Suspicious Neuroimaging Pattern of Thrombotic Microangiopathy

Discussion

Injury to endothelial cells is the inciting factor in the sequence of events leading to TMA. The cascade of the microangiopathic process is the following: loss of physiologic thromboresistance, leukocyte adhesion to damaged endothelium, complement consumption, abnormal vWF release and fragmentation, and increased vascular shear stress.² In TTP, thrombi formation occurs subsequent to the release of multimers of vWF. A specific plasma protease, the ADAMTS13 gene, is responsible for the physiologic degradation of vWF and plays a pathogenic role in a substantial proportion of familial and acute idiopathic cases of TTP.⁸ A deficiency in ADAMTS13 enzyme levels, along with an inhibitory antibody, is found in most patients with idiopathic TTP. Multiple triggers, such as infection, drugs, cancer, chemotherapy, bone marrow transplantation, and pregnancy, are recognized.⁹ In HUS, endothelial cell damage is considered the reason for complement and platelet activation leading to thrombus formation. Several complement genes are mutated in HUS.⁸

Multifocal TMA with intimal-medial dissection by thrombi extending from foci of endothelial damage in small cerebral arteries and arterioles can be secondary to toxins.^10,11 A drug as the toxin is a rare cause of TMA.¹² Antineoplastic therapy, the most reported agent being mitomycin, has been described as an etiology of renal TMA. The association of HIV and TMA is rare but well known; however, HIV-associated TMA is postulated to have a different pathophysiology than idiopathic TTP.¹³ Response to infection may generate antibodies that cross-react with platelet antigens. Platelet production may be impaired by infection of megakaryocyte bone marrow−dependent progenitor cells and decreased production of thrombopoietin.¹⁴ The classic toxin-induced TMA is HUS,¹¹ in which directed or receptor-mediated verotoxin-induced endothelial injury leads to infarction and hemorrhage. Most studies of CNS involvement with HUS have described basal ganglia lesions.^15–19 There are anecdotal reports of territorial infarction and diffuse white matter changes of PRES,^18–21 but they are thought to reflect complications rather than specific manifestations of the disease. The pathophysiology of HUS may be, in part, due to blood-brain barrier breakdown and subsequent edema.¹⁸ Peripheral cortical involvement has not been described as a predominant imaging pattern in HUS.

Although there is a common pathophysiology in TMAs of microvascular occlusion due to endothelial injury and thrombus formation, the clinical findings can be varied, depending on the underlying disease. These patients may present clinically with altered mental status, seizure, or neurologic deficits. The suspicious neuroimaging of multifocal cortical and subcortical hemorrhagic infarctions in correlation with the underlying disease and laboratory findings enables the diagnosis of TMA. Neurologic manifestation of HUS may be due to hypoxia²¹ secondary to metabolic derangements, such as hyponatremia, azotemia, hydration disorders, or due to hypertension.¹¹ As stated earlier, the incidence of TMA varies with the underlying diagnosis. Reviewing cases of TMA in our electronic data base for those with this particular imaging pattern showed a greater incidence in males with the most common diagnosis being DIC.

A systematic review of the literature was performed with a focus on those articles discussing TMA involving the CNS. In our retrospective review, DIC (82%) was the most common TMA.⁴ DIC is associated with many comorbidities including infection, neoplasm, vascular abnormalities, obstetrical and neonatal complications, massive tissue injury, and drug reactions. Clinically, DIC is typified by thrombosis and/or hemorrhage at multiple sites. Characteristic laboratory findings include thrombocytopenia, decreased fibrinogen, increased prothrombin time, and abnormalities in tests for fibrinolysis. In 1980, Buonanno et al⁷ described a series of 9 patients with DIC in whom venous thrombosis predominated as the most common imaging abnormality. The 2 patients with cross-sectional imaging had lobar hemorrhages.The second most common TMA in our retrospective review was mHTN. Patients with mHTN present with elevated blood pressure and papilledema, often with retinal hemorrhage and exudates.²² The most common reported neuroimaging findings are PRES, parenchymal hemorrhage, and infarctions. Garewal et al³ recently reported a case of mHTN presenting with extensive bilateral peripheral infarctions and hemorrhage with pathologic confirmation of a thrombotic microangiopathy. The least common TMA in our retrospective review, TTP, is characterized clinically by thrombocytopenia, microangiopathic hemolytic anemia, neurologic symptoms, fever, and renal dysfunction. This pentad of signs and symptoms is rarely present in its entirety, and often the triad of thrombocytopenia, elevated lactate dehydrogenase, and schistocytosis is sufficient to suggest the diagnosis.⁴ In a review of 12 patients with TTP, Bakshi et al⁶ described 3 imaging patterns: frank hematoma, ischemic infarctions, and reversible bilateral cerebral edema (similar to PRES). In a case report, D'Aprile et al²³ described reversible multifocal gray matter edema. Gruber et al²⁴ presented a case report of multiple small areas of cortical infarction. TTP may manifest as multiple punctate T2 hyperintensities in the cerebral white matter.²⁵ Garewal et al³ described ischemic infarctions in the cortical and subcortical regions and PRES as the most characteristic neuroimaging finding in TTP.

There is possible parallel and/or overlap in the pathophysiology of TMA and PRES. One proposed mechanism of PRES is that severe hypertension leads to failed autoregulation and subsequent hyperperfusion with endothelial injury and vasogenic edema.²⁵ The other hypothesized etiology is vasoconstriction and hypoperfusion resulting in brain ischemia and subsequent vasogenic edema.²⁶ There are numerous pathologies, such as preeclampsia/eclampsia, allogenic bone marrow or organ transplantation, autoimmune disorders, and chemotherapy, recognized to produce the characteristic CT/MR imaging focal of regions of symmetric hemispheric edema, predominantly involving the parietal and occipital lobes.²⁷ The basic pattern of PRES resembles watershed zones, with cortex and subcortical and deep white matter involvement to varying degrees. Histopathologic evidence of acute and chronic vessel injury has been described in postmortem studies, including intimal thickening, segmental vessel narrowing, intimal dissection, and organized thrombi.²⁸ This supports a pathologic process similar to that of TMA. Minute hemorrhages as well as focal hematoma and sulcal hemorrhage can be seen with PRES.²⁹ Excluding patients with allogenic bone marrow transplant, we noted no correlation between blood pressure and hemorrhage in PRES.²⁹ Furthermore, Hefzy et al²⁹ found no statistical significance in the coagulation state between hemorrhagic and nonhemorrhagic patients with PRES. The multifocal hemorrhages may be due to postischemic reperfusion injury.³⁰ This differs in comparison with the subjects in our case series who had coagulopathy (ie, DIC and TTP) or elevated blood pressure (ie, mHTN).

Due to the retrospective nature of this work, there are several caveats. First, our cases have this distinct pattern of peripheral cortical and subcortical hemorrhagic infarction, and the diagnosis of TMA was confirmed with laboratory and clinical data. Biopsy was not feasible in these patients with coagulopathy. The small number of patients and the method of data acquisition (electronic data base and teaching files) preclude ascertaining a definite incidence of TMA in our case series. Minute hemorrhages can be absent on initial CT examinations.²⁹ GRE and SWI sequences were not performed on every patient; therefore, subtle minute hemorrhages in a cortical and subcortical distribution may not have been detected on CT or conventional MR imaging. In patients with suspected TMA, the initial CT may be negative for hemorrhage; however, MR imaging can more sensitive for intraparenchymal hemorrhage, particularly echo-planar imaging−GRE T2*-weighted sequences.³¹ This increased MR imaging sensitivity for parenchymal hemorrhage is depicted in Fig 1. Even more advanced SWI sequences appear to be 3–6 times more sensitive than conventional T2*-weighted GRE sequences in detecting subtle minute hemorrhages.^32,33 It is feasible, therefore, that patients with the particular imaging pattern described herein may not have been included. Last, our distribution of underlying disease is a reflection of our adult patient population. HUS is predominantly a childhood disease and was not seen in our referral base.