- Email: [email protected]
Subretinal lesions in subacute sclerosing panencephalitis
Subretinal Lesions in Subacute Sclerosing Panencephalitis Nhu Q. Nguyen, BS,a Andrew G. Lee, MD,b Chalmer D. McClure, MD, PhD,c and Geoffrey Miller, MDc
Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurologic disorder. A 9-year-old boy was seen who had progressive neurocognitive decline, myoclonic jerking of the extremities, and an abnormal result of an electroencephalogram (EEG). Ophthalmoscopic examination revealed multifocal subretinal lesions. The diagnosis of SSPE was made on the basis of the clinical examination and elevated serum and spinal fluid measles titer. We describe subretinal lesions in a patient with SSPE.
CASE REPORT A 9-year-old boy, born in Colombia and adopted by North American parents at age 6 months, was referred to us for evaluation of a progressive encephalopathy. For approximately a year before our evaluation, there were school difficulties because of poor concentration and distractibility. When he appeared at our institution, he had nocturnal enuresis, altered mental status, and an abnormal gait characterized by sudden loss of tone. His condition continued to deteriorate during the following weeks and included oromotor dysfunction, an inability to walk, and subtle myoclonic jerks. Daily brief “staring” episodes, after which the child resumed his previous activity, were also seen. The medical history during his first 6 months was unclear. Additional history included right eye (RE) amblyopia with best corrected visual acuity of 20/200 RE and optic nerve hypoplasia RE diagnosed in early childhood. His parents stated that although he had had chickenpox, he had not had measles. He received his initial mumpsmeasles-rubella vaccination at age 13 months while in an area with a measles (rubeola) epidemic. Family history was unknown. The patient did not use medications on a regular basis, although he did receive methylphenidate From Texas A & M University School of Medicine, College Station, Texasa; the Departments of Ophthalmology, Neurology, and Neurosurgery, Baylor College of Medicine and the Department of Neurosurgery, M.D. Anderson Cancer Center, University of Texas, Houston, Texasb; and the Department of Ophthalmologyb and the Pediatric Neurology Section,c Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York. Submitted May 1, 1998. Revision accepted October 9, 1998. Reprint requests: Andrew G. Lee, MD, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin, NC 205, Houston, TX 77030 (e-mail: [email protected]). J AAPOS 1999;3:252-4. Copyright © 1999 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/99 $8.00 + 0 75/1/97518
252
August 1999
(Ritalin) for a brief period before his encephalopathy worsened. He had not received any immunizations in the 12 months before he was seen. Neurologic examination revealed fluctuating mental status. Throughout the examination, there were episodes of cessation of activity with brief staring lasting less than 5 seconds. He was dysarthric with poor prosody but intact syntax. He had appropriate orientation. He also had episodic asymmetric extremity myoclonus, which was unassociated with the staring. His muscle tone was increased, and cogwheel rigidity was noted. He was able to move large muscle groups against gravity but unable to stand. Deep tendon reflexes were abnormally brisk, and extensor plantar responses were present. An intention tremor with dysmetria was present in the limbs. Other findings included drooling, incontinence, blood pressure instability, and diaphoresis with a normal core temperature. Sensation could not be adequately assessed. Neuro-ophthalmologic examination revealed a visual acuity of 20/800 RE and 20/30 left eye (LE). The pupils measured 6 mm bilaterally with a poor light reaction RE but a normal light reaction LE. There was a right relative afferent pupillary defect. The results of an external examination of the adnexa oculi were normal. Motility examination showed full ductions and versions, but the boy had a small angle esotropia in the primary position. The results of slit lamp examination of the anterior segment were normal. Visual fields could not be tested reliably because of poor cooperation. The patient made no reflexive saccades to new stimuli. The finding from tactile tonometry was normal. Ophthalmoscopy showed a normal macula, periphery, and vessels in the RE. The right optic disc was small and somewhat tilted, which is consistent with a hypoplastic optic nerve. There may have been mild superimposed optic atrophy, but this was difficult to determine with certainty because of the presence of optic nerve hypoplasia RE. The left optic nerve showed a mild, segmental, optic disc edema (Figure 1). In the LE there were at least 2 multifocal, translucent pigment, epithelial-level lesions that were oval shaped, measured about 1 to 2 disc diameters, and were not associated with chorioretinal scarring (Figures 2 and 3). No vitreous cells were present. Laboratory testing included normal complete blood count, chemistries, and urinalysis. Test results for human immunodeficiency virus and rapid plasma reagin were negative. Cerebrospinal fluid (CSF) studies included a glucose Journal of AAPOS
Journal of AAPOS Volume 3 Number 4 August 1999
FIG 1. Fundus photo of left eye demonstrates segmental optic disc edema and retinal vascular tortuosity and mild dilation.
of 58 mg/dL (normal dependent on serum glucose), protein of 32 mg/dL (normal less than 45 mg/dL), 4 white blood cells, and 0 red blood cells. Repeated CSF studies had similar findings. CSF IgG was elevated at 18.6 mg/dL (normal 0.5-6.1 mg/dL), and oligoclonal banding at the gamma region was detected. Rubeola IgG antibody titer in the CSF was significantly elevated at greater than 1:160; serum rubeola IgG was greater than 1:5000, whereas serum IgM was less than 1:10. The ratio of CSF IgG/albumen, the synthesis rate, and the index were elevated, consistent with the breakdown of the blood-brain barrier and concurrent central nervous system infection. The results of metabolic evaluation including serum medium chain acyl-CoA dehydrogenase, serum amino acids, urine organic acids, and lactate levels were normal. Magnetic resonance imaging of the head did not show any abnormalities on T1- or T2-weighted sequences. On the fluid attenuation inversion recovery sequence, an increased signal was noted in the splenium of the corpus callosum and the hippocampus on the right. There was also a mild increased signal in the white matter of the right occipital and temporal regions. An EEG showed sharp and slow wave complexes in a periodic pattern consistent with that found in SSPE. The patient received isoprinosine (inosiplex) 1000 g, orally, 3 times a day. The drug was obtained from Europe and approved for use in the United States on a compassionate basis. The family chose not to institute treatment with intraventricular or intrathecal alpha-interferon. Seizure prophylaxis was continued with fosphenytoin although clinical seizures were not witnessed. The child’s autonomic functioning stabilized, but his mental status deteriorated to
Nguyen et al
253
FIG 2. Fundus photograph of temporal paramacular region of left eye demonstrates a circumscribed elevated lesion with an indistinct border below the level of the retinal blood vessels (arrow). There was no evidence of chorioretinal scarring or RPE hypertrophy.
FIG 3. Fundus photograph of the inferotemporal arcade of left eye demonstrates a circumscribed subretinal lesion (arrow).
obtundation. Asynchronous multifocal myoclonus persisted. The child was later transferred to a long-term care facility. The findings of further ophthalmologic examinations and neurologic follow-up are not available.
254 Nguyen et al DISCUSSION SSPE (Dawson’s encephalitis) is a neurodegenerative disease that affects children and young adults. Most of the symptomatic patients are between 5 and 15 years of age.1 Clinical findings include lethargy, myoclonus, seizures, dysautonomia, behavioral changes, and progressive encephalopathy with dementia. The course of deterioration is usually gradual over 1 to 3 years, although approximately 10% of patients have a fulminant course (less than 3 months).2,3 Most patients who have the disease had measles (rubeola) before 2 years of age.4 A small number of patients have no clinical history of either measles or reaction to rubeola immunization.5 The occurrence of the disease in male patients is approximately 3 times greater than in female patients.1 Although no proven effective therapy is available, oral inosiplex and intraventricular or intrathecal alpha-interferon may delay disease progression.6 Inosiplex (a complex of inosine and dimethylaminoisopropanol-p-actetamido-benzoate) is thought to inhibit viral replication in host cells and augment cellular immune response. The efficacy of inosiplex as an antiviral or immunomodulatory agent remains controversial.2,6 Abnormally low interferon production in the central nervous system may be involved in SSPE, and interferon has been used with some success in previous studies.6 A multicenter study outside the United States is currently underway to compare oral inosiplex alone with oral inosiplex combined with intraventricular interferon alfa-2b to evaluate efficacy of these medications.7 Patients may have ophthalmologic findings that precede, occur concurrently with, or follow the neurologic signs and symptoms.8,9 The visual disturbances include cortical blindness, homonymous field defects, impaired spatial perception, and formed or unformed visual hallucinations.8-10 Abnormalities of ocular motility, including nystagmus, supranuclear gaze pareses, ocular motor nerve pareses, and other involuntary eye movements, usually occur late in the course of the disease. Ptosis and proptosis have also been reported in rare cases. Other findings include optic neuritis, optic atrophy, retinal vasculitis, and macular or chorioretinal disturbances.8-10 Ophthalmoscopy in the acute phase may demonstrate focal or multifocal white retinal lesions or larger, more ragged gray-white areas. The white lesions resolve rapidly to irregular areas of retinal pigment epithelial (RPE) atrophy and gliotic scarring. There is usually minimal choroidal or vitreal inflammation.8-10 The retinal lesions
Journal of AAPOS Volume 3 Number 4 August 1999
of SSPE may be highly variable and may represent RPE detachments or retinitis. In our patient the identification of retinal abnormalities helped to support the clinical diagnosis of SSPE by excluding other progressive neurologic conditions that are not associated with subretinal lesions. Histopathologically, the acute lesions are patchy areas of focal necrosis, pigment-laden macrophages, and pigmentary loss in the RPE. Later, the lesions demonstrate focal atrophy of the retina and RPE and Cowdry type A and type B intranuclear inclusions and intracytoplasmic inclusions. Immunofluorescent studies have demonstrated the presence of measles virus in the retina. The diagnosis of SSPE is based on the clinical findings of progressive dementia and myoclonus in a child or young adult; elevated serum and CSF measles titers; and an abnormal result of an EEG showing high-amplitude, sharp, slow wave complexes. The ophthalmoscopic findings may allow the diagnosis to be made early in the course of patients with unexplained progressive dementia. SSPE may occur in immunonormal or immunosuppressed individuals, and the disease may be due to an altered measles virus or an altered host response to the virus. Our patient had no known history of measles but had received measles immunization. He was not immunosuppressed from cytotoxic therapy or immunodeficiency state. Unfortunately, there is no effective treatment for SSPE. References 1. Modlin J, Halsey H, Eddins D. Epidemiology of subacute sclerosing panencephalitis. J Pediatr 1979;94:231-6. 2. Dyken P. Subacute sclerosing panencephalitis. Neurol Clin 1985;3:179-96. 3. Risk W, Haddad F. The variable natural history of subacute sclerosing panencephalitis. Arch Neurol 1979;36:610-4. 4. Halsey N, Modline N, Jabbour J. Risk factors in subacuate sclerosing panencephalitis. Am J Epidemiol 1998;111:415-24. 5. Zilber N, Rannon L, Alter M, et al. Measles, measles vaccination, and risk of subacute sclerosing panencephalitis. Neurology 1983;33:1558-64. 6. Yalaz K, Anlar B, Oktem F, et al. Intraventricular interferon and oral inosiplex in the treatment of subacuate sclerosing panencephalitis. Neurology 1992;42:488-91. 7. Gascon G. Treatment of subacute sclerosing panencephalitis. J Child Neurol 1997;12:469-70. 8. Green SH, Wirtschafter JD. Ophthalmoscopic findings in subacuate sclerosing panencephalitis. Br J Ophthalmol 1973;57:780-7. 9. Hiatt RL, Grizzard JT, McNeer P, et al. Ophthalmologic manifestations of subacute sclerosing panencephalitis. Trans Am Acad Ophthalmol Otolaryngol 1971;75:344-50. 10. Gravina RF, Nakanishi AS, Faden A. Subacute sclerosing panencephalitis. Am J Ophthalmol 1978;86:106-9.
Subacute sclerosing panencephalitis (SSPE) is a rare progressive neurologic disorder. A 9-year-old boy was seen who had progressive neurocognitive decline, myoclonic jerking of the extremities, and an abnormal result of an electroencephalogram (EEG). Ophthalmoscopic examination revealed multifocal subretinal lesions. The diagnosis of SSPE was made on the basis of the clinical examination and elevated serum and spinal fluid measles titer. We describe subretinal lesions in a patient with SSPE.
CASE REPORT A 9-year-old boy, born in Colombia and adopted by North American parents at age 6 months, was referred to us for evaluation of a progressive encephalopathy. For approximately a year before our evaluation, there were school difficulties because of poor concentration and distractibility. When he appeared at our institution, he had nocturnal enuresis, altered mental status, and an abnormal gait characterized by sudden loss of tone. His condition continued to deteriorate during the following weeks and included oromotor dysfunction, an inability to walk, and subtle myoclonic jerks. Daily brief “staring” episodes, after which the child resumed his previous activity, were also seen. The medical history during his first 6 months was unclear. Additional history included right eye (RE) amblyopia with best corrected visual acuity of 20/200 RE and optic nerve hypoplasia RE diagnosed in early childhood. His parents stated that although he had had chickenpox, he had not had measles. He received his initial mumpsmeasles-rubella vaccination at age 13 months while in an area with a measles (rubeola) epidemic. Family history was unknown. The patient did not use medications on a regular basis, although he did receive methylphenidate From Texas A & M University School of Medicine, College Station, Texasa; the Departments of Ophthalmology, Neurology, and Neurosurgery, Baylor College of Medicine and the Department of Neurosurgery, M.D. Anderson Cancer Center, University of Texas, Houston, Texasb; and the Department of Ophthalmologyb and the Pediatric Neurology Section,c Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York. Submitted May 1, 1998. Revision accepted October 9, 1998. Reprint requests: Andrew G. Lee, MD, Cullen Eye Institute, Baylor College of Medicine, 6565 Fannin, NC 205, Houston, TX 77030 (e-mail: [email protected]). J AAPOS 1999;3:252-4. Copyright © 1999 by the American Association for Pediatric Ophthalmology and Strabismus. 1091-8531/99 $8.00 + 0 75/1/97518
252
August 1999
(Ritalin) for a brief period before his encephalopathy worsened. He had not received any immunizations in the 12 months before he was seen. Neurologic examination revealed fluctuating mental status. Throughout the examination, there were episodes of cessation of activity with brief staring lasting less than 5 seconds. He was dysarthric with poor prosody but intact syntax. He had appropriate orientation. He also had episodic asymmetric extremity myoclonus, which was unassociated with the staring. His muscle tone was increased, and cogwheel rigidity was noted. He was able to move large muscle groups against gravity but unable to stand. Deep tendon reflexes were abnormally brisk, and extensor plantar responses were present. An intention tremor with dysmetria was present in the limbs. Other findings included drooling, incontinence, blood pressure instability, and diaphoresis with a normal core temperature. Sensation could not be adequately assessed. Neuro-ophthalmologic examination revealed a visual acuity of 20/800 RE and 20/30 left eye (LE). The pupils measured 6 mm bilaterally with a poor light reaction RE but a normal light reaction LE. There was a right relative afferent pupillary defect. The results of an external examination of the adnexa oculi were normal. Motility examination showed full ductions and versions, but the boy had a small angle esotropia in the primary position. The results of slit lamp examination of the anterior segment were normal. Visual fields could not be tested reliably because of poor cooperation. The patient made no reflexive saccades to new stimuli. The finding from tactile tonometry was normal. Ophthalmoscopy showed a normal macula, periphery, and vessels in the RE. The right optic disc was small and somewhat tilted, which is consistent with a hypoplastic optic nerve. There may have been mild superimposed optic atrophy, but this was difficult to determine with certainty because of the presence of optic nerve hypoplasia RE. The left optic nerve showed a mild, segmental, optic disc edema (Figure 1). In the LE there were at least 2 multifocal, translucent pigment, epithelial-level lesions that were oval shaped, measured about 1 to 2 disc diameters, and were not associated with chorioretinal scarring (Figures 2 and 3). No vitreous cells were present. Laboratory testing included normal complete blood count, chemistries, and urinalysis. Test results for human immunodeficiency virus and rapid plasma reagin were negative. Cerebrospinal fluid (CSF) studies included a glucose Journal of AAPOS
Journal of AAPOS Volume 3 Number 4 August 1999
FIG 1. Fundus photo of left eye demonstrates segmental optic disc edema and retinal vascular tortuosity and mild dilation.
of 58 mg/dL (normal dependent on serum glucose), protein of 32 mg/dL (normal less than 45 mg/dL), 4 white blood cells, and 0 red blood cells. Repeated CSF studies had similar findings. CSF IgG was elevated at 18.6 mg/dL (normal 0.5-6.1 mg/dL), and oligoclonal banding at the gamma region was detected. Rubeola IgG antibody titer in the CSF was significantly elevated at greater than 1:160; serum rubeola IgG was greater than 1:5000, whereas serum IgM was less than 1:10. The ratio of CSF IgG/albumen, the synthesis rate, and the index were elevated, consistent with the breakdown of the blood-brain barrier and concurrent central nervous system infection. The results of metabolic evaluation including serum medium chain acyl-CoA dehydrogenase, serum amino acids, urine organic acids, and lactate levels were normal. Magnetic resonance imaging of the head did not show any abnormalities on T1- or T2-weighted sequences. On the fluid attenuation inversion recovery sequence, an increased signal was noted in the splenium of the corpus callosum and the hippocampus on the right. There was also a mild increased signal in the white matter of the right occipital and temporal regions. An EEG showed sharp and slow wave complexes in a periodic pattern consistent with that found in SSPE. The patient received isoprinosine (inosiplex) 1000 g, orally, 3 times a day. The drug was obtained from Europe and approved for use in the United States on a compassionate basis. The family chose not to institute treatment with intraventricular or intrathecal alpha-interferon. Seizure prophylaxis was continued with fosphenytoin although clinical seizures were not witnessed. The child’s autonomic functioning stabilized, but his mental status deteriorated to
Nguyen et al
253
FIG 2. Fundus photograph of temporal paramacular region of left eye demonstrates a circumscribed elevated lesion with an indistinct border below the level of the retinal blood vessels (arrow). There was no evidence of chorioretinal scarring or RPE hypertrophy.
FIG 3. Fundus photograph of the inferotemporal arcade of left eye demonstrates a circumscribed subretinal lesion (arrow).
obtundation. Asynchronous multifocal myoclonus persisted. The child was later transferred to a long-term care facility. The findings of further ophthalmologic examinations and neurologic follow-up are not available.
254 Nguyen et al DISCUSSION SSPE (Dawson’s encephalitis) is a neurodegenerative disease that affects children and young adults. Most of the symptomatic patients are between 5 and 15 years of age.1 Clinical findings include lethargy, myoclonus, seizures, dysautonomia, behavioral changes, and progressive encephalopathy with dementia. The course of deterioration is usually gradual over 1 to 3 years, although approximately 10% of patients have a fulminant course (less than 3 months).2,3 Most patients who have the disease had measles (rubeola) before 2 years of age.4 A small number of patients have no clinical history of either measles or reaction to rubeola immunization.5 The occurrence of the disease in male patients is approximately 3 times greater than in female patients.1 Although no proven effective therapy is available, oral inosiplex and intraventricular or intrathecal alpha-interferon may delay disease progression.6 Inosiplex (a complex of inosine and dimethylaminoisopropanol-p-actetamido-benzoate) is thought to inhibit viral replication in host cells and augment cellular immune response. The efficacy of inosiplex as an antiviral or immunomodulatory agent remains controversial.2,6 Abnormally low interferon production in the central nervous system may be involved in SSPE, and interferon has been used with some success in previous studies.6 A multicenter study outside the United States is currently underway to compare oral inosiplex alone with oral inosiplex combined with intraventricular interferon alfa-2b to evaluate efficacy of these medications.7 Patients may have ophthalmologic findings that precede, occur concurrently with, or follow the neurologic signs and symptoms.8,9 The visual disturbances include cortical blindness, homonymous field defects, impaired spatial perception, and formed or unformed visual hallucinations.8-10 Abnormalities of ocular motility, including nystagmus, supranuclear gaze pareses, ocular motor nerve pareses, and other involuntary eye movements, usually occur late in the course of the disease. Ptosis and proptosis have also been reported in rare cases. Other findings include optic neuritis, optic atrophy, retinal vasculitis, and macular or chorioretinal disturbances.8-10 Ophthalmoscopy in the acute phase may demonstrate focal or multifocal white retinal lesions or larger, more ragged gray-white areas. The white lesions resolve rapidly to irregular areas of retinal pigment epithelial (RPE) atrophy and gliotic scarring. There is usually minimal choroidal or vitreal inflammation.8-10 The retinal lesions
Journal of AAPOS Volume 3 Number 4 August 1999
of SSPE may be highly variable and may represent RPE detachments or retinitis. In our patient the identification of retinal abnormalities helped to support the clinical diagnosis of SSPE by excluding other progressive neurologic conditions that are not associated with subretinal lesions. Histopathologically, the acute lesions are patchy areas of focal necrosis, pigment-laden macrophages, and pigmentary loss in the RPE. Later, the lesions demonstrate focal atrophy of the retina and RPE and Cowdry type A and type B intranuclear inclusions and intracytoplasmic inclusions. Immunofluorescent studies have demonstrated the presence of measles virus in the retina. The diagnosis of SSPE is based on the clinical findings of progressive dementia and myoclonus in a child or young adult; elevated serum and CSF measles titers; and an abnormal result of an EEG showing high-amplitude, sharp, slow wave complexes. The ophthalmoscopic findings may allow the diagnosis to be made early in the course of patients with unexplained progressive dementia. SSPE may occur in immunonormal or immunosuppressed individuals, and the disease may be due to an altered measles virus or an altered host response to the virus. Our patient had no known history of measles but had received measles immunization. He was not immunosuppressed from cytotoxic therapy or immunodeficiency state. Unfortunately, there is no effective treatment for SSPE. References 1. Modlin J, Halsey H, Eddins D. Epidemiology of subacute sclerosing panencephalitis. J Pediatr 1979;94:231-6. 2. Dyken P. Subacute sclerosing panencephalitis. Neurol Clin 1985;3:179-96. 3. Risk W, Haddad F. The variable natural history of subacute sclerosing panencephalitis. Arch Neurol 1979;36:610-4. 4. Halsey N, Modline N, Jabbour J. Risk factors in subacuate sclerosing panencephalitis. Am J Epidemiol 1998;111:415-24. 5. Zilber N, Rannon L, Alter M, et al. Measles, measles vaccination, and risk of subacute sclerosing panencephalitis. Neurology 1983;33:1558-64. 6. Yalaz K, Anlar B, Oktem F, et al. Intraventricular interferon and oral inosiplex in the treatment of subacuate sclerosing panencephalitis. Neurology 1992;42:488-91. 7. Gascon G. Treatment of subacute sclerosing panencephalitis. J Child Neurol 1997;12:469-70. 8. Green SH, Wirtschafter JD. Ophthalmoscopic findings in subacuate sclerosing panencephalitis. Br J Ophthalmol 1973;57:780-7. 9. Hiatt RL, Grizzard JT, McNeer P, et al. Ophthalmologic manifestations of subacute sclerosing panencephalitis. Trans Am Acad Ophthalmol Otolaryngol 1971;75:344-50. 10. Gravina RF, Nakanishi AS, Faden A. Subacute sclerosing panencephalitis. Am J Ophthalmol 1978;86:106-9.