The image above shows extensive cerebral white matter hyperintensities (WMH). We commonly call this “microvascular disease” with the notion, implicit or explicit, that they are caused by the usual vascular risk factors of hypertension, diabetes, dyslipidemia, etc. This past January, Dr. Joanna Wardlaw, receiving the the William M. Feinberg Award for Excellence in Clinical Stroke, delivered a very interesting lecture arguing against this. Citing evidence that less than 2% of the variance in WMH burden is attributable to the usual risk factors, she advanced several other possibilities. One is that the findings are due to blood-brain barrier disruption, allowing water to leak into the perivascular space. Other associations / possible contributing factors include increased arterial pulse pressure and decreased vascular reactivity. She goes on to show that the lesions aren’t always permanent and she describes some promising treatment modalities.
It’s an informative article, and I recommend it in particular because it forces us to get back to basics in a few ways. First, this common and sometimes vexing problem of WMH serves as a reminder that clinical, radiological, and pathological diagnoses are not identical. A stroke is a clinical event. A focus of restricted water diffusion (high DWI signal) is a radiological finding. An infarct is a pathological finding. Conflating these, such as by saying, “We saw the stroke on MRI”, can lead to misdiagnosis, since not everything that appears bright on DWI is an infarct. And even if the lesion seen on MRI is an infarct, it may or may not be the cause of the patient’s presenting symptoms. That’s why residency training programs (should) emphasize the traditional neurological formulation: First, frame the problem succinctly (e.g., “This is an elderly woman presenting with the sudden onset of left hemiparesis”). Second, localize the lesion. Third, develop a differential diagnosis. Having the formulation clearly in mind will guide both the selection and the interpretation of imaging and other diagnostic testing.
Further, Dr. Wardlaw’s paper provides an impetus to review the classic literature on the subject of microvascular disease. As she states in her talk, “Reading original observations is always valuable because subsequent interpretations may drift from the original over time”. In this case, the must-read papers are by C. Miller Fisher, who, in the 1950s and 1960s, painstakingly made thousands upon thousands of ~ 10 micron thick sections of autopsied brains, starting at the “softening” (lacunar infarct) and tracing the feeding vessel back to find the point of occlusion. One was not always apparent (present in 45/50 lesions in his classic, “The Arterial Lesions Underlying Lacunes“). Most occlusions were caused by what he termed “segmental arterial disorganization”, and he noted that “Others have termed this condition hyalinosis, angionecrosis with aneurysm formation, plasmatic destruction, fibrinoid necrosis, fibrinoid arteritis, etc.” It’s a great paper–I highly recommend it.
Other classics by Fisher include: