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Prion-Related Diseases Differential Diagnoses

  • Author: Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS; Chief Editor: Niranjan N Singh, MD, DM  more...
Updated: Oct 27, 2014

Diagnostic Considerations

Other problems to be considered include the following:

  • Nonherpes viral encephalitis
  • Diffuse Lewy body disease
  • Chronic meningitis
  • Dementia as a paraneoplastic syndrome
  • Familial myoclonic dementia
  • Lithium poisoning
  • Dementia in motor neuron disease
  • Limbic encephalitis (and other paraneoplastic syndromes)
  • Hashimoto encephalopathy (or Steroid-responsive encephalopathy associated with autoimmune thyroiditis [SREAT])

Rule out all other causes of dementia, particularly causes of a rapidly progressive dementia that could be treatable, such as herpes encephalitis.[76] In herpes encephalitis, the CSF has pleocytosis and an elevated protein content, while in CJD the cell count and protein content are within the reference range. In addition, herpes encephalitis has characteristic MRI and EEG findings. Other entities that are in the differential diagnosis are neurodegenerative disease such as Alzheimer disease, Pick disease, corticobasal ganglionic degeneration, familial myoclonic dementia, and multisystem atrophy. However, the progression of the dementia and other neurological symptoms is slower in all these disorders compared to CJD.

Also consider Hashimoto encephalitis (also referred to as steroid-responsive encephalopathy associated with autoimmune thyroiditis [STEAT]) in the differential diagnosis.[77, 78, 79] The clinical symptomatology of Hashimoto encephalitis can be very similar to possible CJD, with the presence of a rapidly progressive dementia, myoclonus, ataxia, and psychosis; however, this autoimmune disorder responds well to treatment with immunosuppression. The diagnosis of Hashimoto encephalopathy can be made by finding high serum levels of thyroperoxidase autoantibodies (TPO). Patients with Hashimoto encephalitis do not show the 14-3-3 protein in the CSF nor do they have the typical periodic sharp wave complexes on EEG.

Differential Diagnoses

Contributor Information and Disclosures

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS Professor Emeritus of Neurology and Psychiatry, Clinical Professor of Medicine, Clinical Professor of Family Medicine, Clinical Professor of Neurosurgery, State University of New York Upstate Medical University; Neuroscience Director, Department of Neurology, Crouse Irving Memorial Hospital

Tarakad S Ramachandran, MBBS, MBA, MPH, FAAN, FACP, FAHA, FRCP, FRCPC, FRS, LRCP, MRCP, MRCS is a member of the following medical societies: American College of International Physicians, American Heart Association, American Stroke Association, American Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, National Association of Managed Care Physicians, American College of Physicians, Royal College of Physicians, Royal College of Physicians and Surgeons of Canada, Royal College of Surgeons of England, Royal Society of Medicine

Disclosure: Nothing to disclose.


Arun Ramachandran, MD State University of New York Upstate Medical University

Arun Ramachandran, MD is a member of the following medical societies: American Medical Association

Disclosure: Nothing to disclose.

Specialty Editor Board

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

Disclosure: Received salary from Medscape for employment. for: Medscape.

Florian P Thomas, MD, PhD, Drmed, MA, MS Director, National MS Society Multiple Sclerosis Center; Professor and Director, Clinical Research Unit, Department of Neurology, Adjunct Professor of Physical Therapy, Associate Professor, Institute for Molecular Virology, St Louis University School of Medicine; Editor-in-Chief, Journal of Spinal Cord Medicine

Florian P Thomas, MD, PhD, Drmed, 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

Disclosure: Nothing to disclose.

Chief Editor

Niranjan N Singh, MD, DM Associate Professor of Neurology, University of Missouri-Columbia School of Medicine

Niranjan N Singh, MD, DM 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

Roberta J Seidman, MD Associate Professor of Clinical Pathology, Stony Brook University; Director of Neuropathology, Department of Pathology, Stony Brook University Medical Center

Roberta J Seidman, MD is a member of the following medical societies: American Academy of Neurology, Suffolk County Society of Pathologists, New York Association of Neuropathologists (The Neuroplex), American Association of Neuropathologists

Disclosure: Nothing to disclose.


The authors and editors of Medscape Reference gratefully acknowledge the contributions of previous authors Thomas Wisniewski, MD and Einar M Sigurdsson, PhD to the development and writing of this article.

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Prion-related diseases. Spongiform change in prion disease. This section shows mild parenchymal vacuolation and prominent reactive astrocytosis.
Prion-related diseases. A representation of the human proteinaceous infectious particle, or PrP, gene. Mutations associated with inherited prionoses are shown above the gene, while polymorphisms are shown below the gene. A polymorphism at codon 129 (M versus V) is common in white populations, while a polymorphism at codon 219 (E versus K) is common in Japanese populations. The locations of the 4 putative helical regions, H1-H4, correspond to residues 109-122, 129-141, 178-191, and 202-218, respectively. This diagram does not illustrate all of the alpha-helical regions. A diagonal striped area represents the region of octarepeats, spanning residues 51-91. Octarepeats of 16, 32, 40, 48, 56, 64, or 72 amino acids at codons 67, 75, or 83 are indicated by the rectangle above the octarepeat region. These inserts are associated with familial Creutzfeldt-Jakob disease (CJD).
Shows characteristic signal changes of an MRI taken from a patient with sporadic CJD, using diffusion-weighted imaging (DWI). An abnormal signal is shown in both the basal ganglia (red arrows) and the cortical ribbon (yellow arrow).
Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission
Disease Host Mechanism
Kuru Human Cannibalism
Sporadic CJD Human Spontaneous PrPC to PrPSc conversion or somatic mutation
Iatrogenic CJD Human Infection from prion-containing material, eg, dura mater, electrode
Familial CJD Human Mutations in the PrP gene
vCJD Human Infection from BSE
GSS Human Mutations in the PrP gene
FFI Human D178N mutation in the PrP gene, with M129 polymorphism
Sporadic fatal insomnia Human Spontaneous PrPC to PrPSc conversion or somatic mutation
Scrapie Sheep Infection in susceptible sheep
BSE Cattle Infection from contaminated food
TME Mink Infection from sheep or cattle in food
CWD Mule, deer, elk Unclear
Feline spongiform encephalopathy Cats Infection from contaminated food
Exotic ungulate encephalopathy Nyala, oryx, kudu Infection from contaminated food
Table 2. Paraneoplastic Syndromes, Associated Tumors, and Autoantibodies
Clinical Syndrome Neoplasm Autoantibodies
Limbic encephalitis Small cell lung carcinoma

Testicular/breast, thymoma

Anti-Hu, antiCV2,PCA-2, ANNA-3

Anti-Ma2 Anti-VGKC, anti-CV2

Cerebellar degeneration Breast, ovary, lung, others Anti-Yo, anti-Ma, anti-Ri

Anti-Hu, anti-CV2

Opsoclonus myoclonus Breast, ovarian, small cell carcinoma of lung


Anti-Ri, anti-Yo, Anti-Hu,

Anti-amphiphysin Anti-Hu

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