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Relapsing-remitting, corticosteroid-sensitive, varicella zoster virus optic neuritis
Relapsing-Remitting, CorticosteroidSensitive, Varicella Zoster Virus Optic Neuritis Misha L. Pless, MD*, and Saleem I. Malik, MD†
We report a 13-year-old male who presented with bilateral disc edema after a febrile illness. Rapid loss of vision prompted corticosteroids treatment, which reversed the visual loss and optic disc findings. Both his visual function and disc edema proved exceedingly sensitive to steroids, and he required increasingly slow and prolonged corticosteroids taper to avoid relapse over a period of 1 year. Ultimately, profound visual loss was reversed three times and only after exceptionally slow steroid weaning. Comprehensive systemic investigations and neuroimaging were initially unrevealing. Late in the course of disease, evidence of seroconversion was identified in his serum and cerebrospinal fluid with positive varicella zoster virus antibodies titers. Varicella zoster virus–related optic nerve pathology may present clinically with profound visual loss and disc edema and may reverse only with high-dose corticosteroids treatment. Physicians should carefully consider retesting with late varicella zoster virus titer in patients with relapsing-remitting, steroidsensitive optic neuritides. © 2003 by Elsevier Inc. All rights reserved. Pless ML, Malik SI. Relapsing-remitting, corticosteroidsensitive, varicella zoster virus optic neuritis. Pediatr Neurol 2003;29:422-424.
From the *Departments of Ophthalmology, Neurological Surgery, and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and †Department of Pediatric Neurology, University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
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Introduction Central nervous system involvement with varicella zoster virus is uncommon but has been reported as direct infection, reinfection, or latent reactivation [1-3]. Optic neuritis, encephalitis, cerebral arteritis, and transverse myelitis are known clinical presentations of varicella zoster virus [4-7]. Serology-proven central nervous system infection without previous or concurrent cutaneous exanthem (zoster sine herpete) has also been reported [8]. In cases of ocular or optic nerve varicella zoster virus involvement, complete recovery of visual function is expected. Cerebrospinal fluid does not usually contain varicella zoster virus antibodies, therefore the eventual presence of these antibodies indicates either infection or reactivation of the virus. The case presented in this article is salient in two ways. First, the patient experienced an extraordinary relapsing-remitting course with exquisite corticosteroid-dependence and sensitivity within the year of presentation. Second, varicella zoster virus seroconversion occurred late in the course of disease, which required diligence on the part of the treating clinicians, thereby demonstrating the importance of retesting in the appropriate clinical setting. Case Report A 13-year-old, right-handed male, who had an unremarkable medical history, was observed in the emergency room with a 2-week history of low-grade fever, malaise, and severe headache. Two days before presentation, he began to experience blurred vision. He did not have a history of chicken pox, was up to date on all immunizations, and had not received a varicella zoster virus vaccine as an infant. During the physical examination, mild nuchal rigidity, visual acuity of 20/20, and normal color vision in both eyes were found. Pupil examination and ocular ductions were normal. He had moderate disc edema bilaterally (Fig 1). The cranioorbital computed tomographic scan was unrevealing. The results of the lumbar puncture indicated an opening pressure of 260 mm H2O, protein of 60 mg/dL, glucose of 48 mg/dL, and white blood cell count of 108 mm3 (normal is less than 3), 84% lymphocytes, and 2% atypical lymphocytes. There were no oligoclonal bands, and the immunoglobulin G (IgG) index was 0.65 (normal is up to 0.7). The cerebrospinal fluid polymerase chain reaction for human herpes viruses (herpesvirus-1 and -2), Epstein-Barr virus, varicella zoster virus, cytomegalovirus, and herpesvirus-6 were negative. The cerebrospinal fluid cytologic examination indicated nonmalignant lymphocytes. The flow cytometry analysis indicated normal immune cellular distribution. The cerebrospinal fluid cryptococcal antigen and cultures for Listeria, acidfast bacilli, fungi, and viruses were negative. Aerobic and anaerobic cerebrospinal fluid cultures were also negative. Additional laboratory
Communications should be addressed to: Dr. Pless; Director, Neuro-Ophthalmology; Eye and Ear Institute; 203 Lothrop Street; Pittsburgh, PA 15213. Received December 17, 2002; accepted April 29, 2003.
© 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00306-0 ● 0887-8994/03/$—see front matter
Figure 1. Magnified OS optic nerve photograph.
testing included normal blood counts, serum protein electrophoresis, angiotensin-converting enzyme and complement levels, and negative antinuclear and antineutrophil cytoplasmic antibodies, Sjo¨ gren antibodies, Lyme titers, and human immunovirus serology. Cranioorbital magnetic resonance imaging with angiography and venography were also normal. The patient was treated with 250 mg of acetazolamide administered orally two times daily and then discharged for home. One week later, his visual acuity was 20/30 in the right eye (OD) and 20/25 in the left eye (OS). His color vision was reduced to 25% OD and OS to 75%, as measured with pseudoisochromatic plates. The disc edema had worsened, and there were peripapillary hemorrhages. A lumbar puncture was repeated, and indicated an opening pressure of 150 mm H2O, protein 181 mg/dL, glucose 60 mg/dL, and 23 white blood cells mm3, 98% lymphocytes. His cerebrospinal fluid was tested twice for antibodies to arboviridae, herpesvirus, Epstein-Barr virus, cytomegalovirus, and varicella zoster virus by the complement fixation method; the results were negative. His serum was tested for the same virus antibody titers, and all were negative. He had a normal chest roentgenogram, and his peripheral blood counts were normal. Acetazolamide was discontinued. Treatment with intravenous methylprednisone was begun at 750 mg daily for 3 days, and he was sent home on 60 mg per day of prednisone with a slow taper over a period of 2 months. While taking prednisone, his disc edema slowly improved, and he became asymptomatic regarding his visual acuity and color perception. However, 6 weeks after presentation and while tapering his doses of prednisone (i.e., 40 mg per day), he had an exacerbation with visual acuity of count finger at 6 feet OD and 20/20 OS, which developed over a period of 48 hours. Color vision was nil OD but normal OS by Ishihara plates. He developed a relative afferent pupillary defect on the right side. Both optic discs were severely edematous. He had bilateral extensor plantar responses. A third lumbar puncture indicated an opening pressure of 160 mmH2O, protein of 54 mg/dL, glucose of 41 mg/dL, white blood cell count of 11 mm3, and 73% lymphocytes. Repeated craniocervical magnetic resonance imaging indicated T2-signal hyperintensity in the regions underlying the right insular and the right frontal cortices. Additionally, there was an area of abnormal signal in the cord at the level of the first and second cervical vertebral bodies (Fig 2). His peripheral blood counts, serum protein electrophoresis, angiotensin-converting enzyme level, complement levels, antinuclear and antineutrophil cytoplasmic antibodies, and Sjo¨ gren antibodies were retested and within the normal limits. The cerebrospinal fluid polymerase chain reaction for human herpes viruses (herpesvirus-1 and 2), Epstein-Barr virus, varicella
Figure 2. Unenhanced, T1-weighted, sagittal image (repetition time ⫽ 400, echo time ⫽ 1) of the spine showing increased signal in white matter at the C2-3 cervical level. zoster virus , cytomegalovirus, and herpesvirus-6 were negative once again. Using the complement fixation method, antibodies to arboviridae, herpesvirus, Epstein-Barr virus, and cytomegalovirus were undetectable in the serum and cerebrospinal fluid. This time, however, his serum varicella zoster virus complement fixation assay was positive at 320 (normal is less than 8) and the cerebrospinal fluid varicella zoster virus complement fixation assay was also positive when undiluted. The child was again treated with intravenous methylprednisolone at 1 gm per day for 5 days, as well as a 10-day course of oral acyclovir, and he was discharged home with a slow, 6-month oral prednisone taper. During the fourth month of tapering, that is, when the patient’s prednisone dosage had reached 20 mg per day, he had another episode of visual blurring with a decline in visual function of both eyes. His visual acuity was 20/100 OD and 20/40 OS. Both optic nerves had developed temporal pallor. His oral prednisone was again increased to 60 mg per day, and a slow taper again began over a 6-month period. At 1 year after presentation, he was taking 20 mg of prednisone every other day. His visual acuity was 20/20 OD and OS, his Ishihara color perception was 75% to 80% in either eye, and he had a right-sided afferent pupillary defect. Both optic nerves were pale. Otherwise, he had a normal neurologic examination. Figure 3 is a chronologic composite of the child’s visual field testing during the 18-month treatment period.
Discussion Varicella zoster virus is a herpesvirus whose primary infection results in chickenpox. The virus can persist in a latent form whose reactivation can result in shingles. There are case reports of varicella zoster virus producing neurologic disease without rash (zoster sine herpete) [8]. Various complications, including optic neuritis, aseptic
Pless and Malik: Varicella Zoster Virus Optic Neuritis 423
Figure 3. Composite of several Humphrey 30-2 visual field tests performed over a 11⁄2-year period.
meningitis, myelitis, and encephalitis, have been described [1,3,5,7]. The pathogenesis leading to varicella zoster virus central nervous system involvement is unknown. Immunologic mechanisms, rather than direct invasion, are likely. Molecular mimicry between virus and neural antigen in genetically selected individuals has been postulated. Confirmation of the link between varicella zoster virus and optic neuritis depends on history, serologic testing, and the exclusion of other common etiologies, because direct pathologic examination of involved area is not possible [9,10]. The diagnosis of varicella zoster virus meningoencephalitis is based on intrathecal virus-specific IgG-, IgA-, and IgM-antibody responses demonstrated by immunefixation, as well as polymerase chain reaction methods [11]. Our patient has had exhaustive and unrevealing investigations on multiple occasions. Given the prodrome of high fevers and meningitic symptoms the patient experienced before the onset of optic neuritis, a high index of suspicion of a viral etiology prompted repeated sets of investigations both in the serum and cerebrospinal fluid in an effort to search for a reasonable etiologic culprit. Except for varicella zoster virus seroconversion both in serum and cerebrospinal fluid, no other cause of illness was identified in this patient. Arguably, childhood-onset multiple sclerosis or acute disseminated/recurrent encephalomyelitis with coincidental varicella zoster virus infection represent a distinct possibility, although the fact remains that the child seroconverted to varicella zoster virus in approximately the second month after the onset of symptoms, which suggested varicella zoster virus as the leading and most persuasive etiology. Exquisite response to intravenous corticosteroid treatment cannot be used as a diagnostic
424
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Vol. 29 No. 5
tool, because the long-term outcome of optic neuritis is largely unaffected regardless of corticosteroid treatment, as demonstrated in the optic neuritis treatment trial [12].
References [1] Purvin V, Hrisomalos N, Dunn D. Varicella optic neuritis. Neurology 1988;38:501-3. [2] Selbst RG, Selhorst JB, Harbison JW, Myer EC. Parainfectious optic neuritis report and review following varicella. Arch Neurol 1983; 40:347-50. [3] Dueland AN, Devlin M, Martin JR, et al. Fatal varicella-zoster meningo-radiculitis without skin involvement. Ann Neurol 1991;29:56972. [4] Pina MA, Ara JR, Capablo JL, Omenaca M. Myelitis and optic neuritis caused by varicella. Revista de Neurologia 1997;25:1575-6. [5] Miller DH, Kay R, Schon F, McDonald WI, Haas LF, Hughes RA. Optic neuritis following chicken pox in adult. J Neurol 1986;233: 182-4. [6] Vartdal F, Vandvik B, Norrby E. Intrathecal synthesis of virus specific ologoclonal IgG, IgA and IgM antibodies in a case of varicillazoster meningoencephalitis. J Neurol Sci 1982;57:121-32. [7] Mayo DR, Booss J. Varicella zoster associated neurological disease without skin lesion. Arch Neurol 1989;46:313-5. [8] Gilden DH, Dueland AN, Devlin ME, Mahalingam R, Cohrs R. Varicella zoster reactivation without rash. J Infect Dis 1992;166:30-4. [9] Johnson R, Milbourn PE. Central nervous system manifestations of chickenpox. Can Med Assoc J 1970;102:831-4. [10] Griffith JF, Salam MV, Adams RD. The nervous system disease associated with varicella. Acta Neurol Scan 1970;46:270-300. [11] Dal Canto MC, Robinowitz SG. Experimental models of virus induced demyelination of central nervous system. Ann Neurol 1982;1: 100-27. [12] Beck RW. The optic neuritis treatment trial: Implications for clinical practice. Optic Neuritis Study Group. Arch Ophthal 1992;110: 331-2.
We report a 13-year-old male who presented with bilateral disc edema after a febrile illness. Rapid loss of vision prompted corticosteroids treatment, which reversed the visual loss and optic disc findings. Both his visual function and disc edema proved exceedingly sensitive to steroids, and he required increasingly slow and prolonged corticosteroids taper to avoid relapse over a period of 1 year. Ultimately, profound visual loss was reversed three times and only after exceptionally slow steroid weaning. Comprehensive systemic investigations and neuroimaging were initially unrevealing. Late in the course of disease, evidence of seroconversion was identified in his serum and cerebrospinal fluid with positive varicella zoster virus antibodies titers. Varicella zoster virus–related optic nerve pathology may present clinically with profound visual loss and disc edema and may reverse only with high-dose corticosteroids treatment. Physicians should carefully consider retesting with late varicella zoster virus titer in patients with relapsing-remitting, steroidsensitive optic neuritides. © 2003 by Elsevier Inc. All rights reserved. Pless ML, Malik SI. Relapsing-remitting, corticosteroidsensitive, varicella zoster virus optic neuritis. Pediatr Neurol 2003;29:422-424.
From the *Departments of Ophthalmology, Neurological Surgery, and Neurology, University of Pittsburgh School of Medicine, Pittsburgh, PA; and †Department of Pediatric Neurology, University of Pittsburgh Medical Center, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania.
422
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
Introduction Central nervous system involvement with varicella zoster virus is uncommon but has been reported as direct infection, reinfection, or latent reactivation [1-3]. Optic neuritis, encephalitis, cerebral arteritis, and transverse myelitis are known clinical presentations of varicella zoster virus [4-7]. Serology-proven central nervous system infection without previous or concurrent cutaneous exanthem (zoster sine herpete) has also been reported [8]. In cases of ocular or optic nerve varicella zoster virus involvement, complete recovery of visual function is expected. Cerebrospinal fluid does not usually contain varicella zoster virus antibodies, therefore the eventual presence of these antibodies indicates either infection or reactivation of the virus. The case presented in this article is salient in two ways. First, the patient experienced an extraordinary relapsing-remitting course with exquisite corticosteroid-dependence and sensitivity within the year of presentation. Second, varicella zoster virus seroconversion occurred late in the course of disease, which required diligence on the part of the treating clinicians, thereby demonstrating the importance of retesting in the appropriate clinical setting. Case Report A 13-year-old, right-handed male, who had an unremarkable medical history, was observed in the emergency room with a 2-week history of low-grade fever, malaise, and severe headache. Two days before presentation, he began to experience blurred vision. He did not have a history of chicken pox, was up to date on all immunizations, and had not received a varicella zoster virus vaccine as an infant. During the physical examination, mild nuchal rigidity, visual acuity of 20/20, and normal color vision in both eyes were found. Pupil examination and ocular ductions were normal. He had moderate disc edema bilaterally (Fig 1). The cranioorbital computed tomographic scan was unrevealing. The results of the lumbar puncture indicated an opening pressure of 260 mm H2O, protein of 60 mg/dL, glucose of 48 mg/dL, and white blood cell count of 108 mm3 (normal is less than 3), 84% lymphocytes, and 2% atypical lymphocytes. There were no oligoclonal bands, and the immunoglobulin G (IgG) index was 0.65 (normal is up to 0.7). The cerebrospinal fluid polymerase chain reaction for human herpes viruses (herpesvirus-1 and -2), Epstein-Barr virus, varicella zoster virus, cytomegalovirus, and herpesvirus-6 were negative. The cerebrospinal fluid cytologic examination indicated nonmalignant lymphocytes. The flow cytometry analysis indicated normal immune cellular distribution. The cerebrospinal fluid cryptococcal antigen and cultures for Listeria, acidfast bacilli, fungi, and viruses were negative. Aerobic and anaerobic cerebrospinal fluid cultures were also negative. Additional laboratory
Communications should be addressed to: Dr. Pless; Director, Neuro-Ophthalmology; Eye and Ear Institute; 203 Lothrop Street; Pittsburgh, PA 15213. Received December 17, 2002; accepted April 29, 2003.
© 2003 by Elsevier Inc. All rights reserved. doi:10.1016/S0887-8994(03)00306-0 ● 0887-8994/03/$—see front matter
Figure 1. Magnified OS optic nerve photograph.
testing included normal blood counts, serum protein electrophoresis, angiotensin-converting enzyme and complement levels, and negative antinuclear and antineutrophil cytoplasmic antibodies, Sjo¨ gren antibodies, Lyme titers, and human immunovirus serology. Cranioorbital magnetic resonance imaging with angiography and venography were also normal. The patient was treated with 250 mg of acetazolamide administered orally two times daily and then discharged for home. One week later, his visual acuity was 20/30 in the right eye (OD) and 20/25 in the left eye (OS). His color vision was reduced to 25% OD and OS to 75%, as measured with pseudoisochromatic plates. The disc edema had worsened, and there were peripapillary hemorrhages. A lumbar puncture was repeated, and indicated an opening pressure of 150 mm H2O, protein 181 mg/dL, glucose 60 mg/dL, and 23 white blood cells mm3, 98% lymphocytes. His cerebrospinal fluid was tested twice for antibodies to arboviridae, herpesvirus, Epstein-Barr virus, cytomegalovirus, and varicella zoster virus by the complement fixation method; the results were negative. His serum was tested for the same virus antibody titers, and all were negative. He had a normal chest roentgenogram, and his peripheral blood counts were normal. Acetazolamide was discontinued. Treatment with intravenous methylprednisone was begun at 750 mg daily for 3 days, and he was sent home on 60 mg per day of prednisone with a slow taper over a period of 2 months. While taking prednisone, his disc edema slowly improved, and he became asymptomatic regarding his visual acuity and color perception. However, 6 weeks after presentation and while tapering his doses of prednisone (i.e., 40 mg per day), he had an exacerbation with visual acuity of count finger at 6 feet OD and 20/20 OS, which developed over a period of 48 hours. Color vision was nil OD but normal OS by Ishihara plates. He developed a relative afferent pupillary defect on the right side. Both optic discs were severely edematous. He had bilateral extensor plantar responses. A third lumbar puncture indicated an opening pressure of 160 mmH2O, protein of 54 mg/dL, glucose of 41 mg/dL, white blood cell count of 11 mm3, and 73% lymphocytes. Repeated craniocervical magnetic resonance imaging indicated T2-signal hyperintensity in the regions underlying the right insular and the right frontal cortices. Additionally, there was an area of abnormal signal in the cord at the level of the first and second cervical vertebral bodies (Fig 2). His peripheral blood counts, serum protein electrophoresis, angiotensin-converting enzyme level, complement levels, antinuclear and antineutrophil cytoplasmic antibodies, and Sjo¨ gren antibodies were retested and within the normal limits. The cerebrospinal fluid polymerase chain reaction for human herpes viruses (herpesvirus-1 and 2), Epstein-Barr virus, varicella
Figure 2. Unenhanced, T1-weighted, sagittal image (repetition time ⫽ 400, echo time ⫽ 1) of the spine showing increased signal in white matter at the C2-3 cervical level. zoster virus , cytomegalovirus, and herpesvirus-6 were negative once again. Using the complement fixation method, antibodies to arboviridae, herpesvirus, Epstein-Barr virus, and cytomegalovirus were undetectable in the serum and cerebrospinal fluid. This time, however, his serum varicella zoster virus complement fixation assay was positive at 320 (normal is less than 8) and the cerebrospinal fluid varicella zoster virus complement fixation assay was also positive when undiluted. The child was again treated with intravenous methylprednisolone at 1 gm per day for 5 days, as well as a 10-day course of oral acyclovir, and he was discharged home with a slow, 6-month oral prednisone taper. During the fourth month of tapering, that is, when the patient’s prednisone dosage had reached 20 mg per day, he had another episode of visual blurring with a decline in visual function of both eyes. His visual acuity was 20/100 OD and 20/40 OS. Both optic nerves had developed temporal pallor. His oral prednisone was again increased to 60 mg per day, and a slow taper again began over a 6-month period. At 1 year after presentation, he was taking 20 mg of prednisone every other day. His visual acuity was 20/20 OD and OS, his Ishihara color perception was 75% to 80% in either eye, and he had a right-sided afferent pupillary defect. Both optic nerves were pale. Otherwise, he had a normal neurologic examination. Figure 3 is a chronologic composite of the child’s visual field testing during the 18-month treatment period.
Discussion Varicella zoster virus is a herpesvirus whose primary infection results in chickenpox. The virus can persist in a latent form whose reactivation can result in shingles. There are case reports of varicella zoster virus producing neurologic disease without rash (zoster sine herpete) [8]. Various complications, including optic neuritis, aseptic
Pless and Malik: Varicella Zoster Virus Optic Neuritis 423
Figure 3. Composite of several Humphrey 30-2 visual field tests performed over a 11⁄2-year period.
meningitis, myelitis, and encephalitis, have been described [1,3,5,7]. The pathogenesis leading to varicella zoster virus central nervous system involvement is unknown. Immunologic mechanisms, rather than direct invasion, are likely. Molecular mimicry between virus and neural antigen in genetically selected individuals has been postulated. Confirmation of the link between varicella zoster virus and optic neuritis depends on history, serologic testing, and the exclusion of other common etiologies, because direct pathologic examination of involved area is not possible [9,10]. The diagnosis of varicella zoster virus meningoencephalitis is based on intrathecal virus-specific IgG-, IgA-, and IgM-antibody responses demonstrated by immunefixation, as well as polymerase chain reaction methods [11]. Our patient has had exhaustive and unrevealing investigations on multiple occasions. Given the prodrome of high fevers and meningitic symptoms the patient experienced before the onset of optic neuritis, a high index of suspicion of a viral etiology prompted repeated sets of investigations both in the serum and cerebrospinal fluid in an effort to search for a reasonable etiologic culprit. Except for varicella zoster virus seroconversion both in serum and cerebrospinal fluid, no other cause of illness was identified in this patient. Arguably, childhood-onset multiple sclerosis or acute disseminated/recurrent encephalomyelitis with coincidental varicella zoster virus infection represent a distinct possibility, although the fact remains that the child seroconverted to varicella zoster virus in approximately the second month after the onset of symptoms, which suggested varicella zoster virus as the leading and most persuasive etiology. Exquisite response to intravenous corticosteroid treatment cannot be used as a diagnostic
424
PEDIATRIC NEUROLOGY
Vol. 29 No. 5
tool, because the long-term outcome of optic neuritis is largely unaffected regardless of corticosteroid treatment, as demonstrated in the optic neuritis treatment trial [12].
References [1] Purvin V, Hrisomalos N, Dunn D. Varicella optic neuritis. Neurology 1988;38:501-3. [2] Selbst RG, Selhorst JB, Harbison JW, Myer EC. Parainfectious optic neuritis report and review following varicella. Arch Neurol 1983; 40:347-50. [3] Dueland AN, Devlin M, Martin JR, et al. Fatal varicella-zoster meningo-radiculitis without skin involvement. Ann Neurol 1991;29:56972. [4] Pina MA, Ara JR, Capablo JL, Omenaca M. Myelitis and optic neuritis caused by varicella. Revista de Neurologia 1997;25:1575-6. [5] Miller DH, Kay R, Schon F, McDonald WI, Haas LF, Hughes RA. Optic neuritis following chicken pox in adult. J Neurol 1986;233: 182-4. [6] Vartdal F, Vandvik B, Norrby E. Intrathecal synthesis of virus specific ologoclonal IgG, IgA and IgM antibodies in a case of varicillazoster meningoencephalitis. J Neurol Sci 1982;57:121-32. [7] Mayo DR, Booss J. Varicella zoster associated neurological disease without skin lesion. Arch Neurol 1989;46:313-5. [8] Gilden DH, Dueland AN, Devlin ME, Mahalingam R, Cohrs R. Varicella zoster reactivation without rash. J Infect Dis 1992;166:30-4. [9] Johnson R, Milbourn PE. Central nervous system manifestations of chickenpox. Can Med Assoc J 1970;102:831-4. [10] Griffith JF, Salam MV, Adams RD. The nervous system disease associated with varicella. Acta Neurol Scan 1970;46:270-300. [11] Dal Canto MC, Robinowitz SG. Experimental models of virus induced demyelination of central nervous system. Ann Neurol 1982;1: 100-27. [12] Beck RW. The optic neuritis treatment trial: Implications for clinical practice. Optic Neuritis Study Group. Arch Ophthal 1992;110: 331-2.