Neurology Flashcards
What is an axonal neuropathy?
Primary target: axons
Portions of axon distal to site of injury degenerate (Wallerian
degeneration)
Regeneration starts at site of injury and progresses at 1mm per day
Requires intact Schwann cells to guide direction of growth otherwise a traumatic neuroma develops
What is a demyelinating neuropathy?
Primary target: schwann cells
Individual myelin sheaths degenerate, often in a random pattern
New Schwann cells tend to be less functional: slower nerve conduction
What are the different anatomic patterns of neuropathies?
Mononeuropathy: Single nerve affected
Polyneuropathy: Multiple nerves, usually asymmetrical fashion (often ascending)
Mononeuritis multiplex: haphazard distribution of nerves e.g.vasculitis
Polyradiculopathies: nerve root and peripheral nerve damage, diffuse symmetrical symptoms
What is Guillain barre syndrome?
Immune mediated demyelination, usually following infection e.g. Campylobacter jejuni
Rapidly ascending paralysis
Which systemic autoimmune diseases can result in neuropathies?
Rheumatoid Arthritis
SLE
Sjogren syndrome
Name some inflammatory causes of peripheral neuropathy
Guillain-barre
Neuropathy associated with systemic autoimmune disease
Neuropathy associated with vasculitis
What are some infectious causes of neuropathy?
Leprosy
HIV
Lyme Disease
What is leprosy?
Schwann cells become infected with Mycobacterium leprae
Segmental demyelination results
What is Lyme disease?
Bacteria of Borrelia type
Most common sign of expanding area of redness, erythema migrans, begins at site of a tick bite about a week after it has occurred
What are metabolic, hormonal and nutritional causes of peripheral neuropathy?
Diabetes Mellitus: distal symmetrical polyneuropathy, Caused by metabolic and secondary vascular changes
Uraemic neuropathy: distal symmetrical polyneuropathy
Thyroid dysfunction: mononeuropathies, Carpal Tunnel Syndrome
How can malignancy lead to a peripheral neuropathy?
Direct infiltration or compression by neoplasm
Complication of therapy e.g. radiotherapy
Paraneoplastic: Often preceding diagnosis of tumour, Commonly sensorimotor, Secretion of antibodies by tumour
List some types of causes of peripheral neuropathies
Inflammatory Infectious Metabolic, hormonal, nutritious Toxic Malignancy Trauma Inherited
What can cause diseases of the neuromuscular junction?
Antibody mediated
Congenital
Toxin induced e.g. botulism
How do diseases of the neuromuscular junction present?
Painless weakness
Name antibody mediated causes of neuromuscular disorders
Myasthenia Gravis and Lambert Eaton (presynaptic calcium channel blocked)
What is myasthenia gravis?
Autoantibodies directed against AchR on post synaptic membrane
Commonly associated with thymic abnormalities e.g. thymoma
Usual presentation is with ocular problems: Ptosis and Diplopia
Decrementally decreasing skeletal muscle response with repeated stimulation
What can causes skeletal muscle atrophy?
Loss of innervation Disuse Cachexia Old age Primary myopathies
What are the two types of peripheral nerve injury?
Axonal Neuropathy
Demyelinating Neuropathy
What different patterns of atrophy can occur?
Clusters atrophic fibres: neurogenic disease
Perifascicular atrophy: Dermatomyositis
Sparing Type 1 fibres and loss Type 2: Steroid therapy
What does myopathic mean?
Damage to muscle fibres directly
What does neurogenic muscle damage mean?
Disruption of innervation causing secondary changes in skeletal muscle
What investigations might you do to look at myopathies or muscle weaknesses?
Assess for underlying cause: Glucose, FBC for inflammation
Look for evidence of muscle damage: CK, ALT
Look for pattern of change on neurophysiology
Biopsy muscle to see what is happening
What are the three main types of inflammatory myopathies?
Polymyositis
Dermatomyositis
Inclusion body myositis
What is Polymyositis?
Adult onset inflammatory myopathy
PC: myalgia and weakness
Immune mediated: CD8+ T cell
Endomysial mononuclear cell infiltrate
What is Dermatomyositis?
Juvenile or adult onset
Immune mediated damage to small blood vessels: muscle weakness (starts proximal), Skin changes: Heliotrope rash (lilac discolouration), Gottron papules (dusky red patches over knuckles), GI Involvement (Dysphagia), Interstitial lung disease
Perifascicular infiltrates of mononuclear cells
What can cause toxic myopathies?
Prescription medication e.g. Statins
Recreational drugs
Hormonal imbalances e.g. ICU myopathy, thyrotoxic myopathy, hypothyroidism
What are the classes of inherited diseases of skeletal muscle?
Congenital: present in infancy with static or improving changes e.g. Congenital fibre disproportion
Muscular dystrophies: Progressive muscular damage, Defects in ECM around myofobres, Defects in receptors for ECM
What are muscular dystrophies?
Inherited muscle disease, with progressive damage to muscles
Usually manifest before adulthood
What are the different types of muscular dystrophy?
Duchenne and Becker Muscular Dystrophy
Myotonic Dystrophy
Limb-Girdle muscular dystrophies
Fascioscapulohumeral dystrophy
What is Duchenne muscular dystrophy?
Presents before five years
Lack dystrophin
Clinical features: clumsiness, muscle weakness, pseudo- hypertrophy of the calfs (fatty replacement of muscle)
Mortality by 18 is usual
What is Becker muscular dysrophy?
Presents around 11 years
Reduced dystrophin or protein in abbreviated form
Slower progress that DMD
More prevalent
How can diseases of lipid or glycogen metabolism cause muscular dystrophy?
Rhabdomyolisis on excercising or fasting
Slowly progressive muscle loss
• E.g. Acid Maltase deficiency
What are ion channel myopathies?
Mutations in ion channel proteins
AD conditions
Depending on channel affected: Hypertonia or hypotonia
Hypotonia further subclassified on biochemical basis e.g. hyperkalaemia, hypokalaemia
What is a stroke?
Rapidly developing focal neurologic deficit lasting longer than 24h or causing death, which is attributable to a vascular cause
What is lacunar syndrome?
Motor/sensory involvement of >2 - arm, face, leg, ataxic hemiparesis caused by small vessel occlusion
Subcortical or brainstem infarct
What are the immediate management for ischaemic stroke?
Thrombolytic therapy - alteplase
Mechanical thrombectomy
What are early management steps for ischaemic stroke?
Aspirin
Anticoagulants
What long term prevention can be put into place for ischaemic stroke?
Antiplatelet therapy: Dipyridamole, Clopidogrel, Aspirin
Anticoagulant therapy: Warfarin, Newer (Dabigatran, Apixaban, Rivaroxaban, Edoxaban)
Revascularisation: Carotid endoarterectomy, Angioplasty / Stents
Anti-hypertensives
Statins
What is management strategy for a haemorrhagic stroke?
Surgery
How long from an initial stroke do we have to thrombolyse?
4.5 hours
What findings may suggest haemorrhagic stroke and therefore give reason to avoid thrombolysis?
Seizure at onset of stroke
Symptoms suggestive of subarachnoid haemorrhage
Stroke or serious head injury in last 3 months
Major surgery or serious trauma within 2weeks
Previous intracranial haemorrhage
Intracranial neoplasm, AV malformation or aneurysm
GI or urinary tract haemorrhage within 3 months
LP in preceding week
INR>1.7
What is dementia?
Loss of previously acquired intellectual functions in absence of impairment of arousal
What are typical features of dementia?
Memory loss
Visio-spatial functional deficits
Language deficits
Problems with attention and concentration
How does the ICD10 define dementia for the purposes of diagnosis?
For diagnosis, must have evidence of the following:
Decline in memory: learning new information, severe cases recall of previously learned information. Grade mild to severe, present for 6 months
Decline in other cognitive abilities: deterioration in judgement, thinking, planning, organising and processing of information
Decline in emotional control or motivation, change in social behaviour, eg emotional lability; irritability; apathy; coarsening of social behaviour
How does ICD10 classify types of dementia?
Dementia in Alzheimer’s disease
Vascular dementia e.g. multi-infarct, acute onset
Dementia in other diseases classified elsewhere e.g. CJD, Pick’s disease
Unspecified dementia
What tests would be done in a patient presenting with dementia type symptoms to rule out treatable causes?
CT or MRI head
Blood tests: FBC, ESR, U+E, Glucose, Bone profile, LFT, thyroid function tests, B12, Venereal disease research lab test, ANA, ds DNA
Variably: CXR and EEG
Rarely: LP, HIV serology and brain biopsy
What are the most common causes of dementia?
Alzheimer’s
Vascular dementia
Fronto-temporal lobe dementia
Dementia with Lewy bodies
What factors of a presentation might make you think of more unusual cause for dementia type symptoms?
Patient is young
Short history
Atypical signs and symptoms
What are differences between cortical and sub cortical dementia?
Cortical: amnesia, aphasia, apraxia, impaired perception
Sub cortical: slowed alertness, impaired attention and executive function, forgetfulness, reduced language output, impaired perception, apathetic
Give examples of cortical and sub cortical dementias
Cortical: Frontal or temporal, CJD, Alzheimer’s
Sub cortical: Normal pressure hydrocephalus, Parkinson’s, Huntington’s
Both: Multi-infarct, Dementia with Lewy Bodies
What different clinical courses of dementia are there? And which diagnoses might this point towards?
Acute: infection and paraneoplastic
Subacute: Nutritional, inflammatory and CJD
Chronic Gradual: Alzheimer’s
Chronic Stepwise deterioration: vascular dementia
How long does it usually take Alzheimers to progress from mild to end stage?
5-10 years
What can causes protein aggregation in dementia?
Mutations affecting protein conformation
Mutation affecting processing pathway
Imbalance between production and clearance
How does protein aggregation lead to dementia?
Leads to cell stress
Can be directly toxic to neurones
Aggregates derived from one cell can be taken up by another cell and cause further aggregate production
Can be recognised as intracellular inclusions or extracellular deposits
Which protein aggregates are found in Alzheimers brains?
Amyloid beta: extracellular, forms plaques
Tau: intracellular, forms tangles
How is amyloid beta formed?
Beta and gamma secretase cleaves the amyloid precursor protein to form amyloid beta monomers
These oligomerise and aggregate to form fibrils which go on to form plaques
What is amyloid precursor protein?
Cell surface protein with a single transmembrane domain
Functions as a receptor
What is the non amyloidogenic processing pathway of amyloid precursor protein?
α-secretase cleavage initially
Occurs at cell surface as proteases for α-secretase are involved in shedding surface proteins
Cleaves in the middle of the amyloid beta segment and so precludes its formation
What genetic links are there to Alzheimers disease?
APP gene lies on chromosome 21, increased risk amyloidogenesis: Dose related: Trisomy 21, downs Point mutations in APP: cleavage sites or vary propensity to aggregate Apolipoprotein E (ApoE): ε4 allele dosage increases the risk of AD and causes earlier onset, ε4 allele promotes Aβ formation and deposition
What role does inflammation play in development of Alzheimer’s disease?
Aggregates of protein can elicit an inflammatory response from microglia and astrocytes, unclear as to degree on negative impact
What macro pathology occurs in an Alzheimers brain?
Cortical atrophy especially in frontal, temporal and parietal
areas
Hydrocephalus ex vacuo: volume of csf increases to compensate for brain atrophy
What micro pathology is present in Alzheimer’s disease brains?
Extracellular plaques: Neuritic processes around amyloid core or Diffuse plaques without neuritic response
Intracellular neurofibrillary tangles: Paired helical proteins that
displace or surround the nucleus of the neurone
Associated neuronal loss and glial reaction
What is frontotemporal lobe dementia?
Focal degeneration of frontal and/or temporal lobes
Alterations in personality behaviour and language precede memory loss
Some patients also develop extra-pyramidal motor loss
Commonly develops in sixth decade but can appear earlier and be misdiagnosed as psychosis
What cellular inclusions are often found in frontotemporal dementia?
FLTD-tau: Affected cortical regions show progressive neuronal loss and reactive gliosis
FTLD-TDP (contains TDP43)
Pick bodies: neuronal inclusions
Pick Cells: Ballooned cells
What genetic links are there with frontotemporal dementia?
Familial dementia in about 30% of cases
Some people have mutations affecting tau (phosphoprotein that interacts with microtubules)
Mutations: Missense: leads to aggregation rather than microtubule binding, Point: leads to increased aggregation
What is dementia with Lewy bodies? And what cellular inclusions are present?
Linked to AD and Parkinson’s, typically dementia develops with advancing age
Features: fluctuating course, hallucinations and prominent frontal signs
Dopamine and Acetylcholine neurones lost
Inclusions: α-synuclein, Role in disease, does not show dose relationship
What are risk factors for vascular dementia?
As for atheroma
Hypercoagulability
Thrombi and emboli
What is confusion?
Inability to think clearly and/or rapidly, characterised by:
Difficulty understanding a situation
Disordered or unclear thoughts
Associated with memory loss and/or disorientation
What can aggravate a confusional state?
Environmental or diurnal changes, e.g. ‘sundowning’
What are common causes of confusion?
Infections Head injury Stroke Brain or spinal cord tumour Delirium Dementia Alcohol or drug intoxication Sleep disorders Chemical or electrolyte imbalances Vitamin deficiencies Medication (e.g. TCAs, ADs) Seizure Hypothermia
What higher control functions are performed by the pre frontal cortex?
Restraint behaviours: Concentration, Judgement, Foresight, Focus
Initiating behaviours: Motivation/Drive, Spontaneity, Personality, Curiosity
Ordering behaviour:Planning/SequencingWorking memory, Abstract thought, Perspective
Which structures make up the limbic system?
Hippocampus Amygdala Nucleus accumbens Cingulate gyrus Mammilary body Thalamic and hypothalamic nuclei Entorhinal and perirhinal cortices
What are the functions of the limbic system?
Memory
Learning
Perception (sensory, emotional and spatial)
Motivation
What area of the brain sets emotional thresholds?
Insula
What are the 3 main attentional circuits?
Default mode network (non-specific, self-reference): Medial temporal cortex, Medial prefrontal cortex, Posterior cingulate gyrus
Dorsal attentional network (orienting and processing): Dorsolateral prefrontal cortex, Posterior parietal cortex, Corpus striatum
Ventral attentional network (engagement and activation): Basolateral amygdala, Lateral and inferior frontal cortex, Temporoparietal cortex, Ventral striatum
Which part of the limbic system is associated with reward?
Nucleus accumbens
Has dopaminergic projections from the ventral tegmental area
Which area of the limbic system is associated with fear and negative emotion?
Amygdala
What links the Amygdala to the pre frontal cortex? What happens if this gets cut?
Uncinate fasciculus
Animalistic behaviour, kluver bucy syndrome
What circuits are involved in psychosis?
Dopaminergic Prefrontal cortex – dorsolateral and ventrolateral Anterior cingulate gyrus Basal ganglia – striatum Hippocampus Cerebellum
What pathways are implicated in confusion?
Cholinergic: Nucleus basilis of Meynert (to cortical regions and striatum)
Brainstem pontine nuclei (involved in control of arousal)
What are some common hallucinations?
Hearing voices – auditory hallucination
Hearing sounds – auditory hallucination
Feeling bodily sensations – tactile/somatic/gustatory hallucination
Seeing patterns – visual hallucination
Smelling a foul or pleasant odour – olfactory hallucination
In what circumstances can hallucinations be normal?
Part of the grief process
Hypnagogic (falling asleep) and hypnopompic (waking)
Name some common causes of hallucinations
Delirium
Dementia
Psychiatric disorders, e.g. Schizophrenia and psychosis
Drugs, alcohol or medications
Epilepsy – focal seizures
Narcolepsy
Visual impairment – Charles Bonnet syndrome
What cerebral activity is thought to lead to hallucinations?
Spontaneous activation of sensory centres
Activity in fMRI shows activity as if the hallucination is real
Hallucinatory activity overrides actual sensory input
Temporary disconnect between cortical and thalamic regions
Which two transmitters are involved in the sleep wake cycle?
Histamine
Acetylcholine (ACh)
What neurotransmitter patterns are occurring during wakefulness?
Histamine levels are high and activate cholinergic pathways
Cholinergic pathways activate thalamic reticular nuclei
Enables information to flow freely through this area
Information flow: awareness and arousal – consciousness
What transmitter patterns are occurring during slow wave sleep?
Low light and warmth detected by suprachiasmatic and ventrolateral preoptic nuclei (hypothalamus)
Inhibit histamine cells in tuberomamillary bodies and brainstem
Inhibits the cholinergic pathways
Reduced activity in the thalamus
Prevents information flow: low arousal level
What transmitter patterns are occurring during REM sleep?
Inhibition of histamine and cholingeric neurons increases and begins to decrease other transmitter pathways 5HT and NA (normally dampen cholinergic activity)
Increased cholinergic input to the thalamus
Increased cortical activity: an ‘active mind in an inactive body’
What role does acetylcholine play in control of reward pathways?
Acetylcholine acts at all levels of the reward pathway:
Pontine centres act on the ventral tegmental area
Nucleus Basilis of Meynert(NBM) acts on the nucleus accumbens
NBM and local interneurons act within the prefrontal cortex
What role does acetylcholine play in control of motor activity?
Acts to increase activity in the striatum
Degeneration of cholinergic interneurons can lead to increased or decreased motor activity and changes in motivation
What is delirium?
Acute confusional state
Medical emergency, transient and reversible but associated with poor outcome
Develops over a couple of days
Characterised by: Decreased attention span, Waxing and waning confusion, wide range of other neuropsychiatric abnormalities
What is the neuronal basis of delirium?
Inflammation of tissue leading to: Decreased cholinergic activity Increased serotonin activity Increased dopamine activity Decreased GABAergic transmission Increased stress hormones
What are reversible causes of delirium?
Drugs Emotion (mania or agitated depression) Low oxygen (ischaemia, congestive heart failure, stroke or pulmonary embolus) Infection Retention (urine or faeces) Ictal states Undernutrition Metabolic (thyroid function or organ failure)
What are reversible causes of dementia?
Drugs Emotional illness (including depression or schizophrenia) Metabolic/endocrine disorders Eye/ear/environment Nutritional/neurologic Trauma Infections Alcoholism/anaemia/atherosclerosis
Describe differences between delirium and dementia
Delirium: acute onset, poor attention, fluctuations in consciousness, hallucinations, fear/agitation, disorganised thoughts, myoclonus, postural tremor, flapping tremor, slurred speech, poor memory
Dementia: chronic or subacute onset, dysphasia, other features are in late disease, poor memory
What tests would you do to screen for delirium?
Bloods: Full Blood count, U+Es, LFT, Glucose, CRP
Urine: MSU, MC&S
What drugs are used to treat dementia?
Mild to moderate dementia:
Cholinesterase inhibitors: Donezapil (reversible), Galantamine (reversible)
Cholinergic (nicotinic) receptor agonist: Rivastigmine (reversible, non competitive)
Moderate to severe AD:
Glutamate (NMDA) receptor antagonist: Memantine
Why are Nmda antagonists used in moderate to severe Alzheimers treatment?
Excitotoxicity prevention
What are common side effects of anticholinergic dementia drugs?
Nausea Diarrhoea Vomiting Stomach cramps Loss of appetite and weight loss Headache Dizziness Fatigue and insomnia
What are side effects of memantine?
Less severe and less common than for other AD drugs: Dizziness Headache Fatigue Increased blood pressure Constipation
What drugs might you use to treat hallucinations and psychotic symptoms in delirium?
Antipsychotics: Haloperidol (classical), Olanzapine/Risperidone (atypical)
Benzodiazepines: (can exacerbate symptoms), Lorazepam
How do antipsychotic drugs work?
Classical: D2 antagonist
Atypical: 5HT2 and D2 mainly, also a1 and a2 activity
Describe differences between classical and atypical antipsychotic drugs
First Generation (aka Classical): Primarily potent D2 antagonists, Extrapyramidal effects high, Low efficacy, 30% non-responders Second Generation (aka Atypical): Primarily multiple actions 5HT & DA & others, 5HT2 >D2, Reduced extrapyramidal effects, Better at treating negative symptoms, Higher efficacy, Need therapeutic dose to reach 60% occupancy at D2 for effective response
Which classical antipsychotic drugs are commonly used?
Chlorpromazine Thioridazine Trifluoperazine Haloperidol Zuclopenthixol Sulpiride
Which atypical antipsychotics are commonly used?
Amisulpride (D2/D3)
Aripiprazole (partial agonist D2-4, 5HT2C & 1A)
Quetiapine (D2-4 , 5HT1A, 2A, 2C, 7 , α1&2, H1)
Olanzapine (D1,2&4, 5HT2A, H1, M1)
Paliperidone (metabolite of risperidone)
Risperidone (D2, 5HT2A, α1, H1)
Clozapine (D1, D2, 5HT2A, α1, M1)
Which is the gold standard antipsychotics?
Clozapine
What are side effects of clozapine?
CV effects: QT elongation
What are the main groups of side effects of antipsychotic drugs?
Extrapyramidal Cardiovascular – increased QT interval Metabolic – weight gain/diabetes Hormonal – increased plasma prolactin Other – includes psychiatric
What are Extrapyramidal side effects?
Dystonias (muscle spasms) Parkinsonian symptoms Akathisia (restlessness) Sedation Cardiovascular Prolactin elevation TARDIVE DYSKINESIA
What is tardive dyskinesia?
Disabling involuntary movements: tongue protruding, choreiform movements, grimacing, twisting
What do you do if a patient taking antipsychotics experiences tardive dyskinesia?
Anticholinergic use stopped immediately
Vitamin E & B6, Benzodiazepines, β-blockers can help
Switch to Atypical
What is neuroleptic malignant syndrome?
Rare but potentially fatal side-effect of antipsychotics Caused by over-activation of ANS/metabolic pathways: Hyperthermia Altered level of consciousness Pallor Sweating Tachycardia Fluctuating BP Muscle rigidity Urinary incontinence
What do you do to treat neuroleptic malignant syndrome?
Stop antipsychotic use
Bromocriptine (dopamine agonist)
Dantrolene (muscle relaxant)
Where do benzodiazepines exert their effects?
GABAA receptor (gamma subunit) to increase activity
What are the side effects of benzodiazepines?
Tolerance and dependency Impaired motor coordination (decreased muscle tone) Impaired cognitive performance Sedation Disturbed sleep patterns (decreased SWS) Retrograde amnesia Withdrawal on termination
What are the cardinal features of normal pressure hydrocephalus?
Gait disturbance
Cognitive decline
Urinary incontinence
