Methylphenidate for Attention Problems in Epilepsy Patients: Safety and Efficacy

Abstract

Children with attention deficit hyperactivity disorder (ADHD) have an increased risk of seizures, and children with epilepsy have an increased prevalence of ADHD. Adults with epilepsy often have varying degrees of attentional dysfunction due to multiple factors, including antiseizure medications, frequent seizures, interictal discharges, underlying lesions, and psychiatric comorbidities. Currently, there are no approved medications for the treatment of epilepsy-related attentional dysfunction. Methylphenidate (MPH) is a stimulant, FDA-approved for the treatment of ADHD, and often used for ADHD in the setting of pediatric epilepsy. Large database and registry studies indicate safety of MPH in children with ADHD and epilepsy, with no significant effect on seizure frequency. Small single-dose and open-label studies suggest efficacy of MPH in adults with epilepsy-related attention deficits. MPH represents a possible treatment for attentional dysfunction due to epilepsy, but large, randomized, placebo-controlled, double-blinded studies are needed.

1. Introduction

Attention deficit hyperactivity disorder (ADHD) is the most common comorbidity in children with epilepsy, negatively impacting attention, working memory and learning, impulse control, reward mechanisms, academic success, social cognition, response times, and executive functions (e.g., set shifting, planning) [1–4]. ADHD is a developmental disorder that affects 20–36% of children with epilepsy versus 2.4–15.5% of general pediatric [5–7] and 1–5% of adult [8] populations. This relationship is bidirectional: attentional symptoms are often observed before epilepsy onset [9] and children with ADHD have 2- to 4-fold higher risk of unprovoked seizures than controls [10,11], with a ~1.2–14% prevalence of seizures in children with ADHD [10,12]. Epileptiform EEG abnormalities are more common in children with ADHD without clinical seizures than in controls [13].

Clinical ADHD presentations are similar in children with and without epilepsy. Children with ADHD and epilepsy had symptom rating scores comparable to patients with ADHD alone, although subscores suggested that children with epilepsy had greater inattention and learning difficulties, while children with ADHD alone were more hyperactive [14]. Both groups were likely to demonstrate the combined subtype of ADHD, with inattentive and hyperactive symptoms as well as frequent comorbid anxiety and oppositional defiant disorders [14,15]. There are strong similarities in neural activation patterns in children with ADHD-like symptoms with or without epilepsy, suggesting that the two groups share aberrant neural networks [16]. Further, both groups improve with methylphenidate (MPH) therapy.

Occasionally, ADHD symptoms will persist into adulthood, although patients may no longer meet full Diagnostic and Statistical Manual (DSM) ADHD criteria. Large-scale epidemiological studies identified ADHD symptoms in 15.4–18.4% of adult epilepsy patients [17,18] and a prevalence of reported ADHD more than twice that of people without epilepsy [19]. Hospital and clinic-based data indicate the presence of ADHD symptoms in up to 35% of epilepsy patients [20], which may correlate with seizure frequency and number of ASMs [18]. More often, however, attentional deficits in adult epilepsy patients result not from the developmental disorder of ADHD, but from factors related to the underlying epilepsy. Adults with epilepsy may have increased rates of inattention, hyperactivity, irritability, memory impairment, and decreased processing speed [21]. Attentional and executive dysfunction occur in ~50% of adults with new-onset epilepsy before treatment [22], suggesting that antiseizure medication (ASM) effects alone cannot account for these cognitive deficits. Cognitive deficits are often multifactorial, resulting from interictal discharges and seizures, seizure localization in linguistic, mnemonic, or other cognitive areas, structural lesions, epilepsy onset in early childhood, long epilepsy duration, psychiatric comorbidities, and the epilepsy syndrome [23–25]. Nevertheless, such patients may still benefit from MPH.

Below we will discuss possible mechanisms of attention deficits in ADHD and epilepsy. This will be followed by a review of MPH and its effects on cognition and quality of life in ADHD, safety, including seizure risk, and efficacy for cognitive deficits in epilepsy patients with and without ADHD.

2. Anatomy of Attention Deficits

Epilepsy is a network disorder. While focal seizures cause maximal functional impairment around the seizure onset zone, they can impair the function of interconnected regions. For example, frontal hypometabolism on PET is often seen in patients with mesial temporal lobe epilepsy [26]. Such pathological effects can alter cognitive networks and impair attention, memory, language, and executive functions [22,27,28].

Subcortical activating networks underlying vigilance may contribute to widespread structural and functional effects of mesial TLE, as seizures can also disrupt these subcortical areas and pathways [29]. The ascending reticular activating system (ARAS) projects to temporal, insular, thalamic, and neocortical regions, preferentially to mesial neocortical areas including the anterior cingulate cortex and precuneus [30]. Resting-state functional magnetic resonance imaging (fMRI) demonstrated decreased overall connectivity in subjects with TLE, which was particularly notable between ARAS structures and the neocortex. This decreased connectivity correlated with an increased number of consciousness-impairing seizures and poorer neuropsychological test performance, including attentional impairment [30,31]. In contrast, diffusion tensor imaging and resting-state fMRI revealed increased functional connectivity and fiber numbers of the left dorsolateral prefrontal-thalamic pathways in patients with intractable TLE and impaired executive function [32], possibly due to remodeling in the seizure network.

ADHD may provide insights into mechanisms underlying epilepsy-related attentional deficits. The classic “prefrontal hypothesis” suggests that aberrant prefrontal function and its impact on the striatum and other subcortical structures leads to the development of ADHD. This view fails to account for the variable symptoms seen across patients [33]. Alternative hypotheses include a role of early cerebellar injuries and abnormal norepinephrine metabolism in the locus coeruleus, with age-related maturation of fronto-striatal circuits leading to the typical pattern of symptom amelioration over time [33]. Nevertheless, it remains unlikely that ADHD can be explained by injury to a single area. ADHD represents dysfunction of a wide network of interconnected cortical and subcortical regions, including the dorsolateral prefrontal cortex, striatum, frontal white matter, right inferior parietal cortex, cerebellum, posterior cingulate, thalamus, and temporal lobe [4,34–37]. Activation of fronto-striatal and parietal attention networks was impaired during a “no-go” condition in ADHD subjects, with reduced activity of the caudate nuclei, anterior cingulate cortex, and parietal cortical structures, and increased activity of the insular cortex, correlating with inattention and impulsivity symptom scores [38]. Decreased prefrontal, cerebellar, and anterior cingulate activations also occurred in children and adolescents with ADHD compared to controls during a go/no-go task variant, when stimuli were of unexpected type or timing. These regions overlap with the temporal, thalamic, prefrontal, and mesial neocortical areas of the ARAS network implicated in epilepsy.

3. Methylphenidate

Cognitive deficits are disabling for epilepsy patients, with no approved medical therapy [22]. Attentional and other cognitive symptoms may improve with better seizure control, minimizing ASM polypharmacy, or switching ASMs, but this often fails to resolve these deficits [39]. Cognitive rehabilitation remains the primary treatment modality. While cognitive rehabilitation may provide coping mechanisms, it does not address underlying etiologies. Further, learned strategies may not generalize to tasks outside of the training protocol [40].

MPH may improve attentional deficits due to acquired neurological disorders, such as neurological and hematologic malignancies, dementia, HIV-AIDS, Parkinson’s disease, hypoactive delirium, opiate-induced cognitive dysfunction, post-stroke depression, and traumatic brain injury (TBI) [41,42]. These findings suggest that MPH may improve epilepsy-related cognitive dysfunction.

MPH is a stimulant, a piperazine-substituted phenylisopropylamine, structurally related to amphetamine. Synthesized in 1944, MPH was FDA-approved in 1953 and is currently indicated for ADHD and narcolepsy. MPH increases dopaminergic and noradrenergic transmission in the prefrontal cortex and striatum, partly by impairing dopamine (DA) and norepinephrine (NE) reuptake via inhibition of DAT1 and NET presynaptic transporters, respectively [43,44]. MPH also increases activity of the vesicular monoamine transporter (VMAT), which transports amines (e.g., dopamine, norepinephrine, serotonin, histamine) into vesicles within presynaptic neurons in preparation for release and decreases oxidative decay of extravesicular DA [45]. These actions result in enhanced extracellular DA and NE availability. Additionally, MPH is a 5HT_1A serotonin receptor and α2 adrenergic receptor agonist [46]. In rats, MPH also increases prefrontal histamine levels [47]. Normal prefrontal-initiated inhibition regulates attention and impulse control and minimizes distractibility [48]. It is unknown which pharmacologic effects are most relevant to cognitive improvements. Possible mechanisms of action include DA- and NE-mediated enhancement of specific attentional signaling pathways and broad effects on neuronal firing, synaptic reconfiguration, and synaptic efficacy [49]. Histamine plays a role in cognition and alertness and may contribute via DA- or NE-mediated processes [47].

The half-life of MPH is 2.6–3 hours, followed by nonmicrosomal hydrolytic esterase metabolism throughout the body and excretion in urine. MPH displays low protein-binding and high lipid solubility, quickly reaching its peak brain concentration. Peak plasma concentrations and clinical effects are attained in 1–3 hours after taking immediate release preparations. Food may delay the absorption of MPH, but clinical data have not shown a significant impact on efficacy, so it may be taken fasting or after meals [44].

Although MPH is often dosed by weight, wide ranges in optimal dosage for symptom relief, individual variability in peak plasma concentrations at a given dose, and a lack of correlation between plasma concentration and clinical efficacy suggest that dosing by mg/kg is not the most effective strategy [43,44]. While the maximum dose of most oral MPH formulations is 60mg daily, with a 72mg daily maximum for OROS preparations, higher doses are often used off-label in adults seeking optimal response [44].

3.1. Methylphenidate and ADHD

ADHD symptoms are reduced with MPH treatment, as measured by standard scales such as the Swanson, Nolan and Pelham Scale (SNAP-IV), ADHD Rating Scale (ADHD-RS-IV), and Clinical Global Impressions Scale: ADHD Severity Scale (CGI-ADHD-S) [50–52]. A positive response has been demonstrated with respect to inattention, hyperactivity, and impulsivity [53]. MPH normalized fronto-parieto-cerebellar dysfunction in boys with ADHD as evidenced by resting state fMRI, [54] which correlated with decreased symptom scores (e.g., hyperactivity, distractibility) in 30% of subjects. While most studies suggest a positive effect of MPH, evidence fails to confirm that stimulants completely correct ADHD-related cognitive deficits [1–4]. Unfortunately, methodological differences across studies limit conclusions, as results vary widely due to differing measures to evaluate cognition, MPH doses, and inclusion/exclusion criteria.

3.2. Methylphenidate Effects on Attention and Memory

Attention, as commonly measured by go/no-go paradigms, continuous performance tests (CPTs), and Posner’s Attentional Network Task (ANT) [55], is a complex construct. Posner postulated three distinct, primary attentional networks: alerting, orienting, and executive control [56]. CPTs, such as the Conners’ CPT, are commonly used to assess these networks in ADHD research [57,58], with medium effect sizes for measuring inattention [4,59,60]. The tasks require that subjects attend to a long series of stimuli while responding to targets or withholding responses to non-targets. Some versions of the task, like the Conners’ CPT, are response withholding tasks assessing executive/controlled attention, while others evaluate sustained attention (i.e., vigilance).

CPTs primarily assess omission errors (not responding to a stimulus when required), commission errors (responding to a stimulus when not required), and reaction times (RT). Children with ADHD have slower and more variable RTs, which may result from periodic attentional lapses [4], variable DA signaling [61,62], or interference by resting cognitive states supported by the default mode network [63]. MPH decreases RTs, improves ‘hit’ rates on target stimuli, and increases sustained, focused attention [1]. A meta-analysis examining 60 studies on the cognitive effects of MPH in children and adolescents with ADHD consistently found statistically significant effects of MPH on executive memory, non-executive memory, reaction time, reaction time variability, and response inhibition [64].

ADHD may impair aspects of memory, particularly tasks dependent on attentional and executive control. Working memory tasks tap lateral prefrontal, parietal, and anterior cingulate attentional networks that maintain and manipulate information and are impaired in ADHD [65–67]. Working memory may be viewed as an attentional task, distinct from the encoding, short- and long-term storage, recall, and recognition of declarative information. Nevertheless, attention and memory are intimately linked, as attention selects items for memory, and memories may guide attention [68]. Executive processes influence strategies to encode or recall, which may be impaired in ADHD [69–72]. ADHD is associated with deficits in encoding/learning [67,69,71], immediate/short-term recall [67,73], delayed recall [67,71,73], and prospective memory, the ability to recall events to be performed at a future time [74]. ADHD patients may also show deficits in recognition and source memory, reflecting where, when, and how the to-be-remembered event occurred [67,74].

MPH may enhance memory via increased DA and NE, which regulate the activity of and communication between the ventrolateral prefrontal cortex and hippocampal formation [75]. Children with ADHD demonstrate improved working memory with MPH [76,77]. Few studies address MPH effects on ADHD-related memory deficits in adults, but the limited available data favor treatment. Adults with ADHD had better short-term, prospective, visual, and verbal memory with MPH [74,78], although performance remained impaired relative to controls [74]. While delayed word recall improved with MPH, there were no effects on immediate recall or delayed recognition [75]. The relationship between depression, memory function, and MPH response has been inconsistent [75,78].

3.3. Methylphenidate and Executive Function

Children with ADHD may have deficits in executive function in addition to memory and attention disorders. Most studies in children found that MPH improved planning, cognitive flexibility, and inhibitory control [3]. Executive skills improve as children age and children with ADHD also show improvements as they get older. While data often suggest that adult ADHD is associated with executive dysfunction (e.g., deficits in planning, problem-solving, and cognitive flexibility/set-shifting) [79], findings are mixed and task-dependent [1,3,4,33,59]. Interference tasks and planning are not consistently improved by MPH in adults, possibly due to compensatory strategies, insensitivity of outcome measures, or relatively preserved pretreatment skills [4]. Overall, in children and adults, MPH demonstrates less prominent effects on tasks with an executive component, such as planning and set-shifting, than those without [4].

3.4. Methylphenidate Dose Effects on Cognition

MPH can produce dose-dependent improvements in attention, vigilance, memory, and working memory in ADHD [4,80]. Conversely, higher doses may increase side effects without symptomatic improvement [81] or produce transient improvement that wanes with tolerance while the side effects persist. In healthy people, higher doses paradoxically increased distractibility and impulsivity [1] and produced excessive focus, impaired cognitive flexibility, and a “zombie-like” state in children with ADHD in some [82,83], but not all, studies [84]. As dose effects may depend on the cognitive outcome measures and individual characteristics [1,3], dose-related effects of MPH may not be generalizable.

3.5. Methylphenidate and Quality of Life

Attentional dysfunction negatively impacts quality of life (QOL). Children and adolescents with ADHD have poorer QOL than epilepsy patients, and patients with ADHD and epilepsy have poorer quality of life than those with ADHD or epilepsy alone [14]. Epilepsy patients with ADHD have impaired physical well-being, self-esteem, family relationships, and school functioning compared to epilepsy patients without ADHD. Overall QOL negatively correlates with total ADHD symptom rating scores, as well as subscores reflecting hyperactivity/impulsivity. In 1,361 survey respondents [18], poorer QOL was reported in adults with epilepsy and ADHD symptoms compared to those without ADHD symptoms, controlling for sociodemographic factors, comorbid depression and anxiety, seizure frequency, and number of ASMs. Open-label MPH improves QOL in children [85] and adults [86] with ADHD alone, and in children with ADHD and poorly [87] or well-controlled [88] epilepsy. Reduced inattentive symptoms correlate with improved global QOL [87], underscoring the importance of ADHD treatment.

3.6. Methylphenidate Adverse Events and Drug Interactions

3.6.1. Methylphenidate and Seizure Risk

Stimulant use in epilepsy patients has caused concern for increased seizures. This is not predicted given MPH’s main effects to increase dopaminergic and noradrenergic activity, [89] as neither are associated with lowered seizure threshold. Nevertheless, FDA labelling warns of a lowered seizure threshold, particularly in patients with a history of seizures or EEG abnormalities, and recommends discontinuing the drug in the setting of seizures. The concerns are based on case reports [90–94], although 21 of 105 children and young adults with ADHD and epilepsy had increased seizure frequency in a medical record review [95]. The risk of seizure exacerbation was increased in patients with the combined subtype of ADHD, anxiety, and poorly-controlled epilepsy at baseline. In children with ADHD and active seizures, 5 of 57 patients had increased seizure frequency, but there was no overall group effect [96]. A greater risk of seizures with increasing doses of OROS MPH was seen in 33 children and adolescents with ADHD and epilepsy [97], but none of the subjects met a priori criteria for worsening seizures, and there were “too few seizures….to confidently assess seizure risk.” For all of these studies, there was no control group to assess the well documented effect of variable seizure frequency in epilepsy patients. Some patients will have a worsening or improvement in seizure control after any intervention is introduced simply by chance.

Overall, an increased risk of seizures has not been clearly demonstrated in the literature [39,98,99]. Multiple pediatric studies in patients with epilepsy and ADHD found no effect on seizure frequency in most subjects [88,96,100–104]. In small series of adults with epilepsy and ADHD or cognitive complaints, open-label MPH did not alter seizure frequency or severity [105–107].

The strongest data for MPH safety comes from large-scale database studies. Of 29,604 children and young adults taking MPH in the Hong Kong Clinical Data Analysis and Reporting System medical record database, 69 (0.2%) patients developed new-onset seizures during MPH treatment [108]. The period of risk occurred within 30 days of initiating treatment and lack of risk beyond 30 days was “reassuring” [109]. In patients with ADHD without epilepsy, the incidence of seizures did not differ between MPH and placebo in clinical trials and post-marketing product safety databases, and no seizures were seen in 523 children and adolescents prescribed MPH [110]. In the Swedish Prescribed Drug Register, 995 pediatric epilepsy patients had no change in seizure frequency with ADHD medication [111]. ADHD medication periods were associated with reduced seizure frequency compared to non-medication periods in an individual subject analysis [111]. Similarly, ADHD medication was associated with lower odds of seizures among 801,838 patients with and without a history of epilepsy in a claims database [112].

Most studies found that poorly-controlled epilepsy does not increase risk of seizure exacerbation with MPH therapy. In a small pediatric study, there were no overall changes in seizure frequency with MPH [104]. Of five children with active epilepsy, three had increased seizure frequency, one demonstrated no change, and one had fewer seizures. In a larger open-label study, 2 of 22 patients with poorly-controlled epilepsy had increased seizure frequency with MPH [113]. A similar study found that seizure frequency increased in 4 of 22 patients, but with reduced seizure severity in the sample as a whole [114]. Seizure control may improve with MPH in some patients, consistent with data suggesting that DA receptor signaling can suppress seizure activity [87,115]. MPH was also associated with a trend toward decreased seizure frequency in TBI patients with active epilepsy [116]. While further research is needed, results suggest that MPH may be used in patients with treatment-resistant epilepsy.

Pre-treatment EEG was proposed to assess risk, based on limited data from children without epilepsy who received EEGs prior to stimulant treatment. Seizures occurred with MPH in 1 of 175 patients with a normal EEG but 3 of 30 children with epileptiform abnormalities [117]. In contrast, no alteration in seizure frequency or new-onset seizures occurred in 23 children with ADHD and epilepsy or epileptiform discharges [103]. None of 18 patients with ADHD and centrotemporal spikes without corresponding epilepsy treated with stimulants developed seizures [118]. In 62 children with EEG abnormalities, EEGs improved following MPH treatment [96]. The impact of MPH on EEG is variable, however, with 32% of patients demonstrating increased abnormalities and 28% showing electrographic improvement in a sample of 99 subjects [95]. Currently, routine EEG is not recommended during stimulant treatment, as changes in EEG with MPH are usually unrelated to clinical seizure activity [104,119].

MPH safety data have come primarily from open-label and observational studies. Blinded, placebo-controlled data beyond a single dose are limited [97,100], with the longest trial in 10 pediatric subjects with well-controlled seizures, who had no seizures, significant EEG changes, or effects on ASM levels over four weeks of treatment [100]. While the evidence supports safety of MPH in the setting of epilepsy, effects of MPH on seizure activity should be studied in a randomized, double-blinded, placebo-controlled manner, as advocated by Miller [120].

3.6.2. Other Side Effects of Methylphenidate

A systematic review [121] concluded that MPH 20mg-90mg daily is well-tolerated, with an overall “number needed to harm” of 23, based on dropout rates. Adverse reactions to MPH include tachycardia, palpitations, headache, insomnia, jitteriness, anxiety, irritability, hyperhidrosis, weight loss, decreased appetite, dry mouth, nausea, growth suppression in children, and abdominal pain. Rare complications include priapism [122], peripheral vasculopathy, and hypersensitivity reactions. Data linking stimulants to tic exacerbation have come under scrutiny. Clinically, MPH is commonly used in the setting of tics, with some patients seeing improvement. MPH is not recommended in pregnancy or lactation. Given its short half-life, side effects of MPH should resolve within several hours. Discontinuation symptoms include rebound hyperactivity, depression, and fatigue.

Cardiovascular side effects include minimal and inconsistent increases in blood pressure and heart rate [107,123–126]. These measures should be routinely monitored during treatment. Concurrent treatment with a monoamine oxidase inhibitor (MAOI), or MAOI use within 14 days of starting MPH, is contraindicated, given a risk of hypertensive crisis. Concomitant use of halogenated anesthetics may also risk sudden blood pressure and heart rate increases, and MPH must be held before surgery. Amphetamines, structurally and functionally similar to MPH, can cause subarachnoid and intraparenchymal hemorrhage in the setting of abuse [127,128], but reports of intracerebral hemorrhage with MPH are rare. Sudden death, ischemic stroke, and myocardial infarction may rarely occur in adults [126], but MPH alone is not a significant risk factor for sudden cardiac death. In individuals with underlying structural cardiac disease, however, risks may be increased.

Exacerbation of behavioral disturbances and thought disorder may occur in people with pre-existing psychoses, while patients with bipolar disorder may experience mixed mood or manic symptoms [126]. Clinical experience suggests that exacerbation of psychiatric symptoms is uncommon, and for stable bipolar patients, stimulants can be well-tolerated and effective. Induction of psychotic or manic symptoms in patients without a prior history is rare [129,130]. The risk of psychosis is increased with doses ≥ 120mg daily, which exceeds recommendations [131]. MPH is a Schedule II controlled substance that risks abuse. Children and adults with ADHD are at higher risk for substance use disorders than the general population. Whether therapeutic doses of MPH lead to dependence, however, needs further study [121].

MPH has few drug-drug interactions, outside of the aforementioned agents. It exhibits little CYP450 activity, although inducers of CYP3A4 may lower MPH levels [132]. There are no clinically significant drug-drug interactions between MPH and ASMs [133].

4. Methylphenidate for Cognitive Deficits in Epilepsy

In pediatric epilepsy patients, multiple studies and extensive clinical experience support the efficacy of MPH for ADHD. MPH improves attention, hyperactivity, impulsivity, and QOL in this population [88,96,100–102,104], with 86% of patients with either inattentive or combined inattentive-hyperactive/impulsive subtypes demonstrating a positive response [134]. An International League Against Epilepsy (ILAE) consensus paper reported Level B evidence for safety and efficacy of MPH in children with ADHD and epilepsy [135]. In adults with epilepsy, a case series without objective testing reported benefits of open-label MPH for newly-diagnosed ADHD [105]. A case report of MPH use in an adult with ADHD, refractory epilepsy, and obsessive-compulsive disorder also reported ADHD symptom improvement [136]. Based on findings in ADHD, we propose that MPH should be studied to treat adults with cognitive deficits due to epilepsy.

The few studies of MPH for epilepsy-related cognitive dysfunction in adults are encouraging. MPH showed promise for adult epilepsy-related cognitive impairment in small single dose and open-label trials [60,106,107]. Single-dose MPH 10 and 20 mg improved a combined measure of attention, memory, and psychomotor speed in a double-blind, randomized, placebo-controlled, crossover study [60]. In a subsequent one-month open-label period [107], subjects demonstrated better attention, memory, psychomotor speed, QOL, and depressive symptoms with MPH 10–20 mg taken twice daily. In adults with cognitive deficits associated with focal-onset epilepsy and ASM use, open-label MPH improved attention, memory, information processing speed, quality of life, and overall cognition [106]. These open-label trials were limited, however, by small samples, unblinded designs, and a lack of epilepsy-only control groups. Although these results are promising, larger, longer duration, blinded trials in people with epilepsy are needed to guide clinical practice.

Whether MPH efficacy varies across epilepsy etiologies and syndromes is unknown. Epilepsy commonly occurs in traumatic brain injury (TBI) [137–139]. While some post-traumatic epilepsy patients were included in prior studies [60,105,107], samples were too small to assess TBI as a variable. Studies of MPH in TBI alone yield varying results. A four-week, double-blind, placebo-controlled trial in subjects with mild-moderate TBI demonstrated similar improvements in cognitive functioning, depression, and maintenance of alertness with MPH and placebo, suggesting only that MPH does not impede recovery [140]. In a two-week, double-blind, placebo-controlled crossover study, 10 pediatric subjects with hyperactivity and mild to severe TBI showed no significant changes on measures of behavior, attention, memory, or processing speed [141]. In contrast, other TBI studies found improved visuospatial and working memory, sustained attention, depression, mental fatigue, eye-hand coordination, reaction times, overall cognitive function, and subjective cognitive symptoms with MPH compared to placebo [123,142–146]. No differences in efficacy based on the severity of TBI were noted across studies.

Potential differences in the safety and efficacy of MPH in focal-onset vs. primary generalized epilepsies have not been studied. Adult studies are limited to focal-onset epilepsies [106] or contained too few subjects to draw comparisons [60,105,107]. In children with epilepsy and ADHD, limited data suggest no relationship between seizure type and MPH response [147].

5. Conclusions

ADHD is a common comorbidity in children with epilepsy, with a bidirectional relationship. Adults with epilepsy also commonly exhibit attentional deficits, which are typically multifactorial in etiology, due to ongoing seizures, ASMs, and other causes. The comorbidity of attentional dysfunction and epilepsy may be at least partially explained by abnormalities in the ARAS network.

Epilepsy-related attention deficits are distressing for patients and impair QOL, with no approved medication available. The efficacy of MPH in treating cognitive deficits in ADHD and other neurological disorders suggests possible benefit for epilepsy-related cognitive dysfunction. Studies in children with epilepsy and ADHD demonstrate improvements in attention, hyperactivity, impulsivity, and QOL with MPH. Small, single-dose or open-label studies also suggest benefit in adults with attention difficulties due to epilepsy. MPH has a reasonable safety profile, even in patients with poorly-controlled seizures. Concerns regarding lowered seizure threshold are based primarily on isolated case reports, while large database and registry studies suggest MPH does not worsen seizure control and may lower the risk of seizure occurrence. MPH may provide a much-needed treatment for epilepsy-related attention deficits, but randomized, double-blind, placebo-controlled trials are needed, including larger samples, long-term MPH use, and varied seizure types.

Table 1. Studies of methylphenidate in the setting of epilepsy.

ADD = Attention Deficit Disorder, ADHD = Attention Deficit Hyperactivity Disorder, AED = antiepileptic drug, AEP = Adverse Events Profile, AMP = amphetamines, ARS = Attention Deficit Hyperactivity Disorder Rating Scale-IV, CBCL = Child Behavior Checklist, CGI-I = Clinical Global Impression - Improvement, CGI-S = Clinical Global Impression - Severity, CPT = Continuous Performance Test, EEG = electroencephalogram, ER = extended release, IR = immediate release, MCG = Medical College of Georgia, MPH = methylphenidate, MTA-SNAP-IV = Multimodal Treatment Study for Attention-Deficit/Hyperactivity Disorder Swanson, Nolan, and Pelham, Version IV, NR = not reported, OROS = Osmotic Release Oral System, PNES = psychogenic non-epileptic seizures, QOL = quality of life, QOLCE = Quality of Life in Childhood Epilepsy Questionnaire, QOLIE-89 = Quality of Life in Epilepsy Inventory – 89 question version, QVCE = Quality of Life in Children with Epilepsy, SDMT = Symbol Digit Modalities Test, SSC = Stimulant Side-Effect Checklist, TCA = tricyclic antidepressant, VAS = visual analog scale, WISC-R =Wechsler Intelligence Scale for Children-Revised

Study	Diagnosis	Study Design	N	Age (yrs)	Medication	Efficacy	Seizure Frequency
Adams et al. (2017) [60]	Epilepsy	Double-blind, placebo-controlled, single-dose crossover	35	18–65	IR, 10 mg and 20 mg vs. placebo	Benefit: with 10mg and 20mg, combined cognitive outcome measure based on Conners CPT, SDMT, MCG Paragraph Memory Test	No change
Adams et al. (2017) [107]	Epilepsy	Open-label	Epilepsy = 30 Untreated healthy controls = 14	18–65	IR, 20–40 mg/day × 1 month	Benefit: CPT, QOLIE-89, SSC, AEP	No change
Brikell et al. (2019) [111]	Epilepsy ± initiating ADHD medication	Population- based	995 initiating ADHD medication	<19	Per treating clinician*	NR	No change
Feldman et al. (1989) [100]	Epilepsy + ADD/ADHD	Double-blind, placebo controlled crossover	10	6.8–10.8	0.3 mg/kg bid vs. placebo**	Benefit: Conners’ Teacher Rating Scale and Finger Tapping Task	No seizures during treatment
Finck et al. (1995) [101]	Epilepsy + ADHD	Open-label	20	6–12	0.3–1 mg/kg/day × 0.3–62 months*	Benefit: ADHD criteria score, “neuropsychological status” based on WISC-R, dichotic listening, word list learning, reaction time to simpIe visual material, other unspecified tests	No change
Gonzalez-Heydrich et al. (2010) [97]	Epilepsy + ADHD	Double-blind, placebo controlled, crossover	33	6–18	OROS, maximum of 18, 36, or 54 mg taken for up to 1 week following titration period vs. placebo	Benefit: ARS, CGI-ADHD-I	No change. Too few seizures to assess risk. Increased likelihood of seizures with higher dose.
Gonzalez-Heydrich et al. (2014) [147]	Epilepsy + ADHD symptoms/ diagnosed ADHD treated with MPH or AMP	Retrospective record review	36 (19 MPH-treated)	<18	Mean dose 0.62 mg/kg/day*	Benefit: CGI-S, CGI-I; 63% were “responders” based on CGI-I	No seizures in those who were seizure-free at baseline. Of patients with active seizures at baseline, 1 had increased seizure frequency with MPH.
Gross-Tsur et al. (1997) [104]	Epilepsy + ADHD	Double-blind, placebo controlled crossover	30	6.4–16.4	0.3mg/kg/day × 2 months. On testing days, either placebo or MPH 0.3 mg/kg*	Benefit: CPT; improvement in 70% of subjects per parental report	No seizures in those who were seizure-free at baseline. Of 5 subjects with active seizures, 3 had increased seizure frequency, 1 showed no change, and 1 was seizure-free with MPH.
Gucuyener et al. (2003) [96]	Epilepsy + ADHD	Open-label	ADHD + seizures = 57 ADHD + EEG abnormalities = 62	6–16	0.3–1 mg/kg/day × 12 months**	Benefit: Conners’ Rating Scales (parents and teachers), ADHD symptom scores	5 subjects had increased seizure frequency; no new-onset seizures
Koneski et al. (2011) [113]	Epilepsy + ADHD	Open-label	24	7–16	Maximum 60mg/day, taken qday or bid × 6 months*	Benefit: MTA-SNAP-IV; effective in ~70.8% based on ratings by parents and teachers	2 subjects had increased seizure frequency
McBride (1986) [103]	Seizures or epileptiform abnormalities on EEG + ADD	Open-label	23	4–15	0.33 mg/kg/dose (± 0.13 SD) up to 0.63 mg/kg/day (±0.25 SD)*	NR	No change. No seizures in those who were seizure-free at baseline.
Moore et al. (2002) [106]	Epilepsy	Open-label	11 (8 completers)	16–60	IR (Ritalin), 0.15 mg/kg/day titrated up to 0.30 mg/kg/day if needed × 3 months	Benefit: QOLIE-89 (overall, memory, and attention/concentration scores); MicroCog (attention/mental control, memory, spatial processing, information processing speed, general cognitive function, general cognitive proficiency), VAS Fatigue score	1 subject with increased seizure frequency, 1 with decreased frequency, 1 unchanged, 5 remained seizure-free
Park et al. (2018) [95]	Epilepsy + ADHD	Retrospective record review	105	7–24	IR, ER, or OROS mean dose 0.84 mg/kg/day × 2 weeks-89 months	Benefit: CGI-S; 61.9% were ‘‘responders” based on CGI-I scores, improved ADHD symptoms in 82.8%	21 subjects had increased seizure frequency
Radziuk et al. (2015) [87]	Epilepsy + ADHD	Open-label	30	6–16	0.40–0.50 mg/kg/day × 3 months*	Benefit: QVCE (all domains), MTA-SNAP-IV	Overall decreased seizure frequency and severity. 1 subject withdrew due to seizure worsening.
Santos et al. (2013) [114]	Epilepsy + ADHD	Open-label	22	6–16	Maximum dose 1 mg/kg × 3 months*	Benefit: CBCL (parent ratings); 73% with resolution of clinically significant symptoms based on MTA-SNAP-IV	Overall decreased seizure severity. 4 subjects with increased seizure frequency, resulting in 1 withdrawal. In the remaining 3 subjects, frequency was similar or reduced compared to baseline after initial breakthrough seizures with MPH initiation.
Semrud-Clikeman et al. (1999) [102]	Epilepsy ± ADHD	Single-dose, open-label	Epilepsy + ADHD = 12 Epilepsy alone = 21 ADHD alone = 22 Controls = 15	7–16	Given to groups with ADHD; dose unspecified*	Benefit: CPT	NR
Socanski et al. (2013) [134]	ADHD ± epilepsy	Retrospective record review	ADHD=593 Epilepsy + ADHD = 14	6–14	Dose unspecified*	Benefit: 85.7% of epilepsy patients with positive response	“Majority.... had mild (an easily treated) epilepsy and AED treatment was successful”
van der Feltz-Cornelis (1999) [136]	Epilepsy + ADHD	Case series	1	30	10mg bid increased to 30mg bid with additional 5mg in afternoon**	Benefit: subjective concentration	No seizures during treatment
van der Feltz-Cornelis et al. (2006) [105]	Epilepsy + ADHD	Open-label	Epilepsy = 3 PNES = 3	19–30	10 mg bid × 6 weeks**	Benefit: symptom improvement based on psychiatric interview	No change
Wiggs et al. (2018) [112]	ADHD ± epilepsy	Retrospective record review, claims database	ADHD alone = 798,675 ADHD + seizures = 3163 Non-ADHD controls = 801,831	>5	Per treating clinician. Various formulations of MPH, amphetamines, and atomoxetine included.	NR	Decreased seizure risk; 29% lower odds in ADHD + seizures group, 49% lower odds in ADHD alone group in intra-individual analysis. Long-term use not associated with seizure risk.
Wroblewski et al. (1992) [116]	Epilepsy + severe brain injury	Retrospective record review	30	17–69	Per treating clinician*	NR	Overall trend toward fewer seizures during treatment; 4 patients with increased seizure frequency (3 of the 4 concurrently taking TCAs), 13 unchanged, 13 decreased
Yoo et al. (2009) [88]	Epilepsy + ADHD	Open-label	25	6–17	OROS, 18–54mg/day × ~8 weeks	Benefit: QOLCE (physical restriction, self-esteem, memory, language, other cognition, social interaction, behavior, general health, and overall QOL), ARS, CGI-S; CGI-I “much” or “very much” improved in 64%	2 subjects had seizures during study period without requiring discontinuation

^*formulation (IR, ER, OROS) unspecified

^**bid or tid dosing suggests IR preparation, but this was not specified

Glossary

ADHD

attention deficit hyperactivity disorder

ASM

antiseizure medication

ARAS

ascending reticular activating system

DA

dopamine

DSM

Diagnostic and Statistical Manual

EEG

electroencephalogram

fMRI

functional magnetic resonance imaging

MAOI

monoamine oxidase inhibitor

MPH

methylphenidate

NE

norepinephrine

RT

reaction time

TBI

traumatic brain injury

TLE

temporal lobe epilepsy