Original Article
Swallowing Dysfunction in Nephropathic Cystinosis
N Engl J Med 1990; 323:565-570August 30, 1990
- Abstract
- Abstract
Background.
Nephropathic cystinosis causes renal failure in most patients at approximately 10 years of age. This can be prevented or retarded by cystine-depleting therapy with oral cysteamine. Many patients who do not receive adequate cysteamine therapy undergo renal transplantation, but the accumulation of cystine continues in other organs, resulting in various clinical abnormalities. We report age-related swallowing dysfunction in patients with nephropathic cystinosis.
Methods.
We studied 43 patients with cystinosis (24 who had received a renal transplant and 19 who had not), 3 to 31 years of age. Oral motor function was assessed by a cranial-nerve oral sensorimotor examination, and an oral motor index was calculated for each patient. The oral phase of swallowing was assessed by ultrasonography, and the pharyngeal and esophageal phases were evaluated by videofluoroscopy.
Results.
Approximately half the patients were slow eaters. Oral motor dysfunction, reflected by a higher oral motor index, increased with age. Speech, oral structure and anatomy, and tongue and lip strength were particularly affected. Seven of nine patients 21 to 31 years old had abnormalities in all three phases of swallowing; the deficits were variable in younger patients. In 28 patients with cystinosis, the mean (±SD) duration of oropharyngeal swallowing for a dry swallow (3.06±1.06 seconds) was longer than in 14 normal subjects (1.89±0.57 seconds; P<0.001). This prolongation reflected impairment of the initiation phase of swallowing.
Conclusions.
Swallowing dysfunction is a late complication of nephropathic cystinosis, probably related to muscular dysfunction. Changes in the consistency of foods, swallowing exercises, and long-term cysteamine therapy should be considered for patients with cystinosis who have difficulty in swallowing. (N Engl J Med 1990; 323: 565–70.)
Media in This Article
Figure 1
Oral Motor Index as a Function of Age in Patients with Nephropathic Cystinosis.Figure 2
Sagittal Views of Swallowing during Modified Barium Studies in Patients with Cystinosis.Article Activity
- Article
NEPHROPATHIC cystinosis is a lysosomal storage disease in which cystine accumulates intracellularly in many tissues, including the kidney. Renal failure generally occurs at approximately 10 years of age,1 2 3 4 although glomerular dysfunction can be slowed or halted by the oral administration of cysteamine.5 , 6 This aminothiol participates in a disulfide-interchange reaction with cystine, followed by the removal of the reaction products from the lysosome.1 , 6 Endogenous cystine production continues, but the net result of cysteamine treatment is the depletion of cystine.5 , 6 Before cysteamine became available, over 70 patients in North America with cystinosis underwent renal transplantation, which allowed them to survive into their second and third decades.7 , 8 Although donor kidneys do not accumulate cystine, the effects of the long-standing extrarenal accumulation of cystine are evident in patients who have received a renal transplant. These include decreased visual acuity,9 recurrent corneal erosions,9 pancreatic endocrine10 and exocrine11 insufficiency, central nervous system involvement,8 , 12 and severe myopathy.13
We now report the occurrence of oral motor and swallowing dysfunction in a group of 43 patients with cystinosis (24 of whom had received a renal transplant and 19 who had not) evaluated by a cranial-nerve—based oral sensorimotor examination, oropharyngeal ultrasonography, and pharyngoesophageal video-fluoroscopy between February 1987 and May 1989. Over 35 percent of the patients had dysphagia in one or more of the three phases of swallowing (oral, pharyngeal, and esophageal). The mean durations of both wet and dry swallows were significantly longer in the patients with cystinosis than in normal subjects, and the frequency and severity of oral motor dysfunction increased progressively with age. We conclude that oropharyngeal motor dysfunction is a late muscular complication of cystinosis, and that dysphagia therapy (swallowing exercises and changes in the consistency of foods) and oral cysteamine treatment should be considered for older patients with the disease.
Methods
Patients
Nephropathic cystinosis was diagnosed in all the patients on the basis of elevated leukocyte cystine levels and the presence of cystine crystals in the cornea.1 , 2 All the patients were enrolled in studies of the natural history of cystinosis and the efficacy of cysteamine therapy. The protocols for those studies and for this study of swallowing function were approved by the institutional review boards of the National Institute of Child Health and Human Development and the National Institutes of Health Clinical Center, and informed consent was obtained from all subjects before their participation in the studies. The 19 patients who had not received renal transplants (10 girls and 9 boys) were 3.8 to 13.8 years old (mean, 8.1). All had received oral cysteamine (50 to 90 mg of free base per kilogram of body weight per day, given every six hours) for 0.2 to 10 years (mean, 5.5). Their serum creatinine concentrations ranged from 40 to 310 μmol per liter (0.5 to 3.5 mg per deciliter). The 24 who had received renal transplants (8 female patients and 16 male patients) ranged in age from 9 to 31 years (mean, 18.4) and had received their allografts, on average, 7.7 years before the study began. Only 13 of these 24 patients had received cysteamine, and the average duration of cysteamine therapy was 1.7 years (range, 0.3 to 4.8). Two patients were undergoing regular dialysis for uremia. The remaining 22 had serum creatinine values of 40 to 240 μmol per liter (0.5 to 2.7 mg per deciliter).
Oral Motor Function
A 59-item cranial-nerve—based oral sensorimotor examination14 was used to evaluate the anatomy, symmetry of movement, strength, and range of motion of the lips, tongue, velum, jaw, and facial muscles in phonation, articulation, deglutition, respiration, and expression. This examination included an evaluation of the following 10 areas: oral structure and anatomy, oral—facial symmetry, oral—facial movement and reflexes (gag, cough, swallow, wink), tongue and lip strength, oral sensation, swallowing, speech, articulation, speech fluency, and diadochokinetic rate of speech. Every patient's performance in each of the 10 areas was rated from 1.0 (normal) to 4.0 (severely abnormal). As an example of this grading system, 3.0 in tongue and lip strength would reflect slurred speech and the inability to move a bolus of food over the tongue for swallowing. Using this evaluation system, we calculated an oral motor index for each patient as the numerical mean of the scores for the 10 components described above. The oral-motor-index values were analyzed by grouping patients into those who had and those who had not received renal transplants and in 10-year age categories.
Assessment of Swallowing
The oropharyngeal and esophageal phases of swallowing were assessed objectively by ultrasonography15 and videofluoroscopy with a modified barium-swallow procedure.16 The studies were videotaped for frame-by-frame analysis of oropharyngeal physiology, the duration of the phases of swallowing, and the movement of a bolus of food from the oral cavity through the esophagus. fluoroscopic images of the patients in an upright position were obtained in the lateral and anteroposterior views with use of three 1.6-ml (1/3-teaspoon) swallows of boluses of various consistencies (liquid, medium, and paste-like). The flow and transport of the boluses, the symmetry of transport, peristalsis, structural deviations, and the temporospatial components of swallowing were assessed in this manner. The examination was stopped if aspiration occurred.
Ultrasonography was performed to determine the duration of the oropharyngeal phase of swallowing and to examine the motions of the tongue and hyoid bone needed to initiate and complete swallowing. This technique was noninvasive and did not require the use of contrast material. The subjects performed three consecutive dry swallows and then ingested 10 ml of water three times. On sagittal ultrasound scanning,15 , 17 the hyoid bone casts an echo-free shadow as it moves forward and upward toward the mandible during swallowing. This movement of the hyoid, from resting position forward to a maximal anterior position and back to resting position, demarcates the entire oropharyngeal phase of swallowing.17 Its duration was termed the rest-to-maximum interval and served as a measure of the oral initiation phase of swallowing. The mean rest-to-maximum interval was calculated separately for wet and dry swallows and compared with published normal values.17 The total swallowing time for both wet and dry swallows was also calculated and compared with those in normal subjects. Fourteen normal subjects (seven women and seven men) 18 to 31 years of age served as controls for the assessments of oral motor function and swallowing. Each normal subject had an oral motor index of 1.0. The mean durations of the swallowing intervals in the 14 normal subjects are shown in Table 1Table 1
Duration of Swallow in Patients with Nephropathic Cystinosis and in Normal Subjects.*. Student's two-tailed t-tests were used for statistical analysis.Results
Oral Motor Function
The oral motor index, a measure of the severity of oral motor dysfunction, increased with age in the patients with cystinosis and varied considerably, especially in the older age group (Fig. 1Figure 1
Oral Motor Index as a Function of Age in Patients with Nephropathic Cystinosis.). The results were similar whether or not the patients had received renal transplants or short-term cysteamine therapy. For example, five patients over 20 years old who had received no cysteamine therapy had a mean leukocyte cystine value of 11.0 nmol of half-cystine per milligram of protein and a mean (±SE) oral motor index of 1.8±0.5. In five other patients in whom the mean leukocyte cystine level had decreased from 11.0 to 1.2 nmol of half-cystine per milligram of protein after they had taken oral cysteamine for 8 to 25 months, the mean oral motor index was 1.5±0.3.Several components of oral motor function were analyzed individually. The 24 patients who had received renal transplants had mean scores for speech, oral structure and anatomy, and tongue and lip strength of 1.8±0.2, 1.5±0.2, and 1.7±0.2, respectively. These scores were significantly higher than those of the 19 patients who had not received renal transplants (1.1±0.1, 1.0±0.0, and 1.2±0.1; 0.001<P<0.05). In addition to the scores for speech, oral structure and anatomy, and tongue and lip strength listed above, the scores of the transplantation patients for oral—facial movement and reflexes (1.6±0.2) and swallowing (1.8±0.2) were slightly higher than their scores for speech fluency (1.2±0.1) and articulation (1.4±0.2).
Swallowing Function
In normal persons, a bolus of 10 ml of liquid barium passes through the oropharynx in 1.00 to 1.50 seconds and leaves no residue.17 , 18 Of the 43 patients in our study, 15 had abnormalities in the oral phase of swallowing, 16 in the pharyngeal phase, and 15 in the esophageal phase (Table 2Table 2
Frequency of Dysfunction in the Oral, Pharyngeal, and Esophageal Phases of Swallowing in Patients with Nephropathic Cystinosis, According to Age Group.*). Nine patients had abnormalities in all three phases of swallowing; this group included all seven patients over 21 years of age and two female patients 17 and 18 years old. In the only patient without a renal transplant who had abnormalities in all three phases of swallowing, the difficulty was of behavioral origin; she refused solid foods although she was capable of swallowing. The frequency of swallowing dysfunction increased with age in these patients (Table 2).Specific deficiencies in the oral phase of swallowing included excessive anteroposterior tongue motions. These delayed the initiation of the swallowing reflex and slowed the transport of the bolus across the tongue and into the pharynx. Abnormalities in the pharyngeal phase (Fig. 2Figure 2
Sagittal Views of Swallowing during Modified Barium Studies in Patients with Cystinosis.) involved bolus transport by means of gravity, laryngeal penetration, pooling in the valleculae, piriform sinuses and cricopharyngeal sphincter, and slowed pharyngeal peristalsis. There was also slowed esophageal peristalsis, and three older patients had esophageal reflux.The average duration of oropharyngeal swallowing was significantly prolonged in the 28 patients with cystinosis in whom ultrasound measurements were obtained (Table 1). As compared with the 14 normal subjects, the patients had a markedly longer mean total duration of dry swallows ( 1.89 vs. 3.06 seconds). The difference, 1.17 seconds, was larger than the difference for wet swallows, 0.41 second. The results for the rest-to-maximum interval, which reflected the effort needed to initiate swallowing,17 were similar. The difference between the cystinosis group and the normal subjects in the mean rest-to-maximum interval for dry swallows was 0.93 second, and for wet swallows it was 0.39 second. Of the 28 patients with cystinosis tested, 15 (including 7 of the 10 who were over 18 years of age) had rest-to-maximum intervals for dry swallows that were above the normal range, and 18 had a longer total duration for dry swallows.
Of the 19 patients who had not received a renal transplant, only 1 had difficulty swallowing and 7 (37 percent) were slow eaters. Of the 24 patients who had received a renal transplant, 7 (29 percent) had difficulty swallowing and 14 (58 percent) were slow eaters.
The following case report of a severely affected patient illustrates the progression and extent of swallowing difficulties that may occur in older patients with cystinosis.
Case Report
A 23-year-old man had been found to have cystinosis at 4 months of age. The diagnosis was made because he had an older affected sibling and had proteinuria, glycosuria, and polyuria. He underwent renal transplantation at the age of 11 years; his serum creatinine level ranged from 50 to 90 μmol per liter (0.6 to 1.0 mg per deciliter) thereafter. His mental development was normal. At the age of 23, his height age was 11 1/2 years and his bone age was 18 years. His corneas were cloudy. His leukocyte cystine level was 9.3 nmol of half-cystine per milligram of protein (normal, ≤0.2), and the muscle cystine content was 31.8 nmol of half-cystine per milligram of protein (normal, 0.02 to 0.09).13 He had never received cysteamine.
The patient had experienced progressive loss of speech volume and difficulty with articulation for two years. He had recently noted increased difficulty swallowing and complained of a dry mouth, a lump in his throat, food getting caught in his cheeks, coughing and choking after swallowing, reflux in the oral cavity, hoarseness after swallowing, and drooling.
The results of the oral sensorimotor examination were consistent with severe neuromuscular impairment. Speech and swallowing were moderately to severely impaired, and the oral motor index was 3.0. The patient could not pucker or close his lips or hold them in place against resistance. Tongue strength was severely decreased, and the tongue could not be protruded beyond the vermilion border. Major tongue movements (lateralization, elevation, and circling) were impaired because of an inability to elevate the tip of the tongue. The movement and strength of the jaw were normal. The patient's voice quality was breathy and soft. Partial palatal elevation caused increased nasal speech. The ability to sustain a tone was limited to 5 to 6 seconds (normal, 15 to 20), but pulmonary-function tests were not performed. Speaking volume was reduced, voice pitch was elevated, and the intelligibility of speech was reduced. The patient could not form any bilabial sounds (p, b, and m) because of impaired lip closure, and he could not produce rapid, alternating motions of the lips and tongue.
Ultrasonographic and barium studies revealed excessive lingual pumping and impaired bolus transfer in the oral phase. Defects in the pharyngeal phase included pooling in the valleculae, piriform sinuses, and cricopharyngeal sphincter (Fig. 2B and 2C). Bolus transport through the pharynx was unilateral, fluctuating between the left and right sides. Peristalsis was minimal or absent in the pharyngeal and esophageal phases. There was extreme stasis in the cricopharyngeal sphincter because relaxation of the upper esophageal sphincter was profoundly impaired. Although epiglottal motion provided partial protection of the patient's airway and prevented frank aspiration, trace amounts of aspiration were observed in the laryngeal vestibule after every swallow (Fig. 2B and 2C).
Discussion
Patients with cystinosis now live longer because of renal transplantation7 and therapy with cysteamine,5 which circumvents the defect in the transport of cystine out of lysosomes.19 20 21 22 As longevity increases, the spectrum of clinical involvement in cystinosis has broadened to include abnormalities of the eyes, pancreas, and muscles.8 9 10 11 12 13 It is becoming apparent that virtually every cell type that contains lysosomes can be damaged in cystinosis.
The results of this study demonstrate that cystinosis can result in impaired muscular control of the oropharyngeal mechanism of swallowing. Oral motor dysfunction was age-related (Fig. 1), but the variation in its severity suggests that a subgroup of patients may be particularly susceptible. The abnormalities in swallowing were not due to neuromuscular complications of uremia, since only two patients had severe renal dysfunction. The affected patients had no other apparent reason for difficulties in swallowing, indicating that cystinosis itself was responsible for them.
Several pieces of evidence suggest that the accumulation of cystine causes oropharyngeal-muscle dysfunction in cystinosis. First, the lysosomal content of cystine in muscle cells in culture,23 as well as in skeletal muscle in situ,23 , 24 is increased, and cystine crystals are sometimes found.13 This storage of cystine may result in cell death, reduced muscle mass, and impaired contractile function. If these occurred in the oropharynx, which contains skeletal muscle, the wasting would reduce the ability of the tongue and pharynx to contract and propel a bolus of food (or barium) (as in Fig. 2B and 2C). Similar effects in the esophagus would impair peristalsis. Second, the skeletal muscles of patients with cystinosis appear to accumulate cystine as a function of age,1 , 24 and the older patients we studied clearly had the most profound esophageal and pharyngeal dysphagia. In fact, the most severely affected patient, who died of aspiration, also had striking generalized myopathy.13 Third, certain oral sensorimotor deficits, such as impaired motion of the oral muscles, tongue and lip weakness, dysphagia, and dysphonia, were more common than others. These deficits resulted in elevated oral-motor-index scores for oral structure and anatomy, tongue and lip strength, oral—facial movement and reflexes, swallowing, and speech among the patients who had received renal transplants. They reflect impaired neuromuscular activity rather than impaired neurologic function, since paresis, tremors, fasciculations, rigidity, and flaccidity were not observed. Oral-motor-index scores for speech fluency and articulation, which represent cortically controlled, overlearned components of speech, were not as severely affected as those for the muscular components of oral function, even in the older patients. Finally, the patients with cystinosis had longer rest-to-maximum intervals (the initiation phase of swallowing) for dry swallows (Table 1). These involve a muscular activity, and affected patients used increased tongue pumping and compensatory floor-muscle gestures to stimulate a dry swallow. Wet swallows generally require less muscular effort, and patients with cystinosis had smaller differences for wet than for dry swallows when compared with normal subjects.
Therapeutic maneuvers16 , 17 to lessen the possibility of aspiration should be considered in patients with cystinosis who have swallowing dysfunction. They include changing the consistency of foods, such as thickening food to increase sensation and pureeing it for easier swallowing. In addition, placing a bolus of food closer to the back of the tongue can compensate for tongue weakness, tucking the chin down and into the chest will open the pharynx, and performing exercises in laryngeal adduction can help protect the airway. Patients can also be taught to achieve voluntary control of swallowing.
Long-term cysteamine therapy may also prove effective in preventing further damage to the swallowing mechanism. Cysteamine therapy had no measurable benefit in the patients we studied, probably because of the short duration of the treatment. Long-term oral therapy appears to limit the accumulation of cystine in the kidney,6 and it may do the same in the muscular tissues responsible for swallowing. The verification of this hypothesis awaits the evaluation, 10 to 15 years from now, of a cohort of patients with cystinosis who have been treated with cysteamine from early childhood. Even now, swallowing difficulties in older patients with cystinosis make it reasonable to consider cysteamine therapy in them.3 , 4
We are indebted to the nursing staffs of 9 West and the rehabilitation department of the National Institutes of Health Clinical Center for their dedicated work; and to Ms. Carol Becker and Ms. Jacqueline Sharkey for assistance in preparing the manuscript.
Source Information
From the Department of Rehabilitation Medicine, Warren Grant Magnuson Clinical Center, National Institutes of Health. Bethesda, Md. (B.C.S., E.F.E.); the University of Kentucky College of Medicine, Lexington (E.F.E.); the Section on Human Biochemical Genetics, Human Genetics Branch, National Institute of Child Health and Human Development, Bethesda, Md. (H.C.A., M.D.A., S.G.K., T.C.M., W.A.G.); and the Interinstitute Medical Genetics Program, Clinical Center, National Institutes of Health, Bethesda, Md. (H.C.A., M.D.A.). Address reprint requests to Dr. Gahl at Bldg. 10, Rm. 9S242, Human Genetics Branch, National Institute of Child Health and Human Development, 9000 Rockville Pike, Bethesda, MD 20892.
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Citing Articles
1
Joseph R. Berger, Donita A. Dillon, Byron A. Young, Steven J. Goldstein, Peter Nelson. (2009) Cystinosis of the brain and spinal cord with associated vasculopathy. Journal of the Neurological Sciences 284:1-2, 182-185
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Patricia DeVilliers, Rajesh Gutta, Victor F. Szymela. (2008) Cystinosis, Fanconi syndrome, and odontogenic cysts. Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 106:6, 866-871
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Galina Nesterova, William Gahl. (2008) Nephropathic cystinosis: late complications of a multisystemic disease. Pediatric Nephrology 23:6, 863-878
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Kevin O’Brien, Nadeem Hussain, Bradley A. Warady, David E. Kleiner, Robert Kleta, Isa Bernardini, Theo Heller, William A. Gahl. (2006) Nodular Regenerative Hyperplasia and Severe Portal Hypertension in Cystinosis. Clinical Gastroenterology and Hepatology 4:3, 387-394
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Barbara C. Sonies, Phaedra Almajid, Robert Kleta, Isa Bernardini, William A. Gahl. (2005) Swallowing Dysfunction in 101 Patients with Nephropathic Cystinosis. Medicine 84:3, 137-146
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Gahl, William A., Thoene, Jess G., Schneider, Jerry A., . (2002) Cystinosis. New England Journal of Medicine 347:2, 111-121
Full Text7
Robert Kleta, Yair Anikster, Cynthia Lucero, Vorasuk Shotelersuk, Marjan Huizing, Isa Bernardini, Margaret Park, Jess Thoene, Jerry Schneider, William A. Gahl. (2001) CTNS Mutations in African American Patients with Cystinosis. Molecular Genetics and Metabolism 74:3, 332-337
CrossRef8
William A. Gahl, Ernest M. Kuehl, Fumino Iwata, Anne Lindblad, Muriel I. Kaiser-Kupfer. (2000) Corneal Crystals in Nephropathic Cystinosis: Natural History and Treatment with Cysteamine Eyedrops. Molecular Genetics and Metabolism 71:1-2, 100-120
CrossRef9
YAIR ANIKSTER, CYNTHIA LUCERO, JUANRU GUO, MARJAN HUIZING, VORASUK SHOTELERSUK, ISA BERNARDINI, GERALDINE McDOWELL, FUMINO IWATA, MURIEL I. KAISER-KUPFER, RONALD JAFFE, JESS THOENE, JERRY A. SCHNEIDER, WILLIAM A. GAHL. (2000) Ocular Nonnephropathic Cystinosis: Clinical, Biochemical, and Molecular Correlations. Pediatric Research 47:1, 17
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Vorasuk Shotelersuk, David Larson, Yair Anikster, Geraldine McDowell, Rosemary Lemons, Isa Bernardini, Juanru Guo, Jess Thoene, William A. Gahl. (1998) CTNS Mutations in an American-Based Population of Cystinosis Patients. The American Journal of Human Genetics 63:5, 1352-1362
CrossRef11
M. Broyer, M. J. Tête, G. Guest, J. P. Berthélémé, F. Labrousse, M. Poisson. (1996) Clinical polymorphism of cystinosis encephalopathy. Results of treatment with cysteamine. Journal of Inherited Metabolic Disease 19:1, 65-75
CrossRef12
Lawrence R. Charnas, Carlos A. Luciano, Marinos Dalakas, Roger W. Gilliatt, Isa Bernardini, Kamal Ishak, Valerie A. Cwik, Douglas Fraker, Thomas A. Brushart, William A. Gahl. (1994) Distal vacuolar myopathy in nephropathic cystinosis. Annals of Neurology 35:2, 181-188
CrossRef13
Markello, Thomas C.Bernardini, Isa M.Gahl, William A.. (1993) Improved Renal Function in Children with Cystinosis Treated with Cysteamine. New England Journal of Medicine 328:16, 1157-1162
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Erwin Scharrer, Esther Senn, Siegfried Wolffram. (1992) Stimulation of mucosal uptake of selenium from selenite by some thiols at various sites of rat intestine. Biological Trace Element Research 33:1-3, 109-120
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