Neurology - Dementia, delirium and amnesic syndromes

Question 1

Definition of dementia

Answer 1

= Global impairment of cognition with normal levels of consciousness

Question 2

What is the incidence of dementia?

Answer 2

5% > 65 years

20% > 85 years

Question 3

Mental test scores that would prompt concern about dementia

Answer 3

Mental test covers:

• Orientation
• Long term memory
• Concentration
• Short term memory

>8 = normal
4-7 = mild - moderate dementia

Question 4

What symptoms occur in dementia?

Answer 4

• 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

Question 5

What testes should be performed to rule out reversible causes of dementia?

Answer 5

• 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)

Question 6

What are common causes of dementia?

Answer 6

1) Alzheimer’s disease (65%)
2) Vascular dementia
3) Frontotemporal dementia

Question 7

What patients may present with “pseudo dementia”?

Answer 7

• 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

Question 8

What is normal pressure hydrocephalus? How does it present?

Answer 8

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

Question 9

Causes of dementia in a young person

Answer 9

• New variant CJD
• HIV
• Vasculitis
• Inherited disease

Question 10

Clinical features of dementia affecting frontal lobe function

Answer 10

• 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)

Question 11

What are the clinical features of dementia affecting parietal lobe function?

Answer 11

• Apraxia = Impairment of visuospatial and motor abilities
• Dyslexia = inability to read
• Dyscalculia = deterioration in simple arithmetic

Question 12

Clinical features of dementia affecting temporal lobe function

Answer 12

• 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

Question 13

Alzheimer’s disease (AD)

Answer 13

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

Question 14

How is AD diagnosed?

Answer 14

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

Question 15

Key features of AD

Answer 15

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

Question 16

What does imaging show in AD?

Answer 16

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

Question 17

What is the prognosis in AD?

Answer 17

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

Question 18

What is the most important risk factor in developing AD other than advancing age?

Answer 18

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)

Question 19

Are any factors protective in AD?

Answer 19

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

Question 20

What are the pathological features of AD?

Answer 20

Gross macroscopic features include:

• brain atrophy
• ventricular enlargement
• cortical thinning

Microscopic examination shows plaques and tangles in the cortex

Question 21

What are the plaques seen in AD composed of?

Answer 21

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

Question 22

What are neurofibrillary tangles seen in AD composed of?

Answer 22

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

Question 23

Why is cholinergic transmission reduced in AD?

Answer 23

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)

Question 24

What is cerebral amyloid angiopathy?

Answer 24

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

Question 25

What is the "amyloid cascade hypothesis"?

Answer 25

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

Question 26

How is AB formed?

Answer 26

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

Question 27

What causes familial forms of AD?

Answer 27

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

Question 28

How is AB deposition related to tau?

Answer 28

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)

Question 29

What is the progression of tau pathology in AD?

Answer 29

Tangles first appear in the medial temporal lobe (hippocampus, entorhinal cortex) and spread progressively throughout the limbic lobe and neocortex in six Braak stages

Question 30

How does AB clearance play a role in AD?

Answer 30

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

Question 31

How does beta amyloid damage neurones?

Answer 31

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

Question 32

Cognitive reserve capacity

Answer 32

Alzheimer type changes are present to a variable extent in many cognitively normal older people, which is thought to reflect greater cognitive reserve capacity

Question 33

Frontotemporal dementia

Answer 33

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

Question 34

What are the different variants of FTD?

Answer 34

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

Question 35

What other disease is associated with FTD?

Answer 35

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

Question 36

What are the pathological features of FTD?

Answer 36

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

Question 37

How does inheritance play a role in FTD?

Answer 37

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

Question 38

What is the main difference between AD and FTD?

Answer 38

Patients with FTD have preserved areas of ability such as memory - this distinguishes them from AD

Question 39

What is dementia with Lewy bodies?

Answer 39

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

Question 40

What is the pathological feature in DLB?

Answer 40

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

Question 41

What is the progression of Lewy bodies in DLB?

Answer 41

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

Question 42

What drugs should be avoided in DLB?

Answer 42

L-dopa can exacerbate the psychiatric symptoms in DLB | Antipsychotics may lead to potentially fatal decline in motor function

Question 43

How common is vascular dementia?

Answer 43

It is the third most common cause of dementia (following AD and DLB) - accounts for 10% of cases

Question 44

What are the risk factors for developing vascular dementia?

Answer 44

Same as those for ischaemic heart disease and stroke: - History of stroke - Smoking - High blood pressure - Previous MI - Obesity - Diabetes - Elevated cholesterol

Question 45

What are the clinical features of vascular dementia?

Answer 45

- 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

Question 46

What clinical features suggest vascular dementia rather than Alzheimer's disease?

Answer 46

- 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)

Question 47

Imaging in vascular dementia

Answer 47

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

Question 48

Pathological features of vascular dementia

Answer 48

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

Question 49

How does large vessel disease cause vascular dementia?

Answer 49

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"

Question 50

What is prion disease?

Answer 50

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

Question 51

Clinical features of CJD?

Answer 51

Sporadic and inherited forms of CJD cause a rapidly progressive dementia with myoclonus, ataxia and cortical blindness progressing over weeks to months

Question 52

EEG features of CJD

Answer 52

Characteristic repetitive complexes of triangular waves

Question 53

What is variant CJD (vCJD)?

Answer 53

= 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

Question 54

What conditions can cause cognitive impairment in younger patients?

Answer 54

- 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

Question 55

What is CADASIL?

Answer 55

= inherited white matter disease associated with mutations in the notch-3 gene - presents with hemiplegic migraine, encephalopathy or progressive dementia

Question 56

Delirium

Answer 56

= 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

Question 57

What are the clinical features of delirium?

Answer 57

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

Question 58

What are the two subtypes of delirium?

Answer 58

1) Hypoactive - withdrawn, quiet, sleepy behaviour, is less likely to be recognised 2) Hyperactive - restless, agitated, aggressive

Question 59

What are the 8 features of delirium?

Answer 59

"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

Question 60

What groups are high risk for delirium?

Answer 60

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

Question 61

What can precipitate delirium?

Answer 61

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

Question 62

What other conditions mimic delirium and should be considered as a differential?

Answer 62

- 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

Question 63

What are the key features distinguishing dementia from delirium?

Answer 63

Dementia is slowly progressive, delirium is rapid (hours to days) Consciousness is depressed in delirium but unaffected in dementia (cognitive function declines though)

Question 64

What tests are important in delirium?

Answer 64

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)

Question 65

What are the key aspects in preventing delirium?

Answer 65

1) Maximise orientation 2) Prevent causes - Reduce polypharmacy - Decrease constipation and dehydration - Decrease infection - Assess for hypoxia 3) Promote well being

Question 66

How should delirium be treated?

Answer 66

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

Question 67

What is Wernicke's encephalopathy?

Answer 67

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)

Question 68

What are the pathological features of Wernicke's encephalopathy?

Answer 68

- 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

Question 69

Triad of Wernicke's encephalopathy

Answer 69

- Ophthalmoplegia (most commonly nystagmus, vertical gaze palsy and VI nerve palsy) - Ataxia (affecting gate primarily) - Confusional state (can progress to coma)

Question 70

How is Wernicke's encephalopathy treated?

Answer 70

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

Question 71

Prognosis of Wernicke's encephalopathy

Answer 71

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

Question 72

What does vit B12 deficiency cause?

Answer 72

- Peripheral neuropathy - SACD - Nutritional amblyopia (visual loss) - Cognitive dysfunction ranging from mild confusion to dementia or psychosis (megaloblastic madness)

Question 73

What causes vit B12 deficiency?

Answer 73

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

Question 74

What are the classic haematological abnormalities found in B12 deficiency?

Answer 74

- Megaloblastic macrocytic anaemia - Leukopenia with hyperhsegmented neutrophils - Thrombocytopenia

Question 75

Features of acute alcohol intoxication

Answer 75

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

Question 76

Does acute alcohol withdrawal require treatment?

Answer 76

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

Question 77

What are the 3 symptoms of alcohol withdrawal?

Answer 77

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

Question 78

How long after alcohol withdrawal does tremulousness and hallucinations occur?

Answer 78

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

Question 79

When do seizures usually follow alcohol withdrawal?

Answer 79

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)

Question 80

What would prompt you to think that a patients withdrawal seizures may be caused by something else such as infection or trauma?

Answer 80

Unusual features: - focal seizures - prolonged seizure duration - more than 6 seizures - status

Question 81

What is the benzodiazepine of choice for acute alcohol withdrawal?

Answer 81

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

Question 82

What signs suggest excessive dosing of chlordiazepoxide in acute alcohol withdrawal?

Answer 82

- Hypotension - Respiratory depression - Sedation

Question 83

What is delirium tremens?

Answer 83

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