Neurology - Dementia, delirium and amnesic syndromes Flashcards
Definition of dementia
= Global impairment of cognition with normal levels of consciousness
What is the incidence of dementia?
5% > 65 years
20% > 85 years
Mental test scores that would prompt concern about dementia
Mental test covers:
- Orientation
- Long term memory
- Concentration
- Short term memory
>8 = normal 4-7 = mild - moderate dementia
What symptoms occur in dementia?
- Personality change
- Nocturnal wanderings
- Reversed day-night sleep cycle
- Intellectual decline
- Mood change
Specific profile of higher cognitive function deficits depends on the extent and distribution of pathology in the cerebral cortex
What testes should be performed to rule out reversible causes of dementia?
- CT/ MRI (rule out normal pressure hydrocephalus, subdural haematoma, intracranial tumours)
- Na+ (chronic hyponatraemia)
- Vit B12
- Thyroid function (rule out hypothyroidism)
- Syphilis serology
- LFTs
- Renal function
- ESR (Paraneoplastic syndromes or autoimmune encephalopathy associated with anti voltage gated potassium channel antibodies)
- FBC (raised WCC occurs in Whipple’s disease which can cause dementia)
What are common causes of dementia?
1) Alzheimer’s disease (65%)
2) Vascular dementia
3) Frontotemporal dementia
What patients may present with “pseudo dementia”?
- Severe depression
- Uncontrolled epilepsy
NB - it is useful to do an MSE in patients with dementia to exclude depressive pseudodementia but be aware that depression is an element common to all dementias
What is normal pressure hydrocephalus? How does it present?
May result from a diffuse abnormality of CSF uptake causing ventricular dilation
It has a slowly progressive course
It presents as a triad of:
1) Dementia
2) Incontinence
3) Gait disturbance
Causes of dementia in a young person
- New variant CJD
- HIV
- Vasculitis
- Inherited disease
Clinical features of dementia affecting frontal lobe function
- Executive dysfunction = difficulty in performing complex tasks and planning ahead
- Alterations in behaviour and personality = caused by degeneration of the prefrontal cortex
- Expressive dysphasia = problems with expressive or motor aspects of language (due to degeneration of Broca’s area)
What are the clinical features of dementia affecting parietal lobe function?
- Apraxia = Impairment of visuospatial and motor abilities
- Dyslexia = inability to read
- Dyscalculia = deterioration in simple arithmetic
Clinical features of dementia affecting temporal lobe function
- Receptive dysphasia = difficulty comprehending language (damage to Wernicke’s area)
- Prosopagnosia = inability to recognise familiar faces
- Agnosia = inability to recognise familiar objects
- Episodic memory loss = due to hippocampal atrophy
- Mood changes = amygdala damage
Alzheimer’s disease (AD)
Leading cause of dementia in ALL groups
Vast majority of cases are sporadic but approximately 5% are familial and inherited in an autosomal dominant manner
How is AD diagnosed?
Diagnosis of AD is predominantly clinical, post mortem studies find that it is correct in approx 80% of cases
2 variants of AD can cause diagnostic confusion:
1) Frontal variant - prominent changes in personality and behaviour with disturbed executive function and expressive language. Usually misdiagnosed as FTD
2) Posterior cortical atrophy - parietal lobes are particularly affected leading to visuospatial and perceptual problems. Expressive language and memory are usually preserved
Key features of AD
Both early features are due to severe medial temporal lobe degeneration
i) loss of episodic memory that eventually produces global cognitive decline - i.e. early on new memories cannot be laid down, although childhood memory remains accessible. Later on no memory can be recalled
ii) Spatial disorientation
Disease progresses over 5-15 years with gradual decline in all aspects of cognitive ability plus changes in mood, personality and behaviour
What does imaging show in AD?
May be normal in early disease
Functional brain imaging in early disease shows reduced blood flow and glucose metabolism in posterior temporal lobe and hippocampus before obvious structural changes appear on MRI
Over time there is: progressive cortical atrophy, ventricular dilatation and hippocampal atrophy
What is the prognosis in AD?
Disease progresses relentlessly causing death from pneumonia or inanition after 8-10 years
Key to management is to care for the sufferer on a “symptom by symptom basis” and provide good support and relief for the carer
What is the most important risk factor in developing AD other than advancing age?
Possession of one or more copes of the APOE4 allele, which is present in more than 50% of patients with AD
Other risk factors:
- IHD
- History of head injury
- Low SES
- Susceptibility genes may be responsible for familial forms - mutations in Presenilin 1 and 2 genes and amyloid precursor protein (APP)
Are any factors protective in AD?
AD is more common in females and HRT may be beneficial in post menopausal women
Positive effect of anti-inflammatory drugs is unproven
Moderate alcohol consumption
What are the pathological features of AD?
Gross macroscopic features include:
- brain atrophy
- ventricular enlargement
- cortical thinning
Microscopic examination shows plaques and tangles in the cortex
What are the plaques seen in AD composed of?
Diffuse and neuritic plaques are composed of insoluble aggregates of amyloid beta (AB) peptide (like all forms of amyloid, the deposits take up the stain congo red and show apple-green birefringence under polarised light)
AB is deposited extracellularly in the compartment between neurones
Diffuse plaques = composed of AB but in a non-amyloid form, may be numerous in older people without dementia
Neuritic plaques = plaques associated with cognitive decline
What are neurofibrillary tangles seen in AD composed of?
Neurofibrillary tangles occupy the neuronal cytoplasm and are composed of insoluble filamentous aggregates of hyperphosphorylated tau protein (microtubule transport protein) arranged in paired helical filaments
Why is cholinergic transmission reduced in AD?
The cortex shows widespread loss of neurones, synapses and dendritic spines in AD
Cholinergic transmission is reduced due to degeneration of Meynert’s nucleus (a large cholinergic nucleus in the base of each cerebral hemisphere contributing to diffuse cholinergic system)
What is cerebral amyloid angiopathy?
AB is deposited in the cortical blood vessels in 90% of patients with AD which is called cerebral amyloid angiopathy
Amyloid deposition leads to degeneration of vascular smooth muscle , weakening of vessel wall and predisposition to micro-infarcts and intracerebral haemorrhage
CAA can occur in the absence of dementia and accounts for about 25% of intracerebral haemorrhages in the elderly - the haemorrhage is “cortical” rather than deep like those seen in hypertension
What is the “amyloid cascade hypothesis”?
Deposition of AB protein in the cerebral cortex is believed to be a key initiating event in development of AD leading to tau hyperphosphorylation and tangle formation within neurones
How is AB formed?
AB is produced by proteolytic cleavage of the precursor molecule APP. There are 2 pathways for processing:
- Processing via the primary pathway (alpha secretase) is dominant and does not lead to pathologic AB release
- Processing via the alternative (beta secretase) pathway releases soluble AB peptide with either 40 or 42 amino acids
The ratio of AB40: AB42 is determined by the gamma secretase complex
AB42 forms cortical plaques
AB40 gets deposited in blood vessels leading to cerebral amyloid angiopathy
What causes familial forms of AD?
Mutations in the presenillin or APP genes are responsible for most inherited (autosomal dominant) early onset forms of AD.
There is an imbalance in the AB40:AB42 ratio causing excessive AB42 deposition
How is AB deposition related to tau?
Deposition of AB in the cerebral cortex (particularly AB42) appears to trigger a cascade of events within neurones leading to accumulation of hyperphosphorylated tau
Tau hyperphosphorylation is caused by an imbalance between tau kinases and phosphorylases with excessive kinase activity (e.g. CDK5)
What is the progression of tau pathology in AD?
Tangles first appear in the medial temporal lobe (hippocampus, entorhinal cortex) and spread progressively throughout the limbic lobe and neocortex in six Braak stages
How does AB clearance play a role in AD?
In normal individuals a small amount of AB is continually produced and eliminated
Mechanisms for removal include enzymatic degradation and active transport into blood stream (which decline with age) and perivascular drainage (which also declines with age and is less effective in people with cerebrovascular disease)
Failure of AB clearance rather than build up appears to be important in sporadic cases
How does beta amyloid damage neurones?
Exact mechanism unclear
AB oligomers are known to be associated with neuronal membranes and form pore like structures (similar to those of the membrane attack complex) which allow sodium, water and calcium into cells
Cognitive reserve capacity
Alzheimer type changes are present to a variable extent in many cognitively normal older people, which is thought to reflect greater cognitive reserve capacity
Frontotemporal dementia
Frontotemporal dementia is a clinical term for a rare group of conditions (accounting for 5% of dementias) in which there is selective degenerations of the frontal and temporal lobes
What are the different variants of FTD?
Behavioural variant accounts 50% of cases and features changes in personality and behaviour
Semantic dementia and progressive non fluent aphasia are less common:
- Semantic dementia = loss of ability to understand the meaning of concepts and words
- Progressive non fluent dementia (PNFA) = marked expressive language difficulties (aphasia) with word substitution and word finding problems
What other disease is associated with FTD?
Some patients with FTD also have features of motor neurone disease (MND), whilst a proportion of patients with MND develop FTD
This is due to an overlap in the molecular pathology
What are the pathological features of FTD?
Variable frontal and temporal lobe atrophy called frontotemporal lobar degeneration (FTLD)
In the majority of FTLD cases, pathological inclusions can be identified in neurones and glial cells. These are most often:
- TDP-43 (50%)
- tau (40%)
- FUS (5%)
Importantly, the clinical features depend on the distribution of the pathological changes NOT the particular protein involved
How does inheritance play a role in FTD?
Most cases of FTD are sporadic (60%)
In the 40% of cases with a family history the inheritance pattern is not straightforward
In 10% of FTD cases (a quarter of those with a family history) there is clear autosomal dominant inheritance and a known mutation can normally be identified in:
(i) tau or progranulin genes
(ii) hexonucleotide repeat expansion on chromosome 9
What is the main difference between AD and FTD?
Patients with FTD have preserved areas of ability such as memory - this distinguishes them from AD
What is dementia with Lewy bodies?
DLB is the second most common cause of dementia after Alzheimer’s accounting for up to 20% of cases
In addition to cognitive decline there are several core features:
- Nocturnal visual hallucinations
- Fluctuation in cognitive performance
- Parkinsonism
- Disordered rapid eye movement (REM) sleep
Over 50% of patients show neuroleptic (antipsychotic) sensitivity and autonomic dysfunction
What is the pathological feature in DLB?
Pathological feature of DLB is identical to Parkinson’s disease dementia - widespread Lewy bodies (composed of alpha synuclein)
Many patients also have variable Alzheimer type changes and there appears to be synergistic interaction between AB and alpha synuclein
What is the progression of Lewy bodies in DLB?
Lewy bodies first appear in the olfactory bulbs and medulla before progressing to involve the midbrain, pons, limbic lobe, amygdala and neocortex in six Braak stages
What drugs should be avoided in DLB?
L-dopa can exacerbate the psychiatric symptoms in DLB
Antipsychotics may lead to potentially fatal decline in motor function
How common is vascular dementia?
It is the third most common cause of dementia (following AD and DLB) - accounts for 10% of cases
What are the risk factors for developing vascular dementia?
Same as those for ischaemic heart disease and stroke:
- History of stroke
- Smoking
- High blood pressure
- Previous MI
- Obesity
- Diabetes
- Elevated cholesterol
What are the clinical features of vascular dementia?
- May present with stepwise loss of cognitive ability (consistent with a series of small strokes). This is often referred to as multi-infarct dementia
- Or a gradual decline dominated by generalised slowing of cognition with disturbed frontal executive function (i.e. bradyphrenia or sub-cortical dementia). This is often caused by diffuse white matter disease, sometimes referred to as Binswangers encephalopathy
What clinical features suggest vascular dementia rather than Alzheimer’s disease?
- Fluctuating course
- Patchy cognitive profile
- “Emotional incontinence” (inappropriate laughter or tearfulness)
- Sundowning (symptoms worse in the evening)
- Parkinsonian features caused by damage to the basal ganglia (marche a petit pas)
Imaging in vascular dementia
High signal intensity in the periventricular white matter
Patches of hyper intensity in the deep and subcortical white matter
Old lacunar infarcts are often visible
Pathological features of vascular dementia
Vascular dementia can either be caused by (i) small vessel disease, (ii) large vessel disease or (iii) mixture
Small vessel disease is the most common characterised by hyaline arteriosclerosis ( = replacement of arterial smooth muscle with hyaline) and lipohyalinosis ( = replacement of smooth muscle with lipid laden foam cells). This often happens in response to arterial hypertension and other vascular risk factors
Other features include lacunar infarcts (basal ganglia), generalised attenuation of the subcortical white matter and enlargement of perivascular spaces
How does large vessel disease cause vascular dementia?
Some patients develop dementia after a series of strokes having lost a critical volume of brain tissue (usually at least 50-100ml)
Regional infarcts may be present. In some patients, a strategic infarct in an area critical for memory (e.g. the hippocampus or anteromedial thalamus) leads to an abrupt decline in cognitive ability, referred to as “single stroke dementia”
What is prion disease?
In prion disease, mutated forms of prion protein PrP induce a conformational change in other PrP molecules producing non functional, non metabolisable forms which are cytotoxic
Clinical features of CJD?
Sporadic and inherited forms of CJD cause a rapidly progressive dementia with myoclonus, ataxia and cortical blindness progressing over weeks to months
EEG features of CJD
Characteristic repetitive complexes of triangular waves
What is variant CJD (vCJD)?
= Transmitted from cattle infected with bovine spongiform encephalopathy
Unlike sporadic or familial CJD this form affects younger patients with more prominent psychiatric symptoms as the earliest feature
What conditions can cause cognitive impairment in younger patients?
- Recreational drugs - esp alcohol, and glue
- Cerebral vasculitis
- End stage MS
- Adrenoleukodystrophies resulting from fatty acid dysmetabolism can cause “multiple sclerosis type” pattern with prominent dementia
- Uncontrolled epilepsy
What is CADASIL?
= inherited white matter disease associated with mutations in the notch-3 gene - presents with hemiplegic migraine, encephalopathy or progressive dementia
Delirium
= acute confusional state characterised by rapid onset of global but fluctuating dysfunction of the CNS
Reduced consciousness is not as severe as coma
Occurs in approximately 20% of elderly patients on medical and surgical wards
Associated with increased mortality and longer duration of hospitalisation
What are the clinical features of delirium?
ICD-10 diagnosis requires:
Impaired consciousness and attention
+
Perceptual disturbances (usually visual hallucinations)
OR Cognitive disturbances (reduced concentration, memory, orientation, distracted or muddled thinking, incoherent speech)
+
Developed over a short period of time and fluctuates
+
Evidence it may be related to a physical cause
What are the two subtypes of delirium?
1) Hypoactive - withdrawn, quiet, sleepy behaviour, is less likely to be recognised
2) Hyperactive - restless, agitated, aggressive
What are the 8 features of delirium?
“DELIRIUM”
D - disordered thinking
E - euphoric, fearful, depressed; fluctuating mood and affect (labile)
L - language impaired - speech reduced or slurring
I - illusions/ delusions/ hallucinations (often persecutory)
R - reversal of sleep/wake cycle
I - inattention
U - unaware/ disorientated
M - memory deficits, may be amnesic for the episode
What groups are high risk for delirium?
High risk groups are those that should be screened when they are admitted to hospital:
- Over 65s
- People with diffuse brain injury (dementia or PD)
- Patients with a current hip fracture
- Severely ill
What can precipitate delirium?
Nutritional: vit B12, folate or B1
Intracranial: infection, trauma, CVA, haemorrhage, epilepsy
Extra cranial infection: UTI, pneumonia, septicaemia
Iatrogenic: septicaemia secondary to chemo, sedatives, surgery (anaesthetics, analgesics, blood loss)
Alcohol: acute intoxication, withdrawal
Endocrine: Hyper/hypo thyroid, hyper/hypoglycaemia
Metabolic: hypoxia, renal failure, liver failure, or other system failure
What other conditions mimic delirium and should be considered as a differential?
- Functional psychiatric conditions (mania, depression and late-onset schizophrenia)
- Resposes to major stress, especially pain
- Dissociative disorders
NB - delirium can be difficult to differentiate from dementia (esp Lewy body dementia) because people with established dementia are at risk of delirium
What are the key features distinguishing dementia from delirium?
Dementia is slowly progressive, delirium is rapid (hours to days)
Consciousness is depressed in delirium but unaffected in dementia (cognitive function declines though)
What tests are important in delirium?
Bloods:
- FBC (exclude anaemia, macrocytosis, leucocytosis)
- ESR (infection)
- U&E (dehydration, electrolyte disturbance)
- Glucose
- TFT
- LFT
- Calcium
- folate and B12
- VDRL (i.e. syphilis serology)
Chest X ray
MSU
Head imaging
EEG (if epilepsy is suspected)
What are the key aspects in preventing delirium?
1) Maximise orientation
2) Prevent causes
- Reduce polypharmacy
- Decrease constipation and dehydration
- Decrease infection
- Assess for hypoxia
3) Promote well being
How should delirium be treated?
Identify and treat the underlying cause
If a person with delirium is distressed or poses a risk to themselves or others then medication may be needed:
- Short term antipsychotic (e.g. haloperidol, risperidone) or short acting BDZ
- Minimise physical restraint
- Hypotensive or anticholinergic side effects may precipitate falls or exacerbate confusion
- Long acting benzos should be used for alcohol withdrawal
What is Wernicke’s encephalopathy?
Usually a complication of chronic alcohol abuse (but can occur in some cancers and after bariatric surgery)
It is caused by a deficiency of vitamin B1 (thiamine)
What are the pathological features of Wernicke’s encephalopathy?
- Neuronal loss
- Demyelination
- Gliosis in periventricular gray matter
There may also be proliferation of small blood vessels and petechial haemorrhage
Areas most commonly affected: medial thalamus, mammillary bodies, PAG, vermis and III, IV and VI nuclei
Triad of Wernicke’s encephalopathy
- Ophthalmoplegia (most commonly nystagmus, vertical gaze palsy and VI nerve palsy)
- Ataxia (affecting gate primarily)
- Confusional state (can progress to coma)
How is Wernicke’s encephalopathy treated?
All patients should have thiamine supplements orally or IV (depending on clinical state)
100mg thiamine is given initially BEFORE treatment with glucose - this is because glucose can precipitate Wernicke’s encephalopathy in patients deficient in B vitamins
Prognosis of Wernicke’s encephalopathy
Generally most signs resolved between 1 day - 1 month
Ataxia is only reversible in 40% of patients even with treatment
Major long term complication is Korsakoff’s syndrome
What does vit B12 deficiency cause?
- Peripheral neuropathy
- SACD
- Nutritional amblyopia (visual loss)
- Cognitive dysfunction ranging from mild confusion to dementia or psychosis (megaloblastic madness)
What causes vit B12 deficiency?
1) Pernicious anaemia - defect in production of intrinsic factor associated with atrophic gastritis, anti parietal cell antibodies and achlorydia
2) Gastric resection
3) Vegan diet
What are the classic haematological abnormalities found in B12 deficiency?
- Megaloblastic macrocytic anaemia
- Leukopenia with hyperhsegmented neutrophils
- Thrombocytopenia
Features of acute alcohol intoxication
Alcohol produces a confusional state similar to cerebellar lesions - nystagmus, dysarthria, and limb and gait ataxia
Signs correlate with blood alcohol levels in non alcoholics
Chronic alcoholics may have high alcohol levels without appearing intoxicated - blood alcohol + serum osmolarity are useful
Does acute alcohol withdrawal require treatment?
Treatment is not usually required unless a withdrawal syndrome occurs, but alcoholic patients should be treated with thiamine to prevent malnutrition related to Wernicke’s encephalopathy
What are the 3 symptoms of alcohol withdrawal?
1) Tremulousness and hallucinations
2) Seizures
3) Delirium Tremens (DTs)
Patients with any of these symptoms are ALL at risk of Wernicke’s encephalopathy and should be given thiamine
How long after alcohol withdrawal does tremulousness and hallucinations occur?
This is normally self limiting and occurs within 2 days after cessation of drinking - characterised by:
- Tremors
- Agitation (“must leave hospital”)
- Insomnia
- Tachycardia
- Hallucinations (25%)
If treated with benzodiazepines then progression to worse outcome is avoided
When do seizures usually follow alcohol withdrawal?
Withdrawal seizures usually occur within 48 hours of abstinence
40% of patients have 1 seizure
90% of patients have between 1 and 6
Adequate doses of chlordiazepoxide usually prevent withdrawal seizures. For isolated seizures continue with regime and ensure patient is receiving adequate dose
2mg lorazepam IV as a single dose can be used to treat prolonged or recurrent seizures (on top of existing benzos)
What would prompt you to think that a patients withdrawal seizures may be caused by something else such as infection or trauma?
Unusual features:
- focal seizures
- prolonged seizure duration
- more than 6 seizures
- status
What is the benzodiazepine of choice for acute alcohol withdrawal?
Chlordiazepoxide (provided there is no significant liver disease)
No fixed dosing regime will meet all situations - dose may need to be lowered in elderly people, woman and those with respiratory disease
What signs suggest excessive dosing of chlordiazepoxide in acute alcohol withdrawal?
- Hypotension
- Respiratory depression
- Sedation
What is delirium tremens?
This is the most serious symptom of alcohol withdrawal and normally begins 3-5 days after cessation of drinking and lasts up to 72 hours
There are prominent autonomic features - e.g. sweating, hypertension, and hallucinations
Death is usually from infection, pancreatitis, cardiovascular collapse or trauma
