Exam 1: Myelin and Metabolic Disorders

Question 1

Review – Myelin disorders: Autoimmune

Name the 4 autoimmune diseases/problem/issues that are related to mylelin disorders

Answer 1

—1) Multiple Sclerosis (CNS)

——2) Acute disseminated encephalomyelitis (acute) and acute hemorrhagic encephalomyelitis (hyperacute) (both CNS)

—3) Neuromyelitis optica

4) —Guillain-Barré (PNS)

Question 2

Review – Myelin disorders: —Metabolic

Name a Metabolic diseases/problem/issues that is related to mylelin disorders

Answer 2

—Central pontine myelinolysis —(rapid correction of hyponatremia/osmotic shock),

Marchiafava-Bignami

Question 3

Review – Myelin disorders: Leukodystrophy

*Genetic/storage diseases (—Often due to catabolic enzyme deficiency)*

Name the 3 Leukodystrophy diseases/problem/issues that are related to mylelin disorders

Answer 3

—1) —Krabbe

——2) Metachromatic leukodystrophy (—accumulation of sulfatides)

—3) —Adrenoleukodystrophy (accumulation of very long chain fatty acids),

Pelizaeus-Merzbacher (proteolipid protein gene),

Canavan (Aspartylcyclase activity )

Question 4

Review – Myelin disorders: ——Nutritional

Name a Nutritional diseases/problem/issues that is related to mylelin disorders

Answer 4

—Subacute Combined Degeneration of the Spinal Cord - Vitamin B12 Deficiency – degeneration of posterior, lateral, and other columns (PNS and CNS)

Question 5

Review – Myelin disorders: —

—Myelin disorders can be Dysmyelination or Demyelination.

1) How does each one affect myelin?
2) What types of disorders are releated to each?

Answer 5

—Faulty myelin production** (_Dys_myelination**)

• —Genetic
• ——Metabolic

—Attack on normal myelin (Demyelination)

• ——Immunologic
• ——Toxic/environmental/nutritional/metabolic
• ——Infectious
• ——Other

Question 6

Review – —Myelin is produced in? —

—

Answer 6

—CNS by the oligodendroglial cells

—PNS by Schwann cells

Question 7

Review – —Myelin: —

_____ axons

—Allows _____ conduction of axonal impulses

—Composed of _____ and _____

Answer 7

Review – —Myelin: —

—Insulates axons

—Allows saltatory (i.e. faster) conduction of axonal impulses

—Composed of lipids and proteins

Question 8

Review – ——Loss of myelin leads to?

Answer 8

—• Short-circuits

—• Slowing of conduction

• —Failure of bodily functions

Question 9

Multiple Sclerosis summarys - Etiology:

What is the basic etiology of MS?

Answer 9

autoimmune disease (immunologic)

Question 10

Multiple Sclerosis - Cellular immunity:

• —Initiated by _____ cells react against _____ _____

—T_H1 lymphocytes secrete _____ (IFN-γ) that activate _____ which injure myelin

—T_H17 lymphocytes promote recruitment of _____

—• Plaques (lesions) contain _____ and _____

Answer 10

Multiple Sclerosis - Cellular immunity:

• —Initiated by CD4+ T cells react against self myelin

—T_H1 lymphocytes secrete cytokines (IFN-γ) that activate macrophages which injure myelin

—T_H17 lymphocytes promote recruitment of leukocytes

—• Plaques (lesions) contain macrophages** and **T-lymphocytes (mostly CD4+)

Question 11

Multiple Sclerosis - Cellular immunity:

• —Antibodies also present with uncertain role

—_____ bands seen on CSF electrophoresis

___-cells present

Answer 11

Multiple Sclerosis - Cellular immunity:

• —Antibodies also present with uncertain role

—Oligoclonal bands seen on CSF electrophoresis

—B-cells** present

*—Pathogenetic evidence of infection; —HumanHerpesvirus-6 antibodies are seen in ~40%

**—B-cell depletion can decrease incidence of demyelinating diseases

Question 12

Multiple Sclerosis - —Risk factors/Pathogenesis:

• ——Familial risk

—15-fold increase with _____ relative

—Higher incidence (150-fold) with _____ twins

—• ——Genetic linkage

—___-hapotype of MHC

—Siblings with MS may share same _____ receptor haplotype

Answer 12

Multiple Sclerosis - —Risk factors/Pathogenesis:

—• ——Familial risk

—15-fold increase with 1st-degree relative

—Higher incidence (150-fold) with monozygotic twins

—• ——Genetic linkage

—DR2-hapotype of MHC

—Siblings with MS may share same T-cell receptor haplotype

Question 13

Multiple Sclerosis - —Risk factors/Pathogenesis:

—• ——Weiner

—single-nucleotide polymorphisms (SNPs) associated with a higher risk of developing MS were identified on the interleukin-___ receptor a gene, interleukin-___ receptor a gene, and confirmed in the ___-___ locus.

—• ——Populations

—More common in _____ populations in northern latitudes

——Arguments of _____ factors

Answer 13

Multiple Sclerosis - —Risk factors/Pathogenesis:

—• ——Weiner

single-nucleotide polymorphisms (SNPs) associated with a higher risk of developing MS were identified on the interleukin-2 receptor a gene, interleukin-7 receptor a gene, and confirmed in the HLA-DRA locus.

—• ——Populations

—More common in Caucasian populations in northern latitudes

—Possibly accounts for increased incidence in temperate latitudes (vs. equator)

—Arguments of environmental factors

—Migration studies show that risk can change with moves early in life.

Question 14

Multiple Sclerosis - —Pathogenesis:

—• ———Infections (particularly early in life) may cause breakdown of _____ and entry of lymphocytes into _____

——• _____ antibodies in ~40% of MS patients

—• _____ and ____ have also been suggested as a potential triggers

Answer 14

Multiple Sclerosis - —Pathogenesis:

—• Infections (particularly early in life) may cause breakdown of BBB and entry of lymphocytes into CNS (no agent has been conclusively established)

——• Human HerpesVirus-6 antibodies in ~40% of MS patients – more than EBV and CMV

—• ——EBV and Chlamydia have been suggested as a potential triggers

Question 15

Multiple Sclerosis - Clinical:

—• ————Often begins with _____ nerve involvement (_____ neuritis)

——• Often _____ and _____ course

——• Female-to-Male ratio is ___:1

——• Rarer before ___ and after___

——• _____ seen on MR

——• High _____-signal

Answer 15

Multiple Sclerosis - —Clinical:

—• ————Often begins with optic nerve involvement (—Optic neuritis); —May or may not proceed to MS – only 10 to 50% develop MS.

——• Often remitting and relapsing course

——• Female-to-Male ratio is ~2:1

——• Rarer before 20 and after 50

——• Lesions seen on MR

——• High T₂-signal

—

Question 16

Multiple Sclerosis - Clinical: lesion deficits

Multiple lesions produce variety of deficits.

(I dont think we need to memorize these as much as understand what all can be affected. )

—Visual, —Spinal Cord, —Cerebellar deficits, Lhermitte sign, —Intranuclear ophthalmoplegia and other eye movement disorders, —Depression and psychiatric conditions, and many other findings

Answer 16

Multiple Sclerosis - —Clinical: lesion deficits

—Visual: —Intranuclear ophthalmoplegia, —Pupillary abnormalities, —Nystagmus

—Spinal Cord: —Acute transverse myelitis (spinal cord). —Paralysis, —Sensory loss (dorsal columns), —Bladder control dysfunction

—Cerebellar deficits: —Ataxia, —Scanning speech, —Intention tremor

—Lhermitte sign: Shocklike feeling with neck flection

—Intranuclear ophthalmoplegia and other eye movement disorders

—Depression and psychiatric conditions

—Many other findings

—

Question 17

Multiple Sclerosis - Pathology: (Gross)

_______ in _____ matter of brain and spinal cord

—• Loss of _____ matter – _____ in areas that should be _____

—• In brain, often adjacent to _____ ventricles

• —Firmer than adjacent areas – _____

—• Can show “_____” due to microscopic perivascular pattern

Answer 17

Multiple Sclerosis - —Pathology: (Gross)

Lesions (plaques) in white matter of brain and spinal cord (CNS)

—• Loss of white matter – grey-tan lesions in areas that should be white

—• In brain, often adjacent to lateral ventricles

• —Firmer than adjacent areas – gliosis

—• Can show “fingers” due to microscopic perivascular pattern

Question 18

Multiple Sclerosis - Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Acute (active) plaques

_____ attacking and engulfing myelin

—_____, often ___vascular

—_____ apoptosis

Answer 18

Multiple Sclerosis - —Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Acute (active) plaques

—Macrophages attacking and engulfing myelin

—Inflammation** (lymphocytes and macrophages), often **perivascular

—Oligodendroglial apoptosis

Question 19

Multiple Sclerosis - Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Inactive plaques

—Loss of myelin with fewer _____ cells

—_____ of oligodendroglial cells

—Gliosis

—Relative _____ of axons

Answer 19

Multiple Sclerosis - —Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Inactive plaques

—Loss of myelin with fewer inflammatory cells

—Reduction of oligodendroglial cells

—Gliosis

—Relative preservation of axons (vs. myelin loss)

—Some axonal loss possible

Question 20

Multiple Sclerosis - Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Shadow plaques

—Evidence of _____ – axons with thin myelin

Answer 20

Multiple Sclerosis - —Pathology: (—Micro)

acute (active), inactive, and shadow plaques

—Shadow plaques

—Evidence of remyelination – axons with thin myelin

Question 21

What disorder is shown in the image?

What are we supposed to know about this image?

Answer 21

Multiple Sclerosis

The area around the occipital horns of the lateral ventricle should be myelinated white matter.

Question 22

What disorder is shown in the image?

What are we supposed to know about this image?

Answer 22

Multiple Sclerosis

The Luxol Fast Blue is used in MS sections; Luxol Fast Blue stains myelin blue.

The higher-power images show loss of myelin with relative preservation of axons (i.e. c/w demyelination).

Question 23

What disorder is shown in the image?

What are we supposed to know about this image?

Answer 23

Multiple Sclerosis

Note the presence of multiple lesions. The characteristic “Dawson’s Fingers” are areas of demyelination adjacent to the ventricles (Fig. A).

Figure E shows a high cervical lesion and a lesion in the corpus callosum.

Question 24

Multiple Sclerosis - Pathology: CSF

—_____ bands (_____ antibodies) on immunoelectrophoresis

—Glucose _____

Protein _____

WBC slightly to moderately _____

Answer 24

Multiple Sclerosis - —Pathology: CSF

—Oligoclonal bands (IgG antibodies) on immunoelectrophoresis– antigen not exactly known

—Glucose normal

Protein normal or slightly elevated

WBC slightly to moderately elevated

*Remember the immune basis of MS.

Question 25

Multiple Sclerosis - Different courses:

—Relapsing remitting – Relapses followed by Improvement after _____ (remission); _____ progression (most common)

—Secondary progressive – Follows relapsing, remitting - _____ progression _____ remissions (i.e. remissions less common)

—Primary progressive – Gradual progression _____ remissions

—Relapsing progressive – _____ but still accumulate disability

Answer 25

Multiple Sclerosis - —Different courses:

—Relapsing remitting – Relapses followed by Improvement after attacks (remission); little or slow progression (most common)

—Secondary progressive – Follows relapsing, remitting - Steady progression with or without remissions (i.e. remissions less common)

—Primary progressive – Gradual progression without remissions

—Relapsing progressive – Remissions but still accumulate disability

Question 26

Multiple Sclerosis - Variable course:

—

• ——dependent on form, severity, locations
• ——Untreated remitting/relapsing – 30% disability in _____ years from onset

Answer 26

Multiple Sclerosis - —Variable course:

• —dependent on form, severity, locations
• ——Untreated remitting/relapsing – 30% disability** in **20-25 years from onset

—

Question 27

Multiple Sclerosis - Therapy:

—Emphasizes the _____ nature of MS (examples below)

***—Immunomodulators: _____-beta, —_____zumab***

—Corticosteroids: —_____prednisolone

—Immunosuppressors: —_____trone (inhibits topoisomerase, induces crosslinks and strand breaks), —_____phosphamide

—Other: —Treatment of a variety of symptoms including —fatigue and psychiatric

Answer 27

Multiple Sclerosis - —Therapy:

—Emphasizes the immune/autoimmune nature of MS (examples below)

***—Immunomodulators: —Interferon-beta, —Natalizumab***

—Corticosteroids: —Methylprednisolone

—Immunosuppressors: Mitoxantrone (inhibits topoisomerase, induces crosslinks and strand breaks), —Cyclophosphamide

—Other: —Treatment of a variety of symptoms including —fatigue (Amantadine, CNS Stimulants. Baclofen for spasticity) and psychiatric

Question 28

Devic disease/Neuromyelitis Optica:

Variants/Related Disease of _____?

• seen more in _____, higher _____ : _____ ratio

•— Has antibodies against _____, major water component of astrocytes; areas of demyelination show loss of _____

•— _____ optic neuritis and _____ spinal cord involvement

•— Greater _____ matter involvement; _____ can be present

•— Plasmaphoresis or depletion of _____ with anti-___ antibody

• —NMO-IgG is available per Weiner and is used in _____

Answer 28

Devic disease/Neuromyelitis Optica:

*** Variants/Related Disease of Multiple Sclerosis ***

• seen more in —Asians, higher women : male ratio

•— Has antibodies against aquaporin-4, major water component of astrocytes; areas of demyelination show loss of aquaporin -4

• —Bilateral optic neuritis** and **prominent spinal cord involvement

• —Greater grey matter involvement; necrosis can be present

• —Plasmaphoresis or depletion of B-cells with anti-20 antibody

• —NMO-IgG is available per Weiner and is used in diagnosis

Question 29

—Acute MS – Marburg form:

Variants/Related Disease of _____?

• seen more in _____ individuals

—• _____ course

—• _____ plaques

Answer 29

—Acute MS – Marburg form:

*** Variants/Related Disease of Multiple Sclerosis ***

• seen more in younger individuals

—• Fulminant course

—• Large plaques

Question 30

—A classic MRI image is shown:

Where are the lesions?

What would be the likely histopathological appearance of these lesions?

What would be the most likely initial lesion/symptom in such a patient?

*These are post-mortem MR scans. There is no fluid within the ventricular system.

Answer 30

—A classic MRI image is shown:

Where are the lesions?

What would be the likely histopathological appearance of these lesions?

What would be the most likely initial lesion/symptom in such a patient?

*These are post-mortem MR scans. There is no fluid within the ventricular system.

Question 31

Acute Disseminating Encephalomyelitis:

• ——Follows _____ or _____

• ——Occurs within _____ after infection (_____ course than MS)

—• —_____ symptoms (examples?) vs. focal symptoms of MS

• ——(rapid or slow?) progress

• ——Pathology: —Myelin loss with relative _____ of axons, Neutrophils _____, —_____phasic

• ——Possibly _____ autoimmune reaction to myelin

Answer 31

Acute Disseminating Encephalomyelitis:

• —Follows viral infection or immunization

—• —Occurs within a week or two after infection (faster course than MS)

—• —General symptoms (headache, lethargy, coma) vs. focal symptoms of MS

• ——Rapid progress – 20% fatal; remainder have complete recovery

• ——Pathology: —Myelin loss with relative preservation of axons, —Neutrophils early**, —_Mono_phasic**

• ——Possibly acute autoimmune reaction to myelin

Question 32

Acute Hemorrhagic Encephalomyelitis:

• ———age groups normally affected?

—• ———Follows ______ ______ illness (—_____ ______ in some)

—• ———_____ in many patients

—• ———_____venular demyelination.

—• ———_____ destructive than ADEM. —destruction of _____ vessels. —Necrosis of _____ matter. —Acute hemorrhage, _____ deposition, and _____ in less severely damaged areas

—• ———Possibly _____ autoimmune reaction to myelin

Answer 32

Acute Hemorrhagic Encephalomyelitis:

• ———Young adultsand children

—• ———Follows upper respiratory illness (—Mycoplasma pneumonia in some)

—• ———Fatal in many patients

—• ———Perivenular demyelination. Sometimes widely distributed and confluent

—• ———More destructive than ADEM. —destruction of small vessels. —Necrosis of white and grey matter. —Acute hemorrhage, fibrin deposition, and inflammation in less severely damaged areas

—• ———Possibly hyperacute autoimmune reaction to myelin

*tip to remember. AHE has an H in it, and its the Hyperacute rxn to myelin, vs. ADE which is an acute rxn to myelin

Question 33

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

What does ADE follow?

How does that differ from AHE?

Answer 33

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

ADE: follows —viral infection or immunization

AHE: follows —upper respiratory illness

(—Mycoplasma pneumonia in some)

Question 34

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

What is the pathology of ADE?

How does that differ from AHE?

Answer 34

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

pathology of ADE:

—Myelin loss with relative preservation of axons, —Neutrophils early, Monophasic

pathology of AHE:

—More destructive than ADEM

——Perivenular demyelination. Destruction of small vessels. Necrosis of white and grey matter. —Acute hemorrhage, fibrin deposition, and inflammation in less severely damaged areas

Question 35

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

ADE is a _____ autoimmune reaction to myelin while AHE is a _____ autoimmune reaction to myelin

Answer 35

Acute Disseminating Encephalomyelitis (ADE) vs.

Acute Hemorrhagic Encephalomyelitis (AHE)

ADE is a acute autoimmune reaction to myelin while AHE is a hyperacute autoimmune reaction to myelin

Question 36

Central Pontine Myelinolysis (CPM)

—• Thought to occur with _____ correction of _____natremia (_____ sodium) – osmotic shift

——• Alternative – extreme _____-osmolality or other _____ imbalance

—• —Loss of myelin with _____ axon preservation: —Central _____ pontis. —Pontine _____. —Can occur _____tentorially

——• Rapidly progressive _____; ”_____ syndrome”

——• Seen in _____, _____nourished conditions, severe electrolyte or osmotic imbalance, or in liver transplantation

Answer 36

Central Pontine Myelinolysis (CPM)

——• Thought to occur with rapid correction of hyponatremia (low sodium) – osmotic shift

***You must correct severe hyponatremia in a slow, deliberate manner!!!***

——• Alternative – extreme hypo-osmolality or other metabolic imbalance

——• Loss of myelin with relative axon preservation: —Central basis pontis. —Pontine tegmentum. —Can occur supratentorially

—• Rapidly progressive quadriplegia; ”locked-in syndrome”

—• Seen in alcoholism, malnourished conditions, severe electrolyte or osmotic imbalance, or in liver transplantation

Question 37

Buzz words:

Rapidly progressive quadriplegia

”locked-in syndrome”

hyponatremia followed by IV hypertonic saline

If you see these buzzwords consider?

Answer 37

Buzz words:

Rapidly progressive quadriplegia

”locked-in syndrome”

hyponatremia followed by IV hypertonic saline

Central Pontine Myelinolysis (CPM)

Question 38

Marchiafava-Bignami

• —Myelin loss/necrosis in and around _____ _____ and _____ ______

—• Classically thought to occur in _____ of _____ heritage

• —Abuse of _____ (contaminant?)

• —History of _____ and poor nutrition with overlap with other syndromes (—_____-_____, —Alcoholic _____ dysfunction)

Answer 38

Marchiafava-Bignami

• —Myelin loss/necrosis in and around corpus callosum and anterior commissure

• —Classically thought to occur in alcoholics of Italian heritage

• —Abuse of cheap Italian red wine (contaminant?)

• —History of alcoholism and poor nutrition with overlap with other syndromes (—Wernicke-Korsakoff, —Alcoholic cerebellar dysfunction)

Question 39

Progressive Multifocal Leukoencephalopathy (PML)

• ———Result of infection with _____.

—• ———_____ cells are infected.

—• ———_____ results. See LFB-stained image.

—• ———Astrocytic abnormalities are also present.

—• ———PML is often an _____ infection.

Answer 39

Progressive Multifocal Leukoencephalopathy (PML)

• ———Result of infection with JC virus.

—• ———Oligodendroglial cells are infected.

—• ———Demyelination results. See LFB-stained image.

—• ———Astrocytic abnormalities are also present.

—• ———PML is often an opportunistic infection.

Question 40

Leukodystrophy

• ————_____ defects

—• ————Affects _____ or _____ of components of myelin

• —————Often a _____ disease with buildup of substrate due to problems with _____ enzyme
• —————Substrate can be shuttled to alternative pathway with _____ _____

—• ————Often autosomal _____

Answer 40

Leukodystrophy

•.—Genetic defects

—• ————Affects production or handling of components of myelin

—• ————Often a storage disease with buildup of substrate due to problems with catabolic enzyme

—• ————Substrate can be shuttled to alternative pathway with toxic byproducts

—• ————Often autosomal recessive

Question 41

Sphingolipidoses

• This is a _____ pathway.

• An absent or abnormal _____ leads to _____ of substrate, which can harm the cell by direct or indirect means.

Answer 41

Sphingolipidoses

• This is a catabolic pathway.
• An absent or abnormal enzyme leads to build up of substrate, which can harm the cell by direct or indirect means.

Question 42

Krabbe Disease

• form of _____dystrophy

• —Sphingolipidosis

—• Deficiency of _____ β-galactosidase; required for conversion of galactocerebroside to ceramide and galactose. —Galactocerebroside can _____.

—• Most problems thought to be from?

—• Galactosylsphingosine is produced – toxic to _____ cells

Answer 42

Krabbe Disease

• form of Leukodystrophy
• Sphingolipidosis

—• Deficiency of galactocerebroside β-galactosidase; required for conversion of galactocerebroside to ceramide and galactose. —Galactocerebroside can accumulate.

—• Most problems thought to be from shifting galactocerebroside to alternative pathway

—• Galactosylsphingosine**** is produced – toxic** to **oligodendroglial cells

Question 43

Krabbe Disease

—• Onset ___-___ months; Survival uncommon beyond ___ years

• —Clinically – motor signs, —Stiffness and _____, —Worsening problems with _____

—• Loss of myelin in _____ with characteristic _____ cells (very enlarged multinucleated _____) in CNS clustered around _____; severe _____

Answer 43

Krabbe Disease

—• Onset 3-6 months; Survival uncommon beyond 2 years

• —Clinically – motor signs, —Stiffness and weakness, —Worsening problems with feedings

—• Loss of myelin in PNS and CNS with characteristic globoid cells (very enlarged multinucleated macrophages) in CNS clustered around blood vessels; severe gliosis

Question 44

Buzz words:

“Globoid” cells

If you see these buzzwords consider?

Answer 44

Buzz words:

“Globoid” cells

Krabbe Disease

Much of the white matter is gray/yellow because of the loss of myelin. Inset picture: “Globoid” cells are the hallmark of the disease.

Question 45

Metachromatic Leukodystrophy

• —Deficiency of arylsulfatase A which cleaves _____ for _____-containing lipids; Accumulation of _____ (galactosyl _____)

—• Myelin breakdown

—• Infantile, juvenile, and adult forms; —Infantile – Death by ___-___ years (most common); —Adult – Slower course

• —Therapy – _____ _____ transplantation
• —Pathology; —_____ demyelination _____ gliosis; —Vacuolated macrophages in _____ matter and _____; —Vacuoles contain _____tides

—Metachromatic – shift absorptive spectrum of dyes – toluidine blue and cresyl violet

—Diagnosis – Can identify in _____

Answer 45

Metachromatic Leukodystrophy

• —Deficiency of arylsulfatase A which cleaves sulfate for sulfate-containing lipids; Accumulation of sulfatides (galactosyl sulfatide)

—• Myelin breakdown

—• Infantile, juvenile, and adult forms; —Infantile – Death by 5-10 years (most common); —Adult – Slower course

• —Therapy – bone marrow transplantation
• —Pathology; —Striking demyelination with gliosis; —Vacuolated macrophages in white matter and PNS; —Vacuoles contain sulfatides

—Metachromatic – shift absorptive spectrum of dyes – toluidine blue and cresyl violet

—Diagnosis – Can identify in urine

Question 46

Adrenoleukodystrophy (Several forms)

• ——___-linked form

—• ——Mutations in _____ gene on Xq28

• ———Inability to _____ very-long chain fatty acids (VLCFA’s) within _____
• ———VLCFA’s _____ – toxic affects
• ———Myelin loss in _____ matter (with sparing of the immediate _____ _____) with gliosis and lymphocytic _____

—

Answer 46

Adrenoleukodystrophy (Several forms)

• ——X-linked form

—• ——Mutations in ALD gene on Xq28

• ———Inability to catabolize very-long chain fatty acids (VLCFA’s) within peroxisomes
• ———VLCFA’s accumulate – toxic affects
• ———Myelin loss** in **deep white matter (with sparing of the immediate subcortical U-fibers) with gliosis and lymphocytic inflammation

Question 47

Pelizaeus-Merzbacher

• ——___-linked

—• Gene encodes _____ protein

—• Myelin _____ in cerebral hemispheres but some areas remain producing _____ appearance

—• Early signs: _____ eye movements, _____tonia, choreoathetosis, and pyramidal signs

—• Late signs: _____, _____, ataxia

Answer 47

Pelizaeus-Merzbacher

• ——X-linked

—• Gene encodes proteolipid protein (PLP)

—• Myelin almost completely lost** in **cerebral hemispheres but some areas remain producing tigroid appearance

—• Early signs: Peduncular eye movements, hypotonia, choreoathetosis, and pyramidal signs

—• Late signs: spasticity, dementia, ataxia

Question 48

Subacute combined Degeneration of Spinal Cord

• —Deficiency of vitamin _____

—• —Loss of myelin with _____ in posterior columns, corticospinal and other tracts

—• —_____ and axonal loss can occur

—• —Symptoms: —Begins with slight _____, numbness and tingling in _____ extremities. —Can progress to _____ weakness and total _____

Answer 48

Subacute combined Degeneration of Spinal Cord

• —Deficiency of vitamin B₁₂

—• —Loss of myelin with vacuolization in posterior columns, corticospinal and other tracts

—• —Gliosis and axonal loss can occur

—• —Symptoms: —Begins with slight ataxia, numbness and tingling in lower extremities. —Can progress to spastic weakness and total paraplegia

Question 49

—Vitamin B1 (Thiamine) deficiency

• ——_____-_____ Syndrome

• ——Often seen in _____ with poor _____

—• Early Clinical: Psychoses and _____plegia acutely —

• Late Clinical: —Memory disturbances and _____

—• Midline lesions** – **mamillary bodies, thalamus, periventricular regions; —_____ early; _____ late

_____ leading to atrophy/cystic change in affected areas

—• Treatment; —_____ administration (_____ to glucose); —Correction of other nutritional deficits

Answer 49

—Vitamin B1 (Thiamine) deficiency

• ——Wernicke-Korsakoff Syndrome
• ——Often seen in alcoholics with poor nutrition

—• Early Clinical: Psychoses and ophthalmoplegia acutely —

• Late Clinical: —Memory disturbances and confabulation

—• Midline lesions – mamillary bodies, thalamus, periventricular regions; —Hemorrhagic early; hemosiderin late

—Necrosis leading to atrophy/cystic change in affected areas

—• Treatment; —Thiamine administration (prior to glucose); —Correction of other nutritional deficits

Question 50

—Hepatic Encephalopathy

• —Pathogenesis:

—Follows _____ dysfunction

—Altered _____ in the central nervous system and neuromuscular system

—Elevated blood _____ level and other toxins promote generalized brain _____.

• —Clinical:

—Disturbances in _____ (subtle to coma/death)

—Fluctuating neurologic signs including _____, _____reflexia, and particularly asterixis (i.e. _____ movements)

—_____ if clinical condition is addressed

• —Pathology:

—Few gross changes (outside of edema)

—Alzheimer Type ___ _____ develop – enlarged, folded, cleared nuclei

*Note the lobulated and enlarged _____ nucleus in the lower portion of the photograph

Answer 50

—Hepatic Encephalopathy

• —Pathogenesis:

—Follows liver dysfunction

—Altered neurotransmission in the central nervous system and neuromuscular system

—Elevated blood ammonia level and other toxins promote generalized brain edema.

• —Clinical:

—Disturbances in consciousness (subtle to coma/death

—Fluctuating neurologic signs including rigidity, hyperreflexia, and particularly asterixis (i.e. flapping movements)

—Reversible if clinical condition is addressed

• —Pathology:

—Few gross changes (outside of edema)

—Alzheimer Type 2 astrocytes develop – enlarged, folded, cleared nuclei

*Note the lobulated and enlarged astrocyte nucleus in the lower portion of the photograph

Question 51

——Carbon monoxide

• ——Results in _____ discoloration of skin

—• ——Global hypoxic changes – necrosis of layers ___ and ___ of cortex, hippocampus cerebellar _____ cells

—• ——___lateral necrosis of _____ pallidus

Answer 51

——Carbon monoxide

• —— ——Results in cherry–red discoloration of skin

—• ——Global hypoxic changes – necrosis of layers III and V of cortex, hippocampus, cerebellar Purkinje cells

—• ——Bilateral necrosis of globus pallidus

In picture: Carbon monoxide poisoning. (a) Hemorrhagic discoloration (arrows) of the pallidum in acute carbon monoxide poisoning. The dorsal part of the nucleus is most severely affected. (b) and (c) Examples of symmetric (b) and asymmetric (c) cavitation of the dorsomedial part of the pallidum in survivors of acute carbon monoxide poisoning. Note the ill-defined gray discoloration of the cerebral white matter and thinning of the corpus callosum in (c). (d) Cavitated necrosis (arrows) in the cerebral white matter in a survivor of acute carbon monoxide poisoning. (e) The frontal white matter has a gelatinous gray appearance and is focally cavitated in the brain from a long-term survivor of carbon monoxide poisoning. The arcuate fibers are spared.

Question 52

———Methanol

• ———Degeneration of _____ ganglion cells

• ————___lateral _____ necrosis; focal _____ matter necrosis

Answer 52

—Methanol

• ———Degeneration of retinal ganglion cells
• ————Bilateral putamenal necrosis; focal white matter necrosis

Question 53

————Ethanol

• ————Degeneration of _____-_____ cerebellar _____

—• ————Clinical – _____ ataxia

—

Other Pathology – Ethanol-related (emphasize) including Marchiafava Bignami ——Cerebellar Degeneration, —Wernicke-Korsakoff, ——Myopathy and Neuropathy, Fetal Alcohol Syndrome, —Hepatic Encephalopathy

Answer 53

——Ethanol

• ————Degeneration of anterior-superior cerebellar vermis

—• ————Clinical – truncal ataxia

—

Other Pathology – Ethanol-related (emphasize) including Marchiafava Bignami ——Cerebellar Degeneration, —Wernicke-Korsakoff, ——Myopathy and Neuropathy, Fetal Alcohol Syndrome, —Hepatic Encephalopathy

Question 54

—————Methotrexate and/or Radiation

• —————Necrosis around _____

—• —————Axonal _____

—• —————Radiation can also lead to widespread necrosis

Answer 54

—Methotrexate and/or Radiation

• —————Necrosis around ventricles or vessels

—• —————Axonal spheroids

—• —————Radiation can also lead to widespread necrosis

Question 55

A 50 yo man has ataxia secondary to chronic alcohol abuse**. Imaging of his **cerebellum shows atrophy. What part of the cerebellum is most likely to be atrophic?—————

A. Anterior-superior Vermis

B. Posterior-inferior Vermis

C. Lateral

D. Tonsils

Answer 55

A 50 yo man has ataxia secondary to chronic alcohol abuse**. Imaging of his **cerebellum shows atrophy. What part of the cerebellum is most likely to be atrophic?—————

A.

Anterior-superior Vermis

Question 56

A 35 year-old died 10 years after resection** of her **terminal ileum** due to **Crohn disease. A spinal cord section is shown. What is the etiology?

A. Chronic aluminum toxicity

B. Thiamine deficiency

C. Vitamin A toxicity

D. Vitamin B12 deficiency

E. Vitamin D deficiency

Answer 56

A 35 year-old died 10 years after resection of her terminal ileum due to Crohn disease. A spinal cord section is shown. What is the etiology?

D.

Vitamin B12 deficiency

Question 57

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Answer 57

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