What Is Fungal Meningitis?

Fungal meningitis is an inflammation caused by fungal invasion of the meninges, often coexisting with the brain parenchymal infection, and belongs to deep mycosis. With the influence of antibiotics, hormones, immunosuppressive drugs, especially high doses and long-term application after organ transplantation, the increase in the incidence of AIDS, and the increase in family-raised animals, the incidence of fungal infections in the central nervous system has an increasing trend. There are pathogenic fungi and conditional pathogens that cause fungal infections of the central nervous system. The former includes new types of cryptococcus, bad sporozoites, dermatitis, bacterial dermatophytes, Paracoccus, Schenckii, and capsular histoplasma; the latter includes Candida, Aspergillus, Zygomycetes, Trichosporum, etc. . ^[1]

Fungal meningitis

Overview of fungal meningitis diseases

Introduction to fungal meningitis

Fungal (mycotic) diseases are various diseases of the skin, mucous membranes, subcutaneous tissues and internal organs caused by fungi. Most of the diseases are caused by fungi directly invading tissues or internal organs, but occasionally allergic reactions of skin or internal organs can be caused by fungi. Fungal diseases have been increasing in recent years and may be related to the following reasons: Due to various reasons, the number of patients who have been using broad-spectrum antibiotics, immunosuppressive agents, corticosteroids and anticancer drugs for a long time has increased. These iatrogenic factors are prone to Induced systemic fungal infections; Due to the advancement of medical technology, some diseases, such as leukemia, malignant tumors, diabetes, uremia, immune dysfunction, and autoimmune diseases, have prolonged the life of patients.The existence of these basic diseases is Fungal diseases provide conditions for the onset of disease; Clinicians' vigilance against fungal diseases has increased; Laboratory diagnostic techniques for fungal culture have been greatly improved. As fungal diseases are becoming more common in the clinic, and new progress has been made in the diagnosis and treatment of fungal diseases, in order to encourage clinicians to be more vigilant against fungal diseases and to continuously improve the level of diagnosis and treatment, we have invited relevant doctors to contact Internal medicine is closely related to fungal diseases, to express their views, to make an exchange of experience to readers. ^[2]

Fungal meningitis symptoms

Fungal meningitis is meningitis inflammation caused by pathogenic bacteria invading the central nervous system. The onset is slow. The main symptoms are low fever, headache, vomiting, apathy, and muscle reflex spasm. If not treated in time, it can cause death. Or permanent brain damage. Part of the batch of steroids produced by the New England Chemical Center in Massachusetts is one of the sources of the fungal meningitis epidemic that is currently raging in multiple states. ^[3]

Causes of fungal meningitis

There are pathogenic fungi and conditional pathogens that cause fungal infections of the central nervous system. The former includes new types of cryptococcus, bad sporozoites, dermatitis, bacterial dermatitis, paracoccus, Schenckia sp., And capsular histoplasma; the latter includes Candida, Aspergillus, Zygomycetes, Trichosporum . Fungus is the pathogen of this disease, and there are some clinical differences depending on the type of fungus. The main fungi are characterized by:

Cryptococcus

Cryptococcus is currently known to have 17 species and 7 variants, of which only the new cryptococcus and its variants are pathogenic. The fungus is found in soil and pigeon dung. Pigeons are the most important source of infection. Pigeon dung enters the soil and causes dust to fly after drying. It contains soil particles of new Cryptococcus and dry fungal particles (Cryptococcus with a diameter of about 1mm). In addition to breathing, it enters the alveoli and quickly forms a capsule in the body. The new cryptococcus is pathogenic and immunogenic, and it reacts with the body. When the body's resistance decreases, immune function is suppressed, or head trauma, etc., a central nervous system infection will occur.

Candida

It is a small garden yeast and relies on budding and reproduction. It is widely found in nature, especially in dairy products, fruits, and vegetables, and is one of the normal human flora. Candida albicans is the most common strain of CNS infection, accounting for about 90% of CNS infections.

Aspergillillosis

It belongs to the genus Aspergillus, which is widely distributed in nature, soil, plants, air, normal people's cheeks, interphalangeal and external auditory meatus. Belonging to conditional pathogens. There are more than 200 types of Aspergillus, about 9 of which can cause central nervous system infections. They are Aspergillus fumigatus, Aspergillus white, Aspergillus flavus, Aspergillus oryzae, Aspergillus versicolor, Aspergillus terreus, Aspergillus saurus, etc. Aspergillus fumigatus and Aspergillus flavus are the main pathogens that cause Aspergillus-like infections.

Coccidioidomyces immitis

It is a highly infectious biphasic fungus, which can be infected primary or secondary. Primary infections are most common in lung infections, followed by skin. The symptoms of the disease are generally mild, have a short course, and heal on their own. A small number of patients have severe lung symptoms due to reduced resistance or inhalation of large quantities of coccidia, and can spread to the meninges, skin and bones. Meningeal infections account for approximately 30% of coccidioidomycosis.

Histoplasma capsulatum

The strain is distributed all over the world, but it is more common in North America and is an epidemic in the region. China was first discovered in Guangzhou in 1955. The bacteria are present in the soil, and the human body is ill by inhaling dust containing the fungus. Therefore, the primary disease became a lung infection, and only 10 to 25% of patients developed central nervous system disease.

Blastomyces dermatitidis

It is a biphasic fungus, which may exist in soil or rotten wood, and inhale through the respiratory tract into the lungs or skin and cause disease. It is mainly prevalent in North America, Africa, and China.

Paracoccidioides brasilliensis

It is a biphasic fungus, which exists in soil and plants and is transmitted through the respiratory tract. It is mainly prevalent in South America, and is more common in Brazil and Argentina.

The new Cryptococcus species are widely distributed, with a round or oval shape in the tissues and a thick outer capsule. It is mainly found in soil, pigeon manure, fruits and milk, and can also be separated from normal humans. It has a special large affinity for the central nervous system, and the infection rate of pigeon breeders is high. Fungi invade the human body from the respiratory tract to form lung lesions, and then spread to the brain and the whole body through bloodstream. It can also invade through the digestive tract, skin, or directly into the brain through the blood vessels of the head. In some cases, the infection can be performed by lumbar puncture Into the central nervous system. More than half of the infections occur in healthy people, and they are also associated with malignant tumors, leukemia, lymphoma, chemotherapy, radiation therapy, long-term use of immunosuppressive drugs or antibiotics, acquired immunodeficiency disease, severe malnutrition, and cachexia. In other aspects, the incidence of patients has increased significantly in recent years.

Cryptococcus mainly invades the brain and meninges, the pia mater is diffusely cloudy, and blood vessels are congested and dilated; gelatinous inflammatory exudates can be seen in the subarachnoid space of the brain, with lymphocytes, plasma cells, multinucleated giant cell infiltration, and a large number of Cryptococcus. There may be multiple cysts or granulomas filled with cryptococcus in the brain parenchyma. Granulomas are composed of histiocytes, lymphoid cells, giant cells, and fibroblasts. In addition to the lungs and central nervous system, cryptococcus can invade the skin, mucous membranes and bone marrow. Cryptococcus often becomes a secondary or multiple infectious pathogen of patients with severe tuberculous meningitis, purulent meningitis, etc., and it is worthy of attention during clinical consultation. ^[4]

Clinical manifestations of fungal meningitis

Most are subacute, and a few are chronic.

First, general systemic symptoms

1. Infection such as mild to moderate fever in the early stage, and high fever in the later stage;

2. Meningeal irritation such as neck stiffness, positive Krebs sign;

3. Increased intracranial pressure such as headache, nausea, vomiting, and optic papillary edema. Late headache is severe, and even convulsions, de-cerebral tonic seizures and cerebral hernias occur.

Second, the nervous system symptoms

1. Symptoms of multiple cranial nerve damage When the optic nerve is damaged, low vision or even blindness occurs. Other eye movements, abduction, facial and auditory nerves are often easily affected and the corresponding neurological symptoms and signs appear.

2. Symptoms of brain damage When the lesions spread to the brain parenchyma or / and the formation of intra-brain granulomas, clinical symptoms such as drowsiness, restlessness, delirium and focal localized signs such as paralysis may appear clinically, and may be accompanied by mental retardation and Unconsciousness, severe cases enter a coma.

3. Symptoms of double or multiple infections. Such patients are usually weak due to poor constitution, poor nutrition, and decreased immune function. They can often be accompanied by new infections of other strains or recurrence of previous potential infections of the body. Common cases include tuberculosis and The concomitant toxoplasmosis, etc., promotes the disease to become more serious and complicated, and the clinical manifestations are diversified. It may even become an important cause of death of patients, which is worthy of attention and timely determination. ^[4]

Fungal meningitis test

Fungal meningitis usually shows an increase in mononuclear cells in the cerebrospinal fluid, usually (20 ~ 500) × 106 / L. The proportion of polynuclear leukocytes is often not fixed, but more than 50%, and some fungal meningitis can be manifested as cerebrospinal fluid with multinucleated leukocytes, which are mostly found in Aspergillus, Zygomycetes, and Bacillus infections. Eosinophilic meningitis suggests the possibility of coccidioid infection.

In patients with long-term use of high-dose glucocorticoids and patients with severe immunodeficiency such as AIDS, the number of cerebrospinal fluid cells can be extremely low or even normal during the active phase of cryptococcal meningitis. This behavior is similar to a high-dose cortisone mouse model of cryptococcal meningitis. Although the vast majority of fungal meningitis presents with mononucleosis meningitis, neutrophilic cerebrospinal fluid manifestations can occur in chronic meningitis.

Auxiliary examination of fungal meningitis

First, cerebrospinal fluid pressure increases, the appearance is transparent or slightly cloudy. The white blood cell count showed a mild to moderate increase (20-700) × 10 / L), even up to 5000 × 10 / L, and lymphocytes were the main cause. Increased protein content (0.4g ~ 1g / L), sometimes very high. Reduced sugar and chloride content.

Cerebrospinal fluid smears were stained with ink or / and CSF cells were centrifuged and precipitated on Giemsa and Wright's composite staining slides. Cryptococcus spheroids were mostly found in piles, and spore growth was also seen in some cryptococci. In the former method, the bacterial capsules (not colored) were bright, and the latter were dark blue and the burrs were burr-like (see the figure below). Cerebrospinal fluid Cryptococcus cultures were mostly positive, which could provide a basis for the diagnosis of clinical etiology.

Second, immunological examination of blood and cerebrospinal fluid lactate agglutination test and enzyme-linked immunosorbent test Cryptococcus antigen positive rate is high, which can help to diagnose the cause of the disease.

3. Imaging Examinations: CT or MRI imaging of the brain revealed cerebral edema, hydrocephalus, and focal abnormalities of the brain. Granulomas in the parenchyma of the brain may appear as T1 or slightly lower signal and T2 significantly higher signal on MRI examination. ^[4]

Fungal meningitis treatment

Antifungal treatment for fungal meningitis

The following drugs can be selected or combined as appropriate:

1. Amphotericin-B and its lipid preparation

(1) Amphotericin-B is still the first commonly used drug in clinical practice. Each dose is 0.1mg 0.25mg / kg, diluted with water for injection or 5% glucose solution (not diluted with normal saline to avoid causing precipitation) to 0.1mg per ml of medicine, and then instilled intravenously once a day or every other day. It can be gradually increased to 1mg / kg each time according to the situation. At the same time, intrathecal injection (diluted with cerebrospinal fluid and adding an appropriate amount of dexamethasone 1 mg) once every other day, the first time is 0.1 mg, and it can be gradually increased to 0.5 mg / time afterwards according to the situation. Generally, the medication is continued for 6 weeks. If the condition requires and permits, the treatment course can be appropriately extended until the clinical symptoms have basically disappeared and the cerebrospinal fluid examination is normal to ensure the efficacy and prevent recurrence. When needed, 5-fluorouracil (600 mg ~ 1.2g / day, divided) can be added to enhance the curative effect. The course of treatment can be longer than amphotericin-B alone.

For critically ill patients, spinal and lumbar spinal cord puncture and continuous drainage, irrigation and infusion of cerebrospinal fluid can be added intermittently. Generally, it should not exceed two weeks, and the prevention of iatrogenic infection should be strengthened.

(2) Amphotericin-B liposomes, such as amphotericin-B, have poor curative effects or are difficult for patients to tolerate, they can switch to amphotericin-B liposomes, the first time 1mg (kg / d) Intravenous infusion (at least one hour or more), the next day may be considered to increase to 3mg (kg / d), if the condition needs to be tolerated 6mg (kg / d) to continue to apply. It has certain clinical application advantages because of its lighter side effects than amphotericin-B and its ease of crossing the blood-brain barrier. However, it can only be administered after passing through the filter membrane in the infusion tube.

(3) The doses of amphotericin-B cholesterol complex for adults and children are 3 to 4 mg / kg per day, and intravenous drip once a day. Dissolve it in sterile water for injection, add 5% glucose solution to dilute to 0.6mg / ml, and inject intravenously at a rate of 1mg / kg per hour. Intravenous infusion of this product in a small dose of 5mg / 10ml for more than 15 to 30 minutes before the first administration, and observe 30 minutes after the completion of the infusion. If the patient adapts, it can be officially administered. The infusion time should last for two hours; if the performance is intolerable Acceptance should extend the administration time, each time should last more than 2 hours. For safety.

2. Triazole antifungal drugs The first generation of triazole antifungal drugs commonly used are fluconazole, miconazole and itraconazole. The second-generation triazole antifungal drugs include voriconazole, posaconazole, and lafconazole, which overcome the narrow antibacterial spectrum, low bioavailability, drug interactions, and drug resistance of the first-generation triazoles. Problems, to provide more options for clinical treatment. First as follows:

(1) Fluconazole (Dafukang) is a daily dose of 200 mg to 400 mg. It is administered orally or intravenously in saline until the cerebrospinal fluid test is negative for three consecutive times. However, the general course of treatment should not Less than 7 weeks-8 weeks. This medicine can cross the blood-brain barrier, so generally no intrathecal injection is needed; if the condition requires, you can also inject 20 mg fluconazole diluted with cerebrospinal fluid into the sheath slowly every 3 days at the same time to improve the efficacy.

(2) The daily dose of miconazole is 15 mg / kg, and a slow intravenous drip in 500 ml of 5% glucose solution is continued for 4 to 6 weeks. Therefore, the drug passed the blood-brain barrier poorly, so at the same time, 20 mg of miconazole (repeatedly diluted with cerebrospinal fluid multiple times) must be added slowly intrathecally once every other day. Due to its toxic effect, it has been abandoned by clinicians.

(3) Itraconazole 200mg twice daily for 2 to 1 year. Because of its unsatisfactory effect when used alone, it is now mostly used as an adjuvant or effect consolidation drug.

(4) Voriconazole The treatment mechanism is to inhibit 14-sterol demethylation mediated by cytochrome P450 in fungi, and to inhibit the biosynthesis of ergosterol, thereby having a good broad-spectrum antifungal effect. This product can be administered by slow intravenous drip (must be maintained for more than 1 to 2 hours) or oral administration. The two administration routes of intravenous drip and oral are interchangeable, but it is not suitable for intravenous bolus injection. The drug can be excreted in the urine within 96 hours of intravenous infusion or oral administration.

Adults inject intravenously once every 12 hours within the first 24 hours, 6 mg / kg each time; maintenance dose (24 hours after the start of administration) 2 times daily, 4 mg / kg each time, should not exceed 6 Months. Adults weighing 40kg in the first 24 hours) Orally administered once every 12 hours at 400 mg each time; Maintenance dose (24 hours after the start of administration) administered twice daily at 200 mg each time. When the patient weighs 40kg, each dose should be halved. The elderly do not need to adjust the dosage when using this product. During the treatment process, doctors should closely monitor their potential adverse reactions, and adjust the drug application program and dosage in a timely manner according to the specific conditions of the patient.

(5), voriconazole and posaconazole According to the literature, it has a broad antifungal spectrum, high efficacy, less adverse and side effects, and will become a new antifungal drug for clinical use. However, the second medicine has not yet been marketed in China, and its price is very expensive (1450 yuan / branch). It takes 1 to 2 pcs a day, and it may still be difficult for it to be widely used in the country.

(6) Caspofungin Acetate is a new class of antifungal drugs, which can be used alone or in combination in critically ill patients who do not respond well to the above drugs. A single 70 mg slow intravenous infusion (takes more than 1 hour) is given on the first day, followed by 50 mg daily. The course of treatment depends on the severity of the patient's disease, the effectiveness of the treatment, and the recovery of immune function. Although there is no clinical evidence to prove that the use of larger doses can improve the efficacy, patients who have no clinical response to the treatment and are well tolerated with this product may consider increasing the daily dose to 70 mg. There is no need to adjust the dosage for elderly patients (65 years or older), but the dosage needs to be adjusted according to gender, ethnicity or liver and kidney function impairment.

All the above drugs have certain toxic and side effects, and amphotericin-B is larger. There are mainly high fever, severe headache, nausea, vomiting, liver and kidney dysfunction, anemia, and phlebitis, etc., which need to be paid close attention to and prevented during treatment. Voriconazole often causes visual disturbances such as transient, reversible blurred vision, visual changes, visual enhancement, and / or photophobia, so it is not appropriate to engage in dangerous tasks such as driving or operating machinery at this time.

Symptomatic treatment of fungal meningitis

1. Dehydration of cranial pressure can be given in time with dehydrating diuretics such as mannitol and furosemide. Those with obstructive hydrocephalus can be used for ventricular puncture, irrigation, drainage and administration, but it should be carried out in conjunction with intrathecal administration.

2. Prevention and treatment of concomitant diseases and complications While strengthening the prevention and treatment of respiratory, oral and urinary tract infections, attention should also be paid to the early detection and early treatment of double or triple infectious diseases such as tuberculosis and toxoplasmosis that are easily associated with the disease. .

3. Supportive therapy provides high-protein, high-energy, multi-vitamin diets, and related trace elements and nutrient metabolism drugs (such as Adama, Coenzyme A, Coenzyme Q-10, Wanshuangli and ATP, etc.) to maintain water and electrolyte balance in order to Enhance physical fitness and disease resistance.

4. Neuroprotective agents can be treated with citicoline, brain peptides, Sigma-1 (GM-1), nerve growth factor, Duxil and other drugs to reduce and slow the death and apoptosis of nerve cells.

5. Cellular and humoral immune functions are often low in immunopotentiators in the treatment of such patients, and secondary complement defects can also occur after prolonged illness. Therefore, Ritaxant, Stanozolol and / or fresh plasma should be given as appropriate to enhance Immune Function.

Mycotic meningitis surgery

Larger brain abscesses or granulomas can be treated with surgery.

Fungal meningitis rehabilitation

For those with paralysis and aphasia, functional exercises should be given early to avoid disability or more neurological sequelae caused by disuse and misuse. ^[4]

Cases of fungal meningitis

On October 5, 2012, an outbreak of fungal meningitis occurred in the United States. The case is not contagious and may be caused by injection of a drug contaminated with fungus. As of the 26th, more than 300 people have been infected with fungal meningitis, with 25 deaths. The worst outbreak is in Tennessee.

Investigators are focusing on a steroid produced by the New England Chemicals Center in Framingham, Tennessee, because patients have been injected with back pain in all recent cases. Fungi were detected in at least one sealed pill produced by this pharmaceutical company and further testing is needed to determine if the contaminated drug is the source of the disease.

Fungal meningitis- related events

The U.S. Centers for Disease Control and Prevention said on the 18th that the agency and the U.S. Food and Drug Administration have confirmed that some batches of steroids produced by the New England Chemical Center in Massachusetts are the cause of a fungal meningitis epidemic currently raging in multiple states. Source one.

The Centers for Disease Control and Prevention said that the current fungal meningitis outbreak in the United States is mainly caused by M. oryzae, and laboratory tests have confirmed that a batch of steroids produced by the New England Chemical Center has been contaminated with these fungi.

The New England Chemical Center has three batches of products involved in the outbreak, and the other two batches are still undergoing laboratory testing. According to the Centers for Disease Control and Prevention, as of the 17th, 47 people in the United States have been diagnosed with fungal meningitis through laboratory tests. Of these, 45 people were infected with non-infectious M. umbilicalum and the other two were infected with two A more common fungus that rarely causes meningitis.

The Centers for Disease Control and Prevention states that 20 people have died of fungal meningitis in the United States, and about 14,000 people in 23 states have been injected with contaminated steroids produced by the New England Chemical Center. ^[5]