ORIGINAL ARTICLE Rapidly Progressive Dementia Causes Found in a Greek Tertiary Referral Center in Athens Sokratis G. Papageorgiou, MD, Theodoros Kontaxis, MD, Anastasios Bonakis, MD, Georgios Karahalios, MD, Nikolaos Kalfakis, MD, and Demetrios Vassilopoulos, MD, PhD Abstract: Dementia is generally considered as rapidly progressive [rapidly progressive dementia (RPD)], in cases with overt cognitive impairment, established within months. Data about the relative frequency of underlying diseases in cases of RPD are few and extremely variable, depending on the clinical setting. We examined the relative frequency of the underlying causes of RPD, in a university tertiary referral center, in Athens. A series of consecutive patients presenting with RPD in a 3-year period was included. All patients received a comprehensive clinical, imaging, and laboratory evaluation. Of a total of 279 patients hospitalized for dementia diagnosis, 68 patients had RPD (37 males and 31 females). Mean age at onset ± SD was 65.5 ± 10.0. The most common cause of RPD was secondary dementias, accounting for 18 cases (26.5%). Alzheimer disease and frontotemporal dementia were almost equally represented, accounting for 12 (17.6%) and 11 (16.2%) cases, respectively. Vascular dementia, Creutzfeldt-Jakob disease, and various neurodegenerative diseases accounted for 9 cases each (13.2%). In a tertiary referral center, secondary dementias represented the most frequent cause of cases presenting with RPD. As a substantial number of these cases are potentially treatable, our finding reconfirms and underscores the importance of an exhaustive evaluation in any case presenting with RPD. Key Words: dementia, rapidly progressive dementias, spongiform encephalopathy, secondary dementias, treatable dementias (Alzheimer Dis Assoc Disord 2009;23:337–346) D ementia is generally considered as rapidly progressive [rapidly progressive dementia (RPD)], in cases with overt cognitive impairment, established within months. RPD occurs infrequently in clinical practice and is generally attributed to various conditions affecting the central nervous system (CNS), such as metabolic disorders, Hashimoto encephalopathy,1,2 primary CNS lymphoma,3,4 CNS angiitis,5,6 immune encephalitis, Creutzfeldt-Jakob disease (CJD),7–11 and other spongiform encephalopathies.12 Received for publication April 3, 2008; accepted January 19, 2009. From the Department of Neurology, Eginition Hospital, Medical School, Athens National University, Athens, Greece. Reprints: Sokratis G. Papageorgiou, MD, Department of Neurology, Eginition Hospital, University of Athens, 74, Vassilissis Sofias Avenue, 11528 Athens, Greece (e-mail: sokpapa@med.uoa.gr). Copyright r 2009 by Lippincott Williams & Wilkins Alzheimer Dis Assoc Disord  However, even in the well-known common neurodegenerative dementing diseases, establishment of symptoms can be accelerated, and RPD has been reported in cases of: Alzheimer disease (AD),13–15 frontotemporal dementia (FTD) with motor neuron disease,16,17 and dementia with Lewy bodies (DLB).13,18 Data about the relative frequency of underlying diseases in cases of RPD are few and focusing mainly on cases of patients suspected for CJD.8,19–21 In these studies, the relative frequency of the non-CJD causes was found to be extremely variable. In clinical practice, the diagnostic process for the cases presenting with RPD must be exhaustive including complete laboratory work up and sophisticated neuroimaging studies. Thus, data about the relative frequency of diseases presenting with RPD, could prove very helpful for the decisions regarding the appropriate investigations.22,23 The aim of our study was to estimate the relative frequency of pathologic conditions presenting as RPD, on a prospective series of patients hospitalized for dementia diagnosis, in a tertiary referral center in Athens. SUBJECTS AND METHODS Subjects Patients included in this study were referred to the Cognitive Neurology-Extrapyramidal Disorders Unit, University Department of Neurology, Eginition Hospital, Athens, during a 3-year period (from January 1, 2004 to December 21, 2006), for dementia diagnosis. In general, patients are referred to our unit if they present one of the following: (a) RPD, (b) dementia of undetermined diagnosis or with atypical features, and (c) dementia with early onset (ie, with symptoms starting before the age of 65 y). The age of onset of dementia was defined as the age at which the first well-defined change in cognition and/or behavior in the patient was observed by a close relative or caregiver. All patients were evaluated by neurologic and psychologic examinations and interviews with caregivers for symptoms. Family history was ascertained by information collected from family members and relatives. All patients (except 5) were evaluated by magnetic resonance imaging of the brain including T1, T2, and fluidattenuated inversion-recovery sequences. Gradient echo sequences were obtained only if amyloid disease was suspected. Diffusion tensor imaging sequences were performed only in some of the cases suspected for CJD. In 5 patients with contraindication for magnetic resonance imaging (eg, presence of pacemaker) only brain computed tomography scan was obtained. When appropriate, for the detection of secondary causes of RPD, chest and abdominal Volume 23, Number 4, October–December 2009 www.alzheimerjournal.com | 337 Papageorgiou et al Alzheimer Dis Assoc Disord computed tomography scans were also performed. Functional imaging with single photon emission computed tomography (Tc-99m-HMPAO-SPECT) was performed in 26 patients. To exclude treatable causes of dementia, all patients underwent screening blood tests, including a complete blood count, serum electrolytes, blood sugar, acute C-reactive protein, liver function tests, blood urea nitrogen, serum cholesterol and lipid levels, thyroidstimulating hormone, thyroid hormones and antithyroid antibodies, and treponemal serology. Cases with a suspicion of connective tissue disorder were investigated with the detection of autoantibodies (antinuclear antibodies, antineutrophil cytoplasmic antibodies, anti-double stranded DNA, antiextractable nuclear antigen, anticardiolipin antibodies, etc.) All patients also underwent lumbar puncture for biochemistry and cell count and tau-protein and Ab-42 amyloid measurement in cerebrospinal fluid. For suspected CJD cases, 14-3-3 protein assessment was also performed. Cognitive function was assessed with a battery including: the Mini-Mental State Examination (MMSE),24 digit span forward and backwards, 5-word memory test (immediate and delayed free and cued recall), the Frontal Assessement Battery25 for frontal-executive functions, verbal fluency tests (semantic and phonemic), a naming test, and Clock-Drawing Test. Severity of dementia was graded according to the clinical dementia rating scale.26 Behavioral disturbances were assessed with the Neuropsychiatric Inventory27 and the Frontal Behavioral Inventory.28 Diagnosis Dementia was diagnosed according to the Diagnostic and Statistical Manual of Mental Disorders.29 Dementia was considered as rapidly progressing if the patient was demented in less than 1 year after the appearance of the first cognitive symptom. However, causes of acute cognitive impairment in the context of confusional state, owing to acute infectious, metabolic, or toxic causes (eg, acute viral encephalitis, acute hyponatremia, hypoglycemia, and recent use of anticholinergic drugs) were not classified as RPD. Patients with dementia were consequently grouped according to the most consistent etiologic diagnosis. For the degenerative dementias the diagnosis was based on the existing criteria (where applicable): AD was defined according to the National Institute of Neurological and Communicative Disorders and Stroke and the Alzheimer’s Disease and Related Disorders Association criteria.30 Vascular dementia (VaD) was defined according to the National Institute of Neurological Disorders and StrokeAssociation Internationale pour la Recherche et l’Enseignement en Neurosciences criteria.31 DLB was defined according to the consensus guidelines for the clinical diagnosis of DLB.32 Patients with Parkinson disease of at least 1-year duration, who then developed dementia, were classified as cases of Parkinson disease dementia (PDD). Diagnosis of frontotemporal lobar degeneration (FTLD), and its subtypes: FTD, semantic dementia, and progressive nonfluent aphasia, was given according to the International Consensus Criteria.33 Progressive supranuclear palsy (PSP) was diagnosed according to the Consensus Criteria.34 Diagnosis of CJD was according to the criteria defined by the World Health Organization.35 Cases of dementia owing to secondary-potentially treatable causes [secondary dementia (S-DEM)] were grouped separately. Diagnosis of multiple system atrophy (MSA) was based on the criteria 338 | www.alzheimerjournal.com  Volume 23, Number 4, October–December 2009 suggested by Quinn.36 Diagnosis of cortico-basal degeneration (CBD) was based on the study of Litvan et al.37 Data Analysis Statistical analysis was conducted using the SPSS 13.0 package. Analysis of variance (ANOVA) was used to evaluate differences in age at onset, time of progression to dementia (expressed as the approximate number of months of symptoms to a full dementia syndrome), and MMSE scores among disease groups. If differences were found, Fisher protected least significant difference test was used. Analysis of sex differences between the diagnostic groups was carried out using a 2-tailed w2 test. RESULTS Of a total of 279 patients hospitalized for dementia diagnosis during a 3-year period (from January 1, 2004 to December 21, 2006), a total of 68 subjects (37 males, 54.4% and 31 females, 45.6%) presented with RPD. A detailed description of the demographic, clinical, laboratory, and imaging findings of the whole series of patients is presented in Table 1. These patients had a mean age at onset ± SD of 65.5 ± 10.0 (median: 66.7; range: 35.3 to 82.8 y). Demographic data of the diagnostic categories by etiology, for the 68 patients with RPD are shown in Table 2. The most common cause of RPD was dementia owing to secondary-reversible causes (S-DEM): 18 patients (24%). In detail, the various causes of dementia in this group were: normal pressure hydrocephalus: 4 patients, neurosyphilis: 2 patients, scleroderma: 1 patient, sarcoidosis: 1 patient, systematic lupus erythematosus: 1 patient, CNS primary vasculitis: 1 patient, limbic encephalitis: 1 patient, human immunodeficiency virus encephalitis: 1 patient, CNS tumor (forebrain glioblastoma): 1 patient, Q fever: 1 patient, B12 deficiency: 1 patient, multiple sclerosis: 1 patient, druginduced dementia: 1 patient, and dementia in the context of chronic psychosis: 1 patient. The second most common cause of RPD was AD: 12 patients (17.6%). Eight of them had probable AD, 1 had possible AD and 3 had AD associated with significant cerebrovascular disease. The third most common cause, as referred, was FTLD: 11 patients (16.2%). The fourth cause of RPD, was equally distributed between CJD, VaD, and various neurodegenerative diseases (VDD): 9 patients (13.2%) for each group. In the VDD group there were 2 cases with MSA, 4 with DLB, 1 with PSP, 1 with CBD, and 1 with PDD. ANOVA revealed only a trend for a difference between groups in terms of age at onset (F = 2.36, P = 0.05) and MMSE scores (F = 2.2, P = 0.067). Patients in the S-DEM, FTD, and CJD groups tended to be younger than patients in the rest 3 groups. VaD patients had the highest MMSE scores, whereas patients with various degenerative diseases had the lowest scores. ANOVA revealed a significant difference between groups for the time of progression to dementia (expressed as the approximate number of months of symptoms to a full dementia syndrome) (F = 6.92, P<0.0001). Post hoc tests have shown that CJD patients had a significantly shorter time of progression to dementia, from each of the following groups of patients: AD (P<0.001), FTLD (P<0.005), VaD (P<0.005), and VDD diseases (P<0.001). These groups of patients did not differ from each other. The difference of patients with r 2009 Lippincott Williams & Wilkins Time to Dementia (mo) Sex MMSE NP Bat Serum Findings Cerebrospinal Protein Fluid Findings 14-3-3 51.0 10 F 9 P Normal Normal NP 2 Probable AD Depression 77.5 6 F 17 F Normal Normal NP 3 62.8 7 F 14 F Normal Normal NP 4 Probable AD Treated hyperthyroidism Probable AD 81.0 9 F 9 NP Normal Normal NP 5 Probable AD Depression 56.0 10 F 9 F Normal Normal NP 6 Probable AD 63.0 8 F 15 F Normal Normal NP 7 Probable AD 61.4 11 M 19 F Normal Normal NP 8 Probable AD 80.8 10 F 21 F Normal Normal NP 9 Possible AD 64.0 10 M 25 F Normal Normal NP 10 AD+CVD 78.0 3 F NP Normal Normal NP 11 AD+CVD 73.3 6 M 24 P Normal Normal NP 12 AD+CVD 71.0 9 M 25 NP Normal Normal NP 13 MSA 79.0 8 F 9 NP Normal Normal NP Sleep apnea Sleep apnea Diffuse bilateral cortical Bilateral fronto-parietoatrophy, moderate temporal hypoperfusion hippocampal atrophy Marked cortical atrophy in NP the frontal and parietal lobes. Mild-to-moderate temporal atrophy (R>L) Moderate diffuse cortical NP atrophy CT scan only: diffuse cortical atrophy Bilateral fronto-parietotemporal atrophy. Mild bilateral hippocampal atrophy Mild bilateral frontoparieto-temporal atrophy. Mild-to-moderate bilateral hippocampal atrophy (L>R) Moderate bilateral temporo-parietal atrophy. Moderate hippocampal atrophy. Mild WM hyperintensities Moderate bilateral temporo-parietal atrophy. Mild bilateral hippocampal atrophy Bilateral temporal atrophy, including the hippocampi (R>L) Severe bilateral confluent hyperintensity of the WM. Mild diffuse cortical atrophy CT scan only: moderate diffuse cortical atrophy. Periventricular WM hypodensity. Mild temporo-parietal atrophy. Hyperintensities in the WM Mild bilateral frontal atrophy. Moderate periventricular heperintensities. Mild atrophy of the pons NP Bilateral fronto-parietal hypoperfusion (L>R) Bilateral parietal and left frontotemporal hypoperfusion NP NP Mild bilateral temporoparietal hypoperfusion Normal NP Left frontotemporal hypoperfusion NP Rapidly Progressive Dementia 339 Probable AD — Single Photon Emission Computed Tomography Volume 23, Number 4, October–December 2009 www.alzheimerjournal.com | 1 Magnetic Resonance Imaging  2009 Lippincott Williams & Wilkins Diagnosis Age at Comorbidity Onset Alzheimer Dis Assoc Disord r TABLE 1. Detailed Demographic, Clinical, Laboratory, and Imaging Findings for Each Patient With RPD Diagnosis Age at Comorbidity Onset Time to Dementia (mo) Sex DLB 68.0 11 M 15 DLB 66.5 6 F 16 DLB 74.8 6 17 DLB 62.0 18 PDD 19 NP Bat Serum Findings Cerebrospinal Protein Fluid Findings 14-3-3 NP 6 NP Normal Normal NP F 10 NP Normal Normal NP 11 M 9 F Normal Normal NP 75.0 6 M 11 NP Normal Normal NP PSP 68.3 9 M 20 F Normal Normal Negative 20 CBD 70.5 10 M 16 F Normal Normal NP 21 MSA 71.0 10 M 27 F Normal Normal NP 22 VaD-SIVD 67.1 9 M 19 NP Normal Normal NP 23 VaD-SIVD 81.5 9 F 21 F Normal Normal NP 24 VaD-SIVD 71.0 8 M 14 P Normal Normal NP 25 VaD-SIVD 56.7 4 F 24 P Normal Normal NP 26 VaD-SIVD 82.0 10 F 26 P Normal Normal NP Bilateral mild frontoparietal atrophy Moderate bilateral temporo-parietal atrophy. Mild hyperintensities in the WM CT scan only: mild frontal cortical atrophy Bilateral mild frontoparieto-temporal atrophy. Mild periventricular hyperintensities CT scan only: hypodensity of the periventricular WM Mild bilateral frontal atrophy 2009 Lippincott Williams & Wilkins Right fronto-parietal atrophy Moderate cerebellar atrophy. Mild cortical brain atrophy Marked confluent hyperintensities in the periventricular WM. Lacune in the left caudate. Mild cortical atrophy Marked WM hyperintensities, periventricular (caps and bands). Moderate diffuse cortical atrophy Multiple WM hyperintensities, periventricular, basal ganglia, brainstem Confluent periventricular hypersintensities, multiple lacunes in the basal ganglia, thalami, brainstem. Mild diffuse cortical atrophy CT scan only: mild diffuse cortical and subcortical atrophy. Marked hypodensity of the WM NP NP NP NP NP HMPAO: normal. DaTscan: decreased binding in the corpus striatum bilaterally (L>R) Right fronto-parietal hypoperfusion NP Localized hypoperfusion areas in: left frontal, parietal lobes NP NP NP NP Volume 23, Number 4, October–December 2009 Normal Single Photon Emission Computed Tomography  Normal r NP Magnetic Resonance Imaging Alzheimer Dis Assoc Disord 14 MMSE Papageorgiou et al 340 | www.alzheimerjournal.com TABLE 1. (continued) 74.0 8 F 27 P Normal Normal NP 56.6 9 M 25 F Normal Normal NP VaDStr.Infarct 69.0 9 M 23 F Normal Normal NP 30 VaDStr.Infarct 75.0 3 M 29 F Normal Normal NP 31 FTLD-FTD 71.0 9 F 17 F Normal Normal NP 32 FTLD-FTD 44.8 5 M 15 F Normal Normal NP 33 FTLD-FTD 72.2 8 M 26 F Normal Normal NP 34 FTLD-FTD 75.0 7 F 20 F Normal Normal NP Multiple WM hyperintensities, mild cortical atrophy Multiple WM hyperintensities Bilateral temporo-occipital infarcts, including the left hippocampus. Left-sided infarct is more recent Hyperintensities in WM. Lacune in the right caudate and left thalamus Bilateral frontotemporal atrophy (R> >L) Mild bilateral frontal atrophy No atrophy for age. Few WM hyperintensities Bilateral frontal atrophy 28 VaD-SIVD 29 35 FTLD-FTD 8 M 8 F Normal Normal NP Bilateral frontal atrophy 36 FTD 60.0 9 F Normal Normal NP 37 FTLD-FTD 35.3 7 M 25 F Normal Normal NP 38 70.5 10 M 23 F Normal Normal NP 54.1 11 F 19 F Normal Normal NP 40 FTLDSemDem FTLDSemDem FTLD-MND 70.0 4 F Normal Normal NP 41 FTLD-MND 61.0 3 M Normal 42 NPH 82.8 6 M 19 F Normal 43 NPH 66.3 9 M 24 F Normal 44 NPH 67.0 10 M 17 P Normal 45 NPH 76.0 11 M 6 F Normal Mildly elevated protein Mildly elevated protein Mildly elevated protein. ICP:140 mm H20 Mildly elevated protein. ICP:195 mm H2O ICP:170 mm H2O Bilateral frontal lobe atrophy Severe bilateral frontal atrophy (R>L) extending to the temporal and parietal lobes Bilateral frontotemporal NP atrophy (L>R) Left temporo-parietal Left temporo-parietal atrophy hypoperfusion Right frontotemporal Marked bilateral atrophy frontotemporal hypoperfusion Bilateral temporal atrophy Bilateral temporo-parietal (R>L) hypoperfusion (R > L) 73.8 Negative NP NP NP Right frontotemporal hypoperfusion Right temporal hypoperfusion Bilateral frontal hypoperfusion Bilateral frontotemporal hypoperfusion (L>R) Marked bilateral frontal hypoperfusion (L>R) Severe bilateral frontal hypoperfusion Right frontal hypoperfusion 341 Ventricular enlargement NP NP Ventricular enlargement NP NP Ventricular enlargement NP NP Ventricular enlargement, lacunes in basal ganglia NP Rapidly Progressive Dementia www.alzheimerjournal.com | NP Volume 23, Number 4, October–December 2009 39 Depression NP  2009 Lippincott Williams & Wilkins VaD-SIVD Alzheimer Dis Assoc Disord r 27 Diagnosis Sex MMSE NP Bat Syncopal episodes 66.0 10 M 25 F Normal Normal Mildly elevated protein. ICP:210 mm H20 Mildly elevated protein, positive oligoclonal bands Mildly elevated protein Serum Findings Cerebrospinal Protein Fluid Findings 14-3-3 B12 deficiency 69.0 5 M 12 48 MS 60.9 2 F 14 F B12 = 102 (>180), homocysteine = 20 (<15) Normal 49 59.0 7 F 18 F Normal 50 Drug induced Epilepsy and (topiracongenital mate) hydrocephalus Scleroderma 63.0 5 F 18 P 51 Sarcoidosis 61.6 4 F 11 P 52 69.0 10 F 17 F 53 Systematic lupus erythematosous Primary central nervous system vasculitis 58.3 2 M 0 NP 54 Neurosyphilis 59.9 7 F 2 NP Normal Mildly (scleroderelevated ma was protein, already positive diagnosed oligoclonal elsewhere) bands Elevated Leukocytosis, SACE elevated protein, positive oligoclonal bands Increased: Normal ANA, anti-ds DNA Normal Mildly elevated protein, IgG, albumin and positive oligoclonal bands VDRL:+, Mildly FTAelevated Abs:+. protein, TPHA:1/ positive 10240 oligoclonal bands,VDRL: +,FTAAbs:+ 2009 Lippincott Williams & Wilkins Treated hypothyroidism Normal Normal Mild ventricular enlargement NP NP Multiple lesions, many with NP contrast enhancement NP Ventricular enlargement. No cortical atrophy NP NP Microvascular lesions periventricular, subcortical WM Normal NP Bilateral cortical atrophy, ventricular enlargement. Mild hippocampal atrophy. Periventricular hyperintensities NP NP Diffuse bilateral hyperintensities in the periventricular and subcortical WM Diffuse bilateral hyperintensities in the deep WM Localized left frontal hypoperfusion NP NP Diffuse bilateral confluent hyperintensities in the deep and subcortical WM. Mild cortical atrophy NP NP Volume 23, Number 4, October–December 2009 47 Negative NP Single Photon Emission Computed Tomography  Psychosis r 46 Magnetic Resonance Imaging Alzheimer Dis Assoc Disord Time to Dementia (mo) Age at Comorbidity Onset Papageorgiou et al 342 | www.alzheimerjournal.com TABLE 1. (continued) M NP 56 Limbic encephalitis 44.0 3 F 14 P 57 58 Brain tumor HIV encephalitis 51.0 52.0 1 2 M M 28 15 P NP 59 Q fever 73.0 5 M 29 P 60 CJD 63.0 1 F 18 61 CJD 69.0 5 F 62 CJD 64.0 4 63 CJD 66.0 64 CJD 65 CJD VDRL:+, FTAAbs:+. TPHA:1/ 640. Elevated protein, VDRL:(+), FTAAbs:(+). TPHA:1/ 640, positive oligoclonal bands Normal Positive oligoclonal bands Normal Normal Positive HIV Mildly serology elevated protein Lymphocytosis (110/mm3), elevated protein NP Positive serology for Coxiella burnetii Normal Normal 10 NP Normal Normal M 10 NP Normal Normal 1 M 20 NP Normal Normal 62.0 2 F 20 NP Normal Normal 55.0 1 M 22 NP Normal Normal NP Hyperintensities in the periventricular and subcortical WM NP NP Bilateral hyperintensity of the hippocampi Normal NP NP Basal forebrain glioma High signal regions in left parietal lobe, pons, cerebellum, cerebellar peduncles Multiple hyperintensities in the WM. No atrophy NP NP NP Positive 343 Mild fronto-parietal cortical atrophy. Few subcortical hyperintensities (frontalparietal). No DWI sequences PosiMild cerebral and atrophy. tive Hyperintensity of the head of the right caudate and the putamen. No DWI sequences PosiBilateral hypersignal of the tive head of the caudate nuclei and the putamen (FLAIR sequence. No DWI sequences Slightly No atrophy. No signal posiabnormalities. Bilateral tive parieto-occipital ‘‘ribboning’’ in the DWI sequences PosiHyperintensity of the head tive of the caudate nucleus and the putamen in the left side (FLAIR sequences). No DWI sequences Strong- Mild cerebral and cerebellar ly atrophy. Hyperintensity posiof the head of the caudate tive and the putamen, bilaterally. No DWI sequences NP NP NP NP NP Marked bilateral frontoparieto-temporal hypoperfusion (L>R) NP Rapidly Progressive Dementia 6 Volume 23, Number 4, October–December 2009 www.alzheimerjournal.com | 46.0  2009 Lippincott Williams & Wilkins Neurosyphilis Alzheimer Dis Assoc Disord r 55 Mild bilateral frontoparietal hypoperfusion Marked bilateral frontoparieto-temporal hypoperfusion NP Normal Normal F 16 M CJD 68 73.0 CJD 67 55.0 CJD 66 Diagnosis 49.5 4 5 F 15 NP Normal Normal Strong- Hypersignal of the head of ly the left caudate nucleus posi(FLAIR sequences). No tive DWI sequences PosiBilateral hyperintensity of tive the head of the caudate nuclei and the putamen (FLAIR sequences). Parieto-temporal cortical ribboning (only in DWI sequences) PosiMild cortical atrophy. No tive DWI sequences Normal Normal NP 19 M 2 Single Photon Emission Computed Tomography Magnetic Resonance Imaging Cerebrospinal Protein Fluid Findings 14-3-3 Serum Findings NP Bat MMSE Sex Time to Dementia (mo) Age at Comorbidity Onset TABLE 1. (continued) 344 | www.alzheimerjournal.com AD indicates Alzheimer disease; CBD, cortico-basal degeneration; CJD, Creutzfeldt-Jakob disease; CVD, cerebrovascular disease; CT, computed tomography; DLB, dementia with Lewy bodies; DWI, diffusionweighted imaging; f, female; FLAIR, fluid attenuated inversion recovery; FTD, frontotemporal dementia; FTLD, frontotemporal lobar degeneration; HIV, human immunodeficiency virus; L, left; m, male; MMSE, Mini-Mental State Examination; MND, motor neuron disease; MS, multiple sclerosis; MSA, multiple system atrophy; NP Bat, neuropsychological Battery; NP, not performed; NPH, normal pressure hydrocephalus; PDD, Parkinson disease dementia; PSP, progressive supranuclear palsy; R, right; RPD, rapidly progressing dementia; SACE, serum angiotensin-converting enzyme; SemDem, semantic dementia; SIVD, subcortical ischemic vascular dementia; Str. Infarct, Strategic infarct; VaD, vascular dementia; WM, white matter. Alzheimer Dis Assoc Disord Papageorgiou et al  Volume 23, Number 4, October–December 2009 CJD from patients with S-DEM did not reach statistical significance (P = 0.07). There was no difference between groups in terms of sex, as shown by the w2 test. DISCUSSION In this work, we studied the causes of RPD, among patients referred for evaluation in a tertiary referral center in Athens, Greece. As a rule, all patients of this category are hospitalized to facilitate and expedite the investigation. Series of RPD cases are not abundant in the literature. The few existing studies addressing this issue have included cases with a suspicion of CJD, in which dementia is usually accompanied by other signs of CNS involvement (ie, cerebellar signs, myoclonus).13,19,21,38 In our study, the relative frequency of dementing diseases presenting as RPD was examined in consecutive cases with RPD, independently of the clinical suspicion of CJD. Owing to the lack of other directly comparable series of RPD in the literature, through the discussion we compare our data with those of the existing studies of possible CJD cases. In our series, RPD was most frequently owing to secondary-potentially treatable causes (S-DEM), as these accounted for 18 (26.5%) out of the total of 68 RPD cases. The etiology of these 18 S-DEM cases was extremely variable, the most common cause (normal pressure hydrocephalus) accounting for only 22.2% of the subgroup. In the University of Califorinia at San Francisco (UCSF) cohort of 640 possible CJD cases, the most frequent cause of RPD was CJD.39,40 It should be taken into account that the Department of Neurology at the San Francisco Medical Center, is a major referral center for prion diseases. However, in the remaining 104 non-CJD cases, dementia owing to secondary causes was the most frequent diagnosis (22 patients of the non-CJD causes). This high proportion of S-DEM in a series of RPD cases is concordant to our findings. By contrast, in the German cohort of the Neurologische Klinik und Poliklinik at Georg-AugustUniversitat, in Göttingen, which is also a CJD referral center, S-DEM was the third non-CJD cause of RPD, accounting for 19 among 124 cases of non-CJD causes from the total 484 possible CJD cases.8 The high proportion of the S-DEM cases, designates the importance of a comprehensive evaluation in all cases presenting with RPD, as many of these are potentially reversible under appropriate treatment of the underlying disease.1,3,41 AD was the second most common cause of RPD in our cohort, accounting for 12 cases (17.6%). Although a rapid evolution in AD is considered rare, AD was a frequent cause in the German study and it was the most frequent cause of non-CJD cases presenting with RPD. However, in the UCSF cohort, AD was rare as it accounted for only 3 cases. In our series, FTLD was the third most common cause of RPD (11 cases or 16.2%). In the UCSF cohort,39,40 FTLD was found in 7 patients, whereas no such case was found in the German series.8 Several community and clinicbased studies in various regions of the world have demonstrated that FTLD was rare in demented patients (2% to 4%) and the rate was less than one-tenth of AD (1:10 to 1:30).42–44 However, 2 surveys conducted on presenile subjects have reported a larger proportion of FTLD, equal to that of AD.45,46 In our series of RPD, the r 2009 Lippincott Williams & Wilkins Alzheimer Dis Assoc Disord  Volume 23, Number 4, October–December 2009 Rapidly Progressive Dementia TABLE 2. Diagnosis in Grouped Categories for the 68 Patients With RPD [n; Age at Onset (y) With Dementia] Diagnosis N = 68 (%) Sex (m/f) S-DEM AD FTLD VaD CJD VDD 11/7 4/8 6/5 5/4 5/4 6/3 18 12 11 9 9 9 (26.5%) (17.6%) (16.2%) (13.2%) (13.2%) (13.2%) MMSE M ± SD; Median 15.8 ± 8.2; 17.0 ± 6.3; 19.1 ± 5.8; 23.1 ± 4.5; 16.6 ± 4.3; 13.5 ± 7.0; 17.0 17.0 19.5 24.0 18.0 10.5 MMSE Range Age M ± SD; Median 0-29 9-25 8-26 14-29 10-22 6-27 62.5 ± 10.0; 62.2 68.3 ± 10.0; 67.5 62.5 ± 13.0; 70.0 70.3 ± 9.2; 71.0 61.8 ± 7.5; 63.0 70.6 ± 5.1; 70.5 Time to Dementia (mo) M ± SD; Median Age Range 44.0-82.8 51.0-81.0 35.3-75.0 56.6-82.0 49.5-73.0 62.0-79.0 8.8 ± 3.2; 8.3 ± 2.3; 7.4 ± 2.5; 7.7 ± 2.4; 2.8 ± 1.7; 8.6 ± 2.1; 5.5 9.0 8.0 9.0 2.0 9.0 Time to Dementia (mo); Range 1-11 3-11 3-11 3-10 1-5 6-11 S-DEM: NPH: 4 patients, neurosyphilis: 2 patients, scleroderma: 1 patient, sarcoidosis: 1 patient, systematic lupus erythematosous: 1 patient, CNS vasculitis: 1 patient, limbic encephalitis: 1 patient, human immunodeficiency virus encephalitis: 1 patient, CNS tumor: 1 patient, infection by Coxiella burnetii: 1 patient, combined NPH and B12 deficiency: 1 patient, multiple sclerosis: 1 patient, drug-induced dementia: 1 patient, and dementia in the context of chronic psychosis: 1 patient. Multiple system atrophy: 2 patients, dementia with Lewy bodies: 4 patients, progressive supranuclear palsy: 1 patient, corticobasal degeneration: 1 patient, and Parkinson disease dementia: 1 patient. AD indicates Alzheimer disease; CJD, Creutzfeldt-Jakob disease; f, female; FTLD, frontotemporal lobar degeneration; m, male; MMSE, Mini-Mental State Examination; RPD, rapidly progressive dementia; S-DEM, secondary dementia; VaD, vascular dementia; VDD, various neurodegenerative diseases. mean age of patients was rather low (mean age at onset ± SD = 63.3 ± 12.7, age range: 35.3 to 75). This could explain the frequent occurrence of FTLD in our cohort. VaD was a rather unexpectedly uncommon cause of RPD as it was found in only 9 of our cases (13.2%). This low occurrence is in agreement with other reports, as VaD was the fourth cause of RPD in the German series8 or not encountered at all in the UCSF series.39,40 In our series, CJD had the same frequency with VaD, found in 9 cases (13.2%). The low frequency of CJD in our RPD cases—when compared with the other RPD cohorts— is probably owing to the different referral criteria used. There were 3 cases originally suspected for CJD, who were diagnosed with other diseases (1 with PSP, 1 with frontotemporal dementia with motor neuron disease, and 1 with dementia in the context of chronic psychosis). Finally, 9 cases (13.2%) were due to various brain degenerative diseases such as CBD and PDD. This is in accordance with the UCSF data and suggests that although infrequently, the above disorders can present in the form of RPD. We note that 2 patients had MSA. Although dementia is very rare in MSA cases,47,48 these 2 patients, were demented 1 year after disease (MSA) onset. No group differences were found for age at diagnosis and MMSE scores. However, there was a trend for younger age in patients with secondary dementias, CJD, and FTLD. This is in accordance with the literature where FTLD and CJD occur in younger ages than AD, VaD, and degenerative dementias as CBD and PDD.8,39,40,43,44 Although there was no group difference in terms of sex, there were more women than men in the AD group and the opposite pattern was seen in the FTLD and the secondary dementia groups, as expected from the literature.8,39,40,43–45 Our study addresses a common clinical question, but we have to consider its limitations: (a) the total number of patients referred with RPD is relatively small, (b) it was conducted in a tertiary referral center, with the inherent selection bias of this setting (which makes some causes of dementia to be over or underrepresented) precluding the description of the situation of RPD in the community, and (c) no pathologic confirmation for the clinical diagnoses is available, with the exception of 4 of the 9 CJD cases. 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