Cricopharyngeal Achalasia in Children: Botulinum Toxin Injection as a Tool for Diagnosis and Treatment

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1 The Laryngoscope VC 2013 The American Laryngological, Rhinological and Otological Society, Inc. Cricopharyngeal Achalasia in Children: Botulinum Toxin Injection as a Tool for Diagnosis and Treatment Melissa A. Scholes, MD; Timothy McEvoy, MD; Hayat Mousa, MD; Gregory J. Wiet, MD Objectives/Hypothesis: Characteristics and outcomes of pediatric patients undergoing cricopharyngeus injection with botulinum toxin for the treatment of cricopharyngeal achalasia were reviewed. A parental telephone survey was performed to assess improvement and satisfaction. Study Design: Retrospective review of patients who underwent injection of the cricopharyngeus with botulinum toxin for cricopharyngeal achalasia. A prospective survey of postoperative symptoms and parental satisfaction was also performed. Methods: After institutional review board approval, children with cricopharyngeal achalasia who underwent injection with botulinum toxin were identified. Specific parameters were recorded for each patient. A survey of the parents satisfaction and subjective improvement was then conducted. Results: Six children were identified with cricopharyngeal achalasia, with an age range of 3 months to 10 years. Symptoms varied and five of the six children required some form of altered nutrition. Preoperative studies varied, and the number of injections ranged from one to three per patient. One child had transient worsening of aspiration. Two children benefited from injections and went on to myotomy, while four children did not require myotomy and their symptoms were treated with injections alone. A parental survey was performed via telephone. All parents were satisfied with the procedure. Three children were symptom-free, and three children still exhibit some dysphagia. Conclusions: Botulinum toxin injection is a useful tool to help diagnose and treat pediatric cricopharyngeal achalasia. More research is needed to elucidate optimal dosing, frequency of injections, and when to move on to surgical intervention. Key Words: Cricopharyngeal achalasia, cricopharyngeus, botulinum toxin, dysphagia. Level of Evidence: 4. Laryngoscope, 124: , 2014 INTRODUCTION Cricopharyngeal achalasia (CPA) is a condition characterized by an incomplete relaxation of the upper esophageal sphincter (UES), or by a lack of coordination of the UES opening with pharyngeal contractions. Both etiologies can lead to choking, cough, and aspiration. 1 CPA is a well-described entity in adults and can arise from intrinsic problems confined to the muscle or from underlying neurologic dysfunction causing high UES pressures. Multiple treatments, both medical and surgical, have been developed for this disease. CP achalasia is less well recognized in the pediatric population, being described initially by Utian and Thomas in Pediatric cricopharyngeal achalasia (PCPA) is thought to From the Department of Pediatric Otolaryngology(M.A.S.), Children s Hospital Colorado; and Department of Otolaryngology(M.A.S.), University of Colorado School of Medicine, Aurora, Colorado; and Department of Pediatric Otolaryngology(T.MCE., H.M., G.J.W.); and Department of Pediatric Gastroenterology(H.M.), Nationwide Children s Hospital; and Department of Otolaryngology( T.MCE., H.M., G.J.W.), Ohio State University, Columbus, Ohio, U.S.A Editor s Note: This Manuscript was accepted for publication October 7, The authors have no funding, financial relationships, or conflicts of interest to disclose. Send correspondence to Melissa A. Scholes, MD, Department of Pediatric Otolaryngology, Children s Hospital Colorado, East 16th Avenue, B205, Aurora, CO melissa.scholes@childrenscolorado.org DOI: /lary have a different etiology, although it is poorly understood. An immature neuromuscular system is felt to play a role. Neurologic abnormalities such as Arnold-Chiari malformation have also been associated with cricopharyngeal achalasia. 3 An interesting phenomenon observed in cricopharyngeal achalasia in children, especially infants, is that it can spontaneously resolve even when not associated with a central nervous system disorder. 1 PCPA can present in young infants with prolonged feeding time, failure to thrive, cough with feeds, and pooling of secretions and in older children with choking and coughing. Management Adapting adult treatments for CPA to the pediatric realm have been attempted, such as open or endoscopic myotomy of the cricopharyngeus and botulinum toxin injection. As the experience with botulinum toxin has evolved, it has been found to be a safe and useful method in treating CPA in adults by direct injection of the cricopharyngeus (CP) muscle. There is limited data and reports of the treatment and course of children with CPA. Along with accounts of spontaneous resolution in younger children, there have been small case series and reports of balloon dilatations and cricopharyngeal myotomy, and very limited data about the utility of botulinum toxin. We have been using botulinum toxin in children at our institution to treat refractory CP 1475

2 TABLE I. Preoperative Data. Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Age at 3 months 3 months 6 months 9 months 18 months 10 years presentation Sex male male male male male female Presenting symptoms Preintervention diet Indications for injection cough, FTT (previous myotomy) FTT, emesis emesis, cough regurgitation, drooling aspiration regurgitation, dysphagia NGT G-Tube thickened oral G-tube thickened oral normal oral aspiration, failed CP myotomy, CP bar on esophagram aspiration, FTT, CP bar on esophagram and VSS aspiration, aspiration, CP bar aspiration-related on esophagram pneumonitis, CP bar on VSS CP 5 cricopharyngeal; FTT: failure to thrive; NGT 5 nasogastric tube; VSS 5 video swallow study. aspiration, CP bar on esophagram dysphagia, intermittent incomplete relaxation of CP muscle on esophagram achalasia since We conducted a retrospective chart review of patients with CP achalasia who underwent botulinum toxin injection. Our aims were to assess and compare preoperative and postoperative diagnostic studies, preoperative and postoperative diet, and operative details. We also assessed the time from presentation to diagnosis, the return to normal swallow, and ultimate clinical improvement. We then conducted a parent survey of the patients to gauge overall subjective improvement and satisfaction with the results. MATERIALS AND METHODS After institutional review board approval, a retrospective review was conducted. Our electronic medical record system (EMR) was queried by the diagnosis of dysphagia and cricopharyngeal achalasia for the time period from January 1, 2007, through January 31, A total of 32 patients were found matching these diagnoses. Those 32 patients were then queried for the procedure of direct laryngoscopy and direct laryngoscopy with injection. This yielded six patients. This list was crossreferenced with the treating physician s personal records to make sure no patient was missed. After confirming the patient list, the EMR was investigated for each patient. Specific parameters were recorded for each patient, including: patient age at presentation; gender; main symptoms; time to diagnosis; preintervention diet; preintervention objective studies; operative details including dosing, postoperative objective studies, postoperative swallow-function, and diet. A survey of the parents satisfaction and subjective improvement was conducted and 6/6 surveys were completed. RESULTS Six children were identified with cricopharyngeal achalasia, with an age range of 3 months to 10 years. Symptoms varied but included cough, aspiration, cyanosis, failure to thrive, emesis, and abdominal pain. Five of the six children required some form of altered nutrition, including thickened feeds, nasogastric lavage, and gastrostomy tube feeds (Table I). One of the children had a previous cricopharyngeal myotomy performed at an outside hospital but was referred for 1476 persistence of dysphagia and cricopharyngeal bar on an esophagram. Preoperative studies varied with each patient. All of the patients had a preoperative fluoroscopy study consisting of video swallow studies, esophagrams, or both (Table II). The decision to proceed with botulinum toxin therapy was based on ongoing severe symptoms, the necessity of altered feeds, and parent preference over a cricopharyngeal myotomy. Specific indications for injections in each patient are included in Table I. The number of injections ranged from one to three per patient. The mean dose was 5.6 U/kg, with a range of 1.6 U/kg to 7.9 U/kg and a median of 6.0 U/kg. In those patients with multiple injections, the mean time between injections was approximately 13 months, with a range of 8 to 18 months and a median of 13-and-a-half months. Postoperatively, the patients were followed both clinically and with radiographic studies, including esophagrams or video swallow studies. Of the patients in this study where full follow-up information was available, the time to return to a normal swallow based on radiographic studies ranged from 1 to 12 weeks. The mean time to return to normal radiographic swallow study was 8.25 weeks. One child had transient worsening of aspiration and complete constant relaxation of UES immediately after injection and required 3 weeks of nasogastric tube feeds. This resolved and the child is now tolerating a regular diet. Two of the children benefited from Botox injections and went on to have cricopharyngeal myotomy, while four of the children did not require myotomy and their symptoms resolved after one or two injections. All patients are now tolerating a regular diet (Table III). A parental survey was performed via telephone (Fig. 1). All parents rated their children s symptom severity as most severe (a 4 on a scale of 1 4) prior to injection. Patients with persistent postprocedure symptoms include one child who still has difficulty swallowing some textures, another child with intermittent dysphagia, and another child with intermittent postprandial emesis (Table IV). It is unknown if these symptoms are related to residual cricopharyngeal issues.

3 VSS TABLE II. Diagnostic Methods and Findings. Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 aspiration and vallecular pooling trace penetration, no aspiration aspiration, CP spasm aspiration aspiration Unknown UGI-SBFT CP bar CP bar with pooling WNL CP bar CP bar intermittent CP bar M & I elevated pressure NP no reflux no reflux normal manometry could not perform because of CP contraction EGD normal NP CP bar, esophagitis esophagitis NP esophagitis FL NP 6 NP posterior glotticedema and erythema NP NP NP MRI NP normal NP NP normal normal CP 5 cricopharyngeal; EGD 5 esophagogastroduodenoscopy; FL 5 flexible laryngoscopy; M & I 5 motility and/or impedance; NP 5 not performed; UGI 5 upper gastrointestinal fluoroscopy with small bowel follow through; VSS 5 video swallow study; WNL 5Within normal limits. DISCUSSION PCPA is a different entity then the cricopharyngeal achalasia that we see in adults. Although an exact cause of PCPA is unknown, it is considered to be associated with an immature neuromuscular system. 1 The interstitial cells of Cajal (ICC), which are found in smooth muscle of the gastrointestinal tract, function as pacemakers; at birth they are immature and poorly coupled to smooth muscle cells. 4 Disorganization and decreased numbers of ICC cells have been associated with esophageal disorders such as tracheoesophageal fistula and motility disorders. 5 Immaturity of the ICC cells may explain why there have been reports of spontaneous resolution of PCPA seen in infants. Unfortunately, there have been no studies addressing this theory, likely due to the small number of cases of PCPA. PCPA has also associated with GERD and CNS abnormalities such as Arnold-Chiari malfomation. 3,6 Suboccipital craniectomy and cervical laminectomy for symptomatic Arnold-Chiari malformations may reduce dysphagia and reverse achalasia in this population. 7 In one of the largest case series of PCPA reported, 11 of 15 patients had associated diseases related to the central nervous system, including Arnold-Chiari malformations and cerebral palsy. 8 One child in our study had a genetic abnormality (trisomy 20 p) but the other five had no other comorbidities. Less than 40 cases of trisomy 20 p have been reported in the literature, but cricopharyngeal achalasia or dysphagia has not been reported as a prominent symptom. 9 Symptoms of PCPA can be overt or more indolent and include choking, aspiration, dysphagia, drooling, regurgitation, nasal reflux, weight loss, failure to thrive, recurrent respiratory infections, or any combination of the above. Coughing, aspiration, regurgitation, and emesis were the most common symptoms in our patient series. As these symptoms can be indicative of several disease processes commonly seen in children, a delay in diagnosis of PCPA is common. In this series, the time from the onset of symptoms to diagnosis ranged from 4 to 36 months, with a median of approximately 6 months. Aspiration may call for alternative diets in these children. Usually thickened feeds are implemented, but a nasogastric or gastrostomy tube may be necessary. Five of our six patients required an altered diet prior to intervention (Table I). Physical examination in children with PCPA may not yield much information. Occasionally, they might have drooling, noisy breathing or gagging on oral secretions. Observing the act of swallowing and observing for signs of dysphagia such as coughing or regurgitation can be attempted, depending on the age of the child. Diagnosis is usually made on a contrast esophagram or a videofluoroscopy study showing a prominent cricopharyngeus muscle, usually as a posterior bar or indentation in the upper esophagus (Fig. 1). Endoscopy can also be performed, but this usually gives more information on the mucosal health rather than the presence of a prominent CP muscle. Manometry measures of the upper esophageal sphincter have been used with more frequency. In TABLE III. Botulinum Toxin Total Amounts and Units per Kilogram With Final Outcome. Patient Dates of Injection Total Amounts U/KG Final Outcome 1 9/18/06, 5/15/07, 8/21/07 30 U, 60 U, 60 U 3.4, 5.5, 6.3 myotomy 2 1/15/08,1/8/09 70 U, 70 U 7.0, 7.9 resolution 3 7/13/ U 6.3 resolution 4 10/12/10 60 U 5.8 myotomy 5 3/18/08, 9/16/08 90 U, 100 U 6.1, 5.9 resolution 6 7/17/09 80 U 1.6 resolution 1477

4 Fig. 1. Esophagram from 3-month-old patient showing a filling defect at the level of the posterior cricopharyngeus muscle consistent with cricopharyngeal dysfunction. our patients various studies were performed, most commonly VSS and UGI contrast studies (Table II). As this is a retrospective review, there is no consistency in reporting terms. However, only one of these studies performed was reported as normal, an UGI in a 6 month old. The VSS in this case did show CP muscle contraction. Manometry and impedance studies were performed in four of the six patients with various results. In three of the four esophagogastroduodenscopies (EGD) performed, esophagitis was present. On only one of the EGD s performed was a CP prominence noted, which is consistent with the previously mentioned poor sensitivity for CPA of this procedure. With neurological abnormalities being traditionally associated with PCPA, a MRI may be considered, especially if other neurological symptoms are present. The decision to proceed with magnetic resonance imaging (MRI) scanning should be individualized and based on the patient s overall constellation of symptoms; the data supporting MRI scanning is limited. Three of our study subjects underwent MRI of the brain, which were reported as normal. Medical therapy for the treatment of CP achalasia has largely been unsuccessful, and agents used have significant side effects that outweigh their usefulness. 10 Dilations of the CP muscle and CP myotomy, originally described in adults, have been used in children with some success. Bougie dilatation has been reported sparsely in the literature, with mixed results. 11,12 Dilatations often need to be repeated. Balloon dilation of the CP muscle has also been reported in one patient. 10 CP myotomy, either open or endoscopic, while successful does carry risks including perforation, scarring, and recurrence. Skinner and Shorter argued for treating patients with PCPA with balloon dilation, reserving CP myotomy for those with severe symptoms. 6 Botulinum toxin injection to the CP muscle was first described in 1997 by Blitzer and Brinn. 13 They injected the CP muscle in six adults percutaneously for dysphagia symptoms related to cricopharyngeal hyperfunction. All of their patients had improvement in swallowing, and since then multiple studies in adult populations have shown good efficacy. 13 In 2005, the first report of botulinum toxin injection in a child was published. In this case, the injection was used as a diagnostic tool to confirm the diagnosis of CPA. 14 A case series published in 2011 reported on three pediatric patients with cricopharyngeal achalasia who were treated exclusively with botulinum toxin injection. All three children had resolution of symptoms with resumption of oral diet. 15 In our study, injections of botulinum toxin were performed by two different surgeons using standard laryngoscopy techniques. The toxin was injected into the cricopharyngeal muscle in two to four areas, avoiding the anterior cricopharyngeus because of proximity to the glottis. Varying amounts of toxin were used. The first patient in our study had the lowest dose of toxin per kilogram (3.4U/kg) in our series, likely due to the novelty of the treatment. This patient did have resolution of aspiration but had recurrence and went on to have TABLE IV. Parental Survey Responses (Shortened). Patient 1 Patient 2 Patient 3 Patient 4 Patient 5 Patient 6 Main symptom aspiration feeding difficulty cough with feeds cyanosis with feeds aspiration choking and aspiration Preoperative severity (1 4) Symptom currently better, worse, or same? better better better better better better Current severity (1 4) Persistent symptoms Would you undergo procedure again? Would you recommend procedure? NA 5 not applicable (intermittent) NA textural issues occasional vomiting NA NA occasional dysphagia yes yes no yes yes yes yes yes yes yes yes yes 1478

5 higher amounts injected. The oldest child in our series had the lowest dosage per kilogram due to relatively higher weight and limitations of total toxin administration. The other injections ranged from 5.5 U/kg to 7.9 U/kg (Table III), with a mean of 5.6 U/kg. If we do not include the first lower-dose injection in the series, as well as the injection of the 10 year old who had weight limitations due to an older age, the mean is 6.4U/kg. In a recent retrospective analysis of three patients, Barnes et al. reported dosages (1.4 U/kg-5.1 U/kg), which were lower than what is described in this article. Two children in this study went on to have a myotomy performed. The first child was a 3 month old who had already undergone myotomy at an outside hospital but had persistent symptoms. A VSS showed aspiration and the child had a prominent CP bar on UGI. The child underwent injection, with resolution of symptoms and aspiration. The effect wore off after 3 months and the child began to have difficulty with feeds again. A repeat UGI showed persistent pooling at the CP muscle. After two more injections, which helped for 3 to 6 months, the mother decided to undergo repeat myotomy. This permanently resolved the child s issues. The other child, a 9- month-old male, underwent myotomy after one injection. The family lived out of state and decided that they did not want to travel to our hospital for repeat injections. They could not find anyone locally to perform the procedure, so they had come to our hospital with an uncertain diagnosis. When the botulinum toxin injection relieved the symptoms and the child was diagnoses with PCPA, they decided on surgery. The botulinum toxin injection in these cases did help confirm dysfunction at the level of the cricopharyngeus. A telephone survey was conducted as part of our retrospective study (Fig. 1) to gauge parent s satisfaction with the procedure as well as to assess the patient s current symptoms. All patients had improvement in main preprocedure symptoms. One child had persistent textural issues, one had occasional postprandial emesis, and one has occasional dysphagia. One parent out of six would not have the procedure again. That patient had gross worsening of aspiration 2 days after CP muscle injection. On flexible laryngoscopy the vocal folds were functional. A postprocedure VSS showed incoordination on the hypopharynx during swallowing. It is presumed that the patient had extravasation of botulinum toxin outside the CP muscle and into the constrictors, which caused the dysfunction. The dose used on this patient, 6.3U/kg, was in the middle of the range used in our patients. The patient was sent home with nasogastric tube (NGT) feeds that were discontinued 2 weeks later after a normal VSS. The mother of this patient admitted to having a hard time coping with the complication and NGT, but interestingly said she would recommend this to another parent because it eventually did help. In fact, all parents would recommend the procedure to another parent, all stating that it did help their children (Table IV). As mentioned previously, one of the important features of congenital cricopharyngeal achalasia is the potential for spontaneous resolution. 1 This occurs predominantly in the neonatal and infant population. Since botulinum toxin has a temporary effect and may be repeated, it is a good initial therapy for PCPA, which may resolve with time. It may also be useful is neurogenic dysphagia related to Arnold-Chiari malformation if CPA is a prominent feature. 3 Allowing for spontaneous resolution may avoid a myotomy and its inherent risks. Optimum dosing is still unknown. Our dosages were higher than what had been published in the past. The goal obviously is to have the most benefit with a minimal risk of side effects. Dosages between 5 and 6U/kg seem to be efficacious. Our one complication had an injection dose of 6.3 U/kg, although this was not the highest in the series. Avoiding higher doses and judicious injection may help prevent spread of the toxin and unintended consequences. CONCLUSION Symptoms of cricopharyngeal achalasia in the pediatric population are often nonspecific, which can lead to a delay in diagnosis. Preoperative evaluations may include central nervous system imaging, VSS and/or contrast esophagrams. Manometry can be considered as more experience is gained with this diagnostic modality. Four of the six children in this series were treated exclusively with botulinum toxin, thus avoiding a more invasive procedure. In the two children who went on to have cricopharyngeal myotomy performed, the botulinum toxin was useful in confirming the diagnosis of cricopharyngeal achalasia. There was one complication, aspiration, which did resolve with time. Parental satisfaction was high. Botulinum toxin injection of the cricopharyngeus muscle is a useful tool to help diagnose and treat pediatric cricopharyngeal achalasia. It is a feasible alternative to more invasive surgical procedures. However, more research is needed to elucidate optimal dosing, frequency of injections, and when to move on to surgical intervention. BIBLIOGRAPHY 1. Husain SZ, Di Lorenzo C. Motility Disorders. Diagnosis and treatment for the pediatric patient. Pediatr Clin N Am 2002;49: Utian HL, Thomas RG. Cricopharyngeal achalasia: a case report and review of the literature. Pediatrics 1969;43: Gendell HM, McCallum JE, Reigel DH. Cricopharyngeal achalasia associated with Arnold-Chiari malformation in childhood. Child Brain 1978;4: Daniel EE, Wang Y. Control systems of gastrointestinal motility are immature at birth in dogs. 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