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Vision loss in tuberculous meningitis
Accepted Manuscript Vision loss in tuberculous meningitis
Ravindra Kumar Garg, Hardeep Singh Malhotra, Neeraj Kumar, Ravi Uniyal PII: DOI: Reference:
S0022-510X(17)30033-3 doi: 10.1016/j.jns.2017.01.031 JNS 15093
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
28 September 2016 23 December 2016 9 January 2017
Please cite this article as: Ravindra Kumar Garg, Hardeep Singh Malhotra, Neeraj Kumar, Ravi Uniyal , Vision loss in tuberculous meningitis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.01.031
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ACCEPTED MANUSCRIPT 1 Vision loss in tuberculous meningitis
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Ravindra Kumar Garg Hardeep Singh Malhotra Neeraj Kumar Ravi Uniyal
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Address for correspondence Ravindra Kumar Garg Department of Neurology King George Medical University, Uttar Pradesh, Lucknow India PIN-226003 Phone: 91 9335901790 Email: [email protected]
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Department of Neurology King George Medical University Uttar Pradesh Lucknow, India
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Abstract Vision loss is a disabling complication of tuberculous meningitis. Approximately, 15% of survivors are either completely or partially blind. All the structures of visual pathway can be affected in tuberculous meningitis. Optic nerve and optic chiasma are most frequently and dominantly affected. Thick, gelatinous, exudates, lying over the base of brain, is the pathological hallmark of tuberculous meningitis and is responsible for all its major complications, including vision loss. Strangulation of optic nerves and optic chiasma by the exudates, compression over optic chiasma by dilated third ventricles, raised intracranial pressure, endarteritis, shunt failure, bacterial invasion of optic nerves and drug induced optic nerve damage are important reasons that are considered responsible for vision loss. Prompt antituberculosis treatment is the best management option available. Immune modulatory drugs and cerebrospinal fluid diversion procedures are of limited help. Early recognition and treatment of tuberculous meningitis are only way forward to tackle this problem.
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Keywords: Antituberculosis drugs; Blindness; Optic nerve; Optic chiasma; Meningitis; Mycobacterium tuberculosis
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ACCEPTED MANUSCRIPT 3 Complete or partial vision loss is a common and disabling complication of tuberculous meningitis. Many patients of tuberculous meningitis do survive, following treatment, but with life-long vision loss as sequelae. Vision loss is a known complication of tuberculous meningitis but it has not given due attention Patients of tuberculous meningitis have altered sensorium and often vision loss go unnoticed.
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Optic nerve tuberculoma and tuberculous optochiasmatic involvement in the setting of tuberculous meningitis was first recorded by Cruveilhier and Hjort in 1862 and 1867 respectively. Since then vision loss has regularly been reported.1 Libby in 1920 recorded a classical description of vision loss in tuberculous meningitis.2
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“A few years later a tuberculous adult male who had shown satisfactory improvement in the pulmonary condition developed sudden impairment of vision in each eye, associated with severe, constant headache. A moderate optic neuritis was present. The expert diagnostician summoned declared that the condition could be diagnosed either as brain tumor, syphilitic optic neuritis, or tuberculous meningitis. The ophthalmologist stood out for tuberculous meningitis, the expert on tuberculosis concurring. The patient died within two weeks of tuberculous meningitis, with binocular blindness.”
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Unfortunately, the scenario described by Libb, almost 100 years ago, still remains the same and many patients of tuberculous meningitis have to live rest of his/her life without vision. In this review, we have focused on the various aspects of vision loss in tuberculous meningitis. An extensive review of the literature published in English was carried out using the PubMed and Google Scholar databases. The search items included “tuberculous meningitis and vision loss”, “tuberculous meningitis and blindness”, and “tuberculous meningitis and optic atrophy”. Bulk of related information is either in the form of isolated case reports or case series.
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Epidemiology of tuberculous meningitis Tuberculosis is a top global infectious disease. In 2014, 9.6 million people acquired tuberculosis and 1.5 million patients died from it. Six countries (India, Indonesia, Nigeria, Pakistan, China and South Africa) have the largest pool of tuberculosis patients. In 2014, among 6 314 151 reported cases worldwide, 880 596 had extrapulmonary tuberculosis (including meningeal tuberculosis).3 The exact incidence of tuberculous meningitis in 6 major tuberculosis affected countries is not known but it is expected to be quite high. On the contrary, in developed countries incidence of tuberculous meningitis is low. In European Union countries, during 2002–11, 167,652 cases of extrapulmonary tuberculosis were reported. Meningeal tuberculosis was present in 5.8% of the paediatric cases and 2.9% for all the other age groups combined.4 In United States, among 253,299 tuberculosis cases approximately 19% cases were extra- pulmonary. The proportion of meningeal tuberculosis was 5.4%.5 Tuberculosis patients co-infected with human immunodeficiency virus are more likely to have meningeal and disseminated disease. Vision loss in tuberculous meningitis: the magnitude of problem The incidence of vision loss in tuberculous meningitis is quite variable, ranging up to 56%. In a classical study, by Udani and co-workers, 78 patients of tuberculous meningitis were autopsied. Optic nerve involvement was observed in 14% of patients. Optic nerves and optic chiasma were found encased by the thick adhesive exudate, in the basal meninges.6 Amitava and co-workers noted that among 100 pediatric patients with tuberculous meningitis, 67 had neuro-ophthalmic abnormalities. The most frequent neuro-ophthalmic abnormality recorded
ACCEPTED MANUSCRIPT 4 was retrobulbar neuritis. Raised intracranial tension was recorded in 53 patients with neuroophthalmic abnormalities. By 6 months, 56% of patients with retrobulbar neuritis developed optic atrophy. 7 In another study on pediatric patients with tuberculous meningitis, the outcome of different steroid-dose was evaluated. Out of 63 patients, 9 children had optic atrophy at the time of inclusion. Despite treatment and steroid administration, optic atrophy and vision loss count increased to affect 24 patients. 8
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Vision loss as sequelae Approximately, up to 14% of the survivors have disabling and permanent residual vision loss, after the course of antituberculosis treatment is over. Some of the patients are completely blind; neuro-ophthalmological evaluation, in these patients, often reveals optic atrophy. Patients presenting in advanced stages of tuberculous meningitis are more likely to have permanent vision loss as sequelae. 9-12
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Visual evoked responses in tuberculous meningitis Subclinical visual pathways abnormalities in tuberculous meningitis have also been demonstrated with the help of visual evoked potential evaluation. In a series of 43 patients of tuberculous meningitis, electrophysiological assessment of optic nerves revealed visual evoked potential abnormalities (prolonged P100 latencies) in 27 (62.8%) patients. Clinically, visual abnormalities were noted in 22 (51.3%) patients.13
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Pathogenesis of vision loss in tuberculous meningitis The cause of vision loss in tuberculous meningitis is not precisely known. Thick, gelatinous, exudates lying at base of brain is the pathological hallmark and is responsible for all its major complications. The basal exudate encases the structures of brainstem, vessels of circle of Willis and roots of cranial nerves. 14 In patients with tuberculous meningitis, many pathogenic factors/processes, as described below, have been implicated in the causation of visual abnormalities. The details have been summarized in Table-1.
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Strangulation of optic nerves by exudates Exudates are dominantly present in the suprasellar cistern, the interpeduncular fossa, and other parts of optochiasmatic region. Exudates entrap and strangulate the optic nerve and the optic chiasma.6,15 (Figure-1) (Figure-2)
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Optic neuritis and bacterial invasion Optic nerve damage can also occur because of mycobacterial invasion. 16 Optic nerve invasion of Mycobacterium tuberculosis occur either via hematogenous spread to the nerve or extension from the choroid plexus. The proximal portion of the optic nerve, at the root entry zone, is the most vulnerable. Mycobacterial invasion of optic nerve, clinically, presents as papillitis or retrobulbar optic neuritis. Compression over optic chiasma by dilated third ventricle Hydrocephalus is almost a universal feature of tuberculous meningitis. Obstruction to the flow of cerebrospinal fluid occurs in the posterior fossa; thick exudate blocks the openings of fourth ventricles or Sylvian aqueduct. In patients with obstructive hydrocephalus, enlarging third ventricle compresses the optic chiasma from above, leading to vision loss.17 (Figure-3) Raised intracranial pressure Increased intracranial pressure is also a consistent feature of severe tuberculous meningitis. Several factors, like cerebral edema, hydrocephalus, tuberculoma, and infarcts, are
ACCEPTED MANUSCRIPT 5 responsible for the rise in the intracranial pressure.18 Increased intracranial pressure leads to disturbances in the axoplasmic flow of the optic nerves resulting in papilledema and subsequently, optic neuropathy. Ischemic damage of visual pathways by endarteritis Infarction of the optic nerve trunk and chiasma because of tuberculous endarteritis of vasa nervosa, supplying blood to optic nerve trunk and chiasma, may produce ischemic damage to optic nerve and optic chiasma. 19, 20
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Drug induced Antituberculosis drug-induced vision impairment manifests as a decrease in visual acuity, scotomas, and abnormalities of color vision. Antituberculosis drugs, particularly, ethambutol, isoniazid, streptomycin, linezolid and fluoroquinolones affect vision.21 Ethambutol causes optic neuropathy in approximately up to 5% of patients. The visual symptoms usually start 2– 8 months after ethambutol is started.22 Isoniazid can also produce optic neuritis. 23 There may be complete restoration of vision following withdrawal of isoniazid.24
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Linezolid and fluoroquinolones are the drugs that are now increasingly being used in the treatment of tuberculous meningitis. These drugs have also been reported to produce optic neuropathy and retinopathy. The possible mechanism of linezolid-associated optic nerve toxicity is abnormalities of mitochondrial protein synthesis. 25- 29
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A higher incidence of vision loss, in the intensified-treatment trial using levofloxacin, was noted. In this trial, authors compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day and levofloxacin for the first 8 weeks. Vision loss was higher (3.4% versus 1%; 95% CI 0.22-4.94; p = 0.02) in patients receiving intensified regimen. Even though the observation in terms of p-value was significant, the lower bound of 95% CI does suggest that the contributory effect of either levofloxacin or a higher dose of rifampin to vision loss must be interpreted with caution. 30
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Shunt failure Shunt failure in tuberculous meningitis can be associated with vision loss. Shunt malfunction results in increase in intracranial pressure, papilledema and subsequently optic atrophy. The vision loss, usually, develops gradually but may be abrupt. An ischemic lesion in the pregeniculate anterior visual pathway and infarcts of the occipital lobes are possible reasons for cortical vision loss. 31 Paradoxically, excessive drainage of cerebrospinal fluid, through shunt, can result in low intracranial pressures and may manifest with rapid vision loss. Prolapse of the optic chiasma into an empty sella has been proposed as mechanism responsible for vision loss. Other shunt-related complications (like malpositioning, hemorrhage, subdural hematoma, and ventriculitis) contribute to vision loss, possibly by increasing intracranial tension. 17 Immune reconstitution inflammatory syndrome There are few isolated instances when optic nerves were paradoxically affected in the process of immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected patients of tuberculous meningitis. In one such patient, following antiretroviral therapy multiple tuberculomas appeared in the optochiasmatic region. 32 In other patient, bilateral optic disc swelling with choroiditis, retinitis, and optic neuritis led to a profound vision loss.33
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Optic nerve tuberculoma Intrinsic optic nerve tuberculomas has rarely been reported in tuberculous meningitis. In patients with miliary tuberculosis, tuberculous seedling in optic nerve trunk is likely to occur during hematogenous spread. 34, 35
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Structures of visual pathways involved in tuberculous meningitis Every structure of visual pathway is likely to be affected in tuberculous meningitis. Optic nerve and optic chiasm are most frequently and dominantly affected.
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Ocular Infrequently, intraocular tuberculosis, resulting in vision loss, is seen in patients with tuberculous meningitis. Intraocular tuberculosis is a form of tuberculosis presenting as uveitis. Both choroid and retina are highly vascular structures and are likely to be involved in the process of dissemination of tuberculous infection. Posterior uveitis is the most common presentation of intraocular tuberculosis. 36-38 The choroid lesions usually manifest as choroiditis (focal, multifocal or serpiginous), solitary or multiple choroidal tubercles, and choroidal tuberculoma. Tuberculous retinal involvement manifests as subretinal abscess, retinal vasculitis, subretinal neovascularization, and, rarely, retinal detachments (serous fluid collects between the retina and choroid). Retinal vasculitis may lead to proliferative vascular retinopathy with recurrent vitreous hemorrhage and neovascular glaucoma. Rarely, severe ocular complications, like endophthalmitis and panophthalmitis are encountered. Orbital apex syndrome, manifesting with the oculomotor nerve, trochlear nerve, abducens nerve, and ophthalmic branch of the trigeminal nerve involvement in association with optic nerve dysfunction, is infrequently caused by tuberculosis. 39, 40 Cases of optic nerve head tuberculoma, presenting as optic neuropathy with severe vision loss, has been described. Optic nerve head tuberculoma is seen in patients with miliary tuberculosis.41
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Choroidal tubercles are the most common form of ocular tuberculosis and are considered pathognomonic for miliary tuberculosis. Choroidal tubercles can be seen in tuberculous meningitis, particularly when tuberculous meningitis is part of miliary tuberculosis. Choroidal tubercles are unilateral or bilateral, gray–white or yellowish lesions and are usually less than one quarter of the size of the optic disc. These tubercles are commonly located within 2 disc-diameters from the optic nerve head and can produce an overlying exudative retinal detachment. 42 (Figure-4) Optic nerve and optic chiasma Optic nerve disorders that have been reported in tuberculous meningitis include papillitis, optic nerve tuberculoma, compressive optic neuropathy, retrobulbar neuritis, optic neuritis and anterior ischemic optic neuropathy. Direct involvement of the optic nerve by a tuberculous infection and/or indirect involvement by an inflammatory, degenerative, or vascular process is considered responsible for nerve dysfunction in a patient with tuberculous meningitis.16 Exudates, if dominantly present in the interpeduncular, suprasellar and Sylvian cisterns, result in optochiasmatic arachnoiditis and tuberculoma. The optic nerve and optic chiasma often get immersed in pool of thick exudate lying over basal brain region. Optochiasmatic arachnoiditis is invariably associated with vision loss. 43, 44 (Figure-1; Figure-2)
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Optic radiation and visual cortex Optic radiation and visual cortex are rarely involved in tuberculous meningitis. These patients present with cortical blindness. Cortical blindness is characterized with vision loss with sparing of pupillary responses. Basilar artery involvement, enlarging hydrocephalus, shunt failure and occipital lobe tuberculoma are potential causes of cortical vision loss. (Figure-5)
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Paradoxical vision loss There are many instances when blindness in tuberculous meningitis develops paradoxically while patient is being treated with antituberculosis drugs. 45-49 Sinha and co-workers reported a series of 8 such cases who developed paradoxical vision loss caused by paradoxically developed optochiasmatic tuberculoma. 47 In a large prospective follow up study, Singh and co-workers noted paradoxical optochiasmatic arachnoiditis in 12 (out of 141) patients within 6 months of starting treatment and all with profound vision loss.49 In some patients of paradoxical optochiasmatic tuberculoma, vision improves with high doses of corticosteroids and thalidomide.
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Neuroimaging Basal exudates, hydrocephalus, periventricular infarcts and tuberculoma are cardinal neuroimaging features of tuberculous meningitis. In optochiasmatic arachnoiditis neuroimaging reveals thick, meningeal enhancement. Hydrocephalus is another frequent neuroimaging abnormality. Hydrocephalus, in tuberculous meningitis, is either communicating or the obstructive variety. In communicating hydrocephalus fourth ventricle is dilated. In obstructive type of hydrocephalus, the fourth ventricle is either chinked or unaffected. If optic nerve is inflamed, because of mycobacterial invasion, neuroimaging may show thickening and enhancement of the optic nerve. 50, 51 (Figure-1 to Figure-5) Optic nerve tuberculoma, on neuroimaging, manifests with optic nerve swelling and an intrinsic ring-enhancing lesion inside the nerve. 34, 35
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Magnetization transfer magnetic resonance imaging is a useful technique that helps in differentiating tuberculous meningitis from causes of infective meningitis. Inflamed meninges in tuberculous meningitis show significantly different magnetization transfer ratios than those of inflamed meninges in meningitis of nontuberculous origin. Pre-contrast T1weighted magnetization transfer images have been shown to be 96% sensitive and 100% specific in demonstrating abnormal meninges in patients with tuberculous meningitis. 52 Magnetic resonance spectroscopy is another technique that helps in differentiating tuberculous and non-tuberculous cerebral mass lesions. In magnetic resonance spectroscopic evaluation tuberculous lesions demonstrate a characteristic lipid peaks. Lipids are integral component of mycobacterial cell wall and disintegration of mycobacterial cell wall and its lipid content within the tuberculoma is considered reasons for the marked elevation of lipid peaks.53 Differential diagnosis Tuberculous meningitis is diagnosed on the basis of characteristic clinical, cerebrospinal fluid and neuroimaging features. Demonstration of acid-fast bacillus in cerebrospinal fluid smear, a positive cerebrospinal fluid culture and positive polymerase chain reaction for Mycobacterium tuberculosis are considered diagnostic for tuberculous meningitis.
ACCEPTED MANUSCRIPT 8 An infectious, carcinomatous or immune disorders of meningitis, with a high propensity to optic pathways, can pose diagnostic challenge. The differential diagnosis need be continually reviewed if the patient is not responding to presumptive antituberculosis therapy. The likely cause may vary according to the age and immune status of the patient. For example, in the immunocompromised host, there is an increased risk of fungal infection and neurosyphilis.
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Cryptococcal meningitis Vision loss is a very frequent complication in cryptococcal meningitis. Vision loss is thought to be caused by raised intracranial pressure, direct fungal invasion leading to necrotizing optic neuropathy, or adhesive arachnoiditis. Demonstration of Cryptococcus neoformans in the cerebrospinal fluid is the gold standard for the diagnosis. India ink stains will disclose cryptococci in 50% of human immunodeficiency virus- uninfected patients and in as many as 80% of human immunodeficiency virus -infected patients. Cryptococcal antigen titers in serum are usually elevated in patients with cryptococcal meningitis. 54, 55
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Carcinomatous meningitis Carcinomatous meningitis is dissemination of malignant cells in the leptomeninges. Optic nerve involvement is a frequent and early clinical manifestation of carcinomatous meningitis. Carcinomatous infiltration of the leptomeningeal space should be considered in cases of bilateral simultaneous vision loss with other signs suggestive of leptomeningeal infiltration of the optic nerve sheath.56 Carcinomatous meningitis is seen in patients with solid tumors, lymphomas and leukemia.54 Adenocarcinoma is the most frequent histopathology in patients with carcinomatous meningitis and breast, lung, and melanoma are the most common primary sites. Neuroimaging, cerebrospinal fluid examination for malignant cells, meningeal biopsy, and tissue biopsy help in establishing the diagnosis. 57-59
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Pneumococcal meningitis Visual impairment in pneumococcal meningitis can also be caused by cerebral infarction and cavernous sinus thrombosis. A meta-analysis of 63 studies, involving 3408 pneumococcal meningitis survivors, reported long-term sequelae in 31.7% of patients. The prevalence of visual impairment was 2.4%.60 The diagnosis of pneumococcal meningitis is ascertained on the basis of characteristic manifestation of acute meningitis and demonstration of pneumococci in the cerebrospinal fluid by culture, Gram stain, or latex particle agglutination and/or blood cultures.
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Pituitary apoplexy Pituitary apoplexy is a rare but potentially life-threatening event. In pituitary apoplexy, patients present with sudden onset of headache, vision loss, ophthalmoplegia and coma. Apoplexy commonly occurs in patients with a pre-existing pituitary adenoma. The majority of the patients will have deficiency of one or more anterior pituitary hormones at presentation. Neuroimaging reveals haemorrhage within the pituitary gland and compression of the optic chiasma.61 Neurosyphilis Approximately, 5% of patients with neurosyphilis develop meningitis. Vision loss in neurosyphilis may be caused by chorio-retinitis, retinitis, optic neuropathy, optic chiasmal, or optic tract involvement. In optic neuritis, the optic-nerve sheath is invaded by the spirochete. Optic neuritis often leads to irreversible optic atrophy. The diagnosis of neurosyphilis depends on a positive cerebrospinal fluid test Venereal Disease Research Laboratory (VDRL) test.62, 63
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Neurobrucellosis A few cases of neurobrucellosis have been reported with symptoms and sign of optic neuritis along with meningoencephalitis. Vision loss in neurobrucellosis may also be because of the inflammatory involvement of the optic chiasma. The diagnosis of neurobrucellosis is confirmed either by isolation of Brucella species and/or presence of anti-Brucella antibodies in the cerebrospinal fluid.64
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Sarcoidosis Facial nerve followed by optic nerve are most commonly involved in sarcoidosis. The optic nerve involvement may be seen in up to 38% of patients of neurosarcoidosis. Sarcoidosis also involves the hypothalamus, infundibulum and optic chiasma. 65 The diagnosis is confirmed if histologically non-caseating granulomas is demonstrated in a biopsied specimen.66
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Idiopathic hypertrophic pachymeningitis Idiopathic hypertrophic pachymeningitis is usually presents with severe headache and progressive neurologic deterioration and vision loss. Hypertrophic pachymeningitis causes a localized or diffuse thickening of the dura mater. Idiopathic hypertrophic pachymeningitis is suspected on neuroimaging and is confirmed histopathologically.67
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Lyme disease Elevated intracranial pressure in acute disseminated Lyme disease can manifests as progressive loss of vision. Serological test as recommended by Centers for Disease Control and Prevention using an enzyme-linked immunosorbent assay initially, followed by the more specific Western blot is required.68
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Vogt-Koyanagi-Harada Syndrome Vogt-Koyanagi-Harada syndrome often presents meningoencephalitis, visual blurring, and deafness. Vogt-Koyanagi-Harada syndrome is often associated with neurologic and cutaneous manifestations, including headache, hearing loss, vitiligo and poliosis. Diagnosis is based on ophthalmological and other clinical findings. The characteristic eye signs are intensely pink optic nerves with severe visual loss. 69
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Systemic lupus erythematosus Systemic lupus erythematosus can present with meningoencephalitis and optic neuritis. It shares its clinical features with the pesudotumour cerebri syndrome. Optic neuropathy is estimated to occur in 1% of patients with systemic lupus erythematosus and in some cases, there is associated myelopathy. The diagnosis of systemic lupus erythematosus is established on the basis of a set of clinical and laboratory (American College of Rheumatology) criteria.70 Treatment There are limited options available for the treatment of vision loss in patients with tuberculous meningitis. The available options are antituberculosis treatment, immune modulator drugs and cerebrospinal fluid diversion surgery. The treatment of paradoxically developed vision loss is also far from satisfactory.
ACCEPTED MANUSCRIPT 10 Antituberculosis treatment Antituberculosis treatment is currently the best treatment option available to prevent and treat vision loss in tuberculous meningitis and it should be initiated as promptly as possible. World Health Organization recommends that antituberculosis treatment should initially be started with four drugs, that include isoniazid, rifampicin, pyrazinamide, streptomycin or ethambutol. After two months of intensive phase, in continuation phase, isoniazid and rifampicin are given for seven or ten months. All patients should receive adjunctive dexamethasone treatment initial few weeks. Antituberculosis treatment regimen for human immunodeficiency virus-infected patients of tuberculous meningitis is similar.71
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Intensified antituberculosis treatment regimens Recently, several intensified antituberculosis treatment regimens have been tested in tuberculous meningitis with the hope of achieving improved disability free survival. In first such randomised controlled study of intensified antituberculosis treatment regimen (with higher-dose rifampicin administered intravenously) was associated with a 30% better 6month survival.72 Later, it was demonstrated that a strong concentration-effect relationship with higher rifampicin administration led to this better survival.73 However, a recently tested intensified antituberculosis treatment regimen, with intravenous rifampicin and levofloxacin, did not demonstrate survival benefits, instead a significantly higher proportion of patients on intensified regimen had vision abnormalities.30 Minimum rifampicin target values, that were derived from exposure-response curves with intravenous rifampicin, is achieved only 38% of patients, so, it was argued that that even higher intravenous dosages should be used. Whenever an intensified antituberculosis regimen is used, a close watch on the possibility of enhanced vision loss is warranted. 74
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Immune-modulator drugs Immune-modulator drugs help in reducing the detrimental inflammatory changes. Thalidomide (a potent tumor necrosis factor-α inhibitor) is one such immune-modulator drug that shown significant clinical benefit in children presenting with paradoxical vision loss.75 A randomised controlled trial of thalidomide in children with tuberculous meningitis had to be stopped prematurely because of significant adverse effects in the treatment arm.76
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Neurosurgery Cerebrospinal fluid diversion procedures Two important cerebrospinal fluid diversion procedures, ventriculo-peritoneal shunt and endoscopic third-ventriculostomy are frequently used in tuberculous meningitis. Mostly medically non-responding patients are subjected to cerebrospinal fluid diversion procedures. The exact benefit from cerebrospinal fluid diversion procedures is controversial and deterioration usually occur after the initial improvement. The effect of these surgeries on vision loss is also not clearly known.77, 78 Neurosurgical decompression of optic chiasma In patients with optochiasmatic arachnoiditis and vision loss neurosurgical decompression of optic chiasma, by excising exudates and breaking adhesions, were performed in past. This type of neurosurgery is no longer performed.79 Prognosis Profound vision loss is a frequent and permanent disability among significant number of survivors. For example, in a prospective study, among 88 survivors at 6 months (out of 101), 11 patients had markedly low vision and 9 patients had complete blindness. Presence of
ACCEPTED MANUSCRIPT 11 papilledema (95% CI=1.12-2.29, p = 0.012), vision acuity ≤ 6/18 (95% CI=2.27-11.12, p = 0.001), multiple cranial nerve palsies (95% CI=1.20-1.99, p = 0.001), advanced stage of the disease (95% CI=1.29-1.78, p = 0.020), markedly high cerebrospinal fluid protein (95% CI=1.04-2.01, p = 0.007) and optochiasmatic arachnoiditis (95% CI=1.20-3.35, p = 0.001) were found to predict vision loss.80 Another study noted that among 65 patients of tuberculous meningitis, 78.5% survivors neurological sequelae at one year. Optic atrophy was noted in 37% of survivors. Majority of patients (22/24) with optic atrophy had papilledema on initial evaluation. 81
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Future prospects It is interesting to note that only a small proportion survivors of tuberculous meningitis had permanent and disabling vision loss. Early identification of patients, who are likely to have vision loss either with a biochemical parameter or by advanced neuroimaging technique, will help in effectively dealing with this devastating complication. Recently, significant progress has been made in the development of new diagnostic tools for rapid detection of tuberculosis. With wider availability of the Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis and detection of rifampicin resistance, a timely confirmation of diagnosis of tuberculous meningitis is possible. With advanced neuroimaging techniques, which are now readily available in developing countries, many devastating complications, like optochiasmatic arachnoiditis, will increasingly be recognized. Currently available antituberculosis treatment is far from satisfactory. More effective antituberculous drugs are urgently needed. Role of newer antituberculosis drugs (bedaquiline and delamanid) need to be tested in tuberculous meningitis. Corticosteroids are the most frequently used adjunct treatment. Corticosteroids improve survival but often fail in preventing many of its complication, including paradoxical vision loss. Other adjunct immunotherapies like newer tumor necrosis factor-alpha antagonists (etanercept, infliximab, adalimumab, certolizumab and golimumab) and immunosuppressive agents need to be tried. Most importantly, preventive measures are needed to fight against tuberculosis at global level. The fight against tuberculosis will help in reducing incidence of tuberculous meningitis and its complications.
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Conclusions Vision loss in tuberculous meningitis is a disabling complication and often persist permanently as sequelae. Frequently, vision loss can paradoxically develop. Not much emphasis was given on this issue as most of the patients are often seriously ill and vision loss goes unnoticed. Frequently, patients survive with significant visual morbidity. Early recognition and prompt treatment are probably the only available solutions to this problem.
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Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
ACCEPTED MANUSCRIPT 13 References 1. Panfique, L, Etienne R. Le tuberculom du chiasma. Bull Soc Ophthalm fr 1952; 65: 97–109. 2. Libby GF. Tuberculous Meningitis. Trans Am Ophthalmol Soc 1920; 18: 107–115. 3. World Health Organization. Tuberculosis; WHO Global Tuberculosis: Report 2015. http://www.who.int/tb/publications/global_report/factsheet_global_2015.pdf?ua=1A ssessed on 19Sept 2016
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20. Takahashi T, Isayama Y. Chiasmal meningitis. Neuro-Ophthalmology 1980; 1:1931. http://dx.doi.org/10.3109/01658108009004896 21. Talbert Estlin KA, Sadun AA. Risk factors for ethambutol optic toxicity. Int Ophthalmol 2010;30:63-72.
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22. Ezer N, Benedetti A, Darvish-Zargar M, Menzies D. Incidence of ethambutol-related visual impairment during treatment of active tuberculosis. Int J Tuberc Lung Dis 2013;17:447-55. 23. Sharma P, Sharma R. Toxic optic neuropathy. Indian J Ophthalmol 2011; 59: 137– 141.
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24. Kulkarni HS, Keskar VS, Bavdekar SB, Gabhale Y. Bilateral optic neuritis due to isoniazid (INH). Indian Pediatr 2010;47:533-5. 25. Lee E, Burger S, Shah J, Melton C, Mullen M, Warren F, Press R. Linezolidassociated toxic optic neuropathy: a report of 2 cases. Clin Infect Dis 2003;37:138991.
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26. Rucker JC, Hamilton SR, Bardenstein D, Isada CM, Lee MS. Linezolid-associated toxic optic neuropathy. Neurology 2006;66:595-8.
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27. Das S, Mondal S. Oral levofloxacin-induced optic neuritis progressing in loss of vision. Ther Drug Monit 2012 ;34:124-5. 28. Gallelli L, Del Negro S, Naty S, Colosimo M, Maselli R, De Sarro G. Levofloxacininduced taste perversion, blurred vision and dyspnoea in a young woman. Clin Drug Investig 2004;24:487-9. 29. Libershteyn Y. Ethambutol/Linezolid Toxic Optic Neuropathy. Optom Vis Sci 2016;93:211-7. 30. Heemskerk AD, Bang ND, Mai NT, Chau TT, Phu NH, Loc PP, Chau NV, Hien TT, Dung NH, Lan NT, Lan NH, Lan NN, Phong le T, Vien NN, Hien NQ, Yen NT, Ha DT, Day JN, Caws M, Merson L, Thinh TT, Wolbers M, Thwaites GE, Farrar JJ.
ACCEPTED MANUSCRIPT 15 Intensified Antituberculosis Therapy in Adults with Tuberculous Meningitis. N Engle J Med 2016;374:124-134. 31. Arroyo HA, Jan JE, McCormick AQ, Farrell K. Permanent visual loss after shunt malfunction. Neurology 1985;35:25-9.
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32. Dautremer J, Pacanowski J, Girard PM, Lalande V, Sivignon F, Meynard JL. A new presentation of immune reconstitution inflammatory syndrome followed by a severe paradoxical reaction in an HIV-1-infected patient with tuberculous meningitis. AIDS 2007;21:381-2.
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33. Jaafar J, Hitam WH, Noor RA. Bilateral atypical optic neuritis associated with tuberculosis in an immunocompromised patient. Asian Pac J Trop Biomed 2012;2:586-8.
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34. Lana-Peixoto MA, Bambirra EA, Pittella JE. Optic nerve tuberculoma. A case report. Arch Neurol 1980;37:186-7.
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35. Sivadasan A, Alexander M, Mathew V, Mani S, Patil AK. Radiological evolution and delayed resolution of an optic nerve tuberculoma: Challenges in diagnosis and treatment. Ann Indian Acad Neurol 2013;16:114-7.
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36. Gupta A, Sharma A, Bansal R, Sharma K. Classification of intraocular tuberculosis. Ocul Immunol Inflamm 2015;23:7-13.
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37. Ang M, Vasconcelos-Santos DV, Sharma K, Accorinti M, Sharma A, Gupta A, Rao NA, Chee SP. Diagnosis of Ocular Tuberculosis. Ocul Immunol Inflamm 2016 Jul 5:1-9. [Epub ahead of print] DOI: 10.1080/09273948.2016.1178304. 38. Cutrufello NJ, Karakousis PC, Fishler J, Albini TA. Intraocular tuberculosis. Ocul Immunol Inflamm 2010;18:281-91.
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39. Mehta S, Banker AS, Chauhan R. In: Retinal and Choroidal Manifestations of Selected Systemic Diseases. Fernando Arévalo J (editor). Springer 2013:63-78. Available from: http://www.springer.com/us/book/9781461436454
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40. Malhotra HS, Garg RK, Gupta A, Saxena S, Majumdar A, Jain A. An unusual cause of visual impairment in tuberculous meningitis. J Neurol Sci 2012;318:174-7. 41. Padhi TR, Basu S, Das T, Samal B. Optic disc tuberculoma in a patient with miliary tuberculosis. Ocul Immunol Inflamm 2011;19:67-8. 42. Heiden D, Saranchuk P, Keenan JD, Ford N, Lowinger A, Yen M, McCune J, Rao NA. Eye examination for early diagnosis of disseminated tuberculosis in patients with AIDS. Lancet Infect Dis 2016;16:493-9. 43. Garg RK, Paliwal V, Malhotra HS. Tuberculous optochiasmatic arachnoiditis: a devastating form of tuberculous meningitis. Expert Rev Anti Infect Ther 2011;9:719-29.
ACCEPTED MANUSCRIPT 16 44. Anupriya A, Sunithi M, Maya T, Goel M, Alexander M, Aaron S, Mathew V. Tuberculous optochiasmatic arachnoiditis. Neurol India 2010;58:732-5. 45. Monga PK, Dhaliwal U. Paradoxical reaction in tubercular meningitis resulting in involvement of optic radiation. Indian J Ophthalmol 2009;57:139-41. 46. Garg RK, Malhotra HS, Kumar N. Paradoxical reaction in HIV negative tuberculous meningitis. J Neurol Sci 2014;340:26-36.
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47. Sinha MK, Garg RK, Anuradha HK, Agarwal A, Parihar A, Mandhani PA. Paradoxical vision loss associated with optochiasmatic tuberculoma in tuberculous meningitis: a report of 8 patients. J Infect 2010;60:458-66.
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48. Joseph M, Mendonca TM, Vasu U, Nithyanandam S, Mathew T.Paradoxical growth of presumed optochiasmatic tuberculomas following medical therapy. JAMA Ophthalmol 2013;131:1463-7.
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49. Singh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, Verma R, Sharma PK. Paradoxical reaction in tuberculous meningitis: presentation, predictors and impact on prognosis. BMC Infect Dis 2016;16:306.
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50. Garg RK, Malhotra HS, Jain A. Neuroimaging in tuberculous meningitis. Neurol India 2016;64:219-27.
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51. Torres C, Riascos R, Figueroa R, Gupta RK. Central nervous system tuberculosis. Top Magn Reson Imaging 2014;23:173-89.
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52. Kamra P, Azad R, Prasad KN, Jha S, Pradhan S, Gupta RK. Infectious meningitis: prospective evaluation with magnetization transfer MRI. Br J Radiol 2004;77:38794.
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53. Trivedi R, Saksena S, Gupta RK. Magnetic resonance imaging in central nervous system tuberculosis. Indian J Radiol Imaging 2009;19:256-65.
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54. Saremi F, Helmy M, Farzin S, Zee CS, Go JL. MRI of cranial nerve enhancement. AJR Am J Roentgenol 2005;185:1487-97. 55. Merkler AE, Gaines N, Baradaran H, Schuetz AN, Lavi E, Simpson SA, Dinkin MJ. Direct Invasion of the Optic Nerves, Chiasm, and Tracts by Cryptococcus neoformans in an Immunocompetent Host. Neurohospitalist 2015;5:217-22. 56. Teare JP, Whitehead M, Rake MO, Coker RJ. Rapid onset of blindness due to meningeal carcinomatosis from an oesophageal adenocarcinoma. Postgrad Med J 1991;67:909-11. 57. Shen TY, Young YH. Meningeal carcinomatosis manifested as bilateral progressive sensorineural hearing loss. Am J Otol 2000;21:510-2. 58. Gilbert M, Cantore WA, Chavis PS, Mistr SK. Optic neuritis in evolution. Surv Ophthalmol 2007;52:529-34.
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59. Chan JW. Acute monocular visual loss in carcinomatous hypertrophic pachymeningitis mimicking giant cell arteritis. Rheumatol Int 2006;26:683-4. 60. Jit M. The risk of sequelae due to pneumococcal meningitis in high-income countries: a systematic review and meta-analysis. J Infect 2010;61:114-24. 61. Smith SV, Amram AL, Rodarte EM, Lee AG. Neuro-Ophthalmology Cases for the Neurologist. Neurol Clin 2016;34:611-29.
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62. Smith GT, Goldmeier D, Migdal C. Neurosyphilis with optic neuritis: an update. Postgrad Med J 2006;82:36-9.
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63. Draper EM, Malloy KA. Progressive visual and hearing loss secondary to neurosyphilis.Optom Vis Sci 2012;89:e65-71. 64. Kizilkilic O, Calli C. Neurobrucellosis. Neuroimaging Clin N Am 2011;21:927-37.
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65. Zajicek JP, Scolding NJ, Foster O, Rovaris M, Evanson J, Moseley IF, Scadding JW, Thompson EJ, Chamoun V, Miller DH, McDonald WI, Mitchell D. Central nervous system sarcoidosis--diagnosis and management. QJM 1999;92:103-17.
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66. Iannuzzi MC, Rybicki BA, Teirstein AS. Sarcoidosis. N Engl J Med 2007;357(21):2153-65.
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67. Kupersmith MJ, Martin V, Heller G, Shah A, Mitnick HJ. Idiopathic hypertrophic pachymeningitis. Neurology 2004;62:686-94.
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68. Centers for Disease Control and Prevention. Lyme Disease. https://www.cdc.gov/lyme/ Assessed on 23 September 2016 69. Fang W, Yang P. Vogt-koyanagi-harada syndrome. Curr Eye Res 2008;33:517-23.
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70. Jennekens FG, Kater L. The central nervous system in systemic lupus erythematosus. Part 1. Clinical syndromes: a literature investigation. Rheumatology (Oxford) 2002;41:605-18. 71. World Health Organization. Treatment of tuberculosis: guidelines – 4th ed. (WHO/HTM/TB/2009.420) World Health Organization 2010 (http://whqlibdoc.who.int/publications/2010/9789241547833_eng.pdf assessed on September 23, 2016). 72. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ, Borm G, Aarnoutse RE, van Crevel R. Intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis: an open-label, randomised controlled phase 2 trial. Lancet Infect Dis 2013; 13:27-35. 73. Te Brake L, Dian S, Ganiem AR, Ruesen C, Burger D, Donders R, Ruslami R, van Crevel R, Aarnoutse R. Pharmacokinetic/pharmacodynamic analysis of an
ACCEPTED MANUSCRIPT 18 intensified regimen containing rifampicin and moxifloxacin for tuberculous meningitis. Int J Antimicrob Agents 2015; 45:496-503. 74. van Crevel R, Ruslami R, Aarnoutse R. Therapy for Tuberculous Meningitis. N Engl J Med 2016; 374:2187. 75. van Toorn R, du Plessis AM, Schaaf HS, Buys H, Hewlett RH, Schoeman JF. Clinicoradiologic response of neurologic tuberculous mass lesions in children treated with thalidomide. Pediatr Infect Dis J 2015;34:214-8.
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76. Schoeman JF, Springer P, van Rensburg AJ, Swanevelder S, Hanekom WA, Haslett PA, Kaplan G. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. J Child Neurol 2004;19:250-7.
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77. Bhagwati SN. Ventriculoatrial shunt in tuberculous meningitis with hydrocephalus. J Neurosurg 1971;35:309-13.
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78. Savardekar A, Chatterji D, Singhi S, Mohindra S, Gupta S, Chhabra R. The role of ventriculoperitoneal shunt placement in patients of tubercular meningitis with hydrocephalus in poor neurological grade: a prospective study in the pediatric population and review of literature. Childs Nerv Syst 2013;29:719-25.
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79. Scott RM, Sonntag VK, Wilcox LM, Adelman LS, Rockel TH. Visual loss from optochiasmatic arachnoiditis after tuberculous meningitis. Case report. J Neurosurg 1977;46:524-6.
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80. Sinha MK, Garg RK, Anuradha HK, Agarwal A, Singh MK, Verma R, Shukla R. Vision impairment in tuberculous meningitis: predictors and prognosis. J Neurol Sci 2010;290:27-32.
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81. Kalita J, Misra UK, Ranjan P. Predictors of long-term neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007;14:33-7. Erratum in: Eur J Neurol 2007;14:357.
ACCEPTED MANUSCRIPT 19 Legends Figure-1 Contrast-enhanced axial magnetic resonance imaging shows optochiasmatic arachnoiditis. Figure-2 Gadolinium contrast-enhanced sagittal MRI magnetic resonance imaging shows optochiasmatic arachnoiditis. Basal meninges are marked inflamed.
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Figure-3 Computed tomography of the brain shows dilated ventricles.
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Figure-4 A large choroidal tubercle in patient with miliary tuberculosis with tuberculous meningitis
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Figure-5 A patient with tuberculous meningitis, who paradoxically developed occipital tuberculomas and presented with cortical blindness.
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Table-1: The causes of vision loss in tuberculous meningitis. The table shows anatomical structure responsible for vision loss and the corresponding etiology. Corresponding etiopathogenesis
Frequency of involvement
Tuberculoma Retinal vasculitis Retinal detachments** Antituberculosis drugs-induced retinopathy (ethambutol, linezolid, and fluoroquinolones)
Infrequent
Optic nerve and/ or Optic chiasma
Direct invasion by mycobacteria (papillitis or retrobulbar neuritis)
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Structures involved Choroid and retina
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Common
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Vascular (endarteritis of the chiasma or anterior ischemic optic neuropathy)
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Compression (optic nerve or optochiasmatic tuberculomas, chiasmal compression form dilated third ventricle)
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Raised ICP (secondary optic atrophy)
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Immune mediated (IRIS)
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Treatment related - drugs (ethambutol, isoniazid, linezolid, streptomycin, fluoroquinolones)
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Shunt failure (raised ICP and chiasmal prolapse due to overdrainage)
Optic radiations and visual cortex
Tuberculoma Infarcts secondary to large vessel involvement
**serous fluid between retina and choroid
Rare
ACCEPTED MANUSCRIPT 26 Highlights 1. Vision loss is a disabling complication of tuberculous meningitis. 2. Any structure of visual pathway is affected but optic nerve and optic chiasma are frequently involved. 3. Thick exudates, lying at base of brain, the pathological hallmark, is responsible for vision loss.
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4. Nerve entrapment, hydrocephalus, raised ICP, endarteritis, shunt failure, bacterial invasion of nerves and drug toxicity are responsible.
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5. Antituberculosis treatment is the best treatment option available to prevent and treat vision loss.
Ravindra Kumar Garg, Hardeep Singh Malhotra, Neeraj Kumar, Ravi Uniyal PII: DOI: Reference:
S0022-510X(17)30033-3 doi: 10.1016/j.jns.2017.01.031 JNS 15093
To appear in:
Journal of the Neurological Sciences
Received date: Revised date: Accepted date:
28 September 2016 23 December 2016 9 January 2017
Please cite this article as: Ravindra Kumar Garg, Hardeep Singh Malhotra, Neeraj Kumar, Ravi Uniyal , Vision loss in tuberculous meningitis. The address for the corresponding author was captured as affiliation for all authors. Please check if appropriate. Jns(2017), doi: 10.1016/j.jns.2017.01.031
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ACCEPTED MANUSCRIPT 1 Vision loss in tuberculous meningitis
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Ravindra Kumar Garg Hardeep Singh Malhotra Neeraj Kumar Ravi Uniyal
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Address for correspondence Ravindra Kumar Garg Department of Neurology King George Medical University, Uttar Pradesh, Lucknow India PIN-226003 Phone: 91 9335901790 Email: [email protected]
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Department of Neurology King George Medical University Uttar Pradesh Lucknow, India
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Abstract Vision loss is a disabling complication of tuberculous meningitis. Approximately, 15% of survivors are either completely or partially blind. All the structures of visual pathway can be affected in tuberculous meningitis. Optic nerve and optic chiasma are most frequently and dominantly affected. Thick, gelatinous, exudates, lying over the base of brain, is the pathological hallmark of tuberculous meningitis and is responsible for all its major complications, including vision loss. Strangulation of optic nerves and optic chiasma by the exudates, compression over optic chiasma by dilated third ventricles, raised intracranial pressure, endarteritis, shunt failure, bacterial invasion of optic nerves and drug induced optic nerve damage are important reasons that are considered responsible for vision loss. Prompt antituberculosis treatment is the best management option available. Immune modulatory drugs and cerebrospinal fluid diversion procedures are of limited help. Early recognition and treatment of tuberculous meningitis are only way forward to tackle this problem.
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Keywords: Antituberculosis drugs; Blindness; Optic nerve; Optic chiasma; Meningitis; Mycobacterium tuberculosis
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ACCEPTED MANUSCRIPT 3 Complete or partial vision loss is a common and disabling complication of tuberculous meningitis. Many patients of tuberculous meningitis do survive, following treatment, but with life-long vision loss as sequelae. Vision loss is a known complication of tuberculous meningitis but it has not given due attention Patients of tuberculous meningitis have altered sensorium and often vision loss go unnoticed.
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Optic nerve tuberculoma and tuberculous optochiasmatic involvement in the setting of tuberculous meningitis was first recorded by Cruveilhier and Hjort in 1862 and 1867 respectively. Since then vision loss has regularly been reported.1 Libby in 1920 recorded a classical description of vision loss in tuberculous meningitis.2
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“A few years later a tuberculous adult male who had shown satisfactory improvement in the pulmonary condition developed sudden impairment of vision in each eye, associated with severe, constant headache. A moderate optic neuritis was present. The expert diagnostician summoned declared that the condition could be diagnosed either as brain tumor, syphilitic optic neuritis, or tuberculous meningitis. The ophthalmologist stood out for tuberculous meningitis, the expert on tuberculosis concurring. The patient died within two weeks of tuberculous meningitis, with binocular blindness.”
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Unfortunately, the scenario described by Libb, almost 100 years ago, still remains the same and many patients of tuberculous meningitis have to live rest of his/her life without vision. In this review, we have focused on the various aspects of vision loss in tuberculous meningitis. An extensive review of the literature published in English was carried out using the PubMed and Google Scholar databases. The search items included “tuberculous meningitis and vision loss”, “tuberculous meningitis and blindness”, and “tuberculous meningitis and optic atrophy”. Bulk of related information is either in the form of isolated case reports or case series.
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Epidemiology of tuberculous meningitis Tuberculosis is a top global infectious disease. In 2014, 9.6 million people acquired tuberculosis and 1.5 million patients died from it. Six countries (India, Indonesia, Nigeria, Pakistan, China and South Africa) have the largest pool of tuberculosis patients. In 2014, among 6 314 151 reported cases worldwide, 880 596 had extrapulmonary tuberculosis (including meningeal tuberculosis).3 The exact incidence of tuberculous meningitis in 6 major tuberculosis affected countries is not known but it is expected to be quite high. On the contrary, in developed countries incidence of tuberculous meningitis is low. In European Union countries, during 2002–11, 167,652 cases of extrapulmonary tuberculosis were reported. Meningeal tuberculosis was present in 5.8% of the paediatric cases and 2.9% for all the other age groups combined.4 In United States, among 253,299 tuberculosis cases approximately 19% cases were extra- pulmonary. The proportion of meningeal tuberculosis was 5.4%.5 Tuberculosis patients co-infected with human immunodeficiency virus are more likely to have meningeal and disseminated disease. Vision loss in tuberculous meningitis: the magnitude of problem The incidence of vision loss in tuberculous meningitis is quite variable, ranging up to 56%. In a classical study, by Udani and co-workers, 78 patients of tuberculous meningitis were autopsied. Optic nerve involvement was observed in 14% of patients. Optic nerves and optic chiasma were found encased by the thick adhesive exudate, in the basal meninges.6 Amitava and co-workers noted that among 100 pediatric patients with tuberculous meningitis, 67 had neuro-ophthalmic abnormalities. The most frequent neuro-ophthalmic abnormality recorded
ACCEPTED MANUSCRIPT 4 was retrobulbar neuritis. Raised intracranial tension was recorded in 53 patients with neuroophthalmic abnormalities. By 6 months, 56% of patients with retrobulbar neuritis developed optic atrophy. 7 In another study on pediatric patients with tuberculous meningitis, the outcome of different steroid-dose was evaluated. Out of 63 patients, 9 children had optic atrophy at the time of inclusion. Despite treatment and steroid administration, optic atrophy and vision loss count increased to affect 24 patients. 8
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Vision loss as sequelae Approximately, up to 14% of the survivors have disabling and permanent residual vision loss, after the course of antituberculosis treatment is over. Some of the patients are completely blind; neuro-ophthalmological evaluation, in these patients, often reveals optic atrophy. Patients presenting in advanced stages of tuberculous meningitis are more likely to have permanent vision loss as sequelae. 9-12
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Visual evoked responses in tuberculous meningitis Subclinical visual pathways abnormalities in tuberculous meningitis have also been demonstrated with the help of visual evoked potential evaluation. In a series of 43 patients of tuberculous meningitis, electrophysiological assessment of optic nerves revealed visual evoked potential abnormalities (prolonged P100 latencies) in 27 (62.8%) patients. Clinically, visual abnormalities were noted in 22 (51.3%) patients.13
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Pathogenesis of vision loss in tuberculous meningitis The cause of vision loss in tuberculous meningitis is not precisely known. Thick, gelatinous, exudates lying at base of brain is the pathological hallmark and is responsible for all its major complications. The basal exudate encases the structures of brainstem, vessels of circle of Willis and roots of cranial nerves. 14 In patients with tuberculous meningitis, many pathogenic factors/processes, as described below, have been implicated in the causation of visual abnormalities. The details have been summarized in Table-1.
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Strangulation of optic nerves by exudates Exudates are dominantly present in the suprasellar cistern, the interpeduncular fossa, and other parts of optochiasmatic region. Exudates entrap and strangulate the optic nerve and the optic chiasma.6,15 (Figure-1) (Figure-2)
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Optic neuritis and bacterial invasion Optic nerve damage can also occur because of mycobacterial invasion. 16 Optic nerve invasion of Mycobacterium tuberculosis occur either via hematogenous spread to the nerve or extension from the choroid plexus. The proximal portion of the optic nerve, at the root entry zone, is the most vulnerable. Mycobacterial invasion of optic nerve, clinically, presents as papillitis or retrobulbar optic neuritis. Compression over optic chiasma by dilated third ventricle Hydrocephalus is almost a universal feature of tuberculous meningitis. Obstruction to the flow of cerebrospinal fluid occurs in the posterior fossa; thick exudate blocks the openings of fourth ventricles or Sylvian aqueduct. In patients with obstructive hydrocephalus, enlarging third ventricle compresses the optic chiasma from above, leading to vision loss.17 (Figure-3) Raised intracranial pressure Increased intracranial pressure is also a consistent feature of severe tuberculous meningitis. Several factors, like cerebral edema, hydrocephalus, tuberculoma, and infarcts, are
ACCEPTED MANUSCRIPT 5 responsible for the rise in the intracranial pressure.18 Increased intracranial pressure leads to disturbances in the axoplasmic flow of the optic nerves resulting in papilledema and subsequently, optic neuropathy. Ischemic damage of visual pathways by endarteritis Infarction of the optic nerve trunk and chiasma because of tuberculous endarteritis of vasa nervosa, supplying blood to optic nerve trunk and chiasma, may produce ischemic damage to optic nerve and optic chiasma. 19, 20
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Drug induced Antituberculosis drug-induced vision impairment manifests as a decrease in visual acuity, scotomas, and abnormalities of color vision. Antituberculosis drugs, particularly, ethambutol, isoniazid, streptomycin, linezolid and fluoroquinolones affect vision.21 Ethambutol causes optic neuropathy in approximately up to 5% of patients. The visual symptoms usually start 2– 8 months after ethambutol is started.22 Isoniazid can also produce optic neuritis. 23 There may be complete restoration of vision following withdrawal of isoniazid.24
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Linezolid and fluoroquinolones are the drugs that are now increasingly being used in the treatment of tuberculous meningitis. These drugs have also been reported to produce optic neuropathy and retinopathy. The possible mechanism of linezolid-associated optic nerve toxicity is abnormalities of mitochondrial protein synthesis. 25- 29
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A higher incidence of vision loss, in the intensified-treatment trial using levofloxacin, was noted. In this trial, authors compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day and levofloxacin for the first 8 weeks. Vision loss was higher (3.4% versus 1%; 95% CI 0.22-4.94; p = 0.02) in patients receiving intensified regimen. Even though the observation in terms of p-value was significant, the lower bound of 95% CI does suggest that the contributory effect of either levofloxacin or a higher dose of rifampin to vision loss must be interpreted with caution. 30
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Shunt failure Shunt failure in tuberculous meningitis can be associated with vision loss. Shunt malfunction results in increase in intracranial pressure, papilledema and subsequently optic atrophy. The vision loss, usually, develops gradually but may be abrupt. An ischemic lesion in the pregeniculate anterior visual pathway and infarcts of the occipital lobes are possible reasons for cortical vision loss. 31 Paradoxically, excessive drainage of cerebrospinal fluid, through shunt, can result in low intracranial pressures and may manifest with rapid vision loss. Prolapse of the optic chiasma into an empty sella has been proposed as mechanism responsible for vision loss. Other shunt-related complications (like malpositioning, hemorrhage, subdural hematoma, and ventriculitis) contribute to vision loss, possibly by increasing intracranial tension. 17 Immune reconstitution inflammatory syndrome There are few isolated instances when optic nerves were paradoxically affected in the process of immune reconstitution inflammatory syndrome in human immunodeficiency virus-infected patients of tuberculous meningitis. In one such patient, following antiretroviral therapy multiple tuberculomas appeared in the optochiasmatic region. 32 In other patient, bilateral optic disc swelling with choroiditis, retinitis, and optic neuritis led to a profound vision loss.33
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Optic nerve tuberculoma Intrinsic optic nerve tuberculomas has rarely been reported in tuberculous meningitis. In patients with miliary tuberculosis, tuberculous seedling in optic nerve trunk is likely to occur during hematogenous spread. 34, 35
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Structures of visual pathways involved in tuberculous meningitis Every structure of visual pathway is likely to be affected in tuberculous meningitis. Optic nerve and optic chiasm are most frequently and dominantly affected.
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Ocular Infrequently, intraocular tuberculosis, resulting in vision loss, is seen in patients with tuberculous meningitis. Intraocular tuberculosis is a form of tuberculosis presenting as uveitis. Both choroid and retina are highly vascular structures and are likely to be involved in the process of dissemination of tuberculous infection. Posterior uveitis is the most common presentation of intraocular tuberculosis. 36-38 The choroid lesions usually manifest as choroiditis (focal, multifocal or serpiginous), solitary or multiple choroidal tubercles, and choroidal tuberculoma. Tuberculous retinal involvement manifests as subretinal abscess, retinal vasculitis, subretinal neovascularization, and, rarely, retinal detachments (serous fluid collects between the retina and choroid). Retinal vasculitis may lead to proliferative vascular retinopathy with recurrent vitreous hemorrhage and neovascular glaucoma. Rarely, severe ocular complications, like endophthalmitis and panophthalmitis are encountered. Orbital apex syndrome, manifesting with the oculomotor nerve, trochlear nerve, abducens nerve, and ophthalmic branch of the trigeminal nerve involvement in association with optic nerve dysfunction, is infrequently caused by tuberculosis. 39, 40 Cases of optic nerve head tuberculoma, presenting as optic neuropathy with severe vision loss, has been described. Optic nerve head tuberculoma is seen in patients with miliary tuberculosis.41
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Choroidal tubercles are the most common form of ocular tuberculosis and are considered pathognomonic for miliary tuberculosis. Choroidal tubercles can be seen in tuberculous meningitis, particularly when tuberculous meningitis is part of miliary tuberculosis. Choroidal tubercles are unilateral or bilateral, gray–white or yellowish lesions and are usually less than one quarter of the size of the optic disc. These tubercles are commonly located within 2 disc-diameters from the optic nerve head and can produce an overlying exudative retinal detachment. 42 (Figure-4) Optic nerve and optic chiasma Optic nerve disorders that have been reported in tuberculous meningitis include papillitis, optic nerve tuberculoma, compressive optic neuropathy, retrobulbar neuritis, optic neuritis and anterior ischemic optic neuropathy. Direct involvement of the optic nerve by a tuberculous infection and/or indirect involvement by an inflammatory, degenerative, or vascular process is considered responsible for nerve dysfunction in a patient with tuberculous meningitis.16 Exudates, if dominantly present in the interpeduncular, suprasellar and Sylvian cisterns, result in optochiasmatic arachnoiditis and tuberculoma. The optic nerve and optic chiasma often get immersed in pool of thick exudate lying over basal brain region. Optochiasmatic arachnoiditis is invariably associated with vision loss. 43, 44 (Figure-1; Figure-2)
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Optic radiation and visual cortex Optic radiation and visual cortex are rarely involved in tuberculous meningitis. These patients present with cortical blindness. Cortical blindness is characterized with vision loss with sparing of pupillary responses. Basilar artery involvement, enlarging hydrocephalus, shunt failure and occipital lobe tuberculoma are potential causes of cortical vision loss. (Figure-5)
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Paradoxical vision loss There are many instances when blindness in tuberculous meningitis develops paradoxically while patient is being treated with antituberculosis drugs. 45-49 Sinha and co-workers reported a series of 8 such cases who developed paradoxical vision loss caused by paradoxically developed optochiasmatic tuberculoma. 47 In a large prospective follow up study, Singh and co-workers noted paradoxical optochiasmatic arachnoiditis in 12 (out of 141) patients within 6 months of starting treatment and all with profound vision loss.49 In some patients of paradoxical optochiasmatic tuberculoma, vision improves with high doses of corticosteroids and thalidomide.
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Neuroimaging Basal exudates, hydrocephalus, periventricular infarcts and tuberculoma are cardinal neuroimaging features of tuberculous meningitis. In optochiasmatic arachnoiditis neuroimaging reveals thick, meningeal enhancement. Hydrocephalus is another frequent neuroimaging abnormality. Hydrocephalus, in tuberculous meningitis, is either communicating or the obstructive variety. In communicating hydrocephalus fourth ventricle is dilated. In obstructive type of hydrocephalus, the fourth ventricle is either chinked or unaffected. If optic nerve is inflamed, because of mycobacterial invasion, neuroimaging may show thickening and enhancement of the optic nerve. 50, 51 (Figure-1 to Figure-5) Optic nerve tuberculoma, on neuroimaging, manifests with optic nerve swelling and an intrinsic ring-enhancing lesion inside the nerve. 34, 35
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Magnetization transfer magnetic resonance imaging is a useful technique that helps in differentiating tuberculous meningitis from causes of infective meningitis. Inflamed meninges in tuberculous meningitis show significantly different magnetization transfer ratios than those of inflamed meninges in meningitis of nontuberculous origin. Pre-contrast T1weighted magnetization transfer images have been shown to be 96% sensitive and 100% specific in demonstrating abnormal meninges in patients with tuberculous meningitis. 52 Magnetic resonance spectroscopy is another technique that helps in differentiating tuberculous and non-tuberculous cerebral mass lesions. In magnetic resonance spectroscopic evaluation tuberculous lesions demonstrate a characteristic lipid peaks. Lipids are integral component of mycobacterial cell wall and disintegration of mycobacterial cell wall and its lipid content within the tuberculoma is considered reasons for the marked elevation of lipid peaks.53 Differential diagnosis Tuberculous meningitis is diagnosed on the basis of characteristic clinical, cerebrospinal fluid and neuroimaging features. Demonstration of acid-fast bacillus in cerebrospinal fluid smear, a positive cerebrospinal fluid culture and positive polymerase chain reaction for Mycobacterium tuberculosis are considered diagnostic for tuberculous meningitis.
ACCEPTED MANUSCRIPT 8 An infectious, carcinomatous or immune disorders of meningitis, with a high propensity to optic pathways, can pose diagnostic challenge. The differential diagnosis need be continually reviewed if the patient is not responding to presumptive antituberculosis therapy. The likely cause may vary according to the age and immune status of the patient. For example, in the immunocompromised host, there is an increased risk of fungal infection and neurosyphilis.
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Cryptococcal meningitis Vision loss is a very frequent complication in cryptococcal meningitis. Vision loss is thought to be caused by raised intracranial pressure, direct fungal invasion leading to necrotizing optic neuropathy, or adhesive arachnoiditis. Demonstration of Cryptococcus neoformans in the cerebrospinal fluid is the gold standard for the diagnosis. India ink stains will disclose cryptococci in 50% of human immunodeficiency virus- uninfected patients and in as many as 80% of human immunodeficiency virus -infected patients. Cryptococcal antigen titers in serum are usually elevated in patients with cryptococcal meningitis. 54, 55
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Carcinomatous meningitis Carcinomatous meningitis is dissemination of malignant cells in the leptomeninges. Optic nerve involvement is a frequent and early clinical manifestation of carcinomatous meningitis. Carcinomatous infiltration of the leptomeningeal space should be considered in cases of bilateral simultaneous vision loss with other signs suggestive of leptomeningeal infiltration of the optic nerve sheath.56 Carcinomatous meningitis is seen in patients with solid tumors, lymphomas and leukemia.54 Adenocarcinoma is the most frequent histopathology in patients with carcinomatous meningitis and breast, lung, and melanoma are the most common primary sites. Neuroimaging, cerebrospinal fluid examination for malignant cells, meningeal biopsy, and tissue biopsy help in establishing the diagnosis. 57-59
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Pneumococcal meningitis Visual impairment in pneumococcal meningitis can also be caused by cerebral infarction and cavernous sinus thrombosis. A meta-analysis of 63 studies, involving 3408 pneumococcal meningitis survivors, reported long-term sequelae in 31.7% of patients. The prevalence of visual impairment was 2.4%.60 The diagnosis of pneumococcal meningitis is ascertained on the basis of characteristic manifestation of acute meningitis and demonstration of pneumococci in the cerebrospinal fluid by culture, Gram stain, or latex particle agglutination and/or blood cultures.
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Pituitary apoplexy Pituitary apoplexy is a rare but potentially life-threatening event. In pituitary apoplexy, patients present with sudden onset of headache, vision loss, ophthalmoplegia and coma. Apoplexy commonly occurs in patients with a pre-existing pituitary adenoma. The majority of the patients will have deficiency of one or more anterior pituitary hormones at presentation. Neuroimaging reveals haemorrhage within the pituitary gland and compression of the optic chiasma.61 Neurosyphilis Approximately, 5% of patients with neurosyphilis develop meningitis. Vision loss in neurosyphilis may be caused by chorio-retinitis, retinitis, optic neuropathy, optic chiasmal, or optic tract involvement. In optic neuritis, the optic-nerve sheath is invaded by the spirochete. Optic neuritis often leads to irreversible optic atrophy. The diagnosis of neurosyphilis depends on a positive cerebrospinal fluid test Venereal Disease Research Laboratory (VDRL) test.62, 63
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Neurobrucellosis A few cases of neurobrucellosis have been reported with symptoms and sign of optic neuritis along with meningoencephalitis. Vision loss in neurobrucellosis may also be because of the inflammatory involvement of the optic chiasma. The diagnosis of neurobrucellosis is confirmed either by isolation of Brucella species and/or presence of anti-Brucella antibodies in the cerebrospinal fluid.64
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Sarcoidosis Facial nerve followed by optic nerve are most commonly involved in sarcoidosis. The optic nerve involvement may be seen in up to 38% of patients of neurosarcoidosis. Sarcoidosis also involves the hypothalamus, infundibulum and optic chiasma. 65 The diagnosis is confirmed if histologically non-caseating granulomas is demonstrated in a biopsied specimen.66
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Idiopathic hypertrophic pachymeningitis Idiopathic hypertrophic pachymeningitis is usually presents with severe headache and progressive neurologic deterioration and vision loss. Hypertrophic pachymeningitis causes a localized or diffuse thickening of the dura mater. Idiopathic hypertrophic pachymeningitis is suspected on neuroimaging and is confirmed histopathologically.67
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Lyme disease Elevated intracranial pressure in acute disseminated Lyme disease can manifests as progressive loss of vision. Serological test as recommended by Centers for Disease Control and Prevention using an enzyme-linked immunosorbent assay initially, followed by the more specific Western blot is required.68
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Vogt-Koyanagi-Harada Syndrome Vogt-Koyanagi-Harada syndrome often presents meningoencephalitis, visual blurring, and deafness. Vogt-Koyanagi-Harada syndrome is often associated with neurologic and cutaneous manifestations, including headache, hearing loss, vitiligo and poliosis. Diagnosis is based on ophthalmological and other clinical findings. The characteristic eye signs are intensely pink optic nerves with severe visual loss. 69
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Systemic lupus erythematosus Systemic lupus erythematosus can present with meningoencephalitis and optic neuritis. It shares its clinical features with the pesudotumour cerebri syndrome. Optic neuropathy is estimated to occur in 1% of patients with systemic lupus erythematosus and in some cases, there is associated myelopathy. The diagnosis of systemic lupus erythematosus is established on the basis of a set of clinical and laboratory (American College of Rheumatology) criteria.70 Treatment There are limited options available for the treatment of vision loss in patients with tuberculous meningitis. The available options are antituberculosis treatment, immune modulator drugs and cerebrospinal fluid diversion surgery. The treatment of paradoxically developed vision loss is also far from satisfactory.
ACCEPTED MANUSCRIPT 10 Antituberculosis treatment Antituberculosis treatment is currently the best treatment option available to prevent and treat vision loss in tuberculous meningitis and it should be initiated as promptly as possible. World Health Organization recommends that antituberculosis treatment should initially be started with four drugs, that include isoniazid, rifampicin, pyrazinamide, streptomycin or ethambutol. After two months of intensive phase, in continuation phase, isoniazid and rifampicin are given for seven or ten months. All patients should receive adjunctive dexamethasone treatment initial few weeks. Antituberculosis treatment regimen for human immunodeficiency virus-infected patients of tuberculous meningitis is similar.71
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Intensified antituberculosis treatment regimens Recently, several intensified antituberculosis treatment regimens have been tested in tuberculous meningitis with the hope of achieving improved disability free survival. In first such randomised controlled study of intensified antituberculosis treatment regimen (with higher-dose rifampicin administered intravenously) was associated with a 30% better 6month survival.72 Later, it was demonstrated that a strong concentration-effect relationship with higher rifampicin administration led to this better survival.73 However, a recently tested intensified antituberculosis treatment regimen, with intravenous rifampicin and levofloxacin, did not demonstrate survival benefits, instead a significantly higher proportion of patients on intensified regimen had vision abnormalities.30 Minimum rifampicin target values, that were derived from exposure-response curves with intravenous rifampicin, is achieved only 38% of patients, so, it was argued that that even higher intravenous dosages should be used. Whenever an intensified antituberculosis regimen is used, a close watch on the possibility of enhanced vision loss is warranted. 74
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Immune-modulator drugs Immune-modulator drugs help in reducing the detrimental inflammatory changes. Thalidomide (a potent tumor necrosis factor-α inhibitor) is one such immune-modulator drug that shown significant clinical benefit in children presenting with paradoxical vision loss.75 A randomised controlled trial of thalidomide in children with tuberculous meningitis had to be stopped prematurely because of significant adverse effects in the treatment arm.76
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Neurosurgery Cerebrospinal fluid diversion procedures Two important cerebrospinal fluid diversion procedures, ventriculo-peritoneal shunt and endoscopic third-ventriculostomy are frequently used in tuberculous meningitis. Mostly medically non-responding patients are subjected to cerebrospinal fluid diversion procedures. The exact benefit from cerebrospinal fluid diversion procedures is controversial and deterioration usually occur after the initial improvement. The effect of these surgeries on vision loss is also not clearly known.77, 78 Neurosurgical decompression of optic chiasma In patients with optochiasmatic arachnoiditis and vision loss neurosurgical decompression of optic chiasma, by excising exudates and breaking adhesions, were performed in past. This type of neurosurgery is no longer performed.79 Prognosis Profound vision loss is a frequent and permanent disability among significant number of survivors. For example, in a prospective study, among 88 survivors at 6 months (out of 101), 11 patients had markedly low vision and 9 patients had complete blindness. Presence of
ACCEPTED MANUSCRIPT 11 papilledema (95% CI=1.12-2.29, p = 0.012), vision acuity ≤ 6/18 (95% CI=2.27-11.12, p = 0.001), multiple cranial nerve palsies (95% CI=1.20-1.99, p = 0.001), advanced stage of the disease (95% CI=1.29-1.78, p = 0.020), markedly high cerebrospinal fluid protein (95% CI=1.04-2.01, p = 0.007) and optochiasmatic arachnoiditis (95% CI=1.20-3.35, p = 0.001) were found to predict vision loss.80 Another study noted that among 65 patients of tuberculous meningitis, 78.5% survivors neurological sequelae at one year. Optic atrophy was noted in 37% of survivors. Majority of patients (22/24) with optic atrophy had papilledema on initial evaluation. 81
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Future prospects It is interesting to note that only a small proportion survivors of tuberculous meningitis had permanent and disabling vision loss. Early identification of patients, who are likely to have vision loss either with a biochemical parameter or by advanced neuroimaging technique, will help in effectively dealing with this devastating complication. Recently, significant progress has been made in the development of new diagnostic tools for rapid detection of tuberculosis. With wider availability of the Xpert MTB/RIF assay, which enables simultaneous detection of Mycobacterium tuberculosis and detection of rifampicin resistance, a timely confirmation of diagnosis of tuberculous meningitis is possible. With advanced neuroimaging techniques, which are now readily available in developing countries, many devastating complications, like optochiasmatic arachnoiditis, will increasingly be recognized. Currently available antituberculosis treatment is far from satisfactory. More effective antituberculous drugs are urgently needed. Role of newer antituberculosis drugs (bedaquiline and delamanid) need to be tested in tuberculous meningitis. Corticosteroids are the most frequently used adjunct treatment. Corticosteroids improve survival but often fail in preventing many of its complication, including paradoxical vision loss. Other adjunct immunotherapies like newer tumor necrosis factor-alpha antagonists (etanercept, infliximab, adalimumab, certolizumab and golimumab) and immunosuppressive agents need to be tried. Most importantly, preventive measures are needed to fight against tuberculosis at global level. The fight against tuberculosis will help in reducing incidence of tuberculous meningitis and its complications.
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Conclusions Vision loss in tuberculous meningitis is a disabling complication and often persist permanently as sequelae. Frequently, vision loss can paradoxically develop. Not much emphasis was given on this issue as most of the patients are often seriously ill and vision loss goes unnoticed. Frequently, patients survive with significant visual morbidity. Early recognition and prompt treatment are probably the only available solutions to this problem.
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Conflict of interest On behalf of all authors, the corresponding author states that there is no conflict of interest.
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ACCEPTED MANUSCRIPT 19 Legends Figure-1 Contrast-enhanced axial magnetic resonance imaging shows optochiasmatic arachnoiditis. Figure-2 Gadolinium contrast-enhanced sagittal MRI magnetic resonance imaging shows optochiasmatic arachnoiditis. Basal meninges are marked inflamed.
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Figure-3 Computed tomography of the brain shows dilated ventricles.
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Figure-4 A large choroidal tubercle in patient with miliary tuberculosis with tuberculous meningitis
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Figure-5 A patient with tuberculous meningitis, who paradoxically developed occipital tuberculomas and presented with cortical blindness.
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Figure 4
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AC
CE
PT E
D
MA
NU
SC
RI
PT
24
Figure 5
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Table-1: The causes of vision loss in tuberculous meningitis. The table shows anatomical structure responsible for vision loss and the corresponding etiology. Corresponding etiopathogenesis
Frequency of involvement
Tuberculoma Retinal vasculitis Retinal detachments** Antituberculosis drugs-induced retinopathy (ethambutol, linezolid, and fluoroquinolones)
Infrequent
Optic nerve and/ or Optic chiasma
Direct invasion by mycobacteria (papillitis or retrobulbar neuritis)
RI
PT
Structures involved Choroid and retina
SC
Common
NU
Vascular (endarteritis of the chiasma or anterior ischemic optic neuropathy)
MA
Compression (optic nerve or optochiasmatic tuberculomas, chiasmal compression form dilated third ventricle)
D
Raised ICP (secondary optic atrophy)
PT E
Immune mediated (IRIS)
CE
Treatment related - drugs (ethambutol, isoniazid, linezolid, streptomycin, fluoroquinolones)
AC
Shunt failure (raised ICP and chiasmal prolapse due to overdrainage)
Optic radiations and visual cortex
Tuberculoma Infarcts secondary to large vessel involvement
**serous fluid between retina and choroid
Rare
ACCEPTED MANUSCRIPT 26 Highlights 1. Vision loss is a disabling complication of tuberculous meningitis. 2. Any structure of visual pathway is affected but optic nerve and optic chiasma are frequently involved. 3. Thick exudates, lying at base of brain, the pathological hallmark, is responsible for vision loss.
PT
4. Nerve entrapment, hydrocephalus, raised ICP, endarteritis, shunt failure, bacterial invasion of nerves and drug toxicity are responsible.
AC
CE
PT E
D
MA
NU
SC
RI
5. Antituberculosis treatment is the best treatment option available to prevent and treat vision loss.