Central nervous system effects of alcohol
Alcohol (ethanol) is a CNS depressant with pharmacologic properties similar to those of general anesthetics. Depending on dose, rate of consumption, tolerance, and other factors, acute intoxication can cause cognitive impairment, emotional lability, nystagmus, dysarthia, ataxia, stupor, coma, and death. Jackson (1884) (1) recognized that the highest brain centers are most susceptible to alcohol's effects. Thus early depression of inhibitory centers can transiently stimulate and disinhibit behavior. The behavioral actions of alcohol may result from increased γ-aminobutyric acid (GABA)ergic activity with stimulation of the GABA receptor–mediated Cl− uptake (2). However, alcohol affects multiple ion channels, and the relationship between effects on specific ion channels and different behavioral effects (e.g., intoxication, tolerance, dependence, seizure threshold) remains uncertain (3).
The most dangerous complication of intoxication is respiratory depression. A blood level of 500 mg/dl is lethal in ∼50% of patients. When used with other CNS depressants, much lower blood levels can be fatal (4,5). Seizures can occur during acute intoxication (6) and withdrawal (7). However, animal and human studies suggest that the long-term and immediate effects of alcohol on the CNS are different and often opposite (8) and that with the short-term administration, alcohol has antiepileptic properties (9). Therefore, in evaluating a seizure in an inebriated patient, one must carefully investigate to determine the cause.
Chronic alcoholism is associated with many neurologic disorders (e.g., cerebral atrophy, head injury). Seizures usually occur in individuals who have abused alcohol for a period of ≥10 years (6). Thus some long-term change in brain function (e.g., kindling) (8) or structure (e.g., loss of inhibitory neurons from metabolic deficiencies; cortical scars from head trauma) may be required (4,10). Chronic alcoholism can cause a cerebellar syndrome with nonepileptic action myoclonus, worse during abstinence and relieved during indulgence (11).
Withdrawal reactions are most severe in chronic alcoholics who rapidly taper or discontinue alcohol. Signs and symptoms include fine tremor, irritability, and insomnia in mild cases; in more severely affected subjects, lateral nystagmus (in the opposite direction of the nystagmus during intoxication), sensory illusions and hallucinations, tremulousness, anorexia, nausea, vomiting, anxiety, tachycardia, and diaphoresis may develop.
In chronic alcoholics, withdrawal seizures typically occur between 7 and 48 h after the cessation of drinking. Withdrawal seizures can occasionally occur in patients treated for alcohol withdrawal with benzodiazepines (BZDs; e.g., oxazepam), when the drug is discontinued (11,12). Patients with partial or generalized epilepsies may develop breakthrough seizures from alcohol withdrawal. Those with idiopathic generalized epilepsies may be most susceptible (13).
Delirium tremens (DT) is the most serious complication of alcohol withdrawal. DT occurs in 5% of hospitalized alcoholics and continues to have a mortality of ∼10% despite aggressive management. DT is a specific syndrome, diagnosed only if the following complex of clinical features is present: autonomic hyperactivity (fever, tachycardia, diaphoresis), severe agitated delirium, tremor, illusions, and hallucinations. DT usually begins 2–4 days after the last drink, has an acute or subacute onset, and lasts an average of 56 h (7).
Alcoholism and seizures
Evaluation of seizures in alcoholics
Alcohol abuse predisposes to many medical and metabolic disorders that mimic seizures. For example, syncope with mild convulsive movements may result from disorders associated with alcohol abuse [e.g., cardiomyopathy, arrhythmias, gastrointestinal (GI) hemorrhage, anemia, hypoglycemia, and dehydration]. First, ensure that the episode was a seizure.
Patients who abuse alcohol are at increased risk for seizures from different causes. The history, general medical, and neurologic examinations often point toward a specific etiology. Laboratory studies should include metabolic and hematologic blood tests, chest radiograph, toxicology screens (if there is suspicion of drug abuse or atypical features), lumbar puncture (based on clinical indications and contraindications), and computed tomography (CT) or magnetic resonance imaging (MRI) scans of the head should be considered in all patients with alcohol-related seizures. These neuroimaging tests also should be obtained in patients withdrawing from alcohol in whom the history or neurologic examination suggests new focal neurologic findings. All patients with a history of recent alcohol consumption and a first seizure (or initial seizure for which they sought medical attention) within 24 h of presentation, as well as those at risk of alcohol withdrawal should be considered for admission to the hospital for evaluation and treatment. The decision whether to admit patients with a history of recurrent alcohol-related seizures must be made on an individual basis.
Status epilepticus in alcoholics suggests the possibility of withdrawal from alcohol and short-term sedative/hypnotic agents or AEDs, or a coexisting, treatable CNS insult such as subdural hematoma or meningitis (7,14).
Ethanol: pharmacokinetics and effects on antiepileptic drugs
Alcohol elimination is zero-order (nonlinear) when blood levels are high, but becomes first-order as the levels decrease. Alcohol is metabolized by two enzyme systems into acetaldehyde: alcohol dehydrogenase (ADH; the major pathway, noninducible) and the microsomal ethanol oxidizing system (MEOS; the minor pathway, inducible). Then acetaldehyde is broken down into acetate by aldehyde dehydrogenase (ALDH). The ADH and MEOS systems are the rate-limiting steps. Approximately 50% of Asian people have a genetic variant in ALDH that limits the conversion rate of acetaldehyde and leads to alcohol intolerance. The half-life of ethanol elimination after high doses is ∼4.25 h (15). However, elimination also depends on sex, age, time of intake (ethanol elimination is fastest in late morning, afternoon, and early evening) (16), and presence of food (17) and other drugs within the system.
The hepatic mixed-function oxygenase system metabolizes alcohol and many AEDs. This system converts lipophilic compounds into hydrophilic compounds excreted in the urine. After acute dosing, ethanol inhibits the MEOS system. The hepatic metabolism of other drugs is slowed, partly because of competitive inhibition and enzyme saturation. This prolongs the half-life and enhances the pharmacodynamic effects of these drugs. This is especially true for carbamazepine (CBZ), phenytoin (PHT), primidone (PRM), valproate (VPA), and phenobarbital (PB). PB peak levels occur earlier and are higher when administered with alcohol than when PB is administered alone (18). Effects on respiratory depression also are synergistic. This has important clinical implications; patients can die after ethanol and PB ingestion, with mean ethanol levels found to be ∼175 mg/dl (19).
Acetaldehyde can bind to albumin, potentially becoming a competitive inhibitor for the attachment of AEDs to the serum proteins and increasing free drug levels. However, because acetaldehyde enhances the binding capacity of serum proteins for diazepam (DZP), high acetaldehyde levels (e.g., in chronic alcoholics), may increase DZP binding and decrease free levels (20). The clinical significance of this finding is uncertain (21).
After prolonged administration, enzyme induction leads to large increases in MEOS (2–3 times the normal rate) and relatively small increases in other monooxygenase systems. The induction of the hepatic systems can increase metabolism of both ethanol and other drugs including CBZ, PB, PHT, and PRM (4,5). The combined effects of long-term alcohol use and an AED regimen can increase clearance rates of AEDs, decreasing AED levels. One study found almost a 50% reduction in total PHT serum concentrations in alcoholics as compared with abstinent controls when tested 24 h after the last dose (22). The increased clearance rates may last 1 to 2 months after the cessation of drinking (23).
Liver disease due to chronic alcoholism can cause hypoalbuminemia, thereby reducing the protein binding of most AEDs, as well as decrease liver blood flow. The reduction in protein binding can lower total steady-state serum concentrations (Table 1), complicate interpretation of drug serum concentrations, and increase hepatic clearance rates of hepatically metabolized AEDs such as BZDs, CBZ, PHT, topiramate (TPM), VPA, zonisamide (ZNS), and, to a lesser extent, lamotrigine (LTG) and PB (24,25). With hypoalbuminemia, PHT free fraction may be slightly increased (26), and increased PHT dose can saturate metabolic pathways, increasing levels and producing excessive side effects. Decreased liver blood flow can diminish first-pass effect for drugs with a high intrinsic clearance such as oral chlordiazepoxide or DZP (27). This effect does not appear relevant to other hepatically metabolized drugs such as PHT (28).
|Serum levels with|
|Acute||Chronic||Side effects of AED similar|
to alcohol intoxication
|Benzodiazapines||↑||↑||Ataxia, confusion, dizziness|
|Carbamazepine||↑||↓||Ataxia, blurred vision, dizziness, drowsiness, vertigo, nystagmus, nausea, vomiting|
|Ethosuximide||↑||↓||Agitation, dizziness, nausea, vomiting|
|Primidone||↑||↓||Ataxia, nystagmus, sedation, vertigo, nausea, vomiting|
|Phenobarbital||↑||↓||Ataxia, nystagmus, sedation, vertigo, nausea, vomiting|
|Phenytoin||↑||↓||Ataxia, confusion, tiredness, dizziness, nystagmus, nausea, vomiting|
|Valproic acid||↑||↓||Ataxia, sedation, dizziness, tremor, nausea, vomiting|
Chronic alcoholics may require higher AED doses because of the enhanced clearance rates and more frequent, smaller AED doses to maintain therapeutic serum concentrations. For example, with VPA, both enzyme induction and protein binding must be considered when serum concentrations are interpreted because VPA has variable protein binding and, like other drugs, its clearance is related to free rather than total levels (19,29). Similarly, with CBZ, autoinduction of the enzyme system and changes in protein binding must be considered when interpreting serum concentrations (19,23). An accurate history of a patient's past or present alcohol use or abuse is essential when deciding on an AED.
Is alcohol abuse a risk factor for epilepsy?
Among patients who abuse alcohol, there is an increased prevalence of seizures and epilepsy. However, among patients with epilepsy, there is a decreased risk of alcohol use and abuse as compared with controls, probably because of warnings from physicians and pharmacists regarding increased risk of seizures or medication toxicity. Patients with recurrent episodes of only alcohol-withdrawal seizures do not have epilepsy.
There are currently insufficient data to determine if chronic alcohol abuse predisposes to recurrent seizures separate from head trauma, metabolic and medical disorders, and withdrawal (4,13). In some cases, isolated or multiple episodes of head trauma probably cause posttraumatic epilepsy (30). However, whether or not long-standing alcohol abuse causes physiologic (e.g., kindling) or pathologic (e.g., selective loss of inhibitory neurons) changes that result in recurrent seizures is unknown. In animals, repetitive alcohol withdrawal can kindle the amygdala and facilitate electrical kindling (31). Notably, acute alcohol intake blocks the effects of glutamate on the N-methyl-d-aspartate (NMDA) receptor. Prolonged exposure may lead to receptor supersensitivity, and withdrawal may increase glutaminergic activity and contribute to neurotoxicity and possibly seizure activity (32,33).
For those epilepsy patients who have chronically abused alcohol, the risk of seizures may increase on tapering or cessation of drinking because of an increase in AED metabolization and elimination caused by the relative lack of competing substrate. The physician should monitor drug levels during and after a patient stops chronic alcohol use.
Alcohol use in patients with epilepsy
Several studies showed that small to modest alcohol intake does not increase seizure frequency or significantly alter blood levels of AEDs (9,34). These studies (9,34) demonstrated that social drinking (one to two drinks/occasion) has no significant effect on blood levels of CBZ, ESM, and PHT. And although a marginal significant difference was found in the blood levels of VPA and PB in the same studies, the differences could be attributed to random variation in blood levels (9,34). Regardless, patients should be informed that intake of ethanol with CNS depressants such as PB can be dangerous.
The ability of epilepsy patients to consume limited amounts of alcohol can remove an unnecessary social restriction. Patients with epilepsy should therefore be allowed to use alcohol in small amounts (one to two drinks/occasion, no more than three to six drinks/week). However, exceptions may include patients with a history of noncompliance to AEDs, prior history of alcohol or other substance abuse, or those with alcohol-related seizures. Further exceptions may be adolescents and young adults who have difficulty limiting their alcohol intake. AED side effects can be similar to those of alcohol, leading to increased toxicity (Table 1).
Patients who drink moderate (three to four drinks/occasion) or heavy amounts (more than four drinks/occasion) of alcohol should be warned that they are at increased risk of seizures, with the greatest risk occurring 7–48 h after the last drink (35). Concurrence of withdrawal from moderate to heavy alcohol use and sleep deprivation or missed AED doses can be especially dangerous for epilepsy patients.