Expert Review of Neurotherapeutics

ISSN: 1473-7175 (Print) 1744-8360 (Online) Journal homepage: http://www.tandfonline.com/loi/iern20

Diagnostic challenges in rapidly progressive

dementia

Inga Zerr & Peter Hermann

To cite this article: Inga Zerr & Peter Hermann (2018): Diagnostic challenges in rapidly
progressive dementia, Expert Review of Neurotherapeutics, DOI: 10.1080/14737175.2018.1519397

To link to this article: https://doi.org/10.1080/14737175.2018.1519397

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EXPERT REVIEW OF NEUROTHERAPEUTICS
https://doi.org/10.1080/14737175.2018.1519397

REVIEW

Diagnostic challenges in rapidly progressive dementia

Inga Zerr and Peter Hermann
Clinical Dementia Center and National TSE Reference Center, Department of Neurology, Goettingen University Medical Center, Goettingen,
Germany

ABSTRACT ARTICLE HISTORY

Introduction: Rapidly progressive dementia is a syndrome caused by numerous disease entities. Accurate Received 19 July 2018
diagnosis is crucial as substantial proportion of these diseases is highly treatable. Others might implicate Accepted 30 August 2018
specific hygienic problems. Still, differential diagnosis remains challenging because of a huge overlap of clinical KEYWORDS
presentations. Dementia; rapidly
Areas covered: The paper reviews PubMed-listed research articles with a focus on diagnosis and progressive dementia; prion
treatment of diseases showing rapid cognitive decline such as inflammatory diseases, rapidly progres- diseases; neurodegenerative
sive neurodegenerative diseases, toxic-metabolic encephalopathies and prion diseases. The literature diseases; encephalitis;
was interpreted in the light of experience in clinically differentiating rapid progressing dementia in the differential diagnosis
framework of Creutzfeldt-Jakob-Disease (CJD) surveillance activities. An overview of relevant differential
diagnoses and diagnostic pitfalls as well as therapeutic protocols is presented.
Expert commentary: Over the last years, more and more neurologic disorders causing cognitive
symptoms, in particular various types of immune-mediated diseases have been discovered. To identify
treatable conditions and to enhance knowledge of differential diagnosis and epidemiology, we suggest
an extended diagnostic work up in cases with rapidly progressing dementia. Besides standard methods,
this should include the search for neoplasia as well as atypical encephalitis. High-dose steroid therapy
should be considered in certain clinical situations even when no evidence for inflammation is present.

1. Introduction Biochemical studies of amyloid-β, α-synuclein, tau, and

other proteins involved in the pathophysiology of neurode-
The precise definition of rapid progression in dementia (RPD) is
generative diseases revealed that they share key characteris-
lacking. Although cognitive decline may progress over a very short
tics with prions [6]. To characterize these proteins and their
period of time (days to weeks) in Creutzfeldt–Jakob disease (CJD)
associated diseases, various terms like prion, prion-like, or prio-
or encephalitis, one of the most common definitions implicates a
noid have been suggested but none of them has been widely
progression from the onset of the first symptom to dementia in
accepted, yet. With respect to this, we use the term neurode-
less than 2 years [1]. This is in line with the definition of rapid
generative disease throughout this article.
cognitive decline (RCD) used in clinical criteria for CJD [2]. On the
other hand, definitions using cognitive scores have been proposed
for specific diseases. Rapidly progressive Alzheimer’s disease 2. Epidemiology of RPD
(rpAD) can be defined by a loss of ≥6 MMSE points per year in
Because of different definitions, valid data on the prevalence of
patients with probable Alzheimer’s disease (AD) [3,4]. Rapid pro-
RPD are not available. Former observations from prion disease
gressive forms in other neurodegenerative diseases are increas-
reference centers report that sporadic CJD is the most common
ingly recognized, e.g. they have been reported for dementia with
cause for RPD followed by AD [7,8] but these figures are highly
Lewy bodies (DLB), as well [5]. Although CJD and neurodegenera-
biased for obvious reasons. Some studies performed by CJD
tive diseases like AD show very limited responses to therapeutic
reference centers focused on differential diagnoses and reported
interventions, a clinical overlap with a huge number of highly
that neurodegenerative diseases caused 52% [9], respectively
treatable disorders and conditions underlines the need for thor-
80% [10] of non-CJD cases of RPD. Other diseases like encepha-
ough diagnosis. By reviewing the current literature and consider-
litis, ischemia, or metabolic disorders were reported to be less
ing data from more than 20 years of systematic evaluation within
frequent. Most of these studies were based on neuropathological
the National Reference Center for Prion Diseases in Germany, this
examinations. This introduced another bias because autopsy is
article will point out crucial clinical features and biomarkers (fluid
rather performed in cases of irreversible disorders. Data from the
and imaging) of a wide spectrum of disorders causing RPD. In
University of California, San Francisco [11] and the German CJD
addition, we provide an overview on the most important thera-
Surveillance (Figure 1) [12] have shown that inflammatory dis-
peutic options and focus on those disorders which have been
eases come into focus when clinical data are analyzed.
reported as the most common differential diagnoses.

CONTACT Inga Zerr ingazerr@med.uni-goettingen.de Clinical Dementia Center and National TSE Reference Center, Department of Neurology, Georg-August
University Goettingen, Robert-Koch-Str. 40, Goettingen 37075, Germany
© 2018 Informa UK Limited, trading as Taylor & Francis Group
2 I. ZERR AND P. HERMANN

Figure 1. Data from the national reference center for transmissible spongiform encephalopathies.
Diagnoses of non-CJD cases which had been presented to the NRZ-TSE as suspected prion disease. (n = 118, Hermann et al. 2018).

Based on data from the National Reference Center, the aware- diagnoses highly depends on the nature of the reporting
ness for prion diseases is very high among physicians. European center and on its geographical localization. Nevertheless,
centers reported that the number of probable or definite CJD cases potentially treatable disorders like immune-mediated or infec-
accounted for only a small part of all suspected cases [12,13]. tious encephalitis are important and are observed in a sub-
To estimate the unbiased distribution of differential diag- stantial number of cases in all studies reported.
noses and the rate of treatable conditions, studies from ter-
tiary care centers are needed. Only few of these have been
performed. An overview is given in Table 1. A recent study
3. Etiologies, diagnostic procedures, and
from Brazil [14] reported that 3.7% (n = 61) of all patients
therapeutic options
admitted to a neurological department (2012–2015; n = 1648)
showed RPD. Another study from India [15] reported that 27% 3.1. Neurodegenerative diseases
(n = 187) of all patients with dementia (2008–2016; n = 693)
3.1.1. Sporadic Creutzfeldt–Jakob disease and genetic
showed RPD. These patients were rather young, mean age was
prion diseases
48 years (Brazil), respectively 50 years (India). In all of these
Human prion diseases are caused by misfolded and potentially
cohorts, immune-mediated or infectious diseases of the CNS
transmissible proteins [16]. Given mortality and incidence rates
were the most common causes for RPD. The high rate of
differ from 1.7 (multinational investigation 1993–2002) [17] to
infectious diseases in the Indian cohort was caused by high
2.2 (Germany 2016) [12] per million/year. The most common
rates of subacute sclerosing panencephalitis and
human prion disease is sporadic CJD (90% of cases). It is
neurosyphilis.
characterized by RCD and early occurrence of additional neu-
To sum up, there is evidence that RPD is not a very rare
rological symptoms such as ataxia, cortical visual impairment,
condition. The administered distribution of differential
pyramidal or extrapyramidal signs, and myoclonus. The mean
age at onset is around 65 years and the mean disease duration
Table 1. Differential diagnoses of RPD reported by tertiary referral centers. only about 5–6 months [18]. Other prion diseases have a
Athens, Zhejiang, Sao Paulo, Chandigarh, genetic origin or are caused by transmission (iatrogenic CJD
Greece [61] China [106] Brazil [14] India [15] and variant CJD). Although being rare, CJD is considered as a
(n = 68*) (n = 310**) (n = 61) (n = 187) model disease for RPD.
Infectious 5.9* 21.9 19.7 20.6 For a definite diagnosis, neuropathological investigation is
encephalitis (%)
Immune-mediated 8.8 9.0 45.9 18.2 needed. The clinical criteria for sporadic CJD (WHO criteria)
disease (%) comprise RPD + at least two other neurological signs (cerebellar
Creutzfeldt–Jakob 13.2 7.1 11.5 7.5 or visual, pyramidal or extrapyramidal, myoclonus, akinetic mut-
disease (%)
Neurodegenerative 47.0 24.8 8.2 14.4 ism) [2]. Besides a typical clinical syndrome, at least one technical
diseases (%) investigation (MRI, CSF 14-3-3 or EEG) has to show CJD-typical
Alzheimer’s disease 17.6 14.5 n.a. n.a. results. The EEG may show a specific pattern of periodic sharp-
(%)
Others (%) 29.4 10.3 n.a. n.a. wave complexes [18]. However, this pattern has a poor sensitiv-
Vascular dementia 13.2 ** n.a. 9.6 ity, especially in early disease stages. Elevated proteins 14-3-3 in
(%) CSF are highly sensitive and specific in the differentiation of
Toxic + metabolic * 10.3 n.a. 16.0
(%) sporadic CJD from other neurodegenerative diseases. But as a
Others (%) 11.8 26.9 14.7 13.4 marker of neuronal damage, it has also been reported to be
*Acute infectious diseases and toxic–metabolic disorders had been excluded; elevated in encephalitis, ischemia, or other encephalopathies
**cerebrovascular diseases had been excluded. [9] (Table 2). The CSF real-time quaking-induced conversion

(RT-QuIC) [19,20] is able to detect pathological prion protein
(PrPsc) with a good sensitivity around 90% and a specificity of
nearly 100% [21] and has recently been suggested to be inte-
grated in amended diagnostic criteria [13,22]. To date, only few
false-positive cases have been reported [21,23]. Nevertheless, the
method is expensive and not available in many regions. CJD-
typical findings on MRI include strictly cortical hyperintensities
(‘ribboning’) and/or hyperintensities in the basal ganglia
(Table 3). These patterns show very good diagnostic accuracies
[2,24]. For a deeper view on neuroimaging in CJD and its differ-
ential diagnosis, we recommend reading specific reviews, e.g.
Fragoso et al. [25] or Gaudino et al. [26].
Genetic prion diseases can show deviant syndromes and results
of technical investigations. They are caused by numerous muta-
tions of the prion gene. Some defined syndromes are Gerstmann–
Sträussler–Scheinker, familial CJD, and fatal familial insomnia. The
sensitivity of MRI and CSF markers is lower than in sporadic CJD.
Similar to genetic CJD, variant CJD occurs in younger patients that
often present with psychiatric symptoms and dysesthesia. On MRI,
isolated hyperintensities of the pulvinar are frequent. For a definite
diagnosis, a tonsillar biopsy can be performed. Current diagnostic
criteria have been published by Heath et al. in 2010 [27]. Iatrogenic
CJD can be taken into account, when a patient with CJD has
corresponding risk factors [28].
Therapeutic options are limited to a palliative concept. Only
for doxycycline, (limited) data have shown a benefit in terms
of a prolonged disease progression in certain subtypes when
treated in early stages [29].
3.1.2. (rp)AD
AD is the most common cause for dementia. Cerebral depositions
of amyloid β and hyperphosphorylated tau protein (p-tau) play a
central role in disease pathogenesis. Clinically, most patients show
a slow decline of cognitive functions over many years. Within the
last 10 years, a distinct subtype of the disease called rpAD has been
described. Some clinical features have been observed which differ-
entiate typical AD from rpAD. Despite RCD, rpAD patients often
show early occurrence of myoclonus, disturbed gait, and rigidity as
well as aphasia and hallucinations [30]. This results in a relevant
clinical overlap between rpAD, CJD, and other RPD. In this context,
RCD has been defined as a loss of ≥6 MMSE points per year,
Table 2. CSF abnormalities in different causes of RPD.
Oligoclonal CSF markers of neuronal damage or
Etiology Cell count bands
Prion diseases ↔ Not present
(rp)AD ↔ Not present
Other neurodegenerative ↔ Not present
diseases
Cerebrovascular disease ↔ Not present
(except for (except for
vasculitis) vasculitis)
Immune-mediated ↔ – ↑↑ Present in most
encephalitis cases
Infectious encephalitis ↑ – ↑↑↑ Present
*14-3-3 and tau can be elevated after an acute ischemic event.
EXPERT REVIEW OF NEUROTHERAPEUTICS 3
respective ≥3 per 6 months [3,4]. Other authors proposed a defini-
tion indicating rpAD when the survival time is shorter than 4 years
[31]. In a multicenter study, the mean survival time of rpAD
patients was only 10 months [32]. It is still a subject of discussion
whether rapid progression in AD is a matter of co-pathology (e.g.
cerebrovascular disease, Lewy bodies) but recent studies have
shown that intrinsic factors like a high prevalence of amyloidangio-
pathy [33,34] and the characteristics of amyloid β and its deposi-
tions differentiate rpAD from AD [35–37]. Only few data on the
incidence of rpAD in relation to AD are available but a study using
data from the Alzheimer’s Disease Neuroimaging Initiative data-
base reported that 18% of patients with ‘mild’ AD (MMSE 20–26
points) showed rapid progression in the course of the disease. In
this study, the diagnosis of rpAD is based on a MMSE score loss of
≥4 points within 6 months [38].
The clinical diagnosis of AD is based on the presence of
dementia (impairment of memory function and at least one
additional cognitive domain + impaired function of activities
of daily living) and the exclusion of other causes. Since 2011,
the NIA-AA criteria [39] were extended and include now CSF-
and imaging biomarker. The updated criteria from 2018 [40]
allow the AD diagnosis which is based on biomarkers alone. In
this context, AD has been defined as a disorder defined by
neuropathological changes and not by a clinical syndrome.
According to various publications and recent diagnostic cri-
teria [40], most AD patients show a specific biomarker signa-
ture. This includes CSF, MRI, and PET (see Tables 2 and 3). In
patients with rpAD, the same signature could be observed
[30,38] but CSF markers of neuronal damage like tau (respec-
tive tau in relation to p-tau) and proteins 14-3-3 [30] showed
higher levels than in classical AD forms. In addition, a pro-
nounced hypometabolism displayed by FDG-PET in left angu-
lar and left temporal cortices was predictive for rpAD [38].
Like in all neurodegenerative diseases, no causal therapy
has been established, yet. Nonetheless, a huge amount of
different drugs and treatment strategies is currently under
investigation (e.g. γ-secretase inhibitors, beta-site amyloid per-
cursor protein cleaving enzyme [BACE] inhibitors, and immu-
notherapies) [41]. Current treatment guidelines recommend a
symptomatic medication with acetylcholinesterase inhibitors
or memantine or a combination of both [42]. As long as no
other surrogates Specific CSF markers
14-3-3: ↑ – ↑↑↑ RT-QuIC: positive
Tau: ↑ – ↑↑↑
14-3-3: ↔ – ↑ p-Tau: ↔ – ↑
Tau: ↔ – ↑↑ aβ 1–42: ↔ – ↓
aβ ratio: ↔ – ↓
14-3-3: ↔ – (↑) Not available
Tau: ↔ – (↑) Candidate: α-synuclein↓ in synucleinopathies
14-3-3: ↔ – (↑↑)* Not available
Tau: ↔ – (↑)* Candidates: albumin ratio, neurofilament light chain,
matrix metalloproteinases
14-3-3: ↔ – ↑↑↑ Various known antibodies
Tau: ↔ – ↑↑ (see Table 4)
14-3-3: ↔ – ↑↑↑ Specific PCR
Tau: ↔ – ↑↑ Specific antibodies
CSF culture
4 I. ZERR AND P. HERMANN

data on a specific treatment for rpAD become available, same
treatment strategies as for classical forms should be applied.
3.1.3. DLB
Still being a subject of controversial discussion, there is some
evidence from autopsy-based studies that DLB might be the sec-
ond most common cause for dementia (26% [43]) after AD.
According to recent criteria [44], clinical core features include
dementia, extrapyramidal signs, rapid eye movement (REM) sleep
behavior disorder, visual hallucination, and fluctuating decline of
cognition. These fluctuations can mimic rapid disease progression
and the presence of neurological signs implicates a huge overlap
of up to 40% with clinical WHO criteria for possible CJD [45]. A
study including data from 807 DLB patients observed a mean
disease duration of 8.8 years [46]. However, a subset of DLB
patients shows primary RPD [5] (rpDLB). Despite some marked
DLB features, no specific neuropathological changes could be
identified in rpDLB [47].
Specific findings in EEG and neuroimaging are included in the
diagnostic criteria for DLB [44] (Table 3). Fluid markers are not
part of the diagnostic routine (Table 2) but a decreased concen-
tration of α-synuclein in CSF has been reported [48] and there are
ongoing efforts to develop a method to detect α-synuclein mis-
folded aggregates in patients with Parkinsonism [49,50].
Although a Cochrane review in 2012 could not find a clear
benefit from therapies with acetylcholinesterase inhibitors
[51], donepezil has shown a positive effect on cognition and
behavioral symptoms [52]. Some data indicate that also
memantine has a positive effect on clinical global impression
[53]. Parkinsonism in DLB can be treated with dopamine ago-
nists but a special concern is the occurrence of hallucinations
and other psychotic syndrome. Typical neuroleptic drugs can
lead to severe akinetic and vigilance crises [54]. If necessary,
the use of safer and still effective neuroleptic drugs like cloza-
pine and quetiapine [55] is highly recommended.
3.1.4. Other neurodegenerative diseases
DLB, Parkinson’s disease dementia (PDD), and multiple system
atrophy (MSA) including its subtypes are the three main types of
α-synucleinopathy associated with dementia [56]. PDD is usually
slowly progressive and shares many characteristics with DLB
despite the retarded occurrence of dementia in the clinical
course [44]. Because of its rather fast progressing neurological
multisystemic symptoms, MSA is a relevant differential diagnosis
for CJD and other encephalopathies. A nationwide study from
Iceland reported an incidence of 7 per million person-years, a
mean onset of 65 years, and a rather fast progression displayed
by a mean survival time of 5.7 years [57]. Although dementia is a
feature that makes MSA unlikely [58], recent studies have shown
that subcortical cognitive deficits are frequent [59]. Diagnostic
criteria comprise specific clinical and imaging features [58]
(Table 3). Validated fluid markers are not available [60].
Tauopathies have been reported to account for up to 16.2% of
RPD cases [61] in single centers. Various clinical syndromes have
been described including behavioral variant frontotemporal
dementia (bvFTD), semantic dementia, primary progressive

Table 3. Imaging abnormalities in different causes of RPD.

Imaging
Etiology technique Findings
CJD MRI: HI in gray matter areas (cortical and/or nucleus caudatus and putamen ± HI of the pulvinar and dorsomedial
DWI > FLAIR/ thalamus); corresponding low signal on ADC maps; no white matter involvement and no enhancement of
T2 gadolinium
FDG-PET Hypometabolism in various regions, in some prion diseases (fatal familial insomnia) dominantly in the thalamus
AD MRI: T1 Atrophy of the medial temporal lobe
FDG-PET Hypometabolism of temporal and parietal lobes
Amyloid-PET Amyloid depositions
Other MRI Synucleinopathies: Unspecific atrophy (DLB); atrophy of putamen, middle cerebellar peduncle, pons or cerebellum
neurodegenerative (MSA)
diseases Tauopathies: Atrophy in anterior cingulate, frontoinsula, striatum and amygdala (bvFTD), predominant midbrain
atrophy (PSP); atrophy of dorsal prefrontal and perirolandic cortex, striatum, and brainstem (CBD)
FDG-PET Synucleinopathies: Occipital hypometabolism ± cingulate island sign (DLB), hypometabolism in putamen, brainstem,
or cerebellum (MSA)
Tauopathies: Hypometabolism in frontal lobes, anterior temporal cortex, and anterior cingulate cortex (FTD);
predominant midbrain hypometabolism (PSP)
PET/SPECT DLB: Reduced presynaptic dopamine transporter uptake in basal ganglia
PSP: Postsynaptic striatal dopaminergic degeneration
Myocardial DLB: Low 123iodine MBIG uptake (also reported in MSA)
scintigraphy
Cerebrovascular MRI VD: Chronic territorial infarctions, subcortical HI (FLAIR or T2), lacunes, microbleeds
diseases Acute event (infarction): DWI-HI and low ADC signal of the gray and the white matter corresponding to vessel
territories
CNS vasculitis: Infarction, subcortical HI (FLAIR or T2), leptomeningeal or parenchymal gadolinium enhancement,
microbleeds, mass bleeding
Angiography CNS vasculitis: Typical arterial segmentations
Encephalitis MRI Immune-mediated: Edema resp. T2-HI of cortical regions or basal ganglia (e.g. paraneoplastic limbic encephalitis) or of
the white matter (e.g. SREAT); sometimes gadolinium enhancement of lesions
Infectious: Edema resp. T2-HI of cortical regions (e.g. temporal in HSV-encephalitis) or basal ganglia (e.g. HIV-
encephalopathy) or of the white matter (e.g. PML); abundant gadolinium enhancement of lesions
DWI: Diffusion weighted Image; FLAIR: fluid-attenuated inversion recovery; HI: hyperintensities; FDG: fluorodeoxy-glucose; SPECT: single-photon emission computed
tomography; MBIG: metaiodobenzylguanidine; CJD: Creutzfeldt–Jakob disease; AD: Alzheimer’s disease; DLB: dementia with Lewy bodies; MSA: multisystem atrophy;
FTD: frontotemporal dementia; PSP: progressive supranuclear palsy; CBD: corticobasal degeneration; VD: vascular dementia; bvFTD: behavioral variant frontotem-
poral dementia; SREAT: steroid-responsive encephalopathy associated with autoimmune thyroiditis; PML: progressive multifocal leukoencephalopathy.
 EXPERT REVIEW OF NEUROTHERAPEUTICS 5

Table 4. Inflammatory (infectious and immune-mediated) disorders causing RPD.

Immune-mediated encephalitis*
Paraneoplastic encephalopathies
Antigen Syndrome Associated neoplasia
Hu Diverse SCLC
Yo PCD Breast, gynecologic cancer
Ri Diverse Breast cancer
Ma1 Diverse Diverse
Ma2 Diverse Germ cell tumors
Tr PCD Hodgkin’s lymphoma
Zinc finger protein 4 PCD SCLC
P/Q-type VGCC LEMS, cerebellitis SCLC
Amphiphysin Encephalitis, stiff-person syndromeSCLC, breast cancer
Antibody-associated encephalopathies, possibly associated with neoplasia
Antigen Syndrome Associated neoplasia
NMDAR Encephalitis Ovarian teratoma
LGI 1 Limbic encephalitis
CASPR2 Limbic encephalitis Thymoma (rare)
AMPAR Limbic encephalitis SCLC, thymoma, breast cancer
GABAAR Encephalitis, stiff-person syndrome Thymoma
GABABR Limbic encephalitis SCLC
DPPX Encephalitis, stiff-person syndrome B-cell neoplasia
mGluR5 Encephalitis Hodgkin’s lymphoma
D2R Basal ganglia encephalitis
GlyR Encephalitis, stiff-person syndrome Thymoma, lymphoma (rare)
GAD Stiff-person syndrome, cerebellitis Neuroendocrine (rare)
Others
SREAT
Gluten encephalopathy (celiac disease)
Multiple sclerosis and ADEM
Neurosarcoidosis
Lupus cerebritis
NBD
Infectious agents (other than prions) possibly causing RPD**
Viral Bacterial
HIV Treponema pallidum (Lues)
JC-virus (progressive multifocal leukoencephalopathy) Tropheryma whipplei (Whipple’s disease)
Herpes simplex virus 1, 2 (6, 7) Mycobacterium tuberculosis
Varicella zoster virus Listeria monocytogenes
Measles (sclerosing subacute panencephalitis) Borrelia burgdorferi
Mumps Parasitic/Fungal
Epstein–Barr virus Toxoplasma gondii
Influenza virus Balmuthia
Cytomegalovirus Cryptococcus neoformans
Japanese encephalitis virus Aspergillosis
West Nile virus
Rabies
Parvovirus B19
Hepatitis C
*Based on Lancaster and Dalmau [88], Dalmau and Graus [89], and clinical experience of the German CJD Surveillance group.
**Based on Granerod et al. [87] and clinical experience of the German CJD Surveillance group.
VGCC: Voltage-gated calcium channel; SREAT: steroid-responsive encephalopathy associated with autoimmune thyroiditis; ADEM: acute disseminated encephalo-
myelitis; NBD: neuro-Behcet’s disease; PCD: paraneoplastic cerebellar degeneration; SCLC: small cell lung cancer; NMDAR: n-methyl-D-aspartate receptor; LGI
1: leucine-rich glioma inactivated 1; CASPR2: contactin-associated protein 2; AMPAR: alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor;
GABA: gamma-aminobutyric acid; DPPX: dipeptidyl-peptidase-like protein 6; mGluR5: metabotropic glutamate receptor 5; D2R: dopamine receptor D2;
GlyR: glycin receptor; GAD: glutamic acid decarboxylase.

aphasia (PPA), corticobasal syndrome, and progressive supranuc-
lear palsy (PSP). Many of these syndromes can be caused by
different types of tauopathy and some of them are hereditary.
They can also be classified by biochemical features which show a
huge clinical overlap [62–64]. Some entities show distinct radiolo-
gical features [65,66] (Table 3) but fluid markers have not been
established.
3.2. Cerebrovascular disease
3.2.1. Vascular dementia
Vascular dementia (VD) is considered as a slowly or stepwise
progressing disorder. On the other hand, patients with VD
often suffer from severe cardiac disorders or seizures which
can contribute to RPD. Cerebrovascular disease is also known
as a frequent cofactor in neurodegenerative dementias like AD
and DLB. In a community-based clinical–pathologic cohort
study, 38% all AD patients had infarcts [67]. Criteria combining
clinical and radiological features of VD and AD (respectively
AD and DLB) have been published in 2014 [68]. The term VD
comprises several conditions of different etiology [69], com-
monly used NINDS-AIREN criteria [70] are outdated, a neuro-
pathological gold standard is missing [71], and accurate fluid
markers are still not available. A consensus study is currently
proposing a new classification, which involves the differentia-
tion of mild and major forms of vascular cognitive impairment
6 I. ZERR AND P. HERMANN
and endorses the Neurological Disorders – Canadian Stroke
Network neuropsychological assessment protocols and recom-
mendations for imaging [72].
To date, the diagnosis of VD relies on the presence of dementia
and evidence for cerebrovascular disease on MRI or CT (Table 3).
Some studies have reported an elevated albumin CSF/serum ratio
in VD compared to other dementias [73–75]. Neurofilament light
[76,77] and matrix metalloproteinases [78] have also been identi-
fied as biomarker candidates. However, none of these markers has
been validated sufficiently [79]. Therapeutic options in VD are still
limited to the treatment of risk factors and symptoms like depres-
sion and seizures. However, a meta-analysis from 2007 has shown
that donepezil had a positive effect on cognition scales and activ-
ities of daily living (less than in AD) [80].
3.2.2. Acute vascular events
Data from the German CJD surveillance center indicate that more
than 20% of non-CJD cases had an acute cerebrovascular vascular
event (Figure 1) [12]. Especially recurring cardiac embolism or
secondary seizures and venous thromboses can mimic RPD and
markers of neuronal destruction like CSF tau and 14-3-3 can be
elevated (Table 2). Despite the aforementioned disorders, the
posterior reversible encephalopathy syndrome is an important
differential diagnosis. An altered mental status is one of key clinical
features [81] and may mimic RPD. Some other clinical symptoms
like cortical visual disturbance, seizures, and even MRI abnormal-
ities can be misdiagnosed as CJD, encephalitis, or stroke [82]. For a
diagnosis of acute vascular diseases, the clinical history and MRI (at
best) or CT (sufficient only for detection of hemorrhage) including
angiography are crucial (Table 3).
3.2.3. CNS vasculitis
Numerous disorders are able to cause secondary CNS vasculitis.
These include infections of all kind and other systemic inflam-
matory diseases (e.g. Wegener’s granulomatosis, Behçet’s dis-
ease, giant-cell arteritis, etc.) [83]. Although many case reports
on primary CNS vasculitis can be found, systematic observa-
tions are rare. A study from the Mayo Clinic including 163 cases
over a 29-year period estimated an incidence of 2.4 per million
person-years [83,84]. According to a review in 2012 [85], up to
50% of patients with CNS vasculitis showed cognitive altera-
tions. Other frequent symptoms were headaches and various
neurological signs. Diagnostic criteria have been proposed in
1988 [86] defining meningeal or brain biopsy as gold standard.
Advances in MRI technology and angiography allow early diag-
nosis (see Table 3). Although being considered as a clinical gold
standard, the cerebral angiography shows varying sensitivities
between 40% and 90% [83]. No specific CSF markers were
available but 80–90% of the cases showed mildly increased
leucocyte count or total protein concentration [83]. A treatment
with steroids alone or in combination with cyclophosphamide
showed a response rate of 80–85% [84].
3.3. Inflammatory CNS diseases
3.3.1. Immune-mediated encephalitis
According to a population-based study, 21% of patients with
encephalitis had acute immune-mediated encephalitis, 37% had
unknown causes [87]. Most immune-mediated encephalopathic
syndromes are associated with classic paraneoplastic syndromes
or with antibodies against neuronal cell-surface or synaptic pro-
teins [88,89]. Frequent tumors are lung cancer (50% of patients
with paraneoplastic limbic encephalitis), gynecological tumors,
breast cancer, and lymphoma [90]. The relevant antibodies are
listed in Table 4. Nonetheless, in 7% of 163 cases with limbic
encephalitis that were analyzed in 2018 in a specialized center,
no antibodies could be found [91]. Some diseases are not asso-
ciated with neoplasia or known anti-neuronal antibodies, e.g.
steroid-responsive encephalopathy associated with autoimmune
thyroiditis (SREAT, formerly named Hashimoto’s encephalopathy)
which can present with chronic dementia [92]. MRI alterations
(Table 3) and clinical presentations are heterogeneous. Cognitive
disturbance, psychiatric symptoms, seizures, and ataxia are com-
mon symptoms indicating a huge overlap with other RPD.
CSF analytics usually show slightly or moderately elevated
cell count (lymphocytes) or oligoclonal bands or both
(Table 2). These are clearly pathologic findings that are not
associated with CJD or other neurodegenerative diseases.
Unfortunately, these routine markers remain normal in many
patients. For example, 20% of 100 patients in a study on anti-
n-methyl D-aspartate receptor (NMDAR) encephalitis did not
show elevated leucocytes or oligoclonal bands [93]. Therefore,
an extended search for specific antibodies (Table 4) in the CSF
of patients with RPD and no other suggestive diagnosis is
crucial. The presence of antibodies in blood is less sensitive
[94]. A search for neoplasia and even a probative therapy with
steroids or intravenous immunoglobulin is a therapeutic
option. Plasmapheresis and other immune-modulatory or
immune-suppressive therapeutics can also be effective. In
case of a paraneoplastic syndrome, the identification and
treatment of the tumor might lead to the improvement of
then neurological syndrome.
In the following, we describe anti-NMDAR encephalitis as a
prototype of the autoimmune mediated encephalitis. After a
prodromal phase with influenza-like symptoms, patients show
psychotic symptoms, impaired episodic memory, and seizures
of temporal origin [95]. The disease is associated with neopla-
sia in up to 80% (teratoma in up to 60%) [96]. CSF analyses are
obligate as NMDA receptor antibodies often cannot be found
in peripheral fluids [94]. Elevation of CSF leucocytes at early
stages and decrease in the further course as well as evidence
for intrathecal IgG synthesis are characteristics [97]. FLAIR- or
T2-weighted MRI may show abnormal signal hyperintensities
in the temporal cortex in 50% of the cases [95]. Besides tumor
treatment, the therapy should consist of short-term high-dose
steroid application and at least one additional immunologic
therapy, e.g. plasmapheresis or intravenous immunglobulin
(IVIG) [97]. A good outcome has been reported in up to 75%
sufficiently treated patients [95]. Patients without an asso-
ciated tumor are less likely to respond to therapy. In these
cases, a second-line therapy (rituximab or cyclophosphamide)
can be effective in up to 65% [98].
3.3.2. Infectious encephalitis
Encephalitis can be associated with or directly caused by
numerous viral, bacterial, fungal, and parasitic organisms.
The most common causes are herpes simplex virus and herpes
zoster virus [87]. Usually, infectious CNS diseases present with
 EXPERT REVIEW OF NEUROTHERAPEUTICS 7

an acute onset but a detailed preclinical history is not always
available. Besides, slowly progressing encephalitis with cogni-
tive symptoms can present as a RPD. In many cases, patients
with infectious encephalitis show systemic signs of inflamma-
tion (e.g. fever, altered peripheral markers of inflammation).
An elevated cell count in the CSF is suggestive for encephalitis
(Table 2). MRI findings are heterogeneous depending on the
underlying infectious agent but MRI lesions which enhance
gadolinium should always throw suspicion on infectious
causes (Table 3). In recent years, some atypical (non-herpes)
viral encephalopathies like HIV-associated cognitive impair-
ment have become more and more important [99]. Although
being rare, physicians should also be aware of CNS Whipple’s
disease which is highly treatable. Neurologic symptoms and
MRI lesions are various and may mimic other forms of RPD but
CSF PCR is a specific diagnostic tool [100]. Table 4 gives a
summary of common and unusual infectious agents that are
able to cause RPD.
3.4. Other etiologies of RPD and conditions mimicking
RPD
Regarding experience from the National Reference Center for
Prion Diseases in Germany and the literature [12,101–103],
Table 5 gives an overview of numerous diseases and condi-
tions that may show or might mimic RPD.
3.4.1. CNS neoplasia
Neoplasm of the CNS has been reported to be an important
differential diagnosis for sporadic CJD[11,12]. Especially, the pri-
mary lymphoma of the CNS is known for causing cognitive symp-
toms [104] and its ability to mimic encephalitis or several other
causes of RPD. But also solid or diffuse glioma or leptomeningeal
spread of peripheral tumors can cause cortical symptoms like RPD.
For a diagnosis, MRI (including gadolinium application) and lumbar
puncture (to search for atypical cells) are crucial. Nevertheless, we
suggest that a search for gynecological, abdominal, and thoracic
tumors should be performed in all cases of unclarified RPD.
3.4.2. Mitochondrial disorders and other genetic causes of
RPD
Most mitochondrial disorders have an onset in childhood but
adult forms have to be taken into account when patients
present with RPD, especially in cases of unexplained encepha-
lopathies. The prevalence of pathogenic mutations seems to
be rather high (up to 11/100,000) [105]. Especially in diseases
like mitochondrial encephalomyopathy with lactic acidosis
and stroke-like episodes, but also in several forms of myoclo-
nus epilepsy, dementia can be one of the primary clinical
features [105]. Mitochondrial disorders, storage diseases, and
other rare genetic causes for RPD in adults are listed in
Table 5.
3.4.3. Common clinical conditions mimicking RPD
Some conditions like electrolyte disturbances (e.g. hypona-
tremia), endocrine disorders (e.g. hypothyroidism), intoxica-
tions, or psychiatric disorders are very frequent but can
cause or mimic encephalopathy and dementia (see
Table 5). Those conditions should always be considered in
a standard diagnostic workup.
3.4.4. Concomitant pathologies and comorbidities
The concept mixed dementia is well known, especially in
AD and VD [67,68], and concomitant pathologies (mostly
AD) have been found in 73% of autopsy cases with RPD
[10]. A synergistic effect of different pathologies in one
individual has to be considered in cases of PRD, but in
general, it remains uncertain in which way and to what
extend these pathologies contribute to the speed of cog-
nitive decline. Furthermore, physicians should keep in
mind that comorbidities like infections, cardiac or meta-
bolic diseases as well as secondary symptoms, and com-
plications of initially slowly progressive dementia (e.g.

Table 5. Summary of various other diseases and conditions that may lead to or mimic RPD.
Other diseases and conditions that may lead to or mimic RPD
CNS neoplasia Storage diseases and other genetic causes for RPD Toxic
1. CNS lymphoma 1. Wilson’s disease 1. Alcohol-related dementia
2. Solid neoplasia (primary in the CNS or metastatic) 2. NBIA 2. Benzodiazepine-related dementia
3. Diffuse gliomatosis 3. Lysosomal storage diseases (selected): 3. Methyl intoxication
4. Leptomeningeal spread of other tumors mucopolysaccharidoses, sphingolipidoses, and neuronal 4. Metal intoxications (e.g. lithium,
Metabolic ceroid lipofuscinoses mercury)
1. Hyponatremia and other electrolyte disturbances 4. Huntington’s disease 5. Side effects of chemotherapeutics or
2. Wernicke’s encephalopathy (thiamine) and other 5. CADASIL resp. CARASIL neuroleptic drugs
vitamin deficiency syndromes (e.g. B12, folate, 6. Mitochondrial diseases (selected): MELAS, Leigh Psychiatric
niacin, biotin) disease 1. Severe depression
3. Hepatic encephalopathy 7. PME: Lafora disease, ULD 2. Schizophrenic disorders
4. Uremic encephalopathy 8. Porphyria 3. Hypochondriac delusions
5. Hypothyroidism 9. Methylmalonic academia Others and secondary conditions
6. Hypoparathyroidism 10. DRPLA 1. Hypoxic brain damage
7. Porphyria 2. Epilepsy and secondary seizures
8. Adrenal insufficiency 3. Systemic inflammation (e.g. systemic
9. Extrapontine myelinolysis immune-mediated diseases, septic
encephalopathy)
4. NPH
NBIA: Neurodegeneration with brain iron accumulation; CADASIL: cerebral autosomal dominant arteriopathy with subcortical Infarcts and leukoencephalopathy;
MELAS: mitochondrial encephalopathy, lactic acidosis and stroke-like episodes; PME: progressive myoclonic epilepsies; ULD: Unverricht–Lundborg disease;
DRPLA: dentatorubral-pallidolysial atrophy; NPH: normal pressure hydrocephalus.
8 I. ZERR AND P. HERMANN
seizures, infections) might also accelerate disease progres-
sions and shorten life expectancies.
4. Conclusion
Dementia is a syndrome of major importance for public health
care and RPD is not a rare phenomenon. Although CJD sur-
veillance centers have reported that neurodegenerative dis-
eases are the most frequent differential diagnoses, data from
tertiary care centers show that highly treatable disorders like
encephalitis are the most common causes for RPD. Effective
antiviral and antibacterial therapeutics for many infectious
CNS diseases and immunosuppressive medications for the
treatment of immune-mediated encephalitis are available.
Still, the differential diagnosis of RPD is not trivial which
indicates the need for a thorough diagnostic workup. This
should include MRI and CSF analyses. If these standard proce-
dures show no suggestive or inconclusive diagnostic results,
specific technical measurements or genetic analyses will be
indicated. Even probationary therapeutic attempts can be
considered in some cases. Figure 2 provides an overview.
5. Expert commentary
RPD can be caused by numerous pathologies which require dis-
similar therapeutic strategies. Unfortunately, clinicians often have
Figure 2. Synopsis of diagnostic measurements in cases with RPD.
FLAIR: Fluid-Attenuated Inversion Recovery, DWI: Diffusion Weighted Image, SWI: Susceptibility Weighted Image, FDG: Fluorodeoxy-glucose, PET: Positron Emission Tomography, SPECT:
Single-Photon Emission Computed Tomography, CJD: Creutzfeldt-Jakob Diseasae, AD: Alzheimer’s Disease
to rely on criteria with limited diagnostic accuracies. Another
problem emerges from the mistaken idea that dementia is almost
always caused by neurodegenerative disorders. This may easily
lead to a restriction of diagnostic and therapeutic measurements in
the clinical case management.
For an improvement of the current situation, three major
goals have to be focused:
● The awareness of different etiologies of RPD has to be
raised among clinicians.
● More reliable noninvasive or minimal-invasive clinical
markers have to be identified and validated.
● New therapeutic strategies for neurodegenerative dis-
eases have to be developed and established.
Many causes of RPD are highly treatable and we identified some
studies providing evidence that these conditions are very frequent
among cases with RPD [14,15,106]. An effective treatment of
potentially reversible RPD (e.g. infectious and immune-mediated
encephalitis) has to start as early as possible in the course of the
disease. Therefore, it is crucial to identify those cases at an early
stage. When effective drugs for neurodegenerative diseases
become available, the starting point of the therapy may be even
more important. Recent experimental therapeutic strategies in
Alzheimer’s disease, α-synucleinopathies, and Creutzfeldt–Jakob
disease have been targeting certain proteins in order to avoid

conformation changes and aggregation or to remove existing
aggregations. In this context, one has to keep in mind that patho-
logical changes in the nervous system precede the point of the
clinical onset of these diseases. It is obvious that a substantial
clinical benefit can only be achieved when the destruction of the
neuronal integrity is not too progressed.
In our opinion, a faster and more accurate clinical diagnosis
will achieve more than an improved treatment of RPD. It may
even be a presupposition for a progress in understanding
underlying pathologies and developing new therapeutics in
the whole field of neurodegenerative disorders. Without
doubt, enhanced diagnostics are necessary to evaluate the
effectivity and safety of new drugs in clinical trials.
Concerning clinical diagnostics, it will be important to identify
disease-specific markers that are not only surrogates representing
general neuronal damage. In Alzheimer’s disease, the amyloid-PET
can already be performed in many centers and updated research
criteria [40] are based on specific biomarkers which allow diagnosis
in early or even preclinical stages in some cases. In Creutzfeldt–
Jakob disease, the development and validation of the CSF RT-QuIC
method has been a major improvement. For the first time, patho-
logic prions (PrP scrapie) can be detected without biopsy or neu-
ropathological examination. Ongoing efforts will most likely lead
to tests that can be applied to other biomaterials (e.g. blood or
mucosa [22]). Several proteins behaving like prions have been
identified in recent years and the development of aggregation
assays for such proteins in tauopathies and α-synucleinopathies
is one of the most interesting goals in current biomarker research.
Furthermore, the number of identified antibodies that are asso-
ciated with paraneoplastic or non-paraneoplastic immune-
mediated encephalitis is still increasing.
In general, the aforementioned methods have to be vali-
dated in large cohorts. The technical procedures have to be
improved and standardized to become accessible and afford-
able for small centers all over the world.
6. Five-year view
Hopefully, effective treatment options for AD and maybe other
neurodegenerative diseases will be available in 5 years.
Especially in rapidly progressive forms of these diseases, a
fast and accurate differential diagnoses will be crucial for the
appropriate application of new therapeutics. We expect a
constant progress in the field of biomarker-based differential
diagnosis. Research criteria for a biological definition of AD
have already been published allowing a diagnosis in early or
even preclinical stages [40]. Reliable biomarkers for neurode-
generative diseases like DLB and CJD are available and will be
developed for VD, soon. Furthermore, new antibodies related
to certain immune-mediated diseases and new mutations
related to dementia syndromes will be discovered. Panel diag-
nostic for genetic analyses and the search for antibodies will
become more accessible and achievable. If the awareness for
different types of RPD rises among physicians, these tools will
set the stage for the improvement of differential diagnosis,
therapy, and trial monitoring. Furthermore, it is an essential
step to gain more insight into pathophysiological
mechanisms.
EXPERT REVIEW OF NEUROTHERAPEUTICS 9
Key issues
● Dementia is a syndrome of major importance for public
health care and RPD is not a rare phenomenon in patients
referred to neurological units. Prion reference centers have
reported high rates of CJD and other neurodegenerative
diseases in patients with RPD. In contrast, tertiary care
centers have reported that highly treatable disorders like
encephalitis are the most common causes for RPD.
● The clinical differential diagnosis of RPD is not trivial and
the number of possible causes is extremely high including
all kinds of neurodegenerative diseases, immune-mediated
and infectious diseases, metabolic and toxic disorders, and
genetic diseases.
● This indicates the need for a thorough clinical diagnostic work
up. This has to include a detailed assessment of the clinical
presentation and the patient’s history but also neuroimaging,
fluid markers (CSF and blood) and sometimes genetic analyses.
● Because of the high prevalence of immune-mediated ence-
phalitis among RPD, a search for neoplasia as well as ence-
phalitis-related antibodies should be performed. In
suggestive cases without evidence, a probationary treat-
ment with steroids can be useful.
Funding
This paper was supported by the German Federal Ministry of Health [Grant
no: 1369-341] via the Robert-Koch Institute.
Declaration of interest
I Zerr and P Hermann are employed at the German National Reference Center
for TSE which receives grants from the Robert-Koch Institute to maintain CJD
surveillance and research. The authors have no other relevant affiliations or
financial involvement with any organization or entity with a financial interest in
or financial conflict with the subject matter or materials discussed in the
manuscript apart from those disclosed.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other
relationships to disclose.
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