The kidney is one of the principle homeostatic organs of the body and is involved in the regulation of water, electrolyte, and acid-base balance; the excretion of metabolic waste products; and the synthesis of erythropoietin, renin, and 1,25-DHCC. This section focuses on the neurological manifestations of RF, both acute (ARF) and chronic (CRF), and the neurological complications of its treatment.
Pathogenesis and Pathophysiology. UE regularly occurs when the glomerular filtration rate falls below 10 percent of normal, regardless of whether it occurs with
ARF or CRF. The fact that dialysis can rapidly clear UE suggests that the responsible molecules causing UE are water soluble and small to moderate in size. However,
because renal insufficiency causes a spectrum of biochemical abnormalities, the individual significance of any single abnormality is indeterminable.
Although water, osmolality, acid-base, and electrolyte abnormalities are commonly observed in patients with RF, they do not appear to contribute substantially to the development of UE. The brain water content in uremic patients is normal,  y^] y] and an absence of brain edema in animals with acute uremiaW further argues against water toxicity as the cause of UE. Although the increase in brain osmolality (from 310 to 350 mOsmol/kg water) noted in ARF patients is due to urea, this compound is nontoxic, even at high concentrations.^ Among CRF patients, urea constitutes only half of the osmotically active particles, with the unidentified remainder referred to as idiogenic osmoles. y] The lack of a significant gradient between the blood, CSF, and brain urea concentrations y^ also argues against osmolality variability as the primary cause of UE.
The accumulation of toxic organic acids in the CNS has been proposed as a possible mechanism of UE. y However, studies of CSF acidity in uremic patients^ and of acid-base balance in the CSF, blood, brain, and skeletal muscle of uremic dogs y^ have been normal. Although the permeability of the BBB is increased toward insulin and sucrose, its permeability toward weak acids is decreased. y
Cooper and associates^ studied the brains of 10 patients who had died of uremia and noted the brain content to be normal for K, Cl, and Mg; slightly decreased for Na; and approximately doubled for Ca. In experimental uremia, increased brain Ca levels have been associated with an increase in the PTH level. y] In addition, the increase coincided with the onset of EEG abnormalities, with both appearing about 2 days after onset of the RF. In a study of 20 dialysis patients with EEG slowing, a direct correlation was noted between the plasma concentration of the N-terminal fragment of PTH and the degree of EEG slowing. y] , yj Administration of PTH to normal dogs produces EEG changes similar to those seen in uremic animals. The EEG abnormalities, as well as the increased brain Ca, can be prevented by performing a parathyroidectomy before the induction of RF. y PTH accumulation probably affects the Ca pump,^ suggesting that this hormone is a uremic toxin.y] Although more recent studies have corroborated the relationship between PTH and brain Ca content abnormalities, y] the fact that this hormone is not dialyzable argues against it as the uremic toxin responsible for UE. Ca content may be affected by other system abnormalities.
Uremic neuropathy (UN) is the most common neurological manifestation observed among CRF patients. It is pathologically characterized by axon loss. Its pathogenesis is unknown but, like UE, improvement occurs following dialysis, suggesting that the responsible substances are dialyzable. Because some patients experience neuropathic improvement only when their dialysis time is increased, it is postulated that the responsible substances are larger than urea (because larger molecules require more time to cross dialysis membranes). Hypotheses concerning the role of PTH and Ca metabolism in UN have been advanced and are supported by the following features: (1) PTH increases the Ca content of nerve; (2) increased nerve Ca content slows its conduction velocity; (3) the observed slowing is prevented by performing parathyroidectomy before the administration of PTH; and (4) the PTH level is inversely related to the nerve conduction velocity in uremic patients. Like UE, the strongest argument against PTH as the mediator of UN is its nondialyzability. Also, hyperparathyroidism is not typically associated with a neuropathy.
Epidemiology and Risk Factors. In the United States, although the frequency of ARF is low (roughly 30 patients/ million/year), y] the prevalence of end-stage renal disease increased from 45,000 in 1977 to greater than 165,000 in 1990. yj In the United States, hypertension and diabetes are the leading causes of CRF. y] The most important risk factors for the development of UN are the duration and severity of the RF. y^ In recent years, the appearance of neuropathy in chronic hemodialysis patients has become rare,y] which is the result of earlier treatment, more intensive dialysis, and technical improvements in dialysis membranes (thinner, with greater clearance properties). y^
Clinical Features and Associated Disorders. The clinical features of UE are similar to those of other metabolic encephalopathies. The typical progression of clinical features begins with inattentiveness, impaired concentration, fatigue, apathy, and irritability, which is usually accompanied by motor manifestations (e.g., tremor, asterixis, and myoclonus). Tetany, seizures (focal and generalized), focal neurological signs, and meningeal features are also common. yj , y^ One or more of these features may predominate, and symptom fluctuation is typical. Without treatment, coma develops and Kussmaul breathing may be followed by Cheyne-Stokes breathing. Simultaneous evidence of CNS depression (lethargy, obtundation, coma) and excitation (agitation, myoclonus, seizures) are important features of UE.  In CRF patients, personality changes and features of polyneuropathy may be the earliest features, because the encephalopathic manifestations may not appear until the process is advanced.^ , y^
Asterixis, first described by Adams and Foleyy^ in patients with PSE and later noted by Tyler in uremic patients, y^] is a nonspecific feature of metabolic encephalopathies typically present once higher cortical function is affected.  , y] In patients incapable of voluntarily maintaining a posture (e.g., comatose patients), the examiner can position the ankles of a supine patient near the buttocks and observe for abduction-adduction movements at the hip joints. y^ Myoclonus is often multifocal and is more common in the deeper stages of encephalopathy.^ ,  Uremic twitching (severe asterixis with myoclonus) can be continuous and evident during both wakefulness and sleep,y and may simulate a multifocal seizure disorder,^ chorea, or ballismus. Other motor system abnormalities include muscle cramping and tetany, which may be overt or latent.y] , y]
Seizures, which are relatively uncommon in other metabolic encephalopathies, y>] occur in approximately 25 percent of patients with UE. The seizures are usually generalized,^ although focal motor seizures may also be seen.yj , y^ Seizures occur earlier and more frequently (40 percent) among ARF patients than among CRF patients (10 percent).^ In addition, seizures may occur due to dialysis disequilibrium syndrome (see later), hypertensive encephalopathy, water intoxication, or other metabolic encephalopathies.
Unlike the flaccidity characterizing some metabolic encephalopathies,
limb tone is usually increased in UE and may even be asymmetrical. y] , y] As the disorder progresses, opisthotonic or decorticate posturing may be observed. yj Cranial nerve reflexes (e.g., corneal, oculocephalic, and pupillary) are normal, unless the patient is deeply comatose. y^ Sensory examination abnormalities in a stocking-glove distribution and hyporeflexia suggest the presence of UN. Wernicke's encephalopathy has been reported in hemodialysis patients, which is a reflection of the water-soluble, and hence dialyzable, nature of thiamine.
UN is a symmetrical, sensorimotor, axon loss, dying-back (i.e., it has a distal-proximal gradient) polyneuropathy that is clinically indistinguishable from other polyneuropathies that have a stocking-glove distribution. Although lower extremity vibratory sensation impairment y^ and loss of deep tendon reflexes have been reported as early features, suggesting early large-fiber involvement, a wide spectrum of clinical patterns has been observed. The sensory aspects of UN were recently studied, and paradoxical heat sensation (i.e., the perception of heat in response to low temperature stimulation), was identified in 15 of 36 (42 percent) patients,  more than four-fold greater than the normal population. y] Although burning dysesthesias have been frequently cited as a characteristic feature of UN, Asbury has reported them to be rare, a likely reflection of routine supplementation with thiamine and other water-soluble vitamins. Autonomic symptoms, such as orthostasis, impotence, diarrhea, and hyperhidrosis, are commonly reported. y^ An acute, flaccid quadriplegia has also been reported. yj The restless legs syndrome (see Chapter 54 ) occurs in over 40 percent of uremic patients^ y]  and may be a harbinger of polyneuropathy. Although distal lower extremity cramping has also been suggested to herald polyneuropathy, cramps occur in patients without neuropathic features and are more frequent among patients with ARF. y^ Other features reported in uremic patients include myopathy, y , y^] optic neuropathy, isolated mononeuropathies, flaccid quadriparesis (due to hyperkalemia), and vestibulocochlear and neuromuscular junction disturbances (due to aminoglycoside antibiotics). CTS is another manifestation of uremia that may result from the deposition of amyloid fibrils. The amyloid fibrils are composed of beta-2 microglobulin, a substance that is poorly dialyzed and builds up over time in chronically hemodialyzed patients. The shoulder joints and carpal bones are frequently involved and abnormalities may be seen on plain films of these areas.
Differential Diagnosis and Evaluation. When patients with known RF present with encephalopathic features, concomitant medical problems, such as DKA, hypertensive encephalopathy, hypertensive intracranial hemorrhage, intracranial abscess, infectious meningitis, primary CNS lymphoma, and hepatic or pulmonary insufficiency, should be sought. Current medications should be reviewed for drugs that are metabolized or excreted by the kidney, especially those known to have neurological manifestations. For patients receiving dialysis treatments, determine (1) the temporal relationship between the last dialysis session and the onset of encephalopathic features, (2) the current dialysis regimen, (3) occurrence of neurological symptoms with previous dialysis sessions, and (4) the length of time the patient has been undergoing maintenance dialysis. Initial laboratory studies should include CBC with differential, prothrombin time (PT), partial thromboplastin time
(PTT), electrolytes, BUN and Cr, glucose, liver function tests, Ca, Mg, P, and urinalysis. Finally, if infection is suspected and a source is not immediately apparent, lumbar puncture for CSF analysis should be performed.
Patients with RF who have focal neurological findings or seizures require additional evaluation with head CT or MRI to evaluate for SDH, intracerebral hemorrhage, infarction, abscess, neoplasm, or other focal processes. An EEG is also helpful and typically shows diffuse slowing (indicative of an encephalopathy), may show triphasic waves (consistent with a metabolic process), and sometimes shows paroxysmal activity that includes spikes or sharp waves. y Electrodiagnostic testing helps characterize an identified polyneuropathy and may be used to monitor the course of disease after dialysis has been initiated. Secondary hyperparathyroidism should be considered in those patients noted to have proximal extremity muscle weakness and the appropriate laboratories ordered. y]
Management. Because drugs requiring renal metabolism or excretion can accumulate to toxic levels in patients with RF, medication selection is important for the prevention of neurological side effects. In this population, aminoglycoside antibiotics are commonly used but may cause cochlear, vestibular, or neuromuscular junction disturbances. The use of B vitamin supplementation in those patients undergoing maintenance dialysis can help prevent UN.
UE requires definitive treatment and is directed toward correcting its cause (e.g., urinary tract obstruction), when possible. Otherwise, dialysis is required to manage fluid, electrolyte, and acid-base imbalances commonly seen in this setting. A nutritionist, to recommend dietary guidelines (e.g., salt, protein), can be very helpful. Because tremulousness, asterixis, and myoclonus tend to resolve as the UE improves, they usually do not require specific treatment. When they are severe, asterixis and myoclonus may respond to clonazepam or valproic acid.
The management of seizures in this patient population warrants separate discussion because changes in plasma protein binding and AED metabolism complicate its management. For highly protein-bound AEDs, such as phenytoin, decreased plasma protein binding increases the percentage of unbound (free, active) drug. Normally, phenytoin is about 90 percent protein bound and 10 percent unbound, yet in uremic patients, the percentage of unbound phenytoin may approach 25 to 75 percent.'ria] ,  Because the rate of AED diffusion into the brain is proportional to the unbound fraction, '185] the CNS concentration increases'^1 and adjustments may be required. Because the therapeutic range of total phenytoin is 10 to 20 pg/ml and nonuremic patients have 10 percent in the unbound state, the therapeutic range of free phenytoin is 1 to 2 pg/ml. Therefore, when uremic patients require phenytoin, the required dosage is best determined by following the free phenytoin level. Because phenytoin is not dialyzable, supratherapeutic levels should be used only when necessary for seizure control. A potential for cross-reactivity between phenytoin and its metabolites exists whenever immunological methods are used to determine free phenytoin levels and can result in falsely elevated levels. 'w1 For any given
phenytoin dose, the drug level is lower in patients with RF, Wi a reflection of the increased volume of distribution yj and rate of metabolism.yj , y] The rate of metabolism reduces the half-life of phenytoin to 8.1 hours in uremics. yi The increased proportion of free phenytoin balances the greater volume of distribution and shorter half-life; thus, the same loading and maintenance doses used in nonuremic patients are used in this clinical situation. However, because the half-life is decreased, a dosage regimen of three times a day is favored over a twice-daily regimen.
Although phenobarbital is renally excreted, it is a useful AED for the treatment of epilepsy in this patient population, provided that sedation can be avoided. Because phenobarbital is only 40 to 60 percent protein bound, its level can be decreased by dialysis. When phenobarbital is used, a postdialysis serum phenobarbital level should be obtained and a supplemental dosage provided. Valproic acid is useful for myoclonus and generalized seizures. Seizures occurring during or up to 8 hours after a dialysis run can be a manifestation of the dialysis disequilibrium syndrome. In these patients, prophylactic AEDs are recommended until uremia is controlled. y] Also, decreasing the blood flow rate and duration of dialysis, increasing dialysis frequency, and the administration of hypertonic mannitol during dialysis can help with seizure control.
Treatment of the RF improves the UN, and patients with mild UN typically recover completely with maintenance dialysis. Conversely, patients with severe UN rarely recover, even after several years of treatment, and the slowed nerve conduction velocities are only mildly improved by dialysis. y] Renal transplantation is much more effective at relieving neuropathic symptoms than is maintenance dialysis. W , yj NCS show improvement within days of transplantation W and the improvement continues with complete recovery at times. , y] Neuropathic pain associated with RF can be treated as well with tricyclic antidepressants or Carbamazepine (see Chapte.L2.0. ). Uremic optic neuropathy causes rapidly progressive visual loss that responds to hemodialysis and corticosteroid treatment. U
Complications associated with dialysis include dialysis disequilibrium syndrome (DDS), dialysis dementia, SDH, dialysis headaches, exacerbation of migraine headaches, muscle cramping, neurological vitamin deficiency syndromes, ischemic neuropathy due to the presence of an arteriovenous fistula, and CTS.
DDS refers to a transient form of encephalopathy related to dialysis. Although its pathogenesis is unknown, it most likely results from a shift of water into the brain (i.e., cerebral edema) in response to the rapid reduction of serum osmolality occurring with dialysis. The duration of symptoms reflects the time required for the brain to decrease its own osmolality. In the predialysis state, idiogenic osmoles allowed the brain to protect itself against dehydration (i.e., it countered the increased serum osmolality). Conversely, in the postdialysis state, this previously protective feature becomes detrimental. Arieff and colleagues W compared different rates of hemodialysis in uremic dogs and showed that the amount of cerebral edema was greater in the more rapidly hemodialyzed group. This hypothesis is further supported by the appearance of DDS during the early phases of a hemodialysis program rather than after routine maintenance dialysis has begun. This likely reflects the greater net difference between the predialysis and postdialysis serum concentrations of dialyzable molecules occurring with the earlier dialysis treatments. The onset of DDS is usually around the third or fourth hour of a dialysis run (sometimes up to 24 hours after) and typically lasts several hours. Although DDS is seen in all age groups, it is more common at the extremes of age. Delirium, although infrequently precipitated, often lasts several days. W Symptoms of DDS are usually self-limited and include headache, anorexia, nausea, emesis, hypertension, disorientation, tremors, twitching, blurred vision, fatigue, muscle cramps, restlessness, and dizziness. y] More serious neurological sequelae, such as seizures, coma, and death, were not uncommon before 1970, when aggressive dialysis was used. Uncommon features, including exophthalmos, increased intraocular pressure, W papilledema,^! and increased ICP, have been reported.[l581 If muscle cramping occurs, it may respond to quinine sulfate, 320 mg PO, at the beginning of each dialysis.
The differential diagnosis of DDS includes malignant hypertension, Wernicke's encephalopathy, UE, dialysis dementia, SDH, hyponatremia, hypercalcemia, hypoglycemia, NkHh, hypoxic-ischemic processes, copper and nickel intoxication, and excessive ultrafiltration. y] DDS may respond to an extension of the dialysis period from 4 to 6 hours, or switching to peritoneal dialysis.
Dialysis dementia, also called dialysis encephalopathy, is a rare, subacutely progressive, irreversible, and fatal encephalopathy that was initially described in 1972 in chronic hemodialysis patients.^ The disorder usually begins with memory problems and dysarthric, stuttering, hesitant speech, progressing to mutism, asterixis, myoclonus, dementia, coma, and death.y The speech disorder is initially intermittent, appearing during and just after dialysis, but eventually becomes permanent. y ,  Other features include personality and behavioral changes, and occasionally apraxia of speech. y Delusions, hallucinations, gait disturbances, [ad and focal neurological abnormalitiesy] may also be seen. Seizures are common and usually multifocal.
It is now strongly suspected that dialysis dementia is caused by high brain aluminum content. In 1976, Alfrey and co-workers y] reported that the brain aluminum content was greater in patients with dialysis dementia than it was in normal controls. Although oral P-binding drugs were initially considered to be the source of exogenous aluminum, this did not explain the geographical variation in the incidence of the disorder. Researchers discovered a difference in dialysate aluminum content among various dialysis centers,y.] and epidemiological studies linked dialysis dementia to municipal water supplies with high aluminum levels. Unexplained sporadic cases in centers with low aluminum dialysate content, however, have been reported. y] The high blood aluminum levels in these sporadic cases suggest that the GI absorption of aluminum (oral P-binding drugs) may occasionally cause this syndrome.
In evaluating these patients, it is important to remember
that dialysis dementia is rare and should always be a diagnosis of exclusion. The differential diagnosis includes DDS, hypertensive encephalopathy, structural lesions (e.g., SDH, stroke), and metabolic encephalopathies such as drug intoxications. Trace element intoxications, decreased glucose, electrolyte disorders (increased Ca, decreased Na or phosphorus), hyperosmolal states, hyperparathyroidism, and UE should also be considered. W Changes in dialysis schedule, a change in baseline metabolic status, infection (e.g., dialysis shunt, brain abscess, hepatitis), and treatable encephalopathies (B 12 , folate, TFTs) can present similarily. W Routine laboratory studies, urinalysis, chest x-ray study, and neuroimaging, when focal neurological abnormalities are identified, are also required. If an infectious cause is suspected, CSF examination may be required. The EEG is invariably abnormal, showing characteristic bursts of frontal slowing and epileptiform spikes.
Dialysis dementia does not respond to an increase in weekly dialysis time or renal transplantation. Because deferoxamine crosses the BBB, binds aluminum with greater affinity than do plasma proteins, and results in a dialyzable complex, it can be used to treat this disorder. '203' The CSF aluminum content increases with deferoxamine treatment, a finding that correlates with deterioration, '201' and it has been associated with visual and auditory disturbances. 'ap] Several dosing protocols have been reported, and treatment duration has not yet been determined. ■201 '204' '205' '193' Seizures are treated similarly to those in other patients with RF.
On average, dialysis dementia begins 37 months (range 9 to 84 months) after hemodialysis is initiated and has an average survival of 6 months (range 1 to 15 months).^' However, waxing and waning courses, several-year survivals, and transient symptoms have also been reported. '207' , '208' Reports from Europe and the United States have suggested that dialysis dementia might be part of a larger syndrome, including anemia, bone disease, and a proximal myopathy. '209'
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