Version May 2024
INTRODUCTION — Seizures are not uncommon among patients on hemodialysis [1].
There are many potential causes of seizures among patients on hemodialysis. In most circumstances, seizure activity occurs during or shortly after the hemodialysis procedure because of the hemodynamic and biochemical changes associated with the process [1].
This topic reviews the causes and treatment of seizures in patients on hemodialysis. The management of seizures in patients without kidney failure is presented elsewhere. (See "Overview of the management of epilepsy in adults".)
A review of other acute complications that may occur during dialysis are presented separately. (See "Acute complications during hemodialysis".)
NEW-ONSET SEIZURE
Causes — The evaluation of a new-onset seizure is similar to that of patients who are not on dialysis. The following causes are due to either end-stage kidney disease (ESKD) or treatment with hemodialysis: uremic encephalopathy, dialysis dysequilibrium syndrome (DDS), intradialytic hemodynamic instability, aluminum-associated dialysis dementia, air embolism, hypoglycemia, hypocalcemia, and hyponatremia.
Other causes of seizures among patients on hemodialysis are similar to the general population but may be more common among patients on hemodialysis. Cerebrovascular disease (infarction, cerebral emboli [separate from infarction because dialysis vascular access can lead to infections and septic emboli] [2], hemorrhage and subdural hematoma) is of particular concern in the hemodialysis population. (See "Evaluation and management of the first seizure in adults", section on 'Causes of seizures'.)
Compared with patients not on dialysis, patients on hemodialysis are more vulnerable to drug-induced seizures with certain drugs such as carbapenem and ertapenem because of their markedly decreased clearance.
The following paragraphs discuss the more common causes of seizures that are specific for the dialysis population. Some are independent of dialysis, whereas others are a direct complication of the procedure.
●Uremic encephalopathy – Central nervous system (CNS) dysfunction is observed among patients with severe, untreated uremia but generally not among patients undergoing maintenance hemodialysis unless patients miss multiple treatments. Symptoms range from irritability and restlessness to seizures, coma, and death. Seizures are most often generalized and occur prior to dialysis, often provoking initiation of emergent dialysis. CNS dysfunction abates within days to weeks after the initiation of adequate kidney replacement therapy.
●Dialysis disequilibrium syndrome – DDS may be observed among severely uremic patients who undergo hemodialysis for the first time but generally does not occur among patients who are on maintenance hemodialysis. DDS is characterized by neurologic symptoms of varying severity. Typically, symptoms develop during or immediately after hemodialysis. Early findings include headache, nausea, disorientation, restlessness, blurred vision, and asterixis. More severely affected patients progress to confusion, seizures, coma, and even death. However, DDS also includes many milder signs and symptoms associated with dialysis, such as muscle cramps and dizziness that develop near the end of a dialysis treatment [3-5]. (See "Dialysis disequilibrium syndrome".)
New patients just being started on hemodialysis are at greatest risk, particularly if the blood urea nitrogen (BUN) is markedly elevated (ie, above 170 mg/dL or 60 mmol/L). Other predisposing factors include severe metabolic acidosis, older age, hypocalcemia, and the presence of other CNS disease, such as a preexisting seizure disorder [3,6-9].
●Erythropoiesis-stimulating agents – A rapid rise in blood pressure due to the administration of erythropoiesis-stimulating agents (ESAs) may result in hypertensive encephalopathy accompanied by seizures [10]. The reported incidence ranges from 2 to 17 percent [10-12]. However, most studies that have reported on seizure incidence are from the early 1990s, when ESA doses and hemoglobin targets were higher than are typically used today. (See "Treatment of anemia in patients on dialysis".)
Thus, despite cited incidence above, we believe ESA-related seizures are uncommon today. A 2004 meta-analysis showed no increase in the incidence of seizures among patients treated with an ESA compared with those not treated with an ESA; however, studies included both predialysis and dialysis chronic kidney disease (CKD) patients, which may have resulted in an underestimate of incidence among dialysis patients [12].
There is little evidence of increased incidence of seizures in normotensive patients treated with an ESA. (See "Hypertension associated with erythropoiesis-stimulating agents (ESAs) in patients with chronic kidney disease".)
●Drugs or toxins ─ Many medications can cause seizures in the general population (table 1). Patients on hemodialysis are particularly vulnerable to some drugs because of decreased clearance [13-21]:
•Antibiotics including penicillin, cephalosporins, carbapenem, and ertapenem, particularly when administered at high doses
•Meperidine (due to accumulation of the toxic metabolite, normeperidine)
•L-dopa
•Intravenous (IV) iodinated contrast material (in high doses)
Star fruit ingestion may also cause severe neurologic dysfunction, including seizures and death in dialysis patients [22,23].
●Dialysis dementia – Dialysis dementia is a progressive neurologic disorder that is observed exclusively in patients on dialysis and may manifest as seizures. The cause is exposure to aluminum [24,25] (see "Aluminum toxicity in chronic kidney disease", section on 'Dementia'). The incidence of dialysis dementia has markedly declined because of better water treatment for hemodialysis and the use of non-aluminum-containing phosphate binders for the chronic management of hyperphosphatemia. (See "Contaminants in water used for hemodialysis".)
Immediate management of seizures — The emergency treatment of seizures in the patient on dialysis includes the following:
●Stop dialysis and start infusion of IV fluids and oxygen if indicated.
●Protect the vascular access from harm during the seizure.
●Ensure that the patient is in a safe environment and not at risk from injury (eg, fall risk). If possible, place the patient on their side during the seizure. Do not place anything in the mouth during an active seizure.
●In most instances, 911 (if hemodialysis is occurring in an outpatient clinic) or a rapid response (if hemodialysis is occurring in the hospital setting) should be called, although most seizures last less than five minutes and spontaneously remit.
●If a patient continues to seize, paramedics or the rapid response team must address airway protection and stabilize the patient. Treatment with IV benzodiazepines is the first-line treatment to stop the ongoing seizure activity. The patient should then be evaluated by a clinician to determine further therapy (eg, with IV antiseizure medications). (See "Convulsive status epilepticus in adults: Management".)
Blood should be sampled for serum levels of glucose, calcium, sodium, magnesium, and other electrolytes, marked abnormalities of which may suggest the underlying cause of the seizure. IV glucose should be administered if hypoglycemia is suspected, along with IV thiamine, particularly in at-risk individuals (eg, history of heavy alcohol use).
Further therapies are the same as among the nondialysis population and are discussed elsewhere.
Evaluation — Once the patients have been treated for seizure and dialysis has been stopped, the evaluation of seizure is the same for patients on dialysis as for other patients. Potential causes that should be excluded include uremia itself, subdural hematoma, metabolic disturbances (hyponatremia, hypoglycemia), and drug-induced encephalopathy. In addition, causes of seizure that are not specific for patients on dialysis need to be excluded. (See "Evaluation and management of the first seizure in adults".)
PREVENTION — Prevention of seizures is targeted to specific causes.
Specific causes
●Uremic encephalopathy – Progressive uremic encephalopathy is an absolute indication for the initiation of dialysis. (See "Indications for initiation of dialysis in chronic kidney disease", section on 'Absolute indications for dialysis'.)
The initiation of dialysis prior to the onset of mental status changes prevents seizures.
●Dialysis disequilibrium syndrome – Dialysis disequilibrium syndrome (DDS) is prevented by limiting the reduction in blood urea nitrogen (BUN) per treatment so that there is a gradual reduction that is distributed over several days. This measure prevents seizures but may not prevent mild symptoms such as headache and malaise. (See "Dialysis disequilibrium syndrome", section on 'Prevention'.)
●Erythropoietin therapy – The most important measure to prevent erythropoiesis-stimulating agent (ESA)-induced seizures is to avoid rapid increases in hemoglobin. Hemoglobin target, dosing, and the optimal route of administration are discussed elsewhere. (See "Treatment of anemia in patients on dialysis", section on 'Target Hb levels'.)
●Dialysis-induced hypotension – Prevention of dialysis hypotension involves a variety of maneuvers. This is discussed separately. (See "Intradialytic hypotension in an otherwise stable patient".)
MAINTENANCE ANTISEIZURE THERAPY — The indication for antiseizure medications is the same among patients on hemodialysis as in the general population. Long-term therapy with antiseizure medications may not be required if the patient's seizure is due to a reversible cause. (See "Initial treatment of epilepsy in adults", section on 'When to start antiseizure medication therapy'.)
Medication selection — Among patients on hemodialysis who are selected for antiseizure medication, the selection of a specific medication depends on multiple variables, and no single antiseizure medication is clearly the most effective or best tolerated (table 2). (See "Initial treatment of epilepsy in adults", section on 'Selection of an antiseizure medication'.)
For most patients on hemodialysis, we generally use levetiracetam. Levetiracetam is generally well tolerated, is affordable since generic forms are available, and has few drug-drug interactions. If levetiracetam is used, the preferred dose is 500 to 1000 mg daily, with an extra dose of 250 to 500 mg given at the end of dialysis. (See 'Dosing' below.)
Numerous other agents are effective. Lacosamide is an alternative agent that may be used. Lacosamide also has only a few interactions with other agents, including immunosuppressive agents.
We generally do not use phenytoin or valproic acid among patients on hemodialysis, unless the patient is already stable on one of these agents prior to initiating hemodialysis. Phenytoin and valproic acid have multiple drug-drug interactions and tend to have higher rates of adverse effects [26-31]. (See 'Dosing' below.)
Drug-drug interactions are of particular importance among patients on hemodialysis who are usually on multiple medications (see "Initial treatment of epilepsy in adults", section on 'Pharmacokinetics'). In addition, such patients may eventually receive a kidney transplant and require immunosuppression medications (including glucocorticoids), which have important drug-drug interactions with other agents, such as phenytoin and valproic acid (table 3).
Dosing — Many of the newer and more frequently used antiseizure medications are removed by dialysis. Among patients who are treated with a dialyzable antiseizure medication to prevent recurrent seizures, the dosing regimen must be adjusted to prevent a subtherapeutic plasma level during or after dialysis, which could result in a seizure [32]. The dose of many antiseizure medications require adjustments based upon severity of kidney impairment as detailed for the commonly prescribed antiseizure medications in the table (table 2).
The following drugs are variably removed by dialysis and must be supplemented in order to maintain therapeutic levels [33]:
●Phenobarbital and primidone
Among patients who are on any of these agents, we time the doses such that the medication is given at the end of each dialysis treatment. An alternative approach is to administer an additional dose at the end of each dialysis session.
Carbamazepine and oxcarbazepine are only minimally dialyzed. However, even the small amount that is dialyzed out can result in a decrease in the concentration. The stress of hemodialysis plus the slight decrease in concentration can lower the seizure threshold.
We do not use extended-release formulations. An extended-release formulation, given as a supplemental dose after dialysis, will take a longer time to achieve a therapeutic concentration.
Some agents, such as phenytoin and valproic acid, are not dialyzed and require no postdialysis supplementation [34,35]. Because of this, phenytoin and valproic acid have been commonly used among patients on hemodialysis. However, as noted above, these agents are less commonly used today compared with newer agents. (See 'Maintenance antiseizure therapy' above.)
Among patients who are on phenytoin or valproic acid, serum levels need to be carefully interpreted. Phenytoin and valproic acid are highly protein bound, and there is an unpredictable relationship between free and total drug concentrations [26,27]. In patients with hypoalbuminemia (which is very common among those with end-stage kidney disease [ESKD]), there is displacement of the drug from serum proteins with an increase in the volume of distribution.
As a result, the patient has the same concentration of free drug (which has the pharmacologic effect) in serum at a lower total blood concentration than does the subject with normal kidney function and without hypoalbuminemia. Free levels should be monitored, if available, rather than total levels.
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Dialysis".)
SUMMARY AND RECOMMENDATIONS
●Causes of seizures that are due to either end-stage kidney disease (ESKD) or treatment with hemodialysis include uremic encephalopathy, dialysis dysequilibrium syndrome (DDS), intradialytic hemodynamic instability, aluminum-associated dialysis dementia, air embolism, hypoglycemia, hypocalcemia, and hyponatremia. Other causes of seizures among patients on hemodialysis are similar to the general population but may be more common among patients on hemodialysis. (See 'New-onset seizure' above.)
●The emergency treatment of seizures in the patient on dialysis includes stopping dialysis, ensuring patient safety, and contacting emergency providers if the seizure is not self-limited or the patient is not known to have a seizure disorder. Blood should be sampled for serum levels of glucose, calcium, sodium, magnesium, and other electrolytes. Intravenous (IV) glucose and thiamine should be administered if hypoglycemia is suspected, along with IV thiamine in at-risk individuals. (See 'Immediate management of seizures' above and "Overview of the management of epilepsy in adults".)
●The indication for antiseizure medications is the same among patients on hemodialysis as in the general population. Long-term therapy with antiseizure medications may not be required if the patient's seizure is due to a reversible cause. (See 'Maintenance antiseizure therapy' above.)
●Among patients on hemodialysis who require initiation of an antiseizure medication, we generally use levetiracetam, 500 to 1000 mg daily with an extra dose of 250 to 500 mg given at the end of dialysis (table 2). Levetiracetam is generally well tolerated, is affordable since generic forms are available, and has few drug-drug interactions. Lacosamide is a commonly used alternative. We generally do not use phenytoin or valproic acid unless the patient is already stable on one of these agents prior to initiating hemodialysis. (See 'Maintenance antiseizure therapy' above.)
●Many of the newer antiseizure medications are removed by dialysis. When these drugs are utilized in the hemodialysis patient population, the patient should receive additional medication immediately following hemodialysis to prevent subtherapeutic blood levels. An alternative approach is to time the doses such that the medication is given at the end of each dialysis treatment. (See 'Dosing' above.)
ACKNOWLEDGMENT — The UpToDate editorial staff acknowledges Yousri M Barri, MD, who contributed to earlier versions of this topic review.
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