Case Presentation

1. Case Presentation

2. LW • 85yr old lady • A year ago – past-times included…dancing, playing the drums, organising garden competitions, making straw hats • Over the last year she had had had to give some of this up to care for her husband • He has Alzheimer’s Dementia and his mobility and hearing had been deteriorating • She had been caring for her husband with no external help up until a few months ago

3. About 2-3 months ago there was a family dispute -daughter worried not coping and wanted help at home -father refused to have carers -patient felt stuck in the middle -had become increasingly anxious • 2 months ago son moved more locally with some improvement in his mother’s symptoms • 1 month ago sudden deterioration with increased anxiety and depression • Seen by Dr Bown and started in Mirtazepine 30mg OD but no improvement

4. Over a 2 week period become progressively worse - more and more anxious -“clutching herself” -inconsolable -withdrawn -off food and drink. • GP had instituted 24 hour carers • Referred by GP to try and “break the cycle”

5. On Admission (12/9/08) • Obs normal • Clinically dry • AMTS not possible as not responding to questions- seemed to respond to son non-verbally • Exam normal except ?left facial droop- but no teeth in and son stated this appearance normal for her. Tone symmetrical, moving all 4 limbs, plantars downgoing • Bloods WCC 11.3 Ur 27.8 Neut 9.7 Cr 198 CRP <5 • Rehydrated and CT head planned- no impression given!

6. When we first met her (13/9/08) • AMTS -age, dob, place, time of day, yr correct • Groaning and looked uncomfortable • Short answers to questions • Temp 37.7 • Urine dip positive leucocytes and nitrites +++ • WCC 12.1 Neut 10.8 CRP 9 • Treated for UTI (iv amoxicillin + stat gentamycin) with some improvement • CT Brain- age consistent cerebral atrophy, some white matter small vessel ischaemic change

7. And then 2 days later on a Friday afternoon (15/9/08) • ATSP re: drop in GCS to 7/15 • Had eaten breakfast that am and been talking with nurses. Some vomiting that am, gradual decline in responsiveness • Temp 37.9 • No signs of meningism • Not moving any limbs, reflexes normal, plantars downgoing, PERLA • BM normal. Bloods no change. CXR normal. ABG normal. • Repeat CT head- nil change from previous • LP technically not possible

8. Impression ?worsened sepsis ?uti ?encephalitis ??contribution from mirtazepine (dose had been reduced) ???some psychiatric component • Management -started on empirical aciclovir to cover possible encephalitis -antibiotics for UTI -mirtazepine stopped

9. Over that w/e… • Fluctuating GCS between 7 and 14- sometimes unresponsive, other times groaning, other times sitting up and more alert • Jerking movements of limbs noted-?partial seizures

10. Neurology Review • O/E subtle myoclonus • Imp: likely rapid dementia with intercurrent UTI heralding admission • Advised the need to exclude reversible causes but ? CJD • Suggested Bloods, LP, MRI, EEG

11. Psychiatry Review • Not a depressive illness- may be a depressive component to illness which has an organic cause • But wouldn’t hurt to start citalopram!

12. All this while • Fluctuations in GCS • Variable from day to day from groaning, barely responding to more alert, trying to answer questions, taking some food and water. • Increased tone noted in limbs

13. Results • Bloods- normal autoimmune screen, thyroid peroxidase antibody test, VDRL and plasma viscosity • MRI- movement artefact +++, peri-ventricular small vessel ischaemia and ischaemic damage within the brain stem • EEG- slow and fast activity, very non specific, consistent with organic encephalopathy • LP- WCC 1, RCC 1, protein 0.3, glucose not done, No growth on culture. Negative protein 14-3-3.

14. Re- review • Neurology -No clear neurological pathology -No hard brainstem signs -? Behavioural increase in tone • Psychiatry -Organic illness

15. Rehabilitation • Although fluctuating general trend very very slow improvement • Plan is to try and rehabilitate • Variability continues even now…days where in bed, still looking uncomfortable, minimal conversation to days where sat out in the chair and even walked with zimmer frame • Started on lorazepam 0.5mg bd for tone • Was on citalopram but stopped due to low sodium- no change noted on stopping

16. Food for thought… • Diagnosis is not always possible • Difference in opinion between specialities • Working with disabilities of illness to try and rehabilitate even when you don’t necessarily know what caused them • CJD as a cause of rapid cognitive decline…..

17. CJD

18. Transmissible Spongiform Encephalopathies Under a microscope, the affected brain tissue looks like a sponge

19. Prion protein • Cellular protein found in brain and spinal cord (lower levels in lymphoid tissue) • Function unknown • In CJD an altered form of the normal protein causes normal protein to change conformation and transform into an abnormal prion protein. The latter accumulates as it is resistant to proteases and leads to damage to brain cells • Where does this initial abnormal prion protein originate? -Sporadic ?Somatic mutation -Familial Inherited mutation -Variant Consumption of meat contaminated with brain tissues of cows with BSE

20. Types of CJD Rare disease • Sporadic (Most common- one per million) • Variant (Associated with BSE) • Familial (Mutations in PRNP gene)

21. Clinical Features Sporadic CJD • Median age at death 68 yrs • Median duration of illness 4-5 months • Rapid dementia • Early neurologic symptoms e.g. myoclonus Variant CJD • Younger 20-30’s • Duration 13-14 months • Prominent psychiatric/ behavioural changes (anxiety, withdrawal, apathy, agitation, depression, personality change) • Painful dyesthesiasis • Delayed neurologic signs

22. Investigations • EEG • MRI • CSF • (Genetic testing) Post mortem makes definitive diagnosis

23. EEG Spike and wave pattern

24. EEG • 60-80% will develop characteristic EEG pattern • BUT pattern develops throughout the course of the illness and, in some cases, may not appear until very late. • Therefore, finding a positive EEG may require repeat studies (possibly weekly) even very late into the illness course and these may not always be undertaken.

25. MRI

26. MRI • Generally undertaken to exclude other illnesses • Cerebral atrophy may be seen • In a proportion, abnormalities of signal may be seen in the anterior basal ganglia and sometimes in the cortex. • These changes can be helpful in supporting a diagnosis of sporadic CJD.

27. MRI in Variant CJD Characteristic abnormality seen in the posterior thalamic region (the so called “pulvinar sign”) which is highly sensitive and specific for vCJD

28. CSF • The routine examination of CSF is generally unremarkable • Total protein may be elevated but usually less than 1 gram per litre

29. CSF 14-3-3 Analysis • Normal neuronal protein • Released into the CSF in response to a variety of neuronal insults • Therefore generally a non-specific finding and 14-3-3 analysis cannot be used as a general screening test for sporadic CJD • Other illnesses, which can give a positive 14-3-3 test, include: • Herpes simplex encephalitis • Recent cerebral infarction or haemorrhage • Subarachnoid haemorrhage • Hypoxic brain damage • Glioblastoma

30. CSF 14-3-3 Analysis • However, usually a straightforward clinical matter to exclude the other possible illnesses which may give rise to an elevated 14-3-3 level. • Therefore, in an appropriate clinical context, a positive test is strongly supportive of a diagnosis of sporadic CJD and a negative test is unusual. • In the United Kingdom, the National Laboratory for 14-3-3 CSF test is in the National CJD Surveillance Unit. • If a case meets the diagnostic criteria for “possible 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 “probable sporadic CJD”.

31. Management • No cure • Management is symptomatic • MDT approach • As these diseases are rare, experience in local services is often limited. The National Prion Clinic has been established to provide a clinical service for people with or suspected to have any form of prion disease. Assessment, diagnosis, information, advice, support and counselling is available for patients, their families, health care professionals and members of the public.

32. Potential treatments under investigation Pentosan polysulphate • Not licensed • Infused directly into the brain • MRC trial in 7 patients- may possibly prolong survival but did not halt deterioration in the brain Quinacrine • Very limited evidence from laboratory tests for the potential use of quinacrine in human prion disease, and the evidence to date for any possible clinical benefit is very scarce • MRC trial ongoing

33. Monitoring • The National CJD Surveillance Unit, based in Edinburgh, was established in 1990 to monitor the incidence of all types of CJD and to investigate the occurrence of the disease. • It investigates each case of sporadic and variant disease in detail so that any change in the pattern of CJD following the occurrence of BSE can be detected, and provides up-to-date information on current trends and incidence of the disease.