31‐YEAR‐OLD MAN WITH BALINT'S SYNDROME AND VISUAL PROBLEMS

CLINICAL HISTORY AND NEUROIMAGING

A 31‐year‐old man was hospitalized due to retinitis and progressive personality changes that had started several weeks earlier. He was disorientated and had changes of affect with mood swings as well as signs and symptoms of dementia. Neuropsychologically the patient showed Balint's syndrome (paralysis of visual fixation, optic ataxia, and impairment of visual fixation) with anosognosia, visual and spatial agnosia, ideomotor and ideational apraxia, attention deficits and visual hallucinations. Electroencephalogram (EEG) showed non‐specific abnormalities. The ophthalmological exam revealed retinitis with bilateral macular changes and partial atrophy of the optic nerves. Laboratory tests and cerebrospinal fluid (CSF) examinations were unremarkable. Magnetic Resonance Imaging (MRI) showed diffuse areas with high signal intensity in T2‐weighted images involving periventricular and subcortical white matter of the occipital and parietal lobes. (Figure 1A). Furthermore, a focal 1 cm mass lesion was detected in the sellar region. There was some clinical improvement with steroid treatment, but the patient refused further diagnostic procedures and was released to home.

Figure 1.

He was stable for the next 2.5 years, but then developed behavioral changes with aggressiveness and hallucinations. At admission he was almost blind and had bilateral pyramidal tract signs and symptoms. EEG was desynchronized with diffuse slowing of background activity. T2‐weighted MRI scans showed hyperintense areas mainly involving the temporal and parietal lobes, while the occipital lobes were atrophic (Figure 1B). CSF showed elevated gamma‐globulins and further testing of the CSF yielded a diagnosis. Treatment with interferon and higher doses of steroids produced a good response for the next 10 months. He then developed seizures, painful myoclonic jerks, dystonias, spasticity and hyperalgesia. MRI scans showed increased size of the cystic suprasellar mass (2.5–3 cm, Figure 1C), generalized cortical and subcortical atrophy with focal T2‐hyperintense areas in the frontal lobe. The patient's condition deteriorated rapidly over the next few weeks, resulting in tetraparesis and a decerebrate state. He expired due to pneumonia 48 months after his initial symptoms.

PATHOLOGICAL AUTOPSY FINDINGS

The brain weighed 1010 g. The cortex was thinned with segmental blurring of the gray‐white boundary. The white matter was yellowish, indurated and firm, but in the occipital lobes rarefactions were present. The cystic sellar tumor contained milky‐ grayish fluid. Histologically it was composed of connective tissue strands and septa lined with multilayered squamous epithelium with peripheral palisading of the nuclei (Figure 1D).

In the brain tissue chronic changes of variable duration and distribution were found. The white matter findings included: perivascular and intraparenchymal lymphocytic and macrophage infiltrates, glial reaction, myelin loss and nuclear abnormalities within the glial cells. In the cortex neuronal cell loss, gliosis and sparse intranuclear inclusions were present (Figure 2A) The inclusions were also apparent on plastic‐embedded thick sections stained with toluidine blue (Figure 2B). The perivascular lymphocytic cuffs were CD3 and CD20‐ positive. Moreover the rod and ramified LCA, and CD68‐ positive cells were scattered throughout the nervous tissue. The most intense lymphocytic and rod cells infiltrates and nodular concentrations were encountered in the frontotemporal regions, where multiple foamy macrophages were also noted (Figures 3A and 3B). In the occipital and parietal lobes the loss of myelinated axons was most severe and was accompanied by fibrillary gliosis as seen by GFAP. Ultrastructural examination revealed abnormal filamentous accumulations in both neuronal and oligodendroglial nuclei (Figure 4).

Figure 2.

Figure 3.

Figure 4.

DIAGNOSIS

Subacute sclerosing encephalitis (SSPE) and craniopharyngioma. At the second hospitalization, elevated anti‐ measles antibody titers were detected (1:16 in CSF and 1:256 in the blood).

DISCUSSION

Subacute sclerosing panencephalitis (SSPE) is a chronic neuroinfection caused by a mutant measles virus 1, 3 that usually occurs in children. The clinical differential diagnosis of SSPE includes Schilder sclerosis, leukodystrophies, progressive paralysis, atypical forms of multiple sclerosis and variant CJD 1, 3, 6. Diagnosis is usually based upon a specific presentation with four stages, EEG with periodic stereotyped high voltage discharges, and elevated titers of anti‐measles antibodies in the CSF and blood 3, 4, 7, 9. Stage I of disease is characterized by behavioral changes and cognitive decline. The visual problems and myoclonic jerks are typical for stage II, and stage III symptoms include dystonias, choreoathetosis and spasticity. In stage IV the symptoms progress to autonomic disturbances, coma and vegetative state 6, 9.

Histopathologically, SSPE is an encephalitis with prominent demyelination with variable topography and duration of lesions 1, 5. The occipital lobes are usually the initial location of the changes, and along with the chorioretinitis (which usually accompanies the presentation) are the main causes of visual symptoms 5, 6, 9. During the course of disease the process spreads into contiguous areas, including the basal ganglia and sometimes the spinal cord 5, 7. The perivascular and parenchymal inflammatory infiltrates are composed of lymphocytes, macrophages and activated microglia. Further characteristic and diagnostic findings are intranuclear Cowdry type A inclusions, which can be absent in longstanding cases 2, 4, 5, 8. Depending on duration of the process the active inflammation and/ or chronic destructive‐ reparative changes can be seen as diffuse demyelination, intense fibrillary gliosis, neuronal loss and brain atrophy. In some chronic cases Alzheimer‐ type changes are encountered 1, 4, 8.

Our patient had an unusual clinical picture with a prolonged period of stages I/ II and a fulminant course in the last few weeks of disease. The neuroimaging showed the evolution of the process which corresponded to some clinical symptoms and timing and topography of neuropathological changes. Lesions from the initial MRI correlated with Balint's syndrome, which is associated with bilateral posterior parietal and occipital damage (10). Histologically these areas showed inactive demyelinization, astrogliosis and severe cortical atrophy. In the temporal regions that actively changed in the second MRI there was inflammation along with chronic reparative gliosis and neuronal loss. The T2‐hyperintense frontal areas in the last neuroimaging showed active demyelinating inflammation.

Neuropathological differential diagnosis of SSPE includes other types of viral encephalitides, as well as demyelinating diseases and neurometabolic disorders 4, 5, 8. The clue for the diagnosis is confirmation of the presence of the measles virus nucleocapsids within the inclusions with immunohistochemical, molecular or ultrastructural methods 2, 8, 10. In our case electron microscopy disclosed Paramyxovirus nucleocapsids, both in neuronal and oligodendroglial nuclei. Although SSPE is usually seen in children and young adults, this case demonstrates that SSPE should still be considered in the neurological and neuropathological differential diagnoses even in adult patients. Furthermore this is a first reported case of SSPE coexisting with a brain tumor (craniopharyngioma).

ABSTRACT

A 31‐year‐old man presented with Balint's syndrome. Radiology studies suggested an inflammatory demyelinating process within the occipital and parietal lobes. A cystic sellar/suprasellar mass was also found. Neuroimaging 2.5 years later showed progression of the lesions and growth of the tumor. Based on elevated anti‐measles antibody titers in the cerebrospinal fluid subacute sclerosing panencephalitis (SSPE) was diagnosed. After 4 years of disease the patient died in a decerebrate state with tetraparesis. Neuropathological examination showed brain atrophy with discoloration and irregular induration of the white matter. The sellar tumor was a craniopharyngioma. Microscopically a chronic and active panencephalitis was revealed with intranuclear inclusions. Ultrastructural examination confirmed SSPE by demonstrating measles virus nucleocapsids within the inclusions. SSPE is a rare progressive neurological disorder caused by persistent defective measles virus infection and is usually seen in children and young adults. This disease has been eradicated in many countries by obligatory immunization. This case demonstrates, however, that SSPE should still be considered in the neurological and neuropathological differential diagnoses even in adult patients. Furthermore this is a first reported case of SSPE coexisting with a brain tumor (craniopharyngioma).