Buyse, B.

Demedts, M.

Gysbrechts, C.

Michiels, E.

Verhoef, G.

Elsevier - Publisher Connector 

Temporary obstructive apnoea syndrome attributed to cryptococcus (meningo) encephalitis 

Respiratory Medicine (1996) 90, Y-574 
Temporary obstructive apnoea syndrome attributed to 
cryptococcus (meningo) encephalitis 
B. BuYsE*$, C. GYSBRECHTS~, E. MICHIELS *, G. VERHOEF~ AND M. DEMEDTS* 
Departments of “Pneumology and THaematology, University Hospital Gasthuisberg, Catholic University, 
Leuven, Belgium 
Introduction 
The present case report describes a patient treated 
for leukaemia in whom the tentative diagnosis of a 
cryptococcal (meningo) encephalitis was made. The 
principal manifestation of this (meningo) encephalitis 
was a temporary obstructive sleep apnoea syndrome 
(diagnosed by a polysomnographic study). 
Case Report 
In this 45-year-old man, a diagnosis of a non- 
Hodgkin lymphoma (Stadium 2B) had been made 
2 yr previously, and he was cured after treatment 
with cytostatic drugs and radiotherapy on the medi- 
astinum. Five months ago, he developed a secondary 
acute myeloid leukemia (Type M2). According to 
FAB criteria, remission-induction therapy consisted 
of idarubicine, ara-C, VP-16 and novantrone, and 
his complete remission was consolidated with an 
autologous bone marrow transplantation. The con- 
ditionary regime consisted of cyclophosphamide and 
busulphan and he received his bone marrow infusion 
on 21 November 1994. Subsequently, he developed 
several septicemias (Escherichia coli and coagulase 
negative staphylococci), liver dysfunction probably 
due to veno-occlusive disease and a painful haema- 
turia due to traumatic bladder canulation and 
thrombopenia. At the end of December 1994, the 
patient manifested symptoms compatible with 
encephalopathy (loss of decorum, perplexity). 
In the night of 7 January 1995, snoring and 
obstructive breathing during sleep was first noted. 
Thirty-six hours later, the patient demonstrated a 
variable level of consciousness. When awake, he 
answered questions adequately and did not demon- 
Received 22 May 1995 and accepted in revised form 22 March 
1996. 
$Author to whom correspondence should be addressed at: Depart- 
ment of Pneumology, University Hospital Gasthuisberg, Herestraat, 
49, B-3000 Leuven, Belgium. 
0954.6111/96/090571+04 $12.0010 
strate any neurological abnormality, nor abnormali- 
ties in his breathing pattern. When not stimulated, he 
fell asleep immediately, then presenting an obstruc- 
tive breathing pattern with heavy snoring and 
apnoeas. The patient underwent a detailed clinical 
neurological investigation. No signs demonstrating 
lateralizations nor cranial palsies were found; only a 
nystagmus was present. On rhinolaryngological 
investigation, no abnormalities in pharynx or larynx 
were visualized. At that time, his treatment consisted 
of teicoplanine, ofloxacine, ceftazidime, mesna and 
piritramide for painful haematuria (piritramide was 
started 14 days previously, mean dose 40 mg day ~ ‘, 
dose not raised during the last days), and diuretics for 
the veno-occlusive disease with ascites. The X-ray of 
the chest was normal with a normal cardiac configur- 
ation and without signs of cardiac decompensation. 
Blood pH value was normal (7.4), as were PaCO, 
(42.6 mmHg), HCO, (26.5 meq 1 - ‘), sodium 
(137 meq 1 - I), potassium (3.5 meq l- ‘) and phos- 
phorus (3.6 mg dl - ‘). There was pancytopenia (with 
a haemoglobin of 6.9 g dl- I, a leukopenia of 
2300 mne3 and thrombopenia of 54.109 l- ‘), a 
normal renal function and slightly elevated liver 
enzymes; total bilirubin 4.9 mg dl - ’ (normal values 
0 2-l), alkaline phosphates 348 U l- ’ (normal values 
90-260), glutamyl transferases 66 U 1 - ’ (normal 
values 11-50) and ammonia 57,~~rnoll~ ’ (normal 
values 12-55). A polysomnographic study (Fig. 1) 
was performed between 1 pm and 3.30 pm, which 
revealed 97 obstructive apnoeas, six central apnoeas, 
13 mixed apnoeas and 20 hypopnoeas. Each respir- 
atory event was followed by marked desaturation. 
Oxygen desaturation (190%) was present in 47% of 
the time, with a minimum saturation of 74.5%. 
Analysis of the EEG, EOG and EMG patterns 
showed that the consciousness of the patient changed 
continuously between being awake and light sleep. A 
computed tomographic (CT) scan of the brain dem- 
onstrated a widened ventricle system, clearly wider 
0 1996 W. B. Saunders Company Ltd 
572 B. Buyse et al. 
Hypno 
SaO, 
70 - I I I I I I I I 
I I I I I I I I I I I 
0O:OO 00:15 00:30 00:45 Ok00 01:15 01:30 Ok45 02:OO 02:15 02:30 
Time (h) 
Fig. 1 Results of the first polysomnography (registered on ‘Sleepwalker ~ Medatec’). Event, apnoea (cessation of air flow 
for at least 10 s) or hypopnoea [reduction of air flow (at least 50%) for at least 10 s with desaturation (at least 4%)]; Obs A, 
obstructive apnoea; Cen A, central apnoea; Mix A, mixed apnoea; Cen H, central hypopnoea; Obs H, obstruc- 
tive hypopnoea; Hypno, hypnogram; R, REM sleep; 1,2,3,4, non-REM sleep, Stadiums 1,2,3,4; A, awake; U, unknown; 
SaO,, transcutaneous saturation (%). 
than the CT scan performed 2 months earlier. The 
nuclear magnetic resonance scan only showed totally 
aspecific lesions in the semi-oval centre. A lumbal 
puncture demonstrated an elevated intracerebral 
pressure (500mmH,O), the liquid was clear with 
a normal protein and glucose concentration. The 
cytosis was 0.8 mm ~ 3. Gram- and Ziehl-Nielsen- 
stainings were normal; cultures of lumbal liquid 
showed no growth of micro-organisms, the serology 
for herpes and toxoplasma gondii was also normal. 
Cytomegalovirus isolates on buffy coat, lumbal 
liquid, urine and throat swabbing were also negative. 
The cryptococcal antigen detection test (Latex, 
Crypt0 Antigen System Kit-Immy) performed on 
lumbal liquid demonstrated a titre of l/l. Treatment 
with amfotericine B (60 mg day- ‘) and fluconazol 
(parenteral administration of 400 mg day - ‘) was 
started. Piritramide was stopped. Three days later, 
although the patient was still sleepy, no obstructive 
breathing was noted anymore. The intracerebral 
pressure was lowered to 250 mmH,O and the crypto- 
coccal antigen titre was l/2. The haemoglobin level 
was 7.7 g dl - i at that time. A control polysomno- 
graphic study was performed (Fig. 2) on 23 January 
1995. At that time, the haemoglobin level was 
9 g dl- ‘. Only one hypopnoea was noted and no 
desaturation (saturation below 90%) was seen. A 
cryptococcal antigen detection test on lumbal liquid 
was also performed 3 weeks after the first analysis, 
and demonstrated a titre of zero, and the intra- 
cerebral pressure was lowered to 190 mmH,O 
(normal value). 
Discussion 
The present case report describes a patient demon- 
strating an obvious obstructive sleep apnoea syn- 
drome, which was attributed to a cryptococcal 
(meningo) encephalitis. After treatment with amfo- 
tericine B and fluconazolum, the apnoea problem 
disappeared, and a control polysomnographic study 
performed 14 days after the onset of the apnoea 
syndrome showed that no apnoeas were present. The 
authors are aware that the cryptococcal antigen titre 
is rather low (l/2) to ascertain the diagnosis of 
cryptococcal (meningo) encephalitis. Also, a normal 
cerebrospinal fluid (CSF) (with normal glucose and 
protein concentrations and leucocyte counts) might 
be surprising, although the absence of abnormalities 
of CSF are seen frequently in AIDS patients with 
cryptococcal infections, and occasionally in other 
patients (2). The present patient had immunosuppres- 
sive medications which probably contributed to the 
absence of proteins and pleocytosis. Nevertheless, the 
authors think that this diagnosis is very probable 
because (1) there was a typical compatible constel- 
lation of symptoms and signs (encephalopathy, a 
widened ventricle system and a markedly elevated 
intracerebral pressure), (2) no other germs were 
detected, and (3) there was a clearly favourable effect 
of amfotericine B and fluconazolum; clear clinical 
response, an objective lowering of the intracerebral 
pressure after treatment for 3 days (from 500 to 
250 mmH,O), with normalization (190 mmH,O) after 
treatment for 3 weeks and a normalization of the 
Temporary obstructive apnoea syndrome 573 
150 
A+H1OO- / / / / ~ I I 
index 5o ~ Event 
n I I I I I I I I 
A 
R 
1 
2 Hypno 
3 
4 
100 
80 - 
% 
60 - 
: SaO, 
40 I I I I I I I I 
1 2 3 4 5 6 7 8 
Time (h) 
Fig. 2 Results of the control polysomnography (registered on ‘Somnostar 4100- Sensormedics’). Event, apnoea 
(cessation of airflow for at least 10 s) or hypopnoea [reduction of airflow (at least 50%) for at least 10 s with desaturation 
(at least 4%)]; A+H index, number of apnoeas and hypopnoeas h-l; Hypno, hypnogram; R, REM sleep; 1,2,3,4, non-REM 
sleep, Stadiums 1,2,3,4; A, awake; SaO,, transcutaneous saturation (%). 
cryptococcal antigen titre 3 weeks after treatment 
commenced (cryptococcal antigen titre=O). The 
authors are not aware of other published cases 
of apnoea caused by cryptococcus neoformans, nor 
of apnoea caused of infections in adults, while in 
young children, apnoea is a well-known manifes- 
tation of infections especially by respiratory syn- 
cytial virus (RSV). Church et al. (3) mentioned that 
18% of all infants admitted with RSV developed 
apnoea. Other casuistic observations suggest that 
infections other than RSV may affect vital centres 
and cause apnoeas in babies; listeria monocyto- 
genes (4), echovirus type 2 (4) and enterococcal 
infection (5). 
Theoretically, the abnormal breathing could be the 
resultant of muscle weakness, although no major meta- 
bolic derangements (almost normal hepatic enzymes, 
normal electrolytes, no disturbance in acid-base 
status), except the presence of anaemia, were found in 
the present patient (haemoglobin level of 6.9 g dl~ ‘). 
Theoretically, this anaemia may also have played a 
role in the apnoea syndrome. On one hand, anaemia 
may have reduced respiratory muscle force, but on the 
other hand could also have influenced the respiratory 
control system. Anaemia has been shown to increase 
the duration of apnoeic pauses elicited by laryngeal 
stimulation in piglets (6), to enhance the peripheral 
chemoreceptor-mediated response to hypoxia in goats 
(7), and to blunt the chemoreceptor response to carbon 
dioxide in adults (8). In a retrospective study published 
by Poets et al. (9), the relationship between anaemia 
and apnoea was investigated in 72 infants referred for 
assessment and home monitoring following an appar- 
ently life-threatening apnoea event. Significantly more 
infants than expected had haemoglobin levels below 
the mean. In the present case, haemoglobin levels also 
tended to be higher when apnoeas disappeared 
(Hb 6.9 g dl- ’ when symptomatic; Hb 7.7 g dl - ’ 3 
days later when the patient was sleepy, but no longer 
demonstrated apnoeas; Hb 9 g dl - ’ when the poly- 
somnographic re-evaluation was performed and 
demonstrated normalization). 
The role of piritramide must also be discussed in 
the aetiology of this apnoea problem. Piritramide is 
known to enhance the severity of obstructive sleep 
apnoea, by promoting upper airway instability by 
selectively reducing the innervation to the upper 
airway dilatator muscles (10). Although piritramide 
may have played an additional role in this case, the 
authors argue that it is not the principal cause. 
574 B. Buyse et al. 
Firstly, the patient used piritramide (even in higher 
dose) for several weeks without any problem, and 
secondly, the control polysomnographic study 
showed no evidence of an (even silent) obstruc- 
tive sleep apnoea problem, despite the fact that 
piritramide was restarted. 
Conclusion 
This case report describes a temporary obstructive 
sleep apnoea syndrome in relationship with a crypto- 
coccal infection. Although infections (especially RSV 
infections) may cause apnoea in children under 1 year 
of age, the authors are unaware of such a problem in 
adults. In particular, no case of apnoea in relation to 
cryptococcus neoformans infection was found by the 
authors. It is also of interest to emphasize the poss- 
ible role of anaemia in this apnoea problem, although 
such a relationship has only been described in infants. 
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Temporary obstructive apnoea syndrome attributed to cryptococcus (meningo) encephalitis

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