The Netter Collection of Medical Illustrations VOLUME 7 PART ll

Plate 7-7â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

AUTONOMIC DISTRIBUTION TO THE HEAD AND THE NECK

CENTRAL NERVOUS SYSTEM PERIPHERAL NERVOUS SYSTEM Pupillary
Parasympathetics constrictor m.
Nucleus of Ciliary ganglion Ciliary m.

Edinger- Cranial n. III
Westphal
Pterygopalatine Lacrimal glands
Superior ganglion Nasal mucosal
salivatory
nucleus glands

Cranial n. VII

SubgmanangldioibnularSuSbumbalinndgiubaullagrlagnladnd

Otic ganglion Parotid gland

Inferior Cranial n. IX
salivatory
nucleus

Sympathetics Superior cervical ganglion Pupillary dilator m.
T1-T2 Sweat glands and
vascular smooth
Intermedio- muscle in head
lateral
and neck
cell column

Autonomic Innervation
of Eye

The eye receives a rich innervation by the sympathetic
and parasympathetic systems.

SYMPATHETIC FIBERS ganglion; their contained fibers pass through it without PARASYMPATHETIC FIBERS
The sympathetic preganglionic fibers for the eye arise relaying to become incorporated in the 8 to 10 short The parasympathetic preganglionic fibers for the eye
from the intermediolateral column of the thoracic cord ciliary nerves. Other branches join the ophthalmic nerve are the axons of cells in the autonomic, (Edinger-Westphal)
and travel in the ipsilateral first, second, and, occasion- or its nasociliary branch and reach the eye in the two oculomotor nucleus. They run in the third cranial nerve
ally, in the third thoracic spinal nerves. They pass to three long ciliary nerves that supply the radial muscu- and exit in the motor root of the ciliary ganglion, where
through white rami communicantes to the sympathetic lature in the iris (dilator pupillae). Both long and short they relay. The axons of these ganglionic cells are post-
trunks; the fibers ascend to the superior cervical gan- ciliary nerves also contain afferent fibers from the ganglionic parasympathetic fibers, which reach the eye
glion where they relay, although a few synapse higher cornea, iris, and choroid. Fibers conveyed in the short in the short ciliary nerves and are distributed to the con-
in the internal carotid ganglia. The postganglionic fibers ciliary nerves pass through a communicating ramus strictor fibers of the iris (sphincter pupillae), to the
run either in the internal carotid plexus and enter the from the ciliary ganglion to the nasociliary nerve; this ciliary muscle, and to the blood vessels in the eyeball.
orbit through its superior fissure, or else they run ramus is called the sensory root of the ciliary ganglion. The
alongside the ophthalmic artery in its periarterial parent cells of these sensory fibers are located in the VISUAL CENTERS
plexus. Some of the ocular sympathetic fibers may make trigeminal (semilunar) ganglion, and their central pro- The visual reflex centers are located in the tectal and
a detour through the caroticotympanic nerves and tym- cesses end in the sensory trigeminal nuclei in the brain- pretectal areas of the mesencephalon. They are con-
panic plexus before rejoining the cavernous part of the stem. The sensory trigeminal nuclei have multiple nected to the lateral geniculate bodies (lower visual
internal carotid plexus by means of a branch that interconnections with other somatic and autonomic centers) and to the superior colliculi in which the tecto-
emerges from the anterior surface of the petrous part centers and thus influence many reflex reactions. Other spinal tracts originate; these connections provide the
of the temporal bone near the greater petrosal nerve; sympathetic fibers from the internal carotid plexus anatomic basis for the reflex movements of the head and
thereafter, they accompany the other ocular fibers. reach the eye through the ophthalmic periarterial eyes in response to visual stimuli. The light and accom-
plexus and its subsidiary plexuses around the central modation reflexes are affected through pretectal
Some of the branches passing through the superior retinal, ciliary, scleral and conjunctival arteries (see
orbital fissure form the sympathetic root of the ciliary Plate 7-5).

180 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-8â•… Autonomic Nervous System and Its Disorders

CILIARY GANGLION

Sphincter pupillae muscle Short ciliary nerves Oculomotor Accessory oculomotor
Dilator pupillae muscle Ciliary (parasympathetic) (Edinger-Westphal)
Ciliary muscle root of ciliary ganglion nucleus (parasympathetic)

ganglion

Superior colliculus

Lateral
geniculate body

Optic nerve (II) Ophthalmic Tympanic
Nasociliary nerve nerve (V1) plexus
Long ciliary nerve Trigeminal
Nasociliary (sensory) ganglion Tectospinal tract
root of ciliary ganglion Internal Thoracic part
carotid plexus of spinal cord
Sympathetic root of Internal
ciliary ganglion carotid artery

Ophthalmic artery

Superior cervical sympathetic ganglion

Autonomic Innervation 1st thoracic sympathetic trunk ganglion Preganglionic
of Eye (Continued) sympathetic
Gray ramus communicans cell bodies
connections. Fibers from the lateral geniculate bodies in inter-
are connected through synapses in pretectal nuclei to White ramus communicans mediolateral
the accessory oculomotor nucleus (Edinger-Westphal T1 spinal nerve nucleus
nuclei), which controls the sphincter pupillae and the (lateral
ciliary muscle. Dorsal root ganglion horn) of gray
PUPILLARY LIGHT REFLEX matter
Light causes pupillary constriction, miosis. The impulse
generated by the light travels from the retina by the Preganglionic Sympathetic fibers
optic nerve and optic tract to bilateral pretectal nuclei Postganglionic
in the midbrain, decussating in the posterior commis-
sure. The axons from the pretectal nuclei terminate in Preganglionic Parasympathetic fibers
the accessory oculomotor nuclei. Preganglionic para- Postganglionic
sympathetic information travels via the oculomotor
nerve to the ciliary ganglion. Postganglionic fibers from Afferent fibers
the ciliary ganglion traverse the short ciliary nerves to
innervate the sphincter pupillae muscle of the iris. If Visual pathway
one eye is stimulated by light, both pupils will react;
ipsilateral (direct response) and contralateral (consen- Descending pathway
sual response) pupils both respond because of the ter-
mination of the fibers of the optic tract in the pretectal ganglion. From there, they traverse the long ciliary lateral geniculate bodies, optic radiations, and visual
nuclei bilaterally. nerves to the dilator pupillae. Pupils also dilate in cortical centers. From there, the impulse is thought to
response to pain, presumably due to fibers from the reach the “near response neurons” in the pretectal
Dilation of the pupil, mydriasis, occurs due to post- sensory system reaching the preganglionic neurons nuclei by corticotectal fibers. From the pretectal nuclei,
ganglionic sympathetic innervation from the superior (pupillary skin reflex). the information reaches the oculomotor nuclei. The
cervical ganglion. Preganglionic fibers arise from the parasympathetic fibers reach the sphincter pupillae via
neurons first and second thoracic intermediolateral ACCOMMODATION REFLEX the ciliary ganglion and short ciliary nerves. The para-
column and by the upper thoracic spinal nerves, and In viewing objects that are near, the pupils constrict, the sympathetic fibers cause stimulation of the ciliary
white rami communicantes reach the superior cervical eyes move medially, and the lens changes shape to muscles, which causes relaxation of the zonule, and the
become more convex. The reflex for this begins in the lens becomes more spheric; the medial recti are acti-
retina, and then involves the optic nerve, optic tract, vated by the ventral oculomotor nuclei, causing the eyes
to converge.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 181

Plate 7-9â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

THORACIC SYMPATHETIC CHAIN AND SPLANCHNIC NERVES

Cervicothoracic Left recurrent
(stellate) ganglion laryngeal nerve
Cervical cardiac nerves
Ansa subclavia (sympathetic and vagal)
Cervical cardiac Vagus nerve (X) J\[
nerves (sympathetic
and vagal) Thoracic (sympathetic)
Thoracic cardiac branches
(sympathetic)
cardiac branches

Sympathetic trunk Left recurrent
laryngeal nerve
Vagus nerve (X) J\[ Thoracic cardiac
and branches to branch of vagus nerve
cardiac and pulmonary
plexuses Cardiac plexus
Thoracic Anterior pulmonary
(sympathetic) plexus
cardiac branches

Autonomic Nerves in Thorax Anterior Posterior pulmonary
pulmonary plexus plexus (protruding
The thoracic parts of the sympathetic trunks lie ante- Posterior pulmonary from behind left
rior to the junctions between the heads and necks of the plexus (protruding bronchus)
ribs and posterior to the pleura. There are usually 10 from behind right Sympathetic trunk
or 11 ganglia on each side; the first is often incorpo- bronchus) Thoracic aortic plexus
rated into the cervicothoracic (stellate) ganglion (see 6th intercostal nerve
Plate 7-6), and the last thoracic and first lumbar ganglia Gray and white Esophageal plexus
may also be united. The interganglionic cords are rami communicantes
usually single, but double or triple cords between some 6th thoracic 8th intercostal nerve
adjacent ganglia are not uncommon. The thoracic sympathetic ganglion
trunks supply or receive communicating, visceral, vas- Greater thoracic Gray and white
cular, muscular, osseous, and articular branches. splanchnic nerve rami communicantes
Sympathetic branch Greater thoracic
Each ganglion receives at least one white ramus com- to esophageal plexus splanchnic nerve
municans and contributes at least one gray ramus to the Lesser thoracic
adjacent spinal nerve, although several white and gray Thoracic duct splanchnic nerve
rami communicantes may be attached to each ganglion. Lesser thoracic Anterior vagal trunk
Visceral branches are supplied to the heart and pericar- splanchnic nerve
dium, lungs, trachea and bronchi, esophagus, and Least thoracic Diaphragm
thymus. splanchnic nerve W\SSLK KV^U

Sympathetic Cardiac Nerves. Three pairs of sympa- Azygos vein J\[
thetic cardiac nerves arise from the cervical trunk
ganglia, and the others emerge from the upper thoracic Inferior vena
ganglia. cava J\[

The superior cervical sympathetic cardiac nerves origi- inferior cervical vagal cardiac branches arise in the lower lesser (minor) splanchnic nerve lies slightly lateral to the
nate from the corresponding trunk ganglia. On the third of the neck and descend posterolateral to the greater splanchnic nerve and also usually pierces the
right, the nerve passes posterolateral to the brachioce- brachiocephalic artery and aortic arch on the right side; diaphragmatic crus. The lowest (imus) splanchnic nerve is
phalic artery and aortic arch; on the left, it curves down- on the left side, they descend lateral to the left common inconstant.
ward over the left side of the aortic arch to reach the carotid artery and aortic arch. The thoracic vagal cardiac
cardiac plexus. branches arise at or below the level of the thoracic inlet. Minute twigs from the sympathetic trunks join and
innervate the intercostal arteries. Other sympathetic
The middle cervical sympathetic cardiac nerves are Multiple interconnections exist between all the postganglionic fibers reach these vessels in fascicles
usually larger than the corresponding superior and infe- sympathetic and parasympathetic cardiac nerves and from adjacent intercostal nerves or their branches, and
rior nerves. They arise from the middle cervical and between the cardiac and other visceral branches of the these also carry sudomotor and pilomotor fibers.
vertebral ganglia of the sympathetic trunks and usually sympathetic trunks.
run independently to the cardiac plexus. The muscular, osseous, and articular fibers from the
Other thoracic sympathetic branches supply the thoracic thoracic sympathetic trunks and their branches supply
The inferior cervical sympathetic cardiac nerves consist viscera from the paired greater, lesser, and lowest tho- the adjacent structures concerned; their exact functions
of fibers arising from the cervicothoracic ganglia and racic splanchnic nerves, although these are mainly des- are uncertain.
subclavian ansae. tined to supply abdominal structures and contain a
mixture of preganglionic, postganglionic, and afferent INNERVATION OF HEART
The thoracic sympathetic cardiac nerves are four or five fibers. The greater (major) splanchnic nerve lies medial The heart is supplied by sympathetic nerves arising
slender branches, which run forward and medially from to the ipsilateral sympathetic trunk and enters the mainly in the neck because the heart develops initially
the thoracic trunk ganglia to the cardiac plexus. abdomen by piercing the crus of the diaphragm. The

Parasympathetic Cardiac Nerves. Three pairs of
parasympathetic (vagal) cardiac nerves are usually
present. The superior cervical vagal cardiac branches leave
the vagus nerves in the upper part of the neck. The

182 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-10â•… Autonomic Nervous System and Its Disorders

Autonomic Nerves in Thorax Superior cervical INNERVATION OF HEART Nucleus of
sympathetic Posterior (dorsal) nucleus solitary tract
(Continued) ganglion of vagus nerve
Cardiac
in the cervical region and later migrates into the thorax, Superior cervical Medulla plexus
taking its nerves down with it. The parasympathetic (sympathetic) oblongata
supply is conveyed in cardiac branches of the vagus cardiac nerve Vagus nerves
nerves. Middle cervical Superior cervical
sympathetic (vagal) cardiac branches
The sympathetic preganglionic cardiac fibers leave the ganglion Inferior cervical
spinal cord in the anterior roots of the upper four to (vagal) cardiac branches
five thoracic spinal nerves and enter the white or mixed Middle cervical Ascending
rami communicantes passing to adjacent thoracic sym- (sympathetic) connections
pathetic trunk ganglia. Some of the fibers relay here; cardiac nerve
others ascend in the trunks to form synapses in the Vertebral T1
cervical ganglia, giving rise to the cardiac nerves (see ganglion
earlier discussion). Most cardiac fibers are postgangli- (variation)
onic and pass through the cardiac plexus without relay- Ansa subclavia
ing, to be distributed to the heart wall and its vessels Cervicothoracic
via the coronary plexuses. (stellate) ganglion
1st intercostal
The parasympathetic preganglionic (vagal) fibers are the nerve
axons of cells in the dorsal vagal nucleus. From the
vagal cardiac nerves, they relay in ganglia of the cardiac Inferior cervical T2
plexus or in intrinsic cardiac ganglia, which are located (sympathetic)
mainly in the atrial subepicardial tissue along the coro- cardiac nerve
nary sulcus and around the roots of the great vessels.
The sinoatrial node and the atrioventricular node and Thoracic T3
bundle have a rich supply of parasympathetic innerva- cardiac branch T4
tion. Ventricular ganglia are scanty, but enough of them of vagus nerve
exist to cast doubts on the hypothesis that ventricular 2nd thoracic
innervation is purely sympathetic. sympathetic
ganglion
The more important afferent and efferent pathways
in cardiac innervation are shown in the illustration. The White ramus
peripheral processes of the afferent pseudounipolar communicans
neurons in the posterior root ganglia transmit input
from cardiac receptors of various types and from termi- Gray ramus
nal nerve networks in reflexogenic zones, such as those communicans
in and around the large cardiac venous openings, the Thoracic
interatrial septum, and the ascending aorta. Some of (sympathetic)
their central processes are implicated in spinal reflex cardiac
arcs, whereas others ascend to the dorsal vagal nuclei branches
in the medulla oblongata, the nearby reticular forma- 4th thoracic
tion, or the hypothalamus and frontal cortex. sympathetic
ganglion
The thoracic sympathetic cardiac nerves carry many
afferent pain fibers from the heart and great vessels, and Sympathetic preganglionic
this endows them with a clinical interest disproportion- Sympathetic postganglionic
ate to their small size, because their surgical destruction Parasympathetic preganglionic
Parasympathetic postganglionic
Visceral afferent accompanying
sympathetic fibers
Visceral afferent accompanying
parasympathetic fibers

produces alleviation of angina pectoris. Other cardiac the rate and strength of the heartbeat; usually, they
pain afferents run in the middle and inferior cervical depress cardiac activity. In humans, the afferent vagal
sympathetic cardiac nerves; however, after entering the information pass through cardiac branches of the recur-
corresponding cervical ganglia, they descend within the rent laryngeal nerves to the main vagus nerves, and thus
sympathetic trunks to the thoracic region before passing to the brainstem.
through rami communicantes to the upper four or five
thoracic spinal nerves. Afferent pericardial fibers from the fibrous and parietal
serous pericardium are carried mainly in the phrenic
Afferent vagal fibers from the heart and vessels play an nerves, but those from the visceral serous pericardium
important role in modifying efferent output that adjusts join the coronary arterial plexuses.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 183

Plate 7-11â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
INNERVATION OF BLOOD VESSELS

Cervical sympathetic trunk ganglia Internal carotid nerve
Spinal nerves
White ramus communicans
Gray rami communicantes Cervical cardiac nerves
Brachial plexus

Spinal nerves Upper thoracic Cardiopulmo-
sympathetic nary splanchnic
trunk ganglia and aortic nerves

Lower thoracic Intercostal
sympathetic nerves
trunk ganglia Abdominopelvic
Spinal nerves splanchnic
nerves

Upper lumbar Fibers direct
sympathetic to vessels
trunk ganglia
Innervation of Blood Vessels
Spinal nerves

Gray ramus communicans
Lower lumbar
sympathetic
trunk ganglia

Blood vessels are innervated by afferent and efferent Sympathetic fibers Postganglionic sympathetic
autonomic nerves. All receive sympathetic fibers, but Preganglionic fibers to lumbar and
some may not have a parasympathetic supply. The great Postganglionic sacral plexuses and
vessels near the midline in the neck and body cavities to nerves of lower limb
receive direct innervation from adjacent parts of the
sympathetic trunks. Some of these vessels and their The axons of these ganglionic cells (postganglionic (postganglionic fibers) of the cervical ganglionic cells
branches also obtain supplies from nearby autonomic fibers) may pass in nerves to nearby structures, such as supply the vessels and glands in the head and neck,
plexuses, which contain both sympathetic and parasym- midline vessels and prevertebral plexuses (cardiac, while others contribute to the sympathetic cervical
pathetic elements. Thus the ascending aorta, the aortic celiac, mesenteric), or they may join the lowest cervical, cardiac nerves. Some of the postganglionic fibers arising
arch and its branches, and the superior vena cava receive thoracic, and upper lumbar spinal nerves through gray in the lumbar and sacral ganglia run in lumbar and
offshoots from the cardiac plexus; the pulmonary rami communicantes, to be distributed with them to sacral splanchnic nerves to the mesenteric and hypogas-
vessels, from the pulmonary plexuses; the celiac, vessels and glands in the thoracic and abdominal cavi- tric plexuses, but others pass through gray rami com-
hepatic, gastric, splenic, superior mesenteric, renal, and ties and limbs. municantes to the lumbar, sacral, and coccygeal spinal
adrenal vessels and the portal and inferior caval veins, nerves to be distributed with them and their branches
from the celiac and superior mesenteric plexuses; the Other preganglionic fibers, however, do not relay to vessels, sweat glands, and arrectores pilorum muscles
inferior mesenteric vessels, from the corresponding in adjacent trunk ganglia, but ascend or descend in the loin, lower abdominal wall, buttocks, perineum,
plexus; and the pelvic vessels, from the superior and in the sympathetic trunks to form synapses in the cervi- and lower limbs.
inferior hypogastric plexuses. cal or lower lumbar and sacral ganglia. The axons

The chief outflow of sympathetic preganglionic
fibers is through the anterior roots of spinal nerves T1
to L2. The fibers pass in white rami communicantes to
adjacent sympathetic trunk ganglia, where many relay.

184 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-12â•… Autonomic Nervous System and Its Disorders
CAROTID BODY AND CAROTID SINUS
Glossopharyngeal (IX) nerve
Carotid sinus nerve Vagus (X) nerve
Veins from carotid body Superior cervical sympathetic trunk ganglion
External carotid artery Retromandibular and facial veins
Carotid body Lingual vein
Artery to carotid body Internal jugular vein
Superior thyroid artery Internal carotid artery
Common carotid artery Carotid sinus

Carotid body Carotid sinus

Synaptic ending Nerve fibers Type II (sheath) cells Intima
Media
Adventitia

Free nerve endings

Nerve fibers

Innervation of Blood Vessels Capillaries Thin Encapsulated endings
Basement elastic
(Continued) membrane media
Fibroblast
The vascular nerves from the diverse sources unite Type I (glomus) cells
around individual vessels in wide-meshed perivascular Endothelial cells
adventitial plexuses. Fascicles arising from these sink
inward to form more delicate plexuses between the in peripheral arteries and arterioles (like those in the Carotid Sinus and Carotid Body. The carotid sinus
adventitial and medial coats, from which nerve fibers fingers and toes) and in arteriovenous anastomoses is a dilation in at the beginning of the internal carotid
originate to ramify in the media and in the zone between because they have thicker muscular layers and a richer artery; the tunica media is thin, and adventia are thicker
the media and intima. Subsidiary perivascular plexuses innervation than larger arteries, which have more with multiple terminations of the glossopharyngeal
extend along the vessel branches and are augmented at elastic tissue in their walls. Arteries supplying erectile nerve. The carotid sinus serves as a baroreceptor and
intervals by branchlets from nearby cranial or spinal tissues and the skin are also richly innervated, whereas plays an important role in the control of intracranial
nerves, which contain autonomic fibers. Thus innerva- the nerve supply to veins and venules is comparatively blood pressure. The carotid body is a small reddish
tion is segmental rather than longitudinal, and only sparse. Nerve fibers are often associated with capillar- brown structure behind the bifurcation of the common
relatively short lengths of arteries can be denervated by ies, but their functions are unknown. carotid artery and is a chemoreceptor.
the removal of adventitial cuffs.

Most cranial and spinal nerves contain efferent and
afferent vascular fibers. The oculomotor (III), trigemi-
nal (V), facial (VII), vagus (X), glossopharyngeal (XI),
phrenic, ulnar, median, pudendal, and tibial nerves
contain relatively large numbers of vascular fibers.
Accordingly, lesions involving these nerves are more
likely to produce vasomotor and other autonomic dis-
turbances. Vascular disorders are usually more evident

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 185

Plate 7-13â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Autonomic Nerves and Right sympathetic trunk Anterior,
Ganglia in Abdomen Thoracic duct Posterior
Right greater vagal trunks
There are more sympathetic nerves in the abdomen and and lesser thoracic Left gastric artery
pelvis than anywhere else because these cavities contain splanchnic and plexus
the major parts of the digestive and urogenital systems, nerves Celiac ganglia
the adrenal glands, and the extensive peritoneum. Right phrenic nerve Left greater thoracic
Inferior phrenic splanchnic nerve
The abdominal sympathetic nerves include the arteries and plexuses Left lesser thoracic
lumbar parts of the sympathetic trunks and their Right greater splanchnic nerve
branches and contribute to the celiac, mesenteric, and lesser thoracic Splenic artery
intermesenteric (abdominal aortic), hepatic, renal, splanchnic and plexus
adrenal, superior hypogastric, and other plexuses, nerves Common hepatic
including all subsidiary plexuses. Apart from the lumbar Right suprarenal artery and plexus
sympathetic trunks and branches, however, all the plexus Superior mesenteric
autonomic plexuses mentioned contain both sympa- Right aortico- ganglion and plexus
thetic and parasympathetic elements. renal ganglion Left aorticorenal
Right least thoracic ganglion
The lumbar parts of the sympathetic trunks are splanchnic nerve Left sympathetic
directly continuous above with their thoracic counter- Right renal trunk
parts behind the medial arcuate ligaments, whereas artery and plexus Intermesenteric
below, they pass over the pelvic brim and behind the Right (aortic) plexus
common iliac vessels to become the sacral parts of the sympathetic trunk Inferior mesenteric
sympathetic trunks. The trunks lie in the retroperito- White and gray ganglion
neal connective tissue on the anterolateral aspect of the rami communicantes Left colic artery
lumbar vertebrae, along the medial margins of the psoas Cisterna chyli and plexus
muscles; the right trunk is partly overlapped by the Gray ramus Inferior mesenteric
inferior vena cava and the cisterna chyli, and the left communicans artery and plexus
trunk is just lateral to the abdominal aorta. There are 3rd lumbar ganglion Left common iliac
usually four lumbar ganglia on each side; the interven- of sympathetic trunk artery and plexus
ing cords may be single or split into two or even three 2nd and 3rd lumbar Superior rectal
strands. Each trunk supplies or receives communicat- splanchnic nerves artery and plexus
ing, visceral, vascular, muscular, osseous, and articular Right ureter and plexus Superior hypogastric
branches. Right testicular (ovarian) plexus
artery and plexus Internal and external
Only the upper two or, occasionally, three lumbar 4th lumbar splanchnic iliac arteries and
spinal nerves contribute white rami communicantes to nerve plexuses
1st sacral ganglion Right and left
of sympathetic trunk hypogastric nerves
Gray rami communicantes to inferior hypo-
gastric (pelvic) plexus
the adjacent lumbar trunk ganglia, but every lumbar
spinal nerve receives one or more gray communicating the lower part of the superior hypogastric plexus or the
rami from adjacent trunk ganglia. White rami contain homolateral hypogastric nerve; it communicates with
preganglionic and visceral afferent fibers, whereas gray the ureteric and testicular plexuses.
rami contain vasomotor, sudomotor, and pilomotor
fibers, which are distributed with the lumbar spinal Vascular fibers from the lumbar sympathetic trunks
nerves. and their lumbar splanchnic branches pass to the
abdominal aorta and the inferior vena cava, where they
Three or four lumbar splanchnic nerves arise on each form the delicate intermesenteric and caval plexuses. All
side and are seldom arranged symmetrically. The first the aortic branches and vena caval tributaries are sur-
lumbar splanchnic nerve arises from the first lumbar gan- rounded by subsidiary plexuses continuous with those
glion and ends in the renal, celiac, and/or intermesen- around the parent vessels. Twigs from the right sympa-
teric plexuses, but some fibers may end directly in the thetic trunk also supply the cisterna chyli and the com-
duodenum, pancreas, and gastroesophageal junction. mencement of the thoracic duct. Nerve fibers from the
The second lumbar splanchnic nerve arises from the renal plexus, sometimes reinforced by fascicles from
second lumbar ganglion and ends mainly in the inter- the second and third lumbar splanchnic nerves, usually
mesenteric plexus, although it may give direct contribu- join the plexus around the common or external
tions to the renal plexus, duodenum, and pancreas. The iliac arteries.
third lumbar splanchnic nerve usually originates from the
third and fourth ganglia and ends in the upper part of Muscular, osseous and articular fibers supply the
the superior hypogastric plexus. The fourth lumbar adjacent muscles, vertebrae, and joints in the lumbar
splanchnic nerve, when present, arises from the fourth region. They contain postganglionic (efferent) fibers,
and/or the inconstant fifth lumbar ganglion and joins which are possibly vasomotor, and afferent fibers con-
veying impulses from meningeal, bony, and articular
structures.

186 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-14â•… Autonomic Nervous System and Its Disorders

Right 6th thoracic Esophageal plexus
ganglion of
sympathetic
trunk

Innervation of Stomach and Gray, Left greater thoracic
Proximal Duodenum White splanchnic nerve
rami communicantes Aortic plexus
Sympathetic Fibers. The gastric sympathetic pregangli- Spinal sensory Left 9th thoracic
onic fibers are the axons of cells located in the interme- (dorsal root) ganglion of
diolateral cell columns of the sixth to ninth or tenth ganglion sympathetic trunk
thoracic spinal segments. They reach the celiac plexus Anterior Posterior vagal trunk
via the sympathetic trunk ganglia and the greater (major) (ventral) root and celiac branch
and lesser (minor) thoracic splanchnic nerves. Some of the of spinal nerve Anterior vagal trunk
fibers form synapses in trunk ganglia, but most continue Right greater thoracic and celiac branch of
through them to end in synapses within the celiac and splanchnic nerve vagus nerve (X)
superior mesenteric ganglia. The resulting postganglionic Right lesser thoracic Left gastric artery
fibers may run in fascicles ending directly in the stomach splanchnic nerve
and duodenum, but the majority are conveyed to their Celiac ganglia Celiac trunk
destinations in the perivascular plexuses along the various Least thoracic Splenic artery
branches of the celiac trunk. These plexuses are com- splanchnic nerve Short
posed mainly of sympathetic fibers, but they also gastric
contain parasympathetic fibers derived from the celiac Common arteries
branches of the vagal trunks. The sympathetic postgan- hepatic artery
glionic fibers traverse the intramural enteric ganglia Proper Left,
without relaying, and are distributed mainly to the hepatic artery Right gastro-
gastric musculature and blood vessels. Superior omental
mesenteric (gastroepiploic)
Parasympathetic Fibers. The two vagus nerves form ganglion arteries
an esophageal plexus around the lower esophagus, which Aorticorenal
is reinforced by twigs from the thoracic parts of the ganglia Afferent fibers
sympathetic trunks and from the greater (major) and lesser Right gastric artery
(minor) thoracic splanchnic nerves. Before reaching the Right renal artery
diaphragm, the meshes of the esophageal plexus are Gastroduodenal artery
reconstituted to form anterior and posterior vagal trunks. Posterior and anterior
In general, more fibers from the left vagus enter the superior pancreatico-
anterior trunk, whereas the posterior trunk contains duodenal arteries
more fibers from the right vagus, although the anatomic
relationships are highly variable. The vagal trunks Posterior and anterior Superior
give off gastric, pyloric, hepatic, and celiac branches. inferior pancreatico- mesenteric

Anterior and posterior gastric branches supply the cor- duodenal arteries artery
responding surfaces of the stomach. They run between
the layers of the lesser omentum and give off branches Sympathetic fibers Parasympathetic fibers
that radiate over the surfaces of the stomach and can be
traced for some distance in the subperitoneal tissue Preganglionic Preganglionic
Postganglionic Postganglionic

before they sink into muscle coats; no definite anterior posterior vagal trunk usually reaches the hepatic plexus
or posterior gastric plexuses exist. Often, one branch on through its celiac branch. Both vagal trunks give off
both the anterior and posterior aspects is larger than celiac branches, and the posterior branch is larger than
the others—the greater anterior and greater posterior the anterior. All efferent (preganglionic) vagal fibers
gastric nerves. Pyloric branches arise from the anterior ending in the stomach make synaptic contacts with gan-
vagal trunk or its greater anterior gastric branch and glionic neurons in the gastric parts of the myenteric and
supply the pyloric antrum, pylorus, and superior (first) submucous plexuses; the resulting postganglionic fibers
part of the duodenum. Hepatic branches are provided by are distributed to the gastric musculature, glands, and
both vagal trunks; that from the anterior trunk arises vessels, where they exert both motor and secretory
near the gastric cardiac ostium and is called the hepato- effects (see Plate 7-17).
gastric nerve because it supplies offshoots to the hepatic
plexus and stomach (there may be more than one hepa- Afferent Fibers. Afferent parasympathetic and sym-
togastric nerve). The hepatic contribution from the pathetic fibers pursue reverse routes to those described
for vagal and sympathetic efferent fibers.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 187

Plate 7-15â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

INNERVATION OF THE INTESTINE

Great splanchnic Vagus nerves
nerve Great splanchnic n.

White ramus TII Lesser splanchnic n.

Gray ramus Least splanchnic n.
Celiac ganglia
12th thoracic and plexus
symp. ganglion Superior mesenteric
ganglion
1st lumbar
symp. ganglion L2

Superior
mesenteric
artery
and plexus

L3

Inferior
mesenteric
ganglion

L4 Inferior mesenteric
artery and plexus

L5 SI Hypogastric
1st SI plexus

sacral S2 Superior
symp. S2 hemorrhoidal
gangl artery
and plexus
Innervation of Intestines 1st S2
sacral S3 S3 Pelvic nerve
SYMPATHETIC FIBERS nerve S4 (nervus erigens)
The preganglionic sympathetic fibers to the intestines 2nd sacral Pelvic S5 S4 S3
are the axons of intermediolateral cells located in the nerve plexus S5 Pelvic
lowest four or five thoracic and upper two lumbar spinal
segments. Some form synapses in the sympathetic trunk Sacral S3 plexus
ganglia, but most are conveyed in the thoracic, lumbar, plexus
and sacral splanchnic nerves to the celiac, mesenteric, and
hypogastric plexuses, where they relay. From the celiac S4 S4 Sacral
and superior mesenteric plexuses, an unknown propor- S5 S5 plexus
tion of fibers descend in the intermesenteric and hypogas-
tric nerves to the inferior mesenteric and hypogastric Pelvic nerve Pudendal
plexuses. Postganglionic fibers from ganglionic syn- (nervus erigens) nerve
apses, along with afferent and preganglionic parasym- (somatic)
pathetic fibers, are carried to the intestines in branches Pudendal nerve
of the various plexuses. (somatic)

The parasympathetic supply to the intestines is derived to the intestines as sympathetic postganglionic fibers (pelvic) plexuses and are distributed with their branches.
from the vagus and pelvic splanchnic nerves. The vagal but are still preganglionic and end by forming synapses The preganglionic intestinal fibers pass through the
contributions pass to the celiac plexus in the larger and in the enteric plexuses (see Plate 7-17). ganglia in these plexuses without relaying; like their
smaller celiac branches arising, respectively, from the pos- vagal counterparts, they end by making synaptic con-
terior and anterior vagal trunks. Some fibers are distrib- The pelvic splanchnic nerves arise from the second, tacts in the enteric plexuses. Some branches pass directly
uted with branches of the celiac plexus to the stomach third, and fourth sacral nerves. They contain paraÂ

Plate 7-16â•… Autonomic Nervous System and Its Disorders
AUTONOMIC INERVATION OF SMALL INTESTINE

Innervation of Intestines Anterior vagal trunk
Posterior vagal trunk
(Continued) Celiac branches of anterior
and posterior vagal trunks

Hepatic plexus

Greater thoracic
splanchnic nerves

Celiac ganglia
and plexus
Gastroduodenal
artery and plexus
Lesser thoracic
splanchnic nerves
Least thoracic
splanchnic nerves
Aorticorenal ganglia

Superior mesenteric ganglion

Intermesenteric (aortic) plexus
Inferior pancreaticoduodenal
arteries and plexuses
Superior mesenteric
artery and plexus
Middle colic artery and plexus J\[
Right colic artery and plexus
Ileocolic artery and plexus
Superior mesenteric
artery and plexus
Peritoneum J\[ LKNL
Mesenteric branches

mesenteric plexus, to be distributed with its branches to Mesoappendix (contains
the distal parts of the colon. However, the majority of appendicular artery and
the parasympathetic fibers for these parts of the colon nerve plexus)
pursue a different course: they arise by several filaments
from the pelvic splanchnic nerves or the inferior hypogastric and consist of the two ganglionic strata: the myenteric, influences on the ENS. The cholinergic terminals of
plexuses and run upward across the sigmoid and left colic or Auerbach plexus between the two layers of the exter- the parasympathetic system, acting on the smooth
vessels. They can be traced as far as the left colic flexure, nal muscle, and the submucosal Meissners plexus, muscles of the small and large intestine and also via
and they supply offshoots to the adjacent parts of the which extends from the esophagus to the anal canal and the enteric plexuses, cause increased motility of the
sigmoid and descending colons and communicate with is responsible for peristaltic activity, secretion of intestine and increased secretory activity of the glands.
branches of the inferior mesenteric plexus. mucosal glands, vasoconstriction and vasodilation, Postganglionic fibers of the sympathetic nervous
water absorption, and electrolyte balance. The para- system release norepinephrine, causing decreased
Afferent pathways, in general, follow (in reverse direc- sympathetic and sympathetic exert external regulatory motility.
tion) both the sympathetic and the parasympathetic
supplies to the small and large bowel. The afferent
components of the vagus and pelvic nerves and of the
sympathetic pathways subserve reflex activity, but most
localized sensations referable to the gastrointestinal
tract appear to be mediated through the sympathetic
afferents.

At the anorectal junction, the autonomic innervation
gives way to somatic innervation.

AUTONOMIC SYSTEM ROLE
IN GUT MOTILITY
The enteric nervous system (ENS) is a complex network
of neurons and nerve fibers located within the gut wall

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 189

P late 7-17â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Peritoneal Branch of
layers of straight artery
mesentery (arteriae rectae)
to intestine and
accompanying
nerves

Subserous Myenteric plexus (Auerbach)
plexus lying on longitudinal muscle
Longitudinal coat. Fine tertiary bundles
intramuscular crossing meshes (duodenum
plexus of guinea pig, Champy-
Coujard, osmic stain, x20).

Myenteric
(Auerbach)
plexus

Enteric Plexuses Circular Submucous plexus (Meissner)
intramuscular (ascending colon of guinea
Enteric plexuses exist within the walls of the alimentary plexus pig. Stained by gold impreg-
tract, from the esophagus to the rectum. They form nation, x20).
microscopic networks and consist of bundles of nerve Submucosal
fibers (axons) and dendrites, which link ganglia located (Meissner)
chiefly at nodal points in the meshes. These networks plexus
are most evident between the layers of the muscle coats
(myenteric, or Auerbach, plexus) and in the submucosa Periglandular
(submucous, or Meissner, plexus). Tenuous subserous plexus
plexuses with sparsely disposed nerve cells are present
in those parts of the gastrointestinal tract that possess Visceral
peritoneal coverings. peritoneum
(serosa)
The myenteric (Auerbach) plexus is relatively coarse,
with thicker meshes and larger ganglia. The main, or Subserous
primary, meshes give off fascicles that form secondary connective
networks in the interstices of the primary networks. tissue
These, in turn, split into minute bundles of fibers
that ramify between the muscle tunics and supply Group of multipolar neurons,
them. The submucous (Meissner) plexus is more delicate type II, in ganglion of myenter-
and its meshes are more irregular. Its delicate offshoots ic (Auerbach) plexus (ileum
mostly end in relation to cells forming the muscularis of cat; Bielschowsky, silver
mucosae or form rarefied periglandular plexuses, stain, x200)
while other offshoots end in almost invisible subepithe-
lial plexuses. Longitudinal
muscle
The patterns and densities of these plexuses vary in
different parts of the alimentary tract. They are less well Lumen Intermuscular
defined in the upper part of the esophagus but are well Mucosa and stroma
developed from the stomach to the lower end of the intestinal glands
rectum. The ganglia are not uniformly distributed. The Circular
density of ganglionic cells in the plexuses is lowest in Muscularis muscle
the esophagus, rises steeply in the stomach until it mucosae
reaches a peak at the pylorus, falls to an intermediate Note: Intestinal wall is shown Submucosa Pseudounipolar neuron with-
level throughout the small intestines, and gradually much thicker than in actuality. Submucosal in ganglion of myenteric plex-
increases along the colon to reach another, lesser peak glands us (ileum of cat; Bielschowsky,
in the rectum. silver stain x375)

The extrinsic nerves involved contain efferent and as in other situations, the parasympathetic postgangli- responsible for supplying adjacent vessels and transmit-
afferent sympathetic and parasympathetic fibers derived onic fibers are very much shorter than their sympathetic ting sensory impulses. The sympathetic innervation is
from thoracic, lumbar, and sacral branches of the sym- counterparts. primarily inhibitory to peristalsis and stimulatory to the
pathetic trunks and from the vagus and pelvic splanch- sphincters, while the parasympathetic innervation is the
nic nerves. Most of the sympathetic efferent fibers Many interconnections exist between the myenteric opposite.
entering the enteric plexuses are postganglionic, while and submucous plexuses. In general, the former are
parasympathetic efferent fibers are still preganglionic. mainly concerned with the innervation of the muscle Afferent fibers from the alimentary tract are con-
The vagal fibers form synapses with ganglion cells layers in the visceral walls, whereas the latter are chiefly veyed to the central nervous system (CNS) through the
located in the enteric plexuses, from the esophagus to involved with supplying the glands and muscularis same sympathetic and parasympathetic nerves that
the distal third of the transverse colon; below this level, mucosae and in forming delicate subepithelial plexuses. carry the corresponding efferent fibers. There is also
the preganglionic parasympathetic fibers are carried in The enteric plexuses and their subdivisions are also evidence that local reflex arcs exist.
branches of the pelvic splanchnic nerves. Thus in this

190 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-18â•… Autonomic Nervous System and Its Disorders

Common areas of referred pain in T7 T7 T7 Sympathetic trunk
biliary disease T8 T8 Posterior root
T9 (spinal) ganglion
Right greater thoracic splanchnic nerve T8 T10 Thoracic part of spinal
Posterior vagal trunk T9 cord

Right phrenic nerve to diaphragmatic T9 Left greater thoracic
part of parietal peritoneum T10 splanchnic nerve
Anterior vagal trunk
T10

Innervation of Liver and Hepatic branch of
Biliary Tract anterior vagal trunk
Diaphragm
The liver, biliary tract, and gallbladder receive their Phrenic ganglion
nerve supplies from sympathetic and parasympathetic Celiac ganglia
sources. The preganglionic sympathetic fibers originate Common hepatic artery
mainly in the seventh to tenth thoracic segments and Splenic artery
pass to the celiac plexus via the sympathetic trunk
ganglia and the greater and lesser thoracic splanchnic Anterior hepatic plexus
nerves (see Plates 7-13 and 7-14). Most of the fibers Posterior hepatic plexus
form synapses in the celiac ganglia, although some may
relay in small ganglia located in the porta hepatis. The Aorta
postganglionic sympathetic fibers reach the liver in the Gastroduodenal
hepatic plexuses, which also contain parasympathetic artery and plexus
and afferent fibers. The parasympathetic supply is pro-
vided by branches of the vagal trunks. Sphincter of
hepatopancreatic ampulla
Afferent fibers from the liver and biliary tract are
conveyed through the hepatic and celiac plexuses to the Ramification of nerve
thoracic splanchnic nerves or to branches of the vagus fibers around fine branch
nerves. The sympathetic afferents reach the seventh to of hepatic artery
twelfth thoracic spinal cord segments through the cor-
responding posterior spinal nerve roots, whereas the Sympathetic fibers Parasympathetic fibers Afferent fibers
vagal afferents are carried upward to the brainstem.
The right, and possibly the left, phrenic nerve also Preganglionic Preganglionic
conveys afferents from receptors in the peritoneal Postganglionic Postganglionic
lining over the liver and biliary tract, which can be
stimulated by stretching—as by acute hepatic enlarge- liver lobules to form a widespread parenchymal plexus. the posterior hepatic plexus. The common bile duct (cho-
ment or distention of the gallbladder. The resultant Histochemical studies reveal that the nerve fibers in ledochal duct) is supplied by twigs from both anterior
pain in the right shoulder region associated with relation to the hepatocytes and sinusoids are parasym- and posterior hepatic plexuses and by offshoots from
liver and biliary tract disorders is an example of pathetic, whereas sympathetic fibers remain mainly or the plexus around the gastroduodenal artery and its
referred pain. entirely associated with vessels in the interlobular retroduodenal branches. The arrangement of the nerves
spaces. Direct contacts between the terminations of within the walls of these structures resembles that in
Liver. The hepatic plexuses lie in the right free margin nerve fibers and liver cells have been observed in elec- the enteric plexuses.
of the lesser omentum anterior to the epiploic (omental) tron micrographs.
foramen. They are formed mainly by offshoots from the Both the sphincter ampullae and the sphincter of the
celiac plexus, which contain sympathetic and parasympa- Gallbladder. The gallbladder is supplied by perivas- choledochal duct are supplied by sympathetic and para-
thetic efferent and afferent fibers, supplemented by cular nerve fibers accompanying the right hepatic and sympathetic fibers. The former normally cause contrac-
direct contributions from the anterior vagal trunk and cystic arteries from the anterior hepatic plexus and by tion of the sphincters and dilation of the gallbladder,
by indirect contributions from the right phrenic nerve. other nerve fibers extending along the cystic duct from while the latter produce the opposite effects.
They are arranged in two interconnected groups, one
of which lies along the anterior and lateral sides of the
hepatic artery, and the other, posterior to the common
bile duct and portal vein.

Subsidiary plexuses surround and accompany the
branches of the hepatic artery, portal vein, and right and
left hepatic ducts as they enter and ramify within the
liver; their offshoots penetrate between the cells of the

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 191

P late 7-19â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Anterior Celiac plexus
vagal trunk and ganglia

Right greater thoracic Posterior Left greater thoracic
splanchnic nerve vagal trunk splanchnic nerve

Right phrenic nerve Left phrenic nerve
Right inferior phrenic
artery and plexus Left inferior phrenic
Right suprarenal gland artery and plexus
Right lesser thoracic
splanchnic nerve Left suprarenal
gland
Right least thoracic
splanchnic nerve Left lesser thoracic
splanchnic nerve
Right renal
ganglion and plexus Aorticorenal
ganglia

Left least
thoracic
splanchnic
nerve

Left renal
ganglion
and plexus

Innervation of
Adrenal Glands

The adrenal (suprarenal) glands show a high degree of Right sympathetic trunk Left sympathetic trunk
species variation, and this also applies to their nerve Right 1st lumbar splanchnic nerve Left 1st lumbar splanchnic nerve
supplies. The cortex and medulla differ in their devel- Intermediolateral cell column Superior mesenteric ganglion
opment. The medullary (chromaffin) cells are modified (lateral horn of gray matter)
migrant neuroblasts from the neural crest and are Medulla Cortex
homologous with ganglion cells in the sympathetic T10
trunks. Accordingly, they are innervated directly by
preganglionic fibers. Relative to their size, the adrenal T11 Greater thoracic Postganglionic
medullae are more richly innervated than any other T12 splanchnic nerve fibers supply
viscus. (preganglionic Celiac blood vessels
fibers) ganglion
The preganglionic sympathetic fibers are the axons of
cells located in the intermediolateral gray columns of L1
mainly the lower three or four thoracic and upper one
or two lumbar segments of the spinal cord. They Spinal cord Sympathetic
emerge in the anterior rootlets of the corresponding trunk
spinal nerves, pass in white rami communicantes to the
sympathetic trunks, and leave them in the thoracic and Preganglionic Suprarenal gland
first lumbar splanchnic nerves that run to the celiac, fibers ramify
aorticorenal, and renal ganglia. Some of the fibers con- around cells
veying impulses for the adrenal vessels may relay in of medulla
these ganglia, but the majority continue onward to
enter the adrenal branches of the celiac plexus. fibers spread out over the gland to form a delicate sub- membranes deeply but do not penetrate them. A minor-
capsular plexus from which fascicles penetrate the cortex ity of fibers innervate the medullary arterioles and the
Some of the parasympathetic fibers reaching the celiac to run alongside arterioles in the trabeculae to the central vein, which has an unusually thick muscle coat.
plexus through the vagal trunks may be concerned with medulla. The majority of nerve fibers entering the
adrenal innervation and may relay in small ganglia near gland end in the medulla, where they ramify profusely Multipolar or bipolar neurons, singly or in small
or in the glands, but as yet, no definite proof of this and give off fibers that mostly terminate in synaptic- groups, have been noted within the adrenal medullae.
hypothesis exists. The adrenal parasympathetic supply type contacts with the chromaffin cells. As already Their significance and the destinations of their axons
may well emerge via posterior spinal nerve root effer- stated, these are the homologues of ganglion cells in the have not yet been determined, although it is assumed
ents, which enter the thoracic splanchnic nerves and sympathetic trunks. Some fibers invaginate the cell that the cells are the final relay stations in the parasym-
thereafter follow the same routes as the sympathetic pathetic pathways.
preganglionic fibers; however, the existence of such
posterior root efferents is still unproven. A proportion
of the fibers in the adrenal nerves may be afferent and
enter the spinal cord through the ninth to eleventh
thoracic spinal nerves.

Adrenal Nerves. Numerous fine nerves pass outward
to each gland from the celiac plexus and ganglia. They
are joined by contributions from the terminations of the
greater and lesser thoracic splanchnic nerves, and they com-
municate with the ipsilateral phrenic nerve and renal
plexus.

Many nerve fibers from the adrenal nerves enter the
gland through its hilus and medial margin. Other nerve

192 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-20â•… Autonomic Nervous System and Its Disorders

Gray and white rami 2nd lumbar sympathetic trunk ganglion
communicantes Intermesenteric (abdominal aortic) plexus
L2
Inferior mesenteric ganglion
Right sympathetic L3 Lumbar splanchnic nerves
trunk
and its 3rd Inferior mesenteric artery
lumbar ganglion and plexus
Superior hypogastric plexus
Gray rami (presacral nerve)
communicantes

Autonomic Nerves and Right and left L4 Superior rectal artery
Ganglia in Pelvis hypogastric nerves and plexus
1st sacral L5 Nerves from inferior
Sympathetic fibers reach the pelvis through the sympa- sympathetic S1 hypogastric plexuses to
thetic trunks and the superior hypogastric plexus, and trunk ganglion S2 sigmoid and descending
in visceral and vascular nerves accompanying and sup- Gray rami colon
plying such structures as the colon, ureters, and the communicantes
inferior mesenteric and common iliac vessels. Parasym- Right ureter and
pathetic fibers emerge in the anterior roots of the second, Sacral part of ureteral plexus
third, and sometimes, fourth sacral spinal nerves and sympathetic
leave them in the slender bilateral pelvic splanchnic trunk Seminal vesicle
nerves (nervi erigentes) that join the corresponding Ductus
inferior hypogastric (pelvic) plexuses and are distrib- Sacral deferens
uted with their branches. plexus
Vesical plexus
Sympathetic Fibers. The lumbar and sacral parts of S3 Inferior rectal plexus
the sympathetic trunks are directly continuous at the S4
level of the pelvic brim. The sacral trunks lie in the Prostatic plexus
pelvic fascia behind the parietal peritoneum and rectum, S5 Cavernous plexus
and on the anterior surface of the sacrum, just medial
to its anterior foramina and the nerves and vessels Pelvic splanchnic Posterior
passing through them. Below, they converge and unite nerves (sacral nerve of penis
in a single tiny “ganglion impar” anterior to the coccyx.
In general, four, or sometimes, three sacral trunk parasympathetic supply of pelvic, perineal, gluteal, and lower limb struc-
ganglia exist on each side. No white rami communican- outflow) tures relay in lumbar and sacral trunk ganglia; a minor-
tes are present in this region, but each ganglion supplies ity may form synapses in ganglia within the inferior
one or more gray rami communicantes containing post- Pudendal nerve hypogastric plexuses.
ganglionic sympathetic fibers to the adjoining sacral Right inferior hypogastric
and coccygeal spinal nerves; these fibers are conveyed (pelvic) plexus The parasympathetic fibers in the pelvic splanchnic nerves,
in branches of the sacral and coccygeal plexuses to which arise from the sacral nerves and end in the inferior
vessels, sweat glands, arrectores pilorum muscles, stri- and vaginal fornices replace the prostate gland and hypogastric plexuses, are preganglionic. Some relay in
ated muscles, bones, and joints. seminal vesicles as medial relations. The plexuses ganglia within the plexuses, but many more form syn-
supply branches to the pelvic viscera and genitalia and apses in ganglia located near or within the walls of the
The pelvic sympathetic trunk ganglia also supply often form subsidiary plexuses (such as the rectal, pros- viscera and vessels innervated.
slender rami, the sacral splanchnic nerves, which pass to tatic, and vesical). The branches contain visceral, glan-
the inferior hypogastric plexuses. The majority of sym- dular, vascular, and afferent fibers, often combined in Other branches from the inferior hypogastric plex-
pathetic fibers, however, reach these plexuses through the nerve fascicles supplying the various structures con- uses ascend to assist in the innervation of the distal
the right and left hypogastric nerves, formed just below cerned (see Plates 7-21 to 7-24). The sympathetic efferent colon and the renal pelvises.
the level of the lumbosacral junction by the splitting fibers in these branches, like those in the gray rami com-
of the median superior hypogastric plexus (often mis- municantes connecting the ganglia of the pelvic sym-
leadingly referred to as the “presacral nerve”—a single pathetic trunks to the sacral and coccygeal spinal nerves,
nerve is very rare). Similarly, the right and left hypo- are almost entirely postganglionic because most or all
gastric nerves are more often elongated plexuses con- of the sympathetic preganglionic fibers involved in the
sisting of several nerves interconnected by oblique
strands, which incline downward on each side, behind
the peritoneum and lateral to the sigmoid colon and
rectosigmoid junction, to end in the upper parts of the
homolateral inferior hypogastric plexus.

The inferior hypogastric plexuses are situated on each
side of the rectum, lower part of the bladder, prostate,
and seminal vesicles. In females, the cervix of the uterus

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 193

Plate 7-21â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

AUTONOMIC INNERVATION OF KIDNEYS AND UPPER URETERS

Spinal sensory (posterior Nucleus of solitary tract
root) ganglion Posterior (dorsal) nucleus
of vagus nerve

Gray ramus communicans Medulla oblongata
Vagus nerve (X)

Innervation of Kidneys, Anterior ramus of T10 Descending fibers
Ureters, and (intercostal nerve) Ascending fibers
Urinary Bladder T10
White ramus Spinal cord segments
Kidney and Upper Ureter. The preganglionic sympathetic communicans T11 T10–L1
fibers for the kidneys and upper ureters emerge from the Ganglia of T12 Lesser thoracic
spinal cord through the anterior nerve roots of the sympathetic trunk splanchnic nerve
eleventh and twelfth thoracic spinal nerves, and often, 1st lumbar L1
the tenth thoracic and first lumbar spinal nerves as well. splanchnic nerve Least thoracic
The fibers then pass in white rami communicantes to splanchnic nerve
adjacent ganglia in the sympathetic trunks. They leave Renal artery, Celiac ganglia and plexus
the ganglia in the splanchnic nerves: the lesser, lowest plexus, and Superior mesenteric
thoracic, first lumbar, and second lumbar. The lesser ganglion ganglion
thoracic splanchnic nerve usually ends in the ipsilateral Aorticorenal ganglion
celiac or aorticorenal ganglia, and the other nerves Sympathetic fibers Intermesenteric plexus
mentioned may do the same, although they usually end Preganglionic Superior hypogastric
directly in the renal plexus or in the small renal gan- Postganglionic plexus
glion lying posterior or posterosuperior to the renal
artery. Most of the preganglionic fibers form synaptic Parasympathetic fibers Hypogastric nerve
relays in the aorticorenal or posterior renal ganglia or Preganglionic S2
in smaller ganglia incorporated into the renal plexuses. Postganglionic S3
The postganglionic sympathetic fibers form fascicles that
surround and accompany the upper ureteric, renal, Afferent fibers Inferior hypogastric
pelvic, calyceal, and segmental branches of the renal Sacral plexus S4 (pelvic) plexus
vessels. Pelvic
splanchnic and ureter, in the adventitia of the larger vessels, and
Some parasympathetic fibers are carried through the nerves near the glomeruli.
vagal contributions to the celiac plexus and are con-
veyed onward to the kidneys in the renal branches of renal vessels and their branches and accompany them Urinary Bladder and Lower Ureter. The pregangli-
this plexus; others emerge through the pelvic splanch- into the kidney. They contain mostly unmyelinated onic sympathetic cells concerned with vesical innervation
nic nerves and may reach the renal collecting tubules, fibers, and relatively few of the myelinated type. The are located in the upper two lumbar segments and
renal calyces and renal pelvis and upper ureter by a sympathetic fibers are distributed to the smooth muscle perhaps also in the lowest thoracic segment of the spinal
more indirect route. Such an arrangement is under- in the renal pelvis and calyces, to the vascular muscula- cord. The sites where the preganglionic fibers form
standable on embryologic grounds because the struc- ture, and possibly to the juxtaglomerular cells and synapses with the ganglionic neurons that give off the
tures mentioned are all derived from buds developed glomeruli. The parasympathetic fibers supply the muscle postganglionic fibers have not been determined accu-
from the cloacal ends of the mesonephric (wolffian) in the pelvis, calyces, and upper ureter, but it is uncer- rately. The preganglionic parasympathetic cells are located
ducts. These pelvic parasympathetic fibers join the infe- tain whether they supply the vessels and tubules. Sensory
rior hypogastric plexuses, ascend in the hypogastric nerve endings have reputedly been detected in the pelvis
nerves to the superior hypogastric plexus, and exit in
fine branches that ascend retroperitoneally to enter the
inferolateral parts of the homolateral renal plexus.

Afferent fibers from the kidneys and upper ureter
follow similar routes in the reverse direction, but they
do not form relays in peripheral ganglia; their cell
bodies are located in posterior spinal nerve root ganglia.
The central processes of these ganglion cells enter the
spinal cord mainly through the posterior nerve roots of
the tenth to twelfth thoracic spinal nerves and then
ascend in or alongside the spinothalamic tracts and also
in the posterior white columns of the cord.

Within the renal hilus and sinus, the renal plexus sup-
plies nerve fibers to the renal pelvis, calyces, and upper
ureter. Other nerve fibers form rich plexuses around the

194 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-22â•… Autonomic Nervous System and Its Disorders

INNERVATION OF URINARY BLADDER AND LOWER URETER

Spinal sensory Dorsal (posterior) root Celiac ganglia
(dorsal root) Ventral (anterior) root Superior mesenteric ganglion
ganglion Aorticorenal ganglion
White Rami
L1 Gray communicantes
L2
Renal artery and plexus

Intermesenteric
(aortic) plexus

Innervation of Kidneys, Lumbar part L2 spinal 1st and 2nd lumbar Inferior mesenteric ganglion
Ureters, and Urinary of spinal cord nerve (ventral splanchnic nerves Superior hypogastric plexus
Bladder (Continued) Sacral part ramus) Hypogastric nerves
of spinal cord Sympathetic trunk Ureter Inferior hypogastric
in the second to fourth sacral segments of the spinal Sacral (pelvic) plexus
cord, and their axons (nervi erigentes) relay in ganglia Ascending Descending splanchnic
close to or within the wall of the urinary bladder. The fibers fibers nerves from Urinary bladder
neurons in the anterior gray matter of the sacral spinal sacral
cord S1 to S3, Onuf nucleus, provide the motor supply Gray rami sympathetic
to the external urethral sphincter through the motor communicantes trunk to
branches of the pudendal nerve. Afferent fibers pursue inferior
similar pathways, but in the reverse direction; thus hypogastric
some vesical sensory impulses enter the cord through (pelvic)
the upper lumbar and last thoracic posterior nerve plexus
roots, while others from the neck of the bladder and
the lowest parts of the ureters reach the cord via the S2
pelvic splanchnic nerves and the posterior nerve roots
of the second to fourth sacral nerve segments. S3

Many fascicles from the extrinsic vesical plexuses enter S4
the bladder wall, mainly alongside its blood vessels.
They divide and subdivide and are ultimately carried to Sacral plexus Pudendal nerve
all parts, forming a widespread intramural, or intrinsic, Pelvic splanchnic nerves
vesical plexus. The nerve fasciculi are most conspicuous Vesical plexus
in the trigonal and neighboring regions, becoming Sympathetic Preganglionic Prostatic plexus
more scattered and attenuated toward the fundus. Many fibers
small ganglia are present on the surface or are buried Postganglionic Sphincter urethrae muscle
more deeply between the muscular bundles, and these superior to perineal membrane
are more numerous in the trigonal region. Many fibers Parasympathetic Preganglionic
enter the submucosa and penetrate between the mucosal fibers Bulbospongiosus muscle
cells, where they apparently end in small boutons. Postganglionic
Somatic efferent fibers
Most of the nerve fasciculi in the urinary bladder wall Afferent fibers
contain unmyelinated or finely myelinated fibers. A
small proportion of larger myelinated and, presumably, stimulation of nerve endings in the peritoneum over a sphincter by activation of alpha-adrenergic receptors.
sensory fibers are connected with terminal arboriza- distended bladder. However, “presacral neurectomy” However, the sympathetic nervous system may play a
tions regarded as stretch receptors. Many other putative (removal of the superior hypogastric plexus) rarely minor role in bladder function, and the preponderance
sensory endings have been described in the submucosa completely alleviates discomfort in patients with painful of evidence suggests that human bladder function
and mucous membrane. The parasympathetic nerves and intractable cystitis because only a proportion of the depends on the integrity of the parasympathetic and
may transmit many or most of the afferent fibers from vesical afferent fibers traverse the hypogastric nerves somatic motor innervation of the bladder.
the trigonal area of the urinary bladder and from the and superior hypogastric plexus. Other afferent fibers
lowest parts of the ureters, including those conveying traveling in the perivascular plexuses of the vesical and There are multiple interactive reflex arcs that are
painful impulses. However, some afferents from the iliac arteries may also reach the superior hypogastric important in the volitional control of the bladder. The
neck of the bladder and prostatic urethra may reach the plexus. Beyond the plexus, the fibers run in lumbar first is a connection between the posteromedial frontal
spinal cord via the pudendal nerves. splanchnic nerves to the sympathetic trunks, pass lobe to the pontine nuclei via the basal ganglia. Lesions
through rami communicantes to the upper lumbar and of this loop result in detrusor hyperreflexia and failure
Sensations associated with vesical distention may be lowest thoracic spinal nerves, and enter the spinal cord of volitional suppression of the detrusor reflex. The
mediated through sympathetic pathways because vague through the posterior roots of these nerves. second reflex arc extends from the pontine nuclei to
discomfort may still be experienced by patients with the motor neurons of the sacral region that innervate
transverse lesions of the cord below the level of the The parasympathetic supply to the bladder produces the bladder; again interruption results in detrusor
uppermost lumbar segments. This suggests that there contraction of the walls and relaxation of the sphinc- hyperreflexia. The third reflex arc includes afferents
is an afferent inflow from the bladder through the upper teric mechanism and is thus actively involved in mictu- from the detrusor muscle to the motor neurons of the
lumbar or lowest thoracic posterior spinal nerve roots. rition. Many credit the sympathetic supply with bladder and the fourth involves afferents from the
Alternatively, such sensations may be produced by the opposing effects, such as relaxation of the detrusor external urethral sphincter to the motor nuclei; loss of
muscles of the vesical wall by activation of beta- these reflex arcs results in distention of the bladder with
adrenergic receptors and contraction of the internal failure to empty.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 195

P late 7-23â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

MALE REPRODUCTIVE ORGANS

Sympathetic trunk and ganglia Celiac ganglia

Greater splanchnic T10 Superior mesenteric
nerve (T5–9) ganglion

Gray ramus communicans Left aorticorenal
ganglion
T11
White ramus communicans Renal ganglion

T12
Lesser splanchnic nerve

Least splanchnic nerve

L1
Upper lumbar splanchnic nerves

Innervation of L2 Intermesenteric (aortic)
Reproductive Organs plexus
L3
The nerves supplying the male and female genital Gray ramus communicans Inferior mesenteric
organs contain sympathetic and parasympathetic ganglion
efferent and afferent fibers; their origins are similar in L4
both sexes. Testicular artery and
Testicular artery and plexus plexus
Sympathetic preganglionic fibers are the axons of inter-
mediolateral column cells located in the lowest two or Ductus deferens and plexus Superior hypogastric
three thoracic and upper one or two lumbar segments plexus
of the spinal cord. They emerge in the anterior nerve
roots of the corresponding spinal nerves and leave them Hypogastric nerves
in white rami communicantes passing to adjacent sym-
pathetic trunk ganglia. They course via the thoracic and Inferior extent of S1 Ductus deferens
the upper lumbar splanchnic nerve, the celiac, inter- peritoneum S2 S1 and plexus
mesenteric (aortic) and superior hypogastric plexuses,
and the hypogastric nerves to the inferior hypogastric Pelvic splanchnic Pelvic splanchnic
(pelvic) plexuses. Many of these fibers relay in the lowest nerves S2 nerves
thoracic and upper lumbar sympathetic trunk ganglia
or within the celiac plexus, but others do not relay until Sacral S3 S3 Sacral
they reach ganglia in the inferior hypogastric plexuses. plexus S4 S4 plexus
Consequently, the postganglionic fibers to the pelvic
organs may be either long or relatively short. A minor- S5 S5 Pudendal nerve
ity of the sympathetic fibers for the pelvic viscera
descend in the sympathetic trunks to emerge in the tiny Pudendal nerve Posterior nerves
sacral splanchnic nerves and thus join the inferior hypo- Inferior hypogastric of penis
gastric plexuses. (pelvic) plexus
Epididymis
Preganglionic parasympathetic fibers reach the inferior Vesical plexus
hypogastric plexuses in pelvic splanchnic nerves arising Testis
from the second, third, and fourth sacral spinal nerves. Prostatic plexus
Nerve fibers from the inferior hypogastric plexuses supply
the genital organs, and most of them relay in ganglia (Greater and lesser) cavernous
close to the prostate gland, neck of the bladder, cervix nerves of penis
of the uterus, and upper vagina. Others relay in micro-
scopic ganglia in or near the walls of seminal vesicles, Sympathetic Presynaptic Parasympathetic Presynaptic Afferent fibers
deferent ducts, epididymis, and uterine tubes. There
are no ganglia within the substance of the testes and fibers Postsynaptic fibers Postsynaptic
ovaries. Inconclusive evidence suggests that parasympa-
thetic fibers reach the outer parts of the uterine tubes brain in ascending pathways in the lateral and posterior A superior group arises by rootlets from the renal and
by passing through the celiac plexus into the superior white columns, whereas others form synapses with intermesenteric plexuses, with inconstant contributions
ovarian nerves that help to supply the oviducts. Histo- lateral cornual cells in the related cord segments and from the lumbar splanchnic nerves and the origin of the
chemical studies indicate that parasympathetic innerva- are thus involved in spinal reflex arcs. superior mesenteric plexus. One or two small ganglia are
tion of the genital systems in both sexes is less abundant associated with these rootlets. They communicate with
than sympathetic innervation. MALE REPRODUCTIVE ORGANS the superior ureteric nerves and, on the right side, with
The nerves supplying the testis, epididymis, and ductus branches supplying the duodenum and pancreas. The
Afferent fibers exist in both the sympathetic and para- (vas) deferens are derived from three bilateral sources. rootlets coalesce to form two or three slender nerves,
sympathetic pathways and follow the same routes as which descend on the testicular artery to the testis.
the efferent fibers, but in the reverse direction. Their
parent pseudounipolar cells are situated in the posterior
root ganglia of the lower thoracic, upper lumbar, and
midsacral spinal nerves. The peripheral processes of
these cells transmit impulses from the genital organs,
ducts, and vessels. Their central processes carry the
impulses into the cord, where many are carried to the

196 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-24â•… Autonomic Nervous System and Its Disorders

FEMALE REPRODUCTIVE ORGANS

Sympathetic trunk T5
and ganglion Celiac ganglia
and plexus
T6
Gray ramus communicans

White ramus communicans

Greater Aorticorenal ganglia
splanchnic nerve Superior mesenteric
Lesser ganglion
splanchnic nerve

Innervation of Reproductive Least T11 T11
Organs (Continued) splanchnic nerve Intermesenteric
(aortic) plexus
A middle group arises by rootlets from the superior T12 L1
hypogastric plexus and from the ipsilateral hypogastric Sympathetic trunk
nerve, and often communicates with the middle ureteric Inferior mesenteric
and genitofemoral nerves. The resultant nerves are mostly L1 ganglion
or entirely distributed to the epididymis and the ampulla L4
of the ductus deferens. Lumbar splanchnic nerves Superior hypogastric
plexus
An inferior group of a few small nerves arises from the L3 spinal nerve Hypogastric nerves
inferior hypogastric plexus and from the nerve loops (anterior ramus)
around the lower end of the ureter (see page 195). This
third group is closely associated with small nerves given L4
off from the anterior part of the inferior hypogastric Ovarian artery and plexus
plexus to the seminal vesicles, prostate gland, ejacula-
tory ducts, and the base of the urinary bladder. The Uterine (fallopian) tube Uterus
prostatic and urethral nerve fibers communicate with
branchlets of the pudendal nerves, and offshoots from Note: Pain from
these united nervelets innervate the corpora cavernosa, intraperitoneal pelvic
the corpus spongiosum and the part of the urethra viscera (e.g., uterine
within it, and the bulbourethral glands. The nerve fibers contractions) goes
supplying the cavernous structures and their vessels are via uterovaginal and
termed the penile cavernous nerves, whereas their ramifi- pelvic plexuses,
cations are often called the cavernous plexuses. hypogastric nerves, Inferior extent
FEMALE REPRODUCTIVE ORGANS superior of peritoneum
The autonomic nerves supplying the female genital hypogastric plexus, Ovary Cervix
organs have similar origins to those supplying the male Uterovaginal and
genital organs. lower aortic plexus, lower inferior hypogastric
lumbar splanchnic nerves, S1 S1 (pelvic) plexuses
The superior group coalesces to form two or three
slender nerves, which accompany the ovarian artery and sympathetic trunk from S2 Pelvic splanchnic
supply nerve fibers to it and to the ovary and outer parts L4 to L5 to spinal S2 nerves
of the uterine tube. Their terminal fibers communicate nerves T11, 12.
with uterine fibers innervating the inner end of the Pain from Sacral plexus
uterine tube. Most of the afferent fibers in these nerves subperitoneal S3
enter the spinal cord through the posterior roots of the pelvic viscera S3
tenth and the eleventh thoracic nerve, although a
number may enter through the ninth or twelfth nerves. (e.g., cervical S4 S4
dilation and S5 Vagina S5
The middle group helps to supply the ovaries and the upper vagina)
uterine tube and vessels and gives off fascicles to goes via pelvic splanchnic
the common and external iliac arteries. nerves to S2, 3, 4. Afferent
fibers from lower vagina and perineum go via Pudendal nerve
The inferior group consists of nerves that enter the pudendal nerves to S2, 3, 4. Afferent fibers
cervix of the uterus and the vagina directly, often along-
side branches of the uterine and vaginal vessels, and Sympathetic Preganglionic Parasympathetic Preganglionic
other nerves that ascend with or near the uterine artery, fibers fibers Postganglionic
supplying nerve fibers to the body and fundus of the Postganglionic
uterus, as well as to the artery and its branches. The
terminal nerve fibers supply the uterine end and isthmus The uterine nerves ramify throughout the myome- that supply the vaginal arteries and give off fascicles to
of the uterine tube, where they communicate with cor- trium. The fibers, which are predominantly unmyelin- the muscular and mucous coats of the vagina and
responding nerve fibers from the superior and middle ated and adrenergic in type, are most plentiful around urethra, the erectile tissue of the vestibular bulb and
groups of nerves. the uterine end of the uterine tube, in the cervix, and corpora cavernosa clitoridis, and the greater and lesser
near the arterial branches. vestibular glands. These nerves contain a mixture of
sympathetic and parasympathetic efferent and afferent
The nerves entering the upper part of the vagina fibers.
contain tiny ganglia. They break up into nerve fibers

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 197

P late 7-25â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Autonomic Testing ;OLYTVYLN\SH[VY` :\KVTV[VY [LZ[PUN 8:(9;

Tests are performed to assess both the sympathetic and 2 Normal
parasympathetic systems. Absent
SWEAT TESTING :^LH[ YLZWVUZL ›3 JT 1 Reduced
The thermoregulatory sweat test consists of the visual
detection of skin humidity in response to warm external 0
temperature. A dye that changes color when moist is 1
painted or sprinkled onto the patient’s skin, and the
ambient temperature is raised by 1°â•C› by a heat cradle 0
over the torso. As the patient starts to sweat, the dye 1
changes to a dark purple color. This test measures
abnormalities in the sweat pathways at all levels (affer- 0
ent, central, and efferent). The quantitative sudomotor
axon reflex test (QSART) evaluates postganglionic Normal Early MSA Advanced MSA
sudomotor cholinergic fibers more objectively. It
involves the iontophoresis of acetylcholine, resulting in )7 HUK /9 YLZWVUZL ^P[O =4 *HYKPV]HNHS [LZ[PUN
an axon reflex: an impulse travels antidromically to On Off
reach a branch point and then orthodromically to the 4LHU HY[LYPHS WYLZZ\YL TT /N Valsalva
sweat gland, stimulating the release of acetylcholine 150 100 maneuver
from the nerve terminal to evoke the sweat response. A
multicompartment sweat capsule is attached to the skin 100 75 /LHY[ YH[L ILH[Z TPU
to measure the sweat response at standardized sites. 50
Abnormality indicates that postganglionic sudomotor 0 CONTROL 50
sympathetic axons are dysfunctional. QSART is usually 25
normal in preganglionic lesions. The sympathetic skin 0
response (a voltage change at the skin surface after an
electrical stimulus) also reflects postganglionic sudomo- 150 100
tor function, with results correlating with those of other 75
sweat tests. 100
50 50
25
0 I II III IV 0

ORTHOSTATIC HYPOTENSION

CARDIOVAGAL TESTING Head-up tilting
Cardiovagal function is assessed by measuring the heart
rate response to deep breathing, the Valsalva maneuver MSA, Multisystem atrophy;
(VM), and standing. For the heart rate response to deep VM, Valsalva maneuver
breathing, the patient inspires and expires deeply at six
breaths per minute, and the difference between the than 1.04 is abnormal. The biphasic response that For testing purposes, a 30% maximal contraction for 3
maximum and minimum heart rate response is calcu- occurs on standing is not present with passive tilt. to 5 minutes is required; diastolic BP usually increases
lated. For VM, the subject makes a forced expiration to by more than 15╯mm╯Hg.
maintain a column of mercury at 30 to 40╯mm for 15 HEAD-UP TILTING
seconds, and the ratio of the maximum heart rate during Patients with sympathetic dysfunction have a progres- NEUROCHEMICAL TESTING
the maneuver to the lowest rate occurring within 30 sive decline in blood pressure during head-up tilt to 70 Measurement of supine and upright plasma norepi-
seconds of its conclusion is determined. Concurrent degrees. The heart rate response is also usually attenu- nephrine levels provides a measure of postganglionic
measurement of beat-to-beat blood pressure (BP) ated and does not compensate fully for the fall in blood release of norepinephrine; levels usually double on
enables quantification of baroflex sensitivity. There are pressure. If the patient is being evaluated for neurocar- standing. With preganglionic lesions, supine levels
four main phases to the response to the VM; during diogenic syncope or delayed orthostatic hypotension, are normal, but there is a limited rise or no change
phase I, there is a transient rise in BP due to increased prolonged tilting beyond 10 minutes, often for about in the standing level. In postganglionic lesions of the
intrathoracic and intraabdominal pressure. In early 45 minutes, is needed. sympathetic system, both supine and standing values
phase II (IIe), the reduced venous return results in a fall are low.
in BP followed by a compensatory increase in heart rate ISOMETRIC HANDGRIP
and peripheral resistance, resulting in an increase in BP During sustained handgrip, sympathetic outflow 131I-labeled metaiodobenzylguanidine (MIBG) scin-
in the late phase II (IIL). During phase III, there is a increases due to muscle contraction, increasing the BP. tigraphy is useful in evaluating cardiac sympathetic
transient decline in BP from a reduction in intrathoracic innervation.
pressure, and in phase IV, the BP overshoots due to
normalized venous return and cardiac output in the
presence of persistently increased peripheral resistance.
Late-phase II (IIL) is a function of alpha-adrenergic and
phase IV of beta-adrenergic responses; they can be used
to assess sympathetic adrenergic integrity. Abnormality
may lead to an excessive decline in blood pressure in
phase II, with no BP overshoot in phase IV.

On standing, the heart rate increases, peaking at
about the 15th beat after standing, and then declines to
reach a stable state at about the 30th beat. The ratio of
the R-R interval at the 15th and 30th beats after stand-
ing provides a test of parasympathetic (vagal) function.
It is age dependent, but in young adults, a ratio of less

198 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-26â•… Autonomic Nervous System and Its Disorders

Abnormal Pupillary 7\WPSSHY` SPNO[ YLMSL_ (KPL»Z [VUPJ W\WPS
Conditions

ADIE’S TONIC PUPIL (MMLJ[LK W\WPS 5VYTHS W\WPS
The tonic pupil, or Adie’s pupil, results from parasym- \UYLHJ[P]L [V SPNO[
pathetic denervation. The tonically dilated pupil does Light
not usually respond to light but responds to accom-
modation with slow constriction and then remains con- Methacholine drops
stricted for longer than normal (light-near dissociation).
There is degeneration of the ciliary ganglion and the Short ciliary *VUZ[YPJ[PVU 5V LMMLJ[
short ciliary nerves, sometimes with aberrant reinnerva- nerves
tion. Most cases are idiopathic, but other causes include Optic nerves Ciliary Pilocarpine drops
inflammation, ischemia, tumor, trauma, and paraneo- Optic ganglion
plastic and autonomic neuropathies. When idiopathic, chiasm
it is seen usually in young women, but it may occur in *VUZ[YPJ[PVU 5V LMMLJ[
men and manifest at any age. It is commonly associated
with reduced or absent muscle stretch reflexes in the CN III (YN`SS 9VILY[ZVU W\WPS
lower limbs and sometimes with abnormalities of ther- <Z\HSS` IPSH[LYHS" UVYTHS SLM[ W\WPS
moregulatory sweating. The pupillary abnormality is
commonly unilateral but may become bilateral. ZOV^U OLYL MVY JVTWHYPZVU
7[VZPZ
Although initially the affected pupil is larger than the
contralateral pupil, with time it can become smaller. Optic tract
The pupil is very sensitive to acetylcholine (probably
due to denervation supersensitivity), with strong, tonic 4PVZPZ
constriction; this can be demonstrated by the vigorous
miotic response to methacholine chloride and 0.1% Red nucleus (MMLJ[LK W\WPS 5VYTHS W\WPS
pilocarpine. The intact sympathetic innervation is dem- \UYLHJ[P]L [V SPNO[
onstrated by the normal response to cocaine.
Edinger- Atropine drops
ARGYLL ROBERTSON PUPIL Westphal
This was initially described in neurosyphilis or tabes 5V LMMLJ[ +PSH[PVU
dorsalis. The classic findings include a normal near or nucleus
convergence reflex with normal pupillary responses to Pretectal
accommodation and an abnormal pupillary response to nucleus
light. In addition, the pupils are small, irregular, and
constrict with physostigmine and dilate variably with /VYULY Z`UKYVTL
atropine and cocaine. The location of the lesion in the
brain that causes the abnormal response is thought to Right-sided Normal Hypothalamus
be the rostral midbrain, near the periaqueductal gray. Horner syndrome left eye (origin)
Although previously thought to be pathognomonic of
neurosyphilis, it is now recognized in diabetes, viral 7[VZPZ Central
encephalitis, multiple sclerosis, and other inflammatory pathway
and degenerative diseases of the brain. 4PVZPZ

HORNER SYNDROME *LU[YHS VY 7VZ[NHUNSPVUPJ SLZPVU
Horner syndrome results from loss of sympathetic 7YLNHUNSPVUPJ SLZPVU Cocaine drops
innervation to the eye and is characterized by ptosis
(droopy eyelid), miosis (constricted pupil), and facial Cocaine drops
anhidrosis (impaired facial sweating). Additional find-
ings may include pigmentary changes in the iris. Pupil- 5V LMMLJ[ +PSH[PVU 5V LMMLJ[ +PSH[PVU Postganglionic
lary reactions to light and accommodation are normal. pathway
The anisocoria (inequality in pupil size) is accentuated Hydroxyamphetamine drops Hydroxyamphetamine drops
in dim light. The ptosis is due to paralysis of the Superior
Muller muscle; this is the sympathetically innervated cervical
smooth muscle of the upper eye lid. Acquired Horner ganglion
syndrome may be central, preganglionic, or postgangli-
onic. A central lesion may involve the first-order neuron +PSH[PVU +PSH[PVU 5V LMMLJ[ +PSH[PVU Preganglionic
at any point from the cell origin in the hypothalamus pathway
to its termination in the intermediolateral column of Phenylephrine drops Phenylephrine drops
the spinal cord. Causes include brainstem infarction,
tumor, and syringomyelia (cavitation in the spinal cord). 5V LMMLJ[ 5V LMMLJ[ +PSH[PVU 5V LMMLJ[
Preganglionic Horner syndrome is due to involvement
of the second-order neuron from its origin in the inter- surgery. Postganglionic Horner syndrome results from will cause the affected pupil to dilate (due to alpha-
mediolateral column to its termination in the superior lesions of the third-order neuron in the sympathetic adrenergic supersensitivity), whereas the normal pupil
cervical ganglion; causes include trauma or tumor of the ganglion and the pathway leading to its termination in will constrict. Pharmacologic testing will also differen-
cervical or upper thoracic spinal cord and lesion of the the face and eye, such as by extracranial carotid artery tiate between central, preganglionic, and postgangli-
lower trunk of the brachial plexus, such as by tumors of dissection, intracranial lesion in the carotid canal, or onic lesions. Hydroxyamphetamine (1%) drops instilled
the lung apex, jugular vein puncture, and thyroid cavernous sinus pathology. Use of cocaine eye drops into the eye do not affect the pupil of Horner syndrome
(which block the reuptake of norepinephrine) will help resulting from a lesion of the third-order postgangli-
distinguish true Horner syndrome from physiologic onic neuron, whereas a dilation occurs of normal pupils
anisocoria; 1 hour after instillation of 4% to 10% and in Horner syndrome with an intact third-order
cocaine drops, a normal pupil will have dilated more neuron due to release of norepinephrine. Similarly, 1%
than a pupil with sympathetic dysfunction (irrespective solution of phenylephrine hydrochloride will dilate the
of site of lesion), increasing the baseline anisocoria. pupil in postganglionic lesions (third-order neurons)
Apraclonidine, an alpha-adrenergic receptor agonist but not normal pupils.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 199

Plate 7-27â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Causes of dysautonomia

Abnormal Pupillary Guillain-Barré
Conditions (Continued) syndrome

CLINICAL PRESENTATION OF Lung cancer with Amyloidosis
AUTONOMIC DISORDERS paraneoplastic
syndrome
Patients usually have combinations of parasympathetic Toxins
and sympathetic dysfunction. The former is character- (heavy metal
ized by dry mucous membranes, particularly the poisoning)
eyes and mouth, with gastrointestinal and urogenital
symptoms: early satiety, nausea, vomiting, constipation, Metabolic disorders (diabetes)
diarrhea, urinary bladder dysmotility, and erectile dys- Multiple system atrophy
function. Feelings of light-headedness or syncope,
when assuming an upright posture, and alteration of
sweating are symptoms of impaired sympathetic func-
tion. Sexual dysfunction is due to combined parasym-
pathetic and sympathetic disorders. Signs of autonomic
dysfunction include fixed heart rates, orthostatic hypo-
tension, and tonic pupils, with normal strength and
sensation unless somatic nerves are also affected.

Autonomic disorders may be classified as peripheral
or central and acute or chronic disorders.

ACUTE PERIPHERAL A Synuclein
AUTONOMIC DISORDERS positive neural
BC and glial
Acute/subacute autonomic neuropathies are usually due inclusions in
to toxic, metabolic, autoimmune, or paraneoplastic CHRONIC PERIPHERAL multiple system
causes. Primary autonomic polyneuropathies represent AUTONOMIC DISORDERS atrophy (MSA)
an uncommon subgroup. However, many length- Autonomic neuropathies are common accompaniments
dependent polyneuropathies have associated autonomic of diabetic peripheral neuropathies and correlate with Hereditary autonomic neuropathies are rare disorders.
fiber involvement. Impotence is such an example in duration and control of diabetes. Autonomic testing Hereditary sensory and autonomic neuropathy type III,
diabetic polyneuropathies. reveals evidence of cardiovagal dysfunction manifested also known as Riley-Day syndrome, is an autosomal
by impairment of heart rate response to Valsalva recessive disorder with defective control of blood
Antecedent viral infections may occur in patients maneuver or to deep breathing. pressure, sweating, temperature, and lacrimation in
with autoimmune autonomic neuropathy, suggesting that children. Dysautonomic manifestations are less pro-
it may be a variant of Guillain-Barré syndrome. They Postural orthostatic tachycardia syndrome (POTS) nounced in other hereditary sensory and autonomic
usually have severe generalized disorders, but restricted is seen predominantly in young women. It is character- neuropathies.
milder forms also occur. Orthostatic intolerance and ized by orthostatic symptoms associated with signifi- CENTRAL DISORDERS
gastroÂi

SECTION 8â•…

PAIN

Plate 8-1â•… Cerebrum Spinal Cord and Peripheral Motor and Sensory Systems: PART II
Cerebral cortex:
Pain Pathways Anatomy postcentral gyrus Nonspecific
Ascending Pathways thalamic nuclei
Endorphin System (centromedian)

Pain propagation is initiated with activation of nocicep- Posterior limb of Midbrain Deep layers of
tors, distributed within skin, muscle, joints, and viscera. internal capsule superior colliculus and
These receptors include small-diameter Aδ and C-fiber Ventral posterolateral periaqueductal gray
free nerve endings representing distal primary afferent (VPL) nucleus of
neurons. Cutaneous Aδ fibers (myelinated) mediate sharp thalamus Lateral reticular formation
sensation of first-phase or acute pain known to trigger
withdrawal responses. These include two fiber groups; Pons Pain, temperature
first are high-threshold mechanoreceptors fibers, respond- Pain
ing to mechanical stimuli of high intensity and, after Lower medulla
sensitization, to noxious heat. Mechanothermal receptors Spinothalamic/spinoreticular Pain, temperature
for extreme (i.e., noxious) heat and cold sensation com- system (from all spinal levels) Pain
prise the second group of fibers. Once sensitized, these
receptors are activated by mechanical stimuli at non- Cervical spinal cord Intrinsic dorsal horn neurons promote interaction of
noxious thresholds. Anterior white commissure afferent and efferent nociceptive stimuli and are also
responsible for their transfer to supraspinal structures.
C-type fibers (unmyelinated) slowly propagate dull, Lumbar spinal cord These are classified as (1) projection neurons directly
burning (secondary) pain sensation information. Some Anterior white commissure transmitting information to supraspinal centers, (2)
C fibers are modality-specific and respond only to intersegmental propriospinal neurons integrating several
thermal, mechanical, or chemical noxious stimuli. important for segmental suppression of pain; however, spinal levels, and (3) interneurons having inhibitory or
However, the majority of C fibers are polymodal, which their inhibitory role is not yet confirmed. Almost all of excitatory features. Nociceptive projection neurons
means that they respond to both thermal and mechani- lamina V consists of wide dynamic range (WDR) cells, relay information to various brainstem and diencepha-
cal noxious stimuli, as well as to chemical algesiogenic which have large receptive fields and high-frequency lon regions, including the thalamus, periaqueductal
substances (e.g., potassium ions, prostaglandins, sub- ongoing discharges. WDR neurons demonstrate graded gray, bulbar reticular formation, and limbic structures
stance P, and histamine). A unique C-fiber subtype responses to pressure and noxious stimuli, including within the hypothalamus, amygdala, and other sites.
responds to high-intensity thermal stimuli and also heat, cold, and deep and visceral stimulation. Their There is also a visceral nociceptive pathway within the
mediates flare responses after tissue damage. Some activity represents integration of all dorsal horn afferent postsynaptic posterior column pathway.
C-type nociceptors, designated silent receptors, are pri- inputs. In contrast to lamina I neurons, WDR cells are
marily activated by inflammation. not somatotopically organized; their complex excitatory
and inhibitory receptive fields are musculotopically
The primary afferent fibers travel through dorsal organized. Their main characteristic is to code stimulus
nerve roots entering the dorsal horn of the spinal cord, intensity; they demonstrate increasing frequencies of
where they divide in a “T” pattern traveling two to three response from innocuous to noxious stimulation.
spinal segments within the Lissauer tract in both rostral
and caudal directions, and sending collateral projec-
tions to the gray matter along the entire four- to six-
segment length, thus transmitting pain signals over a
broad spinal cord area.

Both myelinated and unmyelinated primary afferent
fibers project predominantly to the superficial laminae
of the dorsal horn. Although there is considerable
overlap in the projection of fibers, signaling innocuous
and noxious stimuli, there exists some degree of func-
tional segregation at the postsynaptic level in the super-
ficial laminae. Dorsal horn neurons are classified into
three distinct groups. The specific nociceptive neurons
that respond exclusively to noxious stimuli are found in
Rexed laminae I, II, V, and VI. Their receptive fields in
lamina I are punctiform and display somatotopic
organization.

Lamina I neurons are classified into several modality-
selective classes, relaying information from particular
subsets of small-diameter fibers and relating the current
physiologic status of body tissues. The two nociceptive
cell types, nociceptive-specific (NS) and polymodal nocicep-
tive (HPC, for heat, pinch, and cold) have different
characteristics. NS neurons receive mainly Aδ inputs
associated with first-pain, and relay information about
noxious stimuli localization and physical quality. HPC
cells receive polymodal C-nociceptor information and are
associated with second pain. Lamina I cells relate current
physiologic conditions of all body tissues and regulate
spinal cord excitability, and therefore pain behavior,
through the activation of descending inhibitory and
excitatory pathways from the brainstem.

Lamina V neurons are large cells with dendrites
extending across the dorsal horn, receiving myelinated
primary afferent input from Aβ, Aδ, and C fibers.
According to gate control theory, this fiber group is

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Plate 8-2â•… Pain

Pain Pathways Anatomy Somatosensory afferents to the spinal cord
Ascending Pathways
Endorphin System (Continued) Proprioception Conscious
Unconscious
The spinothalamic tract (STT) mediates sensations Ia afferents
of pain, cold, warmth, and touch. This pathway origi-
nates from WDR, SN, and non-nociceptive dorsal horn Touch and I
neurons in laminae I, II, and deeper lamina V. Most pressure
spinothalamic tract axons decussate transversely II
through the anterior white commissure of the spinal Pain (nociception)
cord and ascend through the contralateral anterolateral and temperature III
funiculus. Passing through the brainstem, the spinotha- IV
lamic tract sends collateral projections to the medullary, Dorsal spinocerebellar V
pontine, and midbrain reticular formation, including tract VI
gigantocellularis and paragigantocellularis nuclei and VII
periaqueductal gray matter. These are probably respon-
sible for descending suppressor system activation, as Anterior white
well as behavioral and neurovegetative responses to commissure
pain. Three spinothalamic tract afferent forms are
recognized, including a monosynaptic neospinothalamic Spinothalamic and
pathway (anterior spinothalamic tract) that directly spinoreticular tracts
projects to lateral complex thalamic nuclei involved in
sensory-discriminative pain components. Another is a Lower motor
multisynaptic paleospinothalamic pathway, (dorsal spino- neurons
thalamic tract) projecting to posterior medial and
intralaminar complex thalamic nuclei involved in the To skeletal
motivational-affective aspects of pain. Lastly, there muscle
is a monosynaptic spinothalamic pathway projecting
directly to thalamic medial central nucleus that is Principal fiber tracts of spinal cord
related to affective components of pain sensation.
Dorsal Fasciculus gracilis Septomarginal fasciculus (oval bundle)
The thalamus is the main relay structure for sensory column Interfascicular (semilunar) fasciculus
information destined for the cortex; it is involved in system Fasciculus cuneatus Lateral corticospinal
reception, integration, and transfer of nociceptive (pyramidal) tract
potentials. WDR neurons project to the ventropostero- Dorsolateral fasciculus Rubrospinal tract
lateral (VPL) and ventroposteromedial (VPM) nuclei. SN (tract of Lissauer)
neurons project to the ventroposteroinferior (VPI) nucleus, Lateral reticulospinal
considered the main somatosensory relay. It receives Posterior tract
both noxious and innocuous information of cutaneous, spinocerebellar tract Medial reticulospinal
muscular, and articular origin. This nucleus has numer- tract
ous interconnections with the primary somatosensory Anterior
(SI) cortex. The VPI participates in the processing of spinocerebellar tract Vestibulospinal tract
visceral pain, occurring through the postsynaptic dorsal Spinothalamic and
column pathway with nucleus gracilis projections. spinoreticular tracts

The VPM nucleus is likewise involved in sensory- Spinoolivary tract Anterior
discriminative aspects of thermal, mechanical, and corticospinal tract
tactile information. Owing to its projections to the pre-
frontal cortex, the convergence of fibers arising from Fasciculi proprii Tectospinal tract
the parabrachial region within the lateral pons at the
locus ceruleus level, as well as to amygdala, hypotha- Medial longitudinal (sulcomarginal) fasciculi
lamic, and periaqueductal gray interconnections, the
VPM nucleus is likely involved with emotional pain, as Ascending pathways
well as psychomotor and autonomic reactions to painful Descending pathways
stimuli. Posterior division of the ventromedial nucleus Fibers passing in both directions
(VmPO) and posterior nucleus (PO) are essential parts
of the medial nociceptive system establishing insular the lateral and medial systems. There are three impor- stimuli features and behavioral decisions in relation to
and cingular cortex connections involved in affective- tant cortical regions: primary somatosensory cortex (SI), the prefrontal cortex functions. Conversely, the medial
cognitive aspects of pain. Specific spinothalamic tract secondary somatosensory cortex (SII), and the anterior nociceptive system has more diffuse projections from the
projections, originating from lamina I, suggest that cingulate cortex. The lateral nociceptive system partici- medial thalamus to SI and SII, and limbic structures,
these nuclei are noxious information integration pates directly in the sensory-discriminative ascription such as the insula and the anterior cingulate cortex.
centers, especially for cases of freezing and visceral of nociception involving specific thalamic nuclei, pro- Accordingly, it is predominantly responsible for the
sensations. jecting to SN and WDR neurons of the SI and SII motivational-affective component of pain.
cortices. SN neurons are associated with topographic
The thalamus medial complex receives afferent input localization of peripheral stimuli, whereas WDR neurons The insula relays information from the lateral nocicep-
from laminae I and V of the spinothalamic tract, inter- code the intensity of these stimuli. Nociceptive neurons tive system to the limbic system, mainly via the amygdala
connecting with the striatum and the cerebellum. This in the SII cortex code the painful stimulus in temporal and prefrontal cortex associated with the emotional and
is responsible for the control of attention and motor terms. Both SI and SII cortices have connections with affective component and with memory integral to the
responses, suggesting that this area may be involved in the posteroparietal area and the insula, responsible for painful experience. The anterior cingulate cortex coor-
escape behavior in the presence of harmful stimuli. somatosensory input association with learning and dinates inputs from parietal areas with frontal cortical
memory. This pathway is crucial to assessment of the regions, integrating the perception of threat with the
Ultimately the nociceptive signal is relayed from the appropriate pain behavior.
thalamus to a variety of cortical regions. Two systems of
nociceptive cortical projection are commonly distinguished:

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Plate 8-3â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
PAIN PATHWAYS
Midbrain Cerebral cortex
Medulla
Dorsal root ganglion Thalamus

Periaqueductal gray (PAG)

Opioid pathways from hypothalamus and PAG Midbrain
Locus ceruleus Raphe nuclei

Medulla
NA

5-HT

Enkephalin-containing neuron

Primary afferent Spinal cord Lateral spinal thalamic tract Spinal cord

Descending Nociceptive and development of secondary hyperalgesia. Finally, pontomedullary reticular formation, and other catechol-
Pathways and Neurochemical hyperalgesia encountered during acute opioid absti- aminergic nuclei.
Foundations of Descending nence also entails descending nociceptive facilitation
Pain Modulation from the rostral ventromedial medulla. Major descending projections from the anterolateral
PAG are to the rostral ventromedial medulla, including
DESCENDING NOCICEPTIVE PATHWAYS A number of supraspinal sites activated by nocicep- the nucleus raphe magnus and adjacent reticular formation.
Descending control of spinal nociception arises from tive input contribute to central modulation of pain. The The PAG pain-modulating action is relayed almost
various brain areas and is pivotal in determining the most prominent ones include periaqueductal gray (PAG) exclusively through the RVM that, in turn, sends bilat-
experience of pain, both acute and chronic. Several and rostral ventromedial medulla (RVM). The effects eral descending projections through posterolateral
central nervous system areas exert a top-down modula- of descending modulation are exerted in the spinal spinal funiculi terminating within the spinal dorsal
tion of nociceptive processing. Projections from pre- dorsal horn on the synapse between the primary affer- horn. The RVM is a functional term describing the
frontal, anterior cingulate, and insular cortices, as well ent and projection neurons or on interneurons that midline pontomedullary area in which opioid injection or
as hypothalamus and amygdala to the brainstem pain synapse with projection neurons, by inhibiting the electrical stimulation produces antinociception, that is,
modulatory system, support the notion of emotional release of neurotransmitter from primary afferent analgesia. It includes the nucleus raphe magnus and adja-
and affective regulation of pain transmission. Attention, fibers or by inhibiting the function of neurotransmitter cent reticular formation and projects diffusely to dorsal
anticipation, control over pain, and religious beliefs receptors on the postsynaptic neuron. horn laminae important in nociceptive processing,
affect pain perception, supporting the importance of including superficial layers and deep dorsal horn.
the anterior cingulate cortex and frontal lobes in modu- In awake, behaving animals, anterolateral periaqueduc-
lation of nociceptive processing. tal gray (PAG) stimulation leads to immobility, sympa- With increasing understanding of RVM neuronal
thoinhibition, and analgesia as well as inhibition of physiology, it is recognized that this area is central to
The current model of descending pain modulation nociceptive dorsal horn neurons, including spinotha- the mediation of the bidirectional control of nocicep-
involves both inhibitory and facilitatory influences on lamic tract cells. The PAG contains a large number of tion. It receives projections from serotonin-containing
spinal nociceptive transmission. The balance between neurons. Local injection of opioids, nonspecific enkeph- neurons of the dorsal raphe, neurotensinergic neurons
inhibition and facilitation is dependent on different alin, substance P, and gamma-aminobutyric acid (GABA) of the PAG, and limbic and prelimbic cortex, including
behavioral, emotional, and pathologic conditions. ergic excitants or neuropeptides into the PAG produces the anterior insula. Nonselective stimulation or inacti-
Intense stress or fear is associated with decreased analgesia in animals. Excitatory pathways projecting vation of RVM neurons can either suppress or facilitate
response to pain, whereas inflammation, nerve injury, from the PAG to the brainstem are subject to inhibitory nociception, depending on the functional background.
or sickness is associated with hyperalgesia that partially control by GABAergic inhibitory neurons within the This suggests that there are parallel inhibitory and
can be ascribed to descending facilitatory mechanisms. PAG. Analgesic opioids and cannabinoids relieve GAB- facilitatory output pathways from the RVM to the
Several studies suggest that descending facilitatory Aergic control and thus induce analgesia. The PAG is spinal cord. Adjacent neurons are simultaneously under
systems are also activated by safety signals that follow significantly interconnected with the hypothalamus and facilitatory and inhibitory control from supraspinal
an aversive event. In addition, descending facilitation of limbic forebrain structures, including the amygdala. structures. The equilibrium between inhibition and
spinal nociception contributes to central sensitization This suggests that cognitive and emotional aspects facilitation determines the net effect of descending
influence ascending nociceptive input, further modulat- modulation on nociceptive transmission.
ing the resultant experience of pain.
The RVM includes three distinct types of neurons:
Major brainstem inputs to the PAG originate (1) neurons that begin discharging just before the with-
from the nucleus cuneiformis, the locus ceruleus, the drawal from noxious heat, entering a period of activity

204 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 8-4â•… ENDORPHIN SYSTEM Pain

Descending Nociceptive Periaqueductal gray matter Stimuli from higher
Pathways and Neurochemical Cerebral aqueduct centers (psychologic,
Foundations of Descending placebo effect, etc.)
Pain Modulation (Continued) Morphine
Enkephalin-containing
(“ON-cells”), (2) neurons that stop discharging before neuron
the withdrawal reflex, entering a period of silence Mesencephalon
(“OFF-cells”), and (3) neurons that do not demonstrate
consistent changes in activity when withdrawal reflex Indirect pathways
occurs (“neutral cells”). ON and OFF cells send projec-
tions specifically to laminae I, II, and V of the dorsal Morphine Raphe magnus
horn. Activation of OFF cells produces behavioral anti- nucleus
nociception, and is required for the analgesic opioid Afferent pain fibers in
effect. In contrast, direct, selective activation of ON cells trigeminal nerve Medullary
produces hyperalgesia; their discharge is associated Spinal trigeminal tract reticular
with enhanced nociception. Thus OFF cells exert a net and nucleus neuron
inhibitory effect on nociception, whereas the ON cells Enkephalin-containing neuron
play a facilitatory role in the descending modulation Medulla
of pain. Serotonin pathway oblongata
Spinoreticula
Neutral cells’ role in pain modulation is unexplained. Posterolateral funiculus Lamina I pain interneuron pathway
One theory is that neutral cells are recruited to become Afferent pain neuron Lamina V interneuron Anterolateral
ON or OFF cells during development of chronic pain of dorsal root ganglion funiculus
states, which is supported by wide variations of ON and IIIII I
OFF cells excitability under basal conditions. At least IV Spinal cord
some neutral cells are serotonergic. Considering the V
importance of serotonin in nociceptive modulation, this VI
suggests that neutral cells may be involved in the
descending control of pain transmission.

The locus ceruleus and the A5 and A7 noradrenergic cell
groups of the posterolateral pons are the main source of
noradrenergic input to the dorsal horn. These regions
send bilateral projections that primarily descend to con-
tralateral laminae I, II, and V of the spinal dorsal horn,
exerting an antinociceptive effect. The PAG sends input
to the locus ceruleus and the A7 region. RVM neurons
containing substance P or enkephalin also send input
to A7. Consequently, the posterolateral pontine tegmen-
tum provides a corresponding pathway for the PAG and
RVM to provide descending nociception control over
the spinal dorsal horn. Posterolateral pontine systems may
also provide cortical control of spinal pain transmission.
The anterior insular cortex has locus coeruleus and
RVM connections, suggesting that inhibition of the
insular outflow disinhibits noradrenergic neurons of the
locus ceruleus.

NEUROCHEMICAL FOUNDATIONS OF Enkephalin-containing Spinoreticular neuron
DESCENDING PAIN MODULATION neuron in substantia
gelatinosa (lamina II)
Opioids have long been considered the archetypical
analgesics, with endogenous opioids (“enkephalins”) well as pronociceptive action (in response to mechanical projection neurons, as well as a complex interplay with
believed to play a pivotal role in the modulation of pain stimuli), depending on the activation of different sero- opioid and adenosine antinociceptive systems.
transmission. Recently, however, it has been shown that tonergic receptors.
the monoaminergic pathways mediate modulation of Dopaminergic pathways originate mainly from A11
nociceptive processing. Monoaminergic systems include Noradrenergic neurons originating from locus ceruleus neurons of the periventricular posterior thalamus. Their
serotonergic, noradrenergic, and dopaminergic neurons that and A5 and A7 pontine tegmentum groups provide activation results in diminished response to noxious stimuli
elicit either antinociceptive or pronociceptive effects, inhibition of nociceptive input via presynaptic alpha-2 mediated by D2 receptors, with concomitant inhibition
depending on the type of receptor involved and its loca- receptors. In this case, noradrenergic modulation relies of neurotransmitter release from primary afferents.
tion. Monoaminergic modulation entails complex inter- upon volume transmission, in contrast to the serotoner- Possibly, endogenous opioids provide potentiating
play between primary nociceptive afferents, dorsal horn gic system mediating punctate synaptic transmission. effects that develop from. Conversely, D1 receptor acti-
projection neurons, local interneurons, and glial cells. The effect of this noradrenergic system is essentially an vation engenders facilitated nociception transmission, both
extrasynaptic spread of neuroactive substances that may directly and by opioid antagonism. The possible mecha-
The RVM is the major source of serotonergic input to be involved in late and long-lasting changes of a group nism of action for dopamine may rely on local dopamine
the dorsal horn; it is the final common output for of neurons. The analgesic effects mediated through concentration; low levels activate antinociceptive D2
descending influences from rostral brain regions pro- presynaptic alpha-2 receptors involve presynaptic inhi- receptors, and high levels elicit pronociceptive effects
jecting to the superficial and deep dorsal horn. The bition in primary afferents, postsynaptic inhibition of via D1 receptors.
PAG-RVM serotonergic pathway is considered to be
the major endogenous pain modulatory system and
the main target of supraspinal opioid analgesia. Seroto-
nergic neurons can exert antinociceptive action (in response
to chemical stimuli and neurogenic inflammation) as

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P late 8-5â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Nociceptive Processing and SPINOTHALAMIC AND SPINORETICULAR NOCICEPTIVE PROCESSING IN THE SPINAL CORD
Central Nervous System
Correlates of Pain Gating Mechanism Spinal Mechanisms of Nociceptive Processing

NEUROPATHIC PAIN Dorsal column afferent C and A␦
The International Association for the Study of Pain C and A␦
defines this as pain initiated or caused by a primary lesion C
or dysfunction within the nervous system. The term “dys-
function” may be rather vague, and perhaps using a I
lesion-based definition is more accurate. Peripheral II
neuropathic pain results from a diverse array of insults
to the peripheral nervous system (PNS) variously III
caused by mechanical trauma, metabolic diseases (i.e., IV
diabetes mellitus), infection (i.e., herpes zoster), tumor V
invasion, or neurotoxic chemicals. Among the associ- VI
ated risk factors for neuropathic pain, gender, age, ana- VII
tomic site of the injury, and even the severity of acute
postoperative pain are cited. Epidemiologic studies Spinothalamic/
identify the prevalence of neuropathic pain to be as spinoreticular
high as 5%. tract

Neural injury triggers a range of processes affecting Recruitment by
primary afferent receptors, their axons and cell bodies, Convergence
as well as unleashing a complex immune response in
central neurons and glial cells. Some of these processes
facilitate healing and normative repair, for example,
removal of cell and myelin debris, recruitment of anti-
apoptotic strategies, induction of axonal growth and
sprouting, synaptic remodeling, and remyelination. In
contrast, animal neurophysiologic studies demonstrate
that some of these secondary effects have a maladaptive
effect. Other well-characterized effects leading to
chronic pain include central sensitization, ectopic
impulse generation, reduced central inhibition, neuro-
nal loss, and glial scarring.

PERIPHERAL SENSITIZATION the spinal cord. Ectopic discharges originating in the Dorsal root ganglion neurons express several types of
Various signaling molecules, including cytokines, che- cell body of injured primary afferents may cause anti- sodium channels that are either sensitive or resistant to
mokines, neurotransmitters, neurotrophic factors, and dromic stimulation, the release of mediators, and neu- tetrodotoxin.
excess protons released due to tissue injury and inflam- rogenic inflammation at the periphery. Ectopic impulses
mation, directly activate or sensitize nociceptors. can also generate along neuromas and from the sprout- CENTRAL SENSITIZATION
Increased expression of ion channels involved in pain ing of sympathetic efferents, forming “baskets” around This is a form of activity-dependent synaptic plasticity that
transmission is an important mechanism leading to dorsal root ganglion (DRG) cells. Sympathetic sensory also has a pivotal role in the pathophysiology of neuro-
development of peripheral sensitization. Peripheral coupling is believed to play an important role in pathic pain. It is responsible for secondary hyperalgesia
nerve injury leads to increased expression of specific the pathophysiology of inflammatory pain, complex characterized as increased pain intensity to noxious
voltage-gated sodium (Nav) channels and transient receptor regional pain syndrome (CRPS), diabetic neuropathy, stimuli experienced beyond the distribution of the
potential vanilloid receptor 1 (TRPV1) cation channels in postherpetic neuralgia, phantom limb sensations, and inciting area of injury, and tactile allodynia, defined as
the primary afferent terminals, in axonal sprouts at the other conditions. Also deafferentation (loss of normal pain due to a normally innocuous stimulus. Central
lesion site, demyelinated areas, and adjacent unharmed afferent input) can lead to sensitization and ectopic sensitization represents amplification in the functional
nociceptors in the site of injury. These channel changes discharges in spinal cord or thalamic neurons. status of neurons and nociceptive circuits, caused by
are significant for the expression of neuropathic pain. reduced inhibition, increased membrane excitability,
Voltage-gated sodium channels are important influ- and enhanced synaptic efficacy. Because these changes
Peripheral sensitization has several important rami- ences on the generation of ectopic activity; their role in appear in the central nervous system (CNS) neurons,
fications. It reduces the threshold for nociceptor activa- the pathogenesis of neuropathic pain is supported by the perceived pain does not reflect the presence,
tion, causes primary hyperalgesia (augmentation of the reversal of nociceptive effects by nonselective
normally noxious stimuli), and elicits spontaneous depo- sodium channel blockers such as local anesthetics.
larization in primary afferent fibers (ectopic activity).
Concomitantly, the peripheral injury enables these neu-
rotrophic factors to migrate in a retrograde direction,
thus affecting dorsal root ganglion and dorsal horn cells.

ECTOPIC IMPULSE GENERATION
The persistence of an unpleasant sensory and emotional
experience in the absence of an identifiable ongoing
stimulus is a characteristic feature of neuropathic pain.
This spontaneous pain occurs as a result of ectopic
action potential generation in primary afferent neurons.
It may originate both from ectopic activity in nocicep-
tors and from low-threshold large myelinated afferents
due to central sensitization and altered connectivity in

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Plate 8-6â•… Pain

Nociceptive Processing and CENTRAL NERVOUS SYSTEM NEUROTRANSMITTERS, RECEPTORS, AND DRUG TARGETS
Central Nervous System
Correlates of Pain (Continued) “IONOTROPIC” RECEPTORS Voltage-gated ion
channels
intensity, or duration of peripheral stimuli. On the con-
trary, it corresponds to a pathologic state of responsive- Ion
ness or increased activity of the nociceptive system.
Pore 4 subunits
The development of central sensitization often
requires high-intensity, repetitive, and continuous Voltage-gated K+ channel (extracellular view)
noxious input. Induction and maintenance of central
sensitization is dependent on N-methyl-d-aspartate “IONOTROPIC” RECEPTORS Ligand-gated ion channels
receptors (NMDARs) that are ubiquitous within the
superficial laminae synapses of the dorsal horn. Nor- Ion
mally, the voltage-dependent NMDAR pore is blocked
by a magnesium ion (Mg2+). Continuous release of glu- Ligand 5 subunits
tamate, substance P, and calcitonin gene–related peptide (1 removed
(CGRP) leads to sufficient membrane depolarization to to show pore)
force Mg2+ to leave the NMDAR channel, allowing
glutamate to bind to the receptor and generate an GABA
inward current. This allows entry of calcium ion (Ca2+) receptor
into the neuron, activating various intracellular path-
ways that contribute to the maintenance of central “METABOTROPIC” RECEPTORS G protein–coupled receptors
sensitization. This early, acute phase of central sensiti- Receptor tyrosine kinases
zation results in activation of intracellular kinases that Ligand Others
phosphorylate NMDA subunits and other receptors,
enhancing their activity and density and leading to post- G proteins, enzymes (e.g., tyrosine kinases)
synaptic hyperexcitability. Alterations in transcription in
the dorsal horn contribute to the delayed or late phase Muscarinic cholinergic receptor Second messenger pathways
of central sensitization. Increased synthesis of transmit-
ters and neuromodulators, such as glutamate, substance Select CNS Neurotransmitters and Neuromodulators
P, CGRP, brain-derived neurotrophic factor (BDNF),
or nitric oxide (NO), results in presynaptic functional Acetylcholine Dopamine Glycine Oxytocin
changes in the dorsal horn. All of these processes Adenosine Eicosanoids Histamine Somatostatin
can increase membrane excitability, facilitate synaptic AMP, ADP, ATP Endothelins Neuropeptide Y Substance P
strength, and decrease inhibitory influences on dorsal Anandamide Epinephrine Neurosteroids
horn neurons. Of note, these alterations are not neces- Aspartate FMRF-amide-related Neurotensin (tachykinins)
sarily restricted to the activated synapse (homosynaptic Bombesin NO (nitric oxide) Taurine
facilitation) but can easily spread to adjacent synapses Bradykinin peptides Norepinephrine Vasoactive intestinal
(hetero-synaptic facilitation). Consequently, these modula- Calcitonin gene–related GABA Opioid peptides
tory processes lead to enhanced responsiveness of nociceptive Galanin polypeptide (VIP)
neurons, which lasts longer than the initiating stimuli, peptide (CGRP) Gastrin (endorphins, Vasopressin
or results in activation of nociceptive networks by Cholecystokinin Glutamate enkephalins,
stimuli that are subthreshold compared with the prein- Cytokines Glutamine dynorphins)
jury baseline.
gene-activated growth stimuli may cause sprouting of microglial activation in the dorsal horn; this occurs in
DISINHIBITION Aβ fibers into the superficial layers of dorsal horn. close proximity to the injured afferent. The activated
Several local inhibitory circuits and descending inhibi- Regenerative sprouts may demonstrate ectopic activity spinal microglia express chemokine receptors and release
tory pathways serve to modulate the perception of pain. or be activated by otherwise subthreshold stimuli. immune mediators (interleukin [IL]-1B, IL-6, tumor
However, after peripheral nerve injury, primary affer- Along with central sensitization, these changes manifest necrosis factor-alpha [TNF-alpha], BDNF), inducing
ents, dorsal horn neurons, and gamma-aminobutyric clinically as the ability to generate pain in areas outside of and maintaining maladaptive pain conditions. Media-
acid (GABA)ergic inhibitory neurons undergo a number injured nerve territories, and is usually coupled with a loss tors released by microglia and astrocytes, as well as
of maladaptive changes. Primary afferents express fewer of C-fiber terminals. cytokines/chemokines produced by DRG cells directly
opioid receptors, and dorsal horn neurons are less sus- activate nociceptors, cause peripheral sensitization by
ceptible to inhibition by mu opioid agonists. Activation NEUROIMMUNE INTERACTIONS increasing the excitability of primary afferents, and
of GABAergic receptors may provoke paradoxic Macrophages have a central role in the immune surveil- stimulate adjacent chemokine-expressing neurons.
excitation and spontaneous activity. This loss of local lance of the peripheral nervous system. They clear cel- Changes in the expression and function of the transient
inhibition promotes pain transmission, especially the lular debris and serve as antigen-presenting cells to receptor potential channels and increases in sodium and
Aβ-fiber–mediated pain. activate T lymphocytes. Both macrophages and T cells calcium currents contribute to induction of action
use cytokines and chemokines as means of communica- potentials. TNF-alpha also has been shown to stimulate
LOW-THRESHOLD Aβ-FIBER–MEDIATED PAIN tion with neurons, oligodendrocytes, Schwann cells, DRG neurons and enhance the expression of chemo-
These fibers mediate not only touch, pressure, vibra- and spinal microglia. Peripheral nerve injury unleashes kines, and its antagonists abolish neuropathic pain
tory, and joint movement sensation but also, and very behavior in animal models.
importantly, the suppression of nociceptive pain caused
by rubbing the affected area. However, after neural
lesions, Aβ fibers begin to activate superficial dorsal
horn nociceptive projection neurons. Peripheral injury
induces regenerative responses to help damaged
neurons in reconnecting with their targets. These

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Plate 8-7â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
THALAMUS

Internal Interthalamic 3rd
medullary adhesion ventricle
lamina Pulvinar
Anterior
VPM MmMeeedddiuaianlllary lamina
Lamina
LP LD
VA VL
MD LP Intralaminar Internal
VPL nuclei
M VP VI
CM 3rd ventricle VPL VPM
Reticular nucleus

External Thalamic nuclei Pulvinar
medullary
lamina CM Centromedian Lateral geniculate body
LD Lateral dorsal
Median nuclei Medial geniculate body

Schematic section LP Lateral posterior Schematic representation of thalamus
through thalamus M Medial (external medullary lamina and
(at level of broken MD Medial dorsal
line shown in figure VA Ventral anterior reticular nuclei removed)
at right) VI Ventral intermedial
VL Ventral lateral
VP Ventral posterior Lateral nuclei
VPL Ventral posterolateral
Medial nuclei

VPM Ventral posteromedial Anterior nuclei

Thalamic Pain Syndrome Corpus callosum
Septum pellucidum
Thalamic pain syndrome (TPS), first described by Lateral ventricle
Déjerine and Roussy in 1906, is a central neuropathic Body of caudate nucleus
pain disorder primarily resulting from a thalamic infarct Choroid plexus of lateral ventricle
or hemorrhage referred to as central poststroke pain Stria terminalis
(CPSP). Other nonthalamic central nervous system Superior thalamostriate vein
lesions occasionally have similar symptoms, broadening Body of fornix
the central pain syndrome perspective. The defining Internal cerebral vein
clinical features include an initial contralateral feeling Tela choroidea of 3rd ventricle
of numbness or tingling with compromised tactile sen- Choroid plexus of 3rd ventricle
sation, sometimes with hemiparesis if the adjacent Thalamus
internal capsule is affected. Subsequently, as these Putamen
symptoms gradually dissipate, a persistent, extremely Globus pallidus Lentiform nucleus
uncomfortable allodynia develops, that is, hypersensi-
tivity to stimuli that normally do not cause pain, par- Internal capsule
ticularly to the least degree of mechanical or thermal 3rd ventricle and interthalamic adhesion
stimuli. CPSP usually develops within a few months or, Hypothalamus
rarely, years later after the inciting stroke, occurring in Tail of caudate nucleus
a small percentage of stroke patients, particularly so in Optic tract
senior citizens. There is a broad spectrum of severity; Choroid plexus of lateral ventricle
an annoying numbness to a debilitating condition, Temporal (inferior) horn of lateral ventricle
severely impacting quality of life while undercutting White arrow in left Fimbria of hippocampus
rehabilitation efforts. The patient is often unable to sit interventricular Hippocampus
still only a short time, may wear a glove to avoid touch- foramen (of Monro) Dentate gyrus
ing anything, often pleading—almost crying out—for Mammillary body
help, and eventually experiences psychologic distur- Ependyma Parahippocampal gyrus
bances, bringing the previously self-sufficient, stalwart Pia mater
patient to tears, with eventual concern for potential
suicide risk. Treatment options are typically ineffective; Coronal section of brain: posterior view
the pain severity varies from an annoyance to almost
overwhelming, something most individuals have never touch are often noted. Pain may travel unilaterally from PATHOPHYSIOLOGY
previously experienced. the extremities to sometimes being accompanied by The thalamus plays a central role in modulation of
PAIN CHARACTERISTICS facial paresthesias; anesthesia may also occur in regions sensory information between the periphery and cere-
The patient typically reports a burning, stinging, stab- affected by the stroke. CPSP is more common in right- bral cortex. There are various hypothesized mecha-
bing, or shooting pain; hyperalgesia to temperature and sided strokes. Primarily, this is a very persistent syn- nisms underlying the pathophysiology of CPSP,
drome with daily intermittent pain lasting seconds to including central imbalance, central disinhibition, and
minutes. The occasional relief is limited to a few hours; central sensitization. Central imbalance is associated
however; the hypersensitivity, hyperpathia, or allodynia with the clinical finding of dissociated sensory loss
continue in response to various stimuli.

208 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 8-8â•… Pain

CLINICAL MANIFESTATIONS RELATED TO THALAMUS SITE IN INTRACEREBRAL HEMORRHAGE

Pathology CT scan Pupils Eye Motor Other
Thalamus movements and

sensory
deficits

Constricted, Both lids Slight Aphasia
poorly retracted; contralateral (if lesion
reactive eyes hemiparesis, on
to light positioned but greater left side)
bilaterally downward hemisensory
and loss
medially;
cannot
look
upward

Occasional headache Homonymous (partial) visual field defects
(usually supraorbital or
temporal)

Language defect (partial or complete) only when
dominant hemisphere is involved

Thalamic Pain Syndrome Hemiparesis or hemiplegia On side opposite
(only arm or leg may be affected); involved artery
(Continued) may be fleeting, transient, or permanent
and may appear with or without
sensory deficits

characterized by hypersensitivity to thermal and noxious
stimuli, with preserved sensory perception to touch and
vibration. It is speculated that this symptom pattern is
attributable to an imbalance of inputs among spinotha-
lamic tracts and spared dorsal column/medial lemniscus
activity. Central disinhibition may account for abnormal
thermal sensation with burning pain and cold allodynia
related to the medial thalamus and anterior cingulate
cortex. The concept of central sensitization postulates
that changes in electrophysiologic properties of noci-
ceptive neurons lead to hyperexcitability through mul-
tiple mechanisms. There is still no acceptable precise
clinical correlation with a specific underlying patho-
physiologic mechanism.

TREATMENT a polypharmacy algorithm. Some pain physicians advo- Invasive procedures include deep brain, spinal cord,
Management of CPSP remains a major therapeutic cate tricyclic antidepressants and gabapentin as first- motor cortex stimulation, and various ablative
challenge due to the severity and quality of the pain, line treatment. If improvement in pain intensity is not approaches are reported in small series with modest
the associated unilateral spasticity, and psychologic dis- seen and the pain has a shooting characteristic, then and, unfortunately, often short-lived therapeutic
tress. Each area must be addressed. There are few class anticonvulsants, such as carbamazepine, are added to benefit. Patients with CPSP sometimes also benefit
I randomized controlled therapeutic (RCT) trials. the medication regimen. The timing of incorporation from psychologic treatment addressing chronic pain
Lately, new pharmacologic treatments are emerging. of opioids must be tailored to individual patient risk behaviors, and the poststroke rehabilitation seems to be
One randomized controlled study of pregabalin dem- factors for drug-dependent behavior. of utmost importance in this group of patients.
onstrated significant reduction in pain intensity as well
as improvements in sleep and global patient status.
There is evidence for the dose-dependent analgesic
benefit of opioids in these syndromes. A recent dulox-
etine study demonstrated that despite some advanta-
geous biologic effects, this is no more effective in
controlling neuropathic pain than placebo.

Currently, a multistep pharmacologic approach is
endorsed by some experts specializing in CPSP treat-
ment; however, no trials are yet published, supporting

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 209

Plate 8-9â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Complex Regional Pain

Complex regional pain syndrome (CRPS), previously Acute reflex sympathetic
known as reflex sympathetic dystrophy, is an important dystrophy. Hand swollen,
chronic neuropathic pain syndrome with a distinctive red, and painful.
clinical phenomenology. The epidemiology of CRPS is
difficult to estimate due to the spectrum of symptom
severity and frequent paucity of clinical signs. Studies
maximizing diagnostic sensitivity suggest a postsurgical
incidence as high as 30% and 20% to 25% in extremity
fractures; chronic “severe” CRPS occurs in less than
2% of these patients. The ratio of CRPS occurrence in
women versus men is 2â•:› â•1› to 3â•:› â•1› , and more frequently
affects the arm in adults and leg in children.

PATHOPHYSIOLOGY Associated
This is enigmatic; one CRPS theory suggests that cuta- severe disuse
neous innervation is altered post-traumatically. Human osteoporosis
pathologic studies demonstrate reduced local nocicep-
tive fiber density with aberrant hair follicles and sweat Chronic reflex sympathetic dystrophy.
glands innervation. However, it is not clear whether this Hand atrophic, cold, and painful, with
is the primary pathology or a reaction to the painful slight clawing of fingers.
symptoms.
In chronic reflex sympathetic dystrophy, right upper limb
Other studies propose that some central and periph- atrophic, stiffened. Arm held at rest protectively to avoid pain.
eral sensitization leads to CRPS. Hyperalgesia and
allodynia encountered after initial tissue trauma are lesion, often developing after minor fracture or trauma, in treating neuropathic pain, their usefulness in CRPS
attributed to local release of pronociceptive neuropep- whereas type II CRPS has specific nerve damage. patients is not precisely defined. Anti-inflammatory
tides, leading to enhanced nociceptor responsiveness drugs, including nonsteroidal anti-inflammatory drugs
with lowered thresholds for innocuous thermal and CRPS is diagnosed by clinical evaluation; there are (NSAIDs) and corticosteroids are sometimes effective.
mechanical stimuli. Higher preoperative pain intensity no specific widely recognized diagnostic tests. Various Topical analgesic using capsaicin and lidocaine trans-
may predict postoperative CRPS invoking a central diagnostic tools have their advocates, but the diagnosis dermal patches is sometimes effective. Opioids are
sensitization theory. Neuropeptides and proinflamma- remains clinical. Sympathetic nerve blocks at various sometimes valuable when tolerated because these anal-
tory cytokines released from injured nociceptive fibers levels of the neuraxis are sometimes used to support the gesics have demonstrated efficacy for neuropathic pain,
are implicated in experimental neurogenic inflamma- presence of an autonomic component. If successful but adverse consequences, such as tolerance, abuse, and
tion. Neuropeptides, such as calcitonin gene–related (>50% reduction in pain intensity), a more durable misuse, may become problematic.
peptide (CGRP), substance P, and bradykinin, cause blockade with phenol or a radiofrequency ablation pro-
vasodilation, increase vessel permeability, hyperhidro- cedure may be performed. A number of interventional modalities exist. Those
sis, and hair growth in the affected area, leading to used include regional anesthetic blocks (i.e., sympa-
characteristic CRPS features. TREATMENT thetic blockade), sympathectomy, and somatic blockade
A multidisciplinary approach is used. Early diagnosis when moderate-to-severe pain does not respond to
Sympathetic nervous system dysfunction (SNSD) and prompt treatment favorably influence prognosis. physiotherapy or pharmacotherapy. Neuromodulation,
may account for common autonomic CRPS features. Symptom management is based on pain severity. Phys- such as transcutaneous electrical nerve stimulation
Reduced SNS-induced vasoconstriction predicts iotherapy, including range-of-motion exercise, desensi- (TENS) at the site of the pain and spinal cord stimula-
CRPS and explains the warm, red extremity in acute tization, and isometric strengthening, is a first-line tion (SCS), has also shown promise in the treatment of
CRPS. Concomitantly, SNSD may contribute to treatment. CRPS, and a subpopulation of patients may experience
post-traumatic nociceptive excitation through adren- a durable robust response. These modalities are
ergic receptors expressed on nociceptive fibers. Pharmacotherapy may begin with tricyclic antide- demanding to perform and require a pain medicine
pressants and antiepileptics; although these are effective specialist.
In addition, the central nervous system (CNS) may
have a CRPS pathophysiologic role. The region of
somatosensory cortex representing the affected limb is
considerably reduced. Such brain plasticity is associated
with greater pain intensity, hyperalgesia, and impaired
tactile discrimination. Motor dysfunction accompany-
ing CRPS may be linked to significant reorganization
of central motor circuits.

CLINICAL FEATURES AND DIAGNOSIS
CRPS occurs predominantly with fractures and various
surgeries, including total knee replacement, hip arthro-
plasty, carpal tunnel release, and numerous arthroscopic
procedures. Major clinical CRPS features include spon-
taneous pain, allodynia, hyperalgesia, edema, vasomotor
instability, autonomic dysfunction, and progressive
trophic changes. CRPS pain occurs in a distribution
beyond an initially affected nerve(s); eventually, this
may involve the entire affected limb, and rarely, the
contralateral limb. Weakness and tremor may occur,
leading to profound functional loss. CRPS occurs as two
subtypes: type I CRPS has no identifiable focal nerve

210 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 8-10â•… Pain

Herpes Zoster

Known to the layman as “shingles,” herpes zoster (HZ) Herpes zoster dermatomal vesicles
is an acute neuralgia typically confined to the distribu-
tion of a specific spinal nerve root or cranial nerve. It Varicella-zoster with
is the most common peripheral nervous system infec- presumed underlying
tion. The annual U.S. incidence is 0.5%. After causing
primary infection, known as “chickenpox,” the varicella- keratitis
zoster virus (VZV) becomes latent in trigeminal,
autonomic, and dorsal root ganglia due to acquired deficits result from infections of the facial nerve when TREATMENT
cell-mediated immunity. The virus reactivates later in the geniculate ganglion is affected. This infection, also A live attenuated vaccine (Zostavax; Merck, White-
life, causing an extremely painful vesicular skin rash. referred to as Ramsay Hunt syndrome, is usually associ- house Station, NJ) is approved by the U.S. Food and
Age and immunosuppression are important VZV reac- ated with vesicles in the external ear and sometimes Drug Administration (FDA) for the HZ prevention in
tivation factors; others include stress, trauma, surgery, leads to tinnitus, vertigo, and deafness. patients older than 50 years. Protection against HZ
and a family history of HZ. begins around 4 to 6 weeks postvaccination. This is not
A serious primary complication of acute herpes for treatment of herpes zoster or PHN per se. Antiviral
Herpes zoster complicates 10% of lymphomas, par- zoster (AHZ) is postherpetic neuralgia (PHN), or agents, including acyclovir, valacyclovir, and famciclo-
ticularly Hodgkin disease. One in 25 active shingles chronic neuropathic pain in the affected nerve territory vir reduce the acute and symptomatic period if admin-
patients harbor undetected carcinomas, lymphomas, or that persists after the skin eruptions and acute inflam- istered within 3 days of rash appearance. The latter two
other diminished T-cell immunity pathophysiology, matory response have subsided. Although PHN may drugs also decrease the incidence and severity of PHN,
particularly immunosuppression with corticosteroid or improve over time, the incidence and severity of symp- although not preventing its occurrence.
medication for transplants or human immunodeficiency toms directly correlate with advanced age at rash onset
virus (HIV) infection. and the degree of rash severity. Once the initial lesions For treatment of PHN per se, oxycodone has dem-
of HZ have healed, the scarred regions have decreased onstrated analgesic benefit in the acute and subacute
Postherpetic neuralgia (PHN), characterized by sensation and numbness, although the surrounding skin phase after acute herpes zoster reactivation. Tricyclic
severe and relentless pain highly refractory to treat- is marked by allodynia, hyperalgesia, and hyperesthesia. antidepressants, adjuvants such as gabapentin and pre-
ment, is an important HZ complication. PHN risk The pain may either be characterized as persistent gabalin, topical lidocaine (5%), topical high-dose (8%)
factors include age older than 50 years, female gender, burning or lancinating pain precipitated by friction of capsaicin, and opioid medications are all efficacious for
severe disseminated rash, initially severe pain, and poly- the skin, intense itching and formication can be present PHN pain relief.
merase chain reaction (PCR)-detectable viremia. VZV as well.
is associated with other neurologic complications,
including cerebral arteriopathies, particularly with oph-
thalmic trigeminal zoster. Other potential issues include
cranial nerve palsies, myelitis, segmental motor weak-
ness, and herpetic neuralgia without the zoster rash
(zoster sine herpete)—a difficult diagnosis.

PATHOLOGY
The dorsal root ganglion (DRG) is the primary infec-
tious site. VZV, a DNA-type virus similar to herpes
simplex virus, also causes childhood chickenpox. Sub-
sequently, the VZV probably migrates up the peripheral/
sensory nerve to the DRG, remaining dormant for
years until immunocompromise potentiates reactiva-
tion. Here an acute inflammatory reaction leads to
DRG destruction. Concomitantly, the VZV spreads
peripherally to the skin, producing the rash. The neu-
ropathic pain component of zoster, independent of pain
associated with the actual lesions, occurs with intraneu-
ronal virus replication, leading to neuronal lytic damage,
inflammation, and hemorrhage with virus eruption
from the neurons.

CLINICAL MANIFESTATION
The rash, reminiscent of chickenpox is confined to a
radicular or cranial nerve distribution. Its onset is often
heralded by a few days of either severe localized pain
or nonspecific discomfort in the affected area. The
vesicles appear 72 to 96 hours later. They have an ery-
thematous base with a tight, clear bubble that eventu-
ally becomes opaque and dries and crusts over after 5
to 10 days; scarring and hypopigmentation may occur.
Typically, the pain ceases in 1 to 4 weeks.

More than half of patients are affected in the thoracic
region as with varicella. Ophthalmic trigeminal herpes
zoster is fairly common and carries the risk of corneal
anesthesia and consequent scarring, along with con-
junctivitis, keratitis, and iridocyclitis. This also has the
uncommon potential for middle cerebral artery infarc-
tion from viral arterial wall invasion. Common motor

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 211

P late 8-11â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Third occipital nerve (dorsal
ramus of C3 spinal nerve)

Occipital Neuralgia Epicranial aponeurosis Rectus capitis posterior minor muscle
(galea aponeurotica) Rectus capitis posterior major muscle
Occipital neuralgia (ON), as defined by the Interna- Greater occipital nerve Semispinalis capitis muscle
tional Headache Society, is a paroxysmal shooting pain (dorsal ramus of C2 spinal nerve) J\[ HUK YLMSLJ[LK
within the distribution of the greater, lesser, and third Occipital belly (occipitalis) of Vertebral artery (atlantic part)
occipital nerves. The pain involves occipital and peri- occipitofrontalis muscle Obliquus capitis
auricular areas and may radiate to the lateral scalp and superior muscle
retro-orbital area. Episodes of ON may be provoked Occipital artery
with palpation of the occipital nerves, especially at the Suboccipital nerve (dorsal
anatomic landmark of the occipital notch. Stress and ramus of C1 spinal nerve)
tension may also modulate pain intensity in the distri-
bution of the occipital nerve. Although there is no Posterior arch of
definitive localizing test, multiple studies indicate that atlas (C1 vertebra)
the greater occipital nerve accounts for the majority
(90%) of cases. One study found that, in roughly 8.7% Obliquus capitis
of cases, both the greater and lesser nerves were inferior muscle
involved.
Occipital artery
PATHOLOGY
This uncommon neuralgia has various etiologies, pri- Greater occipital
marily categorized as neurogenic, vascular, muscular, or nerve (dorsal ramus
osteogenic. Parenthetically, it is important to note that of C2 spinal nerve)
the C1 root, suboccipital nerve, is entirely motor in
function, having no sensory component in contrast to Posterior Splenius capitis muscle
all other nerve roots. Trauma to the C2 root due to auricular J\[ HUK YLMSLJ[LK
traction injury or secondary to the arthritic changes at artery Third occipital nerve
the atlantoaxial joint are the primary causes of occipital (dorsal ramus of C3
neuralgia. Another postulated but unproven mechanical Semispinalis capitis spinal nerve)
cause includes nerve entrapment with sustained and splenius capitis Longissimus capitis muscle
contraction or spasm of the posterior neck muscles. muscles in posterior Splenius cervicis muscle
Osteogenic origins include osteoarthritis and arthritic triangle of neck Semispinalis cervicis muscle
degeneration of the spine leading to nerve entrapment Great auricular nerve
by hypertrophied atlantoaxial ligaments. Instances of (cervical plexus C2, 3) Semispinalis capitis muscle J\[
vascular etiology include irritation of C1/C2 nerve Sternocleidomastoid Splenius capitis muscle J\[
roots by diverging branches of the posterior inferior muscle
cerebellar artery and extremely rare dural arteriovenous
fistulas in the cervical regions. Tumors of the second Lesser occipital nerve
and third cervical dorsal roots and multiple sclerosis (cervical plexus C2)
account for more uncommon, neurogenic causes. Most Trapezius muscle
often, however, the inciting factor is not identified with Posterior cutaneous branches of
clinical evaluation, and the neuropathic changes in
greater or lesser occipital nerve are considered idio- dorsal rami of C4, 5, 6 spinal nerves
pathic. Perhaps these pathophysiologic mechanisms
will be more easily identified with the increased avail- nerves (CNs) VIII, IX, and X and the cervical sympa- pain intensity in this region. Most treatments, however,
ability of 3-tesla magnetic resonance imaging (MRI), thetic trunk. Stress-induced muscle tension headaches are aimed at symptom reduction and relief of any
providing more accurate detail. may also occur. On physical examination, dysesthesia accompanying muscle tension. Empiric use of drugs
is elicited along the greater and lesser occipital nerve, based on efficacy data from other neuropathic syn-
CLINICAL MANIFESTATION as well as tenderness to palpation. Diagnosis is con- dromes is common. These agents include adjuvants,
Occipital neuralgia is typically described as stabbing firmed via diagnostic nerve block of the occipital nerve, such as tricyclic antidepressants, and anticonvulsants,
pain with periods of aching pain between the paroxys- along with imaging scans to identify any suspected such as carbamazepine or gabapentin. Botulinum toxin
mal episodes. Retro-orbital pain may be explained by lesions. type A injections are also used. Local anesthetic and
the convergence of nociceptive pathways in the dorsal corticosteroid injections to the greater occipital nerve
root of C2 and the pars caudalis division of the spinal TREATMENT are variably effective. Pulsed radio frequency of the C2
trigeminal nucleus. In addition, visual deficits, ringing Effective management depends on whether an identifi- or C3 dorsal root ganglion is currently being evaluated
in the ears, dizziness, and nasal congestion may accom- able entrapment mechanism is identified. If so, surÂ

Plate 8-12â•… Pain

Longissimus Rectus capitis posterior minor muscle
capitis muscle
Obliquus capitis superior muscle
Semispinalis Rectus capitis posterior major muscle
capitis muscle Obliquus capitis inferior muscle
Splenius capitis
Longissimus capitis muscle Stress Sympathetic
and splenius Emotion pathways
cervicis muscles Spinalis cervicis muscle
Serratus posterior Suprasegmental centers
superior muscle Sympathetic
Longissimus hyperactivity
Iliocostalis cervicis muscle
muscle
Iliocostalis Gamma
Longissimus cervicis efferent
muscle muscle Intrafusal
fiber
Spinalis Iliocostalis Extrafusal contraction
muscle thoracis fiber controls
Serratus muscle contraction spindle
posterior sensitivity
inferior Spinalis
muscle thoracis
muscle
Internal Longissimus
oblique thoracis
muscle muscle

Iliocostalis la afferent
lumborum Spindle
muscle

Myofascial Factors in Low Extrafusal
Back Pain muscle fiber

Myofascial structures are implicated in virtually all Muscle spindles provide feedback mechanism for
acute and chronic low back pain syndromes. Myofascial
pain syndrome (MPS) is strictly defined by the presence muscle tension. Sensitivity of spindles modulated
of local and referred pain that originates from a myo-
fascial trigger point (MTrP). This symptom pattern by gamma efferent system and by sympathetic
overlaps clinically with pain referred from diverse
somatic structures, such as ligaments, periosteum, scar innervaton of spindles. Sympathetic hyperactivity
tissue, skin, and tendons. Trigger points, defined as a
zone of intense pain associated with a hardened muscle Deconditioning of extensor musculature can result in painful spasm of spindles.
band, may be identified on physical examination;
however, it is not uncommon that syndromes with a Noxious Cortical
myofascial component lack a discrete TrP when somatic stimuli (mechanical processing
pain is referred pain from deeper muscles, such as the factors, chemical factors) of pain input
psoas, into the inguinal region. The prevalence varies
from 30% of general medical clinic patients with Deconditioning Cortical
regional pain to as high as 85% to 93% of patients of musculature modulation
presenting to specialty pain management centers. due to decreased
Women are much more likely to suffer from MTrPs. function and (gating) of
PATHOPHYSIOLOGY disuse results in pain input
The development of MPS is often associated with pos- delayed repair
tural derangements, such as muscle overload, dystonia, and continued
and fatigue. Postural abnormality (e.g., scoliosis) may pain
reflect asymmetric extensor or flexor tone in a group of
paraspinal muscles. Secondary causes of myofascial pain Inhibition of m. strength and
are extremely common, including painful spasm with function directly related to
spondylolisthesis or increases in tone with emotional severity of noxious stimuli
stress. The most common cause of myofascial trigger
point (MTrP) formation is repetitive stress on individ- causing sustained muscle fiber contractions, release of CLINICAL MANIFESTATIONS
ual muscles or muscle groups. In the low back, a small vascular and neuroactive substances, and muscle pain Characteristic MPS symptoms begin after discrete
hemipelvis or short leg may lead to MPS. perpetuating the muscle spasm. The abundance of the trauma or insidiously. Patients note varying degrees of
nociceptors in muscle, joints, skin, and blood vessels regional deep aching sensations. Functional complaints
An MTrP is a hyperirritable spot within skeletal explains the pain severity and exquisite muscle tender- include decreased work tolerance, impaired muscle
muscle associated with a hypersensitive palpable nodule ness upon palpation. Possibly, the chronicity of MPSs coordination, stiff joints, fatigue, and weakness, leading
in a taut band. Here the key pathophysiologic abnor- is attributable to altered sensory processing as charac- to sleep disturbances, mood changes, and stress. The
malities are principally located at the muscle center terized by central sensitization with alteration in supra- most reliable physical signs of trigger points are pain
near its motor end-plate zone. Precipitating factors may spinal inhibitory descending pain-control pathways.
facilitate acetylcholine release at motor end plates,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 213

Plate 8-13â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

POSTERIOR ABDOMINAL WALL: INTERNAL VIEW Caval opening

L1 Diaphragm
L2
L3 Central tendon
L4 of diaphragm
L5
Esophagus and
vagal trunks

Right crus of
diaphragm
Left crus of
diaphragm

Median
arcuate
ligament

Aorta and
thoracic duct

Medial
arcuate
ligament

Lateral
arcuate
ligament

Greater, lesser
and least
splanchnic
nerves and
ascending
lumbar vein

Myofascial Factors in Low Quadratus
Back Pain (Continued) lumborum
muscle
recognition, taut band, tender point, referred pain, and Transversus
local twitch response. MTrPs usually appear in muscu- abdominis
lar structures used for posture maintenance, including muscle
quadratus lumborum, gluteus maximus, gluteus medius,
iliocostalis, iliopsoas, levator ani, longissimus thoracis, Internal
lower rectus abdominis, multifidi, piriformis, and hip oblique
rotators. With low back pain, quadratus lumborum, muscle
used for trunk stabilization and posture, is the most
common source of MTrP. Palpation of MTrP will External
reproduce or increase regional pain, possibly eliciting oblique
referred, radiating pain patterns. Sometimes MTrP muscle
activation may evoke autonomic phenomenon, includ-
ing dermal flushing, lacrimation, sweating, and tem- Anterior Sympathetic
perature changes. Chronic MTrP patients require inferior trunk
evaluation for postural abnormalities, ergonomic iliac spine
factors, and hypothyroidism. Anterior Psoas minor
TREATMENT sacrococcygeal muscle
This requires a comprehensive rehabilitation, medica- ligament
tion approach, sometimes including local interventions. Iliacus Psoas major
One attempts to abolish MTrPs and tender spots. muscle muscle
Overall flexibility needs to be restored to the muscle, Anterior superior
while associated precipitating factors require modifica- iliac spine
tion. Medications, including acetaminophen or nonste-
roidal anti-inflammatory drugs (NSAIDs), are initially Anterior
used with local inflammation. Adjuvant analgesics, longitudinal
antidepressants, or anticonvulsants are added for neu- ligament
ropathic components. Inguinal
ligament (Poupart)
Rehabilitation approaches for MPS, including neu-
romuscular relaxation techniques, heat, or electrical Piriformis muscle
therapy may also help. Physical treatments can also be
used in the management of MPS. The “stretch and Rectococcygeus muscle Levator ani (Ischio-)coccygeus
spray” technique is popular, utilizing a vapocoolant Obturator membrane muscle muscle
spray applied just before stretching the involved muscle. Pubic symphysis Ischial spine
Other physical therapies include massage therapy or Pecten pubis (pectineal line) Obturator internus
low-level laser therapy. More unusual treatments Pubic tubercle Perineal membrane muscle
include mud baths and magnetic fields. Urethra and Tendinous arch of
rectoperinealis muscle levator ani muscle
Rectum Lesser trochanter of femur

Opening for femoral vessels

Pectineal ligament (Cooper)
Lacunar ligament (Gimbernat)

Needling of myofascial trigger points is a common needling. The authors of this meta-analysis concluded
MPS treatment. However, no causal relationship that any effect resulting from these therapies is derived
between direct needling of MTrPs and improvement in from the direct needle insertion into the MTrP. Recent
symptoms is established. A systematic 2001 review dis- interest in using the 5-hydroxytryptamine 3 (5-HT3)
cussing randomized controlled trials (RCTs) failed to receptor antagonist tropisetron for injection into
conclusively demonstrate any therapeutic benefit in wet MTrPs associated with MPS has not been tested with
(injection with botulinum or local anesthetic) versus dry an RCT.

214 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 8-14â•… Pain

Lumbar Zygapophyseal Joint Superior Facet joint
Back Pain articular Joint capsule
Facet process
Lumbar zygapophyseal (facet) joint degeneration (ZfJD) is joint Inferior Bilevel
a leading cause of axial predominant chronic low back articular innervation
pain (LBP). Facet-mediated pain is a multifactorial process of synovial
process intimately related to intervertebral disk degen- membrane
eration. These syndromes originate from any structure Trochanteric and capsule
integral to function and configuration of lumbar zyg- region of facet
apophyseal (LZ) joints, including the fibrous capsule, joint
synovial membrane, hyaline cartilage surfaces, and Posterior
bony articulations. Controversy exists regarding the thigh Facet joint and
relative contribution of these structures to the back pain capsule innervated
process. Recent evidence, based on the Kirkaldy-Willis region by dorsal rami from
tripod theory of the spinal motion segment, identifies two spinal levels
LZ joints as primary sources for pain. Epidemiologic Cartilage
studies identify ZfJD as the primary diagnosis in 6% of degeneration Facet joint, composed
chronic LBP patients. of articular processes
of adjacent vertebrae,
PATHOPHYSIOLOGY limits torsion and
LZ joint pain primarily results from repetitive load- translation
bearing strain accumulated over a lifetime; rarely, LZ
joint arthropathy is traced to one inciting event. During Lumbar Synovial Joint Joint space
midlife, cartilaginous changes accelerate, and subchon- spine membrane capsule
dral sclerosis and osteophytes growth are commonly region Articular
observed phenomena. Intervertebral disk disease is the cartilage
initial site of spinal degeneration; facet joint deteriora- Gluteal
tion subsequently develops secondary to biomechanical region Superior
effects. Mechanical consequences of disk degeneration Lateral articular
include reduced disk height and segmental microinsta- thigh process
bility leading to increased facet load. This provokes region Inferior
joint subluxation and cartilage alteration with subse- articular
quent facet joint degeneration. process
Innervation
Rheumatoid arthritis, ankylosing spondylitis, syno- of synovial
vial impingement, chondromalacia facetae, pseudogout, membrane
meniscoid entrapment, and capsular/synovial inflam- and capsule
mation also predispose to chronic facet joint strain.
Degeneration of
Lumbar facet joints are richly innervated with encap- articular cartilage
sulated, unencapsulated, and free nerve endings, and with synovial
contain substance P, calcitonin gene–related peptide inflammation or
(CGRP), as well as neuropeptide Y. Nerve fibers occur capsular swelling
within subchondral bone and intra-articular inclusions may result in
of lumbar zygapophyseal joints, thus signifying that referred pain
facet-mediated pain may originate beyond the joint
capsule. In models of degenerative lumbar spinal disor- Synovial Osteophytes Osteophytic overgrowth
ders, inflammatory mediators, such as prostaglandins inflammation of articular processes of
and the inflammatory cytokines (interleukin [IL]-1beta, Capsular facet joint may impinge
IL-6, and tumor necrosis factor-alpha [TNF]-alpha), swelling on nerve root
occur within facet joint cartilage and synovial tissue.
provide firm diagnosis of facet-mediated LZ pain. number of interventional therapies targeted at these
PAIN-REFERRAL PATTERNS Single photon emission–computed tomography joints. Conservative treatments, including medications,
Lumbar facet joints produce pain referred into the (SPECT) bone scintigraphy may sometimes help iden- physical therapy, or manual therapy, lack specific anal-
groin. Pain emanating from upper facet joints tends to tify active inflammation with some facet-mediated gesic efficacy for the joint pain per se. Nevertheless
extend into the flank, hip, and upper lateral thigh, sources in low back pain individuals. these modalities provide standard first-line treatment
whereas pain from the lower facet joints penetrates for acute-onset LBP.
deeper into the posterolateral thigh. LZ joint–mediated pain is a diagnosis made primarily
by exclusion of other possible etiologies (see Plate 8-13). Intra-articular steroid injection for treatment of LZ
CLINICAL PICTURE This is difficult to confirm, however; positive results joint pain is a somewhat controversial subject. However,
Clinically, LZ joint–mediated back pain overlaps con- with controlled analgesic injections may be supportive in general, it is concluded that intra-articular steroid
siderably with multiple other LBP etiologies. Although of this diagnosis. These nerve blocks are accomplished injections may provide intermediate-term relief to
LZ joint pain is not associated with anatomically specific in two ways. The more reliable method targets the small LZ joint pain patients who appear to have active
neurologic deficits, patients experiencing this referred nerve fibers branching from the dorsal spinal root known inflammation.
somatic pain may demonstrate a pain-inhibited non- to innervate the facet joints, with the so-named medial
myotomal weakness. Similarly, these individuals also branch block. Intra-articular anesthetic injection is also Lumbar medial branch neurotomy (LMBN) has the
report a nondermatomal referred extremity sensory- performed after an appropriate arthrogram. However, most evidence-based support. The thermal coagula-
loss–type complaints reaching as far distal as the foot. these injections have never been tested for validity. tion probe used for a medial branch neurotomy dena-
turates nerve proteins; therefore this provides a more
There are no specific radiographic computed tomog- MANAGEMENT superior clinical effect than medial branch anesthetic
raphy (CT) facet joint abnormalities identified to Controlled prospective studies comparing varied LZ block. Several clinical trials have demonstrated LMBN
joint pain treatments are limited despite increasing efficiency in the treatment of LZ joint pain.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 215

Plate 8-15â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Low Back Pain and Effects Effects of lumbar hyperlordosis on spinal nerve roots
of Lumbar Hyperlordosis
and Flexion on Spinal Nerves Narrowing Opened

Hyperlordosis, also known as saddleback or swayback, Hyperlordosis-intervertebral Flexion-foramen opened
is an excessive vertebral curvature (lordosis). The lum- foramen greatly narrowed more widely; nerve freed
bosacral region plays a pivotal role in terms of mobility Chronic and prophylactic
and weight-bearing potential; any postural aberrations Treatment of lumbar strain Reduction of weight
affecting the lumbosacral angle may lead to low back Acute Correction of posture
pain (LBP). Hyperlordotic posture is a common Absolute bed rest Firm mattress, bed board
contributor to chronic nonspecific LBP syndromes. Warm tub baths, heat pad, hydrocollator Daily low back exercises
Common causes include pregnancy, tight low back Sedation Regular sports activity compatible
muscles, obesity, or congenital disorder. Firm mattress, bed board with age and physique
Diathermy, massage
Lumbar hyperlordosis is 50% more accentuated with Local anesthetic infiltration to trigger zones
standing rather than sitting. This may cause nonspecific Occasionally corset, brace, or strapping
LBP localizing to somatic tissues (e.g., paraspinal
muscles, facet joints) mediated by inflammatory mecha- Exercises for chronic lumbar strain (starting positions in outline)
nisms. In extreme hyperlordosis, exiting nerve root 1. Lie on back, arms on chest, knees bent. Press small of back
entrapment secondary to intervertebral foramen nar- firmly down to floor, tightening muscles of abdomen and buttocks,
rowing with this posture may cause radicular irritation thus tilting pubis forward, exhale simultaneously.
or a frank radiculopathy with sensorimotor deficits. Hold for count of 10, relax and repeat.
Patients with lumbar spinal stenosis (LSS) have reduced
anteroposterior central canal and lateral recess dimen- 2. Lie on back, arms at sides, knees bent. Draw knees up and pull them
sions with hyperlordosis. Associated compromise of firmly to chest with clasped hands several times. Relax and repeat. Also,
microvascular perfusion of the cauda equina possibly repeat exercise using one leg at a time.
accounts for posture-precipitated pain while standing
and walking, known as neurogenic claudication (NC). 3. Lie on back, knees bent, arms folded on chest or at sides. Sit up using
LSS nerve root injury may cause radicular pain charac- abdominal muscles and reach forward. Return slowly to starting position.
terized by sharp, lateralized pain conforming to derma- 4. Begin in a runner’s starting position (one leg
tomal distributions, a radiculopathy, or NC. Straight-leg extended, the other forward as shown, hands
raising stretches the sciatic nerve, simulating radicular on floor). Press downward and forward several
traction that provokes pain in an inflamed or otherwise times, flexing front knee and bringing abdomen
sensitized nerve root. to thigh. Repeat with legs reversed.

In the lumbar spine, the primary motion is flexion/ 5. Stand with hands on 6. Sit on chair, hands
extension with very little segmental rotation. Lumbar back of chair. Squat, folded in lap. Bend
flexion opens the foramen more widely, reducing nerve straightening hollow of forward, bringing chin
root compression. The amount of compressive force back. Return to starting between knees. Return
and tension on the nerve root decreases with spinal position and repeat. slowly to starting
flexion and increases with spine extension. position while tensing
abdominal muscles.
Lordosis typically occurs maximally at L4-S1. A Relax and repeat.
simple radiographic image to determine the postural
status may capture the extent of lordosis. The normal Exercises are best done on hard, padded surface like carpeted floor. Start slowly. Do each only once or
range of lumbar lordosis is 20 degrees to 50 degrees, twice a day, then progressively to 10 or more times within limits of comfort. Pain, but not mild discomfort,
whereas hyperlordosis is defined as greater than 60 is indication to stop.
degrees. LSS patients have physical examination find-
ings denoting loss of lumbar lordosis. Another test for compared with behavior therapy. NSAIDs may acceler- with abdominal exercises. Avoiding sedentary lifestyle,
NC is the stoop test; here the patient walks with an ate the process of returning to usual activities or such as sitting for long periods of time, or wearing a
exaggerated lumbar lordosis until NC symptoms appear work. Of interest, other popular treatment options, lumbar brace may also be helpful. Short-term pain
or are worsened. The patient is then instructed to lean including transcutaneous electrical nerve stimulation relief can be achieved with the use of NSAIDs. A study
forward at the waist; reduction in symptom intensity is (TENS), electromyographic biofeedback, acupuncture, published in 2005 demonstrated the greater benefit of
considered suggestive of NC. and orthoses are not proved to be useful. Iyengar yoga (significant reduction in self-reported dis-
ability and pain, and reduced use of pain medication)
A radiographic study of sagittal lumbar spine mea- Conservative treatment, such as physical therapy, is than educational programs in the management of
surements of 552 asymptomatic subjects with lordosis recommended for patients with LSS or hyperlordosis. CLBP patients. For CLBP, positions that include twists
found that, in pain-free subjects, 65% of lordosis occurs Lumbar extension exercises should be avoided in these and inversions may alleviate hyperlordotic pain. Twist-
between L4-5, and 35% occurs above L4. This study patients because spinal extension and increased lumbar ing motions involve the deeper layer of back muscles
also demonstrated that hyperlordotic patients tended lordosis are known to worsen LSS. Flexion exercises for and reduce the pain symptoms by realigning the verte-
to have acute low back pain, whereas chronic low the lumbar spine are emphasized because these methods bra, increasing intervertebral disk space, and decreasing
back pain patients were hypolordotic, emphasizing increase the spinal canal dimension and decrease stress possible impingement of nerve roots, whereas inver-
the importance of hyperlordosis in chronic LBP on the spine, thereby reducing lumbar lordosis. sions reverse the compressive effects of gravity on the
individuals. Strengthening exercises include back hyperextensions, intervertebral disk space.
hip flexor, and gluteus and hamstring stretches, along
A systematic review of randomized clinical trials of
conservative treatment for acute and chronic low back
pain (CLBP) supports the use of muscle relaxants, non-
steroidal anti-inflammatory drugs (NSAIDs), acetamin-
ophen, manipulation, and active exercise therapy in the
treatment of acute LBP. Hyperlordosis is not always
associated with painful symptoms, and this, per se, is
not an indication for treatment. Analysis of chronic
LBP therapies have shown stronger evidence of the
effectiveness of exercise and manipulation therapy as

216 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 8-16â•… Pain

Examination of the Low Back Spondylolysis and Spondylolisthesis
Pain Patient
Superior articular
Low back pain (LBP) is defined as pain localized process (ear of
between the 12th rib and the inferior gluteal folds, with Scotty dog)
or without leg pain. Although it is the fifth leading Pedicle (eye)
reason for doctor visits, up to 85% of patients in some
population-based studies have nonspecific low back Transverse process
pain, even without specific spinal anomalies or disease. (head)
Many low back pain patients are regarded as being of Isthmus (neck)
nonspecific character because no evaluation (radio-
graphic or otherwise) is carried out to identify an Spinous process
underlying structural lesion. This finding primarily and lamina (body)
relates to the fact that most acute LBP episodes, without
radicular symptoms, resolve spontaneously within 6 Inferior articular
weeks; routine imaging is not sensitive or specific for process (foreleg)
initial evaluation in this setting. Often, LBP may be a
result of a multitude of pathologic processes, including Opposite inferior
degenerative diseases, inflammatory conditions, sys- articular process
temic or local infection, neoplasms, metabolic bone (hindleg)
disease, referred pain, trauma, and congenital disorders. Posterior oblique view showing In spondylolisthesis, Scotty dog appears decapitated
Because of this wide array of etiologies, clinical assess- radiographic Scotty dog. In simple
ment of patient’s condition is essential to establishing spondylolysis, dog appears to be
the correct diagnosis. wearing a collar
Characteristic posture
in left-sided, lower
lumbar disc herniation

CLINICAL EVALUATION Lower back pain and the size of the articular surfaces. The most signifi-
Focused history and physical examinations are fundamen- cant degree of motion is in the thickest disks and largest
tal elements in the assessment of low back pain. They unrelenting night or rest pain, unexplained weight loss, joint surfaces, mostly between L5-S1. Tests for range
are especially helpful in the preliminary classification of and progressive neurologic deficit. of motion include flexion, extension, lateral bending,
acute LBP into one of three groups: (1) nonspecific low and rotation. The clinician should bear in mind,
back pain, (2) LBP potentially associated with radiculopÂ

Plate 8-17â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
OSTEOPOROSIS
Examination of the Low Back
Pain Patient (Continued)

Lateral Bending. Support the iliac crest and have the In early stages (sacroiliitis Bilateral sacroiliitis is early radiographic
patient lean as far left and right as possible. To test for only), back contour may sign. Thinning of cartilage and bone
passive bending, perform this motion on the patient by appear normal but flexion condensation on both sides of sacroiliac
leaning him or her to the left and right by placing a may be limited joints.
hand on his or her shoulder.
Cancer within the vertebral body
Rotation. Place one hand on the pelvis and the other
on the opposite shoulder. Rotate the pelvis and shoul-
der posteriorly and repeat on the other side; note any
asymmetry in motion.

SPECIFIC TESTS
Two specific tests include the straight-leg raise test and
the crossed straight-leg raise test. These are valuable
diagnostic tools for disk herniation and lumbosacral
radiculopathy.

Straight-Leg Raise Test. To perform, have the
patient lie supine with legs relaxed. Lift the patient’s leg
upward by supporting the heel with one hand and
ensuring the knee remains straight with the other hand;
when the patient experiences pain, lower the leg slightly
and dorsiflex the foot to stretch the sciatic nerve. Note
the degree of elevation, description and location of
pain, and effect of dorsiflexion. The test is positive if
pain is felt in the low back or along the sciatic nerve. A
positive test is indicative of lumbosacral radicular
inflammation.

Crossed Straight-Leg Raise Test. To perform, place
the patient in supine position, raise the unaffected leg.
If back or sciatic pain is felt in the opposite leg, this is
suggestive of a lesion, such as a herniated disk, in the
lumbar region.

REFLEX TESTING Cross section showing
Patellar muscle stretch reflex arises predominantly from compression of nerve root
L4 nerve roots, although innervation is also supplied by
L2 and L3 segments of the spinal cord. Damage to the Sagittal view of fracture shown Progressive thoracic kyphosis,
L4 nerve will elicit a significantly decreased patellar in radiograph at left or dowager’s hump, with loss
reflex due to L2 and L3 involvement. of height and abdominal
protrusion
Achilles muscle stretch reflex typically involves the S1
nerve root. Dorsiflex the foot and strike the tendon to DIAGNOSTIC IMAGING CT scans are particularly valuable for detecting trau-
elicit plantar flexion of the foot. Although imaging or other diagnostic tests need not be matic and degenerative changes in cortical bone and
obtained routinely in patients early in the course of have a good sensitivity for detecting herniated disks. It
IMPORTANT FINDINGS acute or subacute nonspecific LBP, they are irreplace- can also demonstrate foraminal and extraforaminal
Mechanical low back pain characterized by aching pain in able in the management of patients with severe or pro- nerve root impingement. CT is superior to plain films
the lumbosacral region presents with paraspinal muscle gressive neurologic deficits or with other serious for detecting infection and neoplasm.
or facet tenderness but no evidence of motor, sensory, underlying conditions.
or reflex deficits. LABORATORY EVALUATION
Plain radiography is of limited use, as it fails to depict This is primarily useful in the clinical setting suggestive
Radicular low back pain is typified by pain that extends a detailed picture of the disease; however, it has been of visceral or other nonmechanical causes for the
below the buttocks into the posterior thigh and often recommended for initial evaluation of possible verte- pain. Initial studies of value are complete blood
below the knee into the lateral leg or back of the calf. bral compression fracture in patients with a history of count, erythrocyte sedimentation rate, and C-reactive
Clinical findings in sciatica due to disk herniation osteoporosis or steroid use. protein, whereas urinalysis, prostate-specific antigen,
include decreased ankle dorsiflexion, tibialis anterior alkaline phosphatase, and protein immunophoresis
and tibialis posterior (L5) or gastrocnemius (S1) Magnetic resonance imaging (MRI) provides superior are valuable when there are clinical clues suggesting
weakness, no ankle jerk (S1), and positive crossed soft tissue detail compared with computed tomography urinary infection and malignant or metabolic
straight-leg test. (CT) and plain radiography. It is the method of choice disease.
for visualization of intrathecal nerve roots, detecting
Lumbar spinal stenosis findings are variable. Classi- intraspinal malignancy and infection within the spine,
cally, patients complain of pain with standing or as well as bone marrow evaluation. MR imaging is less
walking, particularly with hyperextension such as useful for detecting acute spinal fractures.
walking downhill; this is relieved with rest or flexion.
Anterior thigh paresthesias are common. Often, there
are no significant abnormal findings; however, there
may be mild proximal, quadriceps, and iliopsoas (L3-4),
weakness with a decreased patellar reflex. Straight-leg
raising is normal.

218 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 8-18â•… Pain

Diagnosis of Low back, DIAGNOSIS OF HIP, BUTTOCK, AND BACK PAIN
Buttock, and Hip Pain
Lumbar (or sacral) radicular compression (herniated nucleus pulposus,
Discriminating among patterns of referred and neuro- spinal exostosis, arthritis)
genic pain from the lumbar region is a common clinical
challenge. In the context of concomitant hip and spine Sciatic notch, potential site for invasion by tumor coming
pathology, identifying the cause of pain is especially out of pelvis such as lymphoma
difficult. These patients may present with radiating pain
below the knee, back pain, or symptoms evoked by Gluteus medius
internal rotation of the hip. Certain combinations of
signs and symptoms favor one localization over another. Piriformis
Reported odds ratios in one study suggest that signs and Gemelli and obturator internus
symptoms of a limp, groin pain, and limited internal
rotation of the hip are all much more likely to be Tensor fasciae latae
present in a patient with a hip disorder. Similarly, in a Trochanteric bursitis (under gluteus medius or
comparison of patients diagnosed with a hip disorder gluteus maximus)
versus those with a spine disorder or both, patients with
a positive femoral stretch test are 4.76 times more likely Gluteus maximus
to have a spine disorder or a hip and spine disorder.
Ischial bursitis Firm, deeply
In general, true hip pain manifests as groin pain that (over ischial palpable tumor
sometimes radiates to the knee. Thigh pain, buttock tuberosity) of anterior
pain, and pain radiating below the knee are more often Gracilis proximal thigh
attributable to disorders of the lumbar spine or buttock Abductor magnus
and proximal thigh musculature. Strain or tear
LOW BACK PAIN of hamstring
Chronic nonspecific low back pain may result from tendons or mm.
peripheral injury to various neural and non-neural ana- Semimembranosus
tomic structures in the lumbar region. Pain generators
may include the vertebral column, surrounding muscles, Semitendinosus
tendons, ligaments, and fascia, or the neural structures
such as the lumbosacral roots. Hip osteoarthritis, tro- Biceps Long head Iliotibial tract
chanteric bursitis, ischial bursitis, sacroiliac dysfunc- femoris Short head
tion, piriformis syndrome, and osteitis condensans ilii
are examples of somatic conditions that will refer pain External Duodenojejunal
to and from the low back. Hip-joint pathology and oblique junction
bursitis of the greater trochanter can mimic mechanical muscle Body of
or radicular LBP, both in its onset and symptoms. Internal L2 vertebra
oblique Psoas major
It is crucial to distinguish radicular pain from somatic muscle muscle
referred pain because their management is significantly Transversus and fascia
different. Somatic referred pain is the result of noxious abdominis Lumbar
stimulation of structures in the lumbar spine, such as muscle spinal nerve
intervertebral disks, facet joints, or sacroiliac joints, and Transverse
never of the nerve roots. It has a dull, gnawing quality, Tendon of origin of process
and is difficult to localize. Conversely, radicular pain is transversus abdominis
elicited by ectopic discharges from a dorsal root. The and internal oblique Spinal
most common cause of such pain is disk herniation muscles dura mater
complicated by the inflammation of the affected nerve. Serratus posterior Cauda
It is described as lancinating or shocking, and it can inferior muscle equina
involve allodynia in case of nerve damage and neuropÂ

Plate 8-19â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
HIP JOINT INVOLVEMENT IN OSTEOARTHRITIS
Diagnosis of Low back,
Buttock, and Hip Pain Characteristic habitus
and gait
(Continued)

of a referral pain pattern in the lumbosacral spine is low
back pain associated with aching buttock pain. The
lumbosacral region and buttocks are both innervated
by L4-S1. However, the buttock is innervated by the
ventral rami of these nerve roots (the superior and infe-
rior gluteal nerves), and the lumbosacral region is
innervated by the dorsal rami.

Spinal causes for buttock symptoms include facet
joint injury and lateral fissure in the lumbar disk. In
older patients, lateral recess stenosis and degenerative
spondylolisthesis may cause buttock pain.

Muscular or myofascial syndromes can arise in
gluteus maximus and medius, quadratus lumborum, and
the soleus muscle, all producing strong referral patterns
of pain in the region of the sacroiliac joint. This diag-
nosis may be supported by injecting local anesthetic
into a trigger point at which myofascial palpation
reproduces the primary symptom pattern.

HIP PAIN Advanced degenerative changes
Limited internal rotation of the hip, antalgic gait, and in acetabulum
groin pain have been identified as the best predictors of
identifying hip disorders. Pain in the groin or hip with Radiograph of hip shows
single-leg stance, Patrick’s test (also known as the typical degeneration of
FABER test [hip flexion, abduction, and external rota- cartilage and secondary
tion]), along with the presence of a leg-length discrep- bone changes with spurs
ancy, are useful for detecting an underlying hip disorder, at margins of acetabulum
sacroiliac dysfunction, or greater trochanteric bursitis.
Hip internal rotation also can cause increased LBP in Erosion of cartilage and
patients with piriformis syndrome by placing this deformity of femoral head
muscle on stretch. The pain is often ameliorated by
external rotation of the hip in this condition, along with Bursitis is a common cause of hip pain related to Osteitis condensans ilii is a benign cause of LBP
abductor weakness. The groin should be examined for inflammation of one of the three main bursae of the usually found in postpartum women and is thought to
femoral or inguinal hernias. Osteitis pubis, athletic hip. It may be caused by overuse or degenerative develop as a result of mechanical strain placed on the
pubalgia, and adductor tendonitis can produce groin changes in the bursae. Patients with trochanteric bur- sacroiliac joint during pregnancy. The physical exami-
pain that mimics pain associated with disorders of the sitis present with pain over the greater trochanter that nation is unrevealing, except for localized pain in the
hip. Persistent hip pain can originate from intra- is exacerbated by hip adduction. Ischiogluteal bursitis low back.
articular disorders, such as avascular necrosis, osteoar- is often associated with sitting for long periods.
thritis, loose bodies, labral tears, or pyarthrosis. It can
also be secondary to lumbar spine disorder. Nerve
entrapment syndromes involving the ilioinguinal, geni-
tofemoral, and lateral femoral cutaneous nerve of the
thigh may manifest as hip pain or paresthesias.

Osteoarthritis is a common condition affecting the
hip in adults. Motion in the hip becomes progressively
restricted because of synovitis, soft tissue contractures,
and loss of joint congruency. Patients complain of pain
in the groin, buttock, anterior thigh, or knee and often
have an antalgic gait. Examination of the hip shows
limited range of motion and a flexion contracture.

The so-called piriformis syndrome has been attrib-
uted to compression of the sciatic nerve as it exits the
pelvis under the piriformis muscle. Patients are said to
complain of a dull ache in the low back and midbuttock
region, pain with walking up stairs, prolonged sitting, or
walking. There are no sensitive or specific imaging cor-
relates of this putative site of entrapment. As such, this
syndrome remains a controversial clinical diagnosis.

Hamstring syndrome is a pain radiating from the
ischial tuberosity down the posterior aspect of the thigh
into the popliteal fossa. Physical examination reveals
tenderness over the ischial tuberosity and pain with
resisted leg extension.

220 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 8-20â•… Pain

Painful Polyneuropathies PERIPHERAL NERVES OF FEET, MOST COMMON SITE OF PAINFUL PERIPHERAL NEUROPATHIES

The most common causes of painful peripheral neu- Medial dorsal Flexor retinaculum (cut) Lateral calcaneal
ropathy (PPN) include diabetes, human immunodefi- cutaneous nerve, branch of sural nerve
ciency virus (HIV) infection, toxin exposure, alcohol branch of Tibial nerve
abuse, and certain medications; however, in at least one superficial fibular Lateral plantar nerve
third of patients, the precise etiology is enigmatic. (peroneal) nerve Lateral branch of Medial
Painful neuropathies are typically characterized by pro- deep fibular calcaneal Nerve to abductor
gressive pain and paresthesia predominantly affecting Intermediate dorsal (peroneal) nerve to branch digiti minimi muscle
distal nerve fibers, usually beginning symmetrically in cutaneous nerve Extensor hallucis
the feet. The prevalence of PPN in persons older than Medial plantar Quadratus plantae
40 years is nearly 15%, with the incidence being sig- Inferior extensor brevis and muscle and nerve
nificantly higher in diabetics, where the onset of this retinaculum Extensor digitorum nerve
neuropathy sometimes leads to the first diagnosis of (partially cut) brevis muscles Flexor digitorum Abductor digiti
diabetes mellitus. Medial branch of brevis muscle minimi muscle
Lateral dorsal and nerve
Peripheral nerve degeneration is the underlying cutaneous nerve deep fibular Deep branch to
pathophysiologic mechanism. Axons require their neu- (branch of sural (peroneal) nerve Abductor hallucis interosseous
ronal cell bodies to remain healthy to maintain appro- nerve) muscle and nerve muscles,
priate nerve activity and function; however, when 2nd, 3rd, and 4th
neuronal damage occurs, the part of the axon most Dorsal digital Flexor hallucis lumbrical muscles
distal from the lesion is the first to degenerate. This is nerves brevis muscle and
known as “dying back.” (It is comparable to a tree dying and nerve Adductor hallucis
where its top, most distal part, loses its leaves first Superficial peroneal muscle
because this area is most remote from its roots.) The nerve (SPN) 1st lumbrical
cell body remains intact and begins a process to redirect muscle and Superficial
growth of the remaining axon to reestablish connection nerve branch to
or form new ones. In addition, sometimes loss of blood 4th interosseous
supply from disorders, such as polyarteritis nodosa, Common muscle and
affecting the vasa nervorum, results in peripheral nerve plantar Flexor digiti
ischemia, leading to similar injury. digital minimi brevis
nerves muscle
PATHOPHYSIOLOGY OF DIABETIC Common and
PERIPHERAL NEUROPATHY (DPN) Proper plantar Proper plantar
The pathogenesis of DPN is attributed to increased digital nerves digital nerves
oxidative stress, accumulation of sorbitol, and decreased
nitric oxide, leading to microvascular damage. Oxidative Medial dorsal Medial cutaneous nerves
stress results from hyperactivity of the polyol pathway, cutaneous (from SPN) of leg (branches of
causing the intracellular accumulation of polyol. Nerve saphenous nerve)
cells are permeable to glucose independent of insulin. Intermediate
Aldose reductase converts the glucose into sorbitol and dorsal cutaneous
polyol within the cell. Because polyol cannot diffuse out (from SPN)
of the cell, it accumulates within the neuron, making
the cell osmotically active, leading to excess salt and Deep fibular
water influx. In turn, sorbitol is converted to fructose, (peroneal) nerve
and its increased levels lead to advanced glycosylation
end-product (AGE) precursors. AGEs, in turn, accumu- Sural nerve
late on neurovascular proteins and damage tissues. via lateral dorsal
These two pathways lead to a reduction in the cell’s cutaneous branch
Na+/K+ adenosine triphosphatase (ATPase) activity,
further impairing endothelial function. In addition, Superficial fibular Medial calcaneal
nitric oxide is also a key modulator of Na+/K+ ATPase, (peroneal) nerve branches
and endothelial superoxide radicals from the excess (S1, 2)
glucose reduce nitric oxide’s stimulation of the ion pump Sural nerve
via decreased nitric oxide synthase activity. From From Medial
sciatic tibial nerve plantar nerve
Other cellular changes include protein kinase C activa- nerve (L4, 5)
tion, and alterations in fatty acid metabolism, which also
contribute to vascular damage. Lateral dorsal cutaneous Lateral
(from sural) plantar nerve
Decreased perfusion of the peripheral nerve per se is (S1, 2)
another possible cause for the development of PPN. Lateral calcaneal
Hyalinization and hyperplasia of the vasa nervorum (from sural) Saphenous nerve (L3, 4)
impairs nerve fiber function. This is particularly true
with unmyelinated fibers that innervate arterioles needed Sural nerve (S1, 2) via
to shunt arterial and venous supply within the nerve. lateral calcaneal and
This leads to damage by hypoxia and ischemic insult. These lateral dorsal cutaneous
metabolic changes, oxidative stressors, and hypoperfu- branches
sion are responsible for the endothelial and nerve
damage observed in DPN. toward more active degeneration of unmyelinated fibers in particularly prominent in the evening and while trying
patients with peripheral diabetic neuropathy when making to get to sleep, sometimes frequently awakening patients
Although the degree of hyperglycemia affects the comparative morphometric parameter evaluations from their sleep. The pain can be severe, compromising
overall severity of a polyneuropathy, this may not be between diabetic patients with and without peripheral the patient’s ability to walk. that is, an antalgic gait.
specifically causative in its development. There is a trend neuropathy. However, there is no significant difference These individuals walk gingerly, trying to avoid
in the degree of myelinated nerve fiber loss. Skin biopsy pressure-induced painful feet. A thorough history to
studies evaluating intraepidermal nerve fiber (IENF) define other potential etiologies is essential to the diag-
density demonstrate more severe loss of IENF in patients nostic process. Neurologic examination demonstrates
with neuropathic pain, suggesting that IENF damage reduced or absent muscle stretch reflexes with dimin-
may partially explain pain in this condition. IENF ished or absent sensation, particularly for modalities
density measurement from skin biopsy can be used to subserved by the small unmyelinated nerve fibers trans-
evaluate small fiber involvement and is useful for detec- mitting temperature and pain modalities as well as
tion of early changes in patients with diabetes. touch pressure and vibration. This occurs maximally in
a distal superficial sensory distribution, leading to a
CLINICAL MANIFESTATIONS stocking-glove distribution. A distal symmetric polyneu-
The characteristic historical features of chronic painful ropathy, the commonest form of diabetic PN, is char-
neuropathy include burning, shooting, or stabbing sen- acterized by numbness and paresthesias beginning in
sations (with or without “pins and needles”) that are the toes and spreading upward to the legs. In the most
severe instances, involvement of the fingers and hands

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 221

Plate 8-21â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II
PERIPHERAL NEUROPATHIES: CLINICAL MANIFESTATIONS
Painful Polyneuropathies

(Continued)

develops in a “glovelike” pattern. Typically, DPN has a Patient sleeps with
predilection for the most distal nerves fibers. Ataxia, covers off feet because
motor, and autonomic deficits may also be present in
later stages of the disease. of burning sensation

Acute painful neuropathy, which may follow initia- Degeneration of lumbar intervertebral
tion of insulin treatment in poorly controlled diabetes, disks and hypertrophic changes at
features severe pain symptoms, accompanied by hyper- vertebral margins, with spur formation.
esthesias; however, no alterations to the motor or Osteophytic encroachment on
sensory modalities are present. Painful neuropathy intervertebral foramina compresses
related to human immunodeficiency virus (HIV) infec- spinal nerves.
tion will usually present with pain mostly on the soles
and dorsum of the feet, decreased primary sensory Inspection of feet
modalities in the feet, decreased ankle reflexes, and
minimal intrinsic foot weakness. Typical locations
of ulcers
TREATMENT
The therapy for neuropathic pain is largely dependent Charcot joint
on the primary condition. Novel therapeutic strategies
aim to address the underlying neurophysiologic altera- Ulcer
tions because many recent studies have demonstrated
that differences in drug efficacy depend on the cause of Injury and ulceration Atrophy of
the neuropathy. Diabetic painful neuropathy requires a are result of diabetic interosseous mm.
polymodal therapeutic approach. neuropathy
Corn
Several open-labeled uncontrolled studies have sug- Callus Clawfoot deformity
gested that achieving stable normoglycemic state is
helpful in the management of the symptoms, and antagonism of N-methyl-d-aspartate (NMDA) recep- occurs, eventually leading to a severely damaged joint
according to general recommendations, intensive dia- tors (responsible for hyperalgesia and allodynia). An referred to as a Charcot joint (see Plate 8-21).
betes therapy to control blood sugars and hemoglobin alternative treatment commonly used in Europe is
A1C are important initial steps in the treatment of any alpha-lipoic acid, which is thought to stabilize nitric Treatment of HIV-related painful neuropathy poses
form of diabetic neuropathy. oxide metabolites to increase neuronal perfusion. more problems for the clinicians. So far, there are no
positive studies in patients with HIV-related neuropÂ

Plate 8-22â•… Pain

Neurologic Evaluation of CUTANEOUS DISTRIBUTION OF PERIPHERAL NERVES (AFTER DEJONE)
the Somatoform Patient
Ophthalmic branch of trigeminal (V) n. Ophthalmic branch of trigeminal (V) n.
Chronic pain patients often present with symptoms Maxillary branch of trigeminal (V) n.
mimicking a number of neurologic illnesses; one of the Mandibular branch of trigeminal (V) n. Greater occipital (C2)
most challenging clinical scenarios is to distinguish Great auricular (C2, 3)
genuine organic neurologic disorders from primary Cutaneous cervical (C2, 3) Lesser occipital (C2, 3)
somatoform disorders, particularly conversion disor- Supraclavicular (C3, 4)
ders that were previously referred to as hysterical. These Axillary (C5, 6) Great auricular (C2, 3)
patients require the clinician to dedicate the utmost Dorsal antebrachial
diligence to their evaluation. Many fine neurologists cutaneous (C5-T1) Posterior div. of cervical nn.
can recount a number of patients who were previously Medial brachial
assigned a diagnosis of hysteria elsewhere before a cutaneous (C8, T1) Supraclavicular (C3, 4)
careful history and examination, sometimes with a Intercostobrachial (T2)
period of ongoing observation within a different prac- Lateral antebrachial Axillary (C5, 6)
tice venue, led to an organic diagnosis. cutaneous (C5-7)
Medial antebrachial Thoracic Thoracic Dorsal antebrachial
Somatoform diagnoses encompass disorders of soma- cutaneous (C8, T1) nerves nerves cutaneous (C5-T1)
tization, conversion, pain, body dysmorphic disorder, Radial (C5-T1) Lat. Ant. Post. Lat.
and hypochondriasis, according to Diagnostic and Statis- div. div. div. div. Medial brachial
tical Manual of Mental Disorders-IV (DSM-IV) criteria cutaneous (C8, T1)
(American Psychiatric Association). Each is character- Intercostobrachial (T2)
ized by symptoms affecting voluntary motor or sensory
function, having a resemblance to neurologic or medical Lateral
diseases, concomitant involvement of psychologic antebrachial
factors, and unintentional, unfeigned symptoms. In cutaneous (C5-7)
contrast to most acute pain syndromes, chronic pain
states often lack a clear pathoanatomic or pathophysi- Medial
ologic correlate. Our limited understanding of pain antebrachial
mechanisms tends to invite the clinician to suggest psy- cutaneous (C8, T1)
chogenic origins or motives when an immediate organic
cause is not confirmed. A dualistic model of chronic pain, Radial (C5-T1)
perceived as either wholly organic or psychogenic, is
not supported by prevailing basic or clinical under- Ulnar (C8, T1) Median (C5-T1)
standing of pain pathophysiology. Thus diagnostic con-
structs including conversion disorder are less commonly Median (C5-T1) Ulnar (C8, T1)
applied now.
IIiohypogastric (L1) Iliohypogastric (L1)
The biopsychosocial model of pain is the most widely Genitofemoral (L1, 2) Lateral femoral
utilized heuristic means to characterize the experience Ilioinguinal (L1) cutaneous (L2, 3)
of chronic pain. Viewed as a complex interplay of Lateral femoral Posterior femoral
biologic, psychologic, and social factors, this model cutaneous (L2, 3) cutaneous (S1-3)
embraces concepts of both disease and illness. Disease is Femoral (L2-4) Obturator (L2-4)
defined as an objective biologic event involving the Obturator (L2-4) Femoral (L2-4)
disruption of specific bodily organ systems, whereas Common peroneal (L4-S2) Common peroneal (L4-S2)
illness refers to the subjective experience or self-attribution Saphenous (L3, 4) Saphenous (L3, 4)
that a disease is present. Accordingly, the biopsychoso- Superficial peroneal (L4-S1) Superficial peroneal (L4-S1)
cial model distinguishes between nociception and pain. Sural (S1, 2) Sural (S1, 2)
Nociception is defined as the stimulation of nerves that Deep peroneal (L4, 5) Calcaneal (S1, 2)
relay information about potential tissue damage to the Lateral plantar (S1, 2) Medial plantar (L4, 5)
brain. Conversely, pain is the subjective perception result- Lateral plantar (S1, 2)
ing from transduction, transmission, and modulation of
sensory information. This model incorporates concepts Anterior aspect Posterior aspect
of suffering, including fear and apprehension about the
future, triggered by nociception and pain behaviors that Loss of sensory modalities is based on the anatomic location of the inciting lesion. The pattern of loss
provide a means to communicate pain and distress. may follow either a spinal dermatome pattern or one based on peripheral nerve damage. Because exact
peripheral nerve distribution varies among individuals, patterns may differ.
PSYCHOLOGIC FORMULATIONS OF PAIN Note that isolated islands of anesthesia (e.g., axillary and deep peroneal) can exist on an anatomic basis.
BEHAVIOR AND “CONVERSION” DISORDERS
Pain behaviors serve not only to gain attention, or avoid distress or anxiety. In contrast, psychoanalytic explana- The neuromatrix model of pain proposes that pain
undesirable consequences, but may also be considered tions of conversion emphasize unconscious drives, experience results from the integration of outputs from
as pain-reducing strategies or as protective strategies to including sexuality, aggression, or dependency, and the perceptual, behavioral, and homeostatic systems in
diminish exacerbation of pain. So-called “abnormal internalized prohibition against their expression. Other response to injury and chronic stress. It is considered
illness behavior” describes patients who present with psychoanalytic explanations focus on the need to suffer the output of the diffuse brain neural networks rather
symptom complaints in the absence of physical pathol- or identification with a lost object. than a direct response to sensory information. Neuro-
ogy or who present with exaggerated illness behavior. imaging studies are beginning to delineate the neural
It is considered a social mechanism that exempts a Other theories emphasize the role of fear-avoidance processes implicated in the somatoform disorders. The
patient from certain responsibilities, concurrently beliefs and catastrophizing (tendency to engage in nega- cortical correlates of the touch and pain pathways
establishing an obligation to seek treatment and coop- tive thinking and worry about pain) as the catalysts of include the primary and secondary somatosensory
erate in the healing process. In other words, pain behav- persistent pain and disability. Catastrophizing is a strong cortex (S1, S2), insula, and anterior cingulate cortex
ior may offer a more socially legitimate way to express risk factor for increased pain, increased illness behavior, (ACC). However, additional cortical regions associated
and the development of both physical and psychologic with attention, such as posterior parietal cortex (PPC),
disability. Fear-avoidance beliefs stem from a conviction prefrontal cortex, and the temporoparietal junction, can
that pain is synonymous with harm and that any pain- also impact on or be influenced by somatosensory
provoking activity should thus be avoided; such beliefs processing.
are likely to be predictive of pain chronicity and
disability.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 223

Plate 8-23â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Neurologic Evaluation of SOMATOFORM CONVERSION REACTIONS
the Somatoform Patient
Hysterical hemianesthesia
(Continued)
Clinical picture Tests for somatoform anesthesia
Furthermore, attentional state can modulate sensory-
evoked responses. There are also somatosensory inputs No hemianopia or
to circuits involved in the processing of emotional or cranial nerve defects
other aspects of psychosocial behavior that may then
feed back to somatosensory or motor circuits. Func- Variable complaints
tional magnetic resonance imaging (fMRI) during of weakness in
stimulation of the symptomatic limb reveals prominent extremities
abnormalities in somatosensory areas—namely, lack
of activations, novel activations, and stimulus-related Normal muscle
deactivations in the S1, S2, and PPC cortices. One stretch reflexes
notable activation study performed during unperceived Hemianesthesia
noxious stimulation demonstrated activity in the rostral involving all
and pregenual ACC, suggesting these areas are involved modalities
more generally in cognitive processes and emotion.
Hemianesthesia Finger-to-nose test: if Vibration test: unilateral
DIAGNOSIS extending to successfully performed, loss of vibration sensation
Pain behavior in the context of chronic pain has a wide midline demonstrates intact indicates hysteria because
differential diagnosis, requiring clinicians to incorpo- Hemianesthesia proprioception and thus sensation is bilateral if bony
rate historical and examination findings into an unbi- involving genitalia somatoform hemianesthesia skeleton is intact
ased patient-centered global assessment. However, of extremity • involves all modalities
sensory findings, including midline pain/touch sensa- Normal muscle • extends to midline
tion splitting, vibration sense splitting, and inconsisten- stretch reflexes • involves genitalia
cies in symptom reporting and examination responses
on clinical examination, offer useful contexts for the Features of
clinician to carefully assess the role of psychosocial No Babinski response somatoform hemianesthesia:
factors that may be contributing to reported pain inten-
sity. Sometimes somatoform patients report an unequiv- Stocking-glove anesthesia
ocal sensory loss exactly to the midline for all sensory Demarcation
modalities. Testing of vibration perception is some-
times a good means to differentiate the organic from A. Organic (e.g., polyneuritis): sensory loss more B. Somatoform: sensory loss uniform; sharp
the somatoform patient. If the clinician places the profound distally; gradual transition to area of demarcation from area of normal sensation, usually
tuning fork on a midline position, such as the skull or normal sensation at external anatomic landmark (e.g., joint, skin fold)
sternum, and then tilts the double end of the instrument Dissociation rather than along a nerve distribution
to the “affected side,” the somatoform patient will
report lack of any vibratory appreciation. In contrast, Touch Temperature
with the base unchanged and the fork then tilted to Temperature Touch
normal, this patient will appropriately report normal Pain Pain
perception. However, the clinician evaluating such All modalities
symptoms must recognize that certain painful symptom
patterns related to a thalamic stroke or postherpetic A. Organic: different level of loss for each sensory B. Somatoform: single level of loss for all sensory
neuralgia may precisely respect the midline. modality modalities

The concept of la belle indifference, as it was initially outcome in patients treated with such medication for because they address the social aspect of pain behaviors.
described, also applied to patients who were unaware of this indication. However, there are no systematic reviews assessing effi-
sensory loss found on examination. The term has also cacy of these methods.
been used to describe a certain indifference of patients Psychologic and social factors that play a pivotal role
to the symptoms they are presenting with; however, this in the development of abnormal pain behaviors need to Conversion symptoms, especially when acute, may
finding performs poorly as a discriminator of organic be addressed through various interventions. Comorbid undergo spontaneous resolution after explanation and
disease. conditions, such as depression, anxiety, and sleeping suggestion. Some patients may benefit from education
disorders, not only reinforce the undesirable effects of about the patterns of sensorimotor disturbance associ-
TREATMENT pain, but these psychologic factors may interfere with ated with alteration in neurotransmission, as in the case
The biopsychosocial model of pain stresses the multi- successful rehabilitation. There is growing evidence of major depression, thereby providing a cognitive
tude of factors that influence a person’s perception of that cognitive-behavioral therapy (CBT) improves long- framework for treatment. Hypnosis is also a potential
pain and response to it. In accord with this conception, term rehabilitation success for patients with chronic intervention in the management of this disorder; its
it is theorized that a multidimensional approach to pain symptoms. The primary aim of such interventions goals are to enhance symptom reduction and explora-
chronic pain syndromes and abnormal pain behaviors is to improve daily functioning, self-efficacy, and quality tion. This can sometimes also be used to evoke memo-
is most effective at reducing symptoms and associated of life. In case of abnormal pain behaviors, CBT also ries of a traumatic event having a positive link with the
loss of function. Medical and surgical treatments may helps to diminish fear-avoidance beliefs, catastrophiz- symptoms. Although there are many anecdotal accounts
address the biologic underpinnings of pain experience, ing, and other behavioral responses to pain, thus of the efficacy of hypnosis in conversion disorder, a
although their utility in the treatment of abnormal pain modifying the pain experience. Family therapy or psy- recent randomized controlled trial found that hypnosis
behaviors is controversial. As yet, there is no firm evi- chodynamic psychotherapy may prove effective as well, had no additional effect on treatment outcome.
dence that antidepressants or any other pharmaceutical
agent can be regarded as the best approach for treating
somatoform disorders. There is also no information on
the optimum dose, duration of treatment, or long-term

224 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 9â•…

FLOPPY INFANT

P late 9-1â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Neonatal Hypotonia Infant exhibits weakness and
flaccidity of all musculature
Neonatal hypotonia, often referred to as the “floppy Infant hangs like rag doll
infant,” is the main presenting clinical feature of most when lifted under abdomen
neuromuscular diseases of early life. However, disor-
ders of the central nervous system may also manifest
with hypotonia.

Two types of muscle tone can be assessed clinically:
postural and phasic. Postural (antigravity) tone is a sus-
tained, low-intensity muscle contraction in response to
gravity. It is mediated by both gamma and alpha motor
neuron systems in the spinal cord, and it is assessed
clinically by passive manipulation of the limbs. Phasic
tone is a brief contraction in response to a high-intensity
stretch. It is mediated by the alpha motor neuron
system only, and is examined clinically by eliciting the
muscle stretch reflexes. Hypotonia is defined as reduc-
tion in postural tone, with or without a change in phasic
tone. When postural tone is depressed, the trunk and
limbs cannot overcome gravity, and the child appears
hypotonic or floppy.

PHYSICAL EXAMINATION AND ASSESSMENT Infant is unable to Central core Centronuclear
OF A HYPOTONIC CHILD sit up or hold up head. Muscle biopsy specimens in different cases
Head drops back when
After a careful general physical examination, the neu- infant is lifted by its
rologic assessment needs to include an evaluation of hands
primary neonatal reflexes, a sensory examination, and,
most importantly, a motor examination. Muscle tone is Nemaline rod
assessed by passive manipulation of the infant’s limbs.

Muscle tone can be evaluated further by performing
the traction response, vertical suspension, and horizon-
tal suspension maneuvers. A floppy infant exhibits
“head lag,” “slips through” the examiner’s hands on
vertical suspension, and “drapes over” the examiner’s
hand on horizontal suspension.

DIFFERENTIAL ANATOMIC DIAGNOSIS Electron micrograph showing Muscle fibers with well-defined Large number of small fibers with
Neonatal hypotonia may be the manifestation of nemaline body continuous “cores.” Muscle is largely abnormally located central nuclei
pathology involving the central nervous system (CNS), with Z band (ϫ30,000) replaced by adipose tissue (trichrome stain)
the peripheral nervous system (i.e., lower motor unit), (PAS stain).
or both. In infants with cerebral or central hypotonia
(nearly two thirds of these cases), the perinatal or pre- osteogenesis imperfecta, and also benign ligamental such as sepsis, congenital heart disease, hypothyroid-
natal history may suggest a CNS insult. There may also laxity, can present with hypotonia. In addition, a com- ism, rickets, renal tubular acidosis, and others.
be associated global (rather than an isolated gross- bined cerebral and lower motor unit hypotonia occurs in
motor) developmental delay, occasionally seizures, infants and older children as a presenting manifesta- Neuromuscular diseases in infancy manifest primar-
microcephaly, dysmorphic features, and/or malforma- tion of congenital myotonic dystrophy, some con- ily with hypotonia and weakness; however, infants with
tion of the brain and/or other organs. Central hypoto- genital muscular dystrophies, peroxisomal disorders, severe hypotonia but only marginal weakness usually do
nia may be associated with brisk and/or persistent mitochondrial encephalomyopathies, neuroaxonal dys- not have a disorder of the lower motor unit (anterior
primitive reflexes and normal-brisk muscle stretch trophy, leukodystrophies (e.g., globoid cell leukodys- horn cell, peripheral and cranial nerves, neuromuscular
reflexes. The degree of weakness noted in these infants trophy), familial dysautonomia, and asphyxia secondary junction, and muscle). These infants may have genetic
is usually less than the degree of hypotonia (“nonpara- to motor unit disease. Further, hypotonia without sig- conditions, metabolic disturbances, or as discussed
lytic” hypotonia). nificant weakness may be a feature of systemic diseases, above, systemic disorders (e.g., congenital heart disease,
renal failure, etc.).
In lower motor unit hypotonia or peripheral hypotonia,
developmental delay is primarily gross-motor and is
associated with absent or depressed muscle stretch
reflexes and/or muscle atrophy and fasciculations of the
tongue. In general, antigravity limb movements are
decreased and cannot be elicited via postural reflexes.
In these infants, the degree of weakness is proportional
or in excess of the degree of hypotonia (“paralytic” hypo-
tonia). Trauma to the high cervical cord due to traction
in breech or cervical presentation may also initially
manifest itself as flaccid paralysis, which may be asym-
metric, and initially muscle stretch reflexes are absent;
later on, however, upper motor neuron signs develop.

Because muscle tone is also determined by the visco-
elastic properties of muscle and joints, connective tissue
disorders, such as Marfan and Ehlers-Danlos syndromes,

226 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 9-2â•… Floppy Infant

Spinal Muscular Atrophy Infant with typical
Type I (Werdnig- bell-shaped thorax,
Hoffmann Disease) frog-leg posture,
and “jug-handle”
Spinal muscular atrophy (SMA) is an autosomal reces- position of upper
sive hereditary illness. Rarely, variant forms exist, limbs
including X-linked and dominant forms. It is one of the
two most common causes for a floppy infant secondary Muscle biopsy specimen showing
to lesions of the peripheral motor unit. The most groups of small atrophic muscle
common form of SMA is the proximal recessive type, fibers and areas of normal or
which includes a broad range of subtypes, ranging from enlarged fibers (group atrophy)
the severe infantile variant (depicted here) to ambula- (trichrome stain)
tory forms with adult onset.
Baseline tremor in
In the healthy newborn infant, purposeless extremity otherwise normal
movements have a well-defined muscular tone, despite electrocardiogram
the lack of coordinated motor function. Concomitantly, Electromyography (motor units during active contraction)
full-term newborns have well-developed suck and
swallow function. At birth, many SMA type I infants Boy with much Normal
appear normal; however, within a few weeks to months, milder, late-onset
generalized hypotonia and neuromuscular weakness form of disease
develop. A classic hypotonic posture characterized by (Kugelberg-Welander
abducted hips, internal rotation of the forearms, and disease). Marked
frog-legged and jug-handle habitus is typical. Their lordosis and eversion
respiratory pattern is characterized by paradoxic chest of feet.
and abdomen movement resulting from selective inter-
costal muscle weakness with preserved diaphragm Werdnig-Hoffman disease
function. Without supportive treatment, such infants
subsequently develop characteristic bell-shaped defor- Electromyography is a very sensitive primary diag- and/or neurophysiologic testing are not definitive. Dif-
mities of the thorax. Progressive bulbar and respiratory nostic tool; however, it has been largely supplanted by ferential diagnosis includes the very rare recessive
insufficiency results in a vulnerability to both aspiration DNA analysis. However, when DNA testing is normal inherited peripheral neuropathy variants, such as con-
and infectious pneumonias. and significant weakness is manifest, the EMG findings genital hypomyelinating neuropathy that may clinically
are distinct in type I SMA, demonstrating diffuse fibril- mimic WHD, even to the point of tongue fascicula-
Extraocular and facial movements are preserved; lations in virtually all muscles in association with mark- tions. More distally within the motor unit, neuromus-
these infants typically have a bright, attentive counte- edly reduced recruitment of small motor units in the cular junction disorders, including transient neonatal
nance. Careful evaluation of the tongue reveals tongue absence of the typical large complex motor units char- myasthenia gravis and infantile botulism, as well as the
fasciculations. In contrast to adult motor neuron disor- acteristic of reinnervation in milder, more chronic various congenital myopathies and dystrophies, may
ders, fasciculations in limbs are difficult to appreciate forms of the disorder. Muscle biopsy demonstrates find- present as a floppy baby.
due to excessive subcutaneous infantile fat. Abnormal ings typical of neurogenic atrophy, although the reduced
motor milestones with poor head control, inability to reinnervation capacity in SMA type I often results in a Treatment for Werdnig-Hoffmann disease remains
roll and to achieve independent sitting, as expected predominance of small rounded fibers within entirely largely supportive. The prognosis is generally poor,
during the first few months, leads to investigation and denervated fascicles. with onset is in the neonatal period. Many of these
eventual diagnosis of SMA type I. In a most severe infants do not survive until their first birthday. However,
subset, reduced fetal movements occurs prenatally; Other lesions in the motor unit can mimic Werdnig- even in the absence of extensive supportive care,
these infants are born with generalized hypotonia, Hoffmann disease (WHD), but, as a rule, can be dif- historically, up to 30% of infants with SMA type I
weakness, respiratory insufficiency, bulbar dysfunction, ferentiated by clinical and electromyographic findings survive beyond 2 years of age, some into adolescence
and proximal joint contractures. and examination of muscle biopsy specimens if genetic or beyond.

Spinal muscular atrophy with respiratory distress
(SMARD) is distinguished by early respiratory failure
due to diaphragm involvement, especially in association
with more distal presentation of limb weakness.
X-linked SMA manifests as a severe infantile SMA
variant predominantly affecting males.

SMA II infants initially can sit but never become able
to walk and are diagnosed at ages 6 to 24 months.
Kugelberg-Welander disease, SMA III, typically occurs
between ages 2 and 14 years with symptoms of proximal
weakness. These children may have mild elevations of
creatinine kinase (CK, <1000╯IU/L).

More than 95% of SMA I infants have a homozygous
deletion/mutation of exon 7 of the survival motor
neuron 1 gene (SMN1 gene) on chromosome 5q11-13.
Infants who do not have this deletion identified may
have a non–chromosome 5 SMA or a mutation(s) in the
survival motor neuron gene not detectable with the
currently used polymerase chain reaction (PCR)-based
methods. Both SMA II and SMA III have exactly the
same genetic defects as those with type I. When a child
with proximal muscle weakness, shown by electromy-
ography (EMG), demonstrates neurogenic changes,
deoxyribonucleic acid (DNA) testing for SMN1 gene is
the diagnostic tool of choice.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 227

P late 9-3â•… Spinal Cord and Peripheral Motor and Sensory Systems: PART II

Infantile Neuromuscular
Junction (NMJ) Disorders

Infants rarely develop acute NMJ disorders, including Botulinim spores
transient neonatal myasthenia gravis, infantile botu-
lism, and congenital myasthenic syndromes (CMS). Ptosis
Magnesium sulfate treatment for eclampsia is a theo-
retical possibility but not one that is presented to the Floppy infant
child neurologist.
5 Hz
TRANSIENT NEONATAL MYASTHENIA
GRAVIS (TNMG) 50 Hz
Mothers with autoimmune MG have a 15% incidence
of having babies with TNMG despite the finding that Repetitive stimulation at 5 Hz of a hypotonic baby's ulnar nerve; recording at the hypothenar eminence
all infants born to seropositive mothers have circulating demonstrates no facilitation or decrement in the response, whereas 50-Hz stimuli promotes an almost
acetylcholine receptor (AChR) antibodies. These nor- 100% facilitation in the eventual size of the recorded response. Facilitation on 50-Hz stimulation is the
mally cross the placenta, entering the fetal circulation characteristic and diagnostic finding of a presynaptic defect in neuromuscular transmission as occurs with
to bind at fetal NMJs. Once an affected mother has one infantile botulism.
TNMG infant, her subsequent babies are likely to be
affected. life-threatening respiratory crisis. Aspiration often CONGENITAL MYASTHENIA
leads to hospitalization of an alert, afebrile, nonirritable SYNDROMES (CMS)
TNMG infants sometimes have weak fetal move- infant with poorly reactive pupillary light reflexes, oph-
ments, display fetal distress during delivery, or severe thalmoparesis, symmetric facial bulbar weakness, and CMSs are a group of widely differing, rare familial
hypotonia shortly after birth. Other manifestations generalized hypotonia. The mother often notes in ret- NMTDs, each characterized by compromised NMT
include facial diplegia, poor suck/feeding, a weak cry, rospect that her baby is constipated—has not “stooled” safety margins leading to fatigable weakness.
intermittent cyanosis (especially during feeding), and with normal frequency. The face is typically expression-
respiratory weakness and/or failure. Muscle stretch less, drooling, and there may be a high-pitched, mewing These genetically determined “myasthenic” disorders
reflexes, sphincter function, and sensation are pre- cry. Infantile botulism needs consideration in the dif- usually manifest during the first years of life. Clinically,
served. Ptosis and external ophthalmoplegia are para- ferential diagnosis of unexplained respiratory distress in ptosis and extraocular weakness are often more subtle
doxically less frequent than in juvenile MG. Typically, any baby up to 6 months old. than in juvenile myasthenia gravis (JMG). In addition,
symptoms are transient, lasting 3 to 12 weeks. bulbar, neck, and extremity weakness occur sometimes
Electromyography is the diagnostic study of choice; with a restricted distribution.
Transient improvement after injection of 0.1╯mg/kg rapid repetitive motor nerve stimulation (20 or 50╯Hz)
of edrophonium supports this diagnosis; however, this of infants with IB demonstrates significant incremental Respiratory distress leading to sudden death occurs
is often difficult to assess with a ventilated neonate; not responses (23%-313%). This is in keeping with a pre- rarely in one CMS, namely end-plate choline acetyl-
all affected infants respond, and a response does not synaptic defect in neuromuscular transmission, with the transferase deficiency. These infants develop unex-
distinguish TNMG from some forms of CMS. The area that the toxin specifically affects essentially block- pected episodic attacks of apnea associated with bulbar
presence of AChR antibodies provides the definitive ing the release of acetylcholine. The botulinum toxin paralysis occurring precipitously during excitement,
diagnostic study when the clinical setting fits. Once and the Clostridium organism are recoverable from stool. exertion, febrile events, or without a known precipitat-
delivered, the maternal AChR antibodies are no longer ing factor. Some babies have fluctuating ptosis, poor
pathogenic even within breast milk. Supportive treat- Treatment primarily is supportive, often with acute suck and cry, feeding difficulty, and secondary respira-
ment is the primary therapeutic modality and is intubation. Human-derived botulinum immune globu- tory infections.
necessary until symptoms clear. Acetylcholinesterase lin (BIG) is beneficial when administered within the
inhibitors such as pyridostigmine or neostigmine meth- first 3 days. Antitoxin per se is not used for infantile EMGs demonstrate a decremental response similar
ylsulfate may be helpful. Both intervenous immune botulism because of the possible risk of anaphylaxis. to JMG; this may be restricted to certain muscles and
globulin (IVIG) and exchange transfusion provide Early aggressive supportive care will ensure that these present intermittently.
other therapeutic alternatives. children all have an excellent outcome.
Cholinesterase inhibitors provide a primary treat-
INFANTILE BOTULISM (IB) ment option and may be lifesaving.
This rare disorder typically occurs in previously healthy
infants between the third and sixth months of life,
particularly in the Mid-Atlantic states, Utah, and
California, although it is occasionally seen in other
regions. Clostridium botulinum is an obligatory anaero-
bic gram-positive spore-forming rod-shaped bacterium
that is ubiquitous within the immature gut. It releases
a toxin affecting presynaptic ACh release from the
NMJ. In economically developed settings, this is the
most common form of human botulism. The normal
intestinal microflora changes when formula, sometimes
honey, and/or solid foods are introduced into the diet.
Sometimes this may enhance the ability of C. botulinum
to colonize the infant’s colon. This is not a contagious
disease.

Infantile botulism usually has a fairly stereotyped
clinical presentation. Typically, a previously healthy
infant, between ages 10 days and 6 months develops
acute hypotonia, generalized weakness, poor feeding
secondary to bulbar dysphagia, and poor suck that
impairs nursing; also, there sometimes is a potentially

228 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 9-4â•… Floppy Infant

Congenital Myopathies Hypotonic infant can sit
with support but cannot
Shy and Magee introduced the term “congenital myop- stand, and has respiratory
athy” to describe central core disease and myopathy problems and difficulty
present at birth, excluding muscular dystrophy. Clinical holding up head. Some
distinction from the muscular dystrophies is blurred by toes may be foreshortened.
conditions such as nemaline and centronuclear myopÂ