Symptom-led staging for primary progressive aphasia

Abstract

The primary progressive aphasias (PPA) present complex and diverse challenges of diagnosis, management and prognosis. A clinically-informed, syndromic staging system for PPA would take a substantial step toward meeting these challenges. This study addressed this need using detailed, multi-domain mixed-methods symptom surveys of people with lived experience in a large international PPA cohort. We administered structured online surveys to caregivers of patients with a canonical PPA syndromic variant (nonfluent/agrammatic (nvPPA), semantic (svPPA) or logopenic (lvPPA)). In an 'exploratory' survey, a putative list and ordering of verbal communication and nonverbal functioning (nonverbal thinking, conduct and wellbeing, physical) symptoms was administered to 118 caregiver members of the UK national PPA Support Group. Based on feedback, we expanded the symptom list and created six provisional clinical stages for each PPA subtype. In a 'consolidation' survey, these stages were presented to 110 caregiver members of UK and Australian PPA Support Groups, and refined based on quantitative and qualitative feedback. Symptoms were retained if rated as 'present' by a majority (at least 50%) of respondents representing that PPA syndrome, and assigned to a consolidated stage based on majority consensus; the confidence of assignment was estimated for each symptom as the proportion of respondents in agreement with the final staging for that symptom. Qualitative responses were analysed using framework analysis. For each PPA syndrome, six stages ranging from 1 ('Very mild') to 6 ('Profound') were identified; earliest stages were distinguished by syndromic hallmark symptoms of communication dysfunction, with increasing trans-syndromic convergence and dependency for basic activities of daily living at later stages. Spelling errors, hearing changes and nonverbal behavioural features were reported at early stages in all syndromes. As the illness evolved, swallowing and mobility problems were reported earlier in nfvPPA than other syndromes, while difficulty recognising familiar people and household items characterised svPPA and visuospatial symptoms were more prominent in lvPPA. Overall confidence of symptom staging was higher for svPPA than other syndromes. Across syndromes, functional milestones were identified as key deficits that predict the sequence of major daily life impacts and associated management needs. Qualitatively, we identified five major themes encompassing 15 subthemes capturing respondents' experiences of PPA and suggestions for staging implementation. This work introduces a prototypical, symptom-led staging scheme for canonical PPA syndromes: the PPA Progression Planning Aid (PPA ² ). Our findings have implications for diagnostic and care pathway guidelines, trial design and personalised prognosis and treatment for people living with these diseases.

Figure 1.

Development of the Primary Progressive Aphasia Progression Planning Aid (PPA²) The Figure illustrates the different sources of information incorporated in the Primary Progressive Aphasia Progression Planning Aid (PPA²). Data were synthesised from ‘top-down’ sources to characterise what was known from a clinician/researcher perspective (i.e. clinician-led interpretation of patient records, histories and neuropsychological test scores) and from ‘bottom-up’ sources to capture crucial information from those with lived experience of the conditions (i.e. patient/caregiver-derived symptoms and changes which were organised, prioritised and amended to reflect the lived experience of disease progression). The PPA² puts forward two levels that clinicians and people with lived experience of PPA may find useful: the six stages give a granular overview of specific symptoms (see Figures 2-4); the three phases comprise broader markers containing key milestones with implications for management of these diseases (see Figure 5).

Figure 2.

Symptom frequencies and confidence in symptom placement by stage for semantic variant primary progressive aphasia The Figure shows all symptoms included in the svPPA Progression Planning Aid (see Supplementary Table S1). Boxes on the left-hand side denote stages (1 = very mild svPPA; 2 = mild svPPA; 3 = moderate svPPA; 4 = severe svPPA; 5 = very severe svPPA; 6 = profound svPPA). Written symptom labels are colour-coded based on domains of verbal communication (A = black) and nonverbal functioning (B1 = nonverbal thinking, blue; B2 = conduct and wellbeing, red); B3 = physical, green). Horizontal bars indicate the ‘confidence’ of symptom staging, calculated as the percentage of people responding to a given symptom who endorsed placement of that symptom in its final stage (i.e. the highest agreement achieved for placement of that symptom). Symptoms have been ordered within stages in descending order of overall frequency.

Figure 3.

Symptom frequencies and confidence in symptom placement by stage for nonfluent-agrammatic variant primary progressive aphasia The Figure shows all symptoms included in the nfvPPA Progression Planning Aid (see Supplementary Table S2. Boxes on the left-hand side denote stages (1 = very mild nfvPPA; 2 = mild nfvPPA; 3 = moderate nfvPPA; 4 = severe nfvPPA; 5 = very severe nfvPPA; 6 = profound nfvPPA). Written symptom labels are colour-coded based on domains of verbal communication (A = black) and nonverbal functioning (B1 = nonverbal thinking, blue; B2 = conduct and wellbeing, red); B3 = physical, green). Horizontal bars indicate the ‘confidence’ of symptom staging, calculated as the percentage of people responding to a given symptom who endorsed placement of that symptom in its final stage (i.e. the highest agreement achieved for placement of that symptom). Symptoms have been ordered within stages in descending order of overall frequency.

Figure 4.

Symptom frequencies and confidence in symptom placement by stage for logopenic variant primary progressive aphasia The Figure shows all symptoms included in the lvPPA Progression Planning Aid (see Supplementary Table S3. Boxes on the left-hand side denote stages (1 = very mild lvPPA; 2 = mild lvPPA; 3 = moderate lvPPA; 4 = severe lvPPA; 5 = very severe lvPPA; 6 = profound lvPPA). Written symptom labels are colour-coded based on domains of verbal communication (A = black) and nonverbal functioning (B1 = nonverbal thinking, blue; B2 = conduct and wellbeing, red); B3 = physical, green). Horizontal bars indicate the ‘confidence’ of symptom staging, calculated as the percentage of people responding to a given symptom who endorsed placement of that symptom in its final stage (i.e. the highest agreement achieved for placement of that symptom). Symptoms have been ordered within stages in descending order of overall frequency.

Figure 5.

Clinical milestones of primary progressive aphasia evolution The Figure summarises milestone symptoms and associated management implications over the clinical course of primary progressive aphasia syndromes, as identified from the caregiver survey. The left-hand panels show symptoms which (in that phase of the illness) are more prominent in some PPA syndromes than others; the middle panels show symptoms common to all syndromes. The right-hand panels represent key implications for management during each phase of the illness, as predicted from these milestone symptoms. Written symptom labels are colour-coded based on domains of verbal communication (black), nonverbal thinking (blue), nonverbal conduct and wellbeing (red) and physical symptoms (green) (see text for details).