Introduction

As the use of neuromodulation for the treatment of adults with various gastrointestinal (GI) disorders has grown over the past two decades, so has interest in the application of these treatments to children with GI disorders. Some of the advantages inherent to neuromodulation-based treatments are particularly suited to pediatric patients. For children with severe symptoms refractory to medical treatment, neuromodulation is often less invasive than more traditional surgical treatment options. The ability to adjust neurostimulation parameters and the option to reverse treatment are valuable characteristics when treating children who are still in the process of growth and development. Experience with the use of neuromodulation for treatment of children with GI disorders has been growing over the past decade. However, evidence supporting the use of most neurostimulation-based therapies in children remains limited. In this chapter, we will review three of the more established pediatric applications of neuromodulation for the treatment of GI disorders: gastric electrical stimulation (GES), sacral nerve stimulation (SNS), and abdominal transcutaneous electrical stimulation (TES).

Gastric Electrical Stimulation

The use of GES to treat children was first described in the late 2000s, not long after the approval of GES by the US Food and Drug Administration (FDA) as a humanitarian device exemption for the treatment of adults with gastroparesis in 2000. GES involves high-frequency, low-energy electrical stimulation delivered through electrodes implanted along the greater curvature of the stomach. These electrodes are connected to a pulse generator that is implanted in a subcutaneous pocket, as shown in Fig. 119.1 . In the majority of children, permanent implantation follows a period of temporary stimulation, during which stimulation is administered through electrodes attached to the gastric mucosa that are connected to a pulse generator that remains external to the patient, as shown in Fig. 119.2 ( ). The precise mechanism of action (MOA) of GES remains unclear. GES does not alter gastric electrical activity as measured by electrogastrography and does not entrain gastric muscle. GES also has not been shown to have a consistent effect on gastric emptying, and symptomatic improvement can occur without normalization of gastric emptying time ( ).

On the left is a diagram showing the implanted pulse generator and attached electrodes used in permanent gastric electrical stimulation (GES). On the right is an abdominal radiograph of an adolescent treated with permanent GES.

This endoscopic image shows the placement of an electrode into the gastric mucosa for use during a period of temporary gastric electrical stimulation. The electrode has been secured using two endoscopic clips.

In 2008, Islam et al. published the first case series of children treated with GES. Nine children, ages 8–17, underwent temporary and permanent GES for chronic nausea and vomiting, secondary to gastroparesis. The authors found significant improvements in nausea and vomiting scores and health-related quality of life (QOL) measures. Gastric emptying did not improve, which is consistent with findings from the adult literature ( ). In , Hyman et al. published a case report of a 7-year-old boy who was treated with GES for chronic abdominal pain, nausea, vomiting, and feeding intolerance. In 2011, Elfvin et al. reported using GES in three children, each between 2 and 3 years of age. Each had severe nausea and vomiting that was interfering with functioning and was refractory to medications. All three children tolerated temporary and permanent GES placement and experienced a decrease in vomiting frequency of greater than 50% at 6 months after initiation ( ).

In 2013, Teich et al. and Lu et al. described their experience in using GES to treat 24 children with chronic nausea and vomiting at a single center. Children ranged in age from 4 to 19 years and were followed for a median of 6 months. The authors found significant improvements in symptom severity and frequency, with the largest improvement seen in nausea, and in health-related QOL. Improvement was not affected by baseline, gastric emptying status. The number of children requiring transpyloric feeding decreased from 11 to 3 (a decrease of 73%) and the number of children requiring parenteral nutrition decreased from 6 to 3 (a decrease of 50%). One patient required battery replacement within a year of GES placement ( ).

Islam et al. published a second review of their use of GES in children. Ninety-six patients underwent temporary GES and 66 proceeded to permanent GES. Children ranged in age from 2 to 19 years and their mean follow-up was 3.5 years. The authors found significant improvements in symptom scores at all time points when compared to baseline. Hospitalizations, antiemetic and prokinetic medication use, and dependence on tube feeding had all decreased after >12 months of GES treatment. Eleven children (17%) experienced complications requiring further surgery, with five undergoing lead repositioning and five requiring explant of the device. Thirteen patients (19%) had to undergo device replacement after their battery life expired, which, in each instance, was discovered because of symptom recurrence, leading to evaluation ( ).

Although the available literature suggests that GES is safe and can be effective for children with chronic nausea and vomiting refractory to conventional treatment, the evidence certainly remains very limited. Questions remain that will need to be answered before GES becomes a more established treatment in children. The role of placebo effect in the improvement seen after GES remains unclear, although there is limited evidence in adults and anecdotal evidence in children that symptoms worsen when the stimulator is turned off. A better understanding of which patients are more likely to respond to GES treatment is also needed, particularly as gastric emptying does not predict outcome and given the risk of complications requiring further surgery.

Sacral Nerve Stimulation

SNS has been used for the treatment of adults with urological or GI symptoms for nearly three decades, with approval by the FDA for the treatment of adults with urinary incontinence in 1997 and approval for the treatment of adults with fecal incontinence in 2012 ( ). However, experience with its use in children has primarily been limited to the past decade. SNS involves low-amplitude electrical stimulation of the sacral nerve root via an electrode placed percutaneously through the sacral foramen. This electrode is connected to a pulse generator and battery that is implanted in a subcutaneous pocket within the fat of the buttock, as shown in Fig. 119.3 ( ). Permanent implantation often takes place after an initial percutaneous nerve evaluation period during which the pulse generator and battery remain external to the patient and symptom response is monitored ( ). The MOA by which SNS acts remains unclear, but there is evidence that SNS acts primarily through modulation of afferent nerve activity or at a central level rather than through peripheral motor stimulation ( ).

This diagram shows the implanted pulse generator and attached electrode placed at the S3 sacral foramen used in permanent sacral nerve stimulation.

In 2004, Guys et al. published the results of a randomized controlled trial evaluating the efficacy of SNS for children with neurogenic bladder dysfunction. The authors included 42 children, most who had neurogenic bladder secondary to spina bifida, and 21 children were randomized to undergo SNS treatment. Although the authors did not find statistically significant differences in outcomes between the SNS and control groups, their results did indicate some benefit in urodynamic parameters and they concluded that SNS was a promising treatment that warranted further evaluation ( ). In 2006, Humphreys et al. described a multicenter series of 23 children with dysfunctional elimination syndrome refractory to medical treatment who underwent SNS treatment. Urinary incontinence and urinary retention both improved significantly with SNS, and constipation was noted to improve in 11 of 15 children ( ). In 2008, Roth et al. published a report of 20 children treated with SNS at one of the centers included in the paper by Humphreys et al. Eighteen of 20 children proceeded with permanent implantation and the median duration of follow-up was 27 months. The authors found improvement in urinary incontinence in 14 of 16 children, with complete resolution in 12 children. Of the 17 children with constipation at baseline, 12 experienced improvement and 7 experienced complete resolution of symptoms ( ).

In 2010, Haddad et al. published the results of a randomized crossover study that included 33 children with urinary and/or fecal incontinence. The majority of their group had both urinary and fecal incontinence. After SNS implantation, children were randomized to either having their stimulator on for 6 months and then off for 6 months or the opposite sequence with a 45-day washout period. Clinical response was defined as a decrease of greater than 50% in incontinence frequency at the end of the trial period. The authors found response rates of 81% for urinary incontinence and 78% for fecal incontinence when SNS was on when compared to 24% and 17% respectively when SNS was off. Bladder capacity increased during SNS treatment, but there were no significant changes in other urodynamic or anorectal manometry findings ( ).

Subsequent studies have continued to demonstrate the utility of SNS for the treatment of children with dysfunctional elimination syndrome, particularly for the treatment of refractory urinary symptoms ( ). In 2014, Dwyer et al. published a follow-up study to the earlier studies by Humphreys et al. and Roth et al., which included 105 children treated with SNS for dysfunctional elimination syndrome and followed for a median of 2.7 years. Similar to earlier studies, the greatest improvement seen with SNS was in urinary incontinence, with 88% of patients reporting improvement, followed by 79% reporting improvement in constipation. Interestingly, children who received SNS later in the series were offered a single-stage implantation procedure rather than the traditional, two-stage process, and no differences in symptom response were found when comparing the two strategies ( ).

As a number of earlier studies on SNS in children described improvement in constipation and fecal incontinence, interest in the use of SNS to treat children with constipation as their primary indication has been growing over the past 5 years. In 2012, van Wunnik et al. treated 12 adolescent females with functional constipation refractory to optimal conventional therapy with SNS. After 6–12 months of treatment, the authors found significant increases in defecation frequency and decreases in abdominal pain frequency ( ). Van der Wilt et al. published a follow-up study that includes this original group of adolescent females. In 27 females between 10 and 20 years of age with refractory constipation, the authors found significant improvements in defecation frequency, constipation score, and abdominal pain. However, 15 of 27 children were considered to have failed SNS, and 6 of these children underwent subsequent colectomy ( ).

In 2015, Sulkowski et al. published the short-term outcomes of 29 children treated with SNS at a single center. Twenty-two children had constipation, nine had fecal incontinence, and four had both prior to SNS initiation. The authors found significant improvements in both GI symptoms and QOL, at a median of 4–5 months after SNS ( ). A follow-up study by Lu et al. included 25 children with constipation who had each been treated for at least 2 years. At a median of 2.3 years after SNS initiation, patients continued to report improvement in both symptoms and QOL, while nearly all parents reported health-related, patient benefit from SNS treatment. All families surveyed would recommend SNS to other children experiencing similar symptoms ( ).

While these results may be encouraging, the evidence supporting the use of SNS in children with refractory constipation remains limited and consists of uncontrolled, cohort studies. The role of SNS for the management of constipation refractory to conventional treatment, particularly in relation to other treatment options, also remains unclear. A subsequent study from the same center focused on 22 children with refractory constipation dependent on antegrade continence enemas who underwent SNS treatment. SNS treatment allowed a steady decrease in antegrade continence enema frequency over the first year after SNS initiation, with 10 children undergoing appendicostomy or cecostomy closure within 2 years. The authors proposed that SNS may be worth considering in children dependent on antegrade continence enemas, although further studies are certainly needed to better define the role of SNS for the treatment of this population ( ).

Unfortunately, complications of SNS requiring further surgery are relatively common, with rates generally ranging from 17% to 49% ( ). In the largest series of children treated with SNS, Dwyer et al. found that 49% of patients required a subsequent surgical device removal, revision, or replacement after a median of 2.7 years of follow-up for reasons other than symptom resolution. The majority of these procedures were because of device malfunction ( ). It appears that the complication rate following SNS treatment for refractory constipation is comparable, with 25%–44% of patients requiring further surgery ( ).

In summary, SNS is a promising treatment option for children with dysfunctional elimination syndrome refractory to conventional treatment, a group of children with debilitating symptoms and limited treatment options. However, the utility of SNS for children with constipation refractory to conventional treatment, particularly given conflicting evidence in the adult literature, remains to be established ( ). Of particular concern is the high rate of complications requiring further surgery. Higher-quality evidence of its efficacy is needed before SNS becomes an established treatment option for children with refractory constipation.