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`Epilepsy
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`Epilepsy
`
`Carl W. Bazll, MD, PhD
`Caitlin Tynan Doyle Professor of Clinical Neurology
`Director, Division of Epilepsy and Sleep
`Columbia University Department of Neurology
`New York, NY
`
`Derek J. Chong, MD
`Assistant Professor of Clinical Neurology
`Director, ~linical Trials in Epilepsy & Sleep
`Columbia University Department of Neurology
`New York, NY
`
`Daniel Friedman, MD
`Assistant Professor of Neurology
`Depanment of Neurology
`New York University School of Medicine
`New York, NY
`
`OXFORD
`
`UNIVERSITY PRESS
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`To our patients, who have taught us the most about epilepsy, and that
`a life with epilepsy can be every bit as full as life without it.
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`Preface
`
`Epilepsy is a diverse and sometimes complicated condition. It is also very
`common, such that all neurologists, and nearly all physicians, will encoun"
`ter patients with epilepsy. Perhaps more than most other conditions in neu(cid:173)
`rology, epilepsy is further complicated by potential interactions with other
`medical conditions and with a patient's lifestyle.
`This volume contains numerous case examples, meant to Ulustrate sce(cid:173)
`narios that commonly arise in the clinical care of patients with epilepsy and
`ways of approaching them. The first section has chapters that address diag(cid:173)
`nostic questions: How to approach a first seizure? What about diagnostic
`challenges, such as confusion with syncope or parasomnias? Drug therapy
`is indicated for nearly all patients with epilepsy, so the second section con(cid:173)
`tains various scenarios dealing with anticonvulsant drugs, including choos(cid:173)
`ing from the large number of drugs available in each epilepsy syndrome,
`choosing drugs in specific patient populations, drug interactions, and when
`(if ever) it may be appropriate to withdraw anticonvulsant treatment in a
`patient with epilepsy. If drug therapy is not completely effective or is other(cid:173)
`wise unsatisfactory, alternatives are discussed in the third section. Finally,
`the fourth section looks at lifestyle and other issues: the mood and cognitive
`disorders so prevalent in epilepsy, the topic of sudden death in epilepsy,
`issues of bone health and sleep disorders, and implications for driving
`and work.
`Each epilepsy patient is different-these are only a few examples. But we
`hope you will find this volume useful in thinking about the problems you
`encounter in treating people with epilepsy.
`
`vll
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`n
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`Contents
`
`SECTION I DIAGNOSTIC QUESTIONS
`
`1
`
`Febrile Seizures and Other Seizures In Infants 3
`Daniel Friedman
`Febrile seizures are common and are often benign, with little risk of subsequent
`epilepsy. However, febrtle seizures with complex features may increase the risk of
`eptlepsy later in life or may be the heralding seizure of a severe infantile eptlepsy
`syndrome.
`
`2 Benign/Idiopathic Partial Epilepsies (IPE) of Childhood 8
`Derek j. Cbong
`Benign rolandic eptlepsy {BECfS) and the benign occipital eptlepsies have
`specific clinical features and electrographic findings that set them apart from
`other types of eptlepsy. 1he diagnosis of these conditions is imponant as they
`impart a high chance of spontaneous and complete remission.
`
`3 Nonconvulslve Seizures In Acutely 111 Patients 16
`Daniel Friedman
`Seizures without overt convulsive activity are common in critically ill and acute
`brain injury patients. Often the only manifestation is altered mental status, and
`EEG monitoring is required for the diagnosis. Treatment is aimed at controlling
`seizures co limit secondary neuronal injury whtle minimizing the adverse effects
`of therapy.
`-
`
`4 Psychogenic Noneplleptlc 'Seizures 25
`Carl w. Bazil
`About 25% of patients with refractory eptlepsy who are referred to epilepsy
`centers actually are found to have psychogenic noneptleptic seizures. These can be
`very confusing to treating clinicians, as by history they may sound exactly like
`epUeptic s~izures. Correct diagnosis usually requires video~EEG monitoring, and
`diagnosis is critical in redirecting appropriate care for the patient.
`
`5
`
`Frontal Lobe Seizures 32
`Daniel Friedman
`Seizures of frontal lobe origin often have little EEG correlate and can have bizarre
`semiologies that can be p1istaken for nonepileptic seizures. Nocturnal onsets and
`stereotyped features are clues to the diagnosis.
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`7
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`Seizure Versus Parasomnlas 37
`Carl W. Bazil
`Paroxysmal episodes that occur during sleep can be a diagnostic dilemma. History
`may be imperfect or even nonexistent, as patients may not recall the actual
`episode, and witnesses may not be present. Careful history may be able to
`distinguish whether the event is a seizure or a parasomnia, but diagnostic testing
`withpolysomnography and/or video-EEG may-be required to confirm the
`diagnosis.
`
`Seizure Versus Syncope 46
`Carl w. Bazil
`Sudden loss of awareness could represent syncope or seizure. History is usually
`helpful in making the diagnosis, as characteristics such as tongue biting,
`incontinence, and postictal confusion are more suggestive of seizure.
`
`SECTION II TREATMENT CONSIDERATIONS: AEDs
`
`S
`
`9
`
`10
`
`First Unprovoked Seizure 53
`Derek]. Chong
`Up to 10% of the population will have a seizure in their lifetime, yet only 1% of
`the population will have recurrent, unprovoked seizures. The first recognized
`seizure is a frightening occurrence for patients. Standard of care includes an EEG
`and MRI of the head for prognostication of recurrence and to rule out
`symptomatic causes.
`
`Initial Treatment of Idiopathic Generalized Epilepsy 57
`Derek]. Chong
`Patients with idiopathic (or primary) generalized epilepsies are presumed to have
`a low threshold for seizures that may be of genetic origin. These syndromes
`represent 20% of all epilepsy cases. Treatment consists of broad-spectrum agents,
`with some specific medications used for specilic seizure types seen in IGE.
`
`lnltlal Treatment of Localization-Related Epilepsy 66
`Derek]. Chong
`There are over a dozen medications avallable to reduce the risk of panial onset
`seizures. The current motto of "no seizures, no side effects .. requires tailoring the
`choice of medication based on its characteristics and side-effect profile with the
`patient's own priorities. Mood and weight change are among the issues that are
`often important to patients.
`
`:11
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`CONTENTS
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`11 Status Eplleptlcus 71
`Daniel Friedman
`Generalized status epilepticus is a neurologic emergency associated with
`significant morbidity and monality. Prompt diagnosis and treatment; often
`guided by EEG monitoring, is necessary.
`
`12: Adverse Effects of AEDs-Rash 77
`Daniel Friedman
`Skin eruptions are commori rea~ions to AEDs and can rarely be serious and even
`life-threatening, with systemic manifestations. The key to treatment is usually
`discontinuing the offending drug without placing the patient at risk for seizures.
`
`13 Adverse Effects of AEDs-ldlosyncratlc Reactions 82
`Daniel Friedman
`AEDs can have rare hut serious effects that cannot he predicted by their
`mechanisms of action or metabolic pathways. These reactions can include hepatic
`dysfunction, hematologic abnormalities, pancreatitis, and CNS dysfunction.
`
`14 Generic AED Substitutions 88
`Carl w. Bazil
`Patients and insurers often inquire about lower-cost generic alternatives. While
`these may be appropriate for many patients, in epilepsy the additional variability
`introduced when using a generic equivalent requires more vigilance than in most
`other conditions.
`
`15 Withdrawal of AEDs 92
`Carl w. Bazil
`When a patient's seizures have been controlled for many years, it is often
`appropriate to ask whether anticonvulsant treatment may ~ly been withdrawn.
`There are many considerations here, and each patient's concerns and preferences,
`including risk aversion, must be taken into account before a recommendation can
`·be made:
`
`16 AED Failures 97
`Derek]. Chong
`Seizures may continue ro occur with medical treatment or the treatment may
`cause intolerable side effects; both are considered failures. The main choice to
`consider is substitution with another agent in monotherapy versus dual therapy.
`
`17 Drug-Drug Interactions: AEDs 102
`Derek]. Chong
`Many AEDs have effects on each other due to changes in liver enzymes and
`protein binding, particularly those of the older generation. Pharmacodynamic
`effects, including interactions at the level of the receptor, can be important in
`neurotoxic side effects and may play a role in polytherapy efficacy as well.
`
`CONTENTS
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`18 Drug-Drug Interactions: Other Medications 108
`Derek]. Chong
`Enzyme-inducing medications include phenytoin, carbamazepine, phenobarbital,
`and to a lesser extent oxcarbazepine and topiramate. Significant interactions occur
`with medications that are often used concomitantly, such as oral contraceptives
`and warfarin.
`
`19 AEDs In Pregnancy and Lactation 112
`Daniel Friedman
`AEDs pose particular difficulties in pregnant women, including teratogenicity
`and altered metabolism. Many drugs are also excreted in breast milk, though
`most women wi~ epilepsy are able to breast-feed successfully.
`
`20 Treatment of Epilepsy In the Elderly 118
`Derek]. Chong
`Single and recurrent seizures are common in the dderly population. Acute
`symptomatic seizures are less likely to turn into epilepsy and long-tenn treatment
`is often not indicated. In other situations, treatment is important to reduce the
`sequdae of seizures, which could cause significant injury. Tolerability is the most
`important consideration, as many AEDs have the potential ro worsen other
`medical issues that are common in the elderly.
`
`SECTION Ill REFRACTORY EPILEPSY: DIAGNOSIS &
`MANAGEMENT ISSUES, INC"LUDING SURGERY AND
`ALTERNATIVE THERAPIES
`
`21 Refractory Epilepsy: General Approach 127
`Carl W. Bazil
`Patients with epilepsy who have failed two trials of an appropriate anticonvulsant
`drug should be considered for further evaluation. Usually, this includes video(cid:173)
`EEG monitoring to confinn the diagnosis, as a substantial subset will be found to
`have conditions other than epilepsy. If epilepsy is confirmed, the patient may be
`considered for other treatments, including alternative medications, devices, and
`surgery.
`
`22 Refractory Idiopathic Generalized Epilepsy 135
`Daniel Friedman
`Parients with idiopathic generalized epilepsy who continue to have seizures
`despite appropriate AEDs should undergo a trial of valproate, which may be the
`most effective agent in these epilepsies. Video-EEG monitoring. is recommended
`for patients with continued seizures as careful analysis may reveal a focal epilepsy .
`
`.11.1!
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`CONTENTS
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`23 Refractory Localization-Related Epilepsy: Extratemporal Epilepsy and
`Intracranial EEG Recording 139
`Carl w. Bazil
`In refractory patients who have extratemporal onsets, surgical treatment is often
`more compllcated. These patients still have a higher chance of cure with surgery
`than with additional medication trials. In addition ro routine video-EEG
`monitoring and MRI, further imaging stUdies such as PET or SPECT scans may
`help ro localize onset. Intracranial electrode implantation followed by video--EEG
`monitoring is often required to definitively localize seizure onset and distinguish
`from eloquent correx with brain mapping.
`
`24 Complementary and Alternative Therapies 146
`Derek]. Chong ·
`Numerous patient surveys have shown an increase in the use of complementary
`and alternative therapies-they are used by up to 25% of the epileptic
`population. Diet as an altern~tive therapy fur seizures has been effective for many
`patients, while botanicals, biofeedback, and other approaches show promise but .
`have not yet been proven or standardized. Being open-minded but exercising
`caution may be the best approach for the neurologist.
`
`SECTION IV PROGNOSTIC, SOCIAL, AND BEHAVIORAL ISSUES
`
`25 Depression In Epilepsy 153
`Daniel Friedman
`Depressive symptoms are common in patients with epilepsy and occur at much
`higher rates than in the general population. Patients with epilepsy have higher
`rates of suicide as well. Identifying and treating mood disorders can improve the
`quality of life for epilepsy patients.
`.,
`
`26 Psychosis and Seizures 159
`Carl w. Bazil
`Psychosis can rarely occur in the immediate postictal period; this is usually
`transient but can result in injury. More difficult from a diagnostic standpoint may
`be postictal psychosis, as this may begin"days after a seizure.
`In cases of unusual or refractory psychosis, consideration should be given to the
`possibility of unrecognized seizures causing or exacerbating psychosis.
`
`27 Cognitive and Behavioral Issues 164
`Carl w. Bazil
`Two of the most common complaints in patients with epilepsy are mood
`problems and difficulty with cognition. Both have numerous possible causes, but
`treatment choices in patients with epilepsy should always be made with these
`in mind.
`
`CONTENTS
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`28 Sreep Disturbances In Epilepsy 170
`Carl w. Bazil
`Quality sleep is important for everyone but is panicularly important in patients
`with epUepsy. Sleep disruption from any cause can contribute to the intractability
`of epUepsy and can also cause drowsiness, inattention, and apparent memory
`dysfunction. Vigilance for coexisting sleep disorders is an important aspect of
`epilepsy care.
`
`29 Bone Health 176
`Derek]. Chong
`Reduced bone density has been shown to be a significant comorbidity for patients
`with epUepsy. Thus far, it seems that enzyme-inducing medications have the
`greatest risk fur causing problems with bone health. Replacing the potentially
`offending agent is likely necessary. Repletion of vitamin D through
`supplementation appears safe, though it is not known what will be the most
`effective treatments.
`
`30 Sudden Unexpected Death In Epilepsy (SUDEP) 179
`Daniel Friedman
`Patienu with epilepsy have a much higher rate of unexpected sudden death
`compared to the general population. Patients with poorly controlled epUepsy and
`frequent tonic~clonic seizures are at a panicularly high risk.
`
`31 Work, Driving, and Epilepsy 183
`Carl W. Bazil
`Safety is of primary importance in patients with epilepsy. This is particularly
`concerning with driving and in work or other activities that may place the patient
`and others at risk should a seizure occur. The risk of seizure recurrence must be
`considered on an individual basis before recommendations can be made, but
`general guidelines are also helpful in discussing this topic with patients.
`
`Appendices 189
`
`Index 201
`
`AIV
`
`CONTENTS
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`Febrile seizures (seizures that occur with fever in the absence of known
`
`epilepsy, CNS infection, or metabolic disorder) can occur in children
`berween 6 months and 5 years of age. They are typically divided into simple
`and complex febrile seizures. Simple febrile seizures last less than 15 minutes
`and occur once within a 24-hour period. Complex febrile seizures are pro(cid:173)
`longed, recur within 24 hours, or have obvious focal features (e.g.•, clonic
`activity of one limb). A careful hisrory and physical examination is neces(cid:173)
`sary to evaluate for potentially life-threatening infections and to determine
`if the child was neurologically intact prior to the seizures and if the fever
`preceded the seizure, as mild hyperpyrexia may follow seizure activity. In
`infants less than 12 to 18 months of age, signs of meningitis may be difficult
`to appreciate and lumbar puncture should be considered to exclude CNS
`infection. In the case of simple febrile seizures, EEG and brain imaging is
`typically not warranted unless there is a history of preceding neurologic
`abnormality.
`Febrile seizures are common, with an incidence of2o/o to 5% before age 5.
`Febrile seizures tend to recur: approximately 40% of patients will have
`another febrile seizure, bur only 9% experience 3 or more days with febrile
`seizures. Age of onset is/an important factor, as infants less than 1 year of
`age have a 50% chance of recurrence, whereas the rate is only 20% in those
`with onsets at 3 years of age or older. Other predictors of recurrence include
`a family history of febrile seizures, a low fever or a short duration of fever
`prior to the seizure, or complex febrile seizures. The number of risk factors
`
`TABLE H
`
`~e,.~.~.~.~~,~.:~~~~res an~. ~.~,..Facto~~.f~.~,~~~.~~.quent Epile~;J .•
`
`Increased Risks:
`
`Age of febrile seizure
`
`Ages< 3 months and > 5 years
`
`Duration
`
`Frequency
`
`Focal Features
`
`Family history
`
`> 15 min
`
`Seizure recurrence within 24 hours
`
`Obvious (unilateral clonic activity, Todd's paresis)
`
`Afebrile seizures in parent or sibling
`
`Baseline Neurological
`status
`
`Abnormal
`
`4
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`\'./HAT DO I DO NOW? EPILEPSY
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`present increased the risk of febrile seizure recurrence: two or more factors
`predict a 30% chance, and 3 or greater risk factors purports a 60% risk.
`There is no evidence that the number of febrile seizures influences the
`risk of subsequent epilepsy. Furthermore, there is no evidence that simple
`febrile seizures lead to any measurable brain injury. The neurologic impact
`of prolonged febrile seizures and febrile starus epilepticus is unknown, but
`preliminary imaging studies show effects on hippocampal structures. This
`suggests that febrile status epilepticus, like other forms of status epilepticus,
`should be identified early and treated aggressively.
`The rare of subsequent afebrile seizures (i.e., epilepsy) following a simple
`febrile seizure is low and is likely no greater than in the general population.
`Some clinical features, such as febrile seizures before 12 months of age and
`a family history of epilepsy or febrile seizures, may suggest a genetic predis(cid:173)
`position to seizures such as the generaljzed epilepsy with febrile seizures plus
`(GEFS+) syndrome, and these patients are at a slightly higher risk of devel(cid:173)
`oping epilepsy. Patients with complex febrile seizures have a higher rate of
`subsequent epilepsy, with approximately 6% to 8% having unprovoked sei(cid:173)
`zures by age 25. If there are focal features and the seizures are repetitive or
`prolonged, the risk is much higher. Other factors that increase the risk for
`subsequent epilepsy include neurologic abnormalities prior to the seizure,
`younger age at onset, or a family history of epilepsy. Rarely, febrile seizures
`are the first manifestation of severe myoclonic epilepsy of infancy (SMEI or
`Dravet syndrome), a catastrophic epileptic encephalopathy of infancy, most
`often due to a mutation in the SCN 1A gene. This disorder typically presents
`with complex febrile seizures before age 1 in otherwise normally developing
`infants A genetic test is available and should be used tO screen these patients,
`as many with this typically sporadic genetic abnormality will experience
`developmental abnormalities in the following years.
`While the peak incidence of febrile seizures occurs between 18-24
`months of age, a large proportion of all seizures occur before age 1. Mebrile
`seizures in infancy are often due to structural, genetic (single gene), chro(cid:173)
`mosomal, or metabolic abnormalities. Sometimes, afebrile or unprovoked
`seizures have a benign course, such as in benign neonatal convulsions or
`benign infantile seizures. These epilepsy syndromes typically occur in oth(cid:173)
`erwise neurologically normal infants, spontaneously remit, and have only a
`modestly elevated risk of epilepsy later in life. Other conditions, such as
`
`1. FEBRILE SEIZUR~S AND OTHER SEIZUR~S IN INf'ANTS
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`early infantile epileptic encephalopathy (Ohtahara syndrome), West syn(cid:173)
`drome, Dravet syndrome (discussed above), early myoclonic epilepsy, and
`myoclonic epilepsy in infancy, are associated with difficult-to-treat epilepsy
`and significant developmental delay. Because of the poor prognosis of many
`seizures presenting in infancy, it is important to emphasize the ben1gn
`nature of febrile seizures to parents, who are justifiably anxious.
`
`TREATMENT
`
`Because of the benign nature of most febrile seizures, prophylactic treatment
`with antiepileptic drugs (AEDs) is usually not recommended. While AEDs
`such as phenobarbital, primidone and valproic acid have been shown to sup~
`press future febrile seizures, they do not prevent the development of subse(cid:173)
`quent epilepsy and are often associated with neurocognitive side effects that
`typically outweigh any benefits. The use of antipyretics such as acetamino ...
`phen does not appear to prevent seizure recurrence. This suggests that a high
`temperature alone does not provoke febrile seizures and other factors, such
`as inflammatory cytokines, are the proconvulsant stimulus. Acetaminophen
`and ibuprofen are considered safe and effective antipyretics to use in these
`children, but parents should be advised they are being used primarily for'
`comfort. Current practice parameters have instead recommended acute
`abortive therapies such as rectal diazepam (0.5 mg/kg) (max 20 mg) or mida(cid:173)
`zolam administered intranasally (0.2 mglkg; divided per nostril) (max 10 mg
`total) or bucally (0.5 mg/kg)*, to limit the duration of seizures and prevent
`hospitalization. In rare patients where recurrence is frequent or caregivers are
`unable to administer abortive treatment, prophylactic treatment with an oral
`benzodiazepine (e.g. lorazepam, clonazepam) during a febrile illness or
`chronic antiepileptic treatment, typically phenobarbital, can be considered.
`This child had a complex febrile seizure because he had two seizures
`several hours apart. In addition, he has a family history of epilepsy. These '
`two factors suggest he may have a reduced seizure threshold and is at
`increased risk for developing subsequent epilepsy. At this time, no avai·lable
`treatment can reduce that risk. He also has a high risk of febrile seizure
`recurrence because of the age of onset being < 1 year of age. He should(cid:173)
`continue to be immunized as scheduled, including influenza vaccines, to
`reduce the number of chifdhood febrile illnesses. In addition, because his
`
`6
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`WHAT DO I DO NOW? !PILEPSV
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`seizures were repetitive, his parents could be instructed in the use of an
`abortive therapy to prevent seizure clusters. As with most patients, the use
`of chronic AEDs is not recommended in this case.
`*Nasal and buccal routes of midazolam administration are not US FDA
`approved.
`
`Further Reading
`Steering Committee on Quality Improvement and Management, Subcommittee on Febrile
`Seizures: clinical practice guideline for the long-term management of the child with
`simple febrile seizures. Pediatrics. 2008;121(6):128H286.
`Annegers JF, Hauser WA, Shirts SB, Kurland LT •. Factors prognostic of unprovoked seizures
`after febrile convulsions. N Eng/ J Med.1987;316(9):493-498.
`Chungath M, Shorvon s. The mortality and morbidity of febrile seizures. Nature Cfln Pract
`Neurol. 2008;4(11):61 o-621.
`Hirtz D, Berg A, Bettis D, et al. Practice parameter: treatment of the child with a first
`unprovoked sei:wre: Report of the Quality Standards Subcommittee of the American
`Academy of Neurology and the Practice Committee of the Child Neurology Society.
`Neurology. 2003;60(2):166-175.
`Millichap JJ, Koh S, Laux LC, Nordli DR. Child neurology: Dravet syndrome: when to
`suspect the diagnosis. Neurology. 2009;73(13):e59-62.
`
`1. FEBRILE SEIZURES AND OTHER SEIZURES IN INFANT$
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`•
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`the night. He has associated issues with depression,
`anxiety, headaches, and difficulty concentrating. The rest
`of his history and review of systems is negative except
`for non-migrainous headaches over the frontal convexity.
`A first cousin on his mother•s side had a diagnosis of
`benign rolandic epilepsy.
`His mother is worried about the continued seizures
`and is wondering whether the diagnosis and treatment
`plans are correct.
`
`2. BENIGN/IDIOPATHIC PARTIAL EPILEPSIES UP£. OF CHILDHOOD
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`enign childhood epilepsy with centrotemporal spikes (BECTS) is
`often referred to as BECfS or simply benign rolandic epilepsy. It is the
`most common idiopathic partial epilepsy (IPE). Similar to his case, seizures
`classically occur shortly after falling asleep or just R,tior to awakening,
`though any pattern of sleep-awake or awake-only seizures can occur. The
`seizures during wakefulness are exclusively simple partial events, often with
`unilateral paresthesias of the oral mucosal surfaces; unilateral clonic or tonic
`activity involving the face, lips, and tongue; dysarthria; and drooling.
`Stiffness of the jaw or tongue and a choking sensation are common. Unlike
`this case, patients typically recall the wakeful part of the seizures and
`are rarely confused during them. Seizure duration is typically seconds to
`minutes.
`Typical n_ocrurnal seizure activity includes:
`
`1. Brief hemifacial seizures with speech arrest and drooling while still
`conscious.
`2. Hemifacial seizures with loss of awareness, gurgling, or grunting
`that may progress to vomiting.
`3. Secondary generalized tonic-clonic seizures.
`
`, PostJctal Todd's paresis may occur; this would be a clue to a partial origin.
`The typical age of onset is 7 to 8 years but varies widely from age 3 to 13.
`Younger patients tend to present with hemiconvulsions.
`Rarely, status epilepticus can occur. Other variants may occur, such
`as partial motor seizures changing lateralization) paresthesias, jerking of a
`single limb, abdominal pain, blindness, and vertigo.
`The "benign" term is evidenced by over 99% of cases remitting by age 18
`in case series of about 400 patients. Many practitioners begin weaning
`off medication around age 16 if there have been no seizures in the past
`6 months. It is notable that a small subset of BECTS patients who develop
`atonic, atypical absence or myoclonic seizures, termed "pseudo-Lennox,
`syndrome, may have cognitive losses despite eventual seizure remission.
`' BECTS can occur with a known structural abnormality, but seizures in
`these cases also typically remit. In the patient presented above there was one
`unusual seizure, with symptoms lasting over a day. If his seizures were not
`responding to medication, it would be reasonable to obtain an MRI of the
`head. Otherwise, MRI scanning of the head is considered unnecessary in
`
`tO
`
`WHAT DO I DO NOW? EPILEPSY
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 23/216
`
`

`
`..
`
`patients with a normal neurological examination and typical seizures and
`EEG findings. The classic EEG finding is the presence of large-amplitude
`but often simply configured spike or sharp waves with large after-going slow
`waves, with a dipole: the negativity is central and positivity is seen frontally
`(Fig. 2.1, 2.2). The epileptiform discharges may be unilateral or bilateral,
`either synchronous or independent. They may occur during wakefulness
`but become activated by non-REM sleep and drowsy states. If the diagnosis is
`in doubt, repeating the EEG with a sleep state can be helpful, although it needs
`to be interpreted in the clinical context. It appears that only 10% of children
`with these rolandic spikes actually have the clinical seizures. The EEG may
`evolve in terms of location and may even show atypical spike locations.
`However, finding generalized discharges, spike-wave runs, or other types of
`partial seizures would significantly change the diagnosis and thus prognosis.
`There is a familial component, sometimes with an autosomal dominant
`inheritance. Linkage analysis has implicated chromosome 15q 14, though
`BECfS . appears to be heterogeneous. Many siblings show the same
`centro-temporal spikes on EEG, though they may nor necessarily have the
`
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`FIGURE 2 8 1 Epileptiform discharges typical of benign rolandlc epilepsy or BECTS. The
`discharges are lateraltzed with a broad field over left <arrows> temporal (T7) and central
`postero-central (P3) and the right (arrowheads) temporal (TB) or central (C4·P4) regions.
`Note the relatively simple configuration to the majority of the discharges. In this example.
`the spike discharges preceded the onset of one of the patient's typical nocturnal
`hemlconvulsive seizures from sleep arising from C4·TB (*).
`
`2. BENtGN/IDIOPATH\C PARTIAL EPILEPSIES OPE} OY' CHILDHOOD
`
`11
`
`
`
`Argentum Pharm. v. Research Corp. Techs., IPR2016-00204
`RCT EX. 2077 - 24/216
`
`

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`FIGURE 2·2 The first spike In Figure 2.1 displayed In Common Average Referential montage,
`highlighting a typical dipole: upwards negativity over P3, T7, and P7 (arrows) and downwards
`positivity over Fp1, F3, and Fz. The dipole Is classically described as being obvious on long
`blploar montage, though It often requires closer review, as In this case.
`
`clinical seizures. In patients with unusual presentations, the presence of
`similar centro-temporal spikes in their siblings would be more supportive of
`BECTS. Many believe the pathophysiology to be due to abnormal brain
`maturation, with changes in synapses (pruning or development of more
`inhibitory connections) or with changes in the electrical characteristics of
`ion channels with time. There is an increased rate of migraine and other
`headaches with BECTS.
`AED treatment does not improve. the chance of remission, and there
`