The Netter Collection of Medical Illustrations VOLUME 7 PART l

Plate 5-17 Brain: PART I

HYPOTHALAMIC RESPONSES DURING INFLAMMATION MODULATE IMMUNE RESPONSE

CRH Preautonomic neurons
neurons
Limbic forebrain (infralimbic Medullary autonomic
cortex, amygdala) pattern generators
Vagal motor
Cytokine and prostaglandin stimulation ACTH, GH, Prolactin, MSH, Median neurons
of hypothalamus and pituitary ␤-End, TSH, LH, FSH eminence
with
Vascular delivery of Releasing and
neuroendocrine hormones inhibiting factors

to lymphoid organs Norepinephrine, ACTH Preganglionic
epinephrine vagal efferents
Thymus
Bone Cortisol Vagus (X) n.

marrow Adrenal medulla Adrenal cortex Preganglionic
Pulmonary Prevertebral sympathetic ganglia sympathetic

MALT axon

Spleen â•…
Lymph nodes
Gut-associated
lymphoid tissue

(GALT)
Skin

lymphoid
tissue

Fever: Hypothalamic neurons that cause sleepiness, and EP4 receptors are medulla, amygdala, and hypothalamus, which results in
Response to Systemic found on histaminergic neurons in the posterior hypo- an increase in the secretion of corticotropin-releasing
Inflammation (Continued) thalamus, which may cause arousal. However, prosta- hormone (CRH) into the pituitary portal circulation,
glandins are also made by the leptomeninges, and may elevated adrenocorticotropic hormone (ACTH) secre-
hypothalamic nuclei and the medullary raphe that have direct effects on cortical neurons. PGE2 may also tion by the pituitary gland, and increased levels of cir-
produce elevated body temperature. This allows body exacerbate meningeal and vascular pain perception culating adrenal corticosteroids. Cortisol then causes
temperature to rise by about two to three degrees cen- (causing headache, particularly during coughing or demargination of white blood cells that are adherent to
tigrade. Fever in the range of 39° C to 40° C is uncom- straining, which increase intracranial pressure). the endothelium of blood vessels, elevating the circulat-
fortable but may be an adaptive response to help fight ing white blood cell count. Lymphocytes in a variety of
off invading organisms. HYPOTHALAMIC CONTROL OF LYMPHOID tissues also respond directly to ACTH, and to a number
TISSUE IN IMMUNE RESPONSE of other circulating hormones.
Changes in cognitive capacity and sleepiness during A critical part of fighting off any infection is the activa-
a sickness response are less well understood. EP1 and tion of an appropriate immune response. During a sick- There is also direct sympathetic innervation of the
EP3 receptors are found on hypothalamic preoptic ness response, prostaglandin E2 acts on neurons in the lymphoid tissues. This input, which is also under hypo-
thalamic control, may control the production and traf-
ficking of specific lymphocyte subsets.

128 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-18 Hypothalamus, Pituitary, Sleep, and Thalamus

Brain Arcuate nucleus

Hunger signal Third ventricle
Ghrelin Second
order
Stomach neuron

POMC

NPY GABA
AgRP

Food Energy
intake expenditure

Nutrient- Energy
related balance
signals

Adiposity signals

Insulin Leptin

Liver

Adipose
mass

Pancreas Glucose
production

Plasma
glucose

â•…

Regulation of Food Intake, hypothalamus that is just above the pituitary stalk. strong circadian input to feeding, which is mediated by
Body Weight, and These hormones can enter the brain through the the pathway from the suprachiasmatic nucleus to the
Metabolism hypophysial portal vessels, which lack a blood-brain subparaventricular zone and then the dorsomedial
barrier. Here they encounter neurons that have recep- nucleus. Dorsomedial hypothalamic neurons, in turn,
A key function of the hypothalamus is the control of tors for the hormones and form a key circuit in control- send outputs to the lateral hypothalamic area and
feeding, body weight, and metabolism. Two systemic ling eating. Neurons in the arcuate nucleus that contain the paraventricular, ventromedial, and arcuate nuclei,
hormones are known to act on the hypothalamus to the peptide neurotransmitters neuropeptide Y (NPY) which may drive circadian cycles of feeding.
ensure that animals ingest sufficient food for their met- and agouti-related protein (AgRP) form a positive part
abolic needs. Ghrelin, a hormone made by the gastric of the circuit. They contact cells in the paraventricular, The mechanisms by which hypothalamic neurons
mucosa when the stomach is empty, causes increased ventromedial, and dorsomedial nuclei of the hypoÂ

Plate 5-19 Brain: PART I

AUTONOMIC, ENDOCRINE, AND BEHAVIORAL COMPONENTS OF STRESS RESPONSES

Stress behaviors mediated by
cerebral cortex and limbic
forebrain

Hypothalamic endocrine
response (blue)

Hypothalamic autonomic
response (red)

Medial
prefrontal

cortex

Amygdala

Thyrotropin Olfactory bulb
(elevates III to reduce pupillary constriction
metabolism)

VII to reduce sublingual and submaxillary salivation

IX to reduce parotid salivation
X to reduce slowing of heart and GI motility

Adrenocorticotropin (releases To heart Thoracic
To cortisol, provokes stress reaction) (elevates rate) part of
m(aedferfdeecunitlanilnlabglorioSsaepdnldes(unlvegiicuaskcrcoeorcpnayltlatreatescoltaeiuonttsn)dpressed spinal
To vessels of skin Spinal nerve Sympathetic cord
(contraction) and trunk ganglia Sacral
muscles (dilation) part of
spinal
To GI tract vasoconstriction) cord

and vessels (depression Prevertebral ganglion
of motility; vasoconstriction)

Pelvic nerve (sacral parasympathetic outflow)

To lower
bowel and
bladder (evacuation)

â•…

Stress Response the hypothalamus is particularly important in produc- the medulla and the spinal cord. These inputs reduce
ing stress responses. It contains separate populations of fluid loss through salivation (dry mouth), ready the car-
Stress was defined by the Nobel laureate Hans Selye as neurons that regulate anterior and posterior pituitary diovascular system for fight or flight (elevated heart rate
whatever increased the blood levels of corticosteroids. responses, as well as autonomic outputs. Most of the and blood pressure), and direct blood flow to muscular
He was aware that the stimuli for elevated cortisol could corticotropin-releasing hormone (CRH) neurons that vascular beds to prepare for action.
include a very wide range of behavioral and physiologic regulate secretion of adrenocorticotropic hormone
stressors. However, as shown in Plate 5-19, stress (ACTH) are found in the medial part of the paraven- However, it is probably the behavioral responses to
involves much more than just corticosteroid secretion, tricular nucleus. These neurons are activated by virtu- stress that are most familiar and distressing to most
including other endocrine as well as autonomic and ally all stressful stimuli, and they secrete CRH and thus individuals. The most prominent symptom of stress is
behavioral components. drive the systemic secretion of cortisol. The lateral part hyperarousal, in which the individual reacts excessively
of the paraventricular nucleus contains neurons that to daily stimuli. This can include a tendency to become
Behavioral stress may come from many different release vasopressin through the posterior pituitary angry or aggressive more easily. At night, individuals
sources, but the areas that most frequently show gland. This response permits fluid conservation in case who are under stress often have difficulty sleeping.
increased activity under stressful conditions include the there is hemorrhage (e.g., associated with fighting). Positron emission tomography (PET) studies on
medial prefrontal cortex (particularly the cingulate The dorsal and anterior parts of the paraventricular patients with insomnia show activation of the same
gyrus) and parts of the amygdala (particularly the nucleus contain nerve cells that innervate the sympa- brain regions (medial prefrontal cortex, amygdala,
central nucleus). These regions also have direct inputs thetic and parasympathetic preganglionic neurons in hypothalamus) that are activated in animals under
to the hypothalamus. The paraventricular nucleus of experimental stress.

130 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-20 Hypothalamus, Pituitary, Sleep, and Thalamus
Paraventricular
nucleus and lateral Emotional stress or anticipation of exercise may
hypothalamus stimulate sympathetic nerves via hypothalamus

Nucleus of Medial prefrontal cortex
solitary tract Amygdala
Nucleus ambiguus
Ventral medulla Afferent nerve fibers from baroreceptors in carotid
sympathetic pattern sinuses via glossopharyngeal nerves (IX) and in aorta
generators via vagus nerves (X) form afferent limbs of reflex arcs Carotid
Descending tract to vagus and sympathetic efferents sinuses
to spinal IX
intermediolateral
cell column X

Vagus efferent cardiac fibers go chiefly to SA node
and AV node: stimulation causes release of
acetylcholine at nerve endings, slowing heart rate
and conduction; vagal inhibition causes
acceleration of heart rate and conduction

Sympathetic efferent-fiber stimulation accelerates
heart rate, increases force of contraction, and dilates
coronary arteries by releasing norepinephrine at
nerve endings, stimulating ␤ receptors.

Sympathetic trunk

Sympathetic vasoconstriction
Increased pH heightens
catecholamine and lowers
acetylcholine actions.

pH

Output of catecholamines from Circulating catecholamines have same
adrenal medulla promoted by action on arteries as sympathetic
sympathetic stimulation efferent nerves

â•…

Hypothalamic Regulation of pressure and heart rate). It does this by direct projec- The brainstem targets of this descending system
Cardiovascular Function tions to sympathetic and parasympathetic cell bodies, coordinate cardiovascular reflexes. For example, the
as well as to medullary pattern generators. carotid sinus nerve (a branch of the glossopharyngeal
The hypothalamus is a key component of a central nerve) and the aortic depressor nerve (a branch of the
nervous system (CNS) network that governs the heart In the medulla, there are distinct pattern generators vagus nerve) bring information to the nucleus of the
and circulation. Different behaviors, ranging from in the ventromedial and ventrolateral areas. The ven- solitary tract about aortic and carotid stretch. When
emotional responses to motor activities, require activa- tromedial medulla receives inputs from hypothalamic blood pressure is high, neurons in the nucleus of the
tion of different components of the cardiovascular cell groups involved in thermoregulation, and it orga- solitary tract activate cardiovagal neurons in the nucleus
control network. Neurons in the cerebral cortex send nizes patterns of sympathetic response necessary for ambiguus to slow the heart and inhibit neurons in the
inputs to the medial prefrontal cortex, particularly the thermogenesis (increased heart rate and activation of ventrolateral medulla that maintain tonic blood pres-
infralimbic cortex, and the amygdala. These send axons brown adipose tissue, with shifting of blood flow from sure by means of activating sympathetic preganglionic
to the hypothalamic neurons that govern cardiovascular cutaneous to deep vascular bed). This also requires vasoconstrictor neurons. This baroreceptor reflex can
response, including the paraventricular nucleus and elevation of heart rate to deal with the increased cardiac be modified by descending hypothalamic input so that
lateral hypothalamic area. The descending hypotha- demand of hyperthermia. The ventrolateral medulla, by during times of stress, for example, there can be a
lamic axons innervate brainstem sites involved in pro- contrast produces patterns of cardiovascular response simultaneous increase in blood pressure and heart rate
ducing patterns of cardiovascular response, such as the necessary for maintaining blood pressure during erect without activating the baroreceptor reflex.
parabrachial nucleus and both ventromedial and ven- posture, called baroreceptor reflexes.
trolateral medullary reticular formation. Projections from the hypothalamus to the interme-
Other descending hypothalamic axons go directly to diolateral column can directly activate sympathetic gan-
The parabrachial nucleus receives visceral sensory the nucleus of the solitary tract, as well as the pregan- glion cells concerned with cardioacceleration and the
and pain inputs, and organizes patterns of cardiovascu- glionic neurons in the nucleus ambiguus in the medulla, strength of contraction, to increase cardiac output.
lar response seen during arousal due to pain, respiratory which control heart rate through the vagus nerve and Other descending hypothalamic axons can contact
distress, or gastrointestinal discomfort (increased blood the intermediolateral column of the spinal cord, which adrenal preganglionic neurons, resulting in increased
controls vasoconstriction. These may produce patterns circulating adrenalin, which also increases vasoconstric-
of autonomic activation that are organized at a hypo- tion and cardiac output.
thalamic level, such as stress or starvation responses.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 131

P late 5-21 Brain: PART I

Ascending arousal
pathways

Thalamus

LHA
(ORX,
glutamate) vPAG
(DA)

Hypothalamic Regulation BF TMN LDT (ACh) Cerebellum
of Sleep (ACh, (His) PPT (ACh)
GABA)
The brain is kept awake by an ascending arousal system Raphe PB/PC
that takes origin in the rostral pons and caudal mid- Cholinergic pathway to (5-HT) (Glutamate)
brain. The neurons that activate forebrain arousal open up thalamocortical
mainly consist of specific populations of cells that transmission Pons LC
contain monoamine neurotransmitters, acetylcholine Monoaminergic and (NE)
(ACh), and the excitatory transmitter glutamate. The glutamatergic pathways
cholinergic neurons in the pedunculopontine tegmen- to activate cerebral cortex
tal (PPT) and laterodorsal tegmental (LDT) nuclei
provide the major input to the thalamic relay nuclei and VLPO and MnPO
the thalamic reticular nucleus. The latter is a sheet of axons innervate
inhibitory γ-aminobutyric acid (GABA)ergic interneu- the entire
rons that sit on the surface of the thalamus. The cho- ascending
linergic input inhibits the reticular nucleus and activates arousal
the relay nuclei, this enhancing thalamocortical trans- system
mission of sensory information.
Thalamus
At the same time, a series of monoaminergic cell
groups in the upper brainstem provides an ascending VLPO/MnPO LHA
pathway that largely bypasses the thalamus and goes (GABA, Gal) (ORX,
directly to the cerebral cortex. These include noradren- glutamate) vPAG
ergic (NE) neurons in the locus coeruleus (LC), sero- (DA)
toninergic (5-HT) neurons in the dorsal raphe and
median raphe nuclei, dopaminergic (DA) neurons in TMN LDT (ACh) Cerebellum
the ventral periaqueductal gray matter (vPAG) and his- (His) PPT (ACh)
taminergic (His) neurons in the tuberomammillary
nucleus (TMN) in the hypothalamus. These are joined VLPO/MnPO axons Raphe PB/PC
by glutamatergic neurons in the parabrachial and pre- (5-HT) (Glutamate)
coeruleus (PB/PC) nuclei. All of these cell groups send
axons through the lateral hypothalamic area (LHA), Pons LC
where they are joined by ascending axons from the (NE)
orexin (ORX) neurons and from glutamatergic neurons â•…
in the lateral hypothalamic area. The pathway then
passes through the basal forebrain (BF), where addi- altogether. This disparity in activity is thought to cause The ventrolateral preoptic nucleus projects to the com-
tional cholinergic neurons (which innervate cortical the dreaming state. ponents of the ascending arousal system, and its neurons
pyramidal neurons) and GABAergic neurons (which contain both the inhibitory neurotransmitter GABA
innervate cortical inhibitory interneurons) join in. Sleep is regulated at least in part by two populations and the inhibitory neuropeptide galanin (Gal), which
These inputs are thought to excite cerebral cortical of neurons in the preoptic area. Median preoptic appear to be important in turning off arousal and per-
neurons and to enhance their capacity for information (MnPO) neurons appear to fire in response to pro- mitting sleep to occur. GABAergic neurons in the
processing. longed wakefulness but do not by themselves produce median preoptic neurons also contact some of these
sleep. However, neurons in the ventrolateral preoptic same targets. Animals with ventrolateral preoptic
During wakefulness, both of these pathways are (VLPO) nucleus begin firing at the onset of sleep, and lesions may lose a third or more of their total sleep.
active at a maximal rate. As the brain falls asleep, the the two both continue to fire during sleep states.
electroencephalogram slows, the individual enters
slow-wave (non–rapid eye movement [NREM] sleep),
and the firing of all of these cell groups is diminished.
However, intermittently during the sleep cycle, when
the individual enters REM, or active dreaming sleep,
the cholinergic neurons and some of the glutamatergic
neurons in the parabrachial nucleus begin firing again
at a high rate, while the monoamine systems stop firing

132 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 5-22 Hypothalamus, Pituitary, Sleep, and Thalamus
Orexin neurons reinforce the
ascending arousal systems and
stabilize the flip-flop switch

AWAKE ORX SLEEP
LC, A1 VLPO
ORX VLPO MnPO
MnPO DR, TMN
PB/PC
LC, A1 Off
DR, TMN

PB/PC

On

Narcolepsy

Excessive daytime sleepiness
in narcolepsy or sleep apnea

Narcolepsy: A Hypothalamic
Sleep Disorder

Narcolepsy is a puzzling disorder that was first described Cataplexy Sleep paralysis
in the late 1800s. Patients usually have onset of their
symptoms in their teens or twenties, when they become Sudden loss of muscular-postural Momentary paralysis on awakening
unusually sleepy during the day and may fall asleep if tone with laughter or fright lasts seconds to minutes
unstimulated even for a brief time. When a friend tells
a joke, they may suddenly lose their muscle strength â•…
and gradually slide to the floor, unable to stand or even
sit, a condition called cataplexy. Narcoleptic patients In humans, however, genetic mutations are a rare cause the absence of the orexin neurons, the waking state is
also may have sleep paralysis when they are just falling of narcolepsy; most individuals with narcolepsy appear less stable, and individuals fall asleep too easily. They
asleep or just waking up and be conscious but unable to to have loss of their orexin neurons, perhaps due to also enter REM sleep very quickly after sleep onset and
move, or may have dreams intrude into their waking autoimmune attack. can have fragments of REM sleep (dreaming, muscle
state as they fall asleep (hypnagogic hallucinations) or atonia) occurring at the wrong times, accounting for the
wake up (hypnopompic hallucinations). All of these The orexin neurons stabilize the behavioral state by episodes of hypnagogic hallucinations, sleep paralysis,
phenomena represent a weakening of the boundaries reinforcing wakefulness and blocking individuals from and cataplexy.
between different wake-sleep states, particularly with falling directly from wakefulness into REM sleep. In
components of REM sleep (muscle atonia, dreaming)
intruding on wakefulness.

The cause of narcolepsy was quite mysterious until a
new neurotransmitter, orexin (also called hypocretin)
was discovered in 1998. The orexin neurons are found
in the lateral hypothalamic area. They target the main
components of the ascending arousal system, and both
of the orexin receptors are excitatory. Orexin neurons
fire most rapidly during wakefulness, particularly
during wakeful exploration of the environment. Thus
the orexin neurons appear to play a key role in main-
taining and stabilizing a wakeful state.

Soon after their discovery, it became apparent that
gene defects that cause loss of signaling by the orexin
neurons could cause narcolepsy in experimental animals.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 133

Plate 5-23 Brain: PART I

Sleep-Disordered Breathing Snore
ZZZ–Z
Sleep-disordered breathing includes a spectrum of disor- Snore
ders, ranging from snoring to frank cessation of air flow,
or apnea, during sleep. Obstructive sleep apnea occurs Respiration, Snoring ceases, Normal breathing
when relaxation of the tongue and airway muscles loud snoring apnea supervenes in sleep
during sleep causes collapse of the airway, resulting in Obstructive apnea
snoring, reduction in air flow (hypopnea), or even total Normal breathing
blockage of air flow (apnea). Patients with central sleep in sleep
apnea have reduced drive to breathe during sleep (central
sleep apnea). Central sleep apnea may occur as a con- EEG
genital problem in children, where it may be caused by
a mutation in the Phox2b gene, which is necessary for Nasal
development of CO2 chemosensory neurons in the
medulla. However, it can also be caused by damage to Respiration Oral
the medulla or spinal cord causing failure of automatic
breathing during sleep (“Ondine’s curse”). Central Chest
sleep apnea also is often seen in older adults who have
developed congestive heart failure or respiratory disease O2 saturation
(causing waxing and waning Cheyne-Stokes respiration
during sleep). In many older adult patients, a combina- ECG
tion of central and obstructive sleep apnea may be seen,
sometimes called complex sleep-disordered breathing. Recordings from patient with obstructive sleep apnea
The typical patient with obstructive sleep apnea arouses
after a brief interval of struggling to breathe, the airway Polysomnography Continuous positive
opens, and breathing resumes. This cycle may repeat airway pressure
every few minutes all night. The patient often is (CPAP) therapy
unaware that the arousals are occurring but typically
feels sleepy during the day. Sometimes the patient com- aldosterone, promoting increased intravascular fluid sâ•…leep apnea begins with correction of anatomical abnor-
plains of aches and pains or impaired memory or cogni- volume. The elevated central venous pressure paired
tive function, which can be increased by sleep loss. with increased intrathoracic negative pressure increases malities of the airway, including removal of enlarged
Often the bed partner will first realize that something transmural forces affecting the heart, which may cause adenoids and tonsils in children. Reduction of risk
is wrong when snoring sounds become intolerable or cardiovascular remodeling and alteration of cardiopul- factors, such as obesity and drinking alcohol in the
notices the periodic loss of breathing. The episodes of monary physiology. Sleep loss also causes insulin resis- evening, may help. If this is not curative, continuous
apnea are often increased in frequency when the patient tance, which can predispose to diabetes and increased positive airway pressure (CPAP), which uses air pres-
drinks alcoholic beverages or sleeps on his back. body mass, which further worsens the sleep apnea and sure to splint open the airway during sleep, prevents
Obstructive sleep apnea is most common among older hypertension. apneas and reduces daytime sleepiness and cardiovascu-
individuals, men, and those with obesity and large shirt lar risk. Patients with severe and moderate sleep apnea
collar sizes, but it is also seen in older women and in Diagnosis and Treatment. An all-night sleep study significantly benefit from CPAP use by improving
children and young adults who have enlarged tonsils or is the best means to detect and quantify apneic events. daytime alertness and reducing cardiovascular risk.
adenoids, anomalies of craniofacial structure that com- Healthy adults may experience up to four apneas per Often, the treated patient may comment that he had
promise airway diameter, or neuromuscular disorders hour of sleep at night; in children more than 1.5 events/ not realized how sleepy he was until he had experienced
that cause laxity of the airway muscles. hour is considered abnormal. Treatment of obstructive the results of treatment.

Clinical Presentation. Pronounced snoring, a classic
indicator for possible sleep apnea is related to vibraÂ

Plate 5-24 Hypothalamus, Pituitary, Sleep, and Thalamus

Parasomnias REM SLEEP BEHAVIOR DISORDER

Parasomnias are characterized by certain unusual or Patients who lose their ability to be paralyzed during REM sleep begin to act out their dreams and are
unwanted movements or behaviors that occur during usually unaware of these occurrences because the episodes occur during sleep. Often the first episodes
nighttime sleep. are observed by the spouses of the patients.

PERIODIC LIMB MOVEMENTS OF SLEEP (PLMS)
Typically, the patient experiences repeated very brief
episodic leg movements ranging from simple great toe
dorsiflexion to violent flexion of the entire lower
extremity. This may recur at regular intervals, up to
several times per minute, all night long. If the move-
ments are mild, neither the individual patient nor the
bed partner may recognize the PLMs. On the other
hand, if more violent, the movements may awaken the
patient, bed partner, or both. Although mild PLMS
may not be associated with arousals and are of no clini-
cal significance, in some patients the more pronounced
PLMS may cause repeated arousals. As a result, the
patient may develop, daytime sleepiness. PLMs can
often be treated successfully with dopamine agonists,
such as ropinirole or pramipexole, or with benzodiaz-
epines, such as clonazepam.

RESTLESS LEG SYNDROME (RLS) injuring himself or his bed partner during an attack. â•…
RLS often occurs in the same patients as those who Some patients use large straps across the bed to avoid
have PLMs, although there is another group of RLS such excursions. Most patients with idiopathic RBD (no slow-wave sleep and tend to become more brief and less
patients who do not get PLMs. The patient with RLS other predisposing cause) are men, and the peak onset profound during adulthood. Typically, the patient with
perceives an irresistible urge to move the legs, espe- is in the fifties or sixties. Recent studies show that most night terrors suddenly sits up in bed, has dilated pupils,
cially while sitting or lying down; these feelings are patients with idiopathic RBD subsequently develop a a frightened expression, and a rapid pulse. Occasionally,
relieved when the patient stands or walks. The patient synucleinopathy, usually Parkinson disease or diffuse the affected individual may suddenly dash from the bed
often describes the feeling as an uncomfortable sensa- Lewy body dementia, but occasionally multiple systems with such vigor that he or she may sustain an injury.
tion in the legs that is only relieved by leg movement. atrophy. However, the time to diagnosis of these neu- Often, the child returns to sleep without any memory
Many RLS patients demonstrate iron deficiency or low rodegenerative disorders may be quite prolonged, with of the event. If awakened during the night terror, the
ferritin levels, and in those patients treatment with iron about half the patients with RBD developing a synucle- child describes a frightened feeling or image but not a
may help. In addition, the symptoms of RLS may be inopathy within 12 years, and almost 80% by 20 years. complex dream. Although there are no known adverse
successfully treated with dopamine agonists, benzodi- In one case report the patient was found by his new outcomes to night terrors, they can be quite frightening
azepines, or opioid drugs. Antidepressants and stimu- bride to have RBD on his wedding night at age 21 and to parents, and it is important to distinguish them from
lants may exacerbate RLS and PLMS. Two genome-wide did not develop Parkinson disease until age 71. Other other, more rare nocturnal events, such as seizures.
screening studies have identified a genetic polymor- risk factors include the use of antidepressants that
phism that correlates with RLS with PLMs, suggesting prevent reuptake of serotonin or norepinephrine. Sleep walking, or somnambulism, also tends to occur in
that many cases may have a heritable cause. Again, this situation represents the opposite of cata- children during deep slow-wave sleep. The child may
plexy, the development of REM atonia during waking walk and talk, but the speech is typically mumbled and
REM SLEEP BEHAVIOR DISORDER in narcoleptic patients, where these antidepressants incoherent. The patient can generally be led back to
Patients with REM sleep behavior disorder (RBD) suppress the attacks. bed and will not remember the incident the following
exhibit complex motor activity during REM sleep. day. Often, an explanation of the problem to the family
During REM sleep, when active dreaming occurs, there NIGHT TERRORS, SLEEP WALKING, is sufficient.
is activation of reticulospinal pathways that result in AND BED WETTING
profound inhibition of motor neurons, resulting in deep These disorders commonly occur in children and rarely Enuresis, or bed wetting, typically occurs in this same
paralysis of voluntary muscles in intact individuals. In persist into adult life. As a group, these childhood para- age range and also during the deepest part of slow-wave
patients with RBD, this paralysis breaks down and somnias tend to occur during the deepest stage of sleep. In general the patient is not aware of the event,
there are intermittent jerky movements and sometimes awakening in damp bed clothing.
complex behaviors during REM sleep. In many respects,
RBD is the opposite of the cataplexy attacks seen in All of these childhood parasomnias frequently
patients with narcolepsy, who have activation of the respond to drugs that reduce the tendency to fall into
REM sleep paralysis system while awake. RBD patients deep slow-wave sleep, such as tricyclic antidepressants
typically appear to be fighting off attackers and report or benzodiazepines.
dreams that match their actions. However, as with
PLMS, patients with RBD are often unaware of these
occurrences, unless they are reported by a bed partner,
or the patient falls out of bed and is injured during a
foray. RBD is usually treatable with either clonazepam
or melatonin. However, in severe cases, the bed partner
may have to sleep in a different room and the mattress
must be placed on the floor, the furniture removed,
and windows boarded over to prevent the patient from

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 135

P late 5-25 Brain: PART I

Divisions of the Pituitary Thalamus Interventricular
Gland and Its Relationships Hypothalamic sulcus foramen
to the Hypothalamus
Hypothalamic area Paraventricular
The pituitary gland (hypophysis) is a midline structure nucleus
at the base of the hypothalamus, to which it is con-
nected through the pituitary stalk. The gland is approx- Hypothalamohypophyseal tract Supraoptic
imately bean shaped, measures 6╯mm (superior-inferior nucleus
dimension) by 9╯mm (anterior-posterior dimension)
by 13╯mm (transverse dimension), and weighs 500 to Tubero- Supraoptico-
600╯mg. hypophyseal hypophyseal
tract tract
The gland is composed of the adenohypophysis and
the neurohypophysis, which are embryologically, ana- Mammillary body Optic chiasm
tomically, and functionally distinct. The former derives
from the Rathke’s pouch, an ectodermal outgrowth of the Neural Median eminence Hypophyseal
primordial stomodeum, whereas the latter derives from stalk Infundibular stem stalk
the neural ectoderm and can be considered an extension
of the hypothalamus. Neurohypophysis Pars tuberalis Adenohypophysis
Pars intermedia
The adenohypophysis comprises the pars distalis, the
pars intermedia, and the pars tuberalis (a small portion of Infundibular Pars
the adenohypophysis wrapped around the neurohy- process distalis
pophysis in the stalk). The pars distalis is also known as Connective
the anterior lobe (or pars glandularis), whereas the pars Cleft tissue
intermedia is poorly developed in humans. The pars (trabecula)
intermedia contains a connective tissue trabecula sepa-
rating the anterior and posterior lobe as well as a Posterior lobe Anterior lobe
narrow cleft or several small cysts at the site of the oxytocin are synthesized in cell bodies of neurons in the
embryonic Rathke’s pouch. During development, pop- supraoptic and paraventricular nuclei, are transported â•…
ulations of stem cells differentiate into distinct groups down the axons and secreted by exocytosis from axon
of adenohypophyseal secretory cells under the influence terminals in response to nerve impulses. Pituicytes apposed to numerous nerve terminals of nerve axons
of specific transcription factors. are glial cells supporting the axon terminals in the originating in the hypothalamus. Upon excitation,
neurohypophysis. these neurons secrete several distinct releasing and
Several differentiated cell types arise from a common inhibitory hormones into the portal system, which
stem cell precursor, including somatotrophs, lacto- The pituitary gland receives a rich blood supply, travel down the pituitary stalk in portal veins to reach
trophs, mammosomatotrophs, and thyrotrophs. SomatoÂ

Plate 5-26 Hypothalamus, Pituitary, Sleep, and Thalamus

Forebrain Origin of vasopressin
pathways
Posterior Pituitary Gland Cell of supraoptic
Paraventricular Axonal nucleus
The neurohypophysis, including the neural stalk and the nucleus transport of
posterior pituitary lobe, is an extension of the hypo- secretory Fenestrated
thalamus. It is embryologically derived from neural product capillary
ectoderm. During development, magnocellular neurons
of the supraoptic and paraventricular hypothalamic nuclei Supraoptic Brainstem Posterior
send their axons inferiorly to form the neurohypophy- nucleus pathways lobe
sis. These axons terminate in the posterior lobe of the
pituitary. In addition, a smaller number of parvocellular Arterial supply Neurosecretory ending
neurons from the same nuclei send off shorter axons, to hypothalamus (posterior pituitary)
which end in the median eminence or infundibular
stem. Pituicytes, which are glial cells, support these axon Blood-borne signals Axon Axon
terminals. Two nonapeptide hormones are secreted from reaching SON and PVN Pituicyte Collagen space
distinct axon terminals in the neurohypophysis, includ- Neurohypophyseal tract processes Neurosecretory
ing antidiuretic hormone (vasopressin) and oxytocin. After vesicles
secretion, these hormones enter neurohypophyseal cap- Herring bodies Mast cell
illaries and are carried via the inferior hypophyseal Anterior lobe
veins into the systemic circulation. Posterior lobe Endothelium Fibroblast
(neurohypophysis)
Oxytocin and antidiuretic hormone (vasopressin) are Capillary Basement
made by distinct populations of large (magnocellular) Site of vasopressin absorption membrane
neurons in both the paraventricular (PVN) and supra-
optic (SON) nuclei, which release the hormones from Venous drainage of posterior lobe
their axons in the neurohypophysis. The PVN also con- Inferior hypophyseal artery
tains populations of smaller (parvicellular) neuroendo-
crine neurons that produce corticotropin-releasing Posterior pituitary bright spot. Sagittal T1-MRI Ectopic posterior pituitary. Sagittal T1-MRI image
hormone, thyrotropin-releasing hormone, or soma- image showing hyperintensity (arrow) in the showing hyperintensity (arrow) along the posterior
tostatin, which are released into the hypothalamo- posterior aspect of the sella turcica. aspect of the pituitary infundibulum.
hypophyseal portal circulation. Some parvicellular
neurons in the PVN also make either oxytocin or antiÂ

P late 5-27 Brain: PART I

Anatomic Relationships of Optic nerves
the Pituitary Gland Temporal pole of brain
Optic chiasm
The pituitary gland resides in a depression (fossa) in the Right optic tract
body of the sphenoid bone, termed the sella turcica. Pituitary gland
The tuberculum sellae forms the anterior wall of the Oculomotor nerve (III)
sella, and the dorsum sellae forms its posterior wall. Tuber cinereum
The pituitary is covered superiorly by a circular fold of Mammillary bodies
dura mater, the diaphragma sellae. This sellar dia- Trochlear nerve (IV)
phragm is pierced by the pituitary stalk and the hypoph- Trigeminal nerve (V)
yseal vessels. A fold of the arachnoid may herniate Abducens nerve (VI)
through the sellar diaphragm in some patients, thus Pons
extending the subarachnoid space within the sella (see
MRI scan on the right in Plate 5-26 for an example). Hypothalamic sulcus Interventricular foramen Fornix
Chronic pulsatile pressure exerted by the cerebrospinal Anterior commissure Corpus callosum
fluid may expand the sella, leading to the appearance of Lamina terminalis Choroid plexus
an enlarged, “empty sella,” which may be associated with Tuber cinereum of 3rd ventricle
hypopituitarism in some patients. Mammillary body
Chiasmatic cistern Thalamus
The optic chiasm rests superiorly to the diaphragma Optic chiasm Pineal
sellae. Nerve fibers originating in the nasal portion of Diaphragma sellae gland
each retina cross at the chiasm to the contralateral side Interpeduncular cistern
and join ipsilateral nerve fibers originating in the tem- Pituitary gland â•…
poral portion of each retina, which do not cross at Sphenoidal sinus
the chiasm, to form each optic tract. The anatomic Nasal septum
relationship between the pituitary gland and the optic Nasopharynx
chiasm is clinically important, because mass lesions Pontine cistern
within the pituitary may compress either the chiasm or
other portions of the optic apparatus, giving rise to a into the cavernous sinus. Examples of such lesions The thin sellar floor separates the pituitary gland from
variety of visual field defects. Specific places where the include meningiomas, chondrosarcomas and sellar metasta- the underlying sphenoid sinus. The sellar floor can be
arachnoid separates from the pia mater form cisterns ses. Characteristically, pituitary adenomas only rarely expanded by slowly growing sellar masses, leading to
filled with cerebrospinal fluid, including the chiasmatic cause dysfunction of cranial nerves within the cavern- remodeling of the sella, or eroded by sellar masses
cistern and the interpeduncular cistern. These spaces can ous sinuses, with the notable exception of adenomas growing inferiorly. The close relationship between the
be distorted by space-occupying sellar lesions growing undergoing hemorrhagic necrosis (pituitary apoplexy). sella, the sphenoid sinus, and the nasopharynx provides
superiorly from the pituitary. an important access route to pituitary surgeons. Using
The circular sinus lies between the pituitary gland and a trans-sphenoidal approach, many sellar masses can be
The hypothalamus is located superiorly to the pitu- the underlying sphenoid bone in the sella, forming resected with low morbidity.
itary gland and is bounded between the optic chiasm interconnections between the two cavernous sinuses.
anteriorly, the caudal border of the mammillary bodies
posteriorly, and the hypothalamic sulcus superiorly.
Distinct hypothalamic nuclei regulate anterior pituitary
function through the synthesis of several stimulat-
ing hormones (growth hormone–releasing hormone,
corticotropin-releasing hormone, thyrotropin-releasing
hormone, and gonadotropin-releasing hormone) and
inhibiting hormones (somatostatin and dopamine),
released at neuronal axon terminals present in the
median eminence and the infundibulum. These hormones
are carried via the hypophyseal portal system to the
adenohypophysis, where they regulate hormone secre-
tion in a specific manner. The inter-relationships
between the hypothalamus and the posterior pituitary
are detailed in Plate 5-26. Large lesions arising above
the sella may impinge on the hypothalamus, interfering
with its functions.

The cavernous sinuses are located laterally to the pitu-
itary gland, and receive blood from the pituitary via the
hypophyseal veins. Each cavernous sinus contains
several important structures, including the cavernous
portion of the ipsilateral internal carotid artery, the ocu-
lomotor, trochlear, and abducens nerves, as well as the first
two divisions (ophthalmic and maxillary) of the trigeminal
nerve. Each of these nerves may be impinged upon by
space-occupying lesions arising in the sella that extend

138 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 5-28 Hypothalamus, Pituitary, Sleep, and Thalamus

Bitemporal
hemianopsia

Effects of Pituitary
Mass Lesions on the
Visual Apparatus

The close anatomic relationship between the pituitary Pituitary tumor compressing Optic nerves Optic tract
and the optic apparatus, notably the optic chiasm, but or invading optic chiasm Crossed pathways
also the prechiasmatic optic nerves and the postchiasmatic from nasal part of
optic tracts, accounts for the frequent occurrence of retina interrupted
visual deficits in patients with large pituitary mass at optic chiasm
lesions extending superiorly. At the optic chiasm, axons
of the retinal ganglion cells that originate in the nasal MRI showing pituitary macro- MRI showing pituitary macro- MRI showing pituitary macro-
portion of each retina cross to the contralateral side. In adenoma with suprasellar and adenoma with suprasellar and adenoma with suprasellar,
contrast, nerve fibers from the temporal portion of each right cavernous sinus extension. bilateral cavernous sinus bilateral cavernous, and
retina remain on the ipsilateral side past the chiasm to Optic chiasm is raised slightly, extension. The optic chiasm is sphenoid extensions. The optic
form each optic tract, accompanied by nerve fibers but visual fields are normal. compressed, causing bitemporal chiasm is markedly compressed,
crossing from the nasal portion of the contralateral superior quadrant vision loss. causing complete bitemporal
retina. hemianopsia.

A variety of mass lesions may arise within the Images reprinted with permission from Young WF. The Netter Collection of Medical Illustrations,
sella. In addition to benign pituitary adenomas, which Volume 2 – Endocrine System. Elsevier, Philadelphia, 2011.
account for approximately 90% of mass lesions in surÂ

Plate 5-29 Brain: PART I

Anterior Pituitary Hormone Wrinkling
Deficiencies Myxedema facies

There are six types of secretory cells present in the Pallor
adenohypophysis, including somatotrophs (synthesiz- Loss of
ing growth hormone), lactotrophs (producing prolac- axillary
tin), mammosomatotrophs (synthesizing both growth hair
hormone and prolactin), thyrotrophs (producing thyro- Breast
tropin), corticotrophs (synthesizing corticotropin), and atrophy
gonadotrophs (synthesizing both follicle-stimulating Low blood
hormone and luteinizing hormone). The synthesis and pressure
release of these hormones is well orchestrated under the Hypoglycemia
influence of hypothalamic hormones (most of which are hyponatremia
stimulatory and some of which are inhibitory) as well eosinophilia
as systemic (endocrine) negative feedback mechanisms, Loss of
aimed at maintaining homeostatic control. pubic hair

A wide variety of conditions may cause dysfunction Genital
of the hypothalamus or pituitary, leading to selective or and gonadal
universal, partial or complete, acute or chronic loss of atrophy
adenohypophyseal hormone secretion (anterior hypo- Amenorrhea, infertility,
pituitarism). Any space-occupying lesion impinging on vaginal dryness, and atrophy
the anterior pituitary, stalk, or hypothalamus may lead Decreased libido,
to hypopituitarism. In adults, the most common mass infertility,
lesion in the area of the sella is a benign pituitary erectile dysfunction
adenoma. However, many other neoplasms (including
craniopharyngioma, meningioma, chordoma, metasta- Asthenia,
ses, or lymphoma), cystic lesions (including Rathke’s dry skin,
cleft cyst or arachnoid cyst), infiltrative (hemochroma- decreased
tosis), inflammatory (hypophysitis, sarcoidosis) or muscle mass
infectious disorders, aneurysm, infarction, primary
empty sella, radiation therapy, trauma, surgery, or Pituitary causes:
genetic conditions may all cause hypopituitarism. The Pituitary adenoma
underlying cause of hypopituitarism may influence the Pituitary cyst
pattern of hormone loss. Gonadotropin deficiency and Pituitary surgery
growth hormone deficiency tend to occur first in Infiltrative lesion
patients with pituitary adenomas or those who have (e.g., lymphocytic hypophysitis)
received radiation therapy to the hypothalamus and Infarction (e.g., Sheehan syndrome)
sella, while thyrotropin and corticotropin function tend Apoplexy
to be spared until later in the course of these conditions. Genetic disorder (e.g., POU1F1 mutation)
In contrast, corticotropin and thyrotropin deficiency Primary empty sella syndrome
frequently occur first in patients with lymphocytic Metastatic disease to the sella
hypophysitis.
Hypothalamic causes:
Gonadotropin deficiency presents as lack of pubertal Mass lesion (e.g., craniopharyngioma)
development in adolescents, who generally develop a Radiation (e.g., for brain malignancy)
eunuchoid habitus. If the onset of gonadotropin defi- Infiltrative lesion (e.g., sarcoidosis)
ciency occurs in adulthood, patients present with Trauma with skull base fracture
loss of gonadal function, including oligomenorrhea or Infection (e.g., viral encephalitis)
amenorrhea in women, and erectile dysfunction in men.
In addition, low libido and infertility may occur in aches, decreased relaxation phase of Achilles reflexes, â•…
patients of both genders. Patients may also experience and cold intolerance.
loss of body hair (particularly in the presence of concur- Once diagnosed, target organ hormone replace-
rent corticotropin deficiency), fine facial wrinkling, loss Corticotropin deficiency leads to central hypoadrenal- ment therapies are instituted. In particular, glucocorti-
of bone calcium leading to increased fracture risk, and ism, which is potentially the most life threatening of all coid replacement may prove lifesaving in patients
hot flashes. Women may also experience breast atrophy, pituitary hormone deficiencies. These patients often exhibit presenting in adrenal crisis. Levothyroxine is used to
vaginal dryness, and dyspareunia. Men may note loss of fatigue, weight loss, nausea and vomiting, orthostatic replace central hypothyroidism, and sex steroid replace-
stamina, increased body fat, decreased lean body mass, hypotension and dizziness, and diffuse arthralgias. ment is used to replace patients with central hypogo-
and decreased testicular size. Prolactin deficiency may Notable is the lack of cutaneous and mucosal hyperpig- nadism. However, if fertility is of interest, gonadotropin
result in failure of lactation postpartum. mentation, in contrast to patients with primary adrenal therapy is used, including human chorionic gonadotro-
insufficiency (Addison disease). These patients may also pin and follicle-stimulating hormone. Growth hormone
Growth hormone deficiency leads to decreased linear present acutely with shock unresponsive to volume replacement may also be considered. Despite seemingly
growth if it occurs in childhood or adolescence. In expansion and pressors. Eosinophilia and hyponatremia adequate replacement therapies, patients with hypopitu-
adulthood, loss of growth hormone secretion is more may be present. However, hyperkalemia is absent, itarism are at increased risk of cardiovascular mortality,
subtle, but may be associated with fatigue, decreased because aldosterone deficiency does not occur. the underlying reasons still being a matter of consider-
exercise capacity and muscle strength, abnormal body able debate.
composition (decreased lean body mass, loss of bone
calcium, and gain in body fat), dyslipidemia, insulin
resistance, increased cardiovascular risk, and poor
quality of life.

Thyrotropin deficiency leads to central hypothyroidism,
including fatigue, lethargy, weight gain, bradycardia,
dry skin, myxedema, anemia, constipation, muscle

140 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 5-30 Hypothalamus, Pituitary, Sleep, and Thalamus

Severe Anterior Pituitary Severe anterior pituitary deficiency
Hormone Deficiencies
(Panhypopituitarism) Extensive destructiveEtiology
macroadenoma
Extensive space-occupying lesions within the sella or GH deficient Gonadotropins or cranio-
hypothalamus may lead to complete loss of anterior deficient pharyngioma
pituitary function. Of note, the term panhypopituitarism Postpartum necrosis
is indicative of complete loss of both anterior and pos- Occasionally trauma
terior lobe function. Postsurgical
TSH ACTH MSH
Pituitary macroadenomas, which, by definition, exceed deficient deficient deficient
10╯mm in greatest diameter, may cause multiple ante-
rior pituitary hormone deficiencies but only rarely Men Women
cause diabetes insipidus preoperatively. In contrast, Child Adult Loss of body Loss of axillary
large suprasellar tumors that impinge on the hypothala- ÈGrowth ÈSense of hair and pubic hair Hypo- Adrenal Pallor
mus, stalk, and pituitary, including craniopharyngio- Amenorrhea thyroidism cortical
mas, may disrupt both anterior and posterior lobe velocity well-being Infertility Infertility insufficiency
function. Similarly, pituitary surgery or trauma may Short ÈFat mass ÈLibido Vaginal dryness
lead to panhypopituitarism. stature ÈMuscle ÈVitality Hot flashes
mass ÈTesticular Breast atrophy
Gonadotropin deficiency leads to lack of pubertal devel- size
opment, if it occurs before adolescence. Of note, a Erectile
eunuchoid habitus is unlikely to develop in young dysfunction
patients with concurrent growth hormone deficiency.
In adults of both genders, severe gonadotropin defi- Child
ciency leads to central hypogonadism. Severe gonado- Delayed puberty
tropin deficiency of long standing leads to gonadal GH deficiency precludes eunuchoid habitus
atrophy, including decreased size of the ovaries in
women and testes in men. In addition, there is a Panhypopituitarism
decrease in size of the uterus, vagina, and breasts in
women, including thinning of the endometrium and Etiology Extensive tumor
vaginal epithelial atrophy. In men, there is a decrease (usually cranio-
in size of the penis and prostate. pharyngioma)
Postsurgical
Thyrotropin deficiency leads to central hypothyroidism. Occasionally
The thyroid gland becomes atrophic, including thin- trauma
ning of the follicular epithelium. Corticotropin defi-
ciency leads to central hypoadrenalism, involving loss of MSH and
cortisol and adrenal androgen secretion. Portions of the TSH ACTH ACTH deficient
adrenal cortex, including the zona fasciculata and the GH deficient ADH Gonadotropin deficient deficient
zona reticularis, become atrophic in these patients. In deficient deficient
contrast, the zona glomerulosa remains structurally
intact, and aldosterone secretion is unaffected. These Men Women
patients may often exhibit pallor, occurring as a result Loss of body Loss of axillary
of anemia and decreased skin pigmentation resulting Child Adult Diabetes hair and pubic hair Hypo- Adrenal Pallor
from lack of corticotropin action on skin melanocytes. ÈGrowth ÈSense of insipidus Infertility Amenorrhea thyroidism cortical
(latent ÈLibido Infertility insufficiency
Growth hormone deficiency leads to a decrease in velocity well- unless ÈVitality Vaginal dryness
growth velocity in children or adolescents, resulting Short being adrenal ÈTesticular Hot flashes
in short stature if untreated. Hypoglycemia may occur stature ÈFat mass cortical size Breast atrophy
in childhood and appears to be a consequence of ÈMuscle hormones Erectile
growth hormone and glucocorticoid deficiency. Growth mass are present dysfunction
hormone–deficient adults may exhibit low exercise
capacity, abnormal body composition (decrease in lean or
body mass and bone mass and increase in fat mass), administered)
dyslipidemia, insulin resistance, increased cardiovascu- Child
lar risk, and impaired quality of life. Prolactin defi- Delayed puberty
ciency leads to failure of lactation in women and has no GH deficiency precludes eunuchoid habitus
discernible effects in men.
â•…
Lack of antidiuretic hormone secretion leads to central
diabetes insipidus. The presence of diabetes insipidus kidneys. In these patients, glucocorticoid replacement patients with central hypoadrenalism (hydrocortisone
signifies extensive damage to the hypothalamus or may precipitate the clinical onset of central diabetes or prednisone) and central hypothyroidism (levothy-
stalk. Of note, disruption of the pituitary stalk below insipidus. Lack of oxytocin secretion leads to no dis- roxine). Sex steroid replacement (testosterone in men
the diaphragma sellae is less likely to cause diabetes cernible symptoms or deficits in humans. and estrogen-progestin in women) is generally advised,
insipidus than injury to the stalk at the level of the if not contraindicated. If fertility is of immediate inter-
median eminence. In cases where the stalk is damaged Once clinically suspected, the presence of pituitary est, gonadotropin therapy is recommended in patients
distally, some antidiuretic hormone–secreting axon ter- hormone deficiencies can be established through of both genders. Growth hormone replacement is
minals are spared and may secrete sufficient antidiuretic hormone testing. Assays for systemic levels of target advised in children, if not contraindicated. Although
hormone to prevent the development of central diabe- gland hormones (morning cortisol, free thyroxine, and not essential for life, growth hormone replacement in
tes insipidus. It may also be noted that central diabetes testosterone) are most helpful in the diagnosis of hypo- adults is available in the United States and several other
insipidus may be clinically latent in patients with corti- pituitarism. In the case of some hormones, including countries and may improve exercise capacity, body
cotropin deficiency because glucocorticoids have an growth hormone and cortisol, stimulation testing is composition, several cardiovascular risk factors, and
important role in increasing free water clearance in the used to evaluate secretory reserve. Water deprivation overall quality of life. Desmopressin, an analog of antid-
testing is used to diagnose central diabetes insipidus. iuretic hormone that is devoid of vasopressor activity,
is recommended in patients with central diabetes
Replacement therapies are available for all pituitary insipidus.
hormone deficiencies except prolactin and oxytocin.
The respective target gland hormone is administered in

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 141

P late 5-31 Brain: PART I
Rapid drop
Postpartum hemorrhage in blood
pressure

Postpartum Pituitary
Infarction (Sheehan
Syndrome)

In 1937, Sheehan first described the development of Normal pituitary gland Hyperplastic pituitary Thrombosis, necrosis, Scar
pituitary infarction in the setting of hemorrhagic shock of pregnancy and scar formation Rim of
occurring after delivery. This entity is much less com- relatively
monly seen in developed countries today, likely as a normal
result of modern advances in obstetric care. tissue

To understand the development of postpartum pitu- Failure of lactation Prolactin defiTciSeHnt
itary infarction, one has to consider that the pituitary (often first sign postpartum) deficient
gland becomes hyperplastic (approximately doubling in Adrenal cortical insufficiency
mass) during pregnancy as a result of progressive lactotroph (acute initial shock, loss of AdCeTfiHcient
hyperplasia occurring until term. Because there is no pubic and body hair, asthenia, FSdHefaicnidenLtH
concurrent increase in blood supply to the pituitary, hypoglycemia)
lactotroph hyperplasia makes the gland more vulnerable Gonadal insufficiency (amenorrhea)
to vascular insults during pregnancy and the peripartum
period. To highlight the important role of pituitary Hypothyroidism
hyperplasia in the pathogenesis of infarction, it may be Pituitary insufficiency of variable degree
noted that pituitary infarction is very rare in nongravid usually without diabetes insipidus
patients in shock. The precise role of vascular spasm, ACTH, corticotropin; FSH, follicle-stimulating hormone; LH, luteinizing hormone;
thrombosis, and vascular compression as causative TSH, thyrotropin.
factors in the pathogenesis of Sheehan syndrome is still
debated, but the condition ultimately involves infarc- â•…
tion of the anterior pituitary lobe as a result of severe
decrease in blood flow through the gland. Additional risk factors include type 1 diabetes mellitus morning serum cortisol, free thyroxine, estradiol, and
and sickle cell disease. In developed countries, lympho- gonadotropins. Serum prolactin levels may be very low
It may also be noted that the anterior lobe of the cytic hypophysitis, occurring in the third trimester of in these patients. Stimulation testing may be needed
pituitary is more vulnerable to ischemia than the poste- pregnancy or the postpartum period, has become to examine adrenocortical reserve and is essential in
rior lobe because the former receives blood supply more common than Sheehan syndrome as a cause of order to evaluate growth hormone secretion. Standard
through a low-pressure portal system. In contrast, the new onset hypopituitarism in pregnancy and the replacement therapies for pituitary hormone deficien-
posterior pituitary receives direct arterial blood supply puerperium. cies are advised. In particular, prompt glucocorticoid
through the inferior hypophyseal arteries. As a conse- replacement can be lifesaving. However, recovery of
quence, the pars tuberalis and the posterior pituitary Once suspected, the diagnosis involves assays of pituitary function is very uncommon.
lobe are usually spared in these patients, who generally systemic levels of target gland hormones, including
do not develop central diabetes insipidus.

Infarction of the anterior pituitary lobe leads to a
gradual decrease in the size of the pituitary gland, which
is partly replaced by fibrous scar tissue. On magnetic
resonance imaging, there is a gradual decrease in the
size of the pituitary gland, often culminating in the
development of an “empty sella.”

Anterior hypopituitarism of varying severity occurs
in patients with Sheehan syndrome, depending on the
extent of anterior lobe infarction. Loss of 90% of ade-
nohypophyseal cells frequently leads to life-threatening
pituitary failure, whereas loss of 50% to 70 % of ante-
rior pituitary cells generally leads to partial hypopitu-
itarism. Central hypoadrenalism may result in shock
that is refractory to volume expansion and vasopressor
administration. If loss of pituitary function is partial
and/or less severe, initial symptoms may be more
subtle, including failure to lactate and involution of
breasts, followed by postpartum amenorrhea. Other
symptoms may include fatigue, weight loss, lack of
appetite, nausea, dizziness, and loss of axillary and
pubic hair.

Sheehan syndrome should be considered in women
with severe postpartum blood loss requiring blood transfusion.

142 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 5-32 Hypothalamus, Pituitary, Sleep, and Thalamus

Compressed
optic chiasm
Compressed
cranial nerve III
Hemorrhagic
pituitary tumor

Pituitary gland

Pituitary Apoplexy

Pituitary apoplexy denotes the presence of hemorrhagic Compressed optic chiasm
necrosis of the pituitary, which generally occurs within Hemorrhage
a pituitary macroadenoma. In some cases, hemorrhage Pituitary tumor
may occur within a cystic lesion (including Rathke’s Hypophysis (pituitary gland)
cleft cyst). Rarely, pituitary apoplexy may occur as a
result of hemorrhage within the pituitary gland in the MRI showing pituitary tumor apoplexy. Coronal image (left) shows the partially cystic pituitary tumor in
absence of an adenoma or cyst. Pituitary apoplexy is a the sella with the hemorrhagic component extending above the sella. Sagittal image (right) shows fluid-
rare condition. In contrast, asymptomatic hemorrhage fluid level within the area of recent hemorrhage.
within a pituitary adenoma is not uncommon (occur- Images reprinted with permission from Young WF. The Netter Collection of Medical Illustrations, vol
ring in approximately 15% of patients with pituitary 2: Endocrine System. Elsevier, Philadelphia, 2011.
adenomas).
â•…
Patients with pituitary apoplexy present with severe
headache of acute onset, which is typically considered pharmacologic doses of glucocorticoids are often In contrast, patients who maintain a normal level of
as the worst headache ever experienced. Nausea and administered to minimize acute pressure effects from consciousness and show no evidence of increased intra-
vomiting are very common. The rapid expansion of the hemorrhagic sellar mass on neighboring structures. cranial pressure, visual field defects, or ophthalmople-
intrasellar contents frequently leads to compression gia may be observed. These patients may be considered
of the optic chiasm, causing visual field defects. Lateral Patients with impaired level of consciousness or for pituitary surgery if the sellar mass fails to regress
expansion resulting in compression of the nerves other evidence of increased intracranial pressure, visual considerably after the hemorrhage is reabsorbed. Pitu-
coursing through the cavernous sinuses (including field defects, diplopia, or ptosis should be considered itary function needs to be monitored and hormone
the third, fourth, fifth, and sixth cranial nerves), fre- for early (within 1 week) neurosurgical decompression, replacement therapies advised as required. Hypopitu-
quently leads to diplopia, ptosis, facial pain, or numbness. generally performed via the trans-sphenoidal route. itarism is often permanent, regardless of whether
Increased intracranial pressure may occur, leading to Early pituitary surgery is associated with more com- surgery is performed.
impairment in the level of consciousness. Interference plete recovery of visual field deficits than observation.
with hypothalamic function may lead to manifestations
of sympathetic nervous system dysfunction, including
arrhythmias or disordered breathing.

In addition, some of the blood may enter the sub-
arachnoid space, leading to meningeal irritation. Fever
and neck stiffness may thus occur. Analysis of the cere-
brospinal fluid may reveal the presence of red cells and
increased protein content. It is therefore apparent that
pituitary apoplexy should be considered in the differential
diagnosis of patients with suspected subarachnoid hemorrhage
or meningitis.

Life-threatening pituitary failure may occur as a result
of central hypoadrenalism (adrenal crisis). Anterior
hypopituitarism has been reported in up to 90% of
patients with pituitary apoplexy. In contrast, central
diabetes insipidus is uncommon.

Pituitary apoplexy is often spontaneous and often
occurs at presentation of a pituitary adenoma. Identified
risk factors for the development of pituitary apoplexy
include trauma, anticoagulant use (including heparin or
warfarin), coagulation disorders, and administration of
dopamine agonists (including bromocriptine or caber-
goline) or hypothalamic-releasing hormones.

Magnetic resonance imaging typically reveals a focus
of hyperintensity (on noncontrast T1-weighted images)
within a sellar mass. A fluid-fluid level may also be
evident. Impingement on the optic chiasm or the cav-
ernous sinuses is frequently present. Laboratory testing
usually reveals evidence of hypopituitarism.

Pituitary apoplexy is a medical and neurosurgical emer-
gency. These patients should be hospitalized and receive
at minimum a stress dose glucocorticoid coverage to
prevent the development of adrenal crisis. Of note,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 143

Plate 5-33 Brain: PART I

Thalamic Anatomy THALAMIC NUCLEI AND THALAMOCORTICAL RADIATIONS
and Pathology Thalamocortical
radiations

Central sulcus

THALAMIC ANATOMY Thalamic nuclei Internal medullary lamina
The thalamus, along with the hypothalamus and sub- CM Centromedian Intralaminar nuclei
thalamus, form the diencephalon. Anatomically, the LD Lateral dorsal Other medial nuclei
thalamus sits above the hypothalamic sulcus in the third LP Lateral posterior
ventricle and consists of an egg-shaped structure, one MD Medial dorsal MD Midline (median) nuclei
on each side of the brain, connected by a bridge in the VA Ventral anterior Interthalamic adhesion
middle, the massa intermedia. The thalamus is divided VI Ventral intermedial
by a white matter sheet known as the internal medullary VL Ventral lateral
lamina, into the anterior, medial, and lateral groups of VPL Ventral posterolateral
relay nuclei. The lateral group in turn is divided into a VPM Ventral posteromedial
ventral tier of nuclei and the lateral nuclei proper. The
relay nuclei each projects to a specific territory in the Laterodorsal nucleus
cerebral cortex, and in turn neurons in layer VI of each
neocortical area project back to the same specific tha- Anterior nuclei
lamic relay nucleus. The relay nuclei typically innervate
layer IV of the cerebral cortex and provide most of the VL Pulvinar
sensory information to the cerebral cortex. LP/PO

In addition, there are several cell groups along the VA
midline and embedded in the internal medullary lamina
(the intralaminar nuclei). These nuclei send projections From globus VL CM Medial
more diffusely in the cerebral cortex, with projections pallidus and VI VPL VPM geniculate body
favoring layer V, and some project to the striatum as substantia nigra
well. They are sometimes viewed as having a more From Acoustic
generalized arousal function. Reticular nucleus cerebellum pathway
(pulled away)
By contrast, the reticular nucleus sits like a thin sheet Lateral geniculate body
along the surface of the thalamus. While nearly all of
the other thalamic neurons use the excitatory neuroÂ

Plate 5-34 Hypothalamus, Pituitary, Sleep, and Thalamus

AXIAL (HORIZONTAL) SECTIONS THROUGH THE FOREBRAIN:
LEVEL 6 — CAUDATE AND MID-THALAMUS

Thalamic Anatomy and Level of section (head of caudate and mid-thalamus)
Pathology (Continued)
Frontal lobe
parts of the parietal lobe temporal lobe. The lateropos- Claustrum External capsule
terior nucleus (LP) and posterior nucleus (PO) send axons Extreme capsule Anterior limb of
to the region just caudal to the primary somatosensory Insular cortex internal capsule
cortex. The pulvinar nucleus sends axons to the posterior Posterior limb of Head of caudate nucleus
parietal lobe and the lateral surface of the temporal internal capsule Genu of corpus
lobe. The neurons in these cell groups relay integrative Transverse temporal callosum
information that relates the visual and auditory map of gyrus of Heschl Genu of
the world to the personal space of the individual. Auditory radiations internal
Tail of caudate nucleus capsule
THALAMIC PATHOLOGY Temporal lobe
The most common neurologic disorders involving the Anterior
thalamus are small infarcts, sometimes called “lacunar Optic radiation horn of
infarcts.” These are believed to be due to the occlusion Temporal pole of lateral
of small thalamic perforating arteries that arise from the lateral ventricle ventricle
posterior cerebral and posterior communicating arter-
ies. The infarctions are often as small as a single nucleus, Choroid Columns
causing sensory loss on the contralateral body or face if plexus of fornix
the VPL or VPM nuclei are damaged; memory impair- Fimbria
ment if the MD and anterior nuclei are involved; or of fornix Third
motor weakness if the VL or VA nuclei are injured. The ventricle
lateral geniculate nucleus may be involved by an occlu- Occipital
sion of the anterior choroidal artery, resulting in hom- lobe Globus pallidus
onymous hemianopsia. After a pure sensory thalamic
infarct involving VPL or VPM, some patients go on Putamen
to develop pain in the deprived region, known as the Splenium of the
Dejerine-Roussy syndrome. corpus callosum
Thalamus
The thalamic perforating arteries may also hemor- Pulvinar
rhage. This often produces a thalamic syndrome similar
to ischemic infarction. However, as the hemorrhage â•…
grows it may press downward on the midbrain, causing 145
impairment of consciousness or a cluster of eye move-
ment problems known as Parinaud syndrome. In PariÂ

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SECTION 6â•…

DISORDERS OF
CONSCIOUSNESS

(COMA)

P late 6-1 Brain: PART I

Decorticate
rigidity

Plantar flexion Extension Flexion Adduction

Coma Decerebrate
rigidity

The term consciousness refers to a state of awareness of Plantar flexion Extension Flexion Pronation Extension Adduction
self and one’s environment. Assessing consciousness in Decorticate
another person relies on judging that individual’s per- Red nucleus
formance or behavior in some mental function and Oculomotor nerve (III) Decerebrate
arousal or response of awakening to a stimulus. The
word coma originates from the Greek koma (κωμα) and CN V
komatos meaning sleep, and deep sleep, respectively. and ganglion
In this section, the use of the word is as a term to (gasserian)
describe a potentially reversible state of unarousable
unresponsiveness, which is not sleep at all. By this The motor pattern of CN IV
strict definition, there should not be grades of coma,
but many physicians recognize the usefulness of describ- decorticate rigidity
ing and summating a patient’s behavioral response in
three domains of function: motor and verbal response occurs if brainstem
and eye opening (see Plate 14-15 on the Glasgow
Coma Scale score). However, equating the degree activity is impaired CN VII
of abnormal motor response with a depth of coma is above the level of
confusing because neural structures regulating motor CN VIII
function and consciousness are independent. That the red nucleus,
said, it is common practice to use the clinical integrity
of the motor cortex and brainstem nuclei, and their indicated by the CN VI
respective projections, as an indication of the level of dashed line. The
impairment.
motor pattern of
Appropriate localizing and flexor responses in a comatose decerebrate rigidity CN IX
patient imply that sensory pathways are functioning and
that the pyramidal tract from the cerebral cortex to occurs if brainstem Efferent fibers
effector is functioning at least partially (see Plate 6-5). activity is impaired CN XII Afferent fibers
When both sides are tested, unilateral absence of Mixed fibers
responses is consistent with interruption of the cortiÂ

Plate 6-2 Disorders of Consciousness

RETICULAR FORMATION: NUCLEI AND AREAS IN THE BRAINSTEM AND DIENCEPHALON
A. Thalamus and hypothalamus

Disorders of Consciousness B. Midbrain Thalamus:
Lateral RF of the midbrain Intralaminar
Consciousness is a state of wakefulness and awareness nuclei
of self and surroundings. In describing the state between Substantia nigra Reticular
normal consciousness and coma (unarousable unre- nucleus of
sponsiveness), many clinicians refer to a spectrum or Interpeduncular nucleus thalamus
gradation of states of diminished consciousness leading Midline nuclei
to coma. Lethargy has been used to describe a state of C. Pons Locus coeruleus Lateral
reduced wakefulness with deficits in attention; obtunda- A5 hypothalamic
tion, a reduction in alertness and interaction with the area through
environment; and stupor, state of unresponsiveness with Raphe nuclei (pontis) septal nuclei
little or no spontaneous movement, from which the
patient can be aroused temporarily with vigorous stim- Lateral RF Periaqueductal gray matter
ulation. These descriptions are imprecise and have, in Raphe nuclei (dorsal, central superior)
general, been applied to diffuse metabolic pathologies D. Medulla Ventral tegmental nucleus
causing brain dysfunction. Other terminology may be
more specific. For example, the vegetative state, which Lateral RF Parabrachial nucleus
may follow coma, describes a state in which the indi- Parapontine RF (lateral gaze center)
vidual is unaware but has sleep-wake cycles without Medullary RF (gigantocellular) Pontine RF (pontis, caudalis, ovalis)
detectable cerebral cortical dysfunction. The minimally
conscious state describes severely altered consciousness in Raphe nuclei (obscurus A2
association with minimal awareness of self or environ- pallidus, magnus) Respiratory nuclei
ment. Akinetic mutism is a condition of extreme slowing Rostral ventrolateral
or absence of bodily movement, with loss of speech. E. Spinal cord–medullary junction medulla (RVLM)
Wakefulness and awareness are preserved, but cogni-
tion is slowed because of bilateral lesions to the inferior cortex. The ventral tegmental area is located posterome- A1
frontal lobes, cerebral hemispheres, paramedian mesen- dial to the compact nigra, and its dopaminergic neurons Lateral reticular nucleus
cephalic reticular formation (RF), or posterior dien- project chiefly to the accumbens, amygdala, and pre-
cephalon. The locked-in syndrome is a state of preserved frontal cortex. Last, cholinergic neurons in the pons Lamina 7 - caudal RF
consciousness and cognition with complete paralysis of and midbrain project to the thalamus and regulate the A1, nucleus ambiguus; A2, solitary nucleus;
the voluntary motor system because of complete excitability of the thalamic nuclei. Taken together, â•… A5, trigeminal nucleus; RF, reticular formation.
destruction of corticospinal and corticobulbar pathways the outputs from all of these nuclei funnel through the diencephalon. The posterior root projects to relay
at or below the pons, or severe peripheral nervous paramedian midbrain reticular formation and divide nuclei and to intralaminar and other nuclei that have
system disease. Eye movements may be preserved, into posterior and lateral anterior roots in the widespread cortical connections. The anterior root
allowing for some communication, and cortical func- enters the lateral hypothalamic zone and is joined by
tion is intact. projections from other neurons in the hypothalamus
and basal forebrain. Lesions in the medulla or pons do
The anatomic substrate for a disorder in conscious- not affect arousal and wakefulness. However, parame-
ness is dysfunction in the reticular formation and the dian tegmental lesions in the rostral midbrain interrupt
ascending reticular activating system (ARAS) because acti- the ARAS and result in coma.
vation of the cerebral cortex during arousal and wake-
fulness depends on the influence of these structures. In
the absence of the ARAS, stimulation of any of the
sensory pathways (e.g., somatosensory, auditory, and
visual) cannot arouse the cerebral cortex. Three groups
of nuclei in the brainstem (locus ceruleus, raphe, and
ventral tegmental) contribute to the modulating effect
of the ARAS. An additional group of nuclei in the basal
forebrain (basal nucleus of Meynert) also contributes to
the diffuse modulating system.

The main nuclei of the reticular formation are
present in the medulla, pons, and midbrain. The locus
ceruleus is located beneath the lateral part of the floor
of the rostral pontine fourth ventricle. Its axons are
distributed to the cerebral cortex, thalamus, hypothala-
mus, cerebellar cortex, brainstem, and spinal cord.
These norepinephrine-containing neurons are involved
in the regulation of attention, cortical arousal, and the
sleep-wake cycle. The raphe nuclei are clustered in the
midline of the medulla, pons, and midbrain and conÂ

P late 6-3 Brain: PART I

FULL OUTLINE OF UNRESPONSIVENESS SCORE (FOUR)

Eye response
4 ϭ eyelids open or opened, tracking, or blinking to command
3 ϭ eyelids open but not tracking
2 ϭ eyelids closed but open to loud voice
1 ϭ eyelids closed but open to pain
0 ϭ eyelids remain closed with pain

Emergency Management Motor response
and Assessment and 4 ϭ thumbs-up, fist, or peace sign
Neurology Examination 3 ϭ localizing to pain
2 ϭ flexion response to pain
EMERGENCY MANAGEMENT 1 ϭ extension response to pain
AND ASSESSMENT 0 ϭ no response to pain or generalized myoclonus status
The many causes of coma are described elsewhere in
this atlas (see Sections 9—Cerebrovascular Circulation Brainstem reflexes
and Stroke; 11—Infection of the Nervous System; 4 ϭ pupil and corneal reflexes present
12—Neuro-Oncology; and 14—Head Trauma). Imme- 3 ϭ one pupil wide and fixed
diate care, regardless of the cause of diminished con- 2 ϭ pupil or corneal reflexes absent
sciousness, must include attention to adequacy of 1 ϭ pupil and corneal reflexes absent
spontaneous ventÂ

Plate 6-4 Disorders of Consciousness

PROGNOSIS IN COMA RELATED TO SEVERE HEAD INJURIES

Poorer Better

CT scan Subdural Normal
hematoma

Emergency Management and Age Old age Youth
Assessment and Neurology Pupillary Pupil Pupil
Examination (Continued) light remains constricts
reflex dilated
supportive measures, an opiate-receptor antagonist,
such as naloxone, can be given intravenously.

Next, after any necessary immediate treatment is
instituted, steps are taken to determine the cause of
coma with a robust and thorough history and appropri-
ate investigation. The patient’s family, friends, or physi-
cian can often supply useful diagnostic information.
Inquiries may elicit a history of diabetes; previous renal,
hepatic, or cardiac disease; severe depression; or drug
use or abuse. It is important to know what prescription
medications have been used and whether the patient
had experienced any prodromal symptoms, such as
headache, unilateral weakness, and ataxia, or previous
episodes of stupor.

NEUROLOGIC EXAMINATION Caloric Eyes do not Eyes deviate
It is important to carry out careful physical and neuro- testing deviate to irrigated
logic examinations. Evaluation of the patient’s sponta- with side
neous limb and bulbar movements, pupillary reactions, ice water
eye movements, and response to painful stimuli usually Localizes
indicates the level of brain lesion causing coma. If the Motor (defensive gesture)
patient is able to blink, yawn, lick, and swallow, which response â•…
are complex brainstem reflexes, lower brainstem func- to noxious the medial longitudinal fasciculus and parapontine
tion is preserved. stimuli reticular formation (pontine lateral gaze center); and
the vestibular nuclei and nerves (cranial nerve VIII). All
Pupillary size depends on the balance between sym- Decerebrate these structures are located within the pontine tegmen-
pathetic function (descending sympathetic fibers course rigidity tum. Vertical movements are controlled by centers in
in the lateral brainstem tegmentum) and parasympa- the rostral midbrain and caudal diencephalon.
thetic function (parasympathetic fibers exit with the movements toward the side of the stimulation Last, spontaneous limb movements should be
oculomotor [cranial nerve III] in the midbrain). (vestibulo-ocular reflex). In this position, the horizontal observed. If absent, then testing for a response to a
semicircular canal is in a vertical position, and the endo- noxious stimulus is appropriate.
Pupillary reaction depends on the afferent light stimu- lymph falls within the canal, thereby decreasing the rate
lus reaching the superior colliculus, as well as efferent of vestibular afferent firing. The eyes turn toward the
transmission through the oculomotor nerve. The light ipsilateral ear, with horizontal nystagmus to the contra-
reflex arc is located in the diencephalon and midbrain. lateral ear. Horizontal reflex eye movements are con-
trolled by the oculomotor, trochlear (cranial nerve IV),
Eye movements are observed by retracting the upper and abducens (cranial nerve VI) nerves and their nuclei;
eyelids and watching spontaneous activity. When the
head is rotated to one side—a maneuver to be per-
formed only when it is clear that the cervical spine is
not injured—the eyes should move fully and conju-
gately in the opposite direction if the appropriate brain-
stem oculomotor and vestibular centers are preserved
(doll’s eye phenomenon, or oculocephalogyric reflex).
When the head is moved to the right, the eyes move
conjugately to the left; when the head is moved down-
ward, the eyes should roll upward. Ice water introduced
into one ear canal with the patient’s head-of-bed
elevated to 30 degrees should evoke conjugate eye

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 151

P late 6-5 Brain: PART I

Clinical features Pathology (examples) Etiologies

Normal pupils (equal, reactive) Increased subarachnoid or
Normal oculo- extracerebral pressure
cephalic reflex Meningitis
phenomenon Subarachnoid hemorrhage
Bilateral subdural hematoma
Normal corneal reflex Metabolic encephalopathy
Absent or minor focal features (lateral Liver coma
paralysis, sensory or visual loss) Kidney coma
Carbon dioxide narcosis
Differential Diagnosis Hypoxia
of Coma Hypoglycemia
Hypercalcemia
When coma is caused by bilateral cerebral hemisphere Bilateral Hyponatremia
disease, swallowing, yawning, and spontaneous breath- cerebral Diabetic acidosis
ing are normal. The eyes rove spontaneously from hemisphere Hyperosmolar coma
side to side, and the limbs move symmetrically to stimu- disease Toxins or drug overdose
lus. Pupillary and oculomotor reflexes are preserved.
Toxic and metabolic disorders are the most common Bilateral hemispheric Barbiturates
cause of coma resulting from bilateral hemisphere dys- Alcohol
function. Encephalitis, hemorrhage, or infection in the swelling (small ventricles, Other sedative drugs
meninges and subarachnoid space can also adversely obliterated sulci, Lead
affect bilateral hemisphere function. Although infarcts, rounded edges) Multifocal cerebral disease
hemorrhages, tumors, or abscesses can involve both Sequential infarctions
hemispheres, the neurologic deficit becomes bilateral Multiple abscesses
only sequentially. Encephalitis
Multiple areas of brain tumor
When a hemispheric lesion compresses the brain- Multiple cerebral contusions
stem, the patient usually has signs or symptoms of
hemisphere dysfunction, such as hemiparesis. Any Cerebral
space-occupying lesion, such as subdural hematoma, Tumor
infarction, hemorrhage, or tumor, may compress the Unilateral Hemorrhage
rostral brainstem and cause coma. As the lesion enlarges, cerebral Abscess
intracranial pressure rises, and headache, vomiting, hemisphere Third cranial nerve palsy, non- Infarction
decreased alertness and papilledema develop. Signs of lesion with reactive pupil, ptosis Contusion
rostral brainstem diencephalic dysfunction follow. The Extracerebral
midbrain and pons are disrupted sequentially, and signs compression Subdural hematoma
of lower brainstem failure are added to dysfunction of of brainstem
rostral structures.
Right temporal hemorrhage Epidural hematoma
An intrinsic brainstem lesion can cause coma by com- from trauma, with swelling
promising the function of the medial tegmental struc- Contralateral hemiparesis of right hemisphere
tures bilaterally. Primary diencephalic brainstem lesions
are usually due to stroke, either hemorrhagic or infarc- Primary Small pinpoint pupils, Infarction
tion. Head trauma may also directly injure the brain- brainstem absent horizontal Hemorrhage
stem. In midbrain lesions, the pupils are dilated or in lesion eye movements Severe metabolic disturbance,
midposition, and bilateral oculomotor nerve palsy
occurs. The eyes rest downward and outward and do Rigid limbs Large pontine sedative or phenytoin
not adduct or move vertically. Decerebrate posturing of hemorrhage overdose
the limbs is present. Pontine infarct or hematoma cause Severe anoxia
small, poorly reactive pupils and impaired vertical gaze. Phenytoin
The eyes may rest downward and inward, and one eye Narcotics
may be lower than the other. Brainstem function rostral
to the lesion is preserved. Pontine lesions cause small, Cerebellar Vomiting Infarction
reactive pupils, failure of horizontal eye movements, lesion with Inability to walk Hemorrhage
preservation of vertical eye movements (sometimes secondary or ataxia Tumor
with spontaneous bobbing), and decerebrate posturing. brainstem Abscess
Medullary lesions may compromise vasomotor control compression Sixth Contusion
and breathing. Toxic disorders affecting the brainstem
and cerebral hemispheres at multiple levels cause signs cranial Large cerebellar
inconsistent with any single anatomic locus. nerve hemorrhage
palsy
Cerebellar space-occupying lesions cause ataxia and vom-
iting, often followed by abducens (cranial nerve VI) â•…
nerve or lateral gaze palsy to the side of the lesion. Signs
of lower brainstem dysfunction in the pons and medulla of pathology. Endotracheal intubation, controlled result of metabolic encephalopathy from exogenous
then develop. mechanical ventilation, and osmotic diuresis are under- intoxication, for instance, drug overdose, alcohol intoxi-
TREATMENT taken while cranial computed tomography (CT) is cation, or overmedication. Endogenous intoxication is
If a cerebral or cerebellar lesion compresses the brain- performed to determine whether the patient requires caused by organ failure (the lungs and carbon dioxide
stem, immediate treatment is required to avoid irreÂ

Plate 6-6 Disorders of Consciousness

Border zone ischemia (shock, circulatory insufficiency)

Pump with three outflows, If pump is weak,
one outflow blocked. deficit is between
Deficit occurs in zone zones supplied by
supplied by it. three outflows.

Cerebral artery zones Border zone
Anterior Middle Posterior between artery zones

Hypoxic-Ischemic
Brain Damage

At a national level, out-of-hospital cardiac arrests are Infarction Infarction
an all-too-frequent occurrence. One quarter of indi- If brain artery is If total blood flow is
viduals experiencing such an arrest will receive emer- blocked, infarction inadequate, deficit is
gency cardiopulmonary resuscitation. However, fewer occurs in zone mostly at border zone
than 20% of these events will lead to survival at hospital supplied by that vessel. between supply zones.
discharge even with the combined efforts of emergency
and hospital critical care services. Of those who do Diffuse cortical necrosis; persistent vegetative state
survive, many will have profound neurologic injury and
disability. Few anoxic neurons in early anoxia Extensive laminar necrosis

Hypoxic-Ischemic Encephalopathy. Hypoxic- â•…
ischemic encephalopathy is the term used to describe
such injury after cardiac arrest or severe hypoxia causing with severe impairment of motor development and benefit. The only treatment that has been shown to
global injury, or prolonged hypotension causing arterial function. Loss of Purkinje cells in the cerebellum leads to improve the probability of a good outcome in adults
border zone injury. Many variables determine the ataxia and action myoclonus. after ventricular fibrillation or pulseless ventricular
extent and location of injury: the completeness of cir- tachycardia cardiac arrest, or in babies with birth
culatory collapse (full cardiac arrest or hypotension, Hypothermia Treatment. Many drug and anesthetic asphyxia, is physical treatment with the induction of
with some preserved cardiac output), the duration of treatments have been tested in the setting of cardiac moderate hypothermia to achieve a core body tempera-
circulatory compromise accompanying circulatory arrest. The idea has been to use agents that reduce brain ture of 32° C to 34° C. In infants, isolated cooling of
failure, and the blood glucose level at the time of the metabolism or limit the cascade of cellular events that the head after birth asphyxia also achieves a desired
event. Apnea or hypoxia (as in carbon monoxide poison- lead to neuronal death. Currently, no single drug therapeutic effect.
ing or strangulation) with preserved circulatory func- therapy has been found to provide significant clinical
tion often results in pallidal and thalamic necrosis with
preservation of cerebral cortex. Persistent hypotension
leads to arterial border zone ischemic lesions at the
limits of the anterior and middle cerebral artery terri-
tories and the middle and posterior cerebral artery
territories.

Cardiac arrest can cause hippocampal damage, basal
ganglia injury, middle laminar necrosis of the cerebral
cortex, and lesions of the cerebellum and brainstem
nuclei. The order in these regions of the brain also
represents the hierarchy of injury. The most vulner-
able region to brief cerebral ischemia is the hippo-
campus, and the phrase often used to describe this
phenomenon is hippocampal regional vulnerability. Arte-
rial border zone ischemia results in arm weakness,
incoordination during visually directed behavior, and
defective visual and spatial perception. In children,
severe hypotension can lead to more extensive injury,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 153

Plate 6-7 Brain: PART I

The vegetative state. The condition is called persistent when it lasts
without change for more than 1 month.

This patient is yawning but not in conscious Subarachnoid hemorrhage was
response. Such patients may startle, look the cause of the patient’s state.
about, or yawn, but none of these actions is
in conscious response to a specific stimulus.

Vegetative State and
Minimally Conscious State

Survivors of some severe circulatory event, who are Noncontrast brain CT demonstrating ominous sign of diffuse brain injury and possible prelude to a
initially comatose, may pass through a spectrum of persistent vegetative state: subtle disappearance of normal differentiation between gray and white
clinical conditions before partially or fully recovering matter
consciousness. If, after having been in a coma, the
patient opens the eyes but remains unable to initiate Conscious control Vegetative state
voluntary motor activity, this behavior marks the transi-
tion to what is called the vegetative state (VS). The Locked-in syndrome Minimally conscious state 11mg/100 g/min
further transition to minimally conscious state (MCS) is 10
characterized by reproducible evidence of simple vol- 9
untary behavior. Emergence from MCS is signaled by
the return of functional communication or object use. 8
Further developments lead to outcomes ranging from 7
severe disability to a good recovery. If, however, the 6
patient remains in the VS for more than 1 month after 5
the occurrence of brain damage, this condition is called
the persistent vegetative state (PVS). This state is not 4
necessarily irreversible. Reversibility is much less likely 3
in patients in the permanent vegetative state, that is, in 2
VS lasting more than 3 months after hypoxic-ischemic 1
damage or 1 year after traumatic brain injury. 0

To date, VS and the MCS have both been defined by Color-coded cerebral metabolic rate for glucose scans in the sagittal plane showing reduced
clinically observed behavioral responses. For example, metabolism in the precuneus in a patient in a vegetative state (VS, top right) and in a patient in a
VS is characterized by wakefulness in the absence of any minimally conscious state (MCS, bottom right). The red area in the Conscious control (top left) and
awareness of self or environment. Typically, such a Locked-in syndrome (bottom left) scans indicate normal metabolism. Reprinted with permission
person retains autonomic functions with variable pres- from Laureys S, Owen AM, Schiff ND. Brain function in coma, vegetative state, and related
ervation of cranial and spinal reflexes but exhibits no disorders. Lancet Neurol 3:537-546, 2004.
clinical evidence of sustained, reproducible, purposeful,
or voluntary behavioral responses to multisensory stim- variable abnormalities in the basal ganglia, and cerebel- â•…
ulation, nor evidence of language comprehension or lum, and severe thalamic damage. At a functional level,
response to command. MCS describes a spectrum of cerebral metabolic studies and magnetic resonance syndrome in a large-scale frontoparietal network as a
behavior that, at its most basic description, requires imaging have identified that the behavior during result of damage to long-range connectivity. The struc-
evidence of visual pursuit and, at best, involves inter- VS and MCS represents a functional disconnection tures involved include the lateral and medial frontal
mittent responses to command. However, it has now regions, parietotemporal and posterior parietal areas,
become apparent using newer technologies, such as and posterior cingulate and precuneal cortex.
functional magnetic resonance imaging, that the dis-
tinction between VS and MCS cannot be based purely
on observation. A notable proportion of patients con-
sidered to be in VS retain some awareness that is not
consistent with their externally observable behavior.

The neuropathology of postanoxic VS and MCS is
indistinguishable. There is characteristically little or no
damage in the brainstem, but such patients commonly
have evidence of diffuse necrosis in the cerebral cortex,

154 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 6-8 Disorders of Consciousness

Supraorbital
pressure

Brain Death Feels for breath on cheek

Severe hypoxic-ischemic encephalopathy may result in Open No spontaneous
brain swelling of such severity that all blood flow into your respiration
the cranium is blocked, thereby worsening the ischemia eyes.
to a terminal stage. Brain death is a clinical diagnosis Coma; no response Ice water in ear: eyes do not move
based on the absence of neurologic function in the to voice, pain or
context of a diagnosis that has resulted in irreversible other stimuli Corneal reflex lost
coma. In the United States, it indicates death of the â•…
entire brain; in the United Kingdom, it refers to death Pupils dilated, unresponsive to light water and is triggered by the cerebral cortex. The slow
of the brainstem. Coma and apnea must coexist. A com- phase of nystagmus is caused by the oculovestibular
plete neurologic examination that includes the elements “Doll’s eyes”: head turned reflex. In comatose patients with an intact response,
outlined in Plates 6-4 and 6-9 is mandatory to deter- sharply to side, eyes remain cold water will turn both eyes slowly toward the side
mine brain death, with all components appropriately centered being irrigated. These movements are comparable with
documented. The current recommendation in adults and the patient’s head is kept in the midline. Each ear is the slow phase of the nystagmus induced in normal
is that a single evaluation suffices for the diagnosis of irrigated with 50 to 60╯mL of ice water, and this should individuals. Caloric-induced movements are absent
brain death. In children, two assessments should be elicit no movement of the eyes during one minute of when the midbrain or rostral pons is impaired and the
performed, with the duration of interval between tests observation. The aim is to reduce local temperature at oculovestibular path is no longer intact.
varying with age. the tympanic membrane so that there is a gradient with
core body temperature. Both sides are tested with an
Before starting the assessment for brain death, interval of several minutes. In normal individuals, nys-
reversible conditions or conditions that can interfere tagmus is induced in both eyes. The fast phase is toward
with the neurologic examination must be excluded. For the side opposite that which is being irrigated with cold
example, hypothermia, hypotension, and metabolic dis-
turbance that could affect the neurologic examination
must be corrected. After cardiopulmonary resuscitation
or use of therapeutic hypothermia, evaluation for brain
death should be deferred for 24 to 48 hours, or longer
if there are concerns or inconsistencies in the examina-
tion. Sedatives, analgesics, neuromuscular blockers, and
anticonvulsant agents should be discontinued for a rea-
sonable period, based on the elimination half-life of the
pharmacologic agent, to ensure that they do not affect
the examination; blood or plasma levels can be used to
confirm that the drug is in the low to midtherapeutic
range.

The components of the clinical neurologic examination
consistent with brain death include presence of coma,
loss of all brainstem reflexes, apnea (see Plate 6-9), and
absence of spontaneous or induced movements, but
excluding spinal cord events such as reflex withdrawal
or spinal myoclonus.

Irreversible Coma. The patient must exhibit com-
plete loss of consciousness, vocalization, and volitional
activity. Noxious stimuli should produce no eye opening
or eye movement, and no motor response other than
spinal-mediated reflexes.

Loss of All Brainstem Reflexes. The patient exhibits
the following: midposition or fully dilated pupils that
do not respond to light, either directly or consensually
(assessment 1); absence of movement of bulbar muscu-
lature, including facial and oropharyngeal muscles, such
as in response to deep pressure on the condyles at the
level of the temporomandibular joints and over the
supraorbital ridge (assessment 2); absent corneal reflexes
so that touching the cornea with a sterile cotton swab
does not elicit any eyelid movement (assessment 3);
absent oculovestibular reflexes (assessment 4); and
absence of gag and cough on stimulation of the poste-
rior pharynx with a tongue blade or suction catheter
(assessment 5). Assessment of these brainstem functions
should be carried out sequentially and systematically
because they relate to different levels of brainstem func-
tioning (see Plate 6-9). The oculovestibular reflex is
tested by irrigating each ear with ice water (caloric
testing) after first checking that the external auditory
canal is not occluded by wax and that the eardrum is
intact. The head of the bed is elevated to 30 degrees,

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 155

P late 6-9 Brain: PART I

Ventilatory Patterns and Posterolateral view Thalamus (cut surface)
the Apnea Test of brainstem Lateral geniculate body
Optic tract
Pulvinars of thalami Medial geniculate body
Pineal body Brachia of superior and inferior colliculi
Cerebral crus
Superior colliculi Pons
Inferior colliculi Trigeminal nerve (V)
Middle cerebellar peduncle
Trochlear nerve (IV) Vestibulocochlear nerve (VIII)
Superior medullary Facial nerve (VII)
Inferior cerebellar peduncle
velum Hypoglossal nerve (XII)
Superior cerebellar Accessory nerve (XI)

peduncle Olfactory tract
Rhomboid fossa of Anterior perforated
4th ventricle substance
Glossopharyngeal (IX) and Infundibulum (pituitary
vagus (X) nerves stalk)
Mammillary bodies
Cuneate tubercle Temporal lobe (cut surface)
Gracile tubercle Oculomotor nerve (III)
Trochlear nerve (IV)
Dorsal roots of Trigeminal nerve (V)
1st spinal nerve (C1) (sensory root)
Abducent nerve (VI)
Cuneate fasciculus Facial nerve (VII) and
Gracile fasciculus intermediate nerve
(of Wrisberg)
Central Pattern Generator for Breathing. In health, Anterior view Vestibulocochlear
the anatomic origin of the cyclic pattern of breathing of brainstem nerve (VIII)
is the brainstem. Sectioning the brainstem above the Flocculus of cerebellum
pons leaves breathing unaffected when the vagus nerve Optic chiasm Choroid plexus of 4th
(cranial nerve X) carrying afferent information from the Optic tract ventricle
lungs is intact. Vagotomy results in a reduction in the Tuber cinereum Glossopharyngeal nerve
breathing frequency and an increase in tidal volume. Cerebral crus (IX)
Transection below the medulla results in complete Lateral geniculate body Vagus nerve (X)
cessation of breathing. Sectioning above the central Posterior perforated Hypoglossal nerve (XII)
medulla results in rhythmic but irregular breathing, substance Accessory nerve (XI)
with vagotomy slowing the irregular pattern. Transec-
tion at the level of the upper pons leads to a slowing of Pons Vagus Nerve Vagus Nerve
respiration and an increase in tidal volume. If both Middle cerebellar Intact Transected
vagus nerves are cut, the result is the cessation of
breathing at full inspiration (called apneusis), or inspira- Pons peduncle The respiratory
tory spasms interrupted by intermittent expirations Olive pattern after
(called apneustic breathing). The central pattern generator Pyramids lesion (with or
for breathing is located within the medullary center. without vagus
Ventral roots of 1st nerve intact) at
The areas of the brainstem that modulate ventilation spinal nerve (C1) three levels in
are co-localized to the same structure containing the the brainstem
central pattern generator. The areas that are sensitive Decussation of pyramids and high spinal
to changes in hydrogen ion concentration and blood cord.
composition of respiratory gases (chemosensitive areas) Brainstem
are localized to the ventral surface of the medulla, bilat- Level 1Medulla
erally, at the level of cranial nerve roots VIII to XI.
These areas are very superficial, lying about 200 µM Pneumotaxic
below the surface. Additional chemosensitive areas have center
also been found caudally in the area of the XII cranial Level 2
nerve root (hypoglossal). All of these central chemore-
ceptors are sensitive to local changes in cerebrospinal Apneustic
fluid pH induced by rising Paco2. Failure to respond to center
an adequate Paco2 stimulus indicates a failure in the Level 3
medullary respiratory centers.
Medullary
The apnea test is performed if the brainstem reflexes center
are all absent, and it is a requirement of brain death
testing (see Plate 6-8). There are a number of tech- Spinal
niques that are used to perform this test in the intensive cord
care unit. However, the essential feature in brain death
is that the patient must have complete absence of respi-
ratory effort by formal testing using the endogenous
increase in arterial partial pressure of carbon dioxide
(Paco2) as the stimulus to breathing. At baseline, the
patient should start with a Paco2 of approximately
40╯mm Hg. The stimulus to breathing is considered
adequate when there has been a rise in Paco2 by
20╯mm Hg to some value greater than 60╯mm Hg.

156 â•…

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 7â•…

BASAL GANGLIA AND
MOVEMENT
DISORDERS

P late 7-1 Brain: PART I

BASAL NUCLEI (GANGLIA)
Horizontal sections through cerebrum

A B Genu of corpus callosum

Septum pellucidum

Head of caudate nucleus

Column of fornix

Anterior limb

Genu of internal capsule

Posterior limb

Extreme capsule

Putamen Lentiform nucleus
Globus pallidus

3rd ventricle

External capsule

Claustrum
Habenula
Tail of caudate nucleus

Anatomy of the Basal Hippocampus and fimbria
Ganglia and Related
Structures Occipital (posterior) horn
of lateral ventricle
OVERVIEW OF MOVEMENT DISORDERS
For the past 30 years, movement disorders have Pineal body
encompassed the study of a group of conditions char­ Crus of fornix
acterized by poverty of movement, the akinetic-rigid Splenium of corpus callosum
syndromes, and those with excessive movements, the A B Choroid plexus of lateral ventricle
hyperkinetic movement disorders (tremor, dystonia, myo­
clonus, chorea/ballism, tics, and others). This tradi­ Organization of
tional view, in which disorders of basal ganglia resulted basal nuclei (ganglia)
in the aforementioned syndromes, has now expanded to
include the ataxias and disorders of gait and posture. Caudate Putamen Globus
Advances in surgical techniques and imaging studies nucleus pallidus
have broadened the clinical horizon and catchments of
the movement disorders specialist. With the increasing Cleft for internal capsule
indications for botulinum toxin therapy, spasticity and
others disorders are now managed by many movement Striatum Lentiform Caudate Body
disorders neurologists. Corpus nucleus nucleus Head
striatum
Abnormal involuntary movements (AIMs) should be Thalamus
viewed as clinical signs with many causes. For example,
parkinsonism may be the clinical manifestation of a Levels of A A
variety of conditions with different or unclear etiolo­ sections B B
gies. Defining the broad category of the movement dis­ above Pulvinar
order in a given patient precedes the classic approach to
neurologic diagnosis: localizing the lesion and determin­ Lentiform nucleus Medial genic-
ing the etiology of the condition. A careful history with (globus pallidus ulate body
particular attention to family background, pregnancy, medial to putamen) Lateral genic-
labor and delivery, early developmental milestones, ulate body
trauma, infections, medical and psychiatric comorbidi­ Amygdaloid body Tail of caudate nucleus
ties, and use of illicit drugs and medications, especially
neuroleptics, are particularly important when first Interrelationship of thalamus, lentiform nucleus, caudate
evaluating a patient with abnormal involuntary move­ nucleus, and amygdaloid body: left lateral view
ments and may suggest the underlying cause. A detailed
general medical examination with emphasis on eye â•…
movements, presence of Kayser-Fleischer rings (sug­
gesting Wilson disease), and funduscopic examination or deposits (defining phakomatosis, xeroderma pigmen­ placed in context, the cause may become apparent and
looking for retinopathy and optic nerve abnormalities tosum, vitaminosis, gastrointestinal disease, malabsorp­ proper ancillary testing may be undertaken.
(papillitis, papilledema, or optic nerve atrophy suggest­ tion, calcinosis, or cholesterol deposits, especially at the
ing demyelinating diseases, metabolic disorders, or muscle tendons) may prove rewarding. Searching for ANATOMY OF THE BASAL GANGLIA AND
mitochondrial cytopathies); organomegaly (betraying additional clues, with a carefully performed neurologic RELATED STRUCTURES
metabolic or storage diseases); and skin discolorations examination, will help in the understanding of the Anatomically, the basal ganglia constitute a complex
patient’s condition. circuitry that includes neurons of the caudate nucleus,
putamen, subthalamic nucleus (STN) globus pallidus,
Once the abnormal movements have been classified,
and the neurologic accompaniments documented and

158 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-2 Basal Ganglia and Movement Disorders

BASAL GANGLIA AND RELATED STRUCTURES

Connections of the basal ganglia

Frontal Area

6 Precentral cerebral cortex
Area 4
Head
Caudate nucleus Body Area 3, 7, 2Postcentral
cerebral cortex
Tail

Claustrum

Temporal cortex

Thalamus Ventral anterior nucleus Putamen Lenti-
Ventral lateral nucleus External segment Globus form
Centromedian nucleus Internal segment pallidus nucleus
Subthalamus Fasciculus lenticularis
Hypothalamus Ansa lenticularis
Substantia Corticorubral, corticobulbar, and
nigra Pars compacta corticospinal fibers
Pars reticularis Raphe nuclei from upper pons and midbrain (shown separately)

Anatomy of the Basal Projections back to cortex Projections from cortex
Ganglia and Related and basal ganglia and basal ganglia
Structures (Continued) Cortical projection
Dopaminergic Thalamic and Corticostriatal Striatal projection
and substantia nigra (SN). The output of the basal projection of subthalamic projection Pallidal projection
ganglia is directed at the motor thalamus (and from substantia nigra projections
there to the frontal cortex) and the pedunculopontine
nucleus (PPN). Coronal section of brain: posterior view Corpus callosum
Septum pellucidum
Globus Pallidus. Divided by the internal medullary White arrow in left Lateral ventricle
lamina into an external (GPe) and internal (GPi) seg­ interventricular Body of caudate nucleus
ments, the globus pallidus borders laterally with the foramen (of Monro) Choroid plexus of lateral ventricle
putamen, dorsomedially with the internal capsule Stria terminalis
and optic tract and ventrally with the substantia innom­ Ependyma Superior thalamostriate vein
inata, which, in turn, contains three major functional Pia mater Body of fornix
anatomic systems: the ventral striatopallidal system, Internal cerebral vein
the extended amygdala, and the nucleus basalis of Tela choroidea of 3rd ventricle
Meynert. The latter nucleus, with its cholinergic and Choroid plexus of 3rd ventricle
γ-aminobutyric acid (GABA-ergic) projections, plays an Thalamus
important role in disorders of memory and the treat­ Putamen
ment of dementias. The GPi is a major efferent struc­ Globus pallidus Lentiform nucleus
ture of the basal ganglia, using three major projection
systems: the ansa lenticularis, the lenticular fasciculus, Internal capsule
and the pallidotegmental tract. The ansa lenticularis 3rd ventricle and interthalamic adhesion
sweeps ventromedially around the internal capsule, Hypothalamus
joining the lenticular fasciculus to form the thalamic Tail of caudate nucleus
fasciculus, which, in turn, projects to different thalamic Optic tract
nuclei, especially the ventral anterior (VA), ventral Choroid plexus of lateral ventricle
lateral (VL), centromedian, and parafascicular intrala­ Temporal (inferior) horn of lateral ventricle
minar nuclei of the thalamus. The pallidotegmental Fimbria of hippocampus
tract terminates in the pedunculopontine nucleus. Hippocampus
Dentate gyrus
Caudate Nucleus. The caudate nucleus resembles an Mammillary body
elongated and curved exclamation mark. Its main part Parahippocampal gyrus
is an expanded head directly continuous with a smaller
and attenuated body that merges into an elongated â•…
tail. The head bulges into the anterior horn of the
lateral ventricle and forms its sloping floor. The caudate The head tapers into the narrower body that lies in the it separates from the thalamus and lentiform nucleus by
nucleus is separated from the lentiform nucleus by the floor of the central part of the lateral ventricle, lateral the inferior part of the internal capsule and by fibers
anterior limb of the internal capsule, but the separation to the superior surface of the thalamus and separated (including some from the anterior commissure) that
is incomplete because the head of the caudate nucleus from it by a shallow sulcus lodging the stria terminalis spread into the temporal lobe.
and the putamen are connected, especially anteroinfe­ and thalamostriate vein. The tail turns downward along
riorly, by bands of gray matter traversing the white the outer margin of the posterior surface of the thala­ Amygdaloid Body. The tail of the caudate nucleus
matter of the anterior limb. This admixture of gray and mus, with the stria terminalis still lying in a slight ends in a small, almond-shaped expansion, the amygda­
white matter produces the striated appearance that jus­ groove between them. It then curves forward into the loid body, which is a complex of several small nuclei
tifies the term “corpus striatum” applied to these nuclei. roof of the inferior horn of the lateral ventricle, where located in the forepart of the roof of the inferior horn
of the lateral ventricle. The stria terminalis issues from

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 159

Plate 7-3 Brain: PART I

SCHEMATIC AND CROSS SECTION OF BASAL GANGLIA
Simplified schematic diagram of basal ganglia circuitry

Cerebral cortex Glutamatergic
Caudate nucleus GABA
Acetylcholine
Dopamine

Putamen

Globus pallidus Centromedian
(external segment) parafascicular
Globus pallidus complex
(internal segment)

Subthalamic nucleus
Substantia nigra (pars compacta)
Substantia nigra (pars reticularis)

Pedunculopontine nucleus

Anatomy of the Basal Pons
Ganglia and Related
Structures (Continued) Axial (horizontal) sections through the forebrain

the amygdaloid body and runs along the medial side Claustrum Frontal lobe
of the caudate nucleus until it reaches the vicinity of External capsule
the ipsilateral interventricular foramen. Here, some Extreme Anterior limb of
of its fibers join the anterior commissure, others pass capsule internal capsule
to the “septal” region adjacent to the lamina terminalis, Head of caudate nucleus
and the remainder descends to the hypothalamus and Level of section Insular Genu of
anterior perforated substance. (head of caudate cortex corpus callosum
and midthalamus) Posterior limb of Genu of
A nuclear midbrain complex, the substantia nigra internal capsule internal
(SN), is divided into a pigmented and dopamine- capsule
containing pars compacta (SNc) and a cell-poor, Transverse temporal
pigment-free pars reticularis (SNr). Most dopaminergic gyrus of Heschl Anterior
projections go to the striatum, while a smaller propor­ horn of
tion of SNc axons terminate in the prefrontal cortex. Auditory radiations lateral
The SNr is a major primary efferent structure of the Tail of caudate nucleus ventricle
basal ganglia, along with GPi. SNr goes primarily to
thalamus, PPN, and the superior colliculus. Temporal lobe Columns
of fornix
A biconvex structure, the subthalamic nuclei (STN) Optic radiation
receives glutamatergic inputs from the cerebral cortex, Third ventricle
GABA inhibition from the GPe, and provides glutama­ Temporal pole Globus pallidus
tergic innervations to the GPe, GPi, SN, and PPN. of lateral ventricle Putamen
The STN has become a structure of interest because of Splenium of the
its pivotal role in our understanding of basal ganglia Choroid plexus corpus callosum
function. Fimbria of fornix Thalamus
Pulvinar
The postsynaptic dopamine receptors are divided Occipital lobe
into two major broad categories, D1/D5 and D2, D3,
D4 family of receptors, segregated into two main path­ â•…
ways. The direct pathway, subserved by D1 dopamine
receptors, sends its projections to the subthalamic chiefly via the direct pathway, tonic inhibition to the structure of the basal ganglia. Most fugal pathways pass
nuclei via the GPi, and the indirect pathway, via the D2 thalamus is removed, releasing the cortical generators throught the fields of Forel. Presently, the STN is the
family of receptors, influences the STN via the GPe. for normal or desired movement to occur. Therefore preferred target for the surgical treatment of idio­
the presence of abnormal involuntary movements pathic Parkinson disease (iPD), the ventral intermedi­
Recently, the excitatory-inhibitory interplay between results from either failure of inhibition or excessive excita- ate (VIM) thalamus for the treatment of essential and
the direct and indirect pathways has been conceptual­ tion of the surrounding structures. certain other types of tremor, and the GPi for dystonia,
ized as focused selection and tonic inhibition (surround with deep brain stimulation (DBS) being the favored
inhibition hypothesis). By suppressing excitability in an Based on the models discussed above, it is important surgical procedure.
area that is surrounding an activated neural network, to recognize the pallidum as the major outflow
neuronal activity focuses to select desired responses.
Simultaneously, other pallidal neurons projecting to the
thalamus, act to permit desired movements. By decreas­
ing their discharge, through focused striatal output

160 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-4 Basal Ganglia and Movement Disorders
PARKINSONISM: EARLY MANIFESTATIONS

Tremor often improves
or disappears with
purposeful function

Tremor of one hand is a
frequent early manifestation
of parkinsonism

Akinetic-Rigid Syndrome,
Parkinsonism, or
Parkinsonian Syndrome

The parkinsonian syndrome is operationally defined by Difficulty in performing
the presence of Tremor, Rigidity, Akinesia, and Postural/ simple manual functions
gait disturbances (pneumonic: TRAP). The diagnosis may be initial symptom
of parkinsonism is readily made if a given individual has
two of the four cardinal features at the time of presenta­
tion. Although there are many causes for the parkinso­
nian syndrome, idiopathic Parkinson disease is by far
the most common cause, affecting 1% of the population
older than 50 years. It has an insidious onset and pro­
gresses slowly at a variable rate for 10 to 20 years or
more before culminating in severe disability.

IDIOPATHIC PARKINSON DISEASE Writing shows micrographia Improvement after levodopa therapy
Idiopathic Parkinson disease is characterized by the and effects of tremor
presence of tremor, rigidity, or bradykinesia early in the ocular impersistence, may be present in PSP, MSA, â•…
course of the illness, with postural and/or gait distur­ corticobasal degeneration (CBD), Huntington disease
bances usually developing late in the course of the (HD), and the cerebellar ataxias in variable combina­ diagnosis. Although it is usually difficult to diagnose
disease. The presence of atypical symptoms and the rate tions and degrees of severity. Parkinson disease in the preclinical (premotor) stage,
of progression of the disease are important in distin­ It is estimated that approximately 80% of the dopa­ anosmia, constipation, and mood and personality
guishing Parkinson disease from other parkinsonian minergic neurons in the substantia nigra have been lost changes may precede the onset of motor symptoms by
syndromes. For example, early-onset postural instabil­ by the time that Parkinson disease is first diagnosed; a few years. For most patients, the onset of motor symp­
ity, falls, and gait disturbances characterize progressive hence the initial degenerative process leading to par­ toms is subtle and may be obvious first to family
supranuclear palsy (PSP); marked autonomic distur­ kinsonism begins several years before the clinical members or coworkers.
bances, such as erectile dysfunction in men or urinary
bladder incontinence in women may herald the onset Dopamine deficiency is responsible for the patho­
of multiple system atrophy (MSA). Stooping, a masked physiology of motor symptoms in Parkinson disease.
facies, decreased blinking, micrographia, and hypopho­
nia, are common features of parkinsonism but are not
unique to Parkinson disease and may be present in
other parkinsonian syndromes. Severe anterocollis and
camptocormia (bent spine) are more likely to be due to
MSA or paraspinalis muscle fatty atrophy/myopathy
rather than Parkinson disease (see Plate 7-5). Excessive
neck rigidity, priÂm

P late 7-5 Brain: PART I

PARKINSONISM: SUCCESSIVE CLINICAL STAGES

Stage 1: unilateral
involvement; blank
facies; affected arm in
semiflexed position with
tremor; patient leans to
unaffected side

Akinetic-Rigid Syndrome, Stage 4: significant Stage 2: bilateral
Parkinsonism, or disability; limited involvement with
Parkinsonian Syndrome ambulation with early postural
assistance changes; slow,
(Continued) shuffling gait with
may complain of fatigue and weakness. Fatigue may be decreased
Although symptoms improve with dopaminergic disabling in up to 75% of patients. The hand assumes excursion of legs
replacement therapy, tremor and postural and gait dis­ the so-called striatal posture with dorsiflexed wrist,
turbances tend to have only a partial response to treat­ adducted fingers, flexed metacarpophalangeal and distal Stage 3: pronounced
ment, particularly in the later stages of the disease, interphalangeal joints, and extended proximal interpha­ gait disturbances and
suggesting the substrate of such symptoms may lie langeal joints. In some patients, a “striatal foot” may be moderate generalized
somewhere else along the central nervous system. present consisting of a varus position with clawing of disability; postural
Indeed, it has been shown that the pedunculopontine toes. In stage 3 disease, retropulsion and propulsion instability with
nuclei (PPN), a cholinergic structure closely linked to reflect increasing impairment of postural reflexes and tendency to fall
the striatonigral system, may play a major role in gait
control. In addition, preliminary studies using PPN- Stage 5: complete
targeted neuromodulation have shown mild improve­ invalidism; patient
ments in gait difficulties and freezing in some patients, confined to bed or
although the final outcomes in such studies are unclear chair; cannot stand
at this time. or walk even with
assistance
Tremor is a classic feature of parkinsonism. Typically,
it is a rest tremor, disappearing with movement but â•…
resuming when a static posture is achieved, and has a
3-Hz frequency. Although it is most commonly seen in righting responses. Gait is festinating and shuffling. In
Parkinson disease, it may occur in other parkinsonian this stage, the symptoms become increasingly pro­
conditions, such as MSA and in those states induced nounced, and the patient may require assistance in the
by dopamine-blocking or dopamine-depleting medica­ activities of daily living. With further progression, a
tions. Its origin is not clear, but some evidence suggests more advanced stage is reached (stage 4), with severe
that the inferior olives or the cerebellum act as the disability, rigidity, bradykinesia, and gait disturbances.
central oscillators, driving tremor by using the cerebel­ Standing is unsteady; a slight push precipitates severe
lothalamocortical loop as a reverberating system. retropulsion, culminating in a fall if the patient is not
caught or is left unattended. Eventually, the patient
Untreated Parkinson disease may be divided into
five stages. Stage 1 is characterized by mild unilateral
disease. Tremor may be the only visible sign but other
subtle findings, including slowness or rigidity, may be
noted on examination. Gait is usually normal, but there
may be mild decrease in arm swing on the most symp­
tomatic side, and the upper limb may be carried slightly
abducted at the shoulder and flexed at the elbow.
Diminished facial expression, hypophonic speech,
reduced manual dexterity, impaired rapid alternating
movements, and micrographia with poorly formed
letters may be present. As the disease advances to stage
2, there is bilateral involvement with postural changes.
In this stage, the more classic phenotype is observed,
with reduced facial mobility, stooped posture when
standing, reduced arm swing on walking, and en bloc
turning, Rapid alternating movements are impaired.
Movements become slow and deliberate, and patients

162 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-6 Basal Ganglia and Movement Disorders
NEUROPATHOLOGY OF PARKINSON DISEASE

Normal: section through cerebral peduncles Parkinson disease: substantia nigra
and substantia nigra depigmented

Akinetic-Rigid Syndrome,
Parkinsonism, or
Parkinsonian Syndrome

(Continued)

becomes markedly bradykinetic, rigid, and confined to Lewy inclusion bodies in cell of substantia nigra in
a wheelchair or bed (stage 5). Drs. Melvin Yahr and Parkinson disease; may also appear in locus ceruleus
Margaret Hoehn studied the natural progression of and tegmentum, cranial motor nerve nuclei, and
patients suffering with Parkinson disease and developed peripheral autonomic ganglia
a staging scale that bears their names. This classifica­
tion, known as the Hoehn and Yahr staging scale, Neurofibrillary tangle in nerve cell of substantia Section of substantia nigra of normal animal:
emphasizes the disease by progression of symptoms; it nigra as seen in postencephalitic parkinsonism, treatment of section with formaldehyde vapor
is arbitrarily divided into five stages of disease progres­ progressive supranuclear palsy and parkinsonism- causes formation of polymers with monoamines
sion, and although widely used, it provides only a crude dementia complex (dopa and norepinephrine) that fluoresce to
estimate of disease severity. bright green under ultraviolet light
â•…
PATHOLOGY
The pathologic hallmark of Parkinson disease is the loss MULTIPLE SYSTEM ATROPHY abnormalities that characterize Shy-Drager syndrome
of pigmentation of the substantia nigra, decreased In multiple system atrophy (MSA), the unifying patho­ are found eventually in both disorders. Thus MSA is
neuromelanin-containing neurons, and deposition of a logic feature is the oligodendroglial cytoplasmic inclu­ divided in two major groups, MSA-C (cerebellar) and
Lewy body in the motor nucleus of the vagus, locus sion bodies (GCIs), which are present in striatonigral MSA-P (parkinsonism). Other pathologic features
ceruleus, and substantia nigra (see Plate 7-6). The Lewy degeneration (SND), sporadic olivopontocerebellar include variable neuronal cell loss with gliosis in the
body is an intracytoplasmic, eosinophilic inclusion atrophy (OPCA), and Shy-Drager syndrome, nosologic putamen and, to a lesser degree, the pallidum, brain­
composed primarily of ubiquitin, neurofilaments, and entities once considered unrelated disorders but now stem (particularly the basis pontis and inferior olive),
alpha-synuclein, an important component protein nor­ grouped under the rubric of MSA. The autonomic cerebellum, intermediolateral columns of the spinal
mally found throughout the brain, particularly at the cord, and peripheral nerves. When OPCA/MSA-C is
synapse. The role that alpha-synuclein plays in the
pathogenesis of Parkinson disease is not well under­
stood. Point mutations, duplications, or amplifications
in the region of chromosome 4q21 containing the gene
encoding for alpha-synuclein have been found in some
familial, early-onset cases. Excessive alpha-synuclein
leads to protein aggregation and clumping. Other
mutations affecting the genes encoding for parkin, an
important protein of the ubiquitin/proteasome system
(DJ-1 and PINK1), may affect mitochondrial function
leading to impaired free radical handling and energy
production. The high concentration of iron in the sub­
stantia nigra and striatum increases cell vulnerability to
oxidative stress. Recently, the progression of Parkinson
disease and Lewy body deposition with degeneration
have been conceptualized as beginning in the olfactory
bulb and lower brainstem, progressing over time to the
diencephalon, amygdala, and entorhinal and neocortex.

An example of a fully developed clinical syndrome
due to generalized diffuse Lewy deposits is diffuse Lewy
body disease/dementia complex.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 163

P late 7-7 Brain: PART I

PROGRESSIVE SUPRANUCLEAR PALSY

Absent voluntary Loss of vertical excursion precedes
ocular excursion loss of horizontal excursions in
doll’s eye maneuvers

Akinetic-Rigid Syndrome, Frontalis muscle
Parkinsonism, or dystonic contraction
Parkinsonian Syndrome Reduced blinking

(Continued) Masklike facies
Excessive neck rigidity
present, atrophy is predominant in the pons, cerebel­
lum, and medullary olives. Tau and alpha-synuclein
are the predominant components of GCIs. The MRI
appearance is sometimes characteristic (see Plate 7-8).

PROGRESSIVE SUPRANUCLEAR PALSY (PSP) Flexed
Progressive supranuclear palsy (PSP) is characterized elbows
by oculomotor disturbances, parkinsonism, and gait
disturbances with postural instability, the latter a Patient stands in modified
common early manifestation of the disease, preceding hyperextension in contrast
in most cases the typical downward gaze and horizontal to flexed position in
paresis characteristic of the disease (see Plate 7-7). Parkinson disease
Pathologically, there is neuronal cell loss and gliosis
in the periaqueductal gray with deposition of tau-
containing globose neurofibrillary tangles with ubiqui­
tin immunoreactivity, atrophy of diencephalon, globus
pallidus, subthalamic nucleus, and mesencephalon.
This atrophy leads to the “Mickey Mouse” midbrain
sign on axial views or the penguin or hummingbird sign
on sagittal views in brain magnetic resonance imaging.

CORTICOBASAL DEGENERATION (CBD) Neurofibrillary tangles (NFT) in NFT in substantia nigra (stains Astrocytic tuft in pallidum (Gallyas
Corticobasal degeneration (CBD) is characterized by substantia nigra (stained with with tau) stain)
asymmetric cortical atrophy, neuronal cell loss, gliosis, hematoxylin and eosin)
and ballooned neurons in the central sulcus region â•…
(primary motor/primary sensory cortex), with achro­
matic intracytoplasmic neuronal inclusions similar to LEWY BODY DISEASE dementia is second after Alzheimer disease as the cause
the Pick bodies seen in Pick disease/frontotemporal Lewy body disease, also known as dementia with Lewy of dementia, with vascular dementia a close third. The
dementia and primary progressive aphasia. These inclu­ bodies, operationally may be viewed as typical dopa- Lewy body, which is structurally and morphologically
sions with corresponding neuronal cell loss are found responsive parkinsonism with early-onset dementia, similar to that found in idiopathic Parkinson disease, is
predominantly in the diencephalon, thalamus, sub­ fluctuating alertness and attention, confusion, sleep found throughout the cerebral cortex to a variable
stantia nigra, locus ceruleus, and cerebral cortex. Tau disturbances, marked sensitivity to neuroleptic or degree and in the substantia nigra. Ubiquitin, neurofila­
protein, ubiquitin, phosphorylated neurofilaments and, dopamine-blocking agents, and vivid and well-formed ment protein, and alpha-synuclein are components of
to a lesser degree, alpha-synuclein are components of visual hallucinations. In most autopsy series, Lewy body Lewy bodies. In the nucleus basalis and hippocampal
such inclusions, sharing immunoreactive properties formation, scattered senile plaques and neurofibrillary
similar to that found in Pick bodies. CBD (see Plate
7-8) is characterized clinically by asymmetric dystonic
posturing with superimposed stimulus-sensitive and
action-induced myoclonus, giving the affected hand or
limb a tremulous appearance, and by the alien limb
phenomena, limb apraxia, parkinsonism, and gait and
postural instability, with dementia and oculomotor dis­
turbances manifesting later in the course of the disease.

164 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-8 Basal Ganglia and Movement Disorders
CORTICOBASAL DEGENERATION
Contralateral asymmetric
atrophy of parietal lobe

Akinetic-Rigid Syndrome, Apraxia may inhibit everyday
Parkinsonism, or activities such as dressing
Parkinsonian Syndrome
Stiff, jerky limb posturing
(Continued) Patient may exhibit “alien limb”
phenomenon in limb contralateral
to cortical atrophy

tangles are found with granulovacuolar degeneration
simulating that observed in Alzheimer disease.

DRUG-INDUCED PARKINSONISM (DIP) MULTIPLE SYSTEM ATROPHY
Although not a degenerative disorder of the basal
ganglia, drug-induced parkinsonism can mimic idio­ “Hot cross bun” sign typical for MSA
pathic Parkinson disease and may be difficult to dif­
ferentiate in a given individual. Therefore the clinician â•…
should have a high index of suspicion and must perform
a thorough drug history. DIP is discussed here due to and development of novel therapies for PD, levodopa penetrates the cerebral capillaries to diffuse through
the importance in making the diagnosis. Treatment is continues to be the gold standard (see Plate 7-9). Orally the brain parenchyma, where it is picked up and
readily available, and in most instances, identifying the administered levodopa is absorbed into the circulation converted to dopamine in the remaining dopamine-
offending medication(s) is all that is needed to explain principally from the proximal small intestine. It may producing cells. Once secreted into the synaptic
the symptoms and proceed with treatment. At the be detected in blood for several hours following its cleft, dopamine is rapidly deactivated, principally to
most basic level, DIP results from either dopamine administration, reaching maximum peak levels in 2 to homovanillic acid by the enzymes catechol-O-methyl-
receptor blockade, such as that observed with neuro­ 3 hours after ingestion. Rapidly converted to dopamine transferase (COMT) and monoamine oxidase (MAO).
leptic medications, metoclopramide, or certain calcium by the enzyme dopa decarboxylase (DDC; l-amino- To increase available levodopa and to diminish unwanted
channel blockers (flunarizine, cinnarizine), or when acid decarboxylase), approximately 1% of the oral dose peripheral dopamine side effects (nausea, vomiting,
using dopamine-depleting agents (reserpine, tetrabena­
zine). Atypical neuroleptics (clozapine, olanzapine, ris­
peridone, quetiapine, ziprasidone), once believed to be
free of “extrapyramidal side effects,” are now clearly
implicated in some cases of DIP. Interactions with
dopaminergic (D1, D2), histaminergic, muscarinic,
alpha-adrenergic, and serotonergic receptor binding
may account for the phenomenology observed. Selec­
tive serotonin reuptake inhibitors, the most commonly
prescribed antidepressants, may result in DIP by sero­
tonergic down-regulation of dopamine synthesis. Other
medications, such as valproic acid and lithium, may
result in DIP by mechanisms not well understood.
Elimination of the offending agent, dose adjustments,
or identification of drug-interactions (effect potentia­
tion) may result in symptom improvement. Patients
should be educated on the side effects of medications,
particularly when parkinsonism may result as a conse­
quence of their use.

TREATMENT
Current treatment of parkinsonism centers on admin­
istration of levodopa. Despite recent advances in our
understanding of the chemical and pathologic changes

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 165

P late 7-9 Brain: PART I

PARKINSONISM: HYPOTHESIZED ROLE OF DOPAMINE

Caudate nucleus
Corpus striatum Putamen

Globus pallidus

Akinetic-Rigid Syndrome, Dopa taken up by surviving
Parkinsonism, or nigral neurons, converted to
Parkinsonian Syndrome dopamine, and released at the
synaptic junctions in
(Continued) corpus striatum

arterial hypotension), dopa decarboxylase is inhibited Substantia nigra Dopamine
peripherally with carbidopa. The inhibition markedly Cerebral L-Dopa
reduces the conversion of levodopa to dopamine in the peduncle Tyrosine
medullary vomiting center or trigger zone, preventing
its activation. With long-term levodopa use, coupled Blood vessels Dopamine DDC
with the intrinsic pathologic changes occurring in par­ HVA DDC
kinsonism, late motor complications develop in approx­
imately 75% of patients, particularly after 10 years of inhibitor L-Dopa
illness. Wearing off, freezing of gait, unpredictable
responses, and levodopa-induced abnormal involuntary 3-OMD COMT
movements or dyskinesias may complicate medical Entacapone
management. Certain agents, namely dopamine ago­
nists (ropinirole, pramipexole, rotigotine, pergolide, Homovanillic acid (HVA),
cabergoline, and bromocriptine) have been developed dopamine, and other
in hopes of eliminating or delaying the need for metabolites
levodopa. These agents stimulate dopamine receptors
and thus act like dopamine. A dopamine agonist may â•…
provide symptomatic improvement and may delay the
development of motor complications, chiefly by delay­ collection have proven insensitive, and results of studies Surgery
ing the need to introduce levodopa. Nonetheless, most in animal models have correlated poorly with findings By the middle of the 20th century, a handful of surgical
patients will require levodopa at one point in the course in humans. Therefore, at the present time, no clear procedures had been developed for the treatment of
of their disease. Another strategy has been the use of indication and consensus exists for the use of MAO Parkinson disease and other movement disorders (see
catechol-O-methyl transferase (COMT) enzyme inhib­ inhibitors, such as rasagiline or selegiline, vitamins, Plate 7-10). Cortical excisions, capsulotomies, caudoto­
itors to block COMT. Consequently, dopamine remains such as vitamin E, or other elements (coenzyme Q10). mies, ansotomies, pedunculotomies, and pyramidoto­
at the synaptic cleft, leading to increased duration of Rasagiline, selegiline, and amantadine are agents mies, wereperformedwithvariableresults;unfortunately,
on-time (time during which clinical benefit is obtained producing mild symptomatic improvement in some most procedures were fraught with severe side effects
from levodopa) by 1 to 2 hours and stable plasma patients, and thus may allow a delay in levodopa use. and terrible outcomes. In 1952, while performing a
levodopa levels. With progressive loss of neurons and
its attendant decline in buffering capacity, plasma
levodopa levels become the primary driver of the clini­
cal response and motor complications. Of the two
currently available COMT inhibitors, entacapone, a
peripheral COMT inhibitor, is the most commonly
used. Unfortunately, the use of tolcapone, a peripheral
and central COMT inhibitor, has been hampered by
concerns of severe and potentially fatal liver failure.
The latter is an idiosyncratic reaction that is difficult to
predict, complicating tolcapone use.

The hope of “neuroprotective treatments,” that is,
treatments to slow disease progression, have been
marred by controversies and methodologic flaws in
most studies performed to date. Interpretation of the
data has been conflicting; instruments used for data

166 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-10 Basal Ganglia and Movement Disorders

SURGICAL MANAGEMENT OF MOVEMENT DISORDERS

Stereotactic needle guide
Stereotactic frame attached to patient's head creates space
with X, Y, and Z coordinates. Any location within that space
can be targeted by probes using these coordinates. Specific
localization is selected by stereotactic targeting software
using common neuroanatomic sites as reference points.

Sites within globus pallidus, thalamus
and STN used in control of movement disorders

Stereotactic Thalamus
frame
Globus
Caudate pallidus
nucleus

Akinetic-Rigid Syndrome, Patient usually awake Care must be taken to
Parkinsonism, or Thalamotomy/DBS site avoid damage to optic tract
Parkinsonian Syndrome and internal capsule
Ventralis intermedius nucleus (VIM)
(Continued) preferred site for tremor-controlling lesions Deep brain stimulation (DBS)
Pallidotomy/DBS site DBS electrodes
planned pedunculotomy on a 39-year-old patient with Posteroventrolateral region (PVL) of in position in
postencephalitic parkinsonism, Irving Cooper, a New pars interna of globus pallidus (GPi) VIM nucleus of
York neurosurgeon, accidentally ligated the anterior preferred site to treat rigidity, tremor, each thalamus
choroidal artery (this type of insult results in a medial bradykinesia, and dyskinesias.
globus pallidus infarction). To Cooper’s amazement, the Subthalamic nucleus—DBS site
patient survived with resolution of the incapacitating Preferred site to treat Parkinson disease
tremor and rigidity that had hampered his quality of life
up to that point. This event led to an interest in the Stereotactic placement of lesions or electrodes
pallidum as a surgical target. It was not until advances
had occurred in the understanding of the physiology of Thalamotomy/DBS
the basal ganglia in health and disease, in surgical and site (VIM)
imaging techniques, and in intraoperative recording
devices that the current era of lesioning and later Subthalamic
neuromodulation techniques developed. DBS site (STN)

Deep Brain Stimulation (DBS) and Lesioning Pallidotomy/ Subclavicular
Procedures. With few exceptions, lesioning procedures DBS site (PVL) battery pack
such as pallidotomies or thalamotomies, are now rarely
performed. These have been replaced by DBS using High-frequency stimulation (DBS)
implantable quadripolar brain electrodes, particularly, of VIM region of thalamus is predominant
in three main targets, namely the medial globus pallidus treatment of medically refractory tremor.
(GPi), subthalamic nucleus (STN), and ventral inter­ Globus pallidus and STN sites provide
mediate nucleus of the thalamus (VIM nucleus). relief for Parkinson disease and dystonia.
Although STN is the preferred DBS target for the DBS electrodes are implanted and
surgical treatment of Parkinson disease, there is no connected to subclavicular battery pack.
conclusive evidence that STN-DBS is superior to
GPi-DBS. â•…

DBS does not improve symptoms that are resistant marked psychiatric disease, DBS is associated with an It is not clear how DBS works. What is evident is
to levodopa and, consequently, careful documentation increased risk for poor outcome and is generally con­ that DBS provides a nondestructive and reversible
of an adequate response to levodopa is important in traindicated. All parkinsonian symptoms improve with means by which to disrupt neuronal function. DBS
surgical candidates. A positive symptomatic benefit surgery, particularly tremor and medication-related continues to evolve as an important and established
from levodopa exposure predicts a better surgical abnormal involuntary movements on the side contra­ treatment for neurologic diseases, with new indications
outcome than otherwise. There is no clear age cut-off lateral to the procedure. Rigidity and bradykinesia being added continuously. A multidisciplinary approach
for the procedure. Octogenarians undergoing the pro­ respond well but to a lesser degree. Postural instability to management provides the best chances for a good
cedure have done well. In general, surgery is reserved and gait disturbances are less likely to respond. outcome in those who are candidates for surgery.
for those with a confirmed clinical diagnosis of idio­
pathic Parkinson disease who have developed motor
fluctuations and drug-induced dyskinesias despite
optimal medical therapy. Patients should have no
general medical contraindications to surgery and should
be without dementia or psychiatric comorbidities. In
patients with atypical symptoms or a Parkinson-plus
syndrome, a poor response to levodopa, dementia, or

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 167

P late 7-11 Brain: PART I
HYPERKINETIC MOVEMENT DISORDER–IDIOPATHIC TORSION DYSTONIA

In some patients, a dystonic hand
tremor may be present

Hyperkinetic Movement Hypertrophic Dystonic
Disorder neck muscles trunk and
may be head tremor
observed
Tremor may abate with the
finger-to-nose maneuver

DYSTONIA Truncal dystonia Bilateral
Dystonia is a disorder characterized by sustained muscle may lead to lordosis foot
contractions causing twisting and repetitive movements segmental dystonia, characteristically there is involvement dystonia
or abnormal postures. Dystonia may be a symptom, a of two or more adjacent body parts. Hemidystonia
syndrome, or a disease and may be classified by distri­ involves an arm and leg on the same side of the body. â•…
bution, age at onset, and etiology. By definition, no Axial dystonia affects midline structures (trunk and neck
cause for the dystonia is apparent in primary dystonia. muscles) and may cause speech and swallowing diffi­ normal or exaggerated, particularly in patients with a
In a small proportion of patients with dystonia, genetic culty or arching of the back or neck. Multifocal dystonia secondary cause or in patients with cervical dystonia
and chromosomal abnormalities have been identified. refers to abnormal posturing affecting two or more who developed a compressive myelopathy as a conse­
nonadjacent body parts. Involvement of both legs and quence of severe and often early degenerative spine
Childhood-onset primary generalized dystonia, also at least one arm, or axial involvement in combination disease. In some patients, a “dystonic tremor” or myor­
known as Oppenheim dystonia or idiopathic torsion with at least one affected limb is usually observed in rhythmia may be noted.
dystonia, is characterized by involuntary, repetitive, sus­ generalized dystonia. Deep tendon reflexes may be
tained muscle contractions or postures, beginning in In secondary dystonias, a cause is identified, such as
the foot and leg during childhood and progressing to a cerebral infarction, tumors, brain trauma, infections,
more generalized distribution by the second decade of and medication exposure, particularly to dopamine-
life (see Plate 7-11). It was first described in Ashkenazi blocking agents (neuroleptics, metoclopramide). Sec­
Jews expressing the DYT1 mutation on chromosome ondary dystonia can be focal, likely contralateral to the
9. A GAG deletion mutation in the DYT1 gene, which
encodes for the protein torsin A, has been associated
more frequently with the disease. The estimated preva­
lence is 3.4 per 100,000 individuals. This mutation is
also found in non-Ashkenazi individuals throughout
the world.

Other genetic mutations causing childhood-onset
generalized dystonia have been described more recently.
Next to DYT1, perhaps the most important is DYT6,
which is associated with a mutation in the THAP1 gene.

Adult-onset primary dystonia is usually focal or seg­
mental in distribution and may be a forme fruste of
idiopathic generalized dystonia. It may develop in
susceptible individuals who perform repetitive tasks,
such as instrumentalists, typists, dental hygienists, and
writers, or it may appear without known precipitating
factors. Examples of focal dystonia are writer’s cramp,
cervical dystonia (spasmodic torticollis), blepharospasm
(bilateral, involuntary, synchronous, forceful eye
closure), oromandibular dystonia (forceful involuntary
jaw opening or closure), spasmodic dysphonia (adduc­
tor or abductor dysphonia), and musician’s dystonia. In

168 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-12 Basal Ganglia and Movement Disorders
CERVICAL DYSTONIA

Young man with torticollis. Head tilted to left
with chin turned slightly to right because of
contraction of left sternocleidomastoid muscle.

Hyperkinetic Movement
Disorder (Continued)

lesion, or may be due to minor peripheral trauma such the biosynthesis of tetrabiopterin, which, in turn, is an Untreated torticollis in middle-aged woman.
as that resulting from the severe causalgia-dystonia syn­ essential cofactor in the production of dopamine by Thick, fibrotic, tendon-like bands have
drome. It may be hemidystonic or segmental when two tyrosine hydroxylase. Tyrosine hydroxylase is the rate- replaced the sternocleidomastoid muscle,
or more contiguous body parts are affected, or general­ limiting step in the synthesis of dopamine and other making head appear tethered to clavicle.
ized when the trunk and two other contiguous body catecholamines. Dopa-responsive dystonia, also known Two heads of left sternocleidomastoid
parts are involved. Secondary generalized dystonia may as Segawa disease, typically manifests in the first decade muscle are prominent.
result from trivial trauma or, in the appropriate setting, of life as a gait disorder, mimicking cerebral palsy
psychogenic factors may be the sole cause. Dopamine in some patients. In adolescents, the dystonia is â•…
receptor–blocking medications, such as neuroleptics
and phenothiazine-based antiemetics, can produce characterized by diurnal symptom fluctuations and can
acute dystonia after a single dose or tardive dystonia after be accompanied by mild parkinsonism, tremor, spastic
chronic usage. or scissoring gait, and scoliosis. One key feature in the
clinical examination of adolescents or young adults with
Cervical dystonia, probably the most common focal DRD is the marked loss of postural stability noted when
dystonia, results in involuntary contraction of the neck performing the pull-push test. The disorder has an
muscles, causing chin deviation, anterocollis or retro­ excellent response to levodopa, which is the treatment
collis, lateral flexion, and, in many patients, shoulder of choice.
elevation (see Plate 7-12). The continuous activity may
result in muscle hypertrophy, particularly the sterno­
cleidomastoid and neck flexors. Many patients may
notice that specific sensory stimuli or sensory tricks, the
“geste antagoniste,” transiently suppress or attenuate
spasms. Examples of sensory tricks include touching the
face, chin, or elsewhere on the head with a hand, finger,
or object. For many years, this phenomenon and the
higher prevalence of cervical dystonia in women were
mistakenly taken to support the belief that the disorder
is psychogenic in nature. In approximately 75% of
patients, pain is the most prominent feature. Degenera­
tive cervical spine disease is a common complication
and is occasionally associated with a compressive
myelopathy.

Dystonia-plus syndromes include dystonia accompa­
nied by other neurologic findings on examination.
Dopa-responsive dystonia (DRD), an autosomal dominant
condition with incomplete penetrance, is due to a defect
in chromosome 14 encoding for the guanosine triphos­
phate (GTP)-cyclohydrolase enzyme responsible for

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 169

Plate 7-13 Brain: PART I

Chorea/Ballism Hemichorea Hemiballism
Residual unilateral distal Unilateral proximal
Chorea is characterized by random jerky movements choreiform movement ballistic movements
jumping from one body part to another. They are irreg­ 5 years after contralateral
ularly timed, nonrepetitive, and abrupt in character, subthalamic nucleus infarct (acute phase of
varying in severity. In mild cases, they may lead to contralateral
restlessness, intermittent exaggeration of facial expres­ STN infarct)
sion, or fidgetiness of the hands or toes. In more severe
cases, the gait has a dancing quality and limbs exhibiting Huntington disease Bilateral distal
violent and ballistic movements. It can involve proximal Dementia and proximal
and distal muscles. Patients often attempt to mask such choreiform
movements by incorporating them into voluntary activ­ movements of
ities. Ballism can be conceptualized as a severe form of the limbs and
chorea affecting the proximal limb muscles, giving a also the face
“throwing” character to the movement. The most
common form of ballism is seen in parkinsonian patients striatal atrophy, most notably the caudate head, occurs â•…
with severe levodopa-induced abnormal involuntary later in the disease.
movements (dyskinesias) or in patients with contralat­ common in adolescent girls, it is also seen in adults. The
eral subthalamic lesion (infarct, demyelination). Patients Benign hereditary (familial) chorea, an autosomal dom­ clinical features of chorea are similar to those described
may have difficulties maintaining a sustained posture. inant disorder, begins early in childhood. Mild general­ for Huntington disease. Obsessive-compulsive and
When asked to grip the examiner’s hand, pressure ized chorea, affecting the distal extremities more than impulsive disorders and emotional lability may also
cannot be sustained, resulting in the “milkmaid’s grip”; the proximal muscle groups, is the characteristic move­ occur. Prophylaxis with antibiotics is recommended
when asked to protrude the tongue, the tongue will pop ment disorder; when present, minor neuropsychiatric until adulthood for children with Sydenham chorea
out, resulting in the “catch fly sign” or “harlequin’s” tongue features, such as mildly lower scores on cognitive tests, because rheumatic fever recurs in up to one third of
The bon-bon sign may be present (the tongue moves complete the clinical picture. Benign hereditary chorea patients.
involuntarily inside the mouth, hitting the inside wall has been associated with mutations in the TITF-1 gene.
of the cheeks). This latter sign is particularly promi­ Athetosis is a slow writhing movement of the fingers
nent in patients with drug-induced orolingual chorea Sydenham chorea is a manifestation of acute rheumatic and toes, seen most often in patients with cerebral palsy,
(neuroleptic-induced tardive dyskinesia). fever. It is also called “St. Vitus’s dance,” acute chorea, particularly when excited or when trying to communi­
chorea minor, or rheumatic chorea. Although more cate. Dystonic posturing, tremor, ataxia, or scissoring
There are many causes of chorea, such as pregnancy gait usually accompanies athetotic movements.
(chorea gravidarum), Huntington disease, benign hereditary
chorea, neuroacanthocytosis, Sydenham chorea, systemic
lupus erythematosus, focal vascular lesions, medications
(particularly the chronic use of neuroleptics and oral
contraceptives), various metabolic and endocrine disor­
ders (hyperthyroidism, hypoparathyroidism, or hyper­
parathyroidism and hypoglycemia or hyperglycemia),
and others.

In adults, the most common cause of chorea is medi­
cation, especially the use of levodopa in Parkinson
patients or the long-term use of neuroleptic drugs or
metoclopramide, which causes tardive dyskinesia. In
children, Sydenham chorea remains the most common
cause.

The second most common cause of chorea in adults
is Huntington disease (HD). First described by George
Huntington in1872, this autosomal dominant neurode­
generative disorder, with a 100% penetrance, has an
abnormal trinucleotide (CAG) gene expansion, with the
defective gene located in the short arm of chromosome
4. The disorder is characterized by choreiform move­
ments and dementia or behavioral changes. In the
United States, the estimated prevalence is 5 to 10 cases
per 100,000 people. Age at onset is in the fifth to sixth
decades of life, with duration of illness of 15 years in
the adult and 8 to 10 years with the Westphal variant.
Because of its insidious onset, the onset of symptoms is
often not recognized, and abnormal movements are
erroneously attributed to anxiety. Patients often have
personality and behavioral changes early in the disease
and these may be the initial manifestation in more than
50% of cases. Eventually, symptoms become prominent
and disabling. Speech becomes dysarthric. Oculomotor
alterations, such as impaired saccade initiation, particu­
larly an inability to initiate saccadic eye movement
without blinking or head thrusts, are common. Loss of
optokinetic nystagmus can occur after some years. The
only laboratory study available to confirm the diagnosis
is genetic testing. In early stages of the disease, brain
magnetic resonance imaging (MRI) may show nonspe­
cific changes in the neostriatum, caudate, and putamen;

170 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-14 Basal Ganglia and Movement Disorders
Usually called parkinsonian tremor, rest tremor
Rest tremor occurs in a limb that is not voluntarily activated.
It is suppressed with voluntary movement. It may
appear as “pill-rolling.”

Tremor

Tremor is a rhythmic, oscillatory, involuntary move­ Action tremor (example: essential tremor)
ment caused by the alternating activation of agonist and Typically bilateral, essential tremor is the most common movement disorder. It may be accentuated
antagonist muscles. The etiology of tremor is diverse with goal-directed movement of the limbs. Essential tremor affects the hands and cranial musculature
and includes hereditary (familial tremor), degenerative (in this order of prevalence). Most common presentation is the association of hand tremor and a tremor
(Parkinson disease), metabolic (thyroid, parathyroid, or in the cranial musculature (leading to a nodding or no-no head tremor).
hepatic disorders and hypoglycemia), toxins (nicotine,
mercury, lead, carbon monoxide, manganese, arsenic, Although considered benign, it can become incapacitating.
toluene), illicit drug use or medication-induced (neuro­ In severe forms the patient may not be able to perform
leptics, tricyclics, lithium, cocaine, alcohol, adrenaline, essential daily activities, such as drinking from a cup or dressing.
bronchodilators, theophylline, caffeine, steroids, val­
proate, amiodarone, thyroid hormones, vincristine), A useful clinical clue is that alcohol may
peripheral neuropathies (Charcot-Marie-Tooth disease, temporarily alleviate symptoms.
Roussy-Levy syndrome, complex regional pain syn­
drome), and psychogenic disorders. â•…

Tremor may be classified as rest, postural, and inten- its target (end-point accentuation). Another term used sclerosis or stroke involving the superior cerebellar
tional, according to its relation to activity. Rest tremor for cerebellar outflow tremor is rubral tremor. We dis­ peduncular region. In these patients, the tremor is most
is best seen when the limbs are relaxed, resting in the courage the use of such a term because these are not prominent when flexing the forearms at the elbows and
patient’s lap; when necessary, mental exercises may help specific for lesions found only at the red nucleus. We elevating the shoulders laterally to reach a 90-degree
to “bring out” the dyskinesia. A 3- to 5-Hz rest tremor prefer the term cerebellar outflow tremor to describe angle in the fully abducted position. This “phenome­
is a characteristic feature of Parkinson disease (“pill- intention, rubral, or cerebellar tremor. nology” is similar to that in cerebellar outflow tremor,
rolling” tremor), in which it often starts asymmetrically. particularly when severe, and probably represents
One important feature of this type of tremor is its disap­ A “wing beating” tremor has been described in patients involvement of cerebellothalamofugal pathways.
pearance or improvement with limb movement. with Wilson disease and in patients with multiple
Although the tremor may become bilateral with disease
progression, it commonly remains more severe on the
initially affected side.

Postural tremor is seen when the limbs are actively
maintained in a particular posture against gravity
and disappears when the limbs are at rest. Examples
of postural tremors are essential tremor, drug- or toxin-
induced tremor, metabolic conditions, and alcohol
withdrawal states. Physiologic tremors are also postural in
nature and are seen in all individuals at a frequency
of 8 to 12╯Hz. They are enhanced by caffeine, fear, or
anxiety.

Essential tremor is a sporadic condition, but in approx­
imately 50% of those affected, a family history may be
elicited (familial tremor). Typically, a 5- to 8-Hz tremor
is present bilaterally in the hands or arms. A tremor of
the head or vocal cords is also common. Patients often
noticed an improvement in tremor after having a sip of
alcohol. Most cases are mild and do not require treat­
ment, but when necessary, propranolol, primidone, or
certain antiepileptic drugs may be effective.

Intention tremor is the tremor most commonly associ­
ated with disease of the cerebellum and its associated
pathways, but it may be seen in patients with advanced
essential or familial tremor. The tremor, which occurs
during movement, can be unilateral or bilateral,
depending upon the cerebellar lesion, and may affect
upper and lower limbs. It has a frequency of 2 to 4╯Hz
and characteristically worsens as the limb approaches

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 171

P late 7-15 Brain: PART I

Tics and Tourette Syndrome Tics involving the eyes, such as eye-blinking, are the most
common tic in childhood-onset tic disorders. Patients with
Tics are sudden, rapid, stereotyped, repetitive, non­ tic disorders frequently develop other motor tics of the head
rhythmic movements or vocalizations affecting discrete and neck, including grimacing and frowning.
muscle groups. Most experts agree and clinical experi­
ence dictates that tics are preceded by a sensory com­ demonstrated improvement of tics when stimulating â•…
ponent, described by patients as an “urge.” When different targets of the corticostriatothalamic and
patients are asked to prevent movements from occur­ limbic pathways/structures. side effects. Tetrabenazine, a dopamine depletor, may
ring, an uncomfortable inner sensation builds and an be useful in some cases. A stimulant such as methylphe­
urge to “release” develops, resulting in expression of The goal of treatment of tics and Tourette syndrome nidate does not worsen tics as previously thought. It can
the tics. is to relieve some of the more pressing symptoms. For therefore be safely used in those with tics and attention
some affected persons, tics may be the most bothersome deficit disorder. The serotonin reuptake inhibitors are
The spectrum of tics includes transient tics of childhood aspect of their illness. For others, obsessive-compulsive helpful in treating anxiety, depression, or obsessive-
when present for less than 1 year, chronic motor or vocal behaviors, attention deficit with hyperactivity, anxiety, compulsive disorder in patients with tics or Tourette
tics when tics are present for more than 12 months, and or depression may be more distressing. There is no syndrome. Botulinum toxin therapy has proven to be
Tourette syndrome, defined by the presence of both general agreement as to the best treatment for tics. of some value when used in patients with dystonic tics.
motor and vocal tics for more than 12 months. Most authors recommend alpha-2 agonists, such as A behavioral therapeutic approach using habit reversal
guanfacine or clonidine, as first-line therapy. Dopamine- therapy at its core has been shown to be effective in a
Tics may be classified according to complexity of blocking agents are the most potent anti-tic medica­ recent large multicenter study. Thalamic or pallidal
symptoms as simple motor or vocal tics when involving tions but are also associated with a high incidence of deep brain stimulation is a promising strategy in refrac­
only a few muscles or simple sounds, such as eye blink­ tory cases.
ing, shoulder shrugging, facial grimacing, whistling,
grunting, throat clearing, snorting, chirping, or sniff­
ing. Many such youngsters are initially mistakenly diag­
nosed as having chronic rhinitis or “allergies,” or
punished unnecessarily for loud behaviors. Once con­
sidered rare, schoolteachers now easily identify tics and
may be the first to call attention to a child’s unique
behavior. In complex motor or vocal tics, multiple muscle
groups are recruited in orchestrated bouts of involun­
tary movements or utterances of words and sentences
or phrases. Examples include hand gestures, jumping,
touching, pressing, shouting words, or speech blocking.
Some individuals may exhibit copropraxia, the sudden
performance of obscene gestures or echopraxia, the
involuntary spontaneous imitation of someone else’s
movements.

Tourette syndrome (TS) is characterized by multiple
motor and vocal tics. In many TS patients, obsessive-
compulsive behaviors and attention deficit disorder, or
both, may be present. Anxiety, depression, and self-
injury behaviors may complicate the clinical picture.

Tics may be primary or “idiopathic” or secondary, in
which a definable cause is found. Primary tics are by
far the more common in children and adolescents, with
secondary disorders in that age group being rare. In
adults, trauma, encephalitis, stroke, carbon monoxide
poisoning, neurosyphilis, Creutzfeldt-Jakob disease,
and central nervous system (CNS) injury from hypo­
glycemia may result in tics or Tourettism. Some genet­
ics disorders in which tics have been described include
Huntington disease, neuroacanthocytosis, neuroferri­
tinopathy (Hallervorden-Spatz disease), dystonia with
tics, tuberous sclerosis complex, and some cases of
Duchenne muscular dystrophy. A few patients with
Down syndrome, Asperger/autism spectrum, and
fragile X-tremor syndrome have also been reported to
have tics. The use of illicit drugs or medications may
result in tics, Tourettism, or punding, particularly the
use of cocaine, amphetamines, and antiepileptic medi­
cations (phenobarbital, phenytoin, and carbamazepine).
Less commonly, opioids, lithium, levodopa, and antide­
pressants may induce or worsen tics.

The substrate for tics and Tourette syndrome seems
to reside in the basal ganglia and related structures.
Supporting evidence for this concept includes the clini­
cal observation of tic improvement when patients
are treated with dopamine-blocking or dopamine-
depleting agents. Other evidence comes from func­
tional imaging studies demonstrating volumetric striatal
changes and, in some, increased dopamine synaptic
content. Recently, deep brain stimulation has

172 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

P late 7-16 Basal Ganglia and Movement Disorders

Myoclonus Essential myoclonus

Myoclonus is a brief, shocklike muscle jerk, which may Usually multifocal in distribution, often familial, typically
be classified according to origin, (cortical, subcortical, induced by voluntary movements causing a single jerk of
brainstem, and spinal myoclonus) and distribution (focal, the extremity (action myoclonus). Symptoms begin before
segmental, multifocal, or generalized). Cortical myo­ age 20 and frequently are associated with tremor,
clonus may be epileptic (as in Baltic myoclonus or pro­ dystonia, and other movement disorders.
gressive myoclonic epilepsy, photosensitive myoclonus,
epilepsia partialis continua) or part of a neurodegenera­ Commonly, essential
tive disorder (corticobasal degeneration, Alzheimer myoclonus responds
dementia, diffuse Lewy body disease, and others). to ingestion of alcohol.
Myoclonus can be classified according to etiology as
idiopathic/genetic (familial myoclonus, myoclonus- Lance-Adams syndrome (posthypoxic myoclonus)
dystonia), physiologic (hypnic jerks or diaphragmatic Prolonged hypoxia may result in posthypoxic
myoclonus/hiccups) or secondary/symptomatic when a myoclonus, which is usually stimulus sensitive.
cause for the myoclonus is clearly identified. Examples
of the latter group may include encephalitis, hypoxia, A variety of stimuli such as noise, light, and touch can
toxins, storage diseases, and basal ganglia degenera­ provoke this type of myoclonus in multiple areas of the body.
tions, as in Huntington disease, Wilson disease, and
certain other disorders). Myoclonus may be positive due â•…
to a brief muscle contraction or negative when muscle
tone is briefly lost, as in asterixis. (action myoclonus). Limb and truncal ataxia, cerebellar muscles following a distribution suggesting spread up
outflow tremor, and dysarthria are other common the brainstem and down to the cord.
Anoxic brain injuries may result in myoclonus, which, accompaniments. The exact substrate of postanoxic
in turn, may be cortical, diencephalic, or reticular in origin; myoclonus generation is not clear. Postanoxic myoclo­ Essential myoclonus may be idiopathic or familial,
stimulus sensitive or action induced; and segmental, general- nus may be the result of cortical or subcortical injury beginning in the first to second decade of life. In
ized, or multifocal in distribution. This type of myoclonus or be due to alterations in brainstem serotonergic path­ patients with essential myoclonus, the neurologic exam­
may be focal, preferentially affecting the distal limb ways. The serotonergic raphe nuclei have frequently ination fails to demonstrate other deficits. In a few
muscles, or multifocal with spontaneous, reflexive or been implicated. families, lower verbal scores have been reported and
stimulus-sensitive jerks accentuated by movement. Fre­ occasionally mental retardation. Similar to essential
quently, anoxic-induced myoclonus is accompanied by Some forms of myoclonus, particularly those of sub­ tremor, alcohol may help to ameliorate the symptoms,
secondary seizures, particularly after cardiopulmonary cortical origin, are believed to arise from the reticular but the incidence of alcoholism is increased. In patients
arrest. Status epilepticus is found in 32% of postanoxic system primarily from the nucleus reticularis gigantocel- with myoclonus-dystonia, there is an autosomal pattern of
patients, and in many, multifocal myoclonus alone or in lularis. This reticular reflex myoclonus is characterized by inheritance, men are more affected than women, and
combination with generalized tonic-clonic seizures is a brief electromyographic burst lasting 10 to 30╯msec, there is a higher incidence of alcoholism and behavioral
frequently observed. The incidence of myoclonic sei­ with generalized bilateral synchronous activation of disturbances.
zures is bimodal, with the majority of them occurring
within 12 hours after cardiopulmonary resuscitation
and the remaining occurring several days later. Electro­
encephalography (EEG) is useful when evaluating
these patients, particularly when status epilepticus is
suspected. The most frequent EEG findings include
diffuse slowing with or without spike or polyspike com­
plexes that are sometimes time locked to the myoclonic
jerks. A burst-suppression EEG pattern, when recorded,
has a poor prognostic significance. Magnetic resonance
imaging of the brain may show diffusion restriction
in the cortical and subcortical gray matter between
24 hours and 13 days. Isolated myoclonus generally
does not require treatment unless it interferes with
mechanical ventilation or nursing care. Myoclonus
status is refractory to treatment, may require multiple
antiepileptic drugs, and, when accompanied by convul­
sive status epilepticus, is best controlled with deep
anesthesia.

Electrophysiologically, myoclonus is characterized
by a muscle bursts that are less than 75╯msec in dura­
tion. When the cerebral cortex is affected, a “giant”
somatosensory evoked cortical response time locked to
the onset of the jerk in back-averaged EEG may be
obtained.
POSTANOXIC MYOCLONUS
In 1963, James Lance and Raymond D. Adams reported
the first series of patients with the syndrome of
intention or action myoclonus as a sequel to hypoxic
encephalopathy. In postanoxic myoclonus, axial and
proxÂ

Plate 7-17 Brain: PART I
Kayser-Fleischer ring

Degenerative changes in lenticular nuclei

Adolescents more likely have general- Adults more likely
ized dystonia, with involvement of have coarse, proximal
neck (torticollis) and face (grimacing), “wing beating” or
occasionally focal; hypertonicity and “chest beating”
choreoathetosis may coexist. tremor, masked
facies, and
dysarthric speech.

Wilson Disease

Also known as hepatolenticular degeneration, Wilson Postnecrotic type of cirrhosis
disease is an autosomal recessive disorder that occurs in â•…
1 of 30,000 individuals. The abnormal gene, the ATP7B
(adenosine triphosphate) gene, is located on chromo­ liver function. Although not specific, 24-hour urinary sign (globus pallidus hypointensity) is a characteristic
some 13. The defective protein, adenosine tripho­ copper excretion and serum copper and ceruloplasmin MRI finding on T2-weighted imaging seen in 34%
sphatase (ATPase), is involved in the transport and levels are useful screening tests. The single best confir­ of cases.
incorporation of copper into ceruloplasmin and the matory test for the diagnosis is elevated hepatic copper
vesicular compartment near the canalicular membrane levels, but this requires a liver biopsy; this is performed The copper-chelating agent d-penicillamine has
for further bile excretion. only in cases in which the diagnosis is unclear but the been considered the gold standard of therapy. In
index of suspicious is high. On neuroimaging, a brain patients who cannot tolerate penicillamine, trientine,
Although a neurologic disorder, it affects multiple MRI shows atrophy of cerebrum, brainstem, and less another copper-chelating agent, has been used. In
organs, with the liver being the most common and commonly cerebellum. The face of the giant panda patients with cirrhosis or fulminant hepatic failure, liver
earliest affected. Approximately 40% of newly diag­ transplantation is the only option.
nosed cases have hepatic involvement. Neurologic
manifestations include dysarthria, dystonia, rigidity,
wing beating tremor, and choreoathetosis. Children
younger than 10 years rarely present with neurologic
involvement. Progressive dementia, antisocial behavior,
impulsivity, and decreased intellectual performance
further complicate the disease and are important mani­
festations. The Kayser-Fleischer ring, the classic oph­
thalmologic sign of the disease, is a yellow-brown
discoloration of the Descemet membrane, best demon­
strated by slit-lamp examination. In addition, sunflower
cataracts may be noted. Careful bedside ophthalmo­
logic evaluation may reveal Kayser-Fleischer rings
in suspected cases. Other features include hemolytic
anemia, renal failure with tubular dysfunction, nephro­
lithiasis, cardiomyopathy, hypoparathyroidism, amen­
orrhea, and testicular atrophy.

Diagnosis requires a strong index of suspicion and
should be considered in all patients, particularly those
younger than 40 years, presenting with abnormal invol­
untary movements, and those presenting with abnormal

174 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

Plate 7-18 Basal Ganglia and Movement Disorders

Psychogenic Movement Depressed, sloppily dressed, Belligerent
Disorders careless Young woman
exhibiting
Psychogenic (also called hysterical or functional) move­ Overmedication choreiform
ment disorders are disorders without evidence of an Drug side effects movements
organic etiology and for which an underlying psychiat­
ric illness is held responsible. Perhaps one third of Facial expression may be flat, Vibration may be felt
patients diagnosed with psychogenic disorders eventually inappropriately unconcerned, or only on one side.
are found to have an organic neurologic illness, although depressed rather than typically
this may not necessarily relate to the movement disor­ pained. Patient complains
der itself. A movement disorder must not be attributed Complete hemianesthesia or of severe back pain,
to psychogenic causes simply because the clinician glove-and-stocking anesthesia which may radiate
cannot arrive at a definitive organic diagnosis. It is may be present in “all over.”
important for the evaluating physician to await develop­ conversion disorder or
ments if a diagnosis is not immediately obvious. With hypochondriasis/
time, new features may suggest the correct diagnosis or somatization.
the acquisition of more information from the patient or
family may suggest the relevance of psychogenic factors. In some disorders, gait and posture may be dramatic, with exaggerated pain behavior,
implying patient’s need to prove he is really sick.
Certain features may suggest a nonorganic basis for
the movement disorder. Features in the history that â•…
raise this possibility are the abrupt onset of symptoms
and their marked variability in nature or severity over Investigations may be required to exclude possible trial of medications typically used for various organic
short periods of time. In addition, there is often a organic causes for the patient’s symptoms. Symptoms movement disorders, depending on the patient’s clinical
marked disparity between symptom severity and the may have developed on an organic basis and then been state. Psychiatric referral is then required, with careful
functional limitation to which they reportedly lead. perpetuated and elaborated psychogenically. Studies follow-up of the patient. Prognosis is variable. Features
Patients may report that they are unable to work may include brain MRI; serum copper and ceruloplas­ suggesting a good prognosis are acute onset, short
because of their abnormal movements, and yet they can min levels and 24-hour urine copper excretion, thyroid duration of symptoms, healthy premorbid functioning,
perform the activities of daily living, such as using a function studies, and other tests based on clinical sus­ absence of other organic or psychogenic disorders, and
personal computer, shopping, cooking, and the like. In picion. The diagnostic evaluation may also include a presence of an identifiable precipitant.
other words, any disability is selective. It is also impor­
tant to enquire about a past history of psychiatric or
psychogenic illness and to seek any possible secondary
gain, as from pending litigation or workers’ compensa­
tion, which may result from the current symptoms.

The examination findings may also be helpful, espe­
cially the general appearance and affect of the patient.
There may be a combination of different dyskinesias
that vary markedly in nature and distribution over time
and worsen when formally examined. Other signs of
nonorganic neurologic deficits may be present, such as
a nonanatomic sensory loss or a lurching unsteady gait
that never results in falls.

Psychogenic tremor is typically of variable frequency
and can be entrained by such maneuvers as foot tapping.
With mental distraction, tremors or other hyperkinetic
movement disorders may become more intermittent, vari­
able, or irregular. During skilled movements with the
affected limb, they may cease. Loading the limb with
weights may increase rather than diminish tremor
amplitude. Patients with psychogenic dystonia sometimes
report that their symptoms are especially troublesome
at rest, whereas organic dystonia is often more con­
spicuous with volitional activity. In a psychogenic gait
disorder, the gait is often very slow, with excessive ges­
turing and sometimes wild or bizarre motor activity. It
typically is quite variable in severity, lessening with dis­
traction and worsening when the patient is observed
overtly.

No anatomic correlation can be made, and the neu­
rochemical basis of the movement disorder is unknown.
Patients with psychogenic movement disorders typi­
cally are unresponsive to appropriate medications, but
remission may occur with treatment of the underlying
psychiatric disorder. The psychiatric diagnosis may
include various somatoform and factitious disorders,
depression, anxiety, and histrionic personality disor­
ders. A specific psychiatric diagnosis cannot always be
made despite a high index of suspicion for psycho­
genicity, and the neurologist and psychiatrist may differ
in their assessments of the underlying problem.

THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS 175

Plate 7-19 Brain: PART I

Atonic cerebral palsy. Must be Athetoid cerebral palsy.
differentiated from other causes Note grimacing and
of floppy baby syndrome. May show drooling, and
varying degrees of improvement adductor spasm.
or progress to athetoid or
spastic stages.

Athetoses and persistent
asymmetric tonic reflex

Cerebral Palsy

Cerebral palsy (CP) is the term applied to a group of Ataxic cerebral palsy. Diplegia (lower limbs more
slow or nonprogressive motor impairment syndromes Wide gait, tendency affected). Contractures of
resulting from a variety of lesions or congenital brain to fall, inability to hips and knees and talipes
anomalies. Although the initial lesion may be fixed, the walk a straight line. equinovarus (clubfoot).
clinical pattern of presentation might vary with growth
and development. Its incidence is 2 to 2.5 per 1,000 live Hemiplegia on right side. Spastic quadriplegia.
births. The causes are diverse. Approximately 75% of Hip and knee contractures Characteristic “scissors”
cases are due to prenatal injury, with less than 10% due and talipes equinus. position of lower limbs
to birth trauma or asphyxia. Low birth weight and pre­ Astereognosis may due to adductor spasm.
maturity are important risk factors for the occurrence be present.
of cerebral palsy. Other risk factors include chorioam­ â•…
nionitis, teratogenic exposures, hyperbilirubinemia, polyporencephaly, polymicrogyria, and schizencephaly
and hypoglycemia. Cerebral palsy has a higher inci­ on neuroimaging studies. Pseudobulbar signs and optic findings, in addition to corticospinal tract involvement
dence in twins and triplets than in singletons. atrophy is usually present in up to 50% of affected in a smaller proportion of patients. These are key points
children. to remember when assessing adults who come for an
Cerebral palsy is a clinical diagnosis. Delays in evaluation of a new movement disorder and have a
developmental milestones are usually the earliest clue. Mental retardation (60%), visual impairment, and history of neonatal hyperbilirubinemia. Among chil­
Milestones acquired do not show regression. Other oculomotor impairments are common. In those chil­ dren with cerebral palsy, 35% to 60% will have some
early signs include hand preference, prominent fisting, dren who develop cerebral palsy as a consequence of form of epilepsy. Feeding difficulties, swallowing dys­
persistence of neonatal reflexes, and delay in emergence kernicterus, deafness, dystonia, choreoathetosis and, to function, and drooling may complicate the clinical
of protective and postural reflexes. a lesser extent, ataxia are the most common clinical picture.

Topographic classification of CP includes monoplegic,
diplegic, hemiplegic, and quadriplegic. Cases can also be
classified into spastic, dyskinetic, ataxic, hypotonic, and
mixed. Of these, spastic cerebral palsy with diplegia of
the lower extremities and scissoring gait is the most
common, accounting for 70% to 75% of cases. Imaging
demonstrates periventricular leukomalacia around the
lateral ventricles, with ischemia as the most common
pathologic finding. Mild cases manifest with toe
walking, whereas severe cases have flexion of the hips,
knees, and elbows.

In hemiplegic cerebral palsy, the upper limb is pre­
dominantly affected. Palmar grasp reflexes may be
present and can persist for years. Quadriplegic cerebral
palsy, the most severe form, is characterized by

176 THE NETTER COLLECTION OF MEDICAL ILLUSTRATIONS

SECTION 8â•…

CEREBELLUM AND
ATAXIA