Prion Diseases - Neurological Infections

A seminar presented in the Department of Neurology, Believers Church Medical College Hospital, India.

1. PRION DISEASES DR CHRISTA MARIA JOEL MODERATOR: DR ARCHANA M

2. Objectives Introduction History, Epidemiology, Classification Prions - what is it? Etiology and Pathogenesis of Prion Diseases F unctions of Prions. Sporadic Prion Disease Genetic Prion Disease Acquired Prion Disease Prion decontamination Animal Prion Diseases Treatment of Prion diseases Prognosis, complications and differential diagnosis. Case Scenario

3. Introduction Group of uniformly fatal neurodegenerative diseases caused by transformation of an endogenous protein PrP into an abnormal conformation PrPsc. Also known as subacute spongiform encephalopathies. Derived from the term proteinaceous infectious particle , named by Stanley Prusiner. Mistaken for slow viruses . Do not contain nucleic acid . Subacute to chronic clinical course with similar neuropathology. Significant impact on Public Health and Medicine.

4. History of Creutzfeldt Jakob Disease Nomenclature 1920: Case described by Hans Creutzfeldt, Neurologist. 1921, 1923: Alfons Jakob, N eurologist - 4 papers on 5 unusual cases of rapidly progressive dementia. Out of the 5 cases- 2 cases were the actual disease. Initial name : Jakob’s disease or Jakob-Creutzfeldt Disease. Clarence J Gibbs: term Creutzfeldt Jakob Disease. Historically called transmissible spongiform encephalopathies due to 2 properties: transmissibility , and neuropathology spongiform diseases.

5. Epidemiology Incidence: 1-1.5 per million per year. Human prion cases: 6000 cases worldwide. Peak age of onset- 68 years. Lifetime risk of dying: 1 in 9000.

6. Classification Sporadic Prion Disease - Occur spontaneously (85%) Genetic Prion Disease- Mutation in PRNP (15%) Acquired Prion Diseases- Least common(<1%). F amilial CJD Gerstmann-Straussler Scheinker Disease F atal Familial Insomnia.

7. What are Prions? Normal prion protein - PrPc. c- cellular. Prions- abnormal infectious protein- PrPsc. Sc- Scrapie. PrPc and PrPsc: identical amino acid sequences but different 3D structures. Infectious properties and intrinsic ability of its structure to act as a template and convert PrPc into pathological form of PrPsc. PrPc + PrPsc- changes into the shape of PrPsc- accumulation or transformation leads to nerve cell injury and death.

8. Etiology and Pathogenesis Transmissible via multiple routes into non human primates or other species, most efficient- intracerebral. Transmissible agent- protease resistant PrPsc, resistant to chemical and physical agents. PrP amino acid sequence with either methionine or valine at codon 129 affects infectivity and phenotype. Understanding of Pathogenesis- incomplete.

9. Function of PrPc I mportant role in in neuronal development and function. Encoded by PRNP gene- on short arm of chromosome 20. PrPc - membrane bound, resides on nerve cell membranes, attached to outer cell membrane by GPI anchor, binds to many proteins and cellular constituents. Functions- cell signaling, adhesion, proliferation, differentiation and growth.

10. Sporadic Prion Disease- Epidemiology C lassic CJD or sCJD. Incidence- approximately 1.5 per million in all countries. Spontaneous transformation or somatic mutation. R apid disease with mean survival- 6 months. 90% of the patients die within a year of onset. Mean age of onset - 67 years Occurrence at a young (20-40s) or old (>75)- uncommon. Cases younger than 20 years - extremely rare.

11. Molecular Classification of sCJD 6 molecular subtypes. Based on genetic polymorphism at codon 129 in the prion gene and type of protease resistant prion. MM1, MV1- most common forms (70%). VV2 (16%) MV2 (9%) MM2 thalamic (2%) MM2 cortical (2%) VV1 (1%) * Methionine- M, Valine- V.

12. Sporadic CJD- Clinical Features Cognitive changes. Behavioural and personality changes. EPS. Cerebellar dysfunction. Constitutional symptoms. V isual symptoms. Myoclonus. Cortical dysfunction. Sensory symptom. Rapid progression. End stage- akinetic mute state. Most die from aspiration pneumonia.

13. Sporadic CJD- Neuropathology Neuronal loss. Gliosis- early feature Vacuolation- spongiform change- early feature Deposition of PrPsc.

14. Diagnostic criteria of CJD WHO 1998 Revised criteria (WHO 1998): Progressive dementia Myoclonus, Visual or cerebellar disturbance, Pyramidal or EPS, Akinetic mutism PSWCs on EEG, positive 14-3-3 CSF assay, clinical duration to death less than 2 years. No alternative diagnosis. UCSF 2007 criteria: Dementia. Myoclonus, pyramidal or EPS, visual disturbance, cerebellar signs, akinetic mutism, high focal cortical sign. Typical EEG or MRI. No alternative diagnosis. European Criteria 2009: Progressive dementia. Myoclonus, visual or cerebellar disturbance, pyramidal or EPS, akinetic mutism. EEG- periodic discharges, positive 14-3-3 CSF assay, clinical duration to death- <2 years, DWI or FLAIR changes. No alternative diagnosis.

15. Diagnostic tests for sporadic CJD- Laboratory studies CBC LFT ESR ANA All the above tests are unremarkable.

16. Diagnostic tests for sporadic CJD- EEG S harp or triphasic waves (periodic sharp wave complexes), once very second.

17. Diagnostic tests for sporadic CJD- CSF CSF routine: mildly elevated protein (<100 mg/dl). CSF biomarkers: 14-3-3 protein- diagnostic marker- controversial due to poor sensitivity and specificity, merely a marker for rapid neuronal injury. Other CSF markers: total tau, neuron specific enolase, astrocytic s100 beta. Considered unreliable for diagnosis. Biomarkers Sensitivity Specificity 14-3-3 protein 85% 84% t-tau 86% 88% Neuron specific enolase 73% 95% S100 Beta 82% 76%

18. Diagnostic tests for sporadic CJD- MRI Highly sensitive and specific - 91 to 96%. MRI with DWI and FLAIR sequences. Basal ganglia hyperintensities (T2 weighted), cortical gyral hyperintensities- cortical ribboning (DWI and FLAIR). High signal abnormalities in caudate nucleus and putamen or at least 2 cortical regions ( temporoparietal occipital).

19. Development of a Prion specific diagnostic test Bodily fluids-blood, urine or saliva. Protein misfolding cyclic amplification: produce large quantities of PrPsc- similar to PCR. Real time quaking induced conversion- combines technique of PMCA and PrPsc amyloid seeding assay.

20. Variably protease sensitive proteinopathy Very rare form of sCJD. Usually PrPsc - resistant to proteases, enzymes that digest proteins. In this case: protease sensitive. Clinical features: Psychiatric symptoms, frontal dementia, negative diagnostic tests. Mean disease duration: about 2.5 years.

21. Genetic Prion Disease Referred to as familial but its a misnomer. Mutation in the PrP gene PRNP. Autosomal dominant. More than 40 mutations identified. Most important polymorphism - at codon 129, either methionine or valine. Diagnosis- identification of a mutation in the PrP gene PRNP. DNA testing from blood or frozen brain autopsy tissue. Divided into 3 forms based on clinical and pathological forms: Familial CJD Gerstmann Straussler Scheinker disease. Fatal Familial Insomnia.

22. Familial CJD 15 point mutations, insertion mutation, octapeptide repeat insertion mutations with 4 or fewer 24 base pair repeats. Most common mutation - E200K. Present similarly to sCJD- overlapping clinical, MRI and EEG findings.

23. Gerstmann Straussler Scheinker Disease 15 PRNP mutations Subacute progressive ataxia, Parkinsonian disorder, cognitive impairment, dementia, behavioural abnormalities. Usually slower than sCJD- about 5 years. Can present like sCJD- rapid progression, death within a few months. Neuropathology- large PrPsc amyloid plaques - kuru plaques. Identified by use of 18F FDDNP and PET scan- contain smaller fragments of PrPsc.

24. Fatal Familial Insomnia First case: 1986. Single PRNP point mutation D178N with codon 129 M on the same chromosome. Survive longer- about 1.5 years. Brain MRI- normal. FDG PET- thalamic and cingulate hypometabolism before the onset. Neuropathology: profound thalamic gliosis, neuronal loss, atrophy.

25. Acquired CJD Prions are transmissible. Large amount of prions are needed for transmission. Human prion diseases- not contagious. Kuru is an example- now extinct Other acquired- iatrogenic CJD, variant CJD.

26. Kuru First identified forms of acquired human prion disease. 1957- first clinical case of Kuru described by D Carleton Gajdusek. ‘ Kuru’- to shake or tremble Identified among the Fore tribe in Papua New Guinea- endocannibalism. Cerebellar disease. Women and children- severe ataxia. Essentially eliminated- ritual was eliminated several decades ago. IP can go upto 50 years.

27. Iatrogenic CJD 400 cases identified. Use of cadaveric derived human pituitary hormones, dura mater grafts, corneal transplants, reuse of cleaned and sterilised EEG depth electrodes implanted directly into the brain, neurosurgical equipment, blood transfusion. Mostly in France, UK, US. 227 cases- human growth hormone. 4 cases- gonadotropins . 228 cases- contaminated dura mater, mostly in Japan. 6 cases: neurosurgical procedures 2 cases: corneal implants. Symptoms: cerebellar and visual dysfunction. iCJD - declining.

28. Variant CJD First identified- 1995. Most notorious form. In UK, France. Consumption of contaminated beef with bovine spongiform encephalopathy (mad cow), blood transfusion. Younger patients, median age-27, longer duration- 14.5 months. Profound psychiatric symptoms, painful paraesthesia in parts of the body, chorea. Brain biopsy- PrPsc in lymphoreticular system, tonsillar tissue. Florid plaques. June 2014- 225 cases all in the UK and France.

29. Diagnostic Criteria for vCJD Progressive neuropsychiatric disorder- definite vCJD Duration of illness > 6 months. No alternative diagnosis. No familial form of TSE. Early psychiatric features. Persistent painful sensory symptoms. Ataxia. Myoclonus or chorea or dystonia. Dementia EEG: no typical appearance of sporadic CJD in early stages. Bilateral pulvinar high signal - MRI scan. Positive tonsil biopsy.

30. Prion Decontamination Resist normal inactivation methods used to kill viruses and bacteria. WHO recommended: steam sterilisation for 30 minutes at 132 C in a gravity displacement sterilizer . Pre Vacuum steriliser- 18 minutes at 134C. 1N sodium hydroxide or 2% sodium hypochlorite for 1 hour with 134 C autoclaving for 18 minutes. Non fragile items- immersed in 1N sodium hydroxide for 1 hour at room temperature, steam sterilised for 30 minutes at 121 C.

31. Animal Prion Diseases- Scrapie First prion disease- in sheep and goats. Described more than 150 years ago. Not directly transmissible to humans- species barrier, but can pass through cattle. Mid 1980s outbreak of BSE: scrapie contaminated material was fed to cattle. Ataxic illness, weight loss, behavioural changes, death. BSE cases dropped- proper epidemiological control. Ingestion of BSE prions- vCJD in UK. April 2012: 23 isolated cases of BSE in North America, 4 in US and 19 in Canada.

32. Chronic Wasting Disease (CWD) Prion disease of mule, deer, white tailed deer, elk, moose. First clinical case- laste 1960s, North America. Weight loss, behavioural changes, hypersalivation, polydipsia, polyuria, ataxia. Transmissible through blood, urine and saliva. Not clear of transmissibility to humans, but no cases have been noted among humans.

33. Treatment of Human Prion Diseases No known cure for the disease. Potential mechanisms for treatment: Reducing or removing endogenous substrate PrPc. Blocking interaction of PrPc with PrPsc. Removing PrPsc. Blocking PrPsc toxicity. Several medications used but none showed any improvement: oral Flupirtine, Quinacrine, and doxycycline. Intraventricular pentosan polysulphate in UK, Japan- no improvement but prolong survival time.

34. Management of Prion Diseases M anagement of symptoms and comfort care are vital. Selective serotonin reuptake inhibitors, Escitalopram: depression, anxiety, mild agitation. Atypical antipsychotics, Quetiapine: agitation and psychosis. Levetiracetam, valproic acid: myoclonus. Clonazepam: severe myoclonus, agitation.

35. Prognosis and complications Creutzfeldt-Jakob disease: mute, bedridden, stuporous state. Survival of patients rarely prolonged over a year or two except in atypical and some familial cases. Fatal familial insomnia : increasing insomnia and worsening dysautonomia, hyperthermia, tachycardia, and blood pressure instability and die within a year. Kuru : increasing walking disturbances, bedridden, die within a year of onset due to pneumonia and sepsis.

36. Differential Diagnosis Alzheimer’s disease. Lewy Body Disease Hashimoto encephalopathy Paraneoplastic or other autoimmune limbic encephalopathies. Cancers: lymphoma either within outside or inside the nervous system Central nervous system vasculitis. Metabolic or toxic disorders Corticobasal degeneration.

37. Special conditions- Pregnancy Effect of pregnancy on course of prion diseases- no information available. No evidence that children born to pregnant women with CJD develop the disease. Investigation of a child born from a woman with CJD: No evidence of proteinase K- resistant protein in gestational tissues, including the placenta and amniotic fluid. Transmission studies or amplification-based detection assays were not performed. Detection of chronic wasting disease prions in fetal tissues of white-tailed deer using an amplification method, demonstrated vertical transmission of prions.

38. Case Scenario (at BCMCH) 72 year old gentleman. Known comorbidities: old stroke- right paramedian pons, type 2 diabetes mellitus, systemic hypertension, dyslipidemia, chronic kidney disease, benign prostatic hypertrophy and right eye- old vitreous hemorrhage. Presenting complaints: complaints of 2 episodes of vomiting, worsening of weakness of left upper and lower limb, mRs at presentation was 3. Treated in a local hospital and was referred here for further evaluation and monitoring. No head trauma. Examination: GCS: E4V5M6, spastic weakness of left upper and lower limbs with power ⅗.

39. Case scenario: Diagnostic workup & Course Initial blood investigations: normal. MRI brain Stroke protocol with TOF angio: gliotic changes- bilateral arterial temporal and right basifrontal area, grade 4 Fazeka. Treated conservatively- physiotherapy, supportive management. 4th day of admission: fall in GCS, 1 episode of seizure- focal with impaired awareness- Loaded with Levipil, Lacosamide. Sensorium deteriorated. CT brain: no new ischaemic stroke or hemorrhage. MRI brain with contrast: post contrast FLAIR diffuse leptomeningeal enhancement. Different possibilities considered: metabolic encephalopathy, meningitis, infectious or carcinomatous, autoimmune or paraneoplastic encephalitis.

40. Case Scenario- Course EEG (initial): diffuse delta slowing bilateral fronto temporal sharp waves and triphasic waves. LP CSF: normal. Anti TPO, serum ACE levels, CEA, alpha fetoprotein, PSA- normal. CSF autoimmune, Serum paraneoplastic panels, serum NMOSD, CSF OCB: normal. PET scan: no malignancies. 24 hour EEG: slowing of background, intermittent delta slowing, time locked with myoclonus. Repeat MRI brain with contrast: no contrast enhancement. Follow up EEG: periodic sharp wave discharges occurring about once every second and triphasic wave. Review MRI brain: cortical ribboning sign- helped reach the final diagnosis.

41. References Bradley, Daroff . Neurology in clinical practice. 8th edition. Roos, R.P., Greenlee, J.E. Creutzfeldt Jakob Disease. MedLink Neurology (2024). Roos, R.P., Greenlee, J.E. Prion Diseases. MedLink Neurology (2024).

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