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Figure 1.
A severe case showing midperipheral whitening that is confluent in some areas, resembling commotio retinae.

A severe case showing midperipheral whitening that is confluent in some areas, resembling commotio retinae.

Figure 2.
Typical mosaic pattern of whitening in the midperiphery.

Typical mosaic pattern of whitening in the midperiphery.

Figure 3.
Whitening in the macula. Note the sparing of the foveola in both a florid case (left) and a more mild case (right).

Whitening in the macula. Note the sparing of the foveola in both a florid case (left) and a more mild case (right).

Association Between Presence of Retinal Whitening and Vitamin A Status
Association Between Presence of Retinal Whitening and Vitamin A Status
1.
Not Available, World malaria situation 1990. World Health Stat Q. 1992;445257- 266
2.
Not Available, Malaria Research: An Audit of International Activity.  London, England Wellcome Trust1996;
3.
Lewallen  STaylor  TEMolyneux  MEWill  BACourtright  P Ocular fundus findings in Malawian children with cerebral malaria. Ophthalmology. 1993;100857- 861Article
4.
Lewallen  SBakker  HTaylor  TEWills  BACourtright  PMolyneux  ME Retinal findings predictive of outcome in cerebral malaria. Trans R Soc Trop Med Hyg. 1996;90144- 146Article
5.
Sipperly  JOQuigley  HAGass  JDM Traumatic retinopathy in primates: the explanation of commotio retinae. Arch Ophthalmol. 1978;962267- 2273Article
6.
Hayes  KC Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest Ophthalmol. 1974;13499- 510
7.
Sommer  AWest  KP  Jr Vitamin A Deficiency: Health, Survival, and Vision.  New York, NY Oxford University Press1996;
8.
Thurnham  DISingkamani  R The acute phase response and vitamin A status in malaria. Trans R Soc Trop Med Hyg. 1991;85194- 199Article
9.
Natadisastra  GWittpenn  JRWest  KPMuhilal  Not availableMele  LSommer  A Impression cytology: a practical index of vitamin A status. Am J Clin Nutr. 1988;48695- 701
10.
Fuchs  JAusayakhun  SRuckphaopunt  STansuhaj  ASuskind  RM Relationship between vitamin A deficiency, malnutrition, and conjunctival impression cytology. Am J Clin Nutr. 1994;60293- 298
11.
Not Available, Assessment of Vitamin A Status and Impression Cytology: Training Manual.  Baltimore, Md International Center Epidemiologic and Preventive Ophthalmology1988;
12.
Arroyave  GChichester  COFlores  H  et al.  Biochemical Methodology for the Assessment of Vitamin A Status: Report of the International Vitamin A Consultative Group (IVACG).  Washington, DC Nutrition Foundation1982;
13.
Hing  TK Further contributions to the fundus xerophthalmicus. Ophthalmologica. 1965;150219- 238Article
14.
Hero  MHarding  SRiva  CEWinstanley  PAPeshu  NMarsh  K Photographic and angiographic characteristics of retinal appearances in severe malaria in Kenyan children. Arch Ophthalmol. 1997;115997- 1003Article
15.
Lewallen  SWill  BA Retinal haemorrhage in children with malaria. Lancet. 1993;341442Article
Clinical Sciences
March 1998

Association Between Measures of Vitamin A and the Ocular Fundus Findings in Cerebral Malaria

Author Affiliations

From the British Columbia Centre for Epidemiologic and International Ophthalmology, Vancouver (Drs Lewallen and Courtright); International Eye Foundation (Drs Lewallen and Courtright), Malaria Project and Wellcome Trust Centre, University of Malawi College of Medicine (Drs Molyneux and Wills), Blantyre; College of Osteopathic Medicine, Michigan State University, East Lansing (Dr Taylor); Liverpool School of Tropical Medicine, Liverpool, England (Dr Molyneux); and the Wilmer Eye Institute, The Johns Hopkins University School of Medicine, Baltimore, Md (Dr Semba).

Arch Ophthalmol. 1998;116(3):293-296. doi:10.1001/archopht.116.3.293
Abstract

Objective  To investigate the relationship between serum vitamin A levels and conjunctival impression cytology and retinal whitening present in Malawian children with cerebral malaria.

Methods  Standard retinal examination and conjunctival impression cytology were performed at hospital admission on 101 consecutively admitted children with cerebral malaria. Blood samples were drawn from 56 children at 24 hours, frozen at −20°C, and transported for assessment of vitamin A levels by high-performance liquid chromatography. Associations among fundus findings and vitamin A measurements were sought.

Results  The whitening of the retina that we have previously described in children with cerebral malaria was found to be associated with a mean±SD serum vitamin A level of 0.29±0.1 µmol/L, compared with a mean vitamin A level of 0.41±0.2 µmol/L in children without retinal whitening. Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times more likely to have abnormal conjunctival impression cytology results than those without whitening. No child had any clinical or ophthalmologic evidence of chronic vitamin A deficiency.

Conclusions  The retinal whitening described in children with cerebral malaria is associated with low serum vitamin A levels and with abnormal conjunctival impression cytology results and may be due to acute vitamin A deficiency at the tissue level.

MORE THAN 500 million people live in areas where malaria is endemic.1 Cerebral malaria is one of the most severe syndromes of infection by Plasmodium falciparum. In sub-Saharan Africa, malaria is responsible for death in 1 in 20 children younger than 5 years.2 We have described changes in the appearance of the ocular fundus in children with cerebral malaria,3 these changes being predictive of outcome.4 One of the most distinctive of the features was a mosaic pattern of whitening of the retina; this occurs either in the macula or outside the arcades, in the midperipheral retina. Children with extramacular whitening had a relative risk of poor outcome (death or neurologic sequelae) 2.2 times (95% CI, 1.2-3.8) higher than those without this finding.

Occasionally the whitening is severe and coalesces into large areas (Figure 1). In these cases, the ophthalmologic appearance bears a striking resemblance to commotio retinae. The appearance of commotio retinae is due to trauma-induced abnormalities in the outer segment of the rods and cones.5 In animal models, the outer segments of the rods are known to show degeneration in vitamin A deficiency.6

In the past few decades, the important role of vitamin A in host defense against infection has become increasingly well recognized. Vitamin A deficiency, even subclinical deficiency, has been shown to cause reduced childhood survival and to increase the incidence and severity of several infectious diseases; specifically, measles, diarrheal disease, urinary tract infections, otitis media, and possibly respiratory disease.7 One of the difficulties in studying vitamin A is that there is no one best measure of vitamin A status. The various techniques available for assessing vitamin A, along with their limitations, are well described.7 Serum vitamin A levels do not necessarily reflect total body stores of vitamin A and they may drop precipitously in the face of febrile illness; specifically, they have been shown to fall to very low levels during malaria attacks, even in subjects who are not likely to be vitamin A deficient.8 Compared with serum vitamin A measurements, the conjunctival impression cytology technique may be a better measure of target tissue sufficiency of vitamin A. However, while it has been shown to be useful in measuring the vitamin A status of populations,9 its usefulness in individual patients has been questioned.10

We studied both serum vitamin A levels and conjunctival impression cytology results in the context of detailed clinical and ophthalmologic assessments in children with cerebral malaria enrolled in the Malaria Research Project in Blantyre, Malawi, in 1993 and 1994, and present an analysis of the findings.

PATIENTS AND METHODS

The patients in this study were a consecutive subset consisting of two thirds of the patients enrolled in the Malaria Research Project at the Queen Elizabeth Central Hospital in Blantyre during 1992 and 1993, as part of a multicenter trial comparing artemeter with quinine in the treatment of cerebral malaria. Inclusion criteria and clinical assessments have been described elsewhere.4 Permission for this study was granted by the Health Science Research Committee of Malawi and children were enrolled only after informed consent was given by the child's guardian. Briefly, children were admitted if they had P falciparum malaria on blood smear, had a coma score of at least 2 on the Blantyre Coma Scale, and had no other cause of illness identified on clinical or laboratory assessment, which included culture of blood and cerebrospinal fluid. The examination on hospital admission included examination of the external eye by penlight and funduscopic inspection (after pupillary dilation) by indirect ophthalmoscopy by one ophthalmologist (S.L.); results were recorded on a standard form. Conjunctival impression cytology was performed on hospital admission according to previously described methods.11 Briefly, vacuum pump–held precut filter paper circles were applied to the temporal conjunctiva of each eye, placed immediately in fixative and stained with periodic acid–Schiff reagent and Harris hematoxylin, then read in a masked fashion by 2 trained observers (S.L. and P.C.) and graded (based on the presence of goblet cells) as normal, abnormal, or unreadable. Problems with purity of reagents necessitated restaining of a number of conjunctival impression cytology samples. Plasma samples were collected at 24 hours after hospital admission and frozen at −20°C. Samples were transported after several months via liquid nitrogen dry shipper to Baltimore, Md, where one investigator (R.S.) measured vitamin A in a masked fashion using high-performance liquid chromatography.12 Vitamin A reference standards from the National Institute of Standards and Technology, Gaithersburg, Md, and pooled vitamin A reference standards were run with the study samples to monitor accuracy.

RESULTS

We performed retinal examinations and conjunctival impression cytology on 101 children. Fifty-six of these were consecutive admissions and had serum samples available for vitamin A measurement.

Thirty-five (35%) of the children had retinal whitening. In 15 the whitening was confined to the macula, in 3 it was extramacular only, and in 17 there was both macular and extramacular whitening.

Serum vitamin A concentrations ranged from 0.06 to 0.84 µmol/L, with a mean±SD of 0.37±0.15 µmol/L and a median of 0.36 µmol/L. Conjunctival impression cytology results were normal in 65 children, abnormal in 33, and unreadable in 3.

Patients with retinal whitening had a mean±SD serum vitamin A concentration of 0.29±0.11 µmol/L, while children without retinal whitening had a mean±SD serum vitamin A level of 0.41±0.16 µmol/L (P=.002) (Table 1). Children with retinal whitening were 2.77 (95% CI, 1.06-7.3) times as likely to have an abnormal conjunctival impression cytology result as children without retinal whitening. There was no association between serum vitamin A levels or conjunctival impression cytology results and papilloedema or retinal hemorrhages.

The mean±SD serum vitamin A level in children with abnormal conjunctival impression cytology results was 0.34±0.14 µmol/L compared with 0.40±0.16 µmol/L in children with a normal conjunctival impression cytology result (nonsignificant).

There was no association between outcome (death) and serum vitamin A concentration. Nine (27%) children with abnormal conjunctival impression cytology results and 13 children (20%) with normal conjunctival impression cytology results died (nonsignificant).

COMMENT

We have demonstrated an association between 2 different measures of vitamin A status and the retinal whitening that occurs in children with cerebral malaria. A possible explanation for this association is that the retinal whitening is a consequence of low serum vitamin A levels or reduced vitamin A availability at the tissue level. The retinopathy of vitamin A deficiency in humans has been described as consisting of white or yellow lesions, deep in the retina, patchy or punctate, in the midperiphery, and most pronounced along vessels. The typical whitening we see in cerebral malaria is indeed a patchy mosaic (though not punctate), it is frequently most prominent along vessels, and it is deep in the retina (Figure 2). It is often present in the midperiphery but may also or exclusively involve the macula. This last characteristic differs from reports of vitamin A deficiency retinopathy, which is described as always occurring outside the temporal vascular arcade.7,13 We have noted that when the macula is affected in cerebral malaria, the foveola is always completely spared (Figure 3). This could be due to the fact that the foveola is predominantly cones, which do not have the same dependence on vitamin A as do the rods. These considerations, along with our epidemiologic evidence, lend further support to the possibility that the whitening may be a manifestation of vitamin A deficiency at the tissue level. It is not clear, however, whether these children actually have systemic vitamin A deficiency, because the acute-phase reaction itself causes an acute lowering of serum vitamin A concentration.

Reported descriptions of retinopathy in vitamin A deficiency are from patients who have decreased vitamin A stores, either due to limited dietary intake of vitamin A or to disease that leads to limited absorption of ingested vitamin A. These patients presumably are in a true state of chronic vitamin A deficiency. None of the children in our study exhibited the macroscopic conjunctival or corneal manifestations of chronic vitamin A deficiency. Some (those with abnormal conjunctival impression cytology results) may well have had mild or moderate vitamin A deficiency, but others (those with normal conjunctival impression cytology results) are likely to have had sufficient vitamin A stores. Acute lowering of serum vitamin A concentration is a feature of the acute-phase response8 occurring in the children in our study, all of whom had low serum vitamin A levels. Children with both normal and abnormal conjunctival impression cytology results showed retinal whitening, although the retinal lesions were more frequent among those with abnormal conjunctival impression cytology results. A possible interpretation of these findings is that an acute drop in serum vitamin A levels, such as occurs in the acute-phase response in malaria, is enough to cause the retina to show the signs resembling those of vitamin A deficiency, especially in children with already impaired tissue vitamin A status (those with abnormal conjunctival impression cytology results).

We have followed up several children who manifested retinal whitening during the episode of cerebral malaria and have found that the whitening disappears during a period of weeks to months, leaving no sequelae detectable on funduscopy. The children's diets are not supplemented with vitamin A during or after the malaria episode. If acute vitamin A deprivation causes the retinal lesions, then the rise in serum vitamin A levels associated with the cessation of the acute-phase response is enough to allow the retina to recover.

Other recent reports and photographs of fundus findings similar to ours come from Kenyan children with severe malaria. Researchers there found the same pattern of whitening and demonstrated by fluorescein angiography that this is not associated with leakage of vessels.14

We have examined many children in the same setting with coma and fever from other causes, such as encephalitis, meningitis, and poisoning, who are also undergoing an acute-phase reaction, and have never seen this pattern of whitening except in cases of malaria. We have seen it predominantly in cerebral malaria as opposed to less severe malaria15 and the retinal whitening is only one component of the spectrum of retinal changes in children with cerebral malaria.3 It therefore seems likely that additional mechanisms contribute to retinal abnormalities in severe malaria.

Our findings raise many questions about the possible role of altered vitamin A metabolism or availability in the pathophysiology and prognosis of cerebral malaria. Nevertheless, we hope that the identification of inverse correlations between retinal whitening and the levels of tissue and serum vitamin A will encourage further investigations into a phenomenon with potentially important therapeutic implications.

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Article Information

Accepted for publication November 26, 1997.

Funding for the vitamin A and conjunctival impression cytology measurements was provided by the International Eye Foundation, Bethesda, Md, the Hoffmann-LaRoche Sight and Life Programme, Basel, Switzerland, and the US Agency for International Development, Washington, DC (Cooperative Agreement DAN-0045-A-5094-00). Financial support for the care of children with severe and complicated malaria was provided by a grant from the Product Development Unit of the World Health Organization, Geneva, Switzerland.

We thank the patients, their parents, and the staff of the Malaria Research Project, the Department of Paediatrics of the College of Medicine, University of Malawi, and the Senior Medical Superintendent of the Queen Elizabeth Central Hospital, Blantyre (Ministry of Health and Population, Government of Malawi), for encouragement and permission to conduct the study.

Reprints: Susan Lewallen, MD, British Columbia Centre for Epidemiologic and International Ophthalmology, University of British Columbia, St Paul's Hospital, 1081 Burrard St, Vancouver, British Columbia, Canada V6Z 1Y6.

References
1.
Not Available, World malaria situation 1990. World Health Stat Q. 1992;445257- 266
2.
Not Available, Malaria Research: An Audit of International Activity.  London, England Wellcome Trust1996;
3.
Lewallen  STaylor  TEMolyneux  MEWill  BACourtright  P Ocular fundus findings in Malawian children with cerebral malaria. Ophthalmology. 1993;100857- 861Article
4.
Lewallen  SBakker  HTaylor  TEWills  BACourtright  PMolyneux  ME Retinal findings predictive of outcome in cerebral malaria. Trans R Soc Trop Med Hyg. 1996;90144- 146Article
5.
Sipperly  JOQuigley  HAGass  JDM Traumatic retinopathy in primates: the explanation of commotio retinae. Arch Ophthalmol. 1978;962267- 2273Article
6.
Hayes  KC Retinal degeneration in monkeys induced by deficiencies of vitamin E or A. Invest Ophthalmol. 1974;13499- 510
7.
Sommer  AWest  KP  Jr Vitamin A Deficiency: Health, Survival, and Vision.  New York, NY Oxford University Press1996;
8.
Thurnham  DISingkamani  R The acute phase response and vitamin A status in malaria. Trans R Soc Trop Med Hyg. 1991;85194- 199Article
9.
Natadisastra  GWittpenn  JRWest  KPMuhilal  Not availableMele  LSommer  A Impression cytology: a practical index of vitamin A status. Am J Clin Nutr. 1988;48695- 701
10.
Fuchs  JAusayakhun  SRuckphaopunt  STansuhaj  ASuskind  RM Relationship between vitamin A deficiency, malnutrition, and conjunctival impression cytology. Am J Clin Nutr. 1994;60293- 298
11.
Not Available, Assessment of Vitamin A Status and Impression Cytology: Training Manual.  Baltimore, Md International Center Epidemiologic and Preventive Ophthalmology1988;
12.
Arroyave  GChichester  COFlores  H  et al.  Biochemical Methodology for the Assessment of Vitamin A Status: Report of the International Vitamin A Consultative Group (IVACG).  Washington, DC Nutrition Foundation1982;
13.
Hing  TK Further contributions to the fundus xerophthalmicus. Ophthalmologica. 1965;150219- 238Article
14.
Hero  MHarding  SRiva  CEWinstanley  PAPeshu  NMarsh  K Photographic and angiographic characteristics of retinal appearances in severe malaria in Kenyan children. Arch Ophthalmol. 1997;115997- 1003Article
15.
Lewallen  SWill  BA Retinal haemorrhage in children with malaria. Lancet. 1993;341442Article
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