Transcript Chapter 15: Neurological Disorders

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Chapter 15: Neurological Disorders
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders
 Disorders Caused by Infectious
Diseases
Tumors
 Introduction
 Tumor – a mass of cells whose growth is
uncontrolled and that serves no useful function.
 Malignant Tumor – a cancerous tumor; lacks
distinct border and may metastasize.
 Benign Tumor – a noncancerous tumor; has a
distinct border and cannot metastasize.
 Metastasis – process by which cells break off of a
tumor, travel through the vascular system, and
grow elsewhere in the body.
Metastatic Tumor
Tumors (Continued)
 Glioma – a cancerous brain tumor composed of
one of several types of glial cells.
 Malignant gliomas contain tumor initiating cells
which originate from transformations of neural
stem cells
 Rapidly proliferate and give rise to a glioma
 Meningioma – a benign brain tumor composed of
the cells that constitute the meninges.
Malignant Glioma
Malignant Meningioma
Tumors
 Tumors can damage brain tissue by 2 means:
 Compression
 Directly
 Indirectly - blocking flow of CSF, hydrocephalus
 Infiltration
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders
 Disorders Caused by Infectious
Diseases
Seizure Disorders
 Epilepsy - Primary symptom is
seizures, but not all who have
seizures have epilepsy
 Affects about 1% of the
population
 Difficult to diagnose due to the
diversity and complexity of
epileptic seizures
Seizures
Seizures often preceded by an aura, such as
a smell, hallucination, or feeling
 Aura’s nature suggests the epileptic focus
 Warns epileptic of an impending seizure
Seizures
Partial seizures– does not involve the whole
brain, has a definite focus, or source of
irritation
 Scarred region caused by old injury or
developmental abnormality (malformed
blood vessel)
Generalized epilepsy – involves the entire
brain, widespread.
 Often grow from a focus (may be unknown)
Partial Seizures
Simple
 Symptoms are primarily sensory or motor or both
 Symptoms spread as epileptic discharge spreads
 Not associated with a loss of consciousness
Complex
 Often restricted to the temporal lobes
(temporal lobe epilepsy)
 Patient engages in compulsive and repetitive
simple behaviors (automatisms)
 Lead to loss of consciousness
Figure 15.6 Primary Motor Cortex and
Seizures
Generalized Seizures
 Grand mal
 Loss of consciousness
 Tonic-clonic convulsions
 Rigidity (tonus)
 ~15 s
 All muscles contract, arms are
rigidly outstretched
 Tremors (clonus) ~ 30 s
 Muscles begin trembling, jerking –
quick at first, then slower, eyes roll,
face is contorted, tongue may be
bitten, sweating, salivation.
 Firing begins at focus spreads to
other regions
 Corpus callosum
 Resulting hypoxia may cause
brain damage
Generalized Seizures
 Absence (Petit mal)
 Common in children
 Not associated with convulsions
 A disruption of consciousness associated with a cessation of
ongoing behavior
 Unresponsive, usually do not notice their attacks
 Can occur several hundred times/day
Seizures
 Can cause brain damage
 ~ 50% of patients with seizure disorders show damage to the
hippocampus
 Amount of damage – correlated with the number and
severity of seizures
 Status Epilepticus – a condition in which a patient
undergoes a series of seizures without regaining
consciousness
 May cause significant hippocampal damage
 Caused by excessive release of glutamate during seizure
Causes of seizures
 Injury, stroke, developmental abnormality,
effect of a growing tumor
 Febrile seizures
 Infantile fever
 ~3% of children under 5
 Alcohol or barbiturate withdrawal
 Sudden release of the inhibiting effects of alcohol
or barbiturate leaves the brain in a hyperexcitable condition (can be fatal)
Causes of seizures
 Alcohol effects (during
intoxication)
 GABA activation
 NMDA blocked
 Alcohol Withdrawal
 Glutamate rebound
 NMDA receptors
Causes of Seizures
Genetic factors (not common cause)
70 genes (as of now) associated with
seizure disorders
Nearly all genes identified control the
production of ion channels
Treatments
Anticonvulsant drugs (increasing
effectiveness of inhibitory synapses)
Brain surgery – remove region of the
brain surrounding the focus (usually
located in MTL)
Kindling Model of Epilepsy
 A series of alternating bilateral brain
stimulations eventually elicits convulsions – the
kindling phenomenon
 Typically amygdala or hippocampus
 Neural changes are permanent
 Produced by stimulation distributed over time
 Convulsions are similar to those seen in some
forms of human epilepsy – but they only occur
spontaneously if kindled for a very long time
 Kindling phenomenon is comparable to the
development of epilepsy (epileptogenesis)
seen following a head injury
Ronald J Racine
McMaster University
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders
 Disorders Caused by Infectious
Diseases
Stoke
 3rd leading cause of death
 Most common cause of adult disability
 Common consequences of stroke
◦
Amnesia, aphasia, paralysis, coma
 Infarct – area of dead or dying tissue produced by the
stroke
 Penumbra – dysfunctional area surrounding the infarct
◦
Goal of treatment following stroke is to save the penumbra
Cerebrovascular Accidents
Incidence in US – 750,000/year
1-2% by 75
2 major causes:
 Hemorrhagic
 ischemic
Cerebrovascular Accidents
 Hemorrhagic Strokes
Cerebrovascular
accident caused by
the rupture of a
cerebral blood vessel
 Malformed blood
vessel
 Weakened blood
vessel from high blood
pressure
 Blood seeps out and
accumulates within the
brain, putting pressure
on the surrounding
tissue
Fig. 15.7
Cerebral Hemorrhage
Bleeding in the brain
 Cerebral blood vessel ruptures and blood seeps into the
surrounding neural tissue
 Cause
 bursting aneurysm
 Aneurysm
 pathological balloon-like dilation that forms in the wall of an artery
at a point where the elasticity of the artery wall is defective
 Congenital
 Vascular poisons or infection
 Weakened blood vessel from high blood pressure
Cerebrovascular Accidents
 Ischemic Stroke –
cerebrovascular accident
caused by occlusion of a
blood vessel
 Thrombus – blood clot that
forms within a blood vessel,
which may occlude it.
 Embolus – piece of material that
forms in one part of the vascular
system, breaks off, carried by
blood stream until it reaches a
smaller artery
Ischemia – interruption of the
blood supply to a region of
the body.
Fig. 15.7
Damage Due to Cerebral Ischemia
 Does not develop immediately
 Most damage is a consequence of
excess neurotransmitter release –
especially glutamate
 Blood-deprived neurons become
overactive and release glutamate
 Ischemia-induced brain damage
 takes time
 does not occur equally in all parts of
the brain
 mechanisms of damage vary with the
brain structure affected
“Cerebral Penumbra”
Nature Medicine (2008) 14:497-500
 Blood supply interrupted
 Oxygen, glucose and
glycogen depleted
 Na+/K+ transporters stop
working
 Depolarizes the cell
 lnflux of Na+ and Ca2+ triggers
 the release of still more
glutamate
 a sequence of internal
reactions that ultimately kill the
neuron
 Causes cell to swell
 Inflammatory responses
 Microglia- phagocytosis
 Astrocytes- scarring
 Generation of free radicals
 Toxic substances
 Destroy nucleic acids, proteins
and fatty acids
Treatment for Ischemic injury
 Clot dissolving drugs
 Tissue plasminogen activator (tPA) – within 3 hrs
 Can have neurotoxic effects
 Desmoteplase (anticoagulant; vampire bats)
 Not toxic, up to 9 hrs
 Hypothermia
 Animal models show that hypothermia has
neuroprotective effects
 Corbett (MUN)
 Slow to catch on in
human treatment
Treatment for Ischemic injury
 Animal models of stroke
and ischemic injury
 Gerbil, rat
 Biernaskie and Corbett
(2001) Enriched
environment and postischemic training
 Animals housed in
enriched environments
and subjected to
training with affected
limb showed enhanced
dendritic complexity
and length
 Motor assessment: EE
plus training rats were
indistinguishable from
control 4 and 9 weeks
after ischemia
Enriched environment : Corbett (MUN)
Treatment for Ischemic injury
 Physical therapy
 Human studies
 Taub et al (2006)
 Constraint-induced
movement therapy
 Researchers put the good
arm into a sling for 2
weeks after ischemic injury
 Forced patients use the
affected arm
 Controls: relaxation and
fitness exercise
 CI therapy – changes in
connections of primary
motor cortex
See Fig. 15.11
Preview
 Tumors
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Toxic chemicals
 Inherited metabolic disorders
 Down Syndrome
 Degenerative Disorders
 Disorders Caused by Infectious Diseases
Toxic Chemicals
 During pregnancy, impairs fetal development
 Mother contracts rubella (German measles)
 Toxin produced by virus
 Mental retardation
 Mother ingests alcohol during pregnancy
 Mental retardation
 Babies are smaller, and develop more slowly
 Fetal alcohol syndrome – abnormal facial development,
deficient brain development
 Neural adhesion protein – protein that helps guide the
growth of neurons in developing brain
 Decreased plasticity in rats (decreased LTP)
 Alters development of neuronal stem cells
Inherited Metabolic Disorders
 At least 100
 Phenylketonuria (PKU)
 Lack of enzyme that converts phenylalanine into tyrosine
 XS phenylalanine in blood interferes with myelinization of
neurons in CNS
 Given food with phenylalanine, accumulates, severe mental
retardation
 Treatment
 Low-phenylalanine diet
Inherited Metabolic Disorders
 Tay-Sachs disease
 Causes brain to swell and damage itself against the inside of the
skull and dura mater
 Metabolic “storage” disease
 1 or more enzymes are missing, waste products cannot be
destroyed by lysosomes, accumulation
 Lysosomes get larger, cells get larger, brain
swells
 Symptoms begin around 4 months
 Exaggerated startle response, listlessness,
irritability, spasticity, seizures, dementia,
death
Down Syndrome
 Genetic accident
 ~0.15% of births
 Usually occurs during ovulation
 Extra chromosome 21 is created in the egg
 3 chromosome 21s in the zygote
Down Syndrome
 Probability increases with advancing maternal age
Genetics of DS
 Trisomy 21
 Caused by a nondisjunction event.
 a gamete (a sperm or egg cell) is produced with an extra copy of
chromosome 21
 Cause of approximately 95%
 88% from nondisjunction in the maternal gamete
 8% from nondisjunction in the paternal gamete.
Nondisjunction is the failure of chromosome pairs to separate properly
during cell division
 The result of this error is a cell with an imbalance of chromosomes
Down Syndrome
Mosaicism
 When some of the cells in the body are normal and other cells
have trisomy 21
 This can occur in one of two ways:
1.
Nondisjunction event during early cell division in a normal embryo
leads to a fraction of the cells with trisomy 21
2.
Down syndrome embryo undergoes nondisjunction and some of the
cells in the embryo revert to the normal chromosomal arrangement.

Variability in the fraction of trisomy 21, both as a whole and among
tissues.
 Cause of 1–2%
Down Syndrome
Robertsonian translocation
 The long arm of chromosome 21 is attached to another chromosome,
often chromosome 14 or itself (called an isochromosome)
 A person with such a translocation is phenotypically normal.
 During reproduction, there is a significant chance of creating a
gamete with an extra chromosome 21
 Cause of 2–3% of observed cases of Down syndrome.
 No maternal age effect, and is just as likely to have come from fathers
as mothers.
Down Syndrome
Duplication of a portion of chromosome 21
 Region of chromosome 21 will undergo a duplication (rare)
 Leads to extra copies of some, but not all, of the genes on
chromosome 21
 If the duplicated region has genes that are responsible for Down
syndrome physical and mental characteristics, such individuals
will show those characteristics
 Very rare
Down Syndrome
 Consequences
 Disfigurement
 Flattened skull and nose
 Folds of skin over the inner corners of
the eyes
 Short fingers
 Retarded intellectual development
 Often serious medical complications
Preview
 Seizure Disorders
 Cerebrovascular Accidents
 Disorders of Development
 Degenerative Disorders





variant Creutzfeldt-Jackob (BSE)
Parkinson’s Disease
Huntington’s Disease
Alzheimer’s Disease
Multiple Sclerosis
 Disorders Caused by Infectious Diseases
Degenerative Disorders: vCJD
 Transmissible Spongiform Encephalopathies
 Contagious brain disease whose degenerative
process gives the brain a sponge-like appearance.
 Bovine Spongiform Encephalopathy (BSE)
 Creutzfeldt-Jakob Disease (CJD)
 Fatal familial insomnia
 Kuru (humans)
 Scrapie (sheep)
 Prions – protein that can exist in two forms
that differ only in their 3-D shape.
 Stanley Prusiner (discovered 1986)
 Nobel Prize (1997)
 Normal prion protein (synaptic protein)
 Development and learning and memory
 Accumulation of misfolded prion protein is
responsible for TSE.
PRION DISEASES
 PrPc (normal) and PrPsc (prion infected)
PrPC
PrPSC
PrPSC -protease-resistant (prion protein
also heat resistant)
 Abnormal protein taken up into neuron
by retrograde transport
Transmissible Spongiform Encephalopathies
 Encephalopathies
 Encephalopathy gives the brain
a ‘swiss cheese’-like appearance
 Once introduced into the
cell the PrPsc can cause the
PrPc (normal) to become
misfolded
 APOPTOSIS: programmed
cell death
 Caspases: enzymes generated
by the cell initiating cell death
 BSE: caspase 12
Transmissable Spongiform
Encephalopathy
HUMAN PRION DISEASES

Creutzfeldt-Jakob (and vCJD)



Fatal familial insomnia

Autosomal dominant

40 families; affecting ~100 people
Kuru

Fore people of Papa New Guinea; cannabalism
Creutzfeldt-Jakob Disease (CJD)
NEURODEGENERATIVE DISEASE



Rapidly progressive dementia, memory
loss, personality changes and
hallucinations
Physical problems such as speech
impairment, jerky movements, balance
and coordination dysfunction (ataxia),
changes in gait, rigid posture, and seizures
Death
Creutzfeldt-Jakob Disease (CJD)
Three recognized methods of affliction
 Familial
 Sporadic
 Acquired
 Iatrogenic
 Variant (a.k.a. New Variant)

Long incubation periods (4-40 years)
 Species Barrier and multiple exposures
FOOD FOR THOUGHT
50,000 BSE-infected cattle are estimated to
have entered the human food chain
before its recognition in 1986
“You’re sick, Jessy!…Sick, sick, sick!”
vCJD: Age of Onset
British Medical Journal 2001; 322 : 841
vCJD: Epidemiology
BMJ 2001; 323 : 858