The Neuro-Ophthalmology of Tuberculosis

ABSTRACT

Tuberculosis (TB) is a global health concern and central nervous system (CNS) TB leads to high mortality and morbidity. CNS TB can manifest as tubercular meningitis, tuberculoma, myelitis, and arachnoiditis. Neuro-ophthalmological involvement by TB can lead to permanent blindness, ocular nerve palsies and gaze restriction. Visual impairment is a dreaded complication of tubercular meningitis (TBM), which can result from visual pathway involvement at different levels with varying pathogenesis. Efferent pathway involvement includes cranial nerve palsies and disorders of gaze. The purpose of this review is to outline the various neuro-ophthalmological manifestations of TB along with a description of their unique pathogenesis and management. Optochiasmatic arachnoiditis and tuberculomas are the most common causes of vision loss followed by chronic papilloedema. Abducens nerve palsy is the most commonly seen ocular nerve palsy in TBM. Gaze palsies with deficits in saccades and pursuits can occur due to brainstem tuberculomas. Corticosteroids are the cornerstone in the management of paradoxical reactions, but other immunomodulators such as thalidomide and infliximab are being explored. Toxic optic neuropathy caused by ethambutol necessitates careful monitoring and immediate drug discontinuation. Cerebrospinal fluid diversion through ventriculo-peritoneal shunting may be required in patients with hydrocephalus in stage I and II of TBM to prevent visual impairment. Early diagnosis and prompt management are crucial to prevent permanent disability. Prevention strategies, public health initiatives, regular follow-up and timely intervention are essential in reducing the burden of CNS TB and its neuro-ophthalmological complications.

Introduction

Tuberculosis (TB) can involve any organ of the body, amongst which central nervous system (CNS) involvement has the highest mortality and morbidity.¹ The prevalence of CNS TB in general population globally is 2 cases per 100,000 inhabitants.¹ The most recent systematic review reported mortality of up to 40% in hospitalised patients with tubercular meningitis (TBM).¹ CNS TB can manifest as TBM, tuberculoma, myelitis, radiculomyelitis, spinal arachnoiditis and spondylodiscitis.^2,3

Neuro-ophthalmological involvement by TB can occur due to primary infection by Mycobacterium tuberculosis (MTB) or through formation of immune complexes resulting in tuberculomas or due to paradoxical reactions.⁴ It can involve afferent and/or efferent pathways of the visual system. This article will focus on clinical presentation, approach to the diagnosis and management of neuro-ophthalmological complication of CNS TB with respect to the afferent and efferent pathways followed by the investigations which help in establishing the diagnosis and the respective management. As the review is focused on the pathways involved in neuro-ophthalmological manifestation of CNS TB, we have restricted our discussion and have not involved the orbital manifestations of TB or the effects on the eye. Anatomically, neuro-ophthalmological connections can be divided into afferent and efferent pathways. The afferent pathways comprise the optic nerves arising from the retina, optic chiasm, optic tracts, optic radiations and occipital cortex. The efferent pathways include the ocular motor nuclei and their respective cranial nerves.

Search strategy

Two authors (RS and KVM) searched the available literature suitable for further review by going through the titles and abstracts using platforms namely PubMed, Scopus, Medline and Embase. Only English publications were used. Keywords used were “CNS TB”, “TBM”, “TB”, “Neuro-ophthalmological complications”, “vision loss”, “TB optic neuropathy”, “TB optic perineuritis”, “tuberculoma”, “ethambutol induced optic neuropathy”, “toxic optic neuropathy”, “optochiasmatic arachnoiditis”, “ocular palsy”, “vision loss”, “diplopia”. The current study involves review of literature along with authors personal experience in this field. It does not involve human participants or laboratory animals. Written informed consent were taken from all the patients or their relatives whose information and pictures have been included in this review.

Afferent pathway

CNS TB can cause the involvement of afferent visual pathway anywhere from “the cornea to the cortex” i.e., choroid, retina, optic nerves, chiasm, optic tracts, optic radiations and occipital cortex. Visual impairment is considered to be the one of the most devastating complication of TBM. Vision loss can occur at any level of the visual pathway due to varied pathogenesis. It is of foremost importance to delineate the exact cause for the visual impairment to tailor the management of the symptoms and prognosticate the patient. Table 1 illustrates the various anatomical areas involved in vision loss along with the pathogenesis involved.

Table 1.

Localisation of vision impairment (afferent pathway) in central nervous system tuberculosis.

Structure involved	Pathology leading to visual impairment	Clues to diagnosis
Ocular layers (uvea, retinal)	Anterior, intermediate, posterior and pan-uveitis	Unilateral involvement Pupillary sparing Associated ocular pain ± redness ± tearing Imaging negative Careful slit lamp/indirect ophthalmoscopy is needed
	Choroid tubercles
	Neuroretinitis
	Retinal tubercles (rare)
Optic nerve, chiasm	Tuberculoma/abscess compressing nerve/chiasm Chiasmal infarction (endarteritis)	Unilateral/bilateral (depends on the location), RAPD ± rapid onset, painless, optic disc pallor
	Optochiasmatic arachnoiditis	Bilateral, rapid, painless, sluggish pupils/RAPD, optic disc pallor.
	Chronic papilloedema	Subacute to chronic, pupils initially normal, but reaction diminishes in later stages; later develops into optic atrophy
	Papillitis	Can be unilateral, optic disc oedema, RAPD Acute, painless, often bilateral, with pupillary involvement, fundus is normal initially, optic atrophy in later stages
	Tubercular optic neuritis/perineuritis	Pupillary involvement, optic disc changes develop later due to Wallerian degeneration
	Toxic optic neuropathy	Sub-acute to chronic, painless, bilateral, temporal course with ATT, pupillary involvement, optic disc pallor
Optic tracts and radiation	Vasculitic infarcts Tuberculomas	Hemianopic visual field defects Normal pupillary reflexes and fundus examination with optic radiation lesions
Occipital cortex	Vasculitic infarcts Tuberculomas	Hemianopic field defects Normal pupillary reflexes and fundus examination

RAPD = relative afferent pupillary defect; ATT = antitubercular treatment.

The prevalence of visual impairment in CNS TB is variable in the literature. Modi et al. reported visual impairment in 8.6% of patients only,⁵ while Sinha et al. reported visual impairment in 27% of patients, amongst which the most common cause was optochiasmatic arachnoiditis (OCA) (41%), followed by optochiasmatic tuberculomas (22%).⁶ Patients with TBM are prone to suffer vision loss because of various factors including: coexisting nutritional deficiencies (because of significant anorexia, nausea, vomiting, and altered sensorium); hydrocephalus (HCP) (leading to intermittent ischaemia of the axons of optic nerves); use of fixed combinations of antitubercular drugs (neurotoxic effects); and paradoxical reactions (delayed hypersensitivity to tubercular antigens), which are quite common in CNS TB leading to OCA. We will discuss each and every level of involvement along with the pathogenesis involved.

Optic disc and choroid

Papilloedema

HCP is the most common complication seen in TBM and has been reported to occur in 40–87% of patients.^5,7 HCP can be either non-communicating or communicating, based on whether there is blockade in cerebrospinal fluid (CSF) pathway circulation or impairment of absorption of CSF, respectively. HCP can lead to the development of papilloedema due to stasis of axoplasmic flow at the optic nerve head caused by raised intracranial pressure.⁸ Despite a high incidence of HCP in TBM, papilloedema is not the commonest cause of vision loss. This is because HCP is usually communicating and thus higher grades of papilloedema rarely happen with acute disease. It is to be noted here that patients with new onset papilloedema must immediately have neuro-imaging to rule out non-communicating HCP. Asymptomatic papilloedema is reported in a significant number of patients with TBM (27–30%).^5,6 Occasionally, papilloedema can be the presenting feature in TBM and can be easily misdiagnosed as idiopathic intracranial hypertension, especially when the patient lacks systemic symptoms of TB, such as fever, anorexia or loss of weight.⁹ TBM must be ruled out in all patients with papilloedema in the countries where the incidence of TB is high, even in the absence of meningeal signs and systemic symptoms. Chronic papilloedema due to persistently raised intracranial pressure can lead to permanent damage to the optic nerves leading to slowly progressive vision loss and optic atrophy. Visual impairment due to chronic papilloedema is mostly bilateral and progressive. It can be associated with headaches, vomiting, and transient visual obscurations based on the severity of rise in intracranial pressure and the rapidity of progression. Immediate measures must be initiated once HCP presents with papilloedema and visual impairment to save vision as it has been reported as one of the poor prognostic markers in TBM.¹⁰ Treatment of the primary disease with anti-tubercular treatment (ATT) is the mainstay of treatment along with corticosteroids, which must be initiated at the earliest opportunity. The decision for neurosurgical intervention in the form of a CSF diversion procedure should be done on the basis of severity and type of HCP. Not all patients with HCP improve with CSF diversion and the prognosis is significantly affected by the stage of disease, focal neurological deficits, the presence of infarcts, and the time of initiation of ATT.¹⁰

Chorioretinitis and choroid/retinal tubercles

Ocular TB can occur due to direct involvement through MTB or due to hypersensitivity reactions. Posterior uveitis (choroiditis) is the most commonly described form of ocular TB.¹¹ Other involvement described include choroid/retinal tubercles (Figure 1), tuberculoma, tubercular retinal vasculitis, panuveitis, anterior uveitis and intermediate uveitis.¹¹ The diagnosis as well as the treatment of ocular TB is challenging and no guidelines have been developed yet. However, if a patient with TBM develops vision loss, one must rule out the ocular TB to establish the localisation, especially if imaging of the brain does not show any abnormality affecting the visual pathways and the pupillary reactions are normal. A detailed description of primary ophthalmic manifestations of TB is beyond the scope of this review.

Figure 1.

A 28-year-female presented with a 1 month history of fever, headache and three episodes of seizures followed by new onset binocular diplopia on left gaze, painless, bilateral diminution of vision, dysphagia for 5–7 days and drowsiness for 1 day. She was started on with anti-tubercular treatment (rifampicin, isoniazid, pyrazinamide and streptomycin) with intravenous corticosteroids and referred to our centre. Her drowsiness and headache improved. Examination revealed signs of meningeal irritation, a best corrected visual acuity of 6/60 in each eye, a sluggish light reflex on the left, temporal optic disc pallor bilaterally, bilateral lateral rectus palsies (left >> right) (a), and bilateral IX, X, and left XII cranial nerve palsies. On the basis of the history, chronic meningitis was suspected with multiple cranial nerve palsies. Imaging was expected to show involvement of the optic nerves/chiasm with involvement of other cranial nerves. However, gadolinium-enhanced magnetic resonance imaging of her brain showed only minimal hydrocephalus with minimal leptomeningeal enhancement but no exudates and no optochiasmatic arachnoiditis/tuberculoma (b: T2 axial image, c: T1-weighted contrast axial image). What is the cause of visual impairment? The imaging does not explain the severity of the vision loss. Hence, slit lamp examination of the fundus was performed which revealed multiple retinal tubercles (black arrow heads) with a tubercle just over the left macula (d, blue arrow), and swelling of the right macula (e, red arrow), explaining the cause of the visual impairment.

Optic nerves and chiasm

Tubercular optic neuritis

Primary involvement of the optic nerves by MTB leading to optic neuritis has been very rarely reported.¹² It can involve any segment of the nerve, however retrobulbar neuritis is the most common involvement, followed by perineuritis (Figure 2). Both of them are difficult to distinguish clinically as both present with unilateral or bilateral vision loss, with pain on eye movements. Fundoscopic examination in retrobulbar neuritis is normal during the initial course of symptoms, but all patients subsequently develop optic atrophy. However, fundoscopic examination in optic perineuritis usually shows swollen optic discs. Vision loss is central in optic neuritis with profound impairment of colour vision, whereas paracentral loss with sparing of central vision and colour vision is seen in perineuritis. Magnetic resonance imaging (MRI) in tubercular optic neuritis is not always abnormal in the acute stages but must be focused on the optic nerves and chiasm to detect subtle enhancement of these structures.^13,14 One has to order specific sequences to pick up these subtle changes. Fat-suppressed plain and contrast-enhanced T1-weighed imaging in both the axial and coronal planes must be performed.¹⁵ Follow-up imaging generally shows thinning of the optic nerves with prominent optic nerve sheaths. Optic perineuritis, on the other hand, shows typical MRI features with a “tram track appearance” of the optic nerves in axial sections due to contrast enhancement of the optic sheaths.¹⁶ In coronal sections, the margins, i.e. the optic nerve sheaths, enhance, which has been described as “doughnut-like”.¹⁶ These findings can be associated with streaky enhancement of the orbital fat, which is more commonly seen with non-infectious inflammatory pathologies.¹⁶

Figure 2.

A 15-year-female presented with a 15-day history of holocranial headache followed by fever, severe neck pain, neck stiffness and altered sensorium. Examination revealed signs of meningeal irritation, bilateral lateral rectus restriction, bilateral sluggishly reacting pupils, with a normal fundoscopic examination. Cerebrospinal fluid (CSF) analysis showed an opening pressure of 12 cmCSF, 139 cells/mm³ (10% neutrophils, 89% lymphocytes), a protein level of 73 mg%, a glucose level of 37 mg%, negative India ink stain and cryptococcal antigen, and a positive Genxpert Ultra test for Mycobacterium tuberculosis that was rifampicin sensitive. She was started on antitubercular treatment (rifampicin, isoniazid, pyrazinamide and streptomycin) with intravenous corticosteroids. When she regained consciousness she reported only light perception in each eye. Gadolinium-enhanced magnetic resonance imaging of her brain did not show any optochiasmatic arachnoiditis or tuberculomas in the optic pathway. There was no enhancement of the orbital optic nerve (a), but there was minimal enhancement over the left pre-chiasmal optic nerve (b, yellow arrows on a T1-weighted contrast-enhanced image and c, T1-weighted contrast-enhanced coronal image). A diagnosis of tubercular optic neuritis was made and she was given intravenous methylprednisolone followed by oral corticosteroids. After 1 month all the associated symptoms improved significantly except there was no improvement in vision and both optic discs started showing temporal pallor (d, right and e, left). After 3 months’ follow up her vision remained at perception of light bilaterally.

Toxic optic neuropathy

Toxic optic neuropathy (TON) is a devastating complication, frequently seen in Neuro-infectious and Neuro-ophthalmology clinics. It has been reported most commonly due to ethambutol, followed by linezolid and isoniazid.^17,18 The incidence of ethambutol-related optic neuropathy (ETON) is <1% for a dose of <15 mg/kg, 3% for 20 mg/kg, 5–6% for 25 mg/kg and 18–33% for 35 mg/kg.¹⁹ Patients with TON present with subacute onset, progressive, bilateral, painless, usually symmetrical, diminution of vision with loss of colour vision (Figure 3). The loss of colour perception is one of the earliest symptoms¹⁸ and should be followed in all patients, especially those on ethambutol. Perimetric examination reveals central/centrocaecal scotomas. Fundoscopic examination might be normal in the initial stages, however optic disc pallor appears later on.^18,19 Optic disc changes sometimes revert back to normal if the drug is stopped before irreversible damage has occurred. The importance of fundoscopic examination is to rule out other causes of vision loss. Patients on ethambutol must be followed closely for objective evidence of visual impairment with the help of measurement of visual acuity, visual fields and colour vision at every visit. Newer testing modalities might help in the quantification of the optic nerve damage. Prolongation of the P100 of the visual evoked potential and thinning of the temporal retinal nerve fibre layer (RNFL) on optical coherence tomography (OCT) can help in early detection of damage,²⁰ however, these do not always correlate with TON. Ethambutol must be immediately stopped if there are any signs of drug toxicity. Primary physicians and infectious disease specialists treating TB in community health centres must be aware of the appropriate dose of ethambutol to give along with the associated risk of vision loss, especially in elderly patients, diabetic patients and patients with renal dysfunction.

Figure 3.

A 60-year-old diabetic male presented with a 2-month history of progressive, bilateral, painless diminution of vision associated with loss of colour perception as well as colour desaturation. He had been started on antitubercular treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol) for pulmonary tuberculosis 6 months previously. He was taking ethambutol at a dose of 1375 mg/day (21.1 mg/kg/day). On examination he could only count fingers at 1 m with each eye and had sluggish pupillary reactions. Fundal examination revealed bilateral optic atrophy (a, right and b, left). Perimetry showed severe diffuse loss of visual fields (c, right and d, left). Magnetic resonance imaging of his brain showed hyperintense signal in both optic nerves (e, T2-weighted axial image and f, T2-weighted coronal image) with minimal contrast enhancement in the optic chiasm (red arrow g, T1-weighted coronal contrast-enhanced image). A diagnosis of ethambutol-induced optic neuropathy was made and the drug was immediately discontinued. His vision showed no improvement but did not deteriorate further.

Although uncommon, linezolid and isoniazid can cause TON, which is usually similar to ETON.^21,22 Linezolid is mainly used for acute gram-positive infections and is currently being used in drug resistant TB. The drug is known to cause significant adverse effects including cytopaenias, peripheral neuropathy, gastro-intestinal disorders and optic neuropathy.²² Because linezolid is used for longer durations, it has a high tendency of causing adverse effects in patient with TBM. TON due to linezolid is usually seen after around 1–2 months of treatment and has been labelled as a major adverse effect. A recent systematic review and meta-analysis has reported TON due to linezolid in 13.2% of patients.²² One has to be cautious about these adverse effects and educate the patient and careers before starting the treatment.²³ Visual impairment has been found to be reversible to a significant extent if the drug is discontinued after early identification of symptoms, however the evidence is limited and the adequate dosage and duration of linezolid treatment in the treatment of TB is still being debated.^23,24 TON due to isoniazid alone has rarely been reported in the form of a few case reports only.²¹ The limited literature restricts our knowledge about the mechanism and pathogenesis involved in TON due to isoniazid, however it is a common practice to stop isoniazid if the vision loss keeps on progressing even after stopping ethambutol. Levofloxacin-induced optic neuropathy is controversial as we could found only one case in the literature describing vision loss associated with levofloxacin.²⁵ The vision loss was severe (1/60), sudden in onset, unilateral, and developed after a single dose of oral levofloxacin, and occurred along with systemic symptoms of dizziness and respiratory distress with no improvement on follow-up.²⁵

Optochiasmatic arachnoiditis and tuberculoma

Yuhl and Rand in 1951 described the first case of OCA due to TBM.²⁶ It was before the era of the use of corticosteroids in TBM. OCA is caused by inflammation of the arachnoid layer of the intracranial portion of the optic nerves and optic chiasm, which lie in the suprasellar cistern. The pathogenesis of TBM is characterised by the formation of thick gelatinous exudates at the base of brain and meningeal inflammation.²⁶ The exudates form a layer coating the cisternal surfaces of the brainstem and thus interfere with CSF flow, leading to HCP.²⁷ The presence of basal exudates at the ventral aspect of the brainstem leads to entrapment of the optic nerves and chiasm. Thick exudates also encase the major blood vessels passing through the base of brain, thereby the blood supply to the optic nerves and chiasm is also compromised. This is due to vasculitis of the vasa nervosum.²⁸ OCA and tuberculomas over the optic nerve or chiasm causes bilateral, painless, severe visual impairment (Figure 4). If not identified early it can lead to permanent damage to the axons leading to optic atrophy.²⁹ OCA and tuberculoma occur most often after the development of paradoxical reactions in TBM. OCA is the most common cause of vision loss in patient with TBM and has to be ruled out in all cases presenting with vision loss.³⁰ Paradoxical reactions in TBM are characterised by worsening of pre-existing exudates/tuberculomas or the appearance of new exudates/tuberculomas in patients who have shown initial improvement on ATT.²⁹ Paradoxical reactions usually appear during the initial few months (1–4 months) of treatment with ATT when corticosteroids are being tapered or stopped. It is a type of delayed hypersensitivity reaction to the tubercular antigens released from host immune cells leading to intense inflammation and formation of exudates and new tuberculomas.³⁰ Paradoxical reactions are often confused with drug resistant TB.²⁹ Approximately one-third of patients treated with ATT develop paradoxical reactions.²⁸ Brown et al. studied the predictors of paradoxical reactions and concluded that human immunodeficiency virus (HIV) positivity is the strongest predictor apart from culture positive TB. This is because of immune reconstitution seen in patients with HIV after starting ATT.³¹ Diabetes mellitus, on the other hand, reduces the odd of developing paradoxical reactions.³¹ Every patient must have close follow-up with imaging to identify paradoxical reactions at the earliest opportunity. Patient must be immediately evaluated with repeat imaging on the appearance of any new symptoms. It is crucial to do repeat imaging before stopping corticosteroids to look for resolution of exudates/tuberculomas. Escalation of immunosuppression is needed if worsening of vision loss continues despite corticosteroids.

Figure 4.

A 19-year-female was diagnosed with tubercular meningitis and started on antitubercular treatment (ATT) (rifampicin, isoniazid, pyrazinamide and streptomycin) with initial improvement in fever, headache and vomiting. After 2 months of ATT she presented with bilateral, painless, diminution of vision. Fundoscopic examination revealed bilateral optic disc pallor (a, left and b, right). In view of the length of treatment with initial improvement the possibility of optochiasmatic arachnoiditis was considered. Gadolinium-enhanced magnetic resonance imaging of her brain revealed extensive exudates lining the base of the brainstem (c, T1-weighted contrast-enhanced sagittal image), and entrapping the optochiasmatic region, peri-mesencephalic cisterns and bilateral middle cerebral arteries (d, T1-weighted contrast-enhanced axial image), confirming the clinical suspicion.

Chiasmal compression by a dilated third ventricle

Obstructive (non-communicating) HCP with a dilated third ventricle can bulge and compress over the optic chiasm causing bilateral visual field loss.³² This is a frequently overlooked complication as the other features of headaches, gait ataxia, bladder incontinence and alteration of consciousness are often more prominent in the presentation.

Prolapse of the optic chiasm

Rarely, intracranial hypotension due to over drainage from a ventriculoperitoneal (VP) shunt can cause the chiasm to prolapse into an empty sella turcica causing bilateral vision loss.³³

Vasculitic infarcts

Vasculitic infarcts occur due to the endarteritis of the vasa nervosa of the optic nerve and optic chiasm. These usually carry a poorer outcome compared to other compressive and inflammatory causes of vision loss in TBM.⁴

Posterior visual pathways (optic radiations and occipital cortex)

Tuberculomas

Tuberculomas can involve any area of the CNS.³⁴ However, direct involvement of the posterior visual pathway is very rare.³⁵ The symptoms are similar to any other types of pathological involvement of the anterior/posterior visual pathway, which is why diagnosis is usually made on the basis of radiology.³⁶ Contrast-enhanced MRI should be the imaging of choice along with susceptibility weighted imaging to look for calcification.³⁷ The involvement can be unilateral or bilateral. Sparing of the pupillary light reflex, hemianopic defects on perimetry and normal fundoscopic examination distinguishes vision loss due to posterior visual pathway involvement from that of involvement of the anterior visual pathway.³⁶ Visual hallucinations and palinopsia have been reported to occur due to strategic tuberculomas in the occipital lobes.^38,39

Vasculitic infarcts

Vasculitic infarcts involving the basilar artery supplying the posterior visual pathways can cause cortical blindness.⁴

Efferent pathway

The extraocular muscles responsible for movement of the eyes are innervated by the oculomotor (III), trochlear (IV) and abducens (VI) cranial nerves (CN). They arise from their respective nuclei in the brainstem, exit and travel through the subarachnoid space, enter the cavernous sinus and finally enter the orbit through the superior orbital fissure to supply the extraocular muscles.⁴⁰ TBM can affect efferent pathways anywhere in the course of the nerves from their origin until the orbit. Abnormalities in eye movements can also arise from the involvement of pathways for gaze, pursuits and saccades.

Gaze palsy

Gaze palsies can develop because of tuberculomas affecting the gaze centres in the brainstem Figure 5) or in the eye fields in the frontal lobe.^41,42 Patients can develop a conjugate horizontal gaze palsy due to involvement of the paramedian pontine reticular formation in the pons.^41,43 Figure 6 describes such a case with a very rare presentation in TBM. Although rare, internuclear ophthalmoplegia due to disruption of the medial longitudinal fasciculus can be seen due to tuberculomas in the brainstem.^44,45 Horner’s syndrome, pupillary abnormalities, and accommodation deficits are other types of abnormalities which can be occasionally seen.^4,46

Figure 5.

A 30-year-female was diagnosed as definite tubercular meningitis on the basis of the clinical picture, radiological appearance, cerebrospinal fluid analysis and being positive GenXpert Ultra positive for Mycobacterium tuberculosis. She was given antitubercular treatment (ATT) (rifampicin, isoniazid, pyrazinamide and streptomycin) along with dexamethasone. When corticosteroids were stopped after slow tapering at the third month of ATT, she developed sustained gaze towards the left side with an inability to look to the right side. Clinically, the lesion localised to either the left frontal eye field or the right paramedian pontine reticular formation. Gadolinium-enhanced magnetic resonance imaging (MRI) of her brain was repeated, which revealed a large tuberculoma over the right pons at the floor of fourth ventricle (yellow arrow in a, T1-weighted contrast-enhanced axial image and b, T1-weighted contrast-enhanced sagittal image) with multiple tuberculomas in both cerebral and cerebellar hemispheres. She was restarted on dexamethasone followed by the addition of thalidomide (as a steroid sparing agent), following which her symptoms improved completely over the next 10 days. A repeat MRI performed 3 months later revealed marked reduction in the number and size of the tuberculomas (c, T1-weighted contrast-enhanced axial image and d, T1-weighted contrast-enhanced sagittal image).

Figure 6.

A 23-year-female had been diagnosed with tubercular meningitis 7 months previously. She had a poor compliance with medication and presented with a 2 week history of recurrence of fever, continuous headache, and vomiting followed by altered sensorium for 1 day. On examination she was emaciated and stuporous with wincing to painful stimuli but no motor response. She had persistent downgaze (a) with intermittent downbeating nystagmus. Her pupils were not reactive to light and fundoscopic examination revealed bilateral optic disc pallor. Her knee and ankle jerks were absent. Anatomical localisation to the cervico-medullary junction (CVJ) was made in view of the downbeat nystagmus. Gadolinium-enhanced magnetic resonance imaging of her brain and whole spine revealed obstructive hydrocephalus, and extensive exudates around the base of brainstem as well as around the CVJ with myelitis (b, T2-weighted sagittal image of the CVJ and cervical spine; c, T1-weighted contrast-enhanced sagittal image of CVJ and cervical spine; d, T1-weighted contrast-enhanced axial image of the brain; and E, T1-weighted contrast-enhanced sagittal image of the brain). In addition, there was extensive spinal arachnoiditis until the cauda equina and distal nerve roots (f, T1-weighted contrast-enhanced sagittal image of the lower thoracic and lumbosacral spine). Cerebrospinal fluid analysis revealed 450 cells/mm³ (95% lymphocytes), a protein level of 622 mg%, and a glucose level of 14 mg%. The GenXpert Ultra test for Mycobacterium tuberculosis came positive (rifampicin sensitive). The cytology, cryptococcal antigen and India ink tests were negative. She was started on antitubercular treatment (rifampicin, isoniazid, pyrazinamide and streptomycin) along with intravenous dexamethasone and she underwent ventriculoperitoneal shunting. She became conscious and oriented immediately after the shunt procedure and continued to improve further.

Ocular motor cranial nerve palsies

Ocular motor CN palsies are among the most common neuro-ophthalmological symptoms seen in patients with TBM (Table 2). Among them, CN VI palsy is the most common leading to restriction of the lateral rectus muscle; often seen as a false localising sign because of raised intracranial pressure (ICP) in TBM. It is commonly noticed at the time of first presentation of the patient in the emergency services. The nerve commonly gets involved due to its long intracranial course and tethering at Dorello’s canal, which makes it prone to stretch injury by raised ICP.⁴⁷ This is why the involvement is commonly bilateral but asymmetrical.

Table 2.

Efferent ocular pathway involvement in central nervous system tuberculosis.

Structure involved	Mechanism	Clues to diagnosis
Ocular nerve palsies	Raised intracranial pressure – functional palsy of the nerve Basal exudates in the cisternal segment Brainstem tuberculoma involving nucleus/fascicle	Presence of papilloedema Involvement of other cranial nerves Hydrocephalus (ataxia, incontinence, altered sensorium)
Gaze palsy	Pontine/midbrain involvement	Associated bilateral ptosis (midbrain)
INO	Brainstem	Early HCP, long tract signs, associated lower cranial nerve palsies.
Multiple cranial nerve palsies	Basal exudates Brainstem nuclei	Brainstem involvement, associated spinal arachnoiditis (absent reflexes).

HCP = hydrocephalus; INO = internuclear ophthalmoplegia.

Ocular motor CN palsy can also result from direct involvement due to entrapment by exudates.⁴⁸ CN III palsy is more commonly involved through this mechanism in the interpeduncular fossa as the space is a common site for accumulation of exudates.⁴⁰ An incomplete CN III palsy with bilateral ptosis is more common, however complete CN III involvement is occasionally reported.⁴⁰ CN IV palsy is the least common in TBM, which might be due to masking of symptoms by concomitant CN III palsy as well as exit of the nerve through the dorsal surface of the brainstem. Fascicular/nuclear involvement in the brainstem is seen in tuberculomas of the brainstem,^49,50 which are commonly confused with neurocysticercosis (NCC). The absence of a scolex, disc-like enhancement, abscess formation, the presence of exudates and conglomeration are some hard points to differentiate tuberculomas from NCC.⁵¹

Management of neuro-ophthalmological complications of tuberculosis

Management of complications in TBM requires immediate intervention. Therefore, close follow-up of these patients is necessary in a dedicated Neuro-infectious Diseases clinic. Neuro-ophthalmological complications require multidisciplinary effort involving the neurologist, neurosurgeon, infectious disease specialist and ophthalmologist. The primary focus should be on the localisation and pathogenesis of complications, such as HCP, vasculitic infarcts and tuberculomas/exudates. Once localisation has been achieved and the pathology has been delineated, a patient-specific tailored plan should be made regarding the management of worsening symptoms as well as planning of follow-up in terms of clinical and radiological assessment. Timely diagnosis and management are the keys to reduce disability.

Diagnosis

History and examination

A detailed history is the first step in evaluating any patient with TBM and neuro-ophthalmological complications. The following points have to be noted to localise the lesion as well as for documentation for further follow-up.

• Unilateral/bilateral

• If bilateral, simultaneous/sequential

• Sudden, acute, or sub-acute?

• Painful/painless

• Dyschromatopsia or not

• Visual field defect

• Central/peripheral vision loss

• Associated with transient visual obscuration, pain on eye movements, diplopia, ptosis, or other cranial nerve palsy

• Temporal relation with the initiation of ATT

• Response to corticosteroids

• Static/progressive

Likewise, points in the examination that must be looked for are:

• Visual acuity and visual fields

• Pupils: any anisocoria or a relative afferent pupillary defect

• Fundoscopic examination: papillitis; papilloedema; retinitis; choroiditis; or tubercles

• Ocular motor nerve palsy, gaze palsy, concomitant long tract signs

Visual impairment due to involvement of the chiasm (OCA, optochiasmatic tuberculoma, chiasmal infarction, chiasmal compression) is usually bilateral, painless, acute to sub-acute and might lack early optic disc changes and can be only diagnosed on the basis of MRI. Optic disc atrophy will appear later on in all cases due to Wallerian degeneration. TON also involves both eyes with subtle/normal fundoscopic examination. Unilateral vision loss usually indicates pathology limited to the orbit i.e., involvement of choroid/retina or unilateral optic nerve involvement (optic nerve tuberculoma, tubercular optic neuritis/perineuritis). Diagnosis of all these pathologies of the optic nerve requires dedicated MRI. Tubercular optic neuritis/perineuritis is usually bilateral, can be sequential or simultaneous, and does not behave like typical demyelinating optic neuritis, i.e. has a bad prognosis and is poorly responsive to corticosteroids.¹³ Associated signs to be looked for in ocular motor CN palsy include bilateral ptosis and long tract signs in nuclear lesions. Visual field defects in both eyes indicate chiasmal/post-chiasmal affliction. Homonymous hemianopia is seen in post-chiasmal lesions.⁵²

Ancillary tests

Apart from a routine haematological work-up, one must rule out coexisting infection with HIV by an enzyme-linked immunosorbent assay. Liver function tests must be routinely followed on a weekly basis during the first month of initiation of ATT, then monthly. Drug-induced liver injury from ATT occurs most frequently during first 2 months of starting ATT. The Indian population has a higher risk of ATT-induced hepatitis, which has been proposed to be due to a high incidence of slow acetylator phenotype in this population.⁵³

CSF analysis

Diagnosing TBM poses a huge challenge due to paucibacillary disease and technical issues involved with lumbar punctures. Diagnosing tuberculoma is further difficult and often confused with NCC. Detailed CSF work up at the initiation of treatment for CNS TB is mandatory. It must include CSF opening pressure measurement along with other routine analysis. Xpert MTB/RIF Ultra has emerged as the most sensitive diagnostic test.⁵⁴ In 2017, the Technical Expert Group at the World Health Organisation (WHO) concluded that Xpert MTB/RIF Ultra is non-inferior to Xpert MTB/RIF for MTB detection and also for detecting rifampicin resistance.⁵⁵ Hence, WHO recommended the use of Xpert MTB/RIF Ultra as the initial diagnostic test in the CSF and in smear negative culture positive specimens, especially in the paediatric population.⁵⁵

Co-infections must be ruled out in all patients at the beginning of ATT and corticosteroids. The closest mimicker of TBM which is concomitantly reported to infect the CNS is cryptococcus. The management of TBM with cryptococcal meningitis is a huge challenge, especially if the patient develops visual impairment because of poor prognosis associated with co-infection.⁵⁶

Role of imaging

Computed tomography (CT) scanning and MRI are routinely performed in TBM for diagnosis and follow-up. CT scanning gives an idea about gross changes in the brain during clinical worsening, such as due to HCP, the appearance of new abscess/increase in size of tubercular abscess, mass effect, dense basal exudates, and infarction in case of fresh focal neurological deficits. However, CT scanning gives limited information about visual pathway involvement. Hence, gadolinium-enhanced MRI (Gd-MRI) must be included in the protocol of every TBM patient at baseline. The authors follow the protocol of doing Gd-MRI brain at baseline, 1 and 2 months after starting ATT, then every 3 months during treatment. The second and thirds MRIs are done because most of the paradoxical worsening that can start after the initial first month of ATT.

MRI findings of tuberculomas depend on the stage of the tuberculomas, whether they are non-caseating or caseating. Non-caseating tuberculomas are T1 hypodense, hyperintense on T2 as well as fluid attenuated inversion recovery images, and intensely enhancing on contrast enhanced T1-weighed images. However, caseating tuberculomas with solid centres are iso-hypodense in both T1 and T2, but have hyperintense to isointense rims on T2-weighed sequences with ring-like enhancement on contrast enhanced T1-weighted images. Caseating lesions with central necrosis develop central hyperintensity on T2-weighted images with hypodense rims; they are T1 hypodense and show ring-like enhancement.³⁴ Small lesions might go undetected, especially over the optic nerves and chiasm. Therefore, special dedicated fat suppressed cuts focusing on the optic nerve and chiasm must be performed and contrast enhanced T1-weighted sequences must always be included in all follow-up MRIs. Magnetic resonance spectroscopy (MRS) adds another advantage to conventional MRI in defining the biochemical status of tuberculomas. The wall of MTB is composed of lipids. Hence, a dominant lipid peak on MRS with the absence of other metabolites has high specificity and sensitivity in distinguishing tuberculomas from neoplastic and other non-neoplastic inflammatory lesions.⁵⁷

Ophthalmological investigations

A detailed ophthalmological work-up is of utmost importance in patients with involvement of the visual or ocular pathways. It is mandatory to examine best corrected visual acuity, visual fields, colour vision, pupils and fundoscopic examination in all patients with TBM. However, the ophthalmological work up is frequently limited by the presence of an altered sensorium at the initial presentation to the emergency services or neuroinfectious disease clinic. Perimetry should be done for the assessment of field defects that might be present despite unaffected visual acuity. Spectral domain OCT has emerged as a promising tool, which can quantify the severity of optic nerve damage and thus help in follow-up and prognostication. The role of OCT has been recently studied in ETON with studies on the measurement of the RNFL and macular ganglion cell + inner plexiform layer (GC-IPL) thicknesses.⁵⁸ The role of measuring RNFL thickness in ETON has been studied, but it is controversial since some studies have found it to be unaffected⁵⁹ while others have found thickening of the peripapillary RNFL.⁵⁸ In a retrospective analysis of 15 patients, Lee et al. found that patients with ETON had significant thinning of the macular GC-IPL as compared to the healthy controls but the RNFL thickness did not show any significant difference.⁵⁹ GC-IPL analysis can be developed as a quantitative marker to follow patients with ETON. However, whether it can be used for early detection before the symptoms start is controversial. In a prospective longitudinal cohort study, 37 patients taking ethambutol were followed with their GC-IPL thickness measured at baseline, 3 and 6 months. No difference was found in the GC-IPL thickness of patients who did not develop ETON.⁵⁸ This indicates that thinning of the GC-IPL only appears in patients who develop optic neuropathy. The authors think that close follow-up of the patients and education about the side effects are the most important steps which can facilitate early identification of TON and thus affect the outcome. Follow-up screening should be done on a monthly basis in high-risk patients, such as those with renal failure and the paediatric population. Ethambutol should be avoided in patients with altered sensorium, persistent HCP, papilloedema, OCA and optic pathway tuberculomas.

Role of fluoro-deoxyglucose positron emission tomography (FDG-PET)

FDG-PET helps to locate evidence of TB elsewhere in the body. This helps in cases where the diagnosis of TBM is in doubt and also where tissue diagnosis is necessary to determine drug resistance (in case of worsening on ATT). A CT scan of the chest and abdomen can be used as an alternative, but it has to be sequenced separately for different body areas. FDG-PET can visualise the whole body including the brain and spinal cord for any abnormal FDG avidity in a single sitting. Jain et al. reported that FDG-PET helps in the detection of extracranial disease in 94.3% of the patients with TBM.⁶⁰ Whole body FDG-PET can be studied further with the development of specific protocols, not only in TBM but elsewhere too.

Treatment

Medical management

Treatment of CNS TB aims at eliminating MTB from the body with the use of ATT along with management of associated complications, such as: HCP; OCA; tuberculomas; tubercular abscess; entrapment of cranial nerves/brainstem by dense exudates; appearance of new tuberculomas; enlargement of old tuberculomas; spinal arachnoiditis; vasculitis; infarction; and ventriculitis. Multidrug resistant TB must be ruled out in all cases of TBM before starting ATT and if worsening of symptoms occurs on regular intake of ATT. Once drug resistance has been ruled out, identification and management of paradoxical reactions must be the first priority.

Paradoxical reactions

Paradoxical reactions occur 1–4 months after starting ATT, when the immune response is intensified. It is routine practice that corticosteroids are given for the first 4 weeks after initiation of ATT.²⁸ This is the exact time when the immune system is recovering and can lead to the formation of exudates, new tuberculomas, worsening of old tuberculomas, abscess formation, OCA, tubercular optic neuritis, and optic perineuritis. Thus, tapering of corticosteroids must be done with close clinical and radiological follow-up. In our Neuroinfectious Disease clinic, Gd-MRI is done at the initiation of ATT, after 1 and 2 months of treatment, then at 3 monthly intervals whilst on treatment, or on an individual basis.

High dose intravenous corticosteroids (dexamethasone or methylprednisolone) are the primary agents for the treatment of paradoxical reactions.⁶¹ In a Cochrane systematic review and meta-analysis, corticosteroids were found to be effective in reducing mortality in all forms of TB.⁶² However, patients might not respond to high-dose corticosteroids and thus other drugs, such as thalidomide, infliximab, cyclophosphamide, and cyclosporine have been tried by some groups. However, the evidence is small and further trials are required.

Thalidomide is a tumour necrosis factor (TNF)-α inhibitor. Immune response in TBM is mediated through T-cell mediated immunity, macrophages, and natural killer cells. Proinflammatory cytokines, such as interleukin (IL)-2, IL-4, IL-6, IL-1β, interferon-γ and TNF-α are released as a part of host defence mechanisms. Both serum and CSF levels of these cytokines have been found to be raised in patients with TBM.⁶³ Highly significant positive correlations have been found between the presence of exudates and the levels of TNF-α and IL-1β.⁶³ Van Toorn et al. studied the role of thalidomide in children with TBM and paradoxical reactions by following clinical as well as radiological changes. Out of 38 children, four had visual impairment secondary to OCA. The mean dose used was 3.7 mg/kg/day and median duration of treatment in OCA was 2 months. There was full recovery of vision in all the 4 patients with resolution of the imaging changes.⁶⁴ There have been several case reports explaining the safety and tolerability of thalidomide in TBM.^65–67 It has been found to be effective in patients with refractory lesions not responsive to corticosteroids (Figure 7). Modi et al. studied 59 patients who developed vision loss due to OCA, out of which 39 showed clinical as well as radiological improvement after thalidomide was given at 3–5 mg/kg/day for 6 months.⁶⁸ Figures 5 and 7 illustrate two cases in which thalidomide was used as a rescue treatment due to severe paradoxical reactions.

Figure 7.

A 24-year-female developed fever and headache, followed by bilateral diminution of vision over a duration of 4 months. She was diagnosed with tubercular meningitis and started on antitubercular treatment (rifampicin, isoniazid, pyrazinamide, and ethambutol) at a private hospital. She deteriorated and presented to our emergency services. Examination revealed meningeal signs, a visual acuity of 6/18 in her right eye and 6/36 in her left eye, with bilateral optic disc pallor (d, left eye and E, right eye) and bilateral VI cranial nerve palsies (left > right). Gadolinium-enhanced magnetic resonance (MR) imaging showed diffuse leptomeningitis with extensive optochiasmatic arachnoiditis (a, T1-weighted contrast-enhanced axial image) and hydrocephalus (b, T1-weighted contrast-enhanced axial image). MR angiography revealed severe attenuation of the left supraclinoid internal carotid artery and the M1 segment of the left middle cerebral artery with attenuation of left-sided collaterals (c). Ethambutol was substituted with streptomycin and she was started on corticosteroids and thalidomide due to the extensive exudates. (f) and (g) show T1-weighted contrast-enhanced axial brain MR images after 1 and 2 months of thalidomide, respectively with marked reduction in the exudates.

Infliximab is another promising drug, which acts against TNF-α but the data available currently are in the form of case reports or case series. It has been found to reduce severe paradoxical reactions, which did not respond to corticosteroids.^69–71

Other immunomodulators, such as cyclophosphamide and cyclosporine have been used in a few refractory cases with limited evidence and their use is controversial.^72–74

Toxic optic neuropathy

TON is a preventable cause of vision loss. Hence, the priority lies in its early detection and prevention. Primary physicians in community health centres must be made aware of this devastating complication because they are the first contact of the patient after any clinical any worsening. Caution must be taken while using ethambutol in TBM. Use of doses up to 15 mg/kg is associated with visual impairment in only <1% patients⁷⁵ and this is the ideal dose to use.¹⁹ Whether ethambutol should be used in the routine regimen in TBM or not is debatable.⁷⁶ The regimen which the authors routinely use for patients with TBM contains rifampicin, isoniazid, pyrazinamide and streptomycin. There are various reasons behind this protocol without ethambutol:

• Raised ICP is seen in most of the patients at presentation and even on follow up. Therefore, the optic disc is always at risk of axonal loss.

• Patients with an altered sensorium are not able to report visual impairment.

• Paradoxical reactions during the intensive phase of ATT can further add to the disability.

• Nutritional deficiencies, which usually coexist, can contribute to the effects of TON.

Ethambutol is included in the treatment regimen for other forms of neurological TB, such as Pott’s disease of the spine and tuberculomas. There is no effective treatment for TON; early detection and stopping the drug is the best strategy. It is a common practice to stop isoniazid if there is no halt in progression of TON even after stopping ethambutol. Prognosis in TON depends on the time of diagnosis, severity, duration of exposure and the dosage used. Most of the patients have residual visual impairment. All patients with TBM must undergo regular ophthalmological evaluation. Close follow-up must be carried out for patients on ethambutol. Patients must have baseline visual acuity, perimetry, OCT, and fundus photography before starting ethambutol. Patient as well as care givers must be educated about the side effects and told to notify their physician as soon as they notice any new visual symptoms.⁷⁶ The associated drug must be stopped at the very first sign of visual impairment.⁷⁶ Full recovery is rarely seen, however, if detected early, 30–60% of the patients have shown improvement.¹⁹ There is no safe dose described, however a dose of ethambutol of 15 mg/kg has been reported to be associated with the least risk.⁷⁵

Surgical interventions and their indications

Medical management with ATT and corticosteroids is the cornerstone of treatment of TBM. The role of surgical intervention in TBM arises in patients who develop HCP, which is also the most common complication. The indication as well as the timing of the surgery, remain controversial. It is absolutely indicated in patients with deteriorating sensorium with increasing non-communicating HCP and even in patients with increasing communicating HCP who worsen with medical therapy. Vellore grading is one of the most common grading used for patients with TBM. It has four grades (I-IV) based on the presence of neurological deficit and alteration of sensorium.⁷⁷ CSF diversion can be performed by a VP shunt or by an endoscopic third ventriculostomy (ETV).⁷ There are no specific guidelines available regarding the choice of procedure, and it is based on the patient’s clinical status, physician’s decision, surgeon’s expertise and endoscopic resources available. VP shunting is a time-tested procedure and is still preferred as the standard procedure in most centres across the world. Early shunting in moderate to severe HCP with neurological deterioration has been shown to improve morbidity as well as mortality.⁷⁸ Palur et al. followed patients after shunt surgery for 6 months to 13 years and found that the only prognostic factor to affect the outcome was the grade of disease in which the patient presented at the time of admission (as per the Vellore grading of TBM and HCP).⁷⁹ None of the other factors affected the outcome. Therefore, the maximum benefit of shunt surgery is in grade I and II patients.⁷⁹ The presence of gangliocapsular infarcts carries a poor prognosis for patients undergoing shunting.⁷ New onset vision loss or papilloedema in any patient with TBM is an urgent indication for an immediate CT head scan to rule out a new onset HCP.⁸⁰ Non-communicating HCP usually does not respond well to medical treatment and must be treated with CSF diversion, especially if it is associated with any degree of papilloedema and visual impairment.⁸⁰

ETV has emerged as newer modality for CSF diversion in TBM with several advantages over VP shunting. It is a minimally invasive procedure without insertion of any foreign body into the CSF space, so reducing the risk of shunt-related infection, shunt failure, shunt blockage, and discomfits produced by the abdominal end of the shunt. It is performed by fenestration of the floor of the third ventricle between the mammillary bodies at the interpeduncular fossa creating a passage through the third ventricle.⁸¹ ETV is preferred in patients with non-communicating HCP. It creates an alternate passage for CSF circulation and thereby relieves the obstruction in non-communicating HCP. Even in communicating HCP, it is believed to improve CSF dynamics leading to improved resorption of CSF.⁸² There are many reports of successful procedures, with a success rate of 60–77%, however ETV is still not the preferred modality for diverting CSF.^82,83 A recent metanalysis reported a pooled success rate of 59% with technical failure in 9% of cases.⁸⁴ It is a challenging procedure and must be performed only by surgeons with expertise in endoscopic surgeries. In TBM, the floor of the third ventricle is thick and inflamed and the subarachnoid space is covered with thick exudates distorting the normal anatomy, making the procedure more challenging with an blood increased risk of injuring major vessels at the base of brain.^7,85 Having a transparent and thin floor of the third ventricle have been shown to give higher rates of success of ETV.⁸² A randomised trial comparing VP shunting and ETV (including communicating HCP) has shown comparable results and thus ETV is evolving as the initial procedure at many centres.⁸⁶ However, we need larger studies for more evidence and formulation of proper guidelines for selection of the patients for the specific type of procedure.

Prognosis

Management of neuro-ophthalmological complications in TBM requires close clinical supervision (Table 3). The response to treatment is not always satisfactory and thus we require more evidence for other immunomodulatory drugs. The severity of TBM with stages II and III, infarcts in imaging, hemiparesis, worse visual acuity at presentation (< 6/18), and other cranial nerve deficits have been found to be predictors of severe disability and death.⁶ Cranial nerve palsies involving extraocular muscles have a favourable prognosis compared with optic nerve or chiasmal involvement. Symptoms due to pressure effects, paradoxical reaction and tuberculomas have better prognosis compared with ischaemic lesions due to vasculitis.⁸⁷

Table 3.

Special consideration during the management of central nervous system tuberculosis.

Always rule out drug resistant TB Tapering of corticosteroids must be combined with contrast-enhanced MRI Steroid tapering must be gradual Keep patients under close follow-up for the first 3 months Avoid ethambutol in raised ICP, HCP, exudates/tuberculoma over the visual pathways, altered sensorium Regular ophthalmological follow up required if the patient is on ethambutol

HCP = hydrocephalus; ICP = intracranial pressure; MRI = magnetic resonance imaging; TB = tuberculosis.

Prevention and public health considerations

Early detection and appropriate management involve providing continuing education to general and family physicians about TBM and its potential complications. Changes in management strategies may require combined evidence from multi-centric studies, expert opinions, and grassroot level feedback. Public health initiatives involving awareness spreading among communities and removing the social stigma of TB.

Conclusion

Tuberculosis is still the “Captain of Death” in low to middle income countries. The complications of TBM are associated with high mortality and morbidity. Permanent vision loss is one of the dreaded complications which may add a lifelong burden to the family and society. The best strategy still aims at an earlier diagnosis of TBM and prevention of complications by regular follow-up with extreme caution at a centre with good experience at anticipating and managing them.

Funding Statement

The authors reported there is no funding associated with the work featured in this article.

Disclosure statement

No potential conflict of interest was reported by the authors.