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Particularities of tuberculous menigitis in children

Autor: Cornelia Călcîi Svetlana Hadjiu Calistru Iulia Nadejda Lupușor Ludmila Feghiu Corina Grîu Ludmila Cuzneț Mariana Sprincean Revenco Ninel
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SUMMARY
Tuberculous meningitis (MTB) is a subacute meningeal disorder, which is a major problem among children, especially in low income countries. It is often associated with disability and death. Th e aim of the paper is to present diagnostic criteria and particularities of evolution of tuberculous meningitis in the pediatric population in order to describe two clinical cases. Material and methods: Two clinical cases of tuberculous meningitis are reported: with positive evolution in one case and associated with death in the second. Th e patients were hospitalized in 2019 in the neurology unit of the Institute of Mother and Child Health Care, with the initial diagnosis of undetermined meningoencephalitis complicated by occlusive hydrocephalus. Results: CT scan results confi rmed the early association of occlusive hydrocephalus in both cases and pulmonary CT show multiple calcifi cations in the lymph nodes, suggesting the diagnosis of tuberculous meningitis, confi rmed by the GeneXpert technique. Conclusions: Tuberculous meningitis is the most common form of central nervous system tuberculosis. Th e common symptoms of tuberculous meningitis are fever and headache, which also occurs in other neuroinfections, which requires maximum alertness from physicians in order to establish the correct diagnosis.
Key words: meningitis, tuberculosis, tuberculous meningitis

INTRODUCTION
Tuberculous meningitis (MTB) is a major problem among children. It is often associated with disability and death. Worldwide, MTB represents the majority of deaths caused by TB. TB in children is estimated to represent 10-20% of all TB cases in poor countries, accounting 8-20% of tuberculosis-related deaths. Approximately 25% of TB cases in children are extrapulmonary, tuberculous meningitis (MTB) being the worst form [1]. Tuberculous meningitis (MTB) is a subacute meningeal disorder that occurs in different stages. The first stage is characterized by nonspecific symptoms: subfebrility, headache, irritability, drowsiness, malaise, vomiting, photophobia, apathy and weight loss. In infants, there may be decrease of developmental areas, fever, cough, altered consciousness, and convulsions. The neck stiffness is typically absent. This takes about 1-2 weeks. The presence of nonspecific signs and symptoms makes it difficult to suspect and diagnose TBM in the first stage. A history of contact with an tuberculouse patient (~ 50% of cases) may also be important. The second stage is usually characterized by a sudden onset with the following signs: lethargy, neck stiffness, meningeal positive signs, hypertonia, convulsions, vomiting and focal neurologic deficits. Development of hydrocephalus, increased intracranial pressure, encephalitis with focal signs, cranial nerve involvement (30% -50% of cases), most frequently the 6th nerve, and loss of vision are taking place. Most patients are clinically diagnosed at this stage.

This stage is followed by the third stage, which involves the association of decorticat / decerebrat posturing, hemiplegia, coma and eventually death [1]. The aim of the paper is to present diagnostic criteria and particularities of clinical evolution of tuberculous meningitis in the pediatric population starting from the description of two clinical cases. MATERIAL AND METHOD Two clinical cases of positive tuberculous meningitis in one case and death reported in the second case. The patients were hospitalized in the neurology unit of the Institute of Mother and Child Health Care in 2019, with the initial diagnosis of undetermined meningoencephalitis of an etiology complicated with occlusive hydrocephalus.
RESULTS: PRESENTATION OF CLINICAL CASES.
Clinical case 1. A 9-month-old patient was admitted at our Depatment with persistent fever for 2 weeks, repeated vomiting, strabismus appeared 14 days ago. One week before admission, the child was admitted to the district hospital with symptoms of fever, vomiting and regurgitation, strabismus. There was no improvement in the neurological status, inspite of the administered therapy and the child was transferred to Hospital of Mother and Child Health Care with the suspicion of an intracerebral tumor. The child was from the 4th birth, from unexposed to TB mother, born at 39 weeks of gestation, weight -2224 gr, height- 45 cm, being transferred to an orphanage.

The vital parameters at admission: t-38.0 ° C, pulse (Ps) 155 / min, respiratory rate 44 / min, blood pressure 94/52 mmHg, periorbital cyanosis, clear mucous membranes, slight hyperemia of pharynx, low turgidity of tissue, moderate mixed dyspnea, rhythmic, attenuated cardiac heartbeats. Neurological status: Glasgow 15 p, opens the eyes spontaneously, follows, strabismus, pupils (left = right) Right=Left, present photoreaction, muscle tonus 4 p, present cephalic stiffness, positive meningin signs, anterior fontanella 3.0 x 3.0 (cm), tense, pulsating. Initial investigations showed mild anemia, (Hg) 109 g / l, erythrocyte 3.3×106 / l, white blood cell count 9.7×109 / l. Samples for evaluation of renal function, electrolytes and liver samples – within normal limits. The rate of sedimentation of the red blood cells – 8 mm / hr. Cerebrospinal fluid examination revealed cell-protein dissociation: 69 cells / ml, 1.2 g / l protein, 1.0 mmol / l glucose, 92 mmol / l chlorides, 46 lymphocytes. Neurosonographic evaluation showed ventriculomegaly in brain architecture, increased echogenicity, and cerebral CT – pronounced (decompensated, possibly obstructive) tetraventricular hydrocephalus associated with periventricular edema with diffuse narrowing of extraaxial cerebrovascular spaces, right otitis media, right mastoiditis. (Fig. 1). CT of the thorax – calcifications in bilateral parahillary lymph nodes (indirectly indicative of tuberculous origin) and intrathoracic ganglia, pulmonary calcination in S1, S9 on the right and in S9, S10 on the left (Figure 2). The diagnosis was established: Tuberculosis of intrathoracic ganglia. Secondary tuberculous meningitis. Very pronounced, potentially obstructive tetraventricular hydrocephalus. Other anemia due to iron deficiency. Moderate protein-energy malnutrition.
The child was transferred to theTB hospital for specific treatment. Evolution of the case – with improvement. Conclusions in the clinical case 1. The clinical presentation specific to a meningitis, associated with the results of the clinical and paraclinical examinations suggestive for tuberculous meningitis in a specific pulmonary process, specific treatment lead to positive evolution of the disease.
Clinical case 2. A 17-year-old girl, complained of anxiety, hypersalivation, repeated vomiting, diffuse headache, transitory speech disorder, diffuse abdominal pain, apathy, fever at 40 ° C. Two weeks before the patient was given an ambulatory treatment for coughing and sore throat. After 7 days of treatment the condition worsens by headache and rhinorrhea. She is hospitalized in the district hospital where the lumbar puncture was performed and in the CSF there was a cell-protein deviation with the cytosis – 24 cells (lymphocytes), proteinorhea – 1.8 g / l, Pandi +++ , glucose level – 1.85 mmol / l. Treatment with Ceftriaxone was initiated, however, there was no improvement in the condition of the patient and the child was transferred to the neuroscience department of Hospital of Mother and Child Health Care. The cerebral CT examination did not initially report any signs of cerebral damage.

For 6 months, the patient presented psychasthenia and was consulted by the psychiatrist, and 4 months before the occurrence of the abovementioned symptoms the patient was admitted to the intensive care department of Hospital of Mother and Child Health Care with abdominal pain, subfebrility, weakness, loss of appetite, nausea, repeated vomiting, enlarged abdomen. For diagnostic purposes, laparoscopy was performed. Were removed 3 liters of serum fluid. The result of histopathological examination: fragments of muscle tissue and connective tissue with venous congestion, focal hemorrhages by diapedesis, and miliary necrosis with discrete macrophagal cell reaction. Regretfully, the presence of miliary necrosis did not alert the surgeon for a more detailed examination of the patient.
Neurological status at admission: Glasgow 10 p, cranial nerves – no pathological signs, motor deficit – absent, osteotendinous reflexes D = S, exaggerated, present bilateral planar clonus, pronounced meningian signs, instability in Romberg position, intentional tremor. Chest X-rays showed signs of acute respiratory disease. In 2 days the condition of the patient worsens: Glasgow Scale – 8 points, pronounced headache, febrile, toxic syndrome, pronounced neck stiffness, positive meningial signs. A preventive diagnosis has been established: acute meningoencephalitis of unknown etiology. The following examinations were performed: negative influenza virus samples; CSF: citosis 77, neutrophils – 56, protein – 1.68 g / l, glucose – 0.6 mmol / l. Antibacterial treatment with Cefotaxime and anti-emetic therapy (according to the national clinical protocol) was indicated. However, the condition of the patient is getting worse. Due to levels of protein and low glucose levels determined in the CSF, a consultation of the TB specialist, excluded the diagnosis of tuberculous meningitis (despite of lack of specific examinations for tuberculosis). It is suggested – viral meningitis and recommended – Aciclovir. However, the condition of the patient continues to worsen. The third lumbar puncture (over 8 days from admission) was performed: Pandi +++, citosis – 605

(neutrophils – 560, lymph – 45), protein – 2g / l, glucose – 0.8mmol / l . Repeated analysis for the identification of tuberculosis (GeneXpert), which has been shown to be positive, was performed. The CT scan of the thorax determines the presence of fibro-atelectatic areas in S3, S5 on the right, S3, S5, S10 on the left, associated with the presence of bronchiectasis; solitary calcination in the subcarinal lymph node projection. Abdominal CT: Moderate hepatosplenomegaly and signs of acute cholecystitis. Repeated cerebral CT: negative dynamics, with evolution of obstructive hydrocephalus (Figure 3). Repeated consultation of TB specialist: was established diagnosis of tuberculous meningitis and specific anti-tuberculosis treatment was initiated. Despite to intensive treatment, the condition of the patient worsens to coma. More than 15 days after hospitalization, a cardiopulmonary arrest was suddenly installed. Cardio-pulmonary resuscitation measures were initiated, but no effect. Was reported biological death. Clinical-anatomopathological conclusion:, histological and bacteriological examination of the necroscopic material, it was found that the patient suffered from tuberculosis, the generalized form of lung, liver, kidney, intestines, lymph nodes and encephalus, severe tuberculosis complication, followed by cardio-respiratory insufficiency and cerebral edema. Conclusions in the clinical case 2. Clinical presentation with 6-month psychiatric disorders, subfebrility and gastrointestinal manifestations (4 months previously), symptoms of a meningitis with CSF modification (high level of protein, low glucose level) were suggestive for tuberculosis, which was not initially confirmed by specific examinations. The delay in diagnosis and specific treatment has lead to an unfavorable progression of the disease. DISCUSSIONS In the absence of standardized diagnostic criteria, a consensus of definition for tuberculous meningitis (MTB) was proposed in 2010 with a view to its use in future clinical research. The criteria for MTB definition are applicable despite of the age of the patients, the state of the human immunodeficiency virus (HIV) infection or the available resources. Patients are classificated as defined, probable and possible for MTB diagnosis according to these criteria [2].
1. Clinical Criteria include: z Symptoms duration > 5 days (score: 4) z Symptoms suggestive of TB (> 1 of the following): – weight loss / low weight gain; – night sweats; – cough> 2 weeks (1 year); – a close contact; – Pulmonary tuberculin sensitivity test or positive tuberculin or interferon (IFN) susceptibility test in children <10 years (score 2); – focal neurologic deficit (excluding cranial nerve paralysis) (score: 1); – paralysis (score: 1) and altered consciousness (score: 1). The maximum rating for the category is 6. 2. Criteria for cerebrospinal fluid include: – clear appearance (score: 1); – cells 10-500 / μL (score: 1); – lymphocyte prevalence > 50% (score: 1); – protein concentration > 1 g / l; – plasma glucose <50% or absolute CSF glucose <2.2 mmol / L (score: 1). Maximum category rating - 4. 3. Cerebral imaging criteria include: – hydrocephalus (score: 1); – basal meningeal affection (score: 2); – tuberculosis (score: 2); – stroke (score: 1) and pre-contrast: basal hyperdensity. Maximum category rating – 6. 4. Evidence of tuberculosis elsewhere includes: – Chest X-ray suggesting signs of active TB = 2; – milliar TB = 4 (score: 2/4); – computed tomography (CT) / magnetic resonance imaging (MRI) / ultrasound for TB outside the central nervous system (CNS) (score: 2); – fast-identified bacilli or Mycobacterium tuberculosis cultivated from another source (eg sputum, ganglia, gastric lavage, urine and blood cultures) (score 4) and nucleic acid positive amplification of extra-neural M. tuberculosis (NAAT) : 4). Maximum category rating - 4. The patient is labeled as a definitive MTB when the clinical criteria are met with one or more of the following criteria: 1. Classical MTB: CSF - fibrin cloth, called "spider web", Mycelium (M.) tuberculosis cultivated from CSF or M. tuberculosis CSF positive from a patient showing signs or symptoms suggestive for meningitis - TB of the brain or marrow along with symptoms or suggestive signs and changes in CSF; or visible meningitis (autopsy). 2. Probable MTB diagnosis: it is labeled when the clinical input criteria are present plus a total diagnosis score of 10 or more points (when cerebral imaging is not available) or 12 or more points (when brain imaging is available) plus exclusion of alternative diagnostics. At least 2 points should come from either the CRL or cerebral imaging criteria. 3. MTB diagnosis possible: Clinical entry criteria plus a total diagnostic score of 6-9 points (when cerebral imaging is not available) or 6-11 points (when brain imaging is available) plus exclusion of alternative diagnoses [3]. A case of MTB can not be diagnosed or excluded without performing a lumbar pucture or cerebral imaging [3]. A classic MTB case typically shows an CSF of 10-500 cells / μL that are initially polymucrose and lymphocytes later. A low glucose <40 mg / dl (rar <20 mg / dl) or a glucose <50% in the CSF / plasma or a high protein content (400-5000 mg / dl) is sugestive for MTB diagnosis. The lactate level in the CSF is usually elevated to 5-10 mmol / l (normal range, 1.2-2.1 mmol / L). The CSF findings mentioned above are not specific to MTB and can be seen in other conditions, including non-mycobacterial tuberculous (MTB) meningitis, fungal meningitis, Cryptococcus infections, carcinomatous meningitis, and subarachnoid haemorrhage [5]. CSF exams should be done with specific coloring. The yield of the CSF examination may be increased by some simple measures, such as taking at least 10 ml of the CSF sample, performing a repeated examination of the sample and performing a lumbar puncture before or immediately after the start of treatment. Also, it should be centrifuged at a high centrifugation force for 20 minutes followed by a careful examination for at least 20 minutes [6,7]. The most advanced biochemical parameter for TBM control was adenosine deaminase (ADA), with a 95% specificity [8]. The mean ADA activity in TBM patients was significantly higher than those in the non-MTB group (P <0.01), demonstrating its fast and accessible adjuvant role in differentiating TBM from non-TB  [9,10,11,12], ADA measurements have been shown to be useful in predicting poor neurological outcomes in pediatric MTB cases [13]. A recent diagnostic advance is Xpert MTB / rifampicin (RIF), an automated nucleic acid amplification test for MTB, approved by the WHO (WHO) in December 2010. [14] These molecular methods are more useful when anti-tuberculosis drugs have already been initiated. Several studies reveal a decrease in white blood cell CSF leukocytes and protein levels in HIV-positive patients. CSF screening may be quite normal in 5% of HIV-positive patients with TBM. [15, 16] Other diagnostic tests in MTB. These include ancillary tests that help us get a diagnosis of TBM. Tuberculin skin test (Mantoux test): may be unreactive in 50% TB cases in the CNS. Therefore, it is useful to support the diagnosis of TBM when it is positive, but a positive isolated Mantoux can not be used to mark a TBM case, because false positive / false negative reactions are known. Chest radiography: helps locate active TB signs, but can be normal in 20% -50% of TBM cases. Measurement of lymphocyte-released IFN-γ: is a specific test (70% -90%), but with a low sensitivity (50% -70%). It is available for latent TB diagnosis. At present, the use of these tests is limited in developing countries due to the high cost. [17] In various long-term studies, MRI has been shown to have a higher sensitivity than a CT scan. A CT scan may initially be normal in nearly 30% of cases, which does not initially rule out the possibility of a TBM. [16] The usual findings on neuroimages seen in TBM are presented below: – Hydrocephalus - 80%; – Basal meningeal growth - 75%; – Cerebral infarctions; 8-44%; – Tuberculomas - 8-31%. TREATMENT In line with the recently revised guidelines on the National Tuberculosis Control Program (2016), a daily fixed-dose combination of first-line antituberculous drugs was proposed. For newly diagnosed TB cases, intensive phase treatment will consist of 8 weeks of: isoniazid, RIF, pyrazinamide and etambutol in daily doses according to the four weight categories. It will not be necessary to extend the intense phase. Only pyrazinamide will be stopped in the continuation phase, while the remainder will be continued as daily doses. [10] According to the recommendations of the American Tobacco Society / Center for Disease Control and Prevention (CDC) / American Infectious Diseases Society (2003), a 9-12 month regimen is recommended. The recommendations of the British Infectious Disease Society (2009) suggest a minimum of 12 months, while WHO recommendations (2010) warrant treatment for 9-12 months to reduce the risk of disability and mortality. The recommended doses of preparations in a TBM case are as follows: z Rifampicin: 10-15 mg / kg / day (maximum 600 mg) z Isoniazid: 10-15 mg / kg / day (maximum 300 mg) z Pyrazinamide: 30-35 mg / kg / day (maximum 2 g) z Ethambutol: 20 mg / kg / day (maximum 1 g) z Prednisolone: 2-4 mg / kg / day for 4-6 weeks, followed by a reduction in the following 2-3 weeks. Clinical follow-up should be performed at least once a month. Improvement of symptoms, weight gain and monitoring of any adverse reaction to antitubercular treatment (TAT) should be performed. For cases of associated pulmonary tuberculosis, an examination of the sputum should be performed at the end of the intensive phase and at the end of the treatment. In the event of clinical worsening, it can be done at any time, even during the on-going phase. A chest X-ray should be given whenever necessary. The liver function test should be obtained at baseline, 2, 4, 6, and 8 weeks and then monthly for the first few months of treatment. HIV testing should be done in all cases of tuberculosis. Long-term followup is recommended at the end of the 6, 12, 18 and 24 months. During treatment with TAT, the baby should be monitored for TAT side effects. [17] Complications frequently encountered during treatment: due to the initial presence of nonspecific signs and symptoms, lack of certain diagnostic criteria, and low sensitivity of different tests, most cases of TBM are diagnosed very late. As a result, they were associated with an increased risk of further complications. Immediate complications: – Electrolytic disorders: Hyponatremia is the most common (35% -65% cases) / inadequate anti-diuretic hormone (ADH) secretion / renal sensitivity to ADH. – Seizures: Almost 50% of children - seizures. These may be focal or generalized tonic-clonic, depending on CNS involvement. Phenytoin remains the most common antiepileptic drug of choice. Others, including valproate, should be avoided because of the increased risk of hepatotoxicity. Other antiepileptic drugs may affect the metabolism of TAT drugs. – Increased intracranial tension: Must be monitored, with measures of intracranial pressure resistant. – Vasculitis: due to cerebral vasospasm or meningeal inflammation or obliterative vasculopathy. Distal inner carotid artery, proximal middle cerebral artery and its perforating branches remain the most common locations involved. Short-Term Complications: – Communicating hydrocephalus: Approximately 80% of cases of TBM, more common than non-communicative (acetazolamide and furosemide). Surgery and ventriculoperitoneal (VP) manipulation. The possibility of pyogenic meningitis should also be considered. – Paralysis of the cranial nerves – Insipid diabetes – Increased intracranial tension (HIC) Long Term Complications: – Cognitive disability – Epilepsy – Stroke – Hydrocephalus – Mieloradiculopatie – Hypothalamic involvement: obesity, early puberty, diabetes insipidus, Frohlich syndrome (adipozogenital) and growth retardation. Sequelae: – Cognitive defects / intellectual disabilities – Emotional effects: unhappy and anxious, shorttempered, persistent and aggressive – Physical limitations – Headache – Epilepsy – Neurological deficit – Behavior problems – Salivation – Blindness – Deafness – Non-specific PROGNOSIS he clinical picture and time of initiated treatment is the most important determinant of survival and sequelae. Youth age, malnutrition, hydrocephalus, presence of focal neurological deficits, miliary disease, underlying disease or HIV infection are associated with poor prognosis. Nearly 10% -85% of all cases develop sequelae to a maximum in stage three. The recurrence or appearance of new symptoms, physical and radiological signs (unusual expansion, or the formation of a new tuberculous lesion) in a patient who has previously had an improvement in appropriate TAT is called a paradoxical reaction. More commonly seen in HIV coinfected individuals, it can also affect 2% -15% of the HIV-negative population. [17] CONCLUSION: Tuberculosis in children is a major public health problem in countries with a low economic income and tuberculous meningitis is the most common form of central nervous system tuberculosis, a serious complication with high mortality and morbidity. The cardinal symptoms of tuberculous meningitis are fever and headache, which also occurs in other neuroinfections, which requires maximum atention from physicians in order to establish the correct diagnosis. 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