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Drs. Delanty and Needell suggest a possible explanation for the visual hallucinations we described with erythropoietin in end-stage dialysis patients.¹ Based on their own findings, they suggest that transient increases in blood pressure caused by erythropoietin might have resulted in a reversible posterior leukoencephalopathy syndrome, which in turn caused the complex visual hallucinations we described. When dealing with a syndrome of unknown etiology, care must be taken not to dismiss any reasonable explanatory hypothesis. In the absence of CT or MRI neuroimaging in our patients, we cannot rule in or rule out the presence of a posterior leukoencephalopathy. However, we believe that the suggested explanation by Delanty and Needell is highly unlikely based upon their own citations and the nature of the syndrome we described.

There was no correlation in our article between dialysis patients being treated for hypertension and the appearance of hallucinations during erythropoietin administration. Although not reported, blood pressures were recorded in all our cases. All of the dialysis patients were actively treated with antihypertensive medications when indicated, and none of the cases with hallucinations that we reported had uncontrolled or clinically significant blood pressure elevations associated with the hallucinations.

While Delanty and Needell did not provide clinical descriptions in their letter regarding their report currently in press, there is little resemblance between the cases of reversible leukoencephalopathy cited by them and the patients described in our series. In fact, none of their citations describe the syndrome of posterior leukoencephalopathy as manifesting with complex visual hallucinations. For instance, in a description of the reversible leukoencephalopathy syndrome by Hinchey et al.,² the clinical findings consisted primarily of decreased alertness, altered mental functioning, seizures, and visual loss, including cortical blindness. None of the 15 patients described by them reported visual hallucinations. None of the patients we reported resembled the syndrome described by them; our patients had visual hallucinations while alert in the context of relatively preserved sensorium.

Some of the patients with a posterior leukoencephalopathy syndrome described by Hinchey et al.² were attributed to cyclosporine. Although cyclosporine treatment can be associated with a posterior leukoencephalopathy syndrome and can also be associated with complex visual hallucinations, it is not clear that these two phenomena have ever been described as occurring together in the same patient concurrently. In the reports of cyclosporine-induced visual hallucinations cited by Drs. Delanty and Needell³ in support of their argument, a posterior leukoencephalopathy was actually ruled out by brain imaging. This fact is also borne out in other such cases reported in the literature.⁴, ⁵ A more reasonable conclusion is that cyclosporine may sometimes cause two separate syndromes: 1) reversible posterior leukoencephalopathy and 2) complex visual hallucinations. It is also of interest that the cyclosporine-induced visual hallucinations seem to be associated with entoptic visual impairments, as was the case in our dialysis patients.

It is not necessary to postulate an indirect systemic effect of erythropoietin, such as hypertension, to explain how it may affect the brain to cause visual hallucinations. Reports subsequent to the writing of our article have shown that erythropoietin is present in rodent, primate, and human brains, as well as in central nervous system tissues.⁶, ⁷ It is produced by astrocytes and is activated by hypoxia and other factors.⁷ Receptor sites have been identified in neuronal cells whose survival under hypoxic conditions is enhanced by erythropoietin.⁶, ⁷ While it appears that erythropoietin does not cross the blood-brain barrier under normal conditions, it may do so in proportion to the degree of blood-brain barrier dysfunction.⁶ Thus, under some circumstances systemic recombinant erythropoietin might cross the blood-brain barrier and directly affect central nervous system function.

We are pleased that our article has generated the kind of interest shown in Drs. Delanty and Needell's letter, and we hope that questions like theirs may inform future research into the causative mechanisms responsible for the complex visual hallucinations seen with erythropoietin treatment in dialysis patients.

REFERENCES

1. Steinberg H, Saravay SM, Wadhwa N, et al: Erythropoietin and visual hallucinations in patients on dialysis. Psychosomatics 1996; 37:556–563[Abstract/Free Full Text]
2. Hinchey J, Chaves C, Appignani B, et al: A reversible posterior leukoencephalopathy syndrome. N Engl J Med 1996; 334:494–500[Abstract/Free Full Text]
3. Steg RE, Garcia EG: Complex visual hallucinations and cyclosporine neurotoxicity. Neurology 1991; 41:1156
4. Katirji MB: Visual hallucinations and cyclosporine. Transplantation 1987; 43:768–769[Medline]
5. Noll RB, Kulkarini R: Complex visual hallucinations and cyclosporine. Arch Neurol 1984; 41:329–330[Abstract/Free Full Text]
6. Masuda S, Chikuma M, Sasaki R: Insulin-like growth factors and insulin stimulate erythropoietin production in primary cultured astrocytes. Brain Res 1997; 746:63–70[Medline]
7. Marti HH, Gasmann M, Wenger RH, et al: Detection of erythropoietin in human liquor: intrinsic erythropoietin production in the brain. Kidney Int 1997; 51:416–418[Medline]

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