Is There Equipoise Regarding the Optimal Medical Treatment of Patients with Asymptomatic White Matter Hyperintensities?

Abstract

Background and Purpose:

MRI-detected white matter hyperintensity (WMH), or leukoaraiosis, is a manifestation of ischemic microvascular disease that is prevalent in over 70% of community-based adults over 60 years of age. The approach to medical management of WMH in otherwise asymptomatic, stroke-free adults remains unknown.

Methods:

We conducted a survey of the providers in the NINDS StrokeNet to gauge enthusiasm for clinical research to better define the management of WMH. A 7-question survey was emailed to the 29 Regional Coordinating Centers of the StrokeNet, who disseminated the survey to providers “involved in the care of a patient after their stroke.”

Results:

We received 136 responses. There was considerable equipoise regarding specific stroke prevention therapies, including aspirin, statins, or blood pressure target, with no single option receiving >50% endorsement and between 15–32% of respondents choosing the option of “not sure.” Respondents noted significant interest in a trial targeting this patient population, with 83% of respondents indicating moderate to high enthusiasm.

Conclusions:

Stroke providers in StrokeNet, who would be a vital stakeholder in WMH research, routinely encounter such patients and enthusiastically support a clinical trial to resolve open questions on optimal medical management.

Introduction

White matter hyperintensity (WMH) on MRI, also called leukoaraiosis, is a common manifestation of chronic ischemic microvascular disease that is prevalent in over 70% of community-based adults over 60 years of age.^1–4 For asymptomatic patients, WMH heralds greater risk of long-term functional disability related to cognitive impairment, stroke, gait instability, and falls.⁵ The cognitive manifestations of multifocal ischemic white matter injury were first described by the Swiss neurologist Otto Binswanger in the late 19^th century.⁶ The terms leukoaraiosis and WMH entered the medical lexicon in the late 1980s, when advancing neuroimaging techniques allowed their identification and correlation with a multitude of clinical manifestations and risk factors such as hypertension and dyslipidemia.^7–9 The number of publications on WMH, leukoaraiosis, and Binswanger’s disease has increased exponentially in the last decade as the focus transitioned from epidemiologic to interventional research. Despite the link between the preponderance of vascular risk factors and burden of WMH, no expert consensus or guidelines exist with regard to medical management of WMH in otherwise asymptomatic, stroke-free aging adults.

Aggressive control of hypertension, the best established WMH risk factor apart from age, was recently shown to reduce WMH progression in the SPRINT MIND trial.¹⁰ However, the ideal blood pressure target and other potential interventions such as statins or aspirin have not been fully investigated in stroke-free patients with moderate to severe WMH, a group that is highly relevant to clinical practice. Thus, we sampled the current opinions and treatment practices of stroke clinicians for the management of asymptomatic patients with moderate to severe WMH.

Methods

We conducted a survey of the providers in the NINDS StrokeNet to better understand current medical treatment for patients with asymptomatic WMH and enthusiasm for a clinical trial in this patient population. A link to the 7-question survey was emailed to the 29 Regional Coordinating Centers of the StrokeNet, who disseminated the survey to providers “involved in the care of a patient after their stroke.” The survey was hosted on a secure website and accessible for one month. Questions 1–4 had an associated reference case with a moderate WMH burden and were designed to gauge practice patterns for patients with asymptomatic WMH (Table 1). Questions 5–7 probed issues relevant to the approach and feasibility of conducting clinical research with this patient population (Table 2).

Table 1.

Survey questions 1–4 with reference case.

	72 year old female with hypertension is referred for a neurological evaluation of episodic vertigo. The patient has no history of clinical stroke, cognitive impairment, or other neurologic disease. Her PCP obtained an MRI (shown on left), which is significant for a moderate burden of chronic microvascular disease. By the time the patient is seen in neurology clinic her episodic vertigo has resolved, but she has questions about the MRI findings.
Question	Response 1	% (n)	Response 2	% (n)	Response 3	% (n)
Q1. Would you consider this a case of primary or secondary stroke prevention?	Primary stroke prevention	64 (87)	Secondary stroke prevention	25 (34)	Not sure	11 (15)
Q2. Does this patient have a neurologic indication for aspirin?	Yes	46 (62)	No	22 (30)	Not sure	32 (44)
Q3. What would your systolic blood pressure goal be for this patient?	<140 mm Hg	27 (36)	<130 mm Hg	46 (62)	<120 mm Hg	27 (37)
Q4. The patient has an LDL of 95. Would you recommend statin therapy?	Yes	43 (57)	No	43 (57)	Not sure	15 (20)

Table 2.

Survey questions 5–7.

Question	Response 1	% (n)	Response 2	% (n)	Response 3	% (n)	Response 4	% (n)
Q5. How many patients a month with at least a mild burden of white matter hyperintensity and no history of stroke do you see in your inpatient and outpatient practice?	0/month	7 (9)	1–3/month	47 (61)	4–8/month	27 (35)	>8/month	19 (25)
Q6. Please indicate your enthusiasm for a clinical trial that enrolled patients similar to our example and evaluated the efficacy of aggressive risk factor control and/or aspirin?	High enthusiasm	46 (61)	Moderate enthusiasm	37 (49)	Low Enthusiasm	13 (17)	No enthusiasm	5 (7)
Q7. Relying on your experience treating patients similar to our example, how important would the following outcomes be for patients with asymptomatic white matter hyperintensities in a trial of aggressive risk factor control and/or aspirin ?
Q7 sub-question	Not important % (n)		Low importance % (n)		Medium importance % (n)		High importance % (n)
Reduction of ischemic stroke risk	1 (1)		3 (4)		21 (28)		75 (101)
Reduction of mild cognitive impairment/dementia	1 (1)		3 (4)		25 (33)		72 (96)
Increase in intracerebral hemorrhage	1 (1)		17 (23)		34 (45)		48 (63)
Reduction of development of gait imbalance	1 (2)		20 (27)		46 (61)		33 (44)
Increase in cerebral microbleeds on MRI	4 (5)		32 (43)		37 (50)		27 (36)
Reduction of white matter hyperintensity progression	8 (11)		28 (37)		44 (59)		20 (27)

Results

We received 136 responses. The majority (64%) indicated that our reference case would meet their definition of primary stroke prevention. Regarding specific stroke prevention therapies, including aspirin, statins, or blood pressure target, there was equipoise, with no single option receiving >50% endorsement and between 15–32% of respondents choosing the option of “not sure.” Providers reported that they encounter a moderate volume of patients with at least a mild WMH burden and no history of stroke. Respondents noted significant interest in a trial targeting this patient population with 83% of respondents indicating moderate or high enthusiasm. Respondents ranked the clinical outcomes of reduction in ischemic stroke and development of cognitive impairment or dementia as high importance (>70% endorsement), while the remaining radiographic, safety, and clinical endpoints all failed to reach 50% endorsement as high importance.

Discussion

Our survey establishes meaningful practice patterns and attitudes that can inform future WMH research. There is considerable equipoise regarding what constitutes optimal medical treatment for patients with asymptomatic WMH. Stroke providers in StrokeNet, who would be a vital stakeholder in WMH research, routinely encounter such patients and enthusiastically support a clinical trial to resolve open questions on optimal medical management. The time for a clinical trial to examine pragmatic, evidence-driven approaches to management of WMH in stroke-free adults, a common clinical scenario with a high potential impact on the overall population’s brain health, is now.