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
Second magnetic resonance imaging
scan (17 weeks after initial symptoms) showing an increase in the number of
small high signal foci with more confluent areas of high signal intensity,
a scalloped edge in the left occipital region, and a serpiginous scalloped
appearance at the gray matter/white matter interface involving the arcuate
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.
Fresh brain slices showing large
numbers of small, gray, circular lesions in the white matter close to the
cortico–white-matter junction (white arrows). Also seen are irregular
linear lesions along the cortico–white-matter junction (black arrowheads).
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.
Microscopic picture showing small,
spherical, white matter lesions with marked vascular prominence and parenchymal
infiltrate (hematoxylin-eosin, original magnification ×20).
Microscopic section showing the
presence of diagnostic enlarged homogenous oligodendrocyte nuclei, which contain
the papovavirus particles associated with progressive multifocal leukoencephalopathy
(arrows) at the periphery of the focus of demyelination (hematoxylin-eosin,
original magnification ×100).
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:
Downes SM, Black GCM, Hyman N, Simmonds M, Morris J, Barton C. Visual Loss Due to Progressive Multifocal Leukoencephalopathy in a Congenital Immunodeficiency Disorder. Arch Ophthalmol. 2001;119(9):1376-1378. doi: