important points! website: ://play.psych.mun.ca course outline course lectures study questions ...

Important Points!

Website: http://play.psych.mun.ca Course outline Course lectures Study questions Course info (i.e. change of exam date, class cancelled,

assignment info, etc)

Not time in class to cover all material in text, but students are responsible for text and class material for midterms and exams.

Students are responsible for all material covered in class (but not in text).

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

SimpleSimple Symptoms are primarily sensory or motor or both Symptoms spread as epileptic discharge spreads Not associated with a loss of consciousness

Complex 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 malGrand 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) 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 hyper-excitable 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 RacineMcMaster University

Preview

Tumors

Seizure Disorders

Cerebrovascular Accidents

Disorders of Development

Degenerative Disorders

Disorders Caused by Infectious Diseases

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

Stoke

Cerebrovascular Accidents

Incidence in US – 750,000/year

1-2% by 75

2 major causes: Hemorrhagic ischemic

Cerebrovascular Accidents

Hemorrhagic Hemorrhagic StrokesStrokes 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

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

Cerebral Hemorrhage

Cerebrovascular Accidents

Ischemic StrokeIschemic Stroke – cerebrovascular accident caused by occlusion of a blood vessel

Thrombus Thrombus – blood clot that forms within a blood vessel, which may occlude it.

EmbolusEmbolus – 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 Ischemia – interruption of the blood supply to a region of the body.

Fig. 15.7

“Cerebral Penumbra”Nature Medicine (2008) 14:497-500

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

Damage Due to Cerebral Ischemia

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 post-ischemic 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

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

Down Syndrome

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

Genetics of DS

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

Down Syndrome

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 DISEASESPRION DISEASES

PrPc (normal) and PrPsc (prion infected)

PrPSC -protease-resistant (prion protein also heat resistant)

Abnormal protein taken up into neuron by retrograde transport

PrPC PrPSC

Transmissible Spongiform Transmissible Spongiform EncephalopathiesEncephalopathies 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

APOPTOSISAPOPTOSIS: programmed cell death Caspases: enzymes generated

by the cell initiating cell death BSE: caspase 12

Transmissable Spongiform Encephalopathy

HUMAN PRION HUMAN PRION DISEASESDISEASES

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: EpidemiologyvCJD: Epidemiology

BMJ 2001; 323 : 858