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Flashcards in Toxic and metabolic CNS problems Deck (43):
1

What is the mnemonic for thinking through a CNS differential?

• VITAMIN C
• Vascular
• Infectious
• Trauma
• Age-related or degenerative
• Metabolic/toxic
• Inflammatory
• Neoplasm
• Congenital/genetic

2

What are the common acquired metabolic disorders without specific morphological correlates?

• Hypoglycemia - pathology similar to anoxia-ischemia except purkinje cells of cerebellum are relatively spared
• Hyperthermia - pathology similar to anoxia-ischemia
• Hypothermia - few pathological changes
Diabetes
Addison's disease
Thyroid disease
Pancreatic encephalopathy

3

Cyclosporine affects what cell in the CNS?



• oligodendrocyte

4

Radiation and BCNU affects what structure most specifically?

• Blood vessels in particular

5

Methotrexate kills what cell in the CNS?

• astrocytes

6

Toluene is a neurotoxin targeting what?

• Axon (myelin)

7

The metabolic disorders that do have morphological correlates are what?


• Acquired due to abuse, liver damage and dietary deficiencies
• Methanol, ethyl alcohol, hepatic encephalopathy and vitamin deficiencies

8

What can ethanol toxicity do to the brain?

• Cerebral edema in acute intoxication
• Withdrawal state
• Chronic effects
○ Cerebellar degeneration and neuronal loss
○ Cerebral atrophy, especially damage to white matter early in disease

9

What can happen to the meninges with chronic alcohol abuse?

• Meningeal fibrosis
• Remember earliest effects of ethyl alcohol are on white matter

10

What are the features of fetal alcohol syndrome?

• Hyperactivity
• Poor motor skills
• Learning difficulties
• Severely affected kids have intellectual disability

11

What kills you in fulminant liver failure?

• Death due to increased intracranial pressure
• Hepatic encephalopathy
○ Related to elevation of blood ammonia, usually above 200ug/dL
○ HE precipitated by events that cause blood ammonia to rise
§ GI hemorrhage and severe cirrhosis

12

In liver failure, think of ammonia as being the main problem for the CNS. Why is that?

• The liver puts the ammonia into urea and when that's gone there is just ammonia in the blood
• Ammonia is derived from catbolism of proteis and also produced in the colon by urease-containing bacteria
• In portal hypertension (cirrhosis) then treatment involves limiting protein in diet and suppressing colon bacteria with antibiotics

13

What is the pathologic substrate seen in Hepatic encephalopathy?

• Edema
• Alzheimer type II cells
○ In the cortex and basal ganglia
○ Neuronal death in deeper cortical layers and putamen

14

What is Kwashiorkor?

Kwashiorkor is a form of severe protein–energy malnutrition characterized by edema, irritability, ulcerating dermatoses, and an enlarged liver with fatty infiltrates.
*Sufficient calorie intake, but with insufficient protein consumption, distinguishes it from marasmus.
*Kwashiorkor cases occur in areas of famine or poor food supply.[1] Cases in the developed world are rare.[2]

15

What is Maraumus?

Marasmus is a form of severe malnutrition characterized by energy deficiency.
*A child with marasmus looks emaciated. Body weight is reduced to less than 60% of the normal (expected) body weight for the age.[1]
*Marasmus occurrence increases prior to age 1, whereas kwashiorkor occurrence increases after 18 months.
*It can be distinguished from kwashiorkor in that kwashiorkor is protein deficiency with adequate energy intake whereas marasmus is inadequate energy intake in all forms, including protein.

16

Nutritional deficiencies can lead to cachexia and to edema, but what about CNS?

• Signs are apathy, lack of activity
• Glial formation is affected, synaptic branching is lessened and myelin formation is slowed
• Brains show mild reductino in weight without specific gross/microscopic abnormalities
• Most children, however, can have full restoration of neuro development if proper nutrition is restored

17

What are the big three vitamin deficiencies to have on your mind with neurologic damage?

• Vitamin B1
○ Cause of Wernicke's encephalopathy
• Vitamin B12
• Vitamin E

18

What causes Wernicke's encephalopathy?

• Vitamin B1 deficiency
○ Cause of Wernicke's encephalopathy

19

What is going on in Wernicke-Korsakoff syndrome?

• Vitamin B1 and Thiamine deficiency
• Oculomotor abnormalities and mental symptoms
• Most common in alcoholics also in patients with hyperemesis
• Ocular motility problems, nystagmus, ataxia, confusion

20

What deficiency is an example of a toxic metabolic problem that targets a specific tissue (selective vulnerability)?

• Vitamin B1 or Thiamine deficiency
• Mammillary bodies are involved in almost all cases
• Hypothalamus, medial thalamus, periaqueductal grey, floor of 4th ventricle
• Histology varies with stage and severity
• Edema, necrosis, demyelination, neuron loss, gliosis

21

What is going on at the cellular level in the affected brain areas of wernicke's encephalopathy?

• Vitamin B1 or Thiamine deficiency
• Edema, necrosis, demyelination, neuron loss, gliosis
• Mammillary bodies are involved in almost all cases
*pericapillary hemorrhage is part of the problem

22

What pathway is vitamin B1 involved in?

• Pentose phosphate shunt
• Vitamin B1 is a cofactor for transketolase
• D-erythose-4-phosphate into D-Fructose-6-phosphate
• The eventual product that is going down is glyceraldehyde-3-phosphate and fructose-6-phosphate
○ I'm pretty sure these are all important in making ATP
• DISEASE IS ASSOCIATED WITH DECREASED BLOOD TRANSKETOLASE ACTIVITY

23

What is the timecourse of vitamin B1 deficiency?

• Also thiamine deficiency
• After 4 days
○ Reduced alpha-ketoglutarate dehydrogenase complex activity
○ Cytotoxic edema and astrocyte volume increase
• 7-10 days
○ Decreased transketolase activity in astrocytes
○ Increased NO from endothelial cell dysfunction
○ Low intracellular glutamate
○ High extracellular glutamate
○ Loss of cell osmotic gradients
○ Free radical production and increase in cytokines
○ LEADS TO - Cytotoxic and vasogenic edema in astrocytes or neurons
○ LEADS TO - BBB breakdown
• 14 days +
○ DNA fragmentation in neurons
○ Increased lactate in astrocytes or neurons
○ Low pH and focal acidosis
○ Neuronal necrosis
○ Irreversible structureal lesions in specific areas of brain (mammilary bodies)

24

Where is thiamine stored?

• Heart, kidneys, liver, brain, muscles
• Stores can be depleted in weeks
• IV glucose in patient with border-line deficiency may trigger disease

25

What clinical settings carry a risk for Wernicke's encephalopathy?

• Staple diet of polished rice
• Chronic alcohol abuse + malnutrition
• GI surgery recently
• Recurrent vomiting or chronic diarrhea
• Cancer and chemo
• Systemic diseases
• Magnesium depletion
• Chemicals and drugs
○ Nitroglycerin and tolazamide
• Unbalanced nutrition

26

How is vitamin B12 absorbed?

• Vitamin B12 binds intrinsic factor, a protein made by gastric parietal cells
• In terminal ilium the intrinsic factor:B12 complex is absorbed
• Strict vegans can have deficiencies (main source is meat and dairy)
• Malabsorption problems or terminal ileum problems can also result in deficiency
• Body Stores can be depleted in 3-4 YEARS so this is a STRICT vegan problem or a really chronic malabsorption problem

27

Vitamin B12 is known by what other name?

• Cobalamin

28

How might autoimmunity affect vitamin B12 absorption?

• Auto-antigens of gastric parietal cells
• Destruction of parietal cells means no intrinsic factor which cuts B12 absorption to 1% of normal

29

Why does a vitamin B12 deficiency damage the nervous system?

• Uh…not really clear
• Two forms of cobalamin (B12)
○ Adenosylcobalamin and methylcobalamin
○ These are cofactors for different enzymes
• Dysfunction of these enzymes appears to result in abnormal fatty acid incorporation into myelin
• Main result is reduction in myelin instability and likely a problem in DNA synthesis

30

What are the clinical manifestations of B12 deficiency?

• Megaloblastic anemia and/or neurological complications
• Cognitive deficits
• Subacute combined degeneration
• Spinal cord pathology affects ascending and descending tracts
• Symptom progression over weeks
• FIRST SIGN - Slight ataxia, numbness and tingling in lower extremeties
• Can progress rapidly to spastic weakness or even complete paraplegia

31

Subacute combined degeneration in the spinal cord as a result of B12 deficiency looks like what?

• Early signs
○ Sensory symptoms like:
○ Lower limb paresthesias
○ Loss of vibration and position sense
○ Loss of fine touch
• Late
○ Spastic paraparesis
○ Ataxia
○ Lower limb and trunk sensory defects

32

If you find B12 deficiency and neuro signs of degeneration, can vitamin replacement therapy help?

• Yes, as long as the damage wasn't severe or prolonged
• Structural damage in neurons is kinda permanent

33

What is vitamin E important for (CNS)?

• Anti-oxidant that protects cell membranes from free radical damage

34

How does vitamin E deficiency come about?

• Intestinal Malabsorption syndromes
• Cystic fibrosis, celiac, large intestinal resections, abetalipoproteinemia, congential biliary atresia

35

What are the clinical features of vitamin E deficiency?

• Acanthocytosis - Acanthocytes (from the Greek word acantha, which means thorn), or spur cells, are spiculated red cells with a few projections of varying size and surface distribution 
• Sensory periphery neuropathy
• Ataxia
• Retinopathy
• Myopathy
• cardiomyopathy

36

What are the pathological features of vitamin E deficiency?

• Loss of dorsal root nerve cell bodies and degeneration of their axons
• Posterior columns (vibratory and position sense) and spinocerebellar tracts secondarily show axon loss in spinal cord
• Axonal spheroids (same as retraction balls?) in lower medulla

37

What are the iatrogenic neuro toxic problems we discussed?

• Radiation therapy for brain tumors
• Central pontine myelinolysis (CPM)

38

What is the typical radiation damage in the brain?

• Radionecrosis - killing of the blood vessels (large red whorls on histology) leads to hypoxia and necrosis
• Secondary vascular damage to large intracranial blood vessels with atherosclerosis like luminal narrowing and strokes
• Secondary cavernous angiomas within bran parenchyma
• Secondary brain tumors in portals of radiation years to decades after first tumor
○ Meningiomas and GBMS
○ 1-5% of patients (think pediatric treatment)

39

What condition sets the stage for CPM?


• CPM = central pontine myelinolysis
• Disease occurs when chronically hyponatremic patients have their serum sodium rapidly corrected
• Selective sites of vulnerability in ventral pons and extrapontine sites with rich admixture of gray and white matter

40

How might you know if a patient is hyponatremic?

• Excess secretion of antidiuretic hormone (vasopressin)
• Low urine output
• Kidney problems?

41

Hyponatremia is a problem in what types of patients? (can result in CPM if remedied too quickly)

• Alcoholism, burns, sepsis, cancer, liver disease, transplantation, pediatric

42

What are the clinical manifestations of CPM?

• Pontine dysfunction
• Pseudobulpar palsy
○ Difficulty chewing and swallowing because of hyperreflexivity and spasticity in tongue and bulbar region
○ Slurred speech
• quadriparesis

43

What other brain structures are particularly affected in CPM?

• Cerebellum
• Putamen
• Thalamus
• Lateral geniculate

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