Status epilepticus Flashcards
Status epilepticus
Either >=30 min of continuous seizure activity or >=2 sequential seizures spanning this period without full return to baseline
Epidemiology of SE
Overall, estimated to range from 18/100,000 to 41/100,000 with 50
SE episodes/year/100,000
Generalized SE occurs ~6.2/100,000 and is more common in children
There are estimated 126,000 to 195,000 SE events with 22,200 to 42,000 deaths per year in the USA
Classification of SE (USA)
Classification of SE (European)
Non-convulsive status epilepticus (NCSE)
Is commons and continues to be underdiagnosed
May present with AMS, psychosis, other non-convulsive neurological symptoms and deficits
May be missed on routine EEG and diagnosis may not be made wo 24h continuous video-EEG
Risk factors for NCSE
Age <18, history of prior epilepsy, coma, convulsive seizures prior to monitoring
In a study of 570 adults with decreased level of consciousness…
Prevalence of NCSE/SE in adult ICU by diagnosis (n = 570), expressed in %
Ativan trial
May abolish epileptiform discharges with paradoxical improvement of LOC, helps with distinguishing between triphasics vs epileptiform
Etiology of SE in adults and children
Preceding epilepsy history in SE
A variable proportion of patients with status have preceding the history of epilepsy, in some studies estimated up to approximately 45%. In approximately 50% of patients with preceding epilepsy, the epilepsy is acute symptomatic. It is remote symptomatic in 20% cases, idiopathic in 14%, and unclassified in 17%.
Etiology of EPC
Etiology of epilepsia partialis continua is usually due to a fixed or progressive lesion involving the motor strip. These include tumors, vascular lesions (CVA, AVM), infection (abscess —especially TB, encephalitis, HIV, and subacute measles encephalopathy), autoimmune (Ras- mussen), systemic lupus erythematosus (SLE), paraneoplastic, cortical dysplasia, Sturge–Weber syndrome, traumatic brain injury (TBI), multiple sclerosis, gliomatosis cerebri, or progressive multifocal leucoencephalopathy.
Medications that cause SE
Medications that may cause SE include theo- phylline, lithium, isoniazid, cyclosporine, tacro- limus, ifosfamide, amoxapine, flumazenil, and among antiseizure medications (ASMs) tiaga- bine, vigabatrin and valproate.
Uncommon causes of SE
- Paraneoplastic
- Autoimmune
- Infectious (ill-defined)
- Chromosomal, genetic, or congenital dysplastic and inborn errors of metabolism
Paraneoplastic causes of SE
Paraneoplastic etiology, with associated autoantibodies (i) Hu, (ii) Ma2, and (iii) CRMP-5—all of them target intracellular antigens. Most common associated neo- plasms are small cell lung carcinoma (asso- ciated with all of the above antibodies), testicular germ call carcinoma (Ma2), and thymoma (CRMP5). In these conditions, SE may be refractory and respond to tumor removal.
SE clinical stages
Prodromal phase may include confusion, myoclonus, and increasing seizure frequency without intervening loss of consciousness. Stage 1 is divided into incipient (continued seizure of >5 min duration) and early (5–30 min duration).
Complications of tonic-clonic SE
Management of SE - timeline
Evaluation of SE
Labs: Initially, check glucose, chemistry profile —including calcium, magnesium, and phosphate —CBC, and urine toxicity screen ASM levels (if applicable). LP should be done if CNS infection, vasculitis, autoimmune, paraneoplastic, or meningeal neoplastic disease is suspected as a possible cause, after ruling out mass lesions with CT or MRI. Leukocytosis is commonly seen with SE without any infection because of blood–brain barrier breakdown during SE. CSF WBC counts of up to 30 x 10 ^6 can be seen.
Continuous EEG monitoring should be started, if available, if SE has continued for >60 min.
Neuroimaging changes associated with SE (Table 8.8; Figs. 8.1 and 8.2). MRI may be focally abnormal during both convulsive and non-convulsive status epilepticus. This may be misdiagnosed as acute lesions, e.g., stroke or encephalitis. Possible MRI abnormalities during SE include increased FLAIR (fluid-attenuated inversion recovery), T2 signal hyperintensity and high-intensity signal DWI (diffusion-weighted imaging), both local at seizure focus and remote, commonly in the ipsilateral posterior thalamus (pulvinar), contralateral cerebellum, and bilateral splenium of the corpus callosum (Table 8.8; Figs. 8.1 and 8.2). These changes may be due to the prolonged ictal activity increasing glucose utilization, which is not adequately matched by the enhanced blood flow. Blood flow–metabo- lism uncoupling leads to a reduction of high-energy adenosine phosphates and tissue hypoxia. The regional hyperperfusion serves as a compensatory mechanism, but is insufficient to prevent the stimulation of anaerobic glycolysis due to the prolonged ictal activity.
Peri-ictal MRI changes
Treatment of early SE (stage 1)
Primary treatment includes benzodiazepines,
midazolam, lorazepam, and diazepam. Midazo- lam i.m. may be the most effective followed by lorazepam followed by diazepam as shown in 2 large phase 3 studies ([9], Table 8.10).
Diazepam has more rapid onset because of greater lipid solubility. Lorazepam has longer anticonvulsant duration (12 h) than diazepam (30 min) and has less potential for respiratory depression and sedation. Seizure recurrence is common after benzodiazepine administration, especially in acute symptomatic SE.
Comparison of stage I treatments
In a study comparing the efficacy of intra- muscular midazolam with intravenous lorazepam for children and adults in status epilepticus treated by paramedics outside the hospitals, sei- zures were stopped prior to arrival in the hospital in 73% subjects treated with midazolam 10 mg i. m. and 63% subjects treated with lorazepam 4 mg i.v. with 4.5 and 6.5 min to the cessation of convulsions, respectively. Seizures recurred in 11% in both groups. Adverse-event rates were similar in the two groups [10].
Secondary treatments for SE (stage II treatments)
Secondary treatment includes phenytoin or phenobarbital (Table 8.11). It should be admin- istered at the same time as the benzodiazepine.
Phenobarbital may be more effective than phenytoin in suppressing SE, but is less used in practice, possibly because of greater potential for respiratory depression and intubation, particu- larly in combination with benzodiazepines. Comparison of efficacy of lorazepam, pheno- barbital, and phenytoin with or without benzo- diazepam is shown in Table 8.12.
Phenytoin has the advantage of lack of seda-ion or respiratory depression. Maximum CNS concentration is reached in 20 min.
Its potential side effects include bradycardia (7%) and hypotension (27%) [11]. Phenytoin is alkaline and with extravasation causes skin irritation and “purple glove syndrome” which occurs in 1–2% of patients [11].
Phenytoin needs to be administered in normal saline as it precipitates in dextrose. Infusion rate is 50 mg/min for adults, 20 mg/min for the elderly, and <= 25 mg/min for children.
The elderly have a higher risk for cardiovascular complications. Heart rate and blood pressure should be monitored with the reduction of infusion rate if hypotension occurs.
Total blood level and free phenytoin level should be checked at the end of the infusion, within 30 min of infusion if seizures persist or 1–2 h after infusion if seizures stop, in order to help with timing of maintenance treatment.
Fosphenytoin, a phosphate ester prodrug of phenytoin, has replaced phenytoin in many institutions. Fosphenytoin is given as phenytoin equivalent (PE), with the dose of 20 mg/kg. It can be given in dextrose or normal saline.
It is water soluble and can be given i.m. as well as i.v. It may cause paraesthesias and pruritus at injection site. Its bioavailability is 100% compared with phenytoin.
It is rapidly converted to phenytoin (PHT) by serum and tissue alkaline phosphatases. Its conversion half-life to pheny- toin is 7–15 min. Phenytoin levels should be checked 2 h after infusion. It may be difficult to maintain therapeutic levels in infants.
Alternative treatments for Stage 2 SE are shown in Table 8.13. Intravenously formulated ASMs include—in addition to phenobarbital, phenytoin, and benzodiazepine— sodium valproate, levetiracetam, and lacosamide. Valproic acid (VPA) and levetiracetam (LEV) are some-times used for treatment of Stage 2 SE but their efficacy in SE has not been evaluated in con- trolled studies [12]. They have the advantage over PHT and PB of lacking cardiovascular side effects (lacosamide can rarely cause atrial fibril- lation or tachy- or bradycardia).
Treatment of RSE
(convulsive)
Treatment of RSE.
Mainstay treatment is “therapeutic coma” induced with intravenous anesthetics such as propofol, midazolam (or lorazepam), or pentobarbital, together with intu- bation and mechanical ventilation. There are no US RSE treatment guidelines, no randomized studies comparing different agents, and little evidence to guide the choice of agent or duration of treatment. Many centers resort to i.v. anes- thesia after the failure of benzodiazepine + phenytoin or phenobarbital. Some, however, try a third-standard anticonvulsant such as VPA, LEV, or lacosamide (LCM) before anesthesia. In Europe, this approach is common.
Current European guidance recommends titration of propofol and barbiturate to EEG burst suppres- sion, and midazolam to seizure suppression, maintained for at least 24 h [15].
Therapeutic coma lowers metabolic activity of brain tissue, removes the energy mismatch between brain tissue energy use and supply, and allows neuronal recovery, including recovery of normal neuronal synaptic receptor function.
The three most commonly used i.v. anesthetics are shown in Table 8.14, together with dosing and infusion rate. Following initial bolus injection, the rate of infusion/dose of the chosen agent should be titrated quickly up to electrographic seizure suppression and then EEG burst suppression.
The optimal duration of the treatment has not been determined in controlled studies. Different centers use variably 24–48 h of EEG burst sup- pression on the i.v. anesthetic before attempting a taper. i.v. anesthetic is restarted if seizures recur. During i.v. anesthesia, non-anesthetic ASMs should be optimized in preparation for with- drawal of the i.v. anesthetic. The duration of i.v. anesthesia is empirical. Side effects are common, include hypotension, pneumonia, gastric paresis, and immunosuppression, and contribute inde- pendently to poor outcome and death. Mortality and functional outcome is similar in those with and without EEG suppression.
Propofol is the first-line intravenous anes- thetic agent for RSE in many centers because its rapid onset and short duration of action, even after prolonged infusion, allow a greater control of the depth of anesthesia than with pentobarbital or midazolam [14]. Its t1/2 is 2 h, but its effect is shorter (minutes) because of its rapid distribution into peripheral tissues. 1–2 mg/kg load is fol- lowed by infusion at 5–120 mcg/kg/min, with up-titration in increments of 10 mcg/kg/min every 10–15 min to EEG response/side effects.
It has a rapid onset of action: Seizure control occurs in 2–3 min versus 123 min with pento- barbital. It often requires high doses (e.g., 50– 100 mcg/mg/kg/min) to induce burst suppres- sion, often with associated hypotension requiring i.v. pressor support. It has common and poten- tially lethal side effects, chiefly hypotension, metabolic acidosis, pneumonia, and the “propo- fol infusion syndrome” (PRIS). PRIS occurs at high doses with prolonged infusion, e.g., >4 mg/kg/h for more than 24 h, more so with co-treatment with catecholamines and steroids. It consists of unexplained lactic acidosis, rhab- domyolysis with elevated creatinine kinase, hypertriglyceridemia, and widespread ECG changes, including cardiac arrest. Prolonged propofol infusion is associated with other serious systemic complications, most commonly pneu- monia. In one study of adults with RSE, there was 57% mortality with propofol treatment ver- sus 17% with midazolam.
Midazolam rapidly enters brain tissue. It has a powerful short duration. 0.4 mg/kg/h infusion rate is more effective in RSE than 0.2 mg/kg/h infusion rate, with lower mortality of 40% versus 62%. There is a risk of development of acute tolerance with risk of seizure relapse. Break- through seizures may occur in 50% of patients. Side effects include hepatic and renal impair- ment, respiratory, and cardiac depression, although the latter is less pronounced than with barbiturates.
Pentobarbital has longer half-life, making quick adjustments and evaluation of mental sta- tus after discontinuation of the infusion more difficult [16]. It is associated with the greatest incidence of systemic complications, particularly hypotension, splanchnic hypoperfusion (leading to gastric, pancreatic, and hepatic sequelae), immunosuppression, with attendant risks of infections most commonly pneumonia, but also nosocomial iv sepsis via catheter, or UTI; and reduced GI motility. The side effects may limit treatment dose and duration.
Inhalational agents: Inhalational halogenated anesthetics such as isoflurane and desflurane have been used successfully to control seizures in small numbers of patients who do not respond to intravenous agents [14]. The logistical and safety implications of providing inhalational anesthesia in the ICU are substantial, and such treatment is not a realistic option in most circumstances.
Other agents are used in clinical practice in RSE. They include valproate, topiramate, leve- tiracetam, lacosamide, ketamine, and i.v lo- razepam infusion. Evidence of efficacy of VPA, TPM, LEV, LCM, and ketamine is based on uncontrolled studies, retrospective reviews, and case series reports.
Other ancillary treatments used in continued refractory status epilepticus unresponsive to standard treatments have included hypothermia, ketogenic diet, immunotherapy—including IVIG and plasmapheresis—resective surgery, and vagal nerve stimulation. Their use is based on anecdotal and case series evidence only.
RSE treatment monitoring includes monitor- ing of electrolytes, calcium, magnesium, blood gases, and pH, and monitoring for and treatment of concurrent infection, fever, rhabdomyolysis, hypotension, and bradycardia, all of which may worsen RSE outcome.
