in cases of transtentorial herniation, as the
brainstem dysfunction advances. At least one
patient with apneusis due to a brainstem in-
farct responded to buspirone, a serotonin 1A
receptor agonist.
53
ATAXIC BREATHING
Irregular, gasping respiration implies damage
to the respiratory rhythm generator at the pre-
Bo¨tzinger level of the upper medulla.
30
This
cell group can be specifically eliminated in ex-
perimental animals by the use of a toxin that
binds to neurons that express NK-1 receptors.
The resulting irregular, gasping breathing is
eerily similar to humans with bilateral rostral
medullary lesions, and it indicates that suffi-
cient neurons survive in the medullary reticu-
lar formation to drive primitive ventilatory ef-
forts, despite the loss of the neurons that cause
smooth to-and-fro respiration.
54
More complete
bilateral lesions of the ventrolateral medullary
reticular formation cause apnea, which is not
compatible with life unless the patient is artifi-
cially ventilated (Figure 2–5).
A variety of intermediate types of breathing
patterns are also seen with high medullary le-
sions. Some patients may breathe in irregular
clusters or ratchet-like breaths separated by
pauses. In other cases, particularly during in-
toxication with opiates or sedative drugs, the
breathing may slow and decline in depth grad-
ually until it fades into complete arrest.
There is a tendency in modern hospitals to
intubate and ventilate patients with structural
coma to protect the airway and permit treat-
ment of respiratory failure. If the patient fights
intubation or ventilation, paralytic drugs are
often administered. This compromises the abil-
ity of the neurologist to assess brainstem re-
flexes, and in some cases may delay diagnosis
and compromise care. Thus, it is important,
whenever possible, to delay intubation until
after the brief coma examination described
here has been completed.
SLEEP APNEA AND ONDINE’S
CURSE
Obstructive sleep apnea is a common disorder
in which the cross-section of the upper air-
way is anatomically narrow.
55,56
During sleep,
the muscles that keep the upper airway open,
including the genioglossus muscle that pulls
the tongue forward, undergo a gradual loss of
tone. This results in critical narrowing of the
airway and the increased rate of movement of
air tends to further reduce airway pressure,
resulting in sudden closure. Liable to the dis-
order are obese patients, because deposition of
fat in neck tissue reduces airway diameter;
men, because the increased ratio of the length
of the airway to its diameter predisposes to
collapse; and middle aged or older patients,
because muscle tone is more reduced during
sleep with age. However, cases may occur in
thin young adults, or even in children. Sleep
apnea typically occurs in cycles lasting a few
minutes each when the patient falls asleep,
airway tone fails and an obstructive apnea oc-
curs, blood oxygen levels fall, carbon dioxide
rises, and the patient is aroused sufficiently to
resume breathing. This cycle may be repeated
many times over the course of a night. The
fragmentation of sleep and intermittent hyp-
oxia result in chronic daytime sleepiness and
impairment of cognitive function, particularly
vigilance.
Excessive drowsiness during the day and
loud snoring at night may be the only clues.
Lethargy or drowsiness due to neurologic in-
jury may induce apneic cycles in a patient with
obstructive sleep apnea. However, as the level
of consciousness becomes more impaired, it
may be difficult to achieve the periodic arous-
als necessary to resume breathing.
Other patients with pauses in ventilation
have central sleep apnea. Most such patients
have congestive heart failure, and the pauses
are thought to be analogous to the periodic
breathing that is seen in patients who de-
velop Cheyne-Stokes respiration when they fall
asleep.
Failure of automatic breathing is a rare
condition, sometimes called Ondine’s curse,
named after the mythologic wood nymph whose
mortal lover lost autonomic functions when-
ever he went to sleep. In adults, Ondine’s curse
is seen after lesions of the ventrolateral med-
ullary chemosensory areas or bilateral damage
to the descending pathways that control auto-
matic respiration in the lateral columns of the
spinal cord (e.g., as a complication of cordot-
omy to relieve cancer pain).
57–62
In children, it
is most frequently seen as a congenital condi-
tion in infants, sometimes in association with
Hirschsprung’s disease, and either a neuroblas-
toma or pheochromocytoma, often associated
52
Plum and Posner’s Diagnosis of Stupor and Coma
with a mutation in the PHOX2B gene.
63
A
variety of interventions have been successful,
ranging from a rocking bed, which provides con-
tinuous somatic sensory and vestibular stimula-
tion, to negative pressure ventilation, or even
diaphragmatic pacing.
64
YAWNING, HICCUPPING,
VOMITING
The neuronal pattern generators responsible
for coordinating respiratory-related behaviors
also are located in the ventrolateral medulla,
in close proximity to the nucleus ambiguus.
65
Yawning is a motor pattern that involves deep
inspiration associated with wide opening of the
jaw and generalized muscle stretching.
66,67
It
is seen even in patients who are locked in, and
hence is apparently organized at a medullary
level. Yawning may improve the compliance of
the lungs and chest wall, but its function is not
understood. It may be seen in lethargic pa-
tients, but yawning is also seen in complex par-
tial seizures emanating from the medial tem-
poral lobe, and is not of great localizing value.
Hiccups occur in patients with abdominal
or subphrenic pathology (e.g., pancreatic can-
cer) that impinges upon the vagus nerve.
68,69
Dexamethasone may induce hiccups; the mech-
anism is unknown.
70
Hiccups occasionally oc-
cur with lesions in the medullary tegmentum,
including neoplasms, infarction, hematomas,
infections, or syringobulbia. Because stuporous
patients with intracranial mass lesions are often
treated with corticosteroids to reduce brain
edema, it may be difficult to determine whe-
ther pressure on the floor of the fourth ven-
tricle from the mass lesion or the treatment
with corticosteroids is causing the hiccups.
71
Pathologic hiccupping is peculiarly more com-
mon in men; in a study of 220 patients at the
Mayo Clinic with pathologic hiccupping, all but
39 were men.
72
The hiccup reflex consists of a spasmodic
burst of inspiratory activity, followed 35 milli-
seconds later by abrupt glottic closure, so that
the ventilatory effect is negligible. On the other
hand, if the airway is kept open artificially (e.g.,
by tracheostomy), the inrush of air can be suf-
ficient to hyperventilate the patient. As an ex-
ample, one patient in New York Hospital with a
low brainstem infarct and tracheostomy main-
tained his total ventilation for several days by
hiccup alone.
Pathologic hiccups are difficult to treat.
73
A
number of drugs and physical approaches have
been tried, most of which do not work well.
Agents used to treat hiccups include pheno-
thiazines, calcium channel blockers, baclofen,
and anticonvulsants, gabapentin being the most
recent.
74
In steroid-induced hiccups, decreas-
ing the dose usually reduces the hiccups.
73
Vomiting is a reflex response involving co-
ordinated somatomotor (posture, abdominal
muscle contraction), gastrointestinal (reversal
of peristalsis), and respiratory (retching, breath
holding) components that are coordinated by
neurons in the ventrolateral medullary teg-
mentum near the compact portion of the nu-
cleus ambiguus. The vomiting reflex may be
triggered by vagal afferents
75,76
or by chem-
osensory neurons in the area postrema, a small
group of nerve cells that sits atop the nucleus
of the solitary tract in the floor of the fourth
ventricle, just at the level of the obex.
77
In patients with impaired consciousness,
vomiting is frequently due to lesions involving
the lateral pons or medulla, causing vestibular
imbalance. It occasionally occurs in patients
with irritative lesions limited to the region of
the nucleus of the solitary tract.
77
Such vomit-
ing is typically preceded by intense nausea.
More commonly, however, vomiting is due to a
sudden increase in intracranial pressure, such
as occurs in subarachnoid hemorrhage. The
pressure wave may stimulate the emetic re-
sponse directly by pressure on the floor of the
fourth ventricle, resulting in sudden, ‘‘projec-
tile’’ vomiting, without warning. This type of
vomiting is particularly common in children
with posterior fossa tumors. It is also seen in
adults with brain tumor, who hypoventilate
during sleep, resulting in cerebral vasodilation.
The small increase in intravascular blood vol-
ume, in a patient whose intracranial pressure is
already elevated, may cause a sharp increase in
intracranial pressure (see Chapter 3), resulting
in onset of an intense headache that may wa-
ken the patient, followed shortly thereafter by
sudden projectile vomiting. Children with pos-
terior fossa tumors may simply vomit without
headache.
Vomiting is also commonly seen in patients
with brain tumors during chemotherapy or
even radiation therapy. Tissue injury, particu-
larly in the gut, may release emetic hormones,
such as glucagon-like peptide-1 (GLP-1). GLP-
1 is detected by neurons in the area postrema,
Examination of the Comatose Patient
53