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Toxic and metabolic CNS problems Flashcards

1
Q

What is the mnemonic for thinking through a CNS differential?

A
  • VITAMIN C
    • Vascular
    • Infectious
    • Trauma
    • Age-related or degenerative
    • Metabolic/toxic
    • Inflammatory
    • Neoplasm
    • Congenital/genetic
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2
Q

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

A

• 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

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3
Q

Cyclosporine affects what cell in the CNS?

A

• oligodendrocyte

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4
Q

Radiation and BCNU affects what structure most specifically?

A

• Blood vessels in particular

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5
Q

Methotrexate kills what cell in the CNS?

A

• astrocytes

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6
Q

Toluene is a neurotoxin targeting what?

A

• Axon (myelin)

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7
Q

The metabolic disorders that do have morphological correlates are what?

A
  • Acquired due to abuse, liver damage and dietary deficiencies
    • Methanol, ethyl alcohol, hepatic encephalopathy and vitamin deficiencies
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8
Q

What can ethanol toxicity do to the brain?

A

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

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9
Q

What can happen to the meninges with chronic alcohol abuse?

A
  • Meningeal fibrosis

* Remember earliest effects of ethyl alcohol are on white matter

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10
Q

What are the features of fetal alcohol syndrome?

A
  • Hyperactivity
    • Poor motor skills
    • Learning difficulties
    • Severely affected kids have intellectual disability
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11
Q

What kills you in fulminant liver failure?

A

• 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

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12
Q

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

A
  • 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
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13
Q

What is the pathologic substrate seen in Hepatic encephalopathy?

A

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

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14
Q

What is Kwashiorkor?

A

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]
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15
Q

What is Maraumus?

A

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.
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16
Q

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

A
  • 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
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17
Q

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

A

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

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18
Q

What causes Wernicke’s encephalopathy?

A

• Vitamin B1 deficiency

○ Cause of Wernicke’s encephalopathy

19
Q

What is going on in Wernicke-Korsakoff syndrome?

A
  • 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
Q

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

A
  • 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
Q

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

A

• 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
Q

What pathway is vitamin B1 involved in?

A

• 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
Q

What is the timecourse of vitamin B1 deficiency?

A

• 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
Q

Where is thiamine stored?

A
  • Heart, kidneys, liver, brain, muscles
    • Stores can be depleted in weeks
    • IV glucose in patient with border-line deficiency may trigger disease
25
Q

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

A 
• 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
Q

How is vitamin B12 absorbed?

A
  • 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
Q

Vitamin B12 is known by what other name?

A

• Cobalamin

28
Q

How might autoimmunity affect vitamin B12 absorption?

A
  • Auto-antigens of gastric parietal cells

* Destruction of parietal cells means no intrinsic factor which cuts B12 absorption to 1% of normal

29
Q

Why does a vitamin B12 deficiency damage the nervous system?

A

• 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
Q

What are the clinical manifestations of B12 deficiency?

A
  • 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
Q

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

A 
• 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
Q

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

A
  • Yes, as long as the damage wasn’t severe or prolonged

* Structural damage in neurons is kinda permanent

33
Q

What is vitamin E important for (CNS)?

A

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

34
Q

How does vitamin E deficiency come about?

A
  • Intestinal Malabsorption syndromes

* Cystic fibrosis, celiac, large intestinal resections, abetalipoproteinemia, congential biliary atresia

35
Q

What are the clinical features of vitamin E deficiency?

A
  • Acanthocytosis - Acanthocytes (from the Greek wordacantha,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
Q

What are the pathological features of vitamin E deficiency?

A
  • 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
Q

What are the iatrogenic neuro toxic problems we discussed?

A
  • Radiation therapy for brain tumors

* Central pontine myelinolysis (CPM)

38
Q

What is the typical radiation damage in the brain?

A

• 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
Q

What condition sets the stage for CPM?

A
  • 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
Q

How might you know if a patient is hyponatremic?

A
  • Excess secretion of antidiuretic hormone (vasopressin)
    • Low urine output
    • Kidney problems?
41
Q

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

A

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

42
Q

What are the clinical manifestations of CPM?

A 
• Pontine dysfunction
	• Pseudobulpar palsy
		○ Difficulty chewing and swallowing because of hyperreflexivity and spasticity in tongue and bulbar region
		○ Slurred speech
	• quadriparesis
43
Q

What other brain structures are particularly affected in CPM?

A
  • Cerebellum
    • Putamen
    • Thalamus
    • Lateral geniculate

Neuro (59 decks)

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