Management of DementiaDr Mary Ann Kulh, GeriatricianCalvary Public Hospital Bruce, ACT

Patient 1

82 year old lady with gradual onset of “short term” memory loss (e.g. misplaces keys, forgets appointments, repeating herself)

History of hypertension Medications: irbesartan 150mg mane, aspirin 100mg mane MMSE 22/30 (5 lost in orientation, 3 in recall)

What is the diagnosis and what do you do now?

Patient 1

Bloods – EUC, FBC, B12, TSH all normal CT brain – moderate cerebral atrophy with predominance in

frontal and temporal lobes. Mild small vessel chronic small vessel ischaemic change.

What should be done now?

Patient 1

Bloods – EUC, FBC, B12, TSH all normal CT brain – moderate cerebral atrophy with predominance in

frontal and temporal lobes. Mild small vessel chronic small vessel ischaemic change.

What should be done now?

Medications for Alzheimer’s Dementia

Acetylcholinesterase inhibitors (AchEI) for mild to moderate Alzheimer’s dementia Donepezil (Aricept) Rivastigmine (Exelon) Galantamine (Reminyl)

NMDA receptor antagonists (memantine) for moderately severe AD

Produce modest symptomatic benefits in some patients (cognition, function, behaviour)

Benefits are temporary None cure the disease or stop progression Studies currently targeting novel pathogenic pathways in

dementia

Medications for Dementia

Cholinergic Theory of Alzheimer’s Disease Acetylcholine deficiency observed in post-mortem

examination of brains in advanced Alzheimer’s Destruction of cholinergic neurons and resultant

acetylcholine deficit thought to explain cognitive deficits in AD

More recent studies suggest cholinergic activity may not be reduced in early AD, and may even be up-regulated

Cholinesterase Inhibitors

Only subsidised on PBS for Alzheimer’s Disease Diagnosis must be confirmed by a specialist Specialist or GP can write authority prescription for 6

months treatment, quoting initial MMSE or ADAS-cog score. Up to 2 months supply approved by phone, remainder by

written request

Cholinesterase Inhibitors

Repeat MMSE (best done at 3 - 4 months after starting treatment) must improve by 2 points (or ADAS-cog by 4) to qualify for treatment beyond the first 6 months. Written authority prescription by specialist or GP.

Subsequent prescriptions by Streamline Authority 4219; no MMSE required to continue therapy.

New application required if switching from one cholinesterase inhibitor to another

AD diagnosis confirmed by Specialist

MMSE < 10Meet PBS criteria

Baseline CIBIC+

MMSE 10-24

Written PBS authority

Within 6 months repeat baseline test

MMSE ↑ ≥ 2 pointsADAS-cog ↓ ≥ 4 points

CIBIC > much improved

Ongoing PBS authority

MMSE ≥25

Baseline ADAS-cog preferred but not

essential

Cholinesterase Inhibitors: Contraindications Known sensitivity to drug Sensitivity to piperidine derivatives (donepezil) –

loperamide and fentanyl Prescribe with caution to patients with:

Sick-sinus syndrome or other cardiac conduction abnormalities

Moderate to severe asthma or COPD Seizures active gastrointestinal disease, or in patients receiving

non-steroidal anti-inflammatory agents

Cholinesterase Inhibitors: Side-effects

Diarrhea, vomiting, nausea, fatigue, insomnia, and anorexia, but in most cases, such side effects are mild and decline with continued use of the drug.

Rivastigmine: One case of severe vomiting with oesophageal rupture reported to have occurred after re-initiation of treatment at an inappropriate single dose of 4.5mg following interruption of treatment for eight weeks.

Galantamine: three times as many people died while on the drug as those on placebo

Monitor for gastrointestinal symptoms and weight loss

Memantine

Neurotransmitter glutamate plays an integral role in learning and memory

In AD abnormal glutaminergic activity can cause neuronal toxicity and may impair learning

Memantine blocks abnormal glutamate activity Memantine slows cognitive and functional loss in moderately

severe AD (MMSE 5-14)

Memantine: Mechanism of Action

Glutamate excitotoxicity via excessive N-methyl-d-aspartate(NMDA) receptor excitation believed to play role in neuronal death in AD

Excitotoxicity occurs in part because of overactivation of NMDA-sensitive glutamate receptors, permitting excessive Ca2+ influx through the receptor’s associated ion channel

NMDA receptor antagonists may prevent neuronal loss associated with glutamate associated excitotoxicity

Memantine Indications

Moderately severe Alzheimer’s dementia Following indications approved by PBS:

1. MMSE 10 – 14 2. MMSE ≤ 9 with Clinicians Interview Based Impression of

Severity (CIBIS) scale

Needs to be sole PBS subsidised therapy for the indication Can use in conjunction with cholinesterase inhibitors but only

memantine will be PBS subsidised

Patient 2

62 year old retired office clerk Husband deceased Two daughters with separate Enduring Power of Attorney Travelled extensively Family history of dementia in 7 of 12 siblings Non-smoker, no regular EtOH

Presenting Complaint

Visual neglect Difficulty perceiving objects on right side Veering to right hand side of road onto oncoming traffic (Jan

2010)

Visual agnosia Inability to distinguish contents of the fridge

Dressing apraxia Wearing clothes back to front

Mild expressive dysphasia Onset October 2009 MRI brain 2010 reported as “age related atrophy”

Past Medical History

Osteoarthritis – bilateral hip replacements postoperative visual

hallucinations and delirium (Hb 89)

Hypertension and postural hypotension

Hypercholesterolaemia Vitamin D deficiency

Medications: Aspirin 100mg mane Nifedipine XR 30mg mane Cholecalciferol 1000units

mane Meloxicam 15mg mane PRN (Atorvastatin ceased Mar

2011)

Physical Examination

BP 154/82mmHg PR 72 lying, 160/88mmHg PR 72 standing 1 min

Left sided visual neglect on confrontation but normal visual fields

No oculomotor palsy Normal power, reflexes, Babinski reponse on right

Addenbrooke’s Cognitive Examination

Addenbrooke’s Cognitive Examination

Addenbrooke’s Cognitive Examination

Cognitive Assessment

Addenbrooke’s Cognitive Examination Score 65/100, MMSE component 23/30 Deficits in visuospatial skills (inability to copy

intersecting pentagons or cube) Clockface – numbers crowded to right Perceptual abilities – unable to count dots, unable to

identify letters of alphabet Some deficits in memory and verbal fluency

Posterior Cortical Atrophy

• Clinical features:• distinct clinical syndrome

• not just Alzheimer's disease (AD) with prominent visual defects

• Presents with progressive decline in complex visual processing out of proportion to other cognitive difficulties

Posterior Cortical Atrophy

• clinical features:• mean age of onset 58 years (range 51-64)• progresses over a decade or more• visuoperceputal and visuospatial impairments in setting

of normal ophthalmological assessment• complex visual disturbances:

• visual agnosia• environmental disorientation• dressing apraxia• pure alexia• achromatopsia

Hiding in plain sight: a closer look at posterior cortical atrophyBeh SC, Muthusamy B, Calabresi P, et alPract Neurol 2014;0:1–9

Balint’s Syndrome

Comprises: Ocular apraxia: inability to voluntarily direct one’s gaze to a

particular point (Charles and Hillis, 2005). Results in tendency to fix gaze on a single object

Optic ataxia: impairment of goal-directed hand movements towards visually presented targets (Trillenberg et al., 2007). Results in misreaching for objects

Simultanagnosia: inability to perceive two or more objects simultaneously

Damage to bilateral dorsal occipitoparietal regions

Gerstmann’s Syndrome

Comprises:1. Acalculia2. Agraphia3. Finger agnosia4. Left-right disorientation

Left inferior parietal damage in region of angular gyrus

Pathology in PCA

Alzheimer’s pathology predominant Rarely: corticobasal degeneration, dementia with

Lewy Bodies, prion disease Distribution of pathology differs to AD:

High density of neurofibrillary tangles in occipital regions

Management of PCA

No proven treatment

Consider cholinesterase inhibitors

Important to make diagnosis to stop inappropriate further investigation and/or intervention

Supportive measures – assistance with dressing, reduce reliance on visual cues, alternatives to driving

Young-Onset Dementia

Young-Onset Alzheimer’s Disease

Co-existence of cerebrovascular disease, renal and cardiac disease much less common

Autosomal dominant familial AD more common Myoclonus Preserved naming Speech production deficits

Non-amnestic presentation comprised 1/3 of cases (c.f. 5% in older onset) Posterior Cortical Atrophy is most common

Young-Onset Vascular Dementia

Greater association with vascular risk factors Rarer causes of early cerebrovascular disease

should be considered Cerebral Autosomal Dominant Arteriopathy with

Subcortical Infarcts and Leukoencephalopathy (CADASIL)

Amyloid angiopathy (inflammatory type treatable) Vasculitis

Young-Onset Frontotemporal Lobar Degeneration (FTLD)

Accounts for greater proportion of dementias in younger compared to later onset

20-40% of FTLD familial in cases referred to specialist centres

Young-Onset Dementia with Lewy Bodies

Dementia with Lewy Bodies is usually pathologically characterised by Lewy bodies, senile plaques and tangles

Rare younger onset form where only Lewy bodies are present

In younger onset Parkinson’s disease, tend to have dementia less frequently and after longer duration

Investigations for Young-Onset Dementia

Laboratory investigations FBC, biochemical screens Syphilis and HIV serology Auto-antibodies, antineuronal antibodies

Neurogenetics MRI brain Neurophysiology

EEG, nerve conduction studies, EMG Lumbar puncture

Young-Onset Dementia

Early, accurate diagnosis Impact on work and ability to continue working Address driving capability

Roads and Traffic Authority Driver Assessment and Rehabilitation Service (ACT Health) Fitness to Drive Medical Clinic (ACT Health)

Enduring Power of Attorney and Advanced Care Directive Assistance at home and respite services

Disability ACT, National Disability Insurance Scheme (≤65 years) Aged Care Assessment Team (>65 years)

Companion card, Taxi Subsidy

Reference

Rossor MN, Fox NC, Mummery CJ, Schott JM, Warren JD. The Diagnosis of Young-Onset Dementia. Lancet Neurology 2010; 9 (8): 793-806

Beh SC, Muthusamy B, Calabresi P, et al. Hiding in plain sight: a closer look at posterior cortical atrophy. Practical Neurology 2014;0:1–9