63 • OUTCOME OF EPILEPSY SURGERY IN CHILDHOOD 805 recovery of memory deficits in children than in adults undergoing temporal lobectomy. Their data suggest an increased neuronal plasticity in childhood, with a pro- posal of a strong argument in favor of early surgery. Literature review shows a dearth of information on other lobar resections. There are very few studies on post- surgical series in children with frontal lobe and posterior epilepsies (100). Preoperative groups with frontal lobe epilepsy have deficits in the domain of executive func- tioning and motor coordination. Lendt et al (111, 112) compared the one-year postsurgical cognitive profiles in groups of 12 children, one group with temporal and the other with frontal lobe epilepsy. Both groups showed important gains in attention, processing speed, memory, and bimanual coordination. Surgery did not lead to any additional impairment. The neuropsychologic profile in frontal lobe epilepsy (113) is akin to that of adults with frontal lobe lesions. Surgical outcome has no bearing on the postoperative neuropsychologic profile in chil- dren with frontal lobe epilepsy in both good- and poor- seizure-outcome groups. Some gains, albeit insignificant, are made in the domain of motor coordination. Data from other studies lend weight to offering surgery to suit- able candidates, as the benefits from epilepsy surgery far outweigh the risks of inflicting minor deficits in the form of working memory and visual constructional skills (114, 115). The posterior epilepsies are relatively rare in chil- dren. In terms of cognition, the posterior cortex plays an important role in attention and visuoconstructional abili- ties (116, 117). In general the group of patients with pos- terior epilepsies (100) has a low IQ compared to groups of temporal or frontal lobe epilepsy. The deficit is especially in the domain of visuoconstruction performance; also of note is the fact that the effects are even more disabling in children with early-onset damage to the posterior cortex. Sinclair et al (77) studied a group of children undergo- ing extratemporal resections, and within this group the children with frontal lobe epilepsy were relatively better preserved, with a mean full-scale IQ nine points higher than in the children with posterior epilepsies, and the postsurgical outcome mirrored the preoperative assess- ment. Postoperatively, except for an improvement in the sphere of verbal learning, there was no change in the intel- lectual functioning and memory. Similar results of a stable postoperative cognitive profile were seen in a group of 26 children (118). Even though the group is quite small, the data show no impairment or adverse effects of sur- gery on the intelligence or memory. Mabbott and Smith (119) assessed memory in a series of 44 children and adolescents undergoing temporal or extratemporal resec- tion and found no significant decline in memory in either group of children. Children have variable performance on the tasks used for assessment. Within the surgical groups, some children perform poorly within tasks, while others perform well on the same tasks. The observed variability may be dependent on several factors, probably including age, duration of epilepsy, nature of material used to test memory, and number of medications. Also of note is the effect of age at onset; children with older age of seizure onset performed better on tasks of verbal memory and face recognition. Hemispherectomy Many children coming to this procedure have devel- opmental malformations as their underlying respon- sible pathology, such as hemimegalencephaly (120) or widespread hemispheric cortical dysplasia. The remain- ing patients have other etiologies such as Rasmussen encephalitis or vascular pathology. Both the groups tend to have a low IQ/DQ preoperatively; but the deficit is most marked in the group with developmental malforma- tions (121–23). This is particularly relevant, considering the data suggest that age of onset of epilepsy is likely to have a major impact on ultimate developmental out- come, and the onset tends to be earlier in the group with developmental malformations (124, 125). Most studies do not show any significant longitudinal change with regards to developmental and cognitive outcome follow- ing hemispherectomy. There are a few studies that do report some gain (98, 120–122), whereas others have reported loss of skills postoperatively, predominantly in those with acquired pathology (124). In a group of 71 children (124), 11 children showed a decline of more than 15 points in the IQ at follow-up, but eight of the 11 children had Rasmussen syndrome, and the decline may have been a result of the progressive nature of the disease. Even in this study almost 80% of the children had a postoperative neuropsychologic profile similar to or slightly better than the preoperative score. The majority of children who come to hemispher- ectomy are developmentally delayed, as verified by data from the literature. This has not been a criterion to exclude them from a surgical program. Evidence to date suggests that, although we aim to optimize neurodevelopment, we are more likely to prevent possible further cognitive damage from ongoing epilepsy. Data to date suggest the final outcome to be usually comparable to the preopera- tive level of functioning, suggesting a maintenance of the developmental trajectory. Children who are well main- tained preoperatively tend to do better than those with poor developmental skills (126). A recent meta-analysis (127) showed a better outcome in children than in adults, and the short-term cognitive outcomes were maintained in the longer term. Overall, children undergoing left hemi- spherectomy (128) with early-onset epilepsy and devel- opmental malformations have a poor cognitive profile as compared to children with right hemispheric lesions, and this translates to a similar postoperative profile. VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION 806 FUNCTIONAL OUTCOME When deciding on whether resective surgery should be offered, the likelihood of inflicting a possible neurologic deficit should be carefully considered. The presurgical evaluation is undertaken with meticulous care to reduce the chance of causing this deficit, by outlining the elo- quent cortices and, if necessary, using invasive monitoring with subdural grids and functional stimulation. Recently, with the advent of functional imaging to complement the presurgical evaluation and mapping of the motor and language cortex, the need for invasive monitoring for delineation of eloquent cortex has been reduced. In each individual case the risk-benefit ratio needs to be carefully considered. Reorganization (129–132) of the eloquent cortices has a bearing on the eventual area of resection. Early-onset epilepsy may be presumed to lead to a greater chance of relocalization of function, but studies have shown that language and motor function (129–132) may be local- ized within dysplastic cortex. In such cases the risk of postoperative functional deficit is very high. The majority of children with congenital hemiplegia (associated with a structural brain pathology) and early-onset epilepsy can expect little change between pre- and postoperative functional status, although a visual field defect is inevi- table if not present preoperatively. Surgery for right-sided lesions (128) in the acquired pathology group tends to have a better outcome; overall, however, the outcome is poor in the developmental pathologies as compared to the acquired pathologies. Curtiss et al (133) showed a better outcome for right-sided hemispherectomies with under- lying acquired pathologies, but even the left hemispher- ectomies may have better postoperative performance on the subdomains of language function, suggesting that the right hemisphere can support language reorganization, with better receptive language than expressive (134). Also in the study by Curtiss et al (133), postoperative seizure outcome had a positive impact on language development in children with developmental pathologies. Frank aphasia and major language dysfunction are usually not seen after standard temporal lobe resection. The only deficit seen in patients with dominant temporal lobe resection is in naming and, probably, verbal learning (135). This too usually resolves within 6–12 months of surgery. Verbal fluency is unaffected in both dominant and nondominant resection. Hemiparesis is an expected effect of hemispherec- tomy, but focal motor deficits may be seen in focal, lobar, or multilobar resections encroaching upon eloquent cor- tex. The degree of motor deficit will vary with time, and many deficits improve, suggesting that the cause is revers- ible, such as edema or ischemia, or that in the longer term some reorganization can take place. In a group (136) of 15 children posthemispherectomy, etiology-specific differences in reorganization of the remaining cortex were shown. Ambulation is important for independence, and in those undergoing hemispherectomy (137), children who are ambulant prior to surgery continue to remain so after surgery irrespective of developmental and acquired pathologies. In terms of other musculature, they do show slight deterioration in their function within the first few months after surgery, but they usually recover to near the presurgical level of functioning except for finger dexterity and power in the distal upper limb musculature. Formal discussion with the parents and the child regarding the expected motor, visual, or language defi- cit will eventually decide the optimum time for surgery. The risk-benefit assessment should be discussed at length before offering surgery. This is particularly true for chil- dren with progressive conditions such as Rasmussen encephalitis and Sturge-Weber syndrome. BEHAVIORAL AND PSYCHIATRIC OUTCOME The prevalence of behavioral problems in intractable childhood epilepsy is high (138), and a proportion of these children will enter a surgical program for evalu- ation. Psychiatric disorder (34) is reported in 29% of children with idiopathic generalized seizures and in 58% of children with seizures and structural brain abnormal- ity. Davies et al (139) showed that the presence of psy- chiatric disorder and behavioral problems adds to the already significant disability in these children. At times, behavior can be the most challenging aspect of epilepsy management. Surgery for epilepsy has a variable impact on the psychiatric and behavioral outcome postoperatively. Few of the patients improve, few worsen, and few remain the same, while (140) a further proportion develop new symp- toms following surgery for epilepsy (34, 141). Although new symptoms may evolve in previously normal children, it is generally seen that absence of psychiatric disorder preoperatively predicts a good postoperative psychiatric outcome. Thus, epilepsy surgery has a predominantly positive effect on the behavioral outcome in children with intractable epilepsy beginning early in life. Psychiatric and behavioral outcomes in slightly older children are unclear, with variable results, as mentioned previously. Following surgery there appears to be a risk of precipi- tating new psychiatric disorders with a Diagnostic and Statistical Manual (DSM) IV diagnosis in a proportion of these children. When hemispherectomy was first described by MacKenzie in 1938 and subsequently by Krynau in the 1950s, it was noted that significant improvement in behavior could be achieved. In one study (142) 36 of 50 children had severe behavioral problems that resolved in 54% of the children postsurgery and improved in a 63 • OUTCOME OF EPILEPSY SURGERY IN CHILDHOOD 807 further 40%. White (143), looking at 144 surgeries for infantile hemiplegia and epilepsy, saw behavior improve in 80% of the 108 patients with behavioral dysfunction. Later studies show behavioral difficulty in 33% of chil- dren preoperatively, with improvement in all but one child and new symptoms emerging in five children. In the study by Pulsifer et al (124), there was no difference in the pre- and postoperative scores as measured by the Child Behavior Check List (CBCL). The rate of behavioral disorders in children com- ing to temporal lobe resection is high (34), with 83% demonstrating a DSM IV diagnosis at any point pre- and postoperatively. Though poor postoperative seizure control heralds a poor outcome in psychiatric symptoms in adults, studies in children fail to confirm this obser- vation, although in the group of McLellan et al (34), 24% of seizure-free children lost the DSM IV diagno- sis, whereas only 4% from the poor-seizure-outcome group lost their diagnosis. Szabo et al (141), in their small series of five patients, did not find any signifi- cant change between the pre- and postoperative behav- ior in children with pervasive developmental disorder undergoing temporal lobectomy for the treatment of epilepsy. Whether the natural history of the disorder may be influenced by early surgery and seizure control remains under debate (144). Lendt et al (145) looked at a cohort of 56 children, with a study group and a control group of 28 children each. The 28 children underwent surgery, and the control group was managed medically. On review of the CBCL scores, there was normalization of behavior in the study group; at the same time, the control group had new emergent behavioral issues. This study highlights the likelihood of impact of surgery on behavioral outcome as opposed to the natural history of the condition. 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Surgical treatment of severe autistic regression in childhood epilepsy. Pediatr Neurol 1997; 16(2):137–140. 145. Lendt M, Helmstaedter C, Kuczaty S, Schramm J, Elger CE. Behavioural disorders in children with epilepsy: early improvement after surgery. J Neurol Neurosurg Psychiatry 2000; 69(6):739–744. 811 Vagus Nerve Stimulation Therapy in Pediatric Patients: Use and Effectiveness hildhood epilepsies are often char- acterized by a wide range of seizure types and accompanying comor- bidities such as mental retardation or developmental delay (MR/DD), autism, and language disorders, often making treatment difficult. However, advances in our understanding of the underlying mecha- nisms that result in seizures and epilepsy syndromes have also led to advances in epilepsy treatments. Traditionally, the two primary treatment modalities used to control seizures have been mono- and polytherapy with antiepi- leptic drugs (AEDs) and epilepsy surgery. Among pedi- atric patients, the ketogenic diet is used among a small number of children. In 1997, however, the United States (U.S.) Food and Drug Administration (FDA) approved a new, non- pharmacologic treatment—vagus nerve stimulation (VNS) therapy—for adjunctive use among patients aged 12 years and older with partial-onset seizures refractory to standard therapies. Although VNS therapy is not cur- rently approved in the United States for children younger than age 12 years, studies indicate that success with VNS therapy can be achieved independent of patient age and seizure type or syndrome. Reports indicate that VNS ther- apy may have unique benefits for pediatric patients (aged less than 18 years), including improvements in quality of life resulting from the lack of pharmacologic interactions James W. Wheless known to impair development, and success at reduc- ing seizure frequency and severity among patients with age-related and difficult-to-control syndromes such as Lennox-Gastaut syndrome (LGS). This chapter outlines both the safety and effectiveness of VNS therapy among pediatric patients with epilepsy, as discerned from current treatment practices and reports in the literature. THE VAGUS NERVE STIMULATION THERAPY SYSTEM Vagus nerve stimulation (VNS) was the first nonphar- macologic therapy approved by the FDA for the treat- ment of seizures. The treatment, which attenuates seizure frequency, severity, and duration by chronic intermittent stimulation of the vagus nerve, is intended for use as an adjunctive treatment with AED therapies. As of March 2006, more than 35,000 patients with epilepsy have been implanted with the VNS therapy system worldwide, with approximately 30% of those patients being younger than age 18 at the time of their first implant. Approximately one-third of patients receiving VNS therapy experience at least a 50% reduction in seizure frequency with no adverse cognitive or systemic effects (1, 2). Moreover, clinical findings indicate that the effectiveness of VNS therapy continues to improve over time (2–8), independent C 64 VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION 812 of changes in AEDs or stimulation parameters (9). Also notable is the fact that tolerance, which is often accom- panied by a reduction in efficacy for many treatments, does not appear to be a factor with VNS therapy, even after extended (Ͼ10 years) periods of time (2). Response to VNS therapy may be delayed for some patients (8, 10). As a result, the long-term safety and effectiveness seen with this treatment have made VNS therapy a mainstream treatment option for a broad range of epilepsy patients, including children and adolescents. VNS therapy is sec- ond only to AED therapy as a treatment category for childhood epilepsy in the United States. The VNS therapy system consists of the implant- able pulse generator and bipolar VNS therapy lead, a programming wand with software, a tunneling tool, and a hand-held magnet. The original systems consisted of the Model 100 and Model 101. However, in June 2002, Cyberonics, Inc. (Houston, Texas), introduced a new gen- erator model, the Model 102 system, which is thinner (6.9 mm), lighter (25 g), and has less volume (52.2 mm in diameter) than the previous models (11). The smaller size of the Model 102 offers children an improved cos- metic appearance and increased comfort. In addition, the Model 102 has a single- rather than a dual-pin lead, making it easier and faster to implant than the previous models. Both the Model 101 and Model 102 are currently being implanted. The average battery life for the genera- tor (Model 101 or 102) is approximately 7 to 10 years with normal use (11). Increases in stimulation intensities or frequency will decrease battery life. The magnet provided to patients as part of the VNS therapy system allows for on-demand stimulation, which has the potential to abort seizures, either consistently or occasionally, among some patients or caregivers who are able to anticipate the onset of their seizures (12–14). The additional stimulus train that results when the magnet is held over the generator is typically stronger than the programmed stimulus parameters. This added ability of on-demand stimulation provides a greater sense of con- trol for patients and their caregivers over their disorder, which can help improve how they perceive their quality of life. The magnet also allows temporary interruption of stimulation if needed, particularly when singing or play- ing wind instruments or during speaking engagements. However, stopping the stimulus should be done sparingly and with care, as doing so creates the potential risk of breakthrough seizures. Implantation Procedure The implant surgery is most often performed under gen- eral anesthesia and typically lasts about 1 hour (4). The pacemaker-like generator device is generally implanted in the subcutaneous tissues of the upper left pectoral region, with a lead then run from the generator device to the left vagus nerve in the neck, where it is attached by a coiled electrode (Figures 64-1, 64-2) (15, 16). Two inci- sions are made during the procedure: one in the chest to create the generator pocket, and the other along a fold in the neck to expose the vagus nerve for placement of the electrode (Figures 64-3, 64-4). A loop of lead wire is coiled beside the generator to allow for strain relief and patient growth. FIGURE 64-2 Lead wire starting to be placed on the left vagus nerve. FIGURE 64-1 VNS lead wire prior to placement on the left vagus nerve. Cathode electrode (green suture) placed proximal (right side of picture), then anode electrode (white suture), then anchor tether (green suture; caudal; left side of picture). 64 • VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS 813 The procedure is well tolerated in both children and adults (17, 18) and is usually performed as outpatient surgery; however, in some cases, patients may be kept in the hospital overnight for observation. The device is often turned on in the operating room or in the office immediately after surgery, generally with a low initial setting of 0.25 mA (Figure 64-5) (19). The programming wand (Figure 64-6) is used at follow-up visits to check and fine-tune the stimulation settings according to patient comfort and level of seizure control. Instructions concern- ing care of the incision sites, magnet use, and necessary follow-up visits are given to patients and their families before the patient leaves the hospital. The length of battery life for the VNS generator is dependent on the device model implanted and the stimu- lation parameters used (20). Often an increase in seizure frequency or intensity suggests clinical end of service (20). Other indications of battery failure include a sudden stop in sensing stimulation or unexpected changes in stimula- tion. Once a generator reaches end of service, another surgery is required to replace the generator. The entire generator is replaced rather than just the battery so as to prevent opening the hermetically sealed titanium case of the generator, which could lead to a rejection reaction (21). The generator-replacement surgery typically lasts approx- imately 10 to 15 minutes and is performed on an outpa- tient basis. Because the leads remain untouched during a generator replacement, only one incision is needed. Generator replacement is recommended and preferred by patients before the battery is completely depleted so as to prevent an interruption in treatment (20). A 12-year follow-up study showed that multiple device replacement surgeries are well tolerated (2). Often, however, tolerated device currents are lower after reimplantation but are not equated with a reduction in benefit from VNS therapy, which suggests improved battery strength in the newer models of VNS generators; parameter settings other than current are generally the same as with the initial device (20). For patients not obtaining a substantial level of benefit from VNS, it has been suggested that stimula- tion parameters be tapered down over an extended period of time before end of service to allow for explantation of FIGURE 64-3 Implantation of the Model 102. VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION 814 the device before clinical signs of generator dysfunction become evident (20). Potential Complications. Although the implant sur- gery is a relatively simple procedure that is safe and well tolerated by the vast majority of VNS therapy patients, complications can arise. One possible risk resulting from the implant surgery is an infection at the implant site. This risk may be increased in the pediatric population because young children or patients with neurocognitive disorders may tamper with the wound before the incision has had time to heal properly (22–24). Such infections can be treated with antibiotics but typically lead to explanta- tion of the device if antibiotic treatment is not effective or if tampering continues (25, 26). Stimulator pocket infections among the pediatric population have been rela- tively uncommon, however (25, 27). No infections were observed in a recent study of 36 children aged younger than 18 years who were followed up for an average of 30 months (27). The routine lead test performed during surgery also has resulted in reports of bradycardia and asystole in a small number of patients (ϳ0.1%) (28–31). Neither of these cardiac events, however, has occurred after surgery during day-to-day treatment with VNS therapy or in chil- dren; these events are usually transient and self-limiting and are rarely of clinical significance (28–31). Vocal cord paresis, although rare, can be caused by manipulation of the vagus nerve during the implant procedure, but such paresis is most often transient (32). On the whole, the sur- gery required with VNS therapy is much less invasive and generally better tolerated than other traditional epilepsy surgeries. Although side effects associated with the sur- gery cannot be avoided completely, they can be minimized with a correct technical procedure (27). In addition, the implant surgery is not associated with any performance or cognitive impairments and can be reversed if the treat- ment is not effective. Alternative Generator Placements. Depending on the circumstances of the patient, alternative generator place- ments have been reported with successful results. Le et al (22) successfully used an interscapular placement of the generator to reduce the risk of wound tamper- FIGURE 64-4 Neck incision (right) after final closure with Durabond; chest incision after final closure (bottom left). [...]... allocate scarce research funds, and justify new therapies and health care services There are two fundamental types of research on the economics of epilepsy: cost-of-illness and cost-benefit studies Cost-of-illness studies attempt to measure the economic burden of epilepsy to society (1) They are used by advocacy groups to promote research and fund services, and by planning and policymaking groups to allocate... adverse side effects typically associated with drug therapy Although 820 VI • EPILEPSY SURGERY AND VAGUS NERVE STIMULATION TABLE 6 4-2 Epilepsy Syndromes, Seizure Types, and Associated Conditions in which VNS Therapy May Be Helpful EPILEPSY SYNDROME, SEIZURE TYPE, AND/ OR ASSOCIATED CONDITION Simple partial seizures Simple partial seizures progressing to complex partial seizures or secondary generalization... humans receiving VNS therapy as part of their antiepileptic treatment (67) SEIZURE EFFICACY Clinical Trials A series of acute-phase studies with long-term followup data proved the safety and efficacy of VNS therapy for the treatment of refractory epilepsy and thereby led to its approval by the FDA in 1997 Results from two randomized, placebo-controlled, double-blind trials (E03 and E05) were pivotal... represent a broad-based conceptualization of HRQOL in pediatric epilepsy The first four domains focus on aspects of child functioning and well-being Because the family environment is integral to child well-being, the final domain focuses on family adjustment related to the child’s epilepsy Epilepsy and Treatment Assessment in this domain addresses epilepsy- specific information, including neurologic and cognitive... 63:1539–1540 Cyberonics, Inc Physician’s manual VNS Therapy Pulse Model 102 Generator and VNS Therapy (TM) Pulse Duo Model 102 R Generator Cyberonics, 2003 http:// www.vnstherapy.com /Epilepsy/ forvnstherapypatients/manuals.aspx (accessed April 7, 2006) Boon P, Vonck K, Van Walleghem P, et al Programmed and magnet-induced vagus nerve stimulation for refractory epilepsy J Clin Neurophysiol 2001; 18:402–407... Suppl 3:71–79 92 Pellock JM, Hunt PA A decade of modern epilepsy therapy in institutionalized mentally retarded patients Epilepsy Res 1996; 25:263–268 93 Huf RL, Mamelak A, Kneedy-Cayem K Vagus nerve stimulation therapy: 2-year prospective open-label study of 40 subjects with refractory epilepsy and low IQ who are living in long-term care facilities Epilepsy Behav 2005; 6:417–423 94 Gates J, Huf R, Frost... shows the epilepsy syndromes, seizure types, and associated conditions in which VNS therapy may be helpful Additionally, VNS therapy also seems to be a palliative treatment option for patients who have failed cranial surgery (Figure 6 4-9 ) (83, 86) Lennox-Gastaut Syndrome, Infantile Spasms, and Ring Chromosome 20 Syndrome Lennox-Gastaut syndrome (LGS) and infantile spasms are rare but difficult-to-treat... the amount and distribution of direct cost associated with medical care and social service items, such as drug costs and counseling, and indirect costs from the disability and premature mortality effects of epilepsy, such as lost earnings and productivity Cost-of-illness studies may also examine the distribution of cost among patients with different types of epilepsy, such as intractable epilepsy versus... significantly lower adverse-effects treatments Last, second-generation AEDs appeared to be cost effective at a threshold level of about $40,000 per quality-adjusted life year, which is under the $50,000 gold standard (17) 836 VII • PSYCHOSOCIAL ASPECTS Additionally, second-generation AEDs as add-on therapy may be no more expensive than first-generation AEDs as add-on therapy and appear to be cost effective... STIMULATION FIGURE 6 4-6 A programming wand is held by the patient over the device while a physician checks and/ or adjusts stimulation parameters using a handheld computer FIGURE 6 4-7 Stimulation parameters (all duty cycles except low output [ 10 Hz]) 64 • 817 VAGUS NERVE STIMULATION THERAPY IN PEDIATRIC PATIENTS: USE AND EFFECTIVENESS TABLE 6 4-1 Stimulation Parameter Setting Ranges MEDIAN SETTINGS PEDIATRIC . pulse generator and bipolar VNS therapy lead, a programming wand with software, a tunneling tool, and a hand-held magnet. The original systems consisted of the Model 100 and Model 101 . However,. hypomotor, and partial seizures; another atonic, general tonic-clonic, and myoclonic seizures; and the third, multifocal-onset seizures. A 30-year-old man who presented with pharma- coresistant. Wheless known to impair development, and success at reduc- ing seizure frequency and severity among patients with age-related and difficult-to-control syndromes such as Lennox-Gastaut syndrome (LGS). This