Prognosis in chronic progressive neurologic disease: a narrative review

Introduction

Prognostication is the process of estimating a patient’s likely outcome from their medical condition, and is an essential component of patient-centered care. There are two components to prognosis—how well and how long a patient may live with their illness (1). In patients with neurologic disease, the first question is particularly important as many neurologic diseases such as Parkinson’s disease (PD) or multiple sclerosis (MS) lead to gradual increase in symptom burden, such as decreased mobility, cognitive decline, pain, or urinary dysfunction, over a matter of years and can lead to prolonged periods of diminished function and quality of life.

While clinicians may feel reluctant or uncomfortable communicating prognosis, available evidence has shown that many patients and care partners prefer to discuss prognosis and advance care planning with their neurologists, though preferences on timing vary (2-6). An understanding of prognosis is important to inform advance care planning, including end of life plans and any planning for an eventual higher level of care. Furthermore, prognosis can provide critical information for true informed consent when considering risks and benefits for proposed medical interventions. For example, patients with advanced PD may choose to forego a joint replacement or cardiac surgery if they have a poor neurologic prognosis, in terms of either function or longevity. If a patient’s life expectancy is particularly short and symptom burden is high, it may be appropriate for a patient’s neurologist to initiate discussions about possible comfort-oriented care or end of life palliative care.

Prognostication in neurologic disease has unique challenges. We lack high-quality prognostic models to predict disease progression, symptom burden and quality of life, and mortality after a diagnosis of neurologic disease. For some diseases we lack a sensitive prognostic indicator of the terminal phase of disease. Existing frameworks such as US Medicare hospice guidelines; Changes in Health, End-stage disease and Symptoms and Signs (CHESS) scale; and the Gold Standards Framework Prognostic Indicator Guidance have not been specifically tested in neurologic diseases (7-9). Many neurologic diseases, such as MS or PD, have a very heterogeneous disease course, and clinicians may be reluctant to try predicting one patient’s future in the setting of great uncertainty about how their disease will progress in future. Further, neurologic diseases themselves can cause cognitive deficits, neuropsychiatric symptoms, severe dysarthria or anarthria, and other limitations on medical decision-making capacity which can limit a patient’s ability to understand their own prognosis and participate in advance care planning conversations.

We will first review available evidence that can help clinicians prognosticate (I) functional prognosis and disease progression and (II) survival in dementia, PD, amyotrophic lateral sclerosis (ALS), and MS (Table 1). We will then discuss best practices for prognostic communication with patients with neurologic disease and their care partners. Finally, we will address gaps in the literature and suggest directions for future work. We present this article in accordance with the Narrative Review reporting checklist (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1338/rc).

Methods

For this narrative review, we conducted a search in the PubMed database with search terms outlined in Table 2 for articles published in English from 1965 through March 1, 2023. The authors selected literature including retrospective studies, prospective studies, systematic reviews, and qualitative studies about key prognostic factors in the diseases discussed below, and about prognostic communication. Additional literature was found through citations in articles identified in our search.

Prognostication in selected progressive neurologic diseases

Dementia

Dementia is characterized by cognitive decline, often affecting multiple cognitive domains, with resulting impairment in daily functioning. Alzheimer’s disease (AD) is the most common cause of dementia. Dementia with Lewy bodies (DLB) is the second most common, followed by frontotemporal dementia (FTD), vascular dementia, and PD dementia. The number of people with dementia worldwide has been projected to increase from 57.4 million in 2019 to 83.2 million in 2030 and 152.8 million in 2050 (10). As dementia progresses, patients develop increasing dependence on others for care, as well as possible agitation, incontinence, dysphagia, and physical frailty among other symptoms. The disease course and predominant symptoms can vary depending on underlying pathology though all etiologies listed above do continue to progress over time. While some causes of dementia, such as vitamin B12 deficiency, may be reversible with early treatment, we will focus here on progressive, non-reversible causes of dementia.

Functional prognosis

The progression of dementia is highly variable, contributing to difficulty predicting an individual patient’s future disease progression. Some studies have shown faster progression in early-onset AD compared to late-onset AD though evidence is mixed (11). Other factors, such as level of education, cognitive baseline, dementia type, and neuropsychiatric complications have had mixed evidence to support their influence on rate of progression (12).

Survival prognosis

Median survival time after diagnosis of dementia ranges from 3.2 to 6.6 years, with increasing age and male sex associated with increased mortality in dementia across multiple studies (13). One available scale to assess prognosis in AD is the Functional Assessment Staging Tool (FAST), a seven-stage scale with multiple sub-stages representing phases of functional decline in dementia (14). FAST stage 7c, defined by loss of unassisted ambulation, has been used as a marker of hospice eligibility in the United States. However, it has been recognized that these criteria may underestimate mortality among nursing home residents with dementia (15,16). The Advanced Dementia Prognostic Tool (ADEPT) is an alternative measure of mortality in advanced dementia which consists of a 1–32.5 point scale with points assigned for age, nursing home length of stay, male sex, dyspnea, presence of pressure ulcers stage two or greater, activity of daily living score, bedfast status for majority of the day, insufficient oral intake, bowel incontinence, body mass index (BMI) <18.5 kg/m², weight loss greater than 5% total body weight in the past 30 days or greater than 10% in the past 180 days, and congestive heart failure (15). When compared to standard US hospice eligibility criteria, ADEPT demonstrated better accuracy in predicting mortality in nursing home residents aged 65 and older with advanced dementia though still only moderate performance, with an area under the receiver operator curve for prediction of 6-month mortality of 0.67 when applied as a continuous measure, compared to 0.55 for Medicare hospice eligibility guidelines (15). For home-dwelling patients with advanced dementia, the Palliative Support DEMentia Model (PalS-DEM) has been developed to predict 1-year mortality (17). This model uses age, FAST stage, etiology of dementia, medical co-morbidities, stability of overall medical condition (stable, unstable, deteriorating, and terminal), and 30-day hospital readmission rates to generate a 0–14 point score, which is used to divide patients into low-, moderate-, and high-risk groups with median survival of 175, 104, and 19 days respectively. Of the included variables, age was the most important factor, with an average age of 84.8 years in low-risk patients and 89.9 years in high-risk patients in the study.

PD

PD is a neurodegenerative disease which has been predicted to affect over 12 million people worldwide by 2040 (18). Its hallmark motor symptoms including resting tremor, rigidity, bradykinesia or akinesia, and postural instability, though associated non-motor symptoms including depression and anxiety, cognitive impairment, hallucinations, and orthostasis can also contribute to disability and poor quality of life. Patients with PD have variable symptom burden; for some tremor is a predominant feature, for others gait instability, and some may be more burdened by non-motor symptoms. PD is associated with increased mortality though cause of death in persons with PD is heterogeneous, and has been difficult to study since PD is poorly captured on death certificates (19,20).

Functional prognosis

The clinical course of PD is heterogeneous, which contributes to challenges in predicting how well someone may live after a PD diagnosis, but there is some data that can help with prognostication efforts. While there has been some controversy regarding clinical subtypes in PD, the Parkinson’s Progression Markers Initiative study has identified three subtypes—mild-motor predominant, intermediate, and diffuse malignant which are characterized by scoring motor and non-motor symptoms (21). In one retrospective study these subtypes were adapted by rating symptom severity from absent to severely distressing to the patient or poorly controlled despite treatment and creating a symptom score from ratings of various motor and non-motor symptoms. The diffuse malignant subtype, characterized by a composite score of motor and non-motor symptoms in the 75^th percentile was associated with earlier development of recurrent falls, wheelchair dependence, dementia, and facility placement [hazard ratio (HR) 10.9], with a mean of 3.5 years from diagnosis to the first development of one of these milestones compared to 14.3 years in the mild-motor predominant subtype and 8.2 years in the intermediate subtype; and higher risk of death (HR 3.65), with mean survival from diagnosis of 8.1 years for the diffuse malignant subtype compared to 20.2 in the mild-motor predominant subtype and 13.2 years in the intermediate subtype (22). Consideration of clinical subtype at the time of diagnosis can direct patient counseling about future disease progression. Postural instability and cognitive impairment are significant symptoms leading to increased disability and care needs in PD. One prognostic model developed in Dutch and British cohorts of patients with newly diagnosed PD uses age, Unified PD Rating Scale (UPDRS) motor axial score, and semantic fluency measured by the animal fluency test to predict risk of postural instability, dementia, or death by five years from diagnosis (23). Higher age, motor score, and lower animal fluency were associated with increased probability of a poor outcome in this model, though the model does not specify for clinicians or patients whether the risk is for death, dementia, or postural instability.

Survival prognosis

Demographic characteristics including increasing age, male sex, and co-morbid diabetes mellitus, congestive heart failure, and pressure ulcers are associated with increased mortality in PD (24). There is an increased risk of death from pneumonia, and of fracture with subsequent complications and mortality (25,26). Dysphagia and postural instability gait difficulty subtype of disease have been associated with increased mortality in PD (27). It has also been shown that visual hallucinations, recurrent falls, dementia, and nursing home placement typically occur within four to five years of death in PD patients (28). Nursing home placement and development of these symptoms can be considered as potential “landmark” symptoms that may trigger discussions about expected disease progression and life expectancy. In one retrospective study of American military veterans with PD, underweight BMI and decrease in number of dopaminergic medications were seen more frequently in the six to twelve months prior to death (29). While this is the only study to our knowledge to have described dopaminergic prescribing patterns as an indicator of mortality, this points to de-escalation of medications, likely due to side effects such as hallucinations outweighing motor benefits, as another key point in disease progression that may trigger discussions about prognosis with patients and care partners.

ALS

ALS is a progressive neuromuscular disease involving upper and lower motor neurons, leading to progressive weakness, spasticity, dysarthria, dysphagia, and ultimately respiratory failure within three to five years (30). There are three to five cases of ALS per 100,000 people (30). Available treatments—riluzole, edaravone, and more recently sodium phenylbutyrate/tauroursodiol—yield a modest survival benefit at best (31,32).

Functional prognosis

In terms of neurologic prognosis, the site of symptom onset affects duration of time to respiratory failure, with bulbar onset ALS associated with a shorter life expectancy compared to limb onset ALS (30). Other factors known to affect prognosis in ALS include increased age at time of diagnosis and weight loss (31). Decreased pulmonary function portends poorer prognosis, with baseline forced vital capacity (FVC) less than 75% measured early in the disease course associated with median tracheostomy-free survival of 2.91 years compared to 4.08 years for patients with FVC greater than 75%, and with more rapid disease progression (8.0 months compared to 10.0 months to reach a 20-point increase in the Appel ALS score) in one trial (33). The Revised ALS Functional Rating Scale (ALSFRS-R), a 48-point rating scale assessing severity of various symptoms in ALS patients, can be of utility in prognostication as well. ALSFRS-R score at time of diagnosis and at time of non-invasive ventilation (NIV) initiation has also been correlated with survival (34,35).

Survival prognosis

One meta-analysis of predictors of survival in ALS identified age at disease onset (HR 1.03), change in ALSFRS-R (HR 2.37), executive dysfunction (HR 2.10), FTD (HR 2.98), respiratory disease subtype (HR 2.20), and higher levels of neurofilament light chain in serum and cerebrospinal fluid (CSF) as markers of poor prognosis (HR 3.70 in serum, 6.80 in CSF), though neurofilament light chain levels are not routinely checked and therefore are likely of little clinical utility in practice currently (36). A pure upper or lower motor neuron phenotype (HR 0.32), delay in diagnosis (HR 0.97), longer disease duration (HR 0.96), and baseline ALSFRS-R score (HR 0.95) were found to be predictors of good prognosis (36). The impact of long disease duration and delayed diagnosis is likely due a slower rate of disease progression leading to lower mortality. An externally validated personalized prognosis prediction model has been developed in the European population in which age at onset (HR 1.03), rate of change in ALSFRS-R score (HR 6.33), decrease in FVC (HR 0.99), bulbar onset disease (HR 1.71), definite ALS diagnosis (HR 1.71), presence of FTD (HR 1.34), and a C9orf72 repeat expansion (HR 1.45) were associated with shorter time to death, tracheostomy, or NIV over 23 hours daily, while delay in diagnosis was associated with reduced mortality risk (HR 0.52) (37). The model was used to define five prognostic groups: very long, long, intermediate, short, and very short times to death, tracheostomy, or NIV over 23 hours daily. This model demonstrated good agreement between predicted and observed time to the composite endpoint. Notably, this prognostic prediction model does not account for use of any ALS treatments such as riluzole, or for gastrostomy tube placement. Future work is needed to determine how these interventions may interact with other prognostic factors to influence life expectancy.

MS

MS is a chronic demyelinating disease of the central nervous system which may lead to progressive disability from multiple neurologic symptoms (38). There are an estimated 35.9 MS cases per 100,000 people worldwide, though prevalence varies by region, with the highest incidence and prevalence of MS in Europe and North America (39). Women are twice as likely as men to be affected by MS. MS is categorized into subtypes depending on symptom progression and clinical course (40). Relapsing remitting MS is characterized by periods of acute demyelination followed by slower recovery, though not necessarily return to prior baseline. Over time, patients may transition from a relapsing remitting course to secondary progressive MS, in which symptoms accumulate in a progressive manner with fewer or no acute flares. A minority of MS patients have primary progressive MS in which the disease takes a progressive course from the outset. MS patients are often treated with immune therapies to prevent disease progression and resulting disability though choice of therapy is very dependent on clinical subtype, with relapsing remitting MS having the largest number of available disease-modifying therapies.

Functional prognosis

Disease progression and functional prognosis in MS can be predicted to some degree based on demographic and clinical factors. In one prospective study of newly diagnosed MS patients followed for mean 9.78 years, a greater degree of disability at baseline; primary progressive disease course; involvement of a greater number of neurologic systems; greater involvement of visual, cerebellar, sphincter, and pyramidal systems; shorter time between a first and second disease flare; presence of oligoclonal bands (OCB) in CSF; and initial magnetic resonance imaging (MRI) findings suggestive or strongly suggestive of MS were associated with a shorter time to irreversible disability (41). An incomplete recovery after the first disease flare also portends a poorer prognosis, as does higher age and male sex (42). MRI findings can also guide prognosis, with a higher burden of T2-hyperintense lesions and gadolinium-enhancing lesions are associated with a worse functional prognosis in MS (43-45).

Survival prognosis

Patients with MS have been shown to have increased all-cause mortality compared to the general population, with a six- to ten-year decrease in life expectancy (46,47). In one population-based MS cohort, MS patients had a median life expectancy of 74.7 years compared to 81.8 years in the general population (46). There is an increased risk of death from infections such as pneumonia or urinary tract infection (48). These suggest that dysphagia and infectious complications may signal the terminal phase of disease, and warrant future investigation as possible prognostic indicators. In addition to increasing risk for progressive disease as mentioned above, cognitive dysfunction increases risk of mortality. With one retrospective study of an MS cohort followed for 8–16 years, patients with cognitive dysfunction at a regular visit had an increased mortality risk (HR 4.11). In subgroup analysis, patients with progressive MS and cognitive impairment were shown to have higher mortality risk (HR 3.68), while the higher risk of mortality in patients with relapsing remitting MS was not statistically significant (49). In one study, increased disability measured by the Expanded Disability Status Scale (EDSS) was associated with decreasing life expectancy, with severe disability and immobility associated with a life expectancy of slightly greater than one year (43).

Communicating prognosis

Clinicians vary in their willingness to discuss prognosis (50). This may be out of fear of causing anxiety or other negative emotions for patients and their care partners. However, while patient preferences will inevitably vary, many patients do want information about prognosis and discussions on advance care planning early in their care. This has been demonstrated in the PD population as well as in patients with terminal cancer and end stage renal disease (2,51-53). Even in ALS, an invariably terminal disease with relatively short life expectancy, there is evidence that prognosis can be discussed without causing undue negative impact, though the discussion must be tailored to individual needs and coping style (54).

There are multiple serious illness conversation tools available, such as SPIKES, the Ariadne Labs Serious Illness Conversation Guide, and MVP (Medical Situation, Values, and Plan) which can be applied to neurologic disease (55-57). Here we will discuss use of the MVP communication tool to discuss prognosis in neurologic diseases due to its demonstrated memorability and usefulness in medical students who had instruction in this model.

Medical situation

After the initial diagnosis of neurologic disease, some basic information about the typical disease course should be shared with the patient. For neurodegenerative disease such as ALS or PD, this will entail an honest discussion of the progressive nature of the condition, and the benefits and limits of available treatments. For more unpredictable diseases such as relapsing remitting MS, clinicians should share the range of possible outcomes, from minimal symptom burden to severe disability, and the role of disease-modifying therapy (4). After this initial disclosure of basic diagnostic and prognostic information, it may be useful to elicit patient and care partner preferences for timing, content, and style of future information sharing. An illustrative communication guide has been developed for discussion of personalized prognosis in ALS, which emphasizes the need for the discussion be tailored to patient needs and preparedness (54). The authors suggest that prognosis can be shared with varying levels of detail ranging from a general “risk group” without a clear life expectancy associated to more detailed statistics about expected survival. They also acknowledge the right of patients not to know their prognosis.

The need to address functional and longevity prognoses may lead to an overwhelming volume of information for a patient to take in, and close follow up visits may be beneficial early on. One Dutch clinic has described a two-tiered model of “bad news” disclosure for patients newly diagnosed with ALS and progressive muscular atrophy (58). At the initial visit a neurologist shares the diagnosis and a general overview of expected disease progression, future care needs, and treatment options. A second follow-up visit within two weeks a rehabilitation physician reviews this information again, describes the monitoring and care provided in the multidisciplinary clinic, and discusses advance care planning and patient wishes for end of life care. This can be applied to the new diagnosis of other chronic progressive neurologic conditions, or to significant changes in the medical situation that necessitate re-evaluation of care needs and the medical plan, such as development of dyspnea in ALS, significant immobility in MS, or a challenging hospitalization with subsequent functional decline. A close follow up visit can also provide opportunity for detailed discussion of topics that may have been overlooked at the first visit, such as non-motor symptoms in PD.

Given the unpredictable disease course in many neurologic diseases, uncertainty is a challenging but often necessary topic to address. In addition to a discussion of possible outcomes tailored to patient preferences for knowledge, fear of the unknown, avoidance of difficult topics, and denial about future adverse outcomes, among other barriers to communication, may arise in reaction to uncertainty. Some proposed communication strategies to address these barriers include requesting permission to open a dialogue or be direct about future possibilities (59).

Values

An understanding of patient and care partner values in the context of the medical situation is necessary to developing a goal-concordant plan. Because of the potential for long periods of significant disability in many neurologic diseases, it may be helpful to elicit any specific functions of particular value or importance to patients early on. For example, a young construction worker with MS might understandably fear substantial motor impairment and loss of livelihood. While patient values and preferences may change as the medical situation evolves, a sense of overarching patient values and care preferences is ideally obtained early in disease before cognitive impairment or communication barriers develop.

Plan

The plan follows from the medical situation and patient values. This may consistent of advance care planning, decisions about a specific medical intervention, or other interventions depending on patient needs and stage of disease. In one study of patients with PD and their care partners, participants expressed a desire for a “roadmap” of their illness that addresses the expected speed of disease progression, key “road markers” in the disease process such as loss of ability to drive or perform household tasks, and plans for future care needs (60). The MVP process can be repeated at key “road markers” as disease progresses and the medical situation evolves. Care partner involvement is critical in discussions around prognosis and associated advance care planning, as they will often serve as informed medical decision-makers if and when patients reach an advanced stage of disease and lose medical decision-making capacity. Care partners may also help to initiate and navigate advance care planning discussions (61).

Conclusions

Further research is needed to develop prognostication tools in chronic neurologic diseases to help assess what an individual patient’s disease progression and future symptom burden may be. Ideal prognostication tools would be applicable at the time of an initial diagnosis and later at key turning points in the disease process, such as the development of respiratory insufficiency in ALS or malnutrition in dementia, allowing patients and clinicians to re-visit the question of prognosis as disease progresses and patients and care partners may wish to re-visit advance care planning topics. Optimal prognostication models would address the question of how well someone can expect to live with their disease, expected onset of significant symptoms and disability, and life expectancy. Particularly for disease with a variable course, such as PD, MS, and dementia, we may never achieve indicators of the terminal phase of disease that are highly accurate on an individual level. Rather it may be more important to consider predictors of risk for death and other adverse outcomes as well as predictors of need. The goals of these tools may be to prioritize screening and sensitivity over specificity and accuracy to ensure timely referrals for end-of-life palliative care, to facilitate conversations around goals of care, and to allow families and patients the opportunity to avoid unwanted, unnecessary and unhelpful care such as hospitalizations near the end of life or placement in nursing facilities (62).

More work is also needed to understand patient and care partner preferences for timing, content, and style of prognostic communication in neurologic disease, and from this to develop more disease-specific communication tools that address the unique needs of neurologic patients.

Acknowledgments

Funding: This work was supported by the National Institute of Health (No. T32NS007338 to JC, No. AG062745 to BMK).

Footnote

Reporting Checklist: The authors have completed the Narrative Review reporting checklist. Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1338/rc

Peer Review File: Available at https://apm.amegroups.com/article/view/10.21037/apm-22-1338/prf

Conflicts of Interest: Both authors have completed the ICMJE uniform disclosure form (available at https://apm.amegroups.com/article/view/10.21037/apm-22-1338/coif). BMK serves as an unpaid editorial board member of Annals of Palliative Medicine from February 2023 to January 2025. BMK is the president of the International Neuropalliative Care Society. JC reports the funding from the National Institute of Health (No. T32NS007338). BMK reports the funding from the National Institute of Health (No. AG062745) and grants from PCORI- Initiating ambulatory palliative care in Center of Excellence 2021-2023, National Institute on Aging, and National Institute of Nursing Research. The author also got Royalties or licenses from Elsevier and received payment or honoraria for lectures, presentations, speakers bureaus, manuscript writing or educational events from American Academy of Neurology, Parkinson’s Foundation, International Parkinson and Movement Disorders Society, and Davis Phinney Foundation. The authors have no other conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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