Journal of Experimental & Clinical Assisted Reproduction is an Open Access, online, electronic journal published by BioMed Central with full contents available to the scientific and medical community free of charge to all readers. Authors maintain the copyright to their own work, a policy facilitating dissemination of data to the widest possible audience without requiring permission from the publisher. This Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single £330 article processing charge (APC), due at the time of manuscript acceptance for publication. Payment of the APC is not a condition for formal peer review and does not apply to articles rejected after review. Additionally, this fee is waived for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Considering ordinary publication fees related to page charges and reprints, the APC at Journal of Experimental & Clinical Assisted Reproduction is comparable to costs associated with publishing in some traditional print journals, and is less expensive than many. Implementation of the APC within this Open Access framework is envisioned as a modern research-friendly policy that supports networking among investigators, brings new research into reach rapidly, and empowers authors with greater control over their own scholarly publications.

Introduction Journal of Experimental & Clinical Assisted Reproduction  is a scientific and clinical journal established in September 2004, offering rapid peer review of research of the advanced reproductive technologies. Content is administered by two chief editors with offices in New York and Atlanta, with peer review supported by an international editorial board. Importantly, all published manuscripts are freely available to a global audience in full text format to facilitate sharing of investigative insights, laboratory methods, and surgical techniques. No other journal presently has these objectives. The journal considers submissions of the following types: Original research, Reviews, Book reviews, Case reports, Commentaries, Debate articles, Hypotheses, Methodology articles and Short reports. All manuscripts published by  Journal of Experimental & Clinical Assisted Reproduction  are included by PubMed at the National Library of Medicine (United States) [ 1 ], as well as by the national libraries of the Netherlands [ 2 ], Germany [ 3 ], and France [ 4 ]. The evolution of modern academic publishing Creation of the "Open Access" publishing model represented a watershed moment in how research manuscripts are processed, paid for, provided, and protected. Historically, it was the end consumer (the library or reader) who was charged for access to medical, scientific and technical literature. Such payment was traditionally in the form of subscriptions or by access fees levied in exchange for controlled access to particular articles via internet. In contrast, Open Access publishing asks the author to offset the cost of access. The advent of internet technology facilitated the indexing of medical literature with a speed and degree of sophistication impossible before the world wide web. Nevertheless, once an article was located via computer database search, generally only the 250 word abstract could be viewed – even though full text was often required. As no library can offer each issue of every journal, the literature collection/review process increasingly has become a multi-institutional endeavor. Unfortunately the high cost of maintaining multiple subscriptions has actually caused some libraries to provide fewer journals for users [ 5 , 6 ]. More to know, but less to read? With journal holdings at some libraries trending down, smaller academic publishers were early casualties of the reduced demand. Many were lost to consolidation. This resulted in a once diverse publishing community being controlled by only a few organizations with little incentive to change. Meanwhile the number of specialty journals multiplied to keep pace with the growing complexities of medical research. Even as modern research became more multidisciplinary, academic publishers did not make it easy to share findings across dissimilar journals without the reader paying a price. Thus, a paradoxical albeit unintended contraction of access to published medical research resulted. Within the world of academic publishing, limited competition may have registered profits for some but the worldwide impact on readers' access to scholarly literature has been distinctly negative [ 7 ]. It was against this "restricted access" background that the Open Access model of academic publishing was conceived, with a view to maximize rapid collaboration among researchers using a relatively new resource with tremendous potential – the world wide web. Open Access publishing incorporates internet technology which frees the investigator from the limitations of a particular institution's journal holdings as well as the delay of the interlibrary loan. Open Access and the future of academic publishing Implementation of the Open Access publishing model has several important benefits for the scientific community. First, published works are available full text via internet thus making them rapidly accessible to a global audience. Since authors maintain the copyright to their own work, they are free to reproduce it on their own website, link it to related sites, or distribute it according to their own needs without obtaining the publisher's permission first. The only requirement is to acknowledge the article's source. "Reprint requests" are obviated since full text manuscripts are available for free via internet. Such networking has already been shown to boost article citations and impact since these manuscripts are easy to find [ 8 , 9 ]. Second, investigators need only an internet connection and a computer to access every published article with open access – no longer are they limited by their library's journal subscription list. The Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single £330 article processing charge (APC), collected at the time of manuscript acceptance for publication. Payment of the APC is never a condition for any manuscript's formal peer review and does not apply to articles rejected after peer review. Additionally, this fee is not assessed for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Such waiver requests are considered by the chief editors on a case-by-case basis. Since the journal exists as an internet resource there is no page limit to the number of color photographs, diagrams, or figures attached to a particular article. Movie files (<10 MB) accompanying a manuscript may also be published using the journal's electronic publishing platform, a feature particularly suited for articles demonstrating new operative or laboratory techniques. Given the full range of publishing possibilities at  Journal of Experimental & Clinical Assisted Reproduction , it is hoped that the £330 charge will be affirmed as a good value, especially since subsequent costs associated with reprint fees or page charges assessed by many traditional print journals can easily exceed this amount.
Introduction
Journal of Experimental & Clinical Assisted Reproduction  is a scientific and clinical journal established in September 2004, offering rapid peer review of research of the advanced reproductive technologies. Content is administered by two chief editors with offices in New York and Atlanta, with peer review supported by an international editorial board. Importantly, all published manuscripts are freely available to a global audience in full text format to facilitate sharing of investigative insights, laboratory methods, and surgical techniques. No other journal presently has these objectives. The journal considers submissions of the following types: Original research, Reviews, Book reviews, Case reports, Commentaries, Debate articles, Hypotheses, Methodology articles and Short reports. All manuscripts published by  Journal of Experimental & Clinical Assisted Reproduction  are included by PubMed at the National Library of Medicine (United States) [ 1 ], as well as by the national libraries of the Netherlands [ 2 ], Germany [ 3 ], and France [ 4 ].Journal of Experimental & Clinical Assisted ReproductionJournal of Experimental & Clinical Assisted ReproductionThe evolution of modern academic publishing Creation of the "Open Access" publishing model represented a watershed moment in how research manuscripts are processed, paid for, provided, and protected. Historically, it was the end consumer (the library or reader) who was charged for access to medical, scientific and technical literature. Such payment was traditionally in the form of subscriptions or by access fees levied in exchange for controlled access to particular articles via internet. In contrast, Open Access publishing asks the author to offset the cost of access. The advent of internet technology facilitated the indexing of medical literature with a speed and degree of sophistication impossible before the world wide web. Nevertheless, once an article was located via computer database search, generally only the 250 word abstract could be viewed – even though full text was often required. As no library can offer each issue of every journal, the literature collection/review process increasingly has become a multi-institutional endeavor. Unfortunately the high cost of maintaining multiple subscriptions has actually caused some libraries to provide fewer journals for users [ 5 , 6 ].
The evolution of modern academic publishing
Creation of the "Open Access" publishing model represented a watershed moment in how research manuscripts are processed, paid for, provided, and protected. Historically, it was the end consumer (the library or reader) who was charged for access to medical, scientific and technical literature. Such payment was traditionally in the form of subscriptions or by access fees levied in exchange for controlled access to particular articles via internet. In contrast, Open Access publishing asks the author to offset the cost of access.The advent of internet technology facilitated the indexing of medical literature with a speed and degree of sophistication impossible before the world wide web. Nevertheless, once an article was located via computer database search, generally only the 250 word abstract could be viewed – even though full text was often required. As no library can offer each issue of every journal, the literature collection/review process increasingly has become a multi-institutional endeavor. Unfortunately the high cost of maintaining multiple subscriptions has actually caused some libraries to provide fewer journals for users [ 5 , 6 ].More to know, but less to read? With journal holdings at some libraries trending down, smaller academic publishers were early casualties of the reduced demand. Many were lost to consolidation. This resulted in a once diverse publishing community being controlled by only a few organizations with little incentive to change. Meanwhile the number of specialty journals multiplied to keep pace with the growing complexities of medical research. Even as modern research became more multidisciplinary, academic publishers did not make it easy to share findings across dissimilar journals without the reader paying a price. Thus, a paradoxical albeit unintended contraction of access to published medical research resulted. Within the world of academic publishing, limited competition may have registered profits for some but the worldwide impact on readers' access to scholarly literature has been distinctly negative [ 7 ]. It was against this "restricted access" background that the Open Access model of academic publishing was conceived, with a view to maximize rapid collaboration among researchers using a relatively new resource with tremendous potential – the world wide web. Open Access publishing incorporates internet technology which frees the investigator from the limitations of a particular institution's journal holdings as well as the delay of the interlibrary loan.
More to know, but less to read?
With journal holdings at some libraries trending down, smaller academic publishers were early casualties of the reduced demand. Many were lost to consolidation. This resulted in a once diverse publishing community being controlled by only a few organizations with little incentive to change. Meanwhile the number of specialty journals multiplied to keep pace with the growing complexities of medical research. Even as modern research became more multidisciplinary, academic publishers did not make it easy to share findings across dissimilar journals without the reader paying a price. Thus, a paradoxical albeit unintended contraction of access to published medical research resulted. Within the world of academic publishing, limited competition may have registered profits for some but the worldwide impact on readers' access to scholarly literature has been distinctly negative [ 7 ].It was against this "restricted access" background that the Open Access model of academic publishing was conceived, with a view to maximize rapid collaboration among researchers using a relatively new resource with tremendous potential – the world wide web. Open Access publishing incorporates internet technology which frees the investigator from the limitations of a particular institution's journal holdings as well as the delay of the interlibrary loan.Open Access and the future of academic publishing Implementation of the Open Access publishing model has several important benefits for the scientific community. First, published works are available full text via internet thus making them rapidly accessible to a global audience. Since authors maintain the copyright to their own work, they are free to reproduce it on their own website, link it to related sites, or distribute it according to their own needs without obtaining the publisher's permission first. The only requirement is to acknowledge the article's source. "Reprint requests" are obviated since full text manuscripts are available for free via internet. Such networking has already been shown to boost article citations and impact since these manuscripts are easy to find [ 8 , 9 ]. Second, investigators need only an internet connection and a computer to access every published article with open access – no longer are they limited by their library's journal subscription list. The Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single £330 article processing charge (APC), collected at the time of manuscript acceptance for publication. Payment of the APC is never a condition for any manuscript's formal peer review and does not apply to articles rejected after peer review. Additionally, this fee is not assessed for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Such waiver requests are considered by the chief editors on a case-by-case basis. Since the journal exists as an internet resource there is no page limit to the number of color photographs, diagrams, or figures attached to a particular article. Movie files (<10 MB) accompanying a manuscript may also be published using the journal's electronic publishing platform, a feature particularly suited for articles demonstrating new operative or laboratory techniques. Given the full range of publishing possibilities at  Journal of Experimental & Clinical Assisted Reproduction , it is hoped that the £330 charge will be affirmed as a good value, especially since subsequent costs associated with reprint fees or page charges assessed by many traditional print journals can easily exceed this amount.
Open Access and the future of academic publishing
Implementation of the Open Access publishing model has several important benefits for the scientific community. First, published works are available full text via internet thus making them rapidly accessible to a global audience. Since authors maintain the copyright to their own work, they are free to reproduce it on their own website, link it to related sites, or distribute it according to their own needs without obtaining the publisher's permission first. The only requirement is to acknowledge the article's source. "Reprint requests" are obviated since full text manuscripts are available for free via internet. Such networking has already been shown to boost article citations and impact since these manuscripts are easy to find [ 8 , 9 ]. Second, investigators need only an internet connection and a computer to access every published article with open access – no longer are they limited by their library's journal subscription list.The Open Access publishing model is subsidized by authors (or their institutions/funding agencies) in the form of a single £330 article processing charge (APC), collected at the time of manuscript acceptance for publication. Payment of the APC is never a condition for any manuscript's formal peer review and does not apply to articles rejected after peer review. Additionally, this fee is not assessed for authors whose institutions are BioMed Central members or where genuine financial hardship exists. Such waiver requests are considered by the chief editors on a case-by-case basis. Since the journal exists as an internet resource there is no page limit to the number of color photographs, diagrams, or figures attached to a particular article. Movie files (<10 MB) accompanying a manuscript may also be published using the journal's electronic publishing platform, a feature particularly suited for articles demonstrating new operative or laboratory techniques. Given the full range of publishing possibilities at  Journal of Experimental & Clinical Assisted Reproduction , it is hoped that the £330 charge will be affirmed as a good value, especially since subsequent costs associated with reprint fees or page charges assessed by many traditional print journals can easily exceed this amount.Journal of Experimental & Clinical Assisted ReproductionConclusion While several journals have moved to offer free internet access to selected articles, this should not be confused with Open Access [ 10 ]. Free access is typically associated with a 6–12 month delay between publication and actual availability of a manuscript, and even when full-text articles are provided copyright restrictions limit the reader's distribution and reproduction of the work. In contrast, the APC assessed by Journal of Experimental & Clinical Assisted Reproduction guarantees Open Access to all published work and permits the author to keep the copyright to their own data, thus benefiting all who are interested in advancing research in the assisted reproductive technologies.
Conclusion
While several journals have moved to offer free internet access to selected articles, this should not be confused with Open Access [ 10 ]. Free access is typically associated with a 6–12 month delay between publication and actual availability of a manuscript, and even when full-text articles are provided copyright restrictions limit the reader's distribution and reproduction of the work. In contrast, the APC assessed by Journal of Experimental & Clinical Assisted Reproduction guarantees Open Access to all published work and permits the author to keep the copyright to their own data, thus benefiting all who are interested in advancing research in the assisted reproductive technologies.Abbreviations APC = article-processing charge.
Abbreviations
APC = article-processing charge.Competing interests The author(s) declare that they have no competing interests.
Competing interests
The author(s) declare that they have no competing interests.


A fascinating case, with much to learn about diagnosis and treatment of patients with abnormal CSF results. After learning from the case, take our online quiz

DESCRIPTION of CASE A 17-year-old woman, who was born in Bangladesh, presented to an accident and emergency department in the United Kingdom with a history of being unwell for 24 hours. She had a headache and fever, and was vomiting. On questioning, there was no photophobia or neck stiffness. She lives in the United Kingdom and had been for a holiday to Bangladesh 4 months previously. The family members were all well, and none had similar symptoms. The woman had no previous medical history and was on no medication. On examination, she looked unwell, with a temperature of 38.5 °C, pulse 96 beats per minute, blood pressure 112/52 mm Hg, and a respiratory rate of 16 breaths per minute. She had a Glasgow Coma Score of 14, there was no neck stiffness, and her ocular fundi were said to be normal. There were no other significant findings on examination. Immediate investigations showed a normal blood count apart from a raised white blood cell (WBC) count of 11.1 × 10 9  per millilitre (normal range, 4.3–10.8 × 10 9 , per millilitre), with 84% neutrophils. Her erythrocyte sedimentation rate was 15 mm in the first hour (normal range, 1–12 mm), and her C-reactive protein was less than 5 mg/l (normal range, less than 10 mg/l). A malaria screen was negative, and renal and liver function tests were normal. What Clinical Diagnoses Were Being Considered? A clinical diagnosis of probable viral meningitis was made pending the results of further investigations. Chest X ray was normal, as was an unenhanced CT brain scan. Lumbar puncture showed a normal cerebrospinal fluid (CSF) opening pressure, and the CSF was not blood stained. Laboratory analysis showed 1,606 WBC/ml (normally there are less than 5 cells/ml), of which 60% were lymphocytes with protein of 1.08 g/l (normally less than 0.6 g/l) and glucose of 2.9 mmol/l (normally greater than 50% of plasma glucose), with a corresponding plasma glucose of 5.7 mmol/l (normal range, 4–9 mmol/l). No organisms were seen on Gram stain. The CSF was negative for pneumococcal, meningococcal, and  Haemophilus  antigens, and bacterial culture was subsequently negative. The patient was given 2 g of ceftriaxone intravenously immediately, and ceftriaxone treatment was continued following the CSF results. Aciclovir IV, at a dose of 10 mg/kg every 8 hours, was added to cover the possibility of herpes encephalitis. What Was the Subsequent Differential Diagnosis? The differential diagnosis was now viral, bacterial, tuberculous (TB), fungal, or malignant meningitis, or sarcoidosis. Additional investigations were requested, including polymerase chain reaction (PCR) on CSF for viruses and tuberculosis. There were no risk factors for HIV infection (HIV seroconversion can present with meningitis). Mollaret’s meningitis (recurrent aseptic meningitis associated with herpes simplex virus) was a possibility [ 1 ], though this condition characteristically presents as  recurrent  episodes of apparent aseptic meningitis. The following morning the patient’s temperature returned to normal at 37 °C, and she felt better. Referral was made to the Infectious Disease Service. Twenty-four hours after admission, she was afebrile but clinically worse, with marked headache and vomiting. A day later she spiked a fever of 39 °C. No organisms were cultured from the CSF, urine, or blood. CSF bacterial antigens, cryptococcal antigen, and CSF auramine stain (for mycobacteria) were also all negative. The following day the patient complained of further headache, nausea, blurred vision, and photophobia. In addition, she was noted to have bilateral large pupils, which did not react to light, and very pink optic nerves. Papilloedema was thought likely, and no other neurological signs were detected. The original CSF sample was negative on PCR for tuberculosis and herpes simplex virus, C-reactive protein remained at less than 5 mg/l, and a further head CT scan with contrast was normal. The diagnosis was revised to meningoencephalitis. Other agents—such as listeria, tuberculosis (a systematic review found that PCR has a sensitivity of only 56% [95% CI, 46%–66%] for detecting TB meningitis [ 2 ]), and viruses such as others in the herpes group, mumps, and West Nile virus—were considered. The aciclovir was stopped, and quadruple tuberculosis therapy was started. What Did the Eye Signs Mean? The fixed, dilated pupils were of major concern, and urgent ophthalmic review was requested. Examination by the ophthalmologist showed reduced vision at 6/60 right eye and 6/36 left eye. On testing with Ishihara charts, the patient had severely reduced colour vision. Her pupils were large and non-reactive to light or accommodation in both eyes. The eyes were inflamed, with cells present in the aqueous and vitreous humours. The optic nerves were swollen and very pink ( Figure 1 ), but there was normal spontaneous venous pulsation present—demonstrating that this was not papilloedema (see  Video 1 ). Bilateral choroidal infiltrates with overlying serous retinal detachments were also present. Figure 1 Fundal Appearance of the Patient's Eye The large arrow indicates the pink optic nerves; the star shows localised retinal detachment; and the small arrow pointing down shows small, white choroidal granulomas. Video 1 Spontaneous Venous Pulsation of the Veins at the Optic Nerve Head What Was the Final Diagnosis and Treatment? The combination of the clinical symptoms, signs, and ocular features was characteristic of Vogt-Koyanagi-Harada (VKH) syndrome [ 3 ]. All antibiotics were stopped, and high-dose corticosteroids were started at 100 mg prednisolone daily. At one week there was no significant ocular improvement, although the patient's headache and vomiting were now gone, and she felt much better. Additional immunosuppressive therapy was initiated with cyclosporin and mycophenolate, and within a further week the patient's vision started to improve, with settling of the ocular signs. Oral corticosteroids were tapered, as was the cyclosporin, and by one month the patient's vision had returned to normal, and the ocular signs continued to settle. By three months the cyclosporin was discontinued, the steroid dose was reduced to 5 mg daily, and the mycophenolate dose was tapered. By six months all therapy was discontinued. At review six months later, the patient remained well, with normal vision and normal optic nerves.
DESCRIPTION of CASE
A 17-year-old woman, who was born in Bangladesh, presented to an accident and emergency department in the United Kingdom with a history of being unwell for 24 hours. She had a headache and fever, and was vomiting. On questioning, there was no photophobia or neck stiffness. She lives in the United Kingdom and had been for a holiday to Bangladesh 4 months previously. The family members were all well, and none had similar symptoms. The woman had no previous medical history and was on no medication.On examination, she looked unwell, with a temperature of 38.5 °C, pulse 96 beats per minute, blood pressure 112/52 mm Hg, and a respiratory rate of 16 breaths per minute. She had a Glasgow Coma Score of 14, there was no neck stiffness, and her ocular fundi were said to be normal. There were no other significant findings on examination. Immediate investigations showed a normal blood count apart from a raised white blood cell (WBC) count of 11.1 × 10 9  per millilitre (normal range, 4.3–10.8 × 10 9 , per millilitre), with 84% neutrophils. Her erythrocyte sedimentation rate was 15 mm in the first hour (normal range, 1–12 mm), and her C-reactive protein was less than 5 mg/l (normal range, less than 10 mg/l). A malaria screen was negative, and renal and liver function tests were normal.What Clinical Diagnoses Were Being Considered? A clinical diagnosis of probable viral meningitis was made pending the results of further investigations. Chest X ray was normal, as was an unenhanced CT brain scan. Lumbar puncture showed a normal cerebrospinal fluid (CSF) opening pressure, and the CSF was not blood stained. Laboratory analysis showed 1,606 WBC/ml (normally there are less than 5 cells/ml), of which 60% were lymphocytes with protein of 1.08 g/l (normally less than 0.6 g/l) and glucose of 2.9 mmol/l (normally greater than 50% of plasma glucose), with a corresponding plasma glucose of 5.7 mmol/l (normal range, 4–9 mmol/l). No organisms were seen on Gram stain. The CSF was negative for pneumococcal, meningococcal, and  Haemophilus  antigens, and bacterial culture was subsequently negative. The patient was given 2 g of ceftriaxone intravenously immediately, and ceftriaxone treatment was continued following the CSF results. Aciclovir IV, at a dose of 10 mg/kg every 8 hours, was added to cover the possibility of herpes encephalitis.
What Clinical Diagnoses Were Being Considered?
A clinical diagnosis of probable viral meningitis was made pending the results of further investigations. Chest X ray was normal, as was an unenhanced CT brain scan. Lumbar puncture showed a normal cerebrospinal fluid (CSF) opening pressure, and the CSF was not blood stained. Laboratory analysis showed 1,606 WBC/ml (normally there are less than 5 cells/ml), of which 60% were lymphocytes with protein of 1.08 g/l (normally less than 0.6 g/l) and glucose of 2.9 mmol/l (normally greater than 50% of plasma glucose), with a corresponding plasma glucose of 5.7 mmol/l (normal range, 4–9 mmol/l). No organisms were seen on Gram stain. The CSF was negative for pneumococcal, meningococcal, and  Haemophilus  antigens, and bacterial culture was subsequently negative. The patient was given 2 g of ceftriaxone intravenously immediately, and ceftriaxone treatment was continued following the CSF results. Aciclovir IV, at a dose of 10 mg/kg every 8 hours, was added to cover the possibility of herpes encephalitis.What Was the Subsequent Differential Diagnosis? The differential diagnosis was now viral, bacterial, tuberculous (TB), fungal, or malignant meningitis, or sarcoidosis. Additional investigations were requested, including polymerase chain reaction (PCR) on CSF for viruses and tuberculosis. There were no risk factors for HIV infection (HIV seroconversion can present with meningitis). Mollaret’s meningitis (recurrent aseptic meningitis associated with herpes simplex virus) was a possibility [ 1 ], though this condition characteristically presents as  recurrent  episodes of apparent aseptic meningitis. The following morning the patient’s temperature returned to normal at 37 °C, and she felt better. Referral was made to the Infectious Disease Service. Twenty-four hours after admission, she was afebrile but clinically worse, with marked headache and vomiting. A day later she spiked a fever of 39 °C. No organisms were cultured from the CSF, urine, or blood. CSF bacterial antigens, cryptococcal antigen, and CSF auramine stain (for mycobacteria) were also all negative. The following day the patient complained of further headache, nausea, blurred vision, and photophobia. In addition, she was noted to have bilateral large pupils, which did not react to light, and very pink optic nerves. Papilloedema was thought likely, and no other neurological signs were detected. The original CSF sample was negative on PCR for tuberculosis and herpes simplex virus, C-reactive protein remained at less than 5 mg/l, and a further head CT scan with contrast was normal. The diagnosis was revised to meningoencephalitis. Other agents—such as listeria, tuberculosis (a systematic review found that PCR has a sensitivity of only 56% [95% CI, 46%–66%] for detecting TB meningitis [ 2 ]), and viruses such as others in the herpes group, mumps, and West Nile virus—were considered. The aciclovir was stopped, and quadruple tuberculosis therapy was started.
What Was the Subsequent Differential Diagnosis?
The differential diagnosis was now viral, bacterial, tuberculous (TB), fungal, or malignant meningitis, or sarcoidosis. Additional investigations were requested, including polymerase chain reaction (PCR) on CSF for viruses and tuberculosis. There were no risk factors for HIV infection (HIV seroconversion can present with meningitis). Mollaret’s meningitis (recurrent aseptic meningitis associated with herpes simplex virus) was a possibility [ 1 ], though this condition characteristically presents as  recurrent  episodes of apparent aseptic meningitis.recurrentThe following morning the patient’s temperature returned to normal at 37 °C, and she felt better. Referral was made to the Infectious Disease Service. Twenty-four hours after admission, she was afebrile but clinically worse, with marked headache and vomiting. A day later she spiked a fever of 39 °C. No organisms were cultured from the CSF, urine, or blood. CSF bacterial antigens, cryptococcal antigen, and CSF auramine stain (for mycobacteria) were also all negative.The following day the patient complained of further headache, nausea, blurred vision, and photophobia. In addition, she was noted to have bilateral large pupils, which did not react to light, and very pink optic nerves. Papilloedema was thought likely, and no other neurological signs were detected. The original CSF sample was negative on PCR for tuberculosis and herpes simplex virus, C-reactive protein remained at less than 5 mg/l, and a further head CT scan with contrast was normal.The diagnosis was revised to meningoencephalitis. Other agents—such as listeria, tuberculosis (a systematic review found that PCR has a sensitivity of only 56% [95% CI, 46%–66%] for detecting TB meningitis [ 2 ]), and viruses such as others in the herpes group, mumps, and West Nile virus—were considered. The aciclovir was stopped, and quadruple tuberculosis therapy was started.What Did the Eye Signs Mean? The fixed, dilated pupils were of major concern, and urgent ophthalmic review was requested. Examination by the ophthalmologist showed reduced vision at 6/60 right eye and 6/36 left eye. On testing with Ishihara charts, the patient had severely reduced colour vision. Her pupils were large and non-reactive to light or accommodation in both eyes. The eyes were inflamed, with cells present in the aqueous and vitreous humours. The optic nerves were swollen and very pink ( Figure 1 ), but there was normal spontaneous venous pulsation present—demonstrating that this was not papilloedema (see  Video 1 ). Bilateral choroidal infiltrates with overlying serous retinal detachments were also present. Figure 1 Fundal Appearance of the Patient's Eye The large arrow indicates the pink optic nerves; the star shows localised retinal detachment; and the small arrow pointing down shows small, white choroidal granulomas. Video 1 Spontaneous Venous Pulsation of the Veins at the Optic Nerve Head
What Did the Eye Signs Mean?
The fixed, dilated pupils were of major concern, and urgent ophthalmic review was requested. Examination by the ophthalmologist showed reduced vision at 6/60 right eye and 6/36 left eye. On testing with Ishihara charts, the patient had severely reduced colour vision. Her pupils were large and non-reactive to light or accommodation in both eyes. The eyes were inflamed, with cells present in the aqueous and vitreous humours. The optic nerves were swollen and very pink ( Figure 1 ), but there was normal spontaneous venous pulsation present—demonstrating that this was not papilloedema (see  Video 1 ). Bilateral choroidal infiltrates with overlying serous retinal detachments were also present.What Was the Final Diagnosis and Treatment? The combination of the clinical symptoms, signs, and ocular features was characteristic of Vogt-Koyanagi-Harada (VKH) syndrome [ 3 ]. All antibiotics were stopped, and high-dose corticosteroids were started at 100 mg prednisolone daily. At one week there was no significant ocular improvement, although the patient's headache and vomiting were now gone, and she felt much better. Additional immunosuppressive therapy was initiated with cyclosporin and mycophenolate, and within a further week the patient's vision started to improve, with settling of the ocular signs. Oral corticosteroids were tapered, as was the cyclosporin, and by one month the patient's vision had returned to normal, and the ocular signs continued to settle. By three months the cyclosporin was discontinued, the steroid dose was reduced to 5 mg daily, and the mycophenolate dose was tapered. By six months all therapy was discontinued. At review six months later, the patient remained well, with normal vision and normal optic nerves.
What Was the Final Diagnosis and Treatment?
The combination of the clinical symptoms, signs, and ocular features was characteristic of Vogt-Koyanagi-Harada (VKH) syndrome [ 3 ]. All antibiotics were stopped, and high-dose corticosteroids were started at 100 mg prednisolone daily. At one week there was no significant ocular improvement, although the patient's headache and vomiting were now gone, and she felt much better. Additional immunosuppressive therapy was initiated with cyclosporin and mycophenolate, and within a further week the patient's vision started to improve, with settling of the ocular signs. Oral corticosteroids were tapered, as was the cyclosporin, and by one month the patient's vision had returned to normal, and the ocular signs continued to settle. By three months the cyclosporin was discontinued, the steroid dose was reduced to 5 mg daily, and the mycophenolate dose was tapered. By six months all therapy was discontinued. At review six months later, the patient remained well, with normal vision and normal optic nerves.DISCUSSION This young patient presented acutely with a fever and some signs suggestive of meningitis. She was initially treated as having viral meningitis, but the CSF findings indicated that other aetiologies needed to be considered. In particular, in a woman who previously lived in and recently visited Bangladesh, with a lymphocytic meningitis and borderline CSF glucose, tuberculosis had to be considered. Initially the ocular symptoms and signs were not a prominent feature, but the signs were likely to have been present when the patient was first seen. The typical CSF changes associated with meningitis of different aetiologies are shown in  Table 1 . In this case the mixed lymphocytes and neutrophil leucocytosis with a borderline CSF glucose on the patient's initial CSF sample were consistent with bacterial or TB meningitis. Viral infection was far less likely, as only mumps is consistently associated with reduced CSF glucose. Table 1 CSF Changes in the Most Commonly Encountered Types of Meningitis Infectious Causes of Meningitis There is a wide range of infectious causes of meningitis worldwide. The likely infecting organism will be determined by the age and immune status of the patient plus the situation in which the infection was contracted. Thus, in an immunocompetent adult in the UK, enteroviruses are the commonest cause of viral meningitis, with meningococcus and pneumococcus the commonest bacterial agents. Tuberculosis is more common in people who have lived in a highly endemic area. In other parts of the world, the differential diagnosis may include viral infections such as West Nile virus in the continental United States and Japanese B encephalitis in Asia, or other pathogens such as rickettsiae, borrelia (Lyme disease), and protozoa. In the immunocompromised host, listeria must be considered, and there is an increased risk of fungal infection and tuberculosis. Finally, it is important to consider sexual exposure, as both secondary syphilis and HIV seroconversion may present with meningitis. It is important, therefore, in the evaluation and management of patients presenting with a meningoencephalitis that the differential diagnosis be continually reviewed if the patient is not responding to therapy ( Table 2 ). When appropriate investigations have been performed and are negative and symptoms persist, non-infective causes of CSF inflammation must be considered—as turned out to be the case here ( Table 3 ). Table 2 What to Do When the Patient Is Not Getting Better Table 3 Non-Infectious Causes of Abnormal CSF VKH Syndrome VKH syndrome [ 4 , 5 , 6 ] is a systemic disease involving various melanocyte-containing organs. It is rare in white Northern Europeans and white Americans but much more common in people with darker, pigmented skin. For example, among patients presenting with uveitis, about one in ten in Japan and one in 50 in India have VKH syndrome [ 6 , 7 ]. It presents acutely with varying symptoms and signs, which include meningoencephalitis, visual blurring, and deafness. The eye signs are very characteristic and can help to make the diagnosis. The most prominent ocular finding is intensely pink optic nerves (see  Figure 1 ), with severe visual reduction and loss of function, which accounts for the absent pupillary responses. VKH syndrome is usually bilateral, but occasionally the eyes can be affected asymmetrically so that one is very mildly involved. The syndrome is accompanied by marked intraocular inflammation, and there are choroidal infiltrates ( Figure 2 ) associated with serous retinal detachments, which may be localised ( Figure 3 ) or affect the whole retina ( Figure 4 ). It is likely that these detachments are due to the retinal pigment epithelium (RPE) being affected by the underlying inflammatory choroidal granulomas (which heal leaving scars; see  Figure 5 ), and fluid accumulates underneath the retina because of reduced function of the RPE when it becomes inflamed. Figure 2 White Choroidal Infiltrates (Arrow) Seen in VKH Syndrome with Very Pink Optic Nerve Head Figure 3 Localised Retinal Detachment Figure 4 Total Retinal Detachment, Where Whole Retina is Grey in Colour Figure 5 Scarring When Choroidal Granulomas Subside The disorder is caused by an immune response to melanin and affects parts of the body where melanin is found. The initiating stimulus for this response is unknown, but T-cells sensitised to melanin-associated antigens are found in the peripheral blood. In the ear, the melanocytes of the inner ear are the target, and the inflammatory response here results in hearing loss and balance problems. In longstanding untreated cases, depigmentation may occur in other sites such as skin (vitiligo;  Figure 6 ) and eyelashes (poliosis;  Figure 7 ), but these are uncommon when corticosteroids and other immunosuppressive agents are used in treatment. Depigmentation of the RPE can also occur, giving a ‘sunset’ appearance to the dark fundus. Figure 6 Vitiligo on Skin of Forearm Figure 7 Poliosis Note white eyelashes on child. Treatment with high-dose corticosteroids is essential [ 3 ] and should be initially 1–2 mg/kg/day. This treatment can be given orally or intravenously, depending on how unwell the patient is. However, patients commonly need other immunosuppressive agents as well, so as to allow the dose of steroids to be reduced more quickly. Both cyclosporin and mycophenolate are very useful as steroid-sparing agents, with cyclosporin having the advantage of a variable-dose regimen for more rapid onset of action. On the down side, cyclosporin can cause hirsutism, especially in combination with corticosteroids (which can also cause this side effect). Unfortunately, the costs of cyclosporin and mycophenolate may preclude their use in resource-poor settings, with the result that patients may require high-dose corticosteroids for much longer, with all the concomitant side effects. Inadequate initial treatment may increase the risk of recurrence and long-term complications. Treatment is required until the disease goes into remission. The meningoence-phalitic signs and retinal and choroidal signs settle quickly, often within a week or so, whereas the optic nerve inflammation may take longer to settle. The visual prognosis depends on the degree of permanent damage to the optic nerve and the macula area, which often shows considerable pigment clumping as a result of the damage to the RPE. Relapse affecting the optic nerve, choroids, and retina is uncommon, provided that treatment has been given for long enough. However, recurrent anterior uveitis requiring steroid drops is common. This is not a threat to sight if adequately controlled. As with any other cause of intraocular inflammation particularly associated with choroidal involvement, VKH syndrome can lead to reduced vision via cataracts, glaucoma damaging the optic nerve, and new vessels growing into the retina through the damaged RPE (choroidal neovascular membrane). Key Learning Points
 Consider meningitis in the differential diagnosis of a patient presenting with fever and headache. CSF analysis is essential to confirm meningitis and as part of establishing the cause. Consider non-infectious causes when a patient does not respond rapidly to therapy. Blurring of vision must be investigated and may help in determining the underlying diagnosis or the presence of papilloedema.
 Suggested Reading
 Sutlas PN Unal A Forta H Senol S Kirbas D
 2003
 Tuberculous meningitis in adults: Review of 61 cases
 Infection
 31
 387
 391
 Early suspicion and appropriate long-term anti-tuberculosis therapy together with corticosteroids may reduce mortality and morbidity in patients with TB meningitis
 14735380
 Redington JJ Tyler KL
 2002
 Viral infections of the nervous system
 Arch Neurol
 59
 712
 718
 This review is an update on diagnosis and treatment
 12020250
 Thomson RB Jr Bertram H
 2001
 Laboratory diagnosis of central nervous system infections
 Infect Dis Clin North Am
 15
 1047
 1071
 This paper discusses conventional tests, such as culture, and others such as antigen testing and PCR
 11780267
 Rotbart HA
 2000
 Viral meningitis
 Semin Neurol
 20
 277
 292
 The virology, pathogenesis, epidemiology, clinical manifestations, diagnostic studies, and established and potential antiviral therapies for viral meningitis are discussed. A differential diagnosis of the aseptic meningitis syndrome is provided
 11051293
 Negrini B Kelleher KJ Wald ER
 2000
 Cerebrospinal fluid findings in aseptic versus bacterial meningitis
 Pediatrics
 105
 316
 319
 Polymorphonuclear cell predominance in the CSF does not discriminate between aseptic and bacterial meningitis
 10654948
 Kamondi A Szegedi A Papp A Seres A Szirmai I
 2000
 Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis
 Eur J Neurol
 7
 719
 722
 This paper describes the neurological and eye signs in VKH syndrome
 11136362
 Seehusen DA Reeves MM Fomin DA
 2003
 Cerebrospinal fluid analysis
 Am Fam Physician
 68
 1103
 1108
 Lumbar puncture is frequently performed in primary care, and this review outlines the interpretation of the clinical and laboratory findings
 14524396
 Shah KH Edlow JA
 2002
 Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage
 J Emerg Med
 23
 67
 74
 The purpose of this article is to assist emergency physicians in distinguishing traumatic lumbar punctures from subarachnoid hemorrhage
 12217474
DISCUSSION
This young patient presented acutely with a fever and some signs suggestive of meningitis. She was initially treated as having viral meningitis, but the CSF findings indicated that other aetiologies needed to be considered. In particular, in a woman who previously lived in and recently visited Bangladesh, with a lymphocytic meningitis and borderline CSF glucose, tuberculosis had to be considered. Initially the ocular symptoms and signs were not a prominent feature, but the signs were likely to have been present when the patient was first seen.The typical CSF changes associated with meningitis of different aetiologies are shown in  Table 1 . In this case the mixed lymphocytes and neutrophil leucocytosis with a borderline CSF glucose on the patient's initial CSF sample were consistent with bacterial or TB meningitis. Viral infection was far less likely, as only mumps is consistently associated with reduced CSF glucose.CSF Changes in the Most Commonly Encountered Types of Meningitis
Infectious Causes of Meningitis There is a wide range of infectious causes of meningitis worldwide. The likely infecting organism will be determined by the age and immune status of the patient plus the situation in which the infection was contracted. Thus, in an immunocompetent adult in the UK, enteroviruses are the commonest cause of viral meningitis, with meningococcus and pneumococcus the commonest bacterial agents. Tuberculosis is more common in people who have lived in a highly endemic area. In other parts of the world, the differential diagnosis may include viral infections such as West Nile virus in the continental United States and Japanese B encephalitis in Asia, or other pathogens such as rickettsiae, borrelia (Lyme disease), and protozoa. In the immunocompromised host, listeria must be considered, and there is an increased risk of fungal infection and tuberculosis. Finally, it is important to consider sexual exposure, as both secondary syphilis and HIV seroconversion may present with meningitis. It is important, therefore, in the evaluation and management of patients presenting with a meningoencephalitis that the differential diagnosis be continually reviewed if the patient is not responding to therapy ( Table 2 ). When appropriate investigations have been performed and are negative and symptoms persist, non-infective causes of CSF inflammation must be considered—as turned out to be the case here ( Table 3 ). Table 2 What to Do When the Patient Is Not Getting Better Table 3 Non-Infectious Causes of Abnormal CSF
Infectious Causes of Meningitis
There is a wide range of infectious causes of meningitis worldwide. The likely infecting organism will be determined by the age and immune status of the patient plus the situation in which the infection was contracted. Thus, in an immunocompetent adult in the UK, enteroviruses are the commonest cause of viral meningitis, with meningococcus and pneumococcus the commonest bacterial agents. Tuberculosis is more common in people who have lived in a highly endemic area. In other parts of the world, the differential diagnosis may include viral infections such as West Nile virus in the continental United States and Japanese B encephalitis in Asia, or other pathogens such as rickettsiae, borrelia (Lyme disease), and protozoa. In the immunocompromised host, listeria must be considered, and there is an increased risk of fungal infection and tuberculosis. Finally, it is important to consider sexual exposure, as both secondary syphilis and HIV seroconversion may present with meningitis.It is important, therefore, in the evaluation and management of patients presenting with a meningoencephalitis that the differential diagnosis be continually reviewed if the patient is not responding to therapy ( Table 2 ). When appropriate investigations have been performed and are negative and symptoms persist, non-infective causes of CSF inflammation must be considered—as turned out to be the case here ( Table 3 ).What to Do When the Patient Is Not Getting Better
Non-Infectious Causes of Abnormal CSF
VKH Syndrome VKH syndrome [ 4 , 5 , 6 ] is a systemic disease involving various melanocyte-containing organs. It is rare in white Northern Europeans and white Americans but much more common in people with darker, pigmented skin. For example, among patients presenting with uveitis, about one in ten in Japan and one in 50 in India have VKH syndrome [ 6 , 7 ]. It presents acutely with varying symptoms and signs, which include meningoencephalitis, visual blurring, and deafness. The eye signs are very characteristic and can help to make the diagnosis. The most prominent ocular finding is intensely pink optic nerves (see  Figure 1 ), with severe visual reduction and loss of function, which accounts for the absent pupillary responses. VKH syndrome is usually bilateral, but occasionally the eyes can be affected asymmetrically so that one is very mildly involved. The syndrome is accompanied by marked intraocular inflammation, and there are choroidal infiltrates ( Figure 2 ) associated with serous retinal detachments, which may be localised ( Figure 3 ) or affect the whole retina ( Figure 4 ). It is likely that these detachments are due to the retinal pigment epithelium (RPE) being affected by the underlying inflammatory choroidal granulomas (which heal leaving scars; see  Figure 5 ), and fluid accumulates underneath the retina because of reduced function of the RPE when it becomes inflamed. Figure 2 White Choroidal Infiltrates (Arrow) Seen in VKH Syndrome with Very Pink Optic Nerve Head Figure 3 Localised Retinal Detachment Figure 4 Total Retinal Detachment, Where Whole Retina is Grey in Colour Figure 5 Scarring When Choroidal Granulomas Subside The disorder is caused by an immune response to melanin and affects parts of the body where melanin is found. The initiating stimulus for this response is unknown, but T-cells sensitised to melanin-associated antigens are found in the peripheral blood. In the ear, the melanocytes of the inner ear are the target, and the inflammatory response here results in hearing loss and balance problems. In longstanding untreated cases, depigmentation may occur in other sites such as skin (vitiligo;  Figure 6 ) and eyelashes (poliosis;  Figure 7 ), but these are uncommon when corticosteroids and other immunosuppressive agents are used in treatment. Depigmentation of the RPE can also occur, giving a ‘sunset’ appearance to the dark fundus. Figure 6 Vitiligo on Skin of Forearm Figure 7 Poliosis Note white eyelashes on child. Treatment with high-dose corticosteroids is essential [ 3 ] and should be initially 1–2 mg/kg/day. This treatment can be given orally or intravenously, depending on how unwell the patient is. However, patients commonly need other immunosuppressive agents as well, so as to allow the dose of steroids to be reduced more quickly. Both cyclosporin and mycophenolate are very useful as steroid-sparing agents, with cyclosporin having the advantage of a variable-dose regimen for more rapid onset of action. On the down side, cyclosporin can cause hirsutism, especially in combination with corticosteroids (which can also cause this side effect). Unfortunately, the costs of cyclosporin and mycophenolate may preclude their use in resource-poor settings, with the result that patients may require high-dose corticosteroids for much longer, with all the concomitant side effects. Inadequate initial treatment may increase the risk of recurrence and long-term complications. Treatment is required until the disease goes into remission. The meningoence-phalitic signs and retinal and choroidal signs settle quickly, often within a week or so, whereas the optic nerve inflammation may take longer to settle. The visual prognosis depends on the degree of permanent damage to the optic nerve and the macula area, which often shows considerable pigment clumping as a result of the damage to the RPE. Relapse affecting the optic nerve, choroids, and retina is uncommon, provided that treatment has been given for long enough. However, recurrent anterior uveitis requiring steroid drops is common. This is not a threat to sight if adequately controlled. As with any other cause of intraocular inflammation particularly associated with choroidal involvement, VKH syndrome can lead to reduced vision via cataracts, glaucoma damaging the optic nerve, and new vessels growing into the retina through the damaged RPE (choroidal neovascular membrane). Key Learning Points
 Consider meningitis in the differential diagnosis of a patient presenting with fever and headache. CSF analysis is essential to confirm meningitis and as part of establishing the cause. Consider non-infectious causes when a patient does not respond rapidly to therapy. Blurring of vision must be investigated and may help in determining the underlying diagnosis or the presence of papilloedema.
 Suggested Reading
 Sutlas PN Unal A Forta H Senol S Kirbas D
 2003
 Tuberculous meningitis in adults: Review of 61 cases
 Infection
 31
 387
 391
 Early suspicion and appropriate long-term anti-tuberculosis therapy together with corticosteroids may reduce mortality and morbidity in patients with TB meningitis
 14735380
 Redington JJ Tyler KL
 2002
 Viral infections of the nervous system
 Arch Neurol
 59
 712
 718
 This review is an update on diagnosis and treatment
 12020250
 Thomson RB Jr Bertram H
 2001
 Laboratory diagnosis of central nervous system infections
 Infect Dis Clin North Am
 15
 1047
 1071
 This paper discusses conventional tests, such as culture, and others such as antigen testing and PCR
 11780267
 Rotbart HA
 2000
 Viral meningitis
 Semin Neurol
 20
 277
 292
 The virology, pathogenesis, epidemiology, clinical manifestations, diagnostic studies, and established and potential antiviral therapies for viral meningitis are discussed. A differential diagnosis of the aseptic meningitis syndrome is provided
 11051293
 Negrini B Kelleher KJ Wald ER
 2000
 Cerebrospinal fluid findings in aseptic versus bacterial meningitis
 Pediatrics
 105
 316
 319
 Polymorphonuclear cell predominance in the CSF does not discriminate between aseptic and bacterial meningitis
 10654948
 Kamondi A Szegedi A Papp A Seres A Szirmai I
 2000
 Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis
 Eur J Neurol
 7
 719
 722
 This paper describes the neurological and eye signs in VKH syndrome
 11136362
 Seehusen DA Reeves MM Fomin DA
 2003
 Cerebrospinal fluid analysis
 Am Fam Physician
 68
 1103
 1108
 Lumbar puncture is frequently performed in primary care, and this review outlines the interpretation of the clinical and laboratory findings
 14524396
 Shah KH Edlow JA
 2002
 Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage
 J Emerg Med
 23
 67
 74
 The purpose of this article is to assist emergency physicians in distinguishing traumatic lumbar punctures from subarachnoid hemorrhage
 12217474
VKH Syndrome
VKH syndrome [ 4 , 5 , 6 ] is a systemic disease involving various melanocyte-containing organs. It is rare in white Northern Europeans and white Americans but much more common in people with darker, pigmented skin. For example, among patients presenting with uveitis, about one in ten in Japan and one in 50 in India have VKH syndrome [ 6 , 7 ]. It presents acutely with varying symptoms and signs, which include meningoencephalitis, visual blurring, and deafness. The eye signs are very characteristic and can help to make the diagnosis. The most prominent ocular finding is intensely pink optic nerves (see  Figure 1 ), with severe visual reduction and loss of function, which accounts for the absent pupillary responses.VKH syndrome is usually bilateral, but occasionally the eyes can be affected asymmetrically so that one is very mildly involved. The syndrome is accompanied by marked intraocular inflammation, and there are choroidal infiltrates ( Figure 2 ) associated with serous retinal detachments, which may be localised ( Figure 3 ) or affect the whole retina ( Figure 4 ). It is likely that these detachments are due to the retinal pigment epithelium (RPE) being affected by the underlying inflammatory choroidal granulomas (which heal leaving scars; see  Figure 5 ), and fluid accumulates underneath the retina because of reduced function of the RPE when it becomes inflamed.The disorder is caused by an immune response to melanin and affects parts of the body where melanin is found. The initiating stimulus for this response is unknown, but T-cells sensitised to melanin-associated antigens are found in the peripheral blood. In the ear, the melanocytes of the inner ear are the target, and the inflammatory response here results in hearing loss and balance problems. In longstanding untreated cases, depigmentation may occur in other sites such as skin (vitiligo;  Figure 6 ) and eyelashes (poliosis;  Figure 7 ), but these are uncommon when corticosteroids and other immunosuppressive agents are used in treatment. Depigmentation of the RPE can also occur, giving a ‘sunset’ appearance to the dark fundus.Treatment with high-dose corticosteroids is essential [ 3 ] and should be initially 1–2 mg/kg/day. This treatment can be given orally or intravenously, depending on how unwell the patient is. However, patients commonly need other immunosuppressive agents as well, so as to allow the dose of steroids to be reduced more quickly. Both cyclosporin and mycophenolate are very useful as steroid-sparing agents, with cyclosporin having the advantage of a variable-dose regimen for more rapid onset of action. On the down side, cyclosporin can cause hirsutism, especially in combination with corticosteroids (which can also cause this side effect). Unfortunately, the costs of cyclosporin and mycophenolate may preclude their use in resource-poor settings, with the result that patients may require high-dose corticosteroids for much longer, with all the concomitant side effects. Inadequate initial treatment may increase the risk of recurrence and long-term complications.Treatment is required until the disease goes into remission. The meningoence-phalitic signs and retinal and choroidal signs settle quickly, often within a week or so, whereas the optic nerve inflammation may take longer to settle. The visual prognosis depends on the degree of permanent damage to the optic nerve and the macula area, which often shows considerable pigment clumping as a result of the damage to the RPE.Relapse affecting the optic nerve, choroids, and retina is uncommon, provided that treatment has been given for long enough. However, recurrent anterior uveitis requiring steroid drops is common. This is not a threat to sight if adequately controlled. As with any other cause of intraocular inflammation particularly associated with choroidal involvement, VKH syndrome can lead to reduced vision via cataracts, glaucoma damaging the optic nerve, and new vessels growing into the retina through the damaged RPE (choroidal neovascular membrane).Key Learning Points
 Consider meningitis in the differential diagnosis of a patient presenting with fever and headache. CSF analysis is essential to confirm meningitis and as part of establishing the cause. Consider non-infectious causes when a patient does not respond rapidly to therapy. Blurring of vision must be investigated and may help in determining the underlying diagnosis or the presence of papilloedema.
Key Learning Points
Consider meningitis in the differential diagnosis of a patient presenting with fever and headache. CSF analysis is essential to confirm meningitis and as part of establishing the cause. Consider non-infectious causes when a patient does not respond rapidly to therapy. Blurring of vision must be investigated and may help in determining the underlying diagnosis or the presence of papilloedema.Consider meningitis in the differential diagnosis of a patient presenting with fever and headache.CSF analysis is essential to confirm meningitis and as part of establishing the cause.Consider non-infectious causes when a patient does not respond rapidly to therapy.Blurring of vision must be investigated and may help in determining the underlying diagnosis or the presence of papilloedema.Suggested Reading
 Sutlas PN Unal A Forta H Senol S Kirbas D
 2003
 Tuberculous meningitis in adults: Review of 61 cases
 Infection
 31
 387
 391
 Early suspicion and appropriate long-term anti-tuberculosis therapy together with corticosteroids may reduce mortality and morbidity in patients with TB meningitis
 14735380
 Redington JJ Tyler KL
 2002
 Viral infections of the nervous system
 Arch Neurol
 59
 712
 718
 This review is an update on diagnosis and treatment
 12020250
 Thomson RB Jr Bertram H
 2001
 Laboratory diagnosis of central nervous system infections
 Infect Dis Clin North Am
 15
 1047
 1071
 This paper discusses conventional tests, such as culture, and others such as antigen testing and PCR
 11780267
 Rotbart HA
 2000
 Viral meningitis
 Semin Neurol
 20
 277
 292
 The virology, pathogenesis, epidemiology, clinical manifestations, diagnostic studies, and established and potential antiviral therapies for viral meningitis are discussed. A differential diagnosis of the aseptic meningitis syndrome is provided
 11051293
 Negrini B Kelleher KJ Wald ER
 2000
 Cerebrospinal fluid findings in aseptic versus bacterial meningitis
 Pediatrics
 105
 316
 319
 Polymorphonuclear cell predominance in the CSF does not discriminate between aseptic and bacterial meningitis
 10654948
 Kamondi A Szegedi A Papp A Seres A Szirmai I
 2000
 Vogt-Koyanagi-Harada disease presenting initially as aseptic meningoencephalitis
 Eur J Neurol
 7
 719
 722
 This paper describes the neurological and eye signs in VKH syndrome
 11136362
 Seehusen DA Reeves MM Fomin DA
 2003
 Cerebrospinal fluid analysis
 Am Fam Physician
 68
 1103
 1108
 Lumbar puncture is frequently performed in primary care, and this review outlines the interpretation of the clinical and laboratory findings
 14524396
 Shah KH Edlow JA
 2002
 Distinguishing traumatic lumbar puncture from true subarachnoid hemorrhage
 J Emerg Med
 23
 67
 74
 The purpose of this article is to assist emergency physicians in distinguishing traumatic lumbar punctures from subarachnoid hemorrhage
 12217474
Suggested Reading


Atrial septal defect closure is now routinely performed using a percutaneous approach under echocardiographic guidance. Centrally located, secundum defects are ideal for device closure but there is considerable morphological variation in size and location of the defects. A small proportion of atrial septal defects may have multiple fenestrations and these are often considered unsuitable for device closure. We report three cases of multiple atrial septal defects successfully closed with two Amplatzer septal occluders.

Introduction Atrial septal defect (ASD) closure is now commonly performed using a transcatheter, percutaneous approach and with the Amplatzer septal occluder, large defects can be safely closed [ 1 , 2 ]. Device deployment requires a rim of atrial septal tissue surrounding the defect to allow effective capture of the septum by the occluder. The rim of tissue is also important to separate the septal occluder from important structures including the inferior vena cava, coronary sinus and the atrioventricular valves. The majority of patients require a single device for closure of the ASD but a small proportion of patients may have more than one defect in the atrial septum. This can be difficult to diagnose using transthoracic echocardiography (TTE) as abnormal colour flow obscures the origins of the shunt, particularly if the second defect is situated inferiorly. We report three cases of patients referred for ASD closures that were found to have multiple ASDs and the techniques used to close these defects. Case 1 A 34-year old woman was referred for consideration of percutaneous ASD closure. The ASD had been diagnosed when the patient was 12 years old and TTE had suggested that the right ventricle was dilating. At cardiac catheterisation there were mildly elevated right ventricular systolic pressures and a pulmonary to systemic flow ratio of over two. The secundum ASD was estimated to be 15 mm wide using TTE with aneurysmal formation of the interatrial septum. The patient was admitted for percutaneous ASD closure and underwent uncomplicated placement of a 17 mm Amplatzer septal occluder. Transesophageal echocardiography (TEE) during the procedure revealed the presence of a second ASD near the inferior vena cava and a small post-procedure shunt. The septal occluder did not completely cover both defects. Equivalent chest x-ray radiation dose (assuming a single posteroanterior projection chest x-ray is eight centi-Gray/cm 2 ) was 400. Repeat TTE continued to demonstrate left to right shunting and the patient was readmitted for a further device closure six months later. At cardiac catheterisation, the second defect was identified low in the secundum septum between the fossa ovalis and the mouth of the coronary sinus. The defect was successfully closed with a 9 mm Amplatzer septal occluder with no evidence of obstructed flow in either the coronary sinus or the inferior vena cava. Equivalent chest x-ray radiation dose for the second procedure was 187. The patient remained well with no evidence of residual shunt six months following the procedure. Case 2 A 31-year old woman was found to have a secundum ASD during investigations for breathlessness. The defect was estimated to be 10 mm wide on TTE with evidence of right atrial and right ventricular dilatation. Left atrial size was normal. She was referred was further investigation and treatment. Cardiac catheterisation demonstrated a pulmonary to systemic flow shunt of four to one. Peri-procedure TEE revealed that there were two defects; one measuring 24 mm located inferiorly between the inferior vena cava and coronary sinus os with the second defect situated superiorly and measuring 30 mm. The inferior defect was closed using a 24 mm Amplatzer septal occluder. Equivalent chest x-ray radiation dose was 403. The patient was discharged the following day and readmitted three months later for closure of the superior defect. This was performed using a 30 mm Amplatzer septal occluder. The procedure was technical difficult as after deployment of the left sided disc, the device initially lay obliquely in the defect. The final position was satisfactory with no evidence of intra-cardiac shunting (figure  1 ). There was no interference between the two devices and mitral valve function remained normal. Equivalent chest x-ray radiation dose for the second procedure was 727. The patient remained well and at six month follow-up there was no evidence of residual shunt. Figure 1 Stored fluoroscopy following placement of the two Amplatzer septal occluders (ASOs). TEE – Transesophageal echocardiography probe. Case 3 A 30-year old woman was investigated for palpitations and a secundum ASD of approximately 20 mm was diagnosed. TEE suggested that the atrial septum was fenestrated with a small inferior rim of tissue and she was referred for device closure. At cardiac catheterisation it became clear that there were two principal defects, one in the fossa ovalis and the other situated inferior and posterior between the fossa ovalis and the coronary sinus. The superior hole was closed with a 16 mm Amplatzer septal occluder but failed to cover the inferior defect. A 15 mm Amplatzer septal occluder device was subsequently placed successfully across the inferior defect with a stable position (figure  2 ). Equivalent chest x-ray radiation dose for the procedure was 124. Subsequent follow-up revealed a small left to right shunt between the two septal occluders but further intervention was not considered necessary. Figure 2 Transesophageal echocardiography four-chamber image following deployment of the two Amplatzer septal occluders (ASO). LA – left atrium, LV – left ventricle, RA – right atrium, RV – right ventricle.
Introduction
Atrial septal defect (ASD) closure is now commonly performed using a transcatheter, percutaneous approach and with the Amplatzer septal occluder, large defects can be safely closed [ 1 , 2 ]. Device deployment requires a rim of atrial septal tissue surrounding the defect to allow effective capture of the septum by the occluder. The rim of tissue is also important to separate the septal occluder from important structures including the inferior vena cava, coronary sinus and the atrioventricular valves.The majority of patients require a single device for closure of the ASD but a small proportion of patients may have more than one defect in the atrial septum. This can be difficult to diagnose using transthoracic echocardiography (TTE) as abnormal colour flow obscures the origins of the shunt, particularly if the second defect is situated inferiorly. We report three cases of patients referred for ASD closures that were found to have multiple ASDs and the techniques used to close these defects.Case 1 A 34-year old woman was referred for consideration of percutaneous ASD closure. The ASD had been diagnosed when the patient was 12 years old and TTE had suggested that the right ventricle was dilating. At cardiac catheterisation there were mildly elevated right ventricular systolic pressures and a pulmonary to systemic flow ratio of over two. The secundum ASD was estimated to be 15 mm wide using TTE with aneurysmal formation of the interatrial septum. The patient was admitted for percutaneous ASD closure and underwent uncomplicated placement of a 17 mm Amplatzer septal occluder. Transesophageal echocardiography (TEE) during the procedure revealed the presence of a second ASD near the inferior vena cava and a small post-procedure shunt. The septal occluder did not completely cover both defects. Equivalent chest x-ray radiation dose (assuming a single posteroanterior projection chest x-ray is eight centi-Gray/cm 2 ) was 400. Repeat TTE continued to demonstrate left to right shunting and the patient was readmitted for a further device closure six months later. At cardiac catheterisation, the second defect was identified low in the secundum septum between the fossa ovalis and the mouth of the coronary sinus. The defect was successfully closed with a 9 mm Amplatzer septal occluder with no evidence of obstructed flow in either the coronary sinus or the inferior vena cava. Equivalent chest x-ray radiation dose for the second procedure was 187. The patient remained well with no evidence of residual shunt six months following the procedure.
Case 1
A 34-year old woman was referred for consideration of percutaneous ASD closure. The ASD had been diagnosed when the patient was 12 years old and TTE had suggested that the right ventricle was dilating. At cardiac catheterisation there were mildly elevated right ventricular systolic pressures and a pulmonary to systemic flow ratio of over two. The secundum ASD was estimated to be 15 mm wide using TTE with aneurysmal formation of the interatrial septum. The patient was admitted for percutaneous ASD closure and underwent uncomplicated placement of a 17 mm Amplatzer septal occluder. Transesophageal echocardiography (TEE) during the procedure revealed the presence of a second ASD near the inferior vena cava and a small post-procedure shunt. The septal occluder did not completely cover both defects. Equivalent chest x-ray radiation dose (assuming a single posteroanterior projection chest x-ray is eight centi-Gray/cm 2 ) was 400. Repeat TTE continued to demonstrate left to right shunting and the patient was readmitted for a further device closure six months later. At cardiac catheterisation, the second defect was identified low in the secundum septum between the fossa ovalis and the mouth of the coronary sinus. The defect was successfully closed with a 9 mm Amplatzer septal occluder with no evidence of obstructed flow in either the coronary sinus or the inferior vena cava. Equivalent chest x-ray radiation dose for the second procedure was 187. The patient remained well with no evidence of residual shunt six months following the procedure.Case 2 A 31-year old woman was found to have a secundum ASD during investigations for breathlessness. The defect was estimated to be 10 mm wide on TTE with evidence of right atrial and right ventricular dilatation. Left atrial size was normal. She was referred was further investigation and treatment. Cardiac catheterisation demonstrated a pulmonary to systemic flow shunt of four to one. Peri-procedure TEE revealed that there were two defects; one measuring 24 mm located inferiorly between the inferior vena cava and coronary sinus os with the second defect situated superiorly and measuring 30 mm. The inferior defect was closed using a 24 mm Amplatzer septal occluder. Equivalent chest x-ray radiation dose was 403. The patient was discharged the following day and readmitted three months later for closure of the superior defect. This was performed using a 30 mm Amplatzer septal occluder. The procedure was technical difficult as after deployment of the left sided disc, the device initially lay obliquely in the defect. The final position was satisfactory with no evidence of intra-cardiac shunting (figure  1 ). There was no interference between the two devices and mitral valve function remained normal. Equivalent chest x-ray radiation dose for the second procedure was 727. The patient remained well and at six month follow-up there was no evidence of residual shunt. Figure 1 Stored fluoroscopy following placement of the two Amplatzer septal occluders (ASOs). TEE – Transesophageal echocardiography probe.
Case 2
A 31-year old woman was found to have a secundum ASD during investigations for breathlessness. The defect was estimated to be 10 mm wide on TTE with evidence of right atrial and right ventricular dilatation. Left atrial size was normal. She was referred was further investigation and treatment. Cardiac catheterisation demonstrated a pulmonary to systemic flow shunt of four to one. Peri-procedure TEE revealed that there were two defects; one measuring 24 mm located inferiorly between the inferior vena cava and coronary sinus os with the second defect situated superiorly and measuring 30 mm. The inferior defect was closed using a 24 mm Amplatzer septal occluder. Equivalent chest x-ray radiation dose was 403. The patient was discharged the following day and readmitted three months later for closure of the superior defect. This was performed using a 30 mm Amplatzer septal occluder. The procedure was technical difficult as after deployment of the left sided disc, the device initially lay obliquely in the defect. The final position was satisfactory with no evidence of intra-cardiac shunting (figure  1 ). There was no interference between the two devices and mitral valve function remained normal. Equivalent chest x-ray radiation dose for the second procedure was 727. The patient remained well and at six month follow-up there was no evidence of residual shunt.Case 3 A 30-year old woman was investigated for palpitations and a secundum ASD of approximately 20 mm was diagnosed. TEE suggested that the atrial septum was fenestrated with a small inferior rim of tissue and she was referred for device closure. At cardiac catheterisation it became clear that there were two principal defects, one in the fossa ovalis and the other situated inferior and posterior between the fossa ovalis and the coronary sinus. The superior hole was closed with a 16 mm Amplatzer septal occluder but failed to cover the inferior defect. A 15 mm Amplatzer septal occluder device was subsequently placed successfully across the inferior defect with a stable position (figure  2 ). Equivalent chest x-ray radiation dose for the procedure was 124. Subsequent follow-up revealed a small left to right shunt between the two septal occluders but further intervention was not considered necessary. Figure 2 Transesophageal echocardiography four-chamber image following deployment of the two Amplatzer septal occluders (ASO). LA – left atrium, LV – left ventricle, RA – right atrium, RV – right ventricle.
Case 3
A 30-year old woman was investigated for palpitations and a secundum ASD of approximately 20 mm was diagnosed. TEE suggested that the atrial septum was fenestrated with a small inferior rim of tissue and she was referred for device closure. At cardiac catheterisation it became clear that there were two principal defects, one in the fossa ovalis and the other situated inferior and posterior between the fossa ovalis and the coronary sinus. The superior hole was closed with a 16 mm Amplatzer septal occluder but failed to cover the inferior defect. A 15 mm Amplatzer septal occluder device was subsequently placed successfully across the inferior defect with a stable position (figure  2 ). Equivalent chest x-ray radiation dose for the procedure was 124. Subsequent follow-up revealed a small left to right shunt between the two septal occluders but further intervention was not considered necessary.Discussion There is considerable morphological variation of secundum-type ASDs. Podnar  et al  reported the echocardiographic findings of 190 patients with isolated secundum ASDs referred for device closure [ 3 ]. Twenty four per cent had centrally placed defects but the remaining 144 patients had morphological variations. A deficient superior anterior rim was seen in 42%, a deficient inferior posterior rim in 10%, perforated aneurysm of the interatrial septum was seen in 7.9% and 7.3% of patients had multiple septal defects. Experience of multiple ASDs closure using more than one Amplatzer septal occluder remains limited [ 4 , 5 ]. In the worldwide report of use of the Amplatzer septal occluder, 3460 patients received a single device but only 45 patients received two devices for multiple ASDs [ 1 ]. Cao  et al  reported a series of 22 patients who had two septal occluders implanted simultaneously for multiple ASDs [ 6 ]. Closure rate was 97.7% with one device embolisation. In closely positioned multiple defects the septal occluder should be implanted in the largest defect aiming to cover any smaller defects but in widely separated defects more than one device is required. Echocardiographic studies have suggested that patients with multiple ASDs should have a rim of tissue of more than seven millimetres between defects to allow the deployment of two septal occluders [ 6 ]. Continuous echocardiographic monitoring is required for device positioning. When TEE is used, patients usually require a general anaesthetic due to the prolonged oesophageal intubation. The development of intracardiac echocardiography now provides an alternative to TEE for device closure. Benefits include more detailed imaging, a reduced need for general anaesthesia, and reduced radiation exposure [ 7 ]. In particular, use of intracardiac echocardiography allows clearer visualisation of the inferior atrial septum. Three-dimensional echocardiography may allow more detailed assessment of multiple ASD anatomy and septal occluder positioning. One question that remains unclear is whether multiple septal occluders should be deployed simultaneously or implanted as staged procedures. Serious complications during single septal occluder implantation is a rare occurrence (less than 0.3% of cases) but it likely that simultaneous deployment will increase the procedure risk [ 1 , 6 ]. When implanting large devices (greater than 20 mm) with little septal separation it is favourable to deploy the larger device and bring the patient back for a further procedure once the device has stabilised.
Discussion
There is considerable morphological variation of secundum-type ASDs. Podnar  et al  reported the echocardiographic findings of 190 patients with isolated secundum ASDs referred for device closure [ 3 ]. Twenty four per cent had centrally placed defects but the remaining 144 patients had morphological variations. A deficient superior anterior rim was seen in 42%, a deficient inferior posterior rim in 10%, perforated aneurysm of the interatrial septum was seen in 7.9% and 7.3% of patients had multiple septal defects.et alExperience of multiple ASDs closure using more than one Amplatzer septal occluder remains limited [ 4 , 5 ]. In the worldwide report of use of the Amplatzer septal occluder, 3460 patients received a single device but only 45 patients received two devices for multiple ASDs [ 1 ]. Cao  et al  reported a series of 22 patients who had two septal occluders implanted simultaneously for multiple ASDs [ 6 ]. Closure rate was 97.7% with one device embolisation. In closely positioned multiple defects the septal occluder should be implanted in the largest defect aiming to cover any smaller defects but in widely separated defects more than one device is required. Echocardiographic studies have suggested that patients with multiple ASDs should have a rim of tissue of more than seven millimetres between defects to allow the deployment of two septal occluders [ 6 ].et alContinuous echocardiographic monitoring is required for device positioning. When TEE is used, patients usually require a general anaesthetic due to the prolonged oesophageal intubation. The development of intracardiac echocardiography now provides an alternative to TEE for device closure. Benefits include more detailed imaging, a reduced need for general anaesthesia, and reduced radiation exposure [ 7 ]. In particular, use of intracardiac echocardiography allows clearer visualisation of the inferior atrial septum. Three-dimensional echocardiography may allow more detailed assessment of multiple ASD anatomy and septal occluder positioning.One question that remains unclear is whether multiple septal occluders should be deployed simultaneously or implanted as staged procedures. Serious complications during single septal occluder implantation is a rare occurrence (less than 0.3% of cases) but it likely that simultaneous deployment will increase the procedure risk [ 1 , 6 ]. When implanting large devices (greater than 20 mm) with little septal separation it is favourable to deploy the larger device and bring the patient back for a further procedure once the device has stabilised.Conclusions There is considerable variation in atrial septal defect anatomy. A small proportion of patients with an ASD have more than one defect and these can be closed using conventional septal occluders under transoesophageal echocardiography guidance. The use of intracardiac echocardiography should allow more accurate device positioning, particularly defects located low in the atrial septum.
Conclusions
There is considerable variation in atrial septal defect anatomy. A small proportion of patients with an ASD have more than one defect and these can be closed using conventional septal occluders under transoesophageal echocardiography guidance. The use of intracardiac echocardiography should allow more accurate device positioning, particularly defects located low in the atrial septum.