Case Case PresentationPresentation

LWLW 85yr old lady85yr old lady

A year ago – past-times included…dancing, A year ago – past-times included…dancing, playing the drums, organising garden playing the drums, organising garden competitions, making straw hatscompetitions, making straw hats

Over the last year she had had had to give some Over the last year she had had had to give some of this up to care for her husbandof this up to care for her husband

He has Alzheimer’s Dementia and his mobility He has Alzheimer’s Dementia and his mobility and hearing had been deterioratingand hearing had been deteriorating

She had been caring for her husband with no She had been caring for her husband with no external help up until a few months agoexternal help up until a few months ago

About 2-3 months ago there was a family dispute About 2-3 months ago there was a family dispute

-daughter worried not coping and -daughter worried not coping and wanted help wanted help at homeat home

-father refused to have carers-father refused to have carers-patient felt stuck in the middle-patient felt stuck in the middle-had become increasingly anxious-had become increasingly anxious

2 months ago son moved more locally with some 2 months ago son moved more locally with some improvement in his mother’s symptomsimprovement in his mother’s symptoms

1 month ago sudden deterioration with increased 1 month ago sudden deterioration with increased anxiety and depressionanxiety and depression

Seen by Dr Bown and started in Mirtazepine Seen by Dr Bown and started in Mirtazepine 30mg OD but no improvement30mg OD but no improvement

Over a 2 week period become progressively Over a 2 week period become progressively worseworse

- more and more anxious - more and more anxious -“clutching herself”-“clutching herself”-inconsolable-inconsolable-withdrawn-withdrawn-off food and drink. -off food and drink.

GP had instituted 24 hour carersGP had instituted 24 hour carers

Referred by GP to try and “break the cycle”Referred by GP to try and “break the cycle”

On Admission (12/9/08)On Admission (12/9/08) Obs normalObs normal

Clinically dryClinically dry

AMTS not possible as not responding to questions- seemed to AMTS not possible as not responding to questions- seemed to respond to son non-verballyrespond to son non-verbally

Exam normal except ?left facial droop- but no teeth in and son Exam normal except ?left facial droop- but no teeth in and son stated this appearance normal for her. Tone symmetrical, moving stated this appearance normal for her. Tone symmetrical, moving all 4 limbs, plantars downgoingall 4 limbs, plantars downgoing

Bloods Bloods WCC 11.3 WCC 11.3 Ur 27.8Ur 27.8Neut 9.7 Neut 9.7 Cr 198Cr 198CRP <5 CRP <5

Rehydrated and CT head planned- no impression given!Rehydrated and CT head planned- no impression given!

When we first met her When we first met her (13/9/08)(13/9/08)

AMTS -age, dob, place, time of day, yr correctAMTS -age, dob, place, time of day, yr correct

Groaning and looked uncomfortableGroaning and looked uncomfortable

Short answers to questionsShort answers to questions

Temp 37.7Temp 37.7

Urine dip positive leucocytes and nitrites +++Urine dip positive leucocytes and nitrites +++

WCC 12.1 WCC 12.1 Neut 10.8 Neut 10.8 CRP 9CRP 9

Treated for UTI (iv amoxicillin + stat gentamycin) with some Treated for UTI (iv amoxicillin + stat gentamycin) with some improvementimprovement

CT Brain- age consistent cerebral atrophy, some white matter CT Brain- age consistent cerebral atrophy, some white matter small vessel ischaemic changesmall vessel ischaemic change

And then 2 days later on a And then 2 days later on a Friday afternoon (15/9/08)Friday afternoon (15/9/08)

ATSP re: drop in GCS to 7/15ATSP re: drop in GCS to 7/15

Had eaten breakfast that am and been talking with nurses. Some Had eaten breakfast that am and been talking with nurses. Some vomiting that am, gradual decline in responsivenessvomiting that am, gradual decline in responsiveness

Temp 37.9Temp 37.9

No signs of meningismNo signs of meningism

Not moving any limbs, reflexes normal, plantars downgoing, Not moving any limbs, reflexes normal, plantars downgoing, PERLAPERLA

BM normal. Bloods no change. CXR normal. ABG normal.BM normal. Bloods no change. CXR normal. ABG normal.

Repeat CT head- nil change from previousRepeat CT head- nil change from previous

LP technically not possibleLP technically not possible

Impression Impression

?worsened sepsis ?uti ?encephalitis?worsened sepsis ?uti ?encephalitis

??contribution from mirtazepine (dose had been ??contribution from mirtazepine (dose had been reduced)reduced)

???some psychiatric component???some psychiatric component

ManagementManagement

-started on empirical aciclovir to cover possible -started on empirical aciclovir to cover possible encephalitisencephalitis

-antibiotics for UTI-antibiotics for UTI

-mirtazepine stopped-mirtazepine stopped

Over that w/e… Over that w/e…

Fluctuating GCS between 7 and 14- Fluctuating GCS between 7 and 14- sometimes unresponsive, other sometimes unresponsive, other times groaning, other times sitting times groaning, other times sitting up and more alertup and more alert

Jerking movements of limbs noted-?Jerking movements of limbs noted-?partial seizurespartial seizures

Neurology ReviewNeurology Review

O/E subtle myoclonusO/E subtle myoclonus

Imp: likely rapid dementia with Imp: likely rapid dementia with intercurrent UTI heralding admissionintercurrent UTI heralding admission

Advised the need to exclude reversible Advised the need to exclude reversible causes but ? CJDcauses but ? CJD

Suggested Bloods, LP, MRI, EEGSuggested Bloods, LP, MRI, EEG

Psychiatry ReviewPsychiatry Review

Not a depressive illness- may be a Not a depressive illness- may be a depressive component to illness depressive component to illness which has an organic causewhich has an organic cause

But wouldn’t hurt to start But wouldn’t hurt to start citalopram!citalopram!

All this whileAll this while

Fluctuations in GCSFluctuations in GCS

Variable from day to day from Variable from day to day from groaning, barely responding to more groaning, barely responding to more alert, trying to answer questions, alert, trying to answer questions, taking some food and water.taking some food and water.

Increased tone noted in limbsIncreased tone noted in limbs

ResultsResults Bloods- normal autoimmune screen, thyroid Bloods- normal autoimmune screen, thyroid

peroxidase antibody test, VDRL and plasma peroxidase antibody test, VDRL and plasma viscosityviscosity

MRI- movement artefact +++, peri-ventricular MRI- movement artefact +++, peri-ventricular small vessel ischaemia and ischaemic damage small vessel ischaemia and ischaemic damage within the brain stemwithin the brain stem

EEG- slow and fast activity, very non specific, EEG- slow and fast activity, very non specific, consistent with organic encephalopathyconsistent with organic encephalopathy

LP- WCC 1, RCC 1, protein 0.3, glucose not done, LP- WCC 1, RCC 1, protein 0.3, glucose not done, No growth on culture. Negative protein 14-3-3.No growth on culture. Negative protein 14-3-3.

Re- reviewRe- review

NeurologyNeurology

-No clear neurological pathology-No clear neurological pathology

-No hard brainstem signs -No hard brainstem signs

-? Behavioural increase in tone-? Behavioural increase in tone

PsychiatryPsychiatry

-Organic illness-Organic illness

RehabilitationRehabilitation Although fluctuating general trend very very slow Although fluctuating general trend very very slow

improvementimprovement

Plan is to try and rehabilitatePlan is to try and rehabilitate

Variability continues even now…days where in Variability continues even now…days where in bed, still looking uncomfortable, minimal bed, still looking uncomfortable, minimal conversation to days where sat out in the chair conversation to days where sat out in the chair and even walked with zimmer frameand even walked with zimmer frame

Started on lorazepam 0.5mg bd for toneStarted on lorazepam 0.5mg bd for tone

Was on citalopram but stopped due to low sodium- Was on citalopram but stopped due to low sodium- no change noted on stoppingno change noted on stopping

Food for thought…Food for thought…

Diagnosis is not always possibleDiagnosis is not always possible

Difference in opinion between specialitiesDifference in opinion between specialities

Working with disabilities of illness to try Working with disabilities of illness to try and rehabilitate even when you don’t and rehabilitate even when you don’t necessarily know what caused themnecessarily know what caused them

CJD as a cause of rapid cognitive decline…..CJD as a cause of rapid cognitive decline…..

CJDCJD

Transmissible Spongiform Transmissible Spongiform Encephalopathies Encephalopathies

Under a microscope, the affected brain tissue looks Under a microscope, the affected brain tissue looks like alike a

spongesponge

Prion proteinPrion protein Cellular protein found in brain and spinal cord (lower Cellular protein found in brain and spinal cord (lower

levels in lymphoid tissue)levels in lymphoid tissue)

Function unknownFunction unknown

In CJD an altered form of the normal protein causes In CJD an altered form of the normal protein causes normal protein to change conformation and transform into normal protein to change conformation and transform into an abnormal prion protein. The latter accumulates as it is an abnormal prion protein. The latter accumulates as it is resistant to proteases and leads to damage to brain cellsresistant to proteases and leads to damage to brain cells

Where does this initial abnormal prion protein originate?Where does this initial abnormal prion protein originate?-Sporadic -Sporadic ?Somatic mutation?Somatic mutation-Familial-Familial Inherited mutationInherited mutation-Variant-Variant Consumption of meat Consumption of meat

contaminated with brain contaminated with brain tissues of cows tissues of cows with BSEwith BSE

Types of CJDTypes of CJD

Rare diseaseRare disease

Sporadic (Most common- one per Sporadic (Most common- one per million)million)

VariantVariant (Associated with BSE) (Associated with BSE) FamilialFamilial (Mutations in PRNP gene) (Mutations in PRNP gene)

Clinical FeaturesClinical FeaturesSporadic CJDSporadic CJD Median age at death 68 yrsMedian age at death 68 yrs Median duration of illness 4-5 monthsMedian duration of illness 4-5 months Rapid dementiaRapid dementia Early neurologic symptoms e.g. myoclonusEarly neurologic symptoms e.g. myoclonus

Variant CJDVariant CJD Younger 20-30’sYounger 20-30’s Duration 13-14 monthsDuration 13-14 months Prominent psychiatric/ behavioural changes (anxiety, Prominent psychiatric/ behavioural changes (anxiety,

withdrawal, apathy, agitation, depression, personality withdrawal, apathy, agitation, depression, personality change)change)

Painful dyesthesiasisPainful dyesthesiasis Delayed neurologic signsDelayed neurologic signs

InvestigationsInvestigations

EEGEEG MRIMRI CSFCSF (Genetic testing)(Genetic testing)

Post mortem makes definitive Post mortem makes definitive diagnosisdiagnosis

EEGEEG

Spike and wave patternSpike and wave pattern

EEGEEG 60-80% will develop characteristic EEG 60-80% will develop characteristic EEG

patternpattern

BUT pattern develops throughout the BUT pattern develops throughout the course of the illness and, in some cases, course of the illness and, in some cases, may not appear until very late. may not appear until very late.

Therefore, finding a positive EEG may Therefore, finding a positive EEG may require repeat studies (possibly weekly) require repeat studies (possibly weekly) even very late into the illness course and even very late into the illness course and these may not always be undertaken. these may not always be undertaken.

MRIMRI

MRIMRI Generally undertaken to exclude other Generally undertaken to exclude other

illnessesillnesses

Cerebral atrophy may be seenCerebral atrophy may be seen

In a proportion, abnormalities of signal may In a proportion, abnormalities of signal may be seen in the anterior basal ganglia and be seen in the anterior basal ganglia and sometimes in the cortex. sometimes in the cortex.

These changes can be helpful in supporting These changes can be helpful in supporting a diagnosis of sporadic CJD. a diagnosis of sporadic CJD.

MRI in Variant CJDMRI in Variant CJD

Characteristic abnormality seen in the posterior thalamic Characteristic abnormality seen in the posterior thalamic region (the soregion (the so

called “pulvinar sign”) which is highly sensitive and specific called “pulvinar sign”) which is highly sensitive and specific for vCJDfor vCJD

CSF CSF

The routine examination of CSF is The routine examination of CSF is generally unremarkable generally unremarkable

Total protein may be elevated but Total protein may be elevated but usually less than 1 gram per litreusually less than 1 gram per litre

CSF 14-3-3 AnalysisCSF 14-3-3 Analysis Normal neuronal protein Normal neuronal protein

Released into the CSF in response to a variety of neuronal Released into the CSF in response to a variety of neuronal insultsinsults

Therefore generally a non-specific finding and 14-3-3 Therefore generally a non-specific finding and 14-3-3 analysis cannot be used as a general screening test for analysis cannot be used as a general screening test for sporadic CJDsporadic CJD

Other illnesses, which can give a positive 14-3-3 test, Other illnesses, which can give a positive 14-3-3 test, include: include:

Herpes simplex encephalitisHerpes simplex encephalitis Recent cerebral infarction or haemorrhage Recent cerebral infarction or haemorrhage Subarachnoid haemorrhageSubarachnoid haemorrhage Hypoxic brain damageHypoxic brain damage GlioblastomaGlioblastoma

CSF 14-3-3 AnalysisCSF 14-3-3 Analysis However, usually a straightforward clinical matter to However, usually a straightforward clinical matter to

exclude the other possible illnesses which may give rise to exclude the other possible illnesses which may give rise to an elevated 14-3-3 level. an elevated 14-3-3 level.

Therefore, in an appropriate clinical context, a positive test Therefore, in an appropriate clinical context, a positive test is strongly supportive of a diagnosis of sporadic CJD and a is strongly supportive of a diagnosis of sporadic CJD and a negative test is unusual.negative test is unusual.

In the United Kingdom, the National Laboratory for 14-3-3 In the United Kingdom, the National Laboratory for 14-3-3 CSF test is in the National CJD Surveillance Unit.CSF test is in the National CJD Surveillance Unit.

If a case meets the diagnostic criteria for “possible If a case meets the diagnostic criteria for “possible sporadic CJD” and has a duration of less than 2 years then sporadic CJD” and has a duration of less than 2 years then a positive 14-3-3 test allows the case to be classified as a positive 14-3-3 test allows the case to be classified as “probable sporadic CJD”.“probable sporadic CJD”.

ManagementManagement No cureNo cure

Management is symptomaticManagement is symptomatic

MDT approachMDT approach

As these diseases are rare, experience in local As these diseases are rare, experience in local services is often limited. The National Prion services is often limited. The National Prion Clinic has been established to provide a clinical Clinic has been established to provide a clinical service for people with or suspected to have any service for people with or suspected to have any form of prion disease. Assessment, diagnosis, form of prion disease. Assessment, diagnosis, information, advice, support and counselling is information, advice, support and counselling is available for patients, their families, health care available for patients, their families, health care professionals and members of the public.professionals and members of the public.

Potential treatments under Potential treatments under investigationinvestigation

Pentosan polysulphate Pentosan polysulphate

Not licensed Not licensed

Infused directly into the brainInfused directly into the brain

MRC trial in 7 patients- may possibly prolong survival but did not MRC trial in 7 patients- may possibly prolong survival but did not halt deterioration in the brainhalt deterioration in the brain

QuinacrineQuinacrine

Very limited evidence from laboratory tests for the potential use Very limited evidence from laboratory tests for the potential use of quinacrine in human prion disease, and the evidence to date of quinacrine in human prion disease, and the evidence to date for any possible clinical benefit is very scarce for any possible clinical benefit is very scarce

MRC trial ongoingMRC trial ongoing

MonitoringMonitoring The National CJD Surveillance Unit, based The National CJD Surveillance Unit, based

in Edinburgh, was established in 1990 to in Edinburgh, was established in 1990 to monitor the incidence of all types of CJD and monitor the incidence of all types of CJD and to investigate the occurrence of the disease. to investigate the occurrence of the disease.

It investigates each case of sporadic and It investigates each case of sporadic and variant disease in detail so that any change variant disease in detail so that any change in the pattern of CJD following the in the pattern of CJD following the occurrence of BSE can be detected, and occurrence of BSE can be detected, and provides up-to-date information on current provides up-to-date information on current trends and incidence of the disease.trends and incidence of the disease.