Creutzfeldt-Jakob disease differential diagnosis

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Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1] Associate Editor(s)-in-Chief: Mohamadmostafa Jahansouz M.D.[2] Twinkle Singh, M.B.B.S. [3]


Creutzfeldt-Jakob disease must be differentiated from other causes of rapidly progressive dementia, such as variant Creutzfeldt-Jakob disease, Mad Cow disease, Alzheimer disease, Dementia with Lewy bodies, Frontotemporal dementia, Corticobasal degeneration, Normal pressure hydrocephalus, parkinsonian disorder, Paraneoplastic syndrome, Vasculitis, Neurosarcoidosis,Encephalitis, Whipple disease, Rabies, Herpes simplex virus, postinfectious syndrome, Vitamin B12 deficiency, Hypothyroidism, Wernicke-Korsakoff syndrome and urinary tract infections.

Differential Diagnosis of Creutzfeldt-Jakob Disease

  • CJD should be differentiated from other diseases presenting with dementia, ataxia, pyramidal/extrapyramidal signs, myoclonus, rigidity and visual hallucinations. The major differentials of CJD include the following:
Disease Signs and Symptoms Imaging Findings Laboratory Findings
Dementia Rigidity Myoclonus Visual Hallucinations Parkinsonism Speech Impairment Fever Cerebellar Signs (Ataxia, imbalance, dysdiadochokinesia) Hyperkinetic Signs Pyramidal Signs (Spasticity, Hyperreflexia, loss of fine motor skills, upgoing plantars)
Creutzfeldt-Jakob Disease +

(Rapidly progressive)

+ + + - + - + + + On MRI:
  • High signal intensity in the caudate nucleus or putamen at DWI or FLAIR imaging.
  • Focal or diffuse, symmetric or asymmetric involvement (more common) of the cerebral cortex, basal ganglia specially corpus striatum
  • Sparing of peri-rolandic area
  • Cerebellar atrophy
  • Hyperintensity in the globus pallidus on T1-weighted images
On CSF exam:
  • Elevated levels of the 14-3-3 protein


  • Periodic sharp wave complexes
Lewy Body Dementia + + + + + + - - - -
Alzheimer's disease + (Slow progression) + + - - -/+ - - - - On CSF exam:
  • Elevated Tau protein

Neurofibrillary tangles

Senile (neuritic) plaques

Herpes Simplex Encephalitis -/+ - - - - + + -/+ - -/+ On MRI:
  • T2-weighted image shows asymmetric bilateral involvement of the temporal lobes with high signal intensity and swelling
On CSF exam:
  • Elevated leukocyte count (mononuclear pleocytosis)
  • Elevated protein levels
  • Normal or decreased glucose levels


  • 2–3 Hz periodic lateralised epileptiform discharges originating from the temporal lobes
  • Differential diagnosis of Creutzfeldt-Jakob disease includes the following:[1][2][3][4]

Neurodegenerative Diseases

Autoimmune diseases


Toxic or metabolic causes

Clinical and pathologic characteristics of classic CJD and variant CJD:[5]

Characteristic Classic CJD Variant CJD
Median age at death 68 years 28 years
Median duration of illness 4-5 months 13-14 months
Clinical signs and symptoms Dementia; early neurologic signs Prominent psychiatric/behavioral symptoms; painful dysesthesias; delayed neurologic signs
Periodic sharp waves on electroencephalogram Often present Often absent
Signal hyperintensity in the caudate nucleus and putamen on diffusion-weighted and FLAIR MRI Often present Often absent
Pulvinar sign on MRI Not reported Present in >75% of cases
Immunohistochemical analysis of brain tissue Variable accumulation. Marked accumulation of protease-resistant prion protein
Presence of agent in lymphoid tissue Not readily detected Readily detected
Increased glycoform ratio on immunoblot analysis of protease-resistant prion protein Not reported Marked accumulation of protease-resistant prion protein
Presence of amyloid plaques in brain tissue May be present May be present


  1. 1.0 1.1 Paterson RW, Torres-Chae CC, Kuo AL, Ando T, Nguyen EA, Wong K; et al. (2012). "Differential diagnosis of Jakob-Creutzfeldt disease". Arch Neurol. 69 (12): 1578–82. doi:10.1001/2013.jamaneurol.79. PMC 4401069. PMID 23229042.
  2. Kojima G, Tatsuno BK, Inaba M, Velligas S, Masaki K, Liow KK (2013). "Creutzfeldt-Jakob disease: a case report and differential diagnoses". Hawaii J Med Public Health. 72 (4): 136–9. PMC 3689509. PMID 23795314.
  3. Poser S, Zerr I, Schroeter A, Otto M, Giese A, Steinhoff BJ; et al. (2000). "Clinical and differential diagnosis of Creutzfeldt-Jakob disease". Arch Virol Suppl (16): 153–9. PMID 11214918.
  4. Zerr I, Poser S (2002). "Clinical diagnosis and differential diagnosis of CJD and vCJD. With special emphasis on laboratory tests". APMIS. 110 (1): 88–98. PMID 12064260.
  5. Belay ED, Schonberger LB (2002). "Variant Creutzfeldt-Jakob disease and bovine spongiform encephalopathy". Clin. Lab. Med. 22 (4): 849–62, v–vi. PMID 12489284.

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