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An unusual case of optic neuritis
Journal of the Neurological Sciences 304 (2011) 138–141
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short Communication
An unusual case of optic neuritis Daniela Doegel a,⁎, Wolf Mueller b, Martina Deckert c, Thorsten Lenhard d, Annette Schmidt-Bacher e, Brigitte Storch-Hagenlocher d, Armin Biller f, Brigitte Wildemann d a
Department of Neurology, University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany Department of Neuropathology, University Hospital, Heidelberg, Germany Department of Neuropathology, University Hospital, Cologne, Germany d Department of Neurology, University Hospital, Heidelberg, Germany e Department of Ophthalmology, University Hospital, Heidelberg, Germany f Department of Neuroradiology, University Hospital, Heidelberg, Germany b c
a r t i c l e
i n f o
Article history: Received 23 November 2010 Received in revised form 2 February 2011 Accepted 7 February 2011 Available online 12 March 2011 Keywords: Optic neuritis Multiple sclerosis Neuroimmunology Neuroophthalmology Immunosuppression
a b s t r a c t Optic neuritis is a frequent disease with well established tests and therapeutic strategies. However, possible differential diagnoses cover a broad spectrum. Therefore, clinical work-up can be challenging and routine testing and therapies may not be sufficient. In this case, a 26 year old female is described who presented with clinical features of optic neuritis, yet failed to respond to common therapeutic strategies and lost vision on the affected eye. Diagnostic nerve transection was performed, histopathology suggested inflammation. As the second nerve became affected, immunosuppressive therapy with cyclophosphamide was started and stopped further deterioration. Although additional molecular work-up of the transected nerve revealed clonal rearrangement of the B-cell-receptor-locus IgH, overall histopathologic features and the absence of systemic disease suggested an aggressive inflammatory process rather than lymphoma. Additional B-cell depletion with rituximab prompted significant and sustained visual improvement. This case emphasizes the necessity to consider rare differential diagnoses of optic neuritis, when uncommon features arise during the course of disease. Aggressive immunosuppression might be required to achieve stable improvement of vision. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
Typical features of optic neuritis (ON) include subacute loss of vision and painful eye movements. Diagnostic work-up comprises cerebral MRI (cMRI), visually evoked potentials (VEP) and lumbar puncture. In most cases vision improves spontaneously within 2– 4 weeks. Recovery is accelerated if intravenous steroids are given [1,2]. Although the most common etiology is multiple sclerosis (MS), there are numerous other possible causes. Neuromyelitis optica (NMO) and other autoimmune diseases, such as sarcoidosis and systemic lupus erythematosus (SLE) have to be considered as well as infectious, toxic or ischemic neuropathies. Moreover, affection of the eye chambers or infiltrative lesions of the optic nerve may mimic symptoms of ON [3]. Failure of steroid therapy, marked delay of recovery or progressive visual loss is not common for optic neuritis and requires further evaluation.
A 26-year-old woman presented in December 2007 with visual disturbance and painful movement of her right eye, preceded by right temporal headache. Examination showed right superior and temporal visual field defects, visual acuity was normal. Examination of the left eye was unremarkable, as were the neurological and general physical status. VEP showed delayed right P100 peak latency (122 ms) and normal P100 latency on the left side (112 ms). Tibial-evoked potential (TEP) and transcranial magnetic stimulation (TMS) were normal and remained without pathological findings during repeated testing within the next months. MRI revealed enlargement and enhancement of the right optic nerve, white matter lesions were not detectable (Fig. 1). Cerebrospinal fluid (CSF) examination showed minimal lymphocytic pleocytosis (7/ μl), normal total protein and negative oligoclonal bands (OCB). Serology did not reveal evidence of a bacterial or viral etiology. Optic neuritis was suspected and treated with 3 × 1 g intravenous methylprednisolone (IVMP). During the next days visual acuity deteriorated to 20/100 and central scotoma developed. Oral steroids were added and tapered over the next weeks. This was followed by waxing and waning of visual impairment without lasting improvement. In March 2008 the patient presented with central scotoma and progressive temporal field defects. Visual acuity was 20/50 and cMRI
⁎ Corresponding author. Tel.: + 49 6221 56 36029; fax: + 49 6221 56 5348. E-mail address: [email protected] (D. Doegel). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.02.007
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
139
Fig. 1. MR-imaging. 1st column: coronal T2w; 2nd column: coronal T1w; 3rd column: axial T1w. (A) Increased diameter of right optic nerve, circumscribed area with contrast media enhancement. (B) Enduring diameter extension, extensive enhancement of right optic nerve. (C) Increased diameter and enhancement of left optic nerve. (D) Declining diameter of left optic nerve, no blood-brain-barrier disruption.
showed declined nerve enhancement. Despite treatment with 3 × 2 g IVMP she developed further visual deterioration and optic atrophy. Subsequent therapy with plasmapheresis, followed by high dose intravenous immunoglobulins (IVIg) failed. In July 2008 ophthalmologic assessment revealed rightsided blindness with only a small remaining visual field and marked optic atrophy. A VEP was not derivable. MRI showed progressive enhancement along the optic nerve expanding to the optic chiasm and the hitherto healthy left optic nerve. Repeated CSF examination revealed 21/μl cells, predominantly lymphocytes and negative OCB. Routine laboratory blood tests were normal. Antinuclear antibodies (ANA) were 1:160, but subse-
quent titers remained at 1:40. Anti-amphiphysin 2-antibodies were only marginally elevated. Testing for ANCA, ds-DNA, ENA antiaquaporin-4 and anti-neuronal antibodies was negative. Vitamin B12 and folic acid serum concentrations and ACE levels in serum and CSF were normal. The Quantiferon test was negative, as was serology for hepatitis B, hepatitis C and HIV. Genetic testing ruled out Leber's optic atrophy. Somatostatin receptor scintigraphy and FDG-PET imaging did not suggest evidence of optic nerve meningioma or an underlying peripheral solid malignancy. As extensive testing for other differential diagnoses remained inconclusive surgical transection of the right optic nerve was performed in August 2008 for preventive
140
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
and diagnostic reasons. Histopathology showed predominantly perivascular infiltrates of CD3+ T-cells and CD20+ B-cells, microglial activation and reactive gliosis. Severe axonal damage was associated with myelin loss but less prominent active demyelination (Fig. 2). Those findings were consistent with neuritis. In October 2008 the patient complained of disturbed color vision and painful movement of the left eye. Ophthalmologic assessment revealed papilledema, small visual field defects and normal visual acuity. VEP had a distorted wave form with a normal peak latency. Cerebral MRI showed enlargement and enhancement of the left optic nerve. Cervical MRI was normal. CSF findings were unaltered. Vision deteriorated to 20/100 and visual field defects enlarged significantly. Given the threat of bilateral blindness immunosuppressive therapy with intravenous cyclophosphamide pulses was initiated (6 × 750 mg/m²), resulting in subjective and objective regressive visual fields defects and slightly improved visual acuity after the fourth infusion. At this time, molecular analysis of total DNA extracted from the transected nerve biopsy became available and revealed clonal rearrangement of the B-cell-receptor-locus IgH, possibly suggesting a mature non-Hodgkin B-cell lymphoma. Detailed staging, including bone marrow puncture, did not reveal any peripheral lymphoma manifestation. Multidisciplinary case discussion favored the presence of an inflammatory rather than a neoplastic disorder and opted for additional B-cell depletion with rituximab (4 × 375 mg/m²). This was followed by continuous and sustained clinical improvement over the next months. In May 2009 visual acuity had increased to 20/25–20/20 and there were only few remaining scotoma. Clinical course and MRfindings remained stable since then.
3. Comment The young woman described developed atypical ON with progressive bilateral visual disturbance and unilateral blindness unresponsive to successive treatment with high dose IVMP, plasma exchange, and IVIg. The aggressive course of disease with delayed involvement of the optic chiasm and the contralateral optic nerve caused extensive investigation, including nerve transection after the patient had become blind on the right eye. Besides a primary demyelinating process, autoimmune disease or lymphoma was discussed as the likeliest cause. The cumulative risk of developing MS after an episode of ON is 50% within 15 years if white matter lesions are present and 25% if no lesions are found [4]. Although the predominant axonal damage of the optic nerve, the lacking effect of steroids and the absence of cranial white matter lesions for more than 2 years argue against a demyelinating process, MS cannot be ruled out yet. The severity of symptoms and the bilateral affection would be compatible with a forme fruste of NMO, yet AQP4-antibodies were repeatedly negative and plasma exchange was ineffective. Gender, severe clinical course and bilateral manifestation might be features of SLE [5]. However, in most cases the optic nerve becomes involved when other symptoms are already present and bilateral manifestation usually occurs simultaneously. However, some authors stress the possibility of ON due to SLE when clinical and laboratory disease activity is low [6]. Furthermore, steroids and cyclophosphamide might be effective [7]. In our case, criteria for SLE were never met, but sometimes a clear diagnosis is made years after the first symptoms [8]. Isolated optic nerve lymphomas are rare and seem to occur preferably secondary to systemic lymphoma in older patients or in
Fig. 2. Histopathology and Immunohistochemistry. Mixed lymphocytic infiltration, (A, H & E), with T- (B, CD3) and B-cells (C, CD20). Note extensive loss of myelin (D, Luxol/PAS & E, MBP) and axons (F, NF). Normal density of myelin (G–H) and axons (I) in the unaffected human optic nerve.
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
immunosuppressed individuals. However, ophthalmic involvement is frequently observed in primary CNS lymphoma (PCNSL) [9]. In most cases, painless visual disturbance develops over several weeks and, if only the optic nerve is affected, MRI abnormalities resemble those in ON [10,11]. Diagnosis is based on adequate histopathologic findings. In the patient described the primary pathology remained controversial despite extensive testing and even optic nerve biopsy. Although molecular genetic analysis revealed monoclonality of infiltrating B-cells it was finally thought that pseudoclonality might have led to a false positive result, since histopathology suggested inflammation and there were no other convincing morphological, immunophenotypical or clinical criteria to confirm a proliferative process. We cannot, however, exclude that the immunosuppressive and immunomodulating therapy prior to the rightsided optic nerve transection might have hampered histopathologic assessment. Long-lasting remission with stable and marked improvement of vision was finally achieved by sequential immunosuppression with cyclophosphamide and rituximab. Rituximab is variously used for the treatment of non-Hodgkin lymphoma and antibody-mediated autoimmune disorders [12,13]. It has been used in central nervous system lymphomas, but clinical trials investigating the efficacy in PCNSL thus far have not been performed in a representative series of patients. In patients with NMO preliminary evidence from a case series suggests that rituximab reduces frequency of attacks and promotes clinical stabilization [14]. Our case demonstrates the sometimes demanding and challenging evaluation and treatment of a well known disorder and emphasizes the necessity to consider rare differential diagnoses of ON when uncommon symptoms complicate the course of disease. Aggressive immunosuppressive therapy might be imperative to save vision. Appendix A. Supplementary data Supplementary data to this article can be found online at doi:10.1016/j. jns.2011.02.007.
141
References [1] Grauer O, Offenhäusser M, Schmidt J, Toyka KV, Gold R. Glucocorticosteroid therapy in optic neuritis and multiple sclerosis. Evidence from clinical studies and practical recommendations. Nervenarzt 2001;72:577–89. [2] Kiefer G, Rieckmann P. Optic neuritis. First manifestation of multiple sclerosis? Current diagnostic and therapeutic strategies. Ophthalmologe 2001;98:310–9. [3] Martinelli V, Bianchi Marzoli S. Non-demyelinating optic neuropathy: clinical entities. Neurol Sci 2001;22(suppl 2):55–9. [4] The Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis. Arch Neurol 2008;65(6):727–32. [5] Lin YC, Wang AG, Yen MY. Systemic lupus erythematosus associated optic neuritis: clinical experience and literature review. Acta Ophthalmol 2009;87:204–10. [6] Siatkowski RM, Scott IU, Verm AM, Warn AA, Farris BK, Strominger MB, et al. Optic neuropathy and chiasmopathy in the diagnosis of systemic lupus erythematosus. J Neuroophthalmol 2001;21(3):193–8. [7] Galindo-Rodriguez G, Aviña-Zubieta JA, Pizarro S, V Díaz de León, Saucedo N, Fuentes M, et al. Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial. Am J Med 1999;106(1):65–9. [8] Jacobi C, Stingele K, Kretz R, Hartmann M, Storch-Hagenlocher B, Breitbart A, et al. Neuromyelitis optica (Devic's syndrome) as first manifestation of systemic lupus erythematosus. Lupus 2006;15(2):107–9. [9] Herrlinger U. Primary CNS lymphoma: findings outside the brain. J Neurooncol 1999;43(3):227–30. [10] Mavrikakis I, Heran MK, Rootman J. MR findings in a patient with isolated intrinsic optic nerve lymphoma. Ophthal Plast Reconstr Surg 2006;22(6):482–4. [11] Behbehani RS, Vacarezza N, Sergott RC, Bilyk JR, Hochberg F, Savino PJ. Isolated optic nerve lymphoma diagnosed by optic nerve biopsy. Am J Ophthalmol 2005;139(6):1128–3012 12. [12] Gürcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009;9(1):10–25. [13] Hauptrock B, Hess G. Rituximab in the treatment of non-Hodgkin's lymphoma. Biologics Targets Ther 2008;2(4):619–33. [14] Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008;65(11):1443–8.
Contents lists available at ScienceDirect
Journal of the Neurological Sciences j o u r n a l h o m e p a g e : w w w. e l s ev i e r. c o m / l o c a t e / j n s
Short Communication
An unusual case of optic neuritis Daniela Doegel a,⁎, Wolf Mueller b, Martina Deckert c, Thorsten Lenhard d, Annette Schmidt-Bacher e, Brigitte Storch-Hagenlocher d, Armin Biller f, Brigitte Wildemann d a
Department of Neurology, University Hospital, Im Neuenheimer Feld 400, 69120 Heidelberg, Germany Department of Neuropathology, University Hospital, Heidelberg, Germany Department of Neuropathology, University Hospital, Cologne, Germany d Department of Neurology, University Hospital, Heidelberg, Germany e Department of Ophthalmology, University Hospital, Heidelberg, Germany f Department of Neuroradiology, University Hospital, Heidelberg, Germany b c
a r t i c l e
i n f o
Article history: Received 23 November 2010 Received in revised form 2 February 2011 Accepted 7 February 2011 Available online 12 March 2011 Keywords: Optic neuritis Multiple sclerosis Neuroimmunology Neuroophthalmology Immunosuppression
a b s t r a c t Optic neuritis is a frequent disease with well established tests and therapeutic strategies. However, possible differential diagnoses cover a broad spectrum. Therefore, clinical work-up can be challenging and routine testing and therapies may not be sufficient. In this case, a 26 year old female is described who presented with clinical features of optic neuritis, yet failed to respond to common therapeutic strategies and lost vision on the affected eye. Diagnostic nerve transection was performed, histopathology suggested inflammation. As the second nerve became affected, immunosuppressive therapy with cyclophosphamide was started and stopped further deterioration. Although additional molecular work-up of the transected nerve revealed clonal rearrangement of the B-cell-receptor-locus IgH, overall histopathologic features and the absence of systemic disease suggested an aggressive inflammatory process rather than lymphoma. Additional B-cell depletion with rituximab prompted significant and sustained visual improvement. This case emphasizes the necessity to consider rare differential diagnoses of optic neuritis, when uncommon features arise during the course of disease. Aggressive immunosuppression might be required to achieve stable improvement of vision. © 2011 Elsevier B.V. All rights reserved.
1. Introduction
2. Case report
Typical features of optic neuritis (ON) include subacute loss of vision and painful eye movements. Diagnostic work-up comprises cerebral MRI (cMRI), visually evoked potentials (VEP) and lumbar puncture. In most cases vision improves spontaneously within 2– 4 weeks. Recovery is accelerated if intravenous steroids are given [1,2]. Although the most common etiology is multiple sclerosis (MS), there are numerous other possible causes. Neuromyelitis optica (NMO) and other autoimmune diseases, such as sarcoidosis and systemic lupus erythematosus (SLE) have to be considered as well as infectious, toxic or ischemic neuropathies. Moreover, affection of the eye chambers or infiltrative lesions of the optic nerve may mimic symptoms of ON [3]. Failure of steroid therapy, marked delay of recovery or progressive visual loss is not common for optic neuritis and requires further evaluation.
A 26-year-old woman presented in December 2007 with visual disturbance and painful movement of her right eye, preceded by right temporal headache. Examination showed right superior and temporal visual field defects, visual acuity was normal. Examination of the left eye was unremarkable, as were the neurological and general physical status. VEP showed delayed right P100 peak latency (122 ms) and normal P100 latency on the left side (112 ms). Tibial-evoked potential (TEP) and transcranial magnetic stimulation (TMS) were normal and remained without pathological findings during repeated testing within the next months. MRI revealed enlargement and enhancement of the right optic nerve, white matter lesions were not detectable (Fig. 1). Cerebrospinal fluid (CSF) examination showed minimal lymphocytic pleocytosis (7/ μl), normal total protein and negative oligoclonal bands (OCB). Serology did not reveal evidence of a bacterial or viral etiology. Optic neuritis was suspected and treated with 3 × 1 g intravenous methylprednisolone (IVMP). During the next days visual acuity deteriorated to 20/100 and central scotoma developed. Oral steroids were added and tapered over the next weeks. This was followed by waxing and waning of visual impairment without lasting improvement. In March 2008 the patient presented with central scotoma and progressive temporal field defects. Visual acuity was 20/50 and cMRI
⁎ Corresponding author. Tel.: + 49 6221 56 36029; fax: + 49 6221 56 5348. E-mail address: [email protected] (D. Doegel). 0022-510X/$ – see front matter © 2011 Elsevier B.V. All rights reserved. doi:10.1016/j.jns.2011.02.007
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
139
Fig. 1. MR-imaging. 1st column: coronal T2w; 2nd column: coronal T1w; 3rd column: axial T1w. (A) Increased diameter of right optic nerve, circumscribed area with contrast media enhancement. (B) Enduring diameter extension, extensive enhancement of right optic nerve. (C) Increased diameter and enhancement of left optic nerve. (D) Declining diameter of left optic nerve, no blood-brain-barrier disruption.
showed declined nerve enhancement. Despite treatment with 3 × 2 g IVMP she developed further visual deterioration and optic atrophy. Subsequent therapy with plasmapheresis, followed by high dose intravenous immunoglobulins (IVIg) failed. In July 2008 ophthalmologic assessment revealed rightsided blindness with only a small remaining visual field and marked optic atrophy. A VEP was not derivable. MRI showed progressive enhancement along the optic nerve expanding to the optic chiasm and the hitherto healthy left optic nerve. Repeated CSF examination revealed 21/μl cells, predominantly lymphocytes and negative OCB. Routine laboratory blood tests were normal. Antinuclear antibodies (ANA) were 1:160, but subse-
quent titers remained at 1:40. Anti-amphiphysin 2-antibodies were only marginally elevated. Testing for ANCA, ds-DNA, ENA antiaquaporin-4 and anti-neuronal antibodies was negative. Vitamin B12 and folic acid serum concentrations and ACE levels in serum and CSF were normal. The Quantiferon test was negative, as was serology for hepatitis B, hepatitis C and HIV. Genetic testing ruled out Leber's optic atrophy. Somatostatin receptor scintigraphy and FDG-PET imaging did not suggest evidence of optic nerve meningioma or an underlying peripheral solid malignancy. As extensive testing for other differential diagnoses remained inconclusive surgical transection of the right optic nerve was performed in August 2008 for preventive
140
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
and diagnostic reasons. Histopathology showed predominantly perivascular infiltrates of CD3+ T-cells and CD20+ B-cells, microglial activation and reactive gliosis. Severe axonal damage was associated with myelin loss but less prominent active demyelination (Fig. 2). Those findings were consistent with neuritis. In October 2008 the patient complained of disturbed color vision and painful movement of the left eye. Ophthalmologic assessment revealed papilledema, small visual field defects and normal visual acuity. VEP had a distorted wave form with a normal peak latency. Cerebral MRI showed enlargement and enhancement of the left optic nerve. Cervical MRI was normal. CSF findings were unaltered. Vision deteriorated to 20/100 and visual field defects enlarged significantly. Given the threat of bilateral blindness immunosuppressive therapy with intravenous cyclophosphamide pulses was initiated (6 × 750 mg/m²), resulting in subjective and objective regressive visual fields defects and slightly improved visual acuity after the fourth infusion. At this time, molecular analysis of total DNA extracted from the transected nerve biopsy became available and revealed clonal rearrangement of the B-cell-receptor-locus IgH, possibly suggesting a mature non-Hodgkin B-cell lymphoma. Detailed staging, including bone marrow puncture, did not reveal any peripheral lymphoma manifestation. Multidisciplinary case discussion favored the presence of an inflammatory rather than a neoplastic disorder and opted for additional B-cell depletion with rituximab (4 × 375 mg/m²). This was followed by continuous and sustained clinical improvement over the next months. In May 2009 visual acuity had increased to 20/25–20/20 and there were only few remaining scotoma. Clinical course and MRfindings remained stable since then.
3. Comment The young woman described developed atypical ON with progressive bilateral visual disturbance and unilateral blindness unresponsive to successive treatment with high dose IVMP, plasma exchange, and IVIg. The aggressive course of disease with delayed involvement of the optic chiasm and the contralateral optic nerve caused extensive investigation, including nerve transection after the patient had become blind on the right eye. Besides a primary demyelinating process, autoimmune disease or lymphoma was discussed as the likeliest cause. The cumulative risk of developing MS after an episode of ON is 50% within 15 years if white matter lesions are present and 25% if no lesions are found [4]. Although the predominant axonal damage of the optic nerve, the lacking effect of steroids and the absence of cranial white matter lesions for more than 2 years argue against a demyelinating process, MS cannot be ruled out yet. The severity of symptoms and the bilateral affection would be compatible with a forme fruste of NMO, yet AQP4-antibodies were repeatedly negative and plasma exchange was ineffective. Gender, severe clinical course and bilateral manifestation might be features of SLE [5]. However, in most cases the optic nerve becomes involved when other symptoms are already present and bilateral manifestation usually occurs simultaneously. However, some authors stress the possibility of ON due to SLE when clinical and laboratory disease activity is low [6]. Furthermore, steroids and cyclophosphamide might be effective [7]. In our case, criteria for SLE were never met, but sometimes a clear diagnosis is made years after the first symptoms [8]. Isolated optic nerve lymphomas are rare and seem to occur preferably secondary to systemic lymphoma in older patients or in
Fig. 2. Histopathology and Immunohistochemistry. Mixed lymphocytic infiltration, (A, H & E), with T- (B, CD3) and B-cells (C, CD20). Note extensive loss of myelin (D, Luxol/PAS & E, MBP) and axons (F, NF). Normal density of myelin (G–H) and axons (I) in the unaffected human optic nerve.
D. Doegel et al. / Journal of the Neurological Sciences 304 (2011) 138–141
immunosuppressed individuals. However, ophthalmic involvement is frequently observed in primary CNS lymphoma (PCNSL) [9]. In most cases, painless visual disturbance develops over several weeks and, if only the optic nerve is affected, MRI abnormalities resemble those in ON [10,11]. Diagnosis is based on adequate histopathologic findings. In the patient described the primary pathology remained controversial despite extensive testing and even optic nerve biopsy. Although molecular genetic analysis revealed monoclonality of infiltrating B-cells it was finally thought that pseudoclonality might have led to a false positive result, since histopathology suggested inflammation and there were no other convincing morphological, immunophenotypical or clinical criteria to confirm a proliferative process. We cannot, however, exclude that the immunosuppressive and immunomodulating therapy prior to the rightsided optic nerve transection might have hampered histopathologic assessment. Long-lasting remission with stable and marked improvement of vision was finally achieved by sequential immunosuppression with cyclophosphamide and rituximab. Rituximab is variously used for the treatment of non-Hodgkin lymphoma and antibody-mediated autoimmune disorders [12,13]. It has been used in central nervous system lymphomas, but clinical trials investigating the efficacy in PCNSL thus far have not been performed in a representative series of patients. In patients with NMO preliminary evidence from a case series suggests that rituximab reduces frequency of attacks and promotes clinical stabilization [14]. Our case demonstrates the sometimes demanding and challenging evaluation and treatment of a well known disorder and emphasizes the necessity to consider rare differential diagnoses of ON when uncommon symptoms complicate the course of disease. Aggressive immunosuppressive therapy might be imperative to save vision. Appendix A. Supplementary data Supplementary data to this article can be found online at doi:10.1016/j. jns.2011.02.007.
141
References [1] Grauer O, Offenhäusser M, Schmidt J, Toyka KV, Gold R. Glucocorticosteroid therapy in optic neuritis and multiple sclerosis. Evidence from clinical studies and practical recommendations. Nervenarzt 2001;72:577–89. [2] Kiefer G, Rieckmann P. Optic neuritis. First manifestation of multiple sclerosis? Current diagnostic and therapeutic strategies. Ophthalmologe 2001;98:310–9. [3] Martinelli V, Bianchi Marzoli S. Non-demyelinating optic neuropathy: clinical entities. Neurol Sci 2001;22(suppl 2):55–9. [4] The Optic Neuritis Study Group. Multiple sclerosis risk after optic neuritis. Arch Neurol 2008;65(6):727–32. [5] Lin YC, Wang AG, Yen MY. Systemic lupus erythematosus associated optic neuritis: clinical experience and literature review. Acta Ophthalmol 2009;87:204–10. [6] Siatkowski RM, Scott IU, Verm AM, Warn AA, Farris BK, Strominger MB, et al. Optic neuropathy and chiasmopathy in the diagnosis of systemic lupus erythematosus. J Neuroophthalmol 2001;21(3):193–8. [7] Galindo-Rodriguez G, Aviña-Zubieta JA, Pizarro S, V Díaz de León, Saucedo N, Fuentes M, et al. Cyclophosphamide pulse therapy in optic neuritis due to systemic lupus erythematosus: an open trial. Am J Med 1999;106(1):65–9. [8] Jacobi C, Stingele K, Kretz R, Hartmann M, Storch-Hagenlocher B, Breitbart A, et al. Neuromyelitis optica (Devic's syndrome) as first manifestation of systemic lupus erythematosus. Lupus 2006;15(2):107–9. [9] Herrlinger U. Primary CNS lymphoma: findings outside the brain. J Neurooncol 1999;43(3):227–30. [10] Mavrikakis I, Heran MK, Rootman J. MR findings in a patient with isolated intrinsic optic nerve lymphoma. Ophthal Plast Reconstr Surg 2006;22(6):482–4. [11] Behbehani RS, Vacarezza N, Sergott RC, Bilyk JR, Hochberg F, Savino PJ. Isolated optic nerve lymphoma diagnosed by optic nerve biopsy. Am J Ophthalmol 2005;139(6):1128–3012 12. [12] Gürcan HM, Keskin DB, Stern JN, Nitzberg MA, Shekhani H, Ahmed AR. A review of the current use of rituximab in autoimmune diseases. Int Immunopharmacol 2009;9(1):10–25. [13] Hauptrock B, Hess G. Rituximab in the treatment of non-Hodgkin's lymphoma. Biologics Targets Ther 2008;2(4):619–33. [14] Jacob A, Weinshenker BG, Violich I, McLinskey N, Krupp L, Fox RJ, et al. Treatment of neuromyelitis optica with rituximab: retrospective analysis of 25 patients. Arch Neurol 2008;65(11):1443–8.