Toxic & Metabolic Diseases of the CNS Flashcards
(63 cards)
1
Q
When do you suspect a metabolic disorder in a patient?
A
- 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
Q
What are some common symptoms of a metabolic disorder?
*sorry for the long card, I think just be able to recognize these*
A
- 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
Q
What are some suspicous presentations of metabolic disorder? (7)
A
- 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
Q
What is the right thing to do when you have an unresponsive patient with unexplained lethargy, confusion, somnolence or coma?
A
- 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
Q
What is a Lysosomal Storage Disease?
A
- Lysosomes (“intracellular digestive tract”)
- Acid hydrolases breakdown macromolecules
- Lack of any protein essential for normal function of lysosomes
6
Q
What is a neuronal storage disease?
What are some examples?
A
- 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
Q
What is the difference btwn lysosomal storage disease & poisoning?
A
8
Q
Lysosomes at Work
Lysosomes digest ___________.
Lysosome releases ___________ into mitochondria to break down ___________.
A
Old cell components
Digestive enzymes
Macromolecules
9
Q
What are the 6 categories of Lysosomal Storage Diseases?
A
- 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
Q
**Tay Sachs Disease **
Epidemiology
Diagnosis
A
- High incidence in Ashkenazi Jews
- Gene on chr 15 (>100 mutations described)
- Diagnosis
- Enzyme assay of serum, WBC
- Cultured fibroblasts
11
Q
Tay Sachs Disease
Clinical Signs/Symptoms
Progressive Signs/Symptoms
A
- 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
12
Q
In Tay Sach’s Disease, ____ intact genes required for effective Hex A function
A
3
13
Q
Tay Sach’s Disease Pathology
Brain
Microscope
A
-
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
14
Q
What is the treatment for Tay Sach’s Disease?
A
- Experimental stages
- “Chaperone” proteins may help α-subunit fold normally
- Enzyme replacement therapy
15
Q
What is Krabbe’s Globoid Cell Leukocystrophy?
What is the deficiency?
A
- 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
Q
Krabbe’s Globoid Cell Leukodystrophy
Diagnosis
Clinical Course
Treatment
A
- 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
Q
How does Krabbe’s Globoid Cell Leukodystrophy present grossly?
A
- Atrophic brain
- Firm white matter
- Atrophic white matter w/ preservations of “U” fibers
18
Q
How does Krabbe’s Globoid Cell Leukodystrophy present histologically?
A
- 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
19
Q
What is Metachromatic Leukodystrophy?
What is the deficiency?
A
- 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
20
Q
**Metachromatic Leukodystrophy **
Diagnosis
Clinical S/S
Treatment
A
-
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
Q
How does Metachromatic Leukodystrophy present grossly?
A
- Brain is externally normal
- White matter is very firm
- Marked loss of myelin
- Preservation of “U” fibers (subcortical fibers)
22
Q
How does Metachromatic Leukodystrophy present histologically?
A
-
Metachromasia of white matter deposits
- Brown staining
- Acidified cresyl violet stain
23
Q
What is Adrenoleukodystrophy?
Inheritance?
A
-
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
Q
Classic Adrenoleukodystrophy vs. Adrenomyeloneuropathy
A
-
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
25
How does **Adrenoleukodystrophy** present grossly?
* **Gray discoloration of white matter**
* Marked firmness
* “U” fiber preservation
* **Severe demyelination**
26
How does **Adrenoleukodystrophy** present histologically?
* Perivascular inflammation
* PAS+ MΦ
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
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**)
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)
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**
35
What is this?
_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
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
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**
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
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
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
55
How does **Leigh's Disease** present on histology?
Spongiform appearance & vascular proliferation
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
60
How does **Wernicke Encephalopathy** appear on histology?
* Pallor, myelin loss, prominent vessels
* MΦ, presentation of neurons
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?
Vitamin B12 (Cobalamin) Subacute Combined Degeneration of Spinal Cord
