Enuresis and Obstructive Sleep Apnea in Adults

23 Gardne r ID. Suppression of antibacterial immunity by infection with influenza virus. J Infect Dis 1981; 144:225-31 24 Walsh TJ, Hiemenz J'V, Seibel N, et al. Amphotericin B lipid complex in the treatment of 228 cases of invasive mycosis. Abstract. In: Program and abstracts of th e 34th Interscience Conference on Antimicrobial Agents and Chemotherapy (Orlando, FL). Washington, DC: Ameri can Society for Microbiology, 1994 25 Petrikkos G, Sambatakou H, Korantzis J, et al. Amphotericin B lipid complex for the management of systemic mycosis in patients with nephrotoxicity and/or failure of previous antifungal treatment. Abstract 089. In: The 13th Congress of the International Society for Human and Animal Mycology, Parma, Italy, 1997 26 Kitahara M, Seth VK, Medoff G, et al. Activity of amphotericin B, 5-fluorocytosine, and rifampin against six clinical isolates of aspergillus. Antimicrob Agents Chemother 1976; 9:915 27 Lauer BA, Reller LB, Schroter GPJ. Susceptibility of aspergillus to 5-fluorocytosine and amphotericin B alone and in combination. J Antimicrob Chemother 1978; 4:37.5 28 Hughes CE, Harris C, Moody JA, e t al. In vitro activities of amphotericin B in combination with four antifungal agents and rifamp in against Aspergillus spp. Antimicrob Agents Chemother 1984; 25:560 29 Arroyo J, Medoff G, Kobayashi GS. The rapy of murine aspergi llosis with amphotericin B in co mbin ation with rifampin or 5-fluorocytosin e. Antimicrob Ag Chemother 1977; 11:21 30 Polak A. Pharmacokinetics of amphotericin Band flucytosin e. Postgrad Med J 1979; 55:667 31 Carrizosa J, Levinson ME , Lawrence T, e t al. Cure of Aspergillus ustus endocarditis on a prosthetic valve. Arch Intern Med 1974; 133:486 32 D enning DW, Stevens DA. Antifungal and surgical treatment of invasive aspergillosis: review of 2,121 published cases. Rev Infect Dis 1990; 12:1147-1201 33 De nning DW, Tucker RM , Hanson LH , e t la. Treatment of invasive aspergillosis with itraconazole. Am J M ed 1989; 86:791-800 34 Denning DW, Lee JY, Hostetler JS, et al. NIAID mycoses study group multicenter trial of oral itraconazole therapy for invasive aspergillosis. Am J Med 1994; 97:135-44 35 Sugar AM. Use of amphotericin B with azole antifungal drugs: what are we doing? Antimicrob Agents Chemother 1995; 39:1907-12 36 Denning DW, del Favero A, Gluckman E, et al. The efficacy and tolerability of UK 109,496 (vori conazole) in th e treatment of invasive aspergillosis (lA). Abstract P552. The 13th Congress of the International Society for Human and Animal Mycology, Parma, Italy, 1997 37 Caillot D, Casasnovas 0 , Bern ard A, et al. Improved management of invasive pulmonary aspergillosis in neutropenic patients using early thoracic computed tomographic scan and surgery. J Clin Oncol 1997; 15:139-47 38 Roilides E, Holmes A, Blake C, et al. Antifungal activity of elutriated human monocytes against Aspergillus fumigatus hyphae: enhancement by granulocyte-macrophage colony stimulating factor and interferon-gamma. J Infect Dis 1994; 170:894-99 39 Roilides E, Uhlig K, Venzon D, et la. Enhancement of oxidative response and damage caused b yhuman neutrophils to Aspergillus fumigatus hyphae by granulocyte colony stimulating factor and gamma-intetferon. Infect Immun 1993; 61:1185-93 40 Neumunaitis J, Meyers JD, Buckner CD, et al. Phase I trial of recombinant human macrophage colony stimulating factor in 634

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patients with invasive fungal infections. Blood 1991; 78: 907-13 Bernhisel-Broadbent J, Camargo EE , Jaffe HS. Recombinant human interferon-gamma as adjunct th erapy for Aspergillus infection in a patient with chronic granulomatous disease. J Infect Dis 1991; 163:808-11 Clancy CJ, Diaz LE, Nguyen MH. Invasive aspergillus sinusitis in normal hosts: values of adjunctive the rapy with interfe ron a. 34th Conference of th e Infectious Disease Society of America, New Orleans, LA, 1996 Schaffner A , Douglas H, Braude A. Selective protection against conidia by mononuclear and against mycelia by polymorphnuclear phagocytes in resistance to Aspe rgillus: observations of these two lines of defense in vivo and in vitro with human and mouse phagocytes. J Clin Invest 1982; 69:617-31 Chusid MJ, Sohnle PG, Fink JN , et !a. A genetic defect of granulocyte metabolism in a man \vith disseminated aspegillosis . J Lab Clin Med 1981; 97:730-38

Enuresis and Obstructive Sleep Apnea in Adults* Naomi R. Kramer, MD; Alice E. Bonitati, MD, FCCP; and Richa·rd P. Millman, MD, FCCP

Adult enuresis is an unusual symptom of obstructive sleep apnea (OSA). Although it is described as a classic symptom of childhood OSA, enuresis is encountered infrequently in adult sleep medicine. Five adults with enuresis associated with sleep apnea presented to our Sleep Disorders Center. In all five cases, the onset of enuresis was associated with the progression of sleep apnea symptoms. In each case, the enuresis resolved with treatment with nasal continuous positive airway pressure. Current medical literature on the postulated mechanisms of nocturia and enuresis in sleep apnea is reviewed. Based on the experience of the authors and review of the medical literature, one may conclude that severe OSA may lead to new-onset enuresis in adults and that effective treatment of OSA is associated with resolution of enuresis. (CHEST 1998; 114:634-637) Key words: adults; enuresis; obstructive sleep apnea Abbreviations: ANP=atrial naturetic peptide; CPAP=continuous positive aitway pressure; OSA=obstructive sleep apnea

*From the Division of Pulmonary, Sleep, and Critical Care Medicine, Rhode Island Hospital and Brown University School of Medicine, Providence, RI. Manuscript received July 17, 1997; revision accepted December 26, 1997. Correspondence to: Naomi R. Kramer, MD, Sleep Disorders Center, Rhode Island Hospital, 593 Eddy Street, Providence, RI 02903 Selected Reports

Adult enuresis is an unusual symptom of obstructive sleep apnea (OSA). Although it is desc1ibed as a classic symptom of childhood OSA,1· 5 enuresis is encountered infrequently in the clinical practice of adult sleep medicine. Five adults with enuresis associated with sleep apnea presented to the Sleep Disorders Center during 1 year. The purpose of this study is to review the key clinical features and polysomnogram data of these patients in order to better define who is likely to develop this troubling symptom. CASE SERIES Clinical Data All five patients were referred for evaluation of snoring with witnessed apneas and excessive sleepiness. All five patients were male. The mean age at time of presentation was 38::!::9 years. All the patien ts wereobese, with mean(::!:: SEM) body mass index of 38.6::!::2.1 kg/m 2 and neck size of 17.5::!::0.3 em. Comorbid illnesses included hypertensi on (2 patients), moderate COPD (FEY 1 of 1.69 in 1 patient), mode rate alcohol use (3 to 6 alcoholic beverages per night in 2 patie nts), and diabetes mellitus (1 patient). No patients were taking diuretics. Caffeine use was quite extensive in most patients and ranged from 16 oz of soda to 32 oz of coffee plus 12 oz of soda per day. However, no patient used caffeine in the evenin g after dinner. Although all of these patients snored for many years, there had gn ificant increase in snoring, witnessed apnea, and been a si sleepiness associated "vith weight gain in the months prior to presentation. In all five patien ts, en uresis developed during this time period of progressive sleep apnea symptoms. Only one of these patien ts had a prior history of enuresis. The enuresis had previously resolved at age 19 and then recurred at age 29 when he developed symptoms of sleep apnea. In one other patient, enuresis occurred transiently 1 eyar prior to presentation and th en recurred in the 2 to 3 months prior to presentation. He experienced multiple episodes per night requiring three to five changes of underwear pe r night and the use of plastic sheets. In contrast, 2 other patients each experienced only 4 pe isodes of enuresis occurring over 4 to 5months of increasing snoring and sleep apnea symptoms prior to prese ntation . In the fifth patient, the enuresis occurred intermittently. H e would expe rience enuresis on a nightly basis for three to four nights and then it would abate for seve ral nights. This patient also started sle ep walking (not in association with enuresis per se), which be had not don e in childhood. The patient with the most severe enuresis (multiple episodes per night) did not have a higher apnea!hypopnea index, lower oxygen s aturation, or longer duration of respiratory events. He did, however, have the highest body mass index.

Testing In the laborat01y, split-night polysomnograms were recorded for all five patients. Monitoring was accomplished using two EEG leads, two electro-oculogram leads, asubmental electromyogram , a snoring microphone, an airflow thermistor, c hest and abdominal Piezo electrode bands, pulse oximetry, an ECG, and bilate ral anterior tibialis e el ctromyogram. All 5 patients had severe sleep apnea during a baseline pe riod of a minimum 2 h of sleep. The apnea/hypop nea index was 107.4::!::7.7 (mean::!::SEM ) events per hour of sleep with a nadir 0 2 saturation of75.2::!::2.7%. The apnea duration ranged from 10 to 45 s. The mean duration of the longest event of each record was 35 s. Mean sle ep efficiency was 84%, with a range of 60 to 98% during the baseline portion of the record. In three of the five studies, rapid eye movement sleep was not seen during the baseline portion of the record; thus, the degree of sleep apnea may have been underestimated in these patients. Nasal continuous positive airway press ure (CPAP) was titrated during the second half of the study. The optimal pressure ranged from 12.5 to 20 em H 2 0. The apnea!hypopnea index at the optimal CPAP pressure was 10.6 ::!::2.7 with a nadir 0 2 saturation of 91.2::!::1.2% (Table 1). Results of Treatment The pati ents were seen 1 to 2 weeks after th e sleep study and nasal CPAP was started at home. They were again seen for follow-up exa mination in l to 4 months. All the patients reported complete resolution of snoring, daytime sleepiness, and enuresis with use of CPAP. DISCUSSION

To date, the re are a maximum of 17 cases of enuresis associated with sleep apnea reported in aduJts s-u The early reports of e nuresis are included in several general reviews and case series about sleep apnea from the same institution. The refore, it is possible that some patients may have been included in more than one report. It is not clear, however, who expe riences enuresis and why. This study presents five men with OSA and enuresis who presented to the sleep center over a pe riod of 12 months . During the closest calendar year, 1,561 polysomnograms were recorded . Of these, 775 studies were initial studies establishing a diagnosis of OSA in an adult patient. Although a positive history of e nuresis unrelated to othe r medical disorders was documented in only five patients, th e absence of this symptom was not always documented in other patients. Therefore, the true incidence of this symptom cannot

Table !-Clinical Features of Enuresis and Obstructive Sleep Apnea Age

BMI, kglm2

AHI, Baseline

Nadir 0 2 %, Baseline

AHI With CPAP*

Nadir 0 2 %, With CPAP*

46 29 35 42 33 37.0::!::3. 1

46.7 35.2 36.9 38.5 35.7 38.6 ::!:: 2.1

80 109 ll7 105 126 107.4::!::7.7

82 74 74 66 70 73.2::!::2.7

lO

92 89 93 88 94 91.2::!:: 1.2

10 2 19 12 10.6::!::2.7

*p<0.005 compared to baseline. Data is expressed as Mean::!::SEM . BMI = body mass index; AHI =apnea!hypopnea index. CHEST I 114 I 2 I AUGUST, 1998

635

be established. However, it is clearly an infrequently offered complaint The patients were all obese with very severe disease. The enuresis developed in conjunction with weight gain and worsening symptoms of OSA. The onset of enuresis with the onset of sleep apnea symptoms and the resolution of enuresis with CPAP treatment of OSA suggests that the sleep apnea may be the cause of the enuresis in these patients. The mechanism of enuresis in patients with sleep apnea is probably multifactorial. Patients with massive obesity have an increased glomerular filtration rate.l 2 Krieger et aJl 3 demonstrated higher fractional urinary flows , higher fractional sodium and chloride excretion, and a lower percentage of filtered sodium reabsorption in patients with sleep apnea compared with those values in normal subjects. Treatment with nasal CPAP tended to normalize the renal function in the patients with OSA. Furthermore, the use of CP AP was associated with reduced urina1y output and increased Na + resorption. Although this study is limited because patients and normal subjects were not age- and weight-matched, other research has shown similar results. 14 - 16 Subsequent articles by these and other authors suggest a role for atrial naturetic peptide (ANP) in these changes in re nal function 15 - 20 Negative intrathoracic press ure swings associated with respiratory effort against a closed airway are associated with increased venous return. In addition, the hypoxia associated with an apneic event may induce pulmonary vasoconstriction , which can cause right ventricular overload and right atrial distention. The subsequent atrial dilatation may lead to ANP release , and this increase in ANP levels enhances urinary excretion. In support of this , the work by Krieger and his colleagues 17 suggested that the ANP levels correlated with the degree of hypoxemia as well as the degree of negative intrathoracic pressure associated with apneas. Although several articles have demonstrated increased ANP levels in patients with sleep apnea and a decrease in ANP levels with treatment with nasal CPAP, 16-IH not all studies have been consistent in their findings. In a study by Warley et al, 21 ANP levels were not elevated in normal subjects when OSA was simulated in normal subjects with an inspiratory threshold load. The degree of negative inspiratory pressure swings and the degree of hypoxemia were not as severe as those seen in actual patients with OSA in the other studies. Rodenstein et al 22 found changes in diuresis and natriuresis in patients with sleep apnea before and after treatment, similar to those documented by other authors. However, they were not able to demonstrate a change in ANP levels with CPAP. Some of their patients did have left ventricular dysfunction , which can raise ANP levels. This rise in ANP would not be expected necessarily to improve with CPAP. In addition, the blood samples these authors collected were peripheral venous samples drawn in the morning, after the patients were awake. Although Krieger et al 18 found a trend towards lower ANP levels in OSA patients receiving CPAP treatment, the difference in ANP level before and after CP AP therapy only reached statistical signif636

icance when pulmona1y artery samples rather than peripheral venous samples were analyzed. ANP levels are higher in the pulmonary artery than in peripheral venous blood even in normal subjects. In addition, ANP has a very short half-life (2 to 3 min). Therefore, some discrepancy in results between studies may reflect time and site of ANP sampling. Typically, patients with sleep apnea complain of frequent awakenings to urinate. 23 ·24 The fact that a small subset of patients do not fully awaken to urinate, but rather have enuresis, suggests that there may be something abnormal with their arousal response . Perhaps the inordinately high number of arousals that these patients experienced may have blunted their ability to fully wake up. Data from Berry et al 25 suggest that OSA itself (perhaps due to sleep fragmentation) decreases the arousal response to airway occlusion. The apnea duration in patients in this study was not as long as that seen by Berry et aJ.2s (Berry et a! found apnea duration increased as arousal threshold increased.) However, this study did not measure esophageal pressure swings or responses to other stimuli, so data on arousal threshold per se cannot be provided. To dete rmine if an altered arousal threshold is really the key factor in causing enuresis rather than nocturia, a prospective study examining the duration of apnea, changes in esophageal pressure, and arousal response to other stimuli, among other variables, is necessary. It has been shown, however, that sleep fragmentation alone (not associated with respiratory disturbance) impairs the arousal response to acoustic and respiratory stimuli in humans and animals. 26 ·27 The patients presented in this study all had very severe OSA with frequent arousals. In summary, severe OSA may lead to new-onset enuresis in adults. The enuresis resolves with successful treatment of the sleep apnea. Further research in human subjects is necessary to fully elucidate the pathophysiologic features of this disorder.

REFERENCES 1 Guilleminault C, Eldridge FL, Simmons FB, et al. Sleep apnea in eight children. Pediatrics 1976; 58:23-30 2 Weider DJ, Sateia MJ, West RP. Nocturnal enuresis in children with upper airway obshuction. Otolaryngol Head Neck Surg 1991; 10.5:427-32 3 Weider DJ, Hauri PJ. Nocturnal enuresis in children with upper ai1way obstruction. Int J Pediatr Otorhinolaryngol 1985; 9:173-82 4 Timms DJ. Rapid maxillary expansion in the treatment of nocturnal enuresis. Angle Orthod 1990; 60:229-33 5 Guilleminault C, Dement WC. Sleep apnea syndromes and related sleep disorders. In: Guilleminault C, Dement WC, eds. Sleep disorders: diagnosis and treatment. New York: John Wiley & Sons, 1978: 9-28 6 Everae1i K, Pevemagie D, Oosterlinck W. Nocturnal enuresis provoked by an obstructive sleep apnea syndrome. J Urol 1995; 153:1236 7 Guilleminault C, Eldridge FL, Tilkian A, et al. Sleep apnea syndrome due to upper airway obstruction. Arch Intern Med 1977; 137:296-300 8 Yokoyama 0 , Amano T, Lee S, et al. Enuresis in an adult Selected Reports

female with obstructive sleep apnea. Urology 1995; 45:150-54 9 Ulfberg J, Thuman R. A non-urologic cause of nocturia and enuresis-obstructive sleep apnea syndrome (OSAS). Scand J Ural Nephrol 1996; 30:135-37 10 Arai H, Furuta H, Koshino Y, et a!. Long-term effects of a dental appliance therapy: a case of obstructive sleep apnea syndrome with enuresis. Sleep 1997; 20:158-59 11 Guilleminault C, Tilkian A, Dement WC. The sleep apnea syndrome. Ann Rev Med 1976; 2:465-84 12 Fletcher EC. Obstructive sleep apnea and the kidney. J Am Soc Nephrol 1993; 4:1111-21 13 Krieger J, Imbs J, Schmidt M, et a!. Renal function in patients with obstructive sleep apnea: effects of nasal continuous positive airway pressure. Arch Intern Med 1988; 148:1337-40 14 Follenius M, Krieger J, Krauth MO, et a!. Obstructive sleep apnea treatment: peripheral and central effects on plasma renin activity and aldosterone. Sleep 1991; 14:211-17 15 Krieger J, Schmidt M, Sforza E, et a!. Urinary excretion of guanosine 3' :5' -cyclic monophosphate during sleep in obstructive sleep apnea patients with and without nasal continuous positive airway pressure treatment. Clin Sci 1989; 76:31-37 16 Warley ARH, Stradling JR. Abnormal diurnal vmiation in salt and water excretion in patients with obstructive sleep apnoea. Clin Sci 1988; 74:183-85 17 Krieger J, Follenius M, Sforza E, et a!. Effects of treatment with nasal continuous positive airway pressure on atrial natriuretic peptide and arginine vasopressin release during sleep in patients with obstructive sleep apnoea. Clin Sci 1991; 80:443-49 18 Krieger J, Laks L, Wilcox I, et a!. Atrial nattiuretic peptide release during sleep in patients with obstructive sleep apnoea before and during treatment with nasal continuous positive airway pressure. Clin Sci 1989; 77:407-11 19 Ichioka M, Hirata Y, Inase N, eta!. Changes of circulating atrial natriuretic peptide and antidiuretic hormone in obstructive sleep apnea syndrome. Respiration 1992; 59: 164-68 20 Lin C, Tsan K, Lin C. Plasma levels of atrial natriuretic factor in moderate to severe obstructive sleep apnea syndrome. Sleep 1993; 16:37-39 21 Warley ARH, Fontes F, Wilson M, eta!. Lack of effect of an inspiratory threshold load on plasma atrial natriuretic peptide levels. Clin Sci 1990; 78:311-13 22 Rodenstein DO, D'Odemont JR, Pieters T, eta!. Diurnal and nocturnal diuresis and natriuresis in obstructive sleep apnea: effects of nasal continuous positive airway pressure therapy. Am Rev Respir Dis 1992; 145:1367-71 23 Pressman MR, Figueroa WG, Kendrick-Mohamed J, et a!. Nocturia: a rarely recognized symptom of sleep apnea and other occult sleep disorders. Arch Intern Med 1996; 156: 5445-50 24 Krieger J, Petiau C, Sforza E, eta!. Nocturnal pollakiuria is a symptom of obstructive sleep apnea. Ural Int 1993; 50:93-97 25 Berry RB, Kouchi KG, Der DE, eta!. Sleep apnea impairs the arousal response to airway occlusion. Chest 1996; 109: 1490-96 26 Downey B, Bonnet MH. Performance during frequent sleep disruption. Sleep 1987; 10:354-63 27 Phillipson EA, Bowes G, Sullivan CE, et al. The influence of sleep fragmentation on arousal and ventilatory responses to respiratory stimuli. Sleep 1980; 3:281-88

Migration and Right Atrial Perforation of an Accufix Atrial Lead Retention Wire Following Partial Lead Removal During Myomectomy* Edward P. Gerstenfeld, MD; Yogarajah Balarajan, MD; Robert Cooke, PAC; and Robert S. Mittleman, MD

A 36-year-old man with a history of hypertrophic obstructive cardiomyopathy presented to the emergency room with "stabbing" chest pain. He had undergone dual-chamber pacemaker implantation in 1993 using an atrial lead (Accuflx; Telectronics; Englewood, Colo) and a myomectomy in 1996 during which the distal portion of the atrial lead was removed. Digital fluoroscopy revealed that the retention wire had migrated out of the remaining atrial lead and perforated the right atrium. The retention wire was successfully removed percutaneously. The need for complete removal of the retention wire in the Accuflx lead at the time of open-heart surgery is emphasized. (CHEST 1998; 114:637-639) Key words: atrial lead; hypertrophic obstructive cardiomyopathy; lead extraction; pacemaker

A patient who had implantation of a dual chamber

pacemaker experienced "stabbing" pain that resulted from migration of the retention wire out of the atrial lead and perforation of the right atrium. This report recounts the clinical data pertinent to the patient.

CASE REPORT

A 36-year-old man with a history of hypertrophic obstructive cardiomyopathy presented to the emergency department complaining of severe, pleuritic chest pain radiating to his back. A diagnosis of hypertrophic obstructive cardiomyopathy had been made when the patient was a child. Because of symptoms of exertional dyspnea and chest pain refractory to medical therapy, he underwent implantation of a dual-chamber pacemaker in 1993 with the use of an atrial lead (Accufix; Telectronics; Englewood, CO). The atrial lead is now known to be susceptible to fracture of the retention wire, leading to cardiac perforation or embolization (J. W. Dennis; Telectronics; written communication; November 3, 1994). His symptoms persisted, and he was referred to an outside institution where he underwent a myomectomy in 1996. At the time of surgery, the atrial lead was cut at the junction of the superior vena cava and right atrium as recommended, with the intention of removing the retention wire. The rest of the lead was *From the Section of Cardiac Electrophysiology and Pacing, Division of Cardiology, Department of Medicine, University of Massachusetts Medical Center, \Vorcester. Manuscript received November 21, 1997; accepted December 17, 1997. Correspondence to: Edward Gerstenfeld, MD, UMMC, Division of Cardiology, 55 Lake Avenue North, Worcester, MA 01655 CHEST I 114 I 2 I AUGUST, 1998

637