ABSTRACT
Fig. 22-1) a. Long preganglionic axons that synapse in ganglia close to
organs b. Nicotinic cholinergic receptors transduce signals arriving
at postganglionic neurons c. Postganlionic cells stimulate muscarinic cholinergic
receptors on effector cells (second messenger-linked system)
2. Sympathetic (thoracolumbar) division (Fig. 22-2)
a. Sympathetic preganglionic neurons 1) All have cell bodies in intermediolateral cell column 2) Exit spinal cord via ventral roots 3) Axons release acetylcholine, which acts on nicotinic
cholinergic receptors on postganglionic neurons in paravertebral and prevertebral ganglia and adrenal medulla
b. Sympathetic postganglionic neurons 1) Cell bodies are in paravertebral and prevertebral
ganglia 2) Axons project to effector organ 3) All sympathetic postganglionic neurons are adrenergic
and release norepinephrine (NE) except those innervating sweat glands and a few vasodilator neurons
c. Sympathetic postganglionic neurons innervating sweat glands: acetylcholine is major neurotransmitter, stimulates muscarinic cholinergic receptors on secretory
Table 22-1. Parasympathetic (Craniosacral) Autonomic Division
Preganglionic Ganglion of post-Effector organ neuron, nerve Neurotransmitter* ganglionic neuron Neurotransmitter† (function)
cells in sweat glands d. Sympathetic preganglionic neurons synapsing in adrenal
medulla: stimulate nicotinic cholinergic receptors on adrenal chromaffin cells, which secrete epinephrine and small amounts of NE
e. Paravertebral sympathetic ganglia chain 1) Bilateral chains spanning entire vertebral column
from C1 to conus medullaris (coccygeal segments) 2) Afferent neurons
a) Cell bodies in intermediolateral cell column (C8 to L1-L2)
b) Axons pass through ventral horn to the ventral rootlets and, with the spinal nerve, exit through neural foramen
3) Sympathetic paravertebral chain (Fig. 22-3) a) Located immediately adjacent to vertebral bodies b) Communicates with the exiting spinal nerve by
two communicating nerves: white rami commu-
nicantes carry the afferent (preganglionic) input to ganglionic chain and gray rami communicantes carry efferent (postganglionic) output back to spinal nerve
4) Afferent input from the white rami communicantes may a) Synapse in the ganglion at the same level b) Travel up or down the sympathetic paravertebral
chain to synapse at a different level, or c) Extend beyond the sympathetic paravertebral
chain to synapse in a prevertebral ganglia (see below) or adrenal medulla
d) Note: the intermediolateral column is location of all cell bodies of preganglionic sympathetic neurons (extends between C8 and L1)
5) Segmental dominance of presynaptic input: main synaptic input to a ganglion originates from a particular segment of spinal cord
6) Neurotransmitter released at the ganglionic synapse is acetylcholine (acts on nicotinic cholinergic receptors on postsynaptic cells)
f. Prevertebral sympathetic ganglia (Fig. 22-3) 1) Include the celiac, aorticorenal, superior mesenteric,
and inferior mesenteric ganglia 2) Afferent input: neurons with cell bodies in
a) Intermediolateral cell column
b) Axons pass from spinal nerves to white rami communicantes
c) Preganglionic axons exit white rami communicantes and form splanchnic nerves, which synapse in preverebral ganglia
C. Autonomic Innervation of the Urinary System 1. Cortical urinary control center (CUCC)
a. Located in frontal lobe 1) Possible role of prefrontal cortex and anterior cingu-
late cortex in initiation of micturition 2) Left sensorimotor cortex, right lateral frontal cortex,
and bilateral supplementary motor cortices may be involved in both initiation and maintenance of detrusor contraction and bladder emptying
b. Frontal lobes: receive extensive input from other cortices, basal ganglia, and thalamus on appropriateness of micturition, emotional input, and other data to determine the timing of micturition
c. There is also feedback from the lower (pontine) centers on the degree of bladder distension
d. CUCC communicates with the pontine micturition center or pontine urinary control center (PUCC) and also projects directly to the pyramidal cells of the motor cortex (likely the superomedial central gyrus), which
then project to sacral cord to synapse on pudendal motor neurons in ventral horn (a few cross the midline to synapse on contralateral pudendal motor neurons) to provide tone in external urinary sphincter
2. Pontine urinary control center (pontine micturition center) a. Likely diffuse location: PAG, locus ceruleus, and pon-
tine paramedian reticular formation have been implicated
b. Information about the degree of bladder distension is projected to PUCC and then to CUCC
c. PUCC also receives information from cortex and integrates this with sensory feedback information to coordinate activity of the spinal urinary control center (SpUCC)
d. In essence, the switch from continence to micturition occurs in the pons
e. There are also recriprocal connections with amygdala and hypothalamic preoptic area: may be important for micturition response to emotionally charged stimuli
f. The pontine micturition center sends projections to the pelvic and pudendal nuclei in sacral cord located in conus medullaris
3. Spinal urinary control center a. Sympathetic autonomic innervation
1) Sympathetic preganglionic neurons originate from intermediolateral cell column between T12 and L2, synapse in corresponding paravertebral ganglia, inferior mesenteric (prevertebral) ganglion, ganglia in pelvic plexus, vesical plexus (“vesical ganglia”), or intramural vesical ganglia (located primarily at the trigone and bladder neck)
2) Sympathetic nerves innervate urethral smooth muscle (facilitates contraction of urethral smooth muscle) and arterial supply to bladder and not the detrusor muscle
3) Overall effect of sympathetic innervation of the urethral smooth muscle: inhibit micturition through contraction of urethral smooth muscle and possibly inhibition of parasympathetic ganglionic transmission to detrusor muscle
b. Parasympathetic autonomic innervation 1) Pelvic (detrusor motor) nuclei:
a) Located in conus medullaris (sacral cord) at S2, S3, and S4
b) Axons form pelvic splanchnic nerves, which innervate bladder detrusor muscle, ureter, urethral smooth muscle, and prostate
2) Overall effect of the parasympathetic pelvic splanchnic nerves: facilitation of micturition by contraction of detrusor muscle and relaxation of urethral smooth
muscle 3) Final micturition depends on the urethral sphincter
innervated by pudendal nerve (under voluntary control, not autonomic control)
c. Somatic efferent (voluntary control, not autonomic) 1) Pudendal nuclei in conus medullaris (segments S2-4) 2) Axons form the pudendal nerve, which innervates
urethral sphincter muscle (striated, not smooth, muscle) between the fascial layers of the urogenital diaphragm (as well as outer vagina and clitoris, penis, bulbospongiosus, ischiocavernosus, superficial transverse perineal, levator ani, and external anal sphincter muscles); striated sphincter muscle is less well-developed in females than males
d. Sensory afferent input 1) Information about the degree of bladder wall stretch
and contractility is carried by Aδ and C fibers (free nerve endings) to dorsal horn and PUCC
2) Pain sensation from bladder is via sympathetic nerves to dorsal horn cells, then via spinothalamic tract
3) Information about distension of the bladder wall may be conducted via parasympathetic nerves to dorsal horn and then via spinothalamic tract and also dorsal columns
4) Sensory input evoked by bladder distension inhibits the tonic motor excitation of pudendal motor axons innervating the external anal sphincter
D. Autonomic Innervation of the Gastrointestinal System and Enteric Nervous System
1. Extrinsic sympathetic innervation a. Preganglionic cell bodies in intermediolateral cell col-
umn between T9 and L2 1) Preganglionic axons reach the sympathetic paraverte-
bral chain via white rami communicantes 2) Some axons synapse in paravertebral ganglia, and oth-
ers leave the sympathetic chain as thoracic, lumbar, and sacral splanchnic nerves to synapse in prevertebral ganglia (celiac, superior, and inferior mesenteric ganglia) and inferior hypogastric (pelvic) plexus
b. Synapses in both paravertebral and prevertebral ganglia are cholinergic (nicotinic)
c. Prevertebral sympathetic ganglia: mediate inhibitory spinal reflexes and peripheral reflexes
d. Postganglionic neurons 1) Vasomotor neurons innervate submucosal blood ves-
sels; responsible for vasoconstriction of these vessels 2) Motility-regulating neurons innervate myenteric
plexus, submucosal plexus, and smooth muscle sphincters
3) Postganglionic axons originating from celiac and superior mesenteric ganglia: innervate small intestine, appendix, and ascending and transverse colon
4) Postganglionic axons originating from inferior mesenteric ganglion: innervate descending colon, sigmoid colon, and rectum
5) Postganglionic axons originating from inferior hypogastric (pelvic) plexus: innervate lower rectum
2. Extrinsic parasympathetic innervation a. Consists of the vagus (CN X) and pelvic splanchnic nerves b. Vagus nerve efferents
1) Cell bodies in dorsal motor nucleus of X and nucleus ambiguus; axons innervate esophagus, stomach, small intestine, appendix, and ascending and transverse colon (with a proximal-to-distal gradient of innervation, proximal gastrointestinal system receiving the bulk of the innervation)
2) Innervate the enteric nervous system directly (myenteric plexus), releasing acetylcholine to stimulate nicotinic receptors of myenteric plexus
c. Pelvic splanchnic (parasympathetic preganglionic) nerves 1) Cell bodies in sacral spinal cord; axons innervate
descending and sigmoid colon and rectum 2) Axons directly innervate enteric system (myenteric
plexus), as does vagus nerve d. Enteric nervous system acts as “postganglionic” neurons
3. Primary afferents a. Glutamate: primary neurotransmitter b. Do not penetrate the epithelium c. Vagus nerve afferents
1) Cell bodies in interior ganglion of CN X 2) Transmit information from gastrointestinal tract
(from esophagus to splenic flexure) to nucleus solitarius 3) Do not transmit information about pain 4) Transmit information about mechanical distortion
and distension of gut innervated by vagus nerve d. Spinal primary sensory afferents
1) Cell bodies in dorsal root ganglia 2) Transmit nociceptive afferent information (via sym-
pathetic neurons and pelvic plexus and pelvic splanchnic nerves) from descending colon, sigmoid colon, and rectum to dorsal horn of the spinal cord (lamina I), from which axons project to ventromedial thalamus, which projects to insular cortex
3) Transmit information about pain and mechanical distortion and distension of gut innervated by sacral and pelvic splanchnic nerves
4. Enteric nervous system a. The nervous system of the gastrointestinal tract located
in the gut wall
b. Primarily responsible for peristalsis and migrating motor complex
c. Integrates absorptive and secretory functions of the gut with motility
d. Enteric nervous system is essentially a semiautonomous integrative system that retains several stereotyped motility “programs” (e.g., those applied to the fasting state, postprandial state, and emesis), which are selected on the basis of input from periphery or central centers
e. Sensory neurons consist of mechanoreceptors, chemoreceptors, and thermoreceptors 1) Mechanoreceptors: sense mechanical changes in the
gut wall and mesentery (gross movements) and information about contractile state and bowel distension
2) Chemoreceptors: sense changes in luminal contents (including pH, osmolarity, and concentration of nutrients)
3) Mechanoreceptor hypersensitivity in sensing distension of the bowel and contractile tension: possible explanation for pain perceived by patients with irritable bowel syndrome
f. Interneurons 1) Receive and integrate input from sensory neurons
and central nervous system 2) Project to enteric motor neurons 3) Participate in reflex circuits 4) Provide input to other interneurons 5) Provide excitatory or inhibitory input to enteric
motor neurons, which excite or inhibit the corresponding musculature
g. Enteric motor neurons: cell bodies are in ganglia of two major plexuses-myenteric (Auerbach’s) plexus and submucosal (Meissner’s) plexus 1) Myenteric plexus
a) Located between the longitudinal and circular external muscle layers
b) Responsible for regulation of contractility of the external muscle layers
2) Submucosal plexus a) Located in the submucosal layer b) Responsible for regulation of the secretory and
absorptive functions of the gut c) Innervates submucosal arteries
h. Enteric secretomotor neurons 1) Innervate and excite the intestinal crypts of Lieberkühn
and send collaterals to surrounding blood vessels, causing them to vasodilate, thus simultaneously increasing blood flow promoting secretion
2) Hyperactivity of these neurons observed in diarrheal illness
3) Hypoactivity of these neurons observed in constipation
i. Secretion of water, electrolytes, and mucus are followed by peristalsis and propulsive contractions of the gut
j. Peristaltic reflex in nonsphincteric regions 1) With a passing bolus, enteric excitatory musculo-
motor neurons induce contraction of intestinal circular muscles orad to and longitudinal muscles caudad to the bolus (the point of activation of mechanoreceptors sensing the distension)
2) Simultaneously, enteric inhibitory musculomotor neurons inhibit contraction of (and promote relaxation of) the intestinal circular muscles caudad to and longitudinal muscles orad to the point of distension
3) This intrinsic activity of the enteric nervous system is stimulated by parasympathetic preganglionic fibers and inhibited by sympathetic innervation
k. Excitatory musculomotor neurons release acetylcholine and substance P; the predominant inhibitory neurotransmitters are adenosine triphoshate (ATP), vasoactive intestinal polypeptide, and nitric oxide
l. Destruction and absence of the inhibitory musculomotor neurons of the myenteric plexus: continuous contraction of the self-excitable muscular syncytium of nonsphincteric regions 1) This causes failure of normal intestinal propulsion
and, thus, pseudo-obstruction 2) Examples of disorders associated with pseudo-obstruc-
tion (poor or absent motility without a structural obstruction): Chagas’ disease, autoimmune pandysautonomia, paraneoplastic syndrome, Hirschprung’s disease, idiopathic or inherited neuropathies, achalasia (of lower esophageal sphincter)
E. Autonomic Physiology of Sexual Function 1. Central pathways
a. Cerebral cortex 1) Orbitofrontal cortex: associated with emotional and
motivational aspects of sexual arousal 2) Anterior cingulate cortex and hypothalamus: associ-
ated with autonomic and endocrine responses 3) Head of the caudate: has been implicated by data
from positron emission tomography (PET) b. Hypothalamus: regions responsible for mediating sexual
behavior are medial preoptic area in males and ventromedial nucleus in females
c. Spinal cord: ascending fibers carry sensory input from sex organs
2. Peripheral pathways a. Sympathetic innervation
1) Preganglionic fibers a) Originate from intermediolateral cell column
between T11 and L2 b) Exit from spinal cord in ventral roots and enter
paravertebral ganglia (sympathetic chain) c) Some synapse here and others form lumbar and
sacral splanchnic nerves to synapse in prevertebral ganglia (inferior mesenteric ganglia and inferior hypogastric [pelvic] plexus)
d) Synapses are cholinergic (nicotinic) in both paravertebral and prevertebral ganglia
2) Postganglionic fibers to arteries: responsible for maintaining arterial tone
3) Postganglionic fibers to erectile tissue of penis, clitoris, and vestibular bulbs: responsible for psychogenic erection originating from cerebral cortex
4) Postganglionic fibers to smooth muscle in epididymis, vas deferens, seminal vesicles, and prostate gland: responsible for seminal emission and deposition of spermatozoa and seminal fluid
5) Postganglionic fibers to sphincter of the bladder neck: responsible for simultaneous contraction of sphincter for prevention of reflux of semen into bladder
b. Pudendal nerve 1) Originates from anterior horn cells in S2-4 2) Contains afferent input for reflexogenic penile erec-
tion, glandular secretions, seminal emission, and ejaculation
3) Contains somatic efferents for ejaculation 3. Erection
a. Penile erection is autonomically mediated increased blood flow to venous sinuses of corpora cavernosa and corpus spongiosum, accompanied by arterial dilatation and decreased venous outflow, due partly to contraction of ischiovacernosus muscle constricting the proximal corpora cavernosa
b. Occurs from 1) Local stimulation of the genitalia: reflexogenic erec-
tion (sacrospinal reflex) mediated by pudendal afferents and sacral parasympathetic efferents
2) Psychogenic stimulation: supraspinal erection mediated by cortical auditory, visual, olfactory, emotional, imaginative, or other cortical input and lumbar sympathetic efferents
4. Emission a. Mediated by lumbar sympathetic innervation b. Contraction of smooth muscle of epididymis, vas
deferens, seminal vesicles, and prostate gland (as mentioned above)
5. Ejaculation
a. Mediated by pudendal somatic efferents (motor neurons), not by sympathetic innervation
b. Rhythmic contractions of bulbocavernosus, ischiocavernosus, and periurethral striated muscles are responsible for rapid and rhythmic release of semen
6. Orgasm a. In males, mediated by pudendal sensory afferents carry-
ing information about sensations accompanying emission and ejaculation
b. In females, mediated by pudendal sensory afferents carrying information about sensations accompanying rhythmic contraction of vagina and muscles of the pelvic floor
A. Cardiovascular Autonomic Tests 1. Beat-to-beat response to Valsalva maneuver (forced
expiration against resistance) a. Beat-to-beat blood pressure and heart rate response to
Valsalva maneuver b. Four phases of Valsalva response are used to assess adren-
ergic function (Fig. 22-4) c. Phase I
1) Transient increase in blood pressure and decrease in heart rate
2) Mechanical phase: due to compression of thoracic aorta and propulsion of blood into the periphery
d. Phase II 1) Early
a) Increase in heart rate and decrease in blood pressure
b) Poor venous return to the heart decreases cardiac output and, hence, blood pressure
c) This decrease in blood pressure is sensed by lowpressure aortic baroreceptors, which send signals to nucleus solitarius, eventually causing compensatory increase in heart rate
2) Late a) Return of blood pressure to normal and continued
increase in heart rate b) Peripheral vasoconstriction due to vascular sympa-
thetic activation causes normalization of blood pressure
3) Main mediator of late phase is vascular sympathetic innervation: this phase may be blocked by α-blockers and may be reduced or absent in conditions associated with peripheral adrenergic failure
e. Phase III: cessation of forced expiration 1) Transient decrease in blood pressure and increase in
heart rate 2) Mechanical phase: release of mechanical compression
on thoracic aorta causes release of resistance in the pulmonary vasculature and increase in blood flow to pulmonary vessels, hence, a decrease in cardiac output and blood pressure
f. Phase IV 1) Increase in blood pressure and decrease in heart rate 2) Sympathetically mediated overshoot increase in blood
pressure is caused by increased venous return to the heart and increased cardiac output (mediated by increased myocardial contractility) in face of peripheral vasoconstriction (the latter lags behind); accompanying decrease in heart rate is baroreflex-mediated
3) Principal mediator of blood pressure overshoot: cardiac sympathetic innervation; this phase may be blocked by β-blockers
g. Phases I and III are purely mechanical, and phases II and IV are sympathetically derived and are used to assess cardiovascular adrenergic function
h. Absence of phase IV and late phase II responses and a larger decrease in blood pressure in early phase II are noted in conditions associated with generalized adrenergic failure
2. Beat-to-beat response to head-up tilting (passive standing) (Fig. 22-5) a. Head-up tilt is passive form of standing; hence, initial
decrease in blood pressure may be absent or minimal compared with response to standing
b. Normal response: initial transient decrease in blood pressure and increase in heart rate, followed by return of both heart rate and blood pressure to a new plateau (generally close to but higher than baseline)
c. Abnormal response: initial decrease in blood pressure and rise in heart rate; blood pressure continues to decrease, and heart rate does not return to a point close to baseline
d. Indicators of mild adrenergic impairment: excessive oscillations in blood pressure, transient decrease in systolic blood pressure of more than 30 mm Hg, and an increase in heart rate of more than 30 beats per minute
B. Quantitative Sudomotor Axon Reflex Test (Fig. 22-6 and 22-7)
1. Axonal reflex: mediated by postganglionic sympathetic axons (sudomotor axons) to eccrine sweat glands
2. Procedure a. Nerve terminals on sweat gland stimulated by ionto-
phoresis of acetylcholine to the skin under the stimulus compartment of the multicompartmental cell applied to the skin
b. The impulses generated travel antidromically to nearest branch point and then travel orthodromically to nearby sweat glands, stimulating muscarinic receptors on the glands to produce a sweat response that is recorded in a different compartment of the cell at a distance from the stimulus compartment
3. Interpretation of test results a. Normal test: intact postganglionic sympathetic sudo-
motor axons b. Normal test with anhidrosis on thermoregulatory sweat
test: preganglionic localization of lesion c. Abnormal test with anhidrosis on thermoregulatory
sweat test: postganglionic localization of lesion (most
sensitive for postganglionic autonomic neuropathy) d. Small-fiber neuropathy
1) Reduction of sweat response distally 2) There may be persistent sweat activity in mild small-
fiber neuropathies, which may be related to repetitive spontaneous firing of damaged sympathetic axon
3) Painful small-fiber neuropathies are associated with augmentation of somatosympathetic reflexes, causing markedly reduced latencies with persistent sweat
activity e. Complex regional pain syndrome (CRPS): sweat activity
may be reduced or exaggerated
C. Thermoregulatory Sweat Test (Fig. 22-8) 1. Use: evaluation of both central and peripheral efferent
sudomotor pathways 2. Method
a. Increase skin temperature and core body temperature in a sweat chamber with ambient temperature of 48°C to 50°C
b. An indicator powder is applied to the skin before heating (often a mixture of alizarin red, cornstarch, and sodium carbonate in 50:100:50-g ratio)
c. The powder is orange and remains orange when dry, but
turns purple when wet 3. Patterns of sweat loss
a. Distal (length-dependent): seen with peripheral neuropathies with small-fiber involvement
b. Focal: anhidrosis confined to a dermatome or distribution of a peripheral nerve
c. Segmental: focal pattern, confined to a dermatome d. Global: diffuse anhidrosis involving more than 80% of
body 4. False positive
a. Wearing pressure wraps within 12 hours before the test may produce false-positive results, that is, anhidrosis over the distribution that was covered (there is usually straight edges)
b. Reduced diffuse (not focal) anhidrosis with dehydration
and anticholinergic agents (should be avoided within 48 hours before the test)
c. Elderly: there may be focal areas of anhidrosis (often affecting lower body and proximal upper limbs)
A. Degenerative Disorders 1. Autonomic features of multiple system atrophy (see
Chapter 8) a. Due to loss of sympathetic cells in intermediolateral cell
column and paravertebral sympathetic ganglia b. Urogenital dysfunction: male erectile dysfunction, uri-
nary incontinence (detrusor hyperreflexia, overflow incontinence, and urinary dyssynergia), urinary retention, and incomplete bladder emptying
c. Cardiovascular autonomic dysfunction: orthostatic hypotension
d. Sudomotor dysfunction: hypohidrosis or anhidrosis (caution against overheating)
e. Selective loss of anterior horn cells in ventral horn of sacral segments (Onuf’s nucleus)
f. Other autonomic features: gastrointestinal hypomotility and sleep-related respiratory disorders (laryngeal stridor and sleep apnea)
2. Autonomic features of Parkinson’s disease (see Chapter 8) a. Autonomic failure: well-documented; believed due to
neuronal loss and degeneration of preganglionic and postganglionic neurons
b. Lewy bodies seen in both central (substantia nigra) and peripheral neurons
c. Cardiovascular autonomic dysfunction presenting with orthostatic hypotension (primary symptom, secondary to medications, or a combination thereof): dopaminergic drugs produce or exacerbate the symptoms
d. Dysphagia and sialorrhea are likely due to oropharyngeal rigidity
e. Genitourinary dysfunction: male impotence and ejaculatory dysfunction, poor libido, and bladder hyperreflexia
3. Dementia with Lewy bodies (see Chapter 7) 4. Pure autonomic failure
a. Adult onset, sporadic, slowly progressive idiopathic degenerative condition
b. Clinical manifestations 1) Orthostatic hypotension, urinary and sexual
dysfunction
2) No other neurologic complaints (sparing of pyramidal, extrapyramidal, and cerebellar systems)
c. Urinary symptoms: hesitancy, urgency, postvoiding dribbling, and incontinence
d. Sexual dysfunction symptoms: impotence, erectile and ejaculatory dysfunction, and retrograde ejaculation
e. Orthostatism: consciousness may be lost with or without warning
f. Patients should be followed for at least 5 years because other neurologic symptoms may develop, and the diagnosis eventually may be changed (such as Parkinson’s disease or multiple system atrophy)
g. Laboratory findings 1) Very low NE levels when recumbent (this is normal
in patients with multiple system atrophy and Parkinson’s disease)
2) Failure of plasma NE levels to increase during upright posture (subnormal increase seen in patients with multiple system atrophy and some patients with Parkinson’s disease)
3) Neuroendocrine responses to hypotension or centrally acting adrenergic agents such as clonidine are normal in patients with pure autonomic failure or Parkinson’s disease (blunted in patients with multiple system atrophy)
4) Neuroimaging findings: normal h. Pathology features
1) Presence of Lewy bodies in substantia nigra, locus ceruleus, thoracolumbar and sacral cord, sympathetic ganglia, and postganglionic nerves (may be more prominent in peripheral locations)
2) Cell loss in intermediolateral columns and sympathetic ganglia
B. Immune-Mediated Disorders 1. Guillain-Barré syndrome (see Chapter 21)
a. Autonomic dysfunction (hyper-or hypoactivity): relatively common
b. Tachycardia, orthostatic hypotension (alternating with hypertension), bowel and bladder dysfunction, gastrointestinal tract dysmotility, and, less commonly, gastroparesis, pupillary dysfunction, and fecal incontinence
c. Autonomic symptoms may be life-threatening; patients may need to be monitored closely
2. Autoimmune autonomic neuropathy a. May affect any age b. Typically subacute onset of autonomic symptoms, but a
subset of patients present with more gradual onset and slow progression
c. Diffuse autonomic dysfunction (often primarily cholinergic immune-mediated ganglionopathy) affecting both
sympathetic and parasympathetic systems d. Most patients have postural hypotension and gastro-
intestinal tract dysmotility e. Other symptoms: anhidrosis, “sicca” symptoms (dry eyes
and mouth), pupillary involvement, erectile dysfunction, and urinary incontinence
f. Most patients have a monophasic exacerbation, followed by remission without recurrences
g. Serum serology 1) Neuronal (ganglionic) nicotinic acetylcholine receptor
(α3 subunit) antibodies present in approximately 1/3 of patients
2) Presence of this antibody has been associated with sicca complex, pupillary dysfunction, lower gastrointestinal dysfunction, and subacute onset (temporal profile may vary)
3) Antibody level correlates with severity of autonomic signs and symptoms
h. Cerebrospinal fluid: often has elevated protein with normal cells
i. Prognosis: most patients improve spontaneously; recovery is often partial, usually slow, and may take several months to years
j. Treatment 1) Symptomatic management
2) Anectodal reports of response to intravenous immunoglobulin and plasma exchange (especially if given early)
3. Paraneoplastic pandysautonomia a. Associated with lung carcinoma, Hodgkin’s lymphoma,
testicular cancer, pancreatic carcinoma b. Associated with antineuronal nuclear (ANNA)-1 (anti-
Hu) antibodies c. Separate from paraneoplastic ganglionopathy or
Lambert-Eaton syndrome 4. Lambert-Eaton myasthenic syndrome (see Chapter
23) a. Usually paraneoplastic b. Pure cholinergic dysautonomia c. Autonomic failure due to defective presynaptic acetyl-
choline release 5. Paraneoplastic sensory neuronopathy (see Chapters 14
and 21) 6. Sensory neuronopathy related to Sjögren’s syndrome
(see Chapter 21) 7. Multiple sclerosis (see Chapter 14)
a. Related to transverse myelitis or to lesion brainstem or diencephalon
b. Dysfunction of bowel, bladder, or sexual function is common
c. Bladder dysfunction is commonly detrusor hyperreflexia 8. Connective tissue disorders
a. Rheumatoid arthritis, systemic lupus erythematosus, mixed connective tissue disease (see Chapter 14)
b. Anhidrosis of extremities commonly occurs in rheumatoid arthritis because of damage of postganglionic sympathetic efferent fibers
C. Infectious Disorders 1. Leprosy
a. Abnormalities range from focal anhidrosis over hypopigmented areas to more diffuse anhidrosis, postural hypotension, and cardiac denervation
2. Other infectious causes: Chagas’ disease (see Chapter 15), human immunodeficiency virus (and related complications, see Chapter 15), prions (fatal familial insomnia, see Chapter 7)
D. Vascular Disorders 1. Ischemia in basilar artery distribution (e.g., lateral
medullary infarction, or Wallenberg’s syndrome)
E. Hereditary and Congenital Disorders (see also Chapter 21)
1. Associated with hereditary neuropathies
a. For example, hereditary sensory and autonomic neuropathies (HSAN)
b. Autonomic features are prominent in HSAN type III (Riley-Day syndrome)
2. Fabry’s disease a. X-linked recessive disorder due to deficiency of α-galactosidase A
3. Tangier disease a. Caused by deficiency of ATP-binding cascade transporter b. Patients present with slowly progressive sensory small-
fiber neuropathy, motor involvement (including facial diplegia), orange-yellow tonsils, enlarged liver and spleen, hypercholesterolemia, hypertriglyceridemia, reduced or absent high-density lipoproteins, and premature coronary artery disease
4. Porphyrias 5. Hereditary amyloidosis 6. Arnold-Chiari malformation (involving brainstem
autonomic pathways)
F. Diabetes-Related Neuropathy (see also Chapter 21) 1. Common cause of autonomic neuropathy 2. Frequent involvement of unmyelinated fibers 3. Orthostatic hypotension, gastroparesis, impotence,
retention, constipation, gustatory sweating
G. Traumatic Causes 1. Syringomyelia
a. May also be nontraumatic, spontaneous b. Disruption of intermediolateral cell columns and associ-
ated projections c. There may be segmental autonomic deficits, including
segmental hypohidrosis 2. Spinal cord transaction
a. Supine and orthostatic hypotension (hypertension with autonomic dysreflexia)
b. Risk of bradycardia and cardiac arrest (especially with maneuvers stimulating vasovagal reflex, such as suctioning)
c. Enhanced role of vasopressin and the renin-angiotensinaldosterone system in maintaining arterial blood pressure
d. Below the lesion 1) Lack of sudomotor and thermoregulatory responses 2) Severe hypothermia or hyperthermia, anhidrosis
e. Above the lesion (cervical to T5): autonomic dysreflexia 1) Sympathetic system: reflex activation 2) Sacral parasympathetic autonomic system: activation
induced by stimulation of skin or viscera 3) There may be vasodilatation and flushing of skin,
hyperhidrosis, piloerection, pupillary dilatation, and severe hypertension (supine and orthostatic)
f. Bladder function 1) Complete spinal cord transaction: complete loss of
voluntary control of voiding 2) In acute phase: complete urinary retention and
areflexic bladder 3) Soon after acute phase
a) Recovery of reflex bladder activity mediated by spinal reflex pathways
b) Development of bladder hyperactivity due to disruption of bulbospinal inhibitory projections
g. Spinal cord lesions above T12: preserved reflexogenic penile erection (pudendal afferents and sacral parasympathetics), but abolished psychogenic penile erection
H. Localized or Organ-Specific Autonomic Disorders 1. Adie’s pupil (see Chapter 3) 2. Holmes-Adie syndrome
a. Adie’s pupil and deep tendon areflexia, the latter likely due to involvement of dorsal root ganglia
b. Associated with autonomic neuropathy and peripheral neuropathy
c. There may be evidence of widespread autonomic involvement such as orthostatic hypotension and sudomotor abnormalities, as noted on thermoregulatory sweat test
3. Horner’s syndrome (see Chapter 3) 4. Ross syndrome
a. Both sympathetic and parasympathetic patchy denervation (the latter is more prominent)
b. Tonic pupils associated with hyporeflexia and segmental hypohidrosis: believed to be due to involvement of postganglionic cholinergic fibers
c. Hyporeflexia may implicate dorsal root ganglia d. Tonic pupils are likely due to damage to ciliary ganglion
or postganglionic cholinergic parasympathetic fibers, denervation of iris muscles, and misdirected reinnervation by parasympathetic fibers originally destined for ciliary muscle
e. Anhidrosis likely results from damage to sympathetic ganglion cells or postganglionic projections
f. There may be more widespread autonomic manifestations: orthostatic hypotension, Horner’s syndrome
5. Harlequin syndrome a. Sudden onset of unilateral sweating and flushing occur-
ring on one side of face, often induced by exercise b. There may be contralateral gustatory sweating c. Pupil may be smaller ipsilateral to nonflushing side
(hypothesized to be due to sympathetic denervation supersensitivity, with partial denervation) or larger
d. Both sympathetic and parasympathetic patchy denervation
e. Cause: unknown, but viral infection or autoimmune mechanism has been proposed
6. Chagas’ disease a. Infection caused by Trypanosoma cruzi, occurring pre-
dominantly in Latin America b. Combined parasympathetic and sympathetic neuropa-
thy (predominantly parasympathetic) c. Acute stage: high parasitemia and widespread tissue
infiltration, especially cardiac and autonomic ganglionic tissues
d. Chronic stage 1) Parasite leaves bloodstream, but serology tests remain
positive 2) Most of these patients with positive serology tests
remain asymptomatic 3) Approximately 1/3 of these patients develop cardio-
myopathy and may develop cardiac failure and cardiac dysrhythmias
e. Involvement of enteric nervous system: ganglionitis and destruction of Meissner’s and Auerbach’s plexuses, causing dilatation of esophagus (megaesophagus), stomach, or large intestine (megacolon)
f. Involvement of parasympathetic cholinergic innervation of gastrointestinal tract
g. Other autonomic innervations affected: urinary, cardiopulmonary (including the cardiac complications discussed above)
7. Vasospastic disorders a. Raynaud’s phenomenon
1) Episodes of bilateral, symmetric change in skin color, provoked by exposure to cold or emotional stimuli (pallor cyanosis rubor: white-blue-red)
2) Color change is believed due to transient vasospasm of digital arteries inducing local ischemia
3) Raynaud’s syndrome: applies to the condition without an underlying cause
4) Raynaud’s phenomenon: associated with connective tissue disease (e.g., scleroderma), carpal tunnel syndrome, thoracic outlet syndrome, and drugs (amphetamines, β-blockers, ergot alkaloids, bleomycin, nitroglycerin, methysergide, bromocriptine, and cyclosporine)
b. Acrocyanosis 1) Benign, painless disorder 2) Symmetric persistent cyanosis of the distal extremities
that may extend to ankles and wrists, associated with hyperhydrosis and coldness of fingers and toes
3) Results from arterial vasoconstriction 4) Normal pulse, normal oxygen saturation on pulse
oximetry 5) Persistant cyanosis manifesting as bluish discoloration
(not rubor or pallor, as with Raynaud’s phenomenon) 6) Exacerbated with exposure to cold (alleviated with
exposure to heat) c. Livedo reticularis
1) Mottled discoloration of extremities and trunk due to arteriolar vasospasm and obstruction or venous stasis
2) May be benign in the absence of a systemic condition or
3) May be associated with several vasculitides and connective tissue disorders, antiphospholipid antibodies (Sneddon’s syndrome), hyperviscosity syndrome, thrombocythemia, drugs (e.g., amantadine)
8. Pathologic hyperhidrosis a. Essential (primary) hyperhidrosis
1) Affects the palmar, plantar, and axillary regions; is often familial
2) Evidence supports hyperactivity of sympathetic neurons in T2-4 sympathetic ganglia
3) May be treated with β-blockers, anticholinergic agents, and surgical sympathetectomy
b. Idiopathic postmenopausal hyperhidrosis 1) Predominantly affects head and upper trunk 2) Responsive to clonidine (centrally acting α2-adrener-
gic receptor agonist)
c. Facial hyperhidrosis 1) Idiopathic hemifacial hyperhidrosis
a) Associated with hypertrophy of sweat glands b) Gustatory flushing and sweating provoked by heat,
emotions, and eating c) May be treated with stellate ganglion block
2) Gustatory sweating a) May be due to damage of pre-or postganglionic
sympathetic nerves (cervicothoracic sympathectomies) or local damage to autonomic innervation of the face, denervation supersensitivity, and aberrant reinnervation
b) Autonomic denervation in the face may be followed by reinnervation of sweat glands by parasympathetics originally destined for salivary glands
9. Pathologic hypohidrosis and anhidrosis a. Hypohidrosis and anhidrosis cause heat intolerance,
hyperthermia, dry skin, trophic skin changes, and other autonomic features, depending on extent of involvement and cause
b. Chronic idiopathic anhidrosis 1) Acquired widespread anhidrosis 2) Absence of adrenergic or cardiovagal dysfunction
(patients do not experience orthostatic hypotension) 3) Some cases are associated with small-fiber neuropathy 4) Anhidrosis may remain stable or progress
c. Acquired focal anhidrosis 1) Segmental radicular dermatomal, focal, or multifocal
distribution of anhidrosis may be seen with diabetic truncal neuropathies and mononeuritis multiplex (as in vasculitic mononeuropathies and leprosy)
2) Segmental anhidrosis (focal or multifocal) in distribution of sympathetic dermatomes may be seen with sympathectomies, Pancoast’s tumor, and autoimmune acute pandysautonomia
3) Cutaneous disorders causing anhidrosis (not conforming to dermatomal or single nerve distribution): local radiation injury (damaging the sweat glands), psoriasis, and hypohidrotic ectodermal dysplasia
4) Distal (length-dependent) postganglionic anhidrosis: seen in context of peripheral neuropathies affecting sudomotor innervation; examples are diabetic peripheral neuropathy, primary systemic and familial amyloidosis, Tangier disease, Fabry’s disease, and axonal neuropathies caused by drugs and toxins (e.g., chemotherapy agents and heavy metals)
d. Hemianhidrosis 1) Due to central lesions 2) Brainstem lesions (infarcts, tumors, syringobulbia)
cause anhidrosis of hemibody ipsilateral to lesion (cortical infarcts may acutely cause hyperhidrosis contralateral to lesion)
e. Global anhidrosis 1) Inherited (e.g., hereditary sensory and autonomic
neuropathy VI) 2) Acquired (“central” disorders such as multiple system
atrophy and hypothalamic tumor) 10. Erythromelalgia
a. Painful acral erythema on cutaneous warming, associated with intense burning
b. Mechanism believed to involve backfiring (axon reflex) of polymodal C nociceptors
c. Often associated with small-fiber neuropathy d. Associated with
1) Diabetic neuropathy, hereditary sensory neuropathy 2) Drugs (verapamil, nicardipine, pergolide, and
mercury) 3) Vasculitis and collagen vascular diseases 4) Pregnancy 5) Myeloproliferative disorders
e. Treatment 1) Some evidence for relief with aspirin or ibuprofen 2) Other: amitriptyline, β-blockers, capsaicin cream,
clonazepam 11. Red ear syndrome
a. Head pain and unilateral painful, burning red ear b. Pain may radiate to C2 and C3 dermatomes (behind and
below mandible, respectively), occiput, or forehead c. Pain may be induced by heat, exercise, touch, chewing,
coughing, sneezing, or movements of head and neck d. Associated with lesion of C3 root, temporomandibular
joint dysfunction, and possibly migraine headaches e. Mechanism believed to involve backfiring (antidromic
response or axon reflex) of polymodal C nociceptors 12. Cluster and migraine headaches (see Chapter 18) 13. Orthostatic intolerance
a. Dysautonomia of upright position (symptoms relieved by lying down)
b. Symptoms may be attributed to lack of adequate cerebral perfusion (e.g., lightheadedness and dizziness, presyncopal symptoms, disequilibrium, lower limb or overall weakness, headache, difficulty thinking, poor exercise tolerance) or autonomic overactivity (e.g., palpitations, tremulousness, nausea)
c. Symptoms may be exacerbated by exposure to increased ambient heat, exercise, and eating
d. May be classified as neuropathic and hyperadrenergic postural tachycardia syndrome (POTS), hypovolemia syndrome, and vasovagal syncope (the latter two are not
discussed further) e. Postural tachycardia syndrome
1) Usually occurs in individuals between 15 to 50 years old
2) Female:male = 4-5:1 3) May be history of antecedent viral illness and/or family
history 4) Induction of symptoms upon standing and resolution
of symptoms with lying down 5) Increase in heart rate of more than 30 beats/min
and/or absolute rate of more than 120 beats/min 6) May be hyperadrenergic or neuropathic
a) Evidence of associated autonomic neuropathy and related autonomic symptoms with neuropathic POTS, for example, distal anhidrosis on thermoregulatory sweat test or loss of late phase II with Valsalva maneuver
7) Mild POTS is also called mild orthostatic intolerance 8) Excessive increase in heart rate and decrease in blood
pressure (pulse pressure) (Fig 22-5 B) 9) Poor venous tone causes pooling of venous blood in
legs and abdomen (mesenteric venous pool) with standing
10) Differential diagnosis includes a) Thyrotoxicosis b) Dehydration and hypovolemia c) Medication effect d) Pheochromocytoma e) Hypoadrenalism f) Primary autonomic neuropathy such as amyloid
neuropathy 11) Increased supine and upright NE levels (more so with
hyperadrenergic POTS than with neuropathic type) 12) Treatment
a) Liberal salt and fluid intake b) Sleep with head of bed elevated c) Support garments and body stocking for patients
with venous pooling d) Use of fludrocortisone and midodrine for orthosta-
tic hypotension intractable to simple symptomatic measures
e) Use of α-agonist for those with loss of late phase II with Valsalva maneuver
f) Use of low-dose β-blockers (e.g., propranolol) g) Use of low-dose clonidine for hyperadrenergic
POTS (less effective for neuropathic POTS) 14. Complex regional pain syndrome (CRPS)
a. Defined by International Association for the Study of Pain as follows 1) Optional criteria: usually (not always) starts by an
inciting noxious event or cause of immobilization 2) Mandatory criteria
a) Continuing pain and allodynia, or hyperalgesia, disproportionate to the inciting event
b) Pain (at some time) becomes associated with changes in the skin blood flow, edema, and/or abnormal sweating in the region of the pain
c) No evidence of another condition to account for the symptoms
b. Two types of CRPS are recognized by International Association for the Study of Pain 1) Type I (formerly called reflex sympathetic dystrophy):
inciting event (if it exists) spares major peripheral nerves 2) Type II (formerly called causalgia): inciting event
causes damage to a major peripheral nerve c. Inciting event is usually present (rarely absent) and may
be trivial; if present, may be trauma with or without nerve injury, or otherwise, another insult such as hemiplegia from cerebral infarction
d. Quality of the pain varies from deep ache to sharp, burning, and dysesthetic
e. There may be cutaneous hyperalgesia and allodynia (increased perception of pain in response to nonnoxious stimulus)
f. Patients may wear protective gear and clothing to avoid mechanical or thermal stimulation of painful region
g. Abnormal vasomotor activity: skin discoloration and edema in painful region
h. Abnormal sudomotor activity: hypohidrosis i. Other associated manifestations: motor dysfunction and
trophic changes (atrophied skin, hair loss, and pitting nails; nails may be hypertrophied or atrophic)
j. Stage I: pain as described above, hyperalgesia and allodynia, early vasomotor and sudomotor dysfunction (increased swelling and sweating)
k. Stage II (after a few months): pain, sudomotor, and vasomotor dysfunction continue; often, trophic changes as described above
l. Stage III (after a few months to years): persistent pain, sensory and trophic changes, and atrophic muscles
m. Diagnosis 1) Clinical diagnosis 2) Vascular studies to rule out vascular cause 3) Electrodiagnostic testing to rule out neuropathic
process such as peripheral neuropathy or entrapment mononeuropathy
4) Measurement of resting sudomotor activity and also with iontophoresis of acetylcholine to the skin
5) Three-phase bone scan is very sensitive and should be performed early to detect osseous changes sooner than
with plain films 6) Response to sympathetic blocks is often present and
essential for diagnosis; however, response may not be adequate because sympathetic dysfunction may or may not be present
n. Treatment 1) Prevention
a) Avoid tight casts (remove as soon as possible) b) Avoid procedures on patients with previous history
of CRPS if possible; otherwise, sympathetic blockade of the limb undergoing procedure (surgery) may be considered
c) Mobilize patients early 2) Physical therapy and occupational therapy are
absolutely essential a) Goal is to restore mobility, weight-bearing capacity,
reduce swelling, and prevent osteoporesis b) Gentle desensitization, followed by gentle flexibili-
ty, isometric strengthening, followed by more aggressive range-of-motion exercises and strengthening as well as aerobic conditioning
3) Corticosteroids (prednisone or methylprednisolone) a) Class I evidence b) May be most effective early on; recommended for
short-term use (long-term use not usually recommended)
4) Regional sympathetic blockade a) Class III evidence b) May be considered (especially early on) as adjunc-
tive to corticosteroids 5) Tricyclic antidepressants: amitriptyline, nortriptyline,
and doxepin; no adequate data 6) Anticonvulsants: gabapentin (usually ineffective as
sole agent) 7) Topical analgesics: lidocaine transdermal patches may
be helpful for focal CRPS, but not for more diffuse distribution
8) Other: epidural clonidine, transcutaneous clonidine as a patch over allodynic skin, calcium-channel blockers, oral sympathetic antagonists (e.g., terazosin or prazosin)
9) General approach to management a) Treatment must be initiated as soon as possible b) This includes physical therapy, occupational thera-
py, corticosteroids, and concomitant use of nonsteroidal anti-inflammatory drugs, an anticonvulsant (e.g., gabapentin), or an antidepressant (e.g., nortriptyline)
c) A regional sympathetic blockade may then be considered for persistent pain
1. Which of the following statements is true about the role of insular cortex? a. Primary gustatory cortex is located in the anterior
insula b.Insular cortex receives visceral nociceptive input via
sympathetic afferents, with a relay in ventromedial thalamus
c. Insular cortex receives mechanical visceral input via parasympathetic (vagal) afferents via nucleus solitarius and thalamic relay
d.All of the above
2. Sympathetic preganglionic neurons: a. Have cell bodies in the ventral column b.Receive the majority of afferent input from neocortex c. Release norepinephrine, which acts on postganglionic
neurons d.Directly innervate the adrenal medulla
3. Which of the following statements is false about the circumventricular organs? a. Area postrema acts as a chemoemetic center b.They lack a blood-brain barrier
c. They are anatomically close to the ventricular system d.They have an important role in control of emotion-
ally charged autonomic response
4. A 26-year-old woman presents 2 years after sustaining a fall with outstretched arms, placing the majority of her weight on the right hand. Soon after the fall, progressive symptoms of burning pain, hyperalgesia, and allodynia developed in the right hand, together with skin discoloration and edema of the painful area. There has been slow progression of these symptoms, and she recently has noticed atrophic skin and nail beds in the right hand. Which of the following management strategies is not appropriate? a. Avoidance of tight casts b.Early mobilization, physical therapy, and occupa-
tional therapy c. Long-term treatment with corticosteroids d.Concomitant use of nonsteroidal antiinflammatory
drugs and an anticonvulsant or tricyclic antidepressant
e. Regional sympathetic blockade for intractable pain f. All the above are appropriate management strategies
1. Answer: d. All the statements are true about the function of the insula.
