Tuberculosis infection in young children

Classification

By form: basilar meningitis, meningoencephalitis, cerebrospinal meningitis.

According to the nature of the course of tuberculous meningitis: acute, subacute, chronic, recurrent.

PATHOGENESIS AND PATHOMORPHOLOGY

The most characteristic morphological manifestations of tuberculous lesions of the soft membranes of the brain are the rash of miliary tubercles and the appearance of serous-fibrinous exudate in the subarachnoid space. The membranes of the brain lose their transparency and become cloudy, covered with a jelly-like effusion. This process is most intensely expressed at the base of the brain. Tuberculosis tubercles can also be located on the outer surface of the brain, in the area of ​​the lateral (Sylvian) fissure, along the cerebral vessels, but here their number is significantly less than at the base of the brain. The tubercles, the size of a millet grain or slightly smaller, initially have a grayish color and are hardly noticeable, but then, as a result of caseous decay, they acquire a yellowish color and become clearly visible. Inflammatory changes in the acute stage of tuberculous meningitis are of a pronounced exudative nature. Microscopically, diffuse infiltration of the soft meninges with lymphocytes and macrophages is detected; polynuclear cells are less common. The tubercles have a characteristic epithelioid structure and contain giant cells. In the center of several tubercles there is caseous decay. Infiltrates of lymphocytes and plasma cells form around the venous vessels. As a rule, with tuberculous meningitis, not only the membranes, but also the substance of the brain are affected. The ventricles of the brain are distended and contain cloudy fluid.

Tuberculosis infection in young children

Tuberculosis is an infectious disease caused by various mycobacteria (MBT) - M. humanus, M. bovis, M. avium. However, other types of mycobacteria can cause disease, which is commonly called mycobacteriosis. Mycobacteriosis can develop when infected with M. xenopi, M. kasasii, M. ulcerans, etc.

Today we can state that tuberculosis affects all layers of society, all age groups and is especially dangerous for children in the first three years of life. In our opinion, when a child becomes infected in the first year of life, the disease develops in almost 100% of cases.

Along with the increase in incidence, the number of complicated forms of tuberculosis in children (especially young children) has increased significantly, which is a consequence of its late detection.

Children most often become infected with human mycobacteria from adult family members, usually from close relatives. In rural areas, unfavorable for bovine tuberculosis, infants are infected from animals (consumption of fresh milk) with bovine mycobacterium.

Mostly MBT penetrates into the human body aerogenously through inhalation of tiny droplets of the patient’s sputum released when coughing, sneezing, or talking. Infection through dried sputum is much less common. Infection through nutritional or contact routes (through damaged skin or mucous membranes) is possible. Intrauterine infection with the development of so-called congenital tuberculosis is extremely rare.

Along with the listed ways of penetration of the tuberculosis bacillus into the body, there is “iatrogenic” infection as a result of vaccination and revaccination with BCG. Our observations of 420 young children suggest that the further course of tuberculosis infection in young children and especially in the first year of life is determined by a number of factors:

• social factor;
• anatomical and physiological features characteristic of this age group;
• difficulties in identifying and diagnosing the disease.

The social factor is determined by the child’s family environment. As a rule, in 78-85% of cases, children are infected with MTB from their parents or close relatives. In this case, there is a massive in quantity and long-term (constantly for several weeks and even months) effect of the tuberculosis bacillus on the child’s body. Moreover, the younger the children, the more often they become infected from mothers and fathers: in the first year of life - 85%, in the second year - 67.7%, in the third year - 49.5% [5]. It has been established that the lower the awareness of pediatricians about contact children and their tuberculin sensitivity data, the more often tuberculosis is detected as a disease. Thus, respiratory tuberculosis is detected in 68.9% of children in the first year of life, in 37.5% in the second year, and in only 21.6% of cases in the third year [5].

The anatomical and physiological features that presuppose and determine the development and course of tuberculosis are the immaturity of the bronchopulmonary apparatus, the undifferentiation of the lymphatic system, the immaturity of the immune system for the localization and destruction of MBT and, first of all, a delayed-type hypersensitivity reaction, the prevalence of the exudative-alterative component in inflammatory reactions. A significant role in this age group is played by the tendency to frequent acute respiratory infections, the development of rickets and iron deficiency, and the allergic mood of the body. All this contributes to the occurrence of total caseous lesions of the intrathoracic lymph nodes, early lymphohematogenous dissemination, and rapid progression of the process with the development of complications. Self-healing of tuberculosis in this age group, unlike other age groups, is extremely rare. There are only isolated cases of partial regression of the process and its transition to chronic primary tuberculosis with the development of extensive calcified foci in the lungs and lymph nodes.

Diagnosis of tuberculosis at this age is very difficult, especially in the first year of life. Clinical manifestations of tuberculosis do not have specific features; they can occur under the masks of various diseases - ARVI, bronchitis, pneumonia, etc. - or asymptomatic.

Tuberculin diagnostics in the first year of life is not yet carried out on a large scale. When conducting tuberculin diagnostics among vaccinated children in the first 6-8 months of life, difficulties arise in the differential diagnosis of infectious and post-vaccination allergies. When a child is infected in the first days and weeks of life, a parallel formation of a specific allergy occurs. Only at the end of the first year of life and beyond, tuberculin diagnostics makes it possible to more clearly establish the infectious nature of the allergy (the formation of a high level of sensitivity to tuberculin or a hyperergic reaction).

With the generalization of the tuberculosis process (miliary tuberculosis, tuberculous meningitis), anergy to tuberculin is formed in 30-50%.
Ignorance of this phenomenon often leads to diagnostic errors. When conducting X-ray diagnostics, you may encounter a number of difficulties that are caused by the peculiarities of X-ray symeotics of uncomplicated and complicated primary tuberculosis and the anatomical and physiological features of a chest X-ray of a child in the first years of life.

Features of X-ray symeotics are determined by the pathophysiological mechanisms of primary tuberculosis. High tissue reactivity to tuberculosis microbacteria manifests itself in the form of extensive perifocal reactions in the lung tissue, segmental and lobar pulmonary lesions. The tendency to generalization and lymphotropism leads to an increase in intrathoracic lymph nodes.

The anatomical and physiological features are that in the small-sized chest of a child, a relatively large space is occupied by the median shadow formed by the heart and blood vessels, behind which the roots of the lungs are hidden, especially in the first year of life. The large thymus gland covers the area of ​​the superior mediastinum, which also makes visualization of the intrathoracic lymph nodes difficult. In addition, during the study, a small child behaves restlessly, and it is impossible to force him to take a deep breath. All this makes it very difficult to diagnose damage to the intrathoracic lymph nodes. As a result, local intrathoracic tuberculosis is sometimes confirmed radiographically only with dynamic observation and targeted X-ray tomography.

Bacteriological treatment methods in pediatrics, in contrast to therapy for adults, are less informative, since children rarely excrete MBT, and obtaining sputum is very difficult.

Therefore, the diagnosis is established on the basis of many indicators: a detailed medical history - information about BCG vaccination, contacts with a patient with tuberculosis, risk factors for the development of tuberculosis; dynamic monitoring of the course of the disease, X-ray tomographic picture; tuberculin diagnostics.

With the development of primary tuberculosis in young children, an intrathoracic process is diagnosed in 90-92% of cases.

Intrathoracic tuberculosis manifests itself in the form of bronchoadenitis - 89.3% and primary tuberculosis complex, respectively - 10.7%. According to the results of X-ray tomography, bronchoadenitis occurs predominantly in the form of tumorous and infiltrative forms. The “small” form is rare (3.2%). In this case, all groups of intrathoracic lymph nodes are often affected.

The primary tuberculosis complex is characterized by the development of inflammatory changes in the lung tissue, damage to the regional intrathoracic lymph nodes and lymphangitis. The pulmonary component in 96.6% of children is localized in the upper lobes (segments 2, 3, 4, 5), less often in the area of ​​the 6th segment and extremely rarely in segments 8, 9, 10, more often on the right, usually within one or two segments. Unlike other age groups, in young children, lymph node damage is rarely regional, but is characterized by the involvement of several, or even all groups of intrathoracic lymph nodes and often of a tumorous type.

Tuberculosis intoxication is detected extremely rarely, and in the absence of local tuberculosis lesions, a search for other causes of intoxication is required.

A characteristic manifestation of tuberculosis infection in early childhood is a high proportion of complications - 55.4%, and in children of the first year of life the frequency of complications reaches 80%. In the structure of complications, the most common are bronchopulmonary lesions - 55.6% (atelectatic-infiltrative process within one or several segments, lobes or the entire lung), miliary tuberculosis - 19.3%, generalized forms - 13.9%, tuberculous meningitis ( meningoencephalitis) - 11.2%.

Less often, unlike other age groups, the pleura is involved in the process.
In areas of primary affect, bronchopulmonary lesions, or with the progression of caseous necrosis, decay may develop with the subsequent formation of a cavity. With lymphohematogenous dissemination, various organs can be involved in the process: peripheral lymph nodes, skin, eyes, liver, spleen, kidneys, bones. Miliary tuberculosis and tuberculous meningitis are usually characteristic of children in the first year of life who have not been vaccinated with BCG. Often a combination of several variants of complications - pulmonary dissemination - bronchopulmonary damage, pulmonary dissemination - meningitis, etc. The development of complications often gives a more vivid clinical picture, in contrast to uncomplicated forms of primary tuberculosis, which in 38.4% of cases is the reason for hospitalization of the child to a general somatic hospital and requires differential diagnosis. It should be noted that among children with a complicated course of primary tuberculosis, 70-72% are children from migrant families. This fact is important in the diagnosis of tuberculosis for pediatricians in somatic and infectious diseases hospitals.

Clinical manifestations of tuberculosis do not have specific features. In 81.8% of cases, tuberculosis begins gradually [5]. The first signs of the disease appear in the form of moderately severe symptoms of intoxication: decreased appetite, changes in the child’s behavior. On examination, attention is drawn to pallor of the skin, decreased body weight, turgor, tissue elasticity, and enlarged peripheral lymph nodes. In the early stages, an enlargement of the liver and spleen and occasional rises in temperature to subfebrile levels can be detected. The hemogram shows hypochromic anemia, which is not amenable to treatment with iron supplements and nutritional correction. In the blood count, with a normal level of leukocytes, there is a neutrophil shift with the development of lymphopenia. With the addition of complications (miliary tuberculosis, meningitis, bronchopulmonary lesions), intoxication increases, body weight decreases significantly, the temperature becomes subfebrile-febrile, shortness of breath increases, a nonproductive cough appears, and with meningitis, meningeal symptoms develop.

Taking these factors into account, the pediatrician can promptly carry out the mandatory diagnostic minimum to confirm or exclude a specific process.

More than 37 years of results from the use of intradermal administration of BCG and then BCG-M for vaccination and revaccination indicate its beneficial effect on the course of primary tuberculosis infection in vaccinated people. Anti-tuberculosis vaccination reduces the development of such severe forms of the disease as miliary tuberculosis and tuberculous meningitis. It has been noted that primary infection and primary forms of tuberculosis in children vaccinated at birth, compared to unvaccinated ones, proceed more benignly, without complications and lead to a relatively quick favorable outcome [5]. Along with this, two important points should be noted.

First, in conditions of early infection (the first days and weeks of a child’s life), anti-tuberculosis vaccination carried out on the fourth to sixth day of life cannot prevent the development of tuberculosis and its complications, since post-vaccination immunity has not yet formed. This leads to the conclusion that there is a need for mandatory examination of all family members before the child is discharged from the maternity hospital, regardless of whether vaccination was carried out in the maternity hospital or not.

The second is BCG infection. The frequency of post-vaccination complications with the domestic BCG vaccine is 0.02% after vaccination and 0.003% after revaccination [3]. After the introduction of the BCG-M vaccine into practice, the frequency of complications decreased to 0.004% of the number of vaccinated newborns.

The manifestations of BCG infection are as diverse as those of primary tuberculosis, but unlike the latter, they are less aggressive.

In most cases, complications after BCG vaccination are local in nature. These are subcutaneous cold abscesses; ulcers 10 mm or more in diameter at the site of intradermal injection of the vaccine; lymphadenitis of regional lymph nodes (axillary, cervical, supraclavicular and subclavian) when the node enlarges to 1.5 cm or more in the phase of infiltration, abscess formation and calcification. Rarely, BCG osteitis and disseminated BCG infection occur as a consequence of congenital immunodeficiency (chronic granulomatous disease).

In the context of mass BCG vaccination, the high frequency of post-vaccination complications has led to the fact that a fairly large number of children, mainly in the first, less often in the second year of life, require long-term conservative and often surgical treatment.

Thus, a significant reservoir of tuberculosis infection has currently accumulated in the environment. Tuberculosis behaves aggressively, affecting all age and social groups of the population. In all its manifestations, it has the most negative effect on children of early age and especially the first year of life, often leading to death.

Literature
1. Aksenova V. A., Olyanishin V. N. Collection of resumes. Ekaterinburg, 1997. No. 186. P. 57. 2. Mitinskaya L. A. Anti-tuberculosis vaccination with BCG. M., 1975. 3. Mitinskaya L. A., Yukhimenko N. V., Kamaeva V. F. BCG vaccination and shortened courses of treatment of post-vaccination complications using a solution of rifampicin with dimexide. Pediatrics, 1986. No. 6. P. 94-95. 4. Khomenko A. G. Collection of resumes. Ekaterinburg, 1997. pp. 5-7. 5. Chugaev Yu. P. Diagnosis and treatment of tuberculosis in young children. Author's abstract. dis. doc. honey. Sci. M., 1988.

Epidemiology

Among extrapulmonary forms, tuberculous meningitis accounts for only 2-3%. In recent years, 18-20 cases of tuberculosis of the central nervous system and meninges have been registered in the Russian Federation (Tuberculosis in the Russian Federation, 2011). The prevalence of TBM is a generally recognized marker of tuberculosis distress in a territory. In various regions of the Russian Federation, the prevalence of TBM is from 0.07 to 0.15 per 100,000 population. In the context of the HIV epidemic, the incidence of TBM tends to increase.

VISUALIZATION: CT, MRI

The increase in morbidity and mortality from tuberculosis in the world and in Russia is due to the rapid spread of HIV infection [1-3, 10]. Since 2001, the highest rates of growth in the incidence of HIV infection in the world have been recorded in the Russian Federation. In total, in 2010, 509,734 people were registered in the country in whose blood antibodies to HIV were detected by immunoblotting. The total number of patients with tuberculosis in combination with HIV infection reached 24,963 people in 2010 - this is 5% of the number of patients with HIV infection. An important feature of the increase in incidence is the increase in the proportion of people with late stages of HIV infection: from 3.5% in 2005 to 11.4% in 2010, while 24,963 (5%) of them had active tuberculosis [7 , 10].

Until 2005, tuberculous meningitis (TM) was a fairly rare disease and was characterized by predominant damage to the membranes of the base of the brain [4, 6]. Due to the increase in the proportion of late stages of HIV infection from 2006 to the present, there has been a significant increase in the number of patients with TM, which necessitated the introduction of a new indicator into statistical reports [5, 9], reflecting the incidence of TM. Thus, in 2010 it was 0.13 per 100,000 population [5, 8].

The purpose of this work is to study the clinical features, diagnosis and pathomorphology of tuberculous meningoencephalitis (TME) in the late stages of HIV infection.

Material and methods

For the period 2007-2010. The results of observation of 140 patients were analyzed. The main group consisted of 120 patients with TME in the late stages of HIV infection (stage IVB). The comparison group included 20 patients with TM without HIV infection.

The average age of the patients was 30.5±8.5 years, 84.5% were men, 15.5% were women.

In 93.3% of patients in the main group, another localization of tuberculosis was simultaneously detected - damage to the lungs, all groups of lymph nodes, liver, spleen, kidneys, and less often other organs. 6.7% of patients had total damage to organs and systems. Respiratory tuberculosis was found in almost all patients.

TM without HIV infection proceeded mainly as an isolated lesion of the central nervous system; only 6 (30%) patients were diagnosed with disseminated pulmonary tuberculosis.

We studied X-ray data, the results of examining sputum and cerebrospinal fluid (CSF) for the presence of Mycobacterium tuberculosis using bacterioscopy, culture and PCR methods, immune status (CD4, CD8, CD4/CD8, viral load), determination of the content of protein, glucose, chlorides, cellular composition. CT and MRI of the brain were also performed.

In case of death, a pathomorphological examination was carried out in full in accordance with the established protocol. During autopsy, fragments of internal organs were fixed in 10% neutral formalin, processed according to standard methods, histological sections 3-5 microns thick were stained with hematoxylin and eosin, according to Van Gieson, Ziehl-Nielsen. Cytological preparations were studied with Romanovsky-Giemsa, Ziehl-Neelsen, and Gram stains. Immunohistochemistry (IHC) was performed using monoclonal antibodies to Myc. tuberculosis mouse

, clone 1.1/3/1, Vector.

Results and discussion

In 80 (66.7%) patients of the main group, the course of TME in the late stages of HIV infection was characterized by an acute onset without a clear prodromal period, hectic fever with the development of acute impairment of consciousness within 2-3 days from the onset of the disease, followed by the development of meningeal syndrome and symptoms of damage to the cranial nerves. In 40 (33.3%) patients, the onset of TME was asymptomatic or manifested by minimal symptoms and persistent changes in behavior - apathy, inadequate reaction to the environment, disorientation in place and time, partly in one’s own personality, impaired self-care skills, sometimes manifestations of aggression, a pronounced decrease in cognitive functions. In 20.2% of cases, a moderately severe cephalgic syndrome of a diffuse or local nature was observed.

TM without HIV infection was characterized by the presence of a clear prodromal period with the gradual development of intoxication syndrome, an increase in body temperature to febrile levels (90.2% of cases), increasing headache, up to unbearable (80.0%), often accompanied by nausea and no relief. relief by vomiting. Meningeal syndrome at the onset of the disease in patients of the main group was more often absent or mildly expressed, in contrast to TM without HIV infection (25.1 and 93.0%, respectively).

Damage to the cranial nerves in patients of the main group was observed 2.5 times less frequently than in the comparison group, which was obviously due to the convexital localization of damage to the meninges and substance of the brain. This is probably associated with more frequent cerebral and pyramidal symptoms and less pronounced meningeal syndrome.

Patients in the main group had severe immunosuppression: the number of CD4 lymphocytes was 100 cells/μl or less, the CD4/CD8 ratio was from 0.01 to 0.5, the viral load was from 500,000 cop/ml and above. The more acute the course of the disease, the lower the content of CD4 lymphocytes; CD4/CD8 ratio and higher - viral load. In fatal cases, the level of CD4 lymphocytes was 0-50 cells/μl, the CD4/CD8 ratio was 0.02-0.1.

In patients of the main group, the CSF, as a rule, revealed a moderate increase in protein (1-2 g/l), slight pleocytosis (on average 92±36 cells per μl) with a predominance of neutrophils (70-80%). In patients in the comparison group, the protein level in the CSF was significantly higher (from 3 to 10 g/l), pleocytosis reached 400-600 cells, mainly due to lymphocytes. Glucose levels in the main group decreased less significantly (1.3-1.9 mmol/l) than in the comparison group (0.7-0.9 mmol/l). The chloride content in the CSF did not differ significantly between the two groups. In patients of the main group, Mycobacterium tuberculosis was quite often detected in the CSF - by microscopy in 18 (15.0%) cases, culture - in 37 (30.8%), PCR - in 46 (38.3%), which is the most important criterion for diagnosing TM. It is extremely important to detect drug resistance of Mycobacterium tuberculosis in the CSF in 17 (45.9%) bacterial isolates, of which 9 (24.3%) had multiple drug resistance of Mycobacterium tuberculosis to drugs and 3 (8.1%) had extensive drug resistance. .

CT and MRI were used as an auxiliary diagnostic criterion for damage to the brain and membranes in 21 (17.5%) patients: foci of demyelination were identified in 13 (61.9%) patients, cerebrospinal fluid cysts - in 10 (47.6%), displacement of the median structures - in 5 (23.8%), decreased density of the brain substance - in 17 (81%), thickening of the meninges - in 2 (9.5%), impaired cerebrospinal fluid dynamics - in 18 (85.7%).

The study of the characteristics of the course of TME in patients of the main group made it possible to identify differences from the comparison group (see table)

.

Pathologically, TM without HIV infection was characterized by damage predominantly to the basal parts of the brain. The pia mater was jelly-like, swollen, with millet-like grayish miliary tubercles. TME revealed foci of caseous necrosis in the brain substance (Fig. 1)

.
Figure 1. Tuberculous meningoencephalitis in the absence of HIV infection. Caseous-necrotic focus in the substance of the brain, tubercular rashes of the pia mater. Unfixed macropreparation. Microscopically, in TM, in patients with a relatively intact immune status, the pia mater was edematous, with moderate fibrosis, vascular congestion, lymphoid infiltration of varying severity, miliary tubercles consisting of epithelioid cells, Pirogov-Langhans giant cells, with a lymphoid shaft along the periphery. Leukocytes could be detected in the inflammatory infiltrate. Tuberculous granulomas sometimes merged with foci of central caseous necrosis (Fig. 2)
. Figure 2. Tuberculous meningitis (without HIV infection). Fibrosis, pronounced lymphoid infiltration of the meninges, separately located and merging epithelioid giant cell granulomas with necrosis in the center. Hematoxylin and eosin staining. Uv. 200.

In case of TM in the late stages of HIV infection, a total lesion of the pia mater was determined, with the involvement of the convexital surfaces of the brain in the process of sheathing. Due to purulent impregnation, the membranes acquired a yellowish-greenish color (like a “purulent cap”), tuberculate rashes were not visualized (Fig. 3, 4)

.
Figure 3. Tuberculous meningitis due to HIV infection.
a - purulent impregnation of the membrane of the basal parts of the brain; b — damage to the membrane of the convexital surface of the brain. Unfixed macropreparations. Figure 4. Tuberculous meningitis due to HIV infection. a - in the pia mater there is pronounced edema, plethora, extensive purulent-necrotic foci without signs of granulomatous inflammation, pronounced vasculitis. Hematoxylin and eosin staining. Uv. 200; b — fragment with no signs of delineation of foci of tuberculous inflammation. Van Gieson staining. Uv. 200. With the development of TME, foci of destruction such as abscesses were identified in the brain substance. These changes give the impression of nonspecific bacterial inflammation, and only histological examination with additional stains and bacteriological examination can establish the tuberculous etiology of the process. In HIV-associated TME, the pia mater was edematous, sharply congested, with diffuse leukocyte, less often lymphoid-leukocyte infiltration. Purulent-necrotic lesions of a monomorphic structure with no signs of productive inflammation were located perivascularly (epithelioid and giant multinucleated cells were not detected in the vast majority of cases) (Fig. 5, 6)

.
Figure 5. HIV-associated tuberculous meningitis.
Abundance of acid-fast bacteria in the imprint smear of the pia mater. Ziehl-Neelsen staining. Uv. 1000. Figure 6. Mycobacteria in a purulent-necrotic focus of the pia mater. Immunohistochemical study with Myc. Tuberculosis mouse monoclonal antibody, clone 1.1/3/1, Vector. Uv. 1000. Purulent-necrotic foci similar to acute abscesses were also found in the brain matter. Characteristic was the development of vasculitis, including severe destructive forms, thrombovasculitis, which further intensified necrotic processes. In cytological preparations of impression smears of the pia mater and areas of brain destruction, as well as histobacterioscopically with Ziehl-Neelsen staining, a large number of acid-fast bacteria were found in necrotic masses and the cytoplasm of neutrophils (see Fig. 5)

.

Using additional histological stains, the tuberculous etiology of vasculitis was confirmed. Immunohistochemical reaction using Myc monoclonal antibodies. Tuberculosis mouse monoclonal antibody

made it possible to establish the generic affiliation of the pathogen and identify it as Mycobacterium tuberculosis
(see Fig. 6)
.

Thus, according to a pathoanatomical study of 56 people who died from TME with HIV infection, the following features of tuberculous brain damage in the late stages of this infection were established: generalized damage to brain tissue and meninges with multiple foci of necrosis and destruction of brain tissue in 51 (91.1%) sick; the absence of classic basal leptomeningitis and specific tuberculous inflammation, the formation of tubercles and granulomas, a specific shaft of epithelioid cells and Pirogov-Langhans cells in 48 (85.7%). Microscopy of material from foci of necrosis in 40 (71.4%) patients revealed a large number of Mycobacterium tuberculosis.

Here is one of our observations.

Sick, K

., 30 years old, was admitted to tuberculosis hospital No. 11 on December 12, 2008 with a diagnosis of HIV infection, stage IVB (AIDS). Generalized tuberculosis with damage to the brain and meninges (TME with right-sided pyramidal syndrome), lungs (disseminated pulmonary tuberculosis), damage to the intrathoracic lymph nodes.

Social status: unemployed with no fixed place of residence (lives in a rented apartment), low level of income. Height 175 cm. Weight 54.0 kg. Body mass index 17.6 kg/m2. Bad habits: smokes 1 pack of cigarettes a day, opium addiction.

History of the disease: tuberculosis was detected in June 2008, was treated in tuberculosis hospital No. 11 from June to November 2008, and was discharged with positive dynamics of the disease. After discharge he continued to use opiates. He did not receive antiretroviral therapy. The condition worsened in December 2008, when, against the background of general malaise, a high fever appeared and consciousness was impaired. On 12/07/08 he was urgently hospitalized at Infectious Diseases Clinical Hospital No. 2, where infiltrative tuberculosis of the lower lobe of the right lung and intrathoracic lymph nodes was detected. Then he was diagnosed with TME with right-sided pyramidal syndrome, infiltrative tuberculosis of the lower lobe of the right lung, intrathoracic lymph nodes, for which on December 12, 2008 he was transferred to tuberculosis hospital No. 11.

There were no complaints upon admission due to depression of consciousness (stupor). Rigidity of the neck muscles is moderately expressed. Severe Kernig and Brudzinski symptoms. Reacts by opening the eyes to loud speech and painful stimuli. Palpebral fissures D>S. The pupils are round in shape, D=S, reactions to light, and accommodation are reduced. The movements of the eyeballs are limited outward, there is no spontaneous nystagmus. The pharyngeal reflex is reduced. Right-sided hemiplegia with low tone. Tendon and periosteal reflexes of medium vivacity, S

X-ray of the lungs 12/15/08: on the right in the lower lobe there is a limited area of ​​infiltration on both sides, increased pulmonary pattern, the roots are deformed, pleurodiaphragmatic adhesions on the right, the right dome of the diaphragm on the 5th rib.

MRI of the brain from 12/11/08 - multiple foci of hyperintense MR signal in T2 and TIRM modes, located on the right in the frontal and occipital lobes, on the left in the frontal lobe, most pronounced in the temporal (damage to the subcortical nuclei), parietal and occipital lobes. In the left temporal lobe there is a decrease in the MR signal in T1 mode from the pathologically altered substance. In the lesion on the left at the level of the precentral gyrus there is a focus of central necrosis. The left lateral ventricle is significantly compressed. Dislocation of the midline structures at the level of the third ventricle to the right by 7.8 mm, the fissures of the subarachnoid space are widened.

General blood test: hemoglobin Hb 108 g/l, erythrocytes 3.05·1012/l, leukocytes 6.9·109/l, platelets 37·109/l, monocytes 69, lymphocytes 27, ESR 65 mm/h. Biochemical blood test dated 12/08/08: total protein 80 g/l, total bilirubin 4.0 mmol/l, aspartate transaminase 23 U/l, alanine transaminase 16 U/l, urea 8.1 mmol/l, creatinine 64 µM/l, alkaline phosphatase 86 U, glucose 5.1 mmol/l.

General analysis of CSF: turbid, colorless, protein 2.32 g/l, glucose 1.2 mmol/l, chlorides 115 mmol/l, cytosis 32 (51% - neutrophils, 49% - lymphocytes) cells per μl.

Examination of the patient's biological materials for Mycobacterium tuberculosis: sputum and CSF bacterioscopy are negative. Culture of sputum and CSF for Mycobacterium tuberculosis - no growth. Mycobacterium tuberculosis was detected in the CSF using the PCR method.

Immune status: CD4 - 54 cells (12%), CD8 - 341 cells (57%), CD4/CD8 - 0.15.

Clinical diagnosis: HIV infection stage IVB (AIDS). Tuberculosis of multiple localization: tuberculous meningoencephalitis; infiltrative tuberculosis of the lower lobe of the right lung, MBT(-); tuberculosis of intrathoracic lymph nodes in the infiltration phase. Oral candidiasis.

Complications: edema and swelling of the brain. Cachexia. Respiratory failure of the 3rd degree. Pulmonary heart failure of the 3rd degree. Concomitant diseases: toxic-metabolic encephalopolyneuropathy. Liver cirrhosis of mixed etiology (viral and toxic).

The patient received anti-tuberculosis therapy - tavanic, rifadin, isoniazid, pyrazinamide, ethambutol, decongestant - mannitol, dexamethasone, detoxification - reogluman, hepatoprotective - karsil, as well as vascular, nootropic and antioxidant - Cavinton, piracetam, mexidol.

Despite the therapy, the patient's condition continued to deteriorate. Against the background of increasing symptoms of edema and swelling of the brain, death occurred on December 15, 2008.

Pathological diagnosis: HIV infection stage IVB. Generalized tuberculosis with damage to the intrathoracic and para-aortic lymph nodes, lungs (disseminated tuberculosis), brain (tuberculous meningoencephalitis with areas of suppuration), spleen (miliary), acid-fast mycobacterium tuberculosis are detected by all methods. Mycotic esophagitis. Brain edema with dislocation of stem structures. Pulmonary edema. Pulmonary heart failure of the 3rd degree. Addiction. Chronic viral hepatitis C. Cachexia.

A feature of this case was a significant predominance of encephalitis with the presence of gross focal symptoms and the development of dislocation syndrome. The disease occurred against the background of severe immunodeficiency.

In modern conditions, due to the increase in the later stages of HIV infection, there is a significant increase in the number of patients with TME, which, due to immunosuppression, has a severe clinical course with high mortality. In patients with TME with HIV infection, compared with patients with TME without it, a more acute onset of the disease, a predominance of symptoms of encephalitis confirmed by neuroimaging data, a more frequent detection of Mycobacterium tuberculosis in the CSF, and a high frequency of their multidrug resistance were noted. The microscopic picture of the TME in patients in the late stages of HIV infection does not have the specific features characteristic of tuberculous inflammation. Alterative-exudative reactions predominate in the absence of signs of granulomatous inflammation, which requires a morphological differential diagnosis between tuberculous brain damage and nonspecific bacterial inflammation.

Clinical manifestations

The onset of the disease is subacute; there is often a prodromal period with increased fatigue, weakness, headache, anorexia, sweating, sleep inversion, and character changes, especially in children. Body temperature is subfebrile. Vomiting often occurs as a result of headaches. The prodromal period lasts 2-3 weeks. Then, mild meningeal symptoms gradually appear (stiff neck, Kernig's sign, etc.) Signs of damage to the III and VI pairs of the cranial nerves appear early. In the later stages, if the disease is not recognized and specific treatment is not started, paresis of the limbs, aphasia and other symptoms of focal brain damage may occur. The most typical course of the disease is subacute. In this case, the transition from prodromal phenomena to the period of appearance of membrane symptoms occurs gradually, on average within 4-6 weeks. Acute onset is less common (usually in young children and adolescents). A chronic course is possible in patients who were previously treated with specific drugs for tuberculosis of internal organs.

Tuberculous meningitis

Periods of flow

The prodromal period
lasts on average 1-2 weeks. Its presence distinguishes tuberculous meningitis from other meningitis. It is characterized by the appearance of cephalalgia (headache) in the evenings, subjective deterioration of well-being, irritability or apathy. Then the cephalalgia intensifies, nausea occurs, and vomiting may occur. Low-grade fever is often noted. When visiting a doctor during this period, it is not possible to suspect tuberculous meningitis due to the nonspecificity of these symptoms.

Irritation period

manifests itself by a sharp increase in symptoms with a rise in body temperature to 39 °C. The headache is intense, accompanied by increased sensitivity to light (photophobia), sounds (hyperacusis), and touch (cutaneous hyperesthesia). Lethargy and drowsiness worsen. The appearance and disappearance of red spots in various areas of the skin is noted, which is associated with a disorder of the autonomic vascular innervation. Meningeal symptoms occur: rigidity (tension) of the neck muscles, Brudzinski and Kernig symptoms. Initially they are vague in nature, then gradually intensify. By the end of the second period (after 8-14 days), the patient is lethargic, consciousness is confused, and the typical meningeal “pointing dog” posture is characteristic.

Period of paresis and paralysis

(terminal) is accompanied by a complete loss of consciousness, the appearance of central paralysis and sensory disorders. Respiratory and heart rhythm are disturbed, convulsions, hyperthermia up to 41 ° C or low body temperature are possible. If left untreated during this period, tuberculous meningitis leads to death within a week, caused by paralysis of the vascular and respiratory centers of the brain stem.

Clinical forms

Basilar tuberculous meningitis

in 70% of cases it develops gradually with the presence of a prodromal period, the duration of which varies between 1-4 weeks. During the period of irritation, cephalgia increases, anorexia occurs, “fountain” vomiting is typical, drowsiness and lethargy increase. Progressive meningeal syndrome is accompanied by the addition of disorders of the cranial nerves (CN): strabismus, anisocoria, blurred vision, drooping of the upper eyelid, and hearing loss. In 40% of cases, ophthalmoscopy reveals congestion of the optic nerve head. Possible damage to the facial nerve (facial asymmetry). The progression of meningitis leads to the appearance of bulbar symptoms (dysarthria and dysphonia, choking), indicating damage to the IX, X and XII pairs of the cranial nerve. In the absence of adequate therapy, basilar meningitis progresses to the terminal period.

Tuberculous meningoencephalitis

usually corresponds to the third period of meningitis. Typically, the predominance of symptoms of encephalitis: paresis or paralysis of the spastic type, loss of sensitivity, two- or one-sided hyperkinesis. Consciousness is lost. Tachycardia, arrhythmia, respiratory disorders up to Cheyne-Stokes breathing are noted, and bedsores form. Further progression of meningoencephalitis ends in death.

Spinal tuberculous meningitis

rarely observed. As a rule, it manifests with signs of damage to the cerebral membranes. Then, in 2-3 periods, shingles pain occurs, caused by the spread of tuberculosis to the spinal roots. When the cerebrospinal fluid pathways are blocked, the radicular pain is so intense that it cannot be relieved even with the help of narcotic analgesics. Further progression is accompanied by pelvic disorders: first, retention, and then urinary and fecal incontinence. Peripheral flaccid paralysis, mono- and paraparesis are observed.

Radiation diagnostics

CT semiotics: Changes may not be detected on images without contrast enhancement. In later stages, complications such as hydrocephalus and cerebral infarction due to ischemia can be detected. With intravenous contrast enhancement, intense accumulation of the contrast agent in the meninges is observed, mainly on the basal surface of the brain.

MRI semiotics

T1-weighted images: in the initial stages, changes are not detected; shortening of T1 (in the form of an increase in the MR signal) from the meninges can be observed as the disease progresses

T2-weighted image: exudate is usually isointense to cerebrospinal fluid (hyperintense MR signal)

FLAIR: hyperintense MR signal in the basal cisterns and sulci. Post-contrast FLAIR images may have greater specificity than post-contrast T1-weighted images in detecting leptomeningeal enhancement

Contrast-enhanced T1-weighted imaging reveals intense accumulation of contrast material in the meninges, predominantly on the basal surface of the brain. Pointed/linear areas of accumulation in the basal ganglia are characteristic of vasculitis. In rare cases, accumulation of the contrast agent in the ventricular ependyma may occur, which is characteristic of a complication of TBM - ventriculitis.

DIFFERENTIAL DIAGNOSIS is carried out with infectious meningitis of another etiology, neurosarcoidosis, meningeal carcinomatosis.

Fig. 1 CT scan of the brain in the axial plane after contrast enhancement demonstrates the typical accumulation of contrast in the basal cisterns for TBM [3]

Fig. 2 MRI of the brain, axial plane, FLAIR mode: in the basal parts of the brain (sella turcica, interpeduncular, bypass cistern, pineal region) areas of altered MR signal of increased intensity are visualized

Fig. 3 MRI of the brain in the axial plane, a – T1-VI (native), b – T1-WI (post-contrast): in the area of ​​the cisterns of the base of the brain, uneven thickening of the meninges is detected, isointense on T1-WI (a), with intense accumulation of contrast agent (b)

What is meningitis like? Meningitis and its types

There are leptomeningitis - inflammation of the soft and arachnoid membranes, arachnoiditis - inflammation of the arachnoid membrane and pachymeningitis - inflammation of the dura mater. In practice, the term “meningitis” refers primarily to leptomeningitis. The first report of a case of tuberculous meningitis was made in 1768 in the description of the death of a patient, although the connection between meningitis, tuberculosis and its causative agent was not identified until the 19th century.

Until the 20th century, the mortality rate from tuberculous meningitis reached 90%. In the twentieth century, antibodies were obtained against meningitis pathogens, in particular against tuberculous meningitis, which significantly reduced mortality.

However, this disease currently poses a serious problem for phthisiology, despite the presence of a powerful arsenal of anti-tuberculosis drugs.

Unsatisfactory treatment results are due to difficulties in making a diagnosis, late detection and severity of the disease. Errors in diagnosis are often a consequence of the atypical course of the disease.

Tuberculous meningitis (TM) represents approximately 1% of all tuberculosis cases, but is disproportionately important because it kills or disables about half of those affected. The issue of successful prevention, early detection and timely treatment of pyogenic bacterial meningitis through vaccination has meant that in many parts of the world tuberculosis is the most common cause of bacterial tuberculous meningitis. It affects all age groups, but is especially common in young children and people with HIV infection. Incidence is directly related to the prevalence of pulmonary tuberculosis, so optimizing global tuberculosis control is key. WHO estimates that in 2010, there were more than 8.8 million new cases of tuberculosis of various forms worldwide and 1.45 million deaths from the infection. The absolute number of new cases of tuberculosis began to fall in 2006-2007, and a decrease in mortality from tuberculosis was determined by 2 times compared to 1990 data. While these numbers are encouraging, they also mask large regional differences. In the metropolitan area of ​​London, UK, for example, the number of new cases of tuberculosis has doubled over the past 10 years. A similar increase was seen in the Western Province of South Africa, where tuberculous meningitis is the most common cause of childhood meningitis.

Early clinical diagnosis, as is known, has its own difficulties and often turns out to be untimely, with catastrophic consequences for patients. Early diagnosis and early treatment of tuberculous meningitis has long been recognized as the most important factor determining outcome.

The clinical signs of tuberculous meningitis have been well described for a long time; the classic onset is asthenic syndrome. The difficulty is that neck stiffness is usually absent in the early stages of the disease in patients of all ages. In young children, these nonspecific symptoms include poor weight gain, low-grade fever, and lethargy. The only factor that distinguishes the symptoms of tuberculous meningitis from common illnesses such as influenza is the persistence and severity of the symptoms, although this aspect is often missed unless the patient is seen consistently by the same physician. Thus, initially curable tuberculous meningitis can progress to the final stages, up to coma, opisthotonus and death.

The “gold standard” for the diagnosis of TM is the isolation of Mycobacterium tuberculosis from the cerebrospinal fluid by culture; however, this method, being 100% specific, has low sensitivity. According to domestic authors, the diagnosis is confirmed bacteriologically in 4–8% to 27% of cases. According to foreign literature, up to 40% - by bacterioscopy and up to 60% - by culture. These results are received by doctors in the second or third month of hospitalization. Thus, bacteriological examination can only confirm the diagnosis of TM, but cannot help the patient. Highly sensitive and specific diagnostic technologies, such as PCR of cerebrospinal fluid with the isolation of DNA of Mycobacterium tuberculosis, can currently be used and are used only in certain institutions, and the diagnosis necessary for timely specific therapy is established on the basis of the following signs: the presence of tuberculosis contact or transferred to past tuberculosis; gradual cyclical development of the disease; characteristic liquor syndrome. However, the variability of the clinical picture due to previous inadequate specific therapy and the premorbid status of patients, an increase in the proportion of isolated TM, the absence in some cases of a typical cerebrospinal fluid syndrome and a clear uniform approach to diagnosis make timely verification of the diagnosis difficult. It is also difficult to diagnose TM in HIV-infected patients; the clinical picture is often blurred, and the possible causes of symptoms are many times greater.

Attempts to improve laboratory diagnostic methods, in particular microscopy, to date do not exceed 60% reliability. There are currently many studies being conducted around the world that are trying to solve the problem of laboratory diagnosis of TM, but it will be a long time before the impressive results are replicated in large-scale studies and modification of methods becomes a simple and inexpensive solution to a long-standing problem.

Modern neuroimaging capabilities are also a method for diagnosing patients with tuberculous meningitis.

CT scan of the brain can reveal the presence of hyperdense exudate in the basal regions without intravenous contrast enhancement, as well as basal meningeal thickening, infarctions, supplementing the method with contrast enhancement, and possibly determine the presence of tuberculomas. In combination with the clinic, these data are very informative in the diagnosis of tuberculous meningitis in adults and children. However, about 30% of children at the onset of tuberculous meningitis will have an unchanged brain according to MSCT.

MRI is superior to CT in determining the neuroradiological aspects of tuberculous meningitis , especially when they involve the brainstem (Figure 1). High-field MRI using diffusion-weighted programs increases the detection of early infarcts and border zones of encephalitis (cytotoxic edema that underlies tuberculous exudate). IV contrast with gadolinium preparations using MRI allows visualization of leptomeningeal “nodes”, which are present in 90% of cases of tuberculous meningitis in children and 70% of adults. MRI is also valuable for identifying and monitoring tuberculous meningitis associated with cranial nerve neuropathy. The most important of these is opticochiasmatic arachnoiditis, which requires urgent intervention to reduce the risk of blindness (Figure 2). Magnetic resonance angiography can be used to identify vascular lesions, which are present in 60% of cases and most commonly affect the terminal portions of the internal carotid artery and the proximal portions of the middle and anterior cerebral arteries.

(A) Normal brain on CT scan, 3-year-old child with confirmed tuberculous meningitis. (B) Free fluid-suppressed T2-weighted images obtained on the same day as the CT scan at day 5 of clinical manifestations show several infarcts (arrows) in the region of the basal ganglia. Diffusion-weighted MR images (C, D) show diffusion limitation in the region of the basal ganglia.

Tuberculous meningitis with changes in the optic-chiasmal area. MRI (A) T1-weighted image after intravenous contrast enhancement with gadolinium, a 7-year-old boy with significant subtotal loss of vision caused by severe tuberculous meningitis, with changes in the opticochiasmatic region shows increased MR signal intensity due to accumulation of contrast material in thickened membranes almost the entire suprasellar cistern with displacement and compression of the optic nerve in front. Accumulation of contrast in the form of a ring by the wall of a tuberculous abscess. (B) After 3 months of adjuvant therapy, the patient’s vision was restored and subsequent MRIs revealed a significant improvement in opto-chiasmatic arachnoiditis despite the asymptomatic increase in the size of the abscess and the appearance of additional lesions and focal points of abscess formation.

The detection of intracranial tuberculomas by MRI depends on the severity of the process and the size of the changes. Features of imaging depend on the stage of development of tuberculoma (non-caseating and necrotizing).

Tuberculous abscesses are larger than tuberculomas (often >3 cm in diameter), solitary, thin-walled, and often present in numbers of more than two. Magnetic resonance spectroscopy may help distinguish between tuberculous and non-tuberculous brain lesions by increasing lipid levels in tuberculosis.

Despite great strides made in understanding tuberculous meningitis over the past 10 years, many challenges remain. Tuberculous meningitis is still the most dangerous form of tuberculosis. The best way to improve survival is through early diagnosis and treatment, but this goal will not be achieved without replacing current diagnostic tests and using a comprehensive approach to ensure timely diagnosis. New diagnostic approaches are urgently needed, especially given the current prevalence of tuberculosis. The only way for a quick solution today is consistent observation by one doctor, the vigilance of general practitioners, laboratory and radiation diagnostics at the first suspicion of tuberculous meningitis.

Author:

Daria Igorevna Sorokina – radiologist of the consulting department “UK MRI Expert and Clinic Expert”, Novosibirsk

Description example

Descriptive part: In the area of ​​the cisterns of the base of the brain and the Sylvian fissures on both sides, almost symmetrically, a somewhat uneven thickening of the meninges is detected in the form of additional formations of tissue intensity of the MR signal with signs of intense diffuse-inhomogeneous enhancement on post-contrast tomograms. Symmetrical expansion of the temporal horns of the lateral ventricles with periventricular edema. Internal occlusive hydrocephalus.

CONCLUSION: MR picture of widespread uneven thickening of the meninges in the area of ​​the cerebral cisterns and Sylvian fissures. Internal occlusive hydrocephalus. (depending on the medical history, differentiate between proliferative meningitis, leptomeningeal metastasis or tumor-lymphoma).

List of used literature and sources

1. Central Nervous System Tuberculosis: An Imaging-Focused Review of a Reemerging Disease / MS Taheri // Radiology Research and Practice. 2015. - 2015: 202806.
2. Diagnostic imaging. Brain / Anne G. Osborn, Karen L. Salzman, and Miral D. Jhaveri. 3rd edition. ELSEVIER. Philadelphia, 2021. P.1237. ISBN: 978-0-323-37754-6
3. Tuberculous meningitis [Electronic resource] / Radiopaedia.org: website. – URL: https://radiopaedia.org/articles/tuberculous-meningitis (05.11.2018)
4. Diseases of the nervous system: A guide for doctors: / Ed. N. N. Yakhno, D. R. Shtulman. —2nd edition, revised and supplemented. - M.: Medicine, 2001. - p. 744.
5. Neurology: national guide / ch. ed. E.I. Gusev, A.N. Konovalov, V.I. Skvortsova, A.B. Gekht. – M.: GEOTAR-Media, 2009. – 1035 p.
6. Federal clinical guidelines for the diagnosis and treatment of tuberculous meningitis in children / I.F. Dovgalyuk, A.A. Starshinova, N.V. Korneva, L.V. Poddubnaya. – Russian Society of Phthisiologists. 2015.