Neuroscience Week 2: Myelin Disorders Flashcards
MS pathophysiology
lymphocytes infiltrate and attack myelin and oligodendrocytes leading to demyelination and later axonal degeneration
MS Etiology
unknown but is thought to be influences by genetic and environmental factors
Histology Hallmarks of MS
the presence of demyelinated plaques in the brain WM (most localized around the ventricle), spinal cord and optic nerves that can either be active or inactive
Potential pathophysiology of MS
5 listed
Histology of MS
2 types of lesions
Acute inflammatory lesions
lymphocytes and macrophages have crossed blood brain barrier and demyelination around it
myelin staining LFB, myelin is reduced around the vein but intact further away
Chronic lesions are hypocellular with no evidence of active demyelination
MS IHC staining
- stain for active microglia
- acute lesions have active microglia
- chronic lesions don’t have active microglia
Diagnosis of MS
mostly clinically
- presence of signs/symptoms referable to CNS separated in time (more than one event) and space (more than one CNS area involved)
Confirmatory tests
- MRI (Gd-enhanced T1 MRI (acute lesions) and T2 MRI (chronic lesions))
- CSF Analysis (High IgG content and oligoclonal bands are present)
- Evoked potential studies (Abnormal VER and SSER)
Confirmatory tests MS
4 listed
- MRI Gd-enhanced T1 for Acute lesions (Gadolinium enhanced)
- MRI T2 for chronic lesions
- CSF analysis (high IgG content and oligoclonal bands present) typically the IgG is not in the serum but is in the brain
- Evoked potential studies (Abnormal VER and SSER) visual evoked potentials takes longer for signal (light shined in the eye) to transduce
these tests are sensitive but not specific
Signs and Symptoms of MS
6 main systems
- unilateral optic neuritis, changes in vision, double vision, nystagmus
- cognitive impairment (deficits in attention, reasoning and executive function)
- Muscle weakness, stiffness and painful spasms, bladder dysfunction, erectile impotence, constipation
- uncoordinated limb movement and gait ataxia
- Pain and Fatigue
- Temperature sensitivity and exercise intolerance
MS Babinski
positive Babinski and hyper reflexia
Types of MS and most common
4 listed
- Relapsing Remitting MS (RRMS) (most common)
- Secondary Progressive MS (SPMS)
- Primary Relapsing MS (PRMS)
- Primary Progressive MS (PPMS)
Medications to Treat MS
Neuromyelitis Optica AKA
Devic’s Disease
or
NMO
Neuromyelitis Optica Description
Inflammatory CNS demyelinating disorder involving the bilateral optic neuritis and spinal cord demyelination
Neuromyelitis Optica Forms and commonality
2 forms
Relapsing (most common)
&
Monophasic
Neuromyelitis Optica Relapsing form epidemiology
- effects mostly Asians, Africans and Native Americans
- 8,000 NMO patients in the US
- 80% are women
Neuromyelitis Optica Pathogenesis
The disease is characterized by the presence of antibodies against aquaporin-4 the major water channel of astrocytes
Neuromyelitis Optica Signs and symptoms
- loss of vision
- weakness and numbness of arms and legs
- paralysis
- difficulty controlling the bladder and bowels
Neuromyelitis Optica Vs MS
aquaporin-4 antibodies which is the major water channel in astrocytes affecting mostly the optic nerve and spinal cord
Neuromyelitis Optica Treatment
plasmapheresis and depletion of b cells with humanized anti-CD20 antibody (Rituximab)
Acute Disseminated Encephalomyelitis Description
Monophasic autoinflammatory CNS demyelinating disorder
Acute Disseminated Encephalomyelitis AKA
ADEM
ADEM AKA
Acute Disseminated Encephalomyelitis
Encephalomyelitis
inflammation of the brain and the spinal cord
Proposed Acute Disseminated Encephalomyelitis Pathogenesis
appears to be caused by molecular mimicry of
viral infections (mumps, measels, varicella, rubella)
or
Bacterial infection (chlamydia, rickettsia)
or
vaccinations (mumps, rabies, pertussis, rubella)
Acute Disseminated Encephalomyelitis Epidemiology
1/100,000 and affects mostly young and adolescent children
Acute Disseminated Encephalomyelitis Signs and Symptoms
- loss of vision
- ataxia
- paralysis
- some patients develop drowsiness and coma
Acute Disseminated Encephalomyelitis Treatment
anti-inflammatory and immunosuppressive agents
prognosis is generally favorable
Acute Disseminated Encephalomyelitis
AHLE
- is less common
- the hyperacute and frequently fatal form of ADEM with perivenular demyelination and diffuse hemorrhagic CNS necrosis
Progressive Multifocal Leukoencephalopathy AKA
PML
Progressive Multifocal Leukoencephalopathy Description
severe demyelinating disease of the CNS due to lytic infection of oligodendrocytes by the ubiquitous opportunistic polyoma (papova) virus JC (JCV)
Progressive Multifocal Leukoencephalopathy Epidemiology
most cases occur in patients with AIDS, cancer and inflammatory disorders and organ transplant recipients
immunosuppressed patients
Progressive Multifocal Leukoencephalopathy
PML begins with small demyelinating foci and the confluence of these foci results in large irregular white matter lesions that involve the cerebrum, cerebellum and brainstem
Progressive Multifocal Leukoencephalopathy Signs and Symptoms
PML is characterized by a variety of neurological defects
- Visual loss
- paralysis
- disorientation
- dementia
Majority of patients die in a few months
Progressive Multifocal Leukoencephalopathy Diagnosis
PML is diagnosed with
CSF test for JV virus DNA by PCR
or
brain biopsy to look for demyelination / enlarged oligodendrocyte nuclei
Landry-Guillain-Barre Syndrome AKA
GBS
or
idiopathic polyneuritis
Landry-Guillain-Barre Syndrome Epidemiology
the most common form of acute inflammatory peripheral neuropathy 8,000 cases/year in the US
The most common form of GBS in the US is the acute inflammatory demyelinating polyneuropathy (AIDP)
Landry-Guillain-Barre Syndrome the most common form of GBS in the US?
The most common form of GBS in the US is the acute inflammatory demyelinating polyneuropathy (AIDP)
Landry-Guillain-Barre Syndrome Description
polyneuritis - inflammation of the peripheral nerves both motor and sensory
Autoimmune-mediated demyelination of the peripheral nerves that appears 2-4 weeks after viral or allergic reaction
Landry-Guillain-Barre Syndrome Histology
Nerves infiltrated by lymphoid cells with phagocytosis of myelin by macrophages (axons are not damaged)
Landry-Guillain-Barre Syndrome Signs and Symptoms
Ascending muscle weakness
symmetric hyporeflexia and paralysis
in many cases there is respiratory paralysis but most patients recover
Landry-Guillain-Barre Syndrome Treatment
- plasmapheresis and IV-IgG
- Remyelination occurs over 3-4 months because peripheral nervous system can remyelinate
Metachromatic Leukodystrophy AKA
MLD
Metachromatic Leukodystrophy Description
Lysosomal storage disease caused by deficiency of sulfatide sulfohydrolase (sulfatidase, arylsulfatase A)
Metachromatic Leukodystrophy Epidemiology
Inherited with Autosomal Recessive trait
Incidence 1:50,000
more prevalent in Habbanites Jews (1:75) and Navajos (1:2500)
Metachromatic Leukodystrophy Forms
The disease presents in three forms of varying severity
Late infantile (60%) - most severe and die in a few years
Juvenile (20%)
Adult (20%)
Metachromatic Leukodystrophy clinical Features
- blindness
- loss of speech
- decreased intellectual functions
- peripheral neuropathy
- seizures
Metachromatic Leukodystrophy Pathophysiology
Extensive demyelination of CNS and PNS axons
sulfatides accumulate inside OLs, Schwann Cells and Macrophages
they cause metachromasia
Metachromatic Leukodystrophy Deficiency
Sulfatide Sulfohydrolase
causes accumulation of sulfatides
Metachromatic Leukodystrophy Treatment
- There is no effective treatment
- HSCT has been shown to be beneficial
Metachromatic Leukodystrophy Histology
MRI T2 areas of demyelination that are diffuse, also are symmtric
LFB staining of brain white matter has no myelin
Cresyl-Violet staining of white matter deep brown is sulfatides from acidic color change
TEM Schwann cells have a lot of lysosomes with high amounts of sulfatides
Globoid-Cell Leukodystrophy AKA
GCL
or
Krabbe’s Disease
Globoid-Cell Leukodystrophy Description
Lysosomal storage disease caused by a deficiency of ß-galactosidase or galactosylceramidase
Globoid-Cell Leukodystrophy Epidemiology
Autosomal recessive disease
incidence in US 1:100,000
Globoid-Cell Leukodystrophy Genetics
inherited with an autosomal recessive pattern
Globoid-Cell Leukodystrophy Pathophysiology
Galactose-sphingosine or psychosine accumulates in the white matter of psychosine (galactosylsphingosine) which is toxic to oligodendrocytes
Globoid-Cell Leukodystrophy Pathological Hallmark
presence of globoid cells, which are large, globe-shaped, PAS-positive, multinucleated macrophages
Globoid-Cell Leukodystrophy Histology
PNS demyelination with the accumulation of galactocerebroside in Schwann Cells and macrophages
&
Hallmark
presence of globoid cells, which are large, globe-shaped, PAS-positive, multinucleated macrophages
Globoid-Cell Leukodystrophy Treatment
There is no treatment and typically die
Globoid-Cell Leukodystrophy Clinical features
the classic form of Krabbe’s Disease appear normal at birth but rapidly develop irritability, spasticity and progressive disease
Adrenoleukodystrophy AKA
Classical ALD
or
X-linked ALD
Adrenoleukodystrophy Description
severe demyelination and inflammation caused by mutations in ABCD1 gene located on the X-chromosome that codes for ALD protein which transports VLCFas into the peroxisome for ß-oxidation
Adrenoleukodystrophy Etiology
caused by mutations in ABCD1 gene located on the X-chromosome that codes for ALD protein which transports VLCFas into the peroxisome for ß-oxidation
VLCFAs (cholesteryl esters) accumulate (toxic buildup) in many organs particularly the brain WM, testes and adrenal cortex
Adrenoleukodystrophy Clinical Features
onset (6-10) with rapid deterioration
visual loss
ataxia
spasticity
adrenal insufficiency
Adrenoleukodystrophy Treatment
There is no effective treatment to prevent demyelination but the administration of Lorenzo’s Oil and BMT have only minor effects
Adrenoleukodystrophy AMN
Adrenomyeloneuropathy is a milder clinical variant of ALD characterized by adrenal insufficiency and progressive muscle weakness. also has later onset and better prognosis
Charcot-Marie-Tooth Disease Description
Hereditary motor and sensory neuropathy Schwann cells cannot myelinate axons of peripheral nerves
Charcot-Marie-Tooth Disease AKA
CMT
Charcot-Marie-Tooth Disease Epidemiology
one ofthe most inhewrited neurological disorders affecting approximately 1:2,500 people in the US
Charcot-Marie-Tooth Disease Variants
CMT-1A
CMT-1B
CMT-X
CMT-1A
Autosomal dominant caused by duplication of PMP22 gene on chromosome 17
CMT-1B
Autosomal dominant disorder caused by point mutation on P0 gene on chromosome 1
CMT-X
caused by point mutations on Connexin 32 gene on X-chromosome
Charcot-Marie-Tooth Disease Histological hallmark
CMT is characterized by segmental demyelination of peripheral nerves with incomplete remyelination and “onion bulb” formation
Charcot-Marie-Tooth Disease Clinical Features
weakness of the foot and lower leg muscles as well as foot and hand deformities
