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` TheJournal ofTRAUMA®Injury, Infection, and Critical Gare
`
`Factors Predictive of Outcome in Posttraumatic Seizures
`Hung-Chen Wang, MD, Wen-Neng Chang, MD, Hsueh-Wen Chang, PhD, Jih-Tsun Ho, MD, PhD,
`Tzu-Ming Yang, MD, Wei-Che Lin, MD, Yao-Chung Chuang, MD, and Cheng-Hsien Lu, MD
`
`Background: Seizures are important
`neurologic complications of traumatic brain
`injury (TBD. Thereis a need for better de-
`lineation of potential prognostic factors and
`outcomes in patients with posttraumatic sei-
`zures (PTS) who could receive treatment
`whenbrought to the hospital.
`Methods: In this 10-year retrospec-
`tive study, 170 adult patients with PTS
`were enrolled in this study. The degree of
`
`seizure control was analyzed using a Sei-
`zure Frequency Scoring System, which
`classified them into excellent and nonex-
`cellent outcomes.
`Results: There were 170 patients with
`acute symptomatic seizure enrolled in this
`study, 106 of whom had early PTS, whereas
`64 had late PTS. Ofthe 106 early PTS, 58%
`(61 of 106) occurred within 24 hours of
`trauma. Risk factors for developing nonex-
`
`cellent outcome included patients who un-
`dergo surgical intervention and presence of
`late-provoked seizures during the acute
`phase of TBI.
`Conclusions:Seizures are an impor-
`tant neurologic complication of TBI. Re-
`garding the potentially side effects of
`antiepileptic drugs, antiepileptic therapy
`should be carefully administrated in those
`nonexcellent outcome patients.
`J Trauma. 2008;64:883—888.
`
`raumatic brain injury (TBD)is one of the major causes of
`disability, morbidity, and mortality among individuals
`younger than 45 years andis responsible for a significant
`proportion of traumatic deaths in developed countries.!* The
`overall risk of seizures after TBI ranges from 2% to 5% in the
`general population** but is from 7% to 39% in patients with
`cortical injury and neurologic sequelae.
`One population-based study demonstrates that 86% of
`patients with a single late posttraumatic seizure (PTS) had a
`second seizure within 2 years.° Because of the possible ben-
`efits of antiepileptic drugs (AED) to reduce the degree of
`functional morbidity after TBI,
`there is a need for better
`delineation of potential prognostic factors and outcomes in
`nonselected patients admitted to the hospital who could re-
`ceive treatment.
`
`In this study, the role of a numberofclinical observations,
`neuroimaging findings, and Glasgow Coma Scale (GCS) score
`measurements were analyzed in terms of predicting the outcome
`of PTS. We chose to study (1) the clinical relevance of PTS and
`other neurologic complications that occur after TBI; (2) the
`types of seizures that occur during acute phase of TBI; and G)
`the potential prognostic factors during the acute illness for the
`long-term outcome.
`
`Submitted for publication July 18, 2006.
`Accepted for publication February 12, 2007.
`Copyright © 2008 by Lippincott Williams & Wilkins
`From the Departments of Neurosurgery (H.-C.W., J.-T.H., T.-MLY.),
`Neurology (W.-N.C., Y.-C.C., C.-H.L.), and Radiology (W.-C.L.), Chang
`Gung Memorial Hospital, Kaohsiung Medical Center, Chang Gung Univer-
`sity College of Medicine, Kaohsiung, Taiwan, China; and Department of
`Biological Science (H.-W.C.), National Sun Yat-Sen University, Kaohsiung,
`Taiwan, Republic of China.
`Addressfor reprints: Cheng-Hsien Lu, Department of Neurology, Chang
`Gung Memorial Hospital, 123, Ta Pei Road, Niao Sung Hsiang, Kaohsiung
`Hsien, Taiwan, Republic of China; email: chlu99 @ms44.url.com.tw.
`DOI: 10.1097/TA.0b013e31804a7fa4d
`
`PATIENTS AND METHODS
`During a period of 10 years (1994-2003), 9,212 patients
`who suffered from first event TBI were admitted to the
`Department of Neurosurgery at the Chang Gung Memorial
`Hospital
`in Kaohsiung. Chang Gung Memorial Hospital-
`Kaohsiungis a 2,482-bed acute-care teaching hospital, which
`is the largest medical center in southern Taiwan that provides
`both primary and tertiary referral care to patients. Of the
`9,212 patients, 190 suffered from acute symptomatic seizures
`during the acute phase of TBI.
`The definition of PTS was set according to that in previous
`studies: seizure occurring after head trauma that is causally
`related to the traumaitself.”® A provoked (acute symptomatic
`seizure) seizure is one that occurs in close temporalrelation with
`TBI, which is presumedto be the underlying cause. In contrast,
`an unprovoked seizure is a seizure occurring in the absence of
`one or more precipitating factors, and it includes events occur-
`ring in patients with antecedent stable (nonprogressing) CNS
`insults, including TBI (remote symptomatic seizures).”°
`The definition of onset of acute symptomatic seizure
`during hospitalization was modified from those of a previous
`study” classification into two subtypes: early-provoked sei-
`zures as seizures occurring within the first 7 days after injury,
`and late-provoked seizures as those occurring 7 days later but
`before discharge. In contrast, an unprovoked seizure is a
`seizure occurring in the absence of one or more precipitating
`factors, while epilepsy is the occurrence of repeated unpro-
`voked seizures.'° Status epilepticus was modified from those
`of previous reports and defined as both of the following: (1)
`continuous seizures lasting at least 5 minutes; and (2) two or
`more discrete seizures between which there is incomplete
`recovery of consciousness.''!?
`Patients initially treated in other hospitals but subse-
`quently transferred to our hospital for further therapy were
`also included in the study and their initial clinical and labo-
`ratory data at the previous hospital were used for analysis.
`
`Volume 64 ¢ Number 4
`
`883
`
`Gopyrignt © Lippincott Wiliams & Wilkins. Unauthorized reproduction of this article is prohibited.
`AQUESTIVE EXHIBIT 1103 Page 0001
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`TheJournal ofTRAUMASInjury, Infection, and Critical Care
`
`Patients were cxcluded from the study if (1) they had a history
`of TBI; (2) preexisting epilepsy; (3) gunshot wounds or pene-
`trating head injuries; (4) preexisting neurologic conditions with
`various neurologic deficits; and (5) death within 1 month. The
`study had enrolled a total of 170 patients.
`Demographic data of the 170 patients, characteristics and
`circumstances, time interval from TBI to first seizure,
`the
`types of seizure, and several other features were documented,
`including length of hospital stay, the presence and duration of
`chronic epilepsies, neurosurgical interventions, and systemic
`underlying diseases associated with seizures. The GCS score
`was analyzed by neurosurgeons when the patient arrived in
`the emergency room.
`TBI was defined as an alteration in brain function man-
`ifesting as confusion,altered consciousness, seizure, coma, or
`focal sensory or motor neurologic deficit resulting from blunt
`or penetrating force to the head.‘? TBIwasclassified as mild
`(loss of consciousness or amnesia lasting less than 30 min-
`utes), moderate (loss of consciousness for 30 minutes to 24
`hours or a skull fracture), or severe (loss of consciousness or
`amnesia for more than 24 hours, subdural hematoma, intra-
`cerebral hematoma, or brain contusion).”
`All of the patients received brain computed tomography
`(CT) scans soon after arrival at the emergency room. Fur-
`thermore, follow-up brain CT scans were performedif clin-
`ical deterioration was noted, including acute onset of focal
`neurologic deficits, seizures or status epilepticus, and a pro-
`gressively disturbed conscious state. All diagnoses of intra-
`cranial contusion or hematoma were based on brain CT
`evidence.
`Our standard protocol was to administer AEDs only to
`those who had acute symptomatic seizure in TBI, whereas pro-
`phylactic AED therapies were not given to those without such
`symptoms in the acute stage of TBI. We usually administered
`AEDsfor less than 7 days to patients who had early-provoked
`seizures, while AEDs were continued for longer periods to
`prevent the development of unprovoked seizures in those with
`late-provoked seizure. The basis of discontinuing AEDsoflate-
`provoked seizure patients after hospital discharge included all of
`the following: (1) serial electroencephalogram (EEG) showed
`no evidence of epileptiform discharge or seizure-free clinically
`for more than 2 years; and (2) no risk factors for seizures
`recurrence, which include prolonged duration before seizure was
`controlled; high frequency of seizures before control; focal neu-
`rologic abnormalities; poor mentation; complexpartial seizures;
`and consistently abnormal EEGs.'*!5
`The follow-up period was terminated by death or by the
`end of the study itself (December 2004). Therapeutic out-
`comes and the degree of seizure control after discharge were
`analyzed by a Seizure Frequency Scoring System, which is
`slightly modified from Engel etal.’ (Table 1). For purposes
`of analysis, a score of 4 or below was defined as an excellent
`outcome, and 5 or more as nonexcellent.’? The outpatient
`department followed up most patients after discharge, with
`
`Table 1 Scoring System for Seizure Frequency
`Seizure Frequency
`
`0
`1
`2
`3
`4
`
`Excellent outcome
`Seizure free, off antiepileptic drug
`Seizure free, need for antiepileptic drug unknown
`Seizure free, requires antiepileptic drug to remain so
`Nondisabling simple partial seizures
`Nondisabling noctural seizures only
`Non-excellent outcome
`5
`One to three times per yr
`6
`Four to 11 times per yr
`7
`Oneto three times per mo
`8
`Oneto six times per wk
`9
`Oneto three times per d
`10
`Four to 10 times per d
`oe
`More than 10 times per d but not status epilepticus
`
`Presenceof status epilepticus 12
`Slightly modified from Engelet al.”
`
`others interviewed through telephone to identify neurologic
`outcome.
`
`The clinical data, including gender and clinical manifes-
`tations between the two patient groups (“excellent outcome”
`and “nonexcellent outcome”) during the acute phase of TBI,
`was analyzed by means ofa ,* test or Fisher’s exact test. The
`mean ages between the two patient groups were analyzed by
`Student’s ¢ test. GCS score at
`the time of admission and
`duration of hospitalization between the two patient groups
`was analyzed by Wilcoxon rank sum test.
`The association between (1) early or late PTSs and (2)
`presence of surgical intervention, and the survival curve be-
`tween the two patient groups (“excellent outcome” and “non-
`excellent outcome”) were assessed with Kaplan-Meier Plots
`and compared by- log-rank test. Stepwise logistic regression
`was used in evaluating the relationship between clinical fac-
`tors and outcomeof seizure, with adjustments madefor other
`potential confounding factors. All statistical analysis was
`conducted using the SAS software package, version 9.1
`(2002, SAS, Inc., Cary, NC).
`
`RESULTS
`The 170 patients with acute symptomatic seizure in-
`cluded 126 males (age range, 2 months—87 years; mean age,
`39.6 years) and 44 females (age range, 3 months—83 years;
`mean age, 46.5 years). Among these, 134 had excellent out-
`comeand 36 had nonexcellent outcome (Table 2). The degree
`of seizure control after discharge forall 170 casesis listed in
`Figure 1. The mean age at onset was 40.5 years + 24.7 years
`for those who had an excellent outcome and 44.6 years +
`20.9 years for those who had a nonexcellent outcome. The
`mean time length of hospitalization was 21.4 days + 16.8
`days and 33.3 days + 29.7 days for those with excellent and
`nonexcellent outcomes, respectively (p = 0.001).
`No one was excluded because of loss to follow-up. Fol-
`low-upinterval in the 170 patients was 1 month to 204 months
`
`884
`April 2008
`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`
`Factors and Outcomein Posttraumatic Seizures
`
`So
`Table 2 Prognostic Factors of Posttraumatic Seizures
`Excellent Outcome,
`N = 184
`
`p Value
`
`Odds Ratio
`
`95% Cl
`
`Nonexcellent Outcome,
`N = 36
`
`Age(yrs)
`Gender
`Male
`Female
`Clinical features
`Posttraumatic amnesia
`Brief unconsciousness
`Motordeficits
`Severity of brain injuries*
`Mild
`Moderate
`Severe
`GCS at admission
`Neuroimaging finding*
`Depressed skull fracture
`Cortical contusion
`Subdural hematoma
`Epidural hematoma
`Intracerebral hematoma
`Acute symptomatic seizure
`Onset of seizure
`Early-provoked seizures (=7 d)
`Late-provoked seizures (>7 d)
`Subtype of seizure
`Generalized
`Focal with or without
`generalization
`Status epilepticus
`Surgical intervention
`Nonsurgery
`Surgery
`Duration of hospitalization
`
`40.5 + 24.7
`
`44.6 + 20.9
`
`96
`38
`
`94
`72
`53
`
`19
`10
`105
`10.5+3.9
`
`12
`44
`88
`9
`27
`
`95
`39
`
`63
`71
`
`6
`
`30
`6
`
`23
`20
`17
`
`6
`1
`29
`10.4 + 3.7
`
`4
`9
`27
`2
`12
`
`11
`25
`
`17
`19
`
`2
`
`63
`71
`21.4 + 16.8
`
`7
`29
`33.3 + 29.7
`
`0.358
`
`0.155
`
`0.472
`0.845
`0.406
`
`0.577
`
`0.726
`
`0.749
`0.513
`0.288
`7.0
`0.095
`
`=0.001
`
`0.982
`
`0.8677
`
`0.003
`
`=0.001
`
`0.19-1.31
`
`0.61-2.88
`0.44-1.95
`0.35-1.53
`
`0.32-2.39
`0.34-22.47
`
`0.24-2.60
`0.57-3.06
`0.28~1.47
`0.25-5.93
`0.22-1.14
`
`2.48-12.34
`
`0.47-2.07
`
`0.24-6.50
`
`0.51
`
`5.54
`
`3.68
`
`1.51-8.97
`
`The clinical data, including gender andclinical manifestations between the two patient groups(“excellent outcome” and “non-excelient
`outcome”) was analyzed by means of a ¥” test or Fisher’s exact test. The mean ages betweenthe twopatient groups were analyzed by Student’s
`t test. GCS at the time of admission and duration of hospitalization between the two patient groups was analyzed by Wilcoxon rank sum test.
`* Relative to “severe brain injury”.
`* Fifty-one patients had more than one abnormal neuroimaging findings.
`
` $
`
`
`
`Go
`
`&
`
` 3.
` o.
`9
`1
`2
`3 45 67 8
`® Wi B
`Seizure Frequency Scoring System:
`Fig. 1. Results of seizure frequency score. For the purposes of
`analysis, a score of four or below was defined as an excellent
`outcome, and five or more as nonexcellent.
`
`8
`
`curred within 24 hours of trauma. The mean time interval
`between the onset of TBI and early PTSs was 2.1 days +
`1.6 days, and 14.7 days + 5.8 days for the late PTSs (p =
`0.001).
`Regarding seizure subtypes, 77 had generalized seizures
`and 93 had focal seizures with or without generalization. The
`77 generalized seizures included generalized tonic—clonic
`seizures in 73 and myoclonic seizure in 4. Thelatter 93 focal
`seizures included simple focal seizures in 63 and focal sei-
`zures evolving to generalized tonic—clonic convulsions in the
`remaining 30 (Table 3). The frequency of seizures during the
`acute phase of TBI was: 95 had one episode of seizures, 67
`had more than one episode, and 8 progressed to status epi-
`lepticus. Of these eight cases, two had nonexcellent outcome
`and six had excellent outcome (with five seizure-free after
`completing the treatment for TBI). The outcome of PTS was
`strongly associated with the development of early PTSs (p =
`0.001), although no difference was noted between focal and
`generalized seizures (p = 0.982),
`
`(mean, 29.5 months). Aside from TBI, 42 patients had one or
`more other underlying conditions, which included diabetes mel-
`litus (37), hypertension (9), iatrogenic Cushing’s syndrome (6),
`and pneumonia (8).
`During hospitalization, 106 had early PTSs, whereas
`64 had late PTSs. Furthermore, 57.5% (61 of 106) oc-
`
`Volume 64 ¢ Number 4
`885
`Copyright©Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
`AQUESTIVE EXHIBIT 1103 Page 0003
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`TheJournal ofTRAUMASInjury, Infection, and Critical Care
`eeeeeeeeeS
`
`Table 3 Relations Between Therapeutic Outcomes, Neuroimaging Findings, and Seizure Subtypes
` Brain CT at the Time of Admission Outcomes
`
`Excellent
`.
`
`
`Seizure Subtypes Depressed Skull—Contusion EDH SDH ICH . Nonexcellent
`
`
`
`
`Fracture (N= 16)
`(N=50)
`(N=11)
`(N=115)
`(N= 39)
`SeizureFree
`Score3&4
`(N = 36)
`(N = 126) (N = 8)eee
`
`Generalized seizures
`(N = 77)
`Tonic-cionic seizure
`(N = 73)
`Myoclonic seizure
`(N = 4)
`Focal seizures with or
`without generalization
`(N = 93)
`Focal seizures (N = 63)
`Focal seizures evolving
`to tonic-clonic convulsions
`
`(N = 30)
`
`28 (2)*
`
`5
`
`42 (2)
`
`15 (1)
`
`54 (4)
`
`3
`
`0
`
`4
`
`3
`
`0
`
`16 (1)
`
`0
`
`12
`8 (1)
`
`50
`20 (1)
`
`13
`41 (1)
`
`48
`20 (1)
`
`3
`2 (1)
`
`* Values in parentheses indicate number of cases progressed to status epilepticus during acute stage of traumatic brain injury.
`
`Regarding the relationship of the onset of acute symp-
`tomatic seizure (early PTSs and late PTSs) to the frequency
`of seizures during the acute phase of TBI (one episode, more
`than one episode, and presence of status epilepticus), to the
`type of seizures (tonic—clonic seizure, focal seizures evolving
`to tonic-clonic convulsions, and focal seizures), to the sever-
`ity of TBI (mild, moderate, and severe TBI), thestatistical
`analysis showed the following: (1) there was norelationship
`between the onset of acute symptomatic seizure (early PTSs
`and late PTSs) and the frequency of seizures (one episode,
`more than one episode, and presence of status epilepticus)
`(p = 0.298); (2) there was a significantrelationship between
`the onset of acute symptomatic seizure (early PTSs and late
`PTSs) and the subtypes of seizures (generalized tonic-clonic
`seizure, myoclonic seizure, focal seizures evolving to tonic-
`clonic convulsions, focal seizures, and status epilepticus)
`(p = 0.001); and (3) there was no relationship between the
`onset of acute symptomatic seizure (early PTSs and late
`PTSs) and the severity of TBI (mild, moderate, and severe
`TBI, p = 0.425).
`The other clinical data of the [70 patients are listed in
`Table 2. Furthermore, the mean score of GCS score at ad-
`mission between excellent and nonexcellent outcomes was
`10.5 + 3.9 and 10.4 + 3.7, respectively (p = 0.726).
`Among the 170 cases, only 69 had at least one EEGs
`after PTE. Fifty-eight had abnormal EKG readings of which
`38 had EEGreadings that showed a predominantly unilateral
`abnormality, whereas 20 had diffuse abnormality. In the 38
`cases, 10 were tonic—clonic seizures, 14 were focal seizures,
`8 were focal seizures evolving into tonic-clonic convulsions,
`2 were myoclonic seizures, and 4 were status epilepticus. Of
`the latter 20 cases, four were focal seizures, four were focal
`seizures evolving into tonic-clonic convulsions, one was
`myoclonic seizure, and two were status epilepticus. Among
`the 11 cases with normal ERG readings after PTS, 6 were
`tonic—clonic seizures, 2 were focal seizures, 2 were focal
`
`seizures evolving into tonic-clonic convulsions, and 1 was
`status epilepticus.
`During hospitalization, 160 had abnormal neuroimaging
`findings (Table 2). Of these, 128 had excellent outcome while
`32 did not. In the 10 cases with normal neuroimaging find-
`ings, 6 had excellent outcome. There was nostatistically
`significant
`relationship between abnormal neuroimaging
`findings and outcome (excellent and nonexcellent outcomes;
`p = 0.222).
`Of the 170 patients enrolled in this study, 45 received
`more than one AEDs therapy. Of these 45 patients, 36 re-
`ceived 2 AEDs, 7 received 3 AEDs, and 2 received more than
`3 AEDs. The other 125 patients included 103 who received
`phenytoin, 13 who received phenobarbital, 5 who received
`valproic acid, and 4 who received carbamazepine. The mean
`duration of AEDsuse in the late-provoked seizure group was
`37.1 months + 36.4 months. The adverse effects of AEDs
`included the following: hematologic disorders (leukocytosis
`or eosinophilia) in 12, cognitive impairment in 11, abnormal
`liver function in 10, skin rash in 10 (with one progressing to
`Stevens-Johnson Syndrome), gastrointestinal symptoms in 9,
`lethargy or fatigue in 5, tremor in 3, phlebitis in 2, weight
`change in 1, and gingival hyperplasia in 1.
`Comparisons of clinical features and laboratory data be-
`tween excellent or nonexcellent outcome of TBI were listed
`in (Table 2). Statistical analysis of the clinical manifestations
`and laboratory data between the two patient groups revealed
`the following significant findings: onset of acute symptom-
`atic seizures (early or late PTSs; p = 0.001), whether surgical
`intervention was necessary or not (p = 0.003), and duration
`of hospitalization (p = 0.001). Variables used in the logistic
`regression included onset of acute symptomatic seizures
`(early or late PTSs) and necessity of surgical intervention.
`After analysis of all the aforementioned variables, only onset
`of acute symptomatic seizures (early or late PTSs; p = 0.001)
`was independently associated with outcomeof seizures.
`
`886
`
`April 2008
`Copyright © Lippincott Willams & Wilkins. Unauthorized reproduction of this article is prohibited.
`AQUESTIVE EXHIBIT 1103 Page 0004
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`Factors and Outcomein Posttraumatic Seizures
`
`Among the 170 acute symptomatic seizure cases that were
`enrolled in this study, 44 (26%, 44 of 170) progressed to
`unprovoked seizures, whereas 126 (74%, 126 of 170) became
`seizure-free with or without AED therapy. The percent of
`early and late symptomatic seizures accounted for 62% (106
`of 170) and 38% (64 of 170) of episodes in our study,
`respectively.
`The onset of PTSs hassignificant implications for sub-
`sequent treatment and the quality of life of the patient. An
`important question, therefore, is whetherthere are prognostic
`factors that can identify the seizure frequencies of patients
`after the first acute symptomatic seizures. Therisk of devel-
`oping PTSs is primarily analyzed by the severity of the
`antecedent head injury, with high-risk factors that include
`neurologic characteristics such as acute intracranial hema-
`toma, depressed skull fracture, dural penetration, the presence
`of focal neurologic deficits, a deep and lengthy coma, or
`prolonged impairment of consciousness.!7!8
`In this study, we demonstrated that early acute symp-
`tomatic seizures (<7 days) during the acute phase of TBI had
`better outcomesthan for those who did not, though there was
`no difference noted between focal and generalized seizures.
`The mean duration of hospitalization during the acute phase
`of TBI was shorter among those whohadexcellent outcomes.
`Our study also demonstrated that
`there was a significant
`relationship between the onset of acute symptomatic seizure
`(early or late PTSs) and seizure subtypes (generalized tonic—
`clonic seizures, myoclonic seizures, focal seizures evolving
`to tonic-clonic convulsions, and focal seizures). We also
`found that
`the necessity of neurosurgical
`interventions
`strongly influenced the outcomeof seizure frequency.'’ The
`nonexcellent outcome in this study may beattributed to an
`underlying brain pathology, surgical intervention, or a com-
`bination of complications.
`Significant differences in study methods, particularly in
`case ascertainment and inclusion criteria, make study com-
`parisonsdifficult, particularly among subgroups of TBI pa-
`tients. Furthermore, clinical research for seizure prevention
`have several methodologic disadvantages,'*~°* including: (1)
`the patients are heterogeneous and have different propensities
`in developing unprovoked seizures; (2) prolonged period re-
`quired for the occurrence of unprovoked seizures in several
`individuals, which may affect patient compliance; (3) long-
`term treatment in patients developing seizures during the
`treatment; and (4) the increasingly predominant practice of
`starting AEDs after just one seizure, which may lessen the
`difference seen after the study drugs are discontinued and
`changing the natural history of PTS.
`Based on the above studies, AED prophylaxis seems to
`control provoked seizures in patients with TBI, although it
`does not seem to prevent the subsequent development of
`unprovoked seizures, which are poorly tolerated and even
`detrimental to cognitive and behavioral function. Our stan-
`dard protocol in administering AEDs is only for those who
`have had seizures in the acute stage of TBI, continuingthis to
`
`Logrank P= 0.0006
`
`
`
`
`
`Non-excellentoutcome
`
`
` Surgery (n=100}
` No Surgery. (n=70)
`
`O
`
`150
`1:00
`50
`Duration of Follow-up (months)
`Fig. 3. Kaplan-Meier plots indicating the percentages of nonexcel-
`lent outcome in the 170 PTSs patients after traumatic brain injury.
`The patients were divided into two groups: those with and those
`without surgical evacuation. The p value was obtained by log-rank
`comparison of data.
`
`To look at each factor individually, we calculated Kalpan-
`Meier estimates of the fraction developing nonexcellent
`outcome by different times for each subgroup and tested
`for differences by using a log-rank test. Onset of acute
`symptomatic seizures (early or late PTSs) and necessity of
`surgical intervention between the two patient groups (ex-
`cellent and nonexcellent outcome) showed the following:
`onset of acute symptomatic seizures (early or late PTSs:
`p = 0.0001; Fig. 2), and necessity of surgical intervention
`(p = 0.0006; Fig. 3).
`
`DISCUSSION
`The occurrence of seizures after head injury is a recog-
`nized complication of TBI and is known to worsen functional
`outcome significantly afterward.'® Much work has been per-
`formed in preventing the developmentof, or, at least, mini-
`mizing the impact of PTSs.In our study, acute symptomatic
`seizures accounted for 2% (190 of 9,212) of all episodes.
`
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`Copyright © Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.
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`Legrank P<0.0001
`
`Late seizure (n=64)
`
`te-]
`2os
`|
`2
`=:
`2068
`38 oad
`&
`6.27
`
`o2
`
`
`
`
`00>
`
`~T
`Q
`
`t
`T
`T
`150
`100
`50
`Duration of Follow-up (months)
`Fig. 2. Kaplan-Meier plots indicating the perceniage of nonexcel-
`lent outcome in the 170 PTS patients after traumatic brain injury.
`The patients were divided into two groups: those with late PTSs, and
`those with early PTSs. The p value was obtained by log-rank com-
`parison ofdata.
`
`

`

`
`
`TheJournal ofTRAUMA®Injury, Infection, and Critical Care
`
`prevent the development of later epilepsy. We do not use
`prophylactic AEDs therapy for those who do not have sei-
`zures in the acute stage of TBI.
`Although our study demonstrates that the time of onset
`of acute symptomatic seizures after TBI influences the out-
`comeafter PTSs, our study has several limitations. First, this
`is a retrospective analysis and is, therefore, subject to bias of
`unmeasured factors. It was also not possible to assess the
`effect of prophylactic AEDs after the acute stage of TBI to
`prevent later epilepsy or draw any conclusions. Second, only
`those who had acute symptomatic seizures during the acute
`phase of TBI were enrolled. Thus, continued uncertainty was
`present in assessing the incidence of unprovoked seizures
`after TBI in nonselected patients. Third, most patients in this
`study were treated with anticonvulsant medication after their
`first acute symptomatic seizure, in accordance with our study
`protocols. Thus, our findings may underestimate the “true”
`frequency of seizure associated with the “natural history” of
`untreated unprovoked seizures.
`Several studies focused on the effects of AEDs for pre-
`venting seizure after TBI.2!°-° All of their conclusions
`showed that the use of AEDs should be short (usually less
`than 7 days). The adverse effects of AEDs accounted for
`0.6% to 19.4% in different series.2>?© Because this is a
`retrospective study, the start of AED therapy would differ for
`each patient according to the preference of his or her doctor,
`which may cause potential bias in statistical analysis. Fur-
`thermore, our study only focused on patients who had sei-
`zures after acute traumatic head injury. It would be difficult
`to evaluate both the efficacy and adverse effects of AED
`prophylaxis for PTS and draw a conclusion.
`In conclusion,seizures are an important neurologic com-
`plication of TBI. Although antiepileptic therapy is usually
`short-term for patients with early-provoked seizures, 26% (44
`of 170) of cases with early-provoked seizures progress to
`unprovoked seizures. Regarding the potentially side ef-
`fects of AEDs, antiepileptic therapy should be carefully
`administrated in those nonexcellent outcomepatients in-
`cluding those patients who undergo surgical intervention
`and have late-provoked seizures during the acute phase of
`TBI.
`
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`April 2008
`Copyright © Lippincott Willams & Wilkins. Unauthorized reproduction of this article is prohibited.
`AQUESTIVE EXHIBIT 1103 Page 0006
`AQUESTIVE EXHIBIT 1103 Page 0006
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