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1University of Toronto, Division of Neurology, University Health Network Memory Clinic, Toronto Western Hospital, Toronto, ON, Canada *Author for correspondence: Tel.: +1 416 603 5181; Fax: +1 416 603 5768; [email protected]

� Causes of rapidly progressive dementia (RPD) are distinguished by the evolution of symptoms and signs over a number of days, weeks or months. The causes of RPD are diverse, spanning the spectrum of primary and secondary neurological diseases.

� The focus of history taking, examination and cognitive assessment is to elicit specific features supportive of an etiologic diagnosis. Clinical assessment should be used to focus investigations and treatments.

� Attention must be directed to identifying potentially reversible causes of RPD. Patients with fluctuating disease and symptoms of limbic encephalitis (acute-onset memory loss, behavioral changes and seizures) may be particularly responsive to treatments.

� Low-risk, accessible tools with high diagnostic yield – serum screening tests, cerebrospinal fluid analysis, MRI of the brain and EEG – should be completed in all patients. Expanded/extended testing should be requested to target specific diagnoses once the initial assessment is completed.

� Invasive testing should be reserved for refractory cases. A brain biopsy may be required to make the diagnosis. The decision to proceed with invasive testing should weigh the potential benefits against the potential periprocedural risks.

� A trial of immune-modulating treatments is recommended in patients without a specific etiologic diagnosis, once infection has been excluded.

� A marked response following treatment with immune-mediating medications may be seen in antibody-mediated brain diseases and steroid-responsive encephalopathy, and should trigger specific investigations for associated autoantibodies.

� A practical approach to RPD can be applied to narrow the differential diagnosis by prioritizing clinical assessment and the use of widely accessible investigations.

� The goal of assessment remains to rapidly identify and intervene in patients with potentially reversible causes of RPD.

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When dementia progresses quickly: a practical approach to the diagnosis and management of rapidly progressive dementia

REVIEW

Gregory S Day*1 & David F Tang-Wai1

41ISSN 1758-202410.2217/NMT.13.75 © 2014 Future Medicine Ltd Neurodegen. Dis. Manage. (2014) 4(1), 41–56

For reprint orders, please contact: [email protected]

The loss of function in patients with rapidly pro-gressive dementia (RPD) is defined as evolving hyperacutely (over days or weeks), subacutely (over months or 1–2 years) or more rapidly than expected with a known dementia syn-drome [1]. Compared with the more common chronic neuro degenerative causes of dementia, the decline in patients with RPD is readily rec-ognized by family members and caregivers as a dramatic departure from baseline. For this reason, recognizing a patient with RPD is rela-tively easy, often obviating a formal review and debate of diagnostic criteria for dementia/neuro-cognitive disorders [2]. However, discerning the underlying cause of rapidly progressive symp-toms and signs presents a decidedly greater chal-lenge. The potential causes of RPD are extensive (Box 1), emphasizing the need for a standardized approach to evaluation, with the goal of deter-mining cause (or at least etiologic category) and guiding interventions.

The standard approach to the clinical assess-ment of patients with chronic dementia also applies to the patient with RPD [3–5]. A thor-ough history and examination is of paramount importance to establish the baseline health sta-tus, the circumstances surrounding symptom onset, and the order and rate of progression of symptoms. Unique to the evaluation of the patient with RPD is the need to complete the assessment at a speed that matches the pace of the disease. Accordingly, clinical assessment and investigations should be prioritized in an effort to readily identify potentially treatable causes of RPD. This is best accomplished within the framework of a stratified diagnostic strategy that can be applied broadly by physicians operating in a wide variety of clinical settings.

RPD & the differential diagnosisAlthough no population-based studies esti-mating the incidence or prevalence of RPD have been published, case series exploring the

diagnosis in patients with RPD attest to the diversity of pathogenic mechanisms. A defini-tive cause of RPD was identified in 95.4% (644 out of 675) of patients included in the five largest case series (Figure 1) [6–10]. Of these, spongiform encephalopathy attributed to Creutzfeldt–Jakob disease (CJD) represented the most common diagnosis, accounting for 58.5% (377 out of 644) of cases. Cumulatively, neurodegenerative diseases, such as Alzheimer’s disease, represented the second most common cause of RPD (22.5%; 145 out of 644) [6–10]. Remarkably, 18.8% (121 out of 644) of cases were attributed to poten-tially treatable conditions [6–10], emphasizing the critical importance of a thorough and complete diagnostic evaluation in patients with RPD. Importantly, potentially treatable causes of RPD in these series included a number of disorders best characterized as acute encephalopathies (i.e., B12 deficiency, Wernicke’s encephalopa-thy and toxic/metabolic encephalopathies), but not patients diagnosed with delirium. From a practical perspective it remains important to entertain the diagnosis of delirium in all patients presenting with acute changes in mental status, disturbance in attention, disorganized thinking and an altered level of consciousness [2], recog-nizing the high mortality and morbidity associ-ated with diagnosis [11], and the high potential for reversibility.

Developing a rapid approach to the patient with RPDThe systematic approach to RPD does not require the assessing clinician to develop an entirely new skill set, but rather to concen-trate their skills on eliciting specific aspects of the patient history and physical examination (Table 1), and on completing the cognitive assess-ment. This information, in turn, must be used to further refine investigations and treatments with the goal of discerning the cause of RPD among a myriad of possibilities.

SUMMARY Making a diagnosis of rapidly progressive dementia requires practical adaptation of the skills used to assess patients with chronic causes of cognitive impairment. An expedited assessment, commensurate with the accelerated pace of the disease, is required to identify the cause of symptoms amidst a myriad of possibilities. Features upon history, physical examination and cognitive assessment that support specific diagnoses are reviewed, and a stratified approach to testing is presented. The use of readily-accessible investigations is prioritized, acknowledging the implications and applications of novel diagnostic tests. The coordinated use of clinical and laboratory measures are promoted as a means of facilitating rapid evaluation, with the ultimate goal of identifying patients with potentially reversible causes of rapidly progressive dementia.

Neurodegen. Dis. Manage. (2014) 4(1) future science group42

REVIEW Day & Tang-Wai

Refining the history takingThe history should begin by clarifying the base-line health and cognitive status of the patient. The remainder of questions should be posed to document relevant risk factors, especially cere-brovascular risk factors or exposures that may contribute to the presentation (including past medical history, medications, social habits, nutritional status and family history), determine pre-eminent and associated symptoms affecting general health and the integrity of the nervous system, and establish the presence of cognitive and/or behavioral impairment that significantly affects the patient’s activities of daily living. Care must be taken to clearly delineate presenting symptoms and signs, and to determine disease progression, as this information is critical to establish the diagnosis of RPD, and to evaluate the potential relationship between disease onset and relevant exposures [12]. Owing to the high degree of cognitive impairment anticipated in patients with RPD, the patient history must be corroborated with a family member or caregiver. Additional aspects to consider early in the his-tory include the need to differentiate RPD from acute changes superimposed on more chronic cognitive impairment, the implications of age, gender, course and rate of disease of progres-sion on the differential diagnosis, and the pos-sibility that symptoms may represent limbic encephalitis.

�� Is it really a RPD? In studies of chronic dementia, caregivers may underestimate the duration of illness due to a tendency to equate major incidents with the onset of disease (e.g., loss of employment, get-ting lost, social lapses and first seizure) [13]. Prior related symptoms are commonly attrib-uted to ‘normal aging,’ or are overlooked. Thus, to construct a true timeline, questions should specifically inquire about changes in cognition or behavior. Once the diagnosis of RPD is con-firmed, information at each stage of the patient history should be used to refine the differential diagnosis, beginning with the age of the patient.

�� Age of the patientAutoimmune/inflammatory [9,14,15], infectious [16], paraneoplastic [1], and genetic/metabolic/mitochondrial diseases abound during the first five decades of life, and account for many cases of RPD in younger patients (<50 years of age) [8,9]. Conversely, the percentage of patients

Box 1. Primary and secondary causes of rapidly progressive dementia, divided by etiology.

Neurodegenerative � Alzheimer’s disease � Corticobasal degeneration � Dementia with Lewy bodies � Familial spastic paraparesis � Frontotemporal lobar degeneration � Motor neuron disease � Progressive supranuclear palsy � Prion disease (i.e., Creutzfeldt–Jakob) � Progressive subcortical gliosis

Autoimmune/inflammatory†

� Acute disseminated encephalomyelitis � Antibody-mediated brain diseases � Anti-GAD65 autoimmunity � Behçet’s disease � Celiac sprue � Limbic encephalitis � Multiple sclerosis � Neuropsychiatric lupus � Sarcoidosis � Sjögren’s syndrome � Steroid-responsive encephalopathy

Vascular†

� CADASIL � Cerebral amyloid angiopathy � CNS vasculitis‡

� MELAS � Strategic infarction � Subdural hematoma � Vascular dementia

Metabolic†

� Cerebrotendinous xanthomatosis � Extrapontine myelinolysis � Liver failure � MELAS � NBIA � Neuronal ceroid lipofucinosis � Nutritional deficiency (i.e., vitamin B1, B3 or B12, or folate) � Porphyria � Renal failure

For further reviews of potential causes see [1,16,86,87]. †Secondary causes of rapidly progressive dementia. ‡Includes primary and secondary (infectious, neoplastic, connective tissue disease and drug-induced) causes of vasculitis. §Viral causes include HIV, herpes simplex virus, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, West Nile virus, Epstein–Barr virus and human herpes virus-6. Bacterial causes include spirochetal, Bartonella, Mycoplasma, Tropheryma, Mycobacterial and Rickettsial agents. Fungal causes include Coccidioides, Aspergillus, Histoplasma, Cryptococcus and Blastomyces. Parasitic causes include toxoplasmosis, trypanosomiasis, granulomatous amoebic and neurocysticercosis. CADASIL: Cerebral autosomal-dominant arteriopathy with subacute infarcts and leukoencephalopathy; MELAS: Mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms; NBIA: Neurodegeneration with brain iron accumulation disorders; PRES: Posterior-reversible encephalopathy syndrome.

A practical approach to the diagnosis & management of rapidly progressive dementia REVIEW

future science group www.futuremedicine.com 43

with RPD attributable to dementia with Lewy bodies (DLB), Alzheimer’s dementia and/or vascular cognitive impairment increases with advancing age [7,8,17,18]. Variant CJD repre-sents a rare exception to this rule, representing a neurodegenerative cause of RPD in younger patients (median age: 29 years) with prominent psychiatric and sensory symptoms, and remote exposure to the bovine spongiform encepha-lopathy agent [19]. Onset of RPD in late adult-hood, but before 70 years of age may increase the likelihood of secondary reversible causes of RPD (vs older patients) [8], frontal temporal dementia (median age: 50 years) [7,8] or sporadic CJD [6–8,17].

�� Gender differencesGender differences do not appear to associate with specific etiologic diagnoses of RPD [6-10]; however, younger patients with more frequent autoimmune causes of RPD may have been under-represented in the largest case series. Female gender is a well-established risk factor for autoimmune disease, especially during child-bearing years [20]. Female predominance is also reported in most paraneoplastic syndromes [21], anti-NMDA receptor encephalitis (81.1%) [22] and steroid-responsive autoimmune encepha-lopathy (SRE; 85%) [23]. Male predominance is reported with encephalopathy associated with autoantibodies against voltage-gated potassium channel (VGKC) subunits (68.8%) [24], empha-sizing the need to consider the diagnosis in men with RPD – particularly those presenting with hyponatremia and seizures [25].

�� Course & rate of disease progressionStratification based upon the rate of progression (developing over days to weeks versus months to years) and the course of RPD (fluctuating versus relentlessly progressive) may be used to differ-entiate etiologic causes of RPD. Characteristi-cally, CJD and secondary causes of RPD exhibit the most aggressive rates of progression, with symptoms evolving over weeks to months [8]; although hyperacute presentations are described. Unique to CJD, death usually occurs within 12 months of presentation [7]. Time to death is more variable in patients with secondary causes of RPD, in line with the underlying etiology and response to treatment, and is more protracted in patients with other neurodegenerative causes of RPD (1–3 years) [7,8,17,26]. Marked fluctua-tions in cognitive performance are common in patients with autoimmune (especially SRE) [1,21,23], paraneoplastic [21], vascular [27] and psy-chiatric toxic/metabolic causes of RPD, yet are rarely observed in patients with neurodegenera-tive diseases – with the exception of DLB. This finding may help to identify patients with the highest potential for therapeutic response early in the disease course (Figure 2).

�� Are rapidly progressive symptoms due to limbic encephalitis?Limbic encephalitis is a condition characterized by rapid-onset short-term memory loss, behavioral changes and seizures [28]. Misdiagnosis is com-mon, with many patients initially diagnosed with primary psychiatric disease [21,29]. The condition

Box 1. Primary and secondary causes of rapidly progressive dementia, divided by etiology (cont.).

Metabolic† (cont.) � Thyroid/parathyroid dysfunction � Wilson’s disease

Toxic†

� Bismuth � Heavy metal (lead, arsenic and mercury) � Manganese � Medication-induced � PRES � Radiation-induced leukoencephalopathy � Neoplastic � Brain metastases � Lymphomatoid granulomatosis � Paraneoplastic limbic encephalitis � Primary CNS neoplasms

Infectious†,§

� Bacterial � Fungal � Parasites � Viral � Other � Bipolar affective disorder � Hypoxic-ischemic encephalopathy � Normal pressure hydrocephalus � Other psychiatric illnesses � Schizophrenia

For further reviews of potential causes see [1,16,86,87]. †Secondary causes of rapidly progressive dementia. ‡Includes primary and secondary (infectious, neoplastic, connective tissue disease and drug-induced) causes of vasculitis. §Viral causes include HIV, herpes simplex virus, progressive multifocal leukoencephalopathy, subacute sclerosing panencephalitis, West Nile virus, Epstein–Barr virus and human herpes virus-6. Bacterial causes include spirochetal, Bartonella, Mycoplasma, Tropheryma, Mycobacterial and Rickettsial agents. Fungal causes include Coccidioides, Aspergillus, Histoplasma, Cryptococcus and Blastomyces. Parasitic causes include toxoplasmosis, trypanosomiasis, granulomatous amoebic and neurocysticercosis. CADASIL: Cerebral autosomal-dominant arteriopathy with subacute infarcts and leukoencephalopathy; MELAS: Mitochondrial encephalopathy with lactic acidosis and stroke-like symptoms; NBIA: Neurodegeneration with brain iron accumulation disorders; PRES: Posterior-reversible encephalopathy syndrome.



is first suggested on history, and further supported by investigations demonstrating medial temporal lobe T2-weighted hyperintensities on MRI and inflammation within cerebrospinal fluid (CSF).

Although limbic encephalitis was originally considered to be a paraneoplastic disease asso-ciated with a poor outcome, nonparaneoplastic and potentially treatable causes are increasingly described [28,30]. Of the nonparaneoplastic syn-dromes, encephalopathy associated with antibod-ies against CNS NMDA receptors and VGKC subunits are particularly worthy of consideration, as dramatic improvements in cognition and levels of functioning may be seen in both syndromes following administration of antibody-depleting immunotherapies [22,31]. Although these diseases are more common in younger patients, patients at the extremes of age have been reported (anti-NMDA receptor encephalitis: 8 months to 84 years of age [15,32]; VGKC: 2–88 years of age [25]). Specific autoantibody testing is justified; therefore, in all patients with RPD with asso-ciated psychiatric or behavioral disturbances, and movement disorders, seizures or autonomic instability.

�� Additional questionsIt is important to screen for additional symptoms that may associate with specific causes of RPD. Profound weight loss (not due to forgetting meal preparation, as is typically seen in neurodegenera-tive disorders such as Alzheimer’s disease), may herald a neoplastic or paraneoplastic cause of RPD [33]. Recurrent fevers may suggest systemic infections, autoimmune/connective tissue disease or hematologic malignancy. Marked weight loss associated with chronic diarrhea is described with Tropheryma whipplei infection causing Whipple’s disease [34]. When the onset of encephalitis is associated with intense diarrhea, a novel disorder mediated by autoantibodies against DPP6 should also be considered [35]. A history of immunosup-pression (secondary to active disease or medica-tion use) broadens the spectrum of etiologies to include opportunistic malignancies and infec-tious agents in the differential diagnosis. RPD is rarely described in association with Lyme’s disease [36], neurocysticercosis [37], tuberculosis [38] and familial prion diseases.

Finally, a thorough medication review is of great importance, as iatrogenic ‘toxic’ exposures represent a frequent cause of hospitalization in North America, with an elevated risk in elderly individuals [39]. The risk of toxic/metabolic

disturbances causing RPD may be even higher in patients with pre-existing cognitive impairment, raising suspicion in patients with a prior history of mild cognitive impairment or chronic dementia. Patients with DLB may be particularly suscep-tible, with prolonged or even irreversible cognitive decline described following minor surgery [7] or exposure to antipsychotic medications [40].

Refining the physical examinationThe focus of the physical examination is to iden-tify and document signs that corroborate the patient history, support an etiological diagnosis and focus investigations. The CNS is the pri-mary site of compromise in RPD but other areas

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Figure 1. Causes of rapidly progressive dementia. (A) Primary (n = 644) and (B) secondary (n = 121) causes of rapidly progressive dementia in the five largest case series [6–10]. CJD: Creutzfeldt–Jakob disease; NPH: Normal pressure hydrocephalus.



of the body can be involved. Early differentiation between encephalopathies affecting the brain, spinal cord and/or peripheral nervous system is of particular importance in directing neuroimaging and narrowing the differential diagnosis. Taking a ‘head-to-toe’ approach, the following physical findings should be considered together with the patient history to narrow the differential diagnosis.

�� Vital signsCachexia is a common finding in neoplastic or paraneoplastic disease [33] and an independent risk factor for nutritional deficiencies associated with RPD (i.e., Wernicke’s encephalopathy) [41]. Fever and meningismus may suggest a diagnosis of meningitis/encephalitis. Vital signs should be documented with the patient in recumbent and standing positions to look for evidence of ortho-static hypotension compatible with autonomic failure described in neurodegenerative (i.e., DLB) [42], paraneoplastic [43] and antibody-mediated diseases [43,44] with cognitive impairment.

�� General physical examinationLymphadenopathy and/or splenomegaly may point towards a hematologic/lymphogenous or chronic infectious cause of RPD. Abnormalities on cardiac or carotid auscultation may support a

vascular and/or embolic etiology (i.e., endocardi-tis). Dilated ophthalmologic assessment should be performed in all patients with RPD examin-ing for papilledema, vascular beading (suggestive of vasculitis) or lymphomatous/infectious aggre-gates. Finally, all patients should undergo careful dermatologic inspection for rashes or eruptions suggestive of inflammatory or infectious disease, or lacerations, track marks or insect/animal bites that may suggest an extrinsic cause of RPD.

�� Neurological examinationA complete neurological examination is essen-tial. Particular attention should be directed towards identifying upper motor signs (spastic-ity, pyramidal distribution of weakness, relative hyperreflexia, and extensor or asymmetrical plantar responses) and lower motor signs (fas-ciculations, muscle atrophy and motor weak-ness), in an effort to detect patterns associated with specific diseases.

Encephalomyelitis with or without cranial neuropathies is commonly seen with infectious/parainfectious (e.g., West Nile virus, poliomyeli-tis and tic-borne encephalitides) and inflamma-tory/autoimmune disease processes (e.g., acute disseminated encephalomyelitis, paraneoplastic diseases and chronic lymphocytic inflammation

Table 1. Findings on history and physical examination supportive of an etiologic diagnosis.

Finding CJD Neurodegenerative Autoimmune/inflammatory

Vascular Metabolic Toxic Neoplastic/paraneoplastic

Infectious

History

Age (years):Young (<50)Old (≥50)

vCJDsCJD X

XX

XX

XX

XX X

XX

Onset:Acute†

Subacute‡

X X X X X XX X X

Relapsing–remitting X (DLB) X X X XSymptoms of limbic encephalitis X XSystemic signs X X X

Neurological examination

Upper motor neuron signs

X X X X X X

Parkinsonism X X X X X X (SSPE)Myoclonus X X X X XAsterixis X X XPeripheral neuropathy X X†Acute onset occurs over days to weeks. ‡Subacute onset occurs over months to years. CJD: Creutzfeldt–Jakob disease; DLB: Dementia with Lewy bodies; sCJD: Sporadic Creutzfeldt–Jakob disease; SSPE: Subacute sclerosing panencephalitis; vCJD: Variant Creutzfeldt–Jakob disease; X: Expected findings.



with pontine perivascular enhancement respon-sive to steroids), presenting with clinical signs compatible with inflammation of the brain and spinal cord. In a patient with a low likelihood of an infectious or autoimmune cause, the pres-ence of both upper and lower motor neuron signs may suggest a diagnosis of frontotem-poral lobar degeneration (FTLD) with motor neuron disease (MND) [7], and may predict a shorter survival time (2.3 years) [45], com-pared with patients with more typical FTLD (7–8 years) [46,47].

Movement disorders are commonly reported in patients with neurodegenerative [7,48,49] and secondary causes of RPD [50,51]. Stereotyped hyperkinetic movements are reported in associa-tion with CNS Whipple’s disease (oculomasti-catory myorhythmia) [34]; in patients with anti-NMDA receptor encephalitis (orofacial dyski-nesias, among others, in 55% of patients) [52–54]; and anti-LGI1 limbic encephalitis (faciobra-chial dystonic seizures) [55,56]. The recognition of atypical hypokinetic movements in patients with RPD is of equal diagnostic/prognostic significance: catatonia may suggest a diag-nosis of anti-NMDA receptor encephalitis in younger patients [52], while the coassociation of FTLD-MND and parkinsonism may herald an especially rapid decline [49]. Cerebellar ataxia affecting gait and/or limbs, parkinsonism, ops-oclonus myoclonus, chorea and tremor are most often seen in patients with paraneoplastic dis-orders, although prion disorders must also be considered.

It is important to note that the physical exam-ination of the patient with RPD represents a sin-gle measure of a dynamic process. Findings (or lack thereof) must, therefore, be interpreted in light of the stage and severity of disease. Many causes of RPD associated with focal or lateral-ized findings early in the disease process may generalize as the disease progresses. Similarly, processes associated with prominent hypertonia or hyperkinetic movements owing to cortical hyperexcitability, may progress to hypotonia or bradykinesia as neuronal cell bodies are lost. Whenever possible, records should be obtained from prior assessments to document early signs in severely affected patients, and to determine the progression of the disease.

Cognitive testingCognitive assessment is an extension of the phys-ical examination of the patient with impaired

mentation, and is best applied early in the course of illness before progression of the pathol-ogy renders the patient ‘untestable’. A number of tools are available to quantify impairment and identify the cognitive domains affected in the mild-to-moderately impaired patient with RPD (Table 2). Although no measures have been evaluated in RPD, defining cognitive dysfunc-tion may assist with localizing the deficit and clarifying the diagnosis.

Investigating RPD The number of tests that can be ordered for the patient with RPD is expansive, with high costs, associated risks to the patient and potential to unnecessarily delay diagnosis. We support a three-tier testing strategy that allows for a stratified approach to investigations and pri-oritizes identification of potentially reversible causes of RPD (Figure 3). The first tier – core tests – includes low-risk, accessible tools, with a

Slow Fast Fastest

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Psychiatric†

Autoimmune†

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Figure 2. Causes of rapidly progressive dementia stratified by rate of progression and potential reversibility. Disease etiologies in the top right quadrant (shaded) are typically associated with the most rapidly progressive presentations and the greatest potential for response to treatment with appropriate treatments. †Associated with marked fluctuations in course; neurodegenerative disease with prominent fluctuations implies a diagnosis of dementia with Lewy bodies. CJD: Creutzfeldt–Jakob disease; NPH: Normal pressure hydrocephalus.



high diagnostic yield and minimal turn-around times, and should be completed in all patients with RPD. The availability of expanded and extended tests varies between centers; accord-ingly, these tests should be requested on a per patient basis as resources allow.

Serum and CSF studies are the backbone of core tests providing rapid surveillance of organ function (Table 3). Diagnostic lumbar puncture should be completed once a space-occupying lesion and bleeding diathesis has been excluded. Routine CSF analysis should be completed in all cases, including screening for infectious agents. When practical, 3–5 ml of CSF should be stored to facilitate expanded/extended testing in the future, as warranted by changes in clinical con-dition. A toxicology screen (urine and serum) is an important part of the assessment, and should be performed in all patients to exclude iatrogenic causes of cognitive impairment.

HIV infection should be excluded in all patients, due to the association with RPD owing to viral proliferation and/or opportunistic infections [57]. Similarly, testing for Treponema pallidum causing neurosyphilis should be com-pleted, acknowledging the recent resurgence in patients with and without HIV [58,59].

MRI of the brain with and without gado-linium is indispensable in the evaluation of patients with RPD, and is critical to screen for structural (neoplastic, infectious and hemor-rhagic), demyelinating/inflammatory, vascular, neurodegenerative or metabolic causes (Figure 4) [6,7,60,61]. Whenever possible, imaging should be completed under protocols providing sagittal views of the corpus callosum and juxtacorti-cal structures (commonly involved in demy-elinating disease), and coronal views of medial temporal lobes (commonly involved in limbic encephalitis and neurodegenerative diseases). In the presence of renal failure (i.e., estimated glo-merular filtration rate is <30 ml/min/1.73 m2), noncontrast MRI should be obtained to prevent nephrogenic systemic fibrosis [62].

Combined with the patient history and phys-ical assessment, an EEG can be used to support diagnosis and estimate prognosis of patients with acute encephalopathy [63], as some EEG patterns are associated with specific causes of RPD (Table 4). Whenever possible, EEG should be obtained in states of wakefulness, drowsiness and sleep.

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core tests, however, the clinician is advised to select from groups of tests as directed by the differential diagnosis. If no alternate involved organ is identified (i.e., outside of the CNS), brain biopsy remains the invasive procedure of choice for establishing a diagnosis. Histori-cally, the diagnostic sensitivity of biopsy has approached 57–65% in patients with dement-ing conditions, impacting treatment in 11–44% of cases [64,65]. With the advent of autoantibody testing and wider application of CSF biomark-ers, the sensitivity has been reported as high as 73.7% (14 out of 19 cases), altering treatment in 21.1% (four out of 19 cases) [66]. This improve-ment may reflect the improved selection of patients with primarily neurodegenerative pathology, including prion diseases. Beyond

altering treatment, a positive biopsy may prove useful when providing counseling concern-ing the probability of recovery and the risk of relapse. In rare cases, this information may even have direct implications for surviving family members (e.g., FTLD-MND [67,68] and familial prion diseases) [19]. These observations exem-plify the value of brain biopsy in the declining patient in whom expanded/extended investiga-tions have failed to confirm a diagnosis. In all cases, this value must be weighed against the risks associated with the procedure, including hemorrhage, stroke and infection.

Extended testing can be readily completed within most tertiary health centers or in part-nership with commercial diagnostic labora-tories. Novel clinical syndromes are being

ImagingVascular imagingMRI of the spine

Body imaging

Infectious investigationsWest Nile disease

Lyme diseaseJC virus

Duodenal biopsy

CSF biomarkers Amyloid-β42

Total taup-tau

14-3-3NSE

S100b

Antibody panelLimbic encephalitis

Paraneoplastic

OtherEMG/NCS

Genetic studiesPorphyrin screen

TissueOrgan biopsyBrain biopsy

GeneticsGenotypingMicroarray

Laboratory testingResearch-based antibody testing

Nonspecific testing for CNS antigen binding

Extended testing†

Expanded testing

Core testing

Serum screenToxicology screen

Brain MRIEEG

CSF analysis

Advanced neuroimagingFunctional imaging (SPECT, fMRI)

Amyloid PET

Figure 3. Stratified approach to diagnostic testing in rapidly progressive dementia. †Investigations listed under ‘extended testing’ may be classified as ‘expanded testing’ (i.e., SPECT) and considered earlier in the diagnostic algorithm depending on local experience and the availability of resources. CSF: Cerebrospinal fluid; EMG/NCS: Electromyography/nerve conduction studies; fMRI: Functional MRI; JC virus: John Cunningham polyomavirus; p-tau: Phosphorylated tau; SPECT: Single-photon emission computed tomography.



Tabl

e 3.

Res

ults

of c

ore

sero

logi

cal a

nd c

ereb

rosp

inal

flui

d te

sts

supp

orti

ve o

f an

etio

logi

c di

agno

sis.

Test

ing

mod

alit

yC

JDN

euro

dege

nera

tive

Aut

oim

mun

e/in

flam

mat

ory

Vasc

ular

Met

abol

icTo

xic

Neo

plas

tic/

para

neop

last

icIn

fect

ious

Bloo

d

CBC:

H

b, W

BC, M

CV,

sm

ear

XX

XX

Elec

trol

ytes

:N

a+ , Ca2+

, Mg2+

XX

Live

r fun

ctio

n:A

ST, A

LT, a

lkal

ine

phos

phat

ase,

GG

T,

bilir

ubin

, am

mon

ia,

albu

min

X (e.g

., al

coho

l)X

(e.g

., al

kalin

e ph

osph

atas

e w

ith b

ony

inva

sion

)

Crea

tinin

eX

XX

Thyr

oid:

TS

H, T

3, T

4, a

nti-T

PO,

anti-

TG

XX

X (e

.g.,

lithi

um,

amio

daro

ne)

Rheu

mat

olog

ical

scr

een:

ESR,

CRP

, AN

A, E

NA

, RF,

A

NCA

, SPE

P

X (v

ascu

litis)

X (v

ascu

litis)

Vita

min

B12

XIn

fect

ious

:sy

phili

s, L

yme

dise

ase,

H

IV s

erol

ogy

X

Oth

er:

Ant

i-NM

DA

-re

cept

or A

b,

anti-

VGKC

su

buni

t Ab

Hyp

er-

coag

uabi

lity

pane

l

Mar

kers

for

mito

chon

dria

l dy

sfun

ctio

n (i.

e., l

acta

te

and

pyru

vate

)

Toxi

colo

gy

pane

l, dr

ug

leve

ls

Canc

er-s

peci

fic b

iom

arke

rs

(i.e.

, CA

-125

, CEA

, PSA

); pa

rane

opla

stic

pan

el

(ant

i-Hu,

Ri,

Yo, M

a-1/

2,

CV2

[CRM

P5],

GA

D65

, am

phip

hysi

n)

PCR

for s

peci

fic

agen

ts, W

NV

sero

logy

if

expo

sure

s pr

eval

ent

Cere

bros

pina

l flui

d

Cell

coun

t and

diff

eren

tial

++

(vas

culit

is)+

++

Prot

ein

++

++

+G

luco

seLo

w (b

acte

rial/

fung

al)

IgG

inde

x+

++

(par

aneo

plas

tic)

+O

ligoc

lona

l ban

ding

++

(par

aneo

plas

tic)

+Cy

tolo

gyX

X† M

easu

rem

ent r

equi

res u

se o

f pla

stic

(pol

ypro

pyle

ne) t

ubes

to a

void

abs

orba

nce

of b

-am

yloi

d in

to th

e tu

be w

alls

+: H

igh;

++:

Ver

y hi

gh; A

b: A

ntib

ody;

AN

A: A

ntin

ucle

ar a

ntig

en; A

NC

A: A

ntin

eutr

ophi

l cyt

opla

smic

ant

ibod

ies;

CBC:

Com

plet

e bl

ood

coun

t; C

JD: C

reut

zfel

dt–J

akob

dis

ease

; EN

A: E

xtra

nucl

ear a

ntig

en; E

SR: E

ryth

rocy

te

sedi

men

tatio

n ra

te; H

b: H

emog

lobi

n; M

CV:

Mea

n ce

ll vo

lum

e; P

-tau

: Pho

spho

ryla

ted

tau;

RF:

Rhe

umat

oid

fact

or; S

PEP:

Ser

um p

rote

in e

lect

roph

ores

is; T

3: T

riiod

othy

roni

ne; T

4: T

hyro

xine

; T-t

au: T

otal

tau;

TG

: Thy

rogl

obul

in

antib

ody;

TPO

: Thy

roid

per

oxid

ase

antib

ody;

VG

KC: V

olta

ge g

ated

pot

assiu

m c

hann

el; W

BC: W

hite

blo

od c

ell;

WN

V: W

est N

ile v

irus;

X: A

bnor

mal

ity e

xpec

ted.



Tabl

e 3.

Res

ults

of c

ore

sero

logi

cal a

nd c

ereb

rosp

inal

flui

d te

sts

supp

orti

ve o

f an

etio

logi

c di

agno

sis

(con

t.).

Test

ing

mod

alit

yC

JDN

euro

dege

nera

tive

Aut

oim

mun

e/in

flam

mat

ory

Vasc

ular

Met

abol

icTo

xic

Neo

plas

tic/

para

neop

last

icIn

fect

ious

Cere

bros

pina

l flui

d (c

ont.)

Gra

m s

tain

, bac

teria

l/vi

ral/f

unga

l tes

ting

X

Oth

er14

-3-3

(+)

T-ta

u (+

)N

SE (+

)S1

00b

(+)

Alz

heim

er’s:

T-ta

u (+

),P-

tau

(+),

Ab-

42 (l

ow)†

Lact

ate

(+)

PCR

for s

peci

fic

agen

ts

† Mea

sure

men

t req

uire

s use

of p

last

ic (p

olyp

ropy

lene

) tub

es to

avo

id a

bsor

banc

e of

b-a

myl

oid

into

the

tube

wal

ls +:

Hig

h; +

+: V

ery

high

; Ab:

Ant

ibod

y; A

NA

: Ant

inuc

lear

ant

igen

; AN

CA

: Ant

ineu

trop

hil c

ytop

lasm

ic a

ntib

odie

s; CB

C: C

ompl

ete

bloo

d co

unt;

CJD

: Cre

utzf

eldt

–Jak

ob d

isea

se; E

NA

: Ext

ranu

clea

r ant

igen

; ESR

: Ery

thro

cyte

se

dim

enta

tion

rate

; Hb:

Hem

oglo

bin;

MC

V: M

ean

cell

volu

me;

P-t

au: P

hosp

hory

late

d ta

u; R

F: R

heum

atoi

d fa

ctor

; SPE

P: S

erum

pro

tein

ele

ctro

phor

esis;

T3:

Trii

odot

hyro

nine

; T4:

Thy

roxi

ne; T

-tau

: Tot

al ta

u; T

G: T

hyro

glob

ulin

an

tibod

y; T

PO: T

hyro

id p

erox

idas

e an

tibod

y; V

GKC

: Vol

tage

gat

ed p

otas

sium

cha

nnel

; WBC

: Whi

te b

lood

cel

l; W

NV:

Wes

t Nile

viru

s; X:

Abn

orm

ality

exp

ecte

d.

described on an ongoing basis – with [31,35] and without [69] associated autoantibodies. Referral to a tertiary care center should be considered if extended testing is not available at a patient’s center, or if specific immunosup-pressive therapies are required for patients with suspected tumor- or antibody-mediated limbic encephalitis.

Diagnosing CJD Prion diseases remain an important and prev-alent cause of RPD in published case series [6–10]. This pathologically distinct class of dis-ease arises from the intrinsic (sporadic CJD or familial/genetic CJD) or extrinsic (vari-ant CJD or iatrogenic CJD) transformation of the normal cellular PrPc into an abnormal, disease-causing conformation (PrPSc; for review see [70]). The unregulated propagation of this stable protease-resistant monomer throughout interconnected neuronal networks ultimately culminates in extensive neuronal loss, gliosis and vacuolation, and explains the rapid accrual of cognitive dysfunction [70,71].

Updated criteria for the diagnosis of spo-radic CJD have been proposed [72]. While the diagnosis of ‘definite CJD’ continues to require identification of PrPSc with immunohistochem-istry [72], the diagnosis of ‘probable CJD’ has been modified to integrate a compatible clinical history with supportive core/expanded testing, including fluid- attenuated inversion recovery hyperintensities and/or restricted diffusion within cortical, striatal and thalamic areas on MRI [73,74], and CSF studies confirming ele-vated 14-3-3 protein and tau [75,76]. The modi-fied criterion appears to have adequate diagnos-tic sensitivity and specificity in patients with RPD [77,78]. Additional brain-derived proteins have been suggested as sensitive CSF biomark-ers in CJD (i.e., NSE and S100b), and may be combined with other measures to improve diag-nostic sensitivity [79]. EEG findings, including periodic complexes [80], may further support the diagnosis, but lack sufficient specificity to be relied upon for the diagnosis of CJD [78]. Recently described methods for the detection of PrPSc in CSF (real-time quaking-induced conversion measurement of PrPSc) may allow definite CJD to be diagnosed through non-invasive techniques [81]. This test remains to be validated, however, in clinical practice. Finally, the value of autoantibody testing was recently evaluated in a series including patients



with clinically suspected CJD. Autoantibod-ies against neuronal surface antigens were detected within the CSF of 1.7% (six out of 346) of cases [82], emphasizing the importance of expanded/extended testing in patients with-out histopathologically confirmed CJD. Auto-antibodies were not detected in any case of definite CJD [82].

Empiric treatment of RPDEmpiric treatment should be provided to all patients in whom the diagnosis is unclear fol-lowing completion of core testing. Secondary causes of RPD remain the most likely to respond to appropriate therapies; thus, a treatment trial may be viewed as a diagnostic test [8]. A low threshold should be maintained for administra-tion of intravenous acyclovir – particularly in patients presenting with seizures and pyrexia, suggestive of viral encephalitis. Additionally, all patients with a possible history of malnutrition should receive urgent treatment with high doses of intravenous thiamine [41]. Rapid resolution

of encephalopathy following correction of thia-mine deficiency in the brain is compatible with the diagnosis of Wernicke’s encephalopathy. In the majority of RPD cases, nonspecific treat-ments can be administered concurrently with expanded/extended investigations to further narrow the differential diagnosis and improve the selection of therapeutics.

Remarkable responses to immunosuppres-sive therapies have been described in patients with autoantibody-mediated diseases affect-ing the CNS [22,29,31]. This finding justifies the early use of nonspecific immune-modulating therapies in patients with suspected limbic encephalitis (e.g., pulse corticosteroids, intra-venous immunoglobulin and plasmapheresis), in whom infection has been excluded. A treat-ment response should increase suspicion of encephalopathy associated with autoantibodies against neuronal surface antigens (e.g., NMDA receptors or VGKC subunits), differentiating these syndromes from paraneoplastic dis-eases associated with onconeural/intracellular

I J

Figure 4. Diagnostic MRI of the brain in select cases of rapidly progressive dementia. (A & B) Creutzfeldt–Jakob disease: axial fluid-attenuated inversion recovery sequences (FLAIR) images demonstrating striatal (A) thalamus and (B) cortical (arrows) T2-hyperintensities. (C) Limbic encephalitis: coronal FLAIR images demonstrating bilateral limbic/hippocampal T2-hyperintensities. (D & E) Herpes simplex encephalitis: axial T1-weighted images demonstrating right anteromedial temporal lobe hyperintensities. (F) Wernicke’s encephalopathy: axial FLAIR images demonstrating dorsomedial thalamic T2-hyperintensities. (G) Hepatic encephalopathy: sagittal T1-weighted images demonstrating diencephalon hyperintensity. (H & I) Cerebrovascular disease. (H) Axial FLAIR images demonstrating strokes and diffuse ischemic white matter changes. (I) Axial gradient-echo images demonstrating bilateral anterior and dorsomedial thalamic hemorrhage causing acute-onset amnesia. (J) CNS vasculitis: axial T1-weighted images with gadolinium demonstrating enhancement of vessels in the right hemisphere (arrows).



autoantibodies [21,29], which tend not to respond to immune modulation.

ConclusionThe causes of RPD are vast, with symptoms and signs attributable to a variety of diseases capable of disrupting cerebral function. A prac-tical approach to RPD prioritizes the early iden-tification of patients with potentially reversible causes, and, when appropriate, early adminis-tration of disease-modifying therapies. Clues from the patient’s history, physical examination and cognitive assessment can be used together with core investigations to narrow the differ-ential diagnosis, and focus expanded/extended tests in an effort to minimize risk to the patient and maximize the likelihood of establishing a rapid diagnosis in the rapidly declining patient with RPD.

Future perspective Resting state functional MRI measures, recently applied to the differentiation of subtypes of neurodegenerative diseases [83], may be readily applied to the characterization and evaluation of cerebral dysfunction in patients with RPD, offering the potential of an ancillary test to cor-roborate and quantify cognitive impairment in this population. This tool has already been used to evaluate patients with limbic encephalitis, cor-relating memory impairment with hippocampal disconnection, and executive dysfunction with disruptions in subcortical activity in patients with anti-NMDA receptor encephalitis [84]. Equally exciting is the steady characterization of new autoantibodies in patients with encepha-lopathy [29], offering specific diagnoses for condi-tions formerly labeled as ‘chronic encephalitis’ [9]

or ‘encephalitis of unknown etiology’ [85], and offering hope for the expanded application of immune-modulating therapies in RPD. Together, these biomarkers promise to contrib-ute to the clinical evaluation of RPD, equipping the astute clinician with additional noninvasive tools to assist in discerning a diagnosis and rap-idly identifying patients with potentially revers-ible RPD. Even in causes of RPD with no known cure, such as CJD, the application of sensitive and specific noninvasive biomarkers (i.e., CSF real-time quaking-induced conversion measure-ment of PrPSC [81]) may facilitate accurate diagno-sis earlier in the course of illness. Early diagno-sis may provide an opportunity for therapeutic intervention as more agents that alter disease pathogenesis become available.

Financial & competing interests disclosureGS Day is the clinical director of The Anti-NMDA Recep-tor Encephalitis Foundation Inc. (Canada) and is involved in the development and implementation of proj-ects to support the foundation’s goals of improving out-comes in patients with anti-NMDA receptor encephalitis through education and research. The foundation is sup-ported by private donations. GS Day is the recipient of a Future Leaders in Dementia grant, including support for travel (Pfizer, Canada). DF Tang-Wai holds a grant with the Weston Foundation, and is a collaborator on grants from the CIHR, Alzheimer Society of Canada, Parkinson Society of Canada and the Michael J Fox Foundation. The authors have no other relevant affiliations or financial involvement with any organization or entity with a finan-cial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

No writing assistance was utilized in the production of this manuscript.

Table 4. EEG patterns of interest in rapidly progressive dementia.

EEG finding Definition Potential etiologies

Periodic complexes Generalized discharges of synchronous high-voltage spikes or sharp waves

CJD [93]SSPE [94]Rarely Alzheimer’s disease [93] or DLB [95]

Extreme d-brush Rhythmic d activity (1–3 Hz) with superimposed bursts of 20–30 Hz b-frequency activity riding on each d-wave

Anti-NMDA receptor encephalitis [15,96]

Triphasic waves Synchronous, frontally predominant, rhythmic triphasic waves, usually with background slowing

Metabolic disorders (i.e., hepatic encephalopathy) [97], nonconvulsive status epilepticus

PLEDs High-voltage sharp potentials over one or both lobes, occurring every few seconds

Herpes simplex encephalitis (temporal PLED) [80], other focal lesions

Frontal intermittent rhythmic d-activity

Rhythmic, discontinuous high-voltage d-frequency (1–3 Hz) activity that predominates in frontal regions

Processes involving deep midline structures (i.e., hydrocephalus), other focal lesions [63]

CJD: Creutzfeldt–Jakob disease; DLB: Dementia with Lewy bodies; PLED: Periodic lateralized epileptiform discharge; SSPE: Subacute sclerosing panencephalitis.



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