Articles on Medical Diseases and Conditions

Tag: Cerebrospinal Fluid Examination

  • Subdural Hematoma

    The classic subdural hematoma develops after trauma, but in one series 20% did not have a history of trauma. In that same series, 60% of patients were alcoholics, 30% of patients had no lateralizing signs, and one third of the patients had multiple hematomas (with 21% having bilateral subdural hematomas and 14% having additional hematomas elsewhere within the brain or brain coverings).

    CSF findings vary depending on whether the hematoma is recent or several days old. In recent subdurals (within 7 days of injury), the CSF is usually blood tinged or xanthochromic, due to concurrent cerebral contusion from the injury or leakage of RBC breakdown products. In late cases the CSF is most often clear. Protein levels are elevated in most of the acute cases, usually in the range of 50-150 mg/100 ml (0.5-1.5 g/L), and in about 50% of the chronic cases. After several weeks the CSF protein level is usually normal. Cell counts may be slightly elevated in acute or subacute cases (usually < 25 WBCs/mm3) and are usually normal in patients seen later.

    The classic CSF triad of elevated protein level, relatively normal cell count, and xanthochromia is present in only about 50% of the subacute and chronic cases, with the percentage decreasing as the time from injury increases. CT or MRI is the best means of demonstrating the lesion. CT is probably better in the first week.

  • Brain Tumor

    In primary cerebral cortex brain tumor, the CSF usually is clear and colorless, although xanthochromia may be present. Spinal fluid pressure is elevated in 70% of patients. Seventy percent show increased protein levels, with about one half of these more than 100 mg/100 ml (1.0 g/L). CSF glucose levels are normal. The majority (70%) of brain tumor patients have normal cell counts. Of the remainder, about two thirds have counts less than 25/mm3 consisting mostly of lymphocytes. In the few patients with high cell counts, there may be appreciable numbers of neutrophils, and the spinal fluid pattern then resembles that of brain abscess. Most metastatic tumors have CSF findings similar to primary neoplasms.

    In occasional instances, metastatic carcinoma may spread widely over the meninges. In such cases, the findings are similar to those of tuberculous meningitis (elevated cell count, lymphocytes predominating; elevated protein concentration, and decreased glucose level). Cell blocks and cytologic smears of spinal fluid sediment are helpful for diagnosis. Cytology of CSF yields malignant cells in 55%-83%. Malignant lymphoma may involve the meninges in 5%-30% of cases, with CSF cytology said to be positive in 60%-80% of these cases. Acute lymphocytic leukemia in childhood is reported to involve the meninges at some time in up to 50% of cases. CSF cytology is not helpful in the majority of metastatic carcinomas to the brain, which most often do not involve the meninges. However, some investigators cytologically detected as many as 20%-40% of cases. In primary tumors of the brain, the meninges are uncommonly involved, so that CSF cytology detects fewer than 10% of cases.

    CT or MRI is the most helpful procedure for demonstrating either primary or metastatic brain tumors. As noted previously, detection rate is reported to be approximately 90%-95% for primary intracerebral tumors. Radionuclide brain scans are useful if CT is not available; sensitivity is 5%-10% less than that of CT, and nonuniformity of technical details makes results more variable between different institutions.

  • Brain Abscess

    Brain abscess is most commonly due to direct extension of infection from infected middle ear, mastoid sinus, or paranasal sinuses; traumatic injuries, or infected prostheses. There can also be more distant spread from the lungs or from infected emboli. There is increased incidence in immunosuppressed patients. The most frequent organisms cultured are various streptococci, Bacteroides, gram-negative organisms, and Staphylococcus aureus. Mixed infections are present in 30%-60% of cases. Apparently the CSF findings in brain abscess are not significantly influenced by the causative organism or the location of the lesion. About 10% of patients are said to have normal CSF test results. The remainder usually have a picture compatible with aseptic meningitis. The spinal fluid is most often clear, and about 70% of patients are said to have increased pressure. Protein levels are normal in nearly 25% of patients, in about 55% the values are between 45 and 100 mg/100 ml (0.45-1.0 g/L), and in the remaining 20% the values are more than 100 mg/100 ml. The CSF glucose level is normal. Cell counts are variable; about 30% are between 5 and 25, about 25% are between 25 and 100, and about 25% are between 100 and 500/cu mm. Lymphocytes generally predominate, but a significant percentage (5%-25%) of polymorphonuclear neutrophils are said to be nearly always present. In occasional cases, an abscess breaks through to the subarachnoid space and results in purulent meningitis. CT or MRI is very helpful in demonstrating intracerebral abscesses. Radionuclide brain scans are useful if CT is not available.

  • Human Immunodeficiency Virus Meningitis

    As noted in Chapter 17, the HIV-1 (AIDS) virus may produce a mild aseptic meningitis lasting 2-3 weeks as the first clinical manifestation of infection. The exact incidence is unknown, but it is probably greater than the 2%-5% estimated in one report. The majority of patients do not manifest this stage but develop more advanced disease at some time in the future. Later in the disease, more than 30%-70% of patients develop symptoms of CNS infection. Some of these cases are due to superimposed infection by other organisms (Toxoplasma, Cryptococcus) rather than HIV alone. HIV infection of the brain is most often manifested by dementia, but more than 15% develop progressive focal leukoencephalopathy. There is relatively little information about CSF findings in this disorder. In one report, 27% had elevated protein levels and 14% had elevated WBC count, with all cell counts being less than 25/mm3 and with 80%-100% of the cells being mononuclear. The brain abnormalities are best shown by CT or MRI.

  • Viral and Aseptic Meningitis

    Viral meningitis is one component of a syndrome known as aseptic meningitis. The aseptic meningitis syndrome is now usually defined as meningitis with normal CSF glucose levels, normal or elevated protein levels, and elevated cell count with a majority of the cells being lymphocytes. A less common definition is nonbacterial meningitis; a definition no longer used is meningitis with a negative bacterial culture. The CSF findings of aseptic meningitis may be caused by a wide variety of agents, including different viruses, mycobacteria, Listeria, syphilis, Leptospira, Toxoplasma, fungi, meningeal carcinomatosis, and meningeal reaction to nearby inflammatory or destructive processes or to some medications in a few patients. However, viral meningitis is the most common and typical of the conditions that produce this syndrome. The commonest virus group associated with meningitis is enterovirus, which includes ECHO (enteric cytopathic human orphan) virus and coxsackievirus and comprises 50%-80% of viral meningitis patients; the second most common (10%-20%) is mumps. Other viruses include herpes simplex, arbovirus group, herpes zoster-varicella, and lymphocytic choriomeningitis. Although not usually listed, human immunodeficiency virus 1 (HIV-1) (or acquired immunodeficiency syndrome [AIDS]) may be, or may become, one of the most frequent etiologies. There are several reasons for describing the aseptic meningitis syndrome and specifically mentioning viral meningitis. First, it is useful to know what etiologies to expect with this pattern of CSF results. Second, this pattern is not specific for viral etiology. Third, a significant number of patients infected by many of these etiologies do not present with textbook aseptic meningitis findings. This is most true for lymphocytes versus neutrophils as the dominating cell in early enterovirus, mumps, and arbovirus infections. Reports estimate that 20%-75% of patients with viral meningitis have neutrophil predominance in the first CSF specimen obtained. For example, one investigator found that about 50% of enteroviral meningitis patients had more than 10% neutrophils on the first CSF specimen, and about 25% had neutrophils predominating; about 66% had normal protein levels; and about 10% had decreased glucose. Most reports indicate that repeat lumbar puncture in 8-12 hours frequently shows change from neutrophil to lymphocyte predominance, with conversion of the remainder taking place in 24-48 hours. In enterovirus, mumps, herpes simplex, and lymphocytic choriomeningitis, initial CSF glucose is sometimes mildly decreased rather than the expected normal value.

    Differential diagnosis of aseptic meningitis syndrome etiologies generally involves differentiating virus etiology from mycobacterial and cryptococcal infection. CSF culture can be done for all the usual virus possibilities, but viral specimens usually must be sent to a reference laboratory, and the results are not available for several days or even longer. It has been recommended that CSF specimens either be processed in less than 24 hours or be frozen at – 70°C to preserve infectivity. Many viruses lose infectivity when frozen at the usual temperature of – 20°C. Serologic tests are also available but require acute and convalescent serum specimens and thus take even longer than culture. As noted there, herpes simplex type 1 has a predilection for involvement of the temporal lobe of the brain. Cryptococcus and mycobacterial tests have been discussed earlier in this chapter. CSF lactate (lactic acid) has been advocated to separate viral from nonviral etiology but, as discussed earlier, is not always helpful and thus is still somewhat controversial.

  • Central Nervous System Infection by Other Fungi

    Candida is said to be the most common fungal infection of the CNS. About one half of the patients with Candida CNS infection have a lymphocytic pleocytosis and about one half show a predominance of neutrophilis. Some reports have indicated a surprisingly high rate of CNS involvement in the systemic mycoses (blastomycosis, 3%-10%; histoplasmosis, up to 50%; coccidioidomycosis, up to 50%). These fungi most often produce a lymphocytic pleocytosis, but neutrophils may predominate. Cerebrospinal fluid glucose levels are typically reduced but may be normal.

  • Cryptococcal Meningitis

    Cryptococcus neoformans is the most common fungus producing CNS infection and is an important, although not numerically frequent, etiology of meningitis. The organism is discussed in detail in Chapter 16. About 70% of cryptococcal meningitis cases are male, and the majority are of middle age. About one-half are associated with malignancy or other severe diseases or with immunodeficiency (either from underlying disease or from therapy). Meningitis due to Cryptococcus is said to produce an elevated cell count in about 95% of cases (range, 90%-97%). The count is usually less than 300/mm3 and in the majority of cases is less than 150/mm3. In one series, the CSF cell count was less than 100/mm3 in about 60% of patients. More than one half of the cells are lymphocytes. Protein levels are elevated in about 90% of cases. The CSF glucose level is decreased in 50%-75% of cases.

    The LA slide test for cryptococcal antigen in CSF is the best rapid diagnostic test. It is reported to detect about 85%-90% of cases (literature range, 71%-100%). There is a slightly increased detection rate if both CSF and serum are tested. Serum testing alone detects about 50% of cases (range, 18%-71%). The LA test is discussed in detail in Chapter 16. The older procedure for detection of Cryptococcus in CSF was a wet mount using india ink or nigrosin. C. neoformans has a thick gelatinous capsule that gives the appearance of a clear zone or halo around the organism against the dark background of india ink particles. However, only about 50% (range, 40%-79%) of cases can be detected by india ink preparations, and some of these may require repeated examinations. In addition, experience is needed to avoid false positive and negative results. India ink has been replaced by the LA test.

    Although LA tests for cryptococcal antigen are reasonably sensitive, culture of CSF is still considered essential. In some cases, culture may reveal organisms when the CSF cell count, protein levels, and glucose levels are all normal. Culture detects about 80% of patients on initial lumbar puncture (range, 72%-90%). Fungi require different culture media for optimum growth than the standard bacterial media, so the laboratory should be notified if fungi are suspected. In some patients, cryptococcal antigen latex studies on CSF have been positive when cultures were negative, and in a few cases, cultures were positive when the LA test result was negative.

  • Mycobacterial Meningitis

    Mycobacterial meningitis is most common in children between the ages of 6 months and 5 years and in the elderly. Chest x-ray film is reported to show hilar adenopathy in 50%-90% of children, but normal chest findings are more common in adults (in one series, about 50% of adults had normal chest x-ray findings). Purified protein derivative skin test result is negative in 5%-50% of patients. Mild to moderate anemia is frequent. The erythrocyte sedimentation rate is elevated in 80% of patients. CSF findings typically show moderate WBC elevation (usually <500/mm3 and almost always <1,000), with the majority being lymphocytes. However, there frequently are a significant number of neutrophils and sometimes, in the early stages, a majority of neutrophils. Protein level is usually mildly or moderately elevated (in one series, 76% had elevated protein levels on admission). Glucose level is decreased in 50%-85% of patients on admission. To have cell count, protein level, and glucose level all three normal on admission is extremely rare, although this happened in 3 of 21 patients in one report. Diagnosis is based on acid-fast smear, culture, exclusion of other etiologies, evidence of tuberculosis elsewhere, and clinical suspicion. Acid-fast smears on CSF are positive in about 20%-40% of cases (range, 3%-91%), and CSF culture is positive in only 37%-90% of cases. When findings are atypical, a nucleic acid probe with polymerase chain reaction (PCR) amplification on CSF can be helpful if it is available.

  • Cerebrospinal Fluid Findings in Selected Brain Diseases: CNS Syphilis

    Syphilis is discussed in Chapter 15. CNS syphilis can be diagnosed clinically but is much more accurately diagnosed through tests on CSF. In two studies, cell counts were normal (<5 cells) in 19%-62%, between 5 and 10 cells in 24%-69%, and more than 10 cells in 12%-14%. The majority of the cells were mononuclear in 60%-80% of the cases and polymorphonuclear in 20%-40% of the cases. CSF protein was normal in 14%-61% of patients, between 45 and 100 mg/dl in 34%-61%, and more than 100 mg/dl in 5%-25%. The Veneral Disease Research Laboratory (VDRL) test on CSF specimens was reactive in about 55% of the patients (literature range, 10%-70%). A serum VDRL test was reactive in 49%-86% of the patients. It was noted that before penicillin was discovered, CSF studies recorded much higher incidence and degree of abnormalities.

    CNS syphilis usually requires serologic tests for diagnosis. The standard serologic tests for syphilis such as the VDRL usually, but not always, give positive results on peripheral blood specimens when they are positive on CSF. A lack of relationship is most often found in the tertiary stage, when the peripheral blood VDRL test result may revert to normal. Conversely, the CSF response is very often negative when the peripheral blood VDRL result is positive. CNS syphilis usually is a tertiary form with symptoms appearing only after years of infection, and in many patients with syphilis the CNS is not clinically involved at all. Despite lack of clinical CNS symptoms, actual CNS involvement apparently is fairly common (in at least 30%-40% of syphilis cases), beginning in the primary and secondary stage; although specific syphilitic syndromes, if they develop, are not seen until the tertiary stage years later. There is some evidence that concurrent infection by the HIV-1 virus may increase the risk of active CNS syphilis. The best criteria of CNS disease activity are elevated CSF cell count and protein levels (however, CSF WBCs are reported to be elevated in 38%-81% of cases and CSF protein elevated in 39%-86%). A reactive CSF VDRL result indicates disease that has been present for a certain length of time, without necessarily being currently active. The CSF VDRL usually is normal in patients with biologic false positive (BFP) serologic test for syphilis (STS) reactions. After adequate treatment CSF pleocytosis usually disappears within 3 months (range, 1.5-6 months). CSF protein elevation, however, may persist as long as several years.

    The three most important forms of CNS clues are general paresis, tabes dorsalis, and vascular neurosyphilis. In general paresis, the CSF serology almost always is normal in untreated patients. In tabes dorsalis, the CSF serology is said to be abnormal in most early untreated patients, but may be normal in up to 50% of late or “burnt-out” cases. In vascular neurosyphilis, approximately 50% of results are abnormal.

    The FTA-ABS is nearly always reactive in peripheral blood when CSF shows some laboratory abnormality suggestive of neurosyphilis. The FTA-ABS has been shown to be more frequently reactive than the VDRL when testing the CSF of patients with syphilis. Several studies reported 100% of patients with the diagnosis of CNS syphilis had a reactive CSF FTA-ABS response. However, a substantial number of patients who were asymptomatic and had normal CSF cell counts and protein also had a reactive CSF FTA-ABS response. Therefore, the U.S. Centers for Disease Control (CDC) and an important segment of other investigators currently believe that a reactive CSF FTA-ABS response does not necessarily represent active CNS syphilis and that the clinical importance of a reactive FTA-ABS test on spinal fluid is uncertain when the cell count, protein, and spinal fluid VDRL results are normal. There is also the problem of spinal fluid contamination by blood, which could produce false positive results if the contaminating blood contained serum antibodies.

    Based on current CDC recommendations, the FTA-ABS test is usually not done on CSF, since there is no problem of BFP reactions in the spinal fluid VDRL (unless the CSF is contaminated with blood), and the peripheral blood FTA-ABS test is reactive in almost all cases of CNS syphilis. Unfortunately, there is currently no gold standard to determine which patients actually have CNS syphilis and therefore how accurate the various CNS laboratory tests really are.

    Up to 75% of patients with active CNS syphilis may demonstrate oligoclonal bands on CSF electrophoresis (similar to those seen in multiple sclerosis).

  • Cerebrospinal Fluid Examination and Neurologic Disorders

    Pressure

    Reference values for cerebrospinal fluid (CSF) pressure are 100-200 mm H2O. Elevations are due to increased intracranial pressure. The two most common causes of elevated CSF pressure are meningitis and subarachnoid hemorrhage. Brain tumor and brain abscess will cause increased intracranial pressure in most cases but only after a variable period of days or even weeks. An increase is present in many cases of lead encephalopathy. The CSF pressure varies directly with venous pressure but has no constant relationship to arterial pressure. The Queckenstedt sign makes clinical use of this information; increased venous pressure via jugular vein compression increases CSF pressure at the lumbar region, whereas a subarachnoid obstruction above the lumbar area prevents this effect.

    Appearance

    Normal CSF is clear and colorless. It may be pink or red if many red blood cells (RBCs) are present or white and cloudy if there are many white blood cells (WBCs) or an especially high protein content. Usually there must be more than 400 WBCs/mm3 (0.4 Ч 109/L) before the CSF becomes cloudy. When blood has been present in the CSF for more than 4 hours (literature range, 2-48 hours), xanthochromia (yellow color) may occur due to hemoglobin pigment from lysed RBCs. Protein levels of more than 150 mg/100 ml (1.5g/L) may produce a faint yellowish color that can simulate xanthochromia of RBC origin. Severe jaundice may also produce coloration that simulates xanthochromia.

    Glucose

    Reference values are 45 mg/100 ml (2.5 mmol/L) or higher (“true glucose” methods). Values of 40-45 mg/100 ml are equivocal, although in normal persons it is rare to find values below 45 mg/100 ml. The CSF glucose level is about 60% of the serum glucose value (literature range, 50%-80%). In newborns, the usual CSF level is about 80% of the serum glucose level. It takes between 0.5 and 2 hours for maximum change to occur in CSF values after a change in serum values.

    The most important change in the CSF glucose level is a decrease. The classic etiologies for CSF glucose decrease are meningitis from standard bacteria, tuberculosis, and fungi. Occasionally in very early infection the initial CSF glucose value may be normal, although later it begins to decrease. A frequent impression from textbooks is that one should expect a decreased CSF glucose value in nearly all patients with acute bacterial meningitis. Actually, studies have shown that only 60%-80% of children with acute bacterial meningitis have CSF glucose levels below the reference range. Studies on patients of various ages have shown decreased glucose levels in 50%-90% of cases. A major problem is the effect of blood glucose levels on CSF glucose levels. Since elevated blood glucose levels may mask a decrease in CSF values, it is helpful to determine the blood glucose level at the same time that the CSF specimen is obtained, especially in diabetics or if intravenous (IV) glucose therapy is being given. On the other hand, a low CSF glucose level may be due to peripheral blood hypoglycemia, especially if the CSF cell count is normal. Other conditions that may produce a decrease in CSF glucose level are extensive involvement of meninges by metastatic carcinoma and in some cases of subarachnoid hemorrhage, probably due to release of glycolytic enzymes from the RBCs. In leptospiral meningitis and in primary amebic meningoencephalitis, the CSF glucose level is decreased in some patients but not in others. In most other central nervous system (CNS) diseases, including viral meningitis, encephalitis, brain abscess, syphilis, and brain tumor, CSF glucose levels typically are normal when bacterial infection of the meninges is not present. However, decreased levels are sometimes found in aseptic meningitis or in meningoencephalitis due to mumps, enteroviruses, lymphocytic choriomeningitis, and in both herpes simplex virus types 1 and 2 CNS infections. For example, one investigator reports that 10% of cases of meningitis due to enterovirus had decreased CSF glucose. The box summarizes glucose level patterns.

    Protein

    The normal protein concentration of CSF is usually considered to be 15-45 mg/100 ml (0.15-0.45 g/L) (literature range, 9-90 mg/100 ml; 0.09-0.9 g/L). There is considerable discrepancy in the literature regarding the upper reference limit, which is most often listed as 40, 45, and 50 mg/100 ml (international system of units [SI] 0.4, 0.45, 0.5 g/L). Newborn values are different and even more uncertain. From birth to day 30, the range is 75-150 mg/100 ml (0.75-1.50 g/L), with the literature range being 20-200 mg/100 ml and the upper limit varying from 140-200 mg/100 ml. For days 30-90, the reference range is 20-100 mg/100 ml (0.2-1.0 g/L). From day 90 to 6 months of age, the reference range is 15-50 mg/100 ml (0.15-0.50 g/L). Values slowly decline, reaching adult levels by 6 months of age. Over age 60 years, some persons increase the upper reference limit to 60 mg/100 ml (0.6 g/L). As a general but not invariable rule, an increased protein concentration is roughly proportional to the degree of leukocytosis in the CSF. The protein concentration is also increased by the presence of blood. There are, however, certain diseases in which a mild to moderate protein concentration increase may be seen with relatively slight leukocytosis; these include cerebral trauma, brain or spinal cord tumor, brain abscess, cerebral infarct or hemorrhage (CVA), CNS sarcoidosis, systemic lupus, lead encephalopathy, uremia, myxedema, multiple sclerosis (MS), variable numbers of hereditary neuropathy cases, and chronic CNS infections. Diabetics with peripheral neuropathy frequently have elevated CSF protein levels without known cause. Blood in the CSF introduces approximately 1 mg of protein/1,000 RBCs. However, when the RBCs begin to lyse, the protein level may appear disproportionate to the number of RBCs. In acute bacterial meningitis, the CSF protein is elevated in about 94% of cases (literature range, 74%-99%).

    A marked protein elevation without a corresponding CSF cell increase is known as “albuminocytologic dissociation.” This has usually been associated with the Guillain-Barrй syndrome (acute idiopathic polyneuritis) or with temporal (giant cell) arteritis. Actually, about 20% of patients with the Guillain-Barrй syndrome have normal CSF protein levels, and less than 25% have CSF protein levels of 200 mg/100 ml (2.0 g/L) or more.

    Protein may be measured in the laboratory quantitatively by any of several methods. A popular semiquantitative bedside method is Pandy’s test, in which CSF is added to a few drops of saturated phenol agent. This agent reacts with all protein, but apparently much more with globulin. Chronic infections or similar conditions such as (tertiary) syphilis or MS tend to accentuate globulin elevation and thus may give positive Pandy test results even though the total CSF protein level may not be greatly increased. Contamination by blood will often give false positive test results.

    The technical method used can influence results. The three most common methods are sulfosalicylic acid, anazolene sodium (Coomassie Blue dye), and trichloracetic acid. Sulfosalicylic acid and Coomassie Blue are more influenced by the ratio of albumin to globulin than is trichloracetic acid.

    In some CNS diseases there is a disproportionate increase in gamma-globulin levels compared with albumin or total protein levels. Several investigators have noted that increased CSF gamma-globulin levels occur in approximately 70%-85% (literature range, 50%-88%) of patients with MS, whereas total protein levels are elevated in only about 25% of the patients (range, 13%-34%). Various other acute and chronic diseases of the brain may elevate CSF gamma-globulin levels, and this fraction may also be affected by serum hyperglobulinemia. The latter artifact may be excluded by comparing gamma-globulin quantity in serum and CSF.

    The colloidal gold test also depends on changes in CSF globulins and at one time was considered very helpful in the diagnosis of MS and syphilitic tabes dorsalis. However, the colloidal gold procedure has very poor sensitivity (only 25% of MS patients display the classic first zone pattern) and poor specificity and is considered obsolete. When measurement of CSF protein fractions is ordered, the current standard procedure is some method of immunoglobulin quantitation.

    Cell count

    Normally, CSF contains up to five cells/mm3, almost all of which are lymphocytes. In newborns, the reference limits are 0-30 cells/cu mm, with the majority being segmented neutrophils. Also, one study reported at least one segmented neutrophil in 32 percent of patients without CNS disease when centrifuged CSF sediment was examined microscopically. There was correlation with elevated peripheral blood WBC count and presence of some RBCs in the sediment, presumably from minimal blood contamination of the lumbar puncture specimen not grossly evident. As a general rule, any conditions that affect the meninges will cause CSF leukocytosis; the degree of leukocytosis will depend on the type of irritation, its duration, and its intensity. Usually, the highest WBC counts are found in severe acute meningeal infections. The classic variety is the acute bacterial infection. It is important to remember that in a few cases if the patient is seen very early, leukocytosis may be minimal or even absent, just as the CSF glucose level may be normal. Although most investigators state or imply that 100% of patients with acute bacterial infection have elevated cell counts on initial lumbar puncture, in one study, 3% of patients had a WBC count less than 6 WBCs/mm3, and there have been several reports of other isolated cases. Usually, in a few hours a repeat lumbar puncture reveals steadily increasing WBC counts. Therefore, normal initial counts are not frequent but may occur and can be very misleading. Another general rule is that in bacterial infections, polymorphonuclear neutrophils usually are the predominating cell type; whereas in viral infections, chronic nervous system diseases, and tertiary syphilis, lymphocytes or mononuclears ordinarily predominate. However, there are important exceptions. One study reported that about one third of patients with usual bacterial pathogens but with CSF WBC counts less than 1,000/mm3 (1.0 x 109/L) had a predominance of lymphocytes on initial lumbar puncture (the only patient with a WBC count over 1,000 who had lymphocytosis had a Listeria infection). Another exception is tuberculous meningitis, which is both a bacterial and a chronic type of infection. In this case, the cells are predominantly lymphocytes (although frequently combined with some increase in neutrophils). A third exception is unusual nonviral organisms, such as Listeria monocytogenes (most often seen in neonates or in elderly persons or those who are immunocompromised), fungus, and spirochetes (leptospirosis and syphilis). Listeria meningitis may have lymphocytic predominance in some cases and neutrophilic predominance in others. Similarly, in active CNS syphilis the few studies available indicate that if the WBC count is elevated, lymphocytes predominate in 60%-80% of cases. On the other hand, coxsackievirus and echovirus infections may have a predominance of neutrophils in the early stages; in most of these patients, the CSF subsequently shifts to lymphocytosis. Uremia is said to produce a mild lymphocytosis in about 25% of patients. Partial treatment of bacterial meningitis may cause a shift in cell type toward lymphocytosis.

    After therapy is started, WBC values usually decrease. However, in some cases more than 50 WBCs/mm3 may persist at least 48 hours and sometimes longer than 2 weeks following adequate therapy. This tends to be more common with Haemophilus influenzae infection but may also occur with pneumococcal infection. Fungal infections are more commonly associated with persistently elevated neutrophils than bacterial infections, even though fungi typically have CSF lymphocytosis rather than neutrophilia. Nocardia meningitis or brain abscess, however, is one bacterial infection that does tend to show persistent neutrophilia more often than other bacteria.

    In cases of subarachnoid hemorrhage or traumatic spinal fluid taps, approximately 1 WBC is added to every 700 RBCs (literature range, 1 WBC/500-1,000 RBCs). This disagreement in values makes formulas unreliable that attempt to differentiate traumatic tap artifact from true WBC increase. Also, the presence of subarachnoid blood itself may sometimes cause meningeal irritation, producing a mild to moderate increase in polymorphonuclear leukocytes after several hours that occasionally may be greater than 500 WBCs/ mm3. Occasionally a similar phenomenon occurs in patients with intracerebral hematoma. Another exception is the so-called aseptic meningeal reaction that is secondary either to a nearby infection or sometimes to acute localized brain destruction. In these cases, which are not common, there may be a wide range of WBC values, with neutrophils often predominating. When this occurs, however, the CSF glucose level should be normal, since the meninges are not directly infected. Aseptic meningitis is not the same as aseptic meningeal reaction. Aseptic meningitis is due to direct involvement of the meninges by nonbacterial organisms. Viruses cause most cases, but organisms such as amebae sometimes may cause meningitis. Bacterial CSF cultures are negative. The CSF glucose level is usually normal. Protein concentration is usually but not always increased. The WBC count is elevated to a varying degree; the predominant type of cell depends on the etiology. True aseptic meningitis also has to be differentiated from bacterial organisms that do not grow on ordinary culture media (anaerobes, leptospira, mycobacteria, bacteria inhibited by previous or current antibiotic therapy, etc.).

    Neonatal CSF reference range differences from childhood and adult values

    Neonates have higher CSF reference ranges for protein, glucose, and cell count than adults have. Protein was discussed earlier. Cell counts 1-7 days after birth average about 5-20/mm3 (range, 0-32 mm3), with about 60% being segmented neutrophils. Glucose is about 75%-80% of the blood glucose level.

    Culture

    The diagnosis of acute bacterial meningitis often depends on the isolation of the organisms in the spinal fluid. In children, there is some regularity of the types of infection most commonly found. In infants under the age of 1-2 months, group B streptococci are most frequent, closely followed by Escherichia coli. Listeria monocytogenes is often listed as third, followed by other enteric gram-negative bacteria. In children from age 3 months to 5 or 6 years, H. influenzae is the most common organism; Meningococcus is second, and Pneumococcus is third. In older children and adolescents, Meningococcus is first and Pneumococcus is second. In adults, Meningococcus and Pneumococcus are still dominant, but Pneumococcus is more prevalent in some reports. Staphylococci are the etiology in about 4%-7% of cases, most often associated with CNS operations (e.g., shunt procedures), septicemia, or endocarditis. In old age, pneumococci generally are more common pathogens than meningococci, with gram-negative bacilli in third place. However, there can be infection by nearly any type of organism, including Listeria and fungi. Also, in patients who are debilitated or have underlying serious diseases such as leukemia or carcinoma, Listeria and fungi are not uncommon. In many cases, a centrifuged spinal fluid sediment can be smeared and Gram stained so that the organisms can be seen. A (bacterial) culture should be done in all cases where bacterial meningitis is suspected or is even remotely possible. Special provision should be made for spinal fluid to reach the laboratory as quickly as possible; and if any particular organism is suspected, the laboratory should be informed so that special media can be used if necessary. For example, meningococci grow best in a high carbon dioxide atmosphere, and H. influenzae should be planted on media provided with a Staphylococcus streak. Culture is said to detect about 85% (range, 54%-100%) of cases. In one series there was thought to be about 5% false positive culture results due to contamination. Previous or concurrent antibiotic therapy is reported to decrease culture detection rates by about 30% and Gram stain detection rates by about 20%.

    Patterns of Cerebrospinal Fluid Abnormality: Cell Type and Glucose Level

    POLYMORPHONUCLEAR: LOW GLUCOSE
    Acute bacterial meningitis

    POLYMORPHONUCLEAR: LOW OR NORMAL GLUCOSE
    Some cases of early phase acute bacterial meningitis
    Primary amebic (Naegleria species) meningoencephalitis
    Early phase Leptospira meningitis

    POLYMORPHONUCLEAR: NORMAL GLUCOSE
    Brain abscess
    Early phase coxsackievirus and echovirus meningitis
    CNS syphilis (some patients)
    Acute bacterial meningitis with IV glucose therapy
    Listeria (about 20% of cases)

    LYMPHOCYTIC: LOW GLUCOSE
    Tuberculosis meningitis
    Cryptococcal (Torula) meningitis
    Mumps meningoencephalitis (some cases)
    Meningeal carcinomatosis (some cases)
    Meningeal sarcoidosis (some cases)
    Listeria (about 15% of cases)

    LYMPHOCYTIC: NORMAL GLUCOSE
    Viral meningitis
    Viral encephalitis
    Postinfectious encephalitis
    Lead encephalopathy
    CNS syphilis (majority of patients)
    Brain tumor (occasionally)
    Leptospira meningitis (after the early phase)
    Listeria (about 15% of cases)

    Gram stain

    Gram stain of the sediment from a centrifuged CSF specimen should be performed in all cases of suspected meningitis. Gram stain yields about 70% positive results (literature range, 50%-90%) in culture-proved acute bacterial meningitis cases. There is some controversy over whether Gram staining need be done if the CSF cell count is normal. In the great majority of such cases bacteriologic findings are normal. However, occasional cases have been reported of bacterial meningitis without an elevated cell count, most commonly in debilitated or immunosuppressed patients. It may also occur very early in the initial stages of the disease. Gram stain yields unquestioned benefits in terms of early diagnosis and assistance in choice of therapy. However, a negative Gram stain result does not rule out acute bacterial meningitis, and some false positive results occur. The majority of false positive results are due to misinterpretation of precipitated stain or debris on the slide. In some cases the presence of bacteria is correctly reported, but the type of organism may be incorrectly identified due to overdecolorization of the organisms or insufficient familiarity with morphologic variations of bacteria.

    Latex agglutination tests for bacterial antigens

    Recently, rapid slide latex agglutination (LA) tests have become available for detection of pneumococcal, meningococcal, H. influenzae type B, and streptococcal group B bacterial antigen in CSF or in (concentrated) urine. Until the 1980s, CSF bacterial antigen detection was done by counterimmunoelectrophoresis (CIE). This method had an overall sensitivity of about 60%-70% (range, 32%-94%). The LA kits are considerably faster, easier, and have increased detection rates (about 85%-90%; range, 60%-100%). There is some variation in overall sensitivity between different manufacturers’ kits. This is especially true for antibodies against meningococci. The major reason is that several different strains of meningococci may produce infection, and it is necessary to have an antibody against each one that it is desired to detect. The most common strains are type B (about 47% of cases; range 28%-50%), type C (about 30%; range, 23%-63%), type Y (about 10%), type W135 (about 10%) and type A (about 3%). Some kits do not include antibodies against all of these strains. Besides not reaching 100% sensitivity, the LA kits are relatively expensive per patient (in part due to the multiple tests included in each kit to detect the different organisms). Besides LA, there is a commercially available kit based on a coagglutination method. This kit has an overall sensitivity about intermediate between CIE and LA, with similar results to LA for H. influenzae, and less sensitivity for pneumococci and meningococci.

    Cerebrospinal fluid lactate

    A number of published reports have evaluated CSF lactic acid assay in various diseases. In general, patients with acute bacterial, tuberculous, and fungal meningitis have elevated CSF lactate values, whereas normal persons and those with viral (“aseptic”) meningitis do not. Sensitivity of the test for acute bacterial meningitis is about 93%-95% (range, 66%-100%). Most reports indicate clear-cut separation between bacterial and viral infection values (in the sense that the values in viral meningitis are not elevated), but several investigators found that some patients with viral meningitis have elevated CSF lactate levels (about 20% of cases in these reports). However, in all instances of viral meningitis the elevation was less than twice the reference range upper limits. One advantage of CSF lactate is that it may remain elevated 2-3 days after the start of antibiotic therapy. However, values in some cases of treated or partially treated bacterial infection do return to normal relatively early.

    Xanthochromia has been reported to nonspecifically increase CSF lactate levels, although one report states that blood itself does not. CNS tissue destruction from various causes (including brain tumor, head trauma, CVAs, and intracerebral hemorrhage, cerebral hypoxia, and seizures), may also produce elevated CSF lactate levels.

    Because CSF lactate is not specific for bacterial infection, because it is not elevated in all cases of bacterial meningitis, and because there is some uncertainty as to whether lactate elevation excludes the possibility of viral meningitis, the true usefulness of the test is not clear. The availability of LA slide tests further complicates the picture. However, CSF lactate assay could be useful in patients with symptoms of meningitis if CSF Gram stain results are negative and LA test results (if available) are also negative. Such patients could have tuberculous or fungal meningitis, partially treated bacterial meningitis, or meningitis due to other organisms. Increased CSF lactic acid levels, especially if more than twice the upper reference limit, could suggest that further investigation is essential. A normal lactate level is not reliable in excluding bacterial meningitis.

    Reference range for CSF lactate is usually based on specimens from children or adults. One investigator found that neonates 0-2 days old had mean values nearly 60% higher than those obtained after 10 days of life, whereas neonates aged 2-10 days had about 25% higher levels than after age 10 days.

    Computerized tomography, magnetic resonance imaging, and radionuclide brain scanning

    Computerized tomography (CT) and magnetic resonance imaging (MRI) are now important aids in screening for abnormality in the CNS. Both can visualize the ventricular system as well as detect mass lesions both within CNS tissue and outside. In addition, the nature of the lesion can frequently be deduced from density characteristics. Both CT and MRI technology have been changing rapidly, and assessment of their capabilities relates to data currently available. Detection of brain tumors is to some extent influenced by location and type of tumor as well as by technical factors such as use of IV contrast media. Reports indicate CT abnormality in approximately 90%-95% of patients with mass lesions or areas of tissue destruction. Statistics from CT and MRI are not always comparable to radionuclide brain scans, since data from the scans vary according to the number of head positions employed, the isotope preparation used, the time between administration of isotope and scanning, and whether a blood flow study was included. In general, CT is about 10%-15% more sensitive than brain scan in cerebral tumor or about 5%-10% more sensitive when brain scanning is performed with optimal technique. It is somewhat more reliable than brain scanning in detecting posterior fossa lesions. MRI is about 5% more sensitive than CT. In chronic subdural hematoma, detection with CT is about equal to that achieved when brain scanning is combined with cerebral blood flow study. In acute subdural or epidural hematoma, CT is significantly better than radionuclide brain scanning. An important advantage over radionuclide techniques in either acute or chronic subdural hematoma is that CT can frequently permit a more exact diagnosis, whereas abnormalities found by radionuclide techniques are often not specific. MRI is reported to be equal to or slightly better than CT. In cerebral infarct, all three techniques are affected by the time interval after onset. During the first week, CT is somewhat more sensitive than MRI or radionuclide scanning without blood flow study but still detects only 50%-60% of infarcts. The sensitivity of all techniques increases to the 80% range by 3-4 weeks. Intracerebral hematoma is much better seen on CT than brain scan regardless of the time interval and better than MRI in the early stages. None of the three techniques is perfect. In most of the various focal lesion categories, a certain percentage are detected by one technique but not the other, although CT and MRI are generally superior to radionuclide scans. When Hakim’s syndrome (normal pressure hydrocephalus) is a possibility, CT or MRI can rule out the disorder by displaying normal ventricular size. If ventricular dilation is seen, cerebral atrophy may be inferred in some cases, but in many the differentiation between atrophy and normal pressure hydrocephalus cannot be made with adequate certainty.

    Overall advantages of CT over standard radionuclide procedures are ability to visualize the ventricular system, a relatively small but definite increase in detection rate for brain tumors, more specificity in the appearance of many lesions, and better delineation of CNS anatomy. Advantages over MRI are lower cost, better results in early CVA or early hemorrhage, and ability to detect calcifications and show details of bone (which is seen poorly on MRI). Advantages of radionuclide procedures are elimination of the need for x-ray contrast media (which many CT patients must receive), lower cost for equipment and lower charge to the patient, and ability to inspect major blood vessels via blood flow studies. Advantages of MRI are absence of any radiation, slightly and sometimes significantly better detection rate of many lesions compared to CT, better tissue detail, much better visualization of the spinal cord, and in some cases ability to suggest a more exact diagnosis. The major disadvantages are considerably higher cost, slower imaging time, and in some cases, problems with patients who have cardiac pacemakers or internal metal objects.