Cricopharyngeal achalasia in children: botulinum toxin injection as a tool for diagnosis and treatment.

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. LEVEL OF EVIDENCE: 4.

The use of botulinum toxin for pediatric cricopharyngeal achalasia.

OBJECTIVES: Cricopharyngeal achalasia is an uncommon cause of feeding difficulties in the pediatric population, and is especially rare in infants. Traditional management options include dilation or open cricopharyngeal myotomy. The use of botulinum toxin has been preliminarily reported for cricopharyngeal achalasia in children as a modality for diagnosis and management. This study describes the use of botulinum toxin as a definitive treatment for pediatric cricopharyngeal achalasia. METHODS: A retrospective analysis was performed of three patients who were diagnosed with cricopharyngeal achalasia and underwent botulinum toxin injections to the cricopharyngeus muscle. The charts were reviewed for etiology, botulinum toxin dosage delivered, length of follow-up, postoperative need for nasogastric tube placement, and swallow studies. RESULTS: A total of 7 botulinum toxin injections into the cricopharyngeus muscle were performed in three infants with primary cricopharyngeal achalasia between April 2006 and February 2011. Mean dosage was 23.4 units per session (range: 10-44 units), or 3.1 U/kg (range: 1.4-5.3 U/kg). Mean interval period between injections was 3.3 months (range: 2.7-4.0 months). Mean follow-up period was 22.1 months (range: 3.4-44.5 months). One patient required hospital readmission after injection for presumed aspiration but recovered without need for surgical intervention. No long-term complications were noted post-operatively. All patients improved clinically and ultimately had their nasogastric feeding tubes removed. CONCLUSIONS: Botulinum toxin appears to be a safe and effective option in the management of primary cricopharyngeal achalasia in children, and may prevent the need for myotomy.

Metoclopramide does not attenuate cricoid pressure-induced relaxation of the lower esophageal sphincter in awake volunteers.

BACKGROUND: The authors examined the influence of metoclopramide on cricoid pressure-induced relaxation of the lower esophageal sphincter (LES) in awake human volunteers. METHODS: With local institutional review board approval, measurements of LES and intragastric pressures were made in 10 consenting volunteers before cricoid pressure application, during 15 s of cricoid pressure application, and after release of cricoid pressure. The measurements were repeated after 0.15 mg/kg intravenous metoclopramide. Cricoid pressure was applied by one investigator trained to consistently apply a force of 44 N. RESULTS: Cricoid pressure resulted in immediate decrease in LES and barrier pressures from 14.1 +/- 2.9 mmHg to 3.2 +/- 3.7 mmHg and from 9.6 +/- 3.4 mmHg to -1.8 +/- 2.9 mmHg, respectively. These pressures promptly returned to baseline values after release of cricoid pressure. LES and barrier pressures increased after metoclopramide from 14.5 +/- 3.1 to 19.6 +/- 4.7 mmHg and from 10.2 +/- 3.6 to 14.1 +/- 5.5 mmHg, respectively. Cricoid pressure applied after metoclopramide resulted in immediate decreases in LES and barrier pressures to levels comparable to cricoid pressure before metoclopramide, but immediately returned to precricoid values after release of pressure. CONCLUSIONS: The current investigation demonstrates that cricoid pressure reflexly decreases LES tone and barrier pressure in awake subjects. Although metoclopramide increased LES and barrier pressures, it did not attenuate cricoid pressure-induced relaxation of the LES and barrier pressures and thus seems to have no value in preventing gastroesophageal reflux during cricoid pressure. Metoclopramide may be useful in preventing reflux when there is need to release or discontinue cricoid pressure.

Vocal outcome measures after bilateral posterior cricoarytenoid muscle botulinum toxin injections for abductor spasmodic dysphonia.

OBJECTIVE: To review vocal outcome measures, using the Voice Related Quality of Life (VRQOL) index, after simultaneous bilateral posterior cricoarytenoid muscle botulinum toxin injections. STUDY DESIGN: Case series. SETTING: Tertiary care academic clinic. SUBJECTS AND METHODS: Fourteen subjects with abductor spasmodic dysphonia received 37 simultaneous bilateral posterior cricoarytenoid muscle botulinum toxin injections for isolated abductor spasmodic dysphonia (ABSD) over a 16-month period. MAIN OUTCOME MEASURES: VRQOL index. RESULTS: Of the 37 injections, 33 of 37 (89%) resulted in improvement. Three injections resulted in no improvement, and one injection resulted in a worse VRQOL. The overall VRQOL mean improvement was 19.8 (range 5-53), with an average pre/postinjection VRQOL interval of 36 days (range 21-45 days). CONCLUSIONS: Simultaneous bilateral posterior cricoarytenoid muscle botulinum injections result in a statistically significant improvement in VRQOL index scores for a high percentage of ABSD patients, thus improving patient quality of life.

Effect of vascular endothelial growth factor on laryngeal wound healing in rabbits.

OBJECTIVE: Study the effects of vascular endothelial growth factor (VEGF) on laryngeal wound healing in a rabbit model. STUDY DESIGN: Prospective, randomized, blinded. METHODS: The anterior cricoid cartilage of 10 rabbits was split and a VEGF-soaked collagen sponge was sewn between the cut edges. In 10 control animals, the collagen sponge was soaked with phosphate-buffered saline solution. The larynx was harvested on day 10. The degree of epithelial closure, the degree of soft tissue closure, and the presence of inflammatory cells was graded. RESULTS: There was complete epithelial closure in the control group. There was a slightly higher, but not statistically significant, grade of soft tissue closure in the experimental group. The experimental group had a lower but not statistically significant acute inflammatory response score. CONCLUSIONS: The topical application of VEGF through an implanted collagen sponge to an anterior, subglottic incision in a rabbit has no significant effect on tracheal luminal epithelial closure, acute inflammatory response, or soft tissue repair at postsurgical day 10.

Local treatment of cricoid cartilage defects with rhBMP-2 induces growth plate-like morphology of chondrogenesis.

OBJECTIVE: The ultrastructural characteristics of new bone and cartilage, induced at the site of cricoid cartilage defects treated with rhBMP-2 in rabbits, were investigated. STUDY DESIGN AND SETTING: A cricoid defect model was used. Fifteen rabbits were randomly and equally divided into 3 groups. Four rabbits from each group were treated with rhBMP-2, while one rabbit from each group was used as control. The rabbits were killed 1, 2, or 4 weeks after surgery. The healing pattern of the laryngeal wound was evaluated by light and transmission electron microscopy. RESULTS: Mineralized collagen type I matrix, osteoblasts, and osteoclast-like cells were present as early as 1 week after surgery. Well-structured bone trabeculas and growth plate-like structures were present 4 weeks after surgery. CONCLUSION: Intramembranous and endochondral osteogenesis take place at the site of cricoid cartilage defects treated with rhBMP-2. Progenitor cells of cricoid perichondrium form a growth plate-like structure similar to the epiphyseal growth plate. SIGNIFICANCE: This study reveals the pattern of BMP-2-induced repair of airway cartilage defects.

Cell origin in experimental repair of cricoid cartilage defects treated with recombinant human bone morphogenetic protein-2.

We determined the origin of new cartilage and new bone induced by recombinant human bone morphogenetic protein-2 (rhBMP-2) at the site of cricoid cartilage defects in rabbits randomly divided into eight groups. The cricoid cartilage was split vertically along the anterior midline and a strip was excised from the anterior part of the cricoid cartilage in all rabbits. The perichondrium from the anterior part of the cricoid cartilage was trimmed off in four groups; two groups treated with rhBMP-2 and two control groups. In four other groups, the anterior perichondrium was detached and used as a flap with two groups treated with rhBMP-2 and two groups serving as controls. The rabbits were killed 1 week or 4 weeks after surgery. The larynges were removed, fixed and sectioned, and the sections were stained for light microscopy using various cytochemical and immunological techniques. New cartilage was only present close to the host perichondrium adherent to cricoid cartilage in rabbits treated with rhBMP-2. New bone was present 4 weeks after surgery, although calcified matrix and alkaline phosphatase activity could be detected at the site of cricoid defects as early as 1 week after surgery. The cell proliferation marker Ki-67 was strongly expressed in granulation tissue and bone marrow, and it was moderately expressed in muscles adjacent to the cricoid cartilage in rhBMP-2-treated specimens. BMP receptors were strongly expressed in cartilage and moderately expressed in adjacent muscles. We conclude that new cartilage originates from the mesenchymal progenitor cells of host perichondrium adherent to cricoid cartilage in rabbits treated with rhBMP-2. New bone may originate from local muscle.

Effect of recombinant human BMP-2 on the repair of cricoid cartilage defects in young and adult rabbits: a comparative study.

OBJECTIVE: The study evaluated the possible differences in the repair of cricoid cartilage defects treated with recombinant human BMP-2 in young and adult rabbits. METHODS: A cricoid defect rabbit model was used. Thirty rabbits were randomly divided into eight groups. Two groups of young rabbits and two groups of adult rabbits were treated with rhBMP-2 delivered on an absorbable collagen sponge, while the other two groups of young rabbits and two groups of adult rabbits were used as controls. The rabbits were killed at 1 week or 4 weeks after surgery. A histomorphometric analysis and an evaluation of the expression of collagen types I, II, and X, and proliferating cell nuclear antigen as well as a study of distribution of calcified matrix, were performed. RESULTS: rhBMP-2 induced a marked chondrogenesis in both experimental age groups. However, in young rabbits the newly formed cartilage appeared more elongate, and the length of perichondrium involved was greater. The host cricoid cartilage of adult rabbits was calcified in large areas and displayed a strong matrix expression of collagen type X as well as collagen type I in the perichondrium, compared to the cricoid of young rabbits. In spite of these differences no immunohistochemical differences were found in the newly formed cartilage of both age groups treated with rhBMP-2. The cricoid cartilage defect was filled with new bone at 4 weeks in both age groups treated with rhBMP-2. New bone tissue had a well-defined trabecular structure. CONCLUSIONS: rhBMP-2 triggers appositional cartilage growth from the cricoid perichondrium of young rabbits more easily than from that of adult rabbits. The new bone induced by rhBMP-2 showed a similar immunohistochemical and morphological pattern in both age groups of rabbits.

Recombinant human bone morphogenetic protein-2 enhances experimental laryngotracheal reconstruction in rabbits.

OBJECTIVE: Bone morphogenetic protein-2 offers potential benefits for cartilage regeneration. We investigated the effect of recombinant human bone morphogenetic protein-2 (rhBMP-2) on the regeneration of laryngeal cartilage and respiratory epithelium in a rabbit model. MATERIAL AND METHODS: We used a cricoid defect rabbit model. Twenty-four rabbits were randomly divided into four equal groups. Two groups were treated with 5 microg of rhBMP-2 delivered on an absorbable collagen sponge and the other two groups were used as controls. One group of treated rabbits and one group of control rabbits were euthanized 1 week after surgery, while the others were euthanized 4 weeks after surgery. The healing pattern of the laryngeal wound was evaluated by means of histomorphometry. RESULTS: Regeneration of both the epithelial layer and cartilage was significantly better in rabbits treated with rhBMP-2. Four weeks after surgery, the cricoid cartilage defect was completely repaired by new cartilage and new bone in rabbits treated with rhBMP-2. Furthermore, the lining respiratory epithelium healed more rapidly in treated rabbits. CONCLUSION: rhBMP-2, delivered via an absorbable collagen sponge, induces complete regeneration and repair of rabbit cricoid cartilage defects. It also induces faster relining and regeneration of airway epithelium than in control rabbits.

Structural characteristics of repair tissue of cricoid cartilage defects treated with recombinant human bone morphogenetic protein-2.

We examined the structural characteristics of repair tissue induced by recombinant human bone morphogenetic protein-2 in a rabbit model of laryngotracheal reconstruction. Twenty-four New Zealand White rabbits were randomly divided into four groups of six rabbits. Two groups were treated with recombinant human bone morphogenetic protein-2 delivered on an absorbable collagen sponge, while two groups were used as controls. Rabbits were euthanized at 1 and 4 weeks after surgery. The larynx was removed, fixed, and sectioned. The sections were stained with hematoxylin-eosin, safranine O/fast green, and immunostained with an antibody for tissue inhibitor of metalloproteinases-1. In rabbits treated with bone morphogenetic protein-2, the defects were filled with new cartilage and bone at 4 weeks after surgery. There were no discontinuities or gaps at the margins of the cartilage defects. Proteoglycans were synthesized in new cartilage in rabbits treated with bone morphogenetic protein-2, and were present 4 weeks after surgery. The general aspects of the vascular pattern and the pattern of tissue inhibitor of metalloproteinases-1 expression were similar in control and treated rabbits, both 1 week and 4 weeks after surgery. The repair tissue induced by recombinant human bone morphogenetic protein-2 consisted of new cartilage and bone perfectly integrated with host tissue at the site of the cricoid cartilage defects. This new cartilage was able to mature and produce proteoglycans.

Botulinum toxin treatment for cricopharyngeal dysfunction.

Hypertonicity and spasticity of the cricopharyngeal muscle (CPM) often result in dysphagia characterized by difficulty passing a bolus through the upper esophageal sphincter. Past treatments for this problem have included mechanical dilation and endoscopic and transcervical cricopharyngeal myotomy. More recently, botulinum toxin injections into the CPM have been successful, but only in isolated case studies and small series. This study reports pre- and post-botulinum toxin A injection results for 12 subjects, including patient ratings of symptom severity, changes noted during modified barium swallow studies, and, in some cases, manometry of the upper esophageal sphincter. Results indicate that botulinum toxin A treatment provided significant improvement in swallowing as indicated by patient symptom ratings and investigator ratings of function from modified barium swallow studies. Greater improvement was seen in those with more isolated CPM or Xth nerve dysfunction rather than those with more global dysphagia abnormalities.

In vitro regulation of expression of cartilage-derived morphogenetic proteins by growth hormone and insulinlike growth factor 1 in the bovine cricoid chondrocyte.

OBJECTIVES: To delineate the endogenous growth factors that regulate cricoid cartilage growth at the molecular level. Specifically, to attempt to establish the presence of cartilage-derived morphogenetic proteins (CDMPs), cartilage-specific members of the bone morphogenetic protein family, in newborn bovine cricoid chondrocytes and to assess the expression of these endogenous growth factors with the addition of exogenous growth hormone or insulinlike growth factor 1 in an in vitro chondrocyte culture model. METHODS AND DESIGN: Basic science molecular biologic research methods, including high-density monolayer and explant chondrocyte cultures with extraction of messenger RNA and quantitation via Northern blot hybridization via radiolabeled complementary DNA probes. SETTING: Intramural basic science research laboratory. RESULTS: Both CDMP-1 and CDMP-2 were found in newborn cricoid chondrocytes. Addition of exogenous growth hormone did not appear to influence the expression of CDMP-1 or CDMP-2. Addition of exogenous insulinlike growth factor 1 appeared to down-regulate the expression of CDMP-1 but had no effect on the expression of CDMP-2. No major differences in CDMP level of expression were noted between high-density monolayer cultures vs explant cultures. No tissue specificity differences were noted in regulation of CDMPs between cricoid and articular chondrocytes. CONCLUSIONS: Our preliminary studies indicate the presence of endogenous morphogenetic proteins in newborn bovine cricoid chondrocytes. These novel polypeptide hormones (CDMP-1 and CDMP-2) have not been previously reported in laryngeal cartilage chondrocytes. Change in level of transcription of these morphogenetic proteins under various in vitro conditions suggests that these proteins are subject to regulation and/or play a regulatory role in cricoid chondrocyte growth and differentiation. Further experimentation is needed to confirm these findings.

Nitrazepam-induced cricopharyngeal dysphagia, abnormal esophageal peristalsis and associated bronchospasm: probable cause of nitrazepam-related sudden death.

Nitrazepam was used in the treatment of resistant myoclonic epilepsy in 38 children. After the occurrence of nitrazepam-associated swallowing incoordination, high-peaked esophageal peristalsis and related bronchospasm in one patient, we initiated a prospective study of esophageal manometry using a station pull-through technique with a pediatric 4-channel continuous perfusing system. Three more patients were found to have delayed cricopharyngeal relaxation and high-peaked esophageal peristaltic waves. The initial patient developed severe respiratory distress and bronchospasm necessitating ventilatory support while on nitrazepam and improved dramatically with subsequent normal manometric study following nitrazepam discontinuation. Nitrazepam was reintroduced for its anticonvulsant and cognitive benefits and was tolerated at a reduced dosage. We postulate a central nervous system effect of nitrazepam promoting parasympathetic overactivity or vagotonia which can cause potentially fatal respiratory distress. Care must be exercised in nitrazepam use and esophageal manometry may be helpful in defining patients at greater risk for sudden death.

An in vitro model for studying growth and effect of trauma and external agents on the cricoid at the cellular level.

Over the past several years it has become evident that expansion laryngotracheal surgery is effective in the treatment of laryngotracheal stenosis. Several clinical and animal studies have been performed to study the process of laryngotracheal stenosis and its treatment. However, there are still many questions that cannot be addressed by currently used clinical and animal research. Further indepth study of the behavior of the subglottis at the cellular level is necessary. We present an in vitro model for studying chondrocyte metabolism of the bovine cricoid. Cartilage was successfully grown in an explant culture system, and it was shown that the chondrocytes were metabolically active and responded to external agents. This model will serve to study the mechanism of growth and effects of trauma and external agents on the cricoid at the cellular level.