A Case Study on Tubercular Cavernous Sinus Syndrome

Introduction

Tuberculosis is an infectious disease caused by Mycobacterium tuberculosis (M.TB) and most common site of infection is lungs. M.TB is an aerobic, non-spore forming bacillus that resists the decolonization by acid alcohol after staining with basic fuchsin; so the organism is referred to as acid fast bacilli.¹

Cavernous sinus derives its name ‘cavern’ and ‘cave’ from Latin word ‘cavus’ meaning ‘Hollow’. Cavernous refers to porous, particularly when it is filled with tiny blood vessels. Sinus refers to hollow cavity and abnormal passage leading from cavity. The cavernous sinus is a complex network of dural venous sinuses and blood channels responsible for draining deoxygenated venous blood from the cranial cavity. This intricate system collectively ensures the return of blood from the head to the heart, thereby contributing to the maintenance of systemic circulation.

These are seven major dural venous sinuses located between periosteal and meningeal layers of duramater.²

• Superior sagittal
• Inferior sagittal
• Straight
• ransverse
• Sigmoid
• Cavernous
• Superior

Cavernous sinuses are venous structures in middle cranial base surrounded by dural walls which contain neurovascular structures and face the sella turcica which is a depression in the sphenoid bone at the base of brain that holds and protects pituitary gland on one side and the temporal lobe on other side.^2,3

A cavernous sinus has five walls - Lateral & medial walls, a roof, posterior & anterior walls. Lateral wall faces temporal lobe, medial wall faces sella turcica, pituitary gland and sphenoid bone and posterior wall faces posterior cranial fossa.³ Left and right cavernous connect via the intracavernous sinus as it has association with outer structures including cranial nerves III, IV and VI ophthalmic, maxillary branches of cranial nerve V, trigeminal and abducence VI. Cavernous sinus is also known as Anatomical Jewel Box.² Various categories of disease which affects to cause sinus are called ascavernous sinus syndrome. These conditions encompass bacterial or fungal infections, non-infectious inflammation, vascular abnormalities, and neoplastic growths.

CSS (Cavernous sinus syndrome) is mainly characterized by multiple cranial neuropathies.⁴ CSS is a rare potentially life and sight threatening condition. CSS is a condition caused by any pathology involving cavernous sinus which presents as a combination of unilateral ophthalmoplegia (cranial IV, V, VI), autonomic dysfunction (Horner’s syndrome) or sensory CNV1 - CNV2 loss.⁵

Epidemiology

Tuberculosis stands as a significant global public health issue. In 2017, the World Health Organization (WHO) reported an estimated 10.4 million new cases of TB and 1.67 million TB-related deaths. Extra-pulmonary TB (EPTB) primarily affects anatomical sites such as lymph nodes, the pleura, bones and joints, the urogenital tract, and the meninges. Some specific forms of EPTB, including tuberculosis meningitis and miliary TB, contribute to a sustained burden of illness and mortality across various populations. Among the 6.3 million new TB cases identified by WHO in 2017, 16% were categorized as extra-pulmonary TB cases. Generally, EPTB tends to affect individuals with conditions such as diabetes mellitus (DM), HIV infection, as well as both young children (under 15 years of age) and older adults (over 65 years of age). Recent studies have highlighted that women and individuals migrating from regions with high TB incidence face an increased risk of developing EPTB.⁶

It was found that the percentage of patients with EPTB was more in tertiary care centers of India ranging from 30 to 53%. Tuberculosis (TB) ranks as the second most prevalent cause of mortality attributed to a single infectious agent globally, following COVID-19. Of all TB cases, up to 15% manifest as extra-pulmonary TB (EP-TB), with a notable subset affecting the central nervous system (CNS-TB). CNS-TB carries a significant burden of morbidity and mortality.⁷ Tuberculosis involvement of CNS is an important and serious type of extra pulmonary involvement. It has been estimated that approximately 10% of all patients with TB have CNS involvement.⁸ Tuberculomas involving the cavernous sinus is a rare presentation. Under literature review, only sixteen cases have been reported in previous literature of which two cases presented in pediatric age group since 1992. Out of 16 cases, PTB was detected in two cases and was localized to Meckel’s case in three patients. Extra-neural TB was reported in six patients. Cervical lymph node involvement was seen in one patient. In all cases, tuberculous bacilli were absent in CSF and none had culture positivity for MTB.⁹

Etiology

CSS is caused by a pathology or lesion present within the CS that disrupts the function of other anatomical structures. Common causes of CSS and their clinical features are mentioned in Table 1.⁵

Clinical Presentation

Tubercular cavernous sinus syndrome is characterized by:¹¹

• Unilateral and isolated cranial nerve [III, IV, VI] palsy

• Horner syndrome

• Partial or opthalmoplegia

• Proptosis (pulsating exophthalmos suggest a direct carotid cavernous fistula)

• Ptosis

• Ocular and cranial bruits

• Conjunctival congestion, arterialization of conjunctiva veins

• Ocular hypertention

• Optic disc edema or pallor, retinal hemorrhages.

Pathogenesis

Cavernous sinus syndrome can be attributed to various factors, primarily stemming from infections, noninfectious inflammatory conditions, vascular lesions, trauma, and tumors. Most tuberculous infections of CNS are caused by MTB; less commonly, other mycobacterium may be involved. Tuberculous infection in cavernous sinus is a rare condition where the bacilli reach the CNS through hematogenous route, secondary to disease elsewhere in the body.

Rich and Mc Cordock on basis of clinical and experimental observation suggested that CNS TB develops in two stages.¹²

Initially small tuberculous lesions (Rich’s foci) develop in CNS (cavernous, meninges, spinal cord)

↓

Remains dormant for years after initial infection

↓

Later, due to immunological mechanism

↓

Tuberculous lesion rupture into the subarachnoid space and dural venous sinus

Pathogenesis of cavernous sinus syndrome¹¹

Cavernous sinus is a fixed space, so any infection within the sinus has ability to compress internal structures

Due to compression and dysfunction of structures within cavernous sinus

↓

Opthalmoplegia and facial sensory changes occur

↓

Additionally, due to postganglionic sympathetic plexus travelling along the Internal carotid artery (ICA) and cranial nerve VI damage

↓

Ipsilateral loss of sympathetic tone presents as Horner syndrome characterized by drooping of upper eyelid (ptosis), miosis, anisocoria and anhidrosis

↓

So combination of cranial nerve VI palsy and ipsilateral Horner syndrome

↓

Leads to lesion in cavernous sinus which is called as ‘Cavernous Sinus Syndrome’

Diagnosis

Cavernous sinus syndrome (CSS) can be triggered by a range of different factors, encompassing infectious and non-infectious conditions. Therefore, diagnosing CSS relies on identifying the specific underlying cause. Given the diverse possible causes, imaging of the head and orbit along with laboratory tests, are instrumental in confirming the diagnosis.

The patient’s history should be clinically correlated with the physical examination findings, and the appropriate diagnostic tests should be performed which includes blood tests such as complete blood count (CBC), blood cultures and CSF analysis to assess an underlying infection. Serum investigations, including tests such as erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), angiotensin-converting enzyme (ACE), and anti-neutrophilic cytoplasmic antibodies (ANCA), are advised to assess potential inflammatory conditions. To identify the presence of tumors, trauma, or inflammation, the preferred imaging methods involve magnetic resonance imaging (MRI) of the brain and orbits with contrast and magnetic resonance venography(MRV)

Additionally, computed tomography (CT) of the brain and orbits is employed for the detection of trauma or vascular processes.⁵

Complications¹³

Complications include

• Headache

• Visual loss (optic neuropathy due to pappilledema)

• Stroke

• Seizures

• Subarachnoid hemorrhage

• Subdural hemorrhage

• Intraparenchymal hemorrhage

• Blood clots in various parts causing deep vein thrombosis and pulmonary embolism.

Management

Pharmacological therapy

The approach to treating cavernous sinus syndrome hinges on its root cause. The primary culprits for this syndrome are typically tuberculosis infection and tumors. Since the nature of tumor pathology can differ greatly, the treatment approach may vary as well. Surgery and/or radiotherapy represent potential treatment options for addressing a tumor. For infectious etiology such as Mycobacterium tuberculosis which is most common, treatment consists of four drug anti-tubercular therapy, i.e Isoniazid, Rifampicin, Pyrazinamide, Ethambutol for two months’ intensive phase, followed by two drugs i.e Isoniazid and Rifampicin for at least 10 months. Adjunctive corticosteroids should be given regardless of disease severity which reduces inflammation and oedema. For thrombosis condition, anticoagulant medications are useful in prevention of clot propogation.^10,14

Case Presentation

A 40 year old male patient was admitted to Vijayanagara Institute of Medical Science (VIMS), Ballari (Karnataka) with chief complaints of fever three months back and headache since three months. Patient was apparently well till three months after which he suddenly started experiencing low grade fever with evening rise of temperature continuously for two days. On day 3 of fever, patient developed drooping of left eyelid which was complete by day 5. On manually opening it, no chemosis, proptosis, diplopia or visual blurring were noted. For above complaints, patient was admitted to a local hospital. Ptosis started improving on day 6-7 of fever and completely resolved over next 3-4 days. Headache started on day 7 of fever, was initially on right frontal region and later became bitemporal pulling like sensation. No signs of nausea, vomiting, photo or phonophobia and no worsening of headache on moving head were noted. Headache was mild to moderate in intensity, was experienced daily and continuously. One and half months back, the patient developed altered sensorium in the form of disorientation, reduced responsiveness, urinary incontinence for which he was admitted again for 10 days. Since last one month, headache developed in left frontal region along with generalized lethargy, body pain, reduced appetite and history of 10 kg weight loss in the past three months.

Social history: Chronic tobacco chewer, alcoholic and working as tailor. No history of diabetes mellitus, hypertension, stroke.

Family history: Not significant.

On examination

Patient was conscious and oriented

• BP – 80/60 mmHg,

• HR – 90 bpm

• Hyper pigmented scaly patches over abdomen, chest and back

• No hepatosplenomegaly

• Reduced jaw opening

• Speech – normal

• Higher mental function (HMF) – normal

• Visual acuity – Right – 6/9, Left – 6/18 with correction

• Bilateral mild ptosis present • Pupils 3 mm bilaterally equally reactive to light (BERL)

• Extra ocular measurement (EOM) – full and normal

• Fundus – normal

• Tone, power – normal

• Ankles – brisk except bilateral ankle absent

• Plantars – equivocal

• Sensory examination – normal

• Cerebellar signs – absent

• Gait / stance – normal

Laboratory investigations

• Cbc : mild normocytic normochromic anemia with hb: 10g/dl

• Csf pleocytosis : 23.3

• S. B12 : 275 mg/dl (160-950 pg/ml)

• S. Homocysteine : 21.4 Micromoles/liter (5-15 micromoles/liter)

• S. Folate : 3.99 Ng/ml (2.5-20 Ng/ml)

• Crp : 56mg/dl (<10 mg/dl) Cerebrospinal fluid (CSF) analysis result

• Opening pressure : Normal

• Lymphocytes : 2

• Glucose : 65 mg/dL

• Protein : 34 mg/dL

• CSF for antibrucella antibody : negative

• CSF for cryptococcal antigen : negative

• cartridge - based nucleic acid amplification test (CBNAAT) and Acid fast bacteria (AFB) staining : negative

Additional tests

• Mantoux test : Negative

• MRI BRAIN : Acute dural venous sinus thrombosis involving the superior sagittal sinus and bilateral bulky cavernous sinus with T2 hypointensity in right Transverse sinus (TS), Sigmoid sinus (SS), and Internal Jugular Vein (IJV)

• Granulomatous etiology (Figure 1, 2 and 3).

Treatment

Table 2 presents the details of medications provided for the treatment. ATT drugs along with pyridoxine given as vitamin supplement, Naxdom which is a combination of Domperidone and Naproxen sodium for treating chronic headache, B complex and Thiamine as vitamin B supplements were advised. As patient complained of fever, Paracetamol was advised and Prednisolone which belongs to corticosteroids was advised because of the evidence of elevated CRP levels. Pantoprazole was advised to be consumed on an empty stomach to relieve gastric irritation caused by other drugs. Table 3 presents the details of discharge medications.

Discussion

Tuberculosis involving CNS is a serious condition with mortality and morbidity. There is also resurgence in developed countries due to human immunodeficiency virus (HIV), immigration and multi drug resistant strains. Central nervous system tuberculosis may appear as tuberculosis meningitis, tuberculomas, abscess or Pott’s disease.¹⁵

CNS tuberculosis can be among the most challenging and difficult to treat. The clinical syndromes associated with this condition encompass meningitis, the formation of abscesses, or the development of tuberculomas. Tuberculomas are responsible for approximately 10-30% of cases involving CNS disease. Although they tend to affect the cerebral hemispheres more commonly, it is worth noting that unusual locations for CNS tuberculomas are still reported. These atypical locations include the cerebropontine angle, the sellar and suprasellar regions, and as in the case we are discussing, the cavernous sinus.¹⁶

In this case, the patient was admitted with chief complaints of fever and headache since three months. Patient was apparently well three months back after which he suddenly developed low grade fever with evening rise in temperature continuously for two days. On day 3 of fever, patient developed drooping of left eyelid which was continuous for two days. Complete drooping of eyelid was noted on day 5. For above complaints, patient was admitted to local hospital. Ptosis started improving on day 6-7 of fever and resolved over next 3-4 days. Headache started on day 7 of fever, was initially in the right frontal region, then became bitemporal pulling like sensation. Headache was mild to moderate in intensity and it was daily and continuous. One and half months back he developed altered sensorium in the form of disorientation, reduced responsiveness, urinary incontinence for which he was admitted again for 10 days. Since last one month, headache was experienced on left frontal region along with generalized lethargy, body pain, reduced appetite and a history of 10 kg weight loss in the past three months was also provided. Patient was a chronic tobacco chewer, and an alcoholic. On examination, BP was found to be 80/60 mmHg, hyper pigmented scaly patches were observed over abdomen, chest and back with reduced jaw opening. On laboratory investigations, patient was found to be anaemic (Hb 10g/dL) with elevated CRP levels (56 mg/dL). CSF analysis was found to be normal and MRI showed acute dural venous sinus thrombosis involving superior sagittal sinus and bilateral bulky cavernous sinus with T2 hypointensity in right TS, SS, and IJV granulomatous etiology.

Based on the aforementioned tests, patient was diagnosed as tubercular cavernous sinus syndrome and treatment began with four drug antitubercular drug therapy. HRZE regimen, pyridoxine given as vitamin B6 supplement, paracetamol for treating fever, nor adrenaline to elevate blood pressure, mannitol to reduce cerebral edema, heparin to treat acute dural sinus thrombosis, ceftriaxone to treat infection, dexamethasone as an anti-inflammatory and iron folic acid as iron supplement were prescribed. This treatment regimen was continued for 15 days during hospitalization. After the symptoms subsided, the following drugs were prescribed on discharge: ATT (HRZE), naxdom, paracetamol, B complex, thiamine, pantoprazole, pyridoxine and prednisolone dose tapering was done to avoid withdrawal syndrome and dependence.

Conclusion

Extra pulmonary TB remains a significant health problem in developing countries. Prevalence of EPTB has been increasing globally over the last several years, mainly affecting central nervous system. Identification of risk factors that predispose EPTB such as bacterial infections or tumors would allow for targeted strategies to prevent active infection and thereby decreasing the prevalence of EPTB. Well defined educational programs are to be conducted to create awareness regarding EPTB which is a curable condition, thus decreasing the burden of disease and improving the nation’s economy.

Suggestions

• Based on the aforementioned tests, patient was diagnosed with tubercular cavernous sinus syndrome and treatment was started with four drug antitubercular drug therapy HRZE regimen along with corticosteroids. 
• Neuroimaging plays an important role in establishing a definitive diagnosis of CSS. Contrasted CT scan is useful in providing visualization of cranial bones and adjacent structures. MRI is the most sensitive tool for visualization of soft tissues. Both serve as diagnostic tools in identification of causative lesions of CSS and its anatomical relations.
• Some studies found lumbar puncture to be a poor diagnostic tool with low sensitivity in CSS cases.
• The diagnosis of cavernous sinus tuberculoma poses a challenge, as distinguishing it from a tumor solely through imaging is intricate. Molecular techniques such as PCR testing, and potentially GeneXpert MTB/RIF, could potentially aid in the diagnosis, although their utilization in this context has not been established. Additionally, proton MR spectroscopy, diffusion-weighted MRI, and dynamic contrastenhanced MRI may serve as valuable supplementary imaging assessments that can enhance the specificity of the diagnosis.
• In our case presentation, it is notable that neither AFB smear nor mantoux test was positive. So, diagnosis for tuberculosis remains unclear.

Conflict of Interest

None