Cerebral vascular injury in transplant-associated thrombotic microangiopathy

Abstract

Transplant-associated thrombotic microangiopathy (TA-TMA) and atypical hemolytic uremic syndrome (aHUS) are complement-mediated TMAs. The central nervous system (CNS) is the most common extrarenal organ affected by aHUS, and, despite mechanistic overlap between aHUS and TA-TMA, CNS involvement is rarely reported in TA-TMA, suggesting that CNS involvement in TA-TMA may be underdiagnosed and that these patients may benefit from complement blockers. In addition, there are no widely used histologic or radiologic criteria for the diagnosis of TMA in the brain. Thirteen recipients of pediatric hematopoietic cell transplants (HCTs) who had TA-TMA and who underwent autopsy were studied. Seven of 13 brains had vascular injury, and 2 had severe vascular injury. Neurologic symptoms correlated with severe vascular injury. Classic TMA histology was present and most often observed in the cerebellum, brainstem, and cerebral white matter. Abnormalities in similar anatomic regions were seen on imaging. Brain imaging findings related to TMA included hemorrhages, siderosis, and posterior reversible encephalopathy syndrome. We then studied 100 consecutive HCT recipients to identify differences in neurologic complications between patients with and those without TA-TMA. Patients with TA-TMA were significantly more likely to have a clinical concern for seizure, have an electroencephalogram performed, and develop altered mental status. In summary, our study confirms that TA-TMA involves the brains of recipients of HCT and is associated with an increased incidence of neurologic symptoms. Based on these findings, we propose that patients with low- or moderate-risk TA-TMA who develop neurologic complications should be considered for TA-TMA–directed therapy.

Reeling in complement in transplant‐associated thrombotic microangiopathy: You're going to need a bigger boat

“…These observations are also relevant to the study of vascular injury in the brain secondary to complement‐mediated TMAs. Neurologic symptoms are common in complement‐mediated TMAs and Sabulski et al described widespread histologic evidence of central nervous system vascular injury and subsequent tissue damage in patients with TA‐TMA and neurologic symptoms 105 . Acute demyelinating conditions can occur after HSCT as part of post‐transplant dysimmunity and demyelination patterns were also seen in the brains of TA‐TMA patients.…”

“…Neurologic symptoms are common in complementmediated TMAs and Sabulski et al described widespread histologic evidence of central nervous system vascular injury and subsequent tissue damage in patients with TA-TMA and neurologic symptoms. 105 Acute demyelinating conditions can occur after HSCT as part of post-transplant dysimmunity and demyelination patterns were also seen in the brains of TA-TMA patients. These conditions carry significant morbidity and there are currently no good therapy options outside of steroids, immunoglobulin infusions and/or CD20 targeted therapy for B-cell eradication.…”

Thrombotic microangiopathy – the importance of a multidisciplinary approach

“…Importantly, TA-TMA MODS can involve the central nervous system, producing severe vascular injury. TA-TMA should therefore be included in the differential diagnosis when neurologic complications arise in the posttransplant state [23].…”

Thrombotic Microangiopathy After Hematopoietic Stem Cell and Solid Organ Transplantation: A Review for Intensive Care Physicians

“…While neurological toxicity is frequently associated with other TMAs (like TTP and complement-mediated TMA), it is not commonly reported in TA-TMA. 68 Neurological symptoms, including seizures and mental status changes, can indicate the presence of cerebral vasculopathy leading to intracranial hemorrhage, iron deposition, and posterior reversible cerebral encephalopathy. 68 A pediatric case with TA-TMA-associated refractory epileptic seizures and permanent neurological deficits has also been described in the literature.…”

“…68 Neurological symptoms, including seizures and mental status changes, can indicate the presence of cerebral vasculopathy leading to intracranial hemorrhage, iron deposition, and posterior reversible cerebral encephalopathy. 68 A pediatric case with TA-TMA-associated refractory epileptic seizures and permanent neurological deficits has also been described in the literature. 69 Sickle cell disease is associated with chronic inflammation and endothelial dysfunction, which may make these patients especially susceptible to cerebral vasculopathy leading to posterior reversible cerebral encephalopathy after HSCT.…”