An overview of TUBERCULOUS MENINGITIS hemiplegia

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An overview of TUBERCULOUS MENINGITIS hemiplegia Powered By Docstoc
					‫بسم هللا الرحمن الرحيم‬

         ‫‪‬‬   ‫1‬
  An overview of :
           Edited by :
Consultant of infectious diseases
       Imbaba fever hospital

       Chronic Meningitis
 Definition:
chronic inflammation of the meninges with
  characteristic neurological syndromes,
  lasting more than 4 weeks, and associated
  with persistent inflammatory response (CSF

      Chronic Meningitis
 Pathology:
chronic meningitis is not a ― neat ―
 syndrome. Pia-arachnoid covers many
 different structures, such as: cerebral
 hemispheres, brain-stem, cerebellum,
 cranial nerve roots, spinal cord and spinal

         Chronic Meningitis
 Pathology:
Therefore, chronic meningitis can manifest
  by :
cranial nerve palsy,
optico-chiasmatic arachnoiditis
meningovascular syndromes due to infarction,
hydrocephalus due to accumulation of purulent exudate
  around the base of the brain, or meningeal fibrosis
  ………… isolated, or combined forms.
   Clinico-pathological correlation
 Pure pia-arachnoiditis: Headache, back
  pain, neck stiffness.Kerning’s & Brudzinski
 Encephalopathy / Encephalitis:
  Convulsion, confusion, stupor, coma
  grasping and sucking reflex.

 Clinico-pathological correlation
 Cranial neuropathy: Facial weakness,
  double vision, hearingloss, dysphagia,
  dysphonia, dysarthria.
 Myeloradiculitis: radicular pain,
  weakness or numbness of extremities,
  reflex changes, Babinski sign,
  sphincter dysfunction.

 Clinico-pathological correlation
 Meningovascular syndromes:
  bilateral or unilatera hemiplegia,
  cortical blindness, seizure,...
 Hydrocephalus: Psychomotor
  retardation, unsteadiness o gait,
  incontinence, papilledema.
           Chronic Meningitis
            Common causes:
 Infectious
a: bacterial: Tuberculosis, Brucellosis,
 syphilis, Lyme diseas
b: Viral: HIV (rarely HSV or other viral
c: Fungal: cryptococcus, candida,
d: Protozoal & helminthic: (rare)
        Chronic Meningitis
         Common causes:
 non-infectious
a: neoplastic: carcinomas,
  lymphomas, leukemias, some primary
  brain tumors
b: chemical
c: drug induced
d: vasculitis
          Chronic Meningitis
           Common causes:
 non-infectious
granulomatous: SLE, Behcet’s syndrome,
  primary angiitis of CNS, sarcoidosis, Vogt-
  Koyanagi- Harada syndrome. Vogt-
  Koyanagi- Harada syndrome is
  characterized by recurrent meningo-
  encephalitis, uveitis, retinal detachment,
  cataract, glaucoma, alopecia and whitening
  of eyelash and eyebrows.

      Tuberculous meningitis:
                Global view
 Presently, over 2 billion (2000 million)
  people in the world are infected with TB (ie,
  one third of the world's population), of which
  about 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.
      Tuberculous meningitis:
                Global view
 The developing world has 1.3 million cases
  of TB and 40,000 TB-related deaths
  annually among children younger than 15
 TBM complicates approximately 1 of every
  300 untreated primary TB infections.
 In sub-Saharan Africa, because of the
  effects of human immunodeficiency virus
  and AIDS, tuberculosis is now the most
  common form of bacterial meningitis.
     Tuberculous meningitis:
               Global view
 In countries with a high incidence of
  tuberculosis, tuberculous meningitis is
  typically a disease of young children that
  develops three to six months after primary
 In countries with a low incidence of
  tuberculosis, tuberculous meningitis more
  commonly affects adults, and although it
  may follow primary infection, it more
  frequently arises from the reactivation of a
  dormant subcortical or meningeal focus.
                       14   15   16
      World TB Day
 commemorates the day 24
   march in 1882 when Dr
Robert Koch announced his
discovery of the TB bacillus.
  Epidemiology of TB in Egypt
 Ancient Egypt gives us
  some of the earliest
  evidence for
  tuberculosis from the
  ancient world. There
  are several related
  types of the tubercle

 The latest statistics indicate that the
 number of people infected with TB in
Egypt has gone down from 160 cases
per 100,000 inhabitants in 1952, to 16
    cases per 100,000 inhabitants,
 according to Hanem Zaher, general
  manager of the directory of chest
          diseases in Egypt.

   Epidemiology of TB in Egypt
 Tuberculosis prevalence rate per 100,000

 population (WHO)    25
 Tuberculosis death rate per 100,000

 (WHO)   5  Prevalence refers to active
 disease, not latent infection.

 In terms of incidence of
  tuberculosis, Egypt is ranked
  among the mid-level incidence
  countries. Tuberculosis in Egypt is
  considered the second most
  important public health problem
  after Bilharziasis.
 The Annual Risk of Infection - ARI :The
  ARI represents the percentage of population
  that will be infected by tubercle bacilli every
  year. It has been estimated that each
  percent of ARI corresponds to 50 to 60 new
  smear-positive tuberculosis cases per
  100,000 inhabitants per year.

 The Annual Risk of Infection - ARI :Currently,
  the ARI in Egypt stands at 0.32 percent
  (Tuberculin Survey 1994-1996). Accordingly, one
  can expect 15-20 new smear-positive pulmonary
  tuberculosis cases for each 100,000 population
  per year.

 The Annual Risk of
  Infection - ARI:Taking into
 consideration the confidence
 limits, the expected number of
 new smear-positive cases in
 Egypt ranges from 9,300 to
    The actual prevalence of tuberculosis in Egypt
     :The available data on actual prevalence of
     tuberculosis is limited. There are a number of
     reasons for this:
1.   Poor registration of TB cases at MOHP
2.   Private sector does not notify TB cases
3.   Incomplete notification by HIO, Prison, Army,
     Police and Universities
4.   Inappropriate use of diagnostic tools: too much
     reliance upon X-rays, leading to undiagnosed
     smear-positive tuberculosis cases
  Pathogenesis of tuberculous
 Our understanding of the
  pathogenesis of tuberculous
  meningitis dates from the
  meticulous studies that Arnold Rich
  and Howard McCordock conducted
  at Johns Hopkins Hospital in the
  1920s and 1930s.
   Pathogenesis of tuberculous
 In experiments in animals, they showed that
  the meninges could not be directly infected
  by hematogenous spread;
 then, in a brilliant series of postmortem
  examinations, they demonstrated that in
  nearly every case, there was a subcortical
  or meningeal focus from which bacilli gained
  access to the subarachnoid space.

   Pathogenesis of tuberculous
 Neurological tuberculosis
  may develop during :
 primary infection or
reactivation as a consequence of
 immune suppression (most importantly:

   Pathogenesis of tuberculous
Mycobacterium tuberculosis bacilli enter the
 host by droplet inhalation, the initial point of
 infection being the alveolar macrophage.
 Localized infection escalates within the lung,
 with dissemination to the regional lymph
 nodes to produce the primary complex.
 During this stage, a short but significant
 bacteremia is present, which can seed
 tubercle bacilli to other organs in the body.

   Tuberculous meningitis:
Bacilli seed to the meninges or
 brain parenchyma, resulting in the
 formation of small subpial or
 subependymal foci of metastatic
 caseous lesions. These are termed
 Rich foci, after the original
 pathologic studies of Rich and
 McCordick.     30
   Tuberculous meningitis:
The second step in the
 development of TBM is increase in
 size of a Rich focus until it ruptures
 into the subarachnoid space.
The location of the expanding
 tubercle (ie, Rich focus) determines
 the type of CNS involvement.

   Tuberculous meningitis:
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.
   Tuberculous meningitis:
 A thick gelatinous exudate infiltrates
  the cortical or meningeal blood vessels,
  producing inflammation, obstruction, or
 Basal meningitis accounts for the
  frequent dysfunction of cranial nerves
  III, VI, and VII, eventually leading to
  obstructive hydrocephalus due to
  obstruction of basilar cisterns.

  Tuberculous meningitis:
Subsequent neurological
 pathology is produced by
 3 general processes:
adhesion formation,
obliterative vasculitis, and
encephalitis or myelitis.
         Pathological effects
 Papilledema is the most common visual effect of
  TBM. In children, papilledema may progress to
  primary optic atrophy and blindness due to direct
  involvement of the optic nerves and chiasma by
  basal exudates (ie, opticochiasmatic
 In adults, papilledema may progress more
  commonly to secondary optic atrophy, provided
  the patient survives long enough.
 Other causes of visual impairment include
  chorioretinitis, optic neuritis, internuclear
  ophthalmoplegia and, occasionally, abrupt onset
  of painful ophthalmoplegia.

        Pathological effects
Cranial nerve VI is affected most frequently
 by TBM, followed by III, IV, VII and, less
 commonly, CN II, VIII, X, XI, and XII (Zuger
 et al, 1997).
Sudden onset of focal neurological deficits,
 including monoplegia, hemiplegia, aphasia,
 and tetraparesis, has been reported.
 Vasculitis still appears to be the leading
        Pathological effects
Tremor is the most common movement
 disorder seen in the course of TBM. In a
 smaller percentage of patients, abnormal
 movements, including choreoathetosis and
 hemiballismus, have been observed, more
 so in children than in adults. In addition,
 myoclonus and cerebellar dysfunction have
 been observed. Deep vascular lesions are
 more common among patients with
 movement disorders.
 The meninges are
  greatly thickened
  around the base
  of the brain and
  brain stem and a
  thick grey shaggy
  exudate is seen in
  the area.
 Over the cortical
  surfaces the gyri
  are flattened and
  the sulci narrowed
  indicating cerebral
   Tuberculous meningitis: In tuberculous meningitis there is a tendency for the
    exudate to be primarily located on the under surface of the brain, particularly over
    the ventral surface of the brain stem. Because the meningitis is chronic,
    organization of the exudate by fibrous connective tissue plays a prominent part in
    the matted appearance of the exudate.

                                                             39   40
 Clinical presentations of TBM
 In an immunocompetent individual, CNS
  TB usually takes the form of meningitis
  that causes :
an acute to subacute illness characterized
  by fever, headache, drowsiness,
  meningism, and confusion over a period of
  approximately 2-3 weeks.
During the prodromal period, nonspecific
  symptoms are present, including fatigue,
  malaise, myalgia, and fever.

   Clinical presentations of TBM
Often, in the first stage of meningitis,
 patients have infection of the upper
 respiratory tract, a fact that should be
 remembered when the concurrent fever and
 irritability or lethargy seem out of proportion
 to the obvious infection or when general
 symptoms persist after improvement in the
 local manifestations.
Fever and headache can be absent in 25%
 of patients and malaise in as many as 60%
 of patients.          42
  Clinical presentations of TBM
Headache and mental status changes are
 much more common in the elderly.
Visual symptoms include visual impairment
 or blindness and, occasionally, abrupt onset
 of painful ophthalmoplegia.
Sudden onset of focal neurological deficits,
 including monoplegia, hemiplegia, aphasia,
 and tetraparesis, has been reported.

  Clinical presentations of TBM
Tremor and, less commonly, abnormal
 movements, including choreoathetosis and
 hemiballismus, have been observed, more
 so in children than adults. Myoclonus and
 cerebellar dysfunction also have occurred.
The syndrome of inappropriate antidiuretic
 hormone secretion (SIADH) is a common
 complication and is linked to a poor
  Clinical presentations of TBM
"Less frequent" presentations
 include :
atypical febrile seizures in
isolated cranial nerve palsies,
bilateral papilledema, and
acute confusional state.
 Clinical presentations of TBM :

Tuberculous spinal
meningitis may present
in acute, subacute, or
chronic form.
  Clinical presentations of TBM :
The acute form :
  – The clinical picture in primary spinal
    meningitis often is characterized by :
  myelopathy, with
  progressive ascending paralysis,
    eventually resulting in
  basal meningitis and associated
  Clinical presentations of TBM :
The acute form :
  – In some cases with acute onset, in
    addition to variable constitutional
    symptoms, patients develop acute
    paraplegia with sensory deficits and
    urinary retention.
  – The clinical picture often mimics
    transverse myelitis or Guillain-Barré
   Clinical presentations of TBM :
The subacute form :
  – The subacute form often is dominated by
    myeloradiculopathy, with radicular pain and
    progressive paraplegia or tetraplegia.
  A less virulent chronic form might mimic a
    very slowly progressive spinal cord
    compression or a nonspecific arachnoiditis.
  – The dorsal cord seems to be affected most
    commonly, followed by the lumbar and the
    cervical regions.
    Clinical presentations of TBM :
     Tuberculous radiculomyelitis
 is a complication of TBM that has been reported
  only rarely in the modern medical literature.
  – TBRM develops at various periods after TBM, even in
    adequately treated patients after sterilization of the
    cerebrospinal fluid (CSF).
  – The most common symptoms are subacute paraparesis,
    radicular pain, bladder disturbance, and subsequent
  – As in other forms of paradoxical reactions to anti-TB
    treatment, evidence shows that steroid treatment might
    have a beneficial effect.

 Clinical presentations of TBM :
 Two rare forms of TBM are
  serous TB meningitis and TB
 –Serous TB meningitis
  is characterized by signs and
  symptoms of a mild meningitis
  with spontaneous recovery.

Clinical presentations of TBM :
–TB encephalopathy usually occurs in
  a young child with progressive primary TB;
– the presentation is that of reduced levels of
  consciousness with few focal signs and minimal
– Diffuse edema and white matter pallor with
  demyelination are found on pathologic
– The pathogenesis is uncertain but is presumed
  to be immune mediated. Diagnosis is important,
  as anecdotal reports suggest a good response
  to corticosteroids.
 Staging the severity of the disease
 In 1948, British Medical Research Council
  developed a method for staging the severity
  of the disease.
   – Stage I describes the early nonspecific
     symptoms and signs, including apathy,
     irritability, headache, malaise, fever,
     anorexia, nausea, and vomiting, without
     any alterations in the level of

Staging the severity of the disease

–Stage II describes altered
 consciousness without coma or
 delirium but with minor focal
 neurological signs. Symptoms and
 signs of meningism and meningitis
 are present, in addition to focal
 neurological deficits, isolated cranial
 nerve palsies, and abnormal
 involuntary movements.
Staging the severity of the disease

–Stage III describes an
 advanced state with stupor or
 coma, severe neurological
 deficits, seizures, posturing,
 and/or abnormal movements.
– Prognosis is related directly to the clinical stage
  of diagnosis.
  Physical examination
 Perform careful general, systemic, and
  neurologic examinations, looking especially
BCG scar,
papilledema and tuberculomas on
and meningismus.

    Physical examination
 Visual findings :
  – Apart from papilledema, fundus examination
    occasionally might reveal the presence of a
    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
  – In children, fundus examination may reveal
    pallor of the disc.
  – Examination may elicit visual impairment.
      Physical examination
 Neurologic findings :
  – Cranial neuropathies, most often involving CN VI, may
    be noted. CN III, IV, VII and, less commonly, II, VIII, X,
    XI, and XII also may be affected.
  – Focal neurological deficits may include monoplegia,
    hemiplegia, aphasia, and tetraparesis.
  – Tremor is the most common movement disorder seen in
    the course of TBM. 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

           Differential diagnosis :
   Acute Disseminated            Cavernous Sinus
   Encephalomyelitis                Syndromes
   Aseptic Meningitis            Cerebral Venous
   Basilar Artery                   Thrombosis
    Thrombosis                    Confusional States
   Bell Palsy                       and Acute Memory
   Brucellosis
                                  Dizziness, Vertigo, and
   Cauda Equina and                 Imbalance
   Conus Medullaris              Ependymoma
    Syndromes                  59
        Differential diagnosis :
 Epidural Hematoma           Leptomeningeal
 Epilepsia Partialis          Carcinomatosis
  Continua                    Lyme Disease
 Focal Status                Metastatic Disease to
  Epilepticus                  the Brain
 HIV-1 Associated CNS        Metastatic Disease to
  Complications                the Spine and Related
 Intracranial Epidural        Structures
  Abscess                     Multiple Sclerosis
                              Neurocysticercosis
          Differential diagnosis :
   Neuropathy of Leprosy
   Neurosarcoidosis
   Neurosyphilis
   Oligodendroglioma
   Spinal Epidural Abscess
   Status Epilepticus
   Subdural Empyema
   Subdural Hematoma
   Vitamin B-12 Associated Neurological Diseases

Other Problems to be Considered:
 TBM needs to be differentiated from
  other forms of acute and subacute
  meningitis, PTM ,viral infections, and
  cerebral abscess. The radiological
  differential diagnosis includes
  cryptococcal meningitis,
  cytomegalovirus encephalitis,
  sarcoidosis, meningeal metastases,
  and lymphoma.
Predictives of the diagnosis of TBM
 In one study, 5 features were
  independently predictive of the diagnosis
  of TBM (P<0.007):
(1) prodromal stage lasting 7 days or
(2) optic atrophy on fundal examination,
(3) focal deficit,
(4) abnormal movements, and
(5) CSF leukocytes comprising less than
  50% polymorphs.
Predictives of the diagnosis of TBM

 Validation of these criteria on another
  set of 128 patients revealed a
  sensitivity of 98.4% if at least one
  feature were present, and specificity of
  98.3% if 3 or more were present. This
  simple rule is useful for physicians
  working in regions where TB is
     Diagnosis of
Tuberculous meningitis:

                Spinal tap
– Typically, the pressure is higher than normal.
– Inspect the CSF visually and note its gross
  appearance. It typically is clear or slightly turbid.
  If the CSF is left to stand, a fine clot resembling
  a pellicle or cobweb may form. This faintly
  visible "spider's web clot" is due to the very high
  level of protein in the CSF (ie, 1-8 g/L, or 1000-
  8000 mg/dL) typical of this condition.
– Hemorrhagic CSF also has been recorded in
  proven cases of TBM; this is attributed to
  fibrinoid degeneration of vessels resulting in
  hemorrhage (Smith et al, 1947).

               Spinal tap
– Acellular CSF has been reported in elderly
  patients and patients who are HIV positive.
–CSF typically shows elevated
 protein level, marked
 hypoglycorrhachia, and a
 pleocytosis, initially polymorphs
 then lymphocytes.
             Diagnosis of
   Tuberculous meningitis:
 CSF analysis
  usually reveals
Diagnostic yield of
 AFB smear is 10-30%,
CSF culture (after 6-8
 weeks): 45-70% and
PCR is 70-75%.

                Diagnosis of
    Tuberculous meningitis:
 CSF culture  by Bactec fluid media system
  shortens the period of culturing to 1-2 weeks.
 Dot-immunobinding assay
  – A dot-immunobinding assay (Dot-Iba) has
    been standardized to measure circulating
    antimycobacterial antibodies in CSF
    specimens for the rapid laboratory
    diagnosis of TBM (Sumi et al, 2000).

        Diagnosis of
    Tuberculous meningitis
 Dot-immunobinding assay
  – Specific CSF-immunoglobulin G (IgG) antibody
    to M tuberculosis from a patient with culture-
    proven TBM was isolated and coupled with
    activated Cynogen bromide-Sepharose 4B. A
    14-kilodalton antigen present in the culture
    filtrates of M tuberculosis was isolated by
    immunosorbent affinity chromatography and
    used in the Dot-Iba to quantitate specific
    antimycobacterial antibodies.
              Diagnosis of
   Tuberculous meningitis:
 Dot-immunobinding assay
 – The Dot-Iba gave positive results in all 5
   patients with culture-proven TBM; no false
   positive results were obtained from CSF
   specimens from patients with partially treated
   pyogenic meningitis.
 – In the opinion of Sumi et al, the Dot-Iba
   developed in their laboratory is a simple, rapid,
   and specific method and, more importantly, is
   suited for the routine application in laboratories
   with limited resources.
   Use of neurochemical markers has been
investigated in patients with aseptic meningitis
                   or TBM. :
  – CSF levels of amino acids, nitrite (a metabolite of nitric oxide),
    vitamin B-12, and homocysteine were quantitated in both groups of
  – Excitatory amino acids aspartic acid and glutamic acid, GABA,
    glycine, and tryptophan all were increased significantly in both
    groups, whereas levels of taurine were decreased and levels of
    phenylalanine were increased only in patients with TBM.
  – Levels of nitrite and its precursor arginine were significantly higher
    in patients with TBM, whereas they were unchanged in patients
    with aseptic meningitis.
  – Levels of homocysteine were increased significantly and levels of
    vitamin B-12 decreased only in patients with TBM, whereas these
    levels were unchanged in patients with aseptic meningitis. This
    indicates that patients with TBM are particularly prone to vitamin B-
    12 deficiency, resulting in increased levels of homocysteine and
    free radicals, showing the importance of these biological markers in
    development and design of therapeutic approaches.

   Tuberculous meningitis:
Tuberculosis skin test may be negative.
Therefore, with presumptive
 diagnosis, empirical
 antituberculosis therapy (isoniazid,
 rifampin, pyrazinamide and
 streptomycin) must be started as
 early as possible.
 Role of imaging in the diagnosis of
 Chest x-ray: Posteroanterior and lateral
  views may reveal the following:
  –Hilar lymphadenopathy
  –Simple pneumonia
  –Fibronodular infiltrate/cavitation
  –Pleural effusion/pleural scar
 Role of imaging in the diagnosis of
 CT scan and MRI of the brain
  reveal :
basilar meningeal thickening,
edema, and

Role of imaging in the diagnosis of
– Although CT scan and MRI lack
  specificity, they help in monitoring
  complications that require neurosurgery.
– MRI and CT scan are critical for the
  diagnosis of TBRM, revealing loculation
  and obliteration of the subarachnoid
  space along with linear intradural

Role of imaging in the diagnosis of
– Tuberculous spinal meningitis
     – On MRI, the subarachnoid space is obliterated, with focal or
       diffusely increased intramedullary signal on T2-weighted
       images and variable degrees of edema and mass effect.
     – With gadolinium, contrast enhancement often is seen
       surrounding the spinal cord and the roots. The nerve roots
       may appear clumped and show contrast enhancement,
       secondary to inflammation and edema, depending on the
       degree of involvement.
     – Rarely, tuberculomas occur in the spinal cord, and they may
       occur on the surface of the cord, as dural lesions, or deep
       inside in an intramedullary location.
     – Less frequently, intramedullary tuberculous abscesses have
       been reported
Role of imaging in the diagnosis of
– Perform MR angiogram (MRA) and venogram if
    Findings on conventional 4-vessel angiogram as well as MRA
     most typically have included evidence of hydrocephalus,
     narrowing of the arteries at the base of the brain, and narrowed
     or occluded small and medium-sized arteries.
    Imaging studies, both CT scan and MRI, are done with and
     without enhancement, as long as the renal functions of the
     patient are not compromised.
    Basal cisterns often enhance strikingly, corresponding to the
     thick exudate that is observed pathologically. The quadrigeminal
     cistern, interpeduncular fossa, ambient cistern, and chiasmatic
     region are particularly involved, owing to associated
     arachnoiditis. Meningeal enhancement is more common in HIV-
     infected patients.
    Contrast enhancement further delineates focal parenchymal
     and space-occupying lesions, with or without associated
Role of imaging in the diagnosis of
– Skull radiography may reveal evidence of increased
  intracranial tension in children, in the form of sutural
– During follow-up of patients with TBM, intracranial
  calcification may be evident.
    Calcification occurred in two main sites: (1) more commonly, in
     the basal meninges and (2) to a lesser extent, within brain
    Calcification is generally in the sellar region, either as a single
     lesion or as a cluster of small calcifications. These calcifications
     sometimes harbor tubercle bacilli, which may be responsible for
     a relapse of the disease.

 Axial T2weighted MRI shows
  low signal intensity in
  nonenhancing central portion
  of mass (arrow), consistent
  with caseation necrosis.
  Surrounding edema and
  enhancing wall reveal high
  signal intensity.

          Treatment of TBM

 Treatment involves :
1) chemotherapy to control and eliminate the
2) management of hydrocephalus and
   elevated intracranial pressure,
3) and immunomodulation.

       Chemotherapy for TBM
 The best antimicrobial agents in the treatment of
  TBM include :
 isoniazid (INH),
 rifampin (RIF),
 pyrazinamide (PZA), and
 streptomycin (SM),
 all of which enter CSF readily in the presence of
  meningeal inflammation.
 Ethambutol (EMB) is less effective in meningeal
  disease unless used in high doses.

 Antituberculous therapy for TBM
 The second-line drugs include ethionamide,
  cycloserine, ofloxacin, and para-amino salicylic
  acid (PAS).
 INH, RMP, and PZA are bactericidal.
 RMP 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 choice of the
  local physicians and their experience, with little
  evidence to support the use of one over the other.

    Quinolones therapy for TBM
 Data on the use of these agents for the treatment of TB are
 A study from Japan reported patients who had chronic
  cavitary lung TB and were excreting bacilli resistant to
  various anti-TB agents. Of 17 patients who received
  ofloxacin in combination with other anti-TB agents as
  single doses of 300 mg daily for 6-8 months, 14 patients
  showed a decrease in culture positivity and 5 had a
  negative conversion. No adverse effects were observed.
 Another study of ofloxacin reported 22 patients receiving
  300 or 800 mg of ofloxacin in a single daily dose for 9 mo
  to 1 y. All patients tolerated the drug well, and indications
  were noted of higher efficacy at higher doses
   Duration of therapy for TBM
 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
 No guidelines exist as to the components
  and duration of treatment in the case of
  multidrug-resistant TBM.

  Duration of therapy for TBM
 Standard short-course
  chemotherapy involving a two-
  month intensive phase of treatment
  with isoniazid, rifampin,
  pyrazinamide, and ethambutol and
  a four-month continuation phase of
  treatment with isoniazid and
  rifampin is recommended by the
  World Health Organization.
    Duration of therapy for TBM
 Other recommendations,
  including those of the American
  Thoracic Society, are more
  conservative and include a
  continuation phase of six or
  eight months of treatment with
  isoniazid and rifampin.

Management of hydrocephalous
 If the hydrocephalus is
  noncommunicating — a condition
  that can be demonstrated on air
  encephalography — a
  ventriculoperitoneal shunt should
  be placed immediately, which may
  lead to dramatic improvement.
Management of hydrocephalous
 If the hydrocephalus is communicating,
  medical treatment with furosemide and
  acetazolamide will often normalize the
  intracranial pressure within one to two
  weeks. Patients who do not have a
  response to this treatment may undergo
  elective placement of a ventriculoperitoneal

                        Hint :
 There are     two   main types          of    hydrocephalus,
  obstructive            and                   communicating.

  Obstructive         hydrocephalus           refers to
  obstruction of the CSF pathways within the interior of
  the    brain     or   at   the    tentorial     notch.

  Communicating hydrocephalus                    refers
  to an inability of the CSF to pass through the
  arachnoidal villi to get back into the blood stream.
  This can result when the arachnoidal villi become
  inflamed by infection or blood with the inflammatory
  process blocking the microscopic pores through
  which the CSF must pass from the subarachnoid
  space into the blood

 The usefulness of immunomodulation rests on the
  assumption that the inflammatory process in
  tuberculous meningitis, and the vasculitis in
  particular, is a hypersensitivity response.
  Corticosteroids have a long and checkered history
  in this disease, as is again illustrated by Thwaites
  et al. Our own practice in young children is to use
  prednisone for the first month of treatment at a
  dose of 2 to 4 mg per kilogram of body weight, up
  to a maximum of 60 mg, taking into account the
  fact that rifampin accelerates corticosteroid
 Peter R. Donald, M.D., and Johan F. Schoeman, M.D.
   Volume 351:1719-1720 October 21, 2004 Number 17
  Dexamethasone for the
 Treatment of Tuberculous
Meningitis in Adolescents and
  Volume 351:1741-1751 October
       21, 2004 Number 17

        Rationale for the study
 A meta-analysis of all randomized
  controlled trials of corticosteroids for
  tuberculous meningitis suggested that
  corticosteroids were effective in
  reducing the risk of death in children
  but not in patients over 14 years of age
  . Cochrane Database Syst Rev 2000;3:CD00224-CD00224

 They performed a randomized, double-blind,
  placebo-controlled trial in Vietnam in 545 patients
  over 14 years of age who had tuberculous
  meningitis, with or without HIV infection, to
  determine whether adjunctive treatment with
  dexamethasone reduced the risk of death or
  severe disability after nine months of follow-up.
  We conducted prespecified subgroup analyses
  and intention-to-treat analyses.

            Dosage & duration
 Patients with grade II or III disease
  received :
 intravenous treatment for four weeks (0.4 mg per
  kilogram per day for week 1, 0.3 mg per kilogram
  per day for week 2, 0.2 mg per kilogram per day
  for week 3, and 0.1 mg per kilogram per day for
  week 4) and then
 oral treatment for four weeks, starting at a total of
  4 mg per day and decreasing by 1 mg each week.

          Dosage & duration
 patients with grade I disease received :
two weeks of intravenous therapy (0.3 mg
 per kilogram per day for week 1 and 0.2 mg
 per kilogram per day for week 2) and then
four weeks of oral therapy (0.1 mg per
 kilogram per day for week 3, then a total of 3
 mg per day, decreasing by 1 mg each

 In summary, this study provides clinical evidence
  that early treatment with dexamethasone and
  antituberculosis drugs improves survival among
  patients over 14 years of age with tuberculous
  meningitis, regardless of disease severity.
  However, dexamethasone probably does not
  prevent severe disability in the survivors.
 Researchers funded by the Wellcome Trust have
  found that by combining traditional anti-
  tuberculosis drug treatments with an anti-
  inflammatory drug – dexamethasone - they can
  reduce the risk of death by 30%.
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