Case: TB Meningitis

 JR
 19 yo, male, single, student
 Catholic
 Right-handed
 Admitted for the 1st time on Dec. 29, 2006

Chief Complaint
 Weakness

History of Present Illness

 4 weeks PTA
o Mild, generalized headache with generalized body malaise
 3 weeks PTA
o Headache, low grade fever (usually in afternoon)
 2 weeks PTA
o Headache increase in severity
o Fever persistent
o Consult (given Chloramphenicol & Mefenamic Acid)
o Fever lyzed (3-4 days)
o Nape & low back pain
 10 days PTA
o Stay in bed most of the time
o 5 days PTA
o Moderate to severe headache
o On & off fever with difficulty in ambulation
o Double vision
o Difficulty of moving his left arm & leg

Review Of Systems
 Vomiting
 Loss of balance
 Weight loss
 Hemoptysis
 Night sweats
 Chronic cough
 Slurring of speech

Past Medical History

 (-) HPN, diabetes, asthma
 (-) previous surgeries, allergies to food and drugs

Family Medical History

 (-) HPN
 (-) diabetes, heart dse
 (+) chronic cough - father
Personal/Social History
 Non-smoker, non-alcoholic beverage drinker
 (-) exposure to pigeon
 Non-promiscuous

Physical Exam
 Temp. 38.2, RR=20, HR=88, BP=120/80
 Pink conjunctivae, anicteric sclerae,enlarged and matted cervical lymph nodes
 Equal chest expansion, clear breath sounds, no crackles
 Distinct heart sounds, reg rate, no murmurs
 Abdomen flat, soft, non-tender, no masses
 Pink nailbeds, full pulses, (-) edema/cyanosis

Neurologic Exam
 Mental Status Exam
o Drowsy but arousable
o Inconsistently follows simple commands
o Disoriented
 Cranial Nerves
o CN II
 5 mm equal & sluggishly reactive to light
 Indistinct disk borders
 Hazy media
 AV ratio 1:3
 (+) hemorrhages; exudates on fundoscopy
 VA: 20/30 OU
o CN V
 Brisk corneals; bilateral, decreased sensation on the L face
o CN VI
 Bilateral esotropia, limited lateral gaze bilateral
o CN VII
 Shallow L nasolabial fold w/ symmetric forehead wrinkling
o CN IX
 Good gag
o CN XII
 Tongue deviated to the L
 Motor
 5/5 on the right; 3/5 on the left
 Sensory
 50% sensory deficit on pinprick & light touch on the left
 DTRs

Deep Tendon Reflex

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 (+) Babinski/clonus, L
 Autonomics
  Abnormal sweat pattern
 Meningeals
 Rigid neck
 (+) Kernig’s
 Brudzinski signs

Anatomic Localization
 Upper motor neuron lesion {(+) Babinski/clonus, hyperreflexia}
o Tracts involved
 Descending Tract
 Corticospinal Tract
 Corticobulbar Tract
 Ascending Tract
 Lateral spinothalamic tract (deficit on pinprick)
 Anterior spinothalamic tract (deficit on light touch)

Etiologic diagnosis
*Since there are signs of meningitis (rigid neck, (+) Kernig’s sign and (+) Brudzinski sign), the discussion
is focused on its etiologies.

Definition of Terms

Meningitis
 Refers to an inflammatory process of the leptomeninges and CSF within the subarachnoid space
Usually caused by an infection, but chemical meningitis may also occur in response to a nonbacterial
irritant introduced into the subarachnoid space.

o Focused on infection (family history:chronic cough - father)

Meningoencephalitis
 Refers to inflammation of the meninges and brain parenchyma

Classification of Infectious Meningitis

 Acute Pyogenic
o Usually bacterial meningitis
 Aseptic
o Usually acute viral meningitis
 Chronic
o Usually tuberculous, spirochetal, or cryptococcal

ACUTE IN CLINICAL COURSE

Acute Pyogenic (Bacterial) Meningitis
 Cause (organisms) – vary with the age of the patient
o In NEONATES
 Escherichia coli
 group B streptococci
 Streptococcus pneumoniae
 Listeria monocytogenes
o In INFANTS
 Haemophilus influenzae
 introduction of immunization against Haemophilus influenzae
o markedly reduced the incidence of meningitis associated with this
organism in the developed world
  S. pneumoniae
o The most prevalent organism in infants
o In ADOLESCENTS and in YOUNG ADULTS
 Neisseria meningitidis
 is the most common pathogen, with clusters of cases representing frequent
public health concerns.
 Patients typically show systemic signs of infection superimposed on clinical evidence of meningeal
irritation and neurologic impairment
o Headache
o Photophobia
o Irritability
o clouding of consciousness
o neck stiffness.
 A spinal tap yields
o cloudy or frankly purulent CSF, under increased pressure
o with as many as 90,000 neutrophils/mm3
o a raised protein level
o a markedly reduced glucose content
 Bacteria may be seen on a smear or can be cultured, sometimes a few hours before the neutrophils
appear.
 Untreated, pyogenic meningitis can be fatal.
 The Waterhouse-Friderichsen syndrome results from meningitis-associated septicemia with
hemorrhagic infarction of the adrenal glands and cutaneous petechiae.
o It is particularly common with meningococcal and pneumococcal meningitis.
 Effective antimicrobial agents markedly reduce mortality associated with meningitis.
 Immunosuppressed patient
o purulent meningitis
 may be caused by other agents, such as Klebsiella or an anaerobic organism
 may have an atypical course and uncharacteristic CSF findings, all of which make the
diagnosis more difficult.
 Morphology.
o The normally clear CSF is cloudy and sometimes frankly purulent.
o In acute meningitis, an exudate is evident within the leptomeninges over the surface of the brain
o The meningeal vessels are engorged and stand out prominently.
o The location of the exudate varies
 H. influenzae meningitis
 usually basal
 pneumococcal meningitis
 it is often densest over the cerebral convexities near the sagittal sinus.
o From the areas of greatest accumulation, tracts of pus can be followed along blood vessels on
the surface of the brain.
o When the meningitis is fulminant, the inflammation may extend to the ventricles, producing
ventriculitis.

 Microscopic examination
o neutrophils fill the entire subarachnoid space in severely affected areas and are found
predominantly around the leptomeningeal blood vessels in less severe cases.
o In untreated meningitis, Gram stain reveals varying numbers of the causative organism,
although they are frequently not demonstrable in treated cases
o In fulminant meningitis, the inflammatory cells infiltrate the walls of the leptomeningeal veins
with potential extension of the inflammatory infiltrate into the substance of the brain (focal
cerebritis).
 Phlebitis may also lead to venous occlusion and hemorrhagic infarction of the underlying brain.
 Leptomeningeal fibrosis and consequent hydrocephalus may follow pyogenic meningitis, although if it
is treated early, there may be little remaining evidence of the infection.
 In some infections, particularly in pneumococcal meningitis, large quantities of the capsular
polysaccharide of the organism produce a particularly gelatinous exudate that encourages arachnoid
fibrosis, chronic adhesive arachnoiditis.

Acute Aseptic (Viral) Meningitis

 Is a misnomer
 Clinical term referring to the absence of recognizable organisms in an illness with meningeal irritation,
fever and alterations of consciousness of relatively acute onset
 Generally viral
 Clinical course is less fulminant than that of pyogenic meningitis & CSF findings are different
 There is lymphocytic pleocytosis, the protein elevation is only moderate, and the sugar content
is nearly always normal
 Usually self-limiting & treated systematically
 70% of cases, pathogen can be identified, commonly an enterovirus; 80% of cases – echovirus,
coxsakievirus & nonparalytic osteomyelitis
 Morphology
o No distinct macroscopic characteristics except for brain swelling
 Microscopic examination
o Either no abnormality or a mild to moderate infiltration of the leptomeninges with lymphocytes

(the clinical course of the patient is chronic, the acute infections are ruled out)

CHRONIC IN CLINICAL COURSE

Fungal Meningoencephalitis
 Encountered primarily in immunocompromisedpatients
 Brain usually involved only late in disease
o When there is widespread hematogenous dissemination of the fungus, most often Candida
albicans, Mucor (vasculitis), Aspergillus fumigates (vasculitis), and Cryptococcus neoformans
(meningitis)
 Crytococcal meningitis
o Increasing frequency in association with AIDS, may be fulminant or fatal in as little as 2
weeksor indolent, evolving over months or years
o CSF may have few cells but a high concentration of protein
o CSF may have few cells but a high concentration of protein
o Mucoid encapsulated yeasts can be visualized in the CSF by India ink preparations & in
tissue sections by PAS & mucicarmine as well as silver stains

(NO EXPOSURE TO PIGEON, NON-PROMISCUOUS, CRYPTOCOCCAL MENINGITIS IS RULED OUT)

THE DIAGNOSIS IS TUBERCULOUS MENINGITIS
Tuberculous Mengitis
 Synonyms and related keywords:
o TBM
o TB
o Mycobacterium tuberculosis
o M tuberculosis
o Rich foci
o extrapulmonary tuberculosis
o tuberculous spinal meningitis
o tuberculous spondylitis
o tuberculous radiculomyelitis
 o TBRM
o tuberculous meningitis
o CNS infection
o Tuberculosis
o Pott disease
o spinal caries
o skeletal tuberculosis
 Pathophysiology
 Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM)
o result of an immunologically directed inflammatory reaction to the infection.
 The development of TBM is a 2-step process.
o 1st step

enter the host by droplet inhalation

↓
infect alveolar macrophages
↓
Localized infection escalates within the lungs
↓
dissemination to the regional lymph nodes
↓
produce the primary complex
↓
short but significant bacteremia is present that can seed
↓
tubercle bacilli to other organs in the body
↓
bacilli seed to the meninges or brain parenchyma
↓
formation of small subpial or subependymal foci of metastatic caseous lesions (Rich foci)
↓
Tuberculous pneumonia develops with heavier and more prolonged tuberculous bacteremia
↓
Dissemination to the CNS is more likely, particularly if miliary TB develops.

o 2nd step

increase in size of a Rich focus

↓
ruptures into the subarachnoid space
↓
The location of the expanding tubercle (ie, Rich focus) determines the type of CNS involvement
↓
Tubercles rupturing into the subarachnoid space cause meningitis
↓
Those deeper in the brain or spinal cord parenchyma cause tuberculomas or abscesses
↓
While an abscess or hematoma can rupture into the ventricle, a Rich focus does not
↓
A thick gelatinous exudate infiltrates the cortical or meningeal blood vessels
↓
inflammation, obstruction, or infarction
 Usual symptoms
o Headache
o Malaise
o Mental confusion
o Vomiting
 Moderate CSF pleocytosis made up of mononuclear cells or a mixture of polymorphonuclear and
mononuclear cells; the protein level is elevated, often striking, glucose content typically is
moderately reduced or normal
 Morphology
o Subarachnoid space contains a gelatinous or fibrinous exudate, most often at the base of the
brain, obliterating the cisterns and encasing the cranial nerves
o Discrete, white granules scattered over the leptomeninges
o Most common pattern is a diffuse meningoencephalitis

 Microscopic examination
o Mixture of lymphocytes, plasma cells and macrophages
o Well-formed granulomas, often with caseous necrosis and giant cells
o Arteries running through the subarachnoid space may show obliterative endarteritis with
inflammatory infiltrates in their walls, and marked intimal thickening
o Organisms can be seen with acid-fast stains
o The infectious process may spread to the choroid plexusus and ependymal surface, travelling
through the CSF
o Long standing duration
 Dense, fibrous adhesive arachnoiditis may develop, most conspicuous around the
base of the brain
o Development of single (or often multiple) well-circumscribed intraparenchymal mass
(tuberculoma), which may be associated with meningitis
 Several centimeters in diameter, causing significant mass effect
o Usually central core of caseous necrosis surrounded by a typical tuberculous granulomatous
reaction
o Calcification may occur in inactive lesions

 Physical
 Visual findings
o Papilledema
o fundus examination occasionally reveals
 retinal tuberculoma or a small grayish-white choroidal nodule, highly suggestive of TB
 These lesions are believed to be more common in miliary TB than in other forms of
TB.
 In children, may reveal pallor of the disc.
o Examination may elicit visual impairment.
 Neurologic findings
o Cranial neuropathies, most often involving CN VI, may be noted.
o CNs III, IV, VII
o less commonly, CNs II, VIII, X, XI, and XII, also may be affected.
o Focal neurological deficits may include monoplegia, hemiplegia, aphasia, and tetraparesis.
o Tremor is the most common movement disorder seen in the course of TBM.
o In a smaller percentage of patients
 abnormal movements, including choreoathetosis and hemiballismus, have been
observed, more so in children than adults.
 In addition, myoclonus and cerebellar dysfunction have been observed.
  Deep vascular lesions are more common among patients with movement disorders.
 Clinical Features
o Most serious complication
 Arachnoid fibrosis
 Produce hydrocephalous
 Obliterative endarteritis
o Produce arterial occlusion
o Infarction of the underlying brain
 Involves the spinal subarachnoid space
 Spinal roots may also be affected
 Infection by Mycobacterium tuberculosis in patients with AIDS
o Often similar in non-AIDS patient

Approach to diagnosis

Lab Studies
 Complete blood cell count
 Erythrocyte sedimentation rate
 Electrolytes: Mild-to-moderate hyponatremia is present in roughly 45% of patients, in some cases
constituting a true SIADH.
 Serum glucose level
 BUN and creatinine levels
 Serology for syphilis
 Complementation test or its equivalent for fungal infections
 Urinalysis
 CSF analysis
o Cell counts, differential count, cytology
o Glucose level, with a simultaneous blood glucose level
o Protein level
o Acid-fast stain, Gram stain, appropriate bacteriologic culture and sensitivity, India ink
stain
o Cryptococcal antigen and herpes antigen testing
o Culture for M tuberculosis (50-80% of known cases of TBM yield positive results)
o Polymerase chain reaction (PCR): Results imply that PCR can provide a rapid and
reliable diagnosis of TBM, although false-negative results potentially occur in samples
containing very few organisms (<2 colony forming units per mL).
o Syphilis serology
 Tuberculin test:
o Negative results from the purified protein derivative test do not rule out TB; if the 5-
tuberculin test skin test result is negative, repeat the test with 250-tuberculin test.
o Note that this test is often nonreactive in persons with TBM.
 Imaging Studies
o Chest radiography posteroanterior and lateral views may reveal hilar lymphadenopathy,
simple pneumonia, infiltrate, fibronodular infiltrate/cavitation, and/or pleural
effusion/pleural scar.
o CT scanning and MRI of the brain reveal hydrocephalus, basilar meningeal thickening,
infarcts, edema, and tuberculomas
o The characteristic CT finding is a nodular, enhancing lesion with a central hypodense
lesion (Weisberg, 1984).
o Contrast enhancement is essential.
o Early stages are characterized by low-density or isodense lesions, often with edema out
of proportion to the mass effect and little encapsulation.
 o At a later stage, well-encapsulated tuberculomas appear as isodense or hyperdense
lesions with peripheral ring enhancement.
o MRI and CT scanning are critical for the diagnosis of TBRM, revealing loculation and
obliteration of the subarachnoid space along with linear intradural enhancement.
o For tuberculous spinal meningitis, MRI shows that the subarachnoid space is obliterated,
with focal or diffusely increased intramedullary signal on T2-weighted images and
variable degrees of edema and mass effect.

Medical Care
 The duration of chemotherapy for TBM is unclear, and the benefits of adjuvant corticosteroids remain
in doubt. Death may occur as a result of missed diagnoses and delayed treatment.
 The best antimicrobial agents in the treatment of TBM include
o isoniazid (INH)
o rifampin (RIF)
o pyrazinamide (PZA)
o streptomycin (SM)
 all of which enter CSF readily in the presence of meningeal inflammation
 Ethambutol is less effective in meningeal disease unless used in high doses.
 The second-line drugs include ethionamide, cycloserine, ofloxacin, and para-amino salicylic acid
(PAS).
 INH, RIF, and PZA are bactericidal. RIF and SM achieve optimal CSF levels only when the meninges
are inflamed.
 Usually, intrathecal drugs are not necessary. Treatment is best started with INH, RIF, and PZA.
 The addition of a fourth drug is left to the choice of the local physicians and their experience, with little
evidence to support the use of one over the other.
 Evidence concerning the duration of treatment is conflicting.
 The duration of conventional therapy is 6-9 months, although some investigators still recommend as
many as 24 months of therapy.
 No guidelines exist as to the components and duration of treatment in the case of multidrug-resistant
TBM.
 In 2006, Walker et al report that BCG vaccination is partially protective against TB meningitis;
o therefore, a history of BCG vaccination or the presence of a BCG vaccination scar affords
some degree of reassurance when considering a diagnosis of TBM (grade C).

Surgical Care
 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.
 Studies suggest that prompt ventriculoatrial or ventriculoperitoneal shunting improves outcome,
particularly in patients presenting with minimal neurological deficit.
 Unless a mass effect is compromising vital structures, surgical intervention is rarely required in the
treatment of tuberculomas.