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mycoses 33 (7/8) 359-367 acceptedjangenommen: July 27, 1990

Cerebrospinal fluid indices in cryptococcal and

tuberculous meningitis: The spider web coagulum
and its diagnostic significance

Liquor-Befunde bei der Cryptococcose- und Tuber-

kulose-Meningitis: Das Spinngewebsgerinnsel und
seine diagnostische Bedeutung
F. Staibt, M. Seiboldt, E. Antweilert, C. Zimmer2, J. Heitz3 and G. Stoltenburg-

1 Mycology Unit, Robert Koch Institute, Federal Health Office, Berlin, Germany FR
2 Institute for Neuropathology,Klinikum Steglitz, Free University of Berlin, Germany FR
3 Medical Intensive Care Unit, Klinikum Steglitz, Free University of Berlin, Germany FR

Key words. Cryptococcal meningitis, tuberculous meningitis, cerebrospinal fluid (CSF), CSF indices,
spider web coagulum.
SchiUsselwiirter. Cryptococcus-Meningitis, tuberkultise Meningitis, Liquor, Liquorwerte, Spinngewebs-

Summary. The differentiation between a were found to be spider web coagulum

chronic cryptococcal meningitis and a fibres. (2) Cryptococcal meningoencephali-
chronic tuberculous meningitis may cause tis based on the detection of Cryptococcus
problems for the clinician only if standard neoformans in CSF and its antigen in serum
microbiological methods are not applied to and CSF. - At post-mortem, cryptococcal
the diagnosis of both infections. meningoencephalitis was established as
In a male non-AIDS patient (SO y), 11 cause of death. Residual signs of tuberculo-
years after a suggested diagnosis of''tubercu- sis could not be detected in the brain and the
lous meningitis'', meningoencephalitis with meninges. Common clinical similarities of
hydrocephalus was diagnosed and treated cryptococcal and tuberculous meningitis
accordingly without success. Mycobacteri- and the possibility of a double infection are
um tuberculosis was never found. Because discussed. A comparison of the presence of
fibrin fibres of a spider web coagulum in the Cr. neoformans in the meninges of non-
CSF resembled Aspergillus mycelium, the AIDS and AIDS patients is made. The
patient was then treated with amphotericin formation of spider web coagulum in the
B + flu cytosine. Finally, a mycological CSF is discussed. Proposals for the diagno-
examination led to the true diagnosis: (1) In sis, therapy and prophylaxis of cryptococcal
the CSF, resembling Aspergillus hyphae meningitis are made.

F. Staib et al.: CSF indices in cryptococcal meningitis

Zusammenfassung. Die Unterscheidung ei- the CSF, a confusion of both infections may
ner chronischen Cryptococcus-Meningitis occur due to the similarity of the syndrome
von einer The-Meningitis kann fUr den seen in the cerebrospinal fluid [5-8]. It
Kliniker our dann Prohleme hereiten, wenn consists of an increase in protein and a
von Moglichkeiten der mikrohiologischen decrease in glucose combined with a
Diagnostik heider lnfektionen kein Ge- lymphocytic reaction. Such parameters of
hrauch gemacht wird. both infections suggest a certain common
Bei einem SOjiihrigen Nicht-AIDS-Pa- predisposition which also allows the possi-
tienten wurde 11 Jahre nach der klinischen bility of a double infection, perhaps with a
Verdachtsdiagnose The-Meningitis eine clinically different chronic course of infec-
Meningoenzephalitis mit Hydrozephalus- tion and different organ manifestations
hildung hei fehlendem Nachweis vonMyco- (lungs and/or CNS) [2, 3, 5, 8-15].
bacterium tuberculosis als Tuherkulose Due to this fact, a false diagnosis is
erfolglos hehandelt. Wegen der Ahnlichkeit possible in cases of a sole tentative clinical
der Fasern des Spinngewebsgerinnsels im diagnosis or an incomplete microbiological
Liquor mit Aspergillus-Myzel folgte dann examination of the cerebrospinal fluid. On
eine antimykotische Therapie mit Ampho- the occasion of a corresponding case history,
tericin B + Flucytosin. Eine anschlieDende misdiagnosed chronic cryptococcal menin-
medizinisch-mykologische Untersuchung gitis in a non-AIDS patient will be
flihrte zur Kliirung und endgUitigen Diagno- commented and compared with the acute
se: 1. Das fraglicheAspergi//us-Myzel erwies cryptococcal involvement of the meninges in
sich als Spinngewehsgerinnsel. 2. Crypto- AIDS patients [2-4, 7, 16-20]. The forma-
coccus-Meningoenzephalitis durch den tion of spider web coagulum in CSF [21] will
Nachweis von Cryptococcusneojormansim be discussed from a new angle.
Liquor und seines Antigens in Serum und
Liquor. - Als Todesursache konnte die
Cryptococcus-Meningoenzephalitis post Case history
mortem hestiitigt werden. Zeichen einer
ahgelaufenen Tuherkulose waren weder im Patient, male, 50 years. At the age of 38, with
Gehirn noch in den Meningen nachweishar. a tentative clinical diagnosis of tuberculous
Zu Gemeinsamkeiten von Cryptococcose- meningitis, he spent 2 months in the hospital.
und Tuherkulose-Meningitis und der Mog- This diagnosis was established by the
lichkeit einer Doppelinfektion wird Stellung clinician on the basis of the following
genommen. Der Cr. neoformans-Befall der criteria:
Meningen hei Nicht-AIDS- und AIDS- (a) Clinical course: Neurological symptoms
Patienten wird diskutiert; hesondere Beach- indicating an inflammatory process
tung verdient das Spinngewehsgerinnsel im near the basis of the brain, insidiously
Liquor. Auf die Prophylaxe und Therapie rising body temperature, distinct specif-
der Cryptococcose wird hingewiesen, und es ic residues in the lungs (Mendel-
werden Empfehlungen zur Diagnostik der Mantoux-test positive).
Cryptococcose-Meningitis gegehen. (b) Cerebrospinal fluid: Spider web coagu-
lum, elevated level of protein, low level
of glucose, pleocytosis, predominance
Introduction of lymphocytes.
(c) Histological findings in a cervical lymph
The differential diagnosis of chronic menin- node (caseation, necrosis, granulomas
gitis includes tuberculosis as well as crypto- consisting of epitheloid and giant cells).
coccosis [ 1-4]. In case that there has been no Samples of sputum and CSF routinely
complete microbiological examination of examined for Mycobacterium tuberculosis

F. Staib et al.: CSF indices in cryptococcal meningitis

by microscopy as well as by culture were massive edematous-necrotizing encephali-

always found to be negative. The patient tis. State after two drainages of ventricle.
received antituberculous drugs as INH, Tentative diagnosis of convulsions deriving
ethambutol, and rifampicin (rimifon from infantile damage of the brain.
400 mg/ d, rifampicin 600 mg/ d, myambu-
toll200 mg/ d). Mter clinical improvement, The pathological findings. Cryptococcosis
the patient was discharged from the hospital but not tuberculosis. In the lungs, old
but routinely controlled as well as presented tuberculous lesions were found, but M.
to students during lectures in neurology at tuberculosis could not be detected, neither
the Free University of Berlin as an example by microscopy nor by culture. There were no
of "tuberculous meningitis". Eleven years histological findings in the brain which
after the onset of the questionable tubercu- suggest that a tuberculous meningitis was
lous meningitis the patient fell sick again found, neither during the first disease I 1
with CNS symptoms (CSF findings were years ago nor during the second fatal one.
found to be similar to those seen 11 years
ago) which was thought to be tuberculous
meningitis again and thus he was treated Material and method
With tuberculostatics for 4 weeks. Because
there was no improvement but constant For microscopic, cultural, and serological
worsening and development of a hydroce- mycological diagnosis, the clinically and
phalus under intensive care, doubts arose pathologically interesting specimens were
about the diagnosis of tuberculous meningi- examined by methods which have been
tis. The CSF was sent to the neuropatholo- described in detail elsewhere [18,19, 22, 23].
gist for examination who microscopically
had seen fibres which he discussed as
questionable fungal hyphae and mycelium, Results
perhaps of Aspergillus. The neuropatholo-
gist had suggested to consult a specialist in (1) The mycological examination for CSF
medical mycology. The clinician, without in view of a questionable Aspergillus
having this suspicion confirmed by the infection was found to be negative by
medical mycologist started treatment with microscopy, culture and serology.
the standard combination of amphotericin (2) Thefibre-likestructuresintheCSFfound
B + flucytosine [I 9] to control the questiona- microscopically by the neuropathologist
ble aspergillosis of the CNS. and discussed as questionable mycelium
Probably the doubts in this diagnosis of Aspergillus were found to be a spider
arose and the clinician consulted the first web coagulum. For somebody not
author in his capacity as a mycologist, who trained in morphological mycological
asked immediately for samples of CSF, diagnosis, the fibres of the spider web
serum, and tracheal secretion. On the basis coagulum would be considered as similar
of this material, the diagnosis of this chronic to those of Aspergillus mycelium (Fig. 1).
disease was found for the first time in this (3) Beside these fibrillar structures, Crypto-
history of 11 years: Cryptococcosis (see coccus neoformans with its typical
Results and Table 1). After treatment (i. v.) capsule was found microscopically for
with amphotericin B (20 mg/ d)+ flucytosine the first time, leading to a diagnosis of
(4 x 2.5 g/d) for 61 days, the patient died. cryptococcal meningoencephalitis (Figs
I and 2 and Table 1).
The clinical diagnosis at death. Cerebral (4) The Cr. neoformans antigen titres in the
death from cryptococcosis meningitis com- CSF and in serum were found to be
bined with hydrocephalus internus and 1:320 and 1:80, respectively.

F. Staib et al.: CSF indices in cryptococcal meningitis

systemic treatment with amphotericin B Munich likewise did not include cryptococ-
+ flucytosine. cosis in the differential diagnosis of tubercu-
(6) The results of all mycological examina- losis. At post-mortem, fatal generalized
tions have been summarized in Table l. cryptococcosis could be diagnosed cultural-
ly with the help of Staib agar (syn. Guizotia
abyssinica creatinine agar) as well as
Discussion histologically.

There is no doubt that this case of

cryptococcal meningoencephalitis diagno- Simultaneous infection by Mycobacterium
sed mycologically by accident and too late spp. and Cr. neoformans
clearly demonstrates that in cases of a
clinical suspicion of tuberculous meningitis There have been reports of double infections
(and missing detection of the agent) crypto- by Mycobacterium spp. and Cr. neoformans
coccosis has necessarily to be included in the [3, 9-13]. The diagnosis of chronic crypto-
differential diagnosis. This case report has coccosis is typically characterized by a
much in common with a case report by changeable course between remission and
Wiebecke & Staib in 1965 [24]: In the case of relapse [25] which may be aggravated if the
a 25-year-old female patient, microbiolo- remission takes place during therapy against
gists and clinicians of the University of tuberculosis as it must be assumed for the

Figure 1. Native prepttration of the sediment of the protein-rich cerebrospinal fluid. Fibres of the spider web coagulum
(thin arrow) side to side with the typical encapsulated blastospore of Cr. neoformans (thick arrow). Note: The fibres of
spider web coagulum are not transparent and do not show a fine distinct cell wall as it is typical of the hyphae of Aspergillus
spp. x 720.

F. Staib et al.: CSF indices in cryptococcal meningitis

Figure 2. Native preparation of the sediment of the protein-rich CSF. Note: Two budding stages (arrows) of Cr.
nec!formans with typical capsules x 720.

case under discussion [3-5, 17]. Wiebecke & in the CSF. Two findings were established:
Staib could demonstrate in an impressive (I) The questionable mycelium was found to
way that after exactly diagnosed and treated be spider web coagulum. (2) Side to side with
tuberculosis of the lungs, a subsequent fatal these fibrin fibres, Cr. neoformans was
meningoencephalitis could be caused by Cr. detected. The additional detection of the
neoformans under the treatment against M. antigen of Cr. neoformans in CS F and serum
tuberculosis [24]. In the Berlin case under completed the final diagnosis of Cr. neofor-
discussion it must be assumed that there mans-associated meningoencephalitis. The
were topographical relations between the observation that the Cr. neoformans antigen
region of the brain in which the questionable titre in CS F was higher than that in the
tuberculous meningitis took place II years serum proved that the cryptococcal manifes-
ago and the region of the present fatal tation was preferably found in the CNS and
cryptococcosis meningoencephalitis. This that the infection must have been of a longer
question is recently the subject of neuropa- duration, i.e. a chronic course.
thological examinations on which a separate
report will be published. Therapy of Cr. neoformans meningoence-
Mycological examinations of the CSF
Because in the case under discussion, on
In the case under discussion the mycologist account of the wrong tentative mycological
was consulted by the clinician shortly before diagnosis of aspergillosis meningoencepha-
death of the patient for the correctness of the litis, a systemic therapy with amphotericin B
tentative diagnosis of Aspergillus mycelium + flucytosine was started before the diagno-

F. Staib et a!.: CSF indices in cryptococcal meningitis

Table 1. Detection of Cryptococcus neoformans and its antigen in clinical specimens during therapy with
amphotericin B + flucytosine

Date of Detection of Cr. neoformans Detection of Cr. neo-

examination formans antigen-titres

Microscopy Culture Serology

CSF RT Urine Other CSF RT Urine Other Serum CSF

specimens specimens

21.09.1988 + - - - 0 - - - 1:80 1:320

22.09.1988 0 0 - - 0 0 - - - -
28.09.1988 0 - - - 0 - - - - 1:160

02.11.1988 + - - - 0 - - - - 1:160

07.11.1988 - - - - - 0 0 - 1:80 -
17.11.1988 0 - - - 0 - - - - 1:1

23. 11. 1988** 0 AU: Lu 0, 0 AU: Lu 0, 1:20*

Li 0, Li 0, 1:2560**

+ = Detection of Cr. neoformans

0 = No detection of Cr. neoformans
- =Specimen not examined
CSF = Cerebrospinal fluid
RT =Specimens from the respiratory tract
AU = Autopsy, material from the lungs (Lu), liver (Li), lymph node (LN) and the brain (B), especially the
base of the brain and the frontal brain
* =CSF from the frontal brain
** =CSF from the base of the brain
*** = Day of autopsy; day of death 21. 11. 1988.

sis of cryptococcosis was established, the singly, Cr. neoformans could be isolated
microscopically detected cryptococci were from autopsy material (lungs) with the help
no more capable of growth. The antimycotic of the brown colour effect of the colonies of
effect of this therapy had taken place. The Cr. neoformans on Staib agar [24]. If the
efficacy of that therapy and healing of microbiologist who isolated in this case a
cryptococcosis diagnosed and treated in the yeast-like fungus from CSF but thought it to
early stage of cryptococcosis in AIDS beacontaminant(err oneouslybecausethe re
patients has bean described by Staib & is no optimal growth at 37 oq had used Staib
Seibold [18-20]. In the case report by agar for the examination of sputum, he
Wiebecke & Staib mentioned above, surpri- would have isolated with greatest probabi-

F. Staib et al.: CSF indices in cryptococcal meningitis

lity Cr. neoformans and related this to the mentioned observation: (male, homosexual,
questionable disease of the CNS in this 41 years) Cr. neoformans antigen titre in
patient and the isolation of a yeast-like serum 1:100.000; in CSF, 1:1.000; Cr.
fungus from the CSF. At that time there had neoformans CFU count in CSF, 106I ml.
already been reports of therapeutic success CSF indices: Leucocytes 3I 3; protein 28
With amphotericin B in Cr. neoformans mgl dl; glucose 22 mgl dl (glucose in serum
meningitis [9]. In this connexion, Wiebecke 63 mgl dl) [20].
& Staib had drawn attention to the fact that It ensues from these findings in AIDS
in the future, this differential medium for the patients in the course of the Cr. neoformans
examination of specimens from the respira- infection of the meninges, that not the
tory tract should be used in cases presenting protein concentration, but the number of
such clinical problems in order to isolate Cr. CPU of Cr. neoformans or the Cr. neofor-
neoformans before its hematogenous disse- mans antigen titre in the CSF indicate the
mination into the CNS and start systemic stage as well as the prognosis of the infection
antimycotic therapy in time [24]. [18, 19]. Therefore, thechroniccourseof Cr.
neoformans meningitis of non-AIDS pa-
Occurrence of Cr. neoformans in the CSF of tients alone would be the proof of inflamma-
non-AIDS and AIDS patients tion characterized, in the CSF, by an increase
of protein, and elevated count of reactive
It is of interest that in AIDS patients, the cells like in tuberculous meningitis. This is
CSF cell count as well as protein and glucose not found in AIDS patients as it could be
levels may be normal or slightly abnormal, shown above in an example that in the case
whereas in non-AIDS patients suffering of highest counts of CFU of Cr. neoformans
from Cr. neoformans meningitis, these CSF in the meninges, no or only a minimal
indices are mostly abnormal [7, 20]. In non- increase of protein and cell count is found.
AIDS patients the involvement of the
meninges in cryptococcosis can take place in The phenomenon of the spider web coagul-
a chronic course over years [2, 4, 25], um
Whereas in AIDS patients, the occurrence of
Cr. neoformans in the CSF is part of its acute According to the theory of Schmid the spider
hematogenous dissemination from the lungs web coagulum in the CSF in tuberculous
into all organs [ 18, 19]. In AIDS patients, the meningitis is a product of'self-tuberculiniza-
course of the Cr. neoformans infection is tion'[21], in which after cytolysis ofCSFcells,
quantifiable, i.e. with the help of Staib agar the spider web coagulum is formed out of
the CFU count of Cr. neoformans can be cytoplasmatic fibres. Similarly, this pheno-
measured in body fluids and related directly menon may also have been caused by Cr.
to the titres of its antigen which are also neoformansifin Cr. neoformans meningitis, a
detectable in body fluids [18, 19]. Thus, in spider web coagulum is found. Could it be
AIDS patients, the severity of the coloniza- that there is a double infection by Cr.
tion of the meninges by Cr. neofotmans is neoformans and M. tuberculosis in which the
preferably expressed by the level of the CFU delectability of M. tuberculosis is complicated
counts of Cr. neoformansI ml and the titre of to an extent that there is no possibility to
its antigen in the CSF but not by abnormal detect it, but cryptococcosis is found as the
indices of the CSF as they are found in non- dominating infection without, however, being
AIDS patients suffering from chronic Cr. the cause of the spider web coagulum. Thus,
neoformans meningitis [ 18, 19]. One examp- the question arises what spider web coagulum
le of the CSF indices in an AIDS patient formation in the CSF means in cases in which
suffering from cryptococcosis in a late Cr. neoformans is found but not M.
secondary stage shall illustrate the above tuberculosis.

F. Staib et al.: CSF indices in cryptococcal meningitis

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