Epidural space and regional anesthesia

Jos De Andrs
a
, Miguel Angel Reina
b,
*
, Alberto Prats
c
a
Department of Anesthesiology, Consorcio Hospital General Universitario de Valencia, Valencia, Spain
b
Department of Anesthesiology, Hospital Universitario Madrid Monteprncipe, Madrid, Spain
c
Department of Anatomy and Embriology, Facultad de Medicina, Universidad de Barcelona, Barcelona, Spain
a r t i c l e i n f o
Article history:
Received 2 May 2009
Received in revised form 30 June 2009
Accepted 21 July 2009
Keywords:
Regional
Analgesia
Epidural
Anatomy
Fat
Root cuffs
Drug kinetics
Dural sac
Subdural space
a b s t r a c t
Epidural fat provides sufcient cushion for the pulsatile movements of the dural sac, protects nerve struc-
tures, facilitates the movement of the dural sac over the periosteum of the spinal column during exion
and extension, and forms a pharmacologic reservoir of lipophilic substances. Root cuffs have a cellular
component that affects the passage of substances injected epiduraly or near the intervertebral foramen,
depending on the site of injection, preganglionar, postganglionar or ganglionar. We found fat inside root
cuffs but not within the dural sac. Fat in this location may have affect kinetics of lipophilic drugs injected
near nerve root cuffs. Ultrastructural morphology of the cellular component at preganglionar level may
help explain unexpected subdural blockade after injection of local anesthetic via transforaminal route.
Other morphological aspects of nerve root cuffs help to understand the function of the blood-nerve
barrier.
Based in this anatomical knowledge, we can speculate on the possible anesthetic implications of epi-
dural fat in terms of the pharmacokinetics of drugs injected into the epidural space and the tasks of locat-
ing the epidural space and inserting an epidural catheter during anesthetic procedures.
2009 European Federation of International Association for the Study of Pain Chapters. Published by
Elsevier Ltd. All rights reserved.
1. Introduction
The morphology, size and contents of the epidural space (ES)
are of interest in the practice of regional anesthesia, specically
for neuroaxial blockade and in relation to the placement and distri-
bution of the injected solutions.
Our group has worked in the eld of applied anatomy knowl-
edge for the practice of regional anesthesia since 1995, on which
we began the analysis of repercussion of carrying cells or frag-
ments of epithelial tissue into the epidural or intradural space with
epidural or intradural puncture with inappropriately stiffened or
improperly placed needles.
In the present article was view knowledge of the ES, including
new anatomical aspects that may enlighten classical descriptions.
2. Limits of the epidural space
In sagital and parasagital sections, the ES is a cylindrical com-
partment lled with fat and blood vessels, while in axial sections
appears as a circumference with variable thickness (Hogan,
1996a,b).
The ES is lies within the vertebral canal, stretching from the
occipital foramen to the lower limit of the sacral canal. In the ce-
phalic region, the dura mater adheres to the periosteum at the bor-
der of the foramen magnum. In the caudal region, the ES extends
beyond the fundus of the dural sac to the sacral hiatus (Parkin
and Harrison, 1985; Husemeyer and White, 1980; Grenier et al.,
1987).
In axial sections, the vertebral canal is limited anteriorly by the
posterior longitudinal ligament, which covers the vertebral bodies
and intervertebral discs. The posterior longitudinal ligament sepa-
rates the anterior border of the ES from the anterior vertebral
plexus, where the basivertebral veins that penetrate the vertebral
bodies originate (Parkin and Harrison, 1985; Husemeyer and
White, 1980; Grenier et al., 1987).
Laterally, the vertebral canal is limited by the vertebral pedicles
that form the intervertebral foramina, while posteriorly it is delim-
ited by the vertebral laminas and the ligamentum avum (Fig. 1 and
2) The right and left portions of the ligamentum avum join to-
gether at 90 angles. In some places these unions are incomplete,
leaving gaps between them. Such gaps appear more frequently in
the ES at the level of the cervical spine.
The dural sac envelops the spinal cord over its entire extension.
Below the second lumbar vertebra, the spinal cord turns into a -
brous cord (lum terminale) anchored to the inner side of the dural
sac (second sacral vertebra). Beyond the second sacral vertebra, the
1754-3207/$36.00 2009 European Federation of International Association for the Study of Pain Chapters. Published by Elsevier Ltd. All rights reserved.
doi:10.1016/j.eujps.2009.07.004
* Corresponding author.
E-mail address: miguelangel@perticone.e.telefonica.net (M.A. Reina).
European Journal of Pain Supplements 3 (2009) 5563
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dural sac becomes the coccygeal ligament and attaches to the
coccyx.
3. Dural sac xation ligaments
The dural sac is anchored to the vertebral canal over its entire
extent by brous formations that cross the ES: the anterior, lateral
and posterior meningo-vertebral ligaments (Reina et al., 1998a),
the posterior meningo-vertebral ligament is also known as
Giordalengo ligament. The anterior ligaments afxed to the pos-
terior longitudinal ligament are more compact (Plaisant et al.,
1996). In some patients, the brous aps that x the dural sac to
the posterior longitudinal ligament may incompletely divide the
anterior ES in two parts. In the sacral canal, these ligaments be-
come thicken to form a perforated medial septum, the anterior sa-
cral ligament of Trolard. The lateral and posterior meningo-
vertebral ligaments are thinner and do not alter free circulation
of uids injected within the ES.
In 1976 was described a fold of the dural sac in the posterior ES
(Luyendijk, 1976). Posteriorly, several authors (Blomberg, 1986;
Savolaine et al., 1988; Blomberg and Olsson, 1989), described the
plica dorsalis medianalis as a longitudinal but discontinuous -
brous structure in the mid-sagital zone along the posterior ES, par-
ticularly in the lumbar region. This brous septum of the posterior
ES was not found in the histological and cryomicrotome section
Fig. 1. MRI Image reconstruction of lumbar spine. A: Intervertebral foramen. D:
Dural sac and epidural space.
Fig. 2. Formaldehyde preserved samples of lumbar spine in cadavers. A and B:
Sagital view in different levels of the vertebral body. Detail of epidural space and fat.
C: Sacral cut. Detail of epidural space, fat and end of dural sac.
56 J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563
studies carried out by Hogan (Hogan, 1991, 1996a,b). Probably, the
structure described by the above mentioned authors coincides with
the posterior xation edge of the posterior epidural adipose tissue.
4. Dural sac
Ninety percent of the external portion of the thickness of the
dural sac belongs to dura mater (Reina et al., 2002a; De Andrs
et al., 2000). This brous structure confers mechanical resistance
and is also permeable. The remaining internal 10% of the dural
sac is formed by the arachnoid lamina, which is a cellular lamina
of little mechanical resistance. The arachnoid lamina is semiperme-
able, and affects the passage of substances through the thickness of
the dural sac. The shape of the dural sac is cylindrical and its thick-
ness is variable (Fig. 3A). In the cervical region is about 1 mm thick
and becomes gradually thinner as it descends; in the lumbar region
the thickness is 0.320 mm. However, in the lumbar region, there are
differences in thickness between the antero-posterior and lateral
zones for the same vertebral level (Reina et al., 1999a,b).
The histological structure and biomechanical properties can
yield information of interest (Fink and Walker, 1989; Patin et al.,
1993) when studying dural lesions following lumbar puncture
(Reina et al., 2000, 2004a,b,c,d).
4.1. Dura mater
The electron microscope allowed us to examine ultra-structure
of tissues. When studying the thickness of the dura mater with the
help of a scanning electron microscope (SEM), about 80 concentric
dural laminas can be seen (Fig. 3B). Each dural lamina has a thick-
ness of 5 microns (lm) and is made in turn by thinner laminas
(approximately 812 subunits) (Reina et al., 1996, 1997). Collagen
bers are the laminas main component. These collagen bers are
oriented in different directions between the subunits that conform
each dural lamina, but always within the concentric plane of each
dural lamina (Dittmann et al., 1998; Reina et al., 1996a,b). The -
bers do not go across different dural laminas. Each collagen ber
measures approximately 0.1 lm and presents a smooth surface
(Fig. 3C). Elastic bers are also present in lesser proportion. These
bers measure 2 lm in diameter and have a rough surface. Looking
at the dural sac from within the ES, the external surface of the out-
er dural lamina can be seen. In this dural lamina as in the inner
laminas, the bers do not run longitudinal and parallel to the axis
of the vertebral column, as shown by classical descriptions (Ditt-
mann et al., 1998; Reina et al., 1996a,b).
4.2. Arachnoid lamina
The arachnoid lamina had been dened as a ne membrane in
contact with (but not adhering to) the internal surface of the dura
mater. The subdural space was described as a virtual space
between the arachnoid lamina and the dura mater, though this
concept has since been modied (as commented in the section
on the subdural space) (Reina et al., 1998b, 2002b,d). The arach-
noid lamina is a semipermeable membrane and thus exerts a
barrier effect (Fig. 4). Its thickness is about 1520 lm, and is com-
posed of cells strongly bonded by specic membrane junctions
(Reina et al., 1998b) (Fig. 4B). The intercellular space is thought
to contain collagen bers that reinforce this structure in order to
increase its mechanical resistance.
4.3. Trabecular arachnoid layer
The arachnoid trabecular layer is placed internally to the arach-
noid lamina, and is composed of strongly bonded cells, giving up
Fig. 3. Human dural sac. A: Cut at the distal end level of spinal cord. B: Partial
thickness of lumbar dura mater. Detail of dural laminas using Scanning Electron
Microscopy. C: Partial thickness of lumbar dura mater. Detail of collagen bers
(thin) and elastic bers. (thick) por using transmission electron microscopy.
J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563 57
aps that in turn conform the spider web-like trabecular structure
found in the subarachnoid space and in the adventitial layer of
blood vessels (Reina et al., 1999a,b)
.
The arachnoid trabeculate
gives shape to tubular structures for each nerve root, as well as
for the spinal cord. Part of these arachnoid trabeculae extends to
the pia mater (Reina et al.,, 2004a).
4.4. Subdural space
In contrast to classical descriptions, ultra structural studies
show no space between the dura mater and the arachnoid lamina
(Reina et al., 2002a,b,c,d). In the subdural space there is tissue com-
posed of specialized cells called neurothelial cells. These elongated,
fusiform cells with branched extensions are fragile and scantly
cohesive to each other (Reina et al., 1998b, 2002b,d).
The subdural compartment has neurothelial cells located be-
tween the last dural lamina and the barrier arachnoid lamina.
When tearing occurs within the thickness of the subdural compart-
ment, small ssures convene into larger ones, opening up the sub-
dural space; intercellular spaces between neurothelial cells are
most susceptible to tearing, and cellular fragments may be seen
outside torn neurothelial cells (Fig. 5). Low cohesion forces be-
tween neurothelial cells facilitate the widening of a minimal s-
sure to yield a genuine subdural space; other smaller ssures
can be seen parallel to the main space, and are called secondary
subdural spaces (Reina et al., 1998b, 2002b,d).
Mention should be made to the lack of collagen bers surround-
ing the neurothelial cells. Such collagen bers are abundant around
arachnoid cells and in the dural laminas. Arachnoid cells present
specialized junctions, in contrast to the neurothelial cells, that lack
such junctions. It has been reported that tearing of the neurothelial
cells gives rise to a true subdural space that would not be present
otherwise. Therefore, the term virtual subdural space is incorrect
(Reina et al., 1998b, 2002b,d).
The study of the structure of the subdural compartment allows
us to understand the origin of cranial and spinal subdural hemato-
mas associated with cerebrospinal uid (CSF) hypotension (Reina
et al., 2004c,d).
4.5. Properties of the dural sac
The dural sac is mostly composed of collagen bers, with a les-
ser proportion of elastic bers, conferring viscoelastic properties to
this structure. As a result, the diameter of the dural sac can be
modied to establish a balance between CSF pressure and volume.
Variations in thoracic pressure are transmitted across the ES to the
dural sac. Distension of the epidural veins or the injection of a solu-
tion within the ES can also induce modications in the diameter of
the dural sac.
4.6. Spinal nerve root cuff
Prolongations of the dural sac in the sides of the ES conforms
the so-called dural sleeves or spinal nerve root cuff (Fig. 6). These
are formed by lateral extensions of the dura mater and of the
arachnoid lamina, that fuse around nerve roots at their exit of
the vertebral canal (Hogan and Toth, 1999). The dural sac folds
around the nerve root before given away the dural sleeve, such
folding contain CSF. In parts of dural sleeves, the dura mater is
thinner and measures approximately 80 lm in thickness.
5. Epidural space
The ES has areas characterized by a genuine space lled with
adipose tissue, veins and nerves, together with other areas that
show a virtual space where the dural sac rests on the vertebral
bodies, the vertebral pedicles, the vertebral laminas and the liga-
mentum avum (Fig. 2). The external surface of the dural sac is free
and does not adhere to the vertebral canal.
The virtual part of the ES becomes a genuine or true space when
solutions or air are injected in it. In this case the dural sac separates
from its neighboring structures being partially compressed its
diameter is therefore reduced, displacing the CSF. The study of
the epidural fat (EF) and its distribution along the spinal column
helps identifying places where true ES is found.
Fig. 4. Human Arachnoid lamina. A: Duramater opening during spine surgery.
Arachnoid lamina is showed as translucent. B: Different cellular components are
part of the thickness of the Arachnoid lamina and contributes to the dural sacs
semipermeability properties. Specialized membrane junctions between cells pro-
duced the barrier effect. Scanning electron microscopy.
58 J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563
Fig. 5. Subdural compartment and subdural space. A: La lmina aracnoidea (lmina
delgada interna) se separa de la duramadre (lmina externa gruesa) y se forma el
espacio subdural. Scanning electron microscopy. B: Subdural compartment has
neurothelial cells located between the last dural lamina and the barrier arachnoid
lamina. Tearing within the thickness of these cells may open up the subdural space.
Scanning electron microscopy. C: Neurothelial cells observed by Scanning electron
microscopy. Cohesion forces between neurothelial cells are lower than between
arachnoid cells.
Fig. 6. Dural nerve root cuffs. A: scale paper allows for measuring this structure. B:
Thickness of dural nerve root cuff is formed by dural laminas with adipose tissue
among them. Adipocytes from longitudinal and transversal cuts were empty,
displaying an image similar to a honey comb. Dural Lamina was found in the outer
portion of spinal nerve root cuffs. In the inner part are placed motor and sensory
cords. Scanning electron microscopy. C: Surrounding individually each motor and
sensory cord there are transitional Cellular layers that are controlling the
substances crossing of spinal nerve root cuff thickness. Transmission electron
microscopy.
J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563 59
5.1. Anterior, lateral and posterior epidural space
Although the structure of ES is very similar throughout the ver-
tebral canal, small successive morphological changes can be ob-
served between neighboring metameric segments. The posterior
side of the ES in each metameric segment has parts of dural sac at-
tached to the bone, beneath the upper half of each vertebral lam-
ina. Laterally, the dural sac becomes in contact with the
ligamentum avum in zones close to the facet joints. In turn, the
anterior side of the ES is leveled with the intervertebral discs (Ha-
mid et al., 2002). In these areas the space appears interrupted be-
cause the dura mater comes in contact with the vertebral canal.
Below the fth lumbar vertebra, the dural sac diminishes and the
anterior ES increases in size as a result of which, administered local
anesthetic solutions are able to diffuse among non-neural struc-
tures, resulting in less predictable block of nearby nerve roots.
In the lumbar region, the shape of the posterior side of the ES is
triangular (Fig. 1). The apex of this triangle is given by the union of
the superior and inferior vertebral laminas with the ligamentum
avum. Its width reaches and can even exceed 513 mm in adults.
In the dorsal region, the ES gradually narrows, and its width can be
limited to only a few millimeters at the level of the lowest cervical
vertebras disappearing almost entirely on coming into contact
with the rst two vertebras.
5.2. Epidural fat in adults
The EF contributes to shape the real ES. The lumbar EF presents
a metameric and discontinuous topography. Is mainly located in
the posterior part of the ES, in the axial (transverse) plane stretch-
ing towards the intervertebral disc. Deposits of fatty tissue in the
axial plane have a morphology similar to a tetrahedron with a
blunt posterior apex in contact with the ligamentum avum, and
an anterior base oriented towards the posterior surface of the dural
sac, limited laterally by the vertebral arches.
5.3. Lateral, posterior and anterior epidural fat
The EF extends laterally towards the point where articular fac-
ets and ligamentum avum meet (Daniel et al., 1992a,b). The EF is
located between the vertebral arches and laterally to the interver-
tebral foramina, wrapping around nerve roots within the dural
sleeves (Fig. 2). It spreads between half of one vertebral lamina
and the upper portion of the next lower vertebral lamina. The EF
does not adhere to these structures, allowing displacement of the
dura within the vertebral canal during exion (Reina et al., 2006).
The EF adheres to the posterior midline by a vascular pedicle
that enters into the EF at a point where the right and left portions
of the ligamentum avum join together. The volume of these pos-
terior EF deposits increases downwards, from L
12
to L
45
. The
height of these fatty deposits is approximately 21 mm (range 16
25 mm). Their width increases in the crania-caudal direction from
6 mmto 9 mm, 11 mmand 13 mm, respectively, in the four lumbar
interspaces.
The pedicle of the posterior EF coincides topographically with
the plica mediana dorsalis.
Fatty tissue deposits are in contact with the posterior surface of
the dural sac and the vertebral lamina adhering only to the vascu-
lar pedicle.
In the posterior EF, the fatty tissue is homogeneous and without
any apparent brous septae. In the lateral EF, the fatty tissue ap-
pears divided (Daniel et al., 1992a,b). In many samples, a septal
plane extends from the nerve root exit at the vertebral lamina to
the posterior longitudinal ligament.
In the anterior ES, the dura mater joins the vertebral canal at the
height of the discs. It is in this anterior epidural region where the
anterior venous vessels are found.
5.4. Epidural fat in the cervical, thoracolumbar and sacral epidural
space
EF presents a variable distribution in the cervical, upper tho-
racic, lower thoracic, lumbar or sacral territories. This distribution
remains constant within each vertebral level (Reina et al.,
2004a,b,c,d). At cervical level, the fatty tissue is absent or almost
inexistent, and it sometimes forms a small posterior deposit seen
in axial sections of magnetic resonance imaging scans from C
7
to
T
1
, with an enhanced signal in T1-weighted sequences. In the ante-
rior and lateral regions, no EF is generally found.
At thoracic level, the EF forms a broad posterior band with
indentations (Reina et al., 2006). It is thicker in the region of
the intervertebral space and proximal to the intervertebral disc,
and becomes thinner in the middle-zone of the vertebral bodies
and close to the base of the spinous processes of each vertebra.
In the upper-middle thoracic zone (T
17
), the EF follows a continu-
ous pattern and the indentations are more manifest, in the lower
thoracic region (T
812
) the EF becomes discontinuous (Reina
et al., 2006).
At lumbar level, the EF in the anterior and posterior ES is found
apart. The posterior EF acquires its greatest volume close to the
discs of L
34
and L
45
. In some patients, the posterior EF is cup-
shaped with the apex located posteriorly, and part of the EF meets
with fatty tissue from the intervertebral foramen. In humans, the
thickness of the EF in the lower lumbar zone can occupy about
32% of the sagittal diameter of the vertebral canal.
Below L
45
the dural sac ends and the sacral canal begins. In this
zone where the nerve roots are enveloped by the dural sleeves, EF
is the principal component.
5.5. Inuence of age upon epidural fat
The anatomy of the ES can be inuenced by age. At two years of
age, the EF is abundant between the dural sac and the vertebral
laminas. At 10 years of age the EF adopts the adult distribution pat-
tern, with posterior compartments separated due to contact be-
tween the dura mater and the vertebral lamina (Reina et al.,
2006). In adults, the anterior ES is extensively occupied by EF at
caudal level.
5.6. Epidural fat in different pathologies
The usual distribution of the EF and its characteristics can be al-
tered in different pathological conditions (Reina et al., 2007a). In
such cases the morphology of the genuine or real ES is modied.
Epidural lipomatosis is characterized by an increase in EF volume.
This excessive fat deposits around the dural sac causes spinal cord
or nerve root compression, leading to neurological symptoms
(Daniel et al., 1992a,b; Quint et al., 1988). In some patients, the ori-
gin of these excessive EF deposits may be secondary to the admin-
istration of exogenous steroids (Roy-Camille et al., 1991; Fessler
et al., 1992), an increase in endogenous steroids (Cushing syn-
drome), or the ectopic production of glucocorticoids in paraneo-
plastic syndromes (Koch et al., 1999) (paraneoplastic Cushing
syndrome). In other cases the origin is unclear (idiopathic). In
kyphoscoliosis, the EF is distributed asymmetrically, where fatty
tissue predominates in the concave portion of the curvature, while
the spinal cord contacts the vertebral arch. In the stenosis of the
spinal canal, the presence of EF is reduced in the stenotic zone
(Prasartritha et al., 1997).
60 J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563
6. Ligamentum avum
The ligamentum avum occupies the space between interverte-
bral laminas, attaching to the anterior surface of the lower margin
of each upper lamina and to the posterior surface of each lower
lamina. The ligament has an anterolateral extension, reinforcing
the medial portion of the capsule of the facet joint, with which it
fuses laterally. The thickness of the ligamentum avum in the axial
plane, in adult, varies between 3 mm and 5.5 mm. Embryologically,
the ligamentum avum presents right and left portions joining to-
gether in the midline (Lirk et al., 2004). In a number of patients,
such fusion has defects, appearing gaps in the mid-sagittal plane.
In a study of 45 cadavers, these gaps were found in 22% of the cases
in L
12
; 11% in L
23
; 11% in L
34
; 9% in L
45
; and 0% in L
5
S
1
(Lirk
et al., 2004). At the level of this fusion line is where small vascular
pedicles emerge and travel towards the fatty tissue deposits in the
posterior ES. During the performing of an epidural block, these
gaps in the thickness of the ligamentum avum can be wrongly
interpreted as ES do to loss of resistance.
7. Epidural vessels
The main venous plexuses within the ES are the right and left
posterolateral and anterolateral longitudinal plexuses. These veins
lack valves and are located sufciently lateral, therefore are unli-
kely to be damaged when performing lumbar puncture via the
mid-sagittal plane. These longitudinal plexuses join anteriorly,
posteriorly and laterally via transverse plexuses. The veins of the
posterior transverse plexus are more vulnerable, and are located
in the dorsolumbar region close to the vertebral laminas and more
distant from the ligamentum avum. The lateral transverse plex-
uses give rise to the veins that emerge from the vertebral canal
through the intervertebral foramina.
The lymphatic network surrounding and draining the fundus of
the dural sleeves are distributed in front of each intervertebral
foramen, and drain into the longitudinal canals anterior to the
spinal canal.
8. Spinal nerve root cuff
The inuence of spinal nerve root cuffs or dural sleeves on the
distribution of local anesthetics injected in the epidural space is
relevant to anesthetists performing epidural blocks (Bromage,
1978) and selective nerve root blockade (Vad et al., 2002; Gajraj,
2004). Ultrastructural details explained here, may help understand
the role of spinal nerve root cuffs on the spread of substances in-
jected in the epidural space and in selective nerve root blockade;
for example, the effects of solutions containing as little as 2 ml of
local anesthetic and corticoids injected in the epidural space or
close to nerve roots, can last for two months. Nerve root cuffs,
are lateral prolongations of dura mater and arachnoid lamina,
enclosing spinal nerve roots in their way across the epidural space
towards the intervertebral foramen. Nerve root cuffs have internal
cellular and external brillar components, respectively.
8.1. Internal cellular component
Using immune-histochemical techniques, we identied the cel-
lular component of root cuffs as leptomeningeal cells, similar in
nature to arachnoid or pial cells (Fig. 6C). These cells are elongated,
wider around the nucleus, stratied and oriented longitudinal to
the nerve root axis. Using transmission electron microscopy, we
observed transversal and longitudinal samples from nerve roots
and their cuffs at preganglionar, ganglionar and postganglionar
levels. At preganglionar level, the nerve roots and their cuffs occu-
py the epidural space and extend from the dural sac to the dorsal
root ganglion (DRG). Ganglionar level is often placed between the
inner and outer boundaries of the intervertebral foramen occupied
by the dorsal root ganglion. The postganglionar level starts at the
distal end of DRG.
At preganglionar level (Reina et al., 2008), the cellular compo-
nent of the nerve root cuff is 5.813 lm thick, with a number of at
cells ranging between 14 and 20. These cells have cytoplasmic pro-
longations encroaching upon neighboring cells, leaving very little
extracellular space that has a rough appearance and few collagen
bers. The types of unions between cell membranes are desmo-
some, hemidesmosome and tight junctions. Cells contain mito-
chondrias in their cytoplasm and rough endoplasmic reticulum.
Each cell is about 0.150.8 lm thick at both ends and 2.24.9 lm
around the area of its nucleus. Some samples showed the cellular
component arranged in two concentric layers separated by colla-
gen bers that measure 30 lmcorresponding probably to the inner
and outer aspects of the cellular component.
At postganglionar level, the cellular component has 914 single
cell concentric layers and measures 1850 lm. Here, the cells have
a thickness of 1.32.1 lm at the sides, 1.95.8 lm around the nu-
cleus, and the extracellular space 1.32.1 lm, respectively with
collagen bers measuring 0.1 lm. Their unions are of the type des-
mosome and hemidesmosome.
At ganglionar level, the morphology of the cellular component
shows transitional changes between pre and postganglionar levels,
although it resembles more to that at postganglionar level, having
a thickness of 5560 lm and 2530 concentric cellular layers;
these laminas are made of single cell layers. Measurements of
diameters are: 0.170.9 lm at both cellular ends, 1.103.4 lm
around its nucleus and 1.272.15 lm for the extracellular space
between cellular planes that is also occupied by collagen bers.
Here, the cells have similar membrane unions. Ultrastructural as-
pects of the cellular component at pre, post, and ganglionar levels
are similar. At all levels the cells show rough endoplasmic reticu-
lum widely distributed and some cells contain large vacuoles
(0.1 lm), occupying almost half of the cytoplasmic space.
A membranous like structure found in their cytoplasm may be
involved in the production of vesicles (0.050.07 lm) needed for
pinocytosis. Collagen bers together with myelinated and non-
myelinated axons are seen in the inner side of the cellular plane,
they are part of the endoneurial brillar structure. Specialized
membrane unions among cells at pre, post, and ganglionar levels
ensure the barrier effect, avoiding the passage of substances from
the epidural space to nerve axons.
8.2. External brillar component
The brillar component (Reina et al., 2007b) is placed in the
outer portion of the root cuff and has a thickness of 100
150 lm; it is made up mostly by collagen bers arranged in con-
centric laminas with scarce elastic bers (Reina et al., 1998a). Large
numbers of adipocytes separates dural laminas in groups of 35
concentric layers (Fig. 6B). Scanning electron microscopy shows
the distribution of adipocytes; these cells are found all along from
the dural sac to the DRG. Looking at the outer epidural surface of
the root cuff under scanning electron microscopy, we observed
few areas occupied by adipocytes protruding out of the thickness
of the brillar component (Reina et al., 2007b).
On the other hand, the brillar portion in the dural sac contains
about 80 dural laminas (Reina et al., 1996, 1997), with collagen -
bers oriented in different directions (Reina et al., 1996a,b; Nicholas
and Weller, 1988) and few elastic bers; its thickness varies be-
tween 270 and 350 lm at lumbar level (Reina et al., 1999a,b).
However, adipocytes are not found within the thickness of the dur-
al sac (Hogan, 1996a,b; Lirk and Hogan, 2007). Differences in the
J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563 61
thickness of the dura among dural sac and the external brillar
component do not alter the barrier effect, because the cellular
component is exclusively responsible of such effect.
Adipocytes observed by scanning electron microscopy are sim-
ilar to those found in peripheral nerve samples from human sciatic
nerve (Reina et al., 2002a,b,c,d) measure 5070 lm; the fact that
they appear smaller and the absence of spherical shape in some
of them, is probably due to loss of fat from vacuoles during sample
preparation. Fat in root cuffs covers groups of root axons although
no adipocytes are seen enclosing axons individually. This fat is
found occupying either partially or totally de thickness of root cuffs
brillar component, depending on the region studied.
8.3. Accidental subdural blockade after transforaminal injection
At preganglionar level, cellular planes in root cuffs are stratied,
with few extracellular elements. Both cellular and extracellular
morphologies at this level are similar to those described in the sub-
dural spinal compartment, where neurothelial cells show similar
ramications (Reina et al., 1998b, 2002b,d). Probably these cells
occupy a transitional area, exerting small mechanical resistance,
similar to what happens in the subdural compartment (inside the
dural sac). Conversely, cellular components at ganglionar and post-
ganglionar levels are reinforced by large quantities of extracellular
collagen bers.
At ganglionar level, cellular layers are divided by collagen bers
and beyond the DRG, cellular layers take the shape of perineurium.
At preganglionar level, the lack of collagen bers in the cellular
component may reduce its resistance, favouring subdural distribu-
tion of substances after transforaminal injection. The orice pro-
duced by the needle or catheter may aid centripetal spread to
the subdural compartment in the dural sac.
8.4. Fat in root cuffs and drug kinetics
Fat near nerve root axons, could play a dened role in the kinet-
ics of drugs injected in the epidural space. At present, implications
of ultrastructural ndings in relation to the effects on drug kinetics
after epidural injection remains unclear; such effects could be less
marked at the level of the epidural space when compared with
those of root cuffs, because the later structure has fewer capillaries
and distances between fat and axons are shorter. Such delibera-
tions about fat from root cuff should be considered in the context
of epidural fat.
Our observations in relation to the presence of fat inside root
cuffs may imply changes fromprevious concepts. Until now, epidu-
ral fat was found in the epidural space, but not inside root cuffs.
The fat we found inside root cuffs is in direct contact with nerve
root axons, such relationship may play a more dened role in the
kinetics of lipophillic substances injected near nerve roots.
This role could be related to the short distance that a substance
released from the fat inside the root cuff, has to advance to reach
root axons and the increased amount of substance available due
to little vascular absorption from few vessels present in the area.
In our clinical experience, patients with epidural catheter and very
low doses epidural infusions develop motor blockade hours later.
Lateralization of epidural catheters is common event (Hogan,
1999) and if the solution is delivered too close to the root cuff,
fat inside the root cuff may contribute to such effect.
8.5. Permeability of root cuffs
Some lipophillic substances can cross the blood-nerve barrier
when administered either intravenously or near root cuffs. The
blood-nerve barrier has a cellular component enclosing nerve root
axons and avoiding direct action of injected substances. Cells join
together by specialized membrane union limiting the passage of
substances across them. The vascular component of the blood-
nerve barrier is the endothelium from endoneurial blood vessels
in direct relation to nerve axons. These endoneurial blood capillar-
ies are non-fenestrated, limiting the passage of substances across
the barrier. Some authors have explained the increased permeabil-
ity in the area of the DRG compared to other neural structures be-
cause here, the endothelium has less tight junctions.
The blood-nerve barrier is most effective intracranially and in
the spinal cord and less restrictive around peripheral nerves (Reina
et al., 2003) and in DRG (Abram et al., 2006). Injected substances
may reach DRG following intravenous, intrathecal, epidural or par-
avertebral routes, although the last path favors higher concentra-
tions inside DRG. Paravertebral injection of substances do not
guarantee selective nerve blockade due to passage of substance
to the adjacent and opposed ganglions. It has been noticed that
concentrations reached in the adjacent and opposed ganglions
are above half the concentration reached at the targeted ganglion.
The barrier effect exerted by arachnoid lamina may be responsible
for the low concentrations found in the spinal cord. The passage
into the DRG of a substance administered intravenously, may be
aided by the presence of fenestrations in the endothelium of near-
by capillaries.
In previous studies, (Hirakawa et al., 2004) demonstrated that
proteins found in tight junctions, claudin I and occludin, where
identied in axons but not in neuronal bodies fromDRG. In another
study (Olsson, 1968) using rats, that permeability is higher in gan-
glions and lower in the endoneurium of the dorsal and ventral
nerve roots.
9. Conclusions
Epidural fat provides sufcient cushion for the pulsatile move-
ments of the dural sac, protects nerve structures, facilitates the
movement of the dural sac over the periosteum of the spinal col-
umn during exion and extension, and forms a pharmacologic res-
ervoir of lipophilic substances. Root cuffs have a cellular
component that affects the passage of substances injected epidu-
raly or near the intervertebral foramen, depending on the site of
injection, preganglionar, postganglionar or ganglionar. We found
fat inside root cuffs but not within the dural sac. Fat in this location
may have affect kinetics of lipophilic drugs injected near nerve root
cuffs. Ultrastructural morphology of the cellular component at pre-
ganglionar level may help explain unexpected subdural blockade
after injection of local anesthetic via transforaminal route. Other
morphological aspects of nerve root cuffs help to understand the
function of the blood-nerve barrier.
Based in this anatomical knowledge, we can speculate on the
possible anesthetic implications of epidural fat in terms of the
pharmacokinetics of drugs injected into the epidural space and
the tasks of locating the epidural space and inserting an epidural
catheter during anesthetic procedures.
Conict of interest statement
The work has not been funded by any source(s) other than those
described on the title page. This include gifts, research or educa-
tional grants, contracts, equity interest, stock options, direct or
indirect salary support, consultant fee(s), lecture/travel fees or
honoraria received within a period of three years of the date of
submission of the manuscript from any source (including non prof-
it foundations) which has or had nancial interest in the subject
matter, materials, equipment or devices discussed.
Any author or participant have any nancial interest in the sub-
ject matter, materials, or equipment discussed or in competing
62 J. De Andrs et al. / European Journal of Pain Supplements 3 (2009) 5563
materials. Financial interest includes patent(s) patent licensing
arrangement(s), stocks, equity interest, or any other arrange-
ment(s) which may be of actual or potential nancial benet to
any author or participant.
The laboratory in which the research was performed has not
been funded by any foundation or other non-governmental source,
or has any participant in the planning, conduct, or reporting of the
research with a real or potential interest in the subject matter,
materials, equipment or devices discussed or in any competing
product or subject.
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