Creutzfeldt-Jacob disease (CJD)

General

An invariably fatal encephalopathy characterized by rapidly progressive dementia, ataxia and myoclonus

Prions (proteinaceous infectious particles)

Aka transmissible spongiform encephalopathy agents
Creutzfeldt-Jakob disease (CJD) is one of 4 known rare human diseases associated with Prions
Contain no nucleic acids and are also resistant to processes that inactivate conventional viruses
Do not provoke an immune response.
Protease-resistant protein

Normal PrPsen or PrPC

Alpha-helical structure

Disease causing PrPres or PrPSc

PrPsen undergoes post-translational conformation change to PrPres, which has large beta-sheets, and which accumulates in neural cells, disrupting function and leading to cell death and vacuolization

Numbers

Annual incidence of CJD

0.5–1.5 per million population
With little change over time
No geographic clustering (except in locations with large numbers of familial cases).

Over 200 people die of CJD in the U.S. each year

Classification

Idiopathic/sporadic

Sporadic Creutzfeldt-Jacob disease (CJD)
Sporadic fatal insomnia

In ≈ 90% of cases of CJD, no infectious or familial source can be identified, and these cases are considered sporadic.

80% occur in persons 50–70 yrs old.

Sporadic cases show no abnormality in the PrP gene.

There appears to be a genetic susceptibility in the sporadic and iatrogenically transmitted CJD cases, with the majority of these showing specific changes in the human prion protein.

Familial (Autosomal dominant)

Gerstmann-Sträussler-Scheinker disease,
Prion disease associated with octapeptide repeat region insertional mutations,
Fatal familial insomnia

5–15% of cases of CJD

Occur in an autosomal dominant inheritance pattern

Abnormalities in the amyloid gene on chromosome 20 with a penetrance of 0.56.
Since familial CJD is dominantly inherited, analysis for the PrP gene is not indicated unless there is a history of dementia in a 1st degree relative

Acquired (via prions)

From human

Kuru,

Transmitted via handling and ingestion of infected brains in ritualistic funereal cannibalism practiced among the Fore linguistic group in the eastern highlands of Papua, New Guinea,
A practice which was generally abandoned in the 1950s.
Kuru is a subacute, uniformly fatal disease involving cerebellar degeneration

The word “kuru” means “to tremble” in the local language

Iatrogenic CJD

Described only in cases of direct contact with infected organs, tissues, or surgical instruments.
Has been reported with

Corneal transplants,
Intracerebral EEG electrodes sterilized with 70% alcohol and formaldehyde vapor after use on a CJD patient,
Operations in neurosurgical ORs after procedures on CJD patients,
In recipients of pituitary-derived human growth hormone (hGH)

Most cases have occurred in France;
There is no longer a risk of CJD with growth hormone in the U.S. since distribution of pituitary derived hGH was halted in 1985 and current hGH is obtained from recombinant DNA technology),

Dural graft with cadaveric dura mater (Lyodura®)

Most cases have occurred in Japan

Ethylene oxide, autoclaving, formalin, and ionizing radiation do not inactivate the CJD agent
Recommended sterilization procedures for suspected CJD tissues and contaminated materials also appear.

Fully effective (recommended) procedures

Steam autoclaving for 1 hr at 132°C, or
Immersion in 1N sodium hydroxide (NaOH) for 1 hr at room temperature

Partially effective procedures

Steam autoclaving at either 121°C or 132°C for 15–30 mins, or
Immersion in 1N NaOH for 15 mins, or lower concentrations (<0.5N) for 1 hr at room temp, or
Immersion in sodium hypochlorite (household bleach) undiluted or up to 1:10 dilution (0.5%) for 1 hr

❌ Ineffective procedures

Boiling, UV or ionizing radiation, ethylene oxide, ethanol, formalin, beta-propiolactone, detergents, quaternary ammonium compounds, Lysol®, alcoholic iodine, acetone, potassium permanganate, routine autoclaving

From bovine

New variant CJD

Causing: bovine spongiform encephalopathy (BSE), dubbed “mad cow” disease by the lay press.

A variant of CJD (vCJD) was identified in 10 cases of unusually young individuals (median age at death: 29 yrs during 1994–95 in the UK
BSE epidemic may have been exacerbated by the practice of feeding discarded sheep organs (called offals) to the cows (a practice banned since 1989).
This raises the question of possible transmission and mutation of the sheep slow-virus disease, scrapie (which resembles kuru in man) to cows
None of the vCJD patients had periodic spikes on EEG characteristic of classic CJD, the clinical course was atypical (having prominent psychiatric symptoms and early cerebellar ataxia, somewhat similar to kuru), and brain plaques showed unusual features also reminiscent of amyloid plaques seen in kuru.
Comparison of vCJD to sporadic CJD

Characteristic	vCJD	Sporadic
Mean age at onset (yr)	29	60
Mean duration of disease (mo)	14	5
Most consistent and prominent early signs	Psychiatric abnormalities, sensory symptoms	Dementia, myoclonus
Cerebellar signs (%)	100	40
Periodic complexes on EEG (%)	0	94
Pathological changes	Diffuse amyloid plaques	Sparse plaques in 5–10%

Notes

Natural route of infection is unknown

Virulence appears low,

Lack of significant dissemination by respiratory, transplacental transmission, enteric, or sexual contact

No increased incidence in spouses (only a single conjugal pair of cases has been verified), physicians, or laboratory workers

Iatrogenically transmitted cases

Only known case of horizontal transmission of CJD Kuru

Noniatrogenically transmitted cases

Occur in patients >50 yrs old,

And is rare in age < 30.

The incubation period can range from months to decades.
The onset of symptoms following direct inoculation is usually faster (common range: 16–28 mos), but still may be much longer

Up to 30 years with corneal transplant,
4–21 yrs with hGH (Human growth hormone) transmission

In experimental models of CJD, higher inoculation doses produce shorter incubation periods

Pathology

Micro

Classic histologic triad of (all in the absence of an inflammatory response)

Neuronal loss,
Astrocytic proliferation,
Cytoplasmic vacuoles in neurons and astrocytes (status spongiosus)

Mainly involving

Cerebral cortex
Basal ganglia
But all parts of the CNS may be involved

Deposition of amyloid plaques

Plaques are common in kuru, vCJD and some familial spongiform encephalopathies
5–10% of cases

Immunostaining for PrPres is definitive.

Multiple vacuoles giving a spongiform appearance. Unlike edema, the vacuoles are not empty

Diagnostic criteriaᵃ

Clinical criteria	Mental deterioration	Myoclonus	1–2 Hz periodic EEG complexes	Any movement disorder or periodic EEG activity	Duration of illness (months)
Clinically definite	+	+	+	ㅤ	<12
Clinically probable	+	+ OR +	+ OR +	ㅤ	<18
Clinically possible	+	ㅤ	ㅤ	+	<24

ᵃIn patients with normal metabolic status and spinal fluid. If there are early cerebellar or visual symptoms and then muscular rigidity, or if another family member has died of pathologically verified CJD, then upgrade the degree of certainty to the next higher category.

Pathologically confirmed (with unequivocal spongiform changes)

Clinically: requires brain biopsy
Found at autopsy

Complete “diagnostic triad” (dementia, myoclonus and periodic EEG activity) may be absent in up to 25% of cases

Clinical presentation

1/3 initially express vague feelings of fatigue, sleep disorders, or reduced appetite.

1/3 have neurologic symptoms including

Memory loss,
Confusion,
Uncharacteristic behaviour.

1/3 have focal signs including

Cerebellar ataxia,
Aphasia,
Visual deficits (including cortical blindness),
Hemiparesis.

The typical course is inexorable, progression of dementia, often noticeably worse week by week, with subsequent rapid development of pyramidal tract findings (limb weakness and stiffness, pathologic reflexes), late extrapyramidal findings (tremor, rigidity, dysarthria, bradykinesia), and myoclonus (often stimulus-triggered).

Clinical signs of sporadic CJD

Major clinical sign

Sign	Freq (%)
Cognitive deficitsᵃ	100
Myoclonus	>80
Pyramidal tract signs	>50
Cerebellar signs	>50
Extrapyramidal signs	>50
Cortical visual deficits	>20
Abnormal extraocular movements	>20
Lower motor-neuron signs	<20
Vestibular dysfunction	<20
Seizures	<20
Sensory deficits	<20
Autonomic abnormalities	<20

ᵃDementia, psychiatric and behavioral abnormalities

Supranuclear gaze palsy is an occasional finding, also usually late.
In early stages, CJD may resemble Senile dementia of the Alzheimer type (SDAT).
10% of cases present as ataxia without dementia or myoclonus.
Cases with predominant spinal cord findings may be initially mistaken for ALS.
Myoclonus subsides in the terminal phases, and akinetic mutism ensues

Investigations

Radiology

CT or MR

No characteristic findings
Frequently normal looking

Diffuse atrophy may be present, especially late.

But are needed to rule out other conditions

Herpes-simplex encephalitis, recent stroke

Increased intensity on T2WI in areas typically involved (basal ganglion, striatum) in up to 79% of cases (retrospectively).

This is nonspecific but may help differentiate CJD from Senile dementia of the Alzheimer type

Blood tests

Serum assays for S-100 protein are so insensitive and nonspecific that it can only be used as a diagnostic adjunct

CSF

Routine labs

Usually normal
Although protein may occasionally be elevated

Abnormal proteins

Abnormal proteins (designated 130 & 131)

Have been identified in the CSF of patients with CJD,
But the assay is technically difficult and is therefore not practical for routine clinical use
Were identified as the normal neuronal protein 14–3-3, and a relatively simple immunoassay for this was developed for use on as little as 0.05ml of CSF.
Detection of the 14–3-3 protein in the CSF has 96% sensitivity and specificity for CJD among patients with dementia.
False positives may occur in other conditions involving extensive neuronal destruction including:

Acute stroke, herpes encephalitis, multi-infarct dementia, primary CNS lymphoma and rarely SDAT (most cases of SDAT test negative).

Requires CSF (cannot be done on blood)

EEG

Periodic spikes

AKA pseudoperiodic sharp-wave complexes

(0.5–2 per second)

Characteristic finding of bilateral, symmetrical, periodic bi- or triphasic synchronous sharp wave complexes,

Have ≈ 70% sensitivity and 86% specificity.

They resemble PLEDs, but are responsive to noxious stimulus (may be absent in familial CJD19 and in the recent UK variant (see above))

SPECT scan

May be abnormal in vCJD even when EEG is normal

However, the findings are not specific for vCJD

Brain biopsy

Indication

Establishing the diagnosis is deemed important,
As part of a research study
When diagnostic tests are equivocal and other potentially treatable aetiologies are suspected

Due to lack of an effective treatment and the potential for iatrogenic infection in surgery, biopsy is reserved for the above indications

Technique

To prevent aerosolization of the infectious agent, a manual saw is recommended over a power craniotome, and every effort should be made to avoid cutting the dura with the saw.
Recommended decontamination procedures should be followed
Specimens should be clearly labelled as being from suspected CJD patients to alert laboratory personnel to the hazard.
Tissue should be fixed in a saturated 15% phenolized formalin (15g of phenol per dl of 10% neutral buffered formalin with the undissolved phenol layering at the bottom of the solution).
Analysis for classic histologic findings (see above) and/or immunostaining for PrPres are the gold standards of diagnosis.

Tonsillar biopsy

Patients with variant CJD (vCJD) may have detectable levels of variant type 4 of the abnormal prion protein (PrPSc) in their lymphoreticular system, which may be accessed by a 1cmwedge-biopsy ofone palatine tonsil (using careful aseptic precautions)

Outcome

Cannot be treated

Death usually occurs within 1 yr of onset of symptoms

Differential diagnosis

Tertiary syphilis or SSPE

CSF examination to help rule out

Toxicity from bismuth, bromides and lithium must be ruled-out.

Myoclonus is usually more prominent early in toxic/metabolic disorders than in CJD,

Seizures in CJD are usually late.

19. Prions — These are not viruses because they are protein without nucleic acid. They are resistant to nucleases, ultraviolet light, and radiation.

They can be inactivated with autoclaving for 1 hour at 132°C or immersion in 1N NaOH for 15 minutes or 0.5% sodium hypochlorite for 1 hour.

(A) A protease-resistant protein is coded on chromosome 20 and the production may be released by a DNA configuration change.

(B) Prion diseases — kuru (in cannibals of New Guinea), scrapie (in sheep), chronic wasting disease in elk and mink, fatal familial insomnia, Creutzfeldt–Jakob disease (CJD), and Gerstmann–Sträussler syndrome. CJD occurs in 50- to 65-year-old people and manifests as myoclonus, pyramidal, and extrapyramidal degeneration, dementia, ataxia, and visual deterioration.

(C) There is a characteristic EEG with bilateral sharp waves of 1–2 waves/s that resemble periodic lateralized epileptiform discharges, but are reactive to painful stimuli.

(D) May have positive CSF immunoassay for 14-3-3 protein; fairly sensitive and specific

(E) Pathologic examination — demonstrates spongiform changes with astrocytosis but no inflammation most prominently in the cortex, putamen, and thalamus (Fig. 3.46 ). 5–10% of patients develop amyloid kuru plaques. Death occurs in less than 1 year.

(F) Gerstmann–Sträussler syndrome — ataxia, dysarthria, hyporeflexia, and cognitive decline, without myoclonus. Transmission is both autosomal dominant and sporadic, and Kuru plaques are seen in the cerebellum. These diseases can be transmitted to laboratory animals that develop the same microscopic changes.

(G) Fatal familial insomnia — sleep disturbance, agitation, mild cognitive changes, and dysautonomia; characterized by thalamic atrophy

Two main issues dominate the management of CJD in neurosurgical patients in the UK

Implementation of CJD screening questions and quarantining of neurosurgical instruments.

These questions were designed to reduce the risk of spread of sporadic CJD, from patients

Who suffer from the disease,
Have received a human dural graft or those that have had human derived hormone treatments,
Individuals who have had massive blood transfusions from multiple donors.

Since it has been causally proven that eating beef with bovine spongiform encephalopathy (BSE) can cause vCJD in humans, the assumption has been that anyone who has had beef in the 1980s can be harbouring latent vCJD.

Since BSE has been eliminated in the food chain by 1997, patients born after 1997 are thought to have no risk of developing vCJD.
NICE have therefore recommended a new set of instruments be used on these patients, lest they contract the disease from neurosurgical instruments used on older patients who may have been harbouring vCJD.
The requirement to have (i) a whole set of instruments to be kept completely separate and used on a specific cohort of patients presents huge financial and logistical challenges (e.g. tracking systems, single use instruments in high risk patients). This was temporary advice based on the assumption that effective methods for removing CJD infectivity from instruments was likely to be available within 5 years. However, this has not occurred and the patients born in 1997 are now coming to the adult neurosurgical centers which will now have to keep two separate pools of instruments or risk them being potentially being infected with the vCJD agent.

As such, some are now arguing that the costs are disproportionate to the risks (which have been revised down) and guidance should change.

Increased risk of CJD

Recipients of hormone derived from human pituitary glands, e.g. growth hormone, gonadotrophin, are “at increased risk” of transmission of sporadic CJD. In the UK the use of human-derived gonadotrophin was discontinued in 1973, and use of cadaver-derived human growth hormone was banned in 1985. However, use of human-derived products may have continued in other countries after these dates.

Individuals who underwent intradural brain or intradural spinal surgery before August 1992 who received (or might have received) a graft of human-derived dura mater are “at increased risk” of transmission of sporadic CJD (unless evidence can be provided that human-derived dura mater was not used).

Individuals who have had surgery using instruments that had been used on someone who went on to develop CJD, or was “at increased risk” of CJD;

Individuals who have been identified as having received blood or blood components from 300 or more donors since January 1990.

Individuals who have given blood to someone who went on to develop vCJD.

Individuals who have received blood from someone who has also given blood to a patient who went on to develop vCJD,

Individuals who have been treated with certain implicated UK sourced plasma products between 1990 and 2001

Increased risk of vCJD

Individuals who have received labile blood components (whole blood, red cells, white cells or platelets) from a donor who later went on to develop vCJD.

Individuals who have received an organ or tissue from a donor infected with CJD or “at increased risk” of CJD.