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Show Journal of Neuro- Ophthalmology 20( 4): 250- 252, 2000. © 2000 Lippincott Williams & Wilkins, Inc., Philadelphia Retinol- Binding Protein in Idiopathic Intracranial Hypertension ( IIH) John B. Selhorst, MD, Kongkiat Kulkantrakom, MD, James J. Corbett, MD, Enrique C. Leira, MD, and Sophia M. Chung, MD Objective: We postulated that an alteration in endogenous vitamin A ( retinol) metabolism plays a causal role in the pathogenesis of idiopathic intracranial hypertension ( IIH). Materials and Methods: Serum retinol was determined by a fluorometric method from 40 control subjects and 58 patients with idiopathic intracranial hypertension ( IIH). Retinol binding protein ( RBP) was also assayed by quantitative radial immunodiffusion in 17 control subjects and 30 patients with IIH. Results: Mean retinol values were higher in the IIH group compared with the control group, but did not reach a significant level. However, seven of 30 patients with IIH had high RBP levels, but none of the control subjects did. Conclusion: This data suggests that IIH is associated with an abnormality in vitamin A metabolism that is linked to its transport system. Key words: Idiopathic intracranial hypertension- Obesity- Pseudotumor cerebri- Retinol- binding protein- Vitamin A. Idiopathic intracranial hypertension ( IIH) is a syndrome of headaches, papilledema, and elevated intracranial pressure without evidence of an intracranial mass lesion or meningeal inflammation ( 1,2). This condition is also known as pseudotumor cerebri or benign intracranial hypertension. A disorder of metabolism occurring in IIH is suggested by the common features of obesity in young adult females ( 2). IIH is reported with a host of drugs and medical conditions, but these observations are retrospective, are very infrequent, and likely are due to chance ( 3). Interestingly, IIH is more predictably induced by excessive intake of vitamin A in the diet or by supplementary ingestion ( 4- 7). Little is known, however, about the endogenous metabolism of this vitamin in pa- Manuscript received February 8, 2000; accepted September 15, 2000. From the Departments of Neurology and Ophthalmology, Saint Louis University School of Medicine, St. Louis, Missouri; and the Departments of Neurology and Ophthalmology, University of Mississippi, Jackson, Mississippi. Address correspondence and reprint requests to John B. Selhorst, MD, Department of Neurology, Saint Louis University Health Sciences Center, 3635 Vista at Grand Blvd, St. Louis, MO 63110- 0250. Presented in part at the 122nd annual meeting of the American Neurological Association in September 1997, San Diego, CA. tients with IIH. Therefore, a study to define an association of serum vitamin A ( retinol) and retinol- binding protein ( RBP) levels was undertaken to determine whether an alteration in vitamin A metabolism or its transport played a causal role in the pathogenesis of IIH. METHODS Patients with IIH had normal neurologic examinations, neuroimaging studies, and spinal fluid analysis except for papilledema and elevated intracranial pressure. The protocol was approved by the institutional review boards of the participating institutions to obtain serum samples from all consenting participants in this study. Subjects in the control and IIH groups had no history of excessive vitamin A intake in their diets, ingestion of vitamin supplements, oral contraceptive tablets, or supplemental hormones. Serum samples were prospectively collected at two academic medical centers ( Saint Louis University and University of Iowa). Serum vitamin A was assayed in 40 healthy control subjects and 58 patients with IIH as described by Thompson et al ( 8). Serum RBP also was measured in samples from 17 control subjects and 30 patients by a quantitative radial immunodiffusion ( M-partigen immunodiffusion plate plasma retinol- binding protein, Calbiochem Behring Corp., La Jolla, CA). RESULTS In both control and IIH groups, there was no significant difference regarding sex, age, or height. The mean weight in the IIH group, however, was significantly higher than in the control group ( P < 0.001, Student's f- test) ( Table 1). The mean retinol level in the IIH patients was higher than in the control group ( 60.0 ± 20.1 [ SD] versus 51.3 ± 19.0 | xg/ dl), but did not reach a significant level ( P = 0.06). Nineteen of 58 patients in the IIH group had a high vitamin A level, whereas 9 of the 40 subjects in the control group did ( odds ratio, 1.68; 95% CI, 0.38- 7.34) ( Table 2). The mean RBP level in the IIH patients was significantly higher than in the control group ( 4.1 ± 1.7 versus 2.8 ± 1.1 mg/ dl, P = 0.008). Seven of 30 patients in the IIH group had high RBP levels, whereas none of the 17 250 RETINOL- BINDING PROTEIN IN IDIOPATHIC INTRACRANIAL HYPERTENSION 251 TABLE 1. Clinical features TABLE 2. Subjects' retinol and RBP levels Variable Control IIH Control IIH Sex Female Male Age in yrs ( mean) Weight in kg ( mean) Height in cm ( mean) 38 2 35.5 ± 9.8 59.6+ 10.2* 163.8 ± 6.1 55 3 32.3 ± 10.5 95.1 ± 26.8* 164.4 ± 9.6 Retinol Normal High RBP Normal High * P < 0.001. IIH, idiopathic intracranial hypertension. subjects in the control group did ( odd ratio, 10.35; 95% CI, 4.61- 23.92) ( Table 2). All of the elevated RBP samples, however, were from one investigative site that provided 17 of 58 samples. DISCUSSION The pathophysiology of IIH is attributed to excess cerebrospinal fluid ( CSF) production, diffuse cerebral edema, or decreased CSF absorption by arachnoid villi ( 9,10). The latter mechanism is favored by reports that show increased resistance to CSF absorption and decreased clearance of isotope- labeled CSF over the vertex ( 11- 13). The pathogenesis of the impaired CSF absorption remains undetermined. Fibrosis of arachnoid villi has been found in animal studies of hypovitaminosis ( 14), but these changes do not occur with excess vitamin A. ( 15). Vitamin A is essential for the proliferation and differentiation of cells throughout the body ( 16). This dynamic activity and the sensitivity of the arachnoid villi to deficient levels of vitamin A suggests a possible linkage between dysfunction of the subarachnoid villi and high levels of vitamin A or its metabolites. Normally, most of the body's total vitamin A is stored in the stellate cells of the liver and within lipid droplets of hepatocytes. Interestingly, excess vitamin A may be stored in adipose tissue ( 17). Therefore, obese patients, as in IIH, would have added capacity for vitamin A storage and, thereby, excess vitamin A for recycling throughout the body. RBP provides the principal transport mechanism for this fat- soluble vitamin between natural storage sites and cellular tissues throughout the body ( 17). In animals, plasma levels fall in vitamin A- deficient states and rise with injection of vitamin A into deficient animals ( 18). Hence, assays of RBP in humans may reflect the activity of vitamin A transportation in the bloodstream. Interestingly, estrogen and progesterone influence RBP production, and several drugs are known to affect the absorption, binding, storage, or transport of vitamin A ( 19- 21). Perhaps the many drugs reportedly associated with IIH act on vitamin A transport ( 21). In this study, approximately one third of IIH patients had high vitamin A levels, compared with approximately one fourth of the control subjects, but the mean levels in each group were not significantly different. Interestingly, despite a similar overlap in a report of 70 controls and 16 patients with IIH, Jacobson and associates ( 22) recently found a statistically significant difference between el- 31 9 17 0 39 19* 33 7t * Trend not significant; t Significant, see results. RBP, retinol-binding protein. evated serum vitamin A. Because of the active storage and transport of this fat- soluble vitamin, serum retinol determinations are only an indirect measure of total body vitamin A metabolism. Therefore, these inconclusive serum retinol assays do not negate the possibility of an endogenous excess of vitamin A in patients with IIH. The elevated RBP determinations found in patients with IHH in this study were especially intriguing. Importantly, none of the control subjects had elevated RBP levels. These results suggest an active vitamin A transport in patients with IIH. Unbound vitamin A has a toxic effect on cells, but binding to RBP prevents this injury ( 20,23). With an increase in vitamin A transport, cells with RBP receptors would receive an excess of vitamin A ( 17). Excessive transport of vitamin A to the arachnoid villi could possibly result in their malfunction, produce added resistance to CSF absorption, and raise intracranial pressure. Therefore, a chronic increase in vitamin A within arachnoid villi would be the principal pathogenetic mechanism in IIH. These results warrant further investigation of vitamin A and its metabolites in patients with IIH, perhaps to include assays in fat, spinal fluid, and liver. Acknowledgements: The authors are most grateful to Dr. Frank Chytil for his very useful suggestions in preparing this report and the assistance of his biochemistry laboratory at Vanderbilt University in determining levels of serum retinol and RBP. We also appreciate the effort of Mary Althage with this manuscript. REFERENCES 1. Fishman RA. Cerebrospinal Fluid in Diseases of the Nervous System. 2nd ed. Philadelphia: WB Saunders, 1992. 2. Corbett JJ, Savino PJ, Thompson HS, et al. Visual loss in pseudotumor cerebri: follow up of 57 patients from five to 41 years and a profile of 14 patients with permanent severe visual loss. Arch Neurol 1982; 39: 461- 73. 3. Guiseffi V, Wall M, Siegel PZ, et al. Symptoms and disease associations in idiopathic intracranial hypertension ( pseudotumor cerebri): a case- control study. Neurology 1991; 41: 239- 44. 4. Selhorst JB, Waybright EA, Jennings S, et al. Liver lover's headache: pseudotumor cerebri and vitamin A intoxication. JAMA 1984; 252: 3365. 5. 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