Exacerbation of stroke deficit, associated with severe anemia from occult gastrointestinal bleeding; Adenocarcinoma of the right colon, T3 N0 M0
This 60 year old, morbidly obese male presented with an exacerbation of his remote stroke deficit, and notably did not exhibit any new neurological deficits consistent with a different site of lesion from the old stroke. He was found to have marked hypochromic, microcytic anemia with occult blood in the stool on multiple tests. His focal deficits rapidly resolved to baseline following urgent transfusion. Interestingly, he did not exhibit many of the classic symptoms and signs of severe anemia at the time of his presentation, although conjunctival pallor was present. Endoscopy did not document an upper gastrointestinal source of bleeding, and failed on multiple attempts to adequately visualize the right colon. Contrasted CT of the abdomen suggested a soft tissue mass in the right colon. Despite the patient's high surgical risk, these findings prompted exploratory laparotomy, with complete resection of a poorly differentiated adenocarcinoma of the right colon. His postoperative course was complicated by abdominal wall abscess formation, resulting in an extended hospital stay. He is doing well, without evidence of local recurrence or distant metastasis, one year following his surgery.
The cause of the patient's original stroke remains unexplained, despite multiple screening procedures.
Exacerbation of previous deficits, or re-emergence, is common in patients who have sustained a stroke or other focal cerebral insult in the past, and frequently is associated with systemic illness such as urinary tract infection, pneumonia or volume overload. In such cases, a new ischemic cerebrovascular event from arterial or venous occlusion, or a hemorrhage into the site of the previous insult, obviously must be ruled out. However, findings on initial physical examination, chest radiographs, electrocardiogram and laboratory studies often will reveal other disorders potentially contributing to the worsening of a longstanding neurological deficit. Based on the rapid response to transfusion, we believe that anemia, resulting in reduced oxygen delivery to previously compromised brain tissue, caused the exacerbation of previously compensated neurological deficits in this patient. The patient's comorbid conditions, such as diabetes, may have blunted the systemic physiological responses typically seen in symptomatic anemia. We emphasize that the re-emergence of the patient's neurological deficits believed due to severe anemia represented a medical emergency, requiring immediate transfusion to establish causation and prevent further neurological insult.
Although this patient presented with a significant anemia that could explain his fatigue and exacerbation of his previous stroke deficit, the cause of the anemia was not readily discernible initially. A diligent search was therefore necessary to identify a potential cause for his anemia, and given the patient's high surgical risk, to warrant surgical exploration. This case illustrates the realistic setbacks so often encountered in medical care, and underscores the importance of pursuing a diagnosis in the face of initially inconclusive test results.
The pathophysiological mechanisms underlying the phenomenon of re-emergence, or exacerbation of neurological deficits from a remote focal cerebral insult, remain speculative. It is a good clinical rule of thumb to state that regions with the greatest degree of compromise typically fail first when subjected to a global stress. This generalization most obviously applies when the systemic stress is one that is well known to cause or exacerbate ischemia or hypoxia, the usual causes of stroke. However, increasing evidence suggests that other mechanisms may also lead to reversible, focal deficits in the context of a previous cerebral insult, and should be considered in the search for causes of an unexplained exacerbation of previous stroke symptoms.
Patients who sustained a stroke with subsequent partial or full recovery of neurological function were found to exhibit transient re-emergence of their former deficits after receiving midazolam, a short-acting sedative (Lazar et al., 2002). Neurological deficits of patients with mass lesions or carotid disease also have been documented to re-emerge after administration of fentanyl or midazolam (Thal et al., 1996). Recovery of function following brain injury is also disrupted by diazepam (Schallert et al., 1986). These results suggest that brain tissue symptomatically recovered from focal insults is vulnerable to GABA(A)-mediated inhibition. Other anesthetic agents also have been implicated in exacerbation of marginal neurologic dysfunction, such as sufentanil (Benzel et al., 1990), and naloxone was shown some time ago to occasionally reverse "ischemic" neurological deficits in man (Baskin and Hosobuchi, 1981), also suggesting involvement of opiate receptor-dependent mechanisms in recovery from focal cerebral insults.
Evidence is now increasing that neuroinflammation plays an important role in exacerbating injury from many neurological diseases including stroke, Alzheimer's disease and demyelinating diseases. However, further studies are needed to explore how comorbid disease states that activate proinflammatory cytokines can affect the severity of neurological dysfunction from particular lesions. Proinflammatory cytokines may directly injure neurons, may lead to invasion of inflammatory cells from the periphery with secondary immune injury, or may reversibly alter neuronal function (e.g., Neumann, 2001; Clark and Lutsep, 2001).
Many disease states, including blood loss and anemia of chronic disease (e.g., associated with chronic renal failure, chronic inflammatory bowel disease, congestive heart failure or rheumatoid arthritis) are associated with excessive production of cytokines (Silverberg et al., 2001). Moreover, a range of cytokines appear to be overexpressed in patients with malignancies (Kurzrock, 2001). It is possible that such derangements, in addition to the physiologic stress of anemia itself, may have contributed to the re-emergence of this patient's previous neurological deficits.
We gratefully acknowledge the contribution of Dr. Paul E. Schulz (Neurology) and Dr. Beatriz Kinner (Pathology), of the Houston VA Medical Center, to this case.
A number of respondents suggested the possibility of a hypercoagulable state, possibly related to the underlying tumor, in this patient. We cannot definitively rule out this possibility as a risk factor for his remote ischemic event, although laboratory studies at that time did not suggest a coagulation abnormality. The clinical team felt that the virtually identical presentation of the patient's present illness, temporally separate from his first event, was more likely to result from an underlying condition causing exacerbation of old deficits, rather than a second vascular occlusion. Clinical and laboratory evidence of severe anemia suggested a likely stressor. We agree that in the absence of these findings, the possibility of a hypercoagulable state would have been more strongly pursued.
-- Dennis R. Mosier, M.D., Ph.D.
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