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411
www.cmj.hr
We report on three patients with mesencephalic aque-
duct obstruction, which completely blocked the cerebro-
spinal uid communication between the third and fourth
cerebral ventricle, demonstrated by standard and high-
resolution magnetic resonance sequences. Only one pa-
tient developed radiological and clinical presentation of
hydrocephalus, without radiological signs of increased
intraventricular pressure. The remaining two patients did
not show clinical signs of hydrocephalus and had a normal
radiological presentation of the ventricular system. These
ndings contradict the classical concept of cerebrospinal
uid physiology. This concept assumes a unidirectional cir-
culation of cerebrospinal uid through the mesencephal-
ic aqueduct from the secretion site, predominantly in the
choroid plexuses, to the resorption site, predominantly in
the dural venous sinuses. Therefore, the obstruction of the
mesencephalic aqueduct would inevitably lead to triven-
tricular hypertensive hydrocephalus in all patients. The cur-
rent observations, however, accord with the new concept
of cerebrospinal uid physiology, which postulates that
cerebrospinal uid does not circulate unidirectionally be-
cause it is both formed and resorbed along the entire cap-
illary network within the central nervous system.
Received: March 3, 2021
Accepted: July 15, 2021
Correspondence to:
Milan Radoš
University of Zagreb School of
Medicine
Croatian Institute for Brain Research
Šalata 12
10 000 Zagreb, Croatia
mrados3@yahoo.com
Milan Radoš1, Darko
Orešković2, Marijan
Klarica1,3
1Croatian Institute for Brain
Research, Zagreb University School
of Medicine, Zagreb, Croatia
2Department of Molecular Biology,
Ruđer Bošković Institute, Zagreb,
Croatia
3Department of Pharmacology,
Zagreb University School of
Medicine, Zagreb, Croatia
The role of mesencephalic
aqueduct obstruction in
hydrocephalus development: a
case report
CASE REPORT
Croat Med J. 2021;62:411-9
https://doi.org/10.3325/cmj.2021.62.411
CASE REPORT
412 Croat Med J. 2021;62:411-9
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The generally accepted classical concept of cerebrospi-
nal uid (CSF) physiology postulates the mesenceph-
alic aqueduct’s patency as one of the preconditions for
maintaining physiological volumes and pressures in the
CSF system. According to the classical concept, CSF is se-
creted predominantly by the choroid plexuses within the
ventricular system. It then ows unidirectionally into the
subarachnoid space at the skull base, from where it cir-
culates to the resorption site, located predominantly in
the dural sinuses and to a lesser extent in the perineural
lymphatic system (1-7). The CSF is thought to be actively
secreted by the choroid plexuses at an approximate rate
of 20 mL/h (8,9). Therefore, even a short-term obstruction
of the mesencephalic aqueduct inevitably leads to the
development of triventricular hypertensive hydrocepha-
lus, which has a characteristic neuroradiological (dilation
of the third cerebral ventricle and lateral ventricles with
transependymal CSF edema) and clinical presentation
(headache, nausea, visual disturbance, drowsiness, bal-
ance disorder).
In this study, we report on three patients of dierent ages
with mesencephalic aqueduct obstruction. We analyzed
their clinical and neuroradiological ndings from the per-
spective of the classical concept of CSF physiology (1-7)
and the Bulat-Orešković-Klarica hypothesis (10-14).
PATIENT 1
Patient 1 was a male preterm infant born at a gestation-
al age of 25 weeks and 2 days (birth weight 740 g, Apgar
5/7/8, head circumference 23.5 cm) (Table 1). Enteral feed-
ing with breast milk was started from the third day and was
well tolerated. At hospital discharge at the corrected age of
36 weeks and 6 days, he had a good weight gain (2590 g,
30 centiles) and normal head circumference (31 cm, 30 cen-
tiles). Ultrasound exam showed grade II periventricular hem-
orrhage, a consequence of preterm birth. Ophthalmologi-
cal exam demonstrated retinopathy of prematurity stage II.
Neuropediatric and neuropsychological exam at a correct-
ed age of 24 months showed psychomotor development in
TABLE 1. Patients’ clinical status, diagnostic procedures, treatment and clinical outcomes
Patient 1
Clinical status premature birth, grade II periventricular hemorrhage, retinopathy of prematurity stage II
Gestational age at birth 25 weeks and 2 days
Apgar score 5/ 7/8
Birth weight 740 g
Treatment non-invasive mechanical ventilation for 57 days, 14 days of high-ow nasal cannula, i.v. parenteral
nutrition for the rst 18 days, enteral intake of breast milk from the third day
First magnetic resonance (MR) exam term-equivalent age
Second MR exam: 2 years
Clinical outcome at a corrected age of 24 months, psychomotor development was in the broader range of normal
(average for gross motor tasks, lower average for ne motor skills, cognition, and speech)
Patient 2
Clinical status premature birth, respiratory distress syndrome, sepsis development
Gestational age at birth 28 weeks and 6 days
Apgar score 6/8
Birth weight 950 g
Treatment invasive mechanical ventilation for 2 days, non-invasive mechanical ventilation for 26 days, high-
ow nasal cannula for 4 days, antibiotic therapy (ampicillin + gentamycin for 10 days)
MR exam at term-equivalent age
Clinical outcome discharged at a corrected age of 38 weeks and 6 days with a normal clinical status
Patient 3
Clinical status poor concentration, headache, forgetfulness, balance disorder, tinnitus, and double vision lasting
seven months.
occasional urinary incontinence for many years
Age 56 years
MR exam 56 years
Treatment endoscopic ventriculostomy two months after MR imaging
Clinical outcome all the symptoms regressed except tinnitus
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Radoš et al: Mesencephalic aqueduct obstruction and hydrocephalus development
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the broader range of normal (average for gross motor tasks,
lower average for ne motor skills, cognition. and speech).
MRI exams, at term-equivalent age and at age 2, were per-
formed on a 3T MR device (Magnet PrismaFIT, Siemens, Ger-
many) using a 64-channel head and neck coil. In addition
to the standard T1 and T2 sequences, we also used a 3D T2
SPC sequence, which is sensitive to CSF movement arti-
facts (TR/TE = 3200/563 ms, resolution: 320 × 320, voxel size
0.8 × 0.8 × 0.8 mm), high-resolution 3D T2 space ZOOMit
sequence (TR/TE = 1100/126 ms, resolution 164 × 320, vox-
el size: 0.5 × 0.5 × 0.5 mm), and high-resolution T1 MPRAGE
sequence (TR/TE = 2300/3 ms, resolution = 256 × 256, voxel
size = 1 × 1 × 1 mm).
MR scan at term-equivalent age showed a complete ob-
struction of the mesencephalic aqueduct by a membrane
in the caudal half of the aqueduct (Figure 1A, Figure 1D).
T2 SPC sagittal scans showed no artifacts indicative of CSF
movement through the aqueduct (Figure 1B). In contrast,
these artifacts were visible in the foramen of Magendie and
cranio-cervical junction (Figure 1B). Axial and coronal scan
through the brain parenchyma showed the third cerebral
ventricle and lateral ventricles of appropriate size (Figures
FIGURE 1. A magnetic resonance (MR) exam in Patient 1 at term-equivalent age. A mediosagittal T2 ZOOMit section shows a mem-
brane in the caudal half of the mesencephalic aqueduct (arrow in A). Artifacts of cerebrospinal uid movement are visible in the area
of the foramen of Magendie and cranio-cervical junction (arrows in B), but are absent from the mesencephalic aqueduct (arrowhead
in B). An axial T2 ZOOMit section through the mesencephalic aqueduct cranial to the obstruction site shows a maintained aqueduct
lumen (arrow in C). An axial T2 ZOOMit section through the aqueductal membrane shows a complete obstruction of the mesen-
cephalic aqueduct (arrow in D). An axial T2 ZOOMit section through the mesencephalic aqueduct caudal to the obstruction site
shows a maintained aqueduct lumen (arrow in E). Axial (F) and coronal (G) T2 sections through the brain parenchyma show normal
volume of the lateral ventricles and third cerebral ventricle.
CASE REPORT
414 Croat Med J. 2021;62:411-9
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1F and 1G), without radiological signs of triventricular hy-
pertensive hydrocephalus (Evans’ index = 0.28).
At age 2, the scan (Figure 2) showed a passable lumen
of the mesencephalic aqueduct (Figure 2A and 2D), with
pronounced CSF movement artifacts (Figure 2B). The pre-
sented images indicate that a spontaneous rupture of the
aqueduct membrane between the two MR exams estab-
lished the CSF communication between the third and
fourth ventricle.
PATIENT 2
Patient 2 was a preterm female infant born at a gestation-
al age of 28 weeks and 6 days (birth weight 950 g, Apgar
6/8, head circumference 26 cm). After delivery, the pa-
tient developed respiratory distress syndrome requiring
non-invasive and invasive mechanical ventilation. She also
developed sepsis, but recovered completely after antibi-
otic therapy. The child was discharged at a corrected age
of 38 weeks and 6 days, with a bodyweight of 2490 g (3
centiles), head circumference of 32 cm (5 centiles), and
normal clinical status. MR exam was performed at term-
equivalent age with the same MR sequences as described
for Patient 1. The scan showed an obstruction of the cra-
nial portion of the mesencephalic aqueduct (Figures 3A
and 3D), which completely blocked the CSF communica-
tion between the third and fourth cerebral ventricle. T2
SPC sagittal scans showed no artifacts of CSF movement
throughout the mesencephalic aqueduct. The artifacts
FIGURE 2. A magnetic resonance (MR) exam in Patient 1 at the age of 2 years. A mediosagittal MPRAGE section shows a passable
mesencephalic aqueduct without an aqueductal membrane (arrow in A). Cerebrospinal uid movement artifacts are visible on the
T2 SPC sequence in the mesencephalic aqueduct (arrowhead in B). An axial MPRAGE section through the cranial part of the mesen-
cephalic aqueduct shows a maintained aqueduct lumen (arrow in C). An axial MPRAGE section shows the patency of the mesen-
cephalic aqueduct at the level where a membrane was previously visible (arrow in D). An axial MPRAGE section through the caudal
part of the mesencephalic aqueduct shows a maintained aqueduct lumen (arrow in E). Axial (F) and coronal (G) T2 sections through
the brain parenchyma show normal volume of the lateral ventricles and third cerebral ventricle.
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Radoš et al: Mesencephalic aqueduct obstruction and hydrocephalus development
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were visible in the foramen of Magendie and craniocervi-
cal junction (Figure 3B). Axial and coronal sections through
the brain parenchyma (Figure 3F and 3G) showed the third
cerebral ventricle and lateral ventricles of appropriate size
(Evans’ index = 0.26), without radiological and clinical signs
of triventricular hypertensive hydrocephalus.
PATIENT 3
Patient 3 was a 56-year-old man referred for MR exam due
to poor concentration, headache, forgetfulness, balance
disorder, tinnitus, and double vision lasting seven months.
He also complained of occasional urinary incontinence for
many years. The scanning was performed with the same
3T MR device as described for the two other patients. In
addition to standard T1 and T2 cross-sections, high-resolu-
tion T2 CISS cross-sections (TR/TE = 5.3/2.4 ms, resolution
266 × 256; voxel 0.6 × 0.6 × 0.6 mm) were obtained through
the area of the mesencephalic aqueduct.
MR exam showed a complete obstruction of the central
part of the mesencephalic aqueduct by an aqueductal
membrane (Figure 4A, 4B, and 4C). Axial (Figure 4D) and
coronal (Figure 4E) sections through the brain parenchy-
ma showed an enlarged third cerebral ventricle and lateral
ventricles (Evans’ index = 0.44) but no signs of transependy-
mal CSF edema suggestive of intraventricular pressure in-
crease. These clinical and neuroradiological ndings are
FIGURE 3. A magnetic resonance (MR) exam in Patient 2 at term-equivalent age. A mediosagittal T2 ZOOMit section shows an
obstruction in the cranial portion of the mesencephalic aqueduct (arrow in A). Artifacts of cerebrospinal uid movement are visible
in the area of the foramen of Magendie and the cranio-cervical junction (arrows in B), but are completely absent from the mesen-
cephalic aqueduct (arrowhead in B). An axial T2 ZOOMit section through the mesencephalic aqueduct cranial to the obstruction
site shows a maintained aqueduct lumen (arrow in C). An axial T2 ZOOMit section at the obstruction level shows a completely
obstructed aqueduct lumen (arrow in D). An axial T2 ZOOMit section through the mesencephalic aqueduct caudal to the obstruc-
tion site shows a maintained aqueduct lumen (arrow in E). Axial (F) and coronal (G) T2 sections through the brain parenchyma show
adequate volume of the lateral ventricles and third cerebral ventricle.
CASE REPORT
416 Croat Med J. 2021;62:411-9
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characteristic of late-onset aqueductal membranous oc-
clusion (LAMO) hydrocephalus. Based on the clinical pic-
ture and neuroradiological ndings, the patient under-
went endoscopic ventriculostomy two months after MR
imaging, which led to a regression of all symptoms, except
tinnitus.
DISCUSSION
In this study, we demonstrated in three patients how a
blocked mesencephalic aqueduct could result in dier-
ent neuroradiological and clinical outcomes, ranging from
an entirely normal neuroradiological and clinical status to
clinically and neuroradiologically veried hydrocephalus.
MRI scans performed in Patient 1 and Patient 2 at a neona-
tal age showed that it was possible for patients to have a
completely obstructed mesencephalic aqueduct without
showing clinical and radiological signs of triventricular hy-
pertensive hydrocephalus. This nding is in contrast to the
classical concept of CSF physiology, which postulates that
about 500 mL of CSF a day is actively secreted (which is in-
dependent of intraventricular pressure) predominantly in
the choroid plexuses of the lateral ventricles (8,9). This
amount of CSF then passes through the mesenceph-
alic aqueduct before being resorbed predominantly in the
dural venous sinuses. Therefore, an obstruction of the mes-
encephalic aqueduct lasting only a few hours would nec-
essarily change both the CSF volume and pressure within
the third cerebral ventricle and lateral cerebral ventricles
due to the accumulation of newly secreted CSF.
However, both patients’ ndings accord with the Bulat-
Orešković-Klarica hypothesis, which assumes that the in-
tracranial uids exchange is controlled by osmotic and hy-
drostatic forces in the capillaries and interstitium and that
it takes place on the capillary membrane along the entire
nervous system (15-17). This means that depending on
these forces CSF can be formed and resorbed at the same
site. According to this hypothesis, there is no dominant CSF
secretion site or a unidirectional movement. Numerous
studies have shown that ventriculo-cisternal perfusion, as
the only generally accepted method for determining CSF
secretion, is a technical artifact. Namely, ventriculo-cister-
nal perfusion has been shown to measure CSF secretion
even in experimental animals sacriced with anesthetic
overdose (18-21).
Animal experiments showed no expected increase in CSF
pressure or ventricular dilation proximal to the obstruction
FIGURE 4. A magnetic resonance (MR) exam in Patient 3 at the age of 56 years. A mediosagittal T2 sequence shows an aqueductal
membrane obstructing the mesencephalic aqueduct (arrow in A). 3D T2 CISS sections showing the aqueductal membrane com-
pletely dividing the central part of the mesencephalic aqueduct in the sagittal (B) and coronal planes (C). Axial (D) and coronal (E) T2
sections through the brain parenchyma show an enlarged third ventricle and lateral ventricles without transependymal cerebrospi-
nal uid edema that would indicate increased intraventricular pressure.
417
Radoš et al: Mesencephalic aqueduct obstruction and hydrocephalus development
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site in the case of an aqueduct blockade lasting several
hours (20). In addition, clinical observations demonstrated
that long-term stenosis/obstruction of the aqueduct with-
out hydrocephalus development was possible even when
the patient was monitored for ve years (21). Advanced
neuroradiological methods (time-spatial inversion pulse)
that visualize CSF movements showed only pulsatile, os-
cillatory movements of the CSF volume in all directions
within the CSF system, with no net circulation in one di-
rection (22).
Although Patients 1 and 2 had aqueduct obstruction with-
out signs of hydrocephalus, a signicant number of pa-
tients with aqueduct obstruction/stenosis do develop
LAMO hydrocephalus, and some undergo endoscopic
ventriculostomy (Patient 3) or placing of a drainage shunt
due to a worsening clinical status (23-25). Despite obstruc-
tion/stenosis of the mesencephalic aqueduct in patients
with LAMO hydrocephalus, hydrocephalus development
cannot be explained by the classical concept. Namely, the
classical concept cannot clarify why patients with aque-
duct stenosis/obstruction often need surgery only later
in life, as was the case in our Patient 3, although stenosis/
obstruction had most likely been present for a long time,
even before birth in some cases (26-28). Furthermore, these
patients, despite the increase in CSF volume in the lateral
ventricles and third ventricle, did not have an increased in-
traventricular pressure (Patient 3), as would be expected
according to the classical concept.
Thus, the cases described in the current article do not ac-
cord with the generally accepted classical hypothesis, war-
ranting a new explanation of the pathophysiological con-
sequences of the mesencephalic aqueduct obstruction.
Obstruction/stenosis of the mesencephalic aqueduct has
been shown to decrease/interrupt the bidirectional oscilla-
tory movement of CSF through the mesencephalic aque-
duct that physiologically occurs during systole and diasto-
le. This interruption changes the biomechanical load of the
periventricular tissue (29). Prolonged exposure to altered
biomechanical loading in dierent patients could lead to
varying degrees of ventricular dilatation, ranging from nor-
mal ndings to arrested hydrocephalus (30-32), or to neu-
roradiological and clinical presentation of hydrocephalus.
In patients with Chiari type 1 malformation, hydrocepha-
lus often occurs due to the reduction/interruption of bi-
directional CSF movement at the cranio-cervical junction.
However, in Chiari type 1 malformation, assumed intracra-
nial secretion, circulation, and CSF resorption are not dis-
turbed (33,34). A similar pathophysiological mechanism is
likely found in patients with spinal tumors who develop
hydrocephalus (35).
In Patient 1, a spontaneous rupture of the aqueduct mem-
brane established the CSF communication between the
third and fourth brain ventricle. Clinical practice has shown
that sometimes patients with an obstructed mesenceph-
alic aqueduct experience spontaneous ventriculostomy,
which establishes the CSF communication between the
third ventricle and suprasellar cisterns (36-38). This obser-
vation could be explained by the previously mentioned
changes in tissue biomechanical load due to a decreased/
interrupted CSF bidirectional oscillatory movement.
Therefore, CSF obstruction at the aqueduct level causing
ventricular dilatation without pressure rise is completely
inexplicable by the classical hypothesis of CSF physiology.
The described examples, however, accord with the Bulat-
Orešković-Klarica hypothesis, which postulates that the ob-
struction of the mesencephalic aqueduct does not neces-
sarily imply hydrocephalus development. This hypothesis
denes hydrocephalus as a pathological state where CSF is
excessively accumulated inside the cranial part of the CSF
system, predominantly in one or more brain ventricles, as
a consequence of impaired hydrodynamics of intracranial
uids between the CSF, brain (interstitial and intracellular
uids), and blood compartments (13).
Funding This work was supported by University of Zagreb, institutional -
nancial research support (Projects: 1. Regulation of Volume and Pressure of
Cerebrospinal Fluid. No. 380-59-10106-20-2502; and 2. Neuroradiological
Biomarkers of Normal and Impaired Perinatal Brain Development. No. 380-
59-10106-19-4867). This work was co-nanced by the Scientic Centre of
Excellence for Basic, Clinical and Translational Neuroscience project “Experi-
mental and Clinical Research of Hypoxic-Ischemic Damage in Perinatal and
Adult Brain”; GA KK01.1.1.01.0007 funded by the European Union through
the European Regional Development Fund.
Ethical approval Patients or legal guardians consented to data/images
publication.
Declaration of authorship All authors conceived and designed the study;
MR acquired the data; all authors analyzed and interpreted the data; all au-
thors drafted the manuscript; all authors critically revised the manuscript
for important intellectual content; all authors gave approval of the version
to be submitted; all authors agree to be accountable for all aspects of the
work.
Competing interests MK is Dean of the University of Zagreb School of Med-
icine, one of the owners of the Croatian Medical Journal. To ensure that any
possible conict of interest relevant to the journal has been addressed, this
article was reviewed according to best practice guidelines of international
editorial organizations. All authors have completed the Unied Competing
Interest form at www.icmje.org/coi_disclosure.pdf (available on request
from the corresponding author) and declare: no support from any orga-
nization for the submitted work; no nancial relationships with any or-
ganizations that might have an interest in the submitted work in the
previous 3 years; no other relationships or activities that could appear
to have inuenced the submitted work.
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