Spongiform encephalopathies – neurology anoxie

• sporadic (scjd)

• familial (fcjd)

• iatrogenic (icjd)

• new variant (vcjd)

Sporadic CJD: most common human form of

Spongiform encephalopathy, the initial conformational change in prpc to form prpsc

Apparently occurs slowly and spontaneously. It is infective and transmissible. PrPsc accumulates in neurons.

• epidemiology: 1 to 1.5 per million per year. 250 to 400 in the US every year.

• peak age of onset around a unimodal, relatively narrow peak of about 68 years.

• mean survival of about 6 months.

• 6 molecular subtypes based on the genetic polymorphism at codon 129 in the prion gene (MM, MV, or VV) and the type of protease-resistant prior (type 1 or 2).

• MM1 and MV1 are the most common forms (70%), VV2 (16%) starts with ataxia, later onset dementia.Anoxie

• homozygosity for valine or methionine at codon 129 confers increased risk for sporadic CJD.

• clinical findings: dementia, personality changes, visual symptoms, myoclonic jerks, ataxia, pyramidal and extrapyramidal signs. At end-stage, akinetic-mutism (no purposeful movement and not speaking). Cognitive problems are among the first symptoms in scjd and typically include mild confusion, memory loss, personality changes (behavioral and psychiatric symptoms) and difficulty concentrating, organizing, or planning.

• EEG findings: generalized periodic frontal sharp wave complexes, triphasic waves that occur every second. This finding is not seen in new variant CJD. It is seen in about two-thirds of CJD patients, typically only after serial eegs and often not until later stages of illness.Anoxie it is relatively specific, but can be seen in other conditions like AD, lewy body disease, toxic-metabolic and anoxic encephalopathies, PML, hashimoto encephalopathy, VGKC associated encephalopathy. Slow EEG is often seen in scjd.

• CSF shows 14-3-3 protein. Non-specific finding, but helpful for diagnosis in the clinical context. This is not found in new variant CJD. Sensitivity 74% and specificity 56%.

• real-time quaking-induced conversion RT-quic analysis in CSF samples has high specificty ~98% to 100%, although only moderate sensitivity (~80% to 87%), and is more accurate in diagnosis of scjd, than CSF 14-3-3, as the analyte is disease specific.

• MRI shows basal ganglia hyperintensities.

Familial CJD: autosomal dominant.Anoxie mutation in the prion protein gene. Variable among kindreds. Age (23 – 55). Clinical course is longer (8 – 96 months) than in patients with sporadic CJD. Cognitive behavior signs are prominent.

Iatrogenic CJD: sources of infections have occurred in patients who have received corneal transplants, human cadaveric pituitary extracts (growth hormone, gonadotrophin hormones), duramater grafts, depth electrodes, neurosurgical instruments (improper sterlization).

New variant CJD: thought to be due to consumption of beef infected with the agent that causes bovine spongiform encephalopathy (mad cow disease). Patients usually are homozygous for methionine at codon 129. Age of onset is younger (28) and clinical course is longer (14 months) for patients with variant CJD.Anoxie the incubation period ranges 12 to 23 years. Pts with vcjd tend to have psychiatric symptoms. Sensory symptoms such as pain, paresthesias are also seen early in the course of vcjd. 14-3-3 protein and generalized periodic sharp wave complexes are not seen in vcjd, unlike sporadic CJD.

• can be diagnosed with tonsil biopsy, which may show prpsc.

• florid plaques are seen. These are amyloid plaques surrounded by vacuolation.

• MRI shows bilateral pulvinar hyperintensity in variant CJD.


• highly sensitive and specific (91% – 96%) for scjd.

• brain MRI: increased T2 signal in neocortex, thalamus, basal gangila (caudate, and putamen), but not in globus pallidus; most changes are asymmetric. Classic “cortical ribbon sign” (cortical gyral hyperintensities) best noted on DWI, amd FLAIR which is result of neocortical neuronal loss.Anoxie

• scjd: subcortical, cortical and subcortical, and cortical. More prominent in DWI than on FLAIR images

• vcjd: bilateral thalamic hyperintensity in the mesial pars (mainly dorsomedian nucleus) and posterior pars (pulvinar) of the thalamus (double hockey stick sign).

• “pulvinar sign”: characterized by T2 hyperintesity of pulvinar nuclei, often symmetric when bilateral, and reported only with vcjd

• when considering sporadic creutzfeldt-jakob disease, the most sensitive and specific lab finding is the presence of grey matter hyperintensity on the DWI sequence of an MRI, along with an ADC correlate. A FLAIR study may show grey matter high signal; however, this finding can be absent in early stages of the disease.Anoxie the cerebrospinal fluid studies are highly variable, serve only as markers of accelerated neuronal death, and are not prion specific.

CDC’s diagnostic criteria for creutzfeldt-jakob

Disease (CJD), 2010

[adapted from: a) global

Surveillance, diagnosis, and therpay of human transmissible spongiform

Encephalopathies: report of a WHO consultation, february 9-11, 1998, geneva,

Switzerland; and b) zerr I, kallenberg K, summers DM, et al. Brain 2009, 132;


1. Sporadic CJD


Diagnosed by standard

Neuropathological techniques; and/or immunocytochemically; and/or western blot

Confirmed protease-resistant prp; and /or presence of scrapie-associated

Fibrils. Presence of prp sc in brain tissue.



Rapidly progressive dementia;

And at least two out of the following four clinical features:

I) myoclonus

Ii) visual or cerebellar disturbance

Iii) pyramidal (hyperreflexia, focal weakness, extensor response)/extrapyramidal (rigidity, bradykinesia), tremor, or dystonia, typically due to problems in basal ganglia

Iv) akinetic mutism (without purposeful movement and mute: occurs at the end-stage of disease).

AND a positive result on at

Least one of the following laboratory tests

A) a typical EEG (periodic

Sharp wave complexes) during an illness of any duration; and/or

B) a positive 14-3-3

Cerebrospinal fluid (CSF) assay in patients with a disease duration to death of less

Than 2 years

C) no alternative diagnosis on routine investigations.Anoxie


Progressive dementia; and/or at

Least two out of the following four clinical features:

I) myoclonus

Ii) visual or cerebellar signs

Iii) pyramidal/extrapyramidal


Iv) akinetic mutism

AND the absence of a positive

Result for any of the three laboratory tests that would classify a case as

“probable” (see tests a-c above)

AND duration of illness less

Than two years

AND without routine

Investigations indicating an alternative diagnosis.

2. Iatrogenic CJD

Progressive cerebellar syndrome

In a recipient of human cadaveric-derived pituitary hormone; or sporadic CJD

With a recognized exposure risk, e.G., antecedent neurosurgery with dura mater


3. Familial CJD

Definite or probable CJD plus

Definite or probable CJD in a first degree relative; and/or neuropsychiatric


Disorder plus disease-specific PRPN gene mutation

• caused by mutation in prp gene PRNP located in the short arm of chromosome 20.

• AD, and almost everyone with the mutation develops the disease if they live a normal lifespan.

• 40 mutation exist, mostly point mutations but some stop codons, insertions, and deletions are also identified.

• diagnosis of gprd is made by identification of a mutation in the prp gene PRNP.

• DNA from live patient or from extract of frozen brain autopsy tissue.

• gprd is sometimes erroneously referred to familial. ~60% of patients with gprd do not have positive family history of prior disease.

• gprds are divided into 3 forms: predates genetic diagnosis and is not accurate.Anoxie

• fcjd

• gerstmann-straussler-scheinker (GSS) disease

• fatal familial insomnia (FII)

• mutations can sometimes have blends: fcjd + GSS

• usually younger age onset (40 – 60s) when compared to scjd cases; slower course, and live longer (typically few years longer).

• initial symptoms appear parkinsonism or ataxia, mild personality or cognitive changes early on.

• many forms of gprd present identical to scjd clinically, and sometimes pathologically, with rapid onset of clinical symptoms and same tempo of progression to death.

• clinical variability in presentation and course of disease amongst same family members.

• several polymorphism of PRNP exist. The most common one being at codon 129, which can be either methionine (M) or valine (V).Anoxie

• mechanism that is postulated on how disease in gprds occur is presumed (actually unknown) that the mutations in PRNP gene renders the normal prp c, more susceptible to changing conformation (misfolding) into a disease-causing form prp sc. When does this happen? It is presumed that the nascent prp c maintains a normal conformation for most of the patient’s life and does not begin transforming shape into prp scuntil the patient gets older. Another theory believes that there is constant transformation of prp c into prp sc throughout life. But the prp sc is removed by normal cellular protein degradation pathways. However, when one ages, these cellular pathways do not dispose prp sc efficiently, so the prp sc accumulates and causes transformation of nascent prp sc in an exponential manner, resulting in disease.Anoxie