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Clinical Sciences |

Optic Neuritis Associated With Chikungunya Virus Infection in South India FREE

Apoorva Mittal, DO; Saurabh Mittal, DipNB; M. Jayahar Bharati, MSc, PhD; Rengappa Ramakrishnan, MS; Sankarlingam Saravanan, MD; Padmakar S. Sathe, MSc, PhD
[+] Author Affiliations

Author Affiliations: Department of Neuroophthalmology (Drs A. Mittal and S. Mittal), Microbiology Research Centre (Dr Bharati), and Aravind-Zeiss Center of Excellence for Glaucoma (Dr Ramakrishnan), Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, and Sankar Brain and Nerve Center (Dr Saravanan), Tirunelveli, Tamil Nadu, and National Institute of Virology, Pune, Maharashtra (Dr Sathe), India.


Arch Ophthalmol. 2007;125(10):1381-1386. doi:10.1001/archopht.125.10.1381.
Text Size: A A A
Published online

Objective  To define optic neuritis associated with chikungunya virus (CHIKV) infection in a clinical setting.

Methods  This observational case series includes 14 patients with clinical features of CHIKV infection and associated optic neuritis. Complete ophthalmic evaluations were performed, as well as other examinations, including Mantoux test, Widal test, blood profile, color vision, neuroimaging, visual fields, visual evoked potentials, VDRL test, and enzyme-linked immunosorbent assay for CHIKV-specific immunoglobulin. Relevant clinical findings of optic neuritis associated with seropositive CHIKV infection were recorded.

Results  Nineteen eyes (in 14 patients) had optic nerve involvement. The mean ± SD patient age was 45.8 ± 15.6 years. Eight eyes (42%) had papillitis, 4 eyes (21%) had retrobulbar neuritis, 4 eyes (21%) had retrochiasmal (optic tract) neuritis, and 3 eyes (16%) had neuroretinitis. Parenteral corticosteroids were administered in all patients. Color vision, visual fields, and best-corrected visual acuity of 6/12 (or 20/40 Snellen visual acuity) or better improved statistically significantly by the end of 3 weeks (P < .001). Partial to complete recovery of visual function was seen in 10 patients (71%). Four patients had a poor visual outcome; 3 of them were initially seen 1 month after onset of ocular symptoms.

Conclusions  Acute-onset visual loss due to optic neuritis may be associated with CHIKV infection. Visual recovery is good. Corticosteroids accelerated recovery when initiated at an early stage of the disease.

Figures in this Article

Chikungunya virus (CHIKV), an arbovirus, is an important human pathogen responsible for disease characterized by acute febrile illness and crippling joint pain. It is spread by the bite of an infected mosquito. Its name is derived from the Swahili word meaning “that which bends up” in reference to the stooped posture that develops as a result of the arthritic symptoms of the disease, first detected in a febrile human resident of Tanzania in 1953.1 Since then, the virus has been associated with many epidemics in tropical regions of Africa, South Asia, and South America.2 In Africa, the virus is maintained through a sylvatic transmission cycle between wild primates and mosquitoes such as Aedes luteocephalus, Aedes furcifer, and Aedes taylori. In Asia, CHIKV is transmitted among humans primarily by Aedes aegypti and to a lesser extent by Aedes albopictus through an urban transmission cycle.2,3 Large-scale outbreaks of fever caused by CHIKV in Indian Ocean territories during 2005 and 2006 confirmed the reemergence of the virus.3,4 Isolated cases of infection are also seen among individual residents of nonendemic countries who travel to affected regions.5,6

Chikungunya virus infection is characterized by acute-onset fever, headache, rash, low backache, nausea, vomiting, myalgia, and arthralgia (with or without swelling, usually of smaller joints).3 Rarely, neurological complications such as meningoencephalitis have been reported (eg, during the first Indian outbreak in 1972 and in the 2005-2006 French Réunion island outbreak4). To our knowledge, optic nerve inflammation (termed optic neuritis hereafter) associated with CHIKV illness is not mentioned in the literature (via a MEDLINE search). We identified cases of papillitis, neuroretinitis, retrobulbar neuritis, and optic tract inflammation (termed retrochiasmal neuritis) in serologically CHIKV-positive patients during the 2006 outbreak of the disease in South India. In this article, the clinical characteristics of eyes with optic neuritis secondary to CHIKV infection are presented.

This observational case series includes 14 patients with a history of acute-onset fever and joint pain of varying severity initially seen with clinical features suggestive of optic neuritis in the months of September and October during the 2006 outbreak of CHIKV infection among the South Indian population. After obtaining informed consent, a complete ophthalmic examination (including best-corrected visual acuity at j6 m) was performed, as well as intraocular pressure by applanation tonometry, indirect ophthalmoscopy of the dilated fundus, slitlamp biomicroscopy of the anterior and posterior segments, and color vision and visual field examination (Humphrey visual field analysis if possible or Bjerrum field test). Visual evoked potentials and neuroimaging tests were performed at the initial visit to assist in diagnosis. Complete blood profiles, platelet counts (for dengue), Widal test (for typhoid fever), peripheral blood smear for malaria, tuberculin syringe test (Mantoux test for tuberculosis), and VDRL test (for syphilis) were also performed.

For confirmation of the clinical diagnosis of CHIKV infection, blood samples of all patients were investigated for CHIKV-specific serum IgM antibodies using IgM antibody capture enzyme-linked immunosorbent assay at the National Institute of Virology, Pune, Maharashtra, India. Chikungunya virus infection was diagnosed if the patient had acute-onset fever with joint pain of varying severity, positive anti-CHIKV IgM antibodies in serum, and negative test results for dengue, typhoid, malaria, and tuberculosis. All patients having confirmed diagnoses of CHIKV infection and optic neuritis were included in the study.

All patients were advised to undergo treatment with 1000 mg/d of intravenous methylprednisolone in divided doses for 3 days, followed by 1 mg/kg of body weight daily of oral prednisolone for 14 days, with tapering of the corticosteroid dose over 4 weeks. Visual function (color vision, visual fields, and best-corrected visual acuity) was recorded at the initial visit, at the end of 3 days of therapy, and 3 weeks after the initiation of therapy.

Completed data forms were prepared to describe the characteristics of optic neuritis at the initial visit and during follow-up. Data were analyzed using commercially available software (Excel 2002; Microsoft Corp, Redmond, Washington), and results are given as percentages, means, and standard deviations. Pretreatment and posttreatment visual function was assessed using the χ2 test. This study was conducted at a site that has no institutional review board or ethics committee, but prior consent from the hospital advisory board and informed consent from all study patients were obtained.

Fifteen patients with a history of fever and joint pain (probable CHIKV infection) and optic neuritis were investigated for CHIKV serology. Fourteen of these patients were positive for CHIKV-specific immunoglobulin; the cause of the remaining case remains unknown. Clinical features of these 14 patients are detailed herein.

DEMOGRAPHICS

The study included 9 male and 5 female patients (Table 1). All patients were of Indian origin. The ages ranged from 22 to 68 years (mean ± SD age, 45.8 ± 15.6 years), with no age differences between male and female patients (P = .73).

Table Graphic Jump LocationTable 1. Ocular and Systemic Features Among 14 Patients With Chikungunya Virus Infection–Associated Optic Neuritis at the Initial Visita
CHARACTERISTICS OF SYSTEMIC ILLNESS (CHIKV)

All 14 patients had acute-onset fever and joint pain at a mean ± SD of 32.4 ± 17.2 days (range, 12-60 days) before their initial visit at our institution (Table 2). Other symptoms included headache, body ache, vomiting, bladder disturbance, and loss of consciousness. The primary illness lasted a mean ± SD of 10.5 ± 15.5 days (range, 2-60 days).

Table Graphic Jump LocationTable 2. Demographics and Ocular and Systemic Features Among 14 Patients With CHIKV Infection–Associated Optic Neuritisa
OCULAR SYMPTOMS

Patients were initially seen with reports of blurred vision after a mean ± SD of 11.0 ± 14.0 days (range, 0-49 days) of a symptom-free period (Table 1). Nineteen eyes of 14 patients were affected. Five patients (36%) described visual symptoms in both eyes. The mean ± SD duration of ocular complaints at the initial visit was 13.0 ± 16.3 days (range, 1-60 days). Five patients had ocular symptoms overlapping with the course of initial systemic illness.

OCULAR FEATURES

Best-corrected visual acuity varied from 6/6 (or 20/20 Snellen visual acuity) to counting fingers (median, 5/60 [or 20/240 Snellen]) (Figure and Tables 1 and 2). Eleven eyes (58%) of the 19 eyes had vision less than 6/60 (or 20/200 Snellen) at the initial visit. Fourteen eyes had abnormal pupillary reactions. Relative afferent pupillary defect was seen in all unilateral cases. Disc edema was seen in 11 eyes (58%) of 9 patients (2 cases were bilateral); 3 of them had incomplete macular star appearance on ophthalmoscopy, suggesting a diagnosis of neuroretinitis, and the remaining ones were diagnosed as papillitis. Patient 3 (Table 2) with papillitis also had ipsilateral facial palsy with exposure keratitis, and patient 4 had sensory neural deafness. Retrobulbar neuritis was suspected in 4 eyes (21%) of 3 patients (1 patient had bilateral involvement). Patient 13 with retrobulbar neuritis also had bilateral external ophthalmoplegia, left-sided hemiparesis, and upper motor neuron type of facial palsy, suggesting generalized involvement. Two patients at the initial visit had bilateral visual field defect suggestive of retrochiasmal involvement. One of these patients (patient 2) had left incongruous homonymous hemianopia with macular sparing (right optic tract lesion), and the other one (patient 10) had right incongruous homonymous hemianopia with macular involvement (suggestive of left optic tract lesion).

Place holder to copy figure label and caption
Figure.

Pretreatment (bottom of arrowhead) and posttreatment (tip of arrowhead) fundus views of patients 6 (A and B) and 9 (C and D) with neuroretinitis and patient 11 (E through H) with bilateral papillitis. In the pretreatment views, disc edema (A, C, E, and F), flame-shaped hemorrhages (A), and an incomplete macular star (A and C) are evident. With administration of intravenous methylprednisolone, the disc edema, hemorrhages, and exudates decreased (B, D, G, and H) with development of disc pallor (B and D).

Graphic Jump Location

Color vision on Ishihara charts was defective in all patients except patient 2 (in Table 2). Central field testing revealed central or centrocecal scotoma in 6 eyes (32%) and peripheral field defect in 4 eyes (21%); 4 eyes (21%) had visual field defect involving both peripheral and central areas, and the remaining 5 eyes (26%) had poor fixation to the visual target. Visual evoked potentials at the initial visit showed a statistically significant delay in latency in eyes with defective vision (mean ± SD P100 latency, 114.5 ± 14.4 milliseconds; P<.001). Latency was also statistically significantly delayed in affected eyes with unilateral disease compared with the contralateral normal eye (P = .02). Results of computed tomography and magnetic resonance imaging of the brain at the initial visit were normal for all patients.

INVESTIGATIONS

Complete blood profile results were normal in all patients except for 6 patients (43%) who had mild lymphocytosis. Mantoux test, Widal test, and VDRL test results were negative, and all patients had positive anti-CHIKV IgM antibodies in serum samples.

OUTCOMES AND PROGNOSIS

All except patients 3, 8, 13, and 14 had improvement in visual function following administration of methylprednisolone (Table 2 and Table 3). Patient 2 with retrochiasmal neuritis refused intravenous medication; he was given oral corticosteroids (1 mg/kg of prednisolone daily for 14 days initially and then in tapering doses). Patient 13 defaulted follow-up after receiving parenteral methylprednisolone. At the end of 3 weeks, 12 eyes had visual acuity of at least 6/12 (or 20/40 Snellen) (P < .001); 3 eyes had no improvement in their initial visual acuity. Color vision returned to normal in 13 eyes and visual fields improved in 9 eyes (P < .001 for both). Disc pallor (secondary to optic atrophy) developed in 10 eyes, of which 1 eye had disc edema in a stage of resolution.

Table Graphic Jump LocationTable 3. Outcomes Among 19 Eyes With Chikungunya Virus Infection–Associated Optic Neuritisa

Chikungunya virus is a member of the Alphavirus genus of the family Togaviridae. The genus Alphavirus represents a group of enveloped viruses with a single-stranded plus-sense RNA genome. This genus has more than 40 known members that share a minimum amino acid sequence identity of about 45% in the more divergent structural proteins and about 60% in the nonstructural proteins. Eastern equine encephalomyelitis, western equine encephalomyelitis, Venezuelan equine encephalomyelitis, and Ross River viruses are other members of this genus. They are classified as arboviruses because they are maintained in nature by a biological transmission cycle between susceptible vertebrate hosts and hematophagous arthropods, usually ticks and mosquitoes.7

Chikungunya virus is geographically distributed in Africa, India, and Southeast Asia. Chikungunya virus was recognized as producing a self-limiting disease characterized by fever and arthralgia but, during the 2005-2006 epidemic, severe infection associated with multiorgan failure, acute hepatic failure, central neurological involvement, neonatal infection (transplacental or mosquito borne), and death was observed.7 This change in disease characteristics is probably due to the evolution in viral structural and nonstructural proteins reported in the East African CHIKV responsible for this epidemic.810

The pattern of visual sensory system involvement in our CHIKV-infected patients was variable. Twelve patients had optic nerve involvement in the form of papillitis, retrobulbar neuritis, or neuroretinitis. Features suggestive of optic tract involvement were also seen in 2 patients. The rare occurrence of bilateral papillitis and retrobulbar neuritis was also noted. None of the patients had clinical evidence suggesting optic chiasma involvement.

The exact mechanism of optic nerve involvement following CHIKV infection is unknown. Simultaneous onset of systemic and ocular disease in 5 patients (36%) suggests direct viral involvement. The remaining 9 patients (64%) had late optic nerve involvement, suggesting a delayed immune response (postviral infection). Potential immune mechanisms may be similar to those seen in encephalitis; these include immune dysregulation, superantigen induction, hypersensitivity reaction, direct result of the infection, and molecular mimicry between stimulating virus-derived antigens and normal or altered host tissue proteins.11,12 Several characteristics indicate the possibility of an autoimmune mechanism in the pathogenesis of the disease, including delay in onset, partial recovery of disc changes, bilateral involvement in a few patients, and good response to corticosteroid therapy. The involvement of other nerves (in patients 3, 4, and 13) suggests generalized disease secondary to CHIKV infection.

Although an infection by a virus is an important cause of optic neuritis, other organisms and metabolic disturbances are implicated in its cause and pathogenesis.13 Infections such as syphilis, tuberculosis, leptospirosis, and toxoplasmosis prevalent in this region are other important causes associated with optic neuritis. Viruses such as dengue, mumps, measles, varicella zoster, and West Nile are also associated with optic neuritis.1417 Clues observed in the history, examination, and investigative profile may assist in the diagnosis. Dengue infection is endemic in our region; a close resemblance of its clinical symptoms with those of CHIKV infection makes it mandatory to distinguish between the 2 conditions.17 Clinically, dengue infection is associated with abrupt onset of fever with macular or maculopapular rash and blood dyscrasias (thrombocytopenia and neutropenia). Features of dengue shock syndrome (hypotension, circulatory failure, and narrowing of pulse pressure [to < 20 mm Hg]) are not observed with CHIKV infection. The absence of dermatological signs and thrombocytopenia in our patients helped us establish the diagnosis of CHIKV infection.

Confirmation of CHIKV infection can be performed by reverse transcriptase–polymerase chain reaction or by virus isolation.18 These are rapid confirmatory tests of choice if the illness is of less than 4 days' duration. Beyond 4 days, diagnosis is possible only with detection of CHIK-specific IgM in patient serum.19 Because all patients in our study were initially seen after 4 days of initial symptoms, serum samples were investigated for CHIKV-specific IgM. The presence of acute-onset fever with joint pain, negative test results for other common organisms, travel to a CHIKV epidemic area, and positive serology tests for CHIKV helped in confirming the diagnosis.

The overall prognosis in terms of visual acuity, color vision, and visual fields was good. Three-fourths of our study patients had improved visual function. Evidence from the Optic Neuritis Treatment Trial20,21 suggests that administration of intravenous corticosteroids can accelerate the recovery of visual symptoms but cautions that corticosteroid therapy may not have a substantial role in the final outcome (at the end of 1 year) in terms of visual recovery in acute-onset demyelinating or idiopathic optic neuritis.20,21 We administered parenteral corticosteroids (intravenous followed by oral) in our patients and noted that 91% (10 of 11) of patients who were initially seen within 10 days of onset of ocular symptoms had improved visual function; this improvement was seen even at day 3 after initiation of corticosteroid therapy. Three patients in whom treatment was initiated 1 month after onset of visual symptoms had no visual improvement. This suggests that corticosteroid therapy can assist in rapid recovery of visual function if administered in patients with acute presentation of optic neuritis but possibly has no role when treatment is initiated at a late stage of the disease. Development of disc pallor in half of the eyes indicates that some amount of permanent damage occurs in most patients even if they have good visual recovery.

In conclusion, optic neuritis associated with CHIKV infection is primarily an acute-onset inflammatory reaction of the optic nerve. Corticosteroid therapy accelerates the recovery of visual function if administered at the early stage of the disease. Chikungunya virus infection should be an important component of the differential diagnosis in individuals with optic neuritis who reside in tropical regions and in travelers from nonendemic regions to the epidemic areas.

Correspondence: Saurabh Mittal, DipNB, Department of Neuroophthalmology, Aravind Eye Hospital and Postgraduate Institute of Ophthalmology, Tirunelveli, Tamil Nadu, India 627001 (dr_saurabhmittal@hotmail.com).

Submitted for Publication: January 1, 2007; final revision received February 16, 2007; accepted March 6, 2007.

Author Contributions: Dr S. Mittal had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Financial Disclosure: None reported.

Robinson  MC An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53, I: clinical features. Trans R Soc Trop Med Hyg 1955;49 (1) 28- 32
PubMed
Diallo  MThonnon  JTraore-Lamizana  MFontenille  D Vectors of chikungunya virus in Senegal: current data and transmission cycles. Am J Trop Med Hyg 1999;60 (2) 281- 286
PubMed
Ravi  V Re-emergence of chikungunya virus in India. Indian J Med Microbiol 2006;24 (2) 83- 84
PubMed
Quatresous  I Chikungunya outbreak in Réunion, a French “overseas département.” Euro Surveill. 2006;11 (2) E060202.http://www.eurosurveillance.org/ew/2006/060202.asp.June 27, 2007
Centers for Disease Control and Prevention (CDC), Chikungunya fever diagnosed among international travelers: United States, 2005-2006. MMWR Morb Mortal Wkly Rep. 2006;55 (38) 1040- 1042http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5538a2.htm.June 27, 2007
Krastinova  EQuatresous  ITarantola  A Imported cases of chikungunya in metropolitan France: update to June 2006. Euro Surveill 2006;11 (8) E060824.http://www.eurosurveillance.org/ew/2006/060824.asp#1.June 27, 2007
Strauss  JHStraus  EG The alphaviruses: gene expression, replication, and evolution. Microbiol Rev 1994;58 (3) 491- 562
PubMed
Cordel  HInvestigation Group, Chikungunya outbreak on Réunion: update. Euro Surveill. 2006;11 (3) E060302.3.http://www.eurosurveillance.org/ew/2006/060302.asp.June 29, 2007
Khan  AHMorita  KParquet  MDCHasebe  FMathenge  EGMIgarashi  A Complete nucleotide sequence of chikungunya virus and evidence for an internal polyadenylation site. J Gen Virol 2002;83 (pt 12) 3075- 3084
PubMed
Yergolkar  PNTandale  BVArankalle  VA  et al.  Chikungunya outbreaks caused by African genotype, India. Emerg Infect Dis 2006;12 (10) 1580- 1583
PubMed
Schuffenecker  IIteman  IMichault  A  et al.  Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med 2006;3 (7) e263http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1463904July 3, 2007
Mahalingam  SMeanger  JFoster  PSLidbury  BA The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses. J Leukoc Biol 2002;72 (3) 429- 439
PubMed
Kennedy  PG Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 2004;75 ((suppl 1)) i10- i15
Volpe  NJ Optic neuritis: historical aspects. J Neuroophthalmol 2001;21 (4) 302- 309
PubMed
Miller  NRed Optic neuritis. Walsh and Hoyt's Clinical Neuro-ophthalmology. 4th Baltimore, MD Williams & Wilkins1982;227- 248
Chan  CKLimstrom  SATarasewicz  DGLin  SG Ocular features of West Nile virus infection in North America: a study of 14 eyes [published online ahead of print July 21, 2006]. Ophthalmology 2006;113 (9) 1539- 154610.1016/j.ophtha.2006.04.021
PubMed
Chan  DPTeoh  SCTan  CS  et al. Eye Institute Dengue-Related Ophthalmic Complications Workgroup, Ophthalmic complications of dengue. Emerg Infect Dis 2006;12 (2) 285- 289
PubMed
Rohani  AYulfi  HZamree  ILee  HL Rapid detection of chikungunya virus in laboratory infected Aedes aegypti by reverse-transcriptase-polymerase chain reaction (RT-PCR). Trop Biomed 2005;22 (2) 149- 154
PubMed
Kumarasamy  VPrathapa  SZuridah  HChem  YKNorizah  IChua  KB Re-emergence of chikungunya virus in Malaysia. Med J Malaysia 2006;61 (2) 221- 225
PubMed
Beck  RWCleary  PA Optic Neuritis Treatment Trial: one-year follow-up results. Arch Ophthalmol 1993;111 (6) 773- 775
PubMed
Optic Neuritis Study Group, Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997;115 (12) 1545- 1552
PubMed

Figures

Place holder to copy figure label and caption
Figure.

Pretreatment (bottom of arrowhead) and posttreatment (tip of arrowhead) fundus views of patients 6 (A and B) and 9 (C and D) with neuroretinitis and patient 11 (E through H) with bilateral papillitis. In the pretreatment views, disc edema (A, C, E, and F), flame-shaped hemorrhages (A), and an incomplete macular star (A and C) are evident. With administration of intravenous methylprednisolone, the disc edema, hemorrhages, and exudates decreased (B, D, G, and H) with development of disc pallor (B and D).

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1. Ocular and Systemic Features Among 14 Patients With Chikungunya Virus Infection–Associated Optic Neuritis at the Initial Visita
Table Graphic Jump LocationTable 2. Demographics and Ocular and Systemic Features Among 14 Patients With CHIKV Infection–Associated Optic Neuritisa
Table Graphic Jump LocationTable 3. Outcomes Among 19 Eyes With Chikungunya Virus Infection–Associated Optic Neuritisa

References

Robinson  MC An epidemic of virus disease in Southern Province, Tanganyika Territory, in 1952-53, I: clinical features. Trans R Soc Trop Med Hyg 1955;49 (1) 28- 32
PubMed
Diallo  MThonnon  JTraore-Lamizana  MFontenille  D Vectors of chikungunya virus in Senegal: current data and transmission cycles. Am J Trop Med Hyg 1999;60 (2) 281- 286
PubMed
Ravi  V Re-emergence of chikungunya virus in India. Indian J Med Microbiol 2006;24 (2) 83- 84
PubMed
Quatresous  I Chikungunya outbreak in Réunion, a French “overseas département.” Euro Surveill. 2006;11 (2) E060202.http://www.eurosurveillance.org/ew/2006/060202.asp.June 27, 2007
Centers for Disease Control and Prevention (CDC), Chikungunya fever diagnosed among international travelers: United States, 2005-2006. MMWR Morb Mortal Wkly Rep. 2006;55 (38) 1040- 1042http://www.cdc.gov/mmwr/preview/mmwrhtml/mm5538a2.htm.June 27, 2007
Krastinova  EQuatresous  ITarantola  A Imported cases of chikungunya in metropolitan France: update to June 2006. Euro Surveill 2006;11 (8) E060824.http://www.eurosurveillance.org/ew/2006/060824.asp#1.June 27, 2007
Strauss  JHStraus  EG The alphaviruses: gene expression, replication, and evolution. Microbiol Rev 1994;58 (3) 491- 562
PubMed
Cordel  HInvestigation Group, Chikungunya outbreak on Réunion: update. Euro Surveill. 2006;11 (3) E060302.3.http://www.eurosurveillance.org/ew/2006/060302.asp.June 29, 2007
Khan  AHMorita  KParquet  MDCHasebe  FMathenge  EGMIgarashi  A Complete nucleotide sequence of chikungunya virus and evidence for an internal polyadenylation site. J Gen Virol 2002;83 (pt 12) 3075- 3084
PubMed
Yergolkar  PNTandale  BVArankalle  VA  et al.  Chikungunya outbreaks caused by African genotype, India. Emerg Infect Dis 2006;12 (10) 1580- 1583
PubMed
Schuffenecker  IIteman  IMichault  A  et al.  Genome microevolution of chikungunya viruses causing the Indian Ocean outbreak. PLoS Med 2006;3 (7) e263http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1463904July 3, 2007
Mahalingam  SMeanger  JFoster  PSLidbury  BA The viral manipulation of the host cellular and immune environments to enhance propagation and survival: a focus on RNA viruses. J Leukoc Biol 2002;72 (3) 429- 439
PubMed
Kennedy  PG Viral encephalitis: causes, differential diagnosis, and management. J Neurol Neurosurg Psychiatry 2004;75 ((suppl 1)) i10- i15
Volpe  NJ Optic neuritis: historical aspects. J Neuroophthalmol 2001;21 (4) 302- 309
PubMed
Miller  NRed Optic neuritis. Walsh and Hoyt's Clinical Neuro-ophthalmology. 4th Baltimore, MD Williams & Wilkins1982;227- 248
Chan  CKLimstrom  SATarasewicz  DGLin  SG Ocular features of West Nile virus infection in North America: a study of 14 eyes [published online ahead of print July 21, 2006]. Ophthalmology 2006;113 (9) 1539- 154610.1016/j.ophtha.2006.04.021
PubMed
Chan  DPTeoh  SCTan  CS  et al. Eye Institute Dengue-Related Ophthalmic Complications Workgroup, Ophthalmic complications of dengue. Emerg Infect Dis 2006;12 (2) 285- 289
PubMed
Rohani  AYulfi  HZamree  ILee  HL Rapid detection of chikungunya virus in laboratory infected Aedes aegypti by reverse-transcriptase-polymerase chain reaction (RT-PCR). Trop Biomed 2005;22 (2) 149- 154
PubMed
Kumarasamy  VPrathapa  SZuridah  HChem  YKNorizah  IChua  KB Re-emergence of chikungunya virus in Malaysia. Med J Malaysia 2006;61 (2) 221- 225
PubMed
Beck  RWCleary  PA Optic Neuritis Treatment Trial: one-year follow-up results. Arch Ophthalmol 1993;111 (6) 773- 775
PubMed
Optic Neuritis Study Group, Visual function 5 years after optic neuritis: experience of the Optic Neuritis Treatment Trial. Arch Ophthalmol 1997;115 (12) 1545- 1552
PubMed

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