Demyelinating diseases

DEMYELINATING

DISEASES

01/05/2023 DEMYELINATING DISEASES 2

INTRODUCTION

• Demyelinating diseases comprise of diseases of central and peripheral nervous system in which disruption of myelin is a dominant feature.

• Diseases affecting central nervous system (CNS) myelin can be classified on the basis of whether a primary biochemical abnormality of myelin exists (dysmyelinating) or whether some other process damages the myelin or oligodendroglial cells (demyelinating).

• Demyelinating diseases include autoimmune, infectious, toxic, metabolic, and vascular processes; dysmyelinating diseases in which a primary abnormality of the formation of myelin exists include several hereditary disorders



PARTS OF A NEURON• Cell Body

– Contains the nucleus• Dendrites

– Receptive regions; transmit impulse to cell body– Short, often highly branched– May be modified to form receptors

• Axons– Transmit impulses away from cell body– Axon hillock; trigger zone

• Where action potentials first develop– Presynaptic terminals (terminal boutons)

• Contain neurotransmitter substance (NT)• Release of NT stimulates impulse in next

neuron– Bundles of axons form nerves


MYELIN AND WHITE MATTER

• The gray and white matter of the central nervous system (CNS) differ not only in gross morphology but also in water content and macromolecular components, notably membrane lipids.

• Although the gray matter primarily contains neurons and their processes, the white matter is composed predominantly of myelinated bundles of axons

• The oligodendroglial cell membrane is the source of the myelin sheath, which is a tightly wrapped, multilayered membrane composed of a repeating structure characterized by lipid-cytoplasm-lipid-water and which ensheathes axons.

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A co-culture of oligodendrocytes and neurons, in which oligodendrocyte is labelled in green and neuron-specific tubulin in red. An oligodendrocyte is shown extending processes to neurites. Where it engages it will start to ensheath them.

Transmission electron micrograph of a myelinated axon, myelin sheath, which is a tightly wrapped, multilayered membrane


• Cholesterol, galactocerebroside, sphingomyelin, and phospholipids are the lipids found in fully formed white matter and account for the stability and strength

• Proteins are also embedded within the myelin.• Any process, including metabolic injury or ischemia, that

changes the chemical composition of myelin will result in a less stable structure that is more susceptible to injury .

• Because myelination of the CNS is essentially a postnatal process, the neonatal brain contains considerably more water (89% for gray matter and 82% for white matter) than the mature adult brain (82% for gray matter and 72% for white matter)


• Neuroglial cells, namely oligodendrocytes, astrocytes, and microglia, are primarily responsible for the maintenance or “well-being” of the white matter- by providing structural and nutritional support of neurons, regulating the extracellular environment, and acting as scavenger cells

Normal Progression of Myelination

• Proximal pathways before distal (e.g., brainstem before supratentorial brain)

• Sensory (visual and auditory) before motor• Central white matter before peripheral• Posterior before anterior


Drawings of the brain depict the progression of myelination. (a) Myelination progresses in a caudocranial direction from the brain stem, through the posterior limb of the internal capsule, and to the hemispheric white matter, proceeding from the central sulcus toward the poles. (b) Myelination advances from deep to superficial and from posterior to anterior.


Myelinated Regions at Birth (or Shortly After Birth)

• Dorsal brainstem• Inferior, superior cerebellar peduncles• Perirolandic region• Corticospinal tract• Central portion of centrum semiovale• Posterior limb of internal capsule to cerebral peduncle• Ventrolateral thalamus• Optic nerve, chiasm, tract


Myelination and MR Findings

• The most commonly used marker for evaluating normal brain maturation on conventional MR is the progression of myelination.

• Myelination starts in the second trimester of gestation and continues into adulthood, beginning with the peripheral nervous system and then the spinal cord, the brainstem, and finally the supratentorial brain.

• Myelination of the brain evolves in a predictable sequential fashion over the first 2 postnatal years.

• Studies have suggested that the sequence of myelination has functional significance and is correlated with psychomotor development.


• As white matter becomes myelinated, it appears hyperintense on T1-weighted and hypointense on T2-weighted images relative to gray matter

• It is known that the signal changes on T1-weighted MR increases with increase in certain lipids that occur during the formation of myelin from oligodendrocytes .

• The signal changes on T2-weighted MR have been presumed to be histologically as thickening and tightening of the spiral of myelin around the axon and loss of water .


• During the first 6 months of life, T1-weighted images are most useful for evaluating the progression of myelination.

• After 6 months of age, most cerebral white matter appears high in signal intensity on the T1-weighted images, beyond this time the T2-weighted images are generally relied on to further evaluate myelin progression .

• By 24 months of age, the process of myelination is essentially complete except for the terminal zones of myelination found in the occipital-parietal periventricular white matter.

• These regions appear as subtle, ill-defined areas of hyperintensity


Axial T1-weighted images of a 2-week-old infant born at 34 weeks of gestation. Hyperintensity isseen around the fourth ventricle due to myelmnation present in the surrounding structures: medulla (m in a),vermis (v in a), inferior cerebellar peduncle (arrow in a), and dorsal aspect ofthe pons (arrow in b). Increasedsignal intensity is noted in the posterior limb of the internal capsule as well (arrow in c). The unmyelinatedsupratentonial white matter is hypointense with respect to the gray matter, better seen in d.


Matching T1-weighted, T2-weighted, images from three patients ages 5 weeks (A,B), 8 months (D,E), and 3years (G,H).


CONDUCTION OF NERVE FIBRES BEFORE & AFTER DEMYELINATION


Normal myelinated axon

• Lipid-rich myelin sheath produced by oligodendrocytes

• Axon insulation• Sodium channels clustered at nodes of

Ranvier• Increased conduction speed and

metabolic efficiency

Demyelination

• Decreased conduction velocity or block

• Destablization of axonal cytoskeleton• Remodelling of internodal membrane• Progressive axonal loss

MULTIPLE SCLEROSIS


INTRODUCTION• Multiple sclerosis is a demyelinating disease of the central

nervous system caused by an autoimmune reaction that is the result of a complex interaction of genetic and environmental factors.

• Most commonly affects women of childbearing age who are of north European descent.


DEFINITION

• Multiple sclerosis is a chronic progressive, degenerative disorder of the CNS characterized by disseminated demyelination of the nerve fibres of the brain and spinal cord.

• Multiple sclerosis (MS) is characterized by a triad of inflammation, demyelination, and gliosis (scarring); the course can be relapsing-remitting or progressive.


EPIDEMIOLOGY


ETIOLOGYUnknown cause related to

– Infection – Physical injury– Emotional stress– Excessive fatigue– Pregnancy

PATHOLOGY


MORPHOLOGIC FEATURES. The pathologic hallmark is the presence of many scattered discrete areas of demyelination termed plaques.

• Grossly, plaques appear as grey-pink, swollen, sharply defined, usually bilaterally symmetric areas in the white matter.


1. ln active enlarging plaques, the histologic features are accumulation of lymphocytes and macrophages around venules and at the plaque margin where demyelination is occurring. In addition, there is loss of oligodendrocytes and presence of reactive astrocytosis with numerous lipidladen macrophages (microglia) in the plaque. The axons in the plaque are generally intact.

2. In old inactive plaques, there is no perivascular inflammatory cell infiltrate and nearly total absence of oligodendrocytes. Demyelination in the plaque area is complete as there is only limited regeneration of myelin. Gliosis is well-developed but astrocytes are less prominent. Some axonal loss may be present.

Microscopically, the features vary according to the age of the plaque:


PATHOPHYSIOLOGY


•The BBB prevent entrance of T cells into the nervous system. The blood–brain barrier is normally not permeable to these types of cells, unless triggered by infection or a virus, which decreases the integrity of the tight junctions. When the blood–brain barrier regains its integrity, usually after infection or virus has cleared, the T cells are trapped inside the brain.

Blood-brain barrier

breakdown

•The immune system attacks the nervous system, forming plaques or lesions.Commonly involves white matter.Destroys oligodendrocytes- causing demyelinationRemyelination occurs in early phase but not completely.Repeated attacks lead to fewer remyelination.

Autoimmunology

•T-cells attacks on myelin triggers inflammatory processes, stimulating other immune cells and soluble factors like cytokines and antibodies. Leaks form in the BBB cause swelling, activation of macrophages, and more activation of cytokines and other destructive protein

Inflammation


AUTOIMMUNE ACTION


Extravasation

astrocytes BRAIN TISSUE

M Y E L I Noligodendrocyte

B cell

Rolling Adhesion

a4 IntegrinVCAM

B L O O D F L O W

LUMEN OF VENULE

B A S A L L A M I N A

Circulation

Activated T cellProteases

Antigen presenting cell(Astrocyte or Microglial cell)Activated

microglia/macrophages

T CELL REACTIVATIO

NActivated

Macrophage

AutoantibodiesComplement

IL-1, IL-12,chemokines

Cytokines andchemokines

ProteasesTNF-a

O2•-

NO•

AXONAL DAMAGE

MS Disease Pathology




CLASSIFICATION


There are eight types of multiple sclerosis. They are:• Relapsing-remitting• Primary progressive• Secondary progressive• Relapsing progressive• Benign• Spinal form• Neuromyelitis optica• Marburg variant


CLINICAL FEATURES


COMMON SYMPTOMS• Bladder and Bowel dysfunction• Fatigue ( Central in nature)• Pain• Visual disturbances: Optic neuritis, diplopia, nystagmus• Cerebellum and basal ganglia: ataxia, intention tremor• Doral column: Sensory abnormalities (paresthesias), impairment of deep sensation, proprioception• Corticospinal tract: Weakness and spasticity• Frontal lobe dysfunction: Cognitive, memory, learning, and impaired emotional responses, depression• Speech abnormalities: Dysarthria• Brainstem abnormalities: Myokymia, deafness, tinnitus, vertigo, vomiting

Top 3 most prevalent symptoms1. Bladder and Bowel dysfunction2. Fatigue ( Central in nature)3. Pain

Top 3 problems affecting ADLsreported by patients:1. Fatigue2. Balance difficulties3. Weakness


The most common initial symptoms •changes in sensation (33%)•Optic neuritis (20%)•Weakness(exercise induced) (13%)•double vision- internuclear opthalmoplegia (7%)•unsteadiness while walking (5%)•and balance problems (3%)

Lhermitte's sign (25-40%) is an electrical sensation that runs down the back and into the limbs and is produced by bending the neck forwards. The sign

suggests a lesion of the dorsal columns of the cervical cord or of the caudal medulla.

Uhthoff's phenomenon is the worsening of neurologic symptoms in multiple sclerosis when the body gets

overheated from hot weather, exercise, fever,


COMMON SIGNSLhermitte’s sign: Classic but not pathognomonic.• Passive neck flexion causing an electric shock-like sensation radiating to the spine, shoulders as well as other areas. This sign is most likely a result of the increased sensitivity of the myelin to stretch or traction• Upper motor neuron signs: Increased muscle stretch reflex (MSR) and plantar responses, spasticity• Weakness• Decreased sensationNote: Not all new symptoms result from new MS lesion. Temporary aggravation of symptoms in old and previously silent lesions may be caused by fever, heat, stress, fatigue, or other medical problems, especially pulmonary or urinary tract infection, dehydration or medication side-effects. Aggravating factors and other medical problems must either be identified and treated, or ruled out.


SYSTEMIC MANIFESTATIONS

DIAGNOSIS


(a) Clinical Findings• “Lesions scattered in time and space”; a lesion must occur in different locations in the CNS at different points of time.• Neurologic deficits in 2 or more areas, reflecting white matter involvement, at 2 points in time for >24 hours separately by 1 month• Age: 10–59 years, commonly 20–40 years• Two separate attacks with the onset of symptoms at least 1 and up to 6 months apart or progression of the neurologic disease for greater than 6 months• Two separate lesions in which the symptoms cannot be explained by a single lesion• Objective deficits seen on exam• Feature of typical signs and symptoms supported by diagnostic data


(b) Diagnostic Data:– There is no pathognomonic test for MS. All labs are nonspecific and

are to be interpreted within the clinical picture.Cerebral Spinal Fluid (CSF) Examination

• Increased in Protein (myelin basic, 25%), Oligoclonal IgG bands (greatest sensitivity), IgG and WBCs

VEP (Visual Evoked Potentials) (high sensitivity along with MRI)• P100 latency is abnormal (slowing secondary to plaques) in 75%

BAER (Brainstem Auditory Evoked Response)• Investigates the pontine area displaying an absence or delay of wave formation secondary to the demyelinating process

SEP (Sensory Evoked Potentials)• Prolongation of absolute peak or interpeak latency



EMG/NCS• Sensory Nerve Action Potentials (SNAPs), Compound Motor Action Potentials (CMAPs), Conduction Velocity (CV) worsens as the myelin thins• EMG may show Abnormal activity: Fibs, Positive Sharp Waves (PSW), Facial myokymia and a decrease Motor Unit Action Potentials (MUAP)• Single Fiber Electromyography (SFEMG): jitter (Grana, 1994)• Blink Reflex: May be abnormal

MRI (Greatest sensitivity for the diagnosis of MS)• Multifocal areas of increased intensity (plaques) on T2 weighted images are abnormal in 85% of the cases• These ovoid-appearing plaques are located in the periventricular white matter (corpus callosum)• Enhancement with gadolinium may precede the onset of deficits and identify activedisease• May visualize subclinical lesions

CT Scan• Not effective in visualizing lesion of brainstem, cerebellum, and optic nerve.• Cerebral atrophy is most common sign.


MRI of the brain and spinal cord in patient with MS


MRI of the brain in multiple sclerosis. a Asymmetrically scattered foci of abnormal signal, affecting only the white matter, are seen in the periventricular regions and at the anterior and posterior ends of the lateral ventricles. There is mild internal hydrocephalus. b There are typical signal abnormalities in the corpus callosum, extending into the white matter of the hemispheres.



TREATMENT


During an acute exacerbation treatment should include a comprehensive rehabilitation program. Relative rest, hydration, bladder and bowel management, PT and OT speech (swallowing protection) and dietary (nutrition) are essential in the care of the patient.MedicationsImmunomodulator agents: Disease-modifyingCorticosteroids (Methylprednisolone)

• Used in short bursts for acute attacks secondary to its anti-inflammatory and anti-edema effects. Acute attacks = “exacerbation” which is new or worsening MS symptoms lasting > 24 hours and not related to metabolic factors (Urinary Tract Infection [UTI], etc.)

• Dose: ~1000mg/day Intravenous IV for 4–7days with a 2 week taper, switch to PO

• Risks: Gastrointestinal (GI) disturbance, fluid retention, mood swings, electrolyte imbalance, insomnia, acne, hyperglycemia, hypertension (HTN)

• Most responsive symptoms: Optic neuritis, brainstem, motor, acute pain, bowel and bladderGlatiramer acetate C=Copaxone

• Dose: Subcutaneous Injection qd• Side effects: Self-limited transient flushing, injection site reactions, post injection

self-limiting


• Least responsive: Cerebellar, sensory• Long-term use leads to increase increased risk of HTN,

osteoporosis, diabetes, and cataracts• Hastens recovery, but does not prevent further attacks or alter

disease progressionThree Agents to Alter the Course of the Disease (“A, B, C’s”)Interferon-A (Avonex®) A=Avonex• Dose: 6 million units IM Q week• Side effects: flu-like symptoms, myalgia, fever, chills, asthenia• 18% reduction in relapse rate

Interferon-B (Betaseron®) B=Betaseron• Dose: 8 million units Subcutaneous QOD.• Side effects: Flu-like symptoms, increase liver function tests (LFTs),

decreased WBC, myalgia, injection site reaction, injection site necrosis (5%)

• 30% reduction in relapse rate


chest tightness• 32% reduction in relapse rateSerum neutralizing antibodies may form with Avonex® and Betaseron® (25%)

decreasing efficacyImmunosuppression agents are reserved for patients with unresponsive disabling MS.These are commonly used as second-line medications. The side effects need to be weighed when prescribing these medications and patients should be closely monitored.

CyclosporinCyclophosphamide (Cytotoxin®)—modest improvementAzathioprine—mixed resultsPlasmapheresisMethotrexate

Side effects: mucosal ulceration, Bowel Movement (BM) abnormalities, GI.Current Medications Under Review

Mitoxantrone—IV months, antineoplastic, for advanced MS—pending FDA review for this indication.

Intravenous Immunoglobulin (IVIG)—being studied.


PROGNOSIS

ACUTE DISSEMINATED ENCEPHALOMYELITIS


INTRODUCTION• Acute disseminated encephalomyelitis is an immune-mediated

inflammatory demyelinating condition that predominantly affects the white matter of the brain and spinal cord.

• ADEM is a demyelinating syndrome most commonly affecting young adults and children and occurs in association with vaccination (post-vaccination) or systemic infection (parainfectious encephalomyelitis)

• The hallmark of ADEM is the presence of widely scattered small foci of perivenular inflammation and demyelination in contrast to larger confluent demyelinating lesions typical of MS.


PATHOLOGIC FEATURES• ADEM is characterised by

perivascular inflammation, oedema, and demyelination within the CNS. The pathology of encephalomyelitis following infections and vaccines is indistinguishable from each other. ADEM results from an aberrant immune attack on the brain and/or spinal cord, triggered by temporally related infections or vaccinations.

MRI brain T2W image in a 28 years man showing postinfectious ADEMshowing hyperintense bilateral lesions in thalami and in the left parieto-occipital area.


CLINICAL FEATURES• The hallmark clinical feature is the development of a focal or

multifocal neurological disorder following exposure to virus or receipt of vaccine.

• The onset of the CNS disorder is usually rapid, with peak dysfunction within several days.

• Initial features include encephalopathy ranging from lethargy to coma, seizures, and focal and multifocal signs reflecting cerebral(hemiparesis), brainstem (cranial nerve palsies), and spinal cord(paraparesis) involvement. Other reported findings include movement disorders and ataxia.



TREATMENT• Initial treatment is with high-dose glucocorticoids as for

exacerbations of NMO depending on the response, treatment may need to be continued for 4–8 weeks.

• Patients who fail to respond within a few days may benefit from a course of plasma exchange or intravenous immunoglobulin.

TRANSVERSE MYELITIS


TRANSVERSE MYELITIS

• Transverse myelitis is a heterogenous group of inflammatory disorders characterised by acute or subacute motor, sensory and autonomic spinal cord dysfunction.

• Myelitis: non-specific term for inflammation of spinal cord• Transverse: involvement across one level of the spinal cord.• TM occurs with optic neuritis in neuromyelitis optica

( Devic’s disease).



ETIOLOGY• Acquired alteration in the innate or acquired immune system• Cellular injury and dysfunction• Infectious trigger: infectious agent triggers breakdown of immune

tolerance for self-antigens• TM and ADEM: Superantigen-mediated activation of T lymphocytes • Suspected that multiple immune system components contribute to

observed dysfunction including T and B lymphocytes, macrophages, and NK cells

• Mechanism of injury also probably involves multiple pathways including T lymphocyte killing of neural cells, cytokine injury, activation of toxic microglial pathways, immune-complex deposition, and apoptosis


DISEASES ASSOCIATED WITH TM


PATHOLOGY


CLINICAL FEATURES


DIAGNOSTIC CRITERIA



BY,JAYASRI K S

Date post:	17-Jan-2017
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Demyelinating diseases

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