CASE PRESENTATION

MENINGITIS e.c LUNG TUBERCULOSIS WITH

SECONDARY INFECTION

Presented by:
Agus Heriyanto
0110028

Counselor:
H. Tisna Sukarna, dr, SpA, MBA.

DEPARTMENT OF PEDIATRIC
MEDICAL FACULTY
MARANATHA CHRISTIAN UNIVERSITY
BANDUNG
2006

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 I. Patient Identification

Name : Tera Waldiana

Age : 8 years old
Place and date of birth : Bandung, April, 21st 1998
Sex : Female
Consignment from : Bina Sehat
Diagnosed : Febris Convulsion and Hemiparese ec. Susp.encephalitis
dd/ meningitis
Date of hospitalized : May, 16 th 2006
Date of examination : May, 19th 2006
Father : Name : Mr. Entep R. A.
Age : 36 years old
Education : High School graduate
Occupation : Entrepreneur
Salary : -
Address : Sukamelang RT 9/ RW 12 Kel. Andir Kec. Bale Endah
Bandung

Mother : Name : Mrs. Ratna W

Age : 33 years old
Education : Junior High School graduate
Occupation : Housewife
Salary : -
Address : Sukamelang RT 9/ RW 12 Kel. Andir Kec. Bale Endah
Bandung

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 II. Anamnesis
2.1. Heteroanamnesis was given by her mother on May, 19th 2006

Chief complaint: Convulsion

History of present illness:
3 hours before hospitalization, patient had convulsions at about 1 time, it
was 10 minutes length. Convulsion started with stiffness of the hands and feet, body
seizure and loosing conciousnesss. After the convulsion, patient regain conciousness.
Along with convulsion the mouth was foamy, eyes were staring upward, however
vomitting wasn,t present. The next day, patient was brought to doctor, with diagnosis
febrile convulsion, and had been given medication for the convulsi, so the convulsion
didn’t happen for the whole day.
Before admittion, patient went down with fever for about 1 week.The fever
was raising slowly, gradual, patient went to see a doctor and got well. The fever came
along with cough without mucous.
Patient is complaining about headache that comes with the fever. During a
seizure, patient was temporarily half-parallyzed (right of the body) and patient’s lip
also temporarily turned blue. Patient gradually got well afterwards.
Mictie: the color is yellow; there is no blood, normal in frequency and volume,
with no pain.
Defecation: constipating in 2 days.
Past medical history: the patient was never got seizure like this, 3 month fever with
chronic cough, felt down and the right hand(wrist)
movement is relatively limited.
Record of family health: his family denied got sick like this.
Medical effort : The patient was went to Bina Sehat before come to Immanuel
hospital because of the convultion, and had been given Stesolid,
Oxygen, and NaCl, and delivered to Immanuel hospital for next
treatment.

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2.2. Birth History
The patient is the 3rd child from 4 children. No stillbirth and no abortus.
Birth: aterm, spontaneous, directly cry and helped by a traditional (paraji).
Birth weight: 4200 grams. Birth length: 50 cm.
Turn over : 6 months
Sitting down with aid : 8 months
Sitting down without aid : 9 months
Standing up : 11 months
Walking : 14 months
Read : 4 years
Writing : 5 years

2.4. Family Members

No Name Age Sex Condition Relationship
1. Mr. Entep R. A 36 years Male Health Father
2. Mrs. Ratna W 33 years Female Health Mother
3. Arif Saeful 12 years Male Health Brother
4. Sari 10 years female health sister
5. Tera W 8 years female sick patient
6. Rifki 4 years male health brother

2.5. Immunizations
Booster Recommended
Vaccine Basic Vaccination
Vaccination Vaccination
BCG + (scar + ) - - - HiB : none
Polio + + + - - - MMR : none
DPT + + + - - - Hep A : none
Hep B + + + - - - Varicella : none
Measles + - - - Typhim/typha : none
Influenzae : none
2.6. Nutrition and Feeding
0 –6 months : breast feeding on demand
6 months-2 years : breast feeding and Vitalac
2 years- now : family menu

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2.7. Past Illnesses
Typhoid when she was 5 years old.
Chronic cough with fever since 3 months ago

2.8. Family history:

Asma, uncle

III. Physical Examination May,19th 2006

3.1. General appearance
Condition : severe sickness
Consciousness : compos mentis
Activity and position : no force position
General condition : weak

3.2. Vital signs

Pulse : 100 times a minute, regular, equal, strong
Respiration : 40 times a minute, abdominothoracal type
Temperature : 37,8 ºC, axiler
Blood pressure : 110/70 mmhg
Rumple Leede : -

3.3. Measuring
Age : 8 years old
Weight : 30 kg
Height : 131 cm
( 111% standard Weight/Age )
( 95,3 % standard Height/Age )
( 108% standard Weight/Height )
Nutrition status : good (standard Weight/Height )
Circumference of the head : 52,5 cm
Circumference of the chest : 63,5 cm
Circumference of the abdomen : 61 cm
Circumference of the upper arms : 20 cm

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 IV. Systematic examinations

4.1. Skin : icteric - , pale -, cyanosis -, skin’s turgor was immediately returns to its
normal position
4.2. Head
Small Fontanel: closed
Hair : black, disseminated, not easy to yanked out
Eyes : conjunctiva anemic -/-, sclera icteric -/-,light reflek +/+
Nose : nasal flare -/-, secrets -/-
Ears : symmetric, left was equal to right, no discharge
Lips : wet, anemic -, cyanosis -
Mouth : wet mucosa
Gums : no bleeding, no hyperemic, no hypertrophy
Palate : no disparity
Tongue : coated tongue -, wet
Pharynx : hyperemic -
Tonsil : hyperemic -, T0 = T0

4.3. Neck
Nuchal rigidity : +
JVP : 5+0 cmH2O
Lymph node : not palpable

4.4. Thorax
Lungs
Inspection : shape and movement was symmetric, right was equal to left,
retractions (intercostal, suprasternal, epigastrium) -
Palpation : vocal fremitus right was equal to left
Auscultation : vesicular breath sound +/+, rales -/-, wheezing -/-
Heart
Inspections : ictus cordis was not seen
Palpations : ictus cordis was palpable at ICS 4 linea midclavicularis

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 sinistra
Percussions : normal
Auscultations : heart sounds regular, shuffle -

4.5. Abdomen:
Inspections : flat
Auscultations : bowel sound (+) normal
Percussions : tympanic, Traube’s space: tympanic
Palpations : Soepel, tenderness (-),
Liver impalpable
Spleen impalpable,
Kidney impalpable

4.6. Genital : Male, normal

4.7. Anus & Rectal : normal

4.8. Extremities : no disparity

Upper : left: active, right: active
Lower : left: active, right: active
Joint : no disparity
Muscle : norm tonus
Reflex : physiological +/+

4.9. Neurological Examination

Cranial Nerves : normal
Meningeal stimulation : Nuchal rigidity ±
Brudzinky +
Reflex : physiological +/+, pathological -/-

V. Laboratory finding
16/05/2006 03.15
Hb : 12,9 gr/dl

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Ht : 39 %
Leukocyte : 15.500 / mm3
Thrombocyte : 310.000 / mm3
Thorax photo: specific process still active

16/05/2006 12.27
Hb : 12,4 gr/dl
Ht : 39 %
Leukocyte : 13.400 / mm3
Thrombocyte : 305.000 / mm3
IgM and IgG anti dengue negative
PPD tes ++

17/05/206
Rapid ICT TBC POSITIVE
Widal
Titer O Titer H
Typhoid 1/20 -
Paratyphoid A - -
Paratyphoid B - -
Paratyphoid C - -

VI. Resume

Female Patient, 8 years old came to hospital with chief complaint

convulsion. Patient had convulsions 1 time, it was 10 minutes length. Convulsion
started with stiffness of the hands and feet, body seizure and loosing conciousnesss.
After the convulsion, patient regain conciousness. Along with convulsion the mouth
was foamy, eyes were staring upward, however vomitting wasn,t present.

7
 She also had fever for 1 weeks, that was raising slowly, gradually. Fever
was gone after patient went to doctor. The fever came along with cough, however it
was cough without mucous.
She also had headache, during seizure, patient was temporarily half-
parallyzed (right of the body) and patient’s lip also temporarily turned blue. Patient
gradually got well afterwards

Mictie: the color is yellow; there is no blood, normal in frequency and volume,
with no pain.
Past medical history: chronic cough with fever for 3 months, felt down and the right
hand(wrist) movement is relatively limited, seizure -
Record of family health: his family denied got sick like this.
Medical effort : The patient was went to Bina Sehat before come to Immanuel
hospital because of the convultion, and had been given Stesolid,
Oxygen, and NaCl, and delivered to Immanuel hospital for next
treatment.

6.1. Physical examination

General appearance
Condition : severe sickness
Consciousness : Compos mentis
Activity and position : no force position
General condition : weak

Vital signs
Pulse : 100 times a minute, fast, equal, weak
Respiration : 40 times a minute, abdominothoracal type
Temperature : 37,8 ºC, axiler

6.2. Systematic Examination

Skin : icteric -, pale -, cyanosis -
Head
Eyes : anemic conjunctiva -/-, icteric sclera -/-, light reflex +/+
Nose : nasal flare -/-, secrets -/-

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 Lips : wet, anemic -, cyanosis -
Mouth : wet mucous
Thorax
Heart : In normal limits
Lungs : Retraction (-) suprasternal, subcostal,epigastrium, VBS +/+, Rales
-/-, Wheezing -/-
Abdomen
Flat, bowel sound (+) normal, soepel, tympanic, tenderness (-), liver and spleen
impalpable, Traube’s space : tympanic.
Extremities : No disparity
Neurological Examination : Nervi craniales : normal
Meningeal stimulation : Nuchal Rigidity ±
Brudzinky +
Physiological reflex +/+
Pathological reflex : -/-

6.3. Laboratory finding

16/05/2006
Leukositosis
Thorax photo: specific process still active
PPD +
IgM and IgG anti dengue -
17/05/2006
Rapid ICT TBC +
Widal -

VII. Diagnosis

Differential Diagnosis
Meningitis e.c DD/:
Tuberculosis
Bacterial
Viral

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 Mixed infection
Working diagnosis Nutritional status :
Meningitis e.c Good (standard Weight/Height)
Tuberculosis

Additional Diagnosis : -

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VIII. Suggested Further Studies
- Lumbal Punctie
- Culture and resistance test from blood and Spinal fluid
- Thorax photo for evaluation on treatment
- Acid Basil Strain (BTA)
- BSE and Diff Count
- Viral isolation
- CT-scan

IX. Planning Therapy

1. Non Medicamentous
- Fluid : RL 15 drops / minute (16/5-22/5)

2. Medicamentous
- Luminal 3x10mg(16/5)
- Valium 5mg 3x5mg (17/5-22/5)
- Broadced 1gr 2x1gr (16/5-22/5)
- Novalgin 150mg 3x150mg ( 16/5-22/5)
- Netromycin 50mg 2x50mg (16/5-22/5)
- Rifampicin 450mg 1x1 tab (18/5-22/5)
- PZA 500mg 1x1 tab (18/5-22/5)
- Pehadoxin +TB vit 1x1 tab (18/5-22/5)
- Corticosteroid
- Streptomycin

X. Prognosis

Quo ad vitam : dubia ad malam

Quo ad functionam : dubia ad malam

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 XII. Discussion

The Diagnosis of Meningitis e.c Lung TB based on :

Anamnesis :
 Convulsion with fever
 Fever for 1 week + cough with mucous
 Have cough history > 3 week

Physical Verification :
 Condition : severe sickness
 Temperature 37,8 C

Neurological Examination : Nervi craniales : normal

Meningeal stimulation : Nuchal Rigidity +/+
Brudzinky +/+
Physiological reflex +/+

Laboratory Finding 31/05/2005

Leukositosis
Thorax photo: Specific process still active
PPD tes +
Rapid ICT TBC +

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FOLLOW UP

16/05/2006 17/05/2006 18/05/2006

Subjective Headache + Headache +

Fever + Fever +
Cough +, Convulsi –
Convulsi -
General Compos mentis, Compos mentis, Compos mentis,
Appearance severe illness moderate illness Moderate illness
Pulse 100x/minute 98x/minute 92x/minute
Respiration 40x/minute 30x/minute 40x/minute

Temperature 37,8 OC 37.2 OC 37,7 OC

Eye Anemic Anemic Anemic

conjunctiva-/-, Icteric conjunctiva-/-, Icteric conjunctiva-/-, Icteric
sclera -/- sclera -/-, sclera -/-,
Nose Nasal flare (-), Nasal flare (-) Nasal flare (-)
secrets (-) secrets (-) secrets (-)
Neck Nuchal rigidity + Nuchal rigidity + Nuchal rigidity +

Thorax Shape &movement Shape &movement Shape &movement

was symmetric, was symmetric, was symmetric,
retraction - retraction retraction -
(subcostal, -suprasternal, suprasternal,
suprasternal, subcostal, subcostal,
epigastrium) epigastrium epigastrium
Pulmonary VBS +/+, Rh -/-, Wh VBS +/+, Rh -/-, Wh VBS +/+, Rh -/-, Wh
-/- -/- -/-
Heart HS+, Reg, murmur - HS+, Reg, murmur - HS+, Reg, murmur –

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Abdomen Flat, soepel, BS + ↑ Flat, soepel, BS + ↑ Flat, soepel, BS + ↑

Genital Female, no disparity Female, no disparity Female, no disparity

Neurology FR +/+, FR +/+, FR +/+,
Nuchal Rigidity + Nuchal Rigidity + Nuchal Rigidity +
Brudzinsky + Brudzinsky + Brudzinsky +
Extremity Warm, no disparity Warm, no disparity Warm, no disparity

Doctor advice (03:00) dr. Tisna SpA (10:00) dr. Tisna, (09.30) dr. Tisna,SpA
Adv: SpA - Continue the
- inf RL15 gtt/mn - Continue the therapy
- Novalgin therapy PPD
3x150mg OAT :
- Broadced -Rifampicin 450mg
2x1gr PZA 500 mg
- Netromycin INH 300mg
2x50mg 1.
- Check: Hb, 3
Ht, Leu,Tc, x ray
thorax
(18.30)
Dr Tisna SpA Adv:
- luminal 2.
stop
- PPD tommorow
- Anti TB

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 19/05/2006 20/05/2006 21/05/2006

Subjective Headache + Headache + cannot Headache >> can’t

Fever + slept slept
Obstipating 4 days Fever + Fever +
Convulsi - Convulsi -
General Compos mentis, Compos mentis, Compos mentis,
Appearance moderate illness moderate illness Moderate illness
Pulse 100x/minute 100x/minute 108x/minute
Respiration 36x/minute 40x/minute 32x/minute

Temperature 38,3 OC 38,1 OC 37,9 OC

Eye Anemic Anemic Anemic

conjunctiva-/-, Icteric conjunctiva-/-, Icteric conjunctiva-/-, Icteric
sclera -/-, sclera -/-, sclera -/-,
Nose Nasal flare (-), Nasal flare (-) Nasal flare (-)
secrets (-) secrets (-) secrets (-)
Neck Nuchal rigidity + Nuchal rigidity + Nuchal rigidity +

Thorax Shape &movement Shape &movement Shape &movement

was symmetric, was symmetric, was symmetric,
retraction - retraction retraction -
(subcostal, -suprasternal, suprasternal,
suprasternal, subcostal, subcostal,
epigastrium) epigastrium epigastrium
Pulmonary VBS +/+, Rh -/-, Wh VBS +/+, Rh -/-, Wh VBS +/+, Rh -/-, Wh
-/- -/- -/-
Heart HS+, Reg, murmur - HS+, Reg, murmur - HS+, Reg, murmur –

Abdomen Flat, soepel, BS + ↑ Flat, soepel, BS + ↑ Flat, soepel, BS + ↑

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 Liver :1 cm BAC

Genital Female, no disparity Female, no disparity female, no disparity

Neurology FR +/+, FR +/+, FR +/+,
Nuchal Rigidity + Nuchal Rigidity + Nuchal Rigidity +
Brudzinsky + Brudzinsky + Brudzinsky +
Extremity Warm, no disparity Warm, no disparity Warm, no disparity

Doctor advice (10:00) dr. Tisna SpA (10:00) dr. Tisna, (09.30) dr. Tisna,SpA
Adv: SpA - Continue the OAT
- Continue - Continue the therapy
the therapy therapy - Maxpro 2x1/2cth
- Force leave - Bufect 3x1cth
- Imunos 2x1cth
- Luminal 3x30mg

3.
3

4.

22/05/2006 23/05/2006

Subjective Headache + Headache ++

Fever – Fever +
Able to eat
General Compos mentis Compos mentis

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Appearance moderate illness moderate illness
Pulse 108x/minute 120x/minute
Respiration 30x/minute 28x/minute

Temperature 35,5 OC 38,4 OC

Eye Anemic Anemic

conjunctiva-/-, Icteric conjunctiva-/-, Icteric
sclera -/-, sclera -/-,
Nose Nasal flare (-), Nasal flare (-),
secrets (-) secrets (-)
Neck Nuchal rigidity + Nuchal rigidity +

Thorax Shape &movement Shape &movement

was symmetric, was symmetric,
retraction - retraction -
(subcostal, (subcostal,
suprasternal, suprasternal,
epigastrium) epigastrium
Pulmonary VBS +/+, Rh -/-, Wh VBS +/+, Rh -/-, Wh
-/- -/-
Heart HS+, Reg, murmur - HS+, Reg, murmur -

Abdomen Flat, soepel, BS + ↑ Flat, soepel, BS + ↑

Liver :1 cm BAC Liver :1 cm BAC
Genital Female, no disparity Female, no disparity
Neurology FR +/+, FR +/+,
Nuchal Rigidity + Nuchal Rigidity +
Brudzinsky + Brudzinsky +
Extremity Warm, no disparity Warm, no disparity

Doctor advice Able to go home

MENINGITIS TUBERCULOSIS

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Pathophysiology:

Many of the symptoms, signs, and sequelae of tuberculous meningitis (TBM)

are the result of an immunologically directed inflammatory reaction to the infection.
The development of TBM is a 2-step process. 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.

In those who develop TBM, 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. Tuberculous pneumonia develops with heavier and more prolonged
tuberculous bacteremia. Dissemination to the CNS is more likely, particularly if
miliary TB develops.

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. 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,

producing inflammation, obstruction, or infarction. 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. Subsequent
neurological pathology is produced by 3 general processes: adhesion formation,
obliterative vasculitis, and encephalitis or myelitis.

Tuberculomas are conglomerate caseous foci within the substance of the brain.
Centrally located, active lesions may reach considerable size without producing
meningitis (Rich and McCordock, 1933). Under conditions of poor host resistance,
this process may result in focal areas of cerebritis or frank abscess formation, but the

18
usual course is coalescence of caseous foci and fibrous encapsulation (ie,
tuberculoma).

In the tuberculous process, the spinal meninges may be involved owing to

spread of infection from intracranial meningitis, primary spinal meningitis in isolation
as a result of a tuberculous focus on the surface of the cord rupturing into the
subarachnoid space, or transdural extension of infection from caries of the spine.

Pathologically, a gross granulomatous exudate fills the subarachnoid space and

extends over several segments. Vasculitis involving arteries and veins occurs,
sometimes resulting in ischemic spinal cord infarction.

The earliest lesion in the vertebra is invariably due to a hematogenous spread,

often involving the body of the vertebra near an intervertebral disk. The intervertebral
disk almost always is involved with the spread of the disease to the adjacent vertebra
and eventually along the anterior or the posterior longitudinal ligaments or through
the end plate. Soon, a cold abscess develops, either as a paraspinal abscess in the
dorsal and lumbar regions or as a retropharyngeal abscess in the cervical region. As
the disease progresses, increasing decalcification and erosion result in progressive
collapse of the bone and destruction of intervertebral disks, involving as many as 3-10
vertebrae in one lesion, resulting in kyphosis. The abscess may rupture intraspinally,
resulting in primary spinal meningitis, hyperplastic peripachymeningitis, intraspinal
abscess, or tuberculoma.

Tuberculous meningitis (TBM) is difficult to diagnose, and a high index of

suspicion is needed for making an early diagnosis.

 Elucidate the following:

o Medical and social history, including recent contact with

patients with TB

o Known history of positive result on the purified protein

derivative (PPD) test, especially a recent conversion

o History of immunosuppression from a known disease or drug

therapy

19
 o Negative history for bacille Calmette-Guérin (BCG)
vaccination

 Usually, the prodrome is nonspecific, including headache,

vomiting, photophobia, and fever. In one study, only 2% of patients reported
meningitic symptoms. The duration of presenting symptoms may vary from 1
day to 9 months, although 55% presented with symptoms less than 2 weeks in
duration.

 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.

o During the prodromal period, nonspecific symptoms are

present, including fatigue, malaise, myalgia, and fever.

o 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. 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.

 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 prognosis.

20
  Less frequent presentations include atypical febrile seizures in
children, isolated cranial nerve palsies, bilateral papilledema, and acute
confusional state.

 Tuberculous spinal meningitis may present in acute, subacute,

or chronic form.

o The clinical picture in primary spinal meningitis often is

characterized by myelopathy, with progressive ascending paralysis,
eventually resulting in basal meningitis and associated sequelae.

o 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 syndrome.

o The subacute form often is dominated by

myeloradiculopathy, with radicular pain and progressive paraplegia or
tetraplegia.

o A less virulent chronic form might mimic a very slowly

progressive spinal cord compression or a nonspecific arachnoiditis.

o The dorsal cord seems to be affected most commonly,

followed by the lumbar and the cervical regions.

 Tuberculous spondylitis is also known as Pott disease or spinal

caries.

o In regions where the disease is endemic, such as Asia

and Africa, this condition still accounts for 30-50% of all cases of
compressive myelopathy resulting in paraplegia. Spinal TB also
accounts for about 50% of all bone and joint TB.

o In the lumbar region, tuberculous spondylitis may result

in psoas abscess that often calcifies.

o It usually runs a subacute or a chronic course, with back

pain and fever and variable neurological deficits.

21
 o Spondylitis also can result in various symptoms,
including local and radicular pain, limb motor and sensory loss, and
sphincter disturbances.

o Eventually, complete spinal cord compression with

paraplegia, the most dreaded complication, may supervene.

 Tuberculous radiculomyelitis (TBRM) is a complication of

TBM that has been reported only rarely in the modern medical literature.

o TBRM develops at various periods after TBM, even in

adequately treated patients after sterilization of the cerebrospinal fluid
(CSF).

o The most common symptoms are subacute paraparesis,

radicular pain, bladder disturbance, and subsequent paralysis.

o As in other forms of paradoxical reactions to anti-TB

treatment, evidence shows that steroid treatment might have a
beneficial effect.

 Two rare forms of TBM are serous TB meningitis and TB

encephalopathy.

o Serous TB meningitis is characterized by signs and

symptoms of a mild meningitis with spontaneous recovery.

o 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 meningism. Diffuse
edema and white matter pallor with demyelination are found on
pathologic examination. The pathogenesis is uncertain but is presumed
to be immune mediated. Diagnosis is important, as anecdotal reports
suggest a good response to corticosteroids.

STAGING :

22
  In 1948, British Medical Research Council developed a method
for staging the severity of the disease.

o 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
consciousness.

o 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.

o Stage III describes an advanced state with stupor or

coma, severe neurological deficits, seizures, posturing, and/or
abnormal movements.

o Prognosis is related directly to the clinical stage of

diagnosis.

Physical: Perform careful general, systemic, and neurologic examinations,

looking especially for BCG scar, lymphadenopathy, papilledema and tuberculomas on
funduscopy, and meningismus.

 Visual findings

o 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 TB.

o In children, fundus examination may reveal pallor of the

disc.

o Examination may elicit visual impairment.

 Neurologic findings

23
 o 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.

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. 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.

Causes:

 Mycobacterium tuberculosis

o The first description of TBM is credited to Robert

Whytt, on the basis of his 1768 monograph, Observations of Dropsy in
the Brain. TBM first was described as a distinct pathological entity in
1836, and Robert Koch demonstrated that TB was caused by M
tuberculosis in 1882.

o M tuberculosis is an aerobic gram-positive rod that

stains poorly because of its thick cell wall containing lipids,
peptidoglycans, and arabinomannans.

 Mycobacteria vary in appearance from spherical

to short filaments, which may be branched. Although they
appear as short to moderately long rods, they can be curved and
frequently are seen in clumps. Individual bacilli generally are
0.5-1.0 m in diameter and 1.5-10 m long. They are
nonmotile and do not form spores.

 One of the distinct characteristics of

mycobacteria is their ability to retain dyes within the bacilli that
usually are removed from other microorganisms by alcohols

24
 and dilute solutions of strong mineral acids such as
hydrochloric acid. This ability is attributed to a waxlike layer
composed of long-chain fatty acids, the mycolic acids, in their
cell wall. As a result, mycobacteria are termed "acid fast" and
are called acid-fast bacilli (AFB).

o The mechanisms by which neurovirulence may occur

are unknown.

 Risk factors

o Human migration plays a large role in the epidemiology

of TB. Massive human displacement during wars and famines has
resulted in increased case rates of TB and altered geographic
distribution. With the advent of air travel, TB has a global presence. In
the United States, the prevalence of TB, mostly in foreign-born
persons, has increased steadily.

o Once infected with M tuberculosis, HIV co-infection is

the strongest risk factor for progression to active TB; the risk has been
estimated to be as great as 10% per year, compared to 5-10% lifetime
risk among persons infected with TB but not HIV.

 Although patients who are HIV infected and also

have TB are at increased risk for TBM, the clinical features and
outcomes of TB do not seem to be altered by HIV.

 Patients infected with HIV, especially those with

AIDS, are at very high risk of developing active TB when
exposed to a person with infectious drug-susceptible or drug-
resistant TB. They have a higher incidence of drug-resistant
TB, in part due to Mycobacterium avium-intracellulare, and
resulting in worse outcomes.

o Predisposing factors for development of active TB

include malnutrition, alcoholism, substance abuse, diabetes mellitus,
corticosteroid use, malignancy, head trauma, and HIV infection.

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 o Homeless persons, people in correctional facilities, and
residents of long-term care facilities also have a higher risk of
developing active TB than the general population.

Lab Studies:

 Complete blood count

 Erythrocyte sedimentation rate

 Electrolytes: Mild-to-moderate hyponatremia is present in

roughly 45% of patients, in some cases constituting a true syndrome of
inappropriate secretion of antidiuretic hormone (SIADH).

 Serum glucose level

 BUN and creatinine levels

 Serology for syphilis

 Complementation test or its equivalent for fungal infections

 Urinalysis

 Cerebrospinal fluid (also see Procedures)

o Cell counts, differential count, cytology

o Glucose level, with a simultaneous blood sugar level

o Protein

o Acid-fast stain, Gram stain, appropriate bacteriologic

culture and sensitivity, India ink

o Cryptococcal antigen, herpes antigen

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

26
 false-negative results potentially occur in samples containing very few
organisms (<2 colony forming units (CFU)/mL).

o Syphilis serology

 Tuberculin test: Negative result on PPD does not rule out TB; if
the 5-tuberculin test (TU) skin test is negative, repeat the test with 250-TU.
Note that this test is often nonreactive in TBM.

o Despite its many limitations, tuberculin skin testing

(TST) by necessity remains in widespread use. The Centers for Disease
Control and Prevention (CDC), the American Thoracic Society (ATS),
and the Infectious Disease Society of America (IDSA) have updated
the guidelines, and they are quite useful in practice (American
Thoracic Society, 2000).

o These guidelines stress that, in general, one should not

obtain a TST unless treatment would be offered in the event of a
positive test result. Cutoff points for induration (5, 10, or 15 mm) for
determining a positive test result vary by the pretest category into
which the patient falls. While this approach might decrease the
specificity of the test, it increases the sensitivity for capturing those at
highest risk for developing the disease in the short term.

Imaging Studies:

 Chest radiography: Posteroanterior and lateral views may

reveal the following:

o Hilar lymphadenopathy

o Simple pneumonia

o Infiltrate

o Fibronodular infiltrate/cavitation

o Pleural effusion/pleural scar

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  CT scan and MRI of the brain reveal hydrocephalus, basilar
meningeal thickening, infarcts, edema, and tuberculomas (see Image 2).

o The characteristic CT finding is a nodular enhancing

lesion with a central hypodense lesion (Weisberg, 1984). Contrast
enhancement is essential. Early stages are characterized by low-density
or isodense lesions, often with edema out of proportion to the mass
effect and little encapsulation. At a later stage, well-encapsulated
tuberculomas appear as isodense or hyperdense lesions with peripheral
ring enhancement.

o Although CT scan and MRI lack specificity, they help in

monitoring complications that require neurosurgery.

o MRI and CT scan are critical for the diagnosis of

TBRM, revealing loculation and obliteration of the subarachnoid space
along with linear intradural enhancement.

o 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.

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 o Tuberculous spondylitis

 Neuroimaging invariably reveals bone

destruction and fragmentation with involvement of the disk
space and calcified paravertebral mass.

 MRI has an accuracy of 94% in vertebral

osteomyelitis. It reveals hypointense T1-weighted areas in the
vertebral bodies, alternating with areas of hyperintense T2-
weighted signal in the disk spaces and the paravertebral soft
tissue. Infected bone and disk often reveal contrast
enhancement.

 CT scan is superior to MRI in detecting psoas

abscess calcification that, when present, strongly raises the
suspicion of a tuberculous etiology. Epidural deposits are best
shown by MRI, which reveals a soft-tissue mass that is
isointense to hypointense compared with spinal cord on T1-
weighted images and hyperintense on proton-density and T2-
weighted images and has variable degrees of contrast
enhancement.

 Perform MR angiogram (MRA) and venogram if indicated.

o 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.

o Imaging studies, both CT scan and MRI, are performed

with and without enhancement, as long as the renal functions of the
patient are not compromised.

o Basal cisterns often enhance strikingly, corresponding to

the thick exudate that is observed pathologically. The quadrigeminal
cistern, interpeduncular fossa, ambient cistern, and chiasmatic region

29
 are particularly involved, owing to associated arachnoiditis. Meningeal
enhancement is more common in HIV-infected patients.

o Contrast enhancement further delineates focal

parenchymal and space-occupying lesions, with or without associated
hydrocephalus.

 Skull radiography may reveal evidence of increased intracranial

tension in children, in the form of sutural diastasis. During follow-up of
patients with TBM, intracranial calcification may be evident.

o Calcification occurred in two main sites: (1) more

commonly, in the basal meninges and (2) to a lesser extent, within
brain substance.

o 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.

Other Tests:

 The diagnosis of TBM cannot be made or excluded on clinical

grounds. Tuberculin testing is of limited value. Variable natural history and
accompanying clinical features of TBM hinder the diagnosis. Ziehl-Neelsen
staining lacks sensitivity, and culture results are often too late to aid clinical
judgment. Semiautomated radiometric culture systems, such as the Bactec
460, and automated continuously monitored systems have reduced culture
times. Newer methods involving amplification of bacterial DNA by PCR and
comparable systems have not been assessed completely and may not be
suitable for laboratories in developing countries with limited resources.
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.

 Electroencephalogram (EEG): In one study, EEG findings were

abnormal in 24 patients. The EEG abnormalities included diffuse theta-to-delta

30
slowing in 22 patients, intermittent rhythmic delta activity in the frontal region
in 15 patients, right-to-left asymmetry in 5 patients, and epileptiform
discharges in 4 patients. At the end of 3 months, 5 patients had died, while
recovery was poor in 13 patients, partial in 3, and complete in 11. EEG
findings correlated with severity of meningitis and degree of coma; outcome at
3 months was assessed by Barthel index score.

 Evoked potentials: In the same study, brainstem auditory-

evoked potential (BAEP) abnormalities were observed in more than 50% of
patients with TBM. Motor and somatosensory evoked potentials may be
helpful in objective documentation of respective motor and sensory functions
in patients with TBM and altered sensorium.

 Dot-immunobinding assay

o 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). 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. 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.

o 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. This is not yet available for routine use, and proof of
its utility requires further studies.

 Use of neurochemical markers has been investigated in patients

with aseptic meningitis or TBM.

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 o CSF levels of amino acids, nitrite (a metabolite of nitric
oxide), vitamin B-12, and homocysteine were quantitated in both
groups of patients.

o 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.

o Levels of nitrite and its precursor arginine were

significantly higher in patients with TBM, whereas they were
unchanged in patients with aseptic meningitis.

o 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.

Procedures:

 Spinal tap

o For more information about CSF studies, see Lab Studies.

o As in any instance when intracranial pressure is

increased, a spinal tap carries some risk of herniation of medulla, but if
meningitis is suspected, the procedure must be performed regardless of
the risk, using suitable precautions and obtaining informed consent
before the procedure.

o Use manometrics to check CSF pressure. Typically, the

pressure is higher than normal.

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 o 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.

o 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).

o Abnormalities in the CSF depend on a tuberculin

reaction within the subarachnoid space. Acellular CSF has been
reported in elderly patients and patients who are HIV positive.

o CSF typically shows elevated protein level, marked

hypoglycorrhachia, and a pleocytosis, initially polymorphs then
lymphocytes.

 In adults, mean WBC count averages around

223 cells/L (range 0-4000), while the proportion with
neutrophilic pleocytosis (>50% neutrophils) averages 27% (15-
55) and the proportion with normal cell count averages 6% (5-
15). In children, these numbers are 200 cells/L (5-950), 21%
(15-30), and 3% (1-5), respectively.

 Mean protein level in adults averages 224 mg/dL

(range 20-1000), and in children, 219 mg/dL (50-1300). The
proportion with normal protein content averages 6% (0-15) in
adults and 16% (10-30) in children. The proportion with
depressed glucose levels (<45 mg/dL or 40% of serum glucose)
averages 72% (50-85) in adults and 77% (65-85) in children.

o The numbers who have a positive smear average 25%

(range 5-85) in adults and only 3% (0-6) in children, whereas the
numbers with a positive CSF culture average 61% (40-85) and 58%

33
 (35-85) of adults and children, respectively. Failure to respond to
treatment should prompt a search for fungal infections or malignancy.

o Patients with HIV and/or immunosuppression

 While the mean WBC count in the CSF is 230

cells/L, as many as 16% of HIV-infected patients may have
acellular CSF, compared with 3-6% of HIV-negative patients.
Patients whose CSF samples are acellular may show
pleocytosis if a spinal tap is repeated 24-48 hours later. The
proportion who have neutrophilic pleocytosis of the CSF
(>50% neutrophils) is 42% (range 30-55).

 While HIV-infected patients generally have a

mean protein level of 125 mg/dL (range 50-200), as many as
43% of these patients may have a normal CSF protein content.
The proportion who have depressed CSF glucose levels (<45
mg/dL or 40% of serum glucose) averages around 69% (50-85).

 The number who have a positive CSF culture

averages 23%.

 Within a few days after commencement of anti-TB therapy, the

initial mononuclear pleocytosis may change briefly in some patients to one of
polymorphonuclear predominance, which may be associated with clinical
deterioration, coma, or even death. This therapeutic paradox has been regarded
by some authors as virtually pathognomonic of TBM. This syndrome is
probably the result of an uncommon hypersensitivity reaction to the massive
release of tuberculoproteins into the subarachnoid space.

 When CSF analysis offers no clues, and the diagnosis remains

elusive, a brain biopsy may be warranted under appropriate circumstances.
This carries significant risks, however, including epidural hematoma and
hydrocephalus.

34
 Histologic Findings: The Ziehl-Neelsen stain uses the properties of the cell
wall to form a complex that prevents decolorization by acid or alcohol. Fluorochrome
tissue stains also can be helpful in diagnosis of TBM (see Image 3).

 Hematogenous spread leads to perivascular microscopic foci

that form tubercles. These characteristically are associated with central
caseation and epithelioid and giant cells. Gradually they enlarge to form
numerous small macroscopic tuberculomas, which then may coalesce. In
essence, tuberculomas are conglomerate caseous foci within the substance of
the brain that develop from deep-seated tubercles (see Image 4).

 Clinically silent single or multiple enhancing granulomata are

observed in a significant minority of cases of TBM and in some cases of
miliary TB without meningitis (Stevens and Everett, 1978).

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

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. 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.

 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.

35
  Studies have shown that young children with TBM can be
treated safely for 6 months with high doses of anti-TB agents without overt
hepatotoxicity and with a low risk of relapse. Children must be treated for 12
months with combination antibiotic therapy and adjunctive corticosteroids.
Twelve months is probably a conservative estimate of the time required for
bacterial cure. The rationale behind the use of adjuvant corticosteroids lies in
reducing the harmful effects of inflammation as the antibiotics kill the
organisms. The use of corticosteroids in adults is controversial; they may be
indicated in the presence of increased intracranial pressure, altered
consciousness, focal neurological findings, spinal block, and tuberculous
encephalopathy.

 Hyaluronidase has been used in spinal arachnoiditis with good

results. Gourie-Devi and Satish Chandra (1980) recommend the use of
hyaluronidase administered intrathecally in cases of arachnoiditis complicating
TBM.

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 rarely is required in the treatment of tuberculomas.

First-line therapy includes isoniazid, rifampin, pyrazinamide, streptomycin,

and ethambutol. Second-line therapy includes ethionamide, cycloserine, para-
aminosalicylate (PAS), as well as aminoglycosides, capreomycin, and thiacetazone.

36
 Potential new agents include oxazolidinone and iseponicin. Fluoroquinolones
useful in the treatment of TBM include ciprofloxacin, ofloxacin, and levofloxacin. A
new rifamycin called rifapentine has been developed.

Trials for novel agents for the treatment of tuberculosis are under way. Long-
acting rifamycin derivatives and potent fluoroquinolone antibiotics have been studied,
and they lead the way for improved regimens against active and latent tuberculosis.
The recent rapid increase in knowledge of mycobacterial pathogenesis is likely to lead
to the advent of potent new drugs in latent disease as well as against the phenomenon
of persistence. Without a doubt, sustained and increased funding for basic research
plays a key role in eradicating this global epidemic altogether.

Finally, because of the intensity of the inflammatory and fibrotic reactions at

the meningeal site, adjunctive corticosteroids, in addition to standard antituberculous
therapy, is recommended in TM.

Studies have confirmed the benefit of adjunctive corticosteroid therapy on

survival and intellectual outcome of children with tuberculous meningitis, with
enhanced resolution of basal exudates but no effect on intracranial pressure or
incidence of basal ganglia infarction

37