Lecture 4 Infections of the Central Nervous System PDF

Week 02 2.34813: Medical Microbiology II 2.34903: Pharmaceutical Med Micro II BOH/BDS Lecture 04: Infections of the Central Nervous System (CNS) Medical Microbiology 2 ANLangarap-Kilepak Medical Lab Science...

Week 02 2.34813: Medical Microbiology II 2.34903: Pharmaceutical Med Micro II BOH/BDS Lecture 04: Infections of the Central Nervous System (CNS) Medical Microbiology 2 ANLangarap-Kilepak Medical Lab Science SMHS-UPNG Semester 02-2024  Key Points to Remember Bacteria, fungi and viruses are the most common causes of central nervous system (CNS) infections. An infection of the central nervous system can be a life-threatening condition, especially for children with weakened immune systems. Central nervous system infections caused by bacteria or fungi can lead to a brain abscess or bacterial meningitis. Central nervous system infections caused by viruses can lead to viral meningitis or encephalitis. Treatment for CNS infections varies depending on the type of infection, the location of the infection and your child’s overall health.  Anatomy of the Central Nervous System (CNS) The central nervous system is the part of the nervous system consisting of the brain and spinal cord. It integrates the received information and coordinates and influences the activity of all parts of the bodies of bilaterally symmetric animals—i.e., all multicellular animals. Many consider the retina and the optic nerve, as well as the olfactory nerves and olfactory epithelium as parts of the CNS, synapsing directly on brain tissue without intermediate ganglia. As such, the olfactory epithelium is the only central nervous tissue in direct contact with the environment, which opens up for therapeutic treatments. The CNS is contained within the dorsal body cavity, with the brain housed in the cranial cavity and the spinal cord in the spinal canal. In vertebrates, the brain is protected by the skull, while the spinal cord is protected by the vertebrae. The brain and spinal cord are both enclosed in the meninges. Within the CNS, the interneuronal space is filled with a large amount of supporting non-nervous cells called neuroglia or glia  CNS Infections An infection of the central nervous system can be a life-threatening condition, especially for children with weakened immune systems. These infections need quick diagnosis and immediate treatment by an infectious disease specialist. Bacteria, fungi and viruses are the most common causes of CNS infections.  Meningitis and Encephalitis The skull provides the brain with an excellent defense, however, becomes problematic during infections. Any swelling of the brain or meninges that results from inflammation can cause intracranial pressure, leading to severe damage of the brain tissues, which have limited space to expand within the skull. The term meningitis is used to describe an inflammation of the meninges. Typical symptoms can include severe headache, fever, photophobia (increased sensitivity to light), stiff neck, convulsions, and confusion. An inflammation of brain tissue is called encephalitis, exhibitimg signs and symptoms similar to those of meningitis in addition to lethargy, seizures, and personality changes. When inflammation affects both the meninges and the brain tissue, the condition is called meningoencephalitis. All three forms of inflammation are serious and can lead to blindness, deafness, coma, and death. Meningitis and encephalitis can be caused by many different types of microbial pathogens. However, these conditions can also arise from noninfectious causes such as head trauma, some cancers, and certain drugs that trigger inflammation. To determine whether the inflammation is caused by a pathogen, a lumbar puncture is performed to obtain a sample of CSF. If the CSF contains increased levels of white blood cells and abnormal glucose and protein levels, this indicates that the inflammation is a response to an infection.  Brain Abscess Bacteria and Fungi Central nervous system infections caused by bacteria or fungi can cause illnesses such as: Brain abscesses. This is a collection of pus and infected tissue within the brain. Bacterial meningitis. This happens when bacterial infections enter the bloodstream and travel to the brain and spinal cord. Symptoms of bacterial or fungal central nervous system infections may include: Severe headache Back pain Stiff neck Confusion Weakness Fever Seizures Paralysis  Viruses Central nervous system infections caused by viruses can cause illnesses such as: Viral meningitis. This is inflammation of the layers of tissue that cover the brain and spinal cord. Encephalitis. This is infection and inflammation of the brain itself. Symptoms of viral central nervous system infections may include: Fever Irritability Not wanting to eat High-pitched cry Head and neck pain Seizures If you think your child may have a CNS infection, see a doctor immediately. CNS Infections categorized as; A. Meningitis B. Encephalitis C. Brain Abscess  A. MENINGITIS The term “meningitis” applies broadly to inflammation of the meninges. Bacterial meningitis occurs when organisms gain access to the subarachnoid space either through bacteremia (usually from an upper airway source), contiguous spread from dental or sinus infections, traumatic or congenital communications with the exterior, or a neurosurgical procedure. The severe inflammation associated with bacterial meningitis results in edema of the brain and meninges, and eventually increased intracranial pressure once the compensatory mechanisms for cerebrospinal fluid (CSF) displacement have been overwhelmed. Bacterial meningitis is associated with significant morbidity with mortality.  Bacterial meningitidis Primary causative agents of Neonatal meningitis Streptococcus (group B) Escherichia coli Listeria monocytogenes Most frequent causes; (Discussed here) 1. Neisseria meningitides (most prevalent in children) 2. Streptococcus pneumoniae (most prevalent in adults) 3. Haemophilus influenzae 4. Streptococcus (group B) 5. Escherichia coli 6. Listeria monocytogenes 7. Mycobacterium tuberculosis  1. Neisseria meningitides Infection with N. meningitides, also known as meningococcal meningitis, can cause an acute fulminant meningitis, which is a medical emergency. There are 5 main serogroups that are responsible for the majority of meningococcal illness— A, B, C, Y, and W-135. It is the most common form of meningitis in children from 2–18 years of age. Risk factors include living in close quarters, such as dormitory settings. Typical symptoms and signs of the disease include a stiff neck, high fever, headache, and altered mental status (AMS), with at least 2 out of these 4 symptoms being found in more than 90% of all patients. Other signs and symptoms include nausea and vomiting, radicular pain, signs of increased intracranial pressure, such as papilledema, and often focal neurologic deficits, such as cranial nerve VI palsy. Complications of acute fulminant meningitis include Waterhouse– Friderichsen syndrome—bilateral adrenal insufficiency from hemorrhage into the adrenal glands, disseminated intravascular coagulation, coma, and rapid death.  Neisseria meningitides Unlike other noninfectious cases of increased intracranial pressure, if an infectious etiology is suspected, diagnostic LP (lumber puncture) ought to be performed immediately to obtain cultures and to determine susceptibility; empiric antibiotic treatment should begun shortly thereafter. LP performed around 4–8 hrs after antibiotic treatment has been administered has around a 50% sensitivity for revealing the causative organism. CSF, however, will still reveal features characteristic of a bacterial meningitis, including a neutrophilic pleocytosis, increased protein count, with a decreased glucose count. When performed in a timely manner, LP will reveal gram- negative diplococci in the CSF. Empiric antibiotic treatment for suspected bacterial meningitis centers around the treatment for meningococcal meningitis, owing to the severity of this infection, and consists of intravenous administration of a third-generation cephalosporin, such as ceftriaxone or cefotaxime with good CNS penetration. Duration of treatment for meningococcus tends to be shorter than that for other bacterial meningitis infections, averaging around 7 days.  2. Streptococcus pneumoniae Streptococcal meningitis from the causative organism S. pneumoniae is the leading cause of meningitis in the elderly, and one of the leading causes of bacterial meningitis in all adults and children older than 2 months. The illness is usually not as rapid and fulminant as that caused by meningococcal meningitis, but nonetheless can present with similar symptoms. Diagnosis is similar to those patients suspected of having meningococcal meningitis, with LP preceding empiric treatment with a third-generation cephalosporin. CSF should return gram-positive diplococci. In cases where resistance to cephalosporin is suspected, vancomycin should be added for additional coverage. Out of the several species of bacterial meningitis, clinical trials to date have provided the greatest benefits for adjuvant dexamethasone therapy for pneumococcal meningitis. An estimated 1 in 12 cases of streptococcal meningitis is fatal, with 1 in 3–4 survivors suffering neurologic sequelae, including deafness, persistent seizures, and mental retardation in children. Since the advent of the heptavalent pneumococcal vaccine in 2000, pneumococcal meningitis has decreased significantly in children, estimated to be around 77% lower by Center for Disease Control (CDC), while diminishing in adults as well due to herd immunity.  3. Haemophilus influenzae Haemophilus influenzae, particularly serotype B (HiB), is a frequent cause of meningitis in children under the age of 5 years. This organism is a gram-negative rod and a frequent inhabitant of the sinuses, inner and middle ear, respiratory tract, and bloodstream; it commonly causes meningitis via a combination of both direct sinus and hematogenous spread. The frequency of HiB strain has decreased dramatically, however, in the past couple of years since the advent of the HiB vaccine, and is now a distant third behind streptococcus and meningococcus in childhood meningitis. It continues, however, to be a major cause of childhood meningitis worldwide, with 386,000 deaths per year being attributed to the combination of HiB meningitis and pneumonia. (CDC) Approx. 15%–35% of all survivors of HiB meningitis are left with permanent neurologic sequelae, including deafness and mental retardation. Timely administration of corticosteroids has been shown to help decrease the risk of subsequent neurologic deficits. Expanding vaccine coverage into developing countries has the potential to reduce these numbers. Diagnosis of bacterial meningitis in children is similar to that in adults, with neurologic examination and safety of performing an LP in children, and antibiotics should not be delayed for lengthy diagnostic procedures, such as imaging. CT. All children suspected of bacterial meningitis should receive empiric therapy with a third-generation cephalosporin due to the threat of meningococcus. Upon specific diagnosis of HiB meningitis, it is acceptable to continue treatment with a third-generation cephalosporin, but local antibiotic- resistance patterns ought to be taken into account.  4. Group B Streptococcus Group B Streptococcus is one of the leading causes of meningitis in neonates. Its causative agent, Streptococcus agalactiae, is a gram-positive cocci bacterium with beta-hemolytic properties, also capable of causing sepsis and pneumonia in the newborns. Neonates are most frequently infected with this organism during birth during passage through the vaginal canal, as Group B Streptococcus (GBS) is a frequent colonizer of the maternal vaginal canal. It is estimated that 10%–40% of all pregnant women in the United States are colonized with GBS in either the vagina or the rectum, and about half those infants exposed during birth will be colonized, while transmission to newborns with subsequent clinically significant sequelae occurs in about 1.8 out of every 1000 live births. Neonatal GBS infection is characterized as either early, first 7 days of life or late, anytime afterward but usually within the first 2 months of life. Risk factors for early infection include prematurity, low birth weight, preterm labour, premature rupture of membranes, previous infant affected with Group B Streptococcus, intrapartum fever, prolonged rupture of membranes exceeding 18 h, or a history of maternal GBS infection. A combination of these factors may increase the risk for neonatal infection up to 45.5 per 1000 live births. Pathogen-specific risk factors include maternal colonization with the serotype III variety of GBS.  Group B Streptococcus Due to the potential severity of meningitis, all infants under the age of 1 year presenting with a high fever should receive a LP (CSF) to examine for possible meningitis. Empiric treatment of neonatal meningitis consists of ampicillin and cefotaxime or similar third-generation cephalosporin; steroid therapy is often indicated as well, given with or before the administration of antibiotics. Prevention of Group B streptococcal meningitis includes universal screening of all mothers late in pregnancy, around 35–37 weeks, with chemoprophylactic intrapartum administration of antibiotics indicated for those women either colonized or at a higher risk for perinatal infection, possessing the risk factors. First line antibiotic therapy involves intravenous administration of penicillin G, backup with ampicillin and cefazolin recommended for those with mild penicillin allergies and clindamycin, erythromycin, or vancomycin recommended for those with anaphylactic reactions to penicillin. Adverse reactions to chemoprophylaxis include allergic or anaphylactic reactions to medication, as well as development of resistant GBS or other strains of bacteria leading to neonatal meningitis with antimicrobial-resistant pathogens.  5. Escherisia coli Along with Group B Streptococcus, Escherichia coli is one of the leading causes of meningitis in neonates up to 3 months of age, and should be suspected in all infants in this age range presenting with fever of unexplained origin. It is estimated that while 34.1% of neonatal meningitis is caused by Group B Streptococcus, E. coli is the responsible agent for 28.5% of cases. Neonatal E. coli meningitis is transmitted vertically from mother to fetus, and is found more commonly in premature infants and those with low birth weight. The K1 capsular antigen strain of E. coli is particularly associated with increased morbidity and mortality, and is the most common etiologic agent of gram- negative neonatal meningitis. Symptoms includes; fever, failure to thrive, focal neurologic deficits, irritability, decreased feeding, jaundice, vomiting, seizures, apnea, and neurologic sequelae commonly accompany neonatal E. coli meningitis.  Eschericia coli Diagnostic; for suspected infant patients includes blood cultures, throat swab, obtaining a complete blood count,, erythrocyte sedimentation rate and C-reactive protein, examining the urine for bacterial antigens, and LP. CSF is reflective of bacterial meningitis with high protein, low glucose, and neutrophil predominance, and should reveal gram-negative rods. The blood or CSF latex agglutination test is an alternative diagnostic modality that can be used to diagnose both E coli and GBS infection. Empiric treatment consists of ampicillin and cefotaxime or ceftriaxone.  6. Listeria monocytogenes Listerial meningitis is most frequently seen in infants from birth to 3 months of age, and again in elderly patients above the age of 65 years; other populations at risk include immunocompromised patients, pregnant women, and alcoholics. Although meningitis is the most common cerebral manifestation of listeriosis, encephalitis and brain abscess are possible as well. Common sources of Listeria infection include dairy products, such as unpasteurized milk and soft cheese. Neonatal infection is believed to occur either during passage through the birth canal or by way of transplacental infection. Predisposing factors include prematurity and low birth weight. Symptoms are similar to other forms of meningitis, and include fever, nuchal rigidity in adults and elderly, headache in the elderly, irritability and poor feeding in infants, lethargy, and seizures, with seizures being more commonly found than in other forms of meningitis. Findings on LP reveal gram-positive rods, although the characteristic polymorphonuclear pleocytosis may not be present.  Listeria monocytogenes Empiric treatment in the elderly includes covering against both Listeria and S. pneumoniae, and therefore ampicillin ought to be administered in addition to a third-generation cephalosporin. Specific treatment of listerial meningitis includes ampicillin with an aminoglycoside, such as gentamycin. Prognosis of GBS, E. coli, and Listeria neonatal meningitis is good. Mortality in elderly patients with listeriosis is significantly higher than that in the neonates, owing to the frequency of comorbid debilitating conditions found in this group. In a cohort of children with meningitis during the first year of life that were successfully followed-up with at 5 years of age, Bedford et al. demonstrated that almost one-fifth of children with meningitis during the first year of life exhibited permanent, severe, or moderate disabilities, including learning difficulties, visual and hearing disorders, motor difficulties, seizure disorders, speech and language problems, and behavioral difficulties.  7. Mycobacterium tuberculosis Mycobacterial meningitis is frequently present in immunocompromised hosts, such as HIV patients and results from hematogenous spread of the organism through the blood-brain barrier. The causative agent is Mycobacterium tuberculosis, an acid-fast slow-growing aerobic bacterium that primarily affects humans. The transmission of tuberculi is primarily via airborne droplets, and primary site of infection therefore tends to be the lungs. From the lungs, hematogenous spread into the meninges is then possible, especially in patients with poor cell-mediated immunity. CNS tuberculous disease begins with the development of small tuberculous foci in either the brain, spinal cord, or the meninges. Characteristic signs and symptoms are typical of those for meningitis, including headache, stiff neck, a slightly lower fever than in fulminant bacterial meningitis, coupled with the additional findings of possible focal neurologic deficits, and nausea and vomiting.  Mycobacterium tuberculosis A quick and easy test to examine for lifetime exposure is the tuberculin PPD test, which takes advantage of cell-mediated immunity to detect if the individual has ever been exposed. Testing for meningeal infection from CSF usually reveals a lymphocytic pleocytosis and a modest increase in protein coupled with low glucose levels. Antibody and antigen detection, and molecular methods are also utilized, and can help differentiate acute from chronic infections, with varying degrees of specificity for CNS infection vs systemic infection. Contrast-enhanced magnetic resonance imaging (MRI) is the imaging study of choice, and is preferred over CT due to enhanced specificity and sensitivity, as well as better delineation of the lesion. Standard international guidelines for treatment of tuberculosis advise 4-drug therapy with isoniazid, rifampin, pyrazinamide, and ethambutol for a period of 2 months, followed by an additional 6-month period of just isoniazid and rifampin. Isoniazid and pyrazinamide have the best CNS penetration out of the 4 drugs. Although isoniazid is the mainstay of therapy, resistance to it is very common, and several alternative agents have been recommended in the case of isoniazid-resistant strains; these agents include the fluoroquinolones, ethionamide, streptomycin, and amikacin.  FUNGAL MENINGITIS Susceptible patients are usually either immunocompromised or have undergone direct neurosurgical interventions, such as shunt placement. The primary method of spread in most cases involves respiratory infection with subsequent hematogenous dissemination. Symptoms are typical of those of meningitis, including fever, headache, AMS, nausea, vomiting, and neck stiffness, in addition to complications of abscess, papilledema, seizures, and focal neurologic deficits. CSF test for fungal meningitis usually reveals a lymphocytic prevalence with mild depressions in glucose and increased protein. FUNGAL MENINGITIS Common fungal agents of meningitis includes; (for discussion) a) Cryptococcus neoformans b) Candida albicans, c) Histoplasma capsulatum, Blastomycoses, and Coccidiodes immitis. (Table below) Risk factors, transmission, and treatment of fungal meningitis Signs and symptoms of central nervous system infections  FUNGAL MENINGITIS a) Cryptococcus meningitis AIDS and cancer patients are especially prone to cryptococcal meningitis, with the incidence of cryptococcosis dramatically increasing since the rise of the AIDS epidemic. In a multistate case–control study performed by Hajjeh et al, 86% of patients sampled with cryptococcosis had HIV. These patients often do not present with the same symptoms as found in immunocompetent patients, often experiencing a relatively sudden onset of symptoms. Pigeon droppings are one of the important carriers of Cryptococcus; smoking is another significant risk factor. Diagnosis can be made via direct microscopic examination using India Ink staining; cytology or histopathology, serologies, and culture after 48 h can also be used. Amphoterecin is the agent of choice in cryptococcal meningitis, and should be administered along with flucytosine for 2 weeks, followed by fluconazole Highly active antiretroviral therapy for HIV-infected patients is the most efficacious method for cryptococcal prevention. Once infected, however, lifelong fluconazole (or itraconazole in patients that cannot tolerate fluconazole) therapy is required, especially in AIDS patients with CD4 cell counts below 100.  b) Candida albicans Out of the 150 species of Candida known, Candida albicans is the major human pathogen. Frequently present as a vaginal infection in immunocompetent patients, often seen after antibiotic therapy, Candida has the potential to disseminate and cause meningitis primarily in immunosuppressed, especially neutropenic, individuals. In addition to meningitis, candidiasis can cause a vertebral osteomyelitis manifested by chronic progressive lower back pain that can eventually lead to nerve root compression syndromes and loss of function, as well as an endophthalmitis manifest by retinal lesions, which can eventually lead to blindness. Diagnosis; blood cultures shown to be fairly unreliable with poor sensitivity, more reliable techniques, such as the 1,3-β-glucan assay, are used to diagnose invasive candidiasis. Definitive diagnosis of candidal meningitis, however, is made similar to other fungal meningitis via culture and isolation of Candida species from the CSF. Treatment for Candida meningitis involves amphoterecin B and usually flucytosine due to its ability to penetrate the blood–brain barrier. In patients for whom amphoterecin-induced nephrotoxicity is a significant problem, fluconazole or the echinocandins may be used. c) Coccidioidal, Histoplasmoses and Blastomycoses meningitis Rare, Not known in PNG due to lack of studies, however worth noting; Coccidioidal meningitis usually occurs in epidemics, but affects a few hundred people a year at baseline, primarily in the southwestern United States. Diagnosis is usually via serology, as meningitis is usually the result of disseminated pulmonary infection. Although, treated with amphoterecin, these patients often require chronic therapy, prompting a switch to azoles, including fluconazole and itraconazole as the agent of choice for both induction and maintenance. Histoplasmoses and blastomycoses produce a meningitis similar to coccidiomycoses, and are transmitted similarly, that is, respiratory infection followed by blood-borne spread into the meninges and occasionally brain parenchyma, due to the genetic similarities between these species. Unlike coccidiomycosis, histoplasmosis and blastomycosis species tend to be found in central United States and less prevalent yet poses more serious infection to manage. Diagnosis for isolated CNS histoplasmosis infections may require multiple diagnostic modalities, including CSF testing, serologies, or culture. Treatment for both consists of liposomal amphoterecin B, which has been found to achieve better brain tissue concentrations with less nephrotoxicity than standard deoxycholate amphoterecin formation. Itraconazole and fluconazole are recommended in patients unable to tolerate amphoterecin, while there have been several case studies reporting successful treatment of blastomycosis with vorizonazole. AIDS patients may frequently require an azole for lifelong suppressive therapy, or until CD4 counts rise above 200.  LYME DISEASE Rare, Not known in PNG due to lack of studies, however worth noting; Lyme disease, classically obtained from bites from the Ixodes scapularis tick carrying the causative agent Borrelia burgdorferi,. Bacterial species of spirochete class. is primarily seen in the northeastern regions, United States. Neurologic symptoms of Lyme disease are preceded by an annular skin rash termed erythema migrans and nonspecific symptoms of a low-grade fever, malaise, and fatigue. The neurologic symptoms of Lyme disease begin to occur roughly about a month after initial tick bite, and frequently include focal neurologic findings as well as signs and symptoms of meningismus. The pathogenesis of CNS disease includes direct invasion by the bacterium itself in addition to vascular invasion. Focal neurologic findings seen typically where the organism also affect cranial nerves III, IV, V, VII, and VIII. Sensory deficits, especially in the face, are frequently seen. Diagnosis involves performing an LP, which reveals a lymphocytic pleocytosis with moderately elevated protein and decreased glucose. Other tests include serology, enzyme-linked immunosorbent assay (ELISA) followed by confirmation with a Western blot. Treatment of neurologic Lyme disease involves intravenous or intramuscular ceftriaxone or similar third-generation cephalosporin, although many recent studies have found the use of doxycycline to be equally efficacious in adults. Prevention of Lyme disease involves avoiding tick infested areas while repellents containing DEET (diethyl-3-methylbenzamide) are highly effective at preventing tick bites. A vaccine for Lyme disease, approved by the FDA in 1998, due to lack of use.  B. Encephalitis Encephalites are inflammations due to infection of the brain parenchyma, and can be caused by many agents, such as bacterial, viral, fungal, and protozoan. The most common of these agents are viral, and include herpes simplex virus (HSV), cytomegalovirus (CMV), enteroviruses, mumps virus, varicella zoster virus, togaviruses, and flaviviruses. Bacterial causes include syphilis, tuberculosis (discussed earlier). Fungal and protozoan agents are also capable of invading the brain parenchyma, producing rare yet serious illness. Diagnosis of precise etiologic agent involves obtaining a careful history, including travel history, exposure to tick or mosquito bite, immunocompromised status, recent organ transplant, and other unusual exposures. Neuroimaging, especially via MRI, can often reveal lesions specific to particular etiologic agents, including temporal lobe lesions seen in HSV neuroinfection or lesions in the basal ganglia or thalamus seen in West Nile virus and eastern equine encephalitis (EEE).  Encephalitis common agents The most common causative agents (for discussion); 1. Neurosyphilis 2. Herpes simplex encephalitis 3. Equine encephalitis 4. FLAVIVIRUS ENCEPHALITIS a. West Nile encephalitis, b. St. Louis encephalitis, c. Tick-borne encephalitis, d. Progressive multifocal leukoencephalopathy 5. Rabies 6. Primary amoebic meningoencephalitis  1. NEUROSYPHILIS One of the world's oldest infectious diseases, syphilis is caused by the spirochete Treponema pallidum. Initially spread often as a sexually transmitted infection, disseminated, chronic untreated syphilis can affect all aspects of the nervous system, from peripheral nerves to the brain and spinal cord. Most chronic forms of syphilis tend to be asymptomatic, a variety of focal neurologic findings, including cranial nerve abnormalities as well as meningismal signs of fever, headache, and stiff neck, are often seen. Less common than these classical symptoms, neurosyphilis also has the capability of presenting with psychiatric disturbances, movement disorders, hearing loss, dementia, stroke-like syndrome, seizures, or even mimicking amyotrophic lateral sclerosis. Diagnosis of neurosyphilis can be challenging, as no single test is held to be diagnostic of neurosyphilis. Screening is performed with rapid plasma regain or venereal disease research laboratory (VDRL) testing, usually detecting patients after a primary infection. Neurologic symptoms typically succeed initial infection by many months or years, in a patient with a past history of syphilis, therefore, any abnormal neurologic findings should greatly raise clinical suspicion. Fluorescent treponemal antibody-absorption (FTA-Abs) testing of CSF has good sensitivity. HIV remains a significant risk factor for neurosyphilis, and clinical suspicion. Treatment consists of aqueous crystalline penicillin, due to its superior penetration across the blood–brain barrier. Patients with penicillin allergies and neurosyphilis should be desensitized to penicillin, as alternative antibiotics are incapable of penetrating the CNS in doses enough to be efficacious.  2. Herpes simplex encephalitis Viral encephalitis can often be distinguished from bacterial meningitis by the presence of focal neurologic findings in addition to AMS (alterered mental status), especially if new-onset personality or behavioral changes are present (see Table). Herpes simplex encephalitis typically affects the temporal lobe. Focal neurologic findings are often found, including seizures originating from the temporal lobe. Symptoms typically begin with a prodrome of fever and headache, and later include memory loss, AMS, and confusion. Psychiatric manifestations may be present, and patients generally present with a delirium, yet can have a variety of other psychiatric symptoms, including agitation, withdrawal, hallucinations—often olfactory, psychosis, or manic symptoms. Over 90% of all cases of herpes encephalitis are due to herpes simplex virus type I, whereas the others are due to HSV II. Most cases are believed to be due to reactivation of the herpes virus from the trigeminal ganglion or latent virus from the brain parenchyma.  Herpes simplex encephalitis Diagnosis for signs of viral infection in the CSF, such as a normal or reduced glucose level with a pleocytosis and increased number of red cells. Imaging of the brain, such as an MRI, will reveal medial temporal lobe involvement fairly early in the course of illness. Molecular techniques such as PCR assay of the CSF revealing herpes simplex viral DNA is the gold standard for specific diagnosis. Treatment involves high-dose acyclovir. Steroids can be used adjunctively, especially if there is concern about herniation. The course is often fatal, especially if treatment is delayed, and can lead to progressive neurologic dysfunction followed by death occurring within 1 month. Mortality estimates of acute cases range from 20% to 50% with appropriate therapy. Neonatal herpes encephalitis has a similar clinical picture, but can lead to more chronic neurologic deficits in survivors, with 56%–69% of all survivors suffering long-term neurologic complications after treatment. A significant long-term complication of neonatal herpes encephalitis is the subsequent development of cerebral palsy. Other complications include recurrent epilepsy, postinfectious encephalomyelitis, and permanent neuropsychiatric disorders. Viral encephalites  3. Equine encephalitis The equine encephalites, including EEE, western equine encephalitis (WEE), and Venezuelan equine encephalitis (VEE) are caused by alphaviruses, single-stranded positive-sense RNA viruses belonging to the Togaviridae family. Relatively uncommon, these infections, in particular EEE, have the potential to cause much morbidity and possess a high rate of mortality, demanding their urgent and accurate diagnosis. Major incidence along the southeastern USA; hotter swampy locations inhabited by the mosquito Culiseta melanura, its primary vector; birds are the major reservoir of disease. Clinically, nonspecific, and can involve a typical viral flu-like symptoms, including fever, chills, malaise, and myalgias lasting up to a couple of weeks followed by encephalitis involving severe headache, nausea, vomiting, AMS, and focal neurologic with complications of seizures, nerve palsies, coma, and death. Laboratory studies in both diseases reveal a hyponatremia, believed to be secondary to a syndrome of inappropriate antidiuretic hormone (SIADH), in addition to leukocytosis. CSF studies typically show a neutrophil-predominant pleocytosis with elevated protein levels and mildly decreased to normal glucose levels. MRI can be a valuable modality in the diagnosis of EEE, as patients with EEE demonstrate focal radiologic findings of early involvement of the basal ganglia and thalami visible on imaging. Definitive diagnosis is through serology detecting IgM antibodies to viral antigen in the CSF. No specific antiviral therapies currently exist, and management is geared toward treating accompanying complications, such as seizures and increased intracranial pressure. Although a vaccine has been developed by the United States Army against the VEE virus, no vaccines currently exist for the viruses causing EEE or WEE.  4. FLAVIVIRUS ENCEPHALITIS The flaviviruses encompass a large group of viruses causing a widespread range of diseases with high global morbidity and mortality, including the causative agents of a) West Nile encephalitis, b) St. Louis encephalitis, c) Tick-borne encephalitis, d) Progressive multifocal leukoencephalopathy  a) West Nile Since its introduction into New York in 1999, the West Nile virus has spread rapidly throughout the United States, with several thousand reported cases since then and the number only expected to rise. Initial presentation of the West Nile virus usually includes nonspecific flu-like symptoms, such as low-grade fever, malaise, headache, nausea, vomiting, and anorexia, in addition to less common symptoms of eye pain, rash, lymphadenopathy; only around 20% of those infected develop symptomatic disease. Diagnosis is usually serologic, made by the detection of West Nile IgM antibodies in the serum or CSF. False negatives may result, especially early in illness, and false positives may result especially in patients with previous exposure to other flavivirus infections, due to West Nile ELISA testing to detect cross-reacting antibodies. Treatment includes isolating affected patient in an isolated room away from mosquitoes, with supportive care measures of fluid, oxygen, and pressors to prevent against hypotension and lactic acidosis. A live attenuated 17-D vaccine has been developed conferring immunity in 95% of those vaccinated.  b) St. Louis encephalitis St. Louis encephalitis is transmitted by a flavivirus primarily carried by mosquito vectors of the Culex genus that often feed on birds. Although prevalent throughout the western hemisphere, St. Louis encephalitis predominantly sees outbreaks occur in the central United States, as well as parts of Texas, Florida, and the Caribbean. Clinical features include either an encephalitis and/or a viral meningitis picture, flu-like symptoms, including fever, headache, malaise, myalgia, nausea, vomiting, drowsiness, sore throat, and photophobia. Neurologic deficits are seen with presence of seizures present in infected patients and requiring respiratory support. MRI scans of the brain in patients affected by St. Louis encephalitis typically show nonspecific edema, whereas CT scans are normal. Electroencephalograms (EEGs) of the brain often show polymorphic delta activity. Laboratory findings includes, an elevated CSF pressure with a mild increase in protein yet normal glucose levels. Peripherally, an increase in neutrophils with a left shift may be seen. Damage in kidneys can revealing hematuria, proteinuria, or pyuria with viral antigen frequently being detected in the urinary sediment. Diagnosis can be made via ELISA demonstrating rising antibody titers, and more specifically by RT-PCR. Treatment of this disease is largely supportive, with no specific antivirals devised against the causative agent. The case fatality is below 10%, with many experiencing a prolonged convalescence marked by irritability, tremulousness, insomnia, and depression.  c) Tick-borne encephalitis The tick-borne encephalites comprise a group of several closely related flaviviruses that are carried on forest ticks primarily of the various Ixodes species. Cases mainly occur in the warmer spring and summer months, and the majority of the burden of illness is located in Europe and Russia. Clinical symptoms include a biphasic illness, marked by flu-like symptoms, an encephalitic or meningitic picture, nausea, vomiting, fever, headache, and in more severe cases hemorrhagic fever, focal deficits, stiff neck, paralysis, visual disturbances, convulsions, and coma may occur. MRI of the brain shows diffuse edema of deeper structures, whereas spinal MRI might show anterior horn lesions. Diagnosis with molecular tests; such as ELISA or direct isolation of virus from blood. Similar to other flavivirus infections, treatment is largely supportive. Vaccines to many species, however, have been devised and utilized in Europe for higher risk groups.  d) Progressive multifocal leukoencephalopathy Progressive multifocal leukoencephalopathy (PML) is a demyelinating disease of the brain seen primarily in immunocompromised patients, in particular those with HIV. The causative agent is the JC virus, a papovavirus with a double-stranded circular DNA genome that has a penchant to invade oligodendrocytes. Common symptom is limb weakness, followed by cognitive disorders. Other symptoms include disorders of speech, gait abnormalities, visual deficits, limb incoordination, seizures, headache, and sensory deficits. Diagnosis must be differentiaed from multiple sclerosis (MS) and must be ruled out. Seizures, speech disorders, and aphasia are far more prevalent in progressive multifocal encephalopathy than in MS, whereas sensory deficits and limb incoordination are significantly more prevalent in MS than PML. Definitive diagnosis of PML requires the isolation of the JC virus in CSF or brain tissue. Interestingly, the treatment of MS can often lead to subsequent PML, due to immune suppression caused CD4 suppressants. There is no effective treatment for progressive multifocal leukoencephalopathy. Few agents such as mefloquine and cytosine arabinoside have generated through in vitro experiments, with no clinical trials, yet to establish efficacy in human cases of PML. The most effective treatment strategy in those patients co-infected with HIV is to initiate effective highly active antiretroviral therapy with the goal of improving CD4 counts to levels capable of battling the JC virus.  5. RABIES The rabies virus is part of the Rhabdoviridae family of viruses, which comprises a linear, single- stranded negative sense RNA virus found within a bullet-shaped envelop. It is a zoonotic infection, spreading from animals to humans mainly by way of bite, with the primary culprits in the United States being bats, raccoons, and skunks, whereas the primary culprits worldwide are dogs. Animal bite is the primary mode of transmission, infected aerosolized bat urine from entering heavily infested caves is a significant source of disease. Incubation of the virus typically takes place over 1–3 months, and CNS infection takes place through the process of retrograde spread of the virus from peripheral nerves unto the central nerves and finally into the brain parenchyma. Infection with the rabies virus is always fatal once encephalitis occurs, and therefore once a suspected exposure occurs, immediate treatment is of utmost importance. Diagnosis may be made clinically, often including quarantine or killing of the infected animal while observing for signs of infection in the animal. Definitive diagnosis in humans may be made through reverse-transcriptase PCR detecting rabies virus in CNS tissue, CSF, or body secretions. Management consists of thorough wound cleaning, urgent administration of human rabies immune globulin at both the site of infection and one shot intramuscularly, followed by a set of five postexposure vaccinations within the first month. Vaccination is performed via administration of human diploid cell rabies vaccine, 1.0 mL given intramuscularly. Pre-exposure vaccination is recommended for those at a high risk of occupational or recreational exposure.  6. Primary amoebic meningoencephalitis Naegleria fowleri, the causative agent of primary amoebic meningoencephalitis, is a common fresh-water amoebic protozoan found throughout shallow bodies of water in the United States. The typical means of obtaining this infection is by diving in fresh water wherein the organism goes up the patient's nasal cavity and penetrates the cribiform plate, making its way to the brain. Diagnosis - LP often reveals amoebas in the CSF. Although infections with this protozoan are very rare, with a little over 300 cases being reported worldwide, they are extremely deadly, with no effective or specific therapies devised against this organism. Treatment with high-dose amphoterecin combined with flucytosine or fluconazole and possibly rifampicin confer the best chance of survival. Death usually occurs in 1 week.  C. Brain Abscess (Cerebral abscess) Cerebral abscesses can frequently present with a new-onset headache that can evolve over several hours to several weeks, accompanied by focal neurologic deficits. Lethargy, nuchal rigidity, nausea, vomiting, and new-onset seizures often accompany the development of abscesses. The two major causes of brain abscesses include hematogenous spread of pathogens across the blood–brain barrier and via direct contiguous spread from the sinuses after a sinus infection, with the latter accounting for over 70% of all brain abscesses. A minor etiology involves direct trauma to the skull implanting the pathogenic organism. The differential diagnosis for brain abscesses always involves neoplasm, although abscesses tend to be more acute in their onset and are often accompanied by other systemic symptoms, such as fever and leucocytosis and positive blood cultures found in far fewer. History of patient is important in preceding sinus infections, systemic infections, and possible head trauma. CT or MRI are indicated whenever abscess is suspected, with MRI being more sensitive and specific for detecting various aspects of the abscess, including mass effects, surrounding edema, and response to therapy. Abscesses tend to be located most commonly in the frontal and parietal lobes. Fungal abscesses, more focally confined to one part of the brain and organisms are rarely found in the CSF. Less frequent causes including Candida are also found in increased amounts in IV drug users, as well as chronically immunosuppressed patients.  Cerebral abscess Recovery rate correlates with the size of abscess and degree of neurologic dysfunction primarily, Streptococcal infections are among the most common causes of brain abscesses, and frequently result from parameningeal spread into the cranial cavity. Anaerobic organisms, such as Bacteroides, Peptococcus, Peptostreptococcus, and Prevotella also frequently enter the brain by way of contiguous spread from either nasal or oropharyngeal origins. The treatment of choice for streptococcal abscesses includes a third-generation cephalosporin, such as ceftriaxone. Anaerobic abscesses respond best to metronidazole, whereas empiric therapy for the treatment of brain abscesses usually involves a combination of both anaerobic and streptococcal coverage. In patients suspected of being infected with S. aureus, the prospect of methicillin resistance must be taken into account, and empiric treatment with vancomycin is indicated. Suspected Candida infections should employ an antifungal agent, such as amphoterecin B and flucytosine, often followed by an oral agent, such as fluconazole, which has good penetration into the CSF. Treatment for bacterial abscesses includes either administration of antibiotics alone, or surgical removal of abscess via excision or aspiration. If surgery or aspiration is employed, antibiotics should concomitantly be administered. Brain Abscess common agents The most common causative agents; (for discussion) 1. Toxoplasmosis 2. Spinal abscess 3. Arachnoiditis 4. Prions  1. TOXOPLASMOSIS Toxoplasmosis, from the causative agent Toxoplasma gondii, frequently occurs in immunocompromised individuals, such as end-stage HIV patients, those on systemic chemotherapy, in patients with hereditary immunologic disorders, or in the infants of pregnant women exposed to cat litter. Congenital toxoplasmosis presents with mental retardation, seizures due to calcification of basal ganglia, blindness, and death in infants. It is also a frequent cause of cerebral palsy, hypothesized to be caused by inflammatory cytokines secondary to the infection; periventricular leukomalacia appears to be the primary identifiable risk factor portending the development of cerebral palsy. The classic triad seen involves chorioretinitis, hydrocephalus, and intracellular calcification appearing as ring-enhancing lesions seen on CT scan with contrast. In patients with known history of HIV, toxoplasmosis is considered as an AIDS-defining illness, and is usually seen after the CD4 cell count diminishes to 100 or lower. Prevention against toxoplasmosis in susceptible patients requires the combination of trimethoprim and sulfamethoxazole. Once toxoplasmosis has already been diagnosed, specific therapy with pyrimethamine and sulfadiazine should be initiated. In neonatal infections, the prospect of “brain cooling” or induction of cerebral hypothermia has recently gained much attention as a potential method of tempering the effects of cytokine- mediated brain injury, thereby diminishing the likelihood of development of cerebral palsy. Although studies have failed to reveal a clinically significant effect of treating mothers to prevent perinatal spread to foetus, antibiotic treatment of infected newborns in the first year of life has shown to significantly improve clinical outcome.  2. Spinal abscesses In addition to cerebral abscesses, epidural abscesses may also be a cause of fever accompanied by focal neurologic deficits, with the distinguishing feature of back pain commonly present. Although rare, require urgent diagnosis and treatment as they have the potential to lead to permanent neurologic complications. Similar to cerebral abscesses, surgical instrumentation is also a frequent etiology, especially in patients undergoing prolonged spinal surgery procedures or those receiving spinal anesthesia. Intravenous drug abuse is a significant risk factor as well, as is diabetes, older age, any immunocompromised state, or spinal penetrating trauma. The causative organism most frequently implicated is S. aureus. Staphylococcus epidermidis is also frequently prevalent in instrumentation procedures, whereas Pseudomonas aeruginosa plays more of a role in IV drug users and diabetics. In patients with tuberculous spondylitis, M. tuberculosis is the primary organism identified. Common symptoms of spinal abscesses, in addition to fever and back pain, include sensory and motor deficits, pain in a radicular distribution, paresthesias, meningeal symptoms, and often loss of bowel or bladder function. Back pain is the most common symptom, and sepsis may often result. Physical signs may reveal focal tenderness and warmth, erythema, or oedema over the involved area. Clinical suspicion remain high in patients, especially those having undergone recent spinal instrumentation. Diagnosis; Whenever spinal abscess is suspected. The imaging technique of choice is MRI, which has greater specificity and sensitivity than contrast-enhanced CT. Blood cultures should be obtained before the onset of antibiotic therapy, but therapy should not be delayed awaiting results. Antibiotic therapy ought to be continued tailored to the causative organism. Mortality estimates range from 6% to 32%, and frequently depend on the onset of initiation of therapy. Recurrence is uncommon in the absence of ongoing risk factors.  3. Arachnoiditis Another location for spinal inflammation includes the area surrounding the arachnoid space, which also has the potential for infection known as arachnoiditis. Similar to epidural abscesses, spinal instrumentation is a frequently implicated pathology, with immunocompromise, tuberculosis, and trauma comprising the additional common etiologies of infectious arachnoiditis. Symptoms include burning back pain with paresthesias, fever, neurologic defects, and back spasms. Pain may frequently be worse with movement, and often does not follow radicular distribution. Although symptoms may frequently be nonspecific, clinical suspicion following spinal instrumentation should be high and radiographic studies with MRI and blood cultures should be obtained immediately. Treatment with broad-spectrum antibiotics, especially possessing antistaphylococcal coverage, should be initiated. For patients with tuberculous arachnoiditis, treatment with four-drug therapy (TB treatment) should be initiated. In patients outside United States (ie developing countries) neurocysticercosis represents a significant cause of arachnoiditis, and requires antiparasitic treatment, such as praziquantel, along with steroids if significant edema exists. In addition to antibiotics, treatment with tricyclic antidepressants, anticonvulsants, such as gabapentin, and nonsteroidals may be of benefit in alleviating symptoms. Although usually not necessary, surgery may be required in cases of rapidly progressive neurologic deterioration.  4. Prions Prions are infective, malfolding protein particles representing a rare cause of encephalopathic disease that can arise as either sporadic mutations in human beings, can be inherited, derived from contaminated meat, or iatrogenically introduced. Diseases such as kuru have resulted from the consumption of human brain, historically affecting the Fore tribe of Papua New Guinea up until the 1950s, whereas other diseases including bovine spongiform encephalopathy (BSE) and scrapie have resulted from the consumption of infected beef. Creutzfeldt–Jakob disease (CJD) is the most common form of prion disease with an incidence of around one per million, and is primarily acquired in 80%–85% by spontaneous malfolding in the PrPc protein causing it to become the abnormal prion protein PrPsc. Sporadic CJD occurs on average in the sixth to seventh decade of life, whereas inherited conditions tend to become symptomatic in the fourth decade of life. Additionally, there have been documented cases of a new variant CJD, related to BSE, arising over the past 15 years that is under greater risk for spread through blood products; traditional CJD is not believed to be readily transmissible through blood.  Prions In each case, regardless of the transmission, the pathophysiology of disease revolves around a misfolded prion protein that possesses the capability of enzymatically converting other identical proteins nearby into its own protein configuration, conferring upon it additional properties not seen in native properly folded proteins. These properties include resistance to most common techniques of heat destruction and sterilization, resistance to proteases, enhanced stability, propensity to accumulate in lysosomes, and polymerization into amyloid-like structures in the brain, giving the brain its characteristic spongiform appearance. Earliest symptoms of infection with prion proteins and resulting encephalopathy present are nonspecific, and include sleep disturbances, lack of coordination, fatigue, cognitive changes, and weight loss. As the disease progresses, the characteristic symptoms of myoclonal jerks and subacute yet rapidly progressive dementia are seen, as well as the typical periodic slow wave complexes. Diagnosis – CSF analysis is typically normal, but may be useful for containing the sensitive but less specific 14-3-3-protein. Neuroimaging usually reveals no changes in the early stages, but later MRI may show basal ganglia hypersensitivity best seen with diffusion-weighted imaging, and finally followed by diffuse atrophy. Variant CJD due to BSE gives a more characteristic appearance on MRI, with infected patients revealing a positive sign, indicating prominent enhanced signal in the posterior thalamus. There are no effective treatments for prion-based diseases, and the clinical course is characterized by a rapidly progressive encephalopathy with dementia and cerebral wasting, with death usually occurring within 1 year. Vaccines faces challenges in their development.  CONCLUSION Infections of the CNS represent a significant source of morbidity and mortality throughout the world, and demand that physicians in a variety of specialties are familiar enough with their presenting signs and symptoms and can formulate a diagnosis in time before further damage arises. Despite advances in vaccinations, meningitis arising from N. meningitides and S. pneumoniae species in adults and children and from Group B Streptococcus, E. coli, and Listeria species in neonates remain common reasons for presentation to the emergency room. Bacterial meningitis must be differentiated from viral meningitis and encephalitis, commonly caused by herpes simplex viruses, varicella, cytomegalovirus, togaviruses, and flaviviruses. Tuberculosis and various fungal meningitis may also present with similar symptoms, although tend to affect debilitated populations. The Lumber Puncture (LP) is a valuable method of differentiating empirically between common bacterial vs other causes of meningitis and encephalitis. Abscesses tend to present with focal neurologic deficits, and contain unique precipitating events leading to their formation. Prions and cavernous sinus thrombosis represent rare yet devastating sources of infection. MRI and CT are important imaging techniques typically capable of detecting many infections, although a careful history and physical exam remain invaluable.