Brain Lesion Pattern May Guide Diagnosis of Rare Disorder

Patterns of white matter hyperintensities (WMHs) in patients with reversible cerebral vasoconstriction syndrome (RCVS) may offer clues to diagnosing this rare but severe condition, new research suggests.

Investigators studied 65 adult patients with RCVS using MRI and found the total WMH load changed dynamically in parallel with disease severity, peaking during the third week after onset of the condition and then falling in the fourth week.

Moreover, these WMHs were predominantly located in the frontal and periventricular areas of the brain and differed in location from the locations of other neurologic conditions, such as migraine.

"The key message of this study is that these RCVS-related WMHs have disease-specific dynamic changes that could, at least partially, be reversible within the 4-month observation period, providing reassurance to patients and clinicians," Shih-Pin Chen, MD, PhD, attending physician, Department of Neurology, Neurological Institute, Taipei Veterans General Hospital, told Medscape Medical News.

"The dynamics of WMHs are associated with the severity of vasoconstriction during the acute stage of the disease, and prompt evaluation and treatment of the disease might alleviate potential burdens of the brain," he said.

The study was published online June 4 in JAMA Neurology.

Challenging Diagnosis

RCVS is "a neurovascular disorder characterized by abrupt, severe (mainly thunderclap) headaches and reversible segmental vasoconstriction of cerebral arteries," the authors write.

WMHs or leakage of the blood-brain barrier may be the only imaging findings in these patients, who do not have overt vasoconstrictions on initial angiographic studies, "making diagnosis challenging."

"In clinical practice, we observed that a very high proportion of patients with RCVS have WMHs in their brain, and it seems that these lesions could wax and wane along the disease course," said Chen.

"As clinicians, we are often asked by the patients regarding the nature and potential impact or these lesions, especially when accumulating data have shown that WMHs in the general population are associated with increased risks of stroke, dementia, and death," he added.

"Hence, we set forth this study to investigate whether these RCVS-associated WMHs have disease-specific spatiotemporal distribution and also to explore their possible pathogenesis."

The study included 65 patients with RCVS (mean [standard deviation (SD)] age, 50.1 [8.9] years).

Patients underwent clinical, neuroimaging, and laboratory investigations to exclude all other potential causes of thunderclap headaches. They also received oral or intravenous nimodipine therapy with closed blood pressure monitoring immediately upon diagnosis.

In additional, patients underwent sequential MR angiography and transcranial color-coded sonography to ensure the reversibility of the vasoconstrictions.

They were then followed up regularly until they stopped having thunderclap headache attacks and the vasoconstrictions improved markedly or resolved completely.

In additional to the MRI sequences routinely obtained for patients with RCVS, the researchers also obtained isotropic three-dimension FLAIR sequences with a 1-mm slice thickness, using a 3-T MRI machine to enable identification of WMHs at the time of study enrollment and at follow-ups (which were performed at 1 and/or 3 months after study entry).

To investigate potential correlations between clinical characteristics, severity of vasoconstriction, and regional WMH volume, the researchers analyzed periventricular and deep WMHs separately.

They also divided the brain into 13 subregions based on major anatomic segments: bilateral frontal lobes, parietal lobes, limbic areas, subcortical areas, temporal lobes, occipital lobes, brainstem, and cerebellum.

The researchers manually removed any lesions attributable to ischemic stroke, intracerebral hemorrhage, or posterior reversible encephalopathy syndrome (PRES) from the analysis.

Disease Marker

Participants underwent a total of 162 MRI examinations; 33 patients had 2 scans and 32 had 3 scans.

Of the patients, 11% had a history of hypertension, 43% experienced blood pressure surges during headache attacks, and 25% had a history of migraine.

Half of the women were postmenopausal, and 5% were receiving hormone therapy at RCVS onset.

Six of the patients (9%) had secondary causes or associated conditions, including ingestion of pseudoephedrine or sibutramine, massive blood transfusion, and right vertebral artery dissection.

Two of the six patients had PRES, one had intracerebral hemorrhage, one had ischemic stoke, and another had cortical subarachnoid hemorrhage.

The first image was taken a mean of 12.2 (SD, 7.0) days after disease onset.

In almost all the cases (98.5%), WMHs were observed on the initial isotropic three-dimension FLAIR image.

The WMHs were located predominantly in the frontal lobe (40% - 52%) and the periventricular areas (68% - 80%) at all time points but were scarce in the brainstem and cerebellum.

The total WMH volume over the disease course was dynamic.

Maximal WMH volume (mean [SD] volume, 3.05 [4.35] cm³) took place during the third week after headache onset, with a similar change in volume dynamics in periventricular (but not in deep) WMHs.

Like total WMHs, the frontal, parietal, and limbic areas of the brain also exhibited maximal changes in the third week, but the dynamic changes were not statistically significant in temporal, occipital, or subcortical areas.

This temporal trend remained in the periventricular frontal and limbic WMHs, even after being analyzed separately.

WMH volume was significantly decreased (mean reduction, −0.66 [SD, 1.31] cm³; 95% confidence interval, −0.99 to −0.34 cm³; P < .001) when WMH loads on the final MRI scans were compared with the corresponding initial scans in all patients.

There was a strong correlation between the Lindegaard index, measuring vasoconstriction severity, and WHM load during the second week of the disease course (r = .906; P < .001), which was found in periventricular as well as deep white matter.

However, although the correlation remained "remarkable" in the third week (r = .640; P = .008), it became "marginal" when the SMHs were divided into periventricular and deep subgroups.

WMH also correlated with the pulsatility and resistance indices of the internal carotid artery, with a particularly strong correlation in periventricular frontal white matter.

"WMHs in RCVS may be attributed to regional hypoperfusion and transmission of high pulsatile flow to microcirculation," the authors summarize.

"Our findings were mostly consistent with our hypotheses, which were based on clinical observations, namely that the WMHs in RCVS have unique spatiotemporal evolution that is distinct from aging or other neurological disorders, and we speculate that the WMH load might be a disease marker to a certain degree," Chen commented.

He acknowledged being surprised by the finding that the correlation between WMH loads and the severity of vasoconstriction (ie, the Lindegaard index) was exceedingly high during the second week of the disease course, "indicating that a FLAIR imaging during the acute stage of disease might allow us to 'visualize' the severity of disease directly from the brain."

Helpful Diagnostic Tool

Commenting on the study for Medscape Medical News, Nuri Jacoby, MD, attending physician in neurology, Maimonides Medical Center, and assistant professor of neurology, SUNY Downstate College of Medicine, Bronx, New York, who was not involved with the study, called it "well-designed," noting that it is "the first study that looked at the timing of the WMHs as well as their reversibility."

The study "cleverly used bias-free methods of WMH quantification and segmentation," Jacoby observed.

Jacoby noted that the study makes several important contributions.

"If a brain MRI in a patient who presents with thunderclap headaches shows WMHs, it is very helpful to better characterize the location of the hyperintensities in RCVS as compared to other etiologies, which may point clinicians to a correct diagnosis, as WMHs are nonspecific and present in many other diseases," Jacoby said.

"Immediately applicable take-home messages for practicing physicians are that WMHs are very common in RCVS and tend to be periventricular and in the frontal lobes" and "the WMHs are at least partially reversible, an important point to emphasize to patients."

Chen added that future research will continue to focus on "better characterization of the dynamic neurovascular changes, using novel neuroimaging techniques" and "explore the underlying mechanisms, combining systems biology approaches."

This work was supported by grants to several researchers by several divisions of the Taiwan Ministry of Education, the Taipei Veterans General Hospital, theMinistry of Science and Technology of Taiwan, and the Ministry of Science and Technology of Taiwan for the Center for Dynamical Biomarkers and Translational Medicine of National Central University, and the Ministry of Health and Welfare of Taiwan. Chen received research grants from Taipei Veterans General Hospital and the Ministry of Science and Technology of Taiwan. The other authors' disclosures are listed on the original paper. Jacoby has disclosed no relevant financial relationships.

JAMA Neurol. Published online June 4, 2018. Abstract

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