Rapidly Progressive Dementia – Clinical Aspects and Management

European Neurological Review, 2011;6(4):238-245 DOI: http://doi.org/10.17925/ENR.2011.06.04.238


Although no precise definition for rapidly progressive dementia (RPD) exists, this term is generally used to refer to cases with significant and progressive cognitive impairment that occurs over weeks or months. RPD represents an unusual but severe condition that causes distress not only for patients and their relatives but also for the clinicians involved, as multiple investigations and decisions about management must be made urgently to avoid misdiagnosing a treatable condition and to preserve as much of the neural tissue as possible from definite damage. While Creutzfeldt-Jacob disease (CJD) has for a long period of time been regarded as the prototype of RPD, this infrequent but severe condition can be produced by an extensive variety of causes such as various endocrine, metabolic or toxic disorders, central nervous system (CNS) infections, primary or secondary CNS neoplasms, various CNS vasculitides and various autoimmune conditions in which autoantibodies against neural tissue are produced, whether in the presence of a neoplasm or not. However, even in the more common and usually slowly progressive dementias such as Alzheimer’s disease, frontotemporal lobar degeneration, dementia with Lewy bodies and other degenerative dementias, as well as vascular dementia, establishment and progression of the disease is occasionally surprisingly accelerated, leading to a clinical presentation of RPD. The few published case series of RPD have shown that the relative frequency of underlying diseases depends mainly on the clinical setting. Thus, CJD has been found to be the most prevalent cause in referral centres for spongiform encephalopathies, while secondary causes are more prevalent in general referral centres for dementia diagnosis. In clinical practice, for the cases presenting with RPD, the diagnostic procedure must be exhaustive, starting with a detailed clinical evaluation and proceeding to a complete laboratory work-up and sophisticated neuroimaging studies. There has been recent enormous progress in imaging, with sensitive new sequences of magnetic resonance imaging and immunology; as a result, a plethora of antibodies against the CNS can now be detected in cases of autoimmune dementias, which has dramatically changed the diagnostic approach and early management of cases of RPD. The same favourable effect in clinical practice comes from the accumulated knowledge of the complex clinical picture of various causes of RPD, associated specific neurological features (pyramidal signs, ataxia, myoclonus) and systematic features (weight loss, hyponatraemia, hepatic disorders) and their mode of progression.
Keywords: Rapidly progressive dementia, Creutzfeldt-Jakob disease, autoimmune encephalopathies, central nervous system infections
Disclosure: The authors have no conflicts of interest to declare.
Received: October 18, 2011 Accepted November 21, 2011
Correspondence: Sokratis G Papageorgiou, 2nd University Department of Neurology, ‘ATTIKON’ University General Hospital, 1 Rimini Street, Haidari, 124 62, Athens, Greece. E: sokpapa@med.uoa.gr

The term rapidly progressive dementia (RPD) is used to describe cases with a progression course which usually ranges between weeks and months.1–4 The subacute nature of RPD excludes other conditions with fulminant progression such as infectious or metabolic acute encephalopathies, which progress within hours or days and typically commence as an acute confusional state.

In most cases, the cognitive decline observed in RPD can be attributed to a single underlying disorder. Nevertheless, a rapid course might also represent the aggravation of an undiagnosed disease attributable to a secondary cause, usually an infection or a metabolic dysregulation. Various conditions involving the central nervous system (CNS) can emerge as RPD, including Creutzfeld-Jakob disease (CJD) and other spongiform encephalopathies, vascular disorders, autoimmune and paraneoplastic encephalopathies, subacute infections, metabolic and toxic disorders and systemic diseases (see Table 1). However, it is important to point out that even neurodegenerative disorders such as Alzheimer’s disease (AD), dementia with Lewy bodies and frontotemporal dementia present in rare cases as a subacute dementia instead of a slowly progressive deterioration of higher functions.5 CJD is the prevailing cause of RPD in most related studies. Regarding the relative frequency of other disorders which account for cases of RPD, there is marked variability among scientific groups.1–3 In cases of RPD with an early age of onset, the possibility of an infection, hereditary metabolic disorder or autoimmune encephalopathy should be considered.6,7

The early diagnosis of the undergoing disorder in a patient exhibiting an RPD can be particularly demanding owing to the paucity of clinical signs during the early stages of many disorders and to overlapping laboratory findings. The pattern of cognitive deficits is crucial for clinical assessment. Selective memory, executive function and language deficits might favour one potential diagnosis and exclude others. Thus, a detailed neuropsychological evaluation is crucial.2,3

The evaluation of behavioural alterations and neuropsychiatric symptoms is of high importance, since the initial symptoms can be exclusively a depressive-like or a disinhibited behaviour. Associated signs and symptoms, either neurological or systematic, can unveil an undetermined underlying disease. Ataxia, parkinsonism and specific motor or sensory deficits might herald the clinical expression of an otherwise obscure disorder during the progression of various forms of RPD.

  1. Geschwind MD, Shu H, Haman A, et al., Rapidly progressive dementia, Ann Neurol, 2008;64:97–108.
  2. Josephs KA, Ahlskog JE, Parisi JE, et al., Rapidly progressive neurodegenerative dementias, Arch Neurol, 2009;66:201–7.
  3. Papageorgiou SG, Kontaxis T, Bonakis A, et al., Rapidly progressive dementia: causes found in a Greek tertiary referral center in Athens, Alzheimer Dis Assoc Disord, 2009;23:337–46.
  4. Rosenbloom MH, Atri A, The evaluation of rapidly progressive dementia, Neurologist, 2011;17:67–74.
  5. Tschampa HJ, Neumann M, Zerr I, et al., Patients with Alzheimer's disease and dementia with Lewy bodies mistaken for Creutzfeldt-Jakob disease, J Neurol Neurosurg Psychiatry, 2001;71:33–9.
  6. Heinemann U, Schmidt C, Zerr I, Differential diagnosis of rapid progressive dementia, European Neurological Review, 2010;5:21–8.
  7. Kelley BJ, Boeve BF, Josephs KA, Rapidly progressive youngonset dementia, Cogn Behav Neurol, 2009;22:22–7.
  8. Zerr I, Kallenberg K, Summers DM, et al., Updated clinical diagnostic criteria for sporadic Creutzfeldt-Jakob disease, Brain, 2009;132:2659–68.
  9. Schmidt C, Redyk K, Meissner B, et al., Clinical features of rapidly progressive Alzheimer's disease, Dement Geriatr Cogn Disord, 2010;29:371–8.
  10. Chui HC, Lyness SA, Sobel E, et al., Extrapyramidal signs and psychiatric symptoms predict faster cognitive decline in Alzheimer's disease, Arch Neurol, 1994;51:676–81.
  11. Mangone CA, [Clinical heterogeneity of Alzheimer's disease. Different clinical profiles can predict the progression rate], Rev Neurol, 2004;38:675–81.
  12. Viatonou S, Drame M, Jolly D, et al., Predictors of rapid cognitive decline among demented subjects aged 75 or more: ('Sujet Age Fragile – Evaluation et Suivi' Cohort- SAFES), Int J Geriatr Psychiatry, 2009;24:709–15.
  13. Martins CA, Oulhaj A, de Jager CA, et al., APOE alleles predict the rate of cognitive decline in Alzheimer disease: a nonlinear model, Neurology, 2005;65:1888–93.
  14. Kleiman, T, Zdanys K, Black B, et al., Apolipoprotein E epsilon4 allele is unrelated to cognitive or functional decline in Alzheimer's disease: retrospective and prospective analysis, Dement Geriatr Cogn Disord, 2006;22:73–82.
  15. Scarmeas N, Hadjigeorgiou GM, Papadimitriou A, et al., Motor signs during the course of Alzheimer disease, Neurology, 2004;63:975–82.
  16. Roberson ED, Hesse JH, Rose KD, et al., Frontotemporal dementia progresses to death faster than Alzheimer disease, Neurology, 2005;65:719–25.
  17. Forman MS, Farmer J, Johnson JK, et al., Frontotemporal dementia: clinicopathological correlations, Ann Neurol, 2006;599:52–62.
  18. Josephs KA, Knopman DS, Whitwell JL, et al., Survival in two variants of tau-negative frontotemporal lobar degeneration: FTLD-U vs FTLD-MND, Neurology, 2005;65:645–7.
  19. Yener G, Rosen H, Papatriantafyllou J, Frontotemporal degeneration, Continum Lifelong Learning Neurol, 2010;16:191–211.
  20. Gaig C, Valldeoriola F, Gelpi E, et al., Rapidly progressive diffuse Lewy body disease, Mov Disord, 2011;26:1316–23.
  21. Gesswind M, Rapidly progressive dementia: prion disease and other rapid dementias, Continum Lifelong Learning Neurol, 2010;16:31–56.
  22. Rabinovici GD, Wang PN, Levin J, et al., First symptom in sporadic Creutzfeldt-Jakob disease, Neurology, 2006;66:286–7.
  23. Meyer A, Leigh D, Bagg CE, A rare presenile dementia associated with cortical blindness (Heidenhain's syndrome), J Neurol Neurosurg Psychiatry, 1954;17:129–33.
  24. Kovacs GG, Puopolo M, Ladogana A, et al., Genetic prion disease: the EUROCJD experience, Hum Genet, 2005;118:166–74.
  25. Will RG, Alperovitch A, Poser S, et al., Descriptive epidemiology of Creutzfeldt-Jakob disease in six European countries, 1993–1995. EU Collaborative Study Group for CJD, Ann Neurol, 1998;43:763–7.
  26. Steinhoff BJ, Zerr I, Glatting M, et al., Diagnostic value of periodic complexes in Creutzfeldt-Jakob disease, Ann Neurol, 2004;56:702–8.
  27. Zerr I, Schulz-Schaeffer WJ, Giese A, et al., Current clinical diagnosis in Creutzfeldt-Jakob disease: identification of uncommon variants, Ann Neurol, 2000;48:323–9.
  28. Jacobi C, Arlt S, Reiber H, et al., Immunoglobulins and virus-specific antibodies in patients with Creutzfeldt-Jakob disease, Acta Neurol Scand, 2005;111:185–90.
  29. Sanchez-Juan P, Green A, Ladogana A, et al., CSF tests in the differential diagnosis of Creutzfeldt-Jakob disease, Neurology, 2006;67:637–43.
  30. Shiga Y, Miyazawa K, Sato S, et al., Diffusion-weighted MRI abnormalities as an early diagnostic marker for Creutzfeldt- Jakob disease, Neurology, 2004;63:443–9.
  31. Heath CA, Cooper SA, Murray K, et al., Validation of diagnostic criteria for variant Creutzfeldt-Jakob disease, Ann Neurol, 2010;67:761–70.
  32. Will RG, Zeidler M, Stewart GE, et al., Diagnosis of new variant Creutzfeldt-Jakob disease, Ann Neurol, 2000;47:575–82.
  33. 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, AJNR Am J Neuroradiol, 2003;24:1560–9.
  34. Geschwind MD, Haman A, Miller BL, Rapidly progressive dementia, Neurol Clin, 2007;25:783–807.
  35. Itzhaki RF, Wozniak MA, Viral infection and cognitive decline, J Am Geriatr Soc, 2007;55:131.
  36. Brew BJ, AIDS dementia complex, Neurol Clin, 1999;17:861–81.
  37. Dimova PS , Bojinova VS, Case of subacute sclerosing panencephalitis with atypical absences and myoclonic-atonic seizures as a first symptom, J Child Neurol, 2004;19:548–52.
  38. Fox PA, Hawkins DA, Dawson S, Dementia following an acute presentation of meningovascular neurosyphilis in an HIV-1 positive patient, AIDS, 2000;14:2062–3.
  39. Heckman GA, Hawkins C, Morris A, et al., Rapidly progressive dementia due to Mycobacterium neoaurum meningoencephalitis, Emerg Infect Dis, 2004;10:924–7.
  40. Kaplan RF, Jones-Woodward L, Lyme encephalopathy: a neuropsychological perspective, Semin Neurol, 1997;17:31–7.
  41. Matthews BR, Jones LK, Saad DA, et al., Cerebellar ataxia and central nervous system whipple disease, Arch Neurol, 2005;62:618–20.
  42. Bataille B, Delwail V, Menet E, et al., Primary intracerebral malignant lymphoma: report of 248 cases, J Neurosurg, 2000;92:261–6.
  43. Lai R, Rosenblum MK, DeAngelis LM, Primary CNS lymphoma: a whole-brain disease?, Neurology, 2002;59:1557–62.
  44. Kuker W, Nagele T, Thiel E, et al., Primary central nervous system lymphomas (PCNSL): MRI response criteria revised, Neurology, 2005;65:1129–31.
  45. Bakshi R, Mazziotta JC, Mischel PS, et al., Lymphomatosis cerebri presenting as a rapidly progressive dementia: clinical, neuroimaging and pathologic findings, Dement Geriatr Cogn Disord, 1999;10:152–7.
  46. Kohler W, Leukodystrophies with late disease onset: an update, Curr Opin Neurol, 2010;23:234–41.
  47. Pastores G, Leukoencephalopathies and leukodystrophies, Continum Lifelong Learning Neurol, 2010;16:102–19.
  48. Costello DJ, Eichler AF, Eichler FS, Leukodystrophies: classification, diagnosis, and treatment, Neurologist, 2009;15:319–28.
  49. Papageorgiou SG, Christou Y, Kontaxis T, et al., Dementia as presenting symptom of primary hyperparathyroidism: favourable outcome after surgery, Clin Neurol Neurosurg, 2008;110:1038–40.
  50. Auchus AP, Chen CP, Sodagar SN, et al., Single stroke dementia: insights from 12 cases in Singapore, J Neurol Sci, 2002;203–204:85–9.
  51. Flanagan EP, McKeon A, Lennon VA, et al., Autoimmune dementia: clinical course and predictors of immunotherapy response, Mayo Clin Proc, 2010;85:881–97.
  52. Rosenbloom MH, Smith S, Akdal G, et al., Immunologically mediated dementias, Curr Neurol Neurosci Rep, 2009;9:359–67.
  53. Dalmau J, Rosenfeld MR, Paraneoplastic syndromes of the CNS, Lancet Neurol, 2008;7:327–40.
  54. Graus F, Dalmau J, Paraneoplastic neurological syndromes: diagnosis and treatment, Curr Opin Neurol, 2007;20:732–7.
  55. Dalmau J, Gleichman AJ, Hughes EG, et al., Anti-NMDAreceptor encephalitis: case series and analysis of the effects of antibodies, Lancet Neurol, 2008;7:1091–8.
  56. Hart IK, Waters C, Vincent A, et al., Autoantibodies detected to expressed K+ channels are implicated in neuromyotonia, Ann Neurol, 1997;41:238–46.
  57. Tan KM, Lennon VA, Klein CJ, et al., Clinical spectrum of voltage-gated potassium channel autoimmunity, Neurology, 2008;70:1883–90.
  58. Chang CC, Eggers SD, Johnson JK, et al., Anti-GAD antibody cerebellar ataxia mimicking Creutzfeldt-Jakob disease, Clin Neurol Neurosurg, 2007;109:54–7.
  59. Geschwind MD, Tan KM, Lennon VA, et al., Voltage-gated potassium channel autoimmunity mimicking Creutzfeldt- Jakob disease, Arch Neurol, 2008;65:1341–6.
  60. Chong JY, Rowland LP, Utiger RD, Hashimoto encephalopathy: syndrome or myth?, Arch Neurol, 2003;60:164–71.
  61. Kothbauer-Margreiter I, Sturzenegger M, Komor J, et al., Encephalopathy associated with Hashimoto thyroiditis: diagnosis and treatment, J Neurol, 1996;243:585–93.
  62. Arrojo M, Perez-Rodriguez MM, Mota M, et al., Psychiatric presentation of Hashimoto's encephalopathy, Psychosom Med, 2007;69:200–1.
  63. Mijajlovic M, Mirkovic M, Dackovic J, et al., Clinical manifestations, diagnostic criteria and therapy of Hashimoto's encephalopathy: report of two cases, J Neurol Sci, 2010;288:194–6.
  64. Mocellin R, Lubman DI, Lloyd J, et al., Reversible dementia with psychosis: Hashimoto's encephalopathy, Psychiatry Clin Neurosci, 2006;60:761–3.
  65. Poser S, Mollenhauer B, Kraubeta A, et al., How to improve the clinical diagnosis of Creutzfeldt-Jakob disease, Brain, 1999;122:2345–51.
  66. Joseph FG, Scolding NJ, Neurolupus, Pract Neurol, 2010;10:4–15.
  67. Hu WT, Murray JA, Greenaway MC, et al., Cognitive impairment and celiac disease, Arch Neurol, 2006;63:1440–6.
  68. Schielke E, Nolte C, Muller W, et al., Sarcoidosis presenting as rapidly progressive dementia: clinical and neuropathological evaluation, J Neurol, 2001;248:522–4.
  69. Oktem-Tanor O, Baykan-Kurt IH, Gurvit B, et al., Neuropsychological follow-up of 12 patients with neuro-Behcet disease, J Neurol, 1999;246:113–9.
Keywords: Rapidly progressive dementia, Creutzfeldt-Jakob disease, autoimmune encephalopathies, central nervous system infections