Chronic meningitis

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Chronic meningitis
Meningitis - Lumbar puncture.jpg
Healhcare workers performing a lumbar puncture, obtaining a sample of the cerebrospinal fluid aids in the diagnosis of chronic meningitis
Specialty Infectious disease, Microbiology, Neurology, Neurosurgery
Symptoms Headache, lethargy, confusion, fever, nausea, vomiting, visual impairment
Complications Cranial nerve palsies, ophthalmoplegia, seizures, ataxia, psychiatric disorders, hemiparesis, deafness, blindness, intellectual disability
DurationChronic, by definition lasting longer than 4 weeks. With some infections lasting many months
Causes Microorganisms (bacteria and fungi), viruses, and non-infectious causes including cancer, medications, autoimmune disease or inflammatory conditions
Risk factors HIV infection, diabetes, immunosuppression
Diagnostic method Culture of microorganism from the cerebrospinal fluid (CSF), biopsy of tissue or CSF sample with staining of organism, molecular methods such as immunoassay (antigen or antibody assays), nucleic acid amplification, magnetic resonance imaging (MRI) of the brain
Prevention Vaccination, BCG vaccine in tuberculosis meningitis [1]
Medication Antibiotics, antifungals, antivirals in infectious causes
Prognosis Poor

Chronic meningitis is a long-lasting inflammation of the membranes lining the brain and spinal cord (known as the meninges). By definition, the duration of signs, symptoms and inflammation in chronic meningitis lasts longer than 4 weeks. [2] Infectious causes (due to bacteria, fungi and viruses) are a leading cause of chronic meningitis and the infectious organisms responsible for chronic meningitis are different than the organisms that cause acute infectious meningitis. Tuberculosis and cryptococcus are leading causes of infectious chronic meningitis worldwide. Chronic meningitis due to infectious causes are more common in those who are immunosuppressed, including those with HIV infection or in children who are malnourished. Chronic meningitis sometimes has a more indolent course than acute meningitis with symptoms developing more insidiously and slowly. Also, some of the infectious agents that cause chronic infectious meningitis such as mycobacterium tuberculosis , many fungal species and viruses are difficult to isolate from the cerebrospinal fluid (the fluid surrounding the brain and spinal cord) making diagnosis challenging. No cause is identified during initial evaluation in one third of cases of chronic meningitis. [3] Magnetic resonance imaging (MRI) of the brain is more sensitive than computed tomography (CT scan) and may show radiological signs that suggest chronic meningitis, however no radiological signs are considered pathognomonic or characteristic of chronic meningitis. MRI is also normal in many cases of chronic meningitis further limiting its diagnostic utility.

Contents

Worldwide, tuberculosis meningitis is a leading cause of disability and death, with central nervous system tuberculosis (with tuberculosis meningitis being the most common type) occurring in 5-10% of all cases of extrapulmonary tuberculosis and 1% of all cases of tuberculosis overall. [4]

Signs and symptoms

Some of the possible symptoms of chronic meningitis (due to any cause) include headache, nausea and vomiting, fever, and visual impairment. Nuchal rigidity (or neck stiffness with discomfort in trying to move the neck), a classic symptom in acute meningitis, was seen in only 45% of cases of chronic meningitis with the sign being even more rare in non-infectious causes of chronic meningitis. [5] [2] Other signs associated with chronic meningitis include altered mental status or confusion, and papillary edema (swelling of the optic disc). [2]

The headache in chronic meningitis is commonly described as diffuse, poorly localized and constant. Lethargy is a common symptom, with 40% of those with chronic meningitis also having mental status changes. [2] The inflammation in chronic meningitis can affect the cranial nerves as they course through the subarachnoid space leading to cranial nerve palsies. Nerve roots may also be affected in chronic meningitis leading to radiculopathy. [2]

Cause

The causes of chronic infectious meningitis are different than those of acute infectious meningitis. Worldwide, Cryptococcus and tuberculosis are leading infectious causes of chronic meningitis. [3] Immunosuppression (due to a variety of causes) is a major risk factor for the development of chronic infectious meningitis, with Cryptococcus meningitis being the most common cause of chronic meningitis in those who are immunosuppressed. Worldwide, HIV and AIDS (which are characterized by immunosuppression) are major risk factors for the development of chronic infectious meningitis. [3] Diabetes, recent ear surgery or neurosurgery and the presence of a ventriculoperitoneal shunt are other risk factors for development of chronic infectious meningitis. [2] Other fungi that are ubiquitously found in the environment (either in certain regions of the world or globally) are also known to cause chronic infectious meningitis in those who are immunosuppressed. These fungi include coccidiomycosis, histoplasmosis, blastomycosis, aspergillus and cryptococcus gattii (which may also cause chronic meningitis in those with normal immune function). [3] [2]

In 2012-2013, an outbreak of fungal meningitis linked to contaminated steroids designated for epidural spinal injections led to the development of meningitis in about 800 people and more than 100 deaths. [6]

The most common bacterial causes of chronic meningitis include tuberculosis and treponema pallidum (neurosyphillis). Other bacterial causes of chronic meningitis include leptospirosis and brucellosis. [3] HIV is a potential viral cause of chronic meningitis. HIV leads to immunosuppression and subsequent chronic infectious meningitis by a variety of potential opportunistic organisms, however the HIV virus itself may also cause infectious meningitis, usually during the initial phase of HIV infection. [3] Herpes simplex virus, lymphocytic choriomeningitis virus are other viruses that may cause chronic meningitis. [3]

Non-infectious causes of chronic meningitis include potential etiologies that cause meningeal irritation, such as medications, inflammatory diseases, auto-immune diseases and cancer. Chemical inflammation of the meninges may be due to Non-steroidal anti-inflammatory (NSAID) drugs (most commonly with ibuprofen, immunoglobulin therapy, anti-microbials (such as trimethoprim/sulfamethoxazole), immunosuppressants, chemotherapy and anticonvulsants (most commonly lamotrigine and carbamazepine). [3] Auto-immune diseases such as lupus, rheumatoid arthritis or Sjogren syndrome may cause inflammation of the meningitis. Various inflammatory conditions such as neurosarcoidosis, IgG4 related pachymeningitis or leptomeningitis are also known causes of chronic meningitis. [3] Carcinomatous meningitis involves meningeal inflammation due to cancer spread to the meninges. The types of cancers that are most commonly associated with meningeal spread include breast and lung cancer, melanoma skin cancer, lymphomas, and leukemia. [3] Dermoid cysts near the brain or spinal cord, a type of cyst containing developmentally mature tissue, may leak their contents into the subarachnoid space thus leading to meningeal inflammation. [2]

Pathophysiology

The pathogenesis of tuberculosis meningitis involves mycobacterium tuberculosis being shed into the environment via respiratory droplets from an infected person. These droplets are then inhaled to the lungs where the mycobacterium tuberculosis is phagocytosed by macrophages as part of the Th1-helper T cell response and a granuloma forms. [4] Either via disseminated tuberculosis, or by other means, some tubercula gain access to the meninges. Small foci of tuberculous bacilli, known as Rich foci, deposit in the brain, meninges and spinal cord. The tuberculosis bacilli then gain access to the subarachnoid space via the Rich foci and begin the process of meningeal inflammation characterisitc of tuberculosis meningitis. [4]

Diagnosis

Chronic meningitis is defined by signs and symptoms being present longer than 4 weeks, and includes pleocytosis, or the presence of inflammatory cells, in the cerebrospinal fluid. [2] The initial test is usually a lumbar puncture to collect cerebrospinal fluid for analysis. The lumbar puncture in chronic meningitis usually shows a lymphocytic predominant inflammatory pattern, however some infectious agents such as early tuberculosis meningitis, nocardia or brucella may have an neutrophilic predominant inflammation. [2] A eosinophilic predominant inflammation may be seen with some parasites that cause chronic infectious meningitis. [2] The content of protein and glucose in the cerebrospinal fluid also varies depending on the etiology. Many of the organisms responsible for chronic infectious meningitis (especially mycobacterium tuberculosis and most types of fungi) are difficult to grow on culture making diagnosis especially difficult. Large volume lumbar punctures (obtaining more than 10 mL of cerebrospinal fluid) or multiple lumbar punctures may increase diagnostic yield. [3] [2] Serologic testing of the cerebrospinal fluid or blood (testing for specific antibodies or antigens related to an infectious organism) may aid in the diagnosis and is available for infectious causes such as HIV, syphilis, and Lyme disease. [2] Nucleic acid amplification or PCR of the cerebrospinal fluid may also assist in identifying a causative organism. PCR specific to bacterial RNA (16S ribosomal RNA) or fungal RNA (18S ribosomal RNA) further aids in identifying the causative organism. [2] Metagenomic sequencing has been used to detect a wide variety of genetic material in a sample (rather than testing for specific predetermined organisms with PCR) of the cerebrospinal fluid and aids in the diagnosis infectious causes of chronic meningitis that are difficult to isolate by conventional methods. The clinical relevance of detected genetic material in the pathology of chronic infectious meningitis can be further confirmed by comparing the metagenomic genetic material to controls from healthy individuals. [7] [2]

MRI of the brain with contrast may show enhancement of the meninges and the subarachnoid space however MRI may also be normal. [5] [2] MRI is the preferred neuroimaging test to diagnose chronic meningitis, being more sensitive than CT of the brain, however MRI scanners are not available in many resource limited settings where chronic infectious meningitis is prevalent. [4] [2]

Brain biopsy is considered a second line test, that is usually utilized when first-line testing fails to identify a cause of chronic meningitis. Brain biopsy has increased diagnostic yield when highly enhancing brain or meningeal areas on MRI are biopsied. [2]

Treatment

Initial diagnostic evaluation often fails to identify a causative organism in chronic infectious meningitis, and empirical therapy may be initiated to prevent significant disability or death. [2] Empiric therapy is indicated in those who are immunocompromized or who are neutropenic. [3] In those who are immune competent, empiric therapy is less well established and is usually initiated on a case by case basis. [3] In those who undergo empirical therapy in chronic meningitis, treatment involves anti-tuberculosis therapy combined with steroids in areas where tuberculosis is endemic. [2] Anti-fungal empirical therapy is also commonly employed due to fungi's ubiquitous nature and ability to cause opportunistic infections in those who are immunosuppressed. [2] When a causative organism is identified then anti-microbial therapy is targeted specifically to that organism.

Treatment of tuberculosis meningitis consists of a 2 month induction regiment with isoniazid, rifampin, pyrazinamide and ethambutol followed by an extended course (often 7-10 months) of isoniazid and rifampin as maintenance therapy. Isoniazid and pyrazinamide are able to cross the blood-brain barrier. However the duration of maintenance treatment is assumed based on experience with pulmonary tuberculosis, and the optimal duration of therapy in tuberculosis meningitis is not well established. [4] Steroid co-administration is thought to improve outcomes. [4] There is a paucity of information regarding the optimal treatment regiment for multi-drug resistant tuberculosis meningitis (which is by definition resistant to isoniazid and rifampin), but fluoroquinolones and aminoglycosides are able to achieve adequate brain and spinal cord penetration and are often used. [4]

The World Health Organization recommends a screen and treat approach with regards to cryptococcal meningitis in those with HIV. All HIV positive people with low CD4+ T cells should undergo cryptococcal serum antigen testing. Those who screen positive for serum cryptococcal antigen should undergo a lumbar puncture followed by treatment if the cerebrospinal fluid contains cryptococcus. Those who cannot undergo a lumbar puncture but screen positive for cryptococcal antigen in the serum should be presumptively treated for cryptococcus. [4] Cryptococcal meningitis is treated with 2 weeks of induction therapy using the antifungals amphotericin B and flucytosine followed by 8 weeks of induction therapy with fluconazole and then a prolonged duration (at least one year) of lower dose maintenance fluconazole therapy. Lifelong treatment is required in those with AIDS, however in those who begin anti-retroviral therapy and have CD4 T-cells above 200, therapy can be stopped. [3] Steroid co-therapy is not indicated in cryptococcal meningitis and may worsen outcomes and delay recovery. [3]

Hydrocephalus is a common complication in chronic infectious meningitis, including tuberculosis and cryptococcal meningitis. In cases of hydrocephalus, intracranial pressure is controlled by serial therapeutic lumbar punctures (often done daily) until opening pressure normalizes. [3] Diuretics such as furosemide or acetazolamide, osmotic agents such as mannitol, external ventricular drainage, or ventriculoperitoneal shunts may also be used in tuberculosis meningitis to control intracranial pressure. [4]

Prevention

The BCG vaccine has been shown to lower the risk of developing tuberculosis meningitis in those who become infected with tuberculosis. In children who developed tuberculosis meningitis, those who had the BCG vaccine had milder symptoms and were less likely to die from the disease. [1]

Prognosis

The mortality of tuberculosis meningitis is 20-50% even with treatment. A longer duration of presenting symptoms was associated with a higher mortality in tuberculosis meningitis. [4] HIV co-infection, multidrug resistant tuberculosis, or the development of hydrocephalus or focal weakness in tuberculosis meningitis are associated with a poor prognosis. [4] In those who survive tuberculosis meningitis, 30% have longstanding neurological impairments including deafness, blindness, intellectual disability. [4]

The mortality rate in cryptococcal meningitis is 25%. [3]

Epidemiology

Tuberculosis meningitis is more common in children and people who are HIV positive. [4]

Related Research Articles

<span class="mw-page-title-main">Encephalitis</span> Inflammation of the brain

Encephalitis is inflammation of the brain. The severity can be variable with symptoms including reduction or alteration in consciousness, headache, fever, confusion, a stiff neck, and vomiting. Complications may include seizures, hallucinations, trouble speaking, memory problems, and problems with hearing.

<span class="mw-page-title-main">Viral meningitis</span> Medical condition

Viral meningitis, also known as aseptic meningitis, is a type of meningitis due to a viral infection. It results in inflammation of the meninges. Symptoms commonly include headache, fever, sensitivity to light and neck stiffness.

Myelitis is inflammation of the spinal cord which can disrupt the normal responses from the brain to the rest of the body, and from the rest of the body to the brain. Inflammation in the spinal cord can cause the myelin and axon to be damaged resulting in symptoms such as paralysis and sensory loss. Myelitis is classified to several categories depending on the area or the cause of the lesion; however, any inflammatory attack on the spinal cord is often referred to as transverse myelitis.

<span class="mw-page-title-main">Lumbar puncture</span> Procedure to collect cerebrospinal fluid

Lumbar puncture (LP), also known as a spinal tap, is a medical procedure in which a needle is inserted into the spinal canal, most commonly to collect cerebrospinal fluid (CSF) for diagnostic testing. The main reason for a lumbar puncture is to help diagnose diseases of the central nervous system, including the brain and spine. Examples of these conditions include meningitis and subarachnoid hemorrhage. It may also be used therapeutically in some conditions. Increased intracranial pressure is a contraindication, due to risk of brain matter being compressed and pushed toward the spine. Sometimes, lumbar puncture cannot be performed safely. It is regarded as a safe procedure, but post-dural-puncture headache is a common side effect if a small atraumatic needle is not used.

<span class="mw-page-title-main">Pia mater</span> Delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord

Pia mater, often referred to as simply the pia, is the delicate innermost layer of the meninges, the membranes surrounding the brain and spinal cord. Pia mater is medieval Latin meaning "tender mother". The other two meningeal membranes are the dura mater and the arachnoid mater. Both the pia and arachnoid mater are derivatives of the neural crest while the dura is derived from embryonic mesoderm. The pia mater is a thin fibrous tissue that is permeable to water and small solutes. The pia mater allows blood vessels to pass through and nourish the brain. The perivascular space between blood vessels and pia mater is proposed to be part of a pseudolymphatic system for the brain. When the pia mater becomes irritated and inflamed the result is meningitis.

<i>Cryptococcus neoformans</i> Species of yeast

Cryptococcus neoformans is an encapsulated yeast belonging to the class Tremellomycetes and an obligate aerobe that can live in both plants and animals. Its teleomorph is a filamentous fungus, formerly referred to Filobasidiella neoformans. In its yeast state, it is often found in bird excrement. Cryptococcus neoformans can cause disease in apparently immunocompetent, as well as immunocompromised, hosts.

<span class="mw-page-title-main">Cryptococcosis</span> Potentially fatal fungal disease

Cryptococcosis is a potentially fatal fungal infection of mainly the lungs, presenting as a pneumonia, and brain, where it appears as a meningitis. Cough, difficulty breathing, chest pain and fever are seen when the lungs are infected. When the brain is infected, symptoms include headache, fever, neck pain, nausea and vomiting, light sensitivity and confusion or changes in behavior. It can also affect other parts of the body including skin, where it may appear as several fluid-filled nodules with dead tissue.

<span class="mw-page-title-main">Arachnoiditis</span> Inflammation of the arachnoid mater

Arachnoiditis is an inflammatory condition of the arachnoid mater or 'arachnoid', one of the membranes known as meninges that surround and protect the central nervous system. The outermost layer of the meninges is the dura mater and adheres to inner surface of the skull and vertebrae. The arachnoid is under or "deep" to the dura and is a thin membrane that adheres directly to the surface of the brain and spinal cord.

<span class="mw-page-title-main">Aseptic meningitis</span> Medical condition

Aseptic meningitis is the inflammation of the meninges, a membrane covering the brain and spinal cord, in patients whose cerebral spinal fluid test result is negative with routine bacterial cultures. Aseptic meningitis is caused by viruses, mycobacteria, spirochetes, fungi, medications, and cancer malignancies. The testing for both meningitis and aseptic meningitis is mostly the same. A cerebrospinal fluid sample is taken by lumbar puncture and is tested for leukocyte levels to determine if there is an infection and goes on to further testing to see what the actual cause is. The symptoms are the same for both meningitis and aseptic meningitis but the severity of the symptoms and the treatment can depend on the certain cause.

Immune reconstitution inflammatory syndrome (IRIS) is a condition seen in some cases of HIV/AIDS or immunosuppression, in which the immune system begins to recover, but then responds to a previously acquired opportunistic infection with an overwhelming inflammatory response that paradoxically makes the symptoms of infection worse.

<span class="mw-page-title-main">Neurosyphilis</span> Infection of the central nervous system in a patient with syphilis

Neurosyphilis is the infection of the central nervous system in a patient with syphilis. In the era of modern antibiotics, the majority of neurosyphilis cases have been reported in HIV-infected patients. Meningitis is the most common neurological presentation in early syphilis. Tertiary syphilis symptoms are exclusively neurosyphilis, though neurosyphilis may occur at any stage of infection.

<span class="mw-page-title-main">Myelography</span> Medical Imaging Technique

Myelography is a type of radiographic examination that uses a contrast medium to detect pathology of the spinal cord, including the location of a spinal cord injury, cysts, and tumors. Historically the procedure involved the injection of a radiocontrast agent into the cervical or lumbar spine, followed by several X-ray projections. Today, myelography has largely been replaced by the use of MRI scans, although the technique is still sometimes used under certain circumstances – though now usually in conjunction with CT rather than X-ray projections.

<span class="mw-page-title-main">Tuberculous meningitis</span> Medical condition

Tuberculous meningitis, also known as TB meningitis or tubercular meningitis, is a specific type of bacterial meningitis caused by the Mycobacterium tuberculosis infection of the meninges—the system of membranes which envelop the central nervous system.

<span class="mw-page-title-main">Leptomeningeal cancer</span> Medical condition

Leptomeningeal cancer is a rare complication of cancer in which the disease spreads from the original tumor site to the meninges surrounding the brain and spinal cord. This leads to an inflammatory response, hence the alternative names neoplastic meningitis (NM), malignant meningitis, or carcinomatous meningitis. The term leptomeningeal describes the thin meninges, the arachnoid and the pia mater, between which the cerebrospinal fluid is located. The disorder was originally reported by Eberth in 1870. It is also known as leptomeningeal carcinomatosis, leptomeningeal disease (LMD), leptomeningeal metastasis, meningeal metastasis and meningeal carcinomatosis.

<span class="mw-page-title-main">Mollaret's meningitis</span> Medical condition

Mollaret's meningitis is a recurrent or chronic inflammation of the protective membranes covering the brain and spinal cord, known collectively as the meninges. Since Mollaret's meningitis is a recurrent, benign (non-cancerous), aseptic meningitis, it is also referred to as benign recurrent lymphocytic meningitis. It was named for Pierre Mollaret, the French neurologist who first described it in 1944.

<span class="mw-page-title-main">Meningitis</span> Inflammation of the membranes around the brain and spinal cord

Meningitis is acute or chronic inflammation of the protective membranes covering the brain and spinal cord, collectively called the meninges. The most common symptoms are fever, intense headache, vomiting and neck stiffness and occasionally photophobia.

<span class="mw-page-title-main">Cerebrospinal fluid leak</span> Medical condition

A cerebrospinal fluid leak is a medical condition where the cerebrospinal fluid (CSF) that surrounds the brain and spinal cord leaks out of one or more holes or tears in the dura mater. A CSF leak is classed as either nonspontaneous (primary), having a known cause, or spontaneous (secondary) where the cause is not readily evident. Causes of a primary CSF leak are those of trauma including from an accident or intentional injury, or arising from a medical intervention known as iatrogenic. A basilar skull fracture as a cause can give the sign of CSF leakage from the ear nose or mouth. A lumbar puncture can give the symptom of a post-dural-puncture headache.

Drug-Induced Aseptic Meningitis (DIAM) is a type of aseptic meningitis related to the use of medications such as nonsteroidal anti-inflammatory drugs (NSAIDs) or biologic drugs such as intravenous immunoglobulin (IVIG). Additionally, this condition generally shows clinical improvement after cessation of the medication, as well as a tendency to relapse with resumption of the medication.

<span class="mw-page-title-main">Tarlov cyst</span> Medical condition

Tarlov cysts, are type II innervated meningeal cysts, cerebrospinal-fluid-filled (CSF) sacs most frequently located in the spinal canal of the sacral region of the spinal cord (S1–S5) and much less often in the cervical, thoracic or lumbar spine. They can be distinguished from other meningeal cysts by their nerve-fiber-filled walls. Tarlov cysts are defined as cysts formed within the nerve-root sheath at the dorsal root ganglion. The etiology of these cysts is not well understood; some current theories explaining this phenomenon have not yet been tested or challenged but include increased pressure in CSF, filling of congenital cysts with one-way valves, inflammation in response to trauma and disease. They are named for American neurosurgeon Isadore Tarlov, who described them in 1938.

<span class="mw-page-title-main">Lymphocytic pleocytosis</span> Increase in lymphocytes within cerebrospinal fluid

Lymphocytic pleocytosis is an abnormal increase in the amount of lymphocytes in the cerebrospinal fluid (CSF). It is usually considered to be a sign of infection or inflammation within the nervous system, and is encountered in a number of neurological diseases, such as pseudomigraine, Susac's syndrome, and encephalitis. While lymphocytes make up roughly a quarter of all white blood cells (WBC) in the body, they are generally rare in the CSF. Under normal conditions, there are usually less than 5 white blood cells per µL of CSF. In a pleocytic setting, the number of lymphocytes can jump to more than 1,000 cells per µL. Increases in lymphocyte count are often accompanied by an increase in cerebrospinal protein concentrations in addition to pleocytosis of other types of white blood cells.

References

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