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)

See Table 9-1.

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 meningitis^a	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 paresis^b	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 abscess^d		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	≤500^e	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 embolism^f
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 in∼50% 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

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

See Table 9-1.

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

Schroeder C, et al. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med 2005;353:1585.

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

See Table 9-1.

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)

See Tables 9-1, 9-2, and Chapter 15.

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

See Chapter 15.

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

See Chapter 9.

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

See Chapter 11.

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

See Vasculitis, Chapter 5.

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)

CSF—See Tables 9-1, 9-3.

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

	Interpretation of Diagnostic Tests 8th Edition
	© 2007 Lippincott Williams & Wilkins

Interpretation of Diagnostic Tests8th Edition

Interpretation of Diagnostic Tests
8th Edition