Peripheral nerve architecture

fig 1 peripheral nerve drawing c labels


A perspective on the intraneural and extraneural controversy

Dr Carlo D Franco, MD

August, 2012


The irony of the ongoing debate about the safety of intraneural versus extraneural injections is our lack of agreement on what exactly constitutes intraneural, both at the single nerve, and at the plexus level.

In a recent editorial in Regional Anesthesia and Pain Medicine, I was given the opportunity to express some personal ideas about this subject. These ideas are the result of piecing together several widely recognized facts, and in here I present a summary of them.

Peripheral nerve architecture

fig 1 peripheral nerve drawing c labels

Fig. 1. Cross section of a typical peripheral nerve with 3 fascicles (Fa) and a surrounding epineurium (Epin) beyond which the extraneural local connective tissue (Extraneural) is located.

There is wide agreement in our literature on the issue of peripheral nerve architecture. As the diagram of a peripheral nerve in figure 1 shows, a nerve is formed by neural tissue and connective tissue, the latter usually the most abundant. In fact, on average, the brachial plexus consists of only 32% neural tissue. This neural component of a peripheral nerve is made up of bundles of axons arranged into fascicles. The non-neural component is that connective tissue that provides a protective matrix and confers individuality to the nerve, proportionally increasing its presence from roots to terminal nerves. The fine connective tissue surrounding axons inside every nerve fascicle is called endoneurium. The fascicles themselves are surrounded by a highly specialized connective tissue, the perineurium, which is not only composed of fibers, but also has an important cellular component arranged into a layer of tightly connected cells, at which level the nerve-blood barrier resides. In between the fascicles we find a variable amount of connective tissue called "internal" or "interfascicular" epineurium, which condenses externally to form a fibrous-rich outer layer, called "external" epineurium, or simply epineurium. All these layers of connective tissue "belong" to the nerve. The most external of them, the epineurium, represents what the skin is to the whole body.

However, not every bit of connective tissue associated with peripheral nerves forms part of them, as it is evident that peripheral nerves travel through variable amounts of extraneural connective tissue belonging to the regions through which the nerves pass through. Therefore, epineurium (belonging to the nerve), and extraneural connective tissue come in intimate contact with each other leading to the formation of a potential space along nerves. It is at this level that the nerve is able to preserve some degree of mobility to adjust to muscle activity and extremity movement without undue stretching. This potential space can become an actual space, in certain circumstances, as when it gets expanded by the injection of local anesthetic. The visual manifestation of this space under ultrasound imaging is commonly referred to as the "doughnut" sign, but that I prefer to call the "perineural lagoon".

The intraneural concept on individual nerves

Having established the basic architecture of a peripheral nerve, it would be uncontroversial to state that the epineurium represents the boundary between the outside and the inside of a nerve and that the violation of the epineurium constitutes penetration of the nerve. If the insulting agent (e.g., needle) does not reach the perineurium of any fascicle, we call the violation "intraneural, extrafascicular". If any fascicle is penetrated (violation of both the epineurium and perineurium) it becomes an "intraneural-intrafascicular" insult. Beyond the debate on whether the former could be a more benign kind of insult to the nerve than the latter, everybody seems to agree that both violations constitute intraneural insults as defined by the violation of the epineurium of a single nerve.

The intraneural concept on sciatic nerve and plexuses

The problem in our literature has been to extrapolate our straightforward assessment on single nerves to a plexus (network of nerves) or to the sciatic nerve (two contiguous nerves). This extrapolation would not be difficult if we realized that every single nerve structure, whether a nerve in itself or a component of a plexus is surrounded by epineurium. This essential fact has been widely ignored in our literature. As we know, spinal nerves form either individual nerves (e.g., intercostal nerves) or the nerve structures that form the plexuses (e.g., cervical, brachial, lumbar and sacral). As the spinal nerve exits the spinal canal, a sleeve of duramater is evaginated leading to the formation of a perineural cuff. At the level of the intervertebral foramen, the dural cuff becomes histologically continuous with the epineurium of the nerve. This is the case not only for the intercostal nerves, but also for every nerve component that will contribute to the formation of plexuses. That means, for example, that every root, trunk, division and cord of the brachial plexus is individually surrounded by epineurium and so are both individual nerves forming the sciatic nerve for that matter. The diagram in figure 2 shows the divisions of the brachial plexus plus the suprascapular nerve, all located between the anterior and middle scalene muscles in the supraclavicular area. Every one of these nerves is surrounded by its own individual epineurium, as they are immersed in extracellular connective tissue.

fig 2 plexus drawing c labels

Fig. 2. Cross section of the supraclavicular space showing the first rib (1st rib), subclavian artery (SA), anterior scalene (AS) and middle scalene muscles. At this level the 6 divisions plus the suprascapular nerve (Ssc) are under the cover of a fascial layer from the prevertebral fascia (Prev fascia) and immersed in extracellular connective tissue.


In exposed and highly movable places, the nerves forming a plexus are maintained in place by the presence of fascia(s), which in the neck comes from the prevertebral fascia. The penetration of this fascia and the placement of a needle into the extraneural connective tissue surrounding the nerve elements of plexuses does not constitute intraneural placement unless the epineurium of individual nerve structures is violated.

In summary:

1. The connective tissue forming the epineurium of a nerve constitutes the nerve skin. Any violation of the epineurium of the nerve by a needle would represent an intraneural placement of such needle. This definition is independent of whether the perineurium is also violated.

2. Every nerve structure (i.e., an individual nerve, a nerve contributing to a plexus or the two nerve components o the sciatic nerve), is individually surrounded by epineurium. Therefore, the presence of a needle in between the elements of a plexus does not constitute intraneural placement unless the epineurium surrounding any individual nerve structure is violated.

3. Terms such as "subepineurial" and similar should be avoided because they lead to confusion. By definition subepineurial denotes epineurial violation and subsequently, nerve penetration.



1. Franco CD. The connective tissue associated with peripheral nerves. Editorial. Reg Anesth pain Med 2012; 37: 363-365

2. Kawai H, Kawabata H. In: Brachial Plexus Palsy. Singapore: World Scientific; 2000: 1-24

3. Sala-Blanch X, Vandepitte C, Laur JJ, et al. A practical review of perineural versus intraneural injections: a call for standard nomenclature. Int Anesthesiol Clin 2011; 49: 1-12