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_ adults**and **_children_** **—•** ———**Follows _upper respiratory_ illness** (—**_Mycoplasma pneumonia_** in some) **—•** **———Fatal** in many patients **—•** ———****_Peri_**venular _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 ****_hyper_**acute autoimmune reaction** to **_myelin_** \*tip to remember. **_AHE_** has an **_H_** in it, and its the **_H_**yper**_acute_** 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, **Mono**phasic _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 ****_hyper_**acute** 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**?** —• **Galactosyl****_sphingosine_** 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** —• **Galactosyl**_sphingosine_**** 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**, ****_hypo_**tonia**, **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_**, ****_hyper_**reflexia**, 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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