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Peripheral nerves

Histological appearance of the peripheral nerves.

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Hey everyone! It's Nicole from Kenhub, and thanks for joining us today to talk through the histology of peripheral nerves.

So you'll likely already know that our nervous system is comprised of the brain and the spinal cord which together make up the central nervous system, or the CNS for short. And other nerves that serve the rest of the body outside of the CNS are the peripheral nerves, which is our subject, of course, for this tutorial.

The peripheral nerves carry information back and forth between the CNS and the body, so anytime you move any part of the body, you're using your peripheral nerves.

Let's zoom in a little bit and begin our tutorial with an overview of the peripheral nerves using a longitudinal section of a nerve as an example and we'll be looking through the microscope and showing the parts of the nerve fiber in detail. We'll then change our view to a cross-section of a nerve to show the structure of a nerve and the connective tissue contained within it. After that, we'll take a minute to talk about the blood supply and the innervation of the nerves, and by the end, you should be able to describe the structure of a nerve on histology and successfully navigate the quiz we've made to test that knowledge. As a bonus, we'll discuss a clinical scenario where this knowledge is useful namely peripheral neuropathy.

Alright, let's take a closer look at what peripheral nerves are using a longitudinal view as our example.

So, if we take a peripheral nerve and cut it longitudinally like so, we end up with something like this on our micrograph. This section is stained with something called Ladewig's trichrome which colors connective tissue deep blue, the nerve fiber a paler blue, and the nuclei red. So, let's take a closer look at the nerve fibers highlighted here in green.

Speaking accurately, a nerve fiber is an axon or dendrite including its myelin sheath. So, bearing this in mind, let's look at the parts of the nerve fiber.

So let's up the magnification a little bit further, and by doing this, we can see each axon running through the center of each nerve fiber. The axon is like an arm that carries the nerve impulse. On histology, it can be pretty difficult to see each individual axon as they stain fairly faintly and the green highlight gives the game away a little bit but if you need to identify an axon on an image like this, there are a few things to look out for. One, the axon stains faintly purple on H and E. Two, it runs in a line along the length of the nerve. Three, it can be found in the center of the nerve fiber about halfway between the dark blue lines which signify the endoneurium. And, four, they lie within the myelin sheath which shows us this honeycomb-like arrangement on a white background.

There are unmyelinated axons in the body but the fastest conducting and the most efficient nerve fibers are those which are myelinated. So, let's talk a little bit about what myelin is.

Myelin is a fatty membranous tissue which encapsulates the nerve fiber. As fatty tissue does not take up any color from Ladewig stain, it appears white on our slide. So, why is it there? Myelin increases the speed and efficiency of impulse conduction along the nerve, and this is pretty important because the speed of that information could be the difference between life and death. The membranous component of myelin is the cell membrane of Schwann cells in the peripheral nervous system. The cytoplasm of the Schwann cells stains that reddy brown color and is twisted around the axon and this gives the honeycomb appearance. But to understand this a little bit better, we need to have a look at the Schwann cells a little bit more closely.

We've zoomed in again and isolated a couple of nerve fibers, and each of the dots highlighted in green here is the nucleus of a Schwann cell. As mentioned, the reddy brown color is a stain in the cytoplasm of the cells. Fat is abundant in the cell membrane of Schwann cells as with other cells but this does not stain and that accounts for why we see white unstained areas.

Each Schwann cell provides a section of myelination. Here, we're looking at the nerve fiber in cross-section. As you can see, the Schwann cell encapsulates the axon and then wraps around it many times to create a multi-layered myelin coating. And if you're wondering what wraps around it, mostly fat gets pulled around the axon but a little bit of cytoplasm gets pulled around too. So, because the cytoplasm is pulled irregularly, a red-brown honeycomb appearance is the result on a longitudinal section. FYI, each Schwann cell covers two hundred and fifty to one thousand micrometers lengthways along the axon.

In between each Schwann cell is a gap known as the node of Ranvier, and these are important because they permit something called saltatory conduction which is a bit of complicated neurophysiology that we won't get into today, but Schwann cells actually envelop unmyelinated axons as well, the difference being that they do not wrap themselves multiple times around the axon.

Okay, so having looked at the nerve in a longitudinal slice, let's have a look at the peripheral nerve in cross-section.

So, this is a cross-section of the nerve stained again with Ladewig's trichrome, and all of these is our nerve. A nerve is a bundle of nerve fascicles and a nerve fascicle is a bundle of nerve fibers. And as we discussed earlier, a nerve fiber is an axon and its myelin sheath. This image shows both myelinated and unmyelinated fibers, and highlighted in green is one of the nerve fascicles. And here we have a more detailed view of the fibers and this lets us identify whether or not they're myelinated. So, the fibers we've highlighted here are myelinated and we can see here that the axons stain a much deeper purple here than on longitudinal section because a thicker chunk of axon is caught in the slice of tissue. Similar to the longitudinal sections, myelin appears mostly unstained with a few red-brown streaks, and there are also some Schwann cell nuclei stained this deep red color.

So now that we've talked about myelinated fibers, what about the unmyelinated fibers? So, here are some in green right now, and the lack of myelin means these fibers are thinner and more densely packed together as a result. There are still some Schwann cells mixed in amongst them encapsulating the axons but not myelinating them. So, that's why we can still see some Schwann cell nuclei in the vicinity.

Alright, now that we've identified the functional parts of the nerve, we'll zoom back and highlight the connective tissue that holds it all together and maintains the structure of the nerve. There are three major components of this connective tissue which are all held together through connective tissue fibers that extend from each layer tying them all together. And this is the same image as before except this time with the epineurium highlighted in green.

The epineurium surrounds bundles of nerve fascicles and enclose the whole nerve. Small arteries and veins may also be enclosed by the epineurium as we can see here and epineurium is dense irregular connective tissue made primarily of type I collagen. It also contains adipose deposits and together these aspects of the epineurium provide protection to the delicate axons from pulling, shearing and compressive forces.

On Ladewig's stain, connective tissue stains blue so it can be visualize fairly easily and the adipose deposits do not stain and so account for the white, unstained patches within the connective tissue.

The next layer of connective tissue that supports the peripheral nerves is the perineurium which surrounds each individual nerve fascicle and separates them from one another. The fibrous component of perineurium is made predominantly of type III collagen and arteries and veins also pierce the epineurium and branch within the perineurium.

On histology, we can identify perineurium by its location around a nerve fascicle. With Ladewig's trichrome, we can see how it appears as a dense blue ring around a nerve fascicle with some red nuclei scattered within it and this arises from the fibrous and cellular structure it possesses.

So, perineurium is thinner than the epineurium but it consists of two distinct alternating layers – a fibrous layer and a cellular layer. On light microscopy, it's generally pretty difficult to differentiate between the two layers, and the layers alternate with more layers being present the more central that section of nerve is. The reason for this is that each branch coming off the fascicles steals at least one fibrous and one cellular layer to create a continuous perineurium. And this process of branching and dividing the perineurium between the branches continues as we're left with free nerve endings which do not have any perineurial covering.

The fibrous layer of the perineurium provides physical support and as with the epineurium, it's blue on our Ladewig stain but this time it's mostly composed of type III collagen. The cellular layer is made up of perineural cells, and perineurial cells are modified flattened fibroblasts and this cellular layer enforces the blood-nerve barrier. And if you recall anything about the brain, this is similar to the blood-brain barrier having limited permeability to help maintain homeostasis of the endoneurial microenvironment.

Okay, let's up the magnification once more because we want to take a bit of a closer look at nerve fibers within a nerve fascicle. And, so, the endoneurium which is highlighted in green is the most intimate layer of neural connective tissue and it's a loose thin connective tissue as you can see mostly composed of type III collagen which is similar to but thinner than the perineurium. The endoneurium encapsulates each individual nerve fiber providing structure to physically support the nerve fiber and to help keep the fibers arranged in the same direction. Also contained within the endoneurium are the Schwann cells which encapsulate the nerve fiber, blood vessels which supply the nerve fiber with nutrients and remove waste, fibroblasts to produce and replace endoneurium, and lymphocytes and mast cells to provide immune protection.

So, there are some various structures in here called Renaut bodies that can sometimes be seen in the endoneurial sheath and they're fusiform in shape and are postulated to act as shock absorbers at potential sites of nerve compression but at the moment we don't really know.

So, on histology, endoneurium appears as very thin blue lines which you can see just here which wrap around nerve fibers within a nerve fascicle, and you might see some of the other structures that we just listed encapsulated too but more often than not, the axon and the Schwann cells are the only ones that are snuggled up in here.

Okay, that's it for the peripheral nerves and cells. Thanks for sticking with me throughout the tutorial so far. So, now, I want to talk briefly about the blood supply and the innervation of the peripheral nerves which specifically come from two structures that support the nerves. So, let's zoom again into our micrograph now so that we can see these structures a little bit better.

So, the first of these is the vasa nervorum, meaning the vessels of the nerve. So, nerve cells are metabolically active and, therefore, they require a blood supply. So, the vasa nervorum supply blood to and remove waste from the nerve fibers and they run in the nerve within the epineurium with branches piercing the perineurium. So, in the perineurium, they're lined by perineurial cells which create one wall of the blood-nerve barrier and the other wall is formed by the endoneurial sheath, and through these, nutrients exchange in return for waste by diffusion.

The other supporting structure to the nerve supply to the nerve or the nervi nervorum which literally means the nerves of the nerve. Yes, the nerves are innervated by other smaller nerves – that is a fact. We can see a couple of these little nerves just here. So, specifically, the nervi nervorum innervate the nervous connective tissue and the vasa nervorum, and they seem to innervate all layers of the nervous connective tissue.

So, here, they transmit signals about pain and stimulate local inflammation as a defense mechanism. Their effects on the vasa nervorum are to control the degree of vasodilation or constriction and, in this way, blood flow to the nerve can be regulated to promote an inflammatory or healing response to an insult.

Alright, before we round things off, I just want to discuss a clinical situation where knowledge of histology of nerves is pretty important. An example that we're going to be using today is that of peripheral neuropathy.

So, peripheral neuropathy or peripheral nerve disease generally refers to damage to the peripheral nerve fibers highlighted in green here. And it's not a diagnosis but rather it refers to a group of conditions with similar pathophysiologies and, therefore, similar clinical manifestations. And they can be named more specifically by cause once this is discovered. For example, diabetic neuropathy, vitamin B12 deficiency neuropathy or alcohol-induced neuropathy, just to name a few. But no matter the cause, the pathophysiology is pretty similar. So what happens is that in some way, the nerves begin to demyelinate and so their efficiency in conducting signals decreases.

Axonal degeneration also occurs which basically means that the axons die and this happens in both directions as it affects both afferent or sensory nerve fibers and efferent or motor nerve fibers.

So what would a patient experience? Let's think about this logically.

So, the sensory nerves being affected means that the patient will notice changes in sensation and usually this presents as numbness and also we would probably get some abnormal sensations which is medically termed paresthesia such as burning, tingling or prickling but with no stimulus to cause that feeling which is, you can imagine, would be pretty uncomfortable.

Moving up our arm here. So, if you recall, motor nerves supply muscles and they maintain a tone which in turn stops them from wasting away. However, in a peripheral neuropathy, since the signals from motor nerves become reduced, the muscles they supply become hypotonic – so, that is, the resting tone is reduced. They'd also become hyporeflexic meaning that your reflexes when they're tapped with a tendon hammer are not as strong as they should be, and they also start to waste which is known as atrophy.

Fasciculations which are tiny brisk contractions of the muscle can also be observed, and the mechanism causing fasciculations is debated but generally it's considered to be the spontaneous firing of dying motor neurons.

Systemic peripheral neuropathies such as the ones we mentioned previously can affect the entire peripheral nervous system but they affect the longest nerves first and then progress towards the brain – so, in other words, from distal to proximal. The classical description of how these presents is the glove and stocking distribution which refers to the neuropathy affecting the hands and the forearms which is what we would call the gloves and the feet and the lower legs which is what we would call the stockings. And left to progress, the neuropathy will appear to ascend and gradually affect more and more of the body which causes a lot of things. For example, incontinence amongst other symptoms and eventually death through the loss of respiratory function.

So, how would you diagnose peripheral neuropathies?

The diagnosis of peripheral neuropathy is a clinical one. In other words, it's made by a combination of the history and the examination of the patient. However, tests may be used to rule out certain conditions or to find a root cause for the peripheral neuropathy. For example testing for diabetes through measurement of blood sugar levels or blood test screening for vitamin insufficiencies.

As with many health conditions, prevention is better than cure in the case of peripheral neuropathy, and control of the underlying disease is the best way to avoid peripheral neuropathy in the first place.

So in our diabetic patient, good blood sugar control is vital and even in the healthy population to make sure that our diets have appropriate levels of vitamins such as B12 and thiamine.

So once a person has a peripheral neuropathy, they may be able to regain some functions but it's usually irreversible and there are some therapies being tested and investigated but currently treatment is mainly to manage the underlying cause.

So that's it for our clinical notes. Let's quickly recap what we've covered today.

So, today, we saw that the peripheral nerves are all of the nerves in the body not including those of the brain and the spinal cord. We then brought in the microscope and we had a look at a longitudinal section to identify the nerve fibers, the axon which is the signal-conducting part of the nerve fiber, the myelin sheath which is the insulating component, and the Schwann cells which are the cells which make up the myelin sheath.

Next, we switched to a cross-section of a nerve to discuss the arrangement of structures within a nerve. And we saw that a nerve is made up of bundles of nerve fascicles which is further made up of a bundle of nerve fibers especially myelinated fibers and unmyelinated fibers.

The connective tissue layers were also mentioned including the epineurium which surrounds the nerve and bundles of nerve fascicles, the perineurium which encapsulates individual nerve fascicles and can be subdivided into a fibrous layer and a cellular layer, and, finally, we looked at the endoneurium which surrounds the individual nerve fibers.

Once we had a grasp on the internal structure of a nerve, we then looked at the blood supply and innervation of nerves. Firstly, the vasa nervorum which are the blood vessels dedicated to the nerve and its contents and the nervi nervorum which are small nerves supplying the connective tissue layers of the nerve and the vasa nervorum.

And that's it. Thanks for watching this Kenhub tutorial and all the best for your studies!

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