Neuro 5 - dementia and coma Flashcards
Types of mood disorder
Depression - monopolar
Mania - monopolar
Manic depression - bipolar - treated well with mood stablisers
Depression
Emotional symptoms - mood + thought disorder
Biological symptoms - anhedonia, motivational impairment
Cognitive symptoms - difficulty decision making, poor concentration
Psychotic symptoms
- treatment focuses mainly on improving mood and motivational impairments
Mania + bipolar disorder
- need less sleep
- excessive exuberance, enthusiasm, confidence, grandiosity
- increased libido
- behaviours inappropriate to circumstances
- disorders of thought (psychosis)
May need different drugs for both manic and depressive episodes (and psychosis)
Also preventative medication, mood stabilisers (lithium, anti-epileptic drugs, atypical antipsychotics)
Causes of depression
CHEMICAL IMBALANCE - monoamine theory, well supported BUT delayed onset action antidepressants?
- functional deficit in 5-HT (serotonin) and/or noradrenaline/dopamine
NEURODEGENERATION
- neural apoptosis and neurogenesis
IMMUNE RESPONSE
- sickness behaviour
GENES
ENVIRONMENT (stress)
Treatments for depression
Pharmacological
- enhance monoamine levels in CNS - monoamine reuptake inhibitors/monoamine oxidase inhibitors/pre-synaptic receptor antagonists
- specific receptor agonists or antagonists
(consider side effects! if therapy possible, do that)
Cognitive behavioural therapy (mild-moderate depression)
Neurological interventions (30% unresponsive to drugs)
- electroconvulsive shock therapy
- deep brain stimulation
- vagal nerve stimulation
Typical antidepressants
(TCAs and specific reuptake inhibitors)
- monoamine oxidase inhibitors (MAOI)
- tricyclic antidepressants
- SSRIs (selective serotonin reuptake inhibitors)
- selective noradrenaline reuptake inhibitors
Monoamine oxidase inhibitors
MAOIs
eg IPRONIAZID, PHENELZINE, TRANYLCYPROMINE, MOCLOBEMIDE
- inhibits breakdown of monoamines (MAO found in all tissues inc GI tract)
Multiple side effects - ‘cheese reaction’, need low tyramine
Tricyclic antidepressants
eg AMITRIPTYLINE, DESIPRAMINE, CLOMIPRAMINE
- block reuptake of monoamines (mainly NA and 5-HT)
- many have active metabolites, issues
- multiple side effects
- cardiotoxicity, low therapeutic index!
Used less in depression now, often for pain management
Selective reuptake inhibitors
SSRIs - FLUOXETINE (= prozac)
+ SNRIs - REBOXETINE
- block reuptake of 5-HT/NA
- similar efficacy and time-course to TCAs
- lack cholinergic side effects - less weight gain, low toxicity in overdose, no food interaction, reduced drug interactions
BUT - still many side effects , specific to serotonin or noradrenaline related effects
Discontinuation syndrome esp in paroxetine, need to be weaned off gradually 6-8 weeks
Atypical antidepressants
Mixed action
VENLAFAXINE - SSRI at low doses, SNRI at higher
TRAZEDONE - SSRI + 5-HT2 antagonist
NEFAZODONE - SSRI + 5-HT2 antagonist
MIRTAZAPINE - NA and 5-HT antagonist
AGOMELATINE - melatonin agonist and 5-HT2 antagonist
Delayed onset of clinical efficacy of antidepressants
Increased synaptic monoamine concentration
- > activation of somatodendritic autoreceptors - hippocampal neurogenesis
- > receptor adaptation (plasticity) -> increased synaptic concentration - cognitive effects
- > activation of pre-synaptic autoreceptors -> decreased neurotransmitter release - post-synaptic receptor adaptation
DON’T KNOW WHY, these are theories
Alternative applications for antidepressants
SSRIs
- all anxiety disorders - OCD, panic disorder, social phobia, anxiety disorders (esp depression associated), eating disorders
TCAs
- analgesia, migraine prophylaxis
Mood stabilising drugs
Lithium
- mechanism unsure
- effective in controlling mania
- potential toxicity, carefully monitor
+ anticonvulsants - valproic acid, carbamezapine
Dementia definition
- structurally caused
- permanent or progressive
- decline in several dimensions of intellectual function
- interferes substantially with normal social or economical activity
May be static (often following single major injury) or progressive
Causes of dementia
Degenerative - Alzheimer’s, Parkinson’s, Huntingdon’s, MS, MND, Lewy body dementia etc
Vascular - multi-infarct dementia etc
Metabolic/endocrine - hypothyroidism, B12 deficiency
Infective - AIDS-dementia complex, Creutzfeld-Jacob disease etc
Post-neurological insult - open/closed head injury, anoxia, subarachnoid haemorrhage, CO poisoning
Toxic - alcohol, heavy metal, organic solvents
Space occupying lesion - chronic subdural haemorrhage, primary/secondary metastatic intracranial tumour
Other - normal pressure hydrocephalus, epilepsy, systemic lupus etc
Cortical vs subcortical dementia
SUBCORTICAL
- mild-moderate severity
- slow cognition
- memory impairment
- apathy, depression
- extrapyramidal motor abnormalities
- changes to striatum and thalamus
CORTICAL
- more severe sooner
- normal speed of cognition, but with frequent errors
- more severe memory impairment, dysphasia, dyspraxia, agnosia
- depression rarer
- uncommon motor abnormalities
- changes to cortical association areas
Features of Alzheimer’s disease
Neurodegeneration -> loss of cognitive function
4th leading cause of death in elderly, 30% of over 80year olds have
Post mortem shows
- general brain atrophy - shrinkage of cortex, narrowed gyri, widened sulcal margins
- extracellular plaques of β-amyloid (knotted shape)
- intracellular neurofibrillary tangles of tau protein as hyperphosphorylated by overactive kinases (teardrop shape)
(can only be diagnosed definitively on autopsy)
Symptoms of Alzheimer’s disease
MILD
- confusion, memory loss
- disorientation
- problems with routine tasks
- changes in personality and judgement
MODERATE
- difficulty with ADL
- anxiety, depression, paranoia, aggression, agitation, hallucinations
- sleep disturbances
- wandering, pacing
- difficulty recognising family and friends
SEVERE
- aphasia (understanding language)
- apraxia (carrying out tasks)
- agnosia (recognising things)
- loss of speech
- loss of appetite
- loss of bladder and bowel control
- > total dependence on caregiver
Amyloid-β plaques
In Alzheimer’s disease
- amyloid precursor protein (APP) is cleaved by proteases, secretase alpha, beta and gamma
- secretase alpha -> sAPP (secreted, good for cell, harmless growth factor)
- secretase beta and gamma together -> Aβ protein, takes essential intracelullar part of APP
- so altered balance between these enzymes -> amyloiogenesis
Aβ then aggregates, body can’t clear, forms amyloid plaques -> neuronal death
Risk factors for Alzheimer’s disease
Age - risk doubles each 10 years after 65
Family history - genes with mutations in APP?
+ possibles:
- early traumatic head injury
- female
- lower educational level
- high calorie/fat/cholesterol diet, low exercise
Creutzfeld-Jacob disease
CJD
- fatal, rapidly progressive dementia, loss of motor coordination
- survival 6 months average
- no clear gross pathological features
- can be nvCJD, from contact with BSE infected beef, then long incubation period, forms abnormal form of prion protein, converts other proteins around it to this, aggregates
- or spontaneous conformational change
Currently licensed drug therapy for Alzheimer’s
Cholinesterase inhibitors - increase ACh levels (cholinergic cells die early, attempt to compensate)
eg DONEPEZIL, GALANTAMINE, RIVASTIGMINE
Partial NMDA receptor antagonists - neuroprotective, reduce excitability
eg MEMANTINE
(no new licensed drug for 15 years)
Potential targets for treatment of Alzheimer’s
MODIFY Aβ PATHWAY
- alpha/beta/gamma secretase inhibitors? to reduce Aβ formation
- anti-aggregation agents? uses copper + zinc (highly charged) to pull other proteins in - effective but no cognitive effect
- statins? link between high cholesterol and APP changes
- enhance Aβ clearance? with immune therapy
MODIFY TAU PATHWAY (some dementias have only tau changes)
- lithium?
- microtubule modifiers?
- tau aggregation inhibitors?
Deontology
Do your duty
- do not kill/lie/break confidences etc
(may create a corresponding right - right for patient to have doctor fulfil duty)
Consequentialism
Do that which has the best outcomes
- greatest good for the greatest number
= utilitarianism
Virtue ethics
Be virtuous
- person based, what would a virtuous person do?
Four ethical principles
Respect for autonomy - consent, self-rule
Beneficence - provide benefit
Non-maleficence - do no harm
Justice - share resources fairly
(Beauchamp and Childress)
Coma
Absent wakefulness, absent awareness
- lasts more than 6 hours
- cannot be awakened
- fails to respond normally to painful stimuli, light, sound
- lacks normal sleep-wake cycle
- does not initiate voluntary actions
Vegetative state
Wakefulness, absent awareness
- preserved capacity for spontaneous or stimulus-induced arousal
- sleep-wake cycles present
- reflexive and spontaneous behaviours
- complete absence of behavioural evidence for self or environmental awareness
Continuing = 4 weeks + Permanent = 6/12 months +
= post-coma unresponsiveness?
= unresponsive wakefulness syndrome?
Better terminology
Advanced directives
Must not treat if competent adult refuses
- or is assault/battery/trespass to patient
NEEDS - competence and - current refusal or - advance refusal (currently no capacity, but previous specific, written, witnessed refusal of life-support)
May not treat even if competent adult demands - right to refuse but not insist on treatment
Minimally conscious state
Wakefulness, minimal awareness
- severely altered consciousness
- minimal (but clearly discernible) behavioural evidence of self or environmental awareness demonstrated
- inconsistent but reproducible responses above the level of spontaneous or reflexive behaviour
- some degree of interaction with surroundings
Locked-in syndrome
Wakefulness, awareness (paralysed but conscious)
- loss of all brainstem functions
- absence of brainstem reflexes - pupillary, corneal, oculovestibular, cough
- no spontaneous respiratory effort
- will cease to maintain physiological function without ventilator support
(may be kept on life-support to allow best interests decision-making (and organ donation))
Human tissue act 2004
- appropriate consent needed
- for storage and use
- of whole bodies, removal, storage and use of human material (organs, tissues, cells)
- from deceased and living persons
Consent given from
- person (before death), eg organ donation, donate body to science
- nominated representative, chosen by person before death
- someone in qualifying relationship - spouse, parent/child, sibling, grandparent ect down list
(though need general consensus)
Act doesn’t include hair, nails (cells outside body), non-identifiable DNA analysis, storage and use for research, existing collections
Delirium vs dementia
DELIRIUM
- abrupt onset
- fluctuating course
- lasts hours-weeks
- abnormal alertness (high or low)
- disrupted sleep-wake cycle
- impaired attention
- delusional thought
- incoherent speech
- hallucinations and illusions
DEMENTIA
- insidious onset
- slow-progression
- lasts months-years
- normal alertness
- normal sleep-wake cycle
- relatively normal attention
- impoverished thought
- word-finding difficulty in speech
- intact perception early on
Neuropathology principles in dementia
Distribution of abnormalities -> clinical manifestations
Dementias caused by abnormal accumulation of particular proteins/peptides
Distribution of pathophysiological abnormalities generally correlates with distribution of histopathological abnormalities
Same pathophysiological abnormalities can -> different clinical manifestations
Different pathophysiological abnormalities -> same clinical manifestations
Different types of dementia often co-exist
Distribution of abnormalities in dementia
Temporoparietal -> memory impairment, dysphasia, dyspraxia
Frontotemporal -> behavioural disturbances, personality change, language dysfunction
Subcortical -> slowing of thought processes, motor disturbances
Abnormal accumulation of particular proteins/peptides in dementia
Alzheimer’s - Aβ plaques and hyperphosphorylated tau
Frontotemporal dementia - FTLD-Tau - 3R, 4R or 3R + 4R
Parkinson’s disease, Lewy body dementia - Lewy bodies, diffuse plaques
(exception is vascular dementia - no accumulation of peptides, mainly in white matter, microinfarcts)
- atheroma and small vessel disease cause
Reticular formation
Set of interconnected nuclei located throughout brainstem
Includes grey matter immediately below 4th ventricle and around cerebral aqueduct (= periaqueductal grey), and monoamine cell groups
+ non specific nuclei of thalamus, sometimes also hypothalamus considered
Extends caudally into spinal cord
Local projections in reticular formation
Local-circuit interneurones
Functions - reflexive and stereotyped behaviours involving face and head:
> chewing, swallowing, vomiting
> respiratory activities - cough, sneeze, hiccups
> cardiovascular responses
Reticular formation ascending information to cortex
(reticular activating system)
Functions:
- sleep-wake cycle
- mediates various levels of alertness and consciousness
- wakefulness (in mid-line group of thalamus)
- filters incoming stimuli to discriminate irrelevant background stimuli
Reticular formation descending information from spinal cord
Info from:
- posture, equilibrium, autonomic nervous system activity
- sensory (pain) and motor modulation
Also receives information from hypothalamus
Overall functions of reticular formation
SENSORY AND MOTOR FUNCTIONS
- gating + modulating info transfer
- organising, co-ordinating reflexes
AUTONOMIC AND VITAL FUNCTIONS
- regulates autonomic nervous system
- cardiovascular regulation
- control of respiration
ENERGISING/REGULATING FUNCTIONS
- attention
- alertness and sleep
- motivation
- general excitability in CNS (not specific targets, connections to whole cortex)
Neurotransmitter pathways and functions in reticular formation
NORADRENALINE
From lateral tegmental system - to basal ganglia
- autonomic, endocrine, appetite functions
From locus ceruleus system - links all over cortex and cerebellum, so can synchronise brain regions
- alertness, attention
5-HT, SEROTONIN
From Raphe nucleus - to cerebellum and all over cerebral cortex
- sleep, mood/motivation, autonomic NS, pain transmission
ADRENALINE
To hypothalamus
- cardiovascular function
DOPAMINE
From substantia nigra to basal ganglia, and from ventral tegmental area to limbic areas and cortex
- drive/motivation, pleasure
(affected in schizophrenia, addiction)
ACETYLCHOLINE
From basal forebrain nucleus and septal nuclei to all cortex, and from septal nuclei to hippocampus
- alertness/sleep, memory and learning
Cardiovascular control in reticular formation
(in medullary and lower pontine RF)
INPUTS
- baro-/chemoreceptors of aortic arch (via vagus) and carotid sinus (via glossopharyngeal)
- autonomic activity from spinal cord
- autonomic reflex afferents from vagus
- blood and CSF composition from area postrema
OUTPUTS
- dorsal motor nucleus of vagus
- sympathetic outflow in intermediolateral column in cord
Ventilatory control in reticular formation
MEDULLA
- ventral respiratory group - voluntary forced exhalation, and to increase force inspiration
- dorsal respiratory group - most inspiratory movements and timing
PONS
- pneumotaxic centre - coordinates inhale-exhale transition, inhibits inhalation, fine tunes respiration rate
- apneustic centre - coordinates inhale-exhale transition, stimulates inhalation (overridden by pneumotaxic control to end inspiration)
Brainstem lesions and effects on respiratory system
i) Diffuse forebrain depression -> waxing/waning respiration pattern, periods of apnea, Cheyne-Stokes respiration
ii) Midbrain damage -> hyperventilation
iii) Rostral pons damage -> apneusis, briefly halts breathing at full inspiration
iv) Lower pons or upper medulla damage -> irregular/uneven depth respiration, ataxic breathing
Often -> respiratory arrest
Glasgow coma scale
= GCS, coma is score less than 8
Eye opening (E) 4 = spontaneous 3 = to voice 2 = to pain 1 = absent
Vocal response (V) 5 = normal conversation 4 = disoriented 3 = incoherent words 2 = incomprehensible sounds 1 = absent
Motor response (M) 6 = normal 5 = localised response to pain 4 = withdrawal from pain 3 = rigidity with limb flexion 2 = rigidity with limb extension 1 = absent
Sleep
Light - easily awakened
Deep - needs strong sensory stimulus for arousal
REM - 5-30min periods every 90 mins, deep sleep, cerebral cortex very active, dreaming, muscular relaxation
- > decreased plasma volume
- > decreased HR
- > decreased bp
- > decreased rate and force of respiration
- > decreased salivary and lacrimal secretion
- > decreased formation of urine
- > increased sweat secretion
- > decreased muscle tone and reflexes (except ocular muscles)
EEG
= electroencephalogram
- shows changes in level of consciousness, activity in cerebral cortex
Fully alert - low voltage, high frequency Deep sleep - taller, longer waves REM sleep - desynchronised Comatose - reduced voltage and frequency Cerebral cortex death - flat EEG
Types of sleep disorder
Insomnia - difficulty falling/staying asleep
Hypersomnia - excessively sleepy
Narcolepsy/cataplexy - excessively sleepy, daytime sleep attacks
Sleep apnea - pauses or low frequency breathing during sleep
Night terror - extreme terror, temporary inability to regain full consciousness
Somnambulism - sleep walking
Nocturnal enuresis - bed wetting
Movement disorders
