3287 Neuroimaging in Neurologic Disorders CHAPTER 423

FIGURE 423-4 Herpes simplex encephalitis in a patient presenting with altered

mental status and fever. A. and B. Coronal (A) and axial (B) T2-weighted fluidattenuated inversion recovery images demonstrate expansion and high signal

intensity involving the right medial temporal lobe and insular cortex (arrows). C.

Coronal diffusion-weighted image demonstrates high signal intensity indicating

restricted diffusion involving the right medial temporal lobe and hippocampus

(arrows) as well as subtle involvement of the left inferior temporal lobe (arrowhead).

This is most consistent with neuronal death and can be seen in acute infarction as

well as encephalitis and other inflammatory conditions. The suspected diagnosis

of herpes simplex encephalitis was confirmed by cerebrospinal fluid polymerase

chain reaction analysis.

A

B

C

deposits are associated with histologic changes that would suggest

neurotoxicity, even among agents with the highest rates of deposition.

ALLERGIC HYPERSENSITIVITY Gadolinium-DTPA (diethylenetriaminepentaacetic acid) does not normally cross the intact BBB immediately but will enhance lesions lacking a BBB (Fig. 423-3A) as well

as areas of the brain that normally are devoid of the BBB (pituitary,

dura, choroid plexus). However, gadolinium contrast slowly crosses

an intact BBB over time and especially in the setting of reduced renal

clearance or inflamed meninges. The agents are generally well tolerated; overall adverse events after injection range from 0.07–2.4%. True

allergic reactions are rare (0.004–0.7%) but have been reported. Severe

life-threatening reactions are exceedingly rare; in one report, only

55 reactions out of 20 million doses occurred. However, the adverse

reaction rate in patients with a prior history of reaction to gadolinium

is eight times higher than normal. Other risk factors include atopy or

asthma (3.7%). There is no cross reactivity between different classes of

contrast media; a prior reaction to gadolinium-based contrast does not

predict a future reaction to iodinated contrast medium, or vice versa,

more than any other unrelated allergy. Gadolinium contrast material

can be administered safely to children as well as adults, although these

agents are generally avoided in those aged <6 months.

NEPHROTOXICITY Contrast-induced renal failure does not occur

with gadolinium agents. A rare complication, nephrogenic systemic

fibrosis (NSF), has occurred in patients with severe renal insufficiency

who have been exposed to linear (Group 1 and 3) gadolinium contrast

agents. The onset of NSF has been reported between 5 and 75 days

following exposure; histologic features include thickened collagen bundles with surrounding clefts, mucin deposition, and increased numbers

of fibrocytes and elastic fibers in skin. In addition to dermatologic

symptoms, other manifestations include widespread fibrosis of the

skeletal muscle, bone, lungs, pleura, pericardium, myocardium, kidney,

muscle, bone, testes, and dura. The American College of Radiology

recommends that a glomerular filtration rate (GFR) assessment be

obtained within 6 weeks prior to elective gadolinium-based MR contrast agent administration in patients with:

1. A history of renal disease (including solitary kidney, renal transplant, renal tumor)

2. Age >60 years

3. History of hypertension

4. History of diabetes

5. History of severe hepatic disease, liver transplantation, or pending

liver transplantation; for these patients, it is recommended that the

patient’s GFR assessment be nearly contemporaneous with the MR

examination.

The incidence of NSF in patients with severe renal dysfunction

(GFR <30) varies from 0.19–4%. Other risk factors for NSF include

acute kidney injury, the use of nonmacrocyclic agents, and repeated

or high-dose exposure to gadolinium. The American College of

Radiology Committee on Drugs and Contrast Media considers the

risk of NSF among patients exposed to standard or lower doses of

Group 2 gadolinium agents (macrocyclic agents) to be sufficiently low

or possibly nonexistent such that the assessment of renal function is

optional prior to administration. Group 2 agents are strongly preferred

in patients at risk for NSF. Renal function, dialysis status, or informed

consent are not recommended prior to injection of Group 2 agents,

but deference is made to local practice preferences. Patients receiving

any Group 1 (linear) or 3 gadolinium-containing agent should be considered at risk of NSF if they are on dialysis (of any form); have severe

or end-stage chronic renal disease (eGFR <30 mL/min per 1.73 m2

)

without dialysis; eGFR of 30–40 mL/min per 1.73 m2

 without dialysis

(as the GFR may fluctuate); or have acute renal insufficiency. The use

of gadolinium in young children and infants is discouraged due to the

unknown risks and their immature renal systems.

■ COMPLICATIONS AND CONTRAINDICATIONS

From the patient’s perspective, an MRI examination can be intimidating, and a higher level of cooperation is required than with CT. The

ion is “caged” in the cavity of the ligand, and thus the rate of dissociation of gadolinium is slower compared to linear ligands (Group 1

agents). Most agents are excreted by the renal system.

BRAIN ACCUMULATION OF GADOLINIUM It recently has become

evident that gadolinium accumulates in the dentate nuclei and globus

pallidus of the brain after serial administration of some linear Group 1

gadolinium agents. This has not been demonstrated for Group 2 macrocyclic agents. Gadolinium deposition in the brain appears to be dose

dependent and occurs in patients with no clinical evidence of kidney

or liver disease. To date, there have been no reports to suggest these

3288 PART 13 Neurologic Disorders

TABLE 423-4 Common Contraindications to Magnetic Resonance

Imaging

Cardiac pacemaker or permanent pacemaker leads

Internal defibrillatory device

Cochlear prostheses

Bone growth stimulators

Spinal cord stimulators

Electronic infusion devices

Intracranial aneurysm clips (some but not all)

Ocular implants (some) or ocular metallic foreign body

McGee stapedectomy piston prosthesis

DuraPhase penile implant

Swan-Ganz catheter

Magnetic stoma plugs

Magnetic dental implants

Magnetic sphincters

Ferromagnetic inferior vena cava filters, coils, stents—safe 6 weeks after

implantation

Tattooed eyeliner (contains ferromagnetic material and may irritate eyes)

Note: See also http://www.mrisafety.com.

A B C

FIGURE 423-5 Susceptibility-weighted imaging in a patient with familial cavernous malformations. A. Noncontrast computed tomography scan shows one hyperdense

lesion in the right hemisphere (arrow). B. T2-weighted fast-spin echo image shows subtle low-intensity lesions (arrows). C. Susceptibility-weighted image shows numerous

low-intensity lesions consistent with hemosiderin-laden cavernous malformations (arrow).

patient lies on a table that is moved into a long, narrow gap within

the magnet. Approximately 5% of the population experiences severe

claustrophobia in the MR environment. This can be reduced by mild

sedation but remains a problem for some. Movement of the patient

during an MR examination may distort all of the images in sequence;

therefore, uncooperative patients should either be sedated for the MR

study or scanned with CT. Generally, children aged <8 years usually

require conscious sedation in order to complete the MR examination

without motion degradation.

MRI is considered safe for patients, even at very high field strengths.

Serious injuries have been caused, however, by attraction of ferromagnetic objects into the magnet, which act as missiles if brought too close

to the magnet. Likewise, ferromagnetic implants, such as aneurysm

clips, may torque within the magnet, causing damage to vessels and

even death. Metallic foreign bodies in the eye have moved and caused

intraocular hemorrhage; screening for ocular metallic fragments is

indicated in those with a history of metal work or ocular metallic

foreign bodies. Implanted cardiac pacemakers are generally a contraindication to MRI owing to the risk of induced arrhythmias; however,

some newer pacemakers have been shown to be safe and if necessary

MR may be performed if the pacemaker can be safely turned off during

the scan. All health care personnel and patients must be screened and

educated thoroughly to prevent such disasters because the magnet is

always “on.” Table 423-4 lists common contraindications for MRI.

MAGNETIC RESONANCE ANGIOGRAPHY

On routine spin echo MR sequences, moving protons (e.g., flowing

blood, CSF) exhibit complex MR signals that range from high- to

low-signal intensity relative to background stationary tissue. Fast-flowing

blood returns no signal (flow void) on routine T1W or T2W spin echo

MR images. Slower-flowing blood, as occurs in veins or distal to arterial stenosis, may appear high in signal. MR angiography makes use of

pulse sequences called gradient echo sequences that increase the signal

intensity of moving protons in contrast to suppressed low signal background intensity of stationary tissue. This results in a stack of images,

which can be reformatted in any plane to highlight vascular anatomy

and relationships.

Several types of MRA techniques exist. Time-of-flight (TOF) MRA is

normally done without contrast administration and relies on the suppression of nonmoving tissue to provide a low-intensity background

for the high signal intensity of flowing blood entering the section.

A typical TOF MRA sequence results in a series of contiguous, thin

MR sections (0.6–0.9 mm thick), which can be viewed as a stack and

manipulated to create an angiographic image data set that can be reformatted and viewed in various planes and angles, much like that seen

with conventional angiography (Fig. 423-2G).

Phase-contrast MRA has a longer acquisition time than TOF MRA,

but in addition to providing anatomic information similar to that of

TOF imaging, it can be used to reveal the velocity and direction of

blood flow in a given vessel.

MRA is also often acquired during infusion of IV gadolinium

contrast material. Advantages include faster imaging times (1–2 min

vs 10 min), fewer flow-related artifacts, and 4D temporal imaging

resulting in arterial and venous phases. Recently, contrast-enhanced

MRA has become the standard for assessment of the extracranial vascular structures. This technique entails rapid imaging using coronal

three-dimensional TOF sequences during a bolus infusion of gadolinium contrast agent.

MRA has lower spatial resolution compared with conventional filmbased angiography, and therefore the detection of small-vessel abnormalities, such as vasculitis and distal vasospasm, is problematic. MRA

is also less sensitive to slowly flowing blood and thus may not reliably

differentiate complete from near-complete occlusions. Motion, either

by the patient or by anatomic structures, may distort the MRA images,

creating artifacts. These limitations notwithstanding, MRA has proved

useful in evaluation of the extracranial carotid and vertebral circulation

as well as of larger-caliber intracranial arteries and dural sinuses. It has

also proved useful in the noninvasive detection of intracranial aneurysms and vascular malformations.

Vessel wall MR imaging (VWI) is an MR technique that relies on suppression of all moving protons within vessels and CSF, combined with

IV contrast administration (Fig. 423-6). Unlike MRA, VWI is a high

3289 Neuroimaging in Neurologic Disorders CHAPTER 423

FIGURE 423-6 Arterial spin label and vessel wall imaging in a 25-year-old woman with focal cerebral arteriopathy. The patient had an 8-month history of intermittent

weakness of the right side with spasms. Imaging shows evidence of cerebral ischemia. CSF was transiently inflammatory. A. Diffusion-weighted image shows focal region

of reduced diffusion in left parietal lobe. B. T2 FLAIR images show several foci of high signal in left deep subcortical white matter. C. Arterial spin label image demonstrates

reduced cerebral blood flow in left parietal lobe (arrows). D. 3D T1 image without contrast administration. E. 3D T1-weighted Cube vessel wall image following gadolinium

contrast shows focal enhancement of the left proximal middle cerebral artery (arrow). (F): 3D TOF MRA shows focal narrowing of the left supraclinoid internal carotid artery

and proximal middle cerebral artery (arrow).

A B

C D

E F

3290 PART 13 Neurologic Disorders

spatial resolution, 3D, T1-weighted technique used to assess pathology

of the vessel wall itself. This technique can be used to detect, characterize, and differentiate such pathologies as atherosclerosis, vasculitis

(such as primary angiitis of the central nervous system [PACNS]), and

vasculopathies such as reversible cerebral vasoconstriction syndrome

(RCVS), and has been used to assess the wall of aneurysms.

ECHO-PLANAR MRI

Echo planar MRI (EPI) forms the basis of several important MR imaging sequences. EPI uses fast gradients that are switched on and off at

high speeds to create the information used to form an image. With

EPI, all of the information required for processing an image is accumulated in milliseconds, and the information for the entire brain can be

obtained in <1–2 min, depending on the degree of resolution required

or desired. Fast MRI reduces patient and organ motion and is the basis

of perfusion imaging during contrast infusion and kinematic motion

studies. EPI is also the sequence used to obtain diffusion-weighted

imaging (DWI) and tractography (DTI), as well as functional MRI

(fMRI) and arterial spin-labeled (ASL) perfusion studies (Figs. 423-2H,

423-3, 423-4C, and 423-6; and Fig. 426-13).

Perfusion and diffusion imaging are EPI techniques that are useful

in early detection of ischemic injury of the brain and may be useful

together to demonstrate infarcted tissue as well as ischemic but potentially viable tissue at risk of infarction (e.g., the ischemic penumbra).

DWI assesses microscopic motion of water; water protons that move

reduce signal intensity on diffusion-weighted images. Pathology that

reduces microscopic water motion results in relatively higher signal.

Infarcted tissue reduces the water motion within cells and in the

interstitial tissues, resulting in high signal on DWI. DWI is the most

sensitive technique for detection of acute cerebral infarction of <7 days

in duration (Fig. 423-2H). It is also quite sensitive for detecting dying

or dead brain tissue secondary to encephalitis, as well as abscess and

purulent formations (Fig. 423-3B).

Perfusion MRI can be performed by the acquisition of fast EPI

during a rapid IV bolus of gadolinium contrast material or by noncontrast arterial spin labeling (ASL) techniques. With contrast perfusion

imaging, parametric maps of relative cerebral blood volume, mean

transit time (MTT), time to maximum (tMAX), and cerebral blood

flow can be derived. Prolonged MTT and tMAX and reduction in

cerebral blood volume and cerebral blood flow are typical of infarction.

In the setting of reduced blood flow, a prolonged MTT of contrast but

normal or elevated cerebral blood volume may indicate tissue supplied

by slower collateral flow that is at risk of infarction. Perfusion MRI

imaging can also be used in the assessment of brain tumors to differentiate intraaxial primary tumors, whose BBB is relatively intact, from

extraaxial tumors or metastases, which demonstrate a relatively more

permeable BBB.

Diffusion tensor imaging (DTI) is derived from diffusion MRI

sequences. This technique assesses the direction and integrity of protons flowing within white matter architecture. It has proven valuable

in the assessment of subcortical white matter tract anatomy prior to

brain tumor surgery, as well as determining normal and abnormal

white matter architecture in congenital and acquired pathologies such

as traumatic brain injury as well as assessing the integrity of peripheral

nerves (Fig. 423-7).

FIGURE 423-7 Diffusion tractography in cerebral glioma. Associative and descending pathways in a healthy subject (A) and in a patient with parietal lobe glioblastoma

(B) presenting with a language deficit: the mass causes a disruption of the arcuate-SLF complex, in particular of its anterior portion (SLF III). Also shown are bilateral optic

tract and left optic radiation pathways in a healthy subject (C) and in a patient with left occipital grade II oligoastrocytoma (D): the mass causes a disruption of the left optic

radiation. Shown in neurologic orientation, i.e., the left brain appears on the left side of the image. AF, long segment of the arcuate fascicle; CST, corticospinal tract; IFOF:

inferior fronto-occipital fascicle; ILF, inferior longitudinal fascicle; SLF III, superior longitudinal fascicle III or anterior segment of the arcuate fascicle; SLF-tp, temporoparietal portion of the superior longitudinal fascicle or posterior segment of the arcuate fascicle; T, tumor; UF, uncinated fascicle. (Part D used with permission from Eduardo

Caverzasi and Roland Henry.)

A B

C D

3291 Neuroimaging in Neurologic Disorders CHAPTER 423

or cervical subarachnoid space. CT scanning is typically performed

after myelography to better demonstrate the spinal cord and roots,

which appear as filling defects in the opacified subarachnoid space.

CT myelography, in which CT is performed after the subarachnoid

injection of a small amount of contrast material, has replaced conventional myelography for many indications, thereby reducing exposure

to radiation and contrast media. CT is obtained at a slice thickness of

~2.5 mm and reconstructed at 0.625-mm thick slices, which can

quickly be reformatted in sagittal and coronal planes, equivalent to

traditional myelography projections.

■ INDICATIONS

CT myelography and MRI have largely replaced conventional myelography for the diagnosis of diseases of the spinal canal and cord (Table

423-1). Remaining indications for conventional plain-film myelography include the evaluation of suspected meningeal or arachnoid cysts

and the localization of CSF fistulas. Conventional myelography and

CT myelography provide the most precise information in patients with

failed back syndrome following spinal fusion procedures.

■ CONTRAINDICATIONS

Myelography is relatively safe; however, it should be performed with

caution in any patient with elevated intracranial pressure, evidence of

a spinal block, or a history of allergic reaction to intrathecal contrast

media. In patients with a suspected spinal block, MR is the preferred

imaging technique. If myelography is necessary, only a small amount

of contrast medium should be instilled below the block in order to

minimize the risk of neurologic deterioration. Lumbar puncture (LP)

is to be avoided in patients with bleeding disorders, and those with

infections of the overlying soft tissues. Anticoagulant therapy should

be withheld prior to elective LP to avoid epidural or intradural hemorrhage, unless required in emergent situations (Chap. S9).

■ COMPLICATIONS

Headache is the most frequent complication of myelography and is

reported to occur in 5–30% of patients. Nausea and vomiting may

also occur rarely. Postural headache (post-LP headache) is generally

due to continued epidural leakage of CSF from the dural puncture

site. A higher incidence is noted among younger women and with

the use of larger gauge cutting-type spinal needles. If significant headache persists for >48 h, placement of an epidural blood patch should be

considered. Management of LP headache is discussed in Chap. 16. Vasovagal syncope may occur during LP; it is accentuated by the upright

position used during conventional lumbar myelography. Adequate

hydration before and after myelography will reduce the incidence of

this complication.

Hearing loss is a rare complication of myelography. It may result

from a direct toxic effect of the contrast medium or from an alteration

of the pressure equilibrium between CSF and perilymph in the inner

ear. Puncture of the spinal cord is a rare but serious complication of

cervical (C1–2) or high LP. The risk of cord puncture is greatest in

patients with spinal stenosis, Chiari malformations, or conditions that

reduce CSF volume. CT myelography following a lumbar injection and

MRI are safer alternatives to cervical puncture. Reactions to intrathecal

contrast administration are rare; aseptic meningitis and encephalopathy are reported rare complications. The latter is usually dose related

and associated with contrast entering the intracranial subarachnoid space. Seizures rarely occur following myelography, historically

reported in 0.1–0.3% of patients. Risk factors include a preexisting

seizure disorder and the use of a total iodine dose of >4500 mg. Other

reported complications include hyperthermia, hallucinations, depression, and anxiety states. These side effects have been reduced by the

development of nonionic, water-soluble contrast agents as well as by

head elevation and generous hydration following myelography.

SPINE INTERVENTIONS

■ DISKOGRAPHY

The evaluation of back pain and radiculopathy (Chap. 15) may require

diagnostic procedures that attempt either to reproduce the patient’s

fMRI is an EPI technique that localizes regions of activity in the

brain following task activation or at rest (so-called resting state fMRI).

Neuronal activity elicits a slight increase in the delivery of oxygenated

blood flow to a specific region of activated brain. This results in an

alteration in the balance of oxyhemoglobin and deoxyhemoglobin,

which yields a 2–3% increase in signal intensity within veins and local

capillaries. Currently, preoperative somatosensory and auditory cortex

localization is possible, and methods to assess motor and language

function are in development. This technique has proved useful to

neuroscientists interested in interrogating the localization of certain

brain functions.

ARTERIAL SPIN LABELING

ASL is a quantitative noninvasive MR technique that measures cerebral

blood flow (Fig. 423-6). Blood traversing in the neck is labeled by an

MR pulse and then imaged in the brain after a short (2 s) delay. The signal is reflective of blood flow. ASL is an especially important technique

for patients in whom the use of contrast agents is contraindicated.

ASL has become almost standard in many MR protocols because it is

relatively fast to acquire and does not require contrast administration.

Increased cerebral flow is more easily identified than slow flow, which

can be sometimes difficult to quantify. This technique has also been

useful in detecting shunting in arteriovenous malformations and fistulas, as well as increased blood flow in brain tumors, and patients post

TIA, post seizure, or post migraine.

MAGNETIC RESONANCE NEUROGRAPHY

MRN is an MR technique that shows promise in detecting increased

signal in irritated, inflamed, or infiltrated peripheral nerves. T1W

and T2W imaging are obtained with fat-suppressed fast-spin echo

imaging or short inversion recovery sequences. Inflamed peripheral

nerves will demonstrate high signal on T2W imaging. MRN is indicated in patients with radiculopathy whose conventional MR studies

of the spine (cervical or lumbar) are normal, or in those suspected of

peripheral nerve entrapment or trauma. This technique is now also

being used to assess peripheral nerve damage after trauma or from

compressive neuropathies.

POSITRON EMISSION TOMOGRAPHY

PET relies on the detection of positrons emitted during the decay of a

radionuclide that has been injected into a patient. The most frequently

used moiety is 2-[18F]fluoro-2-deoxy-d-glucose (FDG), which is an

analogue of glucose and is taken up by cells competitively with

2-deoxyglucose. Many other radioisotopes are used in other indications. With FDG, multiple images of glucose uptake activity are formed

45–60 min after IV administration of FDG. Images reveal differences

in regional glucose activity among normal and pathologic brain structures. FDG-PET is used primarily for the detection of extracranial

metastatic disease; however, a lower activity of FDG in the parietal

lobes is associated with Alzheimer’s disease, a finding that may simply

reflect atrophy that occurs in the later stages of the disease. Combination PET-CT scanners, in which both CT and PET are obtained at one

sitting, have largely replaced PET scans alone. MR-PET scanners have

also been developed and may prove useful for imaging the brain and

other organs without the radiation exposure of CT. More recent

PET ligand developments include beta-amyloid and tau PET tracers

(Chap. 29). Studies have shown an increased percentage of amyloid

deposition in patients with Alzheimer’s disease compared with mild

cognitive impairment and healthy controls; however, up to 25% of cognitively “normal” patients show abnormalities on amyloid PET imaging (Chap. 431). This may either reflect subclinical disease processes or

variation of normal. Tau imaging may be more specific for Alzheimer’s

disease, and clinical studies are in progress.

MYELOGRAPHY

■ TECHNIQUE

Myelography involves the intrathecal instillation of specially formulated water-soluble iodinated contrast medium into the lumbar

3292 PART 13 Neurologic Disorders

pain or relieve it, indicating its correct source prior to lumbar fusion.

Diskography is now rarely indicated. It is performed by fluoroscopic

placement of a 22- to 25-gauge needle into the intervertebral disk and

subsequent injection of 1–3 mL of contrast media. The intradiskal

pressure is recorded, as is an assessment of the patient’s response to the

injection of contrast material. Little or no pain is felt during injection of

a normal disk, which does not accept much more than 1 mL of contrast

material, even at pressures as high as 415–690 kPa (60–100 lb/in2

). CT

and plain films are obtained following the procedure. Concerns have

been raised that diskography may contribute to an accelerated rate of

disk degeneration; furthermore, patients who suffer from depression

or anxiety are more likely to find diskography painful and in some

cases the procedure-associated pain became persistent, lasting a year or

longer. Thus, it is rarely used as a reliable biomarker of pain generation.

■ SELECTIVE NERVE ROOT AND EPIDURAL SPINAL

INJECTIONS

Percutaneous selective nerve root and epidural administration of

glucocorticoid and anesthetic mixtures may be both therapeutic and

diagnostic. Typically, 1–2 mL of an equal mixture of a long-acting

glucocorticoid such as betamethasone or decadron combined with a

long-acting anesthetic such as bupivacaine 0.75% is instilled under CT

or fluoroscopic guidance in the intraspinal epidural space or adjacent

to an existing nerve root in question as a pain source. This can also be

performed into the facet joints, or around the medial nerve branches

that supply innervation to the facet joints.

ANGIOGRAPHY

Catheter angiography is indicated for evaluating intracranial

small-vessel pathology (such as vasculitis), for assessing vascular

malformations and aneurysms, and in endovascular therapeutic procedures (Table 423-1). As noted above, angiography has been replaced

for many indications by CT/CTA or MRI/MRA.

Angiography carries the greatest risk of morbidity of all diagnostic

imaging procedures, owing to the necessity of inserting a catheter into

a blood vessel, directing the catheter to the required location, injecting

contrast material to visualize the vessel, and removing the catheter

while maintaining hemostasis. Therapeutic transcatheter procedures

(see below) have become important options for the treatment of some

cerebrovascular diseases. The decision to undertake a diagnostic or

therapeutic angiographic procedure requires careful assessment of the

goals of the investigation and its attendant risks.

Patients undergoing angiography should be well hydrated before

and after the procedure. Because the femoral route is used most commonly, the femoral artery must be compressed after the procedure to

prevent a hematoma from developing. The puncture site and distal

pulses should be evaluated carefully after the procedure; complications

can include thigh hematoma or lower-extremity emboli.

■ COMPLICATIONS

A common femoral arterial puncture provides retrograde access via the

aorta to the aortic arch and great vessels. The most feared complication

of cerebral angiography is stroke. Thrombus can form on or inside the

tip of the catheter, rarely arterial dissection or perforation can occur,

and atherosclerotic thrombus or plaque can be dislodged by the catheter or guide wire or by the force of injection and can embolize distally

in the cerebral circulation. Risk factors for ischemic complications

include limited experience on the part of the angiographer, atherosclerosis, vasospasm, low cardiac output, decreased oxygen-carrying

capacity, advanced age, and prior history of migraine. The risk of a

neurologic complication varies but is ~4% for transient ischemic attack

and stroke, 1% for permanent deficit, and <0.1% for death.

Nonionic contrast material is used exclusively in cerebral angiography. Nonionic contrast injected into the cerebral vasculature can be

neurotoxic if the BBB is breached, either by an underlying disease or by

the injection of hyperosmolar contrast agent. Patients with dolichoectasia of the basilar artery can suffer reversible brainstem dysfunction

and acute short-term memory loss during angiography, owing to the

slow percolation of the contrast material and the consequent prolonged

exposure of the brain. Rarely, an intracranial aneurysm ruptures during

an angiographic contrast injection, causing subarachnoid hemorrhage,

perhaps as a result of injection under high pressure.

■ SPINAL ANGIOGRAPHY

Spinal angiography is indicated to evaluate the location of vascular

malformations and to identify the artery of Adamkiewicz (Chap. 442)

prior to aortic aneurysm repair. The procedure is lengthy and requires

the use of relatively large volumes of contrast; the incidence of serious

complications, including paraparesis, subjective visual blurring, and

altered speech, is less than 1%. Gadolinium-enhanced MRA has been

used successfully in this setting, as has iodinated contrast CTA, which

has promise for replacing diagnostic spinal angiography for some

indications.

INTERVENTIONAL NEURORADIOLOGY

This rapidly developing field is providing new therapeutic options for

patients with challenging neurovascular problems. Available procedures include detachable coil therapy for aneurysms, particulate or

liquid adhesive embolization of arteriovenous malformations, stent

retrieval systems for embolectomy in acute stroke, balloon angioplasty

and stenting of arterial stenosis or vasospasm, transarterial or transvenous embolization of dural arteriovenous fistulas, balloon occlusion

of carotid-cavernous and vertebral fistulas, endovascular treatment of

vein-of-Galen malformations, preoperative embolization of tumors,

and thrombolysis of acute arterial or venous thrombosis. Many of these

disorders place the patient at high risk of cerebral hemorrhage, stroke,

or death.

The highest complication rates are found with the therapies designed

to treat the highest risk diseases. The advent of electrolytically detachable coils ushered in a new era in the treatment of cerebral aneurysms

(Chap. 429). Two randomized trials found reductions of morbidity and

mortality at 1 year among those treated for aneurysm with detachable

coils compared with neurosurgical clipping. In many centers, coiling has become standard therapy for many proximal circle of Willis

aneurysms.

Finally, recent studies of stent retrieval systems used to withdraw

emboli have shown improved clinical outcomes in patients presenting

with large vessel occlusions and signs of acute stroke (Chap. 427).

■ FURTHER READING

Bambach S et al: Arterial spin labeling applications in pediatric and

adult neurologic disorders. J Magn Reson Imaging 2020.

Choi JW, Moon WJ: Gadolinium deposition in the brain: Current

updates. Korean J Radiol 20:134, 2019.

Mandell DM et al: Intracranial vessel wall MRI: Principles and expert

consensus recommendations of the American Society of Neuroradiology. AJNR Am J Neuroradiol 38:218, 2017.

Pelz DM et al: Interventional neuroradiology: A review. Can J Neurol

Sci 16:1, 2020.

Schönmann C, Brockow K: Adverse reactions during procedures:

Hypersensitivity to contrast agents and dyes. Ann Allergy Asthma

Immunol 124:156, 2020.

Tournier JD: Diffusion MRI in the brain—theory and concepts. Prog

Nucl Magn Reson Spectrosc 112-113:1, 2019.

Watson RE et al: MR imaging safety events: Analysis and improvement. Magn Reson Imaging Clin N Am 28:593, 2020.

3293Pathobiology of Neurologic Diseases CHAPTER 424

The human nervous system is the organ of consciousness, cognition,

ethics, and behavior; as such, it is the most intricate structure known to

exist. More than one-third of the 23,000 genes encoded in the human

genome are expressed in the nervous system. Each mature brain is

composed of 100 billion neurons, several million miles of axons and

dendrites, and >1015 synapses. Neurons exist within a dense parenchyma of multifunctional glial cells that synthesize myelin, preserve

homeostasis, and regulate immune responses. Measured against this

background of complexity, the achievements of molecular neuroscience have been extraordinary. Advances have occurred in parallel with

the development of new enabling technologies—in bioengineering and

computational sciences; imaging; and cell, molecular, and chemical

biology—and moving forward it is likely that the pace of new discoveries will only increase. This chapter reviews a number of the most

dynamic areas in neuroscience, specifically highlighting advances in

immunology and inflammation, neurodegeneration, and stem cell

biology. In each of these areas, recent discoveries are providing context

for an understanding of the triggers and mechanisms of disease and

offering new hope for prevention, treatment, and repair of nervous

system injuries. Discussions of the neurogenetics of behavior, advances

in addiction science, and diseases caused by network dysfunction can

be found in Chap. 451 (Biology of Psychiatric Disorders); and new

approaches to rehabilitation via harnessing of neuroplasticity, neurostimulation, and computer-brain interfaces are presented in Chap. 487

(Emerging Neurotherapeutic Technologies).

NEUROIMMUNOLOGY AND

NEUROINFLAMMATION

■ OLIGODENDROCYTES AND MYELIN

Myelin is the multilayered insulating substance that surrounds axons

and speeds impulse conduction by permitting action potentials to

jump between naked regions of axons (nodes of Ranvier) and across

myelinated segments. Oligodendrocytes contact axons at paranodes,

where sodium and potassium channels essential for saltatory conduction are clustered. Molecular interactions between the myelin

membrane and axon are required to maintain the stability, function,

and normal life span of both structures. The process of myelination is

directed both by axon-derived cues as well as the physical properties of

the axon-membrane curvature. Importantly, ongoing neuronal activity

influences both the differentiation of oligodendrocytes as well as the

extent of myelination, a process referred to as adaptive myelination. A

single oligodendrocyte usually ensheaths multiple axons in the central

nervous system (CNS), whereas in the peripheral nervous system

(PNS), each Schwann cell typically myelinates a single axon. Myelin

is a lipid-rich material formed by a spiraling process of the membrane

of the myelinating cell around the axon, creating multiple membrane

bilayers that are tightly apposed (compact myelin) by charged protein

interactions. A number of clinically important neurologic disorders

are caused by inherited mutations in myelin proteins (Chap. 446), and

constituents of myelin also have a propensity to be targeted as autoantigens in autoimmune demyelinating disorders (Chap. 447).

Premyelinating oligodendrocyte precursor cells (OPCs) are highly

motile cells that migrate extensively during development and in the

adult brain following injuries to the myelin sheath. OPCs migrate along

the inner (or abluminal) surface of endothelial cells, a process regulated

by Wnt pathway signaling and upregulation of the chemokine receptor

Cxcr4 that drives their attachment and retention to the vasculature. In

the normal adult brain, large numbers of OPCs are widely distributed.

Following demyelination, remyelination is largely dependent on OPCs

424

that differentiate into myelin-producing oligodendrocytes and produce

characteristic thinly remyelinated fibers. In some situations, a second

population of regenerating oligodendrocytes derived from neural stem

cells can mediate more effective remyelination, with thicker lamellae

and greater functional preservation of axons. A recent C14 labeling

study from human multiple sclerosis (MS) lesions indicated that a third

population of nonmitotic preexisting oligodendrocytes may represent

an additional source of remyelinating cells.

Both acquired demyelinating disorders, such as MS, and inherited

ones, such as Pelizaeus-Merzbacher disease (duplication or deletion of

CNS proteolipid protein) and adrenoleukodystrophy (mutations in the

ABCD1 gene responsible for transport of very long chain fatty acids

into the peroxisome for degradation), are associated with progressive

axonal loss. It is now increasingly recognized that oligodendrocyte

dysfunction can contribute to neuronal and axonal loss in a wide variety of CNS disorders including Alzheimer’s disease (AD; Chap. 431),

amyotrophic lateral sclerosis (ALS; Chap. 437), traumatic brain injury

(Chap. 443), and stroke (Chap. 426), among other conditions.

Loss of oligodendrocyte support can produce axonal damage

through a variety of mechanisms, including reductions in the supply

of glucose and other essential nutrients; an increased axonal workload;

impaired glutamate and calcium buffering; mitochondrial damage; loss

of neurotrophins; enhanced susceptibility to reactive oxygen species

including nitric oxide; as well as failure to maintain normal synapses.

A number of molecules have been identified that regulate oligodendrocyte differentiation and myelination, including LINGO-1,

hyaluronan, chondroitin sulfate proteoglycan, the Wnt pathway, Notch

(and its receptor Jagged), fibrinogen, and the M1 muscarinic receptor

Chrm1, all of which are inhibitory. Other targets are the retinoic acid

receptor RXRγ, vitamin D, and thyroid hormone, all of which promote

oligodendrocyte maturation. All are also potential targets for myelin

repair therapies. In the preclinical model of autoimmune demyelination, experimental allergic encephalomyelitis (EAE; Fig. 424-1),

oligodendrocyte-specific knockout of Chrm1 improved remyelination,

protected axons, and restored function, directly demonstrating that

remyelination can be neuroprotective following injury. A pivotal trial

of a monoclonal antibody against LINGO-1 in patients with acute optic

neuritis failed to improve clinical outcomes, a disappointing result

given that the antibody appeared to have promising clinical effects in

an earlier phase 2 trial. More recently, in a preliminary trial of chronic

optic neuritis, a promising result was reported with clemastine, an antihistamine and M1 muscarinic receptor antagonist, raising hope that

clinically effective remyelination might be achievable even in a chronic

demyelinating condition.

■ MICROGLIA AND MACROPHAGES

These represent the major cell types in the nervous system responsible

for antigen presentation and innate immunity. Brain microglia migrate

from the yolk sac early in embryogenesis before the blood-brain barrier

is formed, and are believed to maintain their cell numbers through cell

division within the nervous system and not via repopulation from the

circulation. In mice, most microglia require signaling through colony-stimulating factor 1 receptor (Csf1r), via its natural ligands Csf1r

and IL-34, for survival. Depletion of microglia by administration of a

selective inhibitor of Csf1r (PLX5622) was followed by rapid repopulation, which led to identification of a second population of ramified

microglial precursor cells that do not require Csf1r signaling. Singlecell transcriptome sequencing approaches are now producing evidence

for substantial microglial cell diversity in the CNS.

Microglia play critical roles in sculpting neuronal populations

during development and across the life span, through secretion of

brain-derived neurotrophic factor (BDNF) and other trophic factors

that promote neuronal survival, and also via production of reactive

oxygen species (ROS) and other molecules that mediate cell death.

Microglia regulate development and maintenance of neural circuits

through pruning of excitatory synapses and control of dendritic spine

densities (Fig. 424-2). Mice depleted of microglia during development

exhibit a variety of cognitive, learning, and behavioral deficits, including abnormal social behaviors. These processes are dependent on

Pathobiology of

Neurologic Diseases

Stephen L. Hauser, Arnold R. Kriegstein,

Stanley B. Prusiner