Frequency of Hydrocephalus in patients with Tuberculous Meningitis

Najam Younas Butt¹*, Yasir Malik², M Irshad³

1.2,3, Department of Neurology, Pakistan Institute of Medical Sciences, Islamabad. Pakistan.

Corresponding Author: Najam Younas, Department of Neurology, Pakistan Institute of Medical Sciences, Islamabad. Pakistan.

Copy Right: © 2022 Najam Younas, This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Received Date: October 14, 2022

Published Date: November 01, 2022

Abstract

Introduction: Tuberculosis can involve any organ system of the body. Tuberculosis of nervous system (NS) is not uncommon in our country. Tuberculous meningitis (TBM) is a severe form of extrapulmonary tuberculosis. In countries with high burden of pulmonary tuberculosis, the incidence of TBM is expected to be proportionately high. Common complications include SIADH, hydrocephalus, seizures and stroke. Here in this study I tried to look for hydrocephalus, so that early recognition and treatment of this complication may be carried out.

Objective: To determine the frequency of hydrocephalus in patients with tuberculous meningitis

Study Design: Cross sectional study.

Duration of Study: Six months (15^th September, 2010 to 15^th March, 2011)

Materials and methods This study was conducted in Neurology department of Pakistan Institute of Medical Sciences (PIMS), Islamabad. Nonprobability sampling technique was used. Patients with clinical features of TBM and having suggestive CSF were included and those with cerebral atrophy or congenital neurologic anomalies were excluded. All enrolled patients underwent brief history, clinical examination and CT scan of brain. Then approved proforma was filled by me. In the end data was analyzed in SPSS version 11.

Results: Sample size of 77 patients consisting of 47 male and 30 female patients was taken. Age of the patients ranged 14-72 years (mean=27.3), majority of patients were young. On CT scan brain 59 (76.6%) displayed hydrocephalus, amongst which 34 were male and 25 were female. Other than hydrocephalus tuberculomas were seen in 9 and infarction was seen in 14 patients. . CSF proteins were categorized and then compared with presence of hydrocephalus. All the patients with severely raised proteins had hydrocephalus, whereas 70.5% of the patients with moderately and 77% of the patients with mildly raised proteins exhibited hydrocephalus.

Conclusion: Hydrocephalus is a common complication of TBM. It is seen in 76.6% patients of TBM and it may be related to higher degree of CSF proteins.

Key Wards: Tuberculosis, Meningeal/complications, Hydrocephalus/etiology, Hydrocephalus/radiography.

Tuberculosis most commonly involves lungs as primary site of infection but many other organs are  potentially affected particularly central nervous system (CNS) .Intracranial tuberculosis has two related pathological processes: Tuberculous meningitis (TBM) and intracranial tuberculoma .The development of two pathologies is dependent on the site where Rich focus (tuberculous particle)rupture i.e. in subarachnoid space or brain parenchyma .

Currently, more than 2 billion people (ie, one third of the world’s population) are infected with tuberculosis (TB), of which approximately 10% will develop clinical disease. The incidence of central nervous system (CNS) TB is related to the prevalence of TB in the community, and it is still the most common type of chronic CNS infection in developing countries

Despite great advances in immunology, microbiology, and drug development, TB remains among the great public health challenges.

Poverty; lack of functioning public health infrastructure; lack of funding to support basic research aimed at developing new drugs, diagnostics, and Vaccines; and the co-epidemic of HIV continue to fuel the ongoing epidemic of TB .

TBM may have an acute presentation .Fever ,headache ,signs of meningeal irritation and cranial nerve palsies are major presenting features of TBM in adults [1].Pacs BF etal described common presentations in pediatric group are weight loss (91%),loss of consciousness(96%),motor deficit(63%),meningial irritation(98%),raised intracranial pressure(23%),brainstem dysfunction(39%) and cranial nerve palsies(27%)[2].Sequelae of TBM include seizures,development delay,stroke ,stroke,syndrome of inappropriate Antidiuretic hormone secretion (SIADH) and hydrocephalus.

TBM continues to pose a diagnostic problem.. TBM should be a strong consideration when a patient presents with a clinical picture of meningoencephalitides, especially in high-risk groups. Diagnostic confusion often exists between TBM and other meningoencephalitides, in particularly  partially treated meningitis. TBM must be differentiated not only from other forms of acute and subacute meningitis but also from conditions such as viral infections and cerebral abscess.

The diagnosis of TBM cannot be made solely on the basis of clinical findings. Tuberculin testing is of limited value. Variable natural history and accompanying clinical features of TBM hinder the diagnosis. Spinal tap carries some risk of herniation of the medulla in any instance when intracranial pressure (ICP) is increased.

Early treatment is essential; death may occur as a result of missed diagnoses and delayed treatment. Antimicrobial therapy is best started with isoniazid, rifampin, pyrazinamide; addition of a fourth drug is left to local choice.

Hydrocephalus occurs in 85% cases of tuberculous meningitis [3], which is of two types communicating and obstructive. Communicating type is much more frequently seen in comparison to obstructive.In patients with evidence of obstructive hydrocephalus and neurological deterioration who are undergoing treatment for TBM, placement of a ventricular drain or ventriculoperitoneal or ventriculoatrial shunt should not be delayed.

Early shunting of hydrocephalus is the best option to prevent long term sequelae of TBM [4].All  clinical and radiological parameters show regression in hydrocephalus after shunting [5].Endoscopic third ventriculostomy  is another available solution of hydrocephalus, which has shown promising results in hydrocephalus of chronic tuberculous meningitis.                    

Tuberculous meningitis is a common disease of our society but unfortunately it is rarely worked upon. I planned to conduct a study on frequency of hydrocephalus as a result of TBM, so that hydrocephalus may  be identified in early stage and complications of chronic TBM may be avoided by early shunting.

Meningitis

Definition of meningitis:      

Meningitis is an inflammatory disease of the leptomeninges, the tissues surrounding the brain and spinal cord, and is defined by an abnormal number of white blood cells in the cerebrospinal fluid (CSF). The meninges consist of three parts: the pia, arachnoid, and dura maters. Bacterial meningitis reflects infection of the arachnoid mater and the CSF in both the subarachnoid space and the cerebral ventricles.

Bacterial meningitis was originally recognized in 1805 until the early 1900s it was virtually 100 percent fatal. In 1913, Flexner's introduction of intrathecal meningococcal antiserum prevented some deaths, but the clinical outcome did not dramatically improve until the introduction of systemic antimicrobial therapy in the 1930s.

Incidence and  Epidemiology of bacterial meningitis.

Approximately 1.2 million cases of bacterial meningitis occur annually worldwide [6] [Meningitis is among the  infectious causes of death and is responsible for approximately 135,000 deaths throughout the world each year. Neurologic sequelae are common among survivors.

The epidemiology of bacterial meningitis has changed dramatically over the last 20 years, primarily as a result of the introduction of conjugate vaccines against the common meningeal pathogens, such that in the developed world where vaccination is routinely utilized, bacterial meningitis has become a disease of adults rather than of infants and children [7].

Bacterial meningitis is an important cause of childhood morbidity and mortality world-wide. In the developing world, where the burden of acute meningitis and its long-term sequelae are especially high, staff with limited training at primary health care facilities must be able to recognize the symptoms and signs of meningitis, so that suspected cases can be referred urgently to hospitals [8]

A number of studies have evaluated the prevalence of different organisms that cause bacterial meningitis. The results vary based upon the type of infection: community-acquired, nosocomial, or recurrent.

Etiology of Bacterial Meningitis

Bacterial meningitis can be community-acquired or healthcare-associated

Community – Acquired Meningitis

 The frequency of the different etiologic organisms of bacterial meningitis varies with age. The major causes of community-acquired bacterial meningitis in adults in developed countries are Streptococcus pneumoniae, Neisseria meningitides (N. meningitides), and, primarily in patients over age 50 to 60 years or those who have deficiencies in cell-mediated immunity, Listeria monocytogenes. Meningococcal meningitis is a potentially fatal disease which can affect many 15- to 24-year-old. that  could have been protected from the disease if they had received the vaccination.[9]

Bacterial Meningitis remains a serious disease associated with substantial morbidity and mortality. Most cases are community acquired with S. Pneumoniae being the most common pathogen. Old age, diabetes mellitus, a positive culture, seizures as a complication and late stage in the disease are the important predictors of a poor outcome.[10]

A multicenter study of patients with bacterial meningitis in the United States in 1995 showed that the frequency of the major pathogens varies with age

• In adults up to age 60, S. pneumoniae was responsible for 60 percent of cases, followed by N. meningitidis (20 percent), H. influenzae (10 percent), L. monocytogenes (6 percent), and group B streptococcus (4 percent).
• In adults age 60 and above, almost 70 percent of cases were due to S. pneumoniae, approximately 20 percent to L. monocytogenes, and 3 to 4 percent each to N. meningitidis, group B streptococcus, and H. influenzae. An increased prevalence of L. monocytogenes in elderly adults has been noted in other reports as well.

• Meningitis due to infection with Mycobacterium Tuberculosis is more common in those from countries where Tuberculosis is common, but is also encountered in those with immune problems, such as HIV infected patients.

Nosocomial Meningitis 

Healthcare-associated bacterial meningitis may occur after neurosurgical procedures, head trauma, and following placement of external or internal ventricular catheters. The likely microorganisms that cause meningitis in this setting (ie, staphylococci and gram-negative bacilli) are nnnmdifferent from those that cause meningitis in the community setting.[11]        

Perioperative bacterial meningitis after trans-sphenoidal surgery for pituitary and parasellar lesions is an uncommon but serious complication [12]. PCNSI most commonly manifests as meningitis, subdural empyema, and/or brain abscess [13].Most frequent organisms are Gram-negative bacilli,streptococci, Staphylococcus aureus, and coagulase-negative staphylococci.

Recurrent bacterial meningitis:

Recurrent meningitis is caused by persisting anatomical defects, either congenital or acquired.  It may also occur in patients with internal or external ventricular drains, or following trauma (ie, cranial trauma or after basilar skull fracture with or without clinical evidence of leak of CSF).

Geographical Distribution of bacterial Meningitis:

The distribution of pathogens also depends upon the region of the world reporting cases of bacterial meningitis. As an example, epidemics of meningitis due to N. meningitidis are uncommon in the United States and Europe but occur throughout the developing world, particularly in sub-Saharan Africa which has been plagued by large epidemics of meningococcal meningitis for over a century,] leading to it being labeled the "meningitis belt"

Epidemics typically occur in the dry season (December to June), and an epidemic wave can last two to three years, dying out during the intervening rainy seasons. Meningococcal disease occurs in epidemics in areas where many people live together for the first time, such as army barracks during mobilization, college campuses and the annual Hajj pilgrimage.    

Several factors have been associated with the development of epidemics in the meningitis belt. They include medical conditions (immunological susceptibility of the population), demographic conditions (travel and large population displacements), socioeconomic conditions (overcrowding and poor living conditions), climatic conditions (drought and dust storms), and concurrent infections (acute respiratory infections)

Predisposing Risk factors

There are specific factors that may predispose certain hosts to bacterial meningitis with a particular organism (table 2), the following factors also may increase the risk of bacterial meningitis.

• Recent exposure to someone with meningococcal or Hib meningitis.
• Recent infection (especially respiratory or otic infection).
• Recent travel to areas with endemic meningococcal disease, such as sub-Saharan Africa.
• Penetrating head trauma.
• CSF otorrhea (including congenital defects, such as Mondini dysplasia) or CSF rhinorrhea.
• Cochlear implant devices.
• Anatomic defects (eg, dermal sinus or urinary tract anomaly) or recent neurosurgical procedure (eg, ventricular shunt placement) may predispose to meningitis with Staphylococcus aureus, coagulase-negative staphylococcus, and enteric gram-negative organisms, such as Escherichia coli and Klebsiella species

Pathogenesis

Bacterial meningitis develops when virulence factors of the pathogen overcome host defense mechanisms. For the most common pathogens causing bacterial meningitis in adults (S. pneumoniae, Neisseria meningitidis), meningeal invasion is related to several virulence factors that allow the bacteria to colonize host mucosal epithelium, invade and survive within the bloodstream, cross the blood-brain barrier, and multiply within the CSF.Pathogenesis consists of the  following three stages :

1. Colonization and invasion:

Colonization of the host mucosal epithelium is facilitated by evasion of mucosal secretory IgA through pathogen secretion of IgA protease. IgA protease inactivates the mucosal antibody and facilitates bacterial attachment to host epithelial cells. After successful colonization, invasion occurs across the epithelium via intracellular or paracellular pathways that are mediated by specific binding adhesins of the bacterial surface, many of which are localized to pili in gram-negative pathogens.

 
2. Evasion of the complement system:

The next stage after invasion and entry into the bloodstream, bacteria survive through evasion of the complement system, particularly the alternative complement pathway. The bacterial capsular polysaccharide is the major mechanism for alternative complement evasion. As an example, the capsular sialic acid of N. meningitidis prevents binding of factor B to C3b and subsequent activation of the alternative pathway. For S. pneumoniae, C3b binds inefficiently to factor B on the capsular surface. In either case, the pathogens avoid the bactericidal activity of complement, survive in the bloodstream, and cross the blood-brain barrier into the CSF. 3.Entry into the cerebrospinal fluid.

The exact topographic site of bacterial entry into the CSF is unclear and may be distinct for different pathogens. For some pathogens such as Escherichia coli, experimental evidence suggests that CSF entry occurs at the choroid plexus and is facilitated by the presence of S. fimbriae on the bacterial surface.      

After successful invasion of the CSF, bacteria can multiply to high concentrations (eg, up to 10(7) organisms per milliliter) because of inadequate humoral immunity in the CSF. Specifically, low concentrations  of immunoglobulin and complement within human CSF result in poor opsonic activity, successful bacterial replication, and the subsequent development of inflammation.

Clinical presentation

In adults a severe headache is the most common symptom of meningitis – occurring in almost 90% of cases of bacterial meningitis, followed by nuchal rigidity. The classic triad of diagnostic signs consists of nuchal rigidity, sudden high fever, and altered mental status; however, all three features are present in only 44–46% of all cases of bacterial meningitis.

In adults patients presenting with community-acquired acute bacterial meningitis, the sensitivity of the classic triad of fever, neck stiffness, and altered mental status is low, but almost all present with at least two of the four symptoms of headache, fever, neck stiffness, and altered mental status [14] .

In addition to the classic findings, a number of other manifestations, both neurologic and non-neurologic, can occur in patients with bacterial meningitis, and some findings may be suggestive of a particular bacterial etiology.

• Neurologic complications such as seizures, focal neurologic deficits (including cranial nerve palsies), and papilledema may be present early or occur later in the course. Seizures have been described in 15 to 30 percent nts and focal neurologic deficits in 10 to 35 percent. Hearing loss is
• A late complication. Papilledema is observed in <5 percent of patients at the time of initial presentation.
• Patients with Listeria meningitis have an increased tendency to have seizures and focal neurologic deficits early in the course of infection, and some patients may present with a syndrome of rhombencephalitis (manifested as ataxia, cranial nerve palsies, and/or nystagmus).
• N. meningitidis, can cause characteristic skin manifestations, such as petechiae and palpable purpura.

 
Examination for nuchal rigidity:

Tests for examination of nuchal rigidity (such as Kernig's and Brudzinski's signs) were originally developed and tested in patients with severe, late stage meningitis (such as that caused by tuberculosis).

• The classic Brudzinski's sign refers to spontaneous flexion of the hips during attempted passive flexion of the neck.
• The Kernig's sign refers to the inability or reluctance to allow full extension of the knee when the hip is flexed 90º. Kernig's test is usually performed in the supine position, but it can be tested in the seated patient.

Diagnosis of Bacterial Meningitis:

Laboratory studies —In Routine lab  work is often unrevealing. The white blood cell count is usually elevated, with a shift toward immature forms; however, severe infection can be associated with leukopenia. The platelet count may also be reduced. Leukopenia and thrombocytopenia have correlated with a poor outcome in patients with bacterial meningitis.

Coagulation studies may be consistent with disseminated intravascular coagulation. Results of serum chemistry tests are usually commensurate with the severity of the overall process and may reveal an anion gap metabolic acidosis or hyponatremia.

Blood cultures — Blood cultures are often positive and can be useful in the event that CSF cannot be obtained before the administration of antimicrobials.

Approximately 50 to 90 percent of patients with bacterial meningitis have positive blood cultures.

Cultures obtained after antimicrobial therapy are much less likely to be positive, particularly for meningococcus. Two sets of blood cultures should be obtained from all patients prior to the initiation of antimicrobial therapy.

Cerebrospinal fluid (CSF) analysis:

The usual CSF findings in patients with bacterial meningitis are a white blood cell count of 1000 to 5000/microL (range of <100 to >10,000) with a percentage of neutrophils usually greater than 80 percent, protein of 100 to 500 mg/dL, and glucose <40 mg/dL.

CSF analysis is an important diagnostic tool to differentiate acute bacterial from viral meningitis. Furthermore, when Gram stain and culture are negative, the CSF lactate can provide pertinent, rapid and reliable diagnostic information in distinguishing bacterial from viral meningitis[15] .

Clinicians must recognize that many exceptions exist, and that empiric antibiotic therapy is warranted when bacterial meningitis is suspected clinically even if the CSF abnormalities are not diagnostic.

Pleocytosis:

It is important to note that a false-positive elevation of the CSF white blood cell count can be found after traumatic lumbar puncture, or in patients with intracerebral or subarachnoid hemorrhage in which both red blood cells and white blood cells are introduced into the subarachnoid space. IGeneralized seizures may also induce a transient CSF pleocytosis (primarily neutrophilic), although the CSF WBC count should not exceed 80/microL in this setting.

Gram stain

A Gram stain should be obtained whenever there is suspicion of bacterial meningitis. It has the advantage of suggesting the bacterial etiology one day or more before culture results are available. The following findings may be seen.

• Gram-positive diplococci suggest pneumococcal infection
• Gram-negative diplococci suggest meningococcal infection
• Small pleomorphic gram-negative coccobacilli suggest Haemophilus influenzae infection
• Gram-positive rods and coccobacilli suggest listerial infection

The Gram stain is positive in 10 to 15 percent of patients who have bacterial meningitis but negative CSF cultures. As noted above, the yield of both Gram stain and culture may be reduced by prior antibiotic therapy.

Lumbar Puncture.

A Lumbar puncture (LP) also known as a spinal tap is a diagnostic as well as therapeutic procedure that is performed in order to collect a sample of cerebrospinal fluid (CSF) for biochemical, mirobiological, and cytological analysis, or as a treatment to relieve increased intracranial pressure.

The most common indication for a lumbar puncture is to collect cerebrospinal fluid in a case of suspected meningitis, since there is no other reliable tool with which meningitis, a life-threatening but highly treatable condition, can be excluded.

Indications for CT scan before LP

Every patient with suspected meningitis should have CSF obtained unless lumbar puncture (LP) is contraindicated. It is not uncommon for LP to be delayed while a computed tomographic (CT) scan is performed to exclude a mass lesion or increased intracranial pressure, which rarely leads to cerebral herniation during subsequent CSF removal.      

Based upon these observations and in agreement with the 2004 Infectious Diseases Society of America (IDSA) guidelines for the management of bacterial meningitis, a CT scan of the head before LP should be performed in adult patients with suspected bacterial meningitis who have one or more of the following risk factors.

• Immunocompromised state (eg, HIV infection, immunosuppressive therapy, solid organ or hematopoietic stem cell transplantation)
• History of CNS disease (mass lesion, stroke, or focal infection)
• New onset seizure (within one week of presentation)
• Papilledema.
• Abnormal level of consciousness.

Complications of bacterial meningitis    

Complications due to bacterial meningitis can be divided into systemic and neurologic. Systemic complications such as septic shock, disseminated intravascular coagulation, acute respiratory distress syndrome, and septic or reactive arthritis, are usually the consequence of the bacteremia that frequently accompanies meningitis.

The neurologic complications of bacterial meningitis include:

• Impaired mental status
• Increased intracranial pressure and cerebral edema
• Seizures
• Focal neurologic deficits (eg, cranial nerve palsy, hemiparesis)
• Cerebrovascular abnormalities
• Sensorineural hearing loss
• Intellectual impairment

Treatment of bacterial meningitis 

Bacterial meningitis is a medical emergency, and immediate steps must be taken to establish the specific cause and initiate effective therapy. The mortality rate of untreated disease approaches 100 percent and, even with optimal therapy, there is a high failure rate.

Antibiotic therapy  should be initiated immediately after the performance of the lumbar puncture (LP) or, if a computed tomography scan is to be performed before LP, immediately after blood cultures are obtained

Empiric antibiotic therapy should be initiated before cranial computed tomography. Adjuvant dexamethasone therapy initiated with or prior to the antibiotic therapy reduces mortality and morbidity for patients with pneumococcal meningitis without increasing the rate of side effects16.

Once the CSF Gram stain results are available, the antibiotic regimen should be tailored to cover the most likely pathogen. If the CSF findings are consistent with the diagnosis of acute bacterial meningitis, but the Gram stain is negative, empiric antibiotic therapy should be continued.

Tuberculous meningitis

Central nervous system (CNS) tuberculosis (TB) includes three clinical categories: Tuberculous meningitis, intracranial tuberculoma, and spinal tuberculous arachnoiditis. Tuberculous meningitis is the most severe manifestation of extrapulmonary tuberculosis with a high mortality rate and a high rate of sequelae among survivors.[17]

The hallmark pathological processes are meningeal inflammation, basal exudates, vasculitis and hydrocephalus. Headache, vomiting, meningeal signs, focal deficits, vision loss, cranial nerve palsies and raised intracranial pressure are dominant clinical features. Diagnosis is based on the characteristic clinical picture, neuroimaging abnormalities and cerebrospinal fluid changes. Early diagnosis & prompt treatment  is essential to avoid morbidity & mortality. Cerebrospinal fluid smear examination, mycobacterial culture or polymerase chain reaction is mandatory for bacteriological confirmation Prompt diagnosis and early treatment are crucial. Decision to start antituberculous treatment is often empirical.

WHO guidelines recommend a a prolonged treatment extended to 9 or 12 months. Resistance to antituberculous drugs is associated with a high mortality. Patients with hydrocephalus may need ventriculo-peritoneal shunting. Bacillus Calmette-Guérin(BCG)vaccination protects to some degree against tuberculous meningitis in children. Children with TBM who have been vaccinated with BCG appear to maintain better mentation and have a superior outcome as compared to the unvaccinated [18].

More research is urgently needed to better understand the pathogenesis of disease and to improve its clinical management and outcome. A major stumbling block is the absence of standardised diagnostic criteria. The different case definitions used in various studies makes comparison of research findings difficult, prevents the best use of existing data, and limits the management of disease.[19]

Incidence and Epidemiology

• Incidence :

The exact incidence and prevalence are not known.  Tuberculous meningitis (TBM) is commonly found to occur in the developing countries endemic to tuberculosis [20]. Human immunodeficiency virus-infected patients have a high incidence of tuberculous meningitis [21]. In the United States and in most western countries, the incidence of tuberculous meningitis, which parallels the frequency of systemic tuberculosis has until recently decreased steadily since theSecond World War..

In developing countries, particularly in sub-Saharan Africa, recent estimates of the incidence of tuberculosis suggest that it is 25 times more frequent than in the United States, again largely because of the prevalence of HIV infection.

• Age :

Tuberculous meningitis occurs in persons of all ages but more frequent in young children. Pediatric tuberculosis of the central nervous system (CNS-TB) is a severe form of extrapulmonary TB. It is most common in children between 6 months and 4 years of age. CNS-TB can present as meningitis and/or tuberculoma [22]

Pathophysiology:

Tuberculous meningitis is usually caused by the acid-fast organism Mycobacterium tuberculosis. Scattered tuberculous foci (tubercles) are established in the brain, meninges, or adjacent bone during the bacillemia that follows primary infection or late reactivation TB elsewhere in the body.

The chance occurrence of a subependymal tubercle, with progression and rupture into the subarachnoid space, is the critical event in the development of tuberculous meningitis as decribed by Rich.

The spillage of tubercular protein into the subarachnoid space produces an intense hypersensitivity reaction, giving rise to inflammatory changes typically begin with a dense basal meningeal exudate often resulting from a "Rich focus" along the basal surface of the cerebrum or ventricular ependyma. This inflammatory exudate is made up of small and large mononuclear cells, including epithelioid cells, which also act as macrophages and may fuse to form Langhans' giant cells. Three features dominate the pathology and explain the clinical manifestations of tuberculous meniningitis23.

• Proliferative arachnoiditis, most marked at the base of the brain, produces a fibrous mass involving cranial nerves and penetrating vessels. Spinal arachnoiditis is one of the common and disabling complication of tuberculous meningitis (TBM).

In one study  16 patients were included with a diagnosis of probable or highly probable TBM with symptoms for less than 1 month; three had radiological evidence of spinal arachnoiditis. High cerebrospinal fluid protein appeared to be a risk factor for development of spinal arachnoiditis. MRI is sensitive to detect early spinal arachnoiditis. Earlier diagnosis may be helpful in management of spinal arachnoiditis in TBM [24].

• Vasculitis with resultant thrombosis and infarction involves vessels that traverse the basilar or spinal exudate or are located within the brain substance itself. Cerebral infarction (CI) is a serious complication of tuberculous meningitis (TBM) [24]. It can be asymptomatic or symptomatic, causing stroke. Multiple lesions are common and a variety of stroke syndromes may result, involving the basal ganglia, cerebral cortex, pons, and cerebellum. Intracranial vasculitis is a common feature of autopsy studies and a major determinant of residual neurologic deficits. In one autopsy study of 27 cases, for example, phlebitis and varying degrees of arteritis were demonstrated in 22 cases, including eight patients with associated hemorrhagic cerebral infarction.

Stroke in tuberculous meningitis (TBM) occurs in 15-57% of patients especially in advance stage and severe illness. The majority of strokes may be asymptomatic because of being in a silent area, deep coma or associated pathology such as spinal arachnoiditis or tuberculoma [25].

In another study which concluded that stroke occurs in 45% of patients with TBM both in early and later stage, mostly in basal ganglia region, and predicts poor outcome at 3 months [26].

Cerebral infarction (CI) complicating tuberculous meningitis (TBM) is a major risk factor of permanent disability. The prevention of this complication is an important issue in the quality care of TBM patients27.Even when increased intracranial pressure is treated and full conventional therapy is commenced, cerebral ischemia can develop and is associated with a particularly poor prognosis [28]

• Hydrocephalus is one of the commonest complications of tuberculous meningitis (TBM) occurring in up to 85% of children with the disease 3. It is more severe in children than in adults. It could be either of the communicating type or the obstructive type with the former being more frequently seen. It results from extension of the inflammatory process to the basilar cisterns and impedance of CSF circulation and resorption. Obstruction of the aqueduct develops less frequently, from contraction of exudate surrounding the brainstem or from a strategically placed brainstem tuberculoma.
• Spinal cord. Compression and radiculopathies The spinal cord may be affected in a number of ways in the course of tuberculous infection. In addition to compressing spinal roots and cord, causing spinal block, the inflammatory meningeal exudate may invade the underlying parenchyma, producing signs of posterior and lateral column and spinal root.

Spinal cord symptoms may also accompany tuberculous oteomyelitis of the pine with compression of the cord by an epidural abscess, a mass of granulation tissue (Pott paraplegia).

• •Tuberculomas These are tumor-like masses of tuberculous granulation tissue, most often multiple but also occurring singly, that form in the parenchyma of the brain and range from 2 to 12 mm in diameter The larger ones may produce symptoms of a space-ccupyinglesion and periventricular ones may cause obstructive hydrocephalus.

Tuberculomas occur in young patients from high-risk countries. The anti-tuberculous drug regimen in this series was 2 months of isoniazid, rifampin, pyrazinamide and ethambutol, followed by at least 10 months of isoniazid and rifampin [29].

In developing countries countries they constitute from 5 to 30 percent of all intracranial mass lesions Because of their proximity to the meninges, the CSF often contains a small number of lymphocytes and increased protein (serous meningitis), but the glucose level is not reduced. Tuberculomas occurred in approximately 39% of the patients with TBM. TBM patients with or without tuberculomas had a similar prognosis [30]

Clinical features

The usual patient with tuberculous meningitis presents with a subacute febrile illness that progresses through three discernible phases

• The prodromal phase, lasting two to three weeks, is characterized by low-grade fever, malaise, headache(more than one-half the cases), lethargy, confusion, and stiff neck(75 percent of cases), with Kernig and Brudzinski signs..
• The meningitic phase follows with more pronounced neurologic features, such as meningismus, protracted headache, vomiting, lethargy, confusion, and varying degrees of cranial nerve and long-tract signs.
• The paralytic phase is the stage during which the pace of illness may accelerate rapidly; confusion gives way to stupor and coma, seizures, and often hemiparesis. For the majority of untreated patients, death ensues within five to eight weeks of the onset of illness.

In approximately two-thirds of patients with tuberculous meningitis there is evidence of active tuberculosis elsewhere, usuallyin the lungs and occasionally in the small bowel, bone, kidney, or ear. In young children and infants, apathy, hyperirritability, vomiting and seizures are the usual symptoms.

In adult patients, HIV-infected patients have a high incidence of tuberculous meningitis.21 Untreatedillness is characterized by confusionand progressively deepening stupor and coma, coupledwith cranial nerve palsies, pupillary abnormalities, focal neurologicdeficits, raised intracranial pressure, and decerebrate postures;invariably, a fatal outcome then follows within 4 to 8 weeksof the onset.

A study was done to investigate child behaviour in children who recovered from tuberculous meningitis (TBM) and to compare behaviour profiles of stage II and stage III patients. Results showed that problems with conduct, attention, attention-deficit/hyperactivity problems, affective problems as well as the total problem scores were more pronounced in the patients with stage III TBM.

Finally concluded that general behavioural disinhibitions as well as internalized emotional disorder probably are long-term complications in more than 10% of the survivors of TBM.[31]

 
Deferential Diagnosis

Tuberculous meningitis (TBM) is a major global health problem, and it is sometimes difficult to perform a differential diagnosis of this disease from other diseases, particularly partially treated pyogenic meningitis (PTPM). Other differentials of tuberculous meningitis include   subacute or chronic meningitis syndrome with a CSF formula characterized by a lymphocytic pleocytosis, lowered glucose concentration, and a high protein content. This is seen most commonly with cryptococcosis, occasionally with other deep-seated granulomatous fungal infections, brucellosis, and neurosyphilis. Patients with herpes encephalitis may exhibit a similar CSF formula, including mild lowering of CSF glucose concentration.

Early TBM often presents with atypical features and its differential diagnosis can be difficult. CSF monitoring and careful inspection of the radiographic data can be helpful in the diagnosis of suspected cases, for which early anti-TB treatment is an important means to reduce misdiagnosis [32]

Diagnosis

The diagnosis of tuberculous meningitis can be difficult. Maintaining a high degree of suspicion is vital in order to initiate therapy promptly.The most important investigation  is the lumbar puncture, which preferably should be performed before the administration of antibiotics.

Cerebrospinal fluid examination

The cerebrospinal fluid (CSF) is usually under increased pressure and contains between 50 and 500 white cells per cubic millimeter,rarely more. Early in the disease there may be a atypical  more or less equal number of polymorphonuclear leukocytes and lymphocytes; but after several days, lymphocytes predominate in the majority of cases. In one study Neutrophilic plecytosis at the first spinal tap was found in 32.4% of TBM patients, who had a worse outcome when compared with those patients with typical CSF profiles. [33]

The protein content of the CSF is always elevated, between 100 to 200 mg/dL in most cases, but much higher if the flow of CSF is blocked around the spinal cord. Glucose is reduced to levels below 40 mg/dL. Patients with definite TBM had significantly higher CSF protein, lower CSF glucose, higher CSF cell count and lower CSF lymphocytes [34]

HIV-infected patients had a higher frequency of non-inflammatory CSF (absence of pleocytosis) and of infection by multidrug-resistant strains of Mycobacterium tuberculosis. Protein CSF levels were lower in HIV-infected patients, while and glucose concentration was similar in both groups.

The diagnosis of TBM is often difficult. A reliable, costeffective and rapid diagnostic test, which can be performed in any standard pathology laboratory,could be of help in the diagnosis of TBM. In one study the Adenosine deaminase (ADA) activity in cerebrospinal fluid (CSF) of TBM and non-TBM patients was compared . The results showed that mean CSF ADA activity was found to be significantly higher in CSF of TBM patients, This study concluded that ADA activity in the CSF of TBM patients, using a cutoff value 11.39 U/L/min, can be useful for the early differential diagnosis of TBM. This test can be performed in any pathology laboratory where more sophisticated methods are not available [35].

In another study concentrations of pro- and anti-inflammatory cytokines in serial blood and cerebrospinal fluid (CSF) samples from 21 adults who were being treated for tuberculous meningitis were measured. Results showed that CSF concentrations of lacta

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