Current Pediatrics Reports (2018) 6:178–187 https://doi.org/10.1007/s40124-018-0171-x

PEDIATRIC PALLIATIVE CARE (KS HOEHN, SECTION EDITOR)

Integrative Palliative Care and Management of Refractory Epilepsy Colleen Buhrfiend 1 & Peter Heydemann 1 Published online: 12 May 2018 # Springer Science+Business Media, LLC, part of Springer Nature 2018

Abstract Purpose of Review Integrative palliative care involves a team of professionals working together to improve the quality of a child’s life. In children with refractory epilepsy, the primary focus is to treat the seizures. This manuscript reviews common epileptic encephalopathies which can serve as prototypes for devastating refractory seizure disorders and demonstrate the need for involvement of pediatric palliative care in patients with severe epilepsy. It provides an update on etiology, prognosis, and overall treatment, delivering insightful information for the palliative care team as they work to improve the quality of life. Findings A number of pharmacologic and non-pharmacologic treatments are important in the management of refractory epilepsy. This article reviews the various treatment options for patients with refractory epilepsy and highlights the importance of palliative care. Summary A child neurologist should participate as an integral part of the palliative care team in patients with refractory epilepsy to help guide the discussion about etiology, prognosis, and actively manages seizures as they work with other members of pediatric palliative care team towards improving the quality of life for the patient, caregiver, and family members. Keywords Palliative care . Refractory epilepsy . Epileptic encephalopathies . Epilepsy . Antiepileptic drugs . Ketogenic diet . Principals of pediatric palliative care

Introduction As far back as the eleventh century, hospice care was designed to provide care to travelers who were terminally ill. Hospice comes from the Latin word Hospes which means a guest or rest house for travelers [1]. Later, Dr. Cicely Saunders helped to modernize hospice care by providing care to all terminally ill patients regardless of disease, social class, and religion [1]. Over time, hospice care continued to evolve, and in 1974, Dr. Balfour Mound was the first to use the term palliative [1]. Palliative care differs from hospice in that it includes disorders that may have a prolonged nonfatal course. In 2001, the American Academy of Pediatrics stated that “the components of palliative care are offered at diagnosis and continued throughout the course of illness, whether the outcome ends This article is part of the Topical Collection on Pediatric Palliative Care * Colleen Buhrfiend [email protected] Peter Heydemann [email protected] 1

Rush University Medical Center, Suite 718, 1725 West Harrison Street, Chicago, Il 60612, USA

in cure or death” [2]. To this end, pediatric patients with refractory epilepsy are appropriate for palliative care. Not only do they have intractable seizures but they often have cognitive, psychological, social, and behavioral difficulties. Integrative palliative care includes a team of well-chosen professionals working together to improve the child’s quality of life [2]. In keeping with the guidelines of palliative care, the approach to management of refractory epilepsy may include the following [2, 3]: 1. Identify the underlying etiology for the seizures so that the trajectory of illness, overall prognosis, and management can be determined. This allows for an advanced care plan. 2. Treat the symptoms, in this case, refractory seizures 3. Address comorbidities 4. Support the family by addressing their overall concerns Once a child is diagnosed with a seizure disorder, it is the role of the pediatric neurologist to determine the underlying etiology. This is especially true for patients with refractory epilepsy. Nine to 26% of children with epilepsy have refractory seizures [4, 5]. The international-league against epilepsy (ILEA) defines refractory epilepsy as “the failure of adequate trials of two well tolerated, appropriately chosen and used antiepileptic drug schedules (whether as monotherapies or in

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combination) to achieve sustained seizure freedom” [6]. The number of failed drugs that determines refractory epilepsy has not been well studied, but there are reports in the literature that suggest that seizure freedom is unlikely after the failure of two antiepleptic drugs [6]. It should be noted that seizure freedom means a seizure-free interval of “at least 12 months or a minimum of three times the longest pre-intervention interseizure interval (determined from seizures occurring within the past 12 months) whichever is longest” [6]. Studies have shown that even one seizure per year can negatively impact quality of life. Depression and anxiety were increased in those who had one or more seizures over 2 years time [6]. Therefore, it is reasonable that the pediatric palliative team be consulted if there were at least two failed medications due to ineffectiveness plus severe refractory epilepsy or significant psychosocial involvement. In 2017, the ILAE also classified the causes of seizures into structural, genetic, metabolic, infectious, autoimmune, and unknown [7, 8]. They reported that structural and genetic causes were found to be the most common in children with epilepsy occurring in 26 and 34% respectively. Infectious (2%), metabolic (1%), and autoimmune (0%) causes were much less common. In 43%, a cause was not identified [7]. Although many etiologies can potentially cause refractory seizures, the epileptic encephalopathies are a group of devastating, chronic neurologic syndromes with refractory epilepsy at their core. In fact, epileptic encephalopathy-related seizures are common in infancy and early childhood [9]. In addition, patients with static encephalopathy such as cerebral palsy and progressive neurologic disorders such as Battens disease, subacute sclerosing panencephalitis, and even brain tumors can have refractory seizures. The epileptic encephalopathies can serve as a prototype for devastating refractory seizure disorders and demonstrate the need for involvement of pediatric palliative care in patients with severe epilepsy.

Epileptic Encephalopathies In 2001, the ILAE task force defined the epileptic encephalopathies as disorders “in which the epileptiform abnormalities are believed to contribute to progressive disturbance in cerebral function” [10]. Later, the ILAE updated this definition stating that the “epileptic activity itself contributes to severe cognitive and behavioral impairments beyond what is expected from the underlying pathology alone” [8]. In 2017, the ILAE introduce the terms “developmental and epileptic encephalopathy” meaning that the underlying cause or mutation itself, not just the epileptic activity, may contribute to developmental slowing or regression [8]. As a group, the epileptic encephalopathies can be identified based on their age of onset, electrical

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abnormalities on EEG, seizures, and neurodevelopmental slowing or regression [11•, 12•]. In order to determine the best treatment, it is extremely important to identify the syndrome and determine the underlying etiology. All of these syndromes involve intellectual disability and therefore members of the palliative care team would optimally include a psychologist (for cognitive and behavioral needs) in addition to the usual medical professionals, social worker, and clergy.

Dravet Syndrome Dravet syndrome (DS) is one of the most common epileptic encephalopathies with an incidence of one per 22,000 live births [12•]. It is an infantile-onset epileptic encephalopathy, first described in 1978 by Dr. Charlotte Dravet. It usually presents in the first year of life (6–15 months) with frequent prolonged febrile and non-febrile seizures. The most frequent seizure type is hemiclonic (rhythmical jerking of one side of the body), but generalized-clonic seizures also occur [13, 14, 15••]. Initially, seizures can be difficult to distinguish from complex febrile seizures. The diagnosis of Dravet syndrome should be considered in any infant with frequent prolonged febrile seizures. Genetic testing for Dravet syndrome may facilitate the diagnosis. Birth history and development at the onset of seizures are usually normal. Atypical absence, dyscognitive, myoclonic, and atonic seizures usually develop later, between the ages of 1 and 4 and are accompanied by cognitive and motor decline [13, 14, 15••]. The EEG typically is normal in the first 1–2 years of life and then shows multifocal and generalized epileptiform discharges [15••]. Imaging studies are often normal, or may demonstrate cortical atrophy. Most (70–80%) patients with DS have mutations in the alpha1-subunit of the voltage-gated sodium channel (SCN1A) gene [13, 14, 15••, 16•]. This mutation ultimately impairs the firing of gamma-aminobutyric acid (GABA) interneurons in the hippocampus resulting in a decrease in inhibitory output causing a predisposition for seizures [16•]. Development is normal at the time of seizure onset. This is followed by developmental slowing intermixed with periods of regression [15••]. One study evaluated 21 children, ages 6– 10, using WISC and Vineland Adaptive Behavior Scales. They found that after 6 years of age, none of the children had a normal IQ. The same children were shown to have attention problems, impulsivity, poor planning, and communication skills [15••]. Seizures are life long, although there is improvement in frequency as the child ages, with a decrease in adolescents and adulthood. A crouch pattern gait and parkinsonian features usually present later in life [14, 15••]. Children are at risk for both convulsive and non-convulsive status epilepticus, which can be subtle and difficult to recognize. Mortality is increased: studies report a mortality rate from

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3.1 to 20.8% [15••]. Mortality is often due to status-epilepticus, sudden unexpected death in infancy (SUDEP), and accidents at the time of seizure [14, 15••]. Treatment of DS usually includes valproic acid, clobazam, and stiripentol (which can be imported from foreign countries) [17]. All three of these medications serve to enhance the GABAergic pathways. Others have shown that topiramate in place of clobazam in this trio was also effective [18]. The ketogenic diet (KD) and cannabidiol (CBD) have also been shown to reduce seizures in children with DS. Sodium channel blocking agents are generally avoided. Pediatric palliative care can provide additional support at the time of diagnosis as the knowledge of further developmental decline in addition to refractory seizures is devastating to parents. Care givers frequently have many questions about prognosis, various treatment options, and plans for the future. Pediatric palliative care can assist the family, the pediatric neurologist, and other care providers by facilitating communication through organization of care conferences and increased clinic visits so that the care givers concerns can be addressed.

has an unusual side effect profile which includes potential for permanent visual loss as well as reversible myelin edema [11•, 19••]. Infants with Down syndrome and WS respond very well to ACTH [11•]. Those with WS and glucose transporter type 1 deficiency syndrome (GLUT1) respond very well to the ketogenic diet (KD), and this is considered first-line therapy in patients with this condition [11•, 21]. While WS is an important presentation of Glut-1 deficiency, different seizure types are even more common [21]. If the cause of IS is unknown, then a trial of pyridoxine should be considered to evaluate for pyridoxine-dependent seizures. Genetic testing with an epilepsy panel is available and is helpful in diagnosing the underlying cause of patients with IS. As stated above, many patients with WS will go on to have developmental delay and refractory epilepsy. In addition to developmental delay and seizures, patients with WS, as is the case for other refractory epilepsies, may also struggle with poor sleep, gastrointestinal dysmotility, and agitation. Pediatric palliative care can assist the child neurologist and other health care providers in addressing these symptoms.

West Syndrome

Lennox-Gastaut Syndrome

West syndrome (WS), otherwise known as infantile spasms (IS) or epileptic spasms, is also a common epileptic encephalopathy occurring with an incidence of 2–5/10,000 live births [19••]. It was first described in 1841 by Dr. William West, when he reported spasms in his 4-month-old son [19••]. Onset is typically in the first year of life, peaking between 4 and 7 months, and consists of the triad of spasms occurring in clusters, neurodevelopmental regression, and a hypsarrhythmic (high amplitude disorganized) pattern on electroencephalogram [19••]. Spasms are 1–2 s jerks involving contractions of the muscles of the trunk, neck, and extremities, typically torso flexion at the waist. Causes of WS include hypoxic-ischemic encephalopathy, cerebral malformations, periventricular leukomalacia or hemorrhage, stroke, metabolic conditions, tuberous sclerosis, chromosomal disorders, and many are unknown [19••]. WS is different than other epileptic syndromes in that it is very important for treatment to begin as soon as possible. In all cases, treatment involves abolishing both the clinical spasms and hypsarrhythmia on EEG to minimize neurodevelopmental decline [11, 19••]. Adrenocorticotrophic hormone (ACTH) and corticosteroids are considered first-line therapy in the treatment of WS. There have been a large number of studies evaluating ACTH and corticosteroid protocols using high and low doses of either [19••, 20]. There is still no consensus on a best treatment protocol. Side effects are often limiting with all steroid protocols due to standard steroid side effects. Some special WS situations related to treatment are important to emphasize. Vigabatrin is considered first-line therapy for patients with tuberous sclerosis and WS [11•]. Vigabtrin

Lennox-Gastaut syndrome(LGS) typically occurs during the preschool years, ranging from 2 to 8 years of age [11•, 22]. The features consist of a triad of various drug-resistant seizures (tonic, atypical absence, atonic, myoclonic, and least common focal), an interictal EEG showing diffuse slow spike-and-wave discharges at a frequency of 1.5–2 Hz, and cognitive dysfunction [22, 23••]. The incidence of LGS is 2/100,000, and the underlying etiologies are very similar to those found in West syndrome [11•, 22, 23••]. Approximately 17–30% of patients have a history of West syndrome, and they typically have an unfavorable prognosis [11•]. Children with LGS have such frequent seizures that a minor reduction in seizures allows for improved focus and attention. The drop attacks are a significant cause of injury and a helmet is recommended for protection. In general, valproic acid is considered to be the initial treatment of choice in controlling all seizure types [23••]. Additional medications include topiramate, zonisamide, levetiracetam, rufinamide, and clobazam. Clobazam has been shown to reduce the number of drop seizures by greater than 50%, and other benzodiazepines are effective as well. Rufinamide has shown a reduction in total seizures and is particularly effective for drop attacks [23••, 24]. The ketogenic diet and steroids are also efficacious. Other potential treatments include cannabidiol and IVIG [23••]. The VNS is helpful in reducing all seizure types [22, 24]. Corpus callosotomy is most effective for refractory drop attacks [22, 24]. As patients with LGS have refractory epilepsy and severe cognitive impairment, pediatric palliative care may be

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consulted at the time of diagnosis. Families will require emotional support and assistance which may include aspects of long-term financial planning, an educational plan, and even an ultimate housing plan such as a group home. Pediatric palliative care can assist in long-term planning.

Alternative Treatment Options Vagus Nerve Stimulation Vagus nerve stimulation (VNS) was originally approved in 1997 for refractory epilepsy and was further approved in 2017 for children under age 12. This is supported by recent studies which have shown the efficacy of VNS in children under the age of 12 [25, 26]. The VNS consists of a device that is surgically implanted subcutaneously in the left subclavicular region with a wire that extends to and wraps around the left vagus nerve. The device provides continuous intermittent stimulation to the vagus nerve and can be immediately activated by an external “wand” at the time of a seizure. In 2013, guidelines from the American Academy of Neurology reported that VNS should be considered for both partial and generalized seizures in children, in those with LGS and that its efficacy is likely to improve over time [27]. A long-term retrospective study showed improved seizure control as well as improved quality of life based on measures of “concentration, energy, mood, verbal communication, and progress in school over time” [28]. Side effects include infection at site of implantation, vocal cord paralysis, hoarse voice, coughing, headaches, paresthesias at insertion site, dyspnea, coughing, and pharyngitis [29]. Epilepsy Surgery Epilepsy surgery may take the form of focal resection (for a visible lesion or pure epilepsy focus), functional or total hemispherectomy (e.g., Sturge Weber Syndrome, Rasmussen Syndrome, or hemimegalencephaly), or corpus callosotomy (for refractory drop attacks). Lesional epilepsy surgery is reserved for those with a single resectable epileptic focus. Focal epilepsy surgery may be considered when EEG monitoring reveals a consistent EEG focus for refractory seizures. These decisions are made only in a pediatric surgical epilepsy center. Ketogenic Diet The ketogenic diet (KD) is indicated in drugresistant epilepsy [30•, 31] (see Table 1). Cannabidiol Cannabidiol (CBD) is a purified derivative of the cannabis plant and is devoid of psychoactive properties [32••]. A well-controlled, double blind, prospective, multicenter study was recently published in the New England Journal of Medicine showing efficacy of CBD in patients with Dravet syndrome [33••]. This is not yet approved by the Food and Drug Administration. Critiques of this study note that a metabolite of clobazam is markedly increased with CBD therapy; it remains possible that this is the mechanism of seizure reduction with CBD [32••].

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Music Therapy A recent study by Coppola et al. reported that children and adolescents with refractory epileptic encephalopathies who listened to a set of Mozart’s compositions for 2 h per day for 2 weeks, showed that 70% of subjects demonstrated a reduction in seizure frequency and a significant improvement in behavior (less irritability and tearfulness), reduced aggression, and improved sleep [34•]. These findings await replication. Music therapy is often used during hospice, and palliative care physicians should consider music therapy as a potential treatment in children with seizures at the end of life.

General Approach to Treating Refractory Seizures The usual goals of treating a patient with epilepsy include cessation of all seizures, no side effects, and a good quality of life [29]. Given that patients with refractory epilepsy have frequent seizures, goals change to minimize seizure frequency and perhaps allow tolerable side effects while improving the quality of life [23••, 29]. Steps to Follow [23••] 1. First, it is important to distinguish between seizures and transient events that may mimic seizures such as: Staring spells: Children with refractory epilepsy often have difficulties with focus and attention and may “space out.” Muscle spasms can mimic a myoclonic jerk or tonic seizure in children with spasticity. Syncope or presyncopal episodes can occur with illness, dehydration, or asthenia. 2. When choosing an antiepileptic medication it is important to consider seizure type (focal, generalized, myoclonic, or mixed), a specific epileptic syndrome, the side effects of the antiepileptic medications, patient’s comorbidities, and potential drug interactions (Table 2). 3. Increase the dose gradually over time to minimize side effects. 4. Improved compliance is best with medications that are given one to two times daily. 5. Follow closely for the development of side effects including psychological, behavioral, and cognitive effects (Table 2). 6. Start with one medication. If this is not effective, then add a second medication with a different mechanism of action. If this is ineffective, then start another and wean one of the others. Patients with refractory epilepsy often require polypharmacy in order to gain adequate seizure control. It has been shown that more than 2–3 seizure medications typically do not improve seizure control [6, 35].

182 Table 1

Curr Pediatr Rep (2018) 6:178–187 Ketogenic diet [30•, 31]

Mechanism of action and general information

Indications

Contraindications

Side effects

-The goal of the KD is to induce ketosis through a diet high in fat content and low in carbohydrates. -The ratio of fat to protein and carbohydrates is usually 3:1 to 4:1. - Increased fat metabolism produces ketone bodies that cross the blood-brain-barrier including beta-hydroxybutyrate which is used as a measure of adequate ketosis. -The exact mechanism is unclear, likely alters both the excitatory (Glutamate) and inhibitory (Gamma-aminobutyric acid) pathways. - Variations of the classic ketogenic diet include: modified atkins, medium chain triglyceride, and low glycemic index - This diet is usually managed with the aid of a dietician. -The Charlie Foundation website is an excellent resource for health care providers and families

Drug-resistant epilepsies: -Partial seizures -Generalized seizures Some efficacy in the epileptic encephalopathies: -Ohtahara syndrome, LGS, DS, WS, Myoclonic-astatic epilepsy (Doose syndrome)-very effective) -Glut-1 deficiency-considered first line therapy -Pyruvate dehydrogenase deficiency

-Beta-oxidation defects -Pyruvate carboxylase deficiency -Porphyria -Carnitine disorders

Dehydration, hypoglycemia, electrolyte imbalances, GI upset, diarrhea, vomiting, constipation, hyperuricemia, hypocalcemia, selenium deficiency, low carnitine levels, metabolic acidosis, renal stones, growth retardation, mildly elevated cholesterol and triglycerides, rarely prolonged QTc, and cardiomyopathy

7. Consider the ketogenic diet which can come in liquid form especially for children with gastrostomy tubes. Some children with oral food intake may be interested in the ketogenic diet as well. 8. It is always important to consider potential side effects of antiepileptic drugs in the context of comorbidities. For example, levetiracetam may exacerbate behavioral problems in children especially if a pre-existing behavioral disorder exists. Alternatively, valproic acid, carbamazepine, and lamotrigine have been used as mood stabilizers. In patients who have difficulty maintaining their weight, topiramate, zonisamide, and felbamate should be avoided (Table 2). 9. The treatment of refractory epilepsy should be individualized. In some patients, for example, those with cerebral palsy who are non-ambulatory and cognitively impaired, it may be appropriate to allow for a few seizures to avoid unwanted side effects from polypharmacy or high doses of antiepileptic drugs, or to avoid the imposition of further medication trials.

Mortality and SUDEP A review article by Donner et al. [36••] reports that mortality rate in children with epilepsy was found to be five to ten times greater than the age-matched death rate in the general population. They report that death in children with epilepsy may be due to both epilepsy and non-epilepsy-related causes. Epilepsy-related deaths are often the result of status-epilepticus, aspiration, accidents at the time of seizures, and SUDEP. SUDEP is defined as “sudden and unexpected, nontraumatic, and non-drowning death of a person witnessed or unwitnessed

occurring in benign circumstances, with or without evidence of a seizure and excluding documented status-epilepticus” [36••]. In general, the incidence of SUDEP is low in childhood with the exception of DS. It is reported that SUDEP in DS is 15-fold higher than those with other childhood epilepsies [16•]. Mouse models of DS suggest that parasympathetic activity is increased after a generalized tonic-clonic seizure causing lethal bradycardia [16•]. In general, risk factors for SUDEP include generalized tonic-clonic seizures, nocturnal seizures, early onset epilepsy, and poorly controlled seizures [36••]. Respiratory depression, autonomic dysregulation, and cardiac arrhythmias are believed to be the main factors that contribute to SUDEP. A good discussion of mortality, SUDEP, and management may be found in the article by Donner et al. [36••]. They concluded that it is important to speak to families about their child’s individual risk for mortality and SUDEP [36••]. Seizure Management in Terminally Ill Children Seizures are common at the end of life. They are often the result of disease progression, the inability to swallow oral medications, difficulties with gastrointestinal motility and absorption, and IV access [37••]. The literature is devoid of best practice guidelines for seizure management in this setting. Harris et al. recently published a retrospective study [37••] involving seizure management in children at the end of life. In their review of the literature, they were unable to find any randomized controlled studies. Most were single case studies, and where clinical guidelines were put forth, they did not include an evidence base for their recommendations. Therefore, they reviewed a total of 19 admissions for care, 18 individuals (ages 3 months–25 years), that required management of seizures at the end of life and concluded that the pharmacological management was variable.

Sodium channel blocker

Blocks sodium channels, inhibits glutamate release

Sodium channel blocker

Enhances slow inactivation of sodium channels

Prolongs the inactive state of sodium channels

Inhibits sodium channels calcium Focal, generalized and channels, carbonic anhydrase inhibitor myoclonic epilepsy

Eslicarbazepine

Lamotrigine

Oxcarbazepine

Lacosamide

Rufinamide

Zonisamide:

Adjunctive in patients with LGS May be effective in refractory focal epilepsy

Focal seizures

Focal, GTC seizures

Focal, GTC seizures Primary generalized absence LGS-adjunctive treatment

Focal, GTC seizures

Focal, generalized tonic-clonic(GTC) seizures

Sodium channel blocker

Carbamazepine

Uses

Main Mechanism of Action

Antiepileptic medications: mechanisms, side effects, advantages [29, 42]

Drug

Table 2

Immediate and delayed release formulation, possible mood stabilizer

Insomnia, nausea, vomiting, dizziness, ataxia, tremor, headache, Stevens-Johnson syndrome Can aggravate myoclonic seizures Initiate slowly to avoid Stevens-Johnson syndrome Lamictal levels are increased by Valproic acid No IV preparation

Drowsiness, dizziness, fatigue, anorexia, ataxia, nausea, vomiting, slow thought processing, weight loss, abdominal pain, rash, nephrolithiasis, aplastic anemia-rare Avoid in patient with history of renal stones No IV formulation

Drowsiness, GI upset, vomiting, fatigue, diplopia, hypersensitivity reactions, shortening of QT interval (avoid in patients with familial short QT syndrome and drugs that shorten QT)

Long half-life, dosed once a day

GI upset, nausea, vertigo, blurry vision, diplopia, ataxia, headaches, Well tolerated, IV formulation drowsiness, can prolong PR interval –use with caution in those with cardiac conduction defects

Drowsiness, dizziness, headache, blurred vision, nausea, vomiting, less likely Well tolerated, possible mood stabilizer, bipolar (off label), to cause rash and hyponatremia than carbamazepine, rare anemia, possible use for neuropathic pain pancytopenia, hepatitis, hypersensitivity reactions (off label) No IV preparation Long acting formulation May worsen generalized epilepsy (absence, myoclonic)

Long-acting, better for compliance

Used as a mood stabilizer/bipolar disorder and for trigeminal neuralgia/ neuropathic pain Sustained release formulation Can check blood levels easily

Advantages

Drowsiness, fatigue, dizziness, GI upset, nausea, headache, vertigo, ataxia, diplopia, blurry vision, tremor, hyponatremia, hypersensitivity reactions including SJS Can aggravate generalized epilepsy (myoclonic, absence) No IV preparation

Hyponatremia, bone marrow suppression, aplastic anemia, agranulocytosis, liver toxicity, GI upset, sedation, blurry vision, dizziness, hypersensitivity reactions –Stevens- Johnson syndrome Patients with HLAB*1502 allele, commonly found in patients of Asian descent, are at increased risk for development of Stevens-Johnson syndrome, toxic epidermal necrolysis, consider antigen screening prior to treatment No IV preparation P450 enzyme induction May worsen generalized epilepsy (myoclonic, absence)

All anticonvulsants carry a “suicidal ideation” warning

Common Side effects/disadvantages

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Focal, GTC, absence, myoclonic, and atonic Effective in treatment of LGS, focal seizures West syndrome, first Irreversible inhibitor of GABA-transaminase line therapy for spasms in patients with TS Refractory focal seizures in adults Binds directly to GABA(A) receptor and Focal, GTC, myoclonic enhances GABA activity seizures use limited due to side effects

Probably blocks NMDA excitatory transmission May facilitate GABA function

Glutamate receptor antagonist

NMDA receptor antagonist, sodium channel blocker, enhances the activity of GABA, carbonic anhydrase inhibitor

Enhances GABA, believed to block sodium channels, blocks calcium channels

Felbamate

Perampanel

Topiramate

Valproic acid

Phenobarbital

Vigabatrin

Enhances GABA activity

Benzodiazepines: midazolam diazepam clonazepam lorazepam Clobazam

Advantages

IV formulation, can check blood levels easily, used in treatment of migraine headaches, mood stabilization

Drowsiness, cognitive slowing, slurred speech, nausea, weight loss, headaches, Long acting form available, used in dizziness, paresthesia, blurred vision, dizziness, ataxia, hypohidrosis, treatment of tic disorders metabolic acidosis predisposes to renal stones.

Focal, GTC, myoclonic seizures

Effective for all seizure GI upset, nausea, vomiting, hair loss, weight gain, tremor, constipation, types, focal, GTC, diarrhea, hepatotoxicity, pancreatitis, low carnitine levels, absence, myoclonic thrombocytopenia(dose related) Follow CBC and liver enzymes, Fulminant liver toxicity can occur-risk factors include children under 2 years on polypharmacy and metabolic disorders. Check POLG1 gene for children under 2 or with unexplained developmental delay Hyperammonemic encephalopathy Teratogenic side effects-especially risk of neural tube defects Hepatic enzyme inhibitor

Drowsiness, fatigue, nausea, weight gain, gait difficulties, headaches, irritability, vertigo, ataxia

Aplastic anemia and hepatic failure, can be fatal(can occur at any time, may not occur for several months, may still be at risk after stopping drug), nausea, vomiting, dizziness, diplopia, weight loss, behavioral changes, headache Follow CBC and liver enzymes closely Use only in those who have failed multiple medications due to rare risk of aplastic anemia and liver toxicity Manufacture recommends obtaining a signed consent prior to starting

Drowsiness, nausea, vomiting, irritability, hyperactivity, cognitive impairment, IV formulation, long half- life, can hypersensitivity reaction, hyperactivity in younger children check blood levels easily P450 enzyme induction

Dizziness, headaches, behavioral changes, fatigue Irreversible Visual field defects Abnormal MRI findings ( T2 and restricted diffusion images), occur in infants with IS, does not appear to cause clinical neurologic deficits, is dose related and resolves with discontinuation

sedation, irritability, ataxia, mood changes, respiratory depression in overdose May be used for anxiety, or with other central nervous system depressants, increased drooling non-epileptic myoclonus, sleep Clobazam is less likely to build tolerance and cause sedation

Drowsiness, GI upset, nausea, vomiting, hyperactivity, headaches

Common Side effects/disadvantages

Focal, GTC seizures

Focal and generalized seizures

Generalized absence epilepsy

Inhibits T-type calcium channels (thalamic neurons)

Ethosuximide:

Uses

Main Mechanism of Action

Drug

Table 2 (continued)

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Sodium channel blocker Phenytoin (Fosphenytoin)

Ataxia, coordination difficulties including slurred speech, nausea, vomiting, Good medication for use in Focal, GTC nystagmus, blood dyscrasias, hepatotoxicity, hypersensitivity reactions Can aggravate status-epilepticus in children including Stevens-Johnson syndrome, and when used for prolonged periods generalized may cause gingival hyperplasia, coarse facial features epilepsy(myoclonic, Follow blood levels closely absence) Hepatic enzyme inducer IV formulation can cause skin necrosis at IV site with extravasation, to avoid skin irritation recommend Fosphenytoin Not often used as maintenance drug in children due to difficulty in maintaining therapeutic doses and side effects

IV formulation, overall well tolerated Drowsiness, dizziness, fatigue, headache, behavioral problems, depression, psychosis Vitamin B6 may lessen behavior side effects Exact mechanism unknown, binds to synaptic vesicle protein SV2A 2 vesicle Levetiracetam

Focal seizures, GTC, absence, myoclonic

Advantages Main Mechanism of Action Drug

Table 2 (continued)

Uses

Common Side effects/disadvantages

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In patients with chronic conditions, such as those with refractory epilepsy, it is important to devise an advanced care plan. This plan should include alternative routes for administering antiepileptic medication if oral access becomes unavailable. This can include gastrostomy tube, central venous access, peripheral venous access (IV), and intramuscular, intranasal, rectal, and buccal mucosa. Subcutaneous infusion may also be considered as off label use for administration of some antiepileptic medications [37••, 38]. For children with ongoing severe refractory epilepsy and progressive fatal illnesses such as brain tumors or neurodegenerative diseases, it may be necessary to place a central venous line at the end of life when oral or G-tube feedings are impossible. Frequent seizures at the end of life prohibit a peaceful death and control of seizures at this time is important [37••]. A central line should be considered if alternative routes are not available. At the end of life, pediatric palliative care has been shown to effectively aid families in their decision to forgo lifesustaining treatment in children with cognitive impairment [39]. Goals of care at the end of life often include making the child comfortable, prevention or cessation of suffering, to maintain or improve general health if possible, and in the case of refractory epilepsy to minimize seizures [37••, 39]. Role of the Pediatric Palliative Care Provider The role of pediatric palliative care is to assist in symptom management (physical, social, psychological, spiritual), to aid families, patients, and health care providers in decision making processes, to help coordinate care among treaters, and to improve patient quality of life [40••]. Taking into consideration the definition of refractory epilepsy, it is important to note that the clinical spectrum of children with refractory epilepsy is broad. Some children may have infrequent seizures with normal development and cognition, while others may have frequent seizures with severe developmental delay or regression such as those with epileptic encephalopathies, and yet others fall somewhere in between. Julie Hauer et al. wrote, “Uncertainty is a common theme in PPC, including children with neurologic impairment. There is a wide range of outcomes, even within the same diagnosis” [39]. This is undoubtedly true for children with refractory epilepsy. The uncertainty of when a child will have the next seizure, if the child’s seizure frequency or length will increase, if the child will make developmental gains or lose skills over time, and if the antiepileptic medications will cause harm are common concerns for care givers. The pediatric palliative care specialist can assist the child neurologist by supporting the family for clarification of the prognosis and treatment goals. The palliative care physician and treating neurologist should both understand each other’s prognostic expectations and hopefully agree upon them prior to the palliative care doctor meeting the family. In addition, children with refractory epilepsy can have poor sleep, agitation, muscle spasticity, constipation, reflux,

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drooling, oral-motor dysphagia, and pain. The pediatric palliative care specialist can assist the subspecialists with management of the various symptoms. Some epilepsy treaters are epileptologists with a focus solely on the treatment of seizures, and these doctors may wish to consult with a palliative care physician more regularly. Whereas, a general pediatric neurologist may feel comfortable treating the broad problems of severe epilepsy. Many children with refractory epilepsy do not have significant developmental or cognitive delay. In this patient population, numerous children and adolescents suffer from depression, anxiety, and social withdrawal. William A. Schraegle et al. found that 41% of children with seizures were found to have symptoms of anxiety, depression, and withdrawal [41]. Furthermore, adolescents with epilepsy are at greater risk for suicidal ideation and suicide attempts than the general population [41]. It is important to identify and treat anxiety, depression, and social withdrawal in patients with refractory epilepsy. The pediatric palliative care specialist can develop a partnership with the family and child to assist in the recognition and treatment of these internal psychiatric symptoms.

Conclusion The child neurologist is an integral part of the palliative care team for all children with refractory epilepsy. Together, the palliative care physician and team should be aware of the prognosis and trajectory of the illness, have an understanding of the medications and alternative treatment options for patients with refractory epilepsy, and facilitate effective communication with the family as they work towards achieving the best quality of life.

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Compliance with Ethical Standards Conflict of Interest The authors declare that they have no conflict of interest.

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Human and Animal Rights and Informed Consent This article does not contain any studies with human or animal subjects performed by any of the authors.

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