Epilepsy and MS Flashcards
1
Q
What is a seizure?
A
- A transient occurance of clinical signs due to excessive and hyper-synchronous activity of populations of neurons in the brain
- Due to interconnected neurons reciprocally innervating each other and generating an oscillating patter of activation in the brain
- The oscillating activation of neurons is generally self limiting 60-90 seconds
2
Q
What is epilepsy?
A
- Epilepsy is a group of diseases with enduring alterations of the brain resulting in an abnormally increased predisposition to seizures
- Epilepsy can have a genetic, structural/metabolic or cryptogenic cause
- It is the most common serious neurological condition
- Has an increased prevalence in underdeveloped countries and in lower socioeconomic groups
- The lifetime prevalence of the disease is 2-4%
3
Q
What are the health consequences of epilepsy?
A
- Physical morbidity
- Psychiatric morbidity
- Social morbidity
- Medication side effects (increased risk of heart disease and cancer)
- Mortality:
- SMR is 3x higher than general population
- Due to accidental injury, drowning, asphyxia, suicide and sudden unexplained death in epilepsy
4
Q
How are seizures classified?
A
- Focal onset:
- Arise in a limited number of cortical neurons in one hemisphere - Generalised onset:
- Appear to arise simultaneously in both hemispheres - Unknown onset
5
Q
What are the 3 main classifications of epileptic syndromes?
A
- Genetic (idiopathic)
- Usually involves generalised onset seizures
- Underlying brain structurally and functionally normal
- Onsets in childhood/teenage years and may remit
- Usually respond well to medication
- Likely have a genetic basis e.g. defective ion channels
- 5-10% have Mendelian monogenic inheritance patterns
- 90% have complex inheritance patterns - Structural/Metabolic (symptomatic):
- Seizures result from some identifiable structural/functional brain abnormality
- Uncommonly remit
- Often drug refractory
6
Q
How is the hippocampus remodeled in structural/functional epilepsy?
A
- The hippocampus of the brain is considered the mot common site of epileptic brain activity
- Neurological and cellular mechanisms that generate epileptic neuronal networks include:
1. Loss of inhibitory neurons
2. Gain of excitatory neurons
3. Abberant sprouting of axons
4. Alterations in intrinsic neuronal cellular excitability
5. Alterations in synaptic transmission
6. Alterations in the extra-neuronal environment - These changes are common following brain injury
Main hippocampal changes include:
- Loss of neurons in CA3 and CA1 regions
- Neurogenesis in dentate gyrus
- Hypertrophy and proliferation of glial cells
7
Q
Describe the relationship between age and epilepsy:
A
- New onset epilepsy is common in all ages but there is a bimodal peak in the young and old
- The most common onset occurs in older patients, often due to ischemic brain disease and neurodegenerative brain disease
- The aetiology of new onset epilepsy varies with age:
1. Infancy/early childhood: congenital or perinatal CNS insults
2. Late childhood/early adulthood: idipathic/genetic
3. Adult/eldery: most symptomatic
8
Q
Where are lesions in MS usually located?
A
- Lesions (inflammatory plaques) in MS are generally localised to the white matter within the CNS
- MS lesions can be disseminated throughout the CNS (but there is an anatomical preference to periventricular region of brain)
- Demyelination causes axonal damage in MS and as the disease progresses can cause substantial grey matter atrophy
9
Q
How is demyelinated visualised?
A
- Demyelination can be seen using a Luxol Fast Blue/Periodic acid-Schiff stain
- The stain colours the fatty myelin blue- in areas of significant demyelination there is palor
10
Q
Summarise MS pathogenesis:
A
- Circulating T-cells aberrantly target oligonculeotides/myelin due to mutations in HLA and release cytokines to recruit other inflammatory cells
- Recruited B-cells most likely release autoantibodies (have not been identified) which bind to the myelin
- Macrophages then accumulate around the axon and engulf myelin from the axon creating an inflammatory plaque
- As the macrophages cannot phagocytose the very large quantities of myelin, there is the formation of extracellular depositis of myelin (which also can induce axon damage)
- The demyelination eventually causes axonal degeneration leading to axonal transection and neuronal loss
- Following inflammation and neuronal death there is significant astrogliosis- the astrocytes proliferate and produce large amounts of CSPG which forms a glial scar
- Significant glial scars persist and significant neuronal loss in the brain can cause tissue atrophy and ventricular enlargement
11
Q
Describe the epidemiology of MS:
A
- Most common chronic neurologic disease in young adults (mean age of 30 years)
- Affects women in a 2-3:1 ratio compared to men
- Northern hemisphere Caucasian populations more prone to disease
- Immigration to geographical regions also increases risk (potentially due to higher EBV in colder climates)
- The type of disease also has sexual dimophisms with females more likely to have RRMS and males more likely to have PPMS
12
Q
What are the 3 clinical forms of MS?
A
- Relapsing-Remitting MS:
- 85% of cases
- There is a steady incline in disability with superimposed attacks - Secondary Progressive MS:
- Occurs after 8-10 years with RRMS
- The RRMS suddenly begins to worsen with no periods of remission - Primary Progressive MS:
- Steady increase in disability without identifiable episodes or attacks
13
Q
Describe the clinical presentation of MS:
A
- Highly variable presentation (due to multiple foci of lesions in CNS)
- Paraesthesia (tingling and numbness)
- Retro-bulbar (optic) neuritis
- Sensory or motor impairment
- Cognitive impairment
- Ataxia
- Incontience
- Paralysis
- Fatigue
- Eventual death (due to pneumonia or UTI)
14
Q
Describe the pathological sequelae of MS:
A
- Demyelination:
- Generation of myelin by phagocytic immune cells - Remyelination:
- May occur after demyelination (creating shadow plaques)
- A think layer of myelin may regenerate around neurons that have not undergone axon damage - Glial scar formation:
- Following neuronal cell death and inflammation astrogliosis may occur
- Large amounts of CSPG produced by proliferating atrocytes forms an acellular glial scar which cannot be healed - Axonal Swelling and Damage:
- Occurs early in MS pathogenesis
- Swelling in axons causes blockage of transport molecules within axon and mitochondrial deficit occurs
- Causes demylination and axon death
15
Q
How is MS studies using animal models?
A
- The most common animal model for MS is the EAE model
- Involves incoulation of female mice with myelin oligodendrocyte glycoprotein (MOG), adjuvant and peritussis toxin
- Creates a Th1 mediated autoimmune disease involving inflammatory cell infiltration into the CNS, demyelination, axonal damage and gliosis
