Neuroinflammatory Disorders: Introduction and Classification | Lecturio

[00:00] In this talk, we're going to review neuroinflammatory disorders and we'll begin with an introduction to neuroinflammatory disorders. To begin, let's talk about the pathophysiology. What's going on when there's an immune attack in the brain or central nervous system? Well, we start with the brain.

[00:20] brain, and in the brain lives the neurons. The neurons are protected from the immune system by the blood-brain barrier. What we see here is a schematic showing the neurons in the brain, a blood vessel, and the blood-brain barrier. The immune system is composed, as we know, of T cells, B cells, and natural killer cells, and those are maintained with

[00:40] in the blood vessels and separated from the central nervous system by the blood-brain barrier. The blood-brain barrier is made up of astrocytes. Astrocytes form a thick and protective wall between the blood vessels and the brain and prevent immune cells from infiltrating into the central nervous system.

[01:00] In the central nervous system, the primary immune cell in the immune compartment are the microglia and they're the resident immune mediators that function as immune regulators. And also parasites. Parasites are immune cells located around the periphery of the blood vessels, primarily around meningeal blood vessels and serve

[01:20] an immune function. In autoimmune conditions, what we see is that there's infiltration of that systemic immune response, the T cells, the B cells, the natural killer cells, or some combination of the three into the brain through the blood-brain barrier, resulting in damage to the nerve, to the myelin, to the axon or something.

[01:40] some aspect of the central nervous system. When I think about autoimmune conditions in the central nervous system, there are five key mechanisms, and I want you to understand and at least appreciate some of the things that happen that cause CNS autoimmunity. The first thing we'll talk about is molecular mimicry, where an antigen

[02:00] on a virus mimics an antigen in the brain and as a result of the immune's response to the virus, we see an attack in the brain. The second cause or underlying pathophysiology of CNS autoimmunity are sequestered proteins. And we'll talk about how proteins are normally sequestered from the immune system as a result of an infection.

[02:20] they can be released and this results in an immune attack in the central nervous system. I want you to know about the bystander activation or altered regulation or as a result of some infectious process, there's activation of cytokines which revs up the immune system and can result in a CNS attack. We'll also talk about

[02:40] an abnormal host development. And normally the thymus is involved in creating B-cells and T-cells that attack foreign antigens and are not auto-reactive. And in some circumstances, the body can generate auto-reactive immunity that can result in CNS immune attacks. And then the last thing is we'll talk

[03:00] about paraneoplastic causes of CNS autoimmune. And I want you to understand each of these five underlying pathophysiologic processes that contribute to neuroinflammatory disorders. First, let's talk about molecular mimicry. So here we're looking at a schematic of a neuron, the blood-brain barrier, and the blood-brain artery.

[03:20] vessel as well as a new virus that is expressing an antigen. In the setting of molecular mimicry, the immune system responds to the virus which is normal. That's what you want the body to do to attack the virus and clear it. But in this case, the virus is expressing an antigen that's also expressed in the brain.

[03:40] circumstances, there is a hyperactive immune response to that antigen to kill the virus, but this also results in attacking of that same antigen in the brain and that contributes to the development of a neuroinflammatory disorder or CNS autoimmunity. So this is the first type of CNS autoimmunity.

[04:00] immunity are the first underlying cause of a neuroinflammatory disorder. What about sequestered proteins? How does this work? Well, again, we have our same neurons, which are expressing an antigen protected from the systemic circulation by the blood-brain barrier. Here, some infectious process results in release.

[04:20] of an intracellular antigen that was previously not seen by the immune system. So here you can see in the schematic, infection with a virus can result in release of those intracellular proteins. Normally the body's immune system should attack that antigen, recognizing it as unfamiliar. But in this case, the antigen is also contained.

[04:40] contained within the neurons. As a result of a hyperactive immune response, we see infiltration of that systemic inflammatory response into the brain, and this can contribute to the development of CNS autoimmunity or a neuroinflammatory disorder. What about bystander activation? How does that work?

[05:00] Again, we have the neurons in the brain separated from the systemic circulation by the blood-brain barrier. Here, as a result of some process that irritates, activates cells, we have release of cytokines due to an infectious process. Those cytokines rev up the immune system. The immune system is able to infiltrate into the brain and that sets off this CNS.

[05:20] autoimmune attack. So this is another underlying cause for the development of a neuroinflammatory disorder. What about abnormal host development? How does that work? Normally the thymus is the organ in the body that results in development of B and T cells, normal and autoimmune.

[05:40] immune cells that respond to foreign antigens and destroy potentially auto-reactive antibodies and immune cells. In some circumstances of abnormal development, the body fails to degenerate, discard, and destroy those auto-reactive immune effector cells and as it results,

[06:00] result, they're able to identify antigens such as those on neurons, infiltrate into the brain, and result in the development of CNS autoimmune conditions. And then the last underlying process that can contribute to CNS autoimmunity is a perineoplastic process. Here, patients may develop a tumor.

[06:20] In fact, we're all really developing tumors at all times throughout our lifetime. And the normal process is for the body's immune system to recognize that tumor, to see it as abnormal, and to kill and destroy it. In some circumstances, that antigen that's contained on the tumor is also present on the surface or inside of nerves.

[06:40] The body's immune system is revved up as a result of that cancer and when the immune system can infiltrate into the brain, we have the development of a perineoplastic neurologic disorder. In many cases, the neurologic disorder can precede the development or recognition of the cancer. The body's immune system is doing a good job at keeping the cancer at bay.

[07:00] But we see this neurologic syndrome that develops and really should herald additional workup for an underlying cancer. And so these five causes or underlying pathophysiologic mechanisms are the mechanisms by which CNS autoimmunity can develop. So how do we think about it?

[07:20] think about neuroinflammatory disorders, what is the classification? I like to think about classifying them in three ways. The first is whether they're primary or secondary. The second is by the type of the dominant immune population that's involved, and we'll talk a little bit more about what that means. And then last, I differentiate

[07:40] the isolated single events from recurrent or multiple events over time and this helps us to understand the types of neuroinflammatory disorders we can see and the ones that we're going to diagnose in patients and on test questions. First let's start with step one. Let's understand the difference between a primary CNS neuroendocrine disease.

[08:00] inflammatory disorder and a secondary CNS neuroinflammatory disorder. Primary neuroinflammatory disorders are ones where the autoimmune attack is only in the CNS. There's not a systemic immune disorder. There's not systemic autoimmunity. This is autoimmunity to the brain and to the brain only.

[08:20] Examples of this include multiple sclerosis, neuromyelitis optica, and MOG antibody disorder, which we'll talk a little bit more about. Here, we need to evaluate inflammation within the central nervous system. We're looking for activation of the immune response in the CNS. We can do a lumbar puncture to look for elevated protein and possible

[08:40] possibly mildly elevated cells, we're looking for that immune infiltration into the CNS, or neuroimaging, showing an immune attack on the brain or spinal cord, which is evidenced by increased T2 signal swelling in the central nervous system and often with the presence of enhancement. That enhancement is indicating breakdown of the blood-brain.

[09:00] barrier, which is how the immune system is infiltrating into the central nervous system. There's often not evidence of systemic inflammation. We don't see elevation in ESR or CRP or ANAs or rheumatoid factors or other evidence of an underlying autoimmune condition. The primary process is in the brain or CNS.

[09:20] That differs from secondary CNS neuroinflammatory disorders where the immune attack occurs in the systemic system and then it flows into the brain or central nervous system as a result of the underlying systemic autoimmunity. Examples of this include systemic lupus erythematosus.

[09:40] Sjogren's syndrome, rheumatoid arthritis, and others. And here, the patient has an underlying systemic autoimmune condition that can involve the brain. Our evaluation here involves a two-fold evaluation, both looking for evidence of CNS and immune attack as well as the underlying systemic activation of the immune system.

[10:00] immune system. And we can do that by investigating the CNS with a lumbar puncture. We're looking for increase in CSF protein and potentially mild elevation in cell count or a pleocytosis and neuroimaging showing an immune attack on the brain or spinal cord. In addition, these patients require systemic evaluation for an underlying immune system.

[10:20] autoimmune condition. My typical screen includes an ESR, CRP, ANA, and rheumatoid factor, but we may need to dig deeper based on the history and the examination of the patient if we're concerned about one of these conditions. We may look for double-stranded DNA testing in patients who may have systemic lupus.

[10:40] or Sjogren's antibody, SSA, SSB, or Rho or La antibodies in patients with Sjogren's syndrome, or rheumatoid factor in patients with rheumatoid arthritis, digging for that underlying evidence of a systemic autoimmune condition. Step two in evaluating these patients is to determine

[11:00] Is this a monophasic illness or a recurrent illness? Are there recurrent immune attacks that could occur in the nervous system or is this a single one-time event? So we have monophasic illnesses and recurrent illnesses. The classic monophasic course you're seeing here in this schematic graph

[11:20] And we see evolution over time and patients with a monophasic illness have a single attack. They begin normal. There's onset of disability, which typically occurs subacutely. So over the course of a couple of weeks, patients will develop weakness in the arm or leg. They'll develop a paraperisis. They'll develop vision loss. And that subacute onset is.

[11:40] common in patients who have inflammatory disorders. This peaks often over the course of a couple of weeks and then gradually improves. With patients typically returning to normal, as you see in this graph with no long-term disability, though patients can be left with long-term disability as a result of this monophasic illness.

[12:00] conditions will result in a monophasic course. And that's different from the recurrent course. And here we see a good example of the depiction of what a recurrent autoimmune condition will look like. These patients have periods of relapse where there's new disability and remission, which often returns to normal. Here we have subacute.

[12:20] acute onset of symptoms in each one of these relapses. So patients develop new symptoms over the course of days to weeks. And again, this may be hemibody symptoms or paraperis or new vision changes as a result of wherever the lesion is occurring, the immune attack is occurring in the brain. This peaks over the course of a couple of weeks and then there's spontaneous

[12:40] improvement or improvement more quickly with treatment. Patients often return to normal without disability, but we can see persistent disability after each one of these episodes. And again, with recurrent conditions, patients are at risk for relapses, for new episodes or recurrence of symptoms with each one of these episodes.

[13:00] And this relapsing-remitting course is highly suggestive of a CNS autoimmune condition. We think about autoimmune conditions, perineoplastic conditions. Sometimes infections can have this relapsing-remitting course and occasionally toxic exposures. Those for pathophysiologic processes.

[13:20] are the ones we should consider with this type of a course.

[13:40] you