. Amyloid fibrils have been isolated from amyloid-laden tissues inside the carpal tunnel and the protein identified as β 2 -microglobulin. Circulating β 2 -microglobulin presumably cannot be removed by conventional hemodialysis and accumulates in tissues; the consequent formation of amyloid fibrils appears to have a relatively high affinity for the region of the carpal tunnel, leading to carpal tunnel syndrome. A significant increase in carpal tunnel width and thickness in the palmoradiocarpal ligament, correlating with duration of long-term hemodialysis, has been reported based on ultrasound examination of the wrists of hemodialysis patients. The prevalence of carpal tunnel syndrome and the severity of symptoms have been improved by maneuvers to reduce the levels of β 2 -microglobulin. Uremic tumoral calcinosis may also be responsible in some instances.
Treatment is as in other patients, with decompressive surgery if symptoms fail to respond to conservative measures.
Ulnar Nerve Lesions
A high prevalence (between 41 and 60%) of ulnar neuropathy has recently been reported in patients receiving hemodialysis for end-stage renal disease. This may relate to arm positioning during hemodialysis, underlying polyneuropathy, upper-extremity vascular access, and uremic tumoral calcinosis.
Ischemic Neuropathy
A shunt for access during chronic hemodialysis and inserted between the radial artery and cephalic vein in the upper arm was reported by Bolton and colleagues to have caused an acute distal, ischemic neuropathy in two patients; electrophysiologic evidence was present of axonal degeneration of sensory fibers with mild ischemia, and of both motor and sensory nerve fibers with more severe ischemia. This has been attributed to shunting of arterial blood away from the limb distally, with the nerves being selectively affected because of their greater vulnerability to ischemia. Other cases of this so-called ischemic monomelic neuropathy have since been reported, and the disorder is particularly likely in diabetics with renal failure and preexisting peripheral vascular disease or neuropathy, although it may also occur in nondiabetic patients. Multiple upper-limb mononeuropathies develop, leading to burning pain and to sensory and motor deficits in the forearm and hand. Motor conduction block may be detected electrophysiologically shortly after the onset of symptoms, preferentially involving the median nerve, with clinical and electrophysiologic improvement following ligation or revision of the shunt. In some instances, onset is more insidious; more widespread signs of upper-extremity ischemia due to arterial steal are found distal to the fistula, such as established or impending tissue loss or nonhealing wounds.
In addition to arterial steal and venous hypertension syndromes, other complications of arteriovenous access for hemodialysis include high-output cardiac failure, pseudoaneurysm formation, hemorrhage, noninfectious fluid collections, and access-related infections.
Dialysis Dysequilibrium Syndrome
Several neurologic disturbances may arise during or after hemodialysis, including headache, nausea, anorexia, muscle cramps, irritability, restlessness, agitation, confusion, coma, and seizures; increased intracranial pressure may lead to papilledema. Such symptoms tend to occur at the beginning of a dialysis program and were particularly conspicuous in the past when patients with advanced uremia were dialyzed aggressively. Patients now enter dialysis programs at an earlier stage of renal failure and have shortened dialysis times, and this may account for the reduced incidence of the disorder, which seems more common in children and the elderly than in other age groups. Marked metabolic acidosis and the presence of other CNS disease may also be predisposing factors.
Symptoms typically appear toward the end of a dialysis session, sometimes 8 to 24 hours later, and subside over several hours. When an agitated confusional state develops, it may persist for several days. Many patients manifest exophthalmos and increased intraocular pressure at the height of the syndrome, which may be helpful clinically for diagnostic purposes. Headache is the most common symptom reported by patients undergoing dialysis, and migrainous episodes may be precipitated during or after hemodialysis in patients with preexisting migraine. Headache is otherwise usually diffuse and throbbing in quality. Subdural hematoma sometimes mimics the dysequilibrium syndrome and requires exclusion.
Movement of water into the brain leads to cerebral edema. According to the hypothesis known as the reverse urea effect , a rapid reduction in blood urea level lowers the plasma osmolality, thereby producing an osmotic gradient between blood and brain. Although urea is able to permeate cell membranes, this may take several hours to reach completion; accordingly, there is not enough time for urea equilibration when the blood urea level is reduced rapidly by hemodialysis. There is thus an influx of water into the cells. This results in increased intracranial pressure and cerebral edema. Alternatively or additionally, the osmotic gradient between brain and blood may not reflect simply the movement of urea; unidentified osmotically active substances (“idiogenic osmoles”) are present in the brain of dialyzed uremic animals (but not dialyzed nonuremic animals) and may be responsible. It has been suggested that a decrease in cerebral intracellular pH, reflecting an increased production of organic acids that are osmotically active, is important in this regard.
A number of other disorders, such as uremic encephalopathy, intracranial infection or hemorrhage, cerebral infarction, hyponatremia, hypoglycemia, and medication-related encephalopathy must be excluded before the diagnosis is made with confidence. Prophylactic measures involve the gradual reduction in blood urea level by attention to the hemodialysis technique. In patients with established dialysis dysequilibrium syndrome, mild symptoms usually clear spontaneously over several hours, and symptomatic and supportive measures are all that are required; however, it may be necessary to slow or discontinue the dialysis session. Dialysis is stopped in patients with seizures or an altered level of consciousness and, if necessary, the plasma osmolality can be raised with either hypertonic saline or mannitol. Management is otherwise supportive, and improvement can be expected over the following day.
Wernicke Encephalopathy
Thiamine is a water-soluble vitamin that passes through dialysis membranes. However, dialysis does not remove more thiamine than is normally excreted in the urine, and no consistent change occurs after hemodialysis in plasma levels of the B vitamins. Wernicke encephalopathy has occurred in patients on chronic dialysis, but is relatively infrequent. It has been related to anorexia, vomiting, a diet low in thiamine-containing foods, and intravenous alimentation without thiamine supplementation; other potential causes in uremia are infections that may stress thiamine reserves and the use of repeated infusions of glucose, insulin, and bicarbonate to lower the serum potassium level.
Among patients undergoing dialysis in whom Wernicke encephalopathy develops in the absence of alcoholism or other precipitating factors and is diagnosed at autopsy, ophthalmoplegia may be evident in only occasional instances, but in other cases the full triad of ophthalmoplegia, ataxia, and an altered level of consciousness are encountered. Hypothermia is common. Intravenous administration of thiamine reverses the clinical deficit. Given the reversible nature of the disorder, it is important to consider it in all patients on hemodialysis who exhibit at least one of its classic features; dialysis dysequilibrium syndrome, dialysis dementia, and uremic encephalopathy have each been diagnosed erroneously in patients who were subsequently found to have Wernicke encephalopathy. Indeed, in one series of 30 consecutive patients on regular hemodialysis or peritoneal dialysis who were admitted with an alteration in mental status, 10 had an unexplained encephalopathy after initial evaluation and were eventually found to have thiamine deficiency; nine responded to thiamine supplementation and one died.
Dialysis Dementia
Clinical Aspects
There has been a decline in the incidence of this progressive encephalopathy, which may occur in patients undergoing long-term dialysis. The first symptom is often a stammering hesitancy of speech that eventually progresses to speech arrest, dysarthria, and expressive aphasia. The speech disorder is intensified during and immediately after dialysis and initially may occur only at these times. Other manifestations such as tremor, myoclonus, asterixis, seizures, and dementia become apparent as the disorder advances, and hallucinations and delusional thinking round out the clinical picture. Focal neurologic abnormalities are found occasionally. Symptoms initially occur immediately after dialysis and then clear, but eventually they fail to resolve and the patient becomes increasingly demented. The EEG shows abnormal bursts of high-voltage slow activity and spikes anteriorly. The CSF is normal. The differential diagnosis includes other causes of dementia, but metabolic encephalopathy and structural lesions such as subdural hematoma, normal-pressure hydrocephalus, hypertensive encephalopathy, multi-infarct dementia, and stroke require exclusion.
Pathogenesis
A clustering of cases in areas with aluminum-contaminated water was noted originally, and water-purification measures have led to a substantial reduction in the incidence of the disorder. The disorder results from accumulation of aluminum in the brain and is now rarely encountered because of elimination of aluminum in the dialysate. Phosphate retention occurs in renal failure, leading eventually to hyperparathyroidism, and reduction of the serum phosphate concentration with phosphate binders is therefore important. The substitution of phosphate binders such as calcium carbonate and calcium acetate, and of nonmineral-containing phosphate binders, for oral aluminum-containing phosphate binders has also been important in reducing the aluminum content in the brain. Although parathyroid hormone increases aluminum absorption from the gut, parathyroidectomy has not affected the course of dialysis dementia. The toxicity of aluminum may involve disruption of the inositol phosphate system and calcium regulation, facilitation of oxidative injury, and disruption of basic cell processes. Postmortem immunochemical analysis of frontal cortex of 15 dialysis patients treated with aluminum showed changes in tau protein processing in the brain resembling those seen in Alzheimer disease, although none had signs of dialysis dementia.
Treatment
Diazepam is initially helpful in treating the myoclonus and seizures and in improving speech, but it is less effective later. Increased dialysis time and renal transplantation have not altered the natural history. In untreated patients, death usually occurs within a year of the onset of symptoms. The chelator deferoxamine can remove excess aluminum and thereby reverse acute encephalopathy, as well as the osteomalacia and anemia that may also be associated with aluminum overload. However, its introduction was associated with visual and auditory toxicity and with increased neurologic and other side effects from acute aluminum toxicity (presumably because of the rapid mobilization of stored aluminum) in occasional patients; some patients developed a rapidly progressive and fatal systemic or rhinocerebral mucormycosis. Experimental studies in animals suggest that deferoxamine enhances the pathogenicity of the responsible organism and reduces the effectiveness of treatment with amphotericin. Nevertheless it is the mainstay of treatment for established dialysis dementia.
Several protocols for the administration of deferoxamine have been proposed, and the National Kidney Foundation has published guidelines. A baseline serum aluminum level is determined: normal levels are 6±3 µg/L, but excess aluminum deposition is unlikely when values are less than 20 µg/L. If baseline levels are increased, a low-dose deferoxamine test is performed by administering 5 mg/kg 1 hour before the end of dialysis if aluminum overload (serum aluminum levels of 60 to 200 µg/L) is present or toxicity is suspected clinically. Deferoxamine can be given to symptomatic patients in a single dose of 1 to 6 g (30 to 40 mg/kg) once weekly in the last hour of a dialysis session; however, to avoid the risk of deferoxamine neurotoxicity, it is not given to patients with serum aluminum levels exceeding 120 µg/L until the level is first lowered by withdrawal of aluminum exposure. When serum levels exceed 200 µg/L, daily hemodialysis using high-flux membranes and a low dialysate aluminum concentration, and withdrawal of all aluminum-containing oral agents, is necessary; a low-dose deferoxamine test (5 mg/kg) is given after 4 to 6 weeks of such treatment (if serum levels are<200 µg/L) to determine the timing of further treatment. Further details are given elsewhere. The length of treatment required is uncertain, but it may need to be for many months. Many cases of dialysis dementia have been stabilized or improved by deferoxamine. The need for treatment is unclear in patients with an asymptomatic increase in aluminum levels.
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