Seizures and epilepsy in older adults: Treatment and prognosis

INTRODUCTION — This topic will cover aspects of the management of seizures and epilepsy that are specific to older adults. A more general discussion of the treatment of seizures and epilepsy is presented elsewhere. (See "Overview of the management of epilepsy in adults" and "Initial treatment of epilepsy in adults".)

The clinical presentation of seizures in older adults is frequently different from that of younger adults, and seizures are often difficult to recognize. The etiology, clinical presentation, and diagnosis of seizures and epilepsy in older adults is discussed separately. (See "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis".)

TERMINOLOGY — Seizures are episodes of transient neurologic change due to overexcited, hypersynchronous neuronal activity. Seizures are divided into provoked and unprovoked:

●Provoked seizures, also known as acute symptomatic seizures, occur with an identifiable proximate cause and are not expected to recur in the absence of that particular cause or trigger (eg, hypoglycemia, alcohol withdrawal).

●Unprovoked seizures occur without an identifiable proximate cause, and epilepsy is defined as a condition of recurrent unprovoked seizures. In epilepsy, the seizures appear to occur spontaneously and are expected to recur in the absence of treatment.

APPROACH TO TREATMENT

New-onset seizures — The decision to treat seizures in older adults should be made only after significant deliberation of the benefits and risks of treatment. Factors that should be considered include the degree of certainty about the seizure diagnosis, the individual risk of seizure recurrence, seizure severity, and risk of self-injury. Starting an antiseizure medication in older adults can lead to a variety of negative outcomes such as excessive somnolence, worsening cognition, worsening mood/behavior, and increased risk of falls.

Acute provoked seizures — In general, patients with provoked seizures due to obvious metabolic derangements, medication, or medication withdrawal will not require antiseizure medication treatment. Patients with seizures occurring during a hospitalization for an acute intracranial event (eg, stroke, head trauma, brain surgery) may receive antiseizure medications for a limited time, such as a few weeks to a few months. It is reasonable to withdraw antiseizure medications at the post-discharge follow-up visit if seizures do not recur after the hospitalization. (See "Overview of the management of epilepsy in adults", section on 'Poststroke seizures'.)

After a first unprovoked seizure — The decision to start an antiseizure medication in an older patient with a first unprovoked seizure should be based on risk factors for seizure recurrence rather than age, similar to the decision in younger adults. In the absence of a symptomatic cause of epilepsy, it is appropriate to defer antiseizure medication treatment for patients with a single unprovoked seizure and an unremarkable brain magnetic resonance imaging (MRI) and electroencephalography (EEG). A second unprovoked seizure, however, would be an indication for treatment. (See 'After two or more unprovoked seizures' below.)

For older adults with a first unprovoked seizure, we suggest antiseizure medication treatment only in the setting of clearly documented potential symptomatic cause of epilepsy (eg, stroke, traumatic brain injury, brain tumor) based upon history, an abnormal neurologic examination, a relevant abnormality on brain imaging with computed tomography (CT) or MRI, and/or epileptiform discharges on EEG.

In patients with a first unprovoked seizure who are found to have a relevant brain abnormality on neuroimaging (such as a tumor, remote stroke, or scar tissue from an old head injury or infection), the risk of seizure recurrence is increased. Such patients likely have a sufficiently high risk of seizure recurrence to meet criteria for epilepsy according to International League Against Epilepsy (ILAE) guidelines [1]. These criteria consider patients with a single unprovoked seizure and an estimated risk of recurrence ≥60 percent over ten years to have epilepsy, similar to those with two unprovoked seizures occurring >24 hours apart.

Limited data suggest that the risk of seizure recurrence after single unprovoked seizure in older adults is similar to that of younger adults and that the predictors of recurrence are similar. In a prospective observational study of over 1000 adults presenting with a first-ever unprovoked seizure, 139 of whom were ≥65 years of age (mean 74 years), the likelihood of a seizure recurrence at one year was similar in older compared with younger adults (53 versus 48 percent) [2]. Independent predictors of seizure recurrence included remote symptomatic etiology, first seizure arising from sleep (ie, a seizure that starts when the patient is asleep), epileptiform abnormality on EEG, and focal seizures, but not age. In another prospective observational report, 127 of the 568 adults with a single unprovoked seizure were >60 years of age, and the cumulative risk of recurrence in this age group was 83 percent over three years; however, the overall recurrence rate was higher in this study (78 percent) across all age groups [3].

In a retrospective study of 278 older adults presenting with first-ever seizure (provoked and unprovoked seizures), 43 percent of patients had recurrent seizures during the two-year follow-up period, similar to rates observed in younger patients. Risk factors for seizure recurrence were acute and remote symptomatic etiology, and epileptiform abnormality on EEG, similar to other studies [4].

After two or more unprovoked seizures — The general consensus is to begin treatment with antiseizure medication therapy if a patient has experienced two or more well-documented unprovoked seizures, since seizure recurrence indicates that the patient has a substantially increased risk for additional seizures (ie, epilepsy). (See "Initial treatment of epilepsy in adults", section on 'Second unprovoked seizure'.)

However, in some circumstances (eg, if the diagnosis is uncertain because the events were not witnessed), withholding antiseizure medication treatment may be appropriate. Most prospective studies have not demonstrated any long-term benefit with immediate treatment as opposed to delayed treatment, as discussed separately. (See "Initial treatment of epilepsy in adults", section on 'Benefit of early versus deferred treatment'.)

Status epilepticus

Convulsive status epilepticus — Generalized convulsive status epilepticus (GCSE) is operationally defined as five minutes or more of continuous seizure activity, or more than one seizure without recovery in between. This establishes the critical point at which treatment must be initiated in order to avoid potential serious morbidity; GCSE is a medical emergency that requires prompt evaluation and treatment. The approach to GCSE in older adults is similar to that of younger adults; however, morbidity and mortality are higher in older adults (see 'Prognosis' below). The initial assessment and treatment should proceed simultaneously, as depicted in the algorithm (algorithm 1). Hemodynamic and respiratory monitoring are also required in order to avoid side effects of therapy. The treatment of GCSE is discussed in detail separately. (See "Convulsive status epilepticus in adults: Management".)

The clinical features and diagnosis of GCSE in adults are reviewed in detail separately. (See "Convulsive status epilepticus in adults: Classification, clinical features, and diagnosis" and "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis", section on 'Convulsive and nonconvulsive status epilepticus'.)

Nonconvulsive status epilepticus — Nonconvulsive status epilepticus (NCSE) is a condition of ongoing or intermittent seizure activity without convulsions, without recovery of consciousness between attacks, and lasting more than 10 minutes. NCSE is a challenging diagnosis, particularly in the older patient; a high index of suspicion in a comatose patient is often necessary to confirm NCSE, and the diagnosis is largely based on a confirmatory EEG and response to appropriate treatment. In all patients with NCSE, a concerted effort should be made to diagnose and treat seizures as quickly as possible but with minimal sedation, so as to avoid inducing or prolonging coma and intubation. Clinical aspects of NCSE, including treatment, are reviewed in detail elsewhere. (See "Nonconvulsive status epilepticus: Classification, clinical features, and diagnosis" and "Seizures and epilepsy in older adults: Etiology, clinical presentation, and diagnosis", section on 'Convulsive and nonconvulsive status epilepticus'.)

Aging with epilepsy — Patients with epilepsy onset in earlier years of life will often remain on chronic antiseizure medication therapy. The main consideration is that patients may require dosing adjustments later in life because of the changing physiology associated with aging and changes in drug absorption, metabolism, distribution, and excretion, as well as potential pharmacokinetic or pharmacodynamic interactions with other drugs that may be started in aging patients.

Patient education — An important aspect of caring for a patient with epilepsy includes counseling on safety issues and lifestyle modifications [5]. A few states legally require health care providers to submit confidential reports to local health agencies after diagnosing a patient with seizure(s). Although mandatory reporting is limited to a handful of states, most require health care clinicians to counsel patients to stop driving until they are seizure-free for a certain period of time (see "Overview of the management of epilepsy in adults", section on 'Driving and other restrictions'). Clinicians should also initiate a discussion about alcohol intake, informing patients that heavier consumption (three or more drinks in a 24-hour period) increases the risk of seizures [6].

ANTISEIZURE MEDICATION TREATMENT

Selection of antiseizure medication — Antiseizure medications are the mainstay of treatment. However, their use in older patients is complicated by several factors, including altered pharmacokinetics and increased risk for adverse effects (table 1 and table 2) and drug-drug interactions [7].

The choice of a specific antiseizure medication in an older patient should take into account the types of seizures the patient is experiencing (eg, focal seizure, myoclonic seizures, generalized tonic-clonic seizures), the potential for drug-drug interactions, comorbid medical conditions, and the mode of administration (swallowed completely versus crushed versus gastrostomy tube) [7].

A detailed review of antiseizure medications is provided elsewhere. (See "Antiseizure medications: Mechanism of action, pharmacology, and adverse effects".)

●Efficacy and tolerability – The available evidence, although limited by a paucity of head-to-head comparisons, suggests that the more commonly used antiseizure medications (ie, lamotrigine, levetiracetam, valproate, gabapentin) have similar efficacy and tolerability for older patients with epilepsy.

A 2019 systematic review and meta-analysis identified 18 studies evaluating 12 different antiseizure medications in people at least 60 years of age with epilepsy; 10 studies with 1999 patients were suitable for meta-analysis [8]. The results showed that discontinuation due to adverse events was more likely with carbamazepine compared with lamotrigine (pooled weighted risk ratio [RR] 1.83, 95% CI 1.23-2.43). The probability of seizure freedom was more likely with levetiracetam compared with lamotrigine (RR 0.83, 95% CI 0.68-0.97), although the statistical significance was marginal. There was evidence from individual studies supporting the efficacy and/or tolerability of other antiseizure medications, which were brivaracetam, gabapentin, lacosamide, perampanel, and topiramate. However, there were too few trials to carry out a meta-analysis of additional head-to-head antiseizure medication comparisons or to evaluate the impact of epilepsy type and other patient characteristics on the efficacy and tolerability of antiseizure medications, and the quality of the evidence was generally low or unknown.

A subsequent 2019 network meta-analysis of five randomized controlled trials with 1425 patients evaluated antiseizure medication monotherapy (with carbamazepine, gabapentin, lacosamide, lamotrigine, levetiracetam, phenytoin, and valproic acid) for older adults with epilepsy [9]. In both the pairwise and network meta-analyses, there were no differences in any of the comparisons for seizure freedom at 6 and 12 months; carbamazepine had the highest probability of treatment discontinuation.

●Focal seizures – Focal seizures with impairment of awareness are the most common types of new-onset seizures in older adults. Lamotrigine and levetiracetam are reasonable first-line medications for focal seizures. Lamotrigine is appropriate if the clinical scenario does not require an immediate therapeutic level (eg, seizures are infrequent and/or mild). Levetiracetam is appropriate if there is a more urgent need to reach therapeutic dosing more quickly; it is available in both tablet and liquid formulations.

●Myoclonic seizures – Rarely, in patients with Alzheimer disease or other neurodegenerative conditions, the primary seizure subtype may be myoclonic seizures [10-13]. Levetiracetam and valproate are efficacious [14,15]. Levetiracetam should be used with caution in individuals who have advanced dementia and behavioral issues (eg, patients with trisomy 21 [Down syndrome], patients with features of Alzheimer disease) because of the increased risk of aggressive behavior and irritability.

●Generalized seizures – New-onset generalized seizures are unlikely in older adults, such that observed generalized seizures are more likely to be focal seizures with secondary generalization. Therefore, the approach to therapy is the same as stated above for focal seizures.

Dosing strategies — In all cases, we recommend starting antiseizure medications for older adult patients at low doses and to increase doses gradually. Older patients generally require doses far below standard therapeutic levels and experience toxicity with traditionally therapeutic doses typically used in younger patients. Potential dosing strategies of specific antiseizure medications are as follows:

●Lamotrigine – In older patients >85 years of age, the starting dose of lamotrigine may be as low as 12.5 mg daily with an incremental increase of 12.5 mg per week to a goal dose of 25 mg twice a day. In younger, healthy older patients (65 to 75 years of age), individuals may tolerate a starting dose of 25 mg twice a day with an incremental increase of 25 mg per week, reaching a goal of 50 to 75 mg twice a day. It is reasonable to use the extended-release formulation of lamotrigine for more stable steady-state concentrations, which may improve tolerability [16].

●Levetiracetam – Levetiracetam can be started at a dose of 250 mg twice a day in healthy older patients (<85 years of age) and increased to 500 mg twice a day in three to seven days. In patients ≥85 years of age, levetiracetam should be started at a dose of 125 mg daily or twice daily and increased incrementally by 125 mg/week to a goal dose of 250 mg twice a day.

●Valproate – Available formulations of valproate (active moiety) include valproic acid, valproate sodium, and divalproex sodium. For patients who can swallow tablets whole, the extended-release formulation of divalproex sodium is better tolerated than other forms of valproate. Extended-release divalproex sodium can be started at 250 mg daily and increased by 250 mg/week to a goal dose of 250 to 500 mg twice a day. For patients with swallowing difficulties, divalproex sodium sprinkle capsules (125 mg) can be opened and the sprinkles placed in applesauce. This formulation should be dosed two or three times a day, with a typical starting dose of 125 mg two or three times a day.

●Gabapentin- Available formulations of gabapentin include capsules and tablets. The typical starting dose is 100 mg twice a day and is increased slowly (by 100 mg every week) to a target dose of 300 mg two or three times a day.

Drug-related concerns — Other considerations when selecting an antiseizure medication include the following:

●Compared with younger adults, older adults appear to be more sensitive to side effects of antiseizure medications, experiencing them more frequently and with lower doses.

●General dose-dependent side effects of antiseizure medications that can be particularly problematic in older patients include falls, confusion, impaired gait, sedation, tremor, dizziness, and visual disturbance.

●Carbamazepine and phenytoin have multiple drug-drug interactions (table 3 and table 4) and should probably be avoided in older patients with polypharmacy.

●Carbamazepine, oxcarbazepine, and eslicarbazepine increase the risk of symptomatic hyponatremia, especially in patients receiving selective serotonin reuptake inhibitors (SSRIs) and/or diuretics.

●Topiramate and zonisamide are associated with increased rates of metabolic acidosis, especially if administered in conjunction with metformin.

●Levetiracetam is almost exclusively renally cleared and must be dose-adjusted in individuals with chronic kidney disease.

●Gabapentin and oxcarbazepine can rarely precipitate or induce myoclonic seizures in older patients with advanced dementia.

●Some antiseizure medications (eg, phenytoin, carbamazepine, phenobarbital) increase the rate of bone loss and may increase the risk of bone injury and fracture. It is somewhat reassuring that a case-control study involving 124,655 fracture cases found only a limited increased fracture risk among users of antiseizure medications [17]. Another study found that most of the increased risk of fractures in persons with epilepsy was related to seizures and not to bone biomechanic competence [18]. Gait impairment from antiseizure medication use is another potential contributor to falls and fractures in older patients with epilepsy [19]. These issues are reviewed in detail elsewhere. (See "Antiseizure medications and bone disease".)

●Cost of antiseizure medications can be a significant obstacle to treatment. In the United States, Medicare Part D coverage gaps ("donut hole") could lead to intermittent nonadherence [20].

Therapeutic monitoring — Older patients are less likely to take their antiseizure medications as directed as compared with younger counterparts, with some studies demonstrating nonadherence in one-third to one-half of older adults [21-23]. Nonadherence is associated with increased seizures and injury, higher risk of mortality, and greater health care utilization [24]. Attention to medication costs, more frequent clinic visits, and simpler regimens appear to mitigate these problems [23].

Antiseizure medication discontinuation — Because of the high rates of adverse effects associated with antiseizure medications, it is reasonable to consider drug discontinuation in patients with a reliable history who have been seizure-free for two to three years and who lack a clear remote symptomatic cause for their epilepsy diagnosis. The risk of seizure recurrence, the severity of seizures, and the risk for self-injury are the most important factors in this decision. Patients should be counseled to stop driving, swimming alone, and climbing ladders or operating heavy machinery during the tapering period and for three months after drug discontinuation.

DRUG-RESISTANT EPILEPSY

Definition and treatment options — Patients with epilepsy whose seizures do not successfully respond to antiseizure medication therapy are considered to have drug-resistant epilepsy (DRE). This condition is also referred to as intractable, medically refractory, or pharmacoresistant epilepsy. Drug-resistant is currently defined as the failure of adequate trials of two tolerated, appropriately chosen and administered antiseizure medications (whether as monotherapy or in combination) to achieve seizure freedom. (See "Evaluation and management of drug-resistant epilepsy", section on 'Definition'.)

Resective epilepsy surgery is the treatment of choice for DRE with localization-related or partial epilepsy, as this has the most likely chance of producing remission. Further antiseizure medication trials, vagal nerve stimulation, responsive cortical stimulation, and the ketogenic diet can reduce seizure frequency and improve quality of life but are more likely to be palliative, rather than curative, treatment options. (See "Evaluation and management of drug-resistant epilepsy", section on 'Treatment options'.)

Epilepsy surgery — Although age is not considered an absolute contraindication for epilepsy surgery, experience is limited in the population of older adults. Surgery should only be considered in individuals with DRE without signs/symptoms of a progressive neurodegenerative condition. (See "Surgical treatment of epilepsy in adults".)

While the data regarding the efficacy of epilepsy surgery in older adult patients are sparse, the available literature suggests that surgery is similarly effective in older and younger adults. A retrospective single-center study of epilepsy surgery in older adults (age ≥60 years) reported outcomes for a cohort of 51 patients with one year or more of follow-up and outcomes for 58 patients identified by a systematic review of literature [25]. High rates of freedom from disabling seizures were achieved in both the cohort and the literature groups (80 and 72 percent, respectively). In a comparison of the 51 older cohort patients with 50 consecutive younger adults (ages 25 to 45 years) who had epilepsy surgery at the same center, seizure outcomes and surgical complication rates were similar for the older and younger groups.

Other treatments

●Further antiseizure medication trials – Further trials of antiseizure medications in mono- or polytherapy can sometimes be of benefit in individuals with DRE. This is discussed separately (See "Evaluation and management of drug-resistant epilepsy", section on 'Antiseizure medications'.).

●Vagus nerve stimulation – The vagus nerve stimulator (VNS), a surgically implanted device, is a valid palliative treatment option for patients with DRE, used in conjunction with antiseizure medication therapy.

There is little experience with VNS in older adult patients compared with younger adults. A retrospective review using data from the device manufacturer identified 45 patients over the age of 50 (seven were over 60 years old and only one was over 70 years of age) who received VNS for intractable epilepsy [26]. At three months, 27 percent achieved a 50 percent reduction in seizures; at one year, 67 percent had achieved a 50 percent reduction in seizures. No serious surgical complications occurred. These data compare well with the efficacy of VNS in other populations with epilepsy. However, VNS has also been associated with higher rates of obstructive sleep apnea and respiratory complications, an important consideration in the older population [27]. (See "Vagus nerve stimulation therapy for the treatment of epilepsy" and "Evaluation and management of drug-resistant epilepsy".)

●Stereotactic thermocoagulation – Minimally invasive surgical methods are under investigation as an alternative form of treatment for patients with DRE and may become an attractive option for older patients. Stereotactic laser ablation in mesial temporal lobe epilepsy (SLATE) is a multicenter prospective single-arm clinical trial enrolling patients ages 18 to 70 with seizure freedom as a primary outcome measure [28]. Secondary endpoints include cognitive and quality-of-life outcomes.

●Ketogenic dietary therapies – Ketogenic dietary therapy (KDT) is an effective treatment for children and adults with epilepsy, but there are few data pertaining to its use for DRE in adults. In small case series of adults with DRE, use of the traditional or modified ketogenic dietary therapies was associated with reduced seizure frequency and severity [29-31]. (See "Ketogenic dietary therapies for the treatment of epilepsy".)

PROGNOSIS

Response to antiseizure medications — There are limited long-term prospective data describing the prognosis of older patients with epilepsy. Overall, the data suggest that most older patients respond to antiseizure medications [32-38]. As examples, a single center in Scotland described 117 older adults newly diagnosed with epilepsy and followed longitudinally [33]. The median age at time of diagnosis was 73 years. Sixty-two percent of patients were seizure-free for at least one year with the first antiseizure medication. Another report, a population-based study of epilepsy in Italy, identified 124 older adults newly diagnosed with epilepsy [37]. Approximately two-thirds of these adults achieved a two-year remission with or without medications.

Cognitive outcomes — Older patients with epilepsy rank cognitive problems as their greatest concern [39], and increasing evidence suggests that older patients with epilepsy experience faster cognitive decline, especially in processing speed [40]. The underlying pathophysiologic mechanisms for this observation remain unclear but may result from complex interactions among various factors including seizures, medications, and neurodegenerative and cerebrovascular disease burden [41].

Prognosis with status epilepticus — Older adults who develop status epilepticus have a worse prognosis. Associated mortality during the acute illness is higher in older patients; in one cohort, 35 percent of patients over age 60 years with status epilepticus died as compared with 16 percent of older patients with similar conditions and seizures [42]. In a second cohort, approximately 65 percent of patients over 80 years with status epilepticus died [42,43]. In-hospital mortality is associated with the duration of the seizure activity and also with the number of medical comorbidities [44].

Mortality is also high (18 to 52 percent) among older adults hospitalized with nonconvulsive status epilepticus [45-48]. Aggressive treatment of nonconvulsive status epilepticus may actually play a role in morbidity and mortality through induced hypotension, cardiac arrhythmias, and prolonged sedation [45,46,49].

Long-term mortality — Limited data suggest that new-onset epilepsy in older patients is associated with a high five-year mortality rate. In a retrospective report that analyzed data for 33.6 million Medicare beneficiaries age 65 and older, the five-year mortality rate among the subgroup of 99,990 incident epilepsy cases was 63 percent, whereas the five-year mortality rate for the entire cohort was 29 percent [50].

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: Seizures and epilepsy in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Seizures (The Basics)")

●Beyond the Basics topic (see "Patient education: Seizures in adults (Beyond the Basics)")

SUMMARY AND RECOMMENDATIONS

●The decision to start an antiseizure medication in an older adult patient with a first unprovoked seizure should be based on risk factors for seizure recurrence rather than age, similar to the decision in younger adults. Major risk factors for recurrent seizure include remote symptomatic etiology, first seizure arising from sleep, epileptiform abnormality on electroencephalography (EEG), and structural abnormality on brain magnetic resonance imaging (MRI). (See 'After a first unprovoked seizure' above.)

•For older adult patients with a first unprovoked seizure, we suggest antiseizure medication treatment only in the setting of clearly documented potential symptomatic cause of epilepsy (eg, stroke, traumatic brain injury, brain tumor) based upon history, an abnormal neurologic examination, a relevant abnormality on brain imaging with computed tomography (CT) or MRI, and/or epileptiform discharges on EEG. In the absence of a symptomatic cause of epilepsy, it is reasonable to defer antiseizure medication treatment for patients with a single unprovoked seizure and an unremarkable brain MRI and EEG. (See 'After a first unprovoked seizure' above.)

•For a patient who has two or more well-documented unprovoked seizures, antiseizure medication therapy should be started. (See 'After two or more unprovoked seizures' above and "Initial treatment of epilepsy in adults", section on 'Second unprovoked seizure'.)

●Selection of an antiseizure medication in older adults should be individualized according to seizure or epilepsy type, comorbidities, adverse effect profile, and drug-drug interactions. (See 'Selection of antiseizure medication' above.)

●Antiseizure medications should be started at very low doses and titrated gradually. Target doses are generally much lower in older adults as compared with younger patients. (See 'Dosing strategies' above.)

ACKNOWLEDGMENTS — The UpToDate editorial staff acknowledges Anil Mendiratta, MD, and Hyunmi Choi, MD, MS, who contributed to an earlier version of this topic review.