Creutzfeldt-Jakob disease (CJD) is a human prion disease that exists in four forms; sporadic, genetic, iatrogenic and variant.1 Human prion diseases share common neuropathological features such as spongiform degeneration, astrocytic gliosis and neuronal loss associated with amyloid plaques.2 The prion protein is a cellular protein that changes through an unknown mechanism from its normal structure (PrPc) to PrPsc, which is insoluble, resistant to protease degradation, accumulates is tissues and causes amyloid deposits.1

Sporadic CJD (sCJD) was first identified in the 1920’s as a rare atypical form of dementia.2 The annual UK mortality rate for sporadic CJD (sCJD) was 1.69 cases/million in 2016.3 Surveillance figures have shown the number of deaths has steadily risen since 1985, but this may be due to improved diagnosis with the median age of death being 69 years in 2010-2016.3 Patients with sCJD typically present with a rapidly progressing dementia accompanied by other features including visual loss, myoclonus and cerebellar ataxia with the mean duration of illness being only four months.1 Sporadic CJD may be split into six further subtypes that may determine neuropathological features, but these will not be discussed in this paper.2

Case report

A 77-year-old female was admitted to a District General Hospital, referred by her GP with a 6-8 week history of rapid deterioration in her memory, unsteady gait and jerking right arm. Her past medical history comprised of an NSTEMI, hypertension, aortic regurgitation and diverticular disease. She was a retired secretary, lived with her husband, non-smoker, took minimal alcohol and was relatively fit and active for her age, enjoying swimming weekly and long walks with her husband.

History from her husband cited a very sudden onset of distress one morning after a vivid dream, then a week later sudden onset of confusion and disorientation. Initially, the patient was reviewed by her GP. Initial memory test by the GP was normal and with a history of ongoing family stress a diagnosis of depression was made, antidepressants were offered but refused by the patient. The patient was referred for talking therapy and on the third consultation this was ceased and the patient referred back to the GP due to complaints of double vision during the meeting.

An urgent referral was made to neurology outpatients at the local DGH. The assessment diagnosed the symptoms as functional and she was commenced on citalopram and referred for urgent CT brain. Days after starting the citalopram it was stopped due to increased jerking and diazepam commenced. CT brain with contrast did not show any abnormality.

The patient was reviewed again by the GP and at this stage her gait was so poor that she was “bum shuffling”. She was referred to the emergency department. On admission her vital signs were within normal parameters, AMT 7/10 and confusion screen blood tests unremarkable. Initial neurological assessment documented normal power in limbs, intention tremor right upper limb, nystagmus at extreme right gaze, myoclonic twitches of right cheek and unable to walk. No reflexes checked. The patient had refused MRI due to concerns of claustrophobia and she was admitted to a ward to see the Parkinson’s disease specialist consultant with differential diagnosis of Parkinson’s disease, Parkinson’s plus syndrome and vascular dementia.

Neurological assessment by the consultant identified bilateral tremor in upper limbs, full eye movements, reflexes exaggerated bilaterally in lower limbs, myoclonic jerking of lower limbs, bilateral up going plantars, dysphasia and dysphagia. The patient consented to MRI with oral sedation. (Figures 1 & 2)

The MRI was reported as subtle gyroform area of cortical restricted diffusion involving the left temporal parietal occipital lobe with corresponding subtle T2 and FLAIR hyperintensity. The report suggested that this was more likely of inflammatory aetiology such as encephalitis.

A phone call was made to the local tertiary referral centre who suggested LP, IV acyclovir and urgent neurological opinion at the DGH. Later that day the neurologist reviewed the patient and referred to tertiary referral centre, where unfortunately there were no beds. They were advised to add antibiotics, EEG and to contact the National CJD Research & Surveillance Unit in Edinburgh. The unit advised to save 2mls of LP fluid in the lab, of which they would collect should the CSF result be clear of organism or blood cells. The MRI was shared through PACs.

The following day a neurologist from the tertiary referral centre was onsite at the DGH and assessed the patient. Assessment found stimulus sensitive myoclonus, probable cortical blindness, rigidity and ataxia with rapidly progressive cognitive decline, and placed sporadic CJD high in the differential, with the need to rule out infection/autoimmune cause.

The CSF result was returned that day, no organisms in gram stain and only one red and one white cell seen. The unit were informed of the results.

The following day the surveillance unit collected the sample from the lab. An MDT at the tertiary referral centre highlighted the MRI showed findings typical of sCJD. A team from the surveillance unit assessed the patient and took history from the husband the next day and based on the clinical history, presentation, MRI and CSF findings concluded a diagnosis of probable sCJD (>95% probability). The team advised the patient she had days to weeks to live and for palliative care only and not for parenteral feeding.

Three days later the patient was unable to swallow her saliva and was commenced on a syringe driver, being nursed on her side to aid drainage of saliva and requiring suction for comfort.

The following day the patient passed away. The time from onset of symptoms to death was 66 days. Posthumously the CSF results showed positive for 14-3-3 and real time quaking-induced conversion.

Discussion

According to Iwasaki,4 the clinical course of sCJD can be split into three stages. The first stage consists of non-specific symptoms such as anxiety, depression, visual disorder, memory disturbance and unsteadiness. Iwasaki states that at this stage and even several months before clinical onset there will be changes of hyperintensity in the cerebral cortex and striatum on diffusion weighted MRI.

The second stage involves rapid deterioration of cognition, dysphasia, myoclonus, gait disturbance, brisk tendon reflex and muscle rigidity. The third stage is that of akinetic mutism state and death. Mead & Rudge cite that patients may deteriorate to this state in a number of weeks.5

They also discuss how early presentations are often mistaken for Alzheimer’s, psychosis or depression and as the disease progresses to the second stage, a number of differential diagnosis such as encephalitis, paraneoplastic conditions, Wernicke’s encephalopathy, stroke and hypothyroidism need to be excluded.

Diagnosis of sCJD is based upon three investigations: that of MRI brain, EEG and CSF analysis.1 Abnormalities found on MRI include high signal or FLAIR in the striatum, cerebral cortex and or thalamus. It has been suggested that MRI brain offers >90% sensitivity in sCJD.5

Triphasic periodic complexes on EEG are virtually diagnostic of sCJD,2 however, it can be argued that the EEG offers less value than other investigations such as MRI and CSF, but may suggest alternative diagnosis.5 Being cared for in a DGH with minimal neurology resources, the patient in this case did not receive an EEG, however, based on MRI results and clinical features there was sufficient evidence to support a diagnosis.

CSF fluid is analysed for protein 14-3-3, which has limited specificity as it is not only CJD that may cause its presence. 14-3-3 reflects rapid tissue damage, and therefore may be present in other conditions, however, it is diagnostically useful when used in clinical context.2,5 New advances have been made with regards to CSF testing, including real-time quaking-induced conversion, which is said to have a remarkably high sensitivity and specificity. Both these findings were positive in this case, although the results were not available until after death.2,5

There are no treatment options for sCJD other than supportive care to patients and their relatives.5 It has been cited that Japanese patients have a longer survival than others with sCJD due to the introduction of tube feeding,4 however, this provides ethical dilemmas regarding prolonging the akinetic mutism stage.

This case highlights the almost text book journey of this patient with sCJD. It highlights the non-specific initial psychiatric symptoms followed by a rapid decline in cognition and neurological function to akinetic mutism and finally death. With the help and assistance of the National CJD Research & surveillance unit, Edinburgh, an accurate diagnosis was made which assisted quality end of life care and support to the patient and family.

Conflict of interest: none declared

References

  1. 25th ANNUAL REPORT 2016 Creuzfeldt-Jacob disease surveillance in the UK. The National CJD Research & Surveillance Unit Western General Hospital, Edinburgh, EH4 2XU https://www.cjd.ed.ac.uk/sites/default/files/report25.pdf
  2. Iwasaki, Y. (2016). Creutzfeldt-Jakob disease. Neuropathology, 37(2), 174-188. doi:10.1111/neup.12355
  3. Knight, R. (2006). Aging and Infectious Diseases: Creutzfeldt‐Jakob Disease: A Rare Cause of Dementia in Elderly Persons. Clinical Infectious Diseases, 43(3), 340-346. doi:10.1086/505215
  4. Mead, S., & Rudge, P. (2017). CJD mimics and chameleons. Practical Neurology, 17(2), 113-121. doi:10.1136/practneurol-2016-001571
  5. Will, R. and Ironside, J. (2016). Sporadic and Infectious Human Prion Diseases. Cold Spring Harbor Perspectives in Medicine, 7(1), p.a024364.

 


Rachel Bennett

Advanced Nurse Practitioner, Sherwood Forest Hospitals NHS Foundation Trust

Dr Slavka Ulikova

Specialty Doctor in Geriatrics, Sherwood Forest Hospitals NHS Foundation Trust

Dr Nishantha Silva

Consultant Physician and Geriatrician, Clinical Lead for Parkinson’s Disease, Sherwood Forest Hospitals NHS Foundation Trust

Nishantha.silva@nhs.net