In adults, complement clears excess neurotransmitters and old proteins from the brain and helps to regulate neurogenesis. Now, new findings indicate that patients with previous complement-mediated thrombotic microangiopathy (CM-TMA) have impaired memory and concentration as well as significant, albeit nonspecific, cerebral white matter abnormalities. Pauline Kosalka, MD, a resident at Western University in Canada, and colleagues reported that these neurologic and neurocognitive complications persist in survivors of CM-TMA for months to years after they achieve remission. The researchers published their findings in Blood Vessels, Thrombosis & Hemostasis.
For their study, the investigators used consecutive MRI to evaluate structural changes in the brains of seven patients with a clinical diagnosis of primary CM-TMA who were or had been treated with anti-C5 blocker. They compared the findings to those from six healthy controls. The researchers followed patients for 12 months after study entry and evaluated them with not only structural and quantitative MRI but also standard cognitive and depression testing.
T1 and T2 changes on MRI correlate with white matter edema, axonal loss, neuroinflammation, and early demyelination. The researchers found that several of the patients had white matter changes in the frontal lobe that correlated with cognitive impairment in concentration and short-term memory. These findings persisted for as long as 12 months after the initial study visit. Patients also had abnormalities in depression testing, which the authors proposed could be related to the cingulate and insula abnormalities detected on their scans.
Senior investigator Shih-Han Huang, MD, a nephrologist at Western University, explained that their small exploratory study was the first to evaluate the neurocognitive effects of this rare disease and document long-term structural abnormalities. For example, the researchers described two patients who initiated complement inhibitor therapy a few months after diagnosis and had increased T1 and T2 signals on Z-score maps when compared to subjects who received timely initiation of complement inhibitor therapy. In addition, the three patients in the study with genetic mutations did not show any improvement in neuroimaging despite treatment with complement blockade.
“It’s a scary and devastating disease,” said Dr. Huang, who initiated the study in response to patient complaints about difficulties with concentration and depression. Her analysis addressed the question, “Why are these patients still having symptoms even though everything looks good on the blood panel?” While Dr. Huang anticipated the results, “We were surprised to see how severe the damage is,” she said.
The new findings build on previous research that documented persistent neurologic abnormalities in patients with thrombotic thrombocytopenic purpura (TTP) despite hematologic remission. Dr. Huang explained that complement disorders such as CM-TMA and TTP can cause small vessel disorders that can appear like mini-strokes throughout the brain. Most clinicians look to the platelet counts of patients with CM-TMA to determine if the patient is doing well, but the new results suggest that even if the patient’s platelet counts have normalized, “sometimes disease activity is still going on in the background.”
Dr. Huang described the findings as a wake-up call to physicians. She said there are more aspects to the pathophysiology of CM-TMA than just platelets, and these symptoms should be monitored. She suggests that patients receive baseline brain imaging and, if possible, be routinely monitored for their mood and cognitive outcomes. She encouraged clinicians to continue monitoring symptoms after stopping treatment and re-evaluate the need to initiate treatment even if the platelet count is normal. More studies are needed to understand diseases like CM-TMA and TTP and the long-term health consequences to these young patients, she concluded.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
Kosalka PK, Hannan F, Hamilton J, et al. Characterizing the association between complement-mediated thrombotic microangiopathy and cognitive dysfunction using MRI and neurocognitive assessment [published online ahead of print, 2024 June 24]. Blood Vessels, Thrombosis & Hemostasis. doi: 10.1016/j.bvth.2024.100016.
