Meningitis (Leptomeningitis)

Sources :
1. Adam and Victor’s Principles of Neurology, 11th ed (2019)
2. Current Diagnosis & Treatment : Neurology, 3rd ed (2019)
3. Clinical Neurology (LANGE) 2018
4. J.B.M. Kuks, J.W. Snoek - Textbook of Clinical Neurology (2018, Bohn Stafleu van Loghum)

I. Tuberculous Meningitis
A. Definition
B. Epidemiology
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 and markedly since World War II. Beginning approximately 1985, there
has been a moderate increase in the incidence of systemic tuberculosis (and tuberculous
meningitis) in the United States—a 16 percent annual increase compared to an average
annual decline of 6 percent during the preceding 30 years (Snider and Roper). This was
partly due to the appearance of HIV. In fact, tuberculosis may be the first clinical
manifestation of HIV infection (Barnes et al); among patients with full-blown HIV, the
incidence of tuberculosis is almost 500 times the incidence in the general population
(Pitchenik et al). In developing countries, particularly in subSaharan 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. The trend of
increasing incidence has recently been reversed in regions of the world where HIV has
been brought under better control.[1]

C. General Considerations
Tuberculous meningitis should be considered in patients who present with a
confusional state, especially if there is a history of pulmonary tuberculosis, alcoholism,
corticosteroid treatment, HIV infection, or other conditions associated with impaired
immune responses. It should also be considered in patients from regions (eg, Asia, Africa)
or groups (eg, the homeless and inner-city drug users) with a high incidence of
tuberculosis.[3]

D. Pathogenesis & Pathology (Pathologic Findings)

1. Pathogenesis
Tuberculous meningitis is usually caused by the acid-fast organism
Mycobacterium tuberculosis and exceptionally, by Mycobacterium bovis,
Mycobacterium avian, Mycobacterium kansasii, and Mycobacterium fortuitum (the last
of these after neurosurgical procedures and cranial trauma). The emergence of HIV has
led to a marked increase in cases caused by both the main organism, and also by the
atypical mycobacteria. In a monograph as informative today as it was 70 years ago,
Rich described two stages in the pathogenesis of tuberculous meningitis: first a
bacterial seeding of the meninges and subpial regions of the brain with the formation of
tubercles, followed by the rupture of one or more of the tubercles and the discharge of
bacteria into the subarachnoid space. The concept that tuberculous meningitis always
originates in a tubercle (i.e., part of the miliary disease) in contrast to the conventional
 notion of hematogenous implantation in other bacterial meningitis, has been debated.
[1]
Tuberculous meningitis arises from hematogenous spread of infection from the
lungs or lymph nodes to the brain parenchyma, forming small tubercles (Rich foci) that
rupture into the subarachnoid space or ventricle in the initial weeks following airborne
mycobacterial acquisition. Less often there is spread from nearby otitis or skull
infection or reactivation of latent infection. In other patients, instead of a subacute
pattern of meningitis, after many years of asymptomatic infection, a ruptured
tuberculoma may cause fulminant meningitis. Stroke may result from arteritis in the
large vessels passing through the infected adhesive material at the base of the brain. If
meningeal fibrosis occludes the arachnoid villi, communicating hydrocephalus slowly
develops; acute obstructive hydrocephalus develops if sub-ependymal fibrosis or
midbrain swelling interfere with CSF flow through the ventricles.[2]
Tuberculous meningitis usually results from reactivation of latent infection with
Mycobacterium tuberculosis. Primary infection, typically acquired by inhaling bacillus-
containing droplets, may be associated with metastatic dissemination of blood-borne
bacilli from the lungs to the meninges and the surface of the brain. Here the organisms
remain in a dormant state in tubercles that can rupture into the sub arachnoid space at a
later time, resulting in tuberculous meningitis.[3]

2. Pathologic Findings
Small, discrete white tubercles are scattered over the base of the cerebral
hemispheres and to a lesser degree on the convexities. The brunt of the pathologic
process falls on the basal meninges, where a thick, gelatinous exudate accumulates,
obliterating the pontine and interpeduncular cisterns and extending to the meninges
around the medulla, the floor of the third ventricle and subthalamic region, the optic
chiasm, and the undersurfaces of the temporal lobes. There may be multiple small
abscesses (Fig. 31-3) or a more uniform exudate in the leptomeninges (Fig. 31-3). By
comparison, the convexities are little involved, possibly because the associated
hydrocephalus obliterates the cerebral subarachnoid space. Microscopically, the
meningeal tubercles are like those in other parts of the body, consisting of a central
zone of caseation surrounded by epithelioid cells and some giant cells, lymphocytes,
plasma cells, and connective tissue. The exudate is composed of fibrin, lymphocytes,
plasma cells, other mononuclear cells, and some polymorphonuclear leukocytes. The
ependyma and choroid plexus are studded with minute glistening tubercles. The
exudate also surrounds the spinal cord. Unlike the typical bacterial meningitides, the
disease process is not confined to the subarachnoid space but frequently penetrates the
pia and ependyma and invades the underlying brain, so that the process is truly a
meningoencephalitis.[1]
 Other pathologic changes depend on the chronicity of the disease process and
recapitulate the changes that occur in the subacute and chronic stages of the other
bacterial meningitides (see Table 31-1). Cranial nerves are often involved by the
inflammatory exudate as they traverse the subarachnoid space, indeed, far more often
than with typical bacterial meningitis. Arteries may become inflamed and occluded,
with infarction of brain. Blockage of the basal cisterns frequently results in a
meningeal, obstructive hydrocephalus; marked ependymitis with blocking of the CSF
in the aqueduct or fourth ventricle is a less-common cause. The exudate occasionally
predominates around the spinal cord, leading to multiple spinal radiculopathies and
compression of the cord.[1]
The main pathologic finding is a basal meningeal exudate containing primarily
mononuclear cells (Figure 4-13). Tubercles may be seen on the meninges and surface
of the brain. The ventricles may be enlarged as a result of hydrocephalus, and their
surfaces may show ependymal exudate or granular ependymitis. Arteritis can result in
cerebral infarction, and basal inflammation and fibrosis can compress cranial nerves.[3]
E. Prevention
Vaccination with BCG offers incomplete protection from CNS infection (52–84%)
but is recommended in areas of high prevalence. HIV coinfection is associated with a
higher incidence of meningitis and extrapulmonary infection, so screening and treatment
for this may prevent CNS involvement. Isoniazid given prophylactically to exposed
contacts helps limit acquisition of most infections. However, extensively drug-resistant
tuberculosis (XMDR) is transmitted through contacts more often than it is acquired during
inadequate treatment with first-line therapy. Thus, prevention of epidemics with XMDR
requires much public health effort with new gene probe screening and supervision of
prolonged treatment with multiple antibiotics, not just routine directly observed therapy.[2]

F. Clinical Features & Findings (Symptoms and Signs)

Tuberculous meningitis occurs in persons of all ages. Formerly, it was more frequent
in young children, but now it is more frequent in adults, at least in the United States. The
early manifestations are usually low-grade fever, malaise, headache (more than 50 percent
of cases), lethargy, confusion, and stiff neck (75 percent of cases), with Kernig and
Brudzinski signs. Characteristically, these symptoms evolve much less rapidly in
tuberculous than in bacterial meningitis, usually over a period of a week or two, sometimes
longer. In young children and infants, apathy, hyperirritability, vomiting, and seizures are
the usual symptoms; however, stiff neck may not be prominent or may be absent altogether.
[1]
Because of the inherent chronicity of the disease, signs of cranial nerve involvement
(usually ocular palsies, less-often facial palsies or deafness) and papilledema may be
present at the time that the infection is recognized (20 percent of cases). Occasionally, the
disease may present with the rapid onset of a focal neurologic deficit because of
hemorrhagic infarction, with signs of raised intracranial pressure or with symptoms
referable to the spinal cord and nerve roots. Hypothermia and hyponatremia have been
additional features in several of our cases at the time of discovery of the meningitis.[1]
In approximately two-thirds of patients with tuberculous meningitis there is evidence
of active tuberculosis elsewhere, usually in the lungs and occasionally in the small bowel,
 bone, kidney, or ear. In some patients, however, only inactive pulmonary lesions are found,
and in others there is no evidence of tuberculosis outside of the nervous system. As
mentioned, among our adult patients, tuberculous meningitis is now seen largely in those
with HIV, but also in alcoholics, and in people who have emigrated from Asia, Africa,
India, and certain locations in the former Soviet Union. Except for the emergence of
drugresistant organisms, the HIV infection does not appear to much change the clinical
manifestations or the outcome of tuberculous meningitis. However, others disagree with
this statement, pointing out that the course of the bacterial infection is accelerated in HIV
patients, with more frequent involvement of organs other than the lungs. Whether or not
HIV infection alters the natural history of tuberculous meningitis, treatment of the HIV
infection is of paramount importance and it has been recommended that it should be started
within 2 weeks of the onset of antituberculous therapy.[1]
If tuberculous meningitis is untreated, its course is characterized by confusion and
progressively deepening stupor and coma, coupled with cranial-nerve palsies, pupillary
abnormalities, focal neurologic deficits, raised intracranial pressure, and decerebrate
postures; usually, untreated, a fatal outcome follows within 4 to 8 weeks of the onset.[1]
Systemic symptoms—headache, anorexia, low-grade fever, personality change
including apathy, and overall “poor health” or malaise—can be present for many weeks
before meningeal signs such as back and neck pain or stiffness develop. Lymphadenopathy
is common. Cranial nerve involvement, especially of nerves III, IV, and VI, is present at
the time of diagnosis in one third of patients. Gradual cognitive impairment may progress
to coma; dementia has been described rarely. Seizures are more common in children.
Extrapyramidal signs are unusual, although posturing may be seen as cerebral edema
progresses. Hyponatremia, found in about half of meningitis patients, may contribute to
obtundation and seizures. Hypernatremia from diabetes insipidus is much less common.
Increased intracranial pressure in adults leads to nausea and vomiting in about 25–43% of
patients, with papilledema in 10–15%. Children frequently develop hydrocephalus, which
causes increased intracranial pressure as well. Infants have bulging fontanelles or
separation of sutures. Focal signs are usually attributable to stroke due to vasculitis in large
vessels crossing through fibrotic debris in the basilar meninges. A family history of
tuberculosis, usually pulmonary but occasionally in the skin, lymph nodes or elsewhere, is
found in 25% of children with tuberculous meningitis or tuberculoma. Without treatment,
the average duration of meningitis symptoms to death is approximately 5–8 weeks,
although some cases are more fulminant.[2]
Symptoms usually have been present for less than 4 weeks at the time of presentation
and include headache, fever, neck stiffness, vomiting, and lethargy or confusion. Weight
loss, visual impairment, diplopia, focal weakness, and seizures may also occur. A history of
contact with known cases of tuberculosis is usually absent.[3]
Fever, signs of meningeal irritation, and a confusional state are the most common
findings on physical examination, but all may be absent. Papilledema, ocular palsies, and
hemiparesis or paraparesis are sometimes seen.[3]

G. Laboratory Studies Findings

The most important diagnostic test is lumbar puncture, which preferably should be
performed before the administration of antibiotics. The 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 more-or-less-equal number of polymorphonuclear
leukocytes and lymphocytes, but after several days lymphocytes predominate in the
majority of cases. In some cases, however, M. tuberculosis causes a persistent
polymorphonuclear pleocytosis, the other usual causes of this CSF formula being Nocardia,
Aspergillus, and Actinomyces (Peacock). The protein content of the CSF is always elevated,
between 100 and 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, but rarely to the very
low values observed in conventional bacterial meningitis; the glucose falls slowly and a
reduction may become manifest only several days after the patient has been admitted to the
hospital. The serum sodium is often reduced, in most instances because of inappropriate
ADH secretion or an addisonian state due to tuberculosis of the adrenals. In the past, much
was made of a low concentration of CSF chloride.[1]
CSF analysis shows white cell counts ranging from 50–1000 cells/µL, with a mean of
235 cells/µL. Lymphocytes predominate, although neutrophils are seen early in the disease
course in many patients. Elderly and immunocompromised patients have fewer WBCs in
the CSF, which may even be acellular. The fluid is clear or has a “ground-glass”
appearance, with a clot of sediment formed at the top of the collection tube. Glucose level
is usually less than half of the serum level, or 30 mg/dL, but may be normal. Protein
concentration is elevated, often more than 150 mg/dL, with extreme elevation in the setting
of subarachnoid block by fibrous debris. Elevated lactate levels correlate adversely with
prognosis. Adenosine deaminase levels, although elevated, are not specific for tuberculosis.
[2]
Most children with tuberculous meningitis have positive tuberculin skin tests (85
percent) but the rate is far lower in adults with or without HIV: 40 to 60 percent in most
series. In the current era, interferon-gamma-release assay is used to document previous or
current tuberculosis infection. The blood test appears to be highly, but not perfectly,
sensitive and about 90 percent specific for active tuberculous infection in patients with
meningitis as indicated by Sali and coworkers but caution must be observed in endemic
areas where there are high rates of positivity. The test has been used in CSF with similar
results but it is not clear if this is valuable as a routine test.[1] Only one-half to two-thirds
of patients show a positive skin test for tuberculosis or evidence of active or healed
tubercular infection on chest X-ray; chest CT is more sensitive.[3]
The diagnosis is established by CSF analysis. CSF pressure is usually increased, and
the fluid is typically clear and colorless. Lymphocytic and mononuclear cell pleocytosis of
50 to 500 cells/mL is most often seen, but polymorphonuclear pleocytosis can occur early
and may give an erroneous impression of bacterial meningitis. CSF protein is usually more
than 100 mg/dL and may exceed 500 mg/dL, particularly in patients with spinal
subarachnoid block. The glucose level is usually decreased and may be less than 20 mg/dL.
[3]
The previously used conventional methods of demonstrating tubercle bacilli in the
spinal fluid are inconsistent and often too slow for immediate therapeutic decisions.
Success with the traditional identification of tubercle bacilli in smears of CSF sediment
stained by the Ziehl-Neelsen method is a function not only of their number but also of the
persistence with which they are sought. There are effective means of culturing the tubercle
bacilli; because their the quantity of bacteria is usually small, however, attention must be
paid to proper technique. The amount of CSF submitted to the laboratory is critical; the
more that is cultured, the greater the chances of recovering the organism. Unless one of the
newer techniques is used, growth in culture media is not seen for 3 to 4 weeks.[1] CSF
smear (of sediment after centrifuge) with Ziehl-Neelsen staining can be done rapidly, but
results are positive in less than 20% of patients. Because of low bacillary load in CSF, three
large-volume collections for culture are recommended and special media must be used.
Eight weeks of no growth are required to confirm a negative culture. Even so, culture is
positive only half of the time.[2] Acid-fast bacillus (AFB) smears of CSF (Figure 4-14)
should be performed in all cases of suspected tuberculous meningitis, but they are positive
in only a minority of cases.[3]

Now widely used is polymerase chain reaction amplification from the CSF, which
rapidly permits the detection of small amounts of tubercle bacilli. The sensitivity of this test
is stated to be close to 80 percent but there is a 10 percent false-positive rate. There is also a
rapid culture technique that allows identification of the organisms in less than 1 week.
However, even these new diagnostic methods may give uncertain results or take several
days to demonstrate the organism and they cannot be counted on to exclude the diagnosis.
For these reasons, if a presumptive diagnosis of tuberculous meningitis has been made and
cryptococcosis and other fungal infections and meningeal neoplasia have been reasonably
excluded, treatment can be instituted without waiting for the results of bacteriologic study.
[1]
Therefore, speed of diagnosis is much improved with nucleic acid–based
amplification (PCR) tests such as AMPLICOR or GeneXpert, which have a variable
sensitivity of 50–90% but excellent specificity of 98%. Ideally, these new techniques, with
added testing for rifampin resistance (GeneXpert MTB/Rif), should be performed whenever
tuberculous meningitis is suspected. Resistance to other antibiotics can be detected using
whole genome sequencing. Techniques such as microscopic observation assays have
shorter time to results (6 days) but traditional culture, which takes up to 3 weeks, remains
the only definite way of monitoring antibiotic sensitivity. Multidrugresistant tuberculous
meningitis is present in 3% of CSF isolates in India, using PCR techniques, with only 40%
of cultures being positive. In addition to resistance to isoniazid and rifampin, extensive
drug-resistant organisms do not respond to fluoroquinolones or injectable aminoglycosides.
 Risk factors for multidrug-resistant infection include being from endemic areas, HIV
infection, homelessness, and poverty.[2]
PCR of CSF is diagnostically helpful. Culturing M. tuberculosis from the CSF
usually takes several weeks and requires large quantities of spinal fluid for maximum yield,
so it is useful in confirming a presumptive diagnosis of tuberculous meningitis, but not in
deciding to begin treatment.[3]

H. Imaging Studies
Imaging procedures are informative in patients who present with or develop raised
intracranial pressure, hydrocephalus, or focal neurologic deficits. One or more
tuberculomas may be visualized (Figs. 31-3 and 31-4) or there may be deep cerebral
infarction from occlusion of vessels of the circle of Willis or one of its primary branches.
MR or CT angiography may demonstrate vascular occlusive disease from granulomatous
infiltration of the walls of arteries.[1]

CT and MRI scans show hydrocephalus in 80% of children and up to 23% of adults.
Basal meningeal enhancement is present (Figure 26–7), and thick “en plaque” meninges are
sometimes seen even without contrast administration in the basal cisterns. Stroke is present
in 15–30% and tuberculomas in 5–10% of scans, which are normal in up to 30% of patients
with meningitis. Chest radiograph demonstrates the existence of tubercular infection by
apical scarring, hilar lymphadenopathy, and infiltrates or miliary tuberculosis in 40–50% of
patients.[2]
 Only one-half to two-thirds of patients show a positive skin test for tuberculosis or
evidence of active or healed tubercular infection on chest X-ray; chest CT is more sensitive.
[3] A CT or MRI scan may show enhancement of the basal cisterns and cortical meninges
or hydrocephalus.[3]

I. Differential Diagnosis
Infection due to other pathogens such as fungi, syphilis, Brucella, and partially
treated bacteria and malignancy (especially lymphoma) can mimic tuberculous meningitis.
[2]

J. Complications
Complications include hyponatremia, hydrocephalus, brain edema, visual loss, cranial
nerve (especially III, IV, and VI) palsies, spinal subarachnoid block, and stroke, which
usually affects the internal capsule, basal ganglia, or thalamus.[3]
Morbidity rates are 25–50% in children and higher than 10% in adults. Many of the
complications are secondary to the extreme inflammatory response generated in non–HIV-
infected patients, even when corticosteroids are given to limit this. These include stroke due
to arteritis in small and medium vessels, tuberculomas, and acute hydrocephalus. Other
sequelae include seizures, developmental delay, SIADH, and hyponatremia, which increase
the risk of seizure and brain edema. Syringomyelia occasionally develops many years after
tuberculous meningitis, probably as a result of spinal cord vasculitis. Mortality rates of 2–
20% are cited, even in countries with access to diagnostic facilities and chemotherapeutic
 drugs, including directly observed therapy. Patients who are older than 60 years and those
who are immunodeficient are at increased risk. Optic atrophy can complicate tuberculosis
infection or its treatment. Neurologic complications of antibiotic therapy include
isoniazidinduced neuropathy, ethambutol-induced optic neuritis or other visual dysfunction,
streptomycin-induced ototoxicity and vestibular toxicity, and cycloserine-induced seizures.
[2]
Thirty percent of severely immunosuppressed patients can develop immune
reconstitution inflammatory syndrome, which is treated with steroids and prevented by
delaying antiviral therapy for several weeks. Even in patients who are not infected with
HIV, a paradoxical response to treatment with excessive neutrophilic response in CSF and
extreme inflammation leading to high mortality is sometimes present. This may relate to
genetic influences on eicosanoids that predict the host inflammatory response triggered by
infection. (Conversely, those patients who do not generate sufficient inflammation succumb
to the infection itself.)[2]

K. Treatment
In the United States, the CDC currently recommends a three-drug regimen of oral
antibiotics—daily isoniazid, 10–20 mg/kg (generally 300 mg in adults); rifampin, 10–20
mg/kg (600 mg); and pyrazinamide, 15–30 mg/kg (maximum, 2 g/day). British guidelines
add ethambutol, 15–25 mg/kg/day, for at least 2 months, followed by isoniazid and
rifampin for 4 more months. Suspicion for infection must be high as antibiotics must be
started before the diagnosis is confirmed. Local susceptibility patterns must be checked as
variability is common. Resistance is most common to isoniazid and rifampin, followed by
fluoroquinolones and pyrazinamide, although most information is based on pulmonary
infection, not meningitis.[2]
The World Health Organization recommends the same regimen, plus streptomycin,
20–40 mg/kg/day (maximum, 1 g/day) for 4 weeks, then 7 months of therapy with isoniazid
or rifampin. In immunosuppressed patients, or for those at high risk of infection with
multiple drugresistant organisms, streptomycin 15 mg/kg intramuscularly daily (or highest
tolerated dose), para-aminosalicylic acid, ethionamide, cycloserine, capreomycin,
kanamycin, amikacin, or clofazimine can be added and continued for at least 12 months.
Such prolonged courses of therapy and upward dose titration are required because of poor
neutrophilic reaction to infection and for some antibiotics, rapid acetylation or poor
penetration into the CNS. Also, ethambutol and streptomycin are bacteriostatic, not
bactericidal. If directly observed therapy allows confidence in adherence to treatment,
ineffective antibiotics should be discarded after cultures establish sensitivities. Similarly,
doses of rifampin and isoniazid can be augmented as tolerated, as traditional doses were set
as low as possible when medication was very expensive and demand was high in places
with limited resources. In one case report, intrathecal isoniazid was beneficial but difficult
to administer. Isoniazid must be given with pyridoxine (vitamin B6) 50 mg daily to prevent
peripheral nerve damage.[2]
Dexamethasone, 0.5–1.5 mg/kg/day, has been effective in reducing mortality in
adults and children, although the reduction in morbidity has been variable. The drug is
initially administered intravenously, followed by orally, with taper to complete the course
after 8 weeks. Efficacy is related to reduction of cytokines and inflammatory response to
infection. Noncorticosteroid anti-inflammatories can also be used.[2]