CNS White Matter Disorders

Sections

Overview
ADEM
Neuromyelitis optica (NMO)
PML
Central Pontine Myelinolysis
Essential Immunology
MS Pathophysiology
References

NON-Multiple Sclerosis CNS White Matter Disease

Overview

Acute disseminated encephalomyelitis (ADEM)

Involves a single (monophasic) demyelinating attack.

Neuromyelitis optica (NMO)

Characteristically produces bilateral optic neuritis and a longitudinally extensive transverse myelitis.

Progressive multifocal leukoencephalopathy (PML)

PML involves an opportunistic attack of CNS oligodendrocytes by latent JC virus.

Central pontine myelinolysis (CPM)

Referred to as osmotic demyelination syndrome, because it is an osmotic-induced demyelination of the pons, most notably, and other central nervous system areas.

ADEM

Overview

Acute disseminated encephalomyelitis (ADEM) typically involves a single (monophasic) disseminated attack of CNS demyelination.

MRI Appearance

Typically, numerous white matter hyperintensities scattered asymmetrically throughout the brain.

Differences between ADEM & MS

Epidemiology

Typically ADEM occurs in the pediatric population (5 – 8 y.o.), whereas the age of onset of MS is typically 20 – 50 years old.

Viral prodome

ADEM often occurs in the setting a viral illness. Although it's commonly quoted that vaccines increase the risk of ADEM (especially the MMR vaccine), there is considerable argument about the true risk that vaccines confer in causing ADEM.

Symptoms

There is often encephalopathy and multifocal symptoms at onset.

Simultaneous lesion enhancement

There is simultaneous lesion enhancement because the lesions typically occur at/around the same time.

Basal ganglia involvement

It is not uncommon for there to be basal ganglia involvement in ADEM (whereas this would be categorically bizarre for MS).

Neuromyelitis optica (NMO)

Bilateral optic neuritis

In bilateral optic neuritis, on MRI, we see retrobulbar enhancement of both optic nerves. Unilateral optic neuritis is a key presenting symptom in MS but if the optic neuritis is simultaneously bilateral or sequentially bilateral, think of NMO.

As well, optic neuritis often recovers poorly in NMO (but in MS, it typically recovers much better).

Transverse myelitis

Transverse myelitis in NMO is longitudinally extensive. Thus, the clinical syndrome from the myelitis in NMO is clinically worse than it is in MS – it is more often complete and less likely to recover.

Area postrema involvement

NMO can characteristically attack the area postrema (in the dorsal medulla) and cause nausea and vomiting, as well as hiccups.

Aquaporin-4 (AQP4) IgG antibodies

IgG antibodies to the aquaporin-4 (AQP4) water channel are found in the majority of cases of NMO spectrum disorders (and are likely part of its pathology).

Women:Men, 9:1

Women are roughly 9 times more likely to suffer from NMO than men (in MS, this female:male ratio is closer to 3:1).

Nonwhite Population

NMO is more common in people of nonwhite descent, including Asian, African, or Caribbean populations. Whereas, multiple sclerosis is more a disorder of whites from temperate environments (eg, Northern European).

PML

Consequence of immune-suppression

Progressive multifocal leukoencephalopathy (PML) is an important potential consequence of immunosuppression, especially from the MS drug natalizumab.

MRI appearance

Large, confluent subcortical white matter PML lesions; these lesions commonly affect the cortical U-fibers. As a distinguishing factor, the gray matter border is well-defined while its white matter border is typically poorly defined.

JC Virus

JC virus infection of oligodendrocytes is cause of PML. When people become immuno-suppressed, JC virus can enter the CNS and attack oligodendrocytes.

Symptom presentation

Patients can present with a myriad of potential neurological symptoms including, but not limited to, ataxia, visual disturbances, and encephalopathy. It has an especial predilection for the parieto-occipital regions.

Prognosis

The disease is rapidly fatal, if untreated.

Treatment

Plasmapharesis and immune reconstitution are the current mainstays of treatment.

Central Pontine Myelinolysis

Typical appearance

Osmotic demyelination (central pontine myelinolysis) typically demonstrates white matter T2 (FLAIR) hyperintensity within the center of the pons.

Extrapontine involvement

Although, demyelination can occur in other brain areas, pontine demyelination still accounts for roughly 90% of the disease.

Locked-in syndrome

Notably, it can manifest with locked-in syndrome from the central pontine involvement.

Overly rapid correction of hyponatremia

It occurs from overly rapid correction of hyponatremia (low sodium), which causes such a fast shift in small molecules and water out of CNS cells that demyelination ensues.

Alcoholics/chronic hyponatremia

Anyone with a chronic sodium level less than 120 mEq/L is at risk, this is especially common in alcoholics.

Essential Immunology

Overview

We separate the immune system into innate and adaptive divisions. Both of these functional divisions derive from hematopoietic stem cells in the bone marrow. Hematopoietic stem cells generate all of the formed elements in the blood.

Adaptive immunity

Lymphoid precursor cells

Adaptive immunity (aka acquired immunity) derives from lymphoid precursor cells and produces a targeted defense to microbial invaders. It produces an antigen-specific response via an expansion and differentiation of lymphocytes, which secrete cytokines and antibodies.

Lymphocyte histology (general)

On histology, the lymphocytes possess a large nucleus and agranular cytoplasm. Note that agranulocytes can contain granules (as we'll see with natural killer cells) just not to the density observed in standard granulocytes.

B-cell lymphocytes

B cells generate humoral immunity via antibody production and they present antigens to T cells.

T-cell lymphocytes

T cells generate cell-mediated immunity via cytokines and direct cell-to-cell interactions. They have a wide variety of responsibilities and, notably, T-cells express an antibody-shaped antigen-binding T-cell Receptor (TCR).

T-cells emerge from the bone marrow and pass into the thymus where they mature (hence "T"-cell for "T"hymus). Mature T-cells exit the thymus as CD4+ and CD8+ T-cells and collect within the lymph node, along with the B-cells.

• CD4+ T-cells are cytokine-producing; they subdivide into regulatory T cells (Treg cells) and conventional T helper cells (Th cells): Th1, Th2, Th17.
• CD8+ T-cells trigger cell-death (apoptosis) of pathogenic cells: eg, viral-infected cells, foreign tissues, and tumor cells.
• This maturation occurs during childhood; thus, past adolescence, the thymus no longer serves to form T-cells. This is why thymectomy can be performed in adult myasthenia gravis patients without wiping-out the T-cell population.

Natural killer (NK) cells

Natural killer (NK) cells act both as part of the innate and adaptive immune systems.

• Their innate functions include perforin and granzyme release to kill infected cells and inflammatory cytokine release.
• NK cells comprise a significant amount of cytoplasmic granules, but the density of this granule population is sparse enough that NK cells are still considered agranulocytes.
• Their adaptive immune functions include their antigen specificity, ability for clonal proliferation, and their immunologic memory, which parallels that of T and B cells.
• Natural killer cells (NK cells) also mediate an important function of antibody-dependent cellular cytotoxicity (ADCC).

Innate immunity

Myeloid precursor cells

Innate immunity (aka native immunity) derives from myeloid precursor cells and includes epithelial barriers, other barrier tissues, along with the mononuclear phagocytic and granulocytic cells we address here. It is the first line of defense for the prevention of infection and elimination of microbials.

Mononuclear phagocytic system

Monocytes

Monocytes have a horseshoe-shaped nucleus; they are the precursors for macrophages and dendritic cells.

Macrophages

Macrophages have an oval to bean shaped nucleus. Their pale cytoplasm becomes foamy, if activated: we can think of them like a sponge that builds-up soap suds when put into action. Monocytes differentiate into various forms of macrophages in the tissues: for instance, they become microglia within the brain; alveolar macrophages in the lungs; and Kupffer cells in the liver.
Macrophage Functions:

1. Phagocytosis – they engulf and digest debris and foreign agents (microorganisms). "Sea of Macrophages" is a key finding in demyelination, it connotes their propensity to flourish in states of demyelination has led to the histopathologic descriptor, "sea of macrophages".
2. Antigen-presentation – they serve as antigen-presenting cells (although, as we'll show in a moment, this is primarily the job of dendritic cells);
3. Cytokine release for repair or for induction of inflammation.

Dendritic cells

Dendritic cells have octopus-like tentacles. They are antigen-presenting cells and have (only relatively recently) been shown to be the major antigen-presenting cell line. They serve as a bridge to the adaptive immune system. They display the ingested particles to lymphocytes (especially within the lymph nodes and spleen) to trigger the adaptive immune response.

Granulocytes

Neutrophils

Neutrophils possess a multilobed nucleus and are heavily granulated. They, notably, comprise surface receptors geared for microbial phagocytosis and killing. Note that the term left-shift is commonly used to describe an increase in immature neutrophil precursors, particularly neutrophil band cells, "bands" (typically in response to active infection).

Eosinophils

Eosinophils are bilobed and heavily granulated. They are phagocytic, like neutrophils, but their signature feature is their toxic, antiparasitic basic proteins.

Non-phagocytic granulocytes: basophils & mast cells

Basophils and mast cells are non-phagocytic granulocytes. They are functionally related and bear a common progenitor. These granulocytes are notably involved in inflammatory and allergic (type 1 hypersensitivity) responses.

Non-immune related myeloid cells

Erythrocytes

Erythrocytes are the hemoglobin-containing, oxygen-carrying red blood cells.

Platelets

Platelets (derived from megakaryocytes) are activated in the setting of blood vessel breakage and undergo a conformational transformation (they become spiky and sticky) in order to clump together and plug up the hole.

MS Pathophysiology

Autoreactive antigen presentation

Dendritic cells present antigen – in this case an autoreactive peptide – to the T-cells. This autoreactive antigen presentation triggers production of autoreactive T-cells and the activation of autoreactive B-cells.

Normally, T regulatory cells would destroy these autoreactive cells but in the setting of poor regulatory function (eg, from reduced regulatory T-cell function), these autoreactive cells can flourish.

Molecular Mimicry: Peripheral vs Central

There are two leading schools of thought regarding the molecular mimicry that triggers the formation of autoreactive lymphocytes:

Peripheral Hypothesis

The peripheral hypothesis is that peptides derived from infections, such as HSV, EBV, or influenza and trigger autoreactive T-cells towards myelin proteins, such as: myelin basic protein (MBP), proteolipid protein, and myelin oligodendrocyte glycoprotein (MOG).

Central Hypothesis

The central hypothesis is that CNS auto-antigens pass into regional lymph nodes and induce a peripheral immune response, which triggers a CNS attack.

Autoimmune attack

B-cells and T-cells are recruited into the CNS via break-down in the blood brain barrier, which serves to separate the brain, immunologically, from the rest of the body. Thus, inflammatory mediators from the periphery must break-down the blood-brain barrier.

And show that monocytes and macrophages are also recruited, as well as, there is activation of CNS microglia.

Theses cells mediate their harm via phagocytosis, emission of numerous cytokines and the B-cells mature into plasma cells, which, along with immature B-cells, secrete antibodies, thus causing destruction of the myelin sheath.

Cytokines

Cytokines are cell signaling proteins including various interleukins (eg, Il-10, IL-17A, and IL-23), interferons (eg, IFN-gamma), tumor necrosis factor (TNF-alpha, THF-beta), and chemokines (eg, CCR1 through CCR6).

As a pharmacological correlation,
Show that the interferons and glatiramer acetate act on lymphocytes.

Fingolimod traps T-cells in lymph nodes. It down-regulates sphingosine-1-phosphate receptors on leukocytes and the endothelium. This prevents T-cells from leaving lymph nodes.

Finally, indicate that ocrelizumab is a human monoclonal antibody to CD20; it causes depletion of B-cells that present the CD20 receptor.

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