CHAPTER

NEUROLOGIC INVESTIGATION

THE CEREBROSPINAL FLUID

The cerebrospinal fluid (CSF) is formed partly from the choroid
plexuses of the ventricular system and partly by diffusion through
the ependymal lining of the ventricles. The total CSF volume is
around 120 mL, with a production rate of around 0.3 to 0.4 mL/
min. The fluid leaves the fourth ventricle through the median and
lateral recesses and then circulates over the surface of the spinal cord
and cerebral hemispheres before it is resorbed through the arachnoid villi of the superior sagittal sinus and to a lesser extent through
arachnoid villi in the spinal canal. The ionic composition of the fluid
indicates that it is not simply an ultrafiltrate of blood but is formed
by an active secretion process through the epithelium of the choroid
plexuses. The Na/K pump is the main mechanism underlying CSF
secretion. Na/K-ATPase has been detected in the surface of the choroid plexus epithelium.
CSF is normally obtained from the lumbar or cervical subarachnoid space, the cisterna magna, or the lateral ventricle. In adults, the
spinal cord terminates at the lower border of the first lumbar vertebra,
but the subarachnoid space continues to the level of the second or
third sacral vertebra. Insertion of an 18- to 21-gauge needle, usually
between the third and fourth, or fourth and fifth, lumbar vertebrae,
allows CSF to be assessed without injury to the spinal cord (Fig. 1-1).
After infiltration of local anesthetic, the beveled hollow needle
with stylet is introduced through the skin, subcutaneous tissues, and
finally the dura. The CSF pressure, maximally about 180 mm of
fluid in normal, nonobese subjects, is measured with a manometer
(Fig. 1-2). The CSF pressure of perhaps as much as 5% of the normal population exceed 200 mm, and this is usually attributable to
obesity.
For many patients, measurement of pressure along with protein
and glucose concentrations and cell count suffices as a screening procedure. The upper limit of normal for CSF protein concentration is
0.45 g/L, although the value varies between laboratories. The protein

Fig. 1-1. Lumbar puncture needle in situ.

concentration tends to rise with age and is higher in lumbar than

ventricular CSF. The cell count should not exceed five lymphocytes
per cubic millimeter. Other measurements frequently performed
include syphilis serology, IgG concentrations, and electrophoresis
(Fig. 1-3). A variety of other measurements are used to identify the
presence of unusual proteins, enzymes, infectious agents, and tumor
cells (Table 1-1).

PLAIN RADIOGRAPHY
Skull Radiography
Skull radiography is not used in the routine investigation of the
common neurologic disorders. Plain radiographs have a role in the
investigation of nonaccidental injury or penetrating injury and in the
assessment of ventriculoperitoneal-shunt tubing connections.
Spinal Radiography
Spinal radiography is still performed widely as part of the primary
survey for patients with acute spinal trauma, and less often for those
suspected of having cervical or lumbar nerve root compression,
although it is incapable of providing evidence, at least directly, of any
cord or root entrapment. Lateral and anteroposterior views of the
lumbar spine allow identification of the components of the neural

Fig. 1-2. Measuring CSF pressure.

2 Chapter 1 Neurologic Investigation

TABLE 1-1.CEREBROSPINAL FLUID ANALYSES IN

COMMON USE
TECHNIQUE

TARGET CELL OR DISEASE

Markers of Reactive/Tumor Cells (Immunocytochemistry)

CLA
Marks leukocytes
T2000
Marks reactive T lymphocytes
B1, B2
Mark B lymphocytes
Anti-kappa, anti-lambda
Clonal B lymphocytes (lymphoma)
HMB 45
Melanoma
Cytokeratin
Epithelial cells (carcinoma)
CA-125
Ovarian cancer
1

10 11 12 13 14

Fig. 1-3. CSF electrophoresis. Oligoclonal bands are present in samples 7, 9,

and 11.

arch, together with the shape and size of the intervertebral foramina (Fig. 1-4). Although many views of the cervical spine have been
described, anteroposterior, lateral, and oblique views suffice other
than for traumatic cases (Figs. 1-5 and 1-6). Views of the cervical
or lumbar spine in flexion and extension (Fig. 1-7) are performed
if there is a suggestion of instability of the spinefor example, after
injury. However, most spinal imaging is now performed with computed tomography (CT) or magnetic resonance imaging (MRI).

ULTRASOUND: NONINVASIVE SCANNING

Duplex scanning combines an ultrasound image with a pulsed Doppler flow detector. The neck vessels are first imaged with the ultrasound system and then scanned with the pulsed Doppler system to
identify any significant stenosis and the direction of the flow. The
common, internal, and external carotid arteries are assessed, and
then the subclavian and vertebral arteries (Fig. 1-8). The technique
provides a safe and accurate analysis of the state of the extracranial
vessels, and it can be used serially to assess the progression of atherosclerotic disease or its modification by surgery.
Transcranial Doppler sonography has been used to evaluate intracranial arterial disease, the existence of vasospasm, and the absence
of flow in patients who are brain dead. It allows the detection of
asymptomatic cerebral emboli (Fig. 1-9). Vessels that can be scanned
include the distal carotid siphon, and proximal segments of the anterior, middle, and posterior cerebral arteries.

COMPUTED TOMOGRAPHIC SCANNING

Computed tomographic scanning was originally called computerized
axial tomographic (CAT) scanning, but the term axial was dropped
because, although the images are acquired axially, they are now routinely visualized in any plane. Once the mainstay of neurologic imaging, it is still the first choice in the acute setting. It is of primary use
in trauma cases, for excluding intracranial hemorrhage, for assessing
bones, and in many cases when assessment of vessels (arteries, veins,
and dural sinuses) is necessary. It is used to obtain myelographic
images and in the assessment of acute stroke to obtain cerebral blood
flow and volume maps. Most CT scans are now obtained using helical
(spiral) scanning and using multidetector arrays (multislice scanners).
If used in a spiral mode, with table movement, they enable coverage
of a large volume of patient in a short time and allow arterial and
venous phase imaging with one bolus of IV contrast (e.g., CT angiography and venography). If the table is not moved, the same volume
(e.g., the brain) can be scanned repetitively during the passage of a
bolus of contrast, enabling CT perfusion maps to be obtained. At
present, 256-slice scanners are available (Fig. 1-10).

Tumor Protein Markers

HCG/-fetoprotein/placental
alkaline phosphatase
2-microglobulin
Markers of Infection
ELISA or Western blot

Viral antigens or antibodies

Pineal tumors
Carcinoma
Lyme disease or other antigen assays
HIV-1 infection
Toxoplasmosis
Cysticercosis
Herpes simplex
JC virus
Cryptococcus
Syphilis
Herpes zoster
Epstein-Barr virus
Arbovirus, enterovirus

CLA, Cationic leukocyte antigen; ELISA, enzyme-linked immunosorbent assay; HCG, human
chorionic gonadotropin.

CT Myelography
CT myelography is now seldom performed, but it may be necessary if
MRI is contraindicatedfor example, in a patient with a pacemaker.
The contrast can be inserted into either the lumbar or the cervical
region (Fig. 1-11). Although the latter is a more hazardous procedure, it may be necessary if there is a spinal block between the lumbar
and cervical regions (Fig. 1-12).
CT Angiography
Computed tomographyangiography (CTA) can be performed on
all multislice scanners with spiral capability and can be performed
immediately after standard CT imaging. Intravenous nonionic contrast medium is injected using a pump injector. The technique is particularly applicable for the assessment of carotid and vertebral artery
stenosis (particularly the origins of the vertebral arteries) (Fig. 1-13),
and for assessment of intracranial aneurysm morphology (Fig. 1-14).
CT Perfusion
The injection of a bolus of contrast with continuous scanning enables
the alteration of contrast with time to be plotted. Various parameters can be measured (time to peak, mean transit time, change in
contrast), which enables other parameters to be calculated (cerebral
blood flow, cerebral blood volume) using certain assumptions. These
parameters can be overlaid on a structural slice of brain for ease of
interpretation and have been validated with gold standard cerebral
blood flow measurements (using positron emission tomography
[PET]) (Fig. 1-15).

MAGNETIC RESONANCE IMAGING

The ability of MRI to allow visualization of bodily structures depends
on the presence in those structures of charged hydrogen atoms (protons), whose alignment can be influenced by the application of an
external magnetic field. If the magnetic field is parallel to the bodys
axis, the protons align so that the majority point to the north end of
the magnet, producing a bulk magnetization vector whose amplitude
is determined partly by proton density and partly by the strength of

Magnetic Resonance Imaging 3

B
Fig. 1-4. Normal lumbar spine radiographs. A, Lateral. B, Anteroposterior.

B
Fig. 1-5. Normal cervical spine radiographs. A, Lateral. B, Anteroposterior.

4 Chapter 1 Neurologic Investigation

B
Fig. 1-6. Normal cervical spine radiographs. A, Left posterior oblique. B, Right posterior oblique.

B
Fig. 1-7. Flexion (A) and extension (B) views of the cervical spine.

Magnetic Resonance Imaging 5

Internal

Common

External

Right carotid artery

Fig. 1-9. Transcranial Doppler. An example of an embolic signal appearing as a
short-duration, high-intensity signal in the Doppler spectrum.

Fig. 1-8. Duplex scan of the carotid bifurcation.

Cortical sulcus

Frontal horn

Pineal
gland

Suprasellar
cistern

Sylvian
Fourth
Quadrigeminal
fissure
ventricle
cistern
Fig. 1-10. Normal noncontrasted CT scan at four levels: at the vertex (A), at the level of the frontal horns (B), at the level of the third ventricle (C), and at the level of
the pons (D).

6 Chapter 1 Neurologic Investigation

Fig. 1-11. CT myelogram of the cord. A, Axial source data showing normal cervical cord and dorsal roots. B, Conus and filum.

Fig. 1-12. Reformatted thoracolumbar CT myelogram (A) and MRI (B) showing intramedullary signal change and anterior cord displacement with MRI, but with no
posterior mass seen with MRI and myelography.

the applied magnetic field. Magnetic field strength ranges between

0.25 and 3.0 tesla (T), compared with Earths magnetic field of 0.3
to 0.6 Gauss (1T = 10,000 G).
After equilibration, an electric current is passed through coils
mounted inside the magnet core so that a magnetic field is produced
at a chosen angle (often 90 or 180 degrees) to the main magnets
field. In practice, many and varying currents are used, and it is the
movement of these coils during switching of the powerful currents
that causes MRI scanning to be noisy. The alignment of the charged
protons can be changed by any angle up to 360 degrees. When the
electric current is switched off, the protons gradually return to their
previous alignment, emitting energy as they do so. Capturing this
emitted energy and positioning the source of emission with receiver
coils is the fundamental process that enables images to be obtained.
Two time measures of this decay are determined: T1 and T2. T1
measures time taken to recover the bulk magnetization vector in the
northsouth plane of the main magnet. T2 measures the time taken

for the individual charged particles to fall out of the coherent resonance induced by the radio frequency signal. T1-weighted images
produce pictures in which CSF is dark; in T2-weighted images, the
CSF appears lighter, and the contrast between gray and white matter is particularly prominent. Fluid-attenuated inversion recovery
(FLAIR) images are similar to T2 images but with suppressed CSF.
These are the three common sequences used in neurologic imaging (Fig. 1-16). One of the advantages of MR over CT (in addition
to the improved soft tissue contrast resolution) is that images can
be acquired in the sagittal, axial, or coronal (or indeed any) plane.
At higher field strengths, spatial resolution is improved for a given
acquisition time (Fig. 1-17). Three-dimensional (3D) data sets can
be reconstructed in a 3D format. A midline sagittal image displays
midline structures, including the third and fourth ventricles (Fig.
1-18). Axial images display horizontal brain slices at any level from
the vertex to the foramen magnum and can be targeted to show particular features of interest (Fig. 1-19).

Magnetic Resonance Imaging 7

Fig. 1-13. A, B: CT angiography showing origins of vertebral arteries, with calcified plaque and stenosis at the origin of the left vertebral artery.

P
Fig. 1-14. Axial (A), coronal (B), and sagittal (C) maximum-intensity projection reconstructions of an intracranial CT angiography showing anterior communicating artery
aneurysm morphology, with 3D superior oblique volume reconstructions (D and E).

8 Chapter 1 Neurologic Investigation

Fig. 1-15. Patient with acute right hemiparesis and dysphasia. A, Normal CT (at ictus +2 hrs). B and C, CT angiography showing left middle cerebral artery occlusion.
Cerebral blood volume (CBV) (D) and time-to-peak (TTP) (E) maps show irreversible ischemia in deep white matter and gray matter, and critical ischemia in cortex.
(TTP and cerebral blood flow maps show ischemic and infarcted tissue; CBV shows infarcted tissue.) F, Follow-up CT at 48 hours shows preserved cortex with infarct
corresponding to CBV map.

Fig. 1-16. Coronal T1 (A), axial T2 (B), and axial fluid-attenuated inversion recovery (FLAIR) (C) images through normal brain.

Magnetic Resonance Imaging 9

Fig. 1-17. Coronal 3-mm T2-weighted slices through the hippocampi at 1.5T (A) and 3T (B). Note the improved resolution at 3T, with improved detail of hippocampal
substructures.

Fig. 1-18. Midline sagittal T1-weighted (A) and T2-weighted (B) images demonstrating different appearances of the same structures on different sequences.

Conventional MRI techniques (e.g., spin echo) require a considerable time (up to 15 minutes). Accordingly, faster imaging techniques
have been developedfor example, fast spin echo and gradient echo
imaging. Although many thousands of sequences are now available, the standard sequences suffice in most clinical settings. The
IV contrast media used for MRI scanning are all gadolinium based.
Shortening the T1 relaxation times of lesions enhances the imaging
discrepancy between the lesion and its surrounding tissue.
MRI is also used to visualize the spinal cord and its surrounding
structures. A midline sagittal image is supplemented by axial images
at the relevant levels. Structures demonstrated on the sagittal images
of the cervicothoracic region include the spinal cord, the vertebral
bodies, and the intervertebral discs (Fig. 1-20). Axial views, according to the level, demonstrate the vertebral body, the facet joints,
the spinal cord and nerve roots, and the epidural space (Fig. 1-21).
Images of the lumbar spine demonstrate the vertebral body and neural arches, the discs, and the contents of the spinal canal (Fig. 1-22).
MR Angiography or Venography
Signal from vessels can be obtained using many types of sequences
with MR. Most commonly, 3D time of flight (3D TOF) (Fig.
1-23) or 2D TOF is used (neither needs IV contrast), but contrastenhanced MR angiography (MRA) and black blood MRA are also
available if needed. MR venography (MRV) is often produced using

phase contrast techniques. Carotid MRA does have a tendency to

overestimate tight stenoses.
Contrast-enhanced MRA requires a 3D gradient echo sequence
with a short repetition time of 3 to 7 msec and a short echo time of
1 to 3 msec. With correctly timed gadolinium infusion, high-signal
vascular imaging is obtained because of the T1 shortening of blood
caused by the gadolinium. By using the coronal plane, both carotid
and vertebral arteries can be assessed throughout their cervical and
intracranial portions. Carotid stenoses exceeding 30% are detected
on contrast-enhanced MRA with high sensitivity and specificity.
Contrast-enhanced MRA is a more sensitive technique than time-offlight MRA. The technique is less successful for detecting stenoses of
the vertebral artery origins.
Diffusion-Weighted MRI
Diffusion-weighted imaging (DWI) is of particular value in detecting signal changes in early cerebral infarction, but it is also useful for
differentiating abscesses from metastases (Fig. 1-24). DWI obtains
images sensitized to the distance diffused by water molecules in a set
time. Cytotoxic edema (e.g., caused by ischemia) entails cell swelling,
a reduction in intercellular space, and a reduction in the distance
a water molecule can diffuse. This causes restricted diffusion. DWI
images are usually obtained in three orthogonal planes (right-left,
anteroposterior, superoinferior). These are summed to produce an

10 Chapter 1 Neurologic Investigation

Fig. 1-19. A, Axial MR images showing third nerves in interpeduncular cistern. B, Left fourth nerve crossing prepontine cistern. C, Left fifth nerve exiting pons, and right
entering Meckels cave. D, Both sixth nerves entering Dorellos canal in the clivus. E, Seventh and eighth nerves in the internal auditory meat; F, Twelfth nerve and fifth
nerve leaving lateral medulla and traversing hypoglossal canals.

B
Fig. 1-20. A, B:T2-weighted sagittal MRI of cervical and upper thoracic spine.

Magnetic Resonance Imaging 11

apparent diffusion coefficient (ADC) map that allows for the differences in diffusion distances in normal tissue, which depend on
whether the underlying tissue has myelinated tracts running parallel or perpendicular to the direction of measurement (one DWI
sequence measures distance traveled in one direction only), and that
compensates for any T2 shine through (T2 signal that can shine
through on DWI sequences and give spurious results). Using DWI
sequences, it is also possible to obtain maps of fractional anisotropy,
which is related to diffusion direction and magnitude, particularly in

Fig. 1-21. T2-weighted MRI at the midcervical level.

white matter. This may have clinical uses in white matter diseases,
including multiple sclerosis, diffuse axonal injury, and dementia or
mild cognitive impairment.
MRI Tractography
In vitro, water diffuses freely in any planethat is, it is a vector, having both direction and distance. Using diffusion-weighted sequences
in multiple directions, it is possible to measure both the extent of
diffusion and its direction, which, in vivo, is not free in any plane but
is altered by the presence of myelinated white matter tracts, which
severely restricts diffusion in directions tangential to the direction of
the myelinated fibers. In MRI tractography, these vectors are overlaid
on a structural image and displayed as color maps with brightness
equivalent to increased magnitude (i.e., greater distance of diffusion),
and color can be used to encode direction (Fig. 1-25). White matter
tracts can be displayed using mathematical formulas that use various
assumptions to link neighboring voxels (Fig. 1-26).
MR Perfusion
The principles of MR perfusion are similar to those of CT perfusion coupled with an IV bolus injection of contrast agent to calculate time-to-peak (TTP), relative cerebral blood volume (rCBV),
and relative cerebral blood flow (rCBF) maps (relative because in
MR techniques the measured values are relative, as opposed to the
absolute values obtained with CT perfusion). This is useful in the
assessment of acute stroke and in imaging gliomas. Glioblastoma
multiforme typically demonstrates higher CBV than low-grade gliomas (Fig. 1-27). It is possible that a progressive elevation of CBV in
tumors is one of the earliest markers of transformation of a low-grade
glioma to a high-grade glioma. It is possible to obtain MR perfusion
data without IV contrast using arterial spin labeling techniques, but
this is not widely used.
Functional MR
Blood oxygen leveldependent (BOLD) functional MRI (fMRI)
is the most commonly used method. It measures changes in blood
flow by detecting changes in intravascular oxyhemoglobin concentration. This occurs because in activated cortex there is an increase
in blood flow, mediated by vasodilation, that exceeds the local metabolic requirement, and this results in an increase in the intravascular
oxyhemoglobin concentration (Figs. 1-28 and 1-29). This increase
can be measured, usually using gradient echo sequences. The BOLD
effect is greater at 3T than at 1.5T, so the former (if available) is
preferred.

Fig. 1-22. T2-weighted axial MRI of the lumbar spine.

MR Spectroscopy
The speed of precession (or spinning) of hydrogen atoms is governed by the strength of the external magnetic field. However,
when H is incorporated into chemicals, other atoms vary slightly
in local field strength. This slight variation in local magnetic field
strength (measured in parts per million) can tell us what chemical
the hydrogen atom is part of, and modern scanners allow us to

B
Fig. 1-23. A and B, Reconstructed data from 3D time of flight of circle of Willis.

12 Chapter 1 Neurologic Investigation

Fig. 1-24. Axial postcontrast T1-weighted (A, D), diffusion-weighted (B, E), and apparent diffusion coefficient (C, F) images of abscesses (A, B, C) and metastases
(D, E, F), showing similar ring enhancement on postcontrast T1 but with characteristically restricted diffusion in bacterial abscesses.

Fig. 1-25. Diffusion tensor imaging showing color (superoinferior, blue; anteroposterior, green; right-left, red-orange) encoding of tracts (A), with texture (B), and with
anatomic overlay (C).

Interventional Techniques 13

Fig. 1-26. Fiber tracking of motor fibers from cortex into cerebral peduncle. A, AP view. B, Oblique view.

Fig. 1-27. Biopsy-proven glioblastoma multiforme. Axial T2-weighted (A), postcontrast T1-weighted (B), and perfusion-weighted cerebral blood volume (CBV)
(C) MR images showing bland, nonenhancing mass with markedly raised CBV.

localize the position. Commonly, MR spectroscopy of the brain

is used to assess choline, creatine, N-acetylaspartate, inositol, lactate, and mobile lipid resonances. The varying proportions can
help in grading of primary tumors and assessing dementia (Figs.
1-30 and 1-31).

DIGITAL SUBTRACTION ANGIOGRAPHY

Catheter angiography allows visualization of the carotid and vertebral
arteries via injection of contrast medium through a catheter inserted
via the femoral artery into the aortic arch. For visualization of intracranial vessels, the catheter is then manipulated into the relevant neck
artery before injection of contrast medium. Digital subtraction angiography employs a computerized technique to eliminate background
detail and summate successive images (Figs. 1-32 through 1-35).
Visualization of spinal cord arteries is achieved by catheterizing the
relevant vessels from the thoracic and abdominal aorta (Fig. 1-36).
The need for intracranial angiography is declining as CT angiography and MR angiography have improved.

INTERVENTIONAL TECHNIQUES
Using the arterial (or sometimes venous) tree as an access pathway,
it is now possible to position a microcatheter almost anywhere in
the central nervous system (CNS). Endovascular techniques are now
the first-line treatment for intracranial aneurysms and for most dural
fistula. Arteriovenous malformations are now often treated endovascularly to obliteration or to reduce their size prior to surgery or stereotactic radiosurgery (gamma knife treatment).
It is possible to place stents in the middle and anterior cerebral
arteries, as well as in the internal carotid artery and the carotid bifurcation, although randomized trial data for benefit are lacking, and
these techniques are often used only in medically refractory cases.
Intraarterial clot lysis and aspiration catheters are available and
may be of benefit in the anterior intracranial circulation, but benefit
has not yet been shown in large randomized trials. In the posterior
circulation (particularly with basilar artery occlusion), the outcome
is so poor that intervention is often tried. Major dural venous sinus
occlusion can also be treated this way if there is no improvement with
IV heparin.

14 Chapter 1 Neurologic Investigation

Fig. 1-28. Functional MRI after visual stimulation showing increased activity in visual cortex.

Fig. 1-29. Functional MRI after voluntary movement of left hand.

Fig. 1-30. MR spectroscopy, normal brain spectrum.

Radioisotope Imaging 15

C
Fig. 1-31. MR spectroscopy spectrum in (A) and out of tumor (B), showing increased choline in low-grade tumor. C, Metabolite map of choline.

RADIOISOTOPE IMAGING
Single-Photon Emission CT
Single-photon emission computed tomography (SPECT) can be
carried out with either multidetector or rotating gamma camera
systems. Using a radioactively labeled isotope, usually technetium99m labeled hexamethylpropylene amine oxide, the system allows
quantitative assessment of regional cerebral blood flow. In normal
individuals, symmetrical activity is greatest in a strip corresponding
to cortical gray matter at the periphery of the frontal, temporal, parietal, and occipital lobes. In addition, high flow is found in the region
of the thalami and basal ganglia (Fig. 1-37).
Positron Emission Tomography
Positively charged electrons (positrons) are emitted during the decay
of certain unstable nuclei. When a positron collides with an electron,
the two particles destroy each other and in doing so release energy in

the form of paired photons, which then travel in opposite directions.

Using detectors placed around the head, the origin of the signal can
be localized to a particular tomographic slice of the brain. Accurate
measurement of activity requires a tissue volume of the order of
1 cm3. The isotopes commonly used are of oxygen, carbon, and
nitrogen, with a fluorine isotope substituted for hydrogen.
Cerebral perfusion and blood volume are measured, the former
with H2O labeled with radioactive oxygen (H215O), and the latter
with labeled CO2. Assessment of metabolic activity is achieved either
by calculating an oxygen extraction fraction using 15O2, or by the use
of a labeled glucose analogue (Fig. 1-38).
Transmitter systems in the brain can be studied in conditions such
as Parkinsons disease. PET with radioactively labeled dopa ([18F]
dopa PET) is used to visualize the nigrostriatal dopaminergic system.
[18F]Dopa PET reflects presynaptic dopa uptake, decarboxylation to
dopamine, and storage, with [18F]dopa uptake rate constants correlating with the number of functional dopaminergic neurons.

16 Chapter 1 Neurologic Investigation

Similarly, PET techniques can be used to assess dopaminergic
receptor systems. PET studies with selective D2 receptor ligands such
as 11C-raclopride show a mild increase in D2 site availability in the
putamen of de novo Parkinsons patients (Fig. 1-39). PET studies
have been applied to the study of other neurotransmitter systems,
such as those involving serotonin.

ELECTROPHYSIOLOGY
Electroencephalography
For an electroencephalography (EEG) recording, 16 to 20 scalp electrodes record, amplify, and convert the basic brain rhythms into a
trace drawn on paper moving at 3 cm/sec. Bipolar recording measures
the potential difference between two electrodes. Unipolar recording
measures the difference between a single electrode and, most commonly, an average reference electrode summating potentials from the
other recorders.
The electrodes are attached to the scalp with an adhesive material as the patient sits or lies on a couch (Fig. 1-40). The recording is performed with the patients eyes closed and also with eyes
open. In addition to the resting trace, recording is carried out during

overbreathing and while the patient is exposed to a light flashing at

frequencies from 1 to 20 Hz.
During maturation, the basic EEG rhythms accelerate, so that the
initially predominant theta and delta activities are replaced in the
adult by a dominant alpha rhythm, at 8 to 13 Hz, most conspicuous
in the post-central areas (Fig. 1-41). The alpha rhythm disappears
when the eyes are opened. Intermingled with the alpha rhythm is
beta activity, defined as rhythmic activity faster than 13 Hz. During
overbreathing, particularly in children, slower activity in the form of
theta and even delta activities can appear.
In an attempt to identify epileptic foci, additional techniques have
been devised, either using alternative electrode placements or exposing the patient to a stimulus theoretically capable of activating an otherwise silent focus. Both nasopharyngeal and sphenoidal electrodes
are sometimes used in the investigation of patients with suspected
epilepsy, and the former are generally more successful. Activation
procedures such as sleep deprivation or injection of Metrazol are now
seldom undertaken, but an EEG recording, with the patient asleep
or ambulatory with portable equipment, can be of value in the search
for epileptic activity. Increasingly, recording of activity is performed
from the cortex or with depth electrodes at the time of craniotomy.
Computer-assisted EEG interpretation has been used to permit
a topographic representation of normal and abnormal activity. For
example, the distribution of alpha rhythm can be presented in the
form of a brain map (Fig. 1-42).
Magnetoencephalography
Magnetoencephalography (MEG) is used to localize focal epileptic
discharges by measuring the changes in extracranial magnetic fields
that those discharges generate (Fig. 1-43). There is, in general, a good
correlation between the sites of foci localized by MEG and those discovered by the use of depth electrodes.
Evoked Potentials
Evoked potentials measure conduction along visual, auditory,
somatosensory, and motor pathways, either from the periphery to
the central nervous system (the first three) or vice versa (the last).
Averaging techniques allow the evoked response to be distinguished
from random background activity. Latency measurements are more
reliable than those of amplitude, because the latter are more susceptible to technical error.

LT Carotid
LAO

Fig. 1-32. Digital subtraction angiography. Normal left carotid bifurcation.

RT Carotid
lateral

Visual Evoked Potentials. Stimulation of the retina by an alternating pattern of light and dark squares produces a well-defined positive potential over the occipital cortex. Typically, 100 to 200 visual
presentations are required to obtain a satisfactory averaged response.
A pattern-reversal stimulus (Fig. 1-44) is the most effective, the
response being recorded by a string of electrodes above and below
the inion together with a horizontal row along a line 5 cm above the
inion. Monopolar recordings are made with the reference electrode
placed anteriorly. Full-field stimulation produces a triphasic potential

RT Carotid
lateral

RT Carotid
lateral

Fig. 1-33. Digital subtraction angiography. Normal lateral internal carotid artery arteriogram. Arterial (A), late arterial/capillary (B), and venous (C) phases.

Electrophysiology 17
with a large positive component, preceded and followed by smaller
negative potentials (Fig. 1-45). Topographic mapping confirms the
occipital localization of the evoked response (Fig. 1-46).
Abnormal responses, particularly with respect to latency, have
been identified, most commonly in patients with multiple sclerosis
(MS). Many other neurologic disorders (e.g., Friedreichs ataxia and
Parkinsons disease) can affect latency, although to a lesser degree
than in MS.
Alteration of both waveform and latency can occur with compression of the visual pathway at any site.

are made of the interwave latencies and the amplitude ratio of

waves I to V.
Wave I represents the eighth nerve activation potential, and waves
II and III are derived from the cochlear nucleus and superior olivary
complex, respectively. The origin of waves IV and V is less certain,
although the latter may represent arrival of the signal at the inferior
colliculus. Waves VI and VII are variable and seldom used in clinical
studies.
Measurement of auditory evoked responses has been used in the
investigation of vestibular neurinomas, MS, and intrinsic brainstem
tumors, although this role is now largely historical.

Auditory Evoked Responses. Auditory evoked responses are obtained

Somatosensory Evoked Potentials. After limb stimulation, an

evoked potential can be recorded not only from the relevant peripheral nerve but also from over the spine or the cortex (Fig. 1-49). If
the median nerve is stimulated at the wrist, with recording electrodes
over the neck, four distinct negative potentials can be recorded: N9,
N11, N13, and N14 (Figs. 1-50 and 1-51). A later negative wave
with a latency of about 20 msec can be recorded over the contralateral sensory cortex (N20). Late (vertex) potentials can be evoked by
visual, auditory, or somatosensory stimulation. Their latencies extend
up to about 300 msec.
Measurement of somatosensory evoked potentials (SSEPs) has
found less clinical application than either visual or auditory evoked
potentials. Abnormalities have been found, particularly in patients
with MS, but also in those with cervical spondylosis, spinal trauma,
or brachial plexus lesions. Monitoring of SSEPs has been used during
the course of spinal cord surgery.

by applying a click stimulus via earphones. The clicks, applied unilaterally, are repeated at a frequency of 10 Hz. A masking noise is used
contralaterally. Click intensity is set at about 70 dB above the hearing
threshold. The response to 1000 to 2000 clicks is summated using
electrodes over the earlobe and vertex (Fig. 1-47). The brainstem components are separated into waves I to VII (Fig. 1-48). Measurements

Central Motor Conduction

The corticospinal tract can be stimulated through the scalp either
electrically or by an electromagnetic system. The latter method is
preferable as it causes less discomfort. After transcranial activation of
the motor system, a response can be recorded, principally contralaterally, from the muscles of the limbs or trunk. The type of response and
its latency depend on the stimulus mode (Fig. 1-52).
Subclinical abnormalities of central motor conduction have been
found in patients with MS. The technique has also been used to
study conduction time in patients with motor neuron disease or cervical myelopathy, and during surgery of the spinal cord.
Nerve Conduction Studies and Electromyography
Nerve conduction studies are of great value in the assessment of
peripheral nerve function. A short-duration stimulus is used, usually
0.2 msec, with a repetition rate of 1 Hz. The stimulating electrode is
either positioned at sites where the nerve is close to the skin surface,
or around the digits in the form of a ring (Fig. 1-53). The resulting

Fig. 1-34. Digital subtraction angiography. Normal frontal (Townes projection)

internal carotid artery view.

Vertebral
townes

RT
Vertebral

Lateral

B
Fig. 1-35. Digital subtraction angiography. Normal frontal (A) and lateral (B) vertebral arteriograms.

18 Chapter 1 Neurologic Investigation

Fig. 1-36. A and B, Digital subtraction angiography, two views. Radicular injection demonstrating filling of anterior spinal artery from artery of Adamkiewicz.

Nerve conduction, particularly as measured by H reflexes and F

responses, is also influenced by height. Commonly studied nerves for
sensory conduction include the median, ulnar, and radial nerves in
the upper limbs, and the sural, medial, and lateral plantar nerves in
the lower limbs.
Motor conduction velocities are measured by stimulating the
peripheral nerve at two or more separate sites while recording the
response from the relevant muscle using surface or needle electrodes (Fig. 1-55). A velocity is obtained by dividing the distance
between any two stimulating sites by the latency difference of the two
responses (Fig. 1-56). The figure obtained applies to the most rapidly
conducting fibers in the nerve.
The H Reflex. The H reflex is a monosynaptic reflex response that can

be obtained from the soleus muscle after stimulation of the tibial nerve.
Stimulation of afferent fibers in the tibial nerve triggers a reflex response
in the motor nerves to the soleus via the spinal cord (Fig. 1-57).

The F Wave. The F wave requires a more potent stimulus than the

Fig. 1-37. Single-photon emission computed tomography (SPECT). Normal study.

Low-flow areas (e.g., the skull) appear blue, high-flow areas are yellow.

sensory action potential is satisfactorily recorded by a surface electrode (Fig. 1-54). Conventionally, about 30 repetitive stimulations
are used, with the responses being averaged.
Conduction velocity in the fast conducting fibers in the nerve can
be expressed as a distal latency or as an actual velocity. Conduction
velocity declines with age and slows with a fall in limb temperature.
Cooling increases compound muscle action potential amplitude.

H reflex. With such a stimulus, a depolarizing wave is transmitted

both centrally and distally, with the former then activating anterior
horn cells. The resulting action potential propagates down the motor
nerve, producing a potential several milliseconds after the direct
response. Variation in latency and amplitude of successive F wave
responses occurs because the anterior horn cells activated vary from
stimulation to stimulation (Fig. 1-58). The latency of the F response
is a measure of conduction time in the proximal segment of the relevant nerve. It is particularly valuable in the evaluation of those demyelinating neuropathies in which proximal involvement is likelyfor
example, in chronic inflammatory demyelinating polyneuropathy.

Repetitive Stimulation. Nerve stimulation over a range of frequen-

cies is used in the evaluation of the neuromuscular junction. In normal individuals, a small decrement can occur in the size of the muscle
evoked potential when the nerve is stimulated at 10 Hz or less. At
faster rates of stimulation (10 to 50 per second), a small increment is
sometimes seen initially, and the compound action potential subsequently remains stable.

Electrophysiology 19

Acute stroke (7 hours)

CBF

OEF

CMRO2

PH

K1

CBV
SNOW 3

Fig. 1-38. Cerebral blood flow (CBF), cerebral oxygen metabolism (CMRO2), oxygen extraction fraction (OEF), cerebral blood volume (CBV), and pH in patient 7 hours
after an acute stroke. The OEF image displays a central zone of reduced oxygen extraction, with enhanced extraction at its periphery.

CM 8.2

CM 6.8

CM 5.4

CM 4.0

CM 2.6

CM 1.2

Fig. 1-39. PET images of a normal subject injected with 18F-labeled N-methylspiperone, demonstrating intense uptake of tracer in the basal ganglia.

20 Chapter 1 Neurologic Investigation

B
Fig. 1-40. Electroencephalographic electrode placements. Lateral (A) and anterior (B) views.

NORMAL 16 CHANNEL ELECTROENCEPHALOGRAM

5

7
8

3
4

15

14
9

13
12

11

10

11

12

13

14

15

16

10

1 second
1 second
Fig. 1-41. Normal 16-channel EEG. The electrode placements are shown on the left (position 6).

5.3
v
FpZ
FZ
CZ

2.6

PZ
01

1.3

0Z
02

0
Fig. 1-42. Topographic electroencephalography demonstrating the distribution of
alpha rhythm in a normal subject. A frequency analysis for alpha rhythm is shown
on the left. It reaches its maximal amplitude (red) over the occipital electrodes (O2
and Oz).

ELECTROMYOGRAPHY
Most sampling of muscle for analysis of motor unit activity is done
with a concentric needle electrode (Fig. 1-59). In the relaxed state,
no spontaneous activity can be recorded from healthy muscle except
in the region of the motor endplate. As the needle is inserted, a brief
burst of electrical activity occurs (insertional activity), and it becomes
prolonged in a variety of neuropathic and myopathic disorders.
Abnormal spontaneous activity includes fibrillation potentials,
positive sharp waves, and fasciculation potentials. Fibrillation potentials are biphasic or triphasic and arise from single, or a small number
of, muscle fibers. They are particularly associated with denervation of
muscle (Fig. 1-60, A). Positive sharp waves have a similar connotation (see Fig. 1-60, B).
Fasciculation potentials are larger and readily visible to the naked
eye. They are believed to represent the spontaneous contraction of
fibers belonging to a single motor unit. They can be found in normal
muscle but are particularly associated with motor neuron disease (see
Fig. 1-60, C).

Electromyography 21
MAGNETOENCEPHALOGRAM

A
C

Fig. 1-44. The visual stimulus used for visual evoked responses.

Fig. 1-43. Magnetoencephalogram (MEG). A, Schematic of a squid (superconductive quantum interference device) magnetometer, which is connected to a detection coil and immersed in liquid helium. The magnetometer is positioned close
to the patients head. The output is in voltage proportional to the magnetic field
detected. B, Magnetic spikes were measured at more than 20 sensor positions
located 2 cm apart. In this patient, one similar, unaveraged magnetic spike, out of
a total of four spike types, was displayed over the right temporal region. C, Dots
represent the locations where the magnetic measurements were made. From the
distribution of the amplitude of the same magnetic spike, sampling the signal at the
spike peak, an isofield contour map was made and the equivalent current source
was calculated for this particular field pattern. D, Each of four dots in the temporal
tip represents a different spike type. Electrocorticography (ECoG) showed epileptiform activity in the shaded area of the right temporal lobe, which was surgically
removed. In this case, the MEG results matched well with the ECoG findings.

0 20 40 60 80 100 120 140 160 180 200 220240

Ch1
2V

Ch1
2V

Ch2
2V

Ch2
2V

Ch3
2V

Ch3
2V

Ch4
2V

Ch4
2V

Ch5
2V

Ch5
2V

0 20 40 60 80 100 120 140 160 180 200 220240

msec
msec
Fig. 1-45. Normal visual evoked potential. Averaging techniques allow the evoked potential to be distinguished from any random background activity.

22 Chapter 1 Neurologic Investigation

During muscle contraction, the nature of the motor unit potentials can be assessed. As the force of contraction increases, the motor
unit potentials coalesce to form an interference pattern that eventually completely obscures the baseline (see Fig. 1-60, D). In neuropathic disorders, the motor units lessen in number and tend to be
prolonged and polyphasic. In primary muscle disease, amplitude and
duration of the potentials lessen, often, again, with polyphasia.
Single-Fiber Studies
Recording action potentials from individual muscle fibers shows that
for two fibers belonging to the same motor unit, a slight difference in
timing occurs, which varies slightly between consecutive discharges
because of variability in delay of conduction at their respective neuromuscular junctions (known as jitter) (Fig. 1-61). This phenomenon
is accentuated in myasthenia gravis.

BIOPSY
Muscle Biopsy
Muscle biopsy can be performed by needle or as an open procedure. The former is less invasive and allows multiple samples to be
obtained; the latter allows better assessment of tissue architecture and
is more sensitive for the detection of focal processes such as inflammation. In normal muscle, the fibers lie in close relationship to one
another, with one or more peripheral nuclei. Some variability of fiber
size occurs in normal subjects (Fig. 1-62).
Staining techniques allow separation of muscle into different fiber
types. Myofibrillar adenosine triphosphatase (ATPase) at pH 9.4
produces a dark-staining reaction in type II (fast-reacting) fibers and

a light reaction in type I fibers (Fig. 1-63). With nicotinamide dinucleotide tetrazolium reductase (NADH-tr), the reverse staining reaction is found, with some differential staining among type II fibers.
The distribution of fiber type varies from muscle to muscle. An
increased proportion of one fiber type, or a selective atrophy, is a
recognized consequence of certain muscle disorders.
Nerve Biopsy
Nerve biopsy is sometimes of value when attempting to clarify the
diagnosis or classification of certain peripheral nerve disorders. The
sural nerve is usually chosen, largely because it is very commonly
affected by the peripheral neuropathies, and also because its sacrifice
is of little consequence to most patients. It is of sufficient size to allow
a number of fascicles, each around 3 to 4 cm in length, to be dissected
free from the main trunk (Fig. 1-64). Part of the material is used for
the preparation of teased fibers and part for the preparation of transverse and longitudinal sections.
The teased fiber preparation demonstrates the nodes of Ranvier
and the Schwann cells (Fig. 1-65). The internodal length and its
variability can be calculated, along with the thickness of the myelin
sheath. In transverse section, the nerve fibers appear as circles, the
size of which is determined by the thickness of the myelin sheath.
Groups of fibers are bound together by an encircling connective tissue (the perineurium) (Fig. 1-66), forming a fasciculus. In turn, the
fasciculi are bound together in a further layer of connective tissue,
the epineurium. Blood vessels run within the epineurium and then
divide to supply capillary branches to the individual fibers and their
surrounding endoneurium (Fig. 1-67).


10.6
v
FpZ
FZ
CZ
PZ

.67

0.00

.45
5.3

.79 .22

.24

.11 .00

.68 .27

.38

.87 .68
0

01

1.00 2.03

3.03

3.39 3.26

0Z

5.60

6.98

6.94

A
5.3

02
10.6


Fig. 1-46. Topographic mapping of visual evoked potential. The P2 potential is
shown pointing upward on the left side of the figure and has a maximal amplitude
(red on the right-hand side) at the O2 and Oz channels.

B
Fig. 1-47. Electrode placement (A) and headphones in position (B) for measurement of auditory evoked responses.

Biopsy 23
0

9 msec

2
Ch1 + 2
0.5 V

Fig. 1-48. Normal brainstem evoked potentials using a 70-dB stimulus. Waves VI
and VII are often ill defined and have not been demonstrated here.

B
Fig. 1-49. Electrode placement for somatosensory evoked potentials. Lateral
(A) and posterior (B) views.

N20

5 V
2.5 V

N13/14

N11

N9

7 ms
Fig. 1-50. Early somatosensory evoked potentials N9 and N11.

7 ms
Fig. 1-51. Somatosensory evoked potentials N13, N14, and N20.

24 Chapter 1 Neurologic Investigation

ELECTROMAGNETIC STIMULATION
THENAR relaxed

THENAR contracted

4 mV

19.6 ms

BICEPS BRACHII

Stim.
View from above:
Coil at vertex

5 ms
EMG recorded
on right

Fig. 1-53. Electrodes attached to the little finger with the recording electrode
over the ulnar nerve at the wrist.

Fig. 1-52. Central motor conduction. Response from a normal subject.

Wrist

Sural
5 mV
Elbow

10 V
Median

Ulnar

1 ms
Fig. 1-54. Normal sural, median, and ulnar sensory action potentials.

Erbs point

5 ms
Fig. 1-55. Ulnar motor conduction studies. Stimulating the nerve at the wrist, at
the elbow, and at Erbs point.

Biopsy 25

Conduction velocity
R common peroneal
nerve 47 m/sec

2 mV

Conduction velocity
R post. Tibial nerve
46 m/sec

Stimulus M
artifact wave

5 ms
Fig. 1-56. Measurement of motor conduction velocity in the right common peroneal and right posterior tibial nerves.

H
wave

5 mV
Fig. 1-57. As the stimulus strength increases (from higher to lower), the H reflex
diminishes and the M response appears.

5 mV

5 ms
Fig. 1-58. F wave. A succession of responses recorded from abductor pollicis
brevis after stimulation of the median nerve at the wrist.

Fig. 1-59. Concentric needle electrode in abductor pollicis brevis.

26 Chapter 1 Neurologic Investigation

100 V

100 mS

200 V

100 mS

JITTER

200 V

100 mS

200 V
0.5 mS
Fig. 1-60. Electromyographic findings. A, Fibrillation potentials. B, Positive sharp
waves. C, Fasciculation potentials. D, Normal interference pattern.

200s
1ms
Fig. 1-61. In normal subjects, the slight variability of delay in conduction at the
neuromuscular junctions of two fibers belonging to the same motor unit can be
recorded.

Fig. 1-62. Normal muscle cells are approximately hexagonal in shape. The bluestaining nuclei are visible beneath the cell membrane (H&E 600).

Fig. 1-63. Normal muscle.Type 1 (slow-reactive) fibers are lightly stained and type
II (fast-reactive) fibers are darkly stained (ATPase [at pH 9.4]; 600).

Biopsy 27

Fig. 1-64. Sural nerve biopsy.

Fig. 1-65. Teased-fiber preparation of normal peripheral nerve. A node of Ranvier

is seen toward the left end of the fiber, with a Schwann cell toward the right.

Endoneurium

Blood vessel

A
Connective tisue

Perineurium

Axon

Myelin sheath

Fig. 1-66. Transverse section of normal peripheral nerve. A, H&E 40. B, Methylene blue, azure 2, basic fuchsin; 100.

Longitudinally
arrayed fibers

Blood vessel
Fig. 1-67. Longitudinal section of normal peripheral nerve (Luxol fast blue/Nissl;
40).