toxic metabolic dz

Question 1

Know which acquired toxic/metabolic disorders are WITHOUT morphological correlates (ie., just affect electrochemical transmission)

Answer 1

1. Endocrinological disorders (hypoglycemia, hypo/hyperthermia), acid base imbalance, electrolyte imbalance, renal failure. 2. Many heavy metal toxicities, exposure to toxins in the workplace/ environment. 3. Neurotoxins work at multiple sites in PNS and CNS to cause electrochemical disruption.

Question 2

Effect of methanol on CNS

Answer 2

symmetric putamen hemorrhagic necrosis

Question 3

1. Describe the effects of alcohol on the CNS both acutely and chronically.

Answer 3

a. Acute: 1. Severe cerebral edema and possible death from central cardiorespiratory paralysis
b. Chronic: 1. Meningeal fibrosis 2. Cerebral cortex white matter volume loss, neuronal loss and dendritic reduction; 3. Cerebellar vermis: crests of folia most affected, granule cell neurons> Purkinje cell neurons losta. Acute: 1. Severe cerebral edema and possible death from central cardiorespiratory paralysis
b. Chronic: 1. Meningeal fibrosis 2. Cerebral cortex white matter volume loss, neuronal loss and dendritic reduction; 3. Cerebellar vermis: crests of folia most affected, granule cell neurons> Purkinje cell neurons lost

Question 4

What other factor may play a role in acoholic cerebellar degeneration

Answer 4

Vitamin deficiency (thiamine)

Question 5

Fetal alcohol syndrome - features

Answer 5

1. Hyperactivity, poor motor skills, learning difficulties; severely affected kids have mental retardation 2. No single laboratory test to make diagnosis 3. Brain damage due to liver disease/cirrhosis

Question 6

How does liver disease cause brain damage

Answer 6

In liver failure, ammonia is not converted to urea, so it bypasses the liver then crosses the blood brain barrier where it is taken up by astrocytes (rich in glutamine synthetase which is an enzyme involved in ammonia detox). The astrocyte becomes overwhelmed with ammonia and die. This causes impaired water, electrolyte, pH and neurotransmitter regulation- leading to encephalopathy. Also ammonia increases production of GABA

Question 7

What is hepatic encephalopathy- what causes it, and what are symptoms

Answer 7

1. Asterixis (flapping tremor of outstretched arms), stupor, coma 2. Putative toxins: ammonia, mercaptans, short-chain fatty acids, benzodiazepine-like substances, GABA-like substances, impaired glutamatergic neurotransmission 3. Grey matter astrocytes transform to “Alzheimer II” (metabolically active) astrocytes, especially in deep cerebral cortex and subcortical structures

Question 8

What do Alzheimer II astrocytes look like

Answer 8

astrocytes with swollen, vesicular nuclei and little visible cytoplasm

Question 9

Wilsons dz- who gets it, what is it, what causes it

Answer 9

1. Hepatic failure due to copper accumulation most common presentation in young children, causing hepathic encephalopathy symptoms 2. Choreoathetosis (involuntary movements) and dementia may be present in young adults 3. Autosomal recessive disorder of copper metabolism, gene localized to chromosome 13

Question 10

Wilsons dz treatment

Answer 10

chelating agents such as penicillamine to remove copper can arrest progression

Question 11

Wilsons dz major site of damage and pathogenesis

Answer 11

The putamen is the major site of damage followed by the globus pallidus. Neuronal loss, astrocytosis and Alzheimer type II astrocytes. Direct damage by copper plus astrocyte mediated damage

Question 12

thiamine (vit B1) deficiency - what does it cause, where?

Answer 12

1. Wernicke’s encephalopathy - full triad of ataxia, nystagmus (or ophthalmoplegia) and confusion may be absent 2. Korsakoff’s psychosis (memory loss) 3. Selective vulnerability: mammillary bodies, walls of third ventricle, medial thalamus, inferior colliculi, brainstem tegmentum 4. Peripheral neuropathy

Question 13

Who gets Vitamin B1 deficiency?

Answer 13

alcoholics or pts with hyperemesis

Question 14

What is Wernicke’s encephalopathy

Answer 14

toxic metabolic problem with selective vulnerability- mammillary bodies involved in almost all cases. Hypothalamus, medial thalamus, periaqueductal grey, floor of 4th ventricle. . Edema, necrosis, demyelination, neuron loss, gliosis

Question 15

What does Vitamin B1 do in the nervous system

Answer 15

Involved in pentose phosphate shunt which is facilitated by transketolase.

Question 16

What does glucose do to patient with Vitamin B1 deficiency

Answer 16

. A high sudden intake of glucose, often from intravenous infusion, can precipitate the encephalopathy by consuming thiamine which is utilized as a cofactor in glucose metabolism. Glucose utilization may decrease in areas of lesions in wernickes encephalopathy

Question 17

How is Wernickes encephalopathy and Korsakoffs treated

Answer 17

Thiamine, if administered early enough, will produce rapid reversal of signs and symptoms b/c minimal neuronal loss occurs at early stages

Question 18

Cobalamin (Vit B12) deficiency- what does it cause, where

Answer 18

1. Subacute combined degeneration - early paresthesias (tingling), diminished vibration sense or proprioception, loss of fine touch. late- ataxia (lack of voluntary movement),lower limb/trunk sensory defects, spastic paraparesis. 2. Dementia - psychoses, mood disturbances. 3. Selective vulnerability: posterior and lateral spinal cord white matter, especially in lower cervical and thoracic cord; cerebral white matter

Question 19

Hematologic consequence of B12 deficiency

Answer 19

megaloblastic anemia

Question 20

Main sources of Vitamin B12

Answer 20

meat and dairy

Question 21

How is Vitamin B12 absorbed

Answer 21

B12 binds to intrinsic factor in stomach (produced by parietal cells). Then the complex is transported to terminal ilem where it binds receptors and is absorbed. It is stored in many tissues but if absorption stops, body stores are depleted in 3-4 yrs

Question 22

Causes of Vit B12 deficiency

Answer 22

Vegan diets, malabsorption, pernicious anemia (failure of intrinsic factor production)

Question 23

Vitamin B12 deficiency pathogensis

Answer 23

Two forms of cobalamin: adenosylcobalamin, a cofactor/ coenzyme of methylmalonyl-CoA mutase and methylcobalamin, a co-factor of methionine synthetase. Dysfunction may cause incorporation of abnormal fatty acids into biological membranes, resulting in myelin instability. May also affect DNA synthesis

Question 24

Vit B12 deficiency treatment

Answer 24

B12 replacement therapy unless deficiency is very severe or prolonged

Question 25

Vitamin E deficiency- what causes it, clinical features, pathology

Answer 25

2. Deficiency is most commonly an acquired defect seen in intestinal malabsorption syndromes such as cystic fibrosis, celiac disease, large intestinal resections, 3. Clinical features: acanthocytosis, sensory periphery neuropathy, ataxia, retinopathy, myopathy, cardiomyopathy. 4. Pathological features include loss of dorsal root nerve cell bodies and degeneration of their axons. Hence posterior columns (vibratory and position sense) and spinocerebellar tracts secondarily show axon loss in spinal cord). 5. Axonal spheroids in lower medulla

Question 26

Radiation induced necrosis- where does it cause damage, what happens

Answer 26

Damage occurs more in white matter. Fibrinoid vascular necrosis, Radiation can also cause large vessel vasculopathy, cavernous angiomas, secondary tumors within radiation portals years or decades later (meningiomas, high grade gliomas)

Question 27

Central pontine myelinolysis - what is it, location, what causes it, treatment/prevention

Answer 27

Appeared in 1950s with plastic revolution of tubing and fluid admin. Occurs in pts with chronic medical conditions. Fluid and electrolyte imbalance lead to symmetric demyelination. Usually silent, severe cases have quadraparesis and “locked in syndrome. 5. Ventral pons and extrapontine sites
6. Excessive, rapid correction and/or overcorrection of hyponatremia is causative 7. Slower correction of hyponatremia and possibly administration of organic osmoles such as myoinositol are preventative/therapeutic