A lumbar puncture (LP) is necessary to diagnose meningitis. Cerebrospinal fluid (CSF) culture is the most important study for the diagnosis of neonatal bacterial meningitis because clinical signs are non-specific and unreliable. Blood cultures may be negative in 15-55% of cases, deeming it unreliable as well. However, a CSF/blood glucose ratio below two-thirds has a strong relationship to bacterial meningitis. A LP should be done in all neonates with suspected meningitis, with suspected or proven sepsis (whole body inflammation) and should be considered in all neonates in whom sepsis is a possibility. The role of the LP in neonates who are healthy appearing but have maternal risk factors for sepsis is more controversial; the yield of the LP in these patients may be low.

Early-onset is deemed when infection is within one week of birth. Late-onset is deemed after the first week.

Babies born from mothers with symptoms of Herpes Simplex Virus (HSV) should be tested for viral infection. Liver tests, complete blood count (CBC), cerebrospinal fluid analyses, and chest X-ray should all be completed to diagnose meningitis. Samples should be taken from skin, conjunctiva (eye), mouth and throat, rectum, urine, and the CSF for viral culture and PCR analysis with respect to the sample from CSF.

The diagnosis is established by a computed tomography (CT) (with contrast) examination. At the initial phase of the inflammation (which is referred to as cerebritis), the immature lesion does not have a capsule and it may be difficult to distinguish it from other space-occupying lesions or infarcts of the brain. Within 4–5 days the inflammation and the concomitant dead brain tissue are surrounded with a capsule, which gives the lesion the famous ring-enhancing lesion appearance on CT examination with contrast (since intravenously applied contrast material can not pass through the capsule, it is collected around the lesion and looks as a ring surrounding the relatively dark lesion). Lumbar puncture procedure, which is performed in many infectious disorders of the central nervous system is contraindicated in this condition (as it is in all space-occupying lesions of the brain) because removing a certain portion of the cerebrospinal fluid may alter the concrete intracranial pressure balances and causes the brain tissue to move across structures within the skull (brain herniation).

Ring enhancement may also be observed in cerebral hemorrhages (bleeding) and some brain tumors. However, in the presence of the rapidly progressive course with fever, focal neurologic findings (hemiparesis, aphasia etc.) and signs of increased intracranial pressure, the most likely diagnosis should be the brain abscess.

A 2013 review concluded moderate-quality evidence exists to support use of the procalcitonin level as a method to distinguish sepsis from non-infectious causes of SIRS. The same review found the sensitivity of the test to be 77% and the specificity to be 79%. The authors suggested that procalcitonin may serve as a helpful diagnostic marker for sepsis, but cautioned that its level alone cannot definitively make the diagnosis. A 2012 systematic review found that soluble urokinase-type plasminogen activator receptor (SuPAR) is a nonspecific marker of inflammation and does not accurately diagnose sepsis. This same review concluded, however, that SuPAR has prognostic value, as higher SuPAR levels are associated with an increased rate of death in those with sepsis.

Meningitis can be diagnosed after death has occurred. The findings from a post mortem are usually a widespread inflammation of the pia mater and arachnoid layers of the meninges. Neutrophil granulocytes tend to have migrated to the cerebrospinal fluid and the base of the brain, along with cranial nerves and the spinal cord, may be surrounded with pus – as may the meningeal vessels.

A lumbar puncture is done by positioning the person, usually lying on the side, applying local anesthetic, and inserting a needle into the dural sac (a sac around the spinal cord) to collect cerebrospinal fluid (CSF). When this has been achieved, the "opening pressure" of the CSF is measured using a manometer. The pressure is normally between 6 and 18 cm water (cmHO); in bacterial meningitis the pressure is usually elevated. In cryptococcal meningitis, intracranial pressure is markedly elevated. The initial appearance of the fluid may prove an indication of the nature of the infection: cloudy CSF indicates higher levels of protein, white and red blood cells and/or bacteria, and therefore may suggest bacterial meningitis.

The CSF sample is examined for presence and types of white blood cells, red blood cells, protein content and glucose level. Gram staining of the sample may demonstrate bacteria in bacterial meningitis, but absence of bacteria does not exclude bacterial meningitis as they are only seen in 60% of cases; this figure is reduced by a further 20% if antibiotics were administered before the sample was taken. Gram staining is also less reliable in particular infections such as listeriosis. Microbiological culture of the sample is more sensitive (it identifies the organism in 70–85% of cases) but results can take up to 48 hours to become available. The type of white blood cell predominantly present (see table) indicates whether meningitis is bacterial (usually neutrophil-predominant) or viral (usually lymphocyte-predominant), although at the beginning of the disease this is not always a reliable indicator. Less commonly, eosinophils predominate, suggesting parasitic or fungal etiology, among others.

The concentration of glucose in CSF is normally above 40% of that in blood. In bacterial meningitis it is typically lower; the CSF glucose level is therefore divided by the blood glucose (CSF glucose to serum glucose ratio). A ratio ≤0.4 is indicative of bacterial meningitis; in the newborn, glucose levels in CSF are normally higher, and a ratio below 0.6 (60%) is therefore considered abnormal. High levels of lactate in CSF indicate a higher likelihood of bacterial meningitis, as does a higher white blood cell count. If lactate levels are less than 35 mg/dl and the person has not previously received antibiotics then this may rule out bacterial meningitis.

Various other specialized tests may be used to distinguish between different types of meningitis. A latex agglutination test may be positive in meningitis caused by "Streptococcus pneumoniae", "Neisseria meningitidis", "Haemophilus influenzae", "Escherichia coli" and "group B streptococci"; its routine use is not encouraged as it rarely leads to changes in treatment, but it may be used if other tests are not diagnostic. Similarly, the limulus lysate test may be positive in meningitis caused by Gram-negative bacteria, but it is of limited use unless other tests have been unhelpful. Polymerase chain reaction (PCR) is a technique used to amplify small traces of bacterial DNA in order to detect the presence of bacterial or viral DNA in cerebrospinal fluid; it is a highly sensitive and specific test since only trace amounts of the infecting agent's DNA is required. It may identify bacteria in bacterial meningitis and may assist in distinguishing the various causes of viral meningitis (enterovirus, herpes simplex virus 2 and mumps in those not vaccinated for this). Serology (identification of antibodies to viruses) may be useful in viral meningitis. If tuberculous meningitis is suspected, the sample is processed for Ziehl-Neelsen stain, which has a low sensitivity, and tuberculosis culture, which takes a long time to process; PCR is being used increasingly. Diagnosis of cryptococcal meningitis can be made at low cost using an India ink stain of the CSF; however, testing for cryptococcal antigen in blood or CSF is more sensitive, particularly in people with AIDS.

A diagnostic and therapeutic difficulty is "partially treated meningitis", where there are meningitis symptoms after receiving antibiotics (such as for presumptive sinusitis). When this happens, CSF findings may resemble those of viral meningitis, but antibiotic treatment may need to be continued until there is definitive positive evidence of a viral cause (e.g. a positive enterovirus PCR).

Death occurs in about 10% of cases and people do well about 70% of the time. This is a large improvement from the 1960s due to improved ability to image the head, better neurosurgery and better antibiotics.

Myelitis has an extensive differential diagnosis. The type of onset (acute versus subacute/chronic) along with associated symptoms such as the presence of pain, constitutional symptoms that encompass fever, malaise, weight loss or a cutaneous rash may help identify the cause of myelitis. In order to establish a diagnosis of myelitis, one has to localize the spinal cord level, and exclude cerebral and neuromuscular diseases. Also a detailed medical history, a careful neurologic examination, and imaging studies using magnetic resonance imaging (MRI) are needed. In respect to the cause of the process, further work-up would help identify the cause and guide treatment. Full spine MRI is warranted, especially with acute onset myelitis, to evaluate for structural lesions that may require surgical intervention, or disseminated disease. Adding gadolinium further increases diagnostic sensitivity. A brain MRI may be needed to identify the extent of central nervous system (CNS) involvement. Lumbar puncture is important for the diagnosis of acute myelitis when a tumoral process, inflammatory or infectious cause are suspected, or the MRI is normal or non-specific. Complementary blood tests are also of value in establishing a firm diagnosis. Rarely, a biopsy of a mass lesion may become necessary when the cause is uncertain. However, in 15–30% of people with subacute or chronic myelitis, a clear cause is never uncovered.

The differential diagnosis for sepsis is broad and has to examine (to exclude) the noninfectious conditions that may cause the systemic signs of SIRS: alcohol withdrawal, acute pancreatitis, burns, pulmonary embolism, thyrotoxicosis, anaphylaxis, adrenal insufficiency, and neurogenic shock. Hyperinflammatory syndromes such as hemophagocytic lymphohistiocytosis (HLH) may have similar symptoms and should also be included in differential diagnosis.

"N. fowleri" can be grown in several kinds of liquid axenic media or on non-nutrient agar plates coated with bacteria. "Escherichia coli" can be used to overlay the non-nutrient agar plate and a drop of cerebrospinal fluid sediment is added to it. Plates are then incubated at 37 °C and checked daily for clearing of the agar in thin tracks, which indicate the trophozoites have fed on the bacteria. Detection in water is performed by centrifuging a water sample with "E. coli" added, then applying the pellet to a non-nutrient agar plate. After several days, the plate is microscopically inspected and "Naegleria" cysts are identified by their morphology. Final confirmation of the species' identity can be performed by various molecular or biochemical methods.

Confirmation of "Naegleria" presence can be done by a so-called flagellation test, where the organism is exposed to a hypotonic environment (distilled water). "Naegleria", in contrast to other amoebae, differentiates within two hours into the flagellate state.

Pathogenicity can be further confirmed by exposure to high temperature (42 °C): "Naegleria fowleri" is able to grow at this temperature, but the nonpathogenic "Naegleria gruberi" is not.

Diagnosis is made by clinical observation and the following tests.

(1) Gram stain of the fluid from pustules or bullae, and tissue swab.

(2) Blood culture

(3) Urine culture

(4) Skin biopsy

(5) Tissue culture

Magnetic resonance imaging can be done in case of ecthyma gangrenosum of plantar foot to differentiate from necrotizing fasciitis.

Neonatal sepsis of the newborn is an infection that has spread through the entire body. The inflammatory response to this systematic infection can be as serious as the infection itself. In infants that weigh under 1500 g, sepsis is the most common cause of death. Three to four percent of infants per 1000 births contract sepsis. The mortality rate from sepsis is near 25%. Infected sepsis in an infant can be identified by culturing the blood and spinal fluid and if suspected, intravenous antibiotics are usually started. Lumbar puncture is controversial because in some cases it has found not to be necessary while concurrently, without it estimates of missing up to one third of infants with meningitis is predicted.

In a normal umbilical stump, you first see the umbilicus lose its characteristic bluish-white, moist appearance and become dry and black After several days to weeks, the stump should fall off and leave a pink fleshy wound which continues to heal as it becomes a normal umbilicus.

For an infected umbilical stump, diagnosis is usually made by the clinical appearance of the umbilical cord stump and the findings on history and physical examination. There may be some confusion, however, if a well-appearing neonate simply has some redness around the umbilical stump. In fact, a mild degree is common, as is some bleeding at the stump site with detachment of the umbilical cord. The picture may be clouded even further if caustic agents have been used to clean the stump or if silver nitrate has been used to cauterize granulomata of the umbilical stump.

During the 1950s there were outbreaks of omphalitis that then led to anti-bacterial treatment of the umbilical cord stump as the new standard of care. It was later determined that in developed countries keeping the cord dry is sufficient, (known as "dry cord care") as recommended by the American Academy of Pediatrics. The umbilical cord dries more quickly and separates more readily when exposed to air However, each hospital/birthing center has its own recommendations for care of the umbilical cord after delivery. Some recommend not using any medicinal washes on the cord. Other popular recommendations include triple dye, betadine, bacitracin, or silver sulfadiazine. With regards to the medicinal treatments, there is little data to support any one treatment (or lack thereof) over another. However one recent review of many studies supported the use of chlorhexidine treatment as a way to reduce risk of death by 23% and risk of omphalitis by anywhere between 27-56% in community settings in underdeveloped countries. This study also found that this treatment increased the time that it would take for the umbilical stump to separate or fall off by 1.7 days. Lastly this large review also supported the notion that in hospital settings no medicinal type of cord care treatment was better at reducing infections compared to dry cord care.

Because many "Candida" species are part of the human microbiota, their presence in the mouth, the vagina, sputum, urine, stool, or skin is not definitive evidence for invasive candidiasis.

Positive culture of "Candida" species from normally sterile sites, such as blood, cerebrospinal fluid, pericardium, pericardial fluid, or biopsied tissue, is definitive evidence of invasive candidiasis. Diagnosis by culturing allows subsequent susceptibility testing of causitive species. Sensitivity of blood culture is far from ideal, with a sensitivity reported to be between 21 and 71%. Additionally, whereas blood culture can establish a diagnosis during fungemia, the blood may test negative for deep-seated infections because candida may have been successfully cleared from the blood.

Diagnosis of invasive candidiasis is supported by histopathologic evidence (for example, yeast cells or hyphae) observed in specimens of affected tissues.

Additionally, elevated serum β-glucan can demonstrate invasive candidiasis while a negative test suggests a low likelihood of systemic infection.

The emergence of multidrug-resistant "C. auris" as a cause of invasive candidiasis has necessitated additional testing in some settings. "C. auris"-caused invasive candidiasis is associated with high mortality. Many "C. auris" isolates have been found to be resistant to one or more of the three major antifungal classes (azoles, echinocandins, and polyenes) with some resistant to all three classes - severely limiting treatment options. Biochemical-based tests currently used in many laboratories to identify fungi, including API 20C AUX and VITEK-2, cannot differentiate "C. auris" from related species (for example, "C. auris" can be identified as "C. haemulonii"). Therefore, the Centers for Disease Control and Prevention recommends using a diagnostic method based on matrix-assisted laser desorption/ionization-time of flight mass spectrometry or a molecular method based on sequencing the D1-D2 region of the 28s rDNA to identify "C. auris" in settings were it may be present.

The main organism associated with ecthyma gangrenosum is "Pseudomonas aeruginosa". However, multi-bacterial cases are reported as well. Prevention measures include practicing proper hygiene, educating the immunocompromised patients for awareness to avoid possible conditions and seek timely medical treatment.

Michael Beach, a recreational waterborne illness specialist for the Centers for Disease Control and Prevention, stated in remarks to the Associated Press that wearing of nose-clips to prevent insufflation of contaminated water would be effective protection against contracting PAM, noting that "You'd have to have water going way up in your nose to begin with".

Advice stated in the press release from Taiwan's Centers for Disease Control recommended people prevent fresh water from entering the nostrils and avoid putting their heads down into fresh water or stirring mud in the water with feet. When starting to suffer from fever, headache, nausea, or vomiting subsequent to any kind of exposure to fresh water even if the belief in none of the fresh water has traveled through nostrils, people with such conditions should be carried to hospital quickly and make sure doctors are well-informed about the history of exposure to fresh water.

Lupus is a condition with no known cure. Lupus cerebritis however is treated by suppressing the autoimmune activity.

When it is caused by infections, treatment consists of medication that will primarily cure the infection. For inflammation, steroids can be used to bring down the swelling. If the swelling appears to have increased to a dangerous level, surgery may be needed to relieve pressure on the brain. The formation of an abscess also calls for surgery as it will be necessary to drain the abscess.

Symptoms and the isolation of the virus pathogen the upper respiratory tract is diagnostic. Virus identification is specific immunologic methods and PCR. The presence of the virus can be rapidly confirmed by the detection of the virus antigen. The methods and materials used for identifying the RSV virus has a specificity and sensitivity approaching 85% to 95%. Not all studies confirm this sensitivity. Antigen detection has comparatively lower sensitivity rates that approach 65% to 75%.

There are several methods to diagnose meningeal syphilis. One of the most common ways include visualizing the organisms by immunofluorescence and dark field microscopy. Dark field microscopy initially had the finding that the spirochete has a corkscrew appearance and that it is spirillar and gram (-) bacteria. Another method would also be through the screening test and serology. Serology includes two types of antibody test: Nontreponemal antibody test and Treponemal antibody test (specific test). The Nontreponemal antibody test screens with VDRL (Venereal Disease Research Lab) and RPR (Rapid Plasma Reagin). The Treponemal antibody test (specific test) confirms with FTA-ABS (Fluorescent treponemal antibody-absorption). Brain imaging and MRI scans may be used when diagnosing patients; however, they do not prove to be as effective as specific tests. Specific tests for treponemal antibody are typically more expensive because the earliest anitbodies bind to spirochetes. These tests are usually more specific and remain positive in patients with other treponemal diseases.

In CNS infection cases, "L. monocytogenes" can often be cultured from the blood or from the CSF (Cerebrospinal fluid).

The diagnosis of viral meningitis is made by clinical history, physical exam, and several diagnostic tests. Most importantly, cerebrospinal fluid (CSF) is collected via lumbar puncture (also known as spinal tap). This fluid, which normally surrounds the brain and spinal cord, is then analyzed for signs of infection. CSF findings that suggest a viral cause of meningitis include an elevated white blood cell count (usually 10-100 cells/µL) with a lymphocytic predominance in combination with a normal glucose level. Increasingly, cerebrospinal fluid PCR tests have become especially useful for diagnosing viral meningitis, with an estimated sensitivity of 95-100%. Additionally, samples from the stool, urine, blood and throat can also help to identify viral meningitis.

In certain cases, a CT scan of the head should be done before a lumbar puncture such as in those with poor immune function or those with increased intracranial pressure.

Preventative antifungal treatment is supported by studies, but only for specific high-risk groups in intensive care units with conditions that put them at high risk for the disease. For example, one group would be patients recovering from abdominal surgery that may have gastrointestinal perforations or anastomotic leakage. Antifungal prophylaxis can reduce the incidence of fungemia by approximately 50%, but has not been shown to improve survival. A major challenge limiting the number of patients receiving prophylaxis to only those that can potentially benefit, thereby avoiding the creation of selective pressure that can lead to the emergence of resistance.

Because the risk of meningococcal disease is increased among USA's military recruits, all military recruits routinely receive primary immunization against the disease.

There are five main causes of infections of the central nervous system (CNS): bacterial, viral, fungal, protozoal, and prionic.