Finding in the fundus
In a note to his children and grandchildren from around 1995, Haarr wrote that many years would pass from the time he saw the first patient with striking striped spots on the retina and concomitant neurological symptoms, until he initiated a systematic study of this phenomenon:
Figure 2 From Marius Haarr's doctoral thesis 'What interested me was, what did it look like in his brain? What we call the retina of the eye is nothing more than a visible part of the brain. Was there a nervous system disorder with varying neurological deficits that could be compatible with the ocular fundus picture I had seen? The only thing I could think of in my ignorance was multiple sclerosis.'
Haarr knew that the lesions of multiple sclerosis were caused by lymphocytes that migrate across the blood-brain barrier around venules in the brain and spinal cord. He had also read literature that described similar lymphocyte infiltration around blood vessels in the periphlebitis retina (1) . His hypothesis that the changes in the retina reflect the lesions in the brain in multiple sclerosis was therefore well-founded.
Figure 3 From Marius Haarr's doctoral thesis From 1947 to 1950, Haarr examined 303 patients with multiple sclerosis and 225 control patients with other neurological disorders (including three 'morbus nullus'). The patients were recruited at Ullevål Hospital and Rikshospitalet in Norway, as well as Fredriksberg Hospital, the Military Hospital, Nørre Hospital, Copenhagen Municipal Hospital and Odense County and City Hospital in Denmark. His findings were checked by colleagues where this was possible. However, many patients were examined at home, which meant that perimetry visual field tests could not be performed and there were no colleagues to check the findings.
Haarr found inflammatory infiltrates around the retinal veins in 23 % of the multiple sclerosis patients and 3 % of the control patients (Figure 2). Eighteen uncertain findings were regarded as negative. Active periphlebitis occurred most frequently in those who had had multiple sclerosis for less than 10 years, while the changes had mostly 'dissipated' in cases exceeding 10 years. Haarr examined 24 of the patients several times (Figure 3); 'Case no. 3' was examined a total of 36 times over a period of 40 months. This enabled him to describe how exudative inflammatory changes developed around the venules over the course of several weeks and in some cases receded.
There are therefore strong indications that Haarr was right and that the lesions in the brain and in the retina have the same cause
Haarr considered there to be two possible explanations for the frequent occurrence of retinal periphlebitis in multiple sclerosis: the inflammatory infiltrates in the ocular fundus could either have the same cause as the lesions in the brain, or be sequelae to these (2) . He believed there to be a strong argument for the common cause explanation; both the blood vessel changes and the lymphocyte infiltration were relatively similar. He was also aware that the American immunologist Thomas Rivers had recently developed experimental allergic encephalomyelitis (EAE) – which has many similarities to multiple sclerosis – through immunisation with brain tissue (1, 7) . However, Haarr pointed out a significant difference: the nerve pathways in the retina are not myelinated, and cannot therefore become demyelinated, which is characteristic of both multiple sclerosis and EAE. He thereby indirectly anticipated the subsequent critique of the EAE model, which described multiple sclerosis as an autoimmune reaction to myelin (8) . It has since been demonstrated that there is a common genetic predisposition for uveitis and multiple sclerosis, and that uveitis and multiple sclerosis can occur simultaneously in the same experimental animal model (9) . There are therefore strong indications that Haarr was right and that the lesions in the brain and in the retina have the same cause.