Cryptococcal meningitis

Inflammation of the soft membranes of the brain can be caused not only by bacteria, viruses and protists, but also by a fungal infection. Cryptococcal meningitis develops when the encapsulated yeast Cryptococcus neoformans, which belongs to human opportunistic pathogens, is affected. [1] It was named Busse-Buschke disease because of its first description by Otto Busse and Abraham Buschke in 1894. [2]

According to ICD-10, the disease code is G02.1 (in the section on inflammatory diseases of the central nervous system), as well as B45.1 in the section on mycoses (that is, fungal diseases).

Epidemiology

Eight out of ten cases of cryptococcal meningitis affect people with HIV / AIDS.

According to data published by The Lancet Infectious Diseases in the spring of 2017, among people with HIV or AIDS, this fungus causes about 220 thousand cases of cryptococcal meningitis annually, and more than 180 thousand people die. Most cases of cryptococcal meningitis occur in sub-Saharan Africa.

According to WHO statistics, during 2017, 165.8 thousand cases of cryptococcal meningitis were registered in Africa, 43.2 thousand in Asia, 9.7 thousand in the Americas, and 4.4 in European countries. Thousand cases of the disease.

Causes of the cryptococcal meningitis

The reasons for this type of  meningitis  are infection with the fungus Cryptococcus neoformans (class Tremellomycetes, genus Filobasidiella), which lives in the environment: in the soil (including dust), on rotting wood, in the droppings of birds (pigeons) and bats, etc.... Infection occurs by aerogenic means - by inhalation of aerosol basidiospores of the fungus, although in most people with a sufficient level of immunity, C. Neoformans does not lead to the development of disease and remains an optional intracellular opportunistic microorganism (which cannot infect other people). Read also -  Cryptococci - the causative agents of cryptococcosis [3]

As a rule, cryptococcal meningitis develops in HIV-infected (stage IVB) - as a secondary infection, as well as in people with a poorly functioning immune system in other diseases accompanied by prolonged immunosuppression. [4]

Inflammation of the meninges due to cryptococci is considered a cerebral or extrapulmonary form of  cryptococcosis , which occurs after hematogenous dissemination of C. Neoformans from the airways and lungs to the brain and spinal cord. [5]

Risk factors

The factors at greatest risk of developing cryptococcal meningitis are:

• neonatal period (neonatal period) and prematurity of infants;
• weakening of the immune system in cancer (including leukemia, multiple melanoma, lymphosarcoma), in patients with  HIV infection and AIDS ;
• diabetes;
• viral hepatitis and other immunocomplex diseases;
• sickle cell anemia;
• chemotherapy in the presence of an oncological diagnosis;
• exceeding the permissible rate of ionizing radiation;
• long courses of treatment with antibiotics or steroids;
• installation of intravascular catheters and shunts;
• bone marrow or internal organ transplantation.

Pathogenesis

Cryptococci, protected from human immune cells by a polysaccharide capsule (suppressing phagocytosis), secrete proteases, urease, phospholipase and nuclease, enzymes that can destroy host cells. [6]

And the pathogenesis of cryptococcosis lies in the fact that these enzymes damage cells by lysis of membranes, modification of molecules, dysfunction of cell organelles and changes in the cytoskeleton. [7]

Fungal serine proteases destroy peptide bonds of cellular proteins, degrade immunoglobulins and proteins of immune effector cells, and C. Neoformans replicates inside mononuclear phagocytes (macrophages), which facilitates their proliferation. [8]

In addition, by passing through endothelial cells and by transfer inside infected macrophages, cryptococci disrupt the integrity of the blood-brain barrier (BBB). The fungus spreads through the bloodstream into the cerebrospinal fluid and then into the soft membranes of the brain with the formation of "colonies" of fungal cells in the brain tissues in the form of gelatinous pseudocysts. [9]

Symptoms of the cryptococcal meningitis

The first signs of cryptococcal meningitis are fever (temperature rise to + 38.5-39 ° C) and severe headaches.

Also, clinical symptoms are manifested by nausea and vomiting, seizures, stiffness (stiffness) of the neck, increased sensitivity of the eyes to light, impaired consciousness and behavior. [10]

According to experts, the development of  meningeal syndrome  is slower than with bacterial damage to the meninges.

 

Complications and consequences

Complications and consequences of fungal meningitis caused by cryptococcus are:

• significant increase in intracranial pressure;
• isolated damage to the cranial nerves with paresis / paralysis of the facial and atrophic changes in the optic nerve (leading to ophthalmic problems);
• the spread of the inflammatory process to the tissue of the subcortex and cerebral hemispheres - cryptococcal meningoencephalitis;
• development of a brain abscess (cryptococcoma);
• effusion into the subdural space (under the dura mater);
• spinal cord injury;
• mental changes and decreased cognitive functions.

Diagnostics of the cryptococcal meningitis

In addition to the medical history and medical examination, the diagnosis of C. Neoformans infection in meningitis necessarily includes blood tests: general clinical and biochemical, blood serum analysis for antibodies to C. Neoformans proteins, blood culture.

A  lumbar puncture is performed  and an analysis of the cerebrospinal fluid is done   for antigen and a bacterioscopic analysis (bacterial culture) of the cerebrospinal fluid. [11]

Instrumental diagnostics is carried out using a chest X-ray and magnetic resonance imaging of the brain.

Differential diagnosis

Differential diagnosis includes meningitis and meningoencephalitis of bacterial and viral etiology, brain damage by Histoplasma capsulatum, Coccidioides immitis, Blastomyces dermatidis, or amoebae (including Naegleria fowleri).

Treatment of the cryptococcal meningitis

Etiological treatment is aimed at eradicating cryptococci, for which antifungal drugs are used.

The treatment regimen includes intravenous administration (drip, through a central venous catheter or by peritoneal infusion) of a polyene antifungal antibiotic Amphotericin B (Amphocyl) in combination with antifungal agent Flucytosine (5-fluorocytosine) or Fluconon, which has a fungicidal and fungistatic effect. The dosage of these drugs is calculated depending on the patient's body weight.

Constant monitoring of the patient's condition is necessary, since Amphotericin B has a toxic effect on the kidneys, and side effects of Flucytosine can be inhibition of the hematopoietic function of the bone marrow, respiratory or cardiac arrest, the development of skin lesions in the form of epidermal necrolysis, etc. 

According to recommendations published in the 2010 IDSA (Infectious Diseases Society of America) update, treatment has not changed for ten years. First-line antifungal treatment is based on the induction, consolidation and maintenance of the following three types of patients: [12]

Diseases associated with HIV

• Induction therapy
  • Amphotericin B deoxycholate (0.7-1.0 mg / kg / day) + flucytosine (100 mg / kg / day orally) for 2 weeks (A1 evidence)
  • Liposomal amphotericin B (3-4 mg / kg / day) or amphotericin B lipid complex (5 mg / kg / day; monitoring renal function) + flucytosine (100 mg / kg / day) for 2 weeks (evidence B2)
  • Amphotericin B deoxycholate (0.7 to 1.0 mg / kg / day) or liposomal amphotericin B (3 to 4 mg / kg / day) or amphotericin B lipid complex (5 mg / kg / day, for patients who intolerant to flucytosine) for 4 to 6 weeks (evidence B2)
• Induction therapy alternatives
• Amphotericin B deoxycholate + fluconazole (B1 evidence)
• Fluconazole + flucytosine (evidence B2)
• Fluconazole (B2 evidence)
• Itraconazole (C2 evidence)
• Fluconazole (400 mg / day) for 8 weeks (data A1)
• Fluconazole (200 mg / day) for 1 or more years (A1 evidence)
• Itraconazole (400 mg / day) for 1 or more years (evidence C1)
• Amphotericin B deoxycholate (1 mg / kg / week) for 1 or more years (evidence C1)
• Consolidation therapy
• Supportive therapy
• Supportive care alternatives

Transplant related diseases

• Induction therapy
  • Liposomal amphotericin B (3-4 mg / kg / day) or amphotericin B lipid complex (5 mg / kg / day) + flucytosine (100 mg / kg / day) for 2 weeks (evidence B3)
• Induction therapy alternatives
• Liposomal amphotericin B (6 mg / kg / day) or amphotericin B lipid complex (5 mg / kg / day) for 4-6 weeks (evidence B3)
• Amphotericin B deoxycholate (0.7 mg / kg / day) for 4-6 weeks (evidence B3)
• Fluconazole (400 to 800 mg / day) for 8 weeks (evidence B3)
• Fluconazole (200 to 400 mg / day) 6 months to 1 year (evidence B3)
• Consolidation therapy 
• Supportive therapy

Non-HIV / Transplant-Related Disease

• Induction therapy
  • Amphotericin B deoxycholate (0.7 to 1.0 mg / kg / day) + flucytosine (100 mg / kg / day) for 4 weeks or more (evidence B2)
  • Amphotericin B deoxycholate (0.7-1.0 mg / kg / day) for 6 weeks (evidence B2)
  • Liposomal amphotericin B (3-4 mg / kg / day) or amphotericin B lipid complex (5 mg / kg / day) plus flucytosine, 4 weeks (evidence B3)
  • Amphotericin B deoxycholate (0.7 mg / kg / day) + flucytosine (100 mg / kg / day) for 2 weeks (evidence B2)
• Consolidation therapy
• Fluconazole (400 to 800 mg / day) for 8 weeks (evidence B3)
• Fluconazole (200 mg / day) for 6-12 months (evidence B3)
• Supportive therapy

The combination of amphotericin B and flucytosine was found to be the most effective measure for eliminating infection and showed a greater survival benefit compared with amphotericin alone. However, due to its cost, flucytosine is often not available in resource-limited settings where the burden of disease is significant. Combination of amphotericin B and fluconazole have been studied and have been obtained the best results compared to one with amphotericin B.  [13],  [14], [15]

Without treatment, the clinical course progresses to confusion, seizures, decreased level of consciousness and coma.

Pain-resistant headache can be treated with spinal decompression after adequate neuroimaging evaluation with computed tomography or MRI. The safe maximum volume of cerebrospinal fluid that can be drained in a single lumbar puncture is unclear, but up to 30 ml is often removed with a pressure check after every 10 ml is removed. [16]

Prevention

Prevention of infection by the fungus Cryptococcus neoformans is necessary, first of all, with a weak immune system. [17]It is recommended to avoid dusty areas and work with land, and HIV-positive people should receive ongoing antiretroviral therapy.

Forecast

Without treatment, the prognosis for any fungal meningitis is poor. 

The initial prognosis depends on the predictors of mortality, such as the following  [18],  [19]:

• The opening pressure of the cerebrospinal fluid is more than 25 cm of water. Art.
• Low white blood cell count in cerebrospinal fluid
• Sensory impairment
• Late diagnosis
• Increased titers of CSF antigens
• Infection clearance rate
• The amount of yeast in the CSF exceeds 10 mm ³  (common practice in Brazil) [20]
• Non-HIV patients and prognostic factors in these patients, in addition to those already mentioned:
  • Markers of a weak inflammatory response
  • No headache
  • Major hematologic malignant neoplasm
  • Chronic kidney or liver disease

Mortality varies from country to country depending on the resource settings. It remains high in the United States and France, with 10-week mortality rates ranging from 15% to 26%, and even higher in HIV-free patients due to late diagnosis and dysfunctional immune responses. On the other hand, in resource-limited settings, mortality increases from 30% to 70% in 10 weeks due to late access to care and lack of access to medicines, pressure gauges and optimal monitoring.