Neuropathology of Toxic and Metabolic Syndromes 1

What is Alcohol Use Disorder?

1) Alcohol has both a primary and secondary toxic effect following ingestion
→ alcohol can cause direct toxic effects to the brain resulting in global atrophy of the brain and cerebellar degeneration
→ secondarily can cause nutritional deficits in vitamins like thiamine as well as liver disease. Can specifically cause Wernicke-Korsakoff Syndrome

2) results in a localized loss of neurons especially in the frontal cortex
→ the neurons will shrink in these regions as well, with demyelination and decreased branching of neurons

What is Thiamine Deficiency?

Thiamine or Vitamin B1 can be deficient in patients with alcohol use disorder or burns resulting in Wernicke-Korsakoff Syndrome

1) Wernicke Encephalopathy resulting in confusion, ophthalmoplegia, ataxia and nystagmus
→ Patients can develop severe memory defects later on, producing Korsakoff’s psychosis

2) Patients will develop mini hemorrhages in the hypothalamus, mamillary bodies, periaqueductal gray areas, and fourth ventricle
→ identifiable grossly by a graying of these structures indicative of the micro-hemorrhages, resulting in atrophy of the structure as well
→ patients will have capillary prominence and hemorrhages visible on histology as well

What is Fetal Alcohol Syndrome?

Fetal Alcohol Syndrome is where mothers drinking alcohol/ethanol will cause a direct toxic affect to the brain

1) Causes delayed anomalous growth of the child
→ patients have microcephaly so a small head
→ short palperal fissures and maxillary hypoplasia (small gap in between eyelids and underdeveloped jaw)
→ atrial septal defects

What is the pattern of cerebellar degeneration in alcohol use disorder?

Cerebellar degeneration with alcohol use will occur only in the anterior superior vermis rather than in any other part of the cerebellum

What is Central Pontine Myelinolysis?

Central Pontine Myelinolysis is a neurological disorder associated with alcohol use disorder that results in demyelination of the central part of the pons

1) while it is associated with alcohol, it is also associated with rapid correction of chronic hyponatremia (low sodium)
→ when the sodium is corrected too quickly, the water will shift out of the brain leading to injury of the oligodendrocytes
→ causes secondary demyelination and marked edema and central pontine myelinolysis

2) causes declined mental status and quadriparesis

What is Marchiafava-Bignami Disease?

Marchiafava-Bignami Disease is characterized by loss of myelin in the central corpus callosum

1) Marhiafava-Bignami Disease is associated with alcohol consumption with patients presenting with cognitive impairment, gait issues, seizures and comas

What are the causes and effects of folate deficiency

Folate B9
1) Caused by poor dietary intake or malabsorption as well as pregnancy
→ can also be drug related

2) Folate Deficiencies can result in:
→ neural tube defects
→ subacute combined degeneration
→ peripheral neuropathy

How can Folate Deficiencies be drug related?

Folate Deficiency can be seen in patients that take methotrexate a drug used for treatment of cancers

1) Inhibits dihydrofolate reductase which prevents the activation of folate in the body
→ leads to impaired DNA synthesis but may cause white matter necrosis of the cerebrum or spinal cord

What is Cobalamin Deficiency

Cobalamin (B12) deficiency is seen in patients with a strict vegan diet or patients with rapid cell breakdown/HIV AIDS

1) Patients with Cobalamin Deficiency have pernicious anemia
→ decrease in red blood cells, hemoglobin, and platelets
→ there is an increase in mean corpuscular volume creating very large red blood cells
→ neutrophils will exhibit hypersegmentaiton

2) Subacute Combined Degeneration may also be seen
→ demyelination of the lateral and posterior columns of the spinal cord

What is Heavy Metal Poisoning?

Heavy Metals such as lead, mercury, or arsenic are capable of binding to the sulfhydryl groups in proteins leading to alterations in enzymatic activity.

1) These have a wide variety of mechanisms of injury following binding to sulfhydryl groups
→ mimicking calcium and zinc on proteins (ionic molecular mimicry)
→ mitochondrial apoptosis
→ impair protein synthesis at the endoplasmic reticulum
→ causes cell membrane defects and abnormal gene regulation

What is the presentation of lead or arsenic poisoning?

Lead poisoning can cause:
→ encephalopathy in children
→ motor neuropathy in adults
→ increased risk of cognitive decline

Arsenic
→ peripheral neuropathy through loss of anterior and ventral horn cells
→ advanced cases can cause fibrinoid necrosis and hemorrhage

What can Mercury Poisoning cause?

Mercury is the only metal liquid at room temperature and damages neurons leading to impaired motor and mnemonic function and inhibits cell-division
→ hypersalivation
→ abdominal cramps and diarrhea
→ metallic halitosis or a foul breath that has a iron like smell or taste

1) Chronic exposure can lead to worse symptoms such as quadriplegia and cortical blindness

What is Methanol poisoning?

Methanol is converted into formic acid which will inhibit cytochrome C oxidase

1) results in a characteristic pattern of damage to the putamen
→ lead to a loss of retinal ganglion cells and axons in the optic nerve
→ patients may also present with cerebral edema and hemorrhagic leukoencephalopathy

2) Patient will often have visual issues or blindness along with general CNS issues

What is Carbon Monoxide poisoning?

Carbon monoxide is a gas that will cause bilateral necrosis of the globus pallidus

1) Patients will present with non-specific complaints, with affected tissue having a bright cherry red color at the time of autopsy