Week 8 Flashcards
Seizure
Result from an excessive/synchronous neuronal discharge
This may manifest as:
-behavioural change
-involuntary skeletal muscle contraction
-altered level of awareness
Epilepsy
Tendency to get recurrent seizures/>2 seizures over 24 hours apart
Epidemiology
1 in 103 people has epilepsy
Up to 3% population will have a seizure at some point in their life
Risk factors for epilepsy:
-underlying development/acquired CNS abnormality
-family history
-prolonged/multiple/atypical febrile convulsions (typically between 6m and 6 yr)
Seizure types
Focal (partial) seizure :
-confined to one area of the brain
-may be associated with preserved awareness or impaired cognition
Bilaterally convulsive generalised seizure:
-network tends to start in both sides of the brain simultaneously
-more common in children
Operational (practical) clinical definition of epilepsy
At least 2 unprovoked (or reflex) seizures occurring more than 24 hours apart
One unprovoked (or reflex) seizure and a probability of further seizures similar to the general recurrence risk (at least 60%) after 2 unprovoked seizures occurring over the next 10 years
Diagnosis of an epilepsy syndrome
Epilepsy is considered to be resolved for individuals who had age dependent epilepsy syndrome but are now part the applicable age or those who have remained seizure free for the last ten years with no seizure medicines for the last 5 years
Ancillary investigations for epilepsy
MRI- essential in adults unless strong suspicion of genetic generalised epilepsy
EEG- useful to establish focality
-focal abnormalities increase recurrence risk
-30% ‘hit rate’ on initial EEG may need sleep deprive and/or ambulatory recordings
Refractory epilepsy
Ongoing seizures (>1month) in spite of two adequate trials of antiepileptic drugs
1/3 patients refractory following single AED
Who should be referred for surgical consideration
History suggests focus
Refractory epilepsy
Reasonable age and health
-further investigation
Ideal surgical candidate
Young, prior, febrile seizures, recent seizure onset
Primarily focal seizures
Typical medial temporal lobe symptoms
Hippocampal sclerosis on MRI
The MDTM epilepsy
Neurology
Neurosurgery
Neurophysiology
Neuroradiology
Neuropsychology
Neuropsychiatry
Resective surgery
Refining localisation
Refining resection
Refining localisation- imaging
3T MRI
Quantitative MRI
FDG-PET-radio labelled glucose analog. Epileptogenic lesion generally hypo metabolic
HMPAO SPECT- tracer becomes hydrophilic (stable within neurones)
-image reflects uptake 15s after injection for further 40s
-increased uptake= increased neuronal activity= seizure activity
Refining localisation- functional imaging MEG
WADA- intracarotid Amytal injection- is there a safe alternative?
Functional MRI- speech mapping
MEG magnetoencephalogram:
-record minute magnetic fields generated by intra-neuronal currents
-detected by a series of 300+ magnetic coils within a super conductor (liquid helium)
-interictal recording. ‘Superficial’
Where would we be without the EEG
Subdural electrodes
Discs 4-5mm diameter, 5-10mm apart
In silastic strips (4-8 contacts) or rectangular grids (20-128 contacts)
Intracerebral (depth) electrodes
Serial cyclindrical contacts (4-18) 2-10mm apart, diameter of 1mm or less, recording areas of 3-5mm2
Flexible with retractable rigid stylet used for insertion or semi rigid
Indications for IEEG
To define to EZ when non-invasive data are inconclusive/divergent:
-mesial vs neocortical temporal lobe
-‘dual’ temporal lobe pathology
-rapidly generalising sz
-deep seated lesion (scalp recording limited)
To map eloquent cortical function precisely
-acquired lesions may displace function, longer standing lesions do not
To selectively ablate lesions (thermocoagulation)
Resective epilepsy surgery
Case selection is key
‘Lesion positive’ and single focus and minimal comorbidity
High premorbid IQ= chance of post op deficit
Neuropsychiatric f/u in selected cases is essential
Potentially offers best chance of seizure freedom
Outcomes:
-51% seizure free at 2 years
-36% seizure free at 10 years
-30% seizure free at 25 years
Vagal nerve stimulation VNS
VNS generator generates electrical impulse, surgeon implants generator subcutaneously over the chest and attaches electrodes to the left vagus nerve. Intermittent signals from the VNS device travel up vagus nerve and enter medulla
VNS indications include drop attacks, multi focal epilepsy
Worldwide: 55% mean seizure reduction by year 5 >50% seizure reduction in half patients
Medtronic SANTE (stimulation of anterior thalamus for epilepsy) trial
Electrodes surgically places in the thalamus a deep part of the brain on both sides
Stimulation every 5 minutes
Strength and duration of stimulation can be adjusted
Like vagus nerve stimulator patient can “trigger” stimulation for an aura or seizure
Seizure symptoms
Tend to be stereotyped- same series of symptoms occurs each time
Might be sensory symptoms involving tingling of one side of body
-might spread, might be painful or associated with temp change
If its prolonged may spread into an motor phase were there’s jerking of affected part
If jerking is prolonged patient experiences Todds paresis- weakness of affected area where jerking had occurred
Less commonly: sweating, flushing, pallor, tightness in throat, unusual sensation in stomach (epigastric aura)
Change in hearing or vision
-this is often a positive phenomenon- patient might see coloured shapes that often start from affected fish then spread
-can be difficult to distinguish from other symptoms like migraine
Generalised epilepsy: seizure types
Absence: associated with sudden brief alteration in awareness
Myoclonic: sudden jerking of both upper limbs
Tonic (incl infantile spasms): stiffening of body with eyes and head going back
‘Tonic clonic; tonic stiffening followed by jerking phase
Atonic: eg head drop, can be associated with risk for falling if whole trunk collapses down
Making a diagnosis of epilepsy
The history is key
2 or more stereotyped attacks
Ictal phase: seizures itself time from first symptom to end seizure activity, often encompasses a sense of aura or warning
Post ictal phase:manifest if someone has has a focal seizure as confusion, fatigue, headache. If someone has had pronounced convulsive seizure this phase can be associated with muscle pain, tongue biting,m urinary, faecal incontinence
-this disorientation following seizures often lasts hours/days
Witness account is important
History taking
Ask patient about early life and tendency of seizures
History head injuries
Family history seizures
Recollection of event and witness account
‘Warning’ (smell, taste, emotions, perceptions)
Alteration in awareness
Limb movements
Associated features:
-vocalisation
-frothing at mouth
-incontinence
-lateral tongue biting
-cyanosis
Post ictal symptoms: headaches, myalgia (especially post generalised seziures)
Evidence of nocturnal attacks
Beware:
-frontal lobe seizures: bizarre behaviours/motor automatisms, rapid recovery, minimal post ictal confusion
-brief focal seziures: brief olfactory or visual hallucinations, may leave patient feeling ‘strange or detached’
Which of these could represent a seizure
Recurrent tingling spreading up an arm
Recurrent intrusive imagery associated with fear
Recurrent muffling of sounds ‘white noise’
Recurrent intense ‘rising’ nausea
Examination
Focal neurology
Cardiovascular abnormalities
An ECG is essential: because older patients tend to have syncopal type episodes and seizures
Investigating seziures
Bloods:
-urea/electrolytes
-infective screen (incl CSF)
-infective screen
-drug levels (toxins, antipsychotics)
Imaging: MRI
EEG (diagnostic/localisation vs prognostic)
-chance of capturing epileptiform discharge 35%
Causes of seizures
Genetic: childhood onset, FHx
Previous febrile convulsions
Infective /Autoimmune : meningoencephalitis
Metabolic: hypocalcaemia, hyponatraemia, hypoglycaemia, liver failure, renal failure, anoxia
Toxic: cocaine, amphetamine, toxic levels of penicillin, aminophylline, isoniazid, lowered seizure threshold-TCAs, phenothiazines, drug withdrawal-alcohol,benzodiazepines, barbiturates, anticonvulsants
Malignancy
Structural lesions
Cerebrovascular disease: common cause for seziures in elderly
Underlying malignancy: rare, slow growing intra-cranial tumours
Hippocampal sclerosis:
-scarring of the hippocampus in early childhood
-usually causes temporal lobe seizures
EEG
They are surface recordings of intracranial discharge
Whilst they will help you diagnose where a seizure is coming from this is not always the case
Some cases where seizure discharge is too deep to be picked up by scalp recording
Advantages of EEG: easily accessible, not invasive, painless, well tolerated
Helpful in those who have childhood generalised seizure syndrome especially those who have photosensitive seizure syndrome as you can use flashlight to stimulate brain and try to bring out epileptic discharge
Treatment epilepsy
Generally start AED after second seizure unless underlying structural/invasive cause
Anti epileptics: 2/3rds seizure free with single agent
-side effects (titrate slowly)
-female patients
—caution with valproate- teratogenicity
—contraception
Medication continued for at least 2 years following last seizure
Surgical options epilepsy
Surgery (adults)
-resection of lesion
-vagal nerve stimulation
-deep brain stimulation
Stimulation based procedures are palliative- aim to shorten impact of seizure and lessen severity
Iifestyle advice
Sleep hygiene
Alcohol and drug (cocaine, MDMA) minimisation
Managing stressors
Occupation
-armed forces, lorry driving restrictions
-avoid shift work (chefs, carers)
-avoid heights, open water swimming
Sports: swim with others boxing
Who can offer support to those with epilepsy
Epilepsy action
Specialist nurses
Liaison psychiatry
Driving guidelines
Car drivers
After a single seizure/blackout with seziure markers
-stop driving for minimum 6 months
After diagnosis of epilepsy/single episode with risk of recurrence
-stop driving for minimum 12 months
Up to patient to notify DVLA
Status epilepticus
Convulsive seizure persisting for >5 minutes without recovery
Medical emergency call 999
Secure airway give oxygen
Gain venous access (bloods, glucose)
Antiepileptic: lorazepam iv (2+2mg), levetiracetam/phenytoin/valproate iv infusion
Give glucose and pabrinex if uncertain about seziure aetiology
Transfer to ITU if not recovering
When it doesnt look like epilepsy
Red flags: non epileptic attacks
-multiple attacks types/ non stereotyped
-prolonged attacks
-bilateral jerking with preserved awareness
-emotional post attack
-attacks ‘situation dependent’
-rapid escalation, especially when investigations normal
What do you do if you suspect that its NEAD non epileptic attack disorder
Suggest that episode is ‘atypical for epilepsy’
Discuss role of stress if patient shows insight- ask about dissociative symptoms
Try and avoid prescribing medications
Don’t try and broach diagnosis of NEAD unless patient has discussed NEAD before/is blessed with insight
Refer to neurology especially if recurrent episodes/diagnostic doubt- epilepsy and NEAD commonly co-occur
Who is at risk epilepsy
Elderly
Immunocompromised- pregnancy, immunosuppressed
Drug users
First establish epilepsy
Witness account- behavioural change?
Acute on chronic?
Medication/drug history
Collateral history is key
Acute confusion on a background of dementia
Systemic illness causing delirium
Falls with associated head injury- subdural
Medication- metabolic imbalance
Seizure worsening (aggravated by non compliance)
-non convulsive status epilepticus
Functions of the hypothalamus
General:
-homeostasis and survival
-motivated behaviours
Integration of somatic and autonomic responses:
-cardiovascular system
-blood composition/volume
-food/water intake
-temperature control
-circadian rhythms
-reproductive behaviours
-emotional behaviour
ANS: endocrine systems, behaviour
Clinical considerations
Physical brain injury
-anatomical location-> rare
-bilaterally
Impact of lesions
-diverse symptoms
—nucleus specific
-progressive changes
-location
Inputs and outputs
Inputs: massive integration
-sensory inputs: internal environment, receptors within hypothalamus, viscera via brainstem. Homeostasis
-sensory inputs: olfactory/retina, limbic regions, hippocampus. External environment
Outputs:
-pituitary-> hormone
-brain stem -> ANS, coordination of behaviour
-limbic-> emotion, coordination of behaviour
Structure of the hypothalamus
Anterior-posterior axis
-anterior
—pre optic area:
-set points
-sleep
-reproductive behaviours
—suprachiasmatic nucleus
-posterior
-tuberal
Medial-lateral axis: 3 zones. Lateral, medial, peri-ventricular
-periventricular zone:
—SCN
—Arcuate nucleus (feeding)
—paraventricular nucleus
-medial zone:
—paraventricular: pituitary control, feeding, autonomic control
-lateral zone:
—lateral hypothalamic area
—supraoptic nuclei
-release hormones (post pituitary)
ANS control
Paraventricular nucleus
-brain stem nuclei-> origins of neurons that influence preganglionic SNS/PNS
Evidence:
-stimulation/lesions of hypothalamus
—increase/decrease BP and HR
Endocrine control
The hypothalamus is connected indirectly to the anterior pituitary
-PVN parvocellular cells
Directly to the posterior pituitary
-PVN and SO magnocellular cells
Behavioural control
“Motivated”
Wants/likes/needs-> reward
Complex and varied
Food intake- Role of hypothalamus
Glucose and brain. Constant demand but intermittent supply. Storage
Setpoint distribution-> starvation/obesity
Therefore intake regulation=complex. MS and neurodegenerative disease
Short term regulation
-receptors: glucose, ghrelin
-inputs: mechanoreceptors in gut, glucose receptors in hepatic system
Food intake- hypothalamic nuclei
Long term regulation: fat stores-> leptin-> hypothalamus
Arcuate nucleus: leptin
Paraventricular nucleus and others:
-lesions-> uncontrolled feeding
-controls ANS and signals to pituitary
Lateral hypothalamic area:
-lesions-> eating ceases -> starvation
Motivation to search for food:
-projections widespread
-cortex -> behaviour
NB- GLP 1 agonists
Food intake and weight
Feast -> increases leptin
-hypothalamus
—pituitary hormones
—decreases feeding behaviour
—ANS
ANS and pituitary hormones
->increase metabolic rate
The increase in metabolic rate and decreased feeding behaviour lead to normal body weight
Temperature control
Hypothalamic thermoreceptors
NB pyrexia- change to set point
Integrated response
Autonomic- vasomotor changes in skin
Endocrine- increase/decrease metabolism
Behavioural- shivering, panting, seek warmth/shade
Reproductive behaviour
ANS- sexual organs
Endocrine- puberty, reproductive cycling
Behavioural- courtship
Are biologically male and female brains different
-anatomical differences in males and females= sexual dimorphism nucleus
-sex hormone receptors in many nuclei
The basal ganglia and cerebellum
Cerebellum- closely involved with brainstem mechanisms
Basal ganglia- integration of sensory and motor information
Neither project directly beyond the brain
The cerebellum
Sensorimotor coordination
Control of muscle tone
Motor learning
Cerebellum 3 functional and anatomical components
Spino-cerebellum (medial region): sensory input from the spinal cord, output to the reticular formation and red nucleus. Motor cortex-> spinal cord control over axial musculature and posture
-carries unconscious proprioceptive info from peripheral receptors (muscle spindles, Golgi tendon organs, and joint capsules) through spinal cord and brainstem to cerebellum
Vestibulocerebellum (caudal region): input from and output to vestibular nucleus (ventromedial pathway). Control over posture/balance, also eye movement
Cerebro-ponto-cerebellum (lateral hemispheres): an Intracerebral motor loop cortex-> cerebellum->cortex M1
-instructs the primary motor cortex M1 regarding movement direction, timing and force
-compares intended movements with actual movements sends compensatory instructions to M1
Insights into function from damage to the cerebellum
Ataxia: unsteady staggering gait, spinocerebellem, cerebro-ponto-cerebellum, vestibulocerebellum
Dysmetria: inaccurate termination of movement, spinocerebellum, cerebro-ponto-cerebellum
Hypotonia: reduced muscle tone. Spinocerebellum
Slow saccades, nystagmus: impaired eye movement, vestibulocerebellum
Dysarthria: inarticulate speech due poor oropharyngeal muscular control. Cerebro-ponto-cerebellum
Circuitry of the cerebellar cortex
Final destination of afferent pathways to cerebellum are the purkinje cells (indirect) in the cerebellar cortex have characteristic elaborate apical dendrites; aligned as stacks
Granule cells describe no of cell types: have very small somas receive excitatory input from mossy fibres in pontine nuclei
Deep cerebellar nuclei DCN cells can compare input from mossy and climbing input (sensory feedback)
Before (via collaterals from axons to P cell-excitatory) and after cerebellar processing (via inhibitory P cell output)
-an error signal
Comparator/timer/regulator functions
Coordinated movements leading to meaningful behaviour require integration of sensory cues that inform animal of its environment and state of body, activating and coordinating a multitude of skeletal muscles then ensuring that all movements are timed correctly and take place as intended
Intended movement (afference copy) -cerebellar cortex
Actual movement (efferents copy sensory feedback)
-input to the cerebellum from brain stem carried by climbing fibres and mossy fibres
Comparison DCN
-compensatory output to brain stem and cortex via the thalamus
Summary cerebellar function
Regulates posture indirectly by adjusting output of major descending motor pathways
Acts as a comparator identifying and correcting discrepancies between intended movement actual movement
Acts as a timer sequencing motor activation resulting in smooth performance
Role in motor memory and in instigating learned motor sequences when appropriate
Not required for perception or muscle activation
The basal ganglia
Group of associated subcortical nuclei
‘Dark basements of the brain’
The basal ganglia system ensures that the correct movements are initiated and maintained while unwanted movements are suppressed
In contrast the cerebellum guarantees that movements take place in a smooth coordinated way
Cortico-basal ganglia cortical loop
Integrates motor and sensory information from the cortex
Relays back to the cortex via thalamus
Motor circuit output to premotor/SMA cortex
Selection and initiation of voluntary movement
The motor loop
basal ganglia- outflow-thalamus-SMA cortex-PFC—basal ganglia
GABA/inhibitory- Parkinson’s associates with increased activity in basal ganglia output nuclei
The basal ganglia structures generally included
Striatum STR:
-The caudate nucleus
-putamen
-nucleus accumbens
Subthalamic nucleus STN
Globus pallidus GP: external segment GPe, internal segment GPi
Substantia nigra: reticulata SNr, pars compacts SNc
The basal ganglia- basic circuit
Cortex- glutamate excitation from thalamus
Striatum -GABA inhibition
-GPe-> STN(excitatory)-> SNr/GPi inhibitory
-GPi
Inhibitory signal to thalamus
SNc (dopamine modulation) to striatum
Basal ganglia output inhibits excitatory drive to cortex
Internal organisation of the basal ganglia: direct and indirect pathways
From the striatum, cortical input is relayed to two major basal ganglia areas, SNr and GPi
‘Direct’ pathways: striatonigral and striatopallidal GPi
‘Indirect’ pathways: projections via GPe and STN
Opposing effects on thalamocortical output
Balance between the ‘direct’ and ‘indirect’ pathways
Dopamine derived from SNc plays a key modulatory role
Dopamine and the direct pathway
The direct pathway serves to promote movement
Dopamine acts on excitatory D1 receptors on striato GPi/SNr neurons -> decrease BG output
Facilitates movement
Dopamine and the indirect pathway
The indirect pathway serves to suppress movement
Dopamine acts on inhibitory D2 receptors on striato-GPe neurons
Decrease STN activity
Decrease basal ganglia output
Facilitates movement
The basal ganglia and motor dysfunction
Imbalance
Between the direct and indirect pathways -> motor dysfunction
Hypo kinetic disorders: eg Parkinson’s
Hyperkinetic disorders: eg huntingtons disease, hemiballism, tardive dyskinesia
Parkinson’s disease
“The shaking palsy”
Tremor (usually resting tremor)
Bradykinesia (slowness of movement)
Rigidity (resistance to passive movement)
Affects 0.1% of pop under 50 >50->1%
Progressive disorder-> dementia, depression, bladder disturbance
Average survival after manifestations ~15 years
Primary pathology: degenerative loss >80% of nigrostriatal dopaminergic pathway
Lewy bodies are the pathological hallmark of PD
Neurobiology of PD- treatment rationale
Dopamine loss-> excessive inhibition of thalamo-cortical pathway
Accompanied/driven by increased activity in STN
Treatments for PD
Many drugs to boost dopamine or dopaminergic transmission in brain
L-DOPA remains key (replacement strategy)
-dopamine agonists
-drugs that reduce dopamine breakdown or re-uptake
Deep brain stimulation
No treatments address the underlying degeneration
L-DOPA problems
Effectiveness diminishes over 2-5 years primarily due to the progressive nature of the disease
decreased DA-Ergic nerve terminals
Decreased capacity to convert L-DOPA to dopamine
Result increase L-DOPA frequency
Consequence: development of movement abnormalities (dyskinesia’s)
Huntingtons disease
First described by George Huntington 1872
Excessive “choreiform” movement
Uncontrollable relatively rapid motor patterns
Disrupts normal motor activity
Later stages-> psychiatric disturbance, dementia
Autosomal dominant disorder
Prevalence ca 1 in 15000
Peak age onset 40-45 year
Progressive deterioration over 10-25 years
Primary pathology (in early stages) is loss of striatal output neurons in indirect pathway
Huntingtons disease 2
Loss of striatal output neurons in indirect pathway
Suppression of STN
Decrease BG output
Overactive thalamocortical pathway
Involuntary movement
Drug treatments huntingtons disease
Symptomatic relief only
Tetrabenazine: VMAT inhibitor, decreased DA storage and release
Chlorpromazine: DA antagonist
Baclofen (intrathecal): GABA-B agonist, decrease spinal reflexes
Other hyperkinetic disorders of BG origin
Hemiballismus:
-cause: damage to STN (usually due to stroke, unilateral)
-effect: violent flailing movements of limbs (contralateral)
Tardive dyskinesia:
-cause: increase DA receptor sensitivity due to long term exposure to antipsychotic drugs (dopamine receptor antagonists)
Effect: uncontrolled movement, especially of facial and trunk muscles (extrapyramidal effects)
NB. Dopamine therapy in PD can also-> acute dyskinesia
Substance dependence
Drug abuse- social disapproval, culture
Not misuse :
-wrong indication
-wrong dose
-too long
Dependence
Physical:
-anxiety/insomnia
-N&V
-cramps
-tachycardia
-piloerection
-diarrhoea
Psychological:
-compulsive behaviour
-anxiety
Origins of dependence
Drug variable : degree of reward
User variable: absorption/metabolism. Genetics
Environmental variable: peer pressure
Tolerance
Innate: genetics
Acquired: metabolic, behavioural, pharmacodynamic
Opiates
Heroin, morphine
-pethidine- purely synthetic
IV/smoke:
-rush
-injectable infections
-street ‘pharmacy’
-rapid tolerance- not all effects
Highly rewarding
Reward
GABA inhibit inhibitory effect on dopamine neurone
Mu receptor located on gabaergic interneurons in ventral tegmental area
Opiate receptors inhibit AC so reduce cAMP which excites neurones . DA increases
Reductions inhibit neurone
So if opiate receptors were on dopamine neurones they’d have opposite effect
Opiate overdose
Treatment: naloxone
-structurally similar to morphine agonist to antagonist at opiate receptors
-t1/2 short <1 hour. Most opiates have longer 1/2 life so naloxone would need to given repeatedly
Opiate dependence
Treatment difficult success rate low
-methadone: opiate absorbed more rapidly orally, long half life so then if took heroin would have less effect so less motivation to take. Long half life means withdrawal symptoms would be better. Dose slowly reduced
-psychotherapy
Stimulants caffeine
-caffeine
—social drugs
-withdrawal syndrome
—lethargy
—irritability
—w/e headache
— phosphodiesterase inhibitor so increases cAMP which increases neuronal activity- stimulant
—adenosine receptor antagonist
Stimulants cocaine
Coca leaves
Crack: free base (low melting point), smoked
Inhibits Catecholamine uptake: blocks uptake of dopamine increasing synaptic levels dopamine
-rewarding
-tissue necrosis by blocking uptake catecholamines vasoconstriction of vasculature in nose->reduces blood supply-. Ischaemia-> necrosis
Withdrawal eased with TCA tricyclic antidepressants
Stimulants amphetamine
Catecholamine releaser
Rewarding
Overdose treated with neuroleptics
Ketamine
Methylene-dioxymethamphetamine
MDMA
5-HT releaser (serotonin)
Euphoric effect
Lesions in brain
Cannabis
Cannabis sativa
Three major cannabinoids
Eg tetrahydrocannabinol
All lipid soluble
Cannabinoid receptor
Low doses:
-euphoria
-uncontrollable laughter
-‘sharpened’ sensory awareness
High doses:
-dream-like state
-Ptosis
Cannabis tobacco more carcinogenic
Few users seek treatment
Sedatives
Alcohol
Benzodiazepines
-commonly prescribed
—anxiety, insomnia
—opiate withdrawal
