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Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy

Sections Variant Creutzfeldt-Jakob Disease and Bovine Spongiform Encephalopathy
Overview
Presentation
DDx
Workup
Treatment
Media Gallery
Tables
References

Treatment

Approach Considerations

Although there is no cure for Creutzfeldt-Jakob disease (CJD), interleukins and other drugs may help slow the progression of disease. Medications to help treat the symptoms of CJD include antiepileptics to manage seizures (eg,diphenylhydantoin, carbamazepine, and gabapentin) and, occasionally, clonazepam to treat myoclonus. Antiepileptics are also used to treat violent outbursts.^{[131, 132, 133]}

Dementia in patients with CJD can be treated with donepezil, galantamine, rivastigmine, and memantine. If a person develops disruptive behavior, antipsychotics can be used. Antidepressants may help patients come to terms with the prognosis.

Some general principles for the treatment of patients with variant CJD include the following:

Discontinue any medication that could impair cognition or cause confusion
Many patients need psychiatric care, including antidepressants, which may provide temporary relief
Some patients need treatment to ameliorate sensory symptoms in the limbs
All patients have increasing need for supportive care, including palliative and terminal care
Family members need significant support in coping with both emotional and care needs; they also need reassurance and information regarding the nature of disease transmission

Consultation with the following may be necessary:

Neurologist
Infectious disease specialist
US Centers for Disease Control and Prevention
CJD surveillance unit, Edinburgh, United Kingdom

Experimental Treatments

A number of experimental interventions are currently being studied.^{[134, 135]}They include some of the conventional medications, such as the antimalarial quinacrine and the antipsychotic chlorpromazine, which prevent conversion of the normal prion protein (PrPc) to abnormal prion protein (PrPSc), according to in vitro studies.^[136]These drugs are currently being evaluated in treatment trials.^{[137, 138, 139]}Clinical trials currently ongoing include PRION-1: Quinacrine for Human Prion Disease^[138]and the CJD (Creutzfeldt-Jakob Disease) Quinacrine Study.^[139](Quinacrine is not commercially available in the United States.)

Pentosan polysulphate (PPS) also has effects on prion protein production, replication, and associated cell toxicity. Some experimental results showed that if PPS is given to animals at a time relatively close to the point of experimental infection, an increase in the incubation period of disease may occur; in some instances, animals appear to be completely protected from the development of disease. On the basis of these data, some individuals with prion diseases have been treated with intraventricular PPS. One patient with variant CJD did not show any clear evidence of deterioration for a period of at least 23 months.

Flupirtine has shown some beneficial effects on cognitive function in patients with CJD but without any evidence of increased survival.^[140]One strategy involves designer compounds that interact with PrPSc structure, inhibiting the conformation change of PrPc associated with the disease.^[141]

Another potential approach is immunologic, in which immunization with alpha s-helix peptides is used to reduce cerebral amyloid accumulation.^[142]

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Media Gallery

Incidence of bovine spongiform encephalopathy (BSE) and variant Creutzfeldt-Jakob disease (CJD) in Great Britain. The BSE epidemic peaked in 1992, 4 years after the introduction of the ban on ruminant feed. The associated human disease, variant CJD, was not defined until 1996, 7 years after a ban was introduced in Britain on the use of specified offal from cattle in human food.
Geographic distribution of bovine spongiform encephalopathy (BSE) by country as of January 9, 2004. From http://www.oie.int/eng/info/en_esb.htm.
Time course of epidemic bovine spongiform encephalopathy (BSE) in the United Kingdom, 1986-2000, with dates of major precautionary interventions. SBO stands for specified bovine offal (ie, brain, spinal cord, thymus, spleen, and intestines from cattle aged >6 mo). MBM stands for meat and bone meal (protein residue produced by rendering). From Brown P, Will RG, Bradley R, et al. "Bovine spongiform encephalopathy and variant Creutzfeldt-Jakob disease: background, evolution and current concerns". Emerging Infectious Diseases, 2001;7: 6-16.
Normal fluid-attenuated inversion recovery (FLAIR) image at the level of the basal ganglia shows that the thalamus is normally isointense or slightly hypointense relative to putamen. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Pulvinar sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows marked symmetrical hyperintensity of the pulvinar (posterior) thalamic nuclei, and this sign is present in 100% of cases imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Axial fluid-attenuated inversion recovery (FLAIR) showing periaqueductal gray matter hyperintensity (arrow). Although not a specific sign, periaqueductal hyperintensity is observed in 83% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Hockey stick sign of variant Creutzfeldt-Jakob disease. Fluid-attenuated inversion recovery (FLAIR) image shows symmetrical pulvinar and dorsomedial thalamic nuclear hyperintensity. This combination produces a characteristic hockey stick appearance and is present in 93% of patients imaged with FLAIR imaging. From Collie DA, Summers DM, Sellar RJ, et al. "Diagnosing variant Creutzfeldt-Jakob disease with the Pulvinar sign: MR imaging findings in 86 neuropathologically confirmed cases." Am J Neuroradiol, 2003;24: 1560-9.
Prion protein (PrP) accumulation in the tonsil in variant Creutzfeldt-Jakob disease within follicular dendritic cells and macrophages in a germinal center as demonstrated by PrP immunocytochemistry. From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
The florid plaque in the cerebral cortex in variant Creutzfeldt-Jakob disease comprises a dense core with a paler outer layer of amyloid fibrils surrounded by spongiform change (hematoxylin and eosin stain at high magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (low magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.
Immunocytochemistry for prion protein (PrP) shows strong staining of the florid plaques and multiple smaller plaques and diffuse PrP deposits (higher magnification). From Ironside JW, Frosch MP, Bernardino G. "Human prion diseases." In: Gray F, De Girolami U, Poirier J, eds. Escourelle & Poirier Manual of Basic Neuropathology. Philadelphia, Pa: Elsevier, 2004: 145-57.

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Table 1. Psychiatric Features According to Frequency and Median Time of Onset ^[84])

Psychiatric Features

Early Onset

< 4 mo

Later Onset

4 to < 6 mo

Late Onset

=6 mo

Common

(n =50)

Dysphoria

Withdrawal

Anxiety

Irritability

Insomnia

Loss of interest

Poor memory

Impaired concentration

Disorientation

Agitation

Less common

(n = 25 to < 50)

Behavioral changes

Anergia

Poor performance

Tearfulness

Weight loss

Appetite change

Hypersomnia

Confusion

Hallucinations

Impaired self-care

Paranoid delusions

Inappropriate affect

Rare

(n < 25)

Obsessive features

Losing things

Suicidal ideation

Panic attacks

Psychomotor retardation

Diurnal mood variation

Loss of confidence

Bizarre behavior

Paranoid ideation

Recognition impairment

Confabulation

Lack of emotion

Perseveration

Impaired comprehension

Change in eating preferences

Impaired use of devices

Acalculia

Table 2. Neurologic Features According to Frequency and Median Time of Onset ^[84])

Neurologic Features

Early Onset

< 4 mo

Later Onset

4 to < 6 mo

Late Onset

=6 mo

Common

(n =50)

None

Gait disturbance

Slurring of speech

Hyperreflexia

Impaired coordination

Myoclonus

Incontinence

Eye features

Less common

(n = 25 to < 50)

Pain

Paresthesia

Numbness

Chorea

Extensor plantars

Dysphagia

Clonus

Hypertonia

Primitive reflexes

Rare

(n < 25)

Headaches

Dropping things

Sweatiness

Loss of consciousness

Tremors

Handwriting impairment

Coldness

Odd sensation

Dizziness

Cranial motor weakness

Dysdiadochokinesis

Taste disturbance

Startle response

Hypersensitivity

Peripheral motor weakness

Primitive reflexes

Table 3. WHO Revised Case Definition for variant Creutzfeldt-Jakob Disease ^[65]

Class I	A - Progressive neuropsychiatric disorder B - Duration of illness longer than 6 months C - Routine investigations not suggestive of alternative diagnosis D - No history of iatrogenic exposure E - No history of familial form of transmissible spongiform encephalopathy (TSE)
Class II	A - Early psychiatric symptoms (ie, depression, anxiety, apathy, withdrawal, delusions) B - Persistent painful sensory symptoms (eg, frank pain and/or dysesthesia) C - Ataxia D - Myoclonus or chorea or dystonia E - Dementia
Class III	A - EEG without typical appearance of sporadic CJD (ie, generalized triphasic periodic complexes at approximately one per second) or no EEG B - Brain MRI showing bilateral symmetrical pulvinar high-signal intensity (relative to the signal intensity of the other deep gray matter nuclei and cortical gray matter)
Class IVA	Positive findings on tonsil biopsy (biopsy not routinely recommended and not recommended in cases with EEG appearance typical of sporadic CJD but may be helpful in suspected cases in which the clinical features are compatible with variant CJD without MRI findings of bilateral pulvinar high-signal intensity)
Diagnoses	Definite - Class IA and neuropathological confirmation of variant CJD (spongiform change and extensive prion protein deposition with florid plaques throughout the cerebrum and cerebellum) Probable - Class I, 4 of 5 of class II, class IIIA, and class IIIB; or class I and class IVA Possible - Class I and 4 of 5 of class II and IIIA

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Author

Florian P Thomas, MD, PhD, MA, MS Chair, Neuroscience Institute and Department of Neurology, Director, Hereditary Neuropathy Center, Co-Director, Center for Memory Loss and Brain Health, Co-Director, ALS Center, Hackensack University Medical Center; Associate Dean of Faculty, Founding Chair and Professor, Department of Neurology, Hackensack Meridian School of Medicine

Florian P Thomas, MD, PhD, MA, MS is a member of the following medical societies: Academy of Spinal Cord Injury Professionals, American Academy of Neurology, American Neurological Association, Consortium of Multiple Sclerosis Centers, National Multiple Sclerosis Society, Sigma Xi, The Scientific Research Honor Society

Disclosure: Nothing to disclose.

Chief Editor

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM Adjunct Associate Professor of Neurology, University of Missouri-Columbia School of Medicine; Medical Director of St Mary's Stroke Program, SSM Neurosciences Institute, SSM Health

Niranjan N Singh, MBBS, MD, DM, FAHS, FAANEM is a member of the following medical societies: American Academy of Neurology, American Association of Neuromuscular and Electrodiagnostic Medicine, American Headache Society

Disclosure: Nothing to disclose.

Additional Contributors

Erik Z Krause, DO Assistant Professor, Department of Neurology, Dell Medical School, The University of Texas at Austin; Movement Disorder Specialist, Department of Neurology, Ascension Seton Brain and Spine Institute

Erik Z Krause, DO is a member of the following medical societies: American Academy of Neurology, American Osteopathic Association

Disclosure: Nothing to disclose.

Acknowledgements

Neil A Busis, MD Chief, Division of Neurology, Department of Medicine, Head, Clinical Neurophysiology Laboratory, University of Pittsburgh Medical Center-Shadyside

Neil A Busis, MD is a member of the following medical societies: American Academy of Neurology and American Association of Neuromuscular and Electrodiagnostic Medicine

Disclosure: Nothing to disclose.

Amy A Pruitt, MD Associate Professor of Neurology, University of Pennsylvania School of Medicine; Attending Neurologist, Hospital of the University of Pennsylvania

Amy A Pruitt, MD is a member of the following medical societies: American Academy of Neurology

Disclosure: Nothing to disclose.

Chitharanjan V Rao, MD, MRCP, DM Assistant Professor, Department of Neurology, University of Pittsburgh School of Medicine and University of Pittsburgh Medical Center

Disclosure: Nothing to disclose.

Francisco Talavera, PharmD, PhD Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Medscape Salary Employment