Visual Loss Due to Progressive Multifocal Leukoencephalopathy in a Congenital Immunodeficiency Disorder

A 20-year-old man with Wiskott-Aldrich syndrome (WAS) initially developed a mild visual disturbance that progressed to blindness, increasing neurological deficits, and death within 4 months. Wiskott-Aldrich syndrome is an X-linked immunodeficiency disorder characterized by thrombocytopenia, eczema, and susceptibility to infection.¹ This case illustrates the difficulties in reaching the final diagnosis of progressive multifocal leukoencephalopathy (PML) in this individual and its unusual histopathologic features.

A 20-year-old white man with WAS had a 1-month history of decline in vision. Nine months previously, he had omitted 3 consecutive doses of immunoglobulin, which he had been receiving every 3 weeks since the age of 12 years. This was restarted when he developed lethargy and malaise. His mother had been diagnosed with multiple sclerosis at age 26 years.

An ophthalmological examination revealed a visual acuity of 20/17 OD and 20/20 OS with normal pupillary reactions. Color vision was abnormal, and visual field testing showed bilateral enlarged blind spots with paracentral scotomata. Fundi appeared grossly normal. Results of fundus fluorescein angiography were unremarkable. Electrodiagnostic evaluation was normal apart from delayed visual evoked potentials, which were suggestive of demyelination.

The patient's biochemistry and complete blood cell count were normal except for a low platelet count (12 × 10³/µL). Mutational analysis for Leber hereditary optic neuropathy and for the WAS protein gene demonstrated no Leber mutation, but there was a single nucleotide substitution (C155T) in exon 1 of the WAS gene.

Six weeks later his vision was bilateral finger counting. A magnetic resonance imaging (MRI) scan showed scattered areas of white-matter foci, predominantly peripheral and not periventricular, on proton density and T2-weighted scans. He was given intravenous methylprednisolone sodium succinate because of the possibility of demyelination. No improvement occurred, and he was registered as blind. Reduced sensation and generalized mild weakness (level 4-5) developed in his right-hand side and face. Reflexes were normal and he had no dysphasia.

A repeat MRI scan showed an increase in the number of small high-signal foci together with more confluent areas of high signal intensity and a scalloped edge in the left occipital region (Figure 1). Rapid deterioration occurred with protracted focal seizures, total blindness, loss of consciousness, and death. A postmortem histopathologic examination of the brain revealed the papovavirus particles associated with PML.

The fresh brain was examined and then prepared in slices. Tissue underwent light microscopic examination and was embedded in paraffin wax, sectioned, and stained with hematoxylin-eosin. The brain weighed 1570 g. External examination showed mild diffuse vascular congestion but no focal lesions. Brain slices had large numbers of small, gray, circular lesions in the white matter that were 1 to 3 mm in diameter, many of which were close to the cortico–white-matter junction. In some cases the lesions were also visible within the cortical ribbon. The lesions had the appearance of small regions of demyelination and resembled the individual lesions of PML. In addition to the spherical lesions, there were also irregular linear lesions along the cortico–white-matter junction that in some instances were accompanied by visible, fine-linear white scarring in this area (Figure 2). In the most severely affected gyri, the cortex was also involved and had a darker color, with apparent expansion and softening of its affected parts.

Although the individual lesions were present throughout the cerebral hemispheres, they were most frequent bilaterally in the occipital poles, which were also the major site of linear cortico–white-matter junction lesions and scarring as well as the regions of diffuse cortical involvement. A microscopic examination of the brain sections showed small, spherical, white matter lesions that were atypical of PML because they were associated with a considerable perivascular and parenchymal inflammatory infiltrate (Figure 3). The inflammatory infiltrate was mostly lymphocytic in character but also contained plasma cells that were occasionally binuclear. However, further examination indicated the presence of diagnostic enlarged magenta-colored oligodendrocyte nuclei around the periphery of the foci of demyelination, containing the papovavirus particles associated with PML (Figure 4). Other differences from typical examples of PML were that the pleomorphic astrocytic reaction within the lesions was less florid and that foamy macrophages were not as conspicuous, although there were numerous mononuclear cells within the larger lesions. In a few cases the isolated lesions had the character of "burnt-out" lesions, with no enlarged oligodendrocytes, no significant inflammatory reaction, and a predominantly fibrous gliosis. The linear lesions in the cortico–white-matter junction had the same histological characteristics as the spherical lesions. The diffuse cortical lesions showed demyelination within the cortex and reactive astrocytosis extending through the neuropil and around the neurons, although no enlarged oligodendrocyte nuclei were identified within the affected regions of the cortical ribbon.

Delay in the diagnosis of PML was probably due to visual symptoms dominating this case, late development of neurological signs, and the outstanding longevity and relative good health of the patient. Inherited conditions including Leber hereditary optic neuropathy or the possibility of a contiguous deletion in the same region as the WAS gene, leading to a phenotypic complex of WAS and perhaps an X-linked cone dystrophy, were explored and excluded.

Although the lesions that appeared on the initial MRI scan were not completely typical of multiple sclerosis,² electrodiagnostic test results were was suggestive of optic nerve demyelination. Visual disturbance in multiple sclerosis is almost always due to optic nerve rather than cortical involvement. The reverse is true for PML. Despite increasing central scotomata, the preserved pupillary reflexes should have directed us earlier to a cortical etiology. Typical PML features became more identifiable by the second MRI scan (Figure 1). The histopathologic characteristics of this case include an unusual variant of PML: there was a marked inflammatory response, and the demyelinating lesions had an unusual distribution. The inflammatory response was presumably a reflection of the immune status of this patient. Whereas most cases of PML are associated with immune suppression, no matter what the cause, this case is unusual because a marked inflammatory response was noted.^3,4 A study of ophthalmic signs in patients with acquired immunodeficiency syndrome and PML stated that bilateral occipital lobe PML may lead to cortical blindness, which appears to be a relatively common event but has received inadequate recognition.⁵ The initial features of this case offer a useful model for other immunodeficiencies in which patients experience loss of vision and neurological signs.

Corresponding author: Susan M. Downes, MD, FRCOphth, Oxford Eye Hospital, Radcliffe Infirmary, Woodstock Road, Oxford OX2 6HE, England (e-mail: susan.downes@ophthalmology.oxford.ac.uk).