Toxic & Metabolic Diseases of the CNS Flashcards
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
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
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)
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
What is a Lysosomal Storage Disease?
- Lysosomes (“intracellular digestive tract”)
- Acid hydrolases breakdown macromolecules
- Lack of any protein essential for normal function of lysosomes
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
What is the difference btwn lysosomal storage disease & poisoning?
Lysosomes at Work
Lysosomes digest ___________.
Lysosome releases ___________ into mitochondria to break down ___________.
Old cell components
Digestive enzymes
Macromolecules
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
**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
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
In Tay Sach’s Disease, ____ intact genes required for effective Hex A function
3
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
What is the treatment for Tay Sach’s Disease?
- Experimental stages
- “Chaperone” proteins may help α-subunit fold normally
- Enzyme replacement therapy
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
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
How does Krabbe’s Globoid Cell Leukodystrophy present grossly?
- Atrophic brain
- Firm white matter
- Atrophic white matter w/ preservations of “U” fibers
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
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
**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)
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)
How does Metachromatic Leukodystrophy present histologically?
-
Metachromasia of white matter deposits
- Brown staining
- Acidified cresyl violet stain
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)
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
How does Adrenoleukodystrophy present grossly?
- Gray discoloration of white matter
- Marked firmness
- “U” fiber preservation
- Severe demyelination
How does Adrenoleukodystrophy present histologically?
- Perivascular inflammation
- PAS+ MΦ
What is Hepatic Encephalopathy?
- Complication of severe liver disease or chronic portocaval shunting
- Pathogenesis incompletely understood (related to hyperammonemia)
**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
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
How does Hepatic Encephalopathy present histologically?
Alzheimer type II astrocytes
Hypoglycemia
Definition
Systemic Diseases
Exposures
- Insufficient food intake
- Systemic diseases
- Primary hyperinsulinism
- Severe liver disease
- Adrenal insufficiency
- Exposure to drugs that cause hypoglycemia (insulin)
What are the clinical signs & symptoms of hypoglycemia?
- Headache
- Confusion
- Irritability
- Incoordination
- Lethargy
- Leads to stupor & coma
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)
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
What is this?
CHRONIC Carbon Monoxide Poisoning
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
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
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
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
- Large areas of coagulate necrosis
- Induction of neoplasms (meningiomas, sarcomas, gliomas) yrs after treatment
What are 5 drugs that cause drug toxicity?
- Methotrexate
- Vincristine
- Phenytoin
- Cocaine
- Amphetamine
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
**Vincristine Toxicity **
P.O. administration
Intrathecal administration
- P.O. admin – sensory neuropathy
- Intrathecal admin – axonal swelling
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
What are the effects of Cocaine Toxicity?
- Seizures, strokes, hemorrhages
- Infarcts & hemorrhages due to vasospasm, emboli, hypercoagulability, hypotension, drug contaminants
- Occasionally vasculitis (?allergic)
What are the effects of Amphetamine Toxicity?
- Infarcts & hemorrhages
- Attributed to vasculitis & HTN
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)
Mitochondrial proteins are encoded within the _______ & _______ genome.
mitochondrial
nuclear
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
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)
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
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
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
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
How does Leigh’s Disease present grossly?
- Periventricular gray matter tissue destroyed
- Around cerebral aqueduct & 3rd ventricle
How does Leigh’s Disease present on histology?
Spongiform appearance & vascular proliferation
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
What 2 syndromes are caused by Thiamine Deficiency?
Wernicke Encephalopathy
Korsakoff Syndrome
What are the clinical signs & symptoms of Wernicke Encephalopathy?
- Ophthalmoplegia, nystagmus
- Ataxia
- Confusion, disorientation, eventual coma
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
How does Wernicke Encephalopathy appear on histology?
- Pallor, myelin loss, prominent vessels
- MΦ, presentation of neurons
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 **
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
What is this?
Vitamin B12 (Cobalamin) Subacute Combined Degeneration of Spinal Cord
