toxic and metabolic diseases of the CNS

Question 1

Lysosomal storage disease (LSD)

Answer 1

Lysosomes- intracellular waste disposal, acid hydrolases breakdown macromolecules, LSD can result from a lack of any protein that is essential for normal function of lysosomes

Gangliosidoses- a type of neuronal storage disease, result from accumulation gangliosides (abundant in brain) within neurons, GM2 gangliosidoses- caused by dificiency of lysosoma enzymes- Hexoaminidase A- Taysachs disease, hexosaminidase B (sandhoff disease), activator protein deficiency GM2 gangliosidosis, variant AB

Question 2

Tay sachs disease

Answer 2

Historically high incidence in ashkenazi jews,
diagnosis- enzyme assay of serum (HEXOSAMINODASE A), WBC, or cultured fibroblasts
Typical clinical presentation- normal at birth, 6 moths- psychomotor retardation evident, progression Blindness, motor incoordination, eventual flaccidity, mental deterioation, eventual decerebrate state, cherry red spot in macula, death by 2-3 yrs

Question 3

Taysachs disease pathology

Answer 3

Path- brain Normal little big depending upon duration, survival > 2 years brain is big

Microscopic findings- enlarged balooned neurons filled with PAS positive material (stored gangliosides), storage also in other brain cells (astrocytes and microglia), EM (membranous cytoplasmic bodies

Treatment- still in experimental stages, chaperone proteins may help the alpha subunit to fold normally, enzyme replacement therapy, gene therapy

onion lysosomes

Question 4

Krabbes disease (Globoid cell leukodystrophy)

Answer 4

lysosomal storage disease, autosomal recessive, deficiency of galactocerebroside- B- galactosidase, Enzyme deficiency causes accumulation of toxic compound (psychosine) that injures oligodendrocytes, Galactocerebroside is a component of myelin sheaths, it accumulates in the Globoid cells, both CNS and PNS are affected, Dx- enzyme assay of WBC or cultuted fibroblasts

Question 5

clinical course of Krabbes disease (globoid cell leukodystrophy)

Answer 5

Clinical course- normal development, onset between 3-6 months, 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 in pre-symptomatic phase), death by approx 2 yrs

Globoid cells

Question 6

Metachromatic leukodystrophy

Answer 6

Lysosomal storage disease, autosomal recessive, gene on chr 22, deficiency of Aryl sulfatase A , metachromatic lipids (sulfatides) accumulate in brain, peripheral nerves, and kidney

Sulfatide accumulation leads to breakdown of myelin, but how this happens is not known

Screen of urinary sediment for metachromatic deposits
Dx- demonstrate enzyme deficiency in urine, WBC, or fibroblasts

Question 7

Metachromatic leukodystrophy clinical presentation

Answer 7

Late infantile (most common), intermediate, Juvenile (each childhood type present with gait disorder and motor symptoms, death in 5-10 years, adult - usually present with psychosis and cognitive impairment, eventual motor symptoms

treatment- bone marrow stem cell transplantation (before symptoms appear
White mater very firm

preservation of u fibers, metachromasia, violet stain turns brown

Question 8

Adrenoleukodystrophy (schilder disease)

Answer 8

peroxisomal disorder, peroxisomes- cytoplasmic spherical microbes, contain catalase, involved in fatty acid B-oxidation (and more)

Decreased activity of very long chain fatty acyl CoA sythetase in peroxisomes)
Excess of very long chain fatty acid esters in plasma, cutured fibroblasts, and affected organs (CNS, PNS, adrenals), the classic form of this disease is X linked

Question 9

Adrenoleukodystrophy clinical

Answer 9

classic form- onset 5-9 yrs or 11-21 yrs, dementia, visual/hearing loss, seizures
Adrenal insufficiency Follows neurologic problems

Adrenomyeloneuropathy- occurs in adult (20-30 yrs), slowly progressive leg clumsiness/stiffness, eventual spastic paraplegia, adrenal insufficiency may precede neurologic problems

gray - white matter, , perivascular inflammation, with lots of neutrophils

Question 10

TThiamine (b1) deficiency

Answer 10

Seen predominantly in malnourished chronic alcoholics, other causes- starvation diets, hemodialysis, gastric stapling, extensive gi surgery, hyperalimentation without thiamine supplementation, absence infant formula

2 syndromes- wernicke encephalopathy, Korsakoff syndrome

Question 11

Wernicke encephalopathy

Answer 11

Clinical presentation: Opthalmoplegia, nystagmus, ataxia, confusion, disorientation, eventual coma

Lesions are in mammillary bodies, dorsomedial thalamus, around 3rd and 4th ventricles,,

Question 12

Korsakoff psychosis

Answer 12

Clinical presentation- loss of anterograde episodic memory, confabulation, preserved intelligence and learned behavior
Hypothesized to result from repeated episodes of wernickes encephalopathy

No pathology distinct from wernickes, findings attributed to damage to medial dorsal nucleus of thalamus

Question 13

VitaminB12 cobalamine Subacute combined degeneration of spinal cord

Answer 13

Usually due to pernicious anemia (40% of untreated patients), Clinical: ataxia, romberg, spasticity, decreased reflexes, mental status changes
Pathology- CNS and PNS involvement, spinal cord (anterior and lateral corticospinal tracts and posterior columns are vacuolated and demyelinated, may have secondary axonal degeneration

on the spinal cord the dorsal column and corticospinal tract are taken out

Question 14

CO poisoning

Answer 14

Irreversibly binds to hemoglobin, displacing oxygen
Binds to areas rich in iron (globus pallidus, substantia nigra), and cause necrosis

Degeneration of white matter also occurs, CO poisoning usually accompanied by hypotension/ischemia
Motor, cognitive, psychiatric, and parkinsonian sign/ symptoms

Acute methanol toxicity- basal ganglia hemorrhage (in the basal ganglia)

Question 15

Chronic ethanol toxicity (alcoholism)

Answer 15

clinically - truncal ataxia, nystagmus, limb incoordination

Cerebellar degeneration- Atrophy, especially of anterior suprior vermis, dropout of purkinje cells, internal granular cells, and astrocytosis

Question 16

Fetal alcohol syndrome

Answer 16

Associated with low levels of alcohol consumption
clinical picture- growth retardation, facial deformities- short palpebral fissure, epicanthal folds, thin upper lip, growth retardation of jaw, cardiac defects- atrial septal defect, delayed development and mental deficiency

Pathological findings- microcephaly, cerebellar dysgenesis, heterotopic neurons, hypothesized that acetaldehyde crosses placenta and damages fetal brain

Question 17

radiation toxicity

Answer 17

Delayed effect (months to years later), clinical symptoms of a mass lesion, pathology, large areas of coagulative necrosis, primarily in white matter, vessels with markes thickened walls

Induction of neoplasms (meningiomas, sarcomas, gliomas) years after treatment

Question 18

Medication toxisity

Answer 18

Methotrexate- Intrathecal or intraventricular admin in combination with radiation may produce, disseminated necrotizing leukoencephalopathy, particularly around ventricles and deep white matter, coagulative necrosis with axonal loss and mineralization

Vincristine- Systemic admin- sensory neuropathy, intrathecal admin axonal swelling

Phenytoin- ataxia, nystagmus, slurred speech and sensory neuropathy atrophy of cerebellar vermis and loss of purkinje cells and granule cells

Question 19

Calcineurin inhibitor toxicity

Answer 19

Cyclosporine A and tracolimus, immunosuppressive agents used to prevent transplant rejection and for autoimmune disease
Toxicity can cause posterior reversible leukoencephalopathy syndrome (PRES) headache, altered mental status, cortical blindeness, speech abnormalities, white matter changes on imaging

Question 20

Drug toxicity

Answer 20

Cocaine- seizures, stroke, hemorrhages, infarcts and hemorrhages due to vasospasm, emboli, hypercoaguability, hypotension, drug contaminants, occasionally vasculitis

Amphetamine- infarcts and hemrrhages, attributed to vasculitis and hypotension