Diagnostic Considerations

Other problems to be considered include the following:

Non-herpes 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.^[91]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.^{[92, 93, 94]}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.

The classical clinical presentation of CJD is quite unique; but with such high clinical variability and a variety of symptoms characteristic of more common neurodegenerative diseases, CJD “mimics” are not uncommon and may present a diagnostic challenge. Clinical features suggestive of a “mimic” rather than CJD include generalized seizures, fevers, and hyponatremia. Additionally, MRI signal hyperintensity outside the striatum, thalamus, or cortex is suggestive of pathology other than CJD. Further, visualizing contrast-enhancing lesions on imaging or obtaining CSF with pleocytosis are highly suggestive of a CJD “mimic."^[95]

Differential Diagnoses

Workup

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Media Gallery

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).

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Table 1. Prion-Related Diseases, Hosts, and Mechanism of Transmission

Disease	Host	Mechanism
Kuru	Human	Cannibalism
Sporadic CJD	Human	Spontaneous PrP^C to PrP^Sc 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 PrP^C to PrP^Sc 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 Neuroblastoma	Anti-Ri, anti-Yo, Anti-Hu, Anti-amphiphysin Anti-Hu

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Author

Deepak K Gupta, MD Assistant Professor of Neurological Sciences, The Robert Larner, MD, College of Medicine at The University of Vermont; Movement Disorders Neurologist, Binter Center for Parkinson’s Disease and Movement Disorders, University of Vermont Medical Center

Disclosure: Nothing to disclose.

Coauthor(s)

Magalie E Carey, BS MD Candidate, The Robert Larner, MD, College of Medicine at The University of Vermont

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, 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

Roberta J Seidman, MD Associate Professor of Pathology, Director of Neuropathology, Department of Pathology, Renaissance School of Medicine at Stony Brook University, Stony Brook Medicine

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

Disclosure: Nothing to disclose.

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 Academy of Neurology, American Academy of Pain Medicine, American College of Forensic Examiners Institute, American College of International Physicians, American College of Physicians, American Heart Association, American Stroke Association, National Association of Managed Care 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.

Acknowledgements

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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