Rapidly progressive dementias - aetiologies, diagnosis and management

Abstract

Rapidly progressive dementias (RPDs) are a group of heterogeneous disorders that include immune-mediated, infectious and metabolic encephalopathies, as well as prion diseases and atypically rapid presentations of more common neurodegenerative diseases. Some of these conditions are treatable, and some must be diagnosed promptly because of their potential infectivity. Prion disease is considered to be the prototypical RPD, but over the past two decades, epidemiological reports and the identification of various encephalitis-mediating antibodies have led to a growing recognition of other encephalopathies as potential causes of rapid cognitive decline. Knowledge of RPD aetiologies, syndromes and diagnostic work-up protocols will help clinicians to establish an early, accurate diagnosis, thereby reducing morbidity and mortality, especially in immune-mediated and other potentially reversible dementias. In this Review, we define the syndrome of RPD and shed light on its different aetiologies and on secondary factors that might contribute to rapid cognitive decline. We describe an extended diagnostic procedure in the context of important differential diagnoses, discuss the utility of biomarkers and summarize potential treatment options. In addition, we discuss treatment options such as high-dose steroid therapy in the context of therapy and diagnosis in clinically ambiguous cases.

Fig. 1. Rapidly progressive dementia: disease entities and contributing factors.

The flow chart shows the diseases and other contributing clinical factors that have been implicated in rapid cognitive decline. AD, Alzheimer disease; DLB, dementia with Lewy bodies.

Fig. 2. Probable rapidly progressive dementia aetiologies in relation to time from onset to dementia.

The chart reflects the likelihood of particular disease categories in light of the rapidity of cognitive decline. The time of symptom progression (indicated above disease categories) ranges from immediate onset of relevant cognitive dysfunction (left) to 2 years from onset of first symptoms to presence of dementia (right). Higher colour intensity indicates a typical time frame for each disease category. Patients with Creutzfeldt–Jakob disease usually develop a full dementia syndrome within a time span of a few weeks or a few months after onset. In other rapidly progressive neurodegenerative dementias, this process usually takes from several months up to 2 years. Encephalitides and metabolic encephalopathies are likely to show immediate or subacute onset with very rapid disease progression, whereas vascular encephalopathies are extremely heterogeneous and can show immediate onset of dementia (after stroke, for example), rapid disease progression (vasculitis), or moderate or stepwise progression (classic vascular dementia). This chart is intended to provide a rough overview and exceptions can occur. It is based largely on the literature reviewed in this article, as well as on the authors’ personal experience from their clinical work in a dementia referral centre and in prion disease surveillance.

Fig. 3. MRI findings in rapidly progressive dementia.

a | Diffusion-weighted imaging (DWI) in a 62-year-old woman with the MV2 subtype of sporadic Creutzfeldt–Jakob disease (sCJD), showing hyperintensities of the basal ganglia including the thalamus (arrows). The patient had a history of progressive movement disorder and rapidly progressive cognitive decline that had started about 6 months before the scan. b | DWI in a 54-year-old man with the MM2 sCJD subtype, showing hyperintensities in several posterior cortical regions (arrowheads). At the time of the scan, the patient displayed a moderate dementia syndrome and aphasia without other neurological signs. The symptoms had started about 8 months previously. c | MRI scans in a 67-year-old man with Alzheimer disease and severe cerebral amyloid angiopathy. The T2-weighted image (left) shows several cortical and subcortical post-haemorrhagic lesions, as well as bitemporal atrophy. The susceptibility-weighted image (right) reveals multiple residual signs of microbleeds and macrobleeds. Before the scan, the patient had exhibited mild cognitive impairment for an unknown period. The symptoms progressed to a severe dementia syndrome within 1 year of the scan. d | MRI scans in a 53-year-old man with primary angiitis of the CNS. The DWI (left) shows cortical and subcortical hyperintensities in regions with acute and subacute ischaemia (arrow). The T2-weighted image (right) shows cortical and subcortical ischaemic lesions and lacunes of differing ages. The arrow indicates the same region of subacute ischaemia as indicated in the left image, and the arrowhead indicates an older lacunar ischaemic lesion in the left thalamus. At the time of the scan, the patient showed a mild to moderate dementia syndrome, gait disturbance and dysarthria. The symptoms had started about 1 year previously and worsened continuously with stepwise accelerations. e | MRI scan in a 31-year-old woman with anti-NMDA receptor encephalitis. The arrows indicate diffuse fluid-attenuated inversion recovery (FLAIR) signal hyperintensities of the hippocampal regions in both hemispheres. At the time of the scan, the patient was experiencing recurrent seizures, which had been preceded by a 2-week period of episodic memory impairment and psychotic symptoms. f | MRI scan in a 39-year-old woman with Wernicke encephalopathy. The arrows indicate FLAIR signal hyperintensities of the medial thalamus and pulvinar nucleus in both hemispheres, which are similar to the ‘hockey stick’ sign in variant CJD. At the time of the scan, the patient was experiencing memory impairment, hallucinations, eye movement disturbance and flaccid tetraparesis. These symptoms had started 3 weeks previously. Part f adapted with permission from ref., Cambridge University Press.