Neuroimmunology in Clinical Practice - part 6 pdf

132 THOMAS H. BRANNAGAN III
(Rechthand et al., 1984). CIDP can occur with HIV
infection and occurs in both the early and late stages
of infection (Cornblath et al., 1987).
Diabetes mellitus or Charcot–Marie –Tooth
Disease (CMT), with superimposed CIDP
Patients with diabetes mellitus and CMT may develop
a superimposed CIDP which is a treatable condition.
Both diabetes mellitus and CMT may predispose
patients to CIDP, as a superimposed and treatable
condition (Dyck et al., 1982b; Gorson et al., 2000;
Sharma et al., 2002; Shy et al., 1997; Stewart et al.,
1996; Vital et al., 2003).
Subacute demyelinating polyneuropathy
Patients with an intermediate time course of pro-
gression, from 4–8 weeks, have been designated
subacute inflammatory demyelinating neuropathy.
This entity was first coined by Oh (Oh, 1977), and the
same author and others have described subsequent
patients (Hughes et al., 1992; Oh et al., 2003). Pati-
ents respond to plasmapheresis, IVIg, and unlike
Guillain–Barré syndrome, also improve with corti-
costeroids. Some patients have a monophasic course
and other develop a chronic disorder. In the recent
series by Oh, compared with CIDP, patients with sub-
acute inflammatory demyelinating polyneuropathy
had a higher incidence of preceding viral illnesses, a
lower rate of relapses, and a higher rate of complete
recovery to normal. Compared to patients with GBS,
however, there is a lower rate of antecedent infection
(39% versus 67%) and a higher rate of relapses (17%

versus 3%) (Oh et al., 2003).
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Introduction
Autonomic neuropathy refers to disorders in which
autonomic nerve fibers are selectively or dispropor-
tionately affected compared to sensory or motor nerve
fibers. Some disorders selectively affect autonomic
ganglia neurons and are referred to as autonomic
neuronopathies. These processes can affect the sym-
pathetic, parasympathetic, and enteric arms of the
nervous system or a combination of systems and
thus can present with a large variety of symptoms
(Box 8.1). Orthostatic hypotension (OH) is usually
a more severe and often late finding that many
physicians consider the primary manifestation of
symptomatic autonomic dysfunction. Dysautonomia
results from numerous disease states with diverse
pathogenic mechanisms, many of which have only
symptomatic treatment available. This chapter will
discuss immune-mediated (Box 8.2) or probable
immune-mediated forms of autonomic dysfunction
that have proven or supportive evidence for more
effective forms of treatment. Examples include
Guillain–Barré syndrome, primary immune-mediated
autonomic neuropathies, paraneoplastic syndromes,
and rheumatologic diseases such as Sjögren syn-

drome and systemic lupus erythematosus. These
conditions are important to bear in mind when
evaluating a patient with any form of autonomic
dysfunction because early recognition of some
disease states may lead to preventative treatment
prior to significant nerve or neuronal injury or early
detection of an underlying malignancy.
8
Immune-mediated autonomic neuropathies
Louis H. Weimer and Mill Etienne
Gastrointestinal: Constipation, diarrhea,
postprandial bloating, fullness, nausea,
vomiting, postprandial dizziness,
sweating or orthostatic hypotension
Genitourinary: Urinary retention,
incomplete emptying, incontinence,
frequency
Orthostatic: Lightheadedness, weakness,
fatigue, cognitive changes, visual
disturbances, vertigo, anxiety, palpitations,
pallor, nausea, syncope – exacerbated by
prolonged standing, post-exercise, meals,
warm environment, early morning,
prolonged recumbency, physical
countermaneuvers, speed of postural
change, and medication effects
Secretomotor: Dry eyes and mouth, need
for natural tears, frequent sips of water
Sexual: Erectile dysfunction, ejaculatory
dysfunction, retrograde ejaculation into

bladder
Sudomotor: Reduction or loss of
sweating (distally in polyneuropathies),
excessive, paroxysmal, or inappropriate
sweating, mixed pattern of distal loss
and excessive proximal sweating, heat
intolerance
Vasomotor: Distal color changes,
change in skin appearance, persistently
cold extremities, Raynaud’s phenomenon,
loss of skin wrinkling in water, heat
intolerance, indoor gloves
Visual: Blurred vision, sensitivity to
light/glare, reduced night vision
Other: Unexplained syncope
Box 8.1 Autonomic review of systems.
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140 LOUIS H. WEIMER AND MILL ETIENNE
Autonomic testing
Many common autonomic symptoms, other than
overt symptomatic orthostatic hypotension, are some-
what nonspecific. A combination of symptoms or
exclusion of other causes is often needed before auto-
nomic causes are suspected. More objective evidence
to assess the validity, severity, and progress of disor-
ders is frequently useful and desirable. Conventional
nerve conduction studies and electromyography are
often performed but frequently are of limited direct
diagnostic benefit because many autonomic condi-
tions spare or minimally involve somatic sensory

and motor nerve fibers. Other conditions have clear
somatic neuropathy but unclear degree of autonomic
impairment. For this purpose there are numerous
reliable noninvasive techniques available. Dedicated
autonomic testing laboratories exist in most large
and medium size cities in the United States and in
many cities in Europe, Japan, and Australia. Unlike
motor and sensory nerve conduction studies most
techniques do not directly record autonomic nerve
fiber activity. Instead testing involves induction of
physiologic perturbations followed by the evaluation
of the responses of complex overlapping reflex loops
via the measurement of end-organ function. Although
many systems are potentially testable, the func-
tions deemed most reproducible, reliable, and most
commonly evaluated are cardiovagal (parasym-
pathetic), adrenergic vasoconstriction (sympathetic),
and sudomotor function.
Noninvasive measures of cardiovascular para-
sympathetic function involve the analysis of heart
rate variability and the degree of sinus arrhythmia.
The most common triggers are cyclic deep breathing,
Valsalva maneuver, and active standing. Cardiovas-
cular sympathetic function measures most commonly
assess the blood pressure response to physiological
stimuli, usually active standing or standardized head-
up tilt. The beat-to-beat blood pressure response to
Valsalva is another widely used method and many
show changes prior to orthostatic challenge. Pro-
longed tilt-table testing, with or without pharmaco-

logical provocation, has become an important tool
in the investigation of a predisposition to neurally
mediated syncope (Freeman, 2006). Tilt studies are
also useful in the evaluation of autonomic failure.
Although limited testing can be performed with
conventional equipment and at the bedside, a bat-
tery of tests conducted in a dedicated laboratory is
most desirable and dependable (Box 8.3). Formal
laboratory testing can establish subclinical auto-
nomic involvement, determine additional affected
components not detected by bedside examination,
grade disease severity, chart the clinical course, and
assist in monitoring therapeutic response.
Most physicians are familiar with and accustomed
to performing the bedside examinations of para-
sympathetic and sympathetic function mentioned
in Box 8.3 and described elsewhere in greater detail
(Low, 2003); however, tests of sympathetic cho-
linergic function are not commonly measured or
considered by many physicians. For that reason,
these tests are briefly outlined in more detail, but are
generally less available than other tests discussed
earlier. The quantitative sudomotor action reflex test
(QSART) tests postganglionic sudomotor function. It
is performed by iontophoresing acetylcholine (ACh)
Acute autonomic and sensory neuropathy
Acute autonomic neuropathy
(acute pandysautonomia)
Acute cholinergic pandysautonomia
Enteric neuronopathy

Guillain–Barré syndrome
Holmes–Adie syndrome
Hyperexcitability syndromes
(Isaacs syndrome, Morvan syndrome)
Lambert–Eaton myasthenic syndrome
(LEMS)
Orthostatic intolerance (postural
orthostatic tachycardia syndrome
(POTS)) – some forms
Other paraneoplastic syndromes
(e.g. Anti-Hu, -CV2, -PCA-2, -CRMP-5)
Rheumatologic diseases (e.g. rheumatoid
arthritis, Sjögren syndrome, systemic
lupus erythematosus, mixed connective
tissue disease)
Box 8.2 Immune-mediated autonomic neuropathies.
NICP_C08 04/05/2007 12:26PM Page 140
Immune-mediated autonomic neuropathies 141
diluted in deionized water onto an isolated patch of
skin. The ACh binds to muscarinic receptors on the
eccrine sweat glands as well as nicotinic receptors
on the postganglionic sudomotor axon. Retrograde
impulses are generated that trigger an evoked sweat
response from an adjacent but separate site and then
recorded using a sudrometer; the test is sensitive,
specific, and reproducibile (Hilz and Dutsch, 2006).
The areas of QSART territories and actual induced
sudomotor axon reflex sweating appear to be of
similar size in human skin and vary according to site
(Schlereth et al., 2005). QSART has also been shown

to correlate well with epidermal nerve fiber density
in small fiber painful neuropathy studies (Novak et al.,
2001; Periquet et al., 1999). A device is commer-
cially available and used in numerous centers as well
as in clinical trials (Q-Sweat; WR Medical, Stillwell,
MN). Silastic skin imprinting uses methods similar
to the QSART to stimulate sweat production and
measures sweat output by visualizing and quantify-
ing sweat droplets by examining plastic or silicone
which is allowed to harden over the treated area and
subsequently transilluminated under a dissecting
microscope or with video camera projection (Ravits,
1997). Although the silastic skin imprinting likely
has similar sensitivity to QSART, it is not widely
available (Hilz and Dutsch, 2006).
The thermoregulatory sweat test (TST) evaluates
both central and peripheral sudomotor function. A
moisture-sensitive indicator powder, usually alizarin
red, is dusted over the patient’s entire anterior skin
surface. The patient is placed in a sweat chamber
with temperature between 45–50 °C. As the patient
is heated, the sweat changes the powder color and
the areas of anhidrosis are visualized and quantified
(Hilz and Dutsch, 2006). Although the TST is an
excellent measure of both central and peripheral
sudomotor function, it is only available at a few
centers across the country. The sympathetic skin
response (SSR) is the most commonly performed
sudomotor test and is recorded with routine elec-
tromyography (EMG) equipment. The SSR is best

recorded from the palms of the hands and soles of
the feet, with the reference electrodes on the dorsum
of the hands and feet. Responses can be evoked by
various types of stimulation, such as electrical, star-
tle, cough, or inspiratory gasp stimuli. The response
is variable and tends to habituate with repeated
triggers; moreover there is no clear consensus regard-
ing abnormal responses or uniform testing methods.
Although the test is easy to perform, it is probably the
least sensitive and reproducible of these techniques
and has the most technical constraints including
interpretation (Etienne and Weimer, 2006; Hilz and
Dutsch, 2006).
Microneurography is one special technique that
directly records bursts of efferent muscle sympathetic
nerve activity (MSNA) and is probably the best and
most direct measure of sympathetic activity. How-
ever, because this test is somewhat invasive, tech-
nically difficult, and time consuming it is primarily
used for research purposes and is not a routine
clinical test. MSNA, usually recorded from the per-
oneal nerve, is measured from a recording electrode
inserted into a single nerve fascicle and through
numerous calculations, sympathetic nerve activity
can be measured (Hilz and Dutsch, 2006).
There is a multitude of additional investigational
tools that can be used to evaluate autonomic func-
tion such as for evaluation of pupillary function,
gastric and intestinal motility, bladder function, and
others used by certain laboratories.

Cardiovagal (Parasympathetic function)
Heart rate response to deep breathing (HRDB)
Heart rate response to Valsalva maneuver
Heart rate response to standing (30:15 ratio)
Adrenergic (Sympathetic function)
Blood pressure response to Valsalva maneuver
Blood pressure response to standing or
passive tilt
Blood pressure response to exercise, handgrip,
and pharmacologic agents
Sudomotor (Sympathetic cholinergic
function)
Quantitative sudomotor action reflex
test (QSART) (Q-Sweat)
Thermoregulatory sweat test
Silastic skin imprinting (sweat imprint
methods)
Sympathetic skin response
Box 8.3 Most common and best-accepted autonomic battery measures.
NICP_C08 04/05/2007 12:26PM Page 141
142 LOUIS H. WEIMER AND MILL ETIENNE
Peripheral autonomic neuropathies
Somatic peripheral neuropathies can present acutely,
subacutely, or chronically; disease processes affecting
autonomic nerve fibers are no exception. Although
numerous peripheral neuropathies affect auto-
nomic function, few actually cause severe or disabl-
ing pandysautonomia. Distal dying-back processes
that impair small diameter nerve fibers usually affect
distal vasomotor and sudomotor function leading to

distal temperature and blood flow dysregulation,
cold and dry skin, secondary infection susceptibly,
and diminished sweat function – a familiar picture to
physicians who treat peripheral neuropathy patients.
Four categories of processes are discussed in this
overview: immune-mediated neuropathies with addi-
tional autonomic involvement; more general auto-
immune disorders with autonomic involvement;
pure or predominant autonomic neuropathies with
presumed immune-mediated mechanisms; and
paraneoplastic diseases with known or presumed
antibody associations (Etienne and Weimer, 2006).
Guillain–Barré syndrome (acute inflammatory
demyelinating polyradiculoneuropathy)
In 1859 Landry reported 10 patients with an
“ascending paralysis”; later during World War I
French neurologists described two soldiers with
motor weakness, areflexia, and albuminocytological
dissociation in the cerebrospinal fluid (CSF). This
condition later became known as the Guillain–Barré
syndrome in recognition of the French neurologists
because they first recognized the peripheral nerv-
ous system involvement in this syndrome. In their
1960 paper on Guillain–Barré syndrome (GBS),
Osler and Sidell (Osler and Sidell, 1960) commented
that “paralysis of the heart” is an important cause
of death in GBS. GBS is most commonly an acute
monophasic illness characterized by ascending weak-
ness caused by either demyelinating or axonal forms
of neuropathy; however, GBS can also have wide-

ranging effects on peripheral autonomic pathways.
In fact, there are case reports of autonomic dys-
function as the initial feature of GBS (Cortelli et al.,
1990; Ferraro-Herrera et al., 1997; Zochodne, 1994).
Autonomic involvement can manifest as rapid and
wide fluctuations in blood pressure ranging from
hyper- to hypotensive within short periods of time.
Electrocardiographic changes include tachy- and
bradyarrhythmias, T-wave abnormalities, ST seg-
ment depression, QT prolongation, QRS widening,
sinus pauses, and asystole. In rare instances, patients
may require placement of a temporary pacemaker
because these patients are also at risk of sudden death
from these cardiac changes (Flachenecker et al., 1997).
With the availability of mechanical ventilation, sep-
sis and autonomic complications rival respiratory
failure and thromboembolism as the important causes
of mortality in GBS (Low et al., 2003).
Patients with GBS can present with either auto-
nomic failure or overactivity. The autonomic dys-
function of GBS tends to be more prominent in
patients with axonal involvement, severe respir-
atory dysfunction, and more pronounced weakness.
Winer and Hughes reviewed 100 patients with GBS
and found that 11 patients had cardiac dysrhythmias
sufficient to compromise circulation (Winer and
Hughes, 1988). Seven of those patients died, how-
ever, nonautonomic causes of the dysrhythmias
were not excluded. In the GBS study group plasma-
pheresis trial, 6% of cases had serious arrhythmia

and 3% of patients died (1985). Of the arrhythmias
seen in GBS, tachyarrhythmia is the most frequent
and demands close monitoring. Bradycardia or even
frank asystole is less frequent but can be secondar-
ily triggered by tracheal suctioning, Valsalva-like
maneuvers, as well as other provocative maneuvers.
Early recognition is crucial because in rare instances,
a temporary pacemaker may be necessary (Ferraro-
Herrera et al., 1997; Flachenecker et al., 1997).
Patients with GBS and autonomic dysfunction have
higher urinary and serum catecholamine levels than
GBS patients without autonomic dysfunction or
age-matched healthy controls (Ahmad et al., 1985).
Likewise, excessive sympathetic discharges have been
documented using microneurography in three cases
during hypertensive episodes (Fagius and Wallin,
1983). Sequential testing in a small cohort of patients
has demonstrated both sympathetic and parasym-
pathetic dysfunction in the majority of patients
followed; abnormalities slowly improve with time
and parallel motor recovery (Flachenecker et al.,
1997). Other forms of autonomic dysfunction com-
monly seen in GBS include paroxysmal sweating
bursts, anhidrosis, reduced heart rate variability,
vasomotor changes and instability, urinary reten-
tion, gastrointestinal dysmotility and ileus, incon-
tinence, facial flushing, pupillary changes and
abnormalities on many of the autonomic tests
previously discussed (Toth and Zochodne, 2003;
Wheeler et al., 1984).

Although GBS is a predominantly demyelinat-
ing disease, there is experimental, clinical, and
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Immune-mediated autonomic neuropathies 143
neuropathologic evidence that loss of unmyelinated
autonomic fibers also occurs. Most human autopsy
evidence is limited to examination of autonomic
ganglia; however, experimental allergic neuritis
(EAN) models have shown guinea pig vagal and
splanchnic nerve demyelination and some loss of
unmyelinated fibers (Tuck and McLeod, 1981) and
altered rat heart rate (Wang et al., 2001). Skin
biopsy samples in 20 GBS patients demonstrated
reduced epidermal nerve fiber density and probable
reduction of sweat gland density supporting small-
fiber sensory and autonomic involvement; patients
also had elevated thermal perception thresholds
(Pan et al., 2003).
Management of autonomic dysfunction in GBS
Both plasmapheresis and intravenous immunoglo-
bulin are mainstays of GBS therapy. However, these
treatments do not lead to immediate amelioration of
motor, sensory, or potentially life-threatening auto-
nomic complications. All GBS patients should have
an initial electrocardiogram (ECG) performed and,
if possible, that ECG should be compared to a pre-
morbid ECG to look for changes. A period of cardiac
telemetry is prudent and should be strongly con-
sidered in all GBS patients, whether in an intensive
care setting or not; periodic supine and upright blood

pressure measurements are also useful, especially in
severe cases during the improvement stages. If auto-
nomic dysfunction is detected or suspected, con-
tinual cardiac monitoring, sometimes in an intensive
care unit setting, should be strongly considered.
Although numerous studies have shown an asso-
ciation between severe weakness and severity of
autonomic dysfunction in GBS, not all studies have
verified this correlation so deciding which patients
need close monitoring in an intensive care unit
in advance is difficult. Denervation hypersensitivity
may produce excessive responses to vasoactive sub-
stances; thus, judicious use of small doses of short-
acting agents is best to avoid unexpected hypo- or
hypertension or tachy- or bradycardia. Complica-
tions appear to diminish as improvement begins in
somatic systems. In a seven-year follow-up study of
40 GBS patients, Dornonville de la Cour found that
residual neuropathy affecting large- and medium-
sized myelinated fibers endures long after the acute
attack of GBS producing persistent motor and sen-
sory dysfunction; however, simple cardiovagal heart
rate (HR) variability measures were normal after one
year (Dornonville de la Cour and Jakobsen, 2005).
Chronic inflammatory demyelinating
polyneuropathy
Although autonomic neuropathy is common in
GBS, autonomic dysfunction is not commonly asso-
ciated with chronic inflammatory demyelinating
polyneuropathy (CIDP). The first systematic invest-

igation of autonomic dysfunction in CIDP compared
autonomic function in 17 CIDP patients to that of 20
age-matched controls (Stamboulis et al., 2006). In
that study, they found at least subclinical autonomic
dysfunction in many more than previously estimated.
Eleven CIDP patients had autonomic symptoms and
13 had abnormalities on autonomic function testing.
However, testing abnormalities did not correlate with
symptoms or clinical course. There are other recent
reports of dysautonomia in CIDP patients (Boukhris
et al., 2005; Yamamoto et al., 2005); one reported
improvement in dysautonomia after intravenous
immune globulin (IVIg) administration (Boukhris
et al., 2005).
Acute autonomic neuropathy (AAN)
Acute pandysautonomia or acute autonomic neuro-
pathy (AAN) is a disease state that some believe to
be a variant of GBS (Ramirez et al., 2004) but the
findings are distinct. Diagnosis and treatment are
often delayed because of lack of awareness of the
entity. AAN is a monophasic illness that normally
develops over several weeks and includes dysfunction
of sympathetic, parasympathetic, and enteric systems
although some patients have isolated or predomin-
ant sympathetic or parasympathetic (cholinergic)
variants. Roughly half of cases are preceded by a
viral syndrome (Suarez et al., 1994) and cerebro-
spinal fluid examination in AAN patients often
reveals the albuminocytological dissociation char-
acteristic of GBS. Most commonly patients develop

severe generalized autonomic failure which results in
severe orthostatic hypotension, anhidrosis, decreased
production of saliva and tears, impaired bladder
emptying, erectile dysfunction, and gastrointestinal
(GI) dysmotility. GI dysfunction is quite prominent
in AAN and can present as bloating, early satiety,
nausea, recurrent vomiting and constipation, and
in the worst cases, patients may develop overt ileus.
Recurrent vomiting may prompt intravenous feed-
ing requirements for a period. Occasionally patients
may undergo unnecessary gastrointestinal surgery
because of suspected bowel obstruction (pseudo-
obstruction) (Schroeder et al., 2005). Patients may
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144 LOUIS H. WEIMER AND MILL ETIENNE
have subtle sensory or motor signs; however, the
autonomic dysfunction is far out of proportion to
the sensorimotor abnormalities. Much like in GBS,
subsequent recovery generally occurs but is typic-
ally partial and incomplete. Based on a review of 27
cases, a range of outcomes is expected (Suarez et al.,
1994). One-third of patients make a good functional
recovery, one-third have a partial recovery with sub-
stantial deficits including symptomatic orthostatic
hypotension; the remainder do not improve. Loss of
autonomic ganglion neurons is a proposed reason
for the limited or partial recovery.
Roughly 25% of patients have a restricted cholin-
ergic form (acute cholinergic neuropathy) char-
acterized by dry eyes and mouth, ileus, and other signs

of GI dysmotility, bladder dysfunction, hypohidrosis,
unreactive pupils, fixed heart rate, and sexual dys-
function but not significant orthostatic hypotension
(OH). The lack of OH makes laboratory confirmation
valuable in establishing the diagnosis. A paraneo-
plastic form, which develops in a similar time course,
is indistinguishable on clinical or laboratory grounds
prior to tumor discovery (Low, 2003). Pure sudomo-
tor failure has also been described (Nakazato et al.,
2004; Nakazato et al., 2005) and a chronic form of
AAN is also suspected (Klein et al., 2003; Schroeder
et al., 2005). Botulism ( Jenzer et al., 1975), leprosy
(Agrawal et al., 2005), diphtheria (Idiaquez, 1992),
and porphyria (Meyer et al., 1998) also develop acutely
and can affect autonomic function. HIV infection
can acutely impair autonomic nerves in both early
and late stages (Freeman, 2005; Markarian et al.,
1998) but not in the same time course.
Patients with AAN show marked abnormalities
on autonomic but typically minimal to no electrodi-
agnostic abnormalities in motor and sensory fibers.
Young and colleagues provided the original descrip-
tion in a case with pure autonomic dysfunction and
subsequent spontaneous recovery (Young et al., 1969;
Young et al., 1975). Small inflammatory mono-
nuclear cell infiltrates have been seen in epineurial
sural nerve biopsies with concomitant decreases
in small myelinated and unmyelinated fibers, sup-
porting the immune-mediated disease basis (Suarez
et al., 1994).

Vernino and Lennon developed an assay to detect
serum antibodies against the ganglionic nicotinic
acetylcholine receptor (AChR) after suspecting an
association with AAN. This AChR is similar to, but
not identical to, the neuromuscular junction (NMJ)
nicotinic AChR and is a pentameric transmembrane
complex usually with two α3 and three β subunits
instead of the two α1, β1, δ, and ε subunits found
at the neuromuscular junction. This difference
in structure makes the ganglionic nicotinic AChR
genetically and immunologically distinct from the
AChR found at the NMJ which is why myasthenia
gravis is rarely associated with autonomic dysfunc-
tion. The assay uses radiolabeled ganglionic AChR
solubilized from human neuroblastoma (IMR-32)
membranes as the antigen (Vernino et al., 1998).
Roughly half of AAN patients demonstrate high
ganglionic AChR antibody titers (Klein et al., 2003;
Vernino et al., 1998; Vernino et al., 2000). There
is also a positive correlation between high anti-
body titers and autonomic dysfunction severity,
suggesting that the antibodies play a pathogenic
role (Vernino et al., 2000). A separate study compar-
ing seropositive patients with idiopathic autonomic
neuropathy to those who were seronegative for the
AChR antibodies found that orthostatic intolerance
and prominent cholinergic signs and symptoms are
more common in seropositive patients (Sandroni
et al., 2004). Rarely patients have coexistent auto-
nomic neuropathy and myasthenia gravis; these

patients have shown both types of AChR antibodies
(Vernino et al., 2001).
Although there is a positive correlation between
high antibody titers and severity of autonomic dys-
function, these antibodies are not entirely specific for
this particular entity and are also seen in other dis-
orders with probable immune-mediated mechanisms
including 28% of patients with paraneoplastic auto-
nomic neuropathy, 10% of patients with orthostatic
intolerance, discussed later, and 9% of patients with
isolated GI dysmotility (Schondorf, 1993). However,
none of 150 healthy controls or patients with degen-
erative autonomic disorders, such as multiple sys-
tems atrophy and pure autonomic failure, or gastric
symptoms with normal motility studies, had elevated
antibody titers (Vernino et al., 1998). Vernino and
colleagues also created an animal model, termed
experimental autoimmune autonomic neuropathy
(EAAN), by immunizing rabbits to a fusion protein
containing a recombinant α3-AChR subunit domain,
which induced marked signs of autonomic failure
in these rabbits (Vernino et al., 2003). Reversible
disturbances of sympathetic, parasympathetic, and
enteric autonomic function can be induced in mice
receiving IgG taken from the EAAN rabbits. The
recipient mice developed transient GI dysmotility,
urinary retention, dilated pupils, reduced heart rate
variability, and impaired catecholamine response to
stress (Vernino et al., 2004). The findings in these
NICP_C08 04/05/2007 12:26PM Page 144

Immune-mediated autonomic neuropathies 145
mice are similar to the autonomic deficits known
in patients with AAN and in the EAAN rabbits
(Vernino et al., 2003; Vernino et al., 2004). Milder
murine forms of the syndrome developed after
injection of sera from two of three AAN patients.
Significant autonomic dysfunction also developed in
knockout transgenic mice that lack the ganglionic
AChR α3 subunit (Xu et al., 1999).
Treatment
The AChR antibody assay is not yet commercially
available, but is performed by the discovering re-
search laboratory, so the diagnosis of AAN is usually
made on clinical grounds. Conventional treatment
of autonomic failure (Freeman, 2005) with support-
ive care by managing system-specific problems as
they arise is the mainstay of therapy, the most
critical and most disabling of which is orthostatic
hypotension. In light of the probable immune basis
of this disease state many physicians will empirically
treat with IVIg or plasmapheresis, both of which have
numerous anecdotal reports in support of a beneficial
effect (Heafield et al., 1996; Schroeder et al., 2005;
Smit et al., 1997), claiming improvement or shorter
disease course after use of these treatment modalities.
The disorder is too uncommon to be able to do a pro-
spective trial treating early in the disease course. The
subacute nature of the condition and the frequent
delay in the initial diagnosis hamper initiation of
timely treatment. In addition to the IVIg or plasma-

pheresis, patients are also sometimes treated empir-
ically with oral prednisone followed by a rapid taper;
however, there is no data on the efficacy of steroids
as adjunctive therapy. Because of structural similar-
ities between AChRs, pyridostigmine has also been
suggested but not studied (Vernino et al., 2001).
Treatment differences between ganglionic AChR
seropositive and seronegative patients have not
been examined but are an area worth investigating.
One noteworthy case in the literature demonstrated
a positive effect of plasmapheresis on a patient sero-
positive for AChR antibodies (Schroeder et al., 2005).
The patient is a 43-year-old man with severe pro-
gressive panautonomic failure spanning 20 years
who carried a diagnosis of slowly degenerative pure
autonomic failure but later was discovered to have
AChR ganglionic antibodies. Plasmapheresis transi-
ently but markedly reduced his antibody titers,
reversed longstanding autonomic symptoms and
blunted the degree of orthostatic blood pressure
fall following each cycle that later recurred and
responded to the subsequent treatment cycle.
The patient’s serum markedly attenuated in vitro
calcium influx in cultured neuroblastoma neurons
in response to ACh. Symptomatic therapies are
discussed later.
Immune-mediated paraneoplastic syndromes
The term “paraneoplastic syndrome” refers to symp-
toms or signs resulting from damage to organs or
tissues that are separate from the site of a malignant

neoplasm or its metastases (Darnell and Posner,
2003). Neurological paraneoplastic syndromes are
a heterogeneous group of neurological disorders
often mediated by antibodies produced in response
to a tumor antigen and the antibodies cross-react
with various neural tissues; the antibody targets are
known as onconeural antigens. The symptoms of
paraneoplastic syndromes typically predate the tumor
diagnosis. Thus, early diagnosis may facilitate earlier
discovery of a malignancy and potentially improve
the chances of a cure from the cancer. Paraneoplastic
syndromes include entities that impact autonomic
regulation. Dysautonomia can be a presenting and
predominant feature and thus early recognition
that autonomic dysfunction may be part of a para-
neoplastic syndrome can have an impact on the
patient’s overall prognosis. More details on patho-
genesis, diagnosis, and treatment of paraneoplastic
syndromes are discussed in the chapter on paraneo-
plastic syndromes.
Lambert–Eaton myasthenic syndrome
Lambert–Eaton myasthenic syndrome (LEMS) is an
acquired presynaptic disorder of neuromuscular
transmission. LEMS is characterized by neuro-
muscular weakness and autonomic dysfunction. Over
half of LEMS cases have an associated neoplasm,
over 80% of which are small-cell lung cancer, usu-
ally detected within two years of LEMS onset. LEMS is
characterized by proximal weakness, hyporeflexia,
and dysautonomia. Antibodies to the presynaptic

P/Q type voltage-gated calcium channel (VGCC) are
characteristic but not entirely specific for the condi-
tion; numerous other antibodies are less commonly
seen. In addition to inhibition of neurotransmitter
release at the presynaptic terminal, these antibodies
also inhibit transmitter release from parasympa-
thetic, sympathetic, and enteric neurons – a mechan-
ism that likely underlies the widespread autonomic
dysfunction in LEMS (Waterman, 2001). The assay
NICP_C08 04/05/2007 12:26PM Page 145
146 LOUIS H. WEIMER AND MILL ETIENNE
for the P/Q type of VGCC is widely available (Lennon
and Kryzer, 1995). Autonomic symptoms can pre-
cede the primary LEMS diagnosis. Up to 74% of LEMS
cases are associated with clinical and physiologic
evidence of dysautonomia, including xerostomia,
orthostatic hypotension, impotence, urinary difficult-
ies, constipation, xerophthalmia, tonic pupils, and
impaired sweating (Toth and Zochodne, 2003). LEMS
predominately affects cholinergic systems, although
adrenergic abnormalities are seen (Freeman, 2005).
Few controlled studies of autonomic function before
and after treatment have been undertaken, but auto-
nomic improvement after chemotherapy is described
(Khurana et al., 1988; Newsom-Davis, 2004).
Myasthenia gravis
Myasthenia gravis is rarely associated with auto-
nomic dysfunction. Although there is little to no cross-
reactivity between the common AChR antibodies
and the ganglionic AChR version, rare patients have

both antibodies. In one review of seven seropositive
myasthenic patients with autonomic dysfunction,
three of seven also had ganglionic AChR antibod-
ies and all three of those patients had thymoma.
Improvement in autonomic signs and symptoms
was noted with pyridostigmine, suggesting that an
empiric trial of acetylcholinesterase inhibitors might
benefit patients with AAN (Vernino et al., 2001).
Other paraneoplastic syndromes
Antineuronal nuclear antibodies (ANNA-1 or anti-
Hu) are most commonly associated with small-cell
lung cancer (SCLC) and sensory neuropathy. Sensory
symptoms and signs include dysesthesia, lancinat-
ing pains, proprioceptive loss, numbness, ataxia, and
areflexia. However, the anti-Hu antibody is also found
in other cancers and with other forms of neurologic
impairment (Freeman, 2005; Lucchinetti et al., 1998;
Toth and Zochodne, 2003). Other manifestations
include sensorimotor neuropathy, motor neuro-
pathy, encephalomyelitis, and autonomic neuro-
pathy (Camdessanche et al., 2002; Lucchinetti et al.,
1998; Oh et al., 2005). Some form of neuropathy
develops in the majority of patients with malignancy
and high anti-Hu antibody titers. Also noteworthy is
that anti-Hu antibodies are not found in patients
with SCLC and no neurological disease, suggesting
neurologic specificity.
The autonomic neuropathy associated with the
anti-Hu antibodies can be quite disabling causing
postural hypotension, GI dysmotility, impotence,

urinary retention, pupillary involvement, dry eyes,
and dry mouth. One series of 16 anti-Hu antibody
positive patients found evidence of autonomic
neuropathy in four (Oh et al., 2005). Camdessanche
and colleagues reviewed 20 seropositive patients and
found autonomic dysfunction in six (Camdessanche
et al., 2002). A larger profile of 167 ANNA-1-positive
patients from the Mayo clinic found evidence of
autonomic neuropathy in 18% overall and 27%
of patients studied clinically at Mayo; GI dysmotility
was separately seen in 23% (Lucchinetti et al., 1998).
Autonomic and GI findings were the third most
common associations after pure sensory and sen-
sorimotor neuropathy. Other series have found a
smaller incidence of autonomic findings but did not
specifically search or test for dysautonomia. Reports
of improvement in autonomic function after tumor
treatments have been noted, but most attempts at
immune therapy have not been impressive. Cases
with high antibody titers and autonomic failure but
no detectable cancer are also known.
Paraneoplastic causes should be considered with
unexplained subacute autonomic neuropathy. In
addition to anti-Hu (ANNA-1) and ganglionic AChR
antibodies, the syndrome is associated with other
antibodies including antibodies against Purkinje
cell cytoplasmic type-2 (PCA-2), CV-2, and collapsin
response-mediator protein (CRMP-5). The evidence
suggests considerable overlap of paraneoplastic anti-
bodies, which often coexist but predict an underlying

malignancy (Pittock et al., 2004).
Enteric neuronopathy
Neurons in the gut comprise a complex semiauto-
nomous local nervous system known as the enteric
nervous system (ENS), which controls countless
local reflexes and programs with less critical higher
input. The ENS has approximately 10
8
neurons,
which is approximately the same number of neurons
found in the spinal cord. Serotonin is a prime neuro-
transmitter of the larger enteric motor neurons.
Enteric neuronopathy or enteric ganglionitis
is an inflammatory neuropathy that can be a
paraneoplastic disorder, connective tissue disorder,
inflammatory bowel disease, and a postinfectious
complication. The histopathologic hallmark is an
invasive inflammatory lymphocytic infiltrate in
the myenteric plexus. Enteric ganglionitis can affect
all levels of the GI tract. Clinical manifestations
include esophageal and lower esophageal sphincter
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Immune-mediated autonomic neuropathies 147
dysfunction, gastroparesis, intestinal pseudoobstruc-
tion, and megacolon. Studies suggest a predominantly
T-cytotoxic activity that is likely directed against
proteins expressed by enteric neurons. Patients will
subsequently have progressive neuronal degenera-
tion leading to loss of enteric neurons (Chelimsky
and Chelimsky, 2003; De Giorgio et al., 2004).

Chagas disease caused by Trypanosoma cruzi
provides a model for immune-mediated enteric
neuronopathy. Cross-reactivity between the para-
site and enteric neurons is one probable mechanism
for Chagas enteric neuropathy. Patients with chronic
Chagas infection have high circulating antibody
titers directed against type-2 muscarinic AChRs,
which are widely expressed on smooth muscle
cells but not on neurons (Van Voorhis et al., 1991).
A possible example of cross-reactivity is a recently
reported case of severe gastroparesis in a 31-year-old
woman following acute gastroenteritis (Lobrano et al.,
2006). The autonomic dysfunction was severe enough
to require parenteral nutrition because of a com-
plete lack of gastrointestinal motility despite trials of
numerous prokinetic agents and gastric electrical
stimulation. Autonomic studies revealed minimal
heart rate variability and an abnormal Valsalva
maneuver blood pressure waveform but normal
enteric morphological studies. The patient sub-
sequently died of a pulmonary embolus. At autopsy,
the sympathetic chain revealed decreased myelin-
ated axons with vacuolar degeneration and patchy
inflammation. Enteric neurons in the stomach and
small bowel revealed no evidence of enteric neuro-
pathy or myopathy. This case supports the notion of
immune-mediated autonomic neuropathy produ-
cing gastroparesis following an acute infection.
Paraneoplastic enteric neuropathy, because of
primarily gastrointestinal involvement, tends to come

to a neurologist later in the clinical course. The
disorder is likely an immune-mediated attack of
myenteric and submucosal plexus neurons, which
serve as onconeural antigens for the paraneoplastic
antibody, ANNA-1 (Anti-Hu). Other antibodies have
been implicated with this disease state as well; SCLC
is most common (Chinn et al., 1988; Lennon et al.,
1991). Serum with anti-Hu antibodies obtained
from patients with paraneoplastic gut dysmotility
and exposed to a neuroblastoma cell line and cul-
tured enteric neurons evoked apoptosis in both (De
Giorgio et al., 2004). Intense activation of caspase-3
and apoptotic protease activating factor 1 in both
culture systems suggests that anti-Hu antibodies are
contributory. Hu onconeural antigens are produced
by central, peripheral, and enteric neurons. Other
assayed antibodies include N-type and P/Q-type
voltage-gated calcium channel, ganglionic AChR,
and PCA-2 (Pardi et al., 2002). Lennon had previ-
ously detected other IgG antibodies reactive against
myenteric and submucosal plexus neurons of the
jejunum and stomach (Lennon et al., 1991).
Similar to other paraneoplastic syndromes, the
gastrointestinal symptoms usually precede tumor
discovery, but not all cases have an underlying
tumor. Twelve percent of ANNA-1-positive cases
in the earlier noted Mayo clinic series initially pre-
sented with primary GI complaints (Lucchinetti et al.,
1998). Symptoms include relatively acute onset of
progressive constipation, crampy abdominal pain

and vomiting, which can mimic acute bowel obstruc-
tion and prompt a negative exploratory laparotomy
before the proper diagnosis is considered (Colombel
et al., 1988). Physiologic studies demonstrate delayed
gastric emptying and marked GI dysmotility. A
loss of myenteric plexus neurons with cytoplasmic
vacuoles, secondary axonal loss, and plasma cell and
lymphocytic infiltrates (T cells) is described. Loss of
the interstitial cells of Cajal is a possible contributor
of the GI dysmotility in this syndrome (Pardi et al.,
2002). Symptoms, signs, and testing abnormalities
of more widespread autonomic involvement are fre-
quent in this syndrome and should be preformed in
patients with this presentation; confirmation of
abnormalities separate from GI dysfunction may aid
in diagnosis.
The GI dysmotility is often refractory to phar-
macologic manipulation or surgical intervention.
Symptoms occasionally spontaneously remit and
examples of improvement or resolution following
chemotherapy or radiation therapy for identified
tumors are described (Pittock et al., 2004). No results
of immunologic treatment interventions are known.
Autonomic findings in connective
tissue diseases
Acute, subacute, and chronic autonomic dysfunction
can occur with connective tissue diseases, including
systemic lupus erythematosus (SLE), mixed connect-
ive tissue disease (MCTD), scleroderma, rheumatoid
arthritis, and Sjögren syndrome (Gamez-Nava et al.,

1998; Mori et al., 2005; Sakakibara et al., 2004;
Sorajja et al., 1999). Cardiac autonomic dysfunction
is probably a frequent cause of death in patients with
connective tissue diseases; cardiac autonomic neuro-
pathy and conduction disturbances are common in
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148 LOUIS H. WEIMER AND MILL ETIENNE
people with heart disease related to systemic sclerosis
and human leukocyte antigen B27 (Sander and
Giles, 2002). The clinical significance of autonomic
dysfunction detected by laboratory testing warrants
longitudinal studies of autonomic function in con-
nective tissue disorders. We will briefly consider the
experience in SLE and Sjögren syndrome.
SLE can affect any part of the neuraxis including
autonomic systems. Autonomic neuropathy in SLE
may occur independent of somatic peripheral neuro-
pathy. In a prospective study of 51 patients with SLE
and 30 age- and sex-matched healthy controls, auto-
nomic symptoms were seen in 37% of SLE patients.
On laboratory testing incipient dysfunction was
seen in nine (18%) cases and one (3%) control. The
measured autonomic dysfunction did not correlate
with disease duration, SLE activity, disease damage,
end-organ damage, or the presence or absence of
somatic peripheral neuropathy (Shalimar et al.,
2005). Although studies have shown an association
with autonomic neuropathy and SLE, no relationship
has been shown between autonomic neuropathy and
serologic disease markers (Gamez-Nava et al., 1998)

or anticardiolipin antibodies (Magaro et al., 1992).
Autonomic impairment in Sjögren syndrome
patients is well established; however, reports conflict
over the prevalence. There are also numerous case
reports of Sjögren syndrome patients with isolated
autonomic neuropathy without sensory or motor
neuropathies (Sorajja et al., 1999). Autonomic
improvement after steroid treatment of Sjögren syn-
drome is also reported (Gamez-Nava et al., 1998).
A recent large series of 92 patients with Sjögren-
related neuropathy found three with a predomin-
antly autonomic pattern, but most had some form of
dysautonomia (Mori et al., 2005).
Orthostatic intolerance and postural
orthostatic tachycardia syndrome
Orthostatic symptoms without a concomitant
systemic blood pressure drop are considered to be a
heterogeneous group of disorders commonly known
as postural orthostatic tachycardia syndrome (POTS)
or orthostatic intolerance (OI). Other descriptive terms
include sympathotonic orthostatic hypotension and
idiopathic hypovolemia (Jacob and Biaggioni, 1999;
Weimer and Williams, 2003). Overlap of complaints
with chronic fatigue syndrome, mitral valve pro-
lapse syndrome, and panic and anxiety disorders are
diagnostic challenges, but consistently orthostatic
and not situational triggers help to differentiate these
entities. Despite a “benign” designation, patients often
become severely disabled. A heart rate increase of
30 beats per minute or rate exceeding 120 and ortho-

static complaints within five minutes of standing at
some point in the illness are characteristic and are con-
sidered to be diagnostic criteria. Etiologies are hetero-
geneous but one form is relevant for this discussion
– immune-mediated autonomic neuropathy.
Roughly half of patients report an antecedent viral
syndrome and roughly one-third show laboratory
evidence of a length-dependent autonomic neuro-
pathy ( Jacob and Biaggioni, 1999). These associa-
tions have prompted theories that some have a
restricted form of acute autonomic neuropathy
(Schondorf et al., 1993). The incidence of anteced-
ent viral syndrome is lower than GBS but similar to
AAN. Antibodies to ganglionic AChRs are seen in
roughly 10% of unselected OI patients – an expected
number if 20–30% of these unselected cases have
underlying autonomic neuropathy.
Formal autonomic testing is beneficial for initial
diagnosis and separating out problematic overlap
cases and nonneuropathic mechanisms. Secondary
causes such as hypovolemia, deconditioning, and
medication effects must be excluded. Testing may
provide guidance in the best of multiple treatment
options in this heterogeneous group of underlying
mechanisms ( Jacob and Biaggioni, 1999; Weimer
and Williams, 2003). Symptoms are referable to those
of sympathetic activation and reduced cerebral
perfusion. Testing abnormalities in the neuro-
pathy subset include decreased distal QSART sweat
volumes, Valsalva blood pressure waveform changes,

peripheral sweat loss on TST, and reduced or absent
sympathetic skin potentials. Sudomotor abnormal-
ities appear to be overrepresented in postviral onset
cases. Treatment is similar to that of autonomic failure
discussed below; however, there are some differ-
ences. Volume expansion is beneficial. Beta blockade
is often tried in the early stages but may exacerbate
the condition if the tachycardia is compensatory and
not the source of the symptoms; some patients have
symptomatic relief from limiting the heart rate rise.
Treatment of dysautonomia
Immune-mediated processes allow the potential to
suppress the underlying disease process leading to
improvement; immune-mediated autonomic neuro-
pathies are one example. Some processes discussed
have well-established immune links while others
are presumptive and probable. Treatment of several
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Immune-mediated autonomic neuropathies 149
disorders in this section is described in detail in other
sections – Eaton–Lambert myasthenic syndrome,
Guillain–Barré syndrome, Sjögren disease, etc. Auto-
nomic disturbances in GBS need additional care and
were discussed earlier. Judicious use of small doses
of short-acting agents should be made if necessary,
especially in weak, ventilated patients. Examples of
medications known to cause significant hypotension
in GBS patients include phentolamine, nitroglycerin,
hexamethonium, edrophonium, morphine, and
furosemide. Excessive hypertension is associated

with phenylephrine, ephedrine, dopamine, and
isoprenaline. Complications diminish as overall
improvement occurs. Careful attention to blood
pressure in upright patients, maintaining volume
status, monitoring for arrhythmias during suction-
ing, and avoiding unnecessary vasoactive drugs are
prudent measures.
Other treatments of autonomic failure are aimed
at relieving symptoms, improving function, and
enhancing quality of life and are recently reviewed
(Gibbons and Freeman, 2006). Numerous symp-
tomatic therapies and medications are available.
Symptomatic orthostatic hypotension is the most
critical area of treatment but is usually a complica-
tion occurring later in the disease course or in more
severe forms of disease. However, when present, OH
is generally the most disabling symptom. Asympto-
matic hypotension on standing usually requires no
specific treatment. Cerebral perfusion typically does
not drop significantly until the systolic pressure
is below 80 mm Hg because of compensatory cere-
brovascular autoregulation. In mild cases simple
maneuvers may be sufficient. Measures include rais-
ing the head of the bed 4–6 inches higher than the
foot (slight reverse Trendelenberg), which promotes
the release of renin and stimulates baroreceptors; the
effect is achieved with a hospital bed or by placing
blocks under the head of an ordinary bed. Counter-
pressure support garments that provide abdominal
and lower limb compression (such as Jobst half-body

leotard) can reduce venous pooling, but patients
often find these garments too uncomfortable and
cumbersome to use, especially if they are hampered
by neurologic impairment; abdominal binders can
be a compromise. Physical countermaneuvers such
as squatting and leg crossing may provide immediate
benefit but a compensatory blood pressure drop
occurs with maneuver release. Particular care after
situations that predictably lower blood pressure is
prudent, including after meals, after vigorous exer-
cise, hot temperature, and motionless standing. Both
increased water and salt intake are known to
increase standing blood pressure and orthostatic
tolerance (Shannon et al., 2002).
When more severe medications may be needed, no
single drug is ideal for the treatment of neurogenic
OH. Common useful therapies include supplemental
sodium chloride (2 to 4 g/day) to increase plasma
volume and, if necessary, fludrocortisone, starting
at 0.1 mg/day to increase salt and water retention.
The patient must be watched carefully for excessive
water retention, rising blood pressure, and heart
failure. Oral sympathomimetics, such as ephedrine,
phenylephrine, and tyramine, are usually of limited
benefit; however, midodrine (a selective alpha-1
agonist) is of proven benefit. Anemia is a common
exacerbating condition with autonomic failure.
Epoetin alpha (Epogen) increases hematocrit, reduces
symptoms, and elevates systolic pressure an average
of 10 to 15 mm Hg (Biaggioni et al., 1994). Other

drugs of potential but less consistent benefit include
indomethacin, somatostatin analogs, caffeine, ergot
alkaloids, and nocturnal desmopressin. L-threo-3,
4-dihydroxyphenylserine is used in the rare but dis-
tinctive entity, hereditary dopamine β-hydoxylase
deficiency. This non-US Food and Drug Administra-
tion approved norepinephrine precursor, known as
L-DOPS, appears to also show benefit in more com-
mon chronic autonomic neuropathies, including
immune-mediated forms when other treatment
modalities have failed (Gibbons et al., 2005). Excessive
supine hypertension is a frequent patient concern
and is a controversial topic. A certain degree is
tolerated in order to allow standing without syncope
or severe presyncope. There is limited evidence that
autonomic failure patients are at some increased
risk (Vagaonescu et al., 2000). Use of small doses
of short-acting nocturnal blood pressure lowering
medications, such as clonidine, may be needed in
some cases; patients must be aware of potential
problems of walking to the bathroom during this
period (Shibao et al., 2006). Concomitant treatment
of urinary dysfunction, gastric and intestinal dys-
motility, impotence, and secretomotor dysfunction
is often necessary and is more commonly addressed
by appropriate specialists (Chelimsky and Chelimsky,
2003; Gibbons and Freeman, 2006).
Summary
Greater appreciation and available testing for auto-
nomic disorders has enabled the discovery of specific

immune-mediated disease mechanisms, most notably
NICP_C08 04/05/2007 12:26PM Page 149
150 LOUIS H. WEIMER AND MILL ETIENNE
the elegant work on ganglionic AChR antibodies and
their pathogenic effects. Immune-modulating treat-
ments and a search for and treatment of an under-
lying cancer are important interventions in some
forms and can possibly prevent injury or potentially
reverse symptoms previously considered to be fixed,
but only if the disorder is recognized (Schroeder et al.,
2005). Symptomatic treatment can also enhance
function and improve quality of life. Greater aware-
ness of these entities may allow intervention at
earlier disease stages before significant injury to
autonomic pathways occurs.
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Introduction
Myasthenia gravis (MG) is a well-characterized
autoimmune disease directed at the postsynaptic
acetylcholine receptor or endplate of the neuromus-
cular junction (NMJ). Lambert–Eaton syndrome (LES)
is a rare autoimmune disease affecting the presynaptic
voltage-gated calcium channel. These diseases have
the potential to cause profound muscle weakness,
and, especially in the case of MG, even respirat-
ory arrest. With proper treatment, though, these
diseases can respond dramatically. This chapter
reviews the autoimmune myasthenic syndromes:

acquired myasthenia gravis and Lambert–Eaton
syndrome. The congenital myasthenic syndromes,
inherited disorders of neuromuscular transmission,
are not covered.
Autoimmune myasthenia gravis
History
In the Rotunda of the United States Capitol is a painting
entitled “The Baptism of Pocahontas” (http://www.
aoc.gov/cc/art/rotunda/baptism_pocahontas.cfm).
Pocahontas’s uncle, Chief Opechankanough, is shown
sitting on the floor while almost everyone else stands.
Historical documents describe Opechankanough lead-
ing the Powhatan confederacy into fierce battles
against the Virginia colonists while being carried on
the shoulders of his warriors, and at times needing
others to lift his eyelids to see. The colonists’ descrip-
tions of the great chief from the mid-1600s are likely
the first descriptions of a person suffering from myas-
thenia gravis (Marsteller, 1988).
Sir Thomas Willis wrote the first medical descrip-
tion of myasthenic symptoms in 1672. He wrote of
a woman who “for some time can speak freely and
readily enough, but after she has spoke long, or
hastily, or eagerly, she is not able to speak a word,
but becomes mute as a fish; nor can she recover
the use of her voice under an hour or two” (Keynes,
1961).
Clinicians began defining the clinical syndrome
of MG in the last quarter of the nineteenth century.
Among the notable observations were those of

Oppenheim in 1887, in Berlin, who noted the sim-
ilarities of this fatiguing illness with that of curare
poisoning. In 1895, Jolly described several cases and
coined the term myasthenia gravis pseudoparalytica.
He also demonstrated that a tetanizing electrical
current applied to the nerves of these patients elicited
decremental muscle contractions that improved with
rest (Conti-Fine et al., 1997). In 1934, house officer
Dr. Mary Walker decided to give her myasthenic
patient physostigmine, the antidote for curare, rea-
soning that the similar symptomatology implied a
similar pathophysiology and therapeutic response.
The patient’s weakness transiently improved, and
the therapeutic era of myasthenia began (Blalock
et al., 1941).
At the turn of the twentieth century, physicians
noted the association between thymomas and
MG, which often co-occur. Later, the development
of positive pressure ventilation allowed surgeons
intrathoracic access and could sustain patients
during respiratory failure (Keynes, 1961). In 1934,
Blalock in Nashville removed a thymic tumor from
a 19-year-old girl who had been suffering escalating
relapses of MG. Her symptoms improved after surgery.
He went on to perform thymectomies on MG patients
with and without thymomas, and reported clinical
improvements in a series of 20 patients, 18 of whom
had no thymoma (Blalock et al., 1941).
Our understanding of the immunological basis of
myasthenia began with Wilson and Stoner in 1944,

who reported that a circulating factor was inhibiting
neuromuscular transmission (Wilson and Stoner,
1944). In 1973, Patrick and Lindstrom sought to
create ACh receptor (AChR) antibodies by injecting
rabbits with purified ACh receptors from electric eels.
The rabbits developed not only AChR antibodies but
9
Autoimmune myasthenic syndromes: Myasthenia gravis
and Lambert–Eaton myasthenic syndrome
Andrew Sylvester and Armistead Williams
NICP_C09 04/05/2007 12:25PM Page 153
154 ANDREW SYLVESTER AND ARMISTEAD WILLIAMS
also weakness that improved with physostigmine.
Thus, they unintentionally discovered the role of AChR
antibodies in MG (Patrick and Lindstrom, 1973).
These developments led to an explosion in patho-
physiological research which has made myasthenia
gravis the best understood of all autoimmune diseases.
With the development of immune-directed therapies,
ventilatory support, and critical care medicine, this
disease has outgrown its name and, nowadays, is
rarely fatal.
Clinical features
The clinical hallmark of myasthenic weakness is
weakness that is fatigable and fluctuates. Symptoms
can be transient or persistent, and tend to vary
throughout the day and between days. Weakness
increases with repeated activity and improves with
rest. In the majority of patients (>50%), the initial
symptoms involve the ocular muscles with patients

complaining of symptoms related to ptosis or oculo-
motor dysfunction or both (Grob, 1953). Approxim-
ately 15% of patients present with bulbar symptoms:
dysphagia (6%), dysarthria (5%), and difficulty chew-
ing (4%). Isolated proximal limb weakness is the
presenting symptom less than 5% of the time (Grob,
1953). Rare presentations include neck, respiratory,
or distal limb weakness. Weakness remains localized
to the ocular muscles in 15% of patients, termed ocu-
lar MG. In 85% of cases, signs of generalized weak-
ness develop, usually within the first two years of the
disease. With generalized MG, the weakness often
begins in a few muscle groups and, over the course
of weeks to several months, extends to other parts of
the body. Almost all patients with MG experience
ocular symptoms during the course of the disease,
usually within the first year or two.
The diagnosis of MG ultimately is made clinically,
the characteristic signs and symptoms often suggest-
ing the diagnosis. Patients may report that they are
weaker later in the day. Weakness is typically bilateral
and asymmetric, but can be relatively symmetric.
Some describe worsening with significant heat expos-
ure or severe stress. Patients with ptosis typically
notice the degree fluctuating throughout the day.
Some may not notice drooping of their eyelids until it
obscures their vision. Weakness of the extraocular
muscles causes intermittent or persistent diplopia
or the perception of blurred vision, which resolves
when one eye is covered. Symptoms in the limb mus-

cles are typically more proximal than distal, so com-
mon complaints include fatigability and weakness
with tasks such as brushing hair, walking long dis-
tances, or climbing stairs. Localized muscle atrophy
occurs in roughly 6 to 10% of patients usually in
muscles with longstanding weakness (Oosterhuis
and Bethlem, 1973). There are several forms of dys-
arthria: the nasal speech of palatopharyngeal weak-
ness, the articulation disturbances of tongue or facial
weakness, and the hypophonic or “breathy” quality
of weakness of laryngeal muscle. With dysphagia,
mild involvement may present as the feeling of food
“getting stuck in the throat,” and when more severe
as nasal regurgitation of liquids or frank aspiration.
Masticatory muscle weakness presents with dimin-
ishing chewing force, often worse towards the end of
the meal or with solid foods. If weakness is severe, the
lower jaw may sag open. Facial muscle weakness
can cause diminished facial expressions, inability to
whistle, or even difficulty keeping liquids in the mouth
when drinking. Involvement of the orbicularis oculi
causes difficulty with eye closing. Neck weakness
usually affects the flexors more than the extensors.
When neck extensor weakness is severe, patients
may assume a characteristic pose with their hand
under their chin to hold their head upright. The most
ominous symptoms are those of respiratory muscle
weakness. With myasthenic dyspnea, breathing is
usually shallow, worse lying flat, and more pro-
nounced with exertion. Patients also may note a

weak cough. “Myasthenic crisis” is a life-threatening
condition, and occurs when patients develop weak-
ness of respiration or swallowing so severe as to
require mechanical ventilation or feeding.
Patients with antibodies to muscle specific tyrosine
kinase (MuSK) may display slightly different features
than other myasthenics. Most reports note a greater
tendency to develop bulbar or neck weakness and
less limb weakness. They have a tendency to develop
facial muscle atrophy (Evoli et al., 2003; Zhou et al.,
2004). These patients are more prone to myasthenic
crisis. The clinician should consider this when devis-
ing a treatment plan. The majority of these patients
are female, and the mean age tends to be younger
than patients seropositive for AchR antibodies.
Natural history
Early in the course of the disease, symptoms can be
persistent or transient, with periods of remission for
days, months, or even years. About 20% of patients
experience full or nearly full clinical remissions last-
ing for at least six months (Grob, 1953; Grob, 1958).
Most patients (84%) suffer recurrent relapses. Before
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Autoimmune myasthenic syndromes 155
current treatments and therapeutic strategies were
commonplace, patients often reached maximum
disease severity within the first one to three years
(Grob et al., 1981; Grob et al., 1987). Later in the
course of the disease, many patients’ symptoms
become more chronic.

Exacerbations can be triggered by systemic illness,
infection, physical or emotional stress, drugs that
impair neuromuscular transmission, thyroid dys-
regulation, pregnancy, delivery, or rarely from an
overdose of cholinergic medication. Often, exacerba-
tions have no identifiable precipitant. A list of drugs
known to inhibit neuromuscular transmission is
readily available on the Myasthenia Foundation
website (www.myasthenia.org). Mortality from
MG is usually related to respiratory or bulbar weak-
ness. Death rates have declined dramatically over
the decades with the advent of immunotherapy and
supportive therapies. Mortality was 31% from 1949
to 1957, 15% from 1958 to 1965, 6% from 1966
to 1985, and these days quite rare (significantly
below 5%) (Grob et al., 1981; Grob et al., 1987). With
proper treatment, most patients today can attain a
high functioning status and lead productive lives.
Epidemiology
Myasthenia is an uncommon disease with a pre-
valence of approximately 10 per 100,000. Over the
last 50 years, epidemiological studies show a rising
prevalence (Phillips et al., 1996). Most likely, this is
due to longer lifespans for patients with myasthenia,
improved surveillance and diagnostics, and an increas-
ing proportion of society in the age range at risk for
myasthenia gravis (Zhou et al., 2004).
As with some other autoimmune diseases, the typ-
ical age of onset differs with gender. Women tend
to develop MG in the second or third decade of life,

while men have a higher incidence over the age of
50. The overall incidence is similar in women and
men, but since men tend to develop MG later in life,
the prevalence in women is approximately twofold
higher (Poulas et al., 2000).
About 10% of myasthenic patients have a thymoma,
and their syndrome represents a paraneoplastic
syndrome. Thymomas tend to spread locally. They
are rarely invasive. The incidence of a co-occurring
autoimmune disorder is approximately 10%, particu-
larly thyroid disease, lupus, and rheumatoid arthritis
(Cristensen et al., 1995; Thorlacius et al., 1989).
About 10–20% of newborns from mothers with
myasthenia gravis develop transient myasthenic
symptoms due to transplacental transfer of the
mother’s autoantibodies, termed “transient neonatal
myasthenia”.
Pathophysiology
The following line of evidence, a parallel to Koch’s
postulates for infectious agents, supports the auto-
immune antibody-driven nature of MG. Most cases
have an associated antibody. The antigen is relevant
to the clinical symptoms and pathology. Symptoms
and signs of the disease can be transferred to experi-
mental animals by the transferal of affected serum or
IGg. An animal model of the disease can be made by
immunizing an animal with the antigen. Removing
the antibody improves symptoms.
To treat myasthenia, the clinician should have a
good understanding of physiology and pathophy-

siology of the neuromuscular junction, especially
the significance of the safety factor. The motor nerve
stimulates muscle with acetylcholine, which it syn-
thesizes and stores in vesicles at the presynaptic
terminal. A normal action potential releases 150–200
of these vesicles into the synaptic cleft; each contain-
ing approximately 10,000 molecules of ACh. The
postsynaptic membrane contains muscle endplate
zones with nicotinic ACh receptors aggregated on
the crests of specialized folds. The AChR is a trans-
membrane ion channel that opens to allow an influx
of ions when ACh is bound. Within milliseconds
of the transmission, synaptic acetylcholinesterase
hydrolyzes the ACh. When a sufficient number of
AChRs in the endplate zone are simultaneously
opened, the depolarizing end-plate potential (EPP)
reaches a threshold and triggers muscle contrac-
tion. Under normal circumstances, the number of
ACh receptors opened by a volley of ACh creates an
end-plate potential that well exceeds the threshold
required to make a muscle action potential. This
excess end-plate potential is a “safety factor” that
ensures neuromuscular transmission. With sustained
firing of a motor nerve, the number of ACh vesicles
available for release diminishes. The safety factor
ensures successful muscle depolarization despite this
decline in released ACh.
The predominant form of MG is an autoimmune
destruction of both the ACh receptors and the post-
synaptic end-plate region. Both the humoral and

cellular arms of the adaptive immune system are
involved in sustaining the disease, but antibodies
mediate the final pathology. Eighty-five percent of
patients with generalized myasthenia and 55% of
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156 ANDREW SYLVESTER AND ARMISTEAD WILLIAMS
patients with ocular myasthenia have antibodies
directed towards the AChR. While anti-AChR anti-
bodies are heterogeneous, their target antigens tend
to be located on an extracellular sequence of the
alpha subunit called the main immunogenic region
(Tzartos and Lindstrom, 1980). These autoanti-
bodies exert three pathophysiological effects: blocking
the receptor; cross-linking receptors which stimu-
lates their degradation; and most significantly, stim-
ulating complement-mediated lysis of the end-plate
region. The cumulative immunological damage
reduces the number of available receptors, flattens
the postsynaptic folds of the end-plate region, and
widens the synaptic cleft (Woolf, 1966). The reduc-
tion in available ACh receptors narrows the safety
factor for neuromuscular transmission.
Seronegative myasthenia is a subset of MG with
no detectable anti-AChR antibody. This group
comprises approximately 15% of the patients with
generalized MG, and 40–50% with ocular MG.
Nearly 50% of patients with seronegative MG have
antibodies to MuSK, a component of the complex
that aggregates and anchors ACh receptors in the
end-plate zone (Hoch et al., 2001). MG negative for

MuSK and AChR antibodies is presumed antibody-
mediated, but the antibody or antibodies have not
yet been identified.
The pathogenesis of MuSK antibody-positive
myasthenia is currently obscure, but is a matter of
active research. In patients with MuSK antibodies,
biopsies of affected muscles do not show a significant
decrease in AChR density, and no significant IgG or
complement binding (Selcen et al., 2004; Shiraishi
et al., 2005). One report found MuSK antibodies
may have an antiproliferative effect on muscles,
and downregulate NMJ-related genes (Boneva et al.,
2006). MuSK-associated MG has either minimal or no
associated thymus pathology, theoretically arguing
against a pathogenic role for the thymus in these
patients (Lauriola et al., 2005). MuSK antibodies are
not seen in seropositive patients (McConville et al.,
2004). There is one known case report of a MuSK-
postive, AChR Ab-negative patient with a thymoma.
This is unusual both in that almost all patients with
thymomas and MG are AChR Ab-positive and that
MuSK patients do not typically have any thymus
pathology, much less a thymoma (Saka et al., 2005).
The role of the thymus in MG
The thymus, the organ responsible for maturing and
differentiating T cells while selecting for immuno-
tolerance, is usually abnormal in seropositive MG.
About 70% of patients have thymic lymphoid folli-
cular hyperplasia (TFH) and another 10–15% have
thymoma. In TFH, lymphoid follicules and germinal

centers form at the corticomedullary junction. This
architecture brings AChR-bearing myoid cells into
intimate contact with antigen-presenting cells, the
major histocompatibility complex (MHC)-II positive
interdigitating cells. The myasthenic thymus has all
the cellular components required for autoantibody
production: MHC-II positive antigen-presenting cells,
B cells, T-helper cells and AChR antigen. Thymomas
in MG are functionally similar to normal thymus in
their ability to home and differentiate T cells.
Additional evidence for a primary role of TFH in
seropositive MG comes from animal models. When
rat models of MG are created by passive transfer
of antibodies or after immunization with AChR, the
rats do not develop any of the thymic changes typical
of human MG (Meinl, 1991). This implies that TFH is
not a secondary effect of another pathogenic process.
Conversely, when a piece of a myasthenic patient’s
thymus is implanted into mice with severe combined
immunodeficiency (SCID), the mice produce AChR
antibodies for sustained periods.
Diagnostic testing and evaluation
Serology
The standard serological test is the AChR antibody-
binding test. The most commonly used laboratory
method for this test is an immunoprecipitation test
that uses ACh receptors radiolabeled with alpha-
bungarotoxin. The binding antibody is positive in
nearly 85% in generalized myasthenia, 50–70%
in ocular myasthenia, and 100% of patients with

thymoma. False positives are rare but have been
reported with motor neuron disease, and poly-
myositis. Ten percent of patients with Lambert–Eaton
syndrome have positive AChR antibodies. These can
be differentiated by testing for the P/Q-type calcium
channel receptor antibody if the electrophysiological
studies or physical examination raise a suspicion for
LEMS (Lennon, 1997). Additional AChR antibody
tests include modulating and blocking antibodies.
AchR-modulating antibodies bind to external seg-
ments of the AChR, cross-linking them on the cell
surface and triggering their degradation. They are
positive in approximately 86% of MG patients and
only 3–4% of AChR-binding antibody negative
patients (Howard et al., 1987). AchR-blocking anti-
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