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11/8 Toxic-Metabolic Disorders
Neuro
43
Medical
Graduate
11/10/2011

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Term
general concepts when dealing with toxic/metabolic conditions
Definition
symmetry

selective vulnerability
Term
symmetry
Definition
right and left sides are usually affected equally

focal symptoms are UNlikely

(though not impossible to be asymmetric if the brain was asymmetric at baseline)
Term
selective vulnerability
Definition
certain cell types or brain regions are more sensitive than other to particular toxins or metabolic abnormalitites
Term
global hypoxia/ischemia
Definition
can occur whenever there is a substantial drop in oxygenation or cardiac output
Term
global hypoxia/ischemia

areas at risk
Definition
affects neurons more than glia

cortical neurons - layers 3 and 5; "laminar necrosis"

pyramidal neurons in CA1 of hippocampus

Purkinje cells of cerebellar cortex

(basal ganglia, dentate nuclei or cerebellum, inferior olivary nuclei)
Term
global hypoxia/ischemia

pathology
Definition
thinner paler gray matte in areas of laminar necrosis

eosinophilic, collapsed cytoplasm with pyknotic nuclei and indistinct nucleoli

(looks similar to stroke)
Term
global hypoxia/ischemia

clinical features
Definition
with brief ischemic/hypoxic event:
-syncope
-light headedness
-presyncope
-rapid return to baseline

prolonged event:
-mental status changes (mild confusion to coma)
-impaired new memory formation common
-may have permanent mental status change, epilepsy, myoclonus or ataxia
Term
global hypoxia/ischemia

potential consequences
Definition
mental status changes (due to diffuse cortical involvement)
-come to mild memory impairment

seizures

ataxia

myoclonus
Term
global hypoxia/ischemia

pathophysiology
Definition
same as the mechanisms of injury due to focal ischemia

abnormal electrical excitability, impaired regulation of intracellular calcium, accumulation of neurotoxic excitatory amino acids NTs, abnormal gene expression, apoptosis, and edema

diffuse process, the edema commonly causes increased ICP, which can progress to transtentorial herniation
Term
global hypoxia/ischemia

diagnoses
Definition
usually suggested by clinical setting

these patients often have multiple medical problems
Term
global hypoxia/ischemia

management
Definition
reversal of hypoxia/ischemia and correction of underlying cause asap

no interventions available to reverse any neurologic damage that has occurred

management focused on patient's overall medical condition
Term
carbon monoxide poisoning

clinical features
Definition
ACUTE

carboxyhemoglobin 10-20%: headache, dizziness, visual disturbances, confusion, nausea, ab pain, weakness

carboxyhemoglobin 20-40%: cardiac disturbances, dyspnea, vomiting, loss of consciousness

carboxyhemoglobin 40-60%: coma, seizures, respiratory impairment

SUBACUTE
headache, fatigue, dizziness, paresthesias, ches pain, palpitations, visual disturbances, difficulty concentrating
Term
carbon monoxide poisoning

sequelae
Definition
15-40% of pt who recover from acute or subacute poisoning develop delayed sequelae ~1-4 weeks after the initial exposure

apathy, memory impairment, bizarre behavior, mutism, parkinsonism, choreoathetosis, dystonia
Term
carbon monoxide poisoning

pathophysiology
Definition
CO binds to hemoglobin with 200x the affinity for oxygen

Left shift oxy dissociation curve = reduced oxy deliver to tissues
Term
carbon monoxide poisoning

areas at risk
Definition
preferentially involve:

-globus pallidus
-internal capsule
-hippocampus
-cortex

(same areas of involvement as hypoxia)
Term
carbon monoxide poisoning

pathology
Definition
hours: brain swollen, congested, cherry red

1-2 days: hemorrhage in globus pallidus and petechial hemorrhage in white matter

days-weeks: lesion in the GP appear necrotic or cavitated

Micro: foci of necrosis and/or perivascular hemorrhage in affected areas
Term
carbon monoxide poisoning

diagnosis
Definition
acute - straightforward because of clinical setting

subacute - more difficult, depends of awareness of clinical syndrome

direct spectroscopic measurement of carboxyhemoglodin level in blood is most reliable
Term
carbon dioxide poisoning

management
Definition
immediate removal from site of CO exposure and given 100% O2 by mask

refer for hyperbaric oxygen therapy if loss of consciousness or carboxyhemoglobin level > 30%
Term
thiamine deficiency

clinical features
Definition
occurs because of poor intake, malabsorption, or increased metabolic requirement

acutely: Wernicke's encephalopathy

chronically: Korsakoff syndrome
Term
Wernicke's excephalopathy
Definition
classic triad: confusion, opthalmoplegia, ataxia

more likely in someone who is metabolically challenged
Term
Korsakoff syndrome
Definition
chronic thiamine deficiency

amnesia - inability to form new memories

confabulation - tendency to create fictional memories

difficulty with planning, directing, attention, problem-solving

often in chronic alcoholics who have a co-existing dementia
Term
thiamine deficiency

pathophysiology
Definition
thiamine is precursor for TPP (thiamine pyrophosphate), a cofactor of several critical enzymes in the TCA cycle

deficiency results in insufficient energy production; trouble utilizing glucose

often occurs after periods of high metabolic demand, esp after refeeding or IV glucose --> always admin thiamine along with IV glucose in emergency setting
Term
thiamine deficiency

areas at risk
Definition
mamillary bodies

areas that tend to border 3rd & 4th ventricle, cerebral aqueduct:
medial thalamic nuclei, floor of 3rd ventricle, periaqueductal region, colliculi, nuclei in the pontomedullary tegmentum
Term
thiamine deficiency

pathology
Definition
involved region slightly shrunken, brown discoloration (hemosiderin deposition)

maye petechial hemorrhages

acute lesions are edematous, preservation of neurons

chronic lesions gliotic and slightly spongioticm mild loss of neurons
Term
thiamine deficiency

diagnosis
Definition
recognition of clinical syndromes

extensive testing not often needed - tx is cheap and safe
Term
thiamine deficiency

management
Definition
parenteral treatment with thiamine
Term
vitamin B12 (cyanocobalamin) deficiency

clinical features
Definition
from malabsorption (usually not inadequate intake)

neurologic manifestations develop over a period of months to years

paresthesia lower limbs, gait disturbances, ataxia, upper limb sensory symptoms, poss reduced position/viration, Lhermitte's phenomenon

visual and mental status changes
Term
vitamin B12 deficiency

pathophysiology
Definition
Vit B12 is cofactor for two major physiologic reactions

methylmalonic coA --> succinyl coA (TCA cycle)

homocysteine --> methionine (folate dependent; needed for methylation of myelin basic protein and other CNS proteins)
Term
vitamin B12 deficiency

pathology
Definition
subacute combined degeneration of the spinal cord
-degeneration and spongy vacuolation of both ascending and descending pathways
-posterior columns in thoracic region

progresses with myelin breakdown, axonal degeneration, macrophage infiltration, astrocytic gliosis
Term
vitamin B12

diagnosis
Definition
serum level of vitamin B12 below normal rage is reliable indicator

however normal blood levels may still be deficient if not physiologically enough for that person

measurement of methylmalonic acid and homocysteine more reliable -- elevated if deficient
Term
pernicious anemia
Definition
most common cause of vitamin B12 deficiency

immune-mediated destruction of gastric parietal cells (produce intrinsic factor)

intrinsic factor necessary for vit B12 absorption in ileum

tested for by an assay for antibody to intrinsic factor
Term
vitamin B12 deficiecny

management
Definition
oral supplements can treat deficiency from inadequate intake

IM cobalamin for pernicious anemia
Term
hepatic enecephalopathy

clinical features
Definition
patients with hepatic failure frequently develop cerebral dysfunction

fluctuating attention

confusion

somnolence-->stupor-->coma

asterixis
Term
hepatic encephalopathy

pathogenesis
Definition
unknown

hyperammonemia is a major factor

toxins escape hepatic detoxification and enter the systemic circulation

increased levels of endogenous benzodiazepine receptor ligands; alterations in the metabolism of cerebral serotonin, dopamine, glutamate

can be precipitated by heavy protein load to the liver
Term
hepatic encephalopathy

pathology
Definition
Alzheimer's type II astrocytes

enlarged vesicular nucleus, marginated chromatin, scanty cytoplasm
Term
hepatic encephalopathy

areas affected
Definition
cortex

basal ganglia

thalamus, hypothalamus, subthalamus

dentate nucleus of cerebellum
Term
hepatic encephalopathy

diagnosis
Definition
often apparent from clinical setting

elevated serum ammonia

elevated CSF glutamine

characteristic EEG abnormality - triphasic waves
Term
hepatic encephalopathy

management
Definition
directed toward reducing ammonia levels

laxative to help send protein out bowel instead of to liver (lactulose)
Term
central pontine myelinolysis (CPM)

clinical features
Definition
limb weakness progressing over days-weeks

confusion, abnormal eye movement, dysarthria, dysphagia

hypotension, seizures, dystonia, choreoathetosis
Term
central pontine myelinolysis (CPM)

pathogenesis
Definition
monophasic demyelinating disease predominantly affecting basis pontis

usually in the setting of rapid correction of hyponatremia

mechanism unknown
Term
central pontine myelinolysis (CPM)

pathology
Definition
focal, gray region of myelin destruction in the basis pontis (anterior pons) - dymelination through crossing fibers of tracts in pons

active demyelination with reactive astrocytes and large numbers of foamy lipid-laden macrophages

contain only scanty lymphcytes
Term
central pontine myelinolysis (CPM)

diagnosis
Definition
based primarily on recognition of the typical clinical syndrome in the appropriate clinical setting

demyelinating lesions in characteristic locations on MRI can help
Term
central pontine myelinolysis (CPM)

management
Definition
no specific treatment know to affect course

aggressive support is indicated if identified
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