PatientS., 21 years old, for two weeks notes weakness, drowsiness, increased irritability, loss of appetite, subfebrile condition. There is also an intermittent headache without clear localiza-tion, not relieved by analgesics, vomiting without prior nausea, not associated with food intake. Patient applied for medical help at the local polyclinic. After an examination by a general practitioner, the district police officer diagnosed "AR VI, moderate severity." Symptomatic therapy (antipyretic, antihistamines, vitamin therapy) was prescribed with the next appointment after three days. Against the background of the treatment, the patient's condition deteriorated sharply: the intensity of the headache increased, the temperature rose to 39 ° C, spontaneously emerging and rapidly disappearing red spots on the face and chest began to be noted. Considering the above clinical symptoms and the course of the disease, the local general practitioner appointed a consultation with a neurologist. The study of the neurological status revealed positive meningeal symptoms, dilated pupil, divergent squint. For further examination, the patient was taken to the infectious diseases department. During a lumbar puncture, it was found: increased pressure (fluid flows out in a stream), cyto-sis - 200 cells (neutrophils - 10%, lymphocytes - 90%), chlorides - 70 mmol / 1, sugar - 0.6 mmol /1, protein - 1.2 g / 1. The MBT DNA was detected in the cerebrospinal fluid by PCR. In the general blogd fest: erythrocytes • 3,5×10/1, hemoglobin 4-10 x1099 4210°/ 1, eosinophils -39, stab neutrophils 7%, segmcnted neutroohils of %,1 mphocytes - %. monocytes - 12° SR - 22mm / hour. 47-72% 013108（2 1-8% Questions: 1. Suggest the patient's diagnosis. 2. What pair of cranial nerves is affected in the patient? What other cranial nerves can be affected by this disease? 3. Name the changes in the cerebrospinal fluid that confirm the etiology of the disease. 4. Name the diseases with which you need to carry out differential diagnostics. 5. Make a treatment plan for this patient and explain your choice.
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Clinical Case: Tuberculous Meningitis - Full Analysis
1. Diagnosis
Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis
Rationale based on the case:
| Feature | This Patient | Classic TBM |
|---|---|---|
| Age / demographics | 21 years old | All ages; increasing in young adults |
| Prodrome | 2 weeks of malaise, fatigue, irritability, anorexia, subfebrile | Low-grade fever, malaise, headache over 1-2 weeks is characteristic |
| Headache | Diffuse, not relieved by analgesics | Present in >50% of cases |
| Vomiting without nausea | Yes | Due to raised intracranial pressure |
| Meningeal signs | Positive (Kernig/Brudzinski) | Stiff neck in ~75% |
| Cranial nerve signs | Dilated pupil, divergent squint | Ocular palsies in ~20% |
| CSF pressure | Elevated (stream) | Typically elevated |
| CSF cytosis | 200 cells, 90% lymphocytes | 50-500 cells, lymphocyte predominance |
| CSF glucose | 0.6 mmol/L (very low) | Reduced, usually <40 mg/dL (2.2 mmol/L) |
| CSF protein | 1.2 g/L | Elevated, typically 1-8 g/L |
| CSF chlorides | 70 mmol/L (low; normal ~120-130) | Historically low chlorides recognized |
| PCR for MBT DNA | Positive | PCR sensitivity ~80%; gold standard for rapid diagnosis |
| Transient skin spots (face/chest) | Yes | Can occur in miliary TB with skin involvement |
The subacute/chronic course evolving over 2 weeks (rather than the rapid onset of bacterial meningitis) is a hallmark of TBM. The initial misdiagnosis as ARVI is common - TBM can mimic viral illness in the prodromal phase.
- Adams and Victor's Principles of Neurology, 12th Edition, pp. 728-730
- Harrison's Principles of Internal Medicine 22E, p. 1432
2. Cranial Nerve Involvement
Affected in this patient:
- The dilated pupil and divergent squint (exotropia) point to CN III (Oculomotor nerve) palsy.
- CN III palsy causes: ptosis, mydriasis (dilated pupil), eye deviated outward (divergent) and downward, inability to adduct.
Pathophysiological basis: TBM causes a thick gelatinous exudate at the base of the brain, particularly in the interpeduncular and pontine cisterns. The oculomotor nerve (CN III) exits from the midbrain and traverses the subarachnoid space, where it is directly compressed or infiltrated by this basal exudate.
Other cranial nerves frequently affected in TBM:
| CN | Nerve | Clinical Manifestation |
|---|---|---|
| CN III | Oculomotor | Ptosis, mydriasis, divergent squint - most common |
| CN IV | Trochlear | Vertical diplopia, inability to look down and in |
| CN VI | Abducens | Lateral gaze palsy, convergent squint - most commonly affected overall |
| CN VII | Facial | Peripheral facial palsy |
| CN VIII | Vestibulocochlear | Hearing loss, vertigo |
| CN II | Optic | Papilledema (from raised ICP), visual loss |
| CN IX, X, XII | Glossopharyngeal, Vagus, Hypoglossal | Bulbar symptoms (dysphagia, dysarthria) - less common |
"Signs of cranial nerve involvement (usually ocular palsies, less often facial palsies, or deafness) and papilledema may be present at the time that the infection is recognized (20% of cases)." - Adams and Victor's Principles of Neurology
"Because meningeal involvement is pronounced at the base of the brain, paresis of cranial nerves (ocular nerves in particular) is a frequent finding." - Harrison's Principles of Internal Medicine 22E
3. CSF Changes Confirming Tuberculous Etiology
The CSF in this patient shows the classic TBM profile:
| Parameter | Patient's Value | TBM Pattern | Significance |
|---|---|---|---|
| Pressure | Elevated (stream) | Elevated | Due to inflammation of basal meninges, possible early hydrocephalus |
| Cytosis | 200 cells; neutrophils 10%, lymphocytes 90% | 50-500 cells, predominantly lymphocytic | Lymphocytic pleocytosis is characteristic; early stage may show neutrophils |
| Glucose | 0.6 mmol/L (extremely low) | Typically <2.2 mmol/L | Bacteria and activated cells consume glucose; CSF/serum glucose ratio <0.5 is highly suggestive |
| Protein | 1.2 g/L (elevated) | Usually 1-8 g/L | Reflects BBB disruption and inflammatory exudate |
| Chlorides | 70 mmol/L (low; normal ~120-130 mmol/L) | Low chloride is a recognized historic feature | Reflects hypochloremia and hyponatremia (SIADH commonly accompanies TBM) |
| PCR for MBT DNA | Positive | Gold standard for rapid diagnosis; ~80% sensitivity | Confirms M. tuberculosis etiology definitively |
The combination of:
- Lymphocytic pleocytosis
- Markedly low glucose (hypoglycorrhachia)
- Elevated protein
- Low chlorides
- Positive PCR for MBT DNA
is pathognomonic for TBM. The PCR result is the definitive etiologic confirmation.
"Real-time automated nucleic acid amplification...has a sensitivity of up to 80% and is the preferred initial diagnostic option. Treatment should be initiated immediately upon a positive Xpert MTB/RIF result." - Harrison's Principles of Internal Medicine 22E
4. Differential Diagnosis
The following conditions must be distinguished from TBM:
Infectious Meningitides
-
Bacterial (purulent) meningitis - Neisseria meningitidis, Streptococcus pneumoniae, Listeria
- Differs: more acute onset (hours), CSF shows polymorphonuclear predominance, very low glucose, turbid appearance, positive Gram stain/culture for bacteria; responds to antibiotics rapidly
-
Viral (aseptic) meningitis - Enteroviruses, HSV-2, mumps
- Differs: shorter prodrome, CSF shows lymphocytic pleocytosis but normal glucose, normal protein or mildly elevated; PCR for viruses positive
-
Fungal meningitis (particularly Cryptococcus neoformans)
- Very similar CSF profile; distinguished by India ink preparation, cryptococcal antigen, fungal culture; more common in immunocompromised patients
-
Neurosyphilis - Treponema pallidum
- Lymphocytic CSF, elevated protein; distinguished by VDRL/TPHA serology in CSF and blood
-
CNS Lyme disease (Neuroborreliosis) - Borrelia burgdorferi
- Lymphocytic meningitis; distinguished by tick exposure history, serology, specific intrathecal antibodies
-
Viral encephalitis - HSV-1, EBV, CMV
- More prominent encephalitic features (behavioral changes, seizures); CSF may show RBCs (HSV); PCR confirmation
Non-infectious
-
Carcinomatous (neoplastic) meningitis - disseminated cancer or CNS lymphoma
- Lymphocytic pleocytosis, low glucose; distinguished by cytology showing malignant cells, imaging, history of primary tumor
-
Sarcoid meningitis - Neurosarcoidosis
- Granulomatous, lymphocytic CSF; elevated ACE; bilateral hilar adenopathy on CXR; tissue biopsy showing non-caseating granulomas
-
Autoimmune/aseptic meningitis - drug-induced, SLE, Behcet's disease
Key distinguishing note: Aseptic (viral) meningitis and partially treated bacterial meningitis have intermediate CSF lactate levels overlapping with TBM, making additional testing (PCR, culture, antigen detection) essential. - Henry's Clinical Diagnosis and Management by Laboratory Methods
5. Treatment Plan
Rationale for Treatment Approach
TBM requires four-drug antituberculous therapy (ATT) plus adjunctive corticosteroids. Treatment duration is 12 months (longer than pulmonary TB) because of the poor CNS penetration of some drugs and the severe consequences of inadequate treatment.
"If unrecognized, tuberculous meningitis is uniformly fatal." - Harrison's Principles of Internal Medicine 22E
Phase 1: Intensive Phase (first 2 months - weeks 1-8)
Four-drug regimen (RIPE):
| Drug | Dose (adult) | Rationale |
|---|---|---|
| Isoniazid (INH) | 5 mg/kg/day (max 300 mg PO) | Most effective single drug; excellent CNS penetration |
| Rifampin (RIF) | 10 mg/kg/day (max 600 mg PO) | Bactericidal; good CNS penetration |
| Pyrazinamide (PZA) | 20-35 mg/kg/day (max 2 g PO) | Excellent CNS penetration; active in acidic milieu |
| Ethambutol (EMB) | 15-25 mg/kg/day PO | Added until susceptibility confirmed; can be dropped if fully INH+RIF sensitive |
| Pyridoxine (B6) | 25-50 mg/day PO | Mandatory with INH to prevent peripheral neuropathy |
Phase 2: Continuation Phase (months 3-12)
Two-drug regimen:
- Isoniazid (INH) + Rifampin (RIF) for the remaining 10 months
"CNS TB requires 12 months" total therapy - The Washington Manual of Medical Therapeutics
Adjunctive Corticosteroids (MANDATORY in TBM)
Dexamethasone is the preferred agent:
| Schedule | Dose |
|---|---|
| Weeks 1-2 | 0.4 mg/kg/day IV |
| Weeks 3-4 | 0.3 mg/kg/day |
| Weeks 5-6 | 0.2 mg/kg/day |
| Weeks 7-8 | 0.1 mg/kg/day |
| Weeks 9-12 | Oral taper (4 mg/day → 1 mg/day) |
Alternatively: Prednisolone 1 mg/kg/day (max 60 mg) PO, tapered over 6-8 weeks
Why corticosteroids? A randomized trial (Thwaites et al.) showed adjunctive IV dexamethasone reduced mortality from 41% to 32%. The WHO now recommends corticosteroids for all CNS TB cases. They reduce cerebral edema, decrease vasculitis-related infarction, and lower CSF pressure.
"Glucocorticoids...are only recommended in tuberculous meningitis...Prednisone 1 mg/kg (maximum, 60 mg) PO qday or dexamethasone 12 mg IV qday, tapered over several weeks." - Washington Manual of Medical Therapeutics
Additional Management
- ICP monitoring and management: elevate head of bed 30°; consider osmotic agents (mannitol) if severe intracranial hypertension
- Anticonvulsants: if seizures develop
- Nutritional support: patient has anorexia and significant catabolism
- Monitor liver function tests: all four drugs are hepatotoxic; check LFTs at baseline and monthly
- Monitor visual acuity and color discrimination: EMB can cause optic neuropathy; check regularly
- Screen for HIV: mandatory in any patient with TBM; if HIV positive, start ART within 2-4 weeks of starting ATT (but not simultaneously on day 1 due to immune reconstitution syndrome)
- Contact tracing: notify public health authorities; identify household contacts; administer LTBI prophylaxis to close contacts
- Directly Observed Therapy (DOT): essential to prevent drug resistance
Monitoring Milestones
- Repeat LP at 2-4 weeks to assess CSF response
- Repeat neuroimaging at 6-8 weeks (check for hydrocephalus, tuberculomas)
- If clinical deterioration despite treatment: consider drug-resistant TB, add 5th drug (ethionamide 15-25 mg/kg/day)
Sources:
- Adams and Victor's Principles of Neurology, 12th Edition, pp. 726-731
- Harrison's Principles of Internal Medicine 22E, pp. 1431-1433
- The Washington Manual of Medical Therapeutics, pp. 545-546
- Katzung's Basic and Clinical Pharmacology, 16th Edition
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