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Flashcards in Toxic & Metabolic Diseases of the CNS Deck (63):
1

When do you suspect a metabolic disorder in a patient?

  • Suspect a metabolic disorder when the clinical presentation doesn’t fit the medical textbook definition, doesn’t respond to common treatment or defies “clinical rationale”.
  • Not recognizing a metabolic disorder or delaying treatment can result in irreversible injury to the brain, major organs or death 

2

What are some common symptoms of a metabolic disorder? 

*sorry for the long card, I think just be able to recognize these* 

  • growth failure, failure to thrive, weight loss
  • ambiguous genitalia, delayed puberty, precocious puberty
  • developmental delay, seizures, dementia, encephalopathy, stroke
  • deafness, blindness, pain agnosia
  • skin rash, abnormal pigmentation, lack of pigmentation, excessive hair growth, lumps & bumps
  • dental abnormalities
  • immunodeficiency, thrombocytopenia, anemia, enlarged spleen, enlarged lymph nodes
  • many forms of cancer
  • recurrent vomiting, diarrhea, abdominal pain
  • excessive urination, renal failure, dehydration, edema
  • hypotension, heart failure, enlarged heart, HTN, MI
  • hepatomegaly, jaundice, liver failure
  • unusual facial features, congenital malformations
  • excessive breathing (hyperventilation), respiratory failure
  • abnormal behavior, depression, psychosis 

3

What are some suspicous presentations of metabolic disorder? (7)

  • Unexplained lethargy, confusion, somnolence or coma [do the right thing]
  • Unexplained metabolic acidosis/alkalosis
  • Excessive lactate or ketosis
  • Persistent or recurrent hypoglycemia
  • Chronic & worsening symptoms (progression & regression are alarm signs)
  • Unusual findings on MRI, EEG or pathology
  • Unusual combination of findings indicating a complex disease process or more than 1 etiology (Occam’s Razor vs. Hickam’s dictum) 

 

4

What is the right thing to do when you have an unresponsive patient with unexplained lethargy, confusion, somnolence or coma

  • Physical exam & medical history
  • Glucose, ammonia & pH (STAT)
  • Call metabolic specialist
  • Check electrolytes, CK, LFTs, lactate, urine analysis
  • Store a ‘critical sample’ (hypoglycemia)
  • Start treatment w/o delay (IV glucose)
  • Basic metabolic work-up
  • Acylcarnitine profile, aa profile, urine organic acid profile
  • 3 I’s = infection, intoxication, idiopathic 

5

What is a Lysosomal Storage Disease

  • Lysosomes (“intracellular digestive tract”)
  • Acid hydrolases breakdown macromolecules
  • Lack of any protein essential for normal function of lysosomes 

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6

What is a neuronal storage disease?

What are some examples? 

  • Accumulation of gangliosides (abundant in brain) w/i neurons
  • GM2 gangliosidoses (deficiency of lysosomal enzymes)
    • Hexoaminidase A – Tay-Sachs disease
    • Hexoaminidase B – Sandhoff disease
    • Activator protein deficiency – GM2 gangliosidosis, variant AB

7

What is the difference btwn lysosomal storage disease & poisoning? 

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8

Lysosomes at Work 

Lysosomes digest ___________. 
Lysosome releases ___________ into mitochondria to break down ___________. 

Old cell components 

Digestive enzymes 

Macromolecules 

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9

What are the 6 categories of Lysosomal Storage Diseases?

  • Lysosome assembly (Golgi apparatus)
  • Trafficking of lysosomal enzymes (glycosylation)
  • Enzyme deficiency (single gene defect)
  • Co-factor defect
  • Transporter defect
  • Miner’s disease (silicosis) & asbestosis are NOT considered defects in lysosomal function 

10

Tay Sachs Disease 

Epidemiology

Diagnosis

  • High incidence in Ashkenazi Jews
  • Gene on chr 15 (>100 mutations described)
  • Diagnosis
    • Enzyme assay of serum, WBC
    • Cultured fibroblasts 

11

Tay Sachs Disease

Clinical Signs/Symptoms

Progressive Signs/Symptoms 

  • Clinical S/S
    • Normal at birth
    • 6 mo – psychomotor retardation evident
  • S/S Progression
    • Blindness
    • Motor incoordination
    • Eventual flaccidity
    • Mental deterioration
    • Eventual decerebrate state
    • Cherry spot in macula
  • Death by 2-3 yrs 

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12

In Tay Sach's Disease, ____ intact genes required for effective Hex A function

3

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13

Tay Sach's Disease Pathology

Brain

Microscope

  • Brain
    • Normal/little/big depending upon duration
    • Survival >2 yrs (brain is big)
  • Microscope
    • Enlarged ballooned neurons filled w/ PAS+ material
    • Stored gangliosides 
    • Storage also in other brain cells (astrocytes & microglia)
    • EM – membranous cytoplasmic bodies 

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14

What is the treatment for Tay Sach's Disease?

  • Experimental stages
  • “Chaperone” proteins may help α-subunit fold normally
  • Enzyme replacement therapy 

15

What is Krabbe's Globoid Cell Leukocystrophy?

What is the deficiency?

  • Lysosomal storage disease
  • Autosomal recessive (gene chr 14)
  • Deficiency of galactocerebroside-B-galactosidase
    • Accumulation of toxic compound (psychosine) that injures oligodendrocytes
    • Galactocerebroside is a component of myelin sheaths; accumulates in “Globoid cells”
  • Both CNS & PNS affected

16

Krabbe's Globoid Cell Leukodystrophy

Diagnosis

Clinical Course

Treatment 

  • Diagnosis: enzyme assay of WBC or cultured fibroblasts
  • Clinical course
    • Normal development
    • Onset btwn 3-6 mo
    • Irritability, development ceases
    • Deterioration of motor function
    • Tonic spasms
    • Eventual opisthotonic posture
    • Myotonic jerking
    • Optic atrophy, blindness
    • CSF protein elevated
  • Treatment
    • Umbilical cord/bone marrow transplantation
    • Pre-symptomatic phase 

17

How does Krabbe's Globoid Cell Leukodystrophy present grossly?

  • Atrophic brain
  • Firm white matter
  • Atrophic white matter w/ preservations of “U” fibers 

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18

How does Krabbe's Globoid Cell Leukodystrophy present histologically?

  • Globoid cells
  • Loss of myelin
  • Accumulation of globoid MΦ, cluster around vessels
  • Severe astrocytosis
  • Decreased numbers of oligodendrocytes
  • EM – globoid cells contain crystalloid straight or tubular profiles 

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19

What is Metachromatic Leukodystrophy?

What is the deficiency?

  • Lysosomal storage disease
  • Autosomal recessive (gene on chr 22)
  • Deficiency of Aryl Sulfatase A
  • Metachromatic lipids (sulfatides) accumulate in brain, peripheral nerves, kidney
    • Sulfatide accumulation leads to breakdown of myelin
    • Screen of urinary sediment for metachromatic deposits 

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20

Metachromatic Leukodystrophy 

Diagnosis

Clinical S/S

Treatment 

  • Diagnosis
    • Demonstrate enzyme deficiency in urine, WBC, fibroblasts
  • Clinical S/S
    • Late infantile (most common)
    • Intermediate
    • Juvenile
      • Each childhood type presents w/ gait disorder & motor symptoms
      • Death in 5-10 yrs
    • Adults
      • Psychosis & cognitive impairment
      • Eventual motor symptoms
  • Treatment
    • Bone marrow stem cells transplantation (before symptoms) 

21

How does Metachromatic Leukodystrophy present grossly?

  • Brain is externally normal
  • White matter is very firm
  • Marked loss of myelin
  • Preservation of “U” fibers (subcortical fibers) 

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22

How does Metachromatic Leukodystrophy present histologically? 

  • Metachromasia of white matter deposits
    • Brown staining
  • Acidified cresyl violet stain 

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23

What is Adrenoleukodystrophy?

Inheritance?

  • Peroxisomal disorder
    • Peroxisomes – cytoplasmic spherical “microbodies”
    • Contain catalase
    • Involved in FA β-oxidation (& more)
  • Decreased activity of very long fatty acyl-CoA synthetase (in peroxisomes)
    • Excess of very long chain FA esters in plasma, cultured fibroblasts, & affected organs (CNS, PNS, adrenal glands)
  • X-linked (classic form)

24

Classic Adrenoleukodystrophy vs. Adrenomyeloneuropathy 

  • Classic form
    • Onset 5-9 yrs or 11-12 yrs
    • Dementia, visual/hearing loss, seizures
    • Adrenal insufficiency follows neuro S/S
  • Adrenomyeloneuropathy
    • Adult (20-30 YO)
    • Slowly progressive leg clumsiness/stiffness; eventual spastic paraplegia
    • Adrenal insufficiency may precede neuro S/S

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25

How does Adrenoleukodystrophy present grossly?

  • Gray discoloration of white matter
  • Marked firmness
  • “U” fiber preservation
  • Severe demyelination 

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26

How does Adrenoleukodystrophy present histologically?

  • Perivascular inflammation
  • PAS+ MΦ

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27

What is Hepatic Encephalopathy?

  • Complication of severe liver disease or chronic portocaval shunting
  • Pathogenesis incompletely understood (related to hyperammonemia)

28

Hepatic Encephalopathy 

Early manifestations

Later manifestations

May have...

  • Early
    • inattentiveness
    • short-term memory impairment 
  • Later
    • confusion
    • asterixis (flapping tremor of outstretched hands)
    • drowsiness
    • stupor
    • coma 
  • May have..
    • foul breath (fetor hepaticus)
    • hyperventilation
    • gait disturbances
    • choreoathetosis 

29

Hepatic Encephalopathy

MRI abnormalities 

Progonosis (acute vs. chronic)

  • MRI abnormalities
    • Increased T1 signal in the globus pallidus, subthalamus & midbrain
    • Cortical edema
  • Acute = fatal
  • Chronic or repeated = permanent/progressive neuropsychiatric disturbances
  • Ameliorated w/ liver transplantation 

30

How does Hepatic Encephalopathy present histologically?

Alzheimer type II astrocytes

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31

Hypoglycemia

Definition

Systemic Diseases

Exposures

  • Insufficient food intake
  • Systemic diseases
    • Primary hyperinsulinism
    • Severe liver disease
    • Adrenal insufficiency
  • Exposure to drugs that cause hypoglycemia (insulin

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32

What are the clinical signs & symptoms of hypoglycemia?

  • Headache
  • Confusion
  • Irritability
  • Incoordination
  • Lethargy
  • Leads to stupor & coma 

33

Hypoglycemia

MRI

Histology

Treatment 

  • MRI
    • Signal changes in temporal, occipital & insular cortices, hippocampus & basal ganglia (thalamic sparing) 
  • Prolonged/recurrent bouts = permanent brain damage
  • Treatment
    • Depends on the cause
    • Restoration of glucose for exogenous causes
    • Removal of endogenous causes (liver, pancreatic, adrenal tumors)

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34

Carbon Monoxide Poisoning 

Definition

Signs & Symptoms

  • Irreversibly binds to Hb --> displacing O2
  • Binds to areas rich in iron (globus pallidus, substantia nigra) --> necrosis
  • Degeneration of white matter
  • CO poisoning accompanied by hypotension/ischemia
  • Motor, cognitive, psychiatric & Parkinsonian S/S

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35

What is this? 

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CHRONIC Carbon Monoxide Poisoning 

36

Chronic Ethanol Toxicity (Alcoholism)

Clinical Signs & Symptoms

Effects on the cerebellum 

  • Clinical
    • Truncal ataxia
    • Nystagmus
    • Limb incoordination
  • Cerebellar degeneration
    • Atrophy (esp anterior superior vermis)
    • Dropout of Purkinje cells, internal granular cells, astrocytosis 

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37

What is Fetal Alcohol Syndrome?

What are the pathologic findings?

  • Low levels of alcohol consumption (1 drink/day)
  • Hypothesized that acetaldehyde crosses placenta & damages fetal brain 
  • Pathologic findings
    • Microcephaly
    • Cerebellar dysgenesis
    • Heterotopic neurons 

38

What are the clinical signs & symptoms of Fetal Alcohol Syndrome?

  • Growth retardation
  • Facial deformities
    • Short palpebral fissure
    • Epicanthal folds
    • Thin upper lip
    • Growth retardation of jaw
  • Cardiac defects – atrial septal defect
  • Delayed development & mental deficiency 

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39

What is radiation toxicity?

What can happen years after treatment?

  • Delayed effects (mo-yrs later)
  • Clinical symptoms of mass lesion
  • Pathology
    • Large areas of coagulate necrosis
      • White matter
    • Vessels w/ marked thickened walls
  • Induction of neoplasms (meningiomas, sarcomas, gliomas) yrs after treatment

40

What are 5 drugs that cause drug toxicity?

  • Methotrexate
  • Vincristine
  • Phenytoin
  • Cocaine
  • Amphetamine 

41

What are the effects of Methotrexate Toxicity?

Gross & Histological presentation?

  • Intrathecal or Intraventricular admin in combination w/ radiation may produce:
    • Disseminated necrotizing leukoencephalopathy
    • Particularly around ventricles & deep white matter
    • Coagulative necrosis w/ axonal loss & mineralization
  • Gross & Histology 
    • Coagulative necrosis w/ mineralization 

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42

Vincristine Toxicity 

P.O. administration

Intrathecal administration

  • P.O. admin – sensory neuropathy
  • Intrathecal admin – axonal swelling 

43

What are the effects of Phenytoin Toxicity?

Gross & Histological presentation?

  • Ataxia, nystagmus, slurred speech & sensory neuropathy
  • Atrophy of cerebellar vermis & loss of Purkinje cells & granule cells
  • Gross & Histology 
    • Astrocytosis
    • Purkinje cell loss 

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44

What are the effects of Cocaine Toxicity?

  • Seizures, strokes, hemorrhages
  • Infarcts & hemorrhages due to vasospasm, emboli, hypercoagulability, hypotension, drug contaminants
  • Occasionally vasculitis (?allergic) 

45

What are the effects of Amphetamine Toxicity?

  • Infarcts & hemorrhages
  • Attributed to vasculitis & HTN 

46

What is the clinical significance of Mitochondrial Diseases?

  • Can cause a variety of clinical issues involving numerous organ systems
    • Brain & muscle involvement
    • GI tract, heart and/or peripheral nerves
  • Multigenerational disease (maternal inheritance)

47

Mitochondrial proteins are encoded within the _______ & _______ genome. 

mitochondrial

nuclear 

48

What mutations are involved in Mitochondrial Diseases?

  • Specific mutations --> specific diseases
    • Not always the case
  • ~1000 nuclear genes contribute to mitochondrial phenotypes
  • Mitochondrial diseases underdiagnosed 

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49

How are Mitochondrial Diseases tested for? 

  • No “gold-standard” testing
  • MCW/CHW approach to diagnosis
    • Clinical history/imaging
    • Muscle biopsy pathology (light microscope level)
    • Muscle biopsy pathology (EM level)
    • Electron transport chain activity testing
    • Mitochondrial DNA (mtDNA) content qualification
    • Genetic testing (nuclear & mito genomes) 

50

What are 4 examples of Mitochondrial Syndromes?

  • Mitochondrial encephalomyopathy + lactic acidosis + stroke-like episodes (MELAS)
  • Myoclonic epilepsy w/ ragged red fibers (MERRF)
  • Kears-Sayre Syndrome (KSS)
  • Leigh’s Disease

51

What mutations are in these diseases?

  • Mitochondrial encephalomyopathy + lactic acidosis + stroke-like episodes (MELAS)
  • Myoclonic epilepsy w/ ragged red fibers (MERRF)
  • Kears-Sayre Syndrome (KSS)
  • Leigh’s Disease

  • MELAS
    • Heteroplasmic point mutations in mt-tRNALeu
  • MERRF
    • Heteroplasmic point mutations in mt-tRNALys
  • KSS
    • Large single mtDNA mutation
    • Pigmentary retinopathy & ophthalmoplegia <20 YO
  • Leigh’s Disease
    • Mitochondrial syndrome caused by nuclear mutation 

52

What is Leigh's Disease?

(Subacute Necrotizing Encephalopathy)

  • Mutation in nuclear DNA (& mito DNA)
  • Enzyme deficiency in pathway: pyruvate --> ATP
  • Decreased activity of cytochrome C oxidase
  • Autosomal recessive
  • Lactic acidemia 

53

What are the clinical signs & symptoms of Leigh's Disease?

  • Clinical S/S
    • Arrest of development
    • Hypotonia
    • Seizures
    • Extraocular palsies
  • Death btwn 1 & 2 yrs 

54

How does Leigh's Disease present grossly?

  • Periventricular gray matter tissue destroyed
  • Around cerebral aqueduct & 3rd ventricle

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55

How does Leigh's Disease present on histology?

Spongiform appearance & vascular proliferation 

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56

What is the main patient population of Thiamine (Vitamin B1) Deficiency?

What are some other causes?

Malnourished chronic alcoholics

  • Other causes
    • Starvation diets
    • Hemodialysis
    • Gastric sampling
    • Extensive GI surgery
    • Hyperalimentation w/o thiamine supplementation 

57

What 2 syndromes are caused by Thiamine Deficiency?

Wernicke Encephalopathy

Korsakoff Syndrome

58

What are the clinical signs & symptoms of Wernicke Encephalopathy?

  • Ophthalmoplegia, nystagmus
  • Ataxia
  • Confusion, disorientation, eventual coma 

59

How does Wernicke Encephalopathy appear grossly?

  • Lesions in mammillary bodies, dorsomedial thalamus, around 3rd & 4th ventricles
  • Acute – gray-brown discoloration w/ petechial hemorrhages
  • Chronic – atrophy & discoloration of mammillary bodies 

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60

How does Wernicke Encephalopathy appear on histology?

  • Pallor, myelin loss, prominent vessels
  • MΦ, presentation of neurons 

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61

Korsakoff Psychosis

Clinical Signs/Symptoms

Hypothesis 

  • Clinical S/S
    • Loss of anterograde episodic memory
    • Confabulation
    • Preserved intelligence & learned behavior
  • Hypothesis: repeated episodes of Wernicke’s encephalopathy
  • No pathology distinct from Wernicke’s
  • Findings attributed to damage to medial dorsal nucleus of thalamus 

62

Vitamin B12 (Cobalamin) Subacute Combined Degeneration of Spinal Cord

Definition

Pathology 

  • Pernicious anemia (40% of untreated patients)
  • CNS & PNS involvement
  • Spinal cord
  • Anterior & lateral corticospinal tracts & posterior columns vacuolated & demyelinated
  • May have secondary axonal degeneration 

63

What is this?

 

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Vitamin B12 (Cobalamin) Subacute Combined Degeneration of Spinal Cord