Discussion
The classic teaching that tuberculous pleurisy is a disease
ofthe young characterized by a unilateral exudate, occurring
shortly after primary infection and unaccompanied by clin¬
ical parenchymal disease, is no longer valid. Increasingly, TB
is being seen in an older patient population and its manifes¬
tations in this population differ.
In the review by Sibley1 of 200 cases of tuberculous
pleurisy published in 1950, the mean age of the patients was
20 years. Subsequent series have shown a progressively
of older patients as well as a rise in the
higher proportion
frequency 25of coexisting pulmonary parenchymalanddisease.
Less than years after Sibley's report, Berger
Mejia2
their experience with 49 patients with tuberculous
publishedHalf
pleurisy. of their patients were older than 35 years, 15%
were older than 70 years, and 37% had coexisting paren¬
Similarly, in the review by Epstein and col¬
chymal disease.
of 26 patients with tuberculous effusions seen be¬
leagues3
tween 1978 and 1985, the median age was 56 years, with 19%
of the cases occurring in the setting of reactivation disease.
Fully 13% of their patients had bilateral pleural disease, as
was seen in our patient, a manifestation previously consid¬
ered distinctly unusual.
As the demographic and radiographic patterns of tuber¬
culous pleurisy have evolved, so have the characteristics of
the pleural fluid. Recent series have demonstrated pleural
fluid neutrophilia to be more common then previously ap¬
article by Light et al4 on the
preciated. In the 1973inlandmark
the
differential
of
cell
counts
diagnosis of pleural
utility
effusions, none of the 14 patients with TB had more than
50% PMNs. In contrast, 3 of 28 patients described in the
1991 series of Siebert et al5 had more than 95% PMNs and
15% of the patients of Epstein et al3 had more than 90%
PMNs. Based on animal models and limited human data,
neutrophilia of the pleural fluid has beentoattributed to acuteIn
infection, with expected rapid evolution lymphocytosis.
rabbits, the neutrophilic phase of tuberculous pleural effu¬
sion lasts only 24 h;6 in humans, a 2-week time course has
been described./ Pleural fluid sampling earlier in the course
of infection is unlikely to explain the increased prevalence of
and clearly
neutrophilic effusions in more recent seriesfluid
neutro¬
cannot explain our patient's unilateral pleural
over a 3-week period. Host factors
philia, which was ofstable
other than acuity infection must be invoked, and the co¬
incident presence of a typical lymphocytic tuberculous
effusion in this case localizes these factors to the pleural
space. It is possible that the left pleural involvement
occurred first, with resultant sequestration of all of the pa¬
tient's tuberculin-responsive T cells in this pleural space.8
Such a mechanism has been invoked to explain the initially
negative PPD skin tests seen in up to one third of patients
with tuberculous pleurisy. If sequestration of all reactive
lymphocytes in the left effusioninwasthethe reason for the rel¬
ative absence of lymphocytes
right pleural space,
the patient's pos¬
though, we would expectthea negative PPD;
of
itive skin test attests to
presence circulating tubercu¬
lin-sensitive lymphocytes that could potentially have been
recruited into the right pleural space. It is also possible that
the atypical features of the right effusion resulted from co¬
incident bacterial infection in that pleural space. Negative
850
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bacterial cultures, the failure of the patient to respond
favorably to antibacterial therapy, the lack of change in the
characteristics of the effusion despite two courses of antibi¬
otics, and the need to invoke a second diagnosis all speak
against this.
Conclusion
Pleural TB is a changing disease, both in terms of its de¬
mographics and, likely as a consequence, its features. Pleu¬
ral effusion is occurring in an older population, in the setting
of reactivation disease, and with cellular and biochemical
features once thought atypical. The factors that determine
the manifestations of disease in a given case remain poorly
understood. This case, which we believe to be the first re¬
of bilateral tuberculous pleural effusions of
ported case
different cellular and biochemical
strikingly and persistently
characteristics, illustrates the newly recognized breadth of
manifestations of tuberculous pleural disease and implicates
local pleural space factors as one of their determinants.
References
1
2
3
4
5
6
Sibley JC. A study of 200 cases of tuberculous pleurisy with ef¬
fusion. Am Rev Tuberc 1950; 62:314-23
Berger HW, Mejia E. Tuberculous pleurisy. Chest 1973; 63:88-92
Epstein DM, Kline LR, Albelda SM, et al. Tuberculous pleural
effusions. Chest 1987; 91:106-09
Light RW, Erozan YS, Ball WC. Cells in pleural fluid: their value
in differential diagnosis. Arch Intern Med 1973; 132:854-60
Siebert AF, Haynes J, Middleton R, et al. Tuberculous pleural
effusion: 20-year experience. Chest 1991; 99:883-86
Montgomery LG, Lemon W7S. The cellular reaction ofthe pleura
to infection with Mycobacterium tuberculosis. J Thoracic Surg
1933; 2:429-38
7
Light
RW. Pleural diseases. 3rd ed. Baltimore: Williams &
Wilkins, 1995; 1995; 154-66
8 Rossi GA, Balbi B, Manca F. Tuberculous pleural effusions:
ev¬
idence for selective presence of PPD-specific T-lymphocytes at
site of inflammation in the early phase of the infection. Am Rev
Respir Dis 1987; 136:575-79
Central Alveolar
Hypoventilation Syndrome
(Ondine's Curse) With
Gastroesophageal Reflux*
Shin-ichi Takeda, MD; Yoshitaka Fujii, MD;
Kawahara, MD; Kazuya Nakahara, MD; and
Hisayoshi
Hikaru
MD
Matsuda,
Congenital central hypoventilation syndrome (On¬
dine's curse) is a rare disorder with lack of automatic
control of ventilation during sleep. We have reported
a case of Ondine's curse in a patient who underwent
*From the First Department of Surgery, Osaka University Medical
School (Drs. Takeda, Fujii, and Matsuda), Department of Pediat¬
ric Surgery, Kure National Hospital (Dr. Kawahara), and Depart¬
ment of Surgery, Ootemae Hospital (Dr. Nakahara), Osaka, Japan.
January 23,1996; revision accepted March 13.
Manuscript received
Dr. Takeda, First Department of Surgery, Osaka
Reprint requests:
University Medical School, 2-2 Yamadaoka, Suita City, Osaka 565,
Japan
Selected Reports
Case Report
A full-term female infant weighing 2,860 g was the product of a
normal pregnancy and vaginal delivery. After delivery, the baby
cried immediately and had an Apgar score of 9/10. During the first
8 h of her life, the infant experienced apneic episodes associated
with cyanosis while sleeping. Results of laboratory examination were
normal. Chest radiographs showed neither cardiomegaly nor pul¬
monary disease, and skull radiographs, cranial CT, and EEG were
normal. Because cyanosis persisted without any improvement by
medical treatment, the infant was intubated and placed on a reg¬
imen of mechanical ventilation on the first day of her life. The in¬
fant did well when awake; however, mechanical ventilatory support
was needed when she was sleeping. During the next 2 months, she
received therapeutic trials with caffeine, progesterone, thyroxine,
and oral doxapram for the sake of respiratory stimuli. None of these
drugs were successful in improving sleep apnea. When she was 4
months of age, a tracheostomy was created, but ventilation was en¬
tirely normal while awake. Furthermore the parents gradually be¬
came aware of vomiting usually during sleep. Under a diagnosis of
GER, Nissen's fundoplication was performed when she was 5
months old; thereafter this symptom improved.
At 3 years of age, the patient was referred to our hospital for di¬
aphragm pacer implantation. The patient was evaluated by mea¬
suring end-tidal O2 and CO2 (RM300 Minato Medical Science Ltd;
Osaka, Japan) and ventilatory movement by respiratory inductive
plethysmograph (Respigraph; NIMS; Miami Beach, Fla). Soon af¬
ter she fell sleep, electrodes for monitoring extraocular movements
were attached and polygraphic recording was begun.0'7 Long apnea
persisted associated with oxygen desaturation with hypercapnea
Figure 1.
Upper GI series after implantation of diaphragm pacers.
fundoplication for gastroesophageal reflux
age 5 months. Ventilatory challenge test
during sleep was done to confirm central alveolar hy¬
poventilation. This female patient, without cor pulmo¬
nale, was a good candidate for diaphragm pacing.
Thus, the patient underwent implantation of a dia¬
phragm pacer at age 3 years; she had required me¬
chanical ventilation since birth. Diagnosis, pathogen¬
esis, and problems in the setting of diaphragm pacing
for an infant are discussed.
Nissen's
(GER)
at
(CHEST 1996; 110:850-52)
Key words: congenital central alveolar hypoventilation; diaphragm
pacing; gastroesophageal reflux
Abbreviations: ET=endothelin; GER=gastroesophageal reflux;
LESslower esophageal sphincter; NREM=nonrapid eye move¬
ment
central hypoventilation syndrome, so-called
Congenital
Ondine's
extremely disorder of
lation control,1"0 characterized
curse, is
an
rare
during quiet sleep (non[NREM]). During active sleep (REM),
small irregular respiration was noted 10 to 15 s after interruption
of the mechanical ventilation, followed by spontaneous arousal.
Based on these findings, we have confirmed the diagnosis of con¬
genital central hypoventilation syndrome. The patient was doing
well when awake in room air, and an echocardiogram showed no
evidence of pulmonaryhypertension. Phrenic nerve stimulation test
revealed normal conduction time and satisfactory diaphragm ex¬
cursion. Implantation of diaphragm pacer was thus indicated and
surgery was done at when the patient was 3 years, 1 month old.
When the patient was under general anesthesia, pacing elec¬
trodes were attached to the intrathoracic part of the bilateral
phrenic nerves through third intercostal thoracotomy. Receivers
were implanted in the subcutaneous pocket made on the wall ofthe
abdomen. We applied four pole nerve electrodes with sequential
stimulation system (Astrostim: Atrotech Co., Tampere, Finland)
introduced by Talonen et al,8 which have been widely used re¬
cently.8"10 Bilateralwithout
diaphragm pacing was initiated on the 14th
postoperative day
any problem while sleeping. In the
postoperative periods, manometric study and upper GI series re¬
vealed slight residual GER as shown in Figure 1.
Trials for removal of the tracheostomy tube were unsuccessful
due to upper airway obstruction during pacing. Except for a minor
complication of wire breakage, the diaphragm pacing was unevent¬
ful, and the patient was discharged from the hospital and continued
electrophrenic respiration at home.
venti¬
by hypoventilation during
To our knowledge, only 50 cases have been reported
sleep.
to date in the English-language literatures. This peculiar
syndrome has been believed to be caused presumably by
congenital failure of the central automatic system.3"/ This
report describes 1 case of a 3-year-old infant with Ondine's
curse, who underwent Nissen's fundoplication for gastro¬
esophageal reflux (GER), and finally underwent implanta¬
tion of a diaphragm pacemaker.
Discussion
Congenital central hypoventilation (Ondine's curse) is a
and poorly understood condition; this disorder is
believed to be due to a lack of ventilatory response during
sleep. No specific etiologic anatomic abnormalities have
been identified thus far in these patients.2"5,7 Usually venti¬
lation is normal in these patients when they are awake, but
it becomes markedly depressed or lost during sleep, particrare
CHEST 7110/3/ SEPTEMBER, 1996
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851
ularly in REM periods.5,' According to the studies described
by Paton et al,6 hypoxic and hypercapnic ventilatory re¬
sponses were also impaired even in the awake state, and ac¬
tual normal ventilation can be maintained by behavioral
control.
The most common associated anomaly is Hirshsprung's
disease, which appeared in 17 cases,9,11,12 and GER was also
reported in 1 case.12 In this patient, combination with GER
was apparent during sleep and this combination seemed to
be rare. In terms of motor control, lower esophageal
sphincter (LES) muscle shares a similar neural pathway with
the crural part of the diaphragm. Therefore, contraction of
the diaphragm exerts an important sphincteric action at the
LES, serving as an antireflux barrier.13 One possible expla¬
nation for GER with Ondine's curse is that relaxation of the
LES as well as the diaphragm might coexist during sleep
whether apparent or subclinical.
A high incidence with an associated anomaly named as
has not been fully ex¬
Ondine-Hirshsprung syndrome12
disease
is
generally considered to be
plained. Hirshsprung's
a result of impaired migration of neural crest cells during
development. Recent dramatic progress in molecular biol¬
ogy has provided an insight for explanation of such congen¬
ital disorders. Endothelin-1 (ET-1), discovered as a vaso¬
constrictive peptide having various actions on circulation, has
been found to play an important role in development.14,10
ET-1 knockout mice showed craniofacial anomaly and died
of respiratory failure due to the defect of central respiratory
control.14 However, all the mice that were ETb receptor
(ETb) knockout exhibited a similar anatomic feature with
and this disorder has been ex¬
Hirschsprung's disease;15
of neural crest migration during devel¬
plained asduea defect
to the genetic defect of ETb receptor. We
opment
that
maybe caused
speculate Ondine-Hirshsprungsyndrome
ET
and
of
an
the
system, further mo¬
by genetic disruption
lecular biological studies are needed to elucidate the mech¬
anism of Ondine's curse.
In patients with sleep apnea, prolonged mechanical ven¬
tilation is hazardous and difficult to accomplish at home.
Diaphragm pacing during sleep is a more favorable treat¬
ment in terms of maintaining physiologic respiration.1"3,',9,10
In infants, unilateral pacing is not recommended because of
phrenic nerveto
inadequate ventilation.1'2,9,10 To minimize
has
been
reported
damage, four-pole sequential pacing8
be an improved pacing system, so we applied it for this pa¬
tient. During diaphragm pacing, the tracheostomy had to be
left because of upper airway obstruction, which was proba¬
bly due to the absence of laryngeal muscle activation with¬
out central stimulus.16'1'
One other case of Ondine's curse with GER is reported,
with discussion of possible pathogenesis and therapeutic
yield.12
References
1 Hunt CE, Matalon SV, Thompson TR, et al. Central hypoventi¬
lation syndrome: experience with bilateral phrenic nerve pacing
three neonates. Am Rev Respir Dis 1978; 118:23-8
2 Ruth V, Pesonen E, Raivio KO. Congenital central hypoventila¬
tion syndrome treated with diaphragm pacing. Acta Pediatr Scand
in
1983; 72:295-97
852
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3 Wells
HH, Kattwinkel J, Morrow JD. Control of ventilation in
Ondine's curse. J Pediatr 1980; 96:865-67
4 Oren J, Kelly DD, Shannon DC. Long-term follow-up ofchildren
with congenital central hypoventilation syndrome. Pediatrics
1987; 80:375-80
5 Guilleminault C, McQuitty J, Ariagno RL, et al. Congenital cen¬
tral hypoventilation syndrome in six infants. Pediatrics 1982;
70:684-94
6 Paton JY, Swaminathan S, Sargent CW, et al. Hypoxic and
hypercapnic ventilatory responses in awake children with con¬
genital central hypoventilation syndrome. Am Rev Respir Dis
1989; 140:368-72
7 Yasuma F, Nomura H, Sotobata I, et al.
Congenital central hy¬
poventilation (Ondine's curse): a case report and review of the
literature. Eur J Pediatr 1987; 146:81-3
8 Talonen PP, Baer GA, Hakkinen V, et al. Neurophysiological and
technical considerations for the design of an implantable phrenic
nerve stimulator. Med Biol Eng Comput 1990; 28:31-7
9 Flageole H, Adorph VR, Davis GM, et al. Diaphragmatic pacing
in children with congenital central hypoventilation syndrome.
Surgery 1995; 118:25-8
10 Weese-Mayer DE, Morrow AS, Brouillette RT, et al. Diaphragm
pacing in infants and children: a life-table analysis of implanted
components. Am Rev Respir Dis 1989; 139:974-79
11 El-Halaby E, Goran AG. Hirchsprung's disease associated with
Ondine's curse: report of three cases and review of the literature.
J Pediatr Surg 1994; 29:530-35
A, Elmer C, Lacombe D, et al. Ondine-Hirshsprung
syndrome (Haddad syndrome): further delineation in two cases
12 Verloes
and review of the literature. Eur J Pediatr 1993; 152:75-7
RK, Rochester DF, McCallum RW. Electrical and me¬
chanical activity in the human lower esophageal sphincter during
diaphragmatic contraction. J Clin Invest 1988; 81:1182-89
14 Kurihara Y, Kurihara H, Suzuki H, et al. Elevated blood pressure
and craniofacial abnormalities in mice deficient in endothelin-1.
13 Mittal
Nature 1994; 368:703-10
15 Hosoda K, Hammer RE, Richardson
JA, et al. Targeted and
neural (Piebald-Lethal) mutations of endothelin-B receptor gene
produce megacolon associated with spotted coat color in mice.
CeU 1994; 79:1267-76
16 Glenn WWL, Gee JBL, Cole DDR, et al. Combined central al¬
veolar hypoventilation and upper airway obstruction: treatment
by tracheostomy and diaphragm pacing. Am J Med 1978; 64:
50-60
17 Olson TS, Woodson GE, Heldt GP. Upper airway function in
Ondine's curse. Arch Otolaryngol Head Neck Surg 1992;
118:310-12
Unusual Etiology of Cough in
Woman With Asthma*
a
Frank Sorhage, MD; Diane E. Stover, MD, FCCP; and
Ala Mortazavi, MD
A case of multiple symmetric lipomatosis
(Madelung's
disease) acquired through chronic use of corticoster¬
oids is reported. Presumed symptoms of asthma, which
consisted of a barking cough, were treated with esca*From the Memorial
Sloan-Kettering Cancer Center, New York.
Manuscript received December 28, 1995; revision accepted March
26, 1996.
Reprint
requests: Dr. Stover, Memorial Sloan-Kettering Cancer
Center, Pulmonary Service, 1275 York Avenue, New York, NY
10021
Selected
Reports