Shy-Drager syndrome

We report a 75-year-old Spanish-American woman who received a diagnosis of oculopharyngeal muscular dystrophy after presenting with ptosis and dysphagia. She also complained of snoring and daytime somnolence, and was found to have obstructive sleep apnea (OSA) syndrome attributable to her neuromuscular disorder. This is the first report of OSA syndrome complicating typical, adult-onset oculopharyngeal muscular dystrophy, and should prompt the evaluation of other such patients for sleep-disordered breathing.

Key words: muscular dystrophy; oculopharyngeal; pharynx; sleep; sleep apnea

Abbreviations: CPAP = continuous positive airway pressure; OPMD = oculopharyngeal muscular dystrophy; OSA = obstructive sleep apnea; REM = rapid eye movement

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Oculopharyngeal muscular dystrophy (OPMD) is a rare titan of autosomal-dominant, adult-onset muscular dystrophy with a predilection for pharyngeal and external ophthalmic muscles. (1) Since this disorder can also profoundly affect the upper airway dilator muscles, the prevalence of obstructive sleep apnea (OSA) in this population should be very high. However, only one patient with OSA complicating an unusual case of OPMG has thus far been reported. (2) We present the case report of a patient of Spanish-American descent with straightforward OPMD associated with OSA documented by nocturnal polysomnography.

CASE REPORT

The patient is a 75-year-old, Spanish-American woman who came to medical attention in January of 1998 due to bilateral ptosis, dysphagia for liquids associated with nasal regurgitation dating back 10 years, and hoarseness. She first presented to an ophthalmologic consultant who noted restricted extraocular movements in all directions of gaze and bilateral ptosis. Neurologic consultation confirmed bilateral external ophthalmoplegia without troy other bulbar findings. She had mild girlie weakness with some difficulty arising from chairs. There was a strong family history of OPMD; both her mother mad brother presented with dysphagia. Nerve conduction studies were normal, and repetitive stimulation at 3 Hz of the right posterior tibial and right median nerves were also normal, Results of edrophonium chloride testing were negative. Acetylcholine receptor antibody titer was normal, as was thyroid-stimulating hormone and serum lactate. A swallowing study was normal. Sleep consultation was sought in December of 1998 due to additional complaints of snoring, daytime somnolence (Epworth sleepiness scale (3) score was 14/24), and nocturnal coughing/choking. She endorsed only minimal dyspnea on exertion on presentation, and denied this symptom on subsequent examinations. She had a history of low-back pain, depression, and hypertension. Medications included lisinopril, lansoprazole, and paroxetine. On examination, she was 5 feet tall and 120 lb (body mass index of 23) with obvious ptosis but otherwise normal cranial nerve findings, including normal oropharyngeal appearance and function in the awake state. Nocturnal polysomnography was performed, consisting of EEG (C3/A4, O1/A2), bilateral electrooculograms, submental and anterior tibialis electromyograms, chest and abdominal respiratory effort (piezoelectric bands), nasal/oral airflow (thermocouples), oxyhemoglobin saturation (pulse oximetry), and ECG. Sleep staging was performed using standard criteria (4); apneas were defined as absence of airflow for [greater than or equal to] 10 s, while hypopneas were defined as a [greater than or equal to] 30% decrease in airflow associated with a [greater than or equal to] 4% decrease in oxyhemoglobin saturation or EEG evidence of arousal.

A split-night protocol was followed, with a diagnostic phase lasting 247.5 min and nasal continuous positive airway pressure (CPAP) titration for the remainder of the night. This study demonstrated markedly reduced initial sleep latency of 30 s, and a normal latency to rapid eye movement (RE M) sleep of 112 min. Sleep efficiency was 81.6% (total sleep time was 6 h, 12 min). Sleep architecture was divided as follows: stage 1, 17.7%; stage 2, 65.1%; stage 3, 6.0%; stage 4, 0.0%; stage REM, 11.3%. The apnea-hypopnea index during the diagnostic phase was 37 (apnea index, 2; hypopnea index, 35; toted number of events, 227). The apneas were predominantly obstructive (11 obstructive and 4 central). The respiratory events overall were twice as likely to occur in REM sleep compared to non-REM sleep. Twenty-five desaturations to < 90% were noted. There were only rare periodic limb movements of sleep. During the CPAP titration, she responded well at 8 cm [H.sub.2]O, demonstrating an apnea/ hypopnea index of zero at that pressure, so this was prescribed for her use at home. Serum electrolytes in March 1998 were normal, including carbon dioxide of 28 mmol/L. Arterial blood gas determinations and pulmonary function testing were not performed. Two years later, she was tolerating CPAP well and scored 0 out of 24 points on the Epworth sleepiness scale, indicating complete resolution of her hypersomnolence.

DISCUSSION

OPMD is a rare form of autosomal-dominant, adult-onset muscular dystrophy. Multiple pedigrees have been identified, including French Canadian, French Norman, Italian, English, German, and Japanese. The largest cohort of OPMD patients in the United States has recently been described in individuals of colonial Spanish-American descent in northern New Mexico. (5) This cohort consists of 216 patients from 39 different kindreds, encompassing four generations. Histopathology of striated muscle from patients with OPMD generally demonstrates intranuclear inclusions consisting of tubular filaments, and sometimes rimmed vacuoles. (1,6) A de feet of the polyadenylation binding protein 2 gene on chromosome 14q11, consisting of a (GCG)8-13 triplet-repeat expansion, has been identified in affected individuals. (1,5,7) Symptoms usually begin in the fifth or sixth decade of life, with the hallmark being bilateral, symmetric ptosis. Oropharyngeal dysphagia with pharyngo-oral or pharyngonasal regurgitation occurs in approximately 65% of cases, (8) and external ophthalmoplegia with diplopia, changes in the quality of the voice, and varying amounts of facial, neck, and proximal limb weak ness may develop. The diagnosis is made clinically with supportive evidence from family history, electromyogram, normal creatine kinase, and a negative edrophonium chloride test result, and can be confirmed by muscle biopsy. The differential diagnosis includes myasthenia grams, Lambert-Eaton syndrome, and inflammatory myositis. Symptomatic treatment consists of blepharoplasty for ptosis and cricopharyngeal myotomy for dysphagia.

The pharyngeal muscles are often profoundly affected, (9) raising the question of whether OSA occurs more often in this disorder than in other muscular dystrophies. How ever, only one previous report of OSA in OPMD has appeared, (2) and that patient was atypical in several respects: onset of OPMD was in childhood, there was no family history of neuromuscular disease, and a pharyngeal flap had been performed at age 5 years for nasal speech. Numerous reports are available demonstrating that pharyngeal flap surgery in and of itself is a cause of childhood OSA. (10) In contrast, an unequivocal diagnosis of typical OPMD was made in our patient, and OSA of moderate severity responsive to nasal CPAP was documented. One other report (11) details a patient with OPMD who was unable to maintain upper airway patency following extubation after general endotracheal anesthesia, and presumably represents a more advanced failure of upper airway dilator muscles than in our patient.

The muscles of the upper airway are highly complex in their actions and interactions. Many are known to be responsible for active pharyngeal dilation and maintenance of upper airway patency, (12) thus allowing the pharynx to alter its shape during phonation and swallowing but to function as a rigid conduit for airflow during respiration. OSA is thought to occur when the sleep state is associated with a reduction in the tone of these dilator muscles sufficient to produce a critical degree of upper airway narrowing. Although awake pharyngeal muscle function appeared normal, our patient was not obese and had none of the physical findings (oropharyngeal crowding, retrognathia) that are commonly associated with OSA in nonobese patients. (13) Since normal-appearing awake upper airway function with deterioration during sleep leading to OSA has been reported in other neuromuscular disorders, eg, Shy-Drager syndrome (14) and syringomyelia-syringobulbia, (15,16) pharyngeal dilator muscle dysfunction during sleep attributable to OPMD is strongly suspected in the pathogenesis of this patient's sleep-disordered breathing.

The muscular dystrophies have been associated with both central and obstructive patterns of sleep-disordered breathing. Duchenne and myotonic dystrophies can exhibit either mechanism, while limb-girdle dystrophies display a predominantly central mechanism. (17) Diaphragmatic involvement by muscular dystrophy is presumed to result in the central pattern, while upper airway dilator muscle involvement is thought to result in obstructive events. In contrast, only one report (2) of ventilatory muscle failure in OPMD exists, and that occurred in a highly atypical, juvenile-onset ease. Dysphagia leading to recur rent aspiration and pneumonia may occur in up to 25% of patients with OPMD, (8) but should not result in either central or obstructive sleep-disordered breathing.

This report represents the second reported case of OSA complicating OPMD, and the only report of this disorder in typical, adult-onset OPMD. Further epidemiologic investigation of the prevalence of OSA in this population is warranted.

* From the Division of Pulmonary, Allergy, and Critical Care (Dr. Dedrick) University of New Mexico School of Medicine; and the New Mexico Center for Sleep Medicine (Dr. Brown), Lovelace Sandia Health System, Albuquerque, NM.

Originally presented at the 14th Annual Meeting, Associated Professional Sleep Societies, Las Vegas, NV, June 17 to 22, 2000.

REFERENCES

(1) Brais B. Rouleau GA, Bouchard JP, et al. Oculopharyngeal muscular dystrophy. Semin Neurol 1999; 19:59-66

(2) Lacomis D, Kupsky WJ, Kuban KK, et al. Childhood onset oculopharyngeal muscular dystrophy. Pediatr Neurol 1991; 7:382-384

(3) Johns MW. A new method for measuring daytime sleepiness: the Epworth sleepiness scale. Sleep 1991; 14:540-545

(4) Rechtschaffen A, Kales A. A manual of standardized terminology, techniques and scoring system for sleep stages of human subjects. Los Angeles, CA: Brain Information Service/ Brain Research Institute, 1968

(5) Becher MW, Morrison L, Davis LE, et al. Oculopharyngeal muscular dystrophy in Hispanic New Mexicans, JAMA 2001; 286:2437-2440

(6) Tome FM, Chateau D, Helbling-Leclerc A, et al. Morphological changes in muscle fibers in oculopharyngeal muscular dystrophy. Neuromusc Dis 1997; 7:S63-S69

(7) Hill ME, Creed GA, McMullan TF, et al. Oculopharyngeal muscular dystrophy: phenotypic and genotypic studies in a UK population. Brain 2001; 124:522-526

(8) Duranceau AC, Beauchamp G, Jamieson GG, et al. Oropharyngeal dysphagia and oculopharyngeal muscular dystrophy. Surg Clin North Am 1983; 63:825-832

(9) Weitzner S, Changes in pharyngeal and esophageal musculature in oculopharyngeal muscular dystrophy. Am J Dig Dis 1969; 14:805-810

(10) Ysunza A, Garcia-Velasco M, Garcia-Garcia M, et al. Obstructive sleep apnea secondary to surgery for velopharyngeal insufficieney. Cleft Palate Craniofac J 1993; 30:387-390

(11) Christopher K, Horkan C, Patterson RB et al. Oculopharyngeal muscular dystrophy complication airway management. Chest 2001; 120:2101-2103

(12) Horner RL. Motor control of the pharyngeal musculature and implications for the pathogenesis of obstructive sleep apnea. Sleep 1996; 19:827-853

(13) Strohl KP, Redline S. Recognition of obstructive sleep apnea. Am J Respir Crit Care Med 1996; 154:279-289

(14) Williams A. Hanson D, Calne DB. Vocal cord paralysis in the Shy-Drager syndrome. J Neurol Neurosurg Psychiatry 1979; 42:151-153

(15) Brown LK, Stacy C, Schick A, et al. Obstructive sleep apnea in syringomyelia-syringobulbia. N Y State J Med 1988; 88:152-154

(16) Haponik EF, Givens D, Angelo J. Syringobulbia-myelia with obstructive sleep apnea, Neurology 1983; 33:1046-1049

(17) Brown LK. Sleep-disordered breathing in neurologic disease. Clin Pulm Med 1996; 3:22-35

Manuscript received May 15, 2003; revision accepted July 21, 2003.

Reproduction of this article is prohibited without written permission from the American College of Chest Physicians (e-mail: permissions@chestnet.org).

Correspondence to: Lee K. Brown, MD, FCCP, Professor of Medicine and Pediatrics. University of New Mexico School of Medicine, 1101 Medical Arts Ave NE, Building 2, Albuquerque, NM 87109; e-mail: lkbrown@alum.mit.edu

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