23 Gardner ID.

Suppression of antibacterial immunity by infec

tion with influenza virus. J Infect Dis 1981; 144:225-31
24 Walsh TJ, Hiemenz JW, Seibel N, et al. Amphotericin B lipid
complex in the treatment of 228 cases of invasive mycosis.
Abstract. In: Program and abstracts of the 34th Interscience

Conference

on

Antimicrobial

(Orlando, FL). Washington,

crobiology,

Agents

and

DC: American

1994

Chemotherapy

Society for Mi

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

anti

fungal 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 amphoter
icin 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 as
pergillus to 5-fluorocytosine and amphotericin B alone and in
combination. J Antimicrob Chemother 1978; 4:375
28 Hughes CE, Harris C, Moody JA, et al. In vitro activities of
amphotericin B in combination with four antifungal agents
and rifampin against Aspergillus spp. Antimicrob Agents
Chemother 1984; 25:560
29 Arroyo J, Medoff G, Kobayashi GS. Therapy of murine
aspergillosis with amphotericin B in combination with ri
or 5-fluorocytosine. Antimicrob Ag Chemother 1977;
fampin
11:21
30 Polak A. Pharmacokinetics of amphotericin B and flucytosine.
Postgrad Med J 1979; 55:667
31 Carrizosa J, Levinson ME, Lawrence T, et al. Cure of
Aspergillus ustus endocarditis on a prosthetic valve. Arch
Intern Med 1974; 133:486
32 Denning DW, Stevens DA. Antifungal and surgical treatment
of invasive aspergillosis: review of 2,121 published cases. Rev
Infect Dis 1990; 12:1147-1201

Denning DW, Tucker RM, Hanson LH, et al. Treatment of

invasive aspergillosis with itraconazole. Am J Med 1989;
86:791-800
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
Sugar AM. Use of amphotericin B with azole antifungal
drugs: what are we doing? Antimicrob Agents Chemother
1995; 39:1907-12
Denning DW, del Favero A, Gluckman E, et al. The efficacy

33

34

35
36

and tolerability of UK 109,496 (voriconazole) in the treatment

of invasive aspergillosis (IA). Abstract P552. The 13th Con
gress of the International Society for Human and Animal

Mycology, Parma, Italy, 1997

37 Caillot D, Casasnovas O, Bernard A, et al. Improved man
agement 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 al. Enhancement of
oxidative response and damage caused by human neutrophils
to Aspergillus fumigatus hyphae by granulocyte colony stim
factor and
Infect Immun
ulating

40

1993;
gamma-interferon.
61:1185-93
Neumunaitis J, Meyers JD, Buckner CD, et al. Phase I trial of
recombinant human macrophage colony stimulating factor in

patients with

invasive

907-13

fungal

infections. Blood 1991; 78:

41 Bernhisel-Broadbent J,

42

Camargo EE, Jaffe HS. Recombinant

human interferon-gamma as adjunct therapy for Aspergillus
infection in a patient with chronic granulomatous disease.
J Infect Dis 1991; 163:808-11

Clancy CJ, Diaz LE, Nguyen MH. Invasive

itis in normal hosts: values of adjunctive

aspergillus sinus
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feron a. 34th Conference of the Infectious Disease Society of

America, New Orleans, LA, 1996
43 Schaffner A, Douglas H, Braude A. Selective protection

against conidia by mononuclear and against mycelia by

polymorphnuclear phagocytes in resistance to Aspergillus:
observations of these two lines of defense in vivo and in vitro
with human and mouse phagocytes. J Clin Invest 1982;
69:617-31

44 Chusid

MJ, Sohnle PG, Fink JN, et al. A genetic defect of

granulocyte metabolism in a man with disseminated aspegillosis. J Lab Clin Med 1981; 97:730-38

Enuresis and Obstructive

Apnea in Adults*
Naomi R. Kramer, MD; Alice E. Bonitati,
Richard P. Millman, MD, FCCP

Sleep

MD, FCCP; and

Adult enuresis is an unusual symptom of obstructive

sleep apnea (OSA). Although it is described as a
classic symptom of childhood OSA, enuresis is en
countered 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 con
tinuous 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 airway 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, RL

Manuscript received July 17, 1997; revision accepted December

to: Naomi R. Kramer, MD, Sleep Disorders
Correspondence
Center, Rhode Island Hospital, 593 Eddy Street, Providence, Rl
02903
26, 1997.

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Selected

Reports

A dult enuresis is an unusual symptom of obstructive

-^*- sleep apnea (OSA). Although it is described as a classic
symptom of childhood OSA,15 enuresis is encountered

of adult sleep medi

infrequently in the clinical practice
cine. Five adults with enuresis associated with sleep apnea
to the Sleep Disorders Center during 1 year.
presented
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 patients were obese, with mean ( SEM) body mass index of
38.62.1 kg/m2 and neck size of 17.50.3 cm. Comorbid
illnesses included hypertension (2 patients), moderate COPD
(FEVjl of 1.69 in 1 patient), moderate alcohol use (3 to 6 alcoholic
and diabetes mellitus (1
beveragesNoper night inwere2 patients),diuretics.
Caffeine use was
taking
patient). patients
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 evening after dinner.
Although all of these patients snored for many years, there had
been a significant increase in snoring, witnessed apnea, and
sleepiness associated with weight gain in the months prior to
presentation. In all five patients, enuresis developed during this
time period of progressive sleep apnea symptoms. Only one of
these patients 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 year prior to presentation and
then recurred in the 2 to 3 months prior to presentation. He
to five
multiple episodes per night requiring threesheets.
experienced
In
changes of underwear per night and the use of plastic
contrast, 2 other patients each experienced only 4 episodes of
enuresis occurring over 4 to 5 months of increasing snoring and
sleep apnea symptoms prior to presentation. In the fifth patient,
the enuresis occurred intermittently. He would experience en
uresis on a nightly basis for three to four nights and then it would
abate for several nights. This patient also started sleep walking
(not in association with enuresis per se), which he had not done
in childhood. The patient with the most severe enuresis (multiple
episodes per night) did not have a higher apnea/hypopnea index,
lower oxygen saturation, or longer duration of respiratory events.
He did, however, have the highest body mass index.

Table 1.Clinical Features

Age

kg/m2

AHI,
Baseline

46
29
35
42
33
37.03.1

46.7
35.2
36.9
38.5
35.7
38.62.1

80
109
117
105
126
107.47.7

BMI,

Testing
In the laboratory, split-night polysomnograms were recorded
for all five patients. Monitoring was accomplished using two EEG
leads, two electro-oculogram leads, a submental electromyogram,
a snoring microphone, an airflow thermistor, chest and abdomi
nal Piezo electrode bands, pulse oximetry, an ECG, and bilateral
anterior tibialis electromyogram. All 5 patients had severe sleep
apnea during a baseline period of a minimum 2 h of sleep. The
events per
apnea/hypopnea index was 107.47.7 (meanSEM)
hour of sleep with a nadir 02 saturation of 75.22.7%. The apnea
duration ranged from 10 to 45 s. The mean duration of the
longest event of each record was 35 s. Mean sleep efficiencyofwas
84%, with a range of 60 to 98% during the baseline portion 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 pressure (CPAP) was
titrated during the second half of the study. The optimal pressure
ranged from 12.5 to 20 cm H20. The apnea/hypopnea index at
the optimal CPAP pressure was 10.62.7 with a nadir 02
saturation of 91.21.2% (Table 1).

Results of Treatment
The patients were seen 1 to 2 weeks after the sleep study and
nasal CPAP was started at home. They were again seen for
reported
follow-up examination in 1 to 4 months. All the patients
complete resolution of snoring, daytime sleepiness, and enuresis
with use of CPAP.

DISCUSSION
To date, there are a maximum of 17 cases of enuresis
associated with sleep apnea reported in adults.511 The
general
early reports of enuresis are included in severalfrom
the
reviews and case series about sleep apnea
same institution. Therefore, it is possible that some
patients may have been included in more than one
report. It is not clear, however, who experiences enure
sis and why. This study presents five men with OSA and
enuresis who presented to the sleep center over a
the closest calendar year,
period of 12 months. During
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
enuresis unrelated to other medical disorders was doc
umented in only five patients, the absence of this
symptom was not always documented in other patients.
Therefore, the true incidence of this symptom cannot

of Enuresis and Obstructive Sleep Apnea

Nadir 02 %,
Baseline

AHI With

CPAP*

Nadir 02 %,
With CPAP*

82
74
74
66
70

10
10
2
19
12

92
89
93
88
94

73.22.7

10.62.7

91.21.2

*p<0.005 compared to baseline. Data is expressed as MeanSEM. BMI=body mass index; AHI=apnea/hypopnea index
CHEST/114/2/AUGUST, 1998

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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 symp
toms and the resolution of enuresis with CPAP treat
ment 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.12 Krieger et
al13 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 CPAP was associated with reduced urinaiy
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 sim
ilar results.1416
articles by these and other authors sug
Subsequent
a
role
for
atrial naturetic peptide (ANP) in these
gest
in
renal
function.1520 Negative intrathoracic
changes
pressure 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 colleagues17 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 in
creased ANP levels in patients with sleep apnea and a
decrease in ANP levels with treatment with nasal
CPAP,1618 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 simu
lated 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.
Bodenstein et al22 found changes in diuresis and natriuresis in patients with sleep apnea before and after
treatment, similar to those documented by other au
thors. 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 al18 found a trend
towards lower ANP levels in OSA patients receiving
CPAP treatment, the difference in ANP level before
and after CPAP therapy only reached statistical signif

pulmonary artery samples rather than

peripheral
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. Per
haps the inordinately high number of arousals that these
patients experienced may have blunted their ability to
fully wake up. Data from Berry et al25 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 al.25 (Berry et al 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 determine if an altered
arousal threshold is really the key factor in causing
enuresis rather than nocturia, a prospective study ex
amining the duration of apnea, changes in esophageal
and arousal
to other
icance when

venous

stimuli, among
pressure,
response
other variables, is necessary. It has been shown, how
ever, that sleep fragmentation alone (not associated
with respiratory disturbance) impairs the arousal re
sponse 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 enure
sis in adults. The enuresis resolves with successful treat
ment of the sleep apnea. Further research in human
subjects is necessary to fully elucidate the pathophysio
logic features of this disorder.
1

References
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 obstruction. Otolaryngol Head
Neck Surg 1991; 105:427-32
3 Weider DJ, Hauri PJ. Nocturnal enuresis in children with
upper

airway obstruction.

J Pediatr Otorhinolaryngol
DJ. Rapid maxillary expansion in the treatment of
Int

1985; 9:173-82

4 Timms

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:
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6 Everaert K, Pevernagie D, Oosterlinck W. Nocturnal enuresis

provoked by an

obstructive

sleep

syndrome. J Urol
Eldridge FL, Tilkian A, et al. Sleep apnea
due to

1995; 153:1236
7 Guilleminault C,
8

apnea

syndrome
upper airway obstruction. Arch Intern Med
1977; 137:296-300
Yokoyama O, Amano T, Lee S, et al. Enuresis in an adult

636

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Selected

Reports

female with obstructive sleep apnea. Urology 1995; 45:150-54

Ulfberg J, Thuman R. A non-urologic cause of nocturia and
enuresis.obstructive sleep apnea syndrome (OSAS). Scand
J Urol Nephrol 1996; 30:135-37
10 Arai H, Furuta H, Koshino Y, et al 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
9

Soc

13

Nephrol

1993; 4:1111-21

Krieger J, Imbs J, Schmidt M, et al. 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 al. Obstructive sleep

and
apnea
peripheral central effects on plasma
renin activity and aldosterone. Sleep 1991; 14:211-17
15 Krieger J, Schmidt M, Sforza E, et al. Urinary excretion of
guanosine 3':5'-cyclic monophosphate during sleep in ob
structive sleep apnea patients with and without nasal contin
uous positive airway pressure treatment. Clin Sci 1989;
treatment:

76:31-37

16

17

Warley ARH, Stradling JR. Abnormal diurnal variation in salt

and water excretion in patients with obstructive sleep apnoea.

Clin Sci 1988; 74:183-85

Krieger J, Follenius M, Sforza E, et al. 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

Krieger J, Laks L, Wilcox I, et al. Atrial natriuretic 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, et al. Changes of circulating
atrial natriuretic peptide and antidiuretic hormone in
obstructive sleep apnea syndrome. Respiration 1992; 59:
18

164-68
20 Lin C, Tsan K, Lin C. Plasma levels of atrial natriuretic factor

sleep apnea syndrome.

Sleep 1993; 16:37-39
Warley ARH, Fontes F, Wilson M, et al. Lack of effect of an
inspiratory threshold load on plasma atrial natriuretic peptide
in moderate to

21

severe

obstructive

levels. Clin Sci 1990; 78:311-13

22 Rodenstein DO, D'Odemont JR, Pieters T, et al. 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 al.
Nocturia: a rarely recognized symptom of sleep apnea and
other occult sleep disorders. Arch Intern Med 1996; 156:
5445-50

24

25

Krieger J, Petiau C, Sforza E, et al. Nocturnal pollakiuria

is a symptom of obstructive sleep apnea. Urol Int 1993;
50:93-97
Berry RB, Kouchi KG, Der DE, et al. Sleep apnea impairs

the arousal response

to

airway occlusion. Chest 1996;

27

Edward P. Gerstenfeld, MD; Yogarajah Balarajan, MD;

Robert Cooke, PAC; and Robert S. Mittleman, MD

36-year-old man with a history of hypertrophic

obstructive cardiomyopathy presented to the emer
gency room with "stabbing" chest pain. He had
undergone dual-chamber pacemaker implantation
in 1993 using an atrial lead (Accufix; Telectronics;
Englewood, Colo) and a myomeetomy in 1996 during
which the distal portion of the atrial lead was re
moved. Digital fluoroscopy revealed that the reten
tion 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 Accufix lead at the time of open-heart surgery is
A

emphasized.

(CHEST 1998; 114:637-639)

Key words: atrial lead; hypertrophic obstructive cardiomyopa

thy; lead extraction; pacemaker

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.
A

Case Report
A 36-year-old man with a history of hypertrophic obstructive

cardiomyopathy presented to the emergency department com

plaining 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 pace
maker 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; Telectron
ics; written communication; November 3, 1994). His symp
toms persisted, and he was referred to an outside institution
in 1996.
time of

At the
where he underwent a myomeetomy
at
of
atrial
lead
was
cut
the
the
surgery,
junction the superior
vena cava and right atrium as recommended, with the inten
tion of removing the retention wire. The rest of the lead was

109:

1490-96
26

Migration and Right Atrial

Perforation of an Accufix Atrial
Lead Retention Wire Following
Partial Lead Removal During
Myomeetomy*

Downey B, Bonnet MH. Performance during frequent sleep

disruption. Sleep 1987; 10:354-63

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

and Pacing,
Electrophysiology
of Medicine, University of
Department
Massachusetts Medical Center, Worcester.
received November 21, 1997; accepted December
Manuscript
17, 1997.
Correspondence to: Edward Gerstenfeld, MD, UMMC, Division
of Cardiology, 55 Lake Avenue Noi~th, Worcester, MA 01655
*From the Section of Cardiac
Division of Cardiology,

CHEST/114/2/AUGUST, 1998

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637