Interpretation of Diagnostic Tests
8th Edition

9
Central and Peripheral Nervous System Disorders
Laboratory Tests for Disorders of the Nervous System
Normal CSF Values
Measurement of these components should always be performed on simultaneously drawn blood samples.
Appearance Clear, colorless: no clot
Total cell count  
   Adults, children 0–6/μL (all mononuclear cells)
   Infants <19/μL
   Neonates <30/μL
Glucose  
   Lumbar fluid 45–80 mg/dL (20 mg/dL < blood level)
   Ventricular fluid 5–10 mg/dL > lumbar fluid
Total protein  
   Cisternal 15–25 mg/dL
   Ventricular 5–15 mg/dL
   Lumbar  
   Neonates ≤150 mg/dL
   2–3 weeks 20–80 mg/dL
   3 months–60 years 15–45 mg/dL
   >60 years 15–60 mg/dL
Protein electrophoresis  
   Transthyretin (Prealbumin) 2%–7%
   Albumin 56%–76%
   Alpha-1 globulin 2%–7%
   Alpha-2 globulin 4%–12%
   Beta globulin 8%–18%
   Gamma globulin 3%–12%
IgG <4.0 mg/dL
  <10% of total CSF protein
Albumin index (ratio) <9.0
IgG synthesis rate 0.0–8.0 mg/day
IgG index (ratio) 0.28–0.66
CSF IgG–albumin ratio 0.09–0.25
Oligoclonal bands Negative
Myelin basic protein 0.0–4.0 ng/mL
Chloride 120–130 mEq/L (20 mEq/L > serum values)
Sodium 142–150 mEq/L
Potassium 2.2–3.3 mEq/L
Carbon dioxide 25 mEq/L
pH 7.35–7.40
Transaminase (AST) 7–49 units
Lactate dehydrogenase (LD) ∼10% of serum level
   LD-1 38%–58% (LD-1 > LD-2)
   LD-2 26%–36%
   LD-3 12%–24%
   LD-4 1%–7%
   LD-5 0%–5%
Creatine kinase (CK) 0–5 IU/L
Bilirubin 0
Urea nitrogen 5–25 mg/dL
Amino acids 30% of blood level
Xanthochromia 0
Total volume  
   Adults 90–150 mL
   Neonates 10–60 mL
Generation rate 0.35 mL/min = 500 mL/d
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Conditions in which Normal CSF Is Found
Found In
Korsakoff syndrome
Wernicke encephalopathy
Jakob-Creutzfeldt disease
Tuberous sclerosis (protein is rarely increased)
Idiopathic epilepsy (if protein is increased, rule out neoplasms; if cell count is increased, rule out neoplasm or inflammation)
Narcolepsy, cataplexy, etc.
Parkinson disease
Hereditary cerebellar degenerations
Migraine
Ménière syndrome
Psychiatric conditions (e.g., neurocirculatory asthenia, hysteria, depression, anxiety, schizophrenia) (Rule out psychiatric condition as a manifestation of primary disease, e.g., drugs, porphyria, primary endocrine diseases.)
Transient cerebral ischemia
Amyotrophic lateral sclerosis
Muscular dystrophy
Progressive muscular atrophy
Syringomyelia
Deficiency diseases (e.g., Vitamin B12 deficiency with subacute combined degeneration of spinal cord, pellagra, beriberi)
Subacute myelo-opticoneuropathy (SMON)
Minimal brain dysfunction of childhood
Cerebral palsies
Febrile convulsions of childhood
See Chapter 12 for metabolic and hereditary diseases that affect the nervous system (e.g., gangliosidosis, mucopolysaccharidoses, glycogen storage disease).
Utility of Lumbar Puncture for Various Conditions
  High Specificity Moderate Specificity
High Sensitivity Bacterial, TB, fungal meningitis Viral meningitis, subarachnoid hemorrhage, MS, CNS syphilis, infectious polyneuritis, paraspinal abscess
Moderate Meningeal tumor Viral encephalitis, intracranial hemorrhage, Sensitivity subdural hematoma
Abnormal Cerebrospinal Fluid (CSF)
Gross Appearance
Viscous CSF may occur with metastatic mucinous adenocarcinoma (e.g., colon), large numbers of cryptococci, severe meningeal infection or, rarely, injury to annulus fibrosus with release of nucleus pulposus fluid.
Turbidity may be due to increased WBC (>200/μL), RBC (>400/μL), presence of bacteria (>105/mL), or of other microorganisms (fungi, amebae), contrast media, epidural fat aspirated during lumbar puncture.
Clots or pellicles indicates protein >150 mg/dL.
Protein >100 mg/dL usually causes CSF to look faintly yellow.
CSF with RBC >6,000/μL appears grossly bloody; with RBC = 500 to 6,000/μL appears cloudy, xanthochromic, or pink tinged (in bright light in clear glass tubes containing >1 mL of CSF). RBC count that decreases between first and last tube indicates traumatic tap (occurs in ≤20% of cases). HSV infection should be considered if CSF RBC >500/μL.
Xanthochromia caused by breakdown of Hb-producing bilirubin, oxyHB, metHb; may be due to:
  • Bleeding within 2 to 36 hours. Is detected visually or by spectrophotometer.
  • Can often be detected in <6 hours.
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    Table 9-1. Cerebrospinal Fluid (CSF) Findings in Various Conditions
      Appearance Protein (mg/dL) Glucose (mg/dL) WBC/μL Microbiology/Serology/Other
    Normal
      Ventricular C, colorless no clot 5–15   0–10; ≤32 in term neonates; <10 at 1 month  
      Cisternal 10–25 45–80  
      Lumbar 10–45    
    TB meningitis O, sl yellow, delicate clot 45–500; usually 100–200 <45 in 75% of cases; N in ≤20% Usually 25–100; rarely >500; chiefly L Acid fast stain: 25% sensitive
    Culture: 75% sensitive
    PCR: 100% specific
    Tuberculoma   I N Small number of cells  
    Acute pyogenic meningitis O to Pu, sl yellow; delicate clot; if bloody, rule out anthrax 50–1,500; usually 100–500 Usually 0–45 Usually 1,000–5,000, chiefly P; range 100–10,000 Gram stain 60%–90% sensitive
    Culture: S/S = 80%/100%
    Direct antigen/PCR: S/S = 50%–90%/100%
    Aseptic meningitisa C, T, or X 20 to >200 N ≤500, occ 2,000; first PMNs; later mononuclear cells Identification techniques (e.g., bacterial cultures, PCR) negative
    Viral meningitis Usually clear N or I N 10–1,000; mostly L PCR Specific IgM antigens
    Culture: 40%–70% sensitive
    Seroconversion
    AIDS N 50–100 N ≤300 Culture: 40%–70% sensitive
    HIV antibodies, antigens
    Acute anterior polio C or sl O, may be sl yellow, may be delicate clot 20–350 N 10 to >500, P first, then L Serologic tests
    Stool culture
    AST in CSF is always I
    Mumps N or O 20–125 N 0 to >2,000 IgM and IgG in blood and CSF
    Culture of CSF
    Measles N or O sl I N ≤500 Blood serology
    Herpes zoster N 20–110 N ≤300 in 40% of patients PCR
    Equine, St. Louis encephalitis, choriomeningitis N or sl T 20 to >200 N 10–200; occ to 3,000 Blood serologic tests
    Herpes simplex   I N 10–1,000, chiefly L; RBCs are usually present PCR of CSF has S/S = 98%/>94%; replaces brain biopsy
    CSF culture in congenital infection
    CSF serologic tests
    Rabies   N or sl I N N or ≤100 mononuclear cells Culture, antigen detection, PCR of saliva, CSF, tears, brain, or animal brain Tissue exam
    West Nile meningoen-cephalitis N   N ≤525; mean 40 IgM in serum and CSF PCR of CSF (sens. = 57%) and serum (sens. = 15%) Brain autopsy antigen detected in all
    Postinfectious N 15–75 N 5–200, rarely ≤1,000 Serologic tests for specific viruses
    Rickettsia
    Rocky Mountain spotted fever N Often N N I in 20–50% DFA of skin biopsy
    Serology: paired serum for IgM and IgG
    PCR
    Fungal
    Coccidioido–mycosis   I N early; then D ≤200 early; may be higher later; I eosinophils Culture 50% sensitive CF in
      CSF = 75%–90% sensitive
      Wet prep in 20%
      KOH
      Antigen assay
    Cryptococcal meningitis N ≤500 in 90%; average = 100 D in 55%; average = 30 ≤800; average = 50 (L > P) India ink ≤50% sensitive
    Cryptococcal antigen assay ∼90% sensitive
    Culture ∼90% sensitive
    Histoplasmosis         See Chapter 15
    Toxoplasmosis X ≤2,000 N 50–500; chiefly monocytes Serologic tests in serum
    PCR
    Organism identified in sediment smear
    Syphilis         Positive serologic test in blood
    CSF VDRL and PCR for treponemal DNA have high S/S = 40%–60%
      Tabes dorsalis N 25–100; IgG less marked than in general paresis N 10–80 Early: VDRL titer may be low
    Late: ∼25% of patients may have normal CSF and negative VDRL in blood and CSF
      General paresisb N ≤100; marked I in gamma globulin N ≤175, mononuclear VDRL titer usually high
      Meningovascular syphilis N ≤260 in 66%; IgG in 75% of cases N 10–100; N in 60%  
      Syphilitic meningitis       ≤2,000 L  
      Asymptomatic CNS lues   I protein and cell count are index of activity     Serologic test may be negative in blood but positive in CSF
    Leptospirosis   I ≤80 N ≤500 monos  
    Lyme disease   I IgG and oligoclonal bands   450 L; usually ∼100 B. burgdorferi antibodies in CSF > serum PCR for DNA
    Primary amebic Naegleria, Acanthamoeba) meningitis Sanguino–Pu, may be T or Pu I Usually D 400–21,000; mostly P; also RBC Amoebas seen on Wright stain of CSF
    Culture
    Cysticercosis (Taenia soleum)   Usually 50–200 D in 20% of cases I P and L ≤7% eosinophils in 50% of cases  
    Chronic meningitis.c   Moderate to marked I D 100–400, mostly L  
    Symptoms for 1–4 weeks  
    Cavernous sinus throm-bophlebitis Usually N; may be B Usually N or I Usually N Usually N or I N unless meningitis or empyema
    Brain abscessd   May be ≤75–300 N 25–300; PMN, L, RBCs CSF cultures sterile
    Positive blood cultures in 10%
    Can be caused by almost any organism including fungi, Nocardia
    Extradural abscess   100–400 N Relatively few PMNs and L  
    Subdural empyema   I N ≤Few hundred; mostly PMNs Negative smears and cultures
    Peripheral WBC is I (≤25,000/μL)
    Cord tumor C, occ X ≤3,500 in 85%; N in 15% N ≤100, chiefly L; N in 60%  
    Brain tumor C, occ X; B if hemorrhage into tumor ≤500e May be D if cells are present ≤150; N in 75% Tumor cells in 20%–40% of solid tumors; absence does not exclude tumor
    Leukemia   I D to 50% of blood   Tumor cells identified by special molecular methods
    Pseudotumor cerebri N N N N Increased pressure
    Cerebral thrombosis N ≤100, N in 60% N ≤50; N in 75%; rarely ≤2,000  
    Cerebral embolismf
    Bland Sl X in 1/3 of cases in few days; may be B     May be 10,000 RBC  
    Septic Sl X I N ≤200 with varying L and PMNs; ≤1,000 RBCs Negative culture
    Cerebral hemorrhage N in 15%, X in 10%, B in 75% Usually ≤2,000 N Same as in blood; N in 10%  
    Subarachnoid hemorrhage B; X within 12 hrs; no clot Usually ≤1,000 N Same as in blood  
    Hypertensive encephalopathy I pressure ≤100 N N  
    Postoperative neurosurgery (especially posterior fossa)   I <40 1,000–2,000; mostly PMNs CSF sterile unless postoperative infection
    Traumatic tap B I by blood N Same as in blood  
    Head trauma N, B, or X I if bloody N Same as in blood  
    Acute epidural hemorrhage C unless associated injuries N N N  
    Subdural hematoma, acute C, B, or X, depending on associated injuries N or sl I     Infants are often anemic
    Chronic subdural hematoma Usually X 300–2,000      
    Multiple sclerosis N   N Always >50  
    Polyneuritis
    Polyarteritis; porphyria; beriberi; alcohol effect; arsenic poisoning N; X if protein very I Usually N N N but albumino–cytologic dissociation in Guillain-Barré syndrome that may occur in heavy metal poisoning, infection, etc.  
    Diabetes mellitus Same as polyarteritis, etc. Often ≤300 I Same as polyarteritis, etc.  
    Acute infection Same as polyarteritis, etc. ≤1,500 N Same as polyarteritis, etc.
    Lead encephalopathy N or sl yellow ≤100 N 0–100  
    Sarcoidosis (findings in ≤50%)   sl I; oligoclonal bands may be present D in 50% I in 40%
    Typically 10–100 but ≤6,000
    I ACE in serum or CSF in 50%–70%
    Behçet disease (25% have meningoen-cephalitis)   I N I  
    Alcoholism N N N Usually N  
    Diabetic coma N N I Usually N  
    Uremia N N or I in ∼50% N or I N or I in ∼50%  
    Epilepsy N N N N  
    Eclampsia May be B Usually ≤200 N May be RBCs Uric acid I ≤3× N reflecting marked I in serum
    Guillain-Barré syndrome   50–100 average; albumino–cytologic dissociation   N  
    B, bloody; C, clear; D, decreased; I, increased; L, lymphocytes; N, normal; O, opalescent; occ, occasionally; Pu, purulent; sl, slightly; T, turbid; X, xanthochromic.
    aPossible underlying disorders: infections (e.g., viral, bacterial [e.g., incompletely treated or very early bacterial meningitis], spirochetes [e.g., leptospirosis, syphilis, Lyme disease], TB, fungal, amebic, mycoplasma, rickettsia, helminthic); chemical or drug-induced meningitis; systemic disorders (e.g., vasculitis, collagen vascular disease, SLE, sarcoidosis); neoplasm (e.g., leukemia, metastatic carcinoma
    bCSF is always abnormal in untreated general paresis.
    cPossible underlying disorders: Infections (TB [most common cause], bacteria, spirochetes, fungi, protozoa, amebae, mycoplasma, rickettsia, helminthes); systemic disorders (e.g., vasculitis, collagen vascular disease, sarcoid, neoplasm)
    dFindings depend on stage and duration of abscess.
    eProtein is particularly increased with meningioma of the olfactory groove and with acoustic neuroma. Usually N in brain stem gliomas and “diencephalic syndrome” of infants due to glioma of hypothalamus.
    fUsually same as in cerebral thrombosis.
    Neonates, elderly, immunocompromised, alcoholics more likely to develop meningitis due to Listeria monocytogenes, Streptococcus agalactiae, group B streptococcus; gram-negative bacilli (e.g., E. coli, Klebsiella spp., Serratia marcescens, Pseudomonas aeruginosa, Salmonella spp.)
    Post-trauma, postoperative neurosurgical, CSF shunts—Staphylococcus spp.
    Infants, children—enteroviruses (e.g., echovirus, coxsackievirus).
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    • Traumatic lumbar puncture >1 to 2 hours earlier
    • Hemorrhage into CSF (e.g., subarachnoid or intracerebral hemorrhage); is present in all patients for ≤2 weeks and 70% of patients at 3 weeks
Bilirubin >6 mg/dL
WBCs
CSF WBC may be corrected for presence of blood (e.g., traumatic tap, subarachnoid hemorrhage) by subtracting 1 WBC for each 700 RBCs/μL counted in CSF if the CBC is normal.
  • If significant anemia or leukocytosis is present:
  • (RBC and WBC are cells/μL)
In normal CSF, ratio of WBC/RBC is <1:500. Minimal blood contamination may cause ≤2 PMN/25 RBCs, or ≤10 PMN/25–100 RBCs.
CSF WBC count (>3,000/μL) with predominantly PMNs strongly suggests bacterial cause and >2,000/μL in 38% of cases. When WBC <1,000/μL in bacterial meningitis, one third of cases have >50% lymphocytes or mononuclear cells. However, WBCs are usually PMNs in early stages of all types of meningitis; mononuclear cells only appear in a second specimen 18 to 24 hours later in nonbacterial cases. Predominantly, lymphocytes occur in ≤10% of ABM cases; may be due to early stages or antibiotic treatment or Listeria meningitis.
May be falsely low due to delay in counting.
Neutrophilic leukocytes are found in:
  • Bacteria (e.g., Nocardia, Actinomyces, Arachnia, Brucella)
  • Fungal infections (Blastomyces, Coccidioides, Candida, Aspergillus, Zygomycetes, Cladosporium, Allescheria)
  • Chemical meningitis
  • Other conditions (e.g., SLE)
  • Half-life of neutrophils in CSF is ∼2 hours
Lymphocytic cells are found in:
  • Bacterial infections (e.g., Treponema pallidum, Leptospira, Actinomyces israelii, Arachnia propionica, 90% of Brucella cases, Borrelia burgdorferi [Lyme disease], M. tuberculosis)
  • Fungal infections (e.g., Cryptococcus neoformans, Candida species, Coccidioides immitis, Histoplasma capsulatum, Blastomyces dermatitides, S. schenckii, Allescheria boydii, Cladosporium trichoides)
  • Parasitic diseases (e.g., toxoplasmosis, cysticercosis)
  • Viral infections (e.g., mumps, lymphocytic choriomeningitis, HTLV-III, echovirus). Atypical lymphocytes may be seen in EBV infection and less often in CMV or HSV infection.
  • Parameningeal disorders (e.g., brain abscess)
  • Noninfectious disorders (e.g., neoplasms, sarcoidosis, multiple sclerosis, granulomatous arteritis)
Eosinophils may be found in:
  • Lymphoma
  • Helminth infection (e.g., angiostrongyliasis, cysticercosis)
  • Rarely, other infections (e.g., TB, syphilis, Rocky Mountain spotted fever, coccidioidomycosis)
  • >5% (or >10% neutrophils or significant pleocytosis) may indicate malfunction or infection of a ventriculoperitoneal shunt1
CSF Chemistries
CSF glucose
Decreased by utilization by bacteria (pyogens or tubercle bacilli), WBCs, or occasionally cancer cells in CSF
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Lags behind blood glucose by about 1 hour
May rapidly become normal after onset of antibiotic therapy
Is decreased in only ∼50% of cases of bacterial meningitis
<45 mg/dL is almost always abnormal; <40 mg/dL is always abnormal
Normally is ∼50% to 65% of blood glucose, which should always be drawn immediately before
Normal CSF:serum ratio of glucose = 0.6. In acute bacterial meningitis (ABM), is usually <0.5; a ratio <0.4 has S/S = 80%/96% for distinguishing ABM from acute viral meningitis (AVM); a ratio <0.25 is found in <1% of AVM cases and 44% of ABM cases, even when CSF glucose is normal. A ratio of <8.0 is significant in infants.
<40 mg/dL in 50% to 60% of ABM cases; <15 mg/dL in 30% of ABM cases
May also be decreased in acute infection due to syphilis, Lyme disease, 10% to 20% of cases of lymphocytic choriomeningitis, and encephalitis due to mumps or herpes simplex but generally rare in viral infections or parameningeal processes. May also be decreased in rheumatoid meningitis, lupus myelopathy, and other causes of chronic meningitis such as bacteria (e.g., Brucella, Mycobacterium tuberculosis), syphilis, fungi (Cryptococcus, Coccidioides), parasites (e.g., cysticercosis), granulomatous meningitis (e.g., sarcoid), chemical meningitis, carcinomatous meningitis, hypoglycemia, and subarachnoid hemorrhage.
CSF protein is least specific parameter
Total protein may be corrected for presence of blood (e.g., due to traumatic tap or intracerebral hemorrhage) by subtracting 1 mg/dL of protein for each 1,000 RBCs/μL if serum protein and CBC are normal and CSF protein and cell count are determined on same tube of CSF. Serum protein levels must be normal in order to interpret any CSF protein values and should therefore always be measured concurrently.
May not be increased in early stages of many types of meningitis
Normal in 10% of patients with ABM (20% of cases of meningococcal meningitis)
Usually >150 mg/dL in ABM; increase occurs especially with S. pneumoniae
<100 mg/dL is usual in nonbacterial meningitis (S/S = 82%/98%)
>172 mg/dL occurs in 1% of AVM and 50% of ABM cases
>500 mg/dL is infrequent and occurs chiefly in bacterial meningitis, bloody CSF, or cord tumor with spinal block and occasionally in polyneuritis and brain tumor
>1,000 mg/dL suggests subarachnoid block; with complete spinal block, the lower the level of the cord tumor, the higher the protein concentration
When antibiotic treatment of bacterial meningitis is started before CSF obtained, protein may be only slightly elevated
May show mild-to-moderate elevation in myxedema (25% of cases), uremia, connective tissue disorders, Cushing syndrome
Decreased CSF protein (3–20 mg/dL) may occur in hyperthyroidism, one third of patients with benign intracranial hypertension, after removal of large volumes of CSF (e.g., during pneumoencephalography, traumatic leaks), in children 6 to 24 months old
Combination of CSF protein, glucose, and WBC levels is more useful than individual parameters.
CSF protein, glucose, and WBC levels may not return to normal in50% of patients with clinically cured bacterial meningitis and therefore are not recommended as a test of cure.
CSF lactate has been reported useful to differentiate bacterial from viral meningitis; is independent of serum concentrations. Due to sequelae of increased WBC.
If <3 mmol/L (normal range), viral meningitis is most likely.
If >4.2 mmol/L, bacterial (including TB) or fungal meningitis is most likely.
If 3 to 6 mmol/L with negative Gram stain and prior antibiotic therapy, partially treated bacterial meningitis is most likely. In bacterial meningitis, level is still high after 1 to 2 days of antibiotic therapy.
Mild symptoms with negative Gram stain, few PMNs: CSF lactate may differentiate mild bacterial from very early viral meningitis
May also be increased in non-Hodgkin lymphoma with meningeal involvement, severe cerebral malaria, head injury, and anoxia
CSF and serum ACE are increased in 50% to 70% of cases of neurosarcoidosis; CSF ACE is increased 2×
Reported to be increased in meningitis and Behçet disease and decreased in Alzheimer disease, Parkinson disease, others
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CSF chloride reflects only blood chloride level, but in TB meningitis a decrease of 25% may exceed the serum chloride decrease because of dehydration and electrolyte loss. It is not useful in diagnosis of TB meningitis.
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CSF glutamine >35 mg/dL is associated with hepatic encephalopathy (due to conversion from ammonia).
CSF IL-6 (marker of inflammation) is increased in bacterial meningitis but not in viral or aseptic meningitis or those without meningitis.
CSF tuberculostearic acid (cell wall component of Mycobacterium tuberculosis) by gas–liquid chromatography has been reported to have good S/S.
Footnote
1
Novak R. Cerebrospinal fluid shunts. CAP Today 2004:93.
CSF Enzymes
Normal CSF is not permeable to serum enzymes. Changes in AST are irregular and generally of limited diagnostic value. If determinations of AST, LD, and CK in CSF are all performed, at least one shows marked increase in 80% of patients with cortical stroke (usually due to emboli) but this is not noted in lacunar strokes (usually due to small vessel hypertensive disease). Generally are not useful in CNS diseases.
Transaminase (AST)
Increased In
Large infarcts of brain during first 10 days. In severe cases, serum AST may also be increased; occurs in ∼40% of patients.
∼40% of CNS tumors (various benign, malignant, and metastatic), depending on location, growth rate, etc.; chiefly useful as indicator of organic neurologic disease
Some other conditions (e.g., head injury, subarachnoid hemorrhage)
Lactate Dehydrogenase (LD)
Increased In
Cerebrovascular accidents—increase occurs frequently, reaches maximum level in 1 to 3 days, and is apparently not related to xanthochromia, RBC, WBC, protein, sugar, or chloride levels. Subarachnoid and subdural hemorrhage cause increase of all LD isoenzymes especially LD-3, 4, 5 (not due only to hemolysis).
CNS tumors—LD-5 >9% and decreased LD-1:LD-5 ratio <2.5 in absence of infection or hemorrhage suggests tumor in meninges. LD-5 >10% suggests higher-grade malignancy. Increase in LD-3, LD-4 and occasionally LD-5 may occur in leukemic and lymphomatous infiltration.
Meningitis—is sensitive indicator of meningitis (in specimen with no blood); normal or mild increase in viral meningitis; more marked increase in bacterial meningitis. Bacterial meningitis shows increase of LD-4 and LD-5; viral meningitis shows increase of LD-1 and LD-2; TB meningitis shows increase of LD-1, LD-2, LD-3, (especially LD-3); HIV alone does not alter LD isoenzyme pattern; isoenzyme changes may only appear in later stage and are of low sensitivity.
Creatine Kinase (CK total) is Not Useful
CSF CK-BB Levels Association with Neurologic Injury
In global anoxic or ischemic brain insults due to respiratory or cardiac arrest, CK-BB levels 24 to 72 hours after injury can be used to estimate overall extent of brain damage; good correlation with neurologic prognosis after resuscitation. Less correlation with outcome in head trauma and stroke. Not recommended for estimating stroke size.
  • >40U/L: Correlates with poorer prognosis
  • <5 IU/L: Only mild injury; most patients will awaken, some minimal deficit
  • >10 IU/L: Substantial brain injury; guarded prognosis
  • 5 to 20 IU/L: Mild to moderate; often moderate to severe impairment; guarded prognosis
  • 21 to 50 IU/L: Severe impairment; poor prognosis; few patients awaken; most die in hospital
  • >50 IU/L: Rarely regain minimal reflexes or responsiveness; poor prognosis; usually die in hospital
CSF CK-MM is Normally Absent; If Present, Indicates Blood Contamination Due to Traumatic Tap or Subarachnoid Hemorrhage.
Mitochondrial-CK is Found With High CK-BB Levels; Not Used to Estimate Prognosis or Brain Damage.
Adenosine Deaminase (Enzyme Elaborated by Activated T Lymphocytes) is Increased (>30 U/L); May Aid in Early Diagnosis of TB Meningitis.
Tumor Markers
Increased CSF CEA has been reported helpful in diagnosis of suspected metastatic carcinoma (from breast, lung, bowel) with negative cytology.
Beta-glucuronidase has been reported to be increased in 75% of patients with metastatic leptomeningeal adenocarcinoma and 60% of patients with acute myeloblastic leukemia involving CNS. Normal <49 mU/L, indeterminate = 49 to 70 mU/L, suspicious >70 mU/L.
Lysozyme (muramidase) is increased in various CNS tumors especially myeloid and monocytic leukemias, but is also increased when neutrophils are increased (e.g., ABM).
Minimal residual leukemic disease is detected by flow cytometry since immature leukocytes with these markers (CD10+, TdT+ or CD34+ cells) are not normally present in CSF.
Gamma-aminobutyric acid is decreased in CSF in Huntington disease.
Colloidal gold test is no longer used; replaced by electrophoresis/immunofixation of CSF. IgG in CSF is increased 14% to 35% in two thirds of patients with neurosyphilis. IgG oligoclonal bands may be seen in neurosyphilis and multiple sclerosis.
In eclampsia, CSF shows gross or microscopic blood and increased protein (≤200 mg/dL) in most cases. Glucose is normal. Uric acid is increased (to 3× normal level), in all cases reflecting the marked increase in serum level. In normal pregnancy, CSF values have same reference range as in nonpregnant women.
Dexamethasone Suppression Test (DST)
Blood is drawn at 11 PM, 8 AM, 12 noon, 4 PM, and 11 PM for plasma cortisol levels. One mg of dexamethasone is given immediately after the first sample is taken. An abnormal test result is failure of suppression of plasma cortisol to level ≤5 μg/dL in any sample after the first. Plasma dexamethasone should also be measured to avoid false values due to aberrant clearance of dexamethasone.
Use
A positive DST will “rule in” the diagnosis of endogenous depression but a negative DST will not rule it out, since it may be positive in only 40% to 50% of such patients.
In the presence of a positive DST, appropriate drug treatment (e.g., tricyclic antidepressants) that results in normalization of DST with clinical recovery is a good prognostic sign whereas failure of DST to normalize suggests a poor prognosis and the need for continued antidepressant therapy. Despite clinical improvement, treatment should be continued until DST becomes negative (usually within 10 days). With relapse, DST may become abnormal when symptoms are still mild, before fully developed syndrome develops. The need to continue treatment is indicated if a positive DST that became negative with therapy reverts to positive after drug treatment is discontinued or the drug dosage is lowered.
Interference
Certain drugs or substances that cause nonsuppression, especially phenytoin, barbiturates, meprobamate, carbamazepine, and alcohol (chronic high doses or withdrawal within 3 weeks) can interfere with DST.
Enhanced suppression may be caused by benzodiazepines (high doses), corticosteroids (spironolactone, cortisone, artificial glucocorticoids such as prednisone, [topical and nasal forms]), and dextroamphetamine.
Other drugs that are said to interfere include estrogens (not birth control pills), reserpine, narcotics, and indomethacin.
Medical conditions including weight loss to 20% below ideal body weight, pregnancy or abortion within 1 month, endocrine diseases, systemic infections, serious liver disease, cancer, and other severe physical illnesses, may also cause false-positive test results.
Lithium maintenance therapy will not interfere with DST.
With a 50% prevalence of melancholia in the population studied and fulfillment of certain medical criteria, DST was found to have a S/S = 67%/96%, and a confidence level of 94% in determining diagnosis. Using only the 4 PM blood, the sensitivity was ∼50%. However, there are still no clear indications for routine use of DST in clinical psychiatry, and many of the routine methods are not accurate at the decision level.
Response of TSH to administration of thyrotropin-releasing hormone (TRH) has also been suggested as useful in the diagnosis of unipolar depression and prediction of
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relapse. These patients have a maximum rise in serum TSH level of <7 μU/mL (normal = 17 ± 9). Use of this test with DST is said to add confidence to diagnosis of major unipolar depression; abnormal response to either test before treatment suggests that patient is particularly liable to have early relapse, unless there is laboratory proof as well as clinical evidence of recovery after treatment.
Diseases of the Nervous System
Autoimmune Disorders
Autoimmune Autonomic Failure, Primary2
Autoimmune disorder possibly due to anti–ganglionic acetylcholine receptor antibodies causing dysfunction of efferent sympathetic and parasympathetic pathways resulting in orthostatic hypotension, anhydrosis, decreased production of saliva and tears, erectile dysfunction, impaired bladder emptying and responsive to plasma exchange
Due To
Diabetes mellitus
Amyloidosis
Idiopathic
  • Detection of antibodies binding to neuronal ganglionic acetylcholine receptors detected by radioimmunoprecipitation
Decreased plasma norepinephrine levels
Guillain–Barré Syndrome3
Acute [<2 months’ duration] demyelinating paralyzing symmetrical polyneuropathy due to autoantibodies [70% is reversible, 10% die, 20% have residual defects]
  • CSF shows albumino-cytologic dissociation with normal cell count and increased protein (average 50–100 mg/dL). Protein increase parallels increasing clinical severity; increase may be prolonged. CSF may be normal at first.
  • Biopsy of nerve shows evidence of demyelination and remyelination.
  • Electrophysiological changes may be negative for first 1 to 2 weeks.
Laboratory findings due to associated disease may be present (e.g., evidence of recent infection with Campylobacter jejuni in 15% to 40%, and CMV in 5% to 20% of cases; EBV and Mycoplasma pneumoniae in <2% of cases in western nations, other viral and rickettsial infections, immune disorders, diabetes mellitus, exposure to toxins [e.g., lead, alcohol], neoplasms). No agent was identified in ≤70% of cases.4
Multiple Sclerosis (MS)
  • Diagnosis should not be made not on the basis of CSF findings unless there are multiple clinical lesions in time (by clinical history) and anatomic location (by MRI, evoked potentials, or physical examination).
  • CSF changes are found in >90% of MS patients. Oligoclonal IgG bands or elevated IgG index are the 2 CSF findings recognized as positive.5
  • Qualitative test of IgG on unconcentrated CSF is single most informative test.6
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Best performed using IEF with immunodetection by blotting or fixation run with simultaneous serum sample on adjacent track with positive and negative controls. Should show one of five recognized staining patterns of oligoclonal banding.
Quantitative IgG analysis is informative complementary test but not considered a substitute for qualitative test, which has highest S/S.
90% of MS patients have oligoclonal bands in CSF, at least 2 of which are not present in simultaneously examined serum. A few patients with definite MS may have normal CSF immunoglobulins and lack oligoclonal bands.
Found in 85% to 95% of patients with definite MS and 30% to 40% with possible MS (specificity = 79%); it is the most sensitive marker of MS.
Positive results also occur in ≤10% of patients with noninflammatory neurologic disease (e.g., meningeal carcinomatosis, cerebral infarction), and ≤40% of patients with inflammatory CNS disorders (e.g., neurosyphilis, viral encephalitis, progressive rubella encephalitis, subacute sclerosing panencephalitis, bacterial meningitis, toxoplasmosis, cryptococcal meningitis, inflammatory neuropathies, trypanosomiasis).
Oligoclonal bands in serum may occur in leukemias, lymphomas, some infections and inflammatory diseases, immune disorders.
Not known to correlate with severity, duration, or course of MS.
Persists during remission
During steroid treatment, prevalence of oligoclonal bands and other gamma globulin abnormalities may be reduced by 30% to 50%.
Evaluation of light chains may help in cases of equivocal oligoclonal IgG patterns.
  • IgG index indicates IgG synthesis in CNS. >0.7 occurs in 90% of MS patients; may also occur in other neurological diseases (e.g., meningitis). CSF IgM and IgA may also be increased but are not useful for diagnosis.
  • Myelin basic protein
Indicates recent myelin destruction; increased in 70% to 90% of MS patients during an acute exacerbation and usually returns to normal within 2 weeks. Weakly reactive (4–8 ng/mL) indicates active lesion >1 week old. Normal = <1 ng/mL.
Useful for following course of MS but not for screening
May be helpful very early in course of MS before oligoclonal bands have appeared or in ∼10% of patients who do not develop these bands
Is frequently increased in other causes of demyelination and tissue destruction (e.g., meningoencephalitis, leukodystrophies, metabolic encephalopathies, SLE of CNS, brain tumor, head trauma, amyotrophic lateral sclerosis, cranial irradiation and intrathecal chemotherapy, 45% of patients with recent stroke) and other disorders (e.g., diabetes mellitus, chronic renal failure, vasculitis, carcinoma of vasculitis, immune complex diseases, pancreas)
Falsely increased by contamination with blood
Increased association with certain histocompatibility antigens (e.g., whites with B7 and Dw2 antigen)
  • Albumin index (ratio of albumin serum/CSF) is measure of integrity of blood/CSF barrier. Avoids misinterpreting falsely increased CSF IgG concentrations. Increase indicates CSF contaminated with blood (e.g., traumatic tap) or increased permeability of blood brain barrier (e.g., aged persons, obstruction of CSF circulation, diabetes mellitus, SLE of CNS, Guillain- Barré syndrome, polyneuropathy, cervical spondylosis).
CSF total protein
Normal or may be mildly increased in ∼25% of patients; not very useful test by itself
Decreased values or values >100 mg/dL should cast doubt on diagnosis
CSF gamma globulin is increased in 60% to 75% of patients regardless of whether the total CSF protein is increased. Gamma globulin ≥12% of CSF total protein is abnormal if there is not a corresponding increase in serum gamma globulin; but may also be increased in other CNS disorders (e.g., syphilis, subacute panencephalitis, meningeal carcinomatosis) and may also be increased when serum electrophoresis is abnormal due to non-CNS diseases (e.g., RA, sarcoidosis, cirrhosis, myxedema, multiple myeloma).
CSF IgG concentration
  • Increased (reference range <4.0 mg/dL) in ∼70% of cases, often when total protein is normal
  • Increase in production of IgG is expressed as ratio of CSF to serum albumin to rule out increased IgG due to disruption of blood–brain barrier
CSF IgG does not correlate with duration, activity, or course of MS.
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May also be increased in other inflammatory demyelinating diseases (e.g., neurosyphilis, acute Guillain-Barré syndrome), 5% to 15% of patients with miscellaneous neurologic diseases, and a few normal persons; recent myelography is said to invalidate the test.
  • CSF IgG-albumin ratio indicates in situ production of IgG. Abnormal in 90% of MS patients and 18% of non-MS neurologic patients.
  • CSF IgG synthesis rate (3.3 mg/day) is increased in 90% of MS patients and 4% of non-MS patients.
  • PCR demonstrates expansion of B-cell clones.
Peripheral blood studies and routine CSF tests yield no changes of diagnostic value.
  • CSF WBC is slightly elevated in ∼25% of patients but usually <20 mononuclear cells/μL; >25 cells/μL in <1% of cases. >50 cells/μL should cast doubt on diagnosis. Albumin, glucose, and pressure are normal.
Footnotes
2
Schroeder C, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585.
3
Köller H, Kieseier BC, Jander S, Hartung HP. Chronic inflammatory demyelinating polyneuropathy. N Engl J Med 2005;352:1343–1356. Review.
4
Sivadon-Tardy V, et al. Guillain-Barré syndrome, greater Paris area. Emerg Infect Dis 2006;12:990.
5
McDonald WI, Compston A, Edan G, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50:121–127.
6
Barclay L. New guidelines for standards for CSF analysis in MS. Arch Neurol 2005;62:865–870. Available at: http://wwwmedscape.com. Accessed May 2005.
CNS Trauma
Laboratory findings due to single or various combinations of brain injuries (e.g., contusion, laceration, subdural hemorrhage, extradural hemorrhage, subarachnoid hemorrhage)
Laboratory findings due to complications (e.g., pneumonia, meningitis)
In possible skull fractures
  • Immunofixation electrophoresis with antitransferrin-precipitating antibody is performed to differentiate CSF (desialated) transferrin, found only in CSF, perilymph, aqueous and vitreous humor of eye, from nasal secretions.
  • IgM, prealbumin (transthyretin), and transferrin are higher in CSF than in serum. It has been recommended that nasal secretions may be differentiated from CSF by absence of glucose (using test tapes or tablets) in nasal secretions but this is not reliable because nasal secretions may normally contain glucose. Tears may taste salty to the patient.
Acute Epidural Hemorrhage
CSF is usually under increased pressure; it is clear unless there is associated cerebral contusion, laceration, or subarachnoid hemorrhage.
Subdural Hematoma
CSF findings are variable—clear, bloody, or xanthochromic, depending on recent or old associated injuries (e.g., contusion, laceration).
Chronic subdural hematoma fluid is usually xanthochromic; protein content is 300 to 2,000 mg/dL.
Anemia is often present in infants.
Infections
Abscess, Brain
Localized collection of pus. Aspirate should include performance of Gram stain, aerobic and anaerobic cultures, fungal and acid-fast stains and culture, serum IgG for toxoplasmosis.
Due to
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Source Usual Location Usual Organism
Penetrating trauma, postoperative Site of injury or surgery Staphylococcus aureus, coagula se negative; Staphylococcus spp.; Clostridium spp.; gram-negative organisms*
Teeth, paranasal sinus Frontal lobe Aerobic/anaerobic streptococci Staphylococcus aureus; anaerobes; gram-negative organisms*
Otitis media, mastoiditis Temporal lobe, cerebellum Aerobic/anaerobic streptococci; other anaerobes; gram-negative organisms*
Hematogenous (e.g., congenital/acquired heart disease; pulmonary disease) Middle cerebral artery distribution Streptococcus spp.; sometimes with other organisms
*Gram-negative species (e.g., Proteus, Klebsiella, Pseudomonas)
†Mixed anaerobic (e.g., Streptococci or Bacteroides) and aerobic organisms (e.g., Streptococci, Staphylococci, or S. pneumoniae). Toxoplasma and Nocardia may be due to underlying AIDS. May be caused by almost any organism, including fungi, and Nocardia. 20% of cultures are sterile.
  • CSF shows WBC ∼25 to 300/μL and increased neutrophils, lymphocytes, and RBCs.
    • Lumbar puncture risks brain herniation.
    • Protein may be increased (75–300 mg/dL).
    • Glucose is normal.
    • Bacterial cultures are negative.
    • Findings depend on stage and duration of abscess.
    • With rupture, acute purulent meningitis with many organisms
  • Positive blood cultures in ∼10% of patients.
  • Laboratory findings due to associated primary disease
    • 10% of cases are due to penetrating skull trauma
    • 50% of cases are due to contiguous spread from sinuses, mastoids, middle ear
    • 20% of cases are cryptogenic
    • 20% of cases are due to hematogenous spread of:
      • Dental infections
      • Primary septic lung disease (e.g., lung abscess, bronchiectasis, empyema)
      • Cyanotic congenital heart disease (e.g., septal defects)
      • Other causes
Abscess, Epidural, of Spinal Cord
CSF protein is increased (usually 100–400 mg/dL), and there are relatively few WBCs (lymphocytes and neutrophils).
Most common organism is Staphylococcus aureus, followed by Streptococcus and gram-negative bacilli.
Laboratory findings due to preceding condition (e.g., adjacent osteomyelitis; bacteremia due to dental, respiratory, or skin infections)
Acquired Immune Deficiency Syndrome (AIDS), Neurologic Manifestations
See AIDS (Chapter 15).
Dementia (also called subacute encephalitis) is most common neurologic syndrome with AIDS—in >50% of cases; may be initial or later manifestation.
CSF abnormalities in 85%:
  • Increased protein (50–100 mg/dL) in 60% of patients
  • Mild mononuclear pleocytosis (5–50 cells/μL) in 20% of patients
  • HIV antibodies
Aseptic meningitis—may occur early, late, or chronic recurrent
CSF may show:
  • 20 to 300 cells/μL
  • Increased protein (may be 50–100 mg/dL)
  • ◆HIV culture is usually positive
  • ◆ Increased CSF:serum antibody ratio, indicating local antibody production
Myelopathy—gradual onset; usually associated with dementia
Polymyositis is most common type.
Peripheral neuropathies, some of which may resemble Guillain-Barré syndrome
CSF may show increased protein (50–100 mg/dL) and pleocytosis of 10 to 50 cells/μL.
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Opportunistic CNS infections
  • Viral (e.g., CMV, HSV I and II, papovavirus, EBV)
  • Nonviral (e.g., cryptococcal, toxoplasmosis, Aspergillus fumigatus, Candida albicans, Coccidioides immitis, Mycobacterium avium-intracellulare and M. tuberculosis, Nocardia asteroides, Listeria)
Neoplasms (e.g., Kaposi sarcoma, non-Hodgkin lymphoma)
Vascular (e.g., infarction, hemorrhage, vasculitis)
Associated diseases (e.g., neurosyphilis)
Cerebral Subdural Empyema
Due to
Source Usual Organism
Penetrating trauma, postoperative intracranial surgery Staphylococcus aureus, coagulase-negative; Staphylococcus spp.; Clostridium spp.; gramnegative organisms*
Acute sinusitis Aerobic/anaerobic streptococci anaerobic organisms; gram-negative organisms*
Otitis media Aerobic/anaerobic streptococci; other anaerobes; gram-negative organisms*
Hematogenous Varies with site of primary infection
*Gram-negative species, e.g., Proteus, Klebsiella, Pseudomonas
†Mixed anaerobic (e.g., Streptococci or Bacteroides) and aerobic organisms (e.g., Streptococci, Staphylococci, or S. pneumoniae). Toxoplasma and Nocardia may be due to underlying AIDS. May be caused by almost any organism, including fungi, and Nocardia.
CSF
  • Cell count is increased to a few hundred, with predominance of PMNs.
  • Protein is increased.
  • Glucose is normal.
  • Bacterial smears and cultures are negative.
WBC is usually increased (≤25,000/μL).
Laboratory findings due to preceding diseases.
Encephalitis
Inflammation of brain of various etiologies
Due to
Virus
  • Flaviviridae (e.g., West Nile, Japanese, St. Louis)
  • Togaviridae (e.g., Eastern and Western and Venezuelan equine)
  • Bunyaviridae (e.g., Rift Valley fever)
  • Herpesviridae (e.g., HSV, CMV, VZV)
  • Others (e.g., retrovirus [e.g., HIV], adenovirus, influenza, rabies, mumps, influenza, adenovirus, enterovirus [e.g., coxsackievirus, echovirus, poliovirus])
Bacteria (e.g., listeria, mycoplasma, Lyme disease, Whipple disease, rickettsia, syphilis, TB); see Table 15-2
Fungal (e.g., Cryptococcus, coccidioidomycosis)
Amoebae (e.g., Naegleria, Acanthamoeba)
Protozoa (e.g., malaria, toxoplasmosis)
Prion
  • CSF findings (see Table 9-1)
  • Appropriate culture and serologic tests for specific organism identification and additional laboratory tests—see separate sections for each agent
Meningitis, Aseptic
Inflammation of meninges without identifiable cause; is usually viral
Due to
Infections
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  • Viral (especially poliomyelitis, coxsackievirus A and B, echovirus, HIV, EBV, lymphocytic choriomeningitis, and many others); culture positive in∼40% of cases, especially with enteroviruses (see Chapter 15)
  • Bacterial (e.g., incompletely treated or very early bacterial meningitis, bacterial endocarditis, parameningeal infections such as brain abscess, epidural abscess, paranasal sinusitis)
  • Spirochetes (e.g., leptospirosis, syphilis, Lyme disease)
  • Tuberculous (CSF glucose levels may not be decreased until later stages)
  • Fungal (e.g., Candida, Coccidioides, Cryptococcus)
  • Protozoan (e.g., Toxoplasma gondii)
  • Amebic (e.g., Naegleria, Acanthamoeba)
  • Mycoplasma
  • Rickettsia (e.g., Rocky Mountain spotted fever)
  • Helminths
Chemical meningitis
Drug-induced meningitis (e.g., ibuprofen, trimethoprim, immune globulin, sulfadiazine, azathioprine, antineoplastic drugs)—onset usually within 24 hours of drug ingestion
Systemic disorders
  • Vasculitis, collagen vascular disease (e.g., SLE)
  • Sarcoid
  • Behçet syndrome
  • Vogt-Koyanagi syndrome
  • Harada syndrome
  • Neoplasm (e.g., leukemia, metastatic carcinoma)
CSF
  • Protein is normal or slightly increased.
  • Increased cell count shows predominantly PMNs at first, mononuclear cells seen later.
  • Glucose is normal.
  • Bacterial cultures and bacterial stains are negative.
If glucose levels are decreased, rule out TB, cryptococcosis, leukemia, lymphoma, metastatic carcinoma, sarcoidosis, drug-induced.
Meningitis, Bacterial, Acute (ABM)
  • Gram stain is positive in ∼70% of patients; sensitivity is increased by cytocentrifugation of specimen (sensitive to 104 organisms/mL). Smears for Gram and acid-fast stains must be routinely centrifugedon all CSF specimens because other findings may be normal in meningitis. When Gram stain is positive, CSF is more likely to show decreased glucose, increased protein, and increased WBCs.
    75% of cases are caused by N. meningitidis, S. pneumoniae, H. influenzae.
    In community-acquired cases in adults, 51% are caused by S. pneumoniae, 37% are caused by H. influenzae, and 4% are caused by Listeria monocytogenes. Over age 50, aerobic gram-negative bacilli are also common.
    Gram stain of scrapings from petechial skin lesions demonstrate pathogen in ∼70% of patients with meningococcemia; Gram stain of buffy coat of peripheral blood, and less often, peripheral blood smear may reveal this organism.
    Gram stain of CSF sediment is negative in cases of ABM because at least 105 bacteria/ mL CSF must be present to demonstrate 1 to 2 bacteria/100× microscopic field. Gram stain is positive in 90% of cases owning to pneumococci, 85% of cases owning to H. influenzae, 75% of cases owning to meningococci, but only 30% to 50% of cases owning to gram negative enteric bacilli. If antibiotics have been given before CSF obtained, Gram stain may be negative.
    In 50% of cases owning to Listeria monocytogenes, the Gram stain may be negative and the cellular response is usually monocytic, which may cause this meningitis to be mistakenly diagnosed as viral, syphilis, TB, Lyme disease, etc. Identified by PCR.
    Table 9-2. Etiology of Bacterial Meningitis by Age
    Newborns <1 year 1–5 years 5–14 years >15 years Elderly
    Most frequent Escherichia coli Streptococcus pneumoniae Neisseria meningitides S. pneumoniae S. pneumoniae
    N. meningitidis
    Common Enterobacter aerogenes/Klebsiella pneumoniae
    β-hemolytic streptococcus
    Listeria monocytogenes
    Staphylococcus aureus
    N. meningitides
    S. pneumoniae
    H. influenzae
    S. pneumoniae
    N. meningitides
    S. aureus
    Gram-negative bacilli
    L. monocytogenes
    Uncommon Paracolon bacilli Pseudomas spp. β-hemolytic streptococcus E. coli  
      Pseudomas spp. S. aureus   Pseudomas spp.  
      H. influenzae β-hemolytic streptococcus      
        E. coli      
    Rare N. meningitides Enterobacter aerogenes/
    Klebsiella pneumoniae
    paracolons various other gram-negative organisms
      H. influenzae  
    The frequency of different organisms may vary from year to year, in presence of epidemics, or by geographic location. Occasionally more than one organism is recovered.
    H. influenzae formerly caused most cases between 6 months and 3 years (but was unusual before 2 months), but incidence has declined markedly due to effective vaccination. Enteric bacteria are so rarely found in older children that, in their presence, immunologic defect or congenital dermal sinus should be ruled out. If surgery has not been performed and S. aureus is present, congenital dermal sinus should be ruled out.
    Gram stain of CSF should always be done in addition to culture because it provides a more immediate clue to the causative agent and the proper therapy and because the culture may be negative if the patient received antibiotics soon before the lumbar puncture. Cultures should also be obtained from blood and from petechial skin lesions if present. Gram stain of buffy coat of blood is often useful.
    CSF glucose is very useful in differentiating bacterial from viral meningitis and is a good index to the severity of the infection, with a lower level in more severe infections.
    Newborns with overwhelming pneumococcal infections may have no decrease in glucose or increase of cells.
    CSF should be reexamined in 24 hours as a guide to therapeutic response; a good response shows negative gram-stained smear and culture, increased glucose, and a changing cell count from predominance of PMNs to predominance of mononuclear cells; total cell count and protein may show an initial rise. CSF should be reexamined when therapy is to be stopped; treatment should not be stopped unless CSF is normal except for slight increase of cells (≤∼20 lymphocytes).
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    Stains are positive in <60% of cases of treated ABM, <5% of cases of TB meningitis, 20% to 70% of cases of fungal meningitis and <2% of cases of brain abscess. Sensitivity of Gram stain is increased using fluorescent techniques with acridine orange.
  • Positive CSF bacterial culture has S/S = 92%/95%, false-negative rate = 8%, and false-positive rate = 5%. Culture is more reliable than Gram stain, although results of the stain offer a more immediate guide to therapy.
  • Blood culture is usually positive if patient has not received antibiotics.
    Limulus amebocyte lysate is a rapid specific indicator of endotoxin produced by gram-negative bacteria (N. meningitidis, Hemophilus influenzae type B, E. coli, Pseudomonas). Is not affected by prior antibiotic therapy; is more rapid and sensitive than counterimmunoelectrophoresis (CIE). Is often not routinely available.
    Serological methods are often preferred (e.g., positive in 85% of coccidioidal cases compared with culture, which is positive in 37% of cases) especially in syphilis, brucellosis, Lyme disease. Higher titer in CSF than blood indicates antibody synthesis in CSF. Blood and CSF serology is positive in CNS syphilis (Table 9-1); positive in 7% to 10% of active cases of infectious mononucleosis.
    Detection of bacterial antigen (rapid latex agglutination assay has largely replaced CIE) in CSF for S. pneumoniae, group B streptococcus (Streptococcus agalactiae), H. influenzae, some strains of Neisseria meningitidis. PCR for S. agalactiaehas PPV and PNV >98%.
    • Not affected by previous antimicrobial therapy that might inhibit growth in culture.
    • H. influenzae is now rare due to routine immunization of children.
    • Not likely to be useful if CSF chemistry and cell count are normal unless patient is immunocompromised.
    • False positive for H. influenza may occur due to recent immunization; should not be performed if recently vaccinated.
    • False positive for Group B Streptococcus antigen in urine is common due to its colonization of perineum.
    • For these reasons and cost, is currently done much less frequently.
    Opening pressure is increased (normal = 100–200 mm Hg)
    Laboratory findings due to presence of infection (e.g., increased number of band forms, toxic granulations, Döhle bodies, vacuolization of PMNs)
    Laboratory findings due to preceding diseases, e.g.:
    • Pneumonia, otitis media, sinusitis, skull fracture prior to pneumococcal meningitis
    • Neisseria epidemics prior to this meningitis
    • Bacterial endocarditis, septicemia, etc.
    • Streptococcus pneumoniae in alcoholism, myeloma, sickle cell anemia, splenectomy, immunocompromised state
    • Cryptococcus and M. tuberculosis in steroid therapy and immunocompromised state
    • Gram-negative bacilli in immunocompromised state
    • H. influenzae in splenectomy
    • Lyme disease
    Laboratory findings due to complications (e.g., Waterhouse-Friderichsen syndrome, subdural effusion)
  • Most frequent and important differential diagnosis is between acute bacterial meningitis (ABM) and acute viral meningitis (AVM). The most useful test results are:
    • CSF identification of organism by stain or culture, specific nucleic acid or antigen by PCR
    • Decreased CSF glucose and decreased CSF:serum ratio of glucose even if CSF glucose is normal
    • Increased CSF protein >1.72 gm/L (1% of AVM and 50% of ABM cases)
    • CSF WBC >2,000/μL in 38% of ABM cases and PMN >1,180/μL but low counts do not rule out ABM.
    • Peripheral WBC is only useful if WBC (>27,200/μL) and total PMN (>21,000/μL) counts are very high, which occurs in relatively few patients; leukopenia is common in infants and elderly.
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Meningitis, Chemical
Due to injection of anesthetic, antibiotic, radiopaque dye, etc., or to rupture into CSF of contents of epidermoid tumor or craniopharyngioma
CSF
  • Pleocytosis is mild to moderate, largely lymphocytic.
  • Protein shows variable increase.
  • Glucose is usually normal.
Meningitis, Chronic
(Symptoms for >4 weeks)
Due to
Various infections
  • TB (most common cause)
  • Bacteria (e.g., Brucella)
  • Spirochetes (e.g., leptospirosis, syphilis, Lyme disease)
  • Fungal (e.g., candida, coccidioides, cryptococcus)
  • Protozoan (e.g., Toxoplasma gondii)
  • Amebic (e.g., Naegleria, Acanthamoeba)
  • Mycoplasma
  • Rickettsia
  • Helminths
Systemic disorders
Vasculitis, collagen vascular disease
  • Sarcoid
  • Neoplasm (e.g., leukemia, lymphoma, metastatic carcinoma)
CSF
  • WBC 100 to 400 WBC/μL, preponderance of lymphocytes
  • Glucose often decreased
  • Protein usually moderately or markedly increased
Meningitis, Mollaret
Rare disorder of recurrent episodes [2–7 days each] of aseptic meningitis occuring over several years with symptom-free intervals in which other organ systems are not involved. Usually due to HSV-2 infection and has also been reported due to epidermoid cyst or anatomical defects that are discovered later by MRI or CT scan.
CSF
  • During first 12 to 24 hours may contain up to several thousand cells/μL, predominantly PMNs and 66% of a large type of mononuclear cells (originally “endothelial cells”) that are of unknown origin and significance and are characterized by vague nuclear and cytoplasmic outline with rapid lysis even while being counted in the hemocytometer chamber; they may be seen only as “ghosts” and are usually not detectable after the first day of illness. After the first 24 hours, the PMNs disappear and are replaced by lymphocytes, which, in turn, rapidly disappear when the attack subsides.
    • Protein may be increased ≤100 mg/dL.
    • Glucose is normal or may be slightly decreased.
There is mild leukopenia and eosinophilia.
Meningitis/Encephalomyelitis, Viral, Acute
For other infectious, postvaccinal, postexanthematous, postinfectious, see Chapter 15.
CSF shows increased protein and lymphocytes (see Table 9-1).
Should not be mistaken for TB, parasitic, chemical, incompletely treated bacterial meningitis, etc.
Postinfectious encephalomyelitis patients have an invariable, irreversible demyelinating syndrome; is most commonly associated with varicella and URI (especially influenza) and measles.
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Vaccination has reduced the incidence of acute and postinfectious encephalitis and of poliomyelitis but a few cases of vaccine-associated infections occur.
Coxsackievirus and echovirus usually cause benign aseptic meningitis.
Laboratory findings due to preceding illness (e.g., measles) are noted.
  • Viral culture (see Chapter 15) varies with organism; better for mumps, echovirus, and coxsackievirus than for Herpesviridae. HSV can be cultured from CSF in 50% to 75% of patients with meningitis only during first episode and <5% with encephalitis; rarely positive with recurrences. In Colorado tick fever, viral detection by culture, immunofluorescence, and RT-PCR of whole blood (virus is in RBCs).
  • PCR to detect HSV (S/S >95%), human enteroviruses, and increasing number of organisms in CSF is more significant than in brain tissue where it may represent irrelevant latent infection. Can be confirmed by Southern blotting (S/S = 98%/97%). Brain biopsy has been gold standard for many virus encephalitides using EM, IHC, and culture. PCR has high PPV in AIDS patients with CNS lymphoma due to EBV. Quantitative PCR for determination of viral load is useful in CMV to determine clinical significance and to monitor therapy. PCR detection of HSV DNA in CSF is positive within 24 hours of onset of symptoms. Remains positive during first week of therapy. Has replaced brain biopsy, culture, immunohistochemistry as test of choice.
  • PCR of CSF or fresh brain tissue for panel detection of HSV, varicella-zoster, enterovirus, eastern equine encephalitis, St. Louis encephalitis, CMV, EBV, California serogroup viruses, and rabies (in saliva) makes 72-hour diagnosis possible on one sample and should replace culture, mouse innoculation, immunoassay, serology, and brain biopsy.
  • Mumps IgM antibodies in CSF and serum indicates mumps encephalitis.
  • ELISA to detect IgM in CSF is sensitive and specific for Japanese B encephalitis; is usually present at hospitalization and almost always present by third day of illness.
  • Paired serum samples during acute and convalescent periods may show seroconversion or 4× increase in specific antibody titers.
  • Brain biopsy is currently reserved for patients who do not respond to acyclovir therapy and have unknown abnormality on CT scan or MRI.
  • Brain biopsy is also required for diagnosis of progressive multifocal leukoencephalopathy.
West Nile meningoencephalitis7
  • IgM is found in CSF and serum
  • RT-PCR detects virus in CSF and serum
  • Brain tissue (autopsy) is positive for antigen by immunohistochemical analysis and RT-PCR.
Meningoencephalitis, Amebic
Due to free-living ameba, Naegleria or Acanthamoeba, in contaminated water forced into nasal cavity. Rapid progression to death in 7–10 days.
Increased WBC, predominantly neutrophils.
CSF findings
  • Fluid may be cloudy, purulent, or sanguinopurulent.
  • Protein is increased.
  • Glucose is usually decreased; may be normal.
  • Increased WBCs are chiefly PMNs. RBCs are frequently present also. Motile amebas may be seen in hemocytometer chamber or on wet mount using phase or diminished light.
    • Amebas are seen on Wright’s, Giemsa, H&E stains. Gram stain and cultures are negative for bacteria and fungi.
    • Culture of tissue or CSF on agar or tissue culture demonstrates organisms.
    • Electron microscopy allows precise classification of amebas.
    • IFA and immunoperoxidase are reliable methods to identify amebas in tissue sections.
Footnote
7
Nash D, Mostashari F, Fine A, et al. and the 1999 West Nile Outbreak Response Working Group. The outbreak of West Nile virus infection in the New York City area in 1999. N Engl J Med 2001;344:1807–1814.
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Myelitis
CSF may be normal or may show increased protein and cells (20–1,000/μL—lymphocytes and mononuclear cells) with normal glucose.
Laboratory findings due to causative condition (e.g., poliomyelitis, herpes zoster, TB, syphilis, parasites, abscess, MS, postvaccinal myelitis, paraneoplastic)
Prion Diseases
Tuberculoma of Brain
CSF shows increased protein with small number of cells. The tuberculoma may be transformed into TB meningitis with increased protein and cells (50–300/μL), decreased glucose and chloride.
Laboratory findings due to TB elsewhere
TB meningitis (see Chapter 15)
Inherited Conditions
Bassen-Kornzweig Syndrome
Cerebellar Ataxia, Progressive with Skin Telangiectasis
See Tables 11-6 and 11-7.
Metachromatic Leukodystrophy
See Table 12-13 and Chapter 12 for other conditions that affect the CNS.
Refsum Disease
Rare autosomal recessive lipidosis of the nervous system due to phytanoyl-coenzyme A hydroxylase deficiency with retinitis pigmentosa, peripheral neuropathy, cerebellar ataxia, nerve deafness, and ichthyosis. Stored lipid (phytanic acid) is not synthesized in body but is exclusively dietary.
CSF shows albuminocytologic dissociation (normal cell count with protein usually increased to 100–700 mg/dL).
  • Increased plasma phytanic acid ≥800 μmol/L (normal <19 μmol/L)
von Hippel-Lindau Disease (Hemangioblastomas of Retina and Cerebellum)
Laboratory findings due to associated conditions (e.g., polycythemia, pheochromocytomas, renal cell carcinoma, cysts of kidney and epididymis, benign cysts and nonfunctional neuroendocrine tumors of pancreas)
von Recklinghausen Disease (Multiple Neurofibromas)
CSF findings of brain tumor if acoustic neuroma occurs
Miscellaneous Conditions
Alzheimer Disease (Senile Dementia)
Most common cause of dementia. Major pathology is accumulation of Aβ peptide form of amyloid, which is cleaved from a larger protein, gene for which resides on chromosome 21.
There are no abnormal laboratory findings, but laboratory tests are useful to rule out other diseases that may resemble these syndromes but are amenable to therapy.
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  • Gold standard for diagnosis is histology of brain (biopsy or autopsy).
    Tests under development:
    • Increased Tau protein and decreased β-Amyloid(1-42) in CSF in patients with dementia may rule out other causes (e.g., vascular, tumor, endocrine) leaving Alzheimer as most likely.
    • Neural thread protein detected in first morning urine and CSF.
Recommended tests in all patients with new onset of dementia should include: CBC, urinalysis, electrolyte and blood chemistry panel, screening metabolic panel, serum vitamin B12 and folate measurements, thyroid and other endocrine disorders, serologic test for syphilis.
In patients >age 60 with dementia, the usual causes are Alzheimer type (75%), drugs and alcohol (13%), endocrine (4%), low serum iron, folate, or cobalamin (8%), GU tract infection (2.5%).
Coma and Stupor
Due to
Poisons, drugs, or toxins
  • Sedatives (especially alcohol, barbiturates)
  • Enzyme inhibitors (especially salicylates, heavy metals, organic phosphates, cyanide)
  • Other (e.g., paraldehyde, methyl alcohol, ethylene glycol)
Cerebral disorders
  • Brain contusion, hemorrhage, infarction, seizure, or aneurysm
  • Brain mass (e.g., tumor, hematoma, abscess, parasites)
  • Subdural or epidural hematoma
  • Venous sinus occlusion
  • Hydrocephalus
  • Hypoxia
  • Decreased blood O2 content and tension (e.g., lung disease, high altitude)
  • Decreased blood O2 content with normal tension (e.g., anemia, carbon monoxide poisoning, methemoglobinemia)
  • Infection (e.g., meningitis, encephalitis)
Vascular abnormalities (e.g., subarachnoid hemorrhage, hypertensive encephalopathy, shock, acute myocardial infarction, aortic stenosis, Adams-Stokes, tachycardias)
Metabolic abnormalities
  • Acid–base imbalance (acidosis, alkalosis)
  • Electrolyte imbalance (increased or decreased sodium, potassium, calcium, magnesium)
  • Porphyrias
  • Aminoacidurias
  • Uremia
  • Hepatic encephalopathy
  • Other disorders (e.g., leukodystrophies, lipid storage diseases, Bassen-Kornzweig syndrome)
Nutritional deficiencies (e.g., vitamin B12, thiamine, niacin, pyridoxine)
Endocrine
  • Pancreas (diabetic coma, hypoglycemia)
  • Thyroid (myxedema, thyrotoxicosis)
  • Adrenal (Addison disease, Cushing syndrome, pheochromocytoma)
  • Panhypopituitarism
  • Parathyroid (hypofunction or hyperfunction)
Psychogenic conditions that may mimic coma
  • Depression, catatonia
  • Malingering
  • Hysteria, conversion disorder
Mental Retardation
Laboratory findings due to underlying causative condition (see appropriate separate sections)
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Due to
Prenatal
Infections (e.g., syphilis, rubella, toxoplasmosis, CMV)
Metabolic abnormalities (e.g., diabetes mellitus, eclampsia, placental dysfunction)
Chromosomal disorders (e.g., Down syndrome, 18-trisomy, cri du chat syndrome, Klinefelter syndrome)
Metabolic abnormalities
  • Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease, hemocystinuria, cystathioninuria, hyperglycemia, argininosuccinicaciduria, citrullinemia, histidinemia, hyperprolinemia, oasthouse urine disease, Hartnup disease, Joseph syndrome, familial iminoglycinuria)
  • Lipid metabolism (e.g., Batten disease, Tay-Sachs disease, Niemann-Pick disease, abetalipoproteinemia, Refsum disease, metachromatic leukodystrophy)
  • Carbohydrate metabolism (e.g., galactosemia, mucopolysaccharidoses)
  • Purine metabolism (e.g., Lesch-Nyhan syndrome, hereditary orotic aciduria)
  • Mineral metabolism (e.g., idiopathic hypercalcemia, pseudo- and pseudohypoparathyroidism)
  • Other syndromes (e.g., tuberous sclerosis, Louis-Bar syndrome)
Perinatal
Infections (e.g., syphilis, rubella, toxoplasmosis, CMV, HIV, HSV)
Kernicterus
Prematurity
Anoxia
Trauma
Postnatal
Poisoning (e.g., lead, arsenic, carbon monoxide)
Infections (e.g., meningitis, encephalitis)
Metabolic abnormalities (e.g., hypoglycemia, malnutrition)
Postvaccinal encephalitis
Cerebrovascular accidents
Trauma
Neuritis/Neuropathy, Multiple
Laboratory findings due to causative disease
Infections:
  • Epstein-Barr (mononucleosis associated: CSF shows increased protein and up to several hundred mononuclear cells)
  • Diptheria: CSF protein is 50 to 200 mg/dL
  • Lyme disease
  • HIV
  • Hepatitis associated
  • Leprosy
Postvaccinal effect
Metabolic conditions (e.g., pellagra, beriberi, combined system disease, pregnancy, porphyria, diabetes mellitus). CSF usually normal. In ∼70% of patients with diabetic neuropathy, CSF protein is increased to >200 mg/dL.
  • Uremia: CSF protein is 50 to 200 mg/dL; occurs in a few cases of chronic uremia
    • Collagen disease
  • Polyarteritis nodosa: CSF usually normal; nerve involvement in 10% of patients SLE
  • Neoplasm (leukemia, multiple myeloma, carcinoma): CSF protein often increased; may be associated with an occult primary neoplastic lesion outside CNS
  • Amyloidosis
  • Sarcoidosis
  • Toxic conditions due to drugs and chemicals (especially lead, arsenic, etc.)
  • Alcoholism—CSF usually normal
  • Bassen-Kornzweig syndrome
  • Refsum disease
  • Chédiak-Higashi syndrome
  • Immune mediated (e.g., Guillain-Barré syndrome)
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Cranial Nerve, Multiple
Laboratory findings due to causative conditions
  • Metabolic (e.g., diabetes mellitus, renal failure, chronic liver disease, myxedema, porphyria)
  • Trauma
  • Aneurysms
  • Tumors (e.g., meningioma, neurofibroma, carcinoma, cholesteatoma, chordoma)
  • Infections (e.g., herpes zoster)
  • Benign polyneuritis associated with cervical lymph node tuberculosis or sarcoidosis
Neuritis of One Nerve or Plexus
Laboratory findings due to causative disease
  • Diabetes mellitus
  • Infections (e.g., HIV, diphtheria, herpes zoster, leprosy)
  • Sarcoidosis
  • Polyarteritis nodosa
  • Tumor (leukemia, lymphoma, carcinomas)—may find tumor cells in CSF
  • Trauma
  • Serum sickness
  • Bell’s palsy
  • Idiopathic
  • Drugs, toxic substances
Facial Palsy, Peripheral Acute
Laboratory findings due to causative disease
Idiopathic (Bell palsy)—occasional slight increase in cells in CSF
Infection
  • Viral (e.g., varicella zoster, HSV, HIV, EBV, poliomyelitis, mumps, rubella)
  • Bacterial (e.g., Lyme disease, syphilis, leprosy, diphtheria, cat scratch disease, Mycoplasma pneumoniae)
  • Parasitic (e.g., malaria)
  • Meningitis
  • Encephalitis
  • Local inflammation (otitis media, mastoiditis, osteomyelitis, petrositis)
    • Trauma
    • Tumor (acoustic neuromas, tumors invading the temporal bone)
    • Granulomatous (e.g., sarcoidosis) and connective tissue diseases
    • Diabetes mellitus
    • Hypothyroidism
    • Uremia
    • Drug reaction
    • Postvaccinal effect
    • Paget disease of bone
    • Melkersson-Rosenthal syndrome
    • Lyme disease and Guillain-Barré syndrome may produce bilateral palsy.
Hemianopsia, Bitemporal
Laboratory findings due to causative disease
  • Usually pituitary adenoma
  • Also metastatic tumor, sarcoidosis, Hand-Schuller-Christian disease, meningioma of sella, and aneurysm of circle of Willis
Ophthalmoplegia
Laboratory findings due to causative disease
  • Diabetes mellitus
  • Myasthenia gravis
  • Hyperthyroid exophthalmos
Trigeminal Neuralgia (Tic Douloureux)
Laboratory findings due to causative disease
  • Usually idiopathic
  • May also stem from multiple sclerosis or herpes zoster
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Retrobulbar Neuropathy
Laboratory findings due to causative disease
CSF is normal or may show increased protein and ≤200/μL lymphocytes.
  • Multiple sclerosis ultimately develops in 75% of these patients.
Autonomic Neuropathy
Laboratory findings due to causative disease
  • Diabetes mellitus is most common
  • Amyloidosis
  • Acute porphyria
  • Guillain-Barré syndrome
  • Thallium poisoning
Pseudotumor Cerebri
Intracranial hypertension of unknown etiology with neurological complex of headache and papilledema without mass lesion or ventricular obstruction.
CSF is normal except for increased opening pressure.
Laboratory findings due to associated conditions (only obesity has been reported consistently)
  • Addison disease
  • Infection
  • Metabolic (acute hypocalcemia and other “electrolyte disturbances,” empty sella syndrome, pregnancy)
  • Drugs (e.g., psychotherapeutic drugs, sex hormones and oral contraceptives, corticosteroid administration usually after reduction of dosage or change to different preparation)
  • Immune diseases (e.g., SLE, polyarteritis nodosa, serum sickness)
  • Other conditions (e.g., sarcoidosis, Guillain-Barré syndrome, head trauma, various anemias, chronic renal failure)
Reye Syndrome
Acute noninflammatory encephalopathy with fatty changes in liver and kidney and rarely heart and pancreas. Occurs typically in children recovering from influenza, varicella, or nonspecific viral illness and is associated with use of aspirin.
Seizures That May Have Laboratory Abnormalities
Associated Conditions
Brain tumors, abscess, etc.
Circulatory disorders (e.g., thrombosis, hemorrhage, embolism, hypertensive encephalopathy, vascular malformations, angiitis)
Hematologic disorders (e.g., sickle cell anemia, leukemia, TTP)
Metabolic abnormalities
  • Carbohydrate metabolism (e.g., hypoglycemia [<40 mg/dL], hyperglycemia [>400 mg/dL], glycogen storage disease)
  • Amino acid metabolism (e.g., phenylketonuria, maple syrup urine disease)
  • Lipid metabolism (e.g., leukodystrophies, lipidoses)
  • Electrolytes (e.g., sodium [<120 or >145 mEq/L], calcium [<7 mg/dL], magnesium)
  • Hyperosmolality (>300 mOsm/L)
  • Other disorders (e.g., porphyria, eclampsia, renal failure)
Drugs (crack cocaine, amphetamines, ephedrine, etc.)
Allergic disorders (e.g., drug reaction, postvaccinal)
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Infections
  • Meningitis, encephalitis
  • Postinfectious encephalitis (e.g., measles, mumps)
  • Fetal (e.g., rubella, measles, mumps)
  • Others
Degenerative brain diseases
Neoplastic Lesions
Brain Tumor
CSF
CSF is clear, but is occasionally xanthochromic or bloody if there is hemorrhage into the tumor.
WBC may be increased ≤150 cells/μL in 75% of patients; normal in others.
Protein is usually increased. Protein is particularly increased with meningioma of the olfactory groove and with acoustic neuroma.
  • Tumor cells may be demonstrable in 20% to 40% of patients with all types of solid tumors, but failure to find malignant cells does not exclude meningeal neoplasm.
Atypical WBCs in leukemia or lymphoma
Tumor antigens/markers may indicate source of some metastatic tumors.
Glucose may be decreased if cells are present.
Brain stem gliomas, which are characteristically found in childhood, are usually associated with normal CSF.
Usually normal in “diencephalic syndrome” of infants due to glioma of hypothalamus
Glomus Jugulare Tumor
CSF protein may be increased.
Leukemic Involvement of CNS
Intracranial hemorrhage is principal cause of death in leukemia (may be intracerebral, subarachnoid, subdural).
More frequent when WBC is >100,000/μL and with rapid increase in WBC, especially in blast crises
Platelet count frequently decreased
Evidence of bleeding elsewhere
CSF findings of intracranial hemorrhage.
  • Meningeal infiltration of leukemic cells:
    • CNS is involved in 5% of patients with ALL at diagnosis and is the major site of relapse.
    • PCR is used to detect minimal residual cells that are not recognized morphologically.
    • Meninges are involved in <30% of patients with malignant lymphoma; most prevalent in diffuse large cell (“histiocytic”), lymphoblastic, and immunoblastic leukemia; occurs in one third to one half of patients with Burkitt’s lymphoma and 15% to 20% of patients with non-Hodgkin lymphoma.
    • Hodgkin disease seldom involves CNS.
    • Involvement by chronic lymphocytic leukemia, well-differentiated lymphocytic lymphoma and plasmacytoid lymphomas is very rare.
CSF may show
Increased pressure and protein
Glucose decreased to <50% of blood level
  • Increased cells that are often not recognized as blast cells because of poor preservation and that may be identified by cytochemical, immunoenzymatic, immunofluorescent, and flow cytometry techniques
  • Malignant cells found in 60% to 80% of patients with meningeal involvement
Complicating meningeal infection (e.g., various bacteria, opportunistic fungi)
Spinal Cord Tumor
  • CSF protein is increased. It may be very high and is associated with xanthochromia when there is a block of the subarachnoid space.
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With complete block, for cord tumors located at lower levels, protein concentration is higher.
Tumor cells may be demonstrable.
Vascular Disorders
Arteritis, Cranial
Cerebrovascular Accident (Nontraumatic, Stroke)
Blood Tests for Cerebrovascular Accidents
Plasma DNA concentration measured by PCR assay for β–globin gene present in all nucleated cells of the body is reported to correlate with stroke severity and predict mortality and morbidity in ER.8
Preliminary studies indicate S-100b (marker of astrocytic activation) and B-type neurotrophic growth factor may be a useful adjunct to CT scanning.9
Autoantibodies to brain-specific antigen N-methyl-D-aspartate receptor may assist diagnosis of stroke or assess risk of TIA.10
Due to
Hemorrhage
  • Ruptured berry aneurysm (45% of patients)
  • Hypertension (15% of patients)
  • Angiomatous malformations (8% of patients)
  • Miscellaneous causes (e.g., brain tumor, blood dyscrasia)—infrequent
  • Undetermined cause (rest of patients)
Occlusion (e.g., thrombosis, embolism, etc.) in 80% of patients
Especially if blood pressure is normal, always rule out ruptured berry aneurysm, hemorrhage into tumor, angioma, and coagulopathies (see Chapter 11).
Berry Aneurysm
In early subarachnoid hemorrhage (<8 hours after onset of symptoms), the test for occult blood may be positive before xanthochromia develops. After bloody spinal fluid occurs, WBC/RBC ratio may be higher in CSF than in peripheral blood.
Bloody CSF clears by 10th day in 40% of patients. CSF is persistently abnormal after 21 days in 15% of patients. ∼5% of cerebrovascular episodes due to hemorrhage are wholly within the parenchyma and CSF findings are normal.
Laboratory findings due to other diseases that occur with increased frequency in association with berry aneurysm (e.g., coarctation of the aorta, polycystic kidneys, hypertension).
Hemorrhage, Cerebral
Increased WBC (15,000–20,000/μL); higher than in cerebral infarct (e.g., embolism, thrombosis)
Increased ESR
Urine
  • Transient glycosuria
  • Laboratory findings of concomitant renal disease
Laboratory findings due to other causes of intracerebral hemorrhage (e.g., leukemia, aplastic anemia, polyarteritis nodosa, SLE, and other coagulopathies)
Thrombosis, Cerebral
  • CSF
    • Protein may be normal or increased to ≤100 mg/dL.
    • Cell count may be normal or ≥10 WBC/μL during first 48 hours and rarely ≥2,000 WBC/μL transiently on third day.
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Table 9-3. Differentiation between Bloody Cerebrospinal Fluid (CSF) Due to Subarachnoid Hemorrhage and Traumatic Lumbar Puncture
CSF Finding Subarachnoid Hemorrhage Traumatic Lumbar Puncture
CSF pressure Often increased Low or normal
Blood in tubes for collecting CSF CSF and blood uniformly mixed in all tubes Earlier tubes more bloody than later tubes; RBC count decreases in later tubes
CSF clotting No clots Often clots
Xanthochromia in supernatant Present if >2 hrs since hemorrhage Absent unless patient is icteric; may appear if examination is delayed >2 hrs
Immediate repeat of lumbar puncture at higher level CSF same as initial puncture CSF clear
Increased CRP and ESR are risk factors for development of stroke.
Increased CRP is associated with a poorer short-term prognosis.
Laboratory findings due to some diseases that may be causative
  • Hematologic disorders (e.g., polycythemia, sickle cell disease, thrombotic thrombopenia, macroglobulinemia); see Chapter 11
  • Vasculitis (e.g., polyarteritis nodosa, Takayasu syndrome, dissecting aneurysm of aorta, syphilis, meningitis); see Chapter 5
  • Hypotension (e.g., myocardial infarction, shock)
Footnotes
8
Rainer TH, Wong LK, Lam W, et al. Prognostic use of circulating plasma nucleic acid concentrations in patients with acute stroke. Clin Chem 2003;49:562–569.
9
Reynolds MA, Kirchick HJ, Dahlen JR, et al. Early biomarkers of stroke. Clin Chem 2003;49:1733–1739.
10
Dambinova SA, Khounteev GA, Izykenova GA, et al. Blood test detecting autoantibodies to N-methyl-D-aspartate neuroreceptors for evaluation of patients with transient ischemic attack and stroke. Clin Chem 2003;49:1752–1762.
Embolism, Cerebral
  • CSF
    • Usually findings are the same as in cerebral thrombosis.
    • Hemorrhagic infarction develops in one third of patients, usually producing slight xanthochromia; some of these patients may have grossly bloody CSF (10,000 RBCs/μL).
    • Septic embolism (e.g., bacterial endocarditis) may cause increased WBC (≤200/μL with variable lymphocytes and PMNs), increased RBC (≤1,000/μL), slight xanthochromia, increased protein, normal glucose, and negative culture.
Laboratory findings due to underlying causative disease
  • Bacterial endocarditis
  • Nonbacterial thrombotic vegetations on heart valves
  • Chronic rheumatic mitral stenosis with atrial thrombi
  • Mural thrombus due to underlying myocardial infarction
  • Myxoma of left atrium
  • Fat embolism in fracture of long bones
  • Air embolism in neck, chest, or cardiac surgery
Thrombosis of Cerebral Veins and Sinuses11
Produces hemorrhagic infarcts in ∼40% of cases
Due to
85% have prothrombotic cause or risk factors genetic (see Chapter 11) or acquired (e.g., pregnancy, nephrotic syndrome).
Infections (e.g., otitis, mastoiditis, sinusitis, meningitis)
Trauma (e.g., head injury, neurosurgery)
Inflammation (e.g., SLE, sarcoidosis, Wegener granulomatosis)
Hematologic (e.g., polycythemia, thrombocythemia)
Drugs (e.g., oral contraceptives)
Others (e.g., cancer)
Hypertensive Encephalopathy
Laboratory findings due to changes in other organ systems and to other conditions (e.g., cardiac, renal, endocrine, toxemia of pregnancy)
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Laboratory findings due to progressive changes that may occur (e.g., focal intracerebral hemorrhage)
CSF frequently shows increased pressure and protein ≤100 mg/dL.
Footnote
11
Stam J. Thrombosis of the cerebral veins and sinuses [review]. N Engl J Med 2005;352:1791–1798.
Spinal Cord Infarction
CSF changes same as in cerebral hemorrhage or infarction
Laboratory findings due to causative condition
  • Polyarteritis nodosa
  • Dissecting aneurysm of aorta
  • Arteriosclerosis of aorta with thrombus formation
  • Iatrogenic (e.g., aortic arteriography, clamping of aorta during cardiac surgery)
Laboratory findings due to underlying causative disease
  • Primary brain tumors, metastatic tumors, leukemias, and lymphomas
  • Pituitary adenomas (CSF protein and pressure usually normal)
  • Infections (e.g., tuberculoma)
  • Parasites forming abscesses, granulomas, cysts or migrating lesions (e.g., Taenia solium, Echinococcus, schistosomiasis, toxoplasmosis, amebiasis, trichinosis, cryptococcosis)
Laboratory findings due to associated genetic conditions (e.g., tuberous sclerosis, neurofibromatosis)
Thrombophlebitis of Cavernous Sinus
CSF is usually normal unless there is associated subdural empyema or meningitis, or it may show increased protein and WBC with normal glucose, or it may be hemorrhagic. Mucormycosis may cause this clinical appearance in diabetic patients.
Laboratory findings due to preceding infections, complications (e.g., meningitis, brain abscess), or other causes of venous thromboses (e.g., sickle cell disease, polycythemia, dehydration)
Laboratory findings due to involvement of cranial nerves