From this case series, we report two patients with severe AN who presented with ischemic stroke associated with a hypercoagulable state. These cases provide novel insights: clinicians should suspect development of ischemic stroke in patients with severe AN receiving intensive care, and specific approaches such as rehydration would be required in AN patients with an ischemic stroke.
First of all, our case reports suggest that patients with severe AN are at a higher risk of developing ischemic stroke than the general population. Based on the estimated annual incidence of juvenile (age 15-49 years) stroke of 10.8/100 000 (range 8.4 to 13.0) and men being at a higher risk than women(9), the incidence rate in our cohort (2/19) seemed to be higher than that in the general population. Our cases suggest that careful management, especially in the presence of neurological deficits, is needed for patients with severe AN.
In general, dehydration is thought to be involved in the occurrence of ischemia. Some researchers have suggested that dehydration may be an independent risk factor for in-hospital/postoperative ischemic stroke(10)(11). Moreover, dehydration combined with low blood pressures seems to induce cerebral hypoperfusion, which can exacerbate ischemic stroke(12). Our cases presented here showed high values of the BUN/Cre ratio (approximately 40) associated with a low blood pressure, suggesting that dehydration was the primary pathophysiologic mechanism underlying the development of ischemic stroke. However, there are currently no consensus diagnostic criteria for dehydration in patients with stroke. The BUN/Cre ratio is the most commonly used laboratory marker of dehydration(12); meanwhile, the BUN/Cre may overestimate dehydration in patients with AN, due to the decreased muscle volume(13). The values of BUN were nearly within normal range in our cases, indicating that other possible mechanisms might also exist. According to previous reports, dehydration was associated with a poor prognosis and functional outcome after acute ischemic stroke(14), and early rehydration therapy during acute ischemic stroke could improve the prognosis and the functional outcome(15). However, we were unable to apply these findings to patients with AN, since congestive heart failure is a common complication associated with refeeding syndrome(4). In our cases, water restriction to 1 ml/1 kcal was well tolerated, without the development of any cardiac complications. Rehydration therapy with careful monitoring is necessary, and further studies are warranted to establish the prevalence of dehydration and design a rehydration protocol for acute ischemic stroke in patients with severe AN.
In our presented cases, the elevated levels of βTG4/PF4 and TAT reflected increased platelet activation and thrombin formation, respectively, indicating that lacunar infarction was unlikely in our patients, since lacunar infarction is not known to be associated with a hypercoagulable state(16–18). Our extensive workup to determine the etiology of the cerebral infarction revealed no source of embolism. Based on these profiles, this case report suggests that ischemic stroke in cases of severe AN seems to be caused by arteriosclerosis. In fact, patient 1 might have had arteriosclerosis, because her CAVI and ABI were elevated. A previous report indicated that patients with AN had an increased platelet distribution width (PDW; an index of platelet size heterogeneity), suggestive of dysregulated thrombopoiesis(19). There have been no studies on the relationships between the PDW and ischemic stroke; however, a significant association has been reported between increased PDW and a high risk of myocardial infarction, suggesting that increased PDW may induce arteriosclerosis(20). As for dysfunction of the coagulation system, little has been reported on parameters of the coagulation profile, especially the plasma levels of thrombin, in patients with AN. Our cases presented here suggest that severe AN patients have systemic arteriosclerosis due to impaired platelet function and coagulopathy, which is consistent with previous reports(6,7).
The relationships among dehydration, arteriosclerosis, and severe malnutrition are quite complex. As described above, undernourishment in association with severe AN may induce hypoperfusion due to dehydration and arteriosclerosis in association with platelet dysfunction. On the other hand, hypovolemia caused by dehydration can elevate the plasma aldosterone level, which has been linked to vascular stiffening(21), and dehydration itself may be associated with cardiovascular disease through impaired endothelial function(22). These ideas are summarized in Figure 2.
This case report includes several limitations. First of all, this study was conducted at a single general hospital. Multicenter studies are warranted to establish the best treatments for ischemic stroke in patients with AN. Second, not all patients included in our cohort had undergone MRI assessments, because of insufficient equipment. Third, ischemic stroke secondary to paradoxical embolism could not be excluded, because transesophageal echocardiography was not performed in the patients; however, we consider it as having been unlikely as our patients showed relatively low serum D-dimer levels.
In conclusion, we report here two patients with severe AN with ischemic stroke caused by hypoperfusion and partial arteriosclerosis associated with severe malnutrition. Our extensive clinical workup to determine the etiology of ischemia just revealed a hypercoagulable state, without any apparent embolic or atheromatous source. Further extensive group studies or group-based studies are needed to elucidate the etiology of ischemic stroke in patients with severe AN.