Developmental outcome with and without successful intervention

DEVELOPMENTALOUTCOME WITH AND WITHOUT SUCCESSFULINTERVENTION

Rochelle Caplan,* Prabha Siddarth,* Gary Mathern, t Harry Vinters, t Susan Curtiss, § Jennifer Levitt,* Robert Asarnow,* and W. Donald Shields II *Departments of Psychiatryand Biobehavioral Sciences, t Neurosurgery, t Pathology, §Linguistics,and IINeurology and Pediatrics University of California, LosAngeles Los Angeles, California 90095

I, Introduction II. Reviewof Literature A. Seizure Control B. Cognition C. Behavior D. Language E. Summary III. Developmental Outcome of UCLA SurgicallyTreated Infantile Spasms (IS) and Non-IS Cohorts A. Social Communication B. Cognition C. Language D. Neuropathology E. Morphometry F. Summary IV. Mechanisms of Developmental Outcome References

A review of the literature on the developmental outcome of medically and surgically treated symptomatic infantile spasms (IS) indicates that poor seizure control, severe mental retardation, and marked behavioral disorders are found at long-term outcome of symptomatic IS. The 2-year outcome findings of the UCLA Pediatric Epilepsy Surgery Research Group in children with symptomatic infantile spasms and in children with early onset intractable symptomatic epilepsy other than IS (non-IS) demonstrate impaired development of cognition, language, and social communication despite improved seizure control. The social communication deficits of these children are similar to those found in autistic children. Finally, the underlying pathology of the resected brain, rather than ongoing

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seizures and seizure type, plays an important role in development of the remaining brain tissue and the outcome of early onset symptomatic IS and non-IS.

© 2002, Elsevier Science (USA).

h Introduction

Since its earliest descriptions, the outcome of infantile spasms (IS) was considered bleak (West, 1841). During the past two decades, there has been remarkable development of antiepileptic drugs, epilepsy surgery, and electrostimulation techniques, as well as development of reliable and valid outcome measures for infants and children with developmental delay. Nevertheless, to date only a few studies have been conducted on the developmental outcome of these children. To further our understanding of IS and the treatment of this disorder, studies on the developmental outcome of IS should address the following issues. First, does the developmental outcome of IS reflect the impact of ongoing seizures, underlying pathology, or both these factors? Second, is the outcome of children with IS specific for this type of seizure disorder or similar to that of children with other forms of early onset intractable epilepsy (hereafter referred to as non-IS)? Third, how does medical and surgical intervention affect the developmental outcome of children with symptomatic IS? This chapter addresses these questions as it reviews the pertinent literature on the developmental outcome of symptomatic IS and summarizes the findings of a multidisciplinary study conducted by the UCLA Epilepsy Surgery Research Group following surgical intervention for IS and for nonIS. It concludes with a discussion of possible mechanisms underlying the developmental outcome of symptomatic IS.

II. Review of Literature

A. SEIZURECONTROL

The 5- to 10-year outcome of medically treated symptomatic IS indicates uncontrolled seizures in 4 4 - 6 0 % of the children (Chakova et al., yr1998; Cusmai et aL, 1993; Czochanska et al., 1994; Holden et al., 1997; Koo et al., 1993; Siemes et al., 1998). Large epilepsy surgery centers have f o u n d 60% seizure control after surgical intervention (Duchowny et al., 1998;

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Holthausen et al., 1993; Mathern et aL, 1999; Pinard et al., 1999; Sugimoto et aL, 1999; Wyllie et al., 1998). Matthern et al. (1999) have shown that between 2 and 5 years after surgery, there is an increase in the number of surgically treated IS patients with class 2-5 seizures (i.e., 5-30 seizures per month) and a decrease in those in class 1 (i.e., without seizures). During the first 2 years after surgery, a time of active brain development, surgical intervention might be more beneficial in terms of controlling seizures than medical intervention in these children (Matthern et al., 1999). These high rates of poor seizure control at long-term outcome underscore the severity of the pathology underlying symptomatic IS. Surgical intervention, however, might be more beneficial than medical intervention during the short-term postoperative period. Further studies are needed to examine the relationship of long-term seizure outcome with behavioral, cognitive, and linguistic variables in surgically treated patients with symptomatic IS and non-IS.

B. COGNITION The cognitive outcome studies of medically treated children with symptomatic IS describe mental retardation in 81-95% (for a review, see Asarnow et al., 1997). Asarnow et al. (1997) noted that most of these studies have not used psychometric instruments. Furthermore, these studies include mixed groups of children with cryptogenic and symptomatic IS and have not differentiated between the effects of poor seizure control and associated neurological deficits. According to Asarnow et aL (1997), the five studies that used psychometric instruments found developmental quotients (DQs) in the severely retarded range in medically treated IS children (Favata et aL, 1987; Glaze et al., 1988; Riikonen, 1982; Seki et al., 1977). In contrast, 50% of 20 patients from the UCLA symptomatic IS cohort had a significant improvement in the Vineland Adaptive Behavioral Scale (Sparrow et al., 1984) with a DQ greater than 51 2 years after epilepsy surgery. Children with early surgery and better presurgical DQ scores had a larger postsurgical increase in their DQ scores than those with later surgery and lower presurgical DQ scores. These findings suggest that, at short-term follow-up, surgically treated IS patients are not as retarded as medically treated children with symptomatic IS. High rates of mental retardation in medically treated early onset intractable symptomatic epilepsy other than IS (Steffenburg et al., 1998), however, suggest that poor cognitive outcome might not be specific for IS, but for early onset intractable epilepsy.

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Only 12.5% of the surgical patients of Asarnow et al. (1997) had DQs greater than 79 compared to 66% in outcome studies of children with cryptogenic IS (Dulac et al., 1993). Presurgical developmental level and age at surgery are related to the cognitive outcome 2 years after surgery in IS patients. In medically treated symptomatic IS patients, the long-term cognitive outcome is associated with poor seizure control and neurological deficits, two confounding factors associated with the severity of underlying brain damage (Koo et al., 1993). In cryptogenic IS, however, an absence of significant mental regression with preserved visual function; an absence of focal interictal electroencephalographic (EEG) abnormalities after intravenous diazepam; and a reappearance of hypsarrhythmia between consecutive spasms of a cluster are associated with improved development and seizure control at the 2-year follow-up (Dulac et al., 1993).

C. BEHAVIOR Several studies demonstrated transient autistic disorder (Krug et al., 1980; Olsson et al., 1988; Riikonen and Amnell, 1981), as well as autistic disorder at long-term follow-up in children with medically controlled IS (Riikonen and Amnell, 1981). Riikonen and Amnell (1981) reported that 11% of children with IS develop autistic disorder. Chugani etal. (1996) described bilateral temporal lobe hypometabolism in the positron emission tomography scans of 18 medically intractable IS patients, 10 of whom met DSM-IV criteria for autistic disorder. Jambaque et al. (1993) found a relationship between impaired visual attention, a feature of autistic disorder, and reduced cerebral blood flow in the parietal lobe of children with medically treated IS. Although the 11% incidence of autistic disorder in children with IS is much higher than the 0.05-0.1% in the general population (for a review, See Fombonne, 1999), none of these studies used well-established instruments to make this diagnosis. In addition to autistic disorder, 13% of the 214 medically treated IS patients of Riikonen and Amnell (1981) had transient and longterm hyperkinesis based on retrospective parent and chart reporting. Although they reported psychosis in 2% of their IS patients, they did not describe the criteria for this diagnosis nor the type of psychosis. Other than a description of improved behavior following callostomy for intractable IS (Pinard et al., 1999), there have been no other prospective studies of psychopathology in medically and surgically treated IS. None of the previously reviewed studies used standardized behavioral instruments.

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D. L~NGUAGE

To the best of our knowledge, there have been no studies on linguistic outcome in children with symptomatic IS. Studies in children who have undergone hemispherectomy for intractable epilepsy, some of whom had IS, demonstrate different linguistic findings based on age of onset and the underlying neuropathology. In the UCLA pediatric surgery series, Curtiss (Curtiss and de Bode, 1999; Curtiss et al., 2001) found that 31.8% of 48 right hemispherectomy patients and 16.7% of left hemispherectomy patients had no language development after surgery. Furthermore, postsurgical seizure control, an indicator of the functional status of the remaining hemisphere, was associated with the severity of linguistic delay in these children. VarghaKhadem et al. (1991) and Curtiss and de Bode (1999) found a relationship between age of onset and language development after right, not left hemispherectomy. However, the children in these studies had both late and early onset intractable epilepsy, and the number of IS patients was not specified.

E. SUMMARY Poor seizure control, severe mental retardation, and marked behavioral disorders are found at long-term outcome of symptomatic IS. Surgical intervention might improve seizure control and decrease the severity of mental retardation.

III. Developmental Outcome of UCLA Surgically Treated Infantile Spasms (IS) and Non-IS Cohorts

A. SOCIALCOMMUNICATION 'The Early Social Communication Scale (ESCS) measures preverbal use of gestures, such as social interaction, joint attention, and behavior regulation (Mundy et al., 1996). In social interaction, children elicit or respond to interpersonal interactions involving physical contact or turn taking. In joint attention they direct the attention of the experimenter to an object or event, but not to obtain the object or affect the event. Children initiate joint attention through eye contact or pointing and they respond to requests for joint attention, such as looking at an object or event with the experimenter. In behavior regulation, children point, make eye contact, or tap an object to request aid in obtaining objects or affecting events.

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A 2-year follow-up of 41 IS and 18 non-IS patients described in Table I using the ESCS demonstrated a significant postsurgical increase in the use of social interaction in the IS (F = 22.53, df = 1, 42, p < 0.001) and non-IS groups (F = 4.81, df = 1, 29, p < 0.03) and in the n u m b e r of nonIS subjects who attained ceiling scores on the response to joint attention (x 2 = 3.97, p < 0.04). There was no statistically significant increase in the initiation of j o i n t attention and in the use of behavior regulation in both IS and non-IS patients. C o m p a r e d to normal children (Fig. 1), however, children with intractable symptomatic IS and non-IS were severely delayed in the use o f social interaction, j o i n t attention, and behavior regulation both before and 2 years after epilepsy surgery. A trend for a larger increase in the use of behavior regulation in the non-IS c o m p a r e d to the IS group (F = 3.16, df = 1, 162, p < 0.07) was associated with cognitive (F = 7.70, df = 1, 117, p < 0.06) rather than age differences between these groups. We also used Kasari et al. (1990) and Yirmiya etal.'s (1989) modification of the maximally discriminate movement coding system (MAX) (Izard, 1979), a reliable and valid anatomically based system for coding discrete facial m o v e m e n t changes related to emotion. The MAX classifies 10 fundamental expressions into the following categories: positive expressions (i.e., surprise, astonishment, positive blends, and all intensities of enjoyment-joy), negative expressions (i.e., including sadness, anger, disgust, contempt, discomfort-pain, fear, and negative blends), neutral expressions, and interest expressions. TABLE I DESCRIPTIONOF IS AND NON-IS GROUPS

Variable type N Gender Male Female Age of onset (years) Age at surgery (years) Type of surgery Hemispherectomy Multilobar resection Lobectomy Callosotomy Other Side of surgery Left Right Midline

IS

Non-IS

41

18

18 30 0.24 (SD = 0.29) 1.8 (SD = 1.68)

14 14 0.33 (SD = 0.29) 3.3 (SD = 2.46)

19 11 5 3 3

14 4 0 0 0

21 17 3

13 5 0

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DEVELOPMENTAL O U T C O M E

Non-infantile spasm subjects

Infantile spasm subjects

o~

21l

Social interaction

Initiates joint attention 40 ~, 3O 0

~= 20 "

10

Responds joint attention 10 o¢,¢;r O LL

Behavior regulation 60

/

~¢- 4 0

== O"

LL

20

30 60 90 Chronological age (months)

0

30 60 90 Chronological age (months)

120

FIG. 1. Presurgical a n d postsurgical nonverbal c o m m u n i c a t i o n in IS a n d non-IS patients. Solid bold line equals nonverbal c o m m u n i c a t i o n scores in 91 n o r m a l subjects. Each solid line charts presurgical a n d postsurgical scores for individual patients.

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Following surgery, the IS and non-IS groups used significantly more positive affect than before surgery. From a functional perspective, however, the increase in affect was not found specifically during social interaction and j o i n t attention, conditions during which normal children use positive affect to engage, share, and communicate with others (Kasari et al., 1990; Mundy et al., 1992). T h e r e was a trend for the IS patients, however, to spend more time using positive affect during the initiation of j o i n t attention than the non-IS subjects (F = 2.84, d f 1, 76, p < 0.09). Thus, impaired social communication and dissociation between nonverbal communication and positive affect were found in children with early onset of medically intractable symptomatic epilepsy both before surgery and at the 2-year follow-up. In light of the high rate of autistic disorder in medically treated IS patients (Riikonen and Amnell, 1981), deficits in social communication, a precursor of autistic disorder (BaronCohen et al., 1996), might be associated with early onset intractable epilepsy with and without IS. T h e r e was no association between the postsurgical change in social communication measures and seizure-related (i.e., seizure control, age of onset, duration of illness), surgical (hemispherectomy or multilobar resection), lateralization (left vs right), and localization (with or without frontal lobe) variables. These findings suggest that the underlying pathology rather than seizure-related and surgical factors might impair the development of social communication and normal hemispheric specialization for expression of affect (Borod et al., 1997; Davidson, 1992; Dawson et al., 1992; Fox, 1994) in early onset symptomatic IS and non-IS.

B. COGNITION The mean postsurgical Vineland based D Q was 47 (SD = 18) in the IS group and 36 (SD = 18) in the non-IS group at the 12-month follow-up. O t h e r than the response to j o i n t attention (r = 0.41, p < 0.05), a measure o f visual attention, there was no association between the postsurgical change in nonverbal communication and cognitive variables in the IS group. These findings suggest that impaired development of nonverbal communication in children with intractable symptomatic IS is not simply a function o f their mental retardation, but might be specific to this disorder.

C. LANGUAGE We scored emergent language through parental response to the Infant and Toddler McArthur Communicative Developmental Scales (Fenson

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DEVELOPMENTAL OUTCOME TABLE II MEAN SPOKEN LANGUAGERANK (SLR) IN IS AND NON-IS PATIENTS IS

Non-IS

All (N = 17)

Left (N = 9)

Right (N = 8)

All N = 10)

Left (N = 8)

Right (N = 2)

3.0 (0-.5)

3.8 ( 2 - 5 )

2.1 (0-4.5)

1.8 ( 0 - 4 )

2,1 ( 0 - 4 )

0.5 ( 0 - 1 )

etal., 1990) using the spoken language rank (SLR) (0 = no speech, 5 = target grammar). As indicated in Table II, we found p o o r language outcomes in the IS group with a mean SLR of only 2.2 and considerable variability within the cohort with individual scores ranging from 0 to 5. T h e r e was a clear difference in the SLR of the children with left-and rightsided surgery. Non-IS subjects had a mean SLR similar to that of IS subjects and, as f o u n d in the IS group, the few children with fight-sided surgery had smaller SLRs than those with left-sided surgery, The postoperative change in nonverbal communication correlated significantly with SLR in the non-IS (rsocial Interaction = 0 . 8 4 , p < 0.002; rinitiation of Joint Attention = 0.67, p < 0.68; rBehaviorRegulation = 0.56, p < 0.09), but not in the IS. These findings indicate that after surgery only few of these children progressed to a very early stage of language development, that of acquiring vocabulary. Furthermore, pathology in either hemisphere severely impacts the development of language and might prevent both hemispheric and regional specialization of the brain for language in early onset intractable symptomatic IS and non-IS. As found in children with an autistic disorder (Sigman et al., 1999), language development in the IS patients was not related to the preverbal development of gestures.

D . NEUROPATHOLOGY

Figure 2 demonstrates different patterns in the IS and non-IS groups regarding the relationship between postsurgical change in joint attention and behavior regulation with cortical dysplasia (CD), measured according to Farrelll et al. (1992) and Mischel et al. (1995). Based on evidence that CD occurs at early stages of brain development (Mischel et al., 1995), we predicted that children with severe CD would have a worse social communication outcome than those with mild CD. However, IS patients with CD had a significantly greater postsurgical increase in their social interaction (F = 3.65, df = 1, 72, p < 0.06), response to j o i n t attention (F = 9.75, df = 1, 72, p < 0.002), and behavior regulation

278

CAPI,AN

ROCHELLE

et aL

Non-infantile spasm subjects

Infantile spasm subjects

Social interaction

20

g.

CD

e-

~r

lO

CD

Initiates joint attention

40 ~. 3O t-.

CD CD

20

~- 10

Behavior regulation 2O

=o =~ 10

{7" IJ-

nonCD 0 0

30 60 90 Chronological age (months)

30 60 90 Chronological age (months)

FIG.2. Presurgical and postsurgical nonverbal communication scores in IS and non-IS patients with and without CD.

scores ( F = 13.69, df = 1, 72, p < 0.0004) t h a n those w i t h o u t CD. F u r t h e r m o r e , t h e r e was a g r e a t e r postoperative increase i n the use o f n o n v e r b a l gestures i n those with severe c o m p a r e d to m i l d CD (Fsocial Int~rac~on = 2.61, df = 2, 27, p < 0.09; FJointAttention = 3.15, df ----2, 27, p < 0.05). I n the n o n IS g r o u p , c h i l d r e n with CD a n d w i t h o u t CD differed o n l y i n the postsurgical c h a n g e i n the i n i t i a t i o n o f j o i n t a t t e n t i o n ( F = 4.94, df ---- 1, 23, p < 0.03).

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Thus, unlike our predictions, an increased severity of CD might enable more compensatory developmental mechanisms in the remaining brain than mild CD. The presence and severity of CD were unrelated to the postoperative change in the facial expression of affect. The stage at which CD occurs in fetal development CD might, therefore, specifically impair the development of neural circuits involved in preverbal gestural communication. Hippocampal data available for 14 IS subjects, as described in Mathern et al. (1996, 1997) and Katzir et al. (2000), indicated that the number of neurons in the fascia dentata of the hippocampus was associated with the postsurgical change in social interaction (r = 0.56, p < 0.05). Although not significant (N = 9), children with increased abnormal mossy fiber sprouting, however, had smaller postsurgical changes in the initiation of joint attention (r = -0.33) and use of behavior regulation (r =- -0.31). There was no association between measures of hippocampal pathology and the postsurgical change in the facial expression of positive affect. These pilot findings imply that hippocampal pathology might be associated with the severity of postsurgical nonverbal communication deficits. There is neuropathology (Kemper and Bauman, 1993; Raymond et al., 1989) and neuroimaging evidence for abnormal brain development and hippocampal abnormalities in autistic disorder (Aylward et al., 1999; De Long and Heinz, 1997; Otsuka et al., 1999), a disorder with impaired social communication (i.e., nonverbal communication, facial expression of affect, language, pragmatics). Impaired social communication in the IS subjects together with CD and hippocampal abnormalities in the resected tissue, implies that the underlying pathology might impact development of the nonresected brain and of social communication skills. E. MORPHOMETRY

Table III presents morphometric data of two IS patients. Case 1, a girl with onset of IS at age 5 months, underwent a left parieto-temporal-occipital resection at age 8 months. Seizures changed to intractable complex partial events, and she had extension of the multilobar resection, removal of the hippocampus, and insertion of a shunt at age 5 years 11 months. She had the MRI at age 10 years 11 months and is currently 12years 7 months. Despite surgery, she continues to have poorly controlled seizures, profound mental retardation and language delay, poor social relatedness, aggression toward others, and self-injurious behaviors. Case 2, a boy with onset of IS at age 4 months, underwent a left functional hemispherectomy at age 1 year 5 months. He is currently a 12-year 6-month-old socially relating fifth grader with an IQ of 62 and had his MRI at age 11 years. Other than three

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ROCHELLE C A P L A N et al. TABLE III MRI VOLUMES FROMTWO SURGICALLYTREATED IS PATIENTS

Variable measured

Case 1: Bad outcome

Case 2: Good outcome

Age at imaging (years) Total brain without cerebrospinal fluid (CSF) (cm"~) Total brain with CSF (cma) Total CSF volume (cm3) Total gray matter (cm3) Total white matter (cm3) Total nonresected frontal gray (cm3) Total nonresected temporal gray (cm3)

10.9 882.0 1031.6 142.7 575.4 309.2 105.4 62.6

ll 1064.1 1458.6 394.46 774.8 288.9 166.8 112.29

questionable recent complex partial seizures, he has not had clinically overt seizures. As evident f r o m Table III, despite the similar age at postsurgery, case 2 with the better outcome, but larger resection (i.e., hemispherectomy) had larger volumes in the nonresected h e m i s p h e r e than case 1 with p o o r o u t c o m e and multilobar resection. These pilot findings suggest that the developmental, behavioral, and seizure outcomes following surgery for early onset intractable seizures might be associated with the volume of the nonresected hemisphere. A small volume of frontal and temporal lobe gray matter, p r o f o u n d mental retardation, and very p o o r c o m m u n i c a t i o n skills raise the question of how the underlying pathology and intractable seizures impact the d e v e l o p m e n t of the nonresected fronto-temporal regions, areas involved in the d e v e l o p m e n t of communication, language, and higher level linguistic functions.

F. SUMMARY I m p a i r e d preverbal social communication, cognition, and language d e v e l o p m e n t are consistent findings in both children with IS a n d non-IS before and after surgical intervention. T h e social c o m m u n i c a t i o n deficits of both groups of children do not a p p e a r to reflect their severe mental retardation. Dissociation between the preverbal gestural and the verbal skills of the IS group, but not the non-IS group, implies specific deficits in social c o m m u n i c a t i o n skills in IS similar to those f o u n d in autistic disorder (Sigman et al., 1999). T h e association o f the postsurgical developm e n t of nonverbal c o m m u n i c a t i o n with n e u r o p a t h o l o g y a n d m o r p h o m e t r y measures, but not with measures of seizure control a n d antiepileptic drugs suggest that the underlying pathology, rather than ongoing seizures, impairs

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normal development of the remaining nonresected brain tissue in symptomatic IS and non-IS. The p o o r developmental outcome of early onset intractable symptomatic epilepsy supports this hypothesis.

IV. Mechanisms of Developmental Outcome Tile literature review of the developmental outcome in symptomatic IS and the findings of the UCLA mulfidisciplinary study address the theoretical questions raised in Section I as follows. First, p o o r postoperative seizure control reflects the impact of the underlying pathology on develo p m e n t of the nonresected brain and is not the primary cause of the developmental impairment. Second, similar developmental trajectories in IS and non-IS subjects suggest that the underlying pathology rather than the type of seizures is associated with the developmental outcome of these children. Third, the underlying pathology also impairs the regional specialization and hemispheric lateralization of the nonresected brain n e e d e d for normal acquisition of preverbal social communication skills and language. Fourth, continued severe mental retardation in these children, like p o o r seizure control, reflects diffuse involvement of the nonresected cortical structures. Finally, volumetric and other m o r p h o m e t r i c measures of the nonresected brain might provide important predictive information on the developmental outcome after surgery.

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