Subacute sclerosing panencephalitis, first described by Dawson in 1933, is a progressive degenerative disease of die central nervous system caused by measles slow virus.1'2 As a result of successful immunization programs, cases are becoming increasingly rare. Clinical manifestations appear between the ages of 2 and 21, with peak incidence occurring between the ages of 5 and 15. Ocular involvement, especially chorioretinitis, is a well-recognized association in subacute sclerosing panencephalitis, but previously has been known to occur only at the onset of or several months prior to neurologic signs and dementia.3
This article reports an adolescent girl with subacute sclerosing panencephalitis in whom an atypical chorioretinitis preceded die onset of the neurologic clinical features by 7 years.
A 16-year-old Filipino girl was well until 5 months prior to admission when she presented with abnormal movements and deterioration in her school work. She had a past medical history of measles at age 9 months. At age 9 years, she had a sudden marked loss of vision in her left eye that worsened over 1 month. On ophthalmologic examination, a left afferent pupillary defect and a swollen hyperemic disc with markedly dilated retinal veins were present. Flourescein angiography revealed marked dilatation of superficial disc capillaries. Delayed filling of die retinal veins was prominent, and small varicosities appeared along the vessels (Figure 1).
Figure 1 : Fundus of the left eye at initial presentation. Hyperpermeability of the retinal vessels at the posterior pole is noted with marked venous distension (A). The macular region shows superficial hemorrhages with cotton wool spots and the beginning of early macular scarring (B).
An infectious disease consult was obtained, and a complete work-up, including computed tomography (CT) of the brain, was normal. She was treated with a short dose of oral prednisone. On follow-up examinations, her vision had improved. Small, scattered pale patches remained prominent in the left fundus. The fovea had a pigmented scar with traction lines running toward it from multiple directions consistent with macular chorioretinitis. Further ophthalmologic examination over the next year was without change, and die cause was believed to be a vasculitis of unknown etiology.
Figure 2: Pallor temporally in the left eye is prominent with extensive scarring in the macular region. The inferior temporal veins show perivascular sheathing.
In March 1996, her family noted daily startles where she would lose her balance. A CT scan of the brain was normal and die movements were believed to be psychogenic in nature; therefore, counseling was recommended. However, as the months passed, facial twitching developed associated with grimacing, and personality changes. The school reported increasing cognitive decline with impaired comprehension, deterioration in her writing, and extreme difficulty with mathematics. This was in contrast to her previous above-average grades.
At the Royal Alexandra Hospital for Children in Sydney, Australia, an electroencephalogram (EEG) showed typical periodic complexes. Cerebrospinal fluid (CSF) protein was 0.32 g/L, glucose was 3.5 mmol/L, and measles complement fixation titer was 8. Her CSF measles IgG was elevated and measles IgM negative. Magnetic resonance imaging of the brain was normal. A diagnosis of subacute sclerosing panencephalitis was made, and die parents requested active treatment. She was then referred to Hasbro Children's/Rhode Island Hospital.
Examination in both Sydney and Rhode Island revealed a cooperative and friendly 16-year-old girl with hesitant and periodic stuttering speech. She had difficulty with short-term memory and could not perform simple calculations, becoming confused when asked to do more complex mathematics. On neurologic examination, she had axial and appendicular myoclonus, best seen with her arms outstretched. A shivering-like movement through her arms with facial grimacing and retropulsion was observed, associated with a brief pause in her speech.
Video EEG telemetry at both institutions yielded similar results. Periodic slow wave complexes time-locked to synchronous generalized myoclonic spasms occurred every 7-9 seconds. A second lumbar puncture showed CSF IgG of 44 mg/dL, measles IgG of 1:32, and measles IgM of 1:8. The measles antibody titer was 64 in her serum and 16 in her CSF. A CT brain scan was normal.
Her visual acuity was 20/80 in the left eye with an afferent pupillary defect. The right eye was normal and ocular movements were full. The left optic nerve was pale temporally with significant scarring and abnormal pigmentation in the macular region (Figure 2). Sheathing of the left inferior temporal vein was noted with scattered areas of pigment clumping (Figures 3 and 4). Ophthalmologic findings were consistent with an old infectious chorioretinitis.
Treatment was initiated with oral inosiplex (100 mg/kg/day) and intraventricular a-interferon 2b (Intron A, Schering Slough Ine, Galloping Hill, NJ) starting at 1 00,000 units daily and increasing to 1,400,000 units twice weekly. The myoclonus persisted and carbamazepine was started with resolution of the movements.4 At 8 weeks, the inosiplex dosage was decreased to 50 mg/kg/day because of an elevated uric acid of 6.6 mg/dL. Sertraline 12.5 mg daily also was begun for treatment of a depressed mood.
Initial assessment with the Neurological Disability Index (NDI) found her to be clinical stage IIB based on die presentation of agnosia and myoclonus.5 After 8 weeks of treatment, she had improved to stage I, having only mild cognitive deficits. Her speech was fluent and she could walk independently. Fine motor tasks had improved greatly but difficulties with attention span and calculation persisted. Myoclonic spasms became infrequent, and the periodic slow wave complexes on EEG were recorded only in sleep.
Figure 3: On presentation, the fundus of the left eye showed hyperpigmentation surrounding a light central area in the macular region.
Figure 4: Pigment splinters and contracture of the internal limiting membrane of the retina is noted.
At her 1-year follow-up examination, her parents reported general improvement, although behavioral problems such as inability to follow directions and general disinhibition were present. Generalized seizures also had developed during febrile periods after intraventricular injections. Neurologic examination revealed frontal lobe signs of increased impulsivity and perseveration when asked to complete a complex task. Simple mathematics continued to be problematic. Left hemiplegic dystonic posturing was noted; however, no myoclonic spasms or periodic hesitations were observed.
Ocular involvement in subacute sclerosing panencephalitis has been described at die onset of or several weeks prior to the development of neurologic signs in 50% of patients.6,7 Ophthalmologic presentations are cortical blindness, nystagmus, ptosis, and extraocular muscle palsies.8,9 Fundus changes include papilledema, often as an early clinical sign,10 and optic neuritis caused by intranuclear inclusions within die optic nerve.8 Macular chorioretinitis is die most characteristic fundus finding9"12 and is seen in one diird of cases.13 The typical retinal lesion initially consists of edema and retinal folds with hemorrhages in the macular region.14 The retinal changes are attributed to direct viral invasion because inclusion bodies have been seen in die neuronal cells of the retina and die optic nerve. Electron microscopy shows microtubular structures compatible with viral nucleocapside within die retinal neuroepithelium.9,15'16
At the time of neurologic presentation, our patient had optic atrophy with pallor temporally in the left eye. A gliotic retinal scar with hyperplastic pigmentary changes was present at the edge of the lesion, taking on a splinter-like appearance. Fluorescein studies demonstrated focal deficits in the retinal pigment epithelium without evidence of significant exudative lesions of the choroid as described previously in subacute sclerosing panencephalitis.817
A number of case reports have documented visual loss due to a macular chorioretinitis as the first manifestation of subacute sclerosing panencephalitis,11'1819 but until now, die longest reported interval between presentation with chorioretinitis and die onset of neurologic regression was 24 mondis. Our patient developed visual loss due to chorioretinitis 7 years prior to her signs and symptoms of dementia and myoclonic jerks associated with typical EEG and CSF changes diagnostic of subacute sclerosing panencephalitis. This is die earliest documented presentation of a patient with macular chorioretinitis as the first manifestation of subacute sclerosing panencephalitis.
Subacute sclerosing panencephalitis should be considered in the differential diagnosis of unexplained chorioretinitis or optic atrophy.20 The diagnosis can be confirmed by increased CSF IgG and measles antibody titers, and an IgG synthesis index can be calculated.21,22
At the present time, if a pre-neurologic symptomatic diagnosis of subacute sclerosing panencephalitis is made, how to best treat the patient is uncertain. The question presents as to whether prophylactic treatment would prevent ultimate neurologic deterioration. Obtaining serial IgG synthesis index determinations and an immunologic profile, including cytokines and cytokine shifts, might indicate a rational basis for treating with relatively lowrisk oral immunomodulatory drugs. If it can be determined how die measles virus genome is altered, by obtaining infected cells or tissue, it might be possible to combine an antiviral drug with immunomodulatory drugs to suppress expression of the disease, similar to "combination therapy" approaches now being used in acquired immunodeficiency syndrome.
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