2014 continuum.pdf

Autonomic Neuropathies
Valeria Iodice, MD, PhD; Paola Sandroni, MD, PhD, FAAN
ABSTRACT
Purpose of Review: This article focuses on the most prevalent forms of autonomic
neuropathies, but also discusses conditions such as focal and dysfunctional syndromes
(altered autonomic function in the absence of structural lesions). The goal of this review is
to allow the reader to promptly recognize these disorders, identify potentially reversible
or treatable causes, and implement the appropriate treatment as well as supportive care.
Recent Findings: Secondary forms of autonomic neuropathies (eg, diabetes mellitus,
amyloidosis) are much more common than primary forms, of which autoimmune
ganglioneuropathies represent a major component. However, the spectrum of the
latter is continuously evolving and has diagnostic and therapeutic implications. Testing
modalities such as autonomic testing, serum autoimmune antibody testing, and skin
biopsies are becoming more widely available.
Summary: Autonomic neuropathies are relatively common conditions, and, because
of the prognostic implications as well as impact on patient quality of life, they should be
promptly recognized and treated aggressively. Testing is critical as other conditions may
mimic autonomic neuropathies. Treatment is symptomatic in many cases, but specific
therapies are also available in selected autonomic neuropathies.
Continuum (Minneap Minn) 2014;20(5):1373–1397.
INTRODUCTION
Autonomic peripheral neuropathies are
peripheral neuropathies in which symp-
toms of autonomic dysfunction are
either the only features or the predom-
inant clinical features overshadowing
the symptoms of somatic small fiber
involvement.1
The autonomic nervous
system is critically involved in the
maintenance of homeostasis, and as
such controls the function of every
organ system. Patients with autonomic
neuropathies usually present with a
multitude of symptoms and signs, even
if they may be monosymptomatic or
paucisymptomatic at first. The most
common concerns result from dysfunc-
tion of the cardiovascular (eg, ortho-
static hypotension or intolerance),
gastrointestinal (eg, early satiety, nau-
sea, constipation, or diarrhea), urogen-
ital (eg, neurogenic bladder or erectile
dysfunction), secretomotor (eg, im-
paired thermoregulation or sicca com-
plex), and pupillomotor (eg, blurry
vision) systems. Other disorders, such
as primary organ specific pathology, or
medication effect may be responsible
for the above concerns and should
therefore be excluded.
The increased availability of autono-
mic testing, combined with other neu-
rophysiologic studies and skin biopsies,
has allowed for increased detection of
autonomic dysfunction and small fiber
neuropathies. These sensitive and repro-
ducible testing modalities, when properly
performed, are invaluable in diagnosing
and monitoring these disorders.
The acquired autonomic neuropa-
thies are classified according to their
temporal profile (acute, subacute,
chronic) and their presumed pathogenic
basis (Table 12-1 and Table 12-2).
Hereditary forms are listed in Table 12-3.
Address correspondence to
Dr Valeria Iodice, University
College London, National
Hospital for Neurology and
Neurosurgery, Queen Square,
London, UK, WC1N 3BG,
valeria.iodice@uclh.nhs.uk.
Relationship Disclosure:
Drs Iodice and Sandroni
report no disclosures.
Unlabeled Use of
Products/Investigational
Use Disclosure:
Drs Iodice and Sandroni
discuss the unlabeled use of
ephedrine, octreotide,
acarbose, voglibose,
erythropoietin, desmopressin,
yohimbine, pyridostigmine,
and dihydroergotamine for
the treatment of orthostatic
hypotension.
* 2014, American Academy
of Neurology.
1373
Continuum (Minneap Minn) 2014;20(5):1373–1397 www.ContinuumJournal.com
Review Article
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

TABLE 12-1 Classification of Acute Autonomic Neuropathies and Laboratory Tests
Acute/Subacute Autonomic Neuropathy Evaluation/Laboratory Tests
Immune-mediated neuropathy
Autoimmune autonomic neuropathy
Generalized
!3 ganglionic
nicotinic
acetylcholine
receptor
Autoimmune autonomic ganglionopathy
Focal-restricted
Acquired idiopathic generalized
anhidrosis/chronic idiopathic anhidrosis
Acute cholinergic neuropathy
Acute sympathetic neuropathy
Postural orthostatic tachycardia syndrome Skin biopsy (neuropathic subtype)
Autoimmune gastrointestinal dysmotility
Chronic regional pain syndrome
Holmes-Adie syndrome Pupillometry
Ross syndrome
Erythromelalgia
Guillain-Barré syndrome CSF analysis
Paraneoplastic autonomic neuropathy
Paraneoplastic panautonomic
neuropathy
Antineuronal nuclear antibody 1
(ANNA-1), Purkinje cell cytoplasmic
antibodies 2 (PCA-2), collapsin
response-mediator protein-5 (CRMP-5)
Paraneoplastic enteric neuropathy ANNA-1, CRMP-5, voltage-gated
potassium channel
Lambert-Eaton myasthenic syndrome P/Q voltage-gated calcium
channel antibodies
Acute porphyria Urinary and stool porphyrins,
%-aminolevulinic synthetase level
Infectious disease
Botulism Neurotoxin in the serum, stool, or contaminated food
or by culturing Clostridium botulinum from the stool
Drugs/toxic neuropathy
Perhexiline maleate
Amiodarone
Chemotherapy agent (eg, cisplatinum,
vincristine, paclitaxel, taxol,
doxorubicin, cytosine arabinoside)
Vacor
Pentamidine
Heavy metals (eg, thallium, arsenic, mercury)
History of symptom onset following
exposure to a specific drug agent/toxin
Gold
+
Podophyllin
Heavy metals screening (thallium in particular)
Marine toxins
Organic solvent (acrylamide)
CSF = cerebrospinal fluid.
1374 www.ContinuumJournal.com October 2014

ACUTEAUTONOMICNEUROPATHIES
Autoimmune Autonomic
Ganglionopathy
Autoimmune autonomic ganglionopathy,
previously called acute pandysautonomia,
autoimmune autonomic neuropathy, idi-
opathic autonomic neuropathy, and sub-
acute autonomic neuropathy,2
is an
immune-mediate disorder characterized
by prominent or selective involvement of
autonomic nerve fibers or ganglia
that leads to severe and diffuse
autonomic failure.3
The onset can be
acute, subacute, or gradual with spon-
taneous but typically incomplete recov-
ery in about one-third of patients.3Y5
KEY POINTS
h Autonomic
neuropathies present
with wide clinical
variation and etiology.
Some have isolated
autonomic involvement,
and others have
concomitant sensory or
motor involvement.
h Autoimmune
autonomic
ganglionopathy is
heterogeneous in
severity, distribution of
autonomic failure, and
response to treatment.
TABLE 12-2 Classification of Chronic Autonomic Neuropathies and
Laboratory Tests
Chronic Autonomic Neuropathy Evaluation/Laboratory Tests
Metabolic/nutritional
Diabetes mellitus Fasting glucose,
2-hour glucose tolerance,
glycosylated hemoglobin
Uremia Kidney function testing
Ethyl alcohol Liver function testing
Systemic disorder
Primary systemic amyloidosis Immunofixation of serum and
urine with free light chain assay
Fat aspirate and bone marrow
biopsy for Congo red staining
Mass spectroscopy
Echocardiogram with
strain assessment
Troponin T and N-terminal
pro b-type natriuretic peptide
Associated with immune-mediated disorders
Sjögren syndrome Lip biopsy, Schirmer test, anti-Ro
(SSA)/anti-La (SSB) antibodies,
antinuclear antibody (ANA),
extractable nuclear antigen
(ENA), rheumatoid factor (RF)
Systemic lupus erythematosus ANA, ENA, RF
Mixed connective tissue disease ANA, ENA, RF
Rheumatoid arthritis Anti-cyclic citrullinated peptide
antibodies, ANA, ENA, RF
Celiac disease Celiac antibodies screening with
intestinal biopsy, ANA, ENA, RF
Infectious disease
HIV HIV testing
Leprosy Biopsy lesion/nerve biopsy
Chagas disease Trypanosoma cruzi antigens/
lysate-based enzyme-linked
immunosorbent assay (ELISA)
HIV = human immunodeficiency virus.
1375

However, a slowly progressive course
does not rule out autoimmune auto-
nomic ganglionopathy, and low anti-
body titers can be associated with the
chronic form of autoimmune auto-
nomic ganglionopathy.6
Clinical and laboratory data suggest
that an underlying immunologic basis is
responsible in about 50% of patients with
autoimmune autonomic ganglionopathy
ganglionic (!3-type) nicotinic acetylcho-
line receptor (AChR) autoantibodies
TABLE 12-3 Classification of Hereditary Autonomic Neuropathy
Hereditary Autonomic
Neuropathies Locus/Gene
Familial amyloidosis 18q12.1/TTR
11q23.3/APOA1
9q33.2/GSN
15q21.1/B2M
Fabry disease Xq22.1/GLA
Allgrove syndrome 12q13.13/AAAS
Navajo Indian neuropathy 2p23.2/MPV17
Tangier disease 9Q31/ABCA1
Multiple endocrine
neoplasia type 2b
10q11.21/RET
Mitochondrial cytopathies
(mitochondrial-neuro-gastro-
intestinal encephalomyopathy [MNGIE])
Mitochondrial DNA point mutations
Hereditary sensory and autonomic
neuropathy (HSAN) type IA (HSANIA)
9q22.1-22.3/SPTLC1
HSANIC 14q24/SPTLC2
HSANID 14q11/ATL1
HSANIE 19p13/DNMT1
HSANIIA 12p13.33/WNK1 (previous symbol is HSNII)
HSANIIB 5p15/FAM134B
HSANIIC 2q37/KIF1A (previous symbol is ATSV)
HSANIID 2q24/SCN9A
HSANIII/Riley-Day syndrome
or familial dysautonomia
9q31-q33/IKBKAP
HSANIV 1q21-q22/NTRK1
HSANV 1q21-q22/NTRK1
1p11.2-p13.2/NGF
HSANVI 6p12/DST
HSANVII 3p22/SCN11A
TTR = transthyretin; APOA1 = apolipoprotein A-I; GSN = gelsolin; B2M = "-2 microglobulin; GLA =
!-galactosidase; AAAS = achalasia, adrenocortical insufficiency, alacrima; MPV17 = mitochondrial inner
membrane protein; ABCA1 = ATP-binding cassette, sub-family A, member 1; RET = ret proto-oncogene;
DNA = deoxyribonucleic acid; SPTLC1 = serine palmitoyltransferase subunit 1; SPTLC2 = serine
palmitoyltransferase subunit 2; ATL1 = atlastin; DNMT1 = DNA methyltransferase 1; WNK1 = lysine
deficient protein kinase 1; FAM134B = family with sequence similarity 134, member B; KIF1A = kinesin
family 1A; SCN9A = sodium channel voltage gated, subunit 9 !; IKBKAP = inhibitor of kappa light
polypeptide gene enhancer in B-cells, kinase complex-associated protein; NTRK1 = neurotrophic tyrosine
kinase; DST = dystonin; SCN11A = sodium channel voltage gated, subunit 11 !.

who present with high titers.7Y11
Patients
typically develop generalized autonomic
failure, including orthostatic hypoten-
sion, anhidrosis, and parasympathetic
failure (gastrointestinal dysmotility, uri-
nary retention, and secretomotor dys-
function). However, a spectrum of
autoimmune autonomic neuropathies
exists, including at one extreme the acute
autoimmune autonomic ganglionopathy
(idiopathic or paraneoplastic) character-
ized by widespread and severe sympa-
thetic and parasympathetic failure. Focal
acute autoimmune dysautonomia may be
restricted to the cholinergic system (acute
cholinergic neuropathy)12
or the sympa-
thetic system (acute sympathetic neu-
ropathy).13
Some cases are postviral and
manifest as postural orthostatic tachycar-
dia syndrome (POTS) or focal or restrict-
ed autonomic involvement (Table 12-4).
Guillain-Barré syndrome (GBS) is at the
TABLE 12-4 Focal (Dysfunctional) and Restricted Autoimmune Autonomic Neuropathy
Clinical Entity
Evidence of
Immune Disorder Clinical Features
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Other
Antibodies/
Paraneoplastic
Acquired
idiopathic
generalized
anhidrosis/chronic
idiopathic
anhidrosis
Acute/subacute onset;
antecedent viral
infection; inflammatory
infiltrates surrounding
the sweat glands;
response to
immunotherapy
(glucocorticoids)
Generalized anhidrosis;
concomitant sharp pain
or cholinergic urticarial/
heat intolerance;
absence of other
autonomic dysfunction
Variably positive Negative
Acute
cholinergic
neuropathy
antecedent viral
infection; response
to immunotherapy
Xerostomia,
xerophthalmia;
hypotonic bladder;
gastrointestinal
hypomotility;
pupillomotor
dysfunction;
erectile failure
Positive Negative
Acute
sympathetic
neuropathy
antecedent viral
infection; response
to immunotherapy
Orthostatic hypotension;
ejaculatory dysfunction;
sphincter dysfunction;
Horner syndrome;
hypohidrosis/anhidrosis
Positive Negative
Holmes-Adie
syndrome/Ross
syndrome
Acute/subacute
onset; antecedent
viral infection
Tonic pupils, areflexia, and
segmental hyperhidrosis
Negative Negative
Erythromelalgia Associated with
other autoimmune
diseases; response
to immunotherapy
Increased temperature
of the affected skin;
pain aggravated
by warming
Negative Negative
Familial form, associated
with SCN9A gene
mutation
Burning extremity pain;
red, hot, distal extremities;
erythema of affected skin
Continued on next page
1377

other end of the spectrum, where the
brunt of the disorder falls on the somatic
nervous system.3,7,14
Some cases with the same pheno-
type can be antibody negative and
respond to immunomodulatory ther-
apy too,15
suggesting that autoim-
mune autonomic ganglionopathy may
be caused by other unidentified anti-
bodies and that the postganglionic
sympathetic pathways could be in-
volved by another immunologic block-
ade, potentially reversible.16
Antecedent infections have been
reported irrespective of the presence
or absence of the antiganglionic AChR
antibody, including upper respiratory
tract infections and gastrointestinal tract
infections.5,17
Autoimmune autonomic
ganglionopathy has also been described
following vaccination, surgical proce-
dures, and interferon therapy.18,19
Some patients with autoimmune au-
tonomic ganglionopathy, whether sero-
positive or seronegative, respond to
treatment with IV immunoglobulin (IVIg)
or plasma exchange, although when used
as a single agent, subsequent treatments
are required in most relapsing patients to
maintain the improvement.
TABLE 12-4 Focal (Dysfunctional) and Restricted Autoimmune Autonomic Neuropathy
(Continued)
Clinical Entity
Evidence of
Immune Disorder Clinical Features
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Other
Antibodies/
Paraneoplastic
Autoimmune
gastrointestinal
dysmotility
Subacute
(G6 months);
antecedent event;
coexisting organ-
specific autoimmune
disorder; neoplasm
Intestinal pseudo-
obstruction; achalasia;
gastroparesis/slow
intestinal transit;
pyloric stenosis;
rarely anal spasm
Variably positive Neuronal
voltage-gated
calcium channel
(N-type and
P/Q-type);
neuronal
voltage-gated
potassium
channel (VGKC);
antineuronal
nuclear
antibody, type 1
Chronic regional
pain syndrome
Acute/subacute;
antecedent event
(eg, surgery, but also
includes injections,
local infections);
response to IV
immunoglobulin G
Sensory abnormalities;
warm, red, swollen,
and painful extremity;
hyperhidrosis/
hypohidrosis;
trophic changes;
motor disturbance
Negative Negative
Postural
orthostatic
tachycardia
syndrome
antecedent viral
infection
Heart rate rise 930 beats/min
on standing, without
orthostatic hypotension
Orthostatic intolerance,
postural palpitations,
gastrointestinal, bladder
dysfunction, syncope
Variably positive Negative
SCNA9 = sodium channel voltage gated, subunit 9 !.

The response to treatment and nat-
ural history may range from a single
episode of disease to a relapsing-
remitting course to the development
of chronic manifestations. The more
severely affected patients who do not
respond to plasma exchange or IVIg
monotherapy may benefit from a com-
bined therapy or from the addition of
immunosuppressant agents, as some
patients seem to require prolonged
immunotherapy for sustained clinical
improvement (Case 12-1).
Current available treatments include
agents used in monotherapy (IVIg,
plasma exchange) or in combination,
including novel immunosuppressant
agents such as mycophenolate
mofetil and rituximab (Table 12-5 and
Table 12-6).
Focal and Possible Autoimmune
Autonomic neuropathies most frequently
encountered in clinical practice in which
KEY POINT
h Seronegativity does not
exclude an autoimmune
pathogenesis of
autonomic neuropathy,
and treatment with
plasma exchange,
IV immunoglobulin, or
immunosuppressant
agents can be of benefit
in treating seropositive
and seronegative
patients.
Case 12-1
A 33-year-old woman developed severe constipation, loss of appetite, nausea,
orthostatic intolerance, and sicca complex over 1 month. Neurologic examination
showed fixed and dilated pupils. Autonomic function tests showed generalized
autonomic failure, and thermoregulatory sweat test (TST) demonstrated 35%
anhidrosis. Plasma norepinephrine values were markedly reduced (18.1 pg/mL
supine and 81.8 pg/mL standing), indicating a ganglionic and postganglionic
pathology. Ganglionic nicotinic acetylcholine receptor (AChR) autoantibody was
markedly increased at 18.8 nmol/L (normal less than 0.018 nmol/L).
She received seven courses of IV immunoglobulin (IVIg) (0.4 g/kg, twice a
week) without improvement in autonomic symptoms except for some
reduction in upper gastrointestinal concerns, and TST anhidrosis increased to
47%. The patient underwent a series of plasma exchange treatments,
during which she progressively improved; after the eighth plasma exchange
treatment, her pupil size became normal. Bladder and bowel function improved,
as did Quantitative Sudomotor Axon Reflex Test (QSART) responses. This clinical
improvement was accompanied by a progressive improvement
of autonomic symptoms. However, her antibody level remained elevated at
22.37 nmol/L and symptomatic improvement was transient. After the ninth
plasma exchange treatment, her TST increased to 93% and her antibody titer
remained very high at 23.31 nmol/L. Because of the transient nature of her
improvement and the persistently high antibody titers, after the tenth course
of plasma exchange, the patient received azathioprine (100 mg per day) for
4 months without improvement. She then started mycophenolate mofetil for
11 months, resulting in progressive improvement of her gastrointestinal
symptoms, orthostatic intolerance, and bladder function. TST percentage
progressively decreased (78% to 35% to 20%), and this improvement was
associated with an improvement of autonomic symptoms and a marked
reduction of antibody titer to 6.86 nmol/L.
Comment. This case demonstrates that autoimmune autonomic
ganglionopathy may require sustained immunotherapy. A reasonable
approach, until definitive clinical trials are available, is to begin with
monotherapy with plasma exchange or IVIg and add additional
immunosuppressant medication as needed. As the mechanisms of action among
current treatments do not typically overlap, the use of combination therapy may
increase the efficacy and provide a longer duration of clinical improvement.
1379

TABLE 12-5 Treatment of Autoimmune Autonomic Ganglionopathy with IV Immunoglobulin G:
Regimen and Clinical Outcome
Author
Design and
Participants
IV Immunoglobulin G
Regimen and Timing
Clinical Outcome
and Timing
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Heafield (1996)20
Case report;
acute
idiopathic
dysautonomia
0.4 g/kg/d for 5 days
for 2 courses
Resolution of orthostatic
hypotension and pupillary
areflexia 36 hours after starting
treatment; anhidrosis persisted
NA
Smit (1997)21
Case report;
acute
idiopathic
dysautonomia
1 g/kg/d for 2 days
30 days after onset
Resolution of pupillary
areflexia, constipation,
and syncope; improved
bladder function 5 days
after starting treatment;
bladder function improved
5 days after starting
treatment
NA
Mericle (1997)22
Case report;
acute
idiopathic
dysautonomia
400 mg/kg/d on days
1, 2, 3, 5, and 8;
no reported timing
after onset
On day 3 pupillary areflexia
resolved, orthostatic
intolerance improved, and
incontinence resolved; at
the end of the treatment
dysesthesia disappeared
NA
Venkataraman
(1998)23
Case report;
acute
idiopathic
dysautonomia
400 mg/kg/d for
5 consecutive days
with fludrocortisone
(no reported dose)
after 2.5 months
Orthostatic hypotension,
vomiting, and nausea
improved; bowel
incontinence and urinary
retention resolved on day 2
NA
Quan (2000)24
Case report;
acute
idiopathic
dysautonomia
400 mg/kg/d for
5 consecutive days with
fludrocortisone 0.1 mg
2 times/d, followed by
prednisone 50 mg/d
for 2 weeks
Asymptomatic after 1 week NA
Ishitobi (2004)25
Case report;
isolated
orthostatic
hypotension
postcold
with fever
400 mg/kg/d for 5 days,
2 months after the onset
Orthostatic hypotension
improved; no exact timing
NA
Modoni (2007)26
Case report;
acute
idiopathic
dysautonomia
400 mg/kg/d for 5 days
6 months after onset
Orthostatic intolerance
recovered and bladder
function recovered;
secretomotor and
gastrointestinal functions
also recovered 5 days
after the last infusion
Positive

an autoimmune etiology is suspected
and which might represent a focal or
restricted form of autoimmune auto-
nomic neuropathy are described in
Table 12-4.28Y34
Guillain-Barré syndrome. GBS is the
most common immune-mediated
polyneuropathy, with incidence of
0.6 to 4 cases per 100,000 per year
throughout the world.35,36
Acute
autonomic dysfunction develops in
approximately two-thirds of patients
with GBS and is a significant cause of
mortality in these patients.35,36
TABLE 12-5 Treatment of Autoimmune Autonomic Ganglionopathy with IV Immunoglobulin G:
Regimen and Clinical Outcome (Continued)
Author
Design and
Participants
IV Immunoglobulin G
Regimen and Timing
Clinical Outcome
and Timing
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Fischer (2010)13
Case report;
acute
sympathetic
failure
Immunoglobulin
monthly for 3 months;
no regimen specified
Improvement of autonomic
symptoms and sudomotor
function normalized; no need
for additional antihypotensive
agent at follow-up
Positive
(low titer)
Kimpinski
(2013)27
Case report;
acute adrenergic
failure postviral
pharyngitis
Induction dose of 2 g/kg
and subsequently 1g/kg
monthly over a 5-month
period for a total of
6 treatments
Improvement of
autonomic symptoms;
absent orthostatic
hypotension at follow-up
Negative
NA = Not available.
TABLE 12-6 Combined Immunomodulatory Treatment of Autoimmune Autonomic
Ganglionopathy
Author Design Intervention Clinical Outcome
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Gibbons (2008)37
Case series
study of
three patients
Plasma exchange (PE)
for 5 courses
No benefit Positive
IV immunoglobulin
G (IVIg) 0.4 g/kg/d
for 5 days
No benefit
Mycophenolate mofetil
(MMF) 1000 mg twice
a day with prednisone
60 mg/d followed
6 months later by
PE for 5 courses
Improvement of orthostatic
intolerance, bladder,
and bowel function;
resolved pupillary
areflexia and decreased
blurring of vision
KEY POINT
h Autoimmune autonomic
neuropathies have a variable
presentation and can include
those with focal or restricted
autonomic neuropathies
with low antibody titers.
1381

Prominent autonomic dysfunction, in-
cluding orthostatic hypotension, abnor-
mal sweating, paralytic ileus, urinary
retention, and bowel abnormalities, have
been described in GBS. In some patients,
orthostatic hypotension and paralytic
ileus may be the presenting symptoms
of the disorder, occurring several days
before the sensory and motor involve-
ment.38,39
Sympathetic and parasympa-
thetic function can be either reduced or
overactive in GBS. Poor outcome has
TABLE 12-6 Combined Immunomodulatory Treatment of Autoimmune Autonomic
Ganglionopathy (Continued)
Author Design Intervention Clinical Outcome
Ganglionic
!-3 Nicotinic
Acetylcholine
Receptor
Antibody
Iodice (2009)15
Case series
study of
six patients
Case 1 IVIg for 2 courses No benefit Positive
PE for 2 courses
followed by MMF
1000 mg twice a day
Permanent and
complete recovery
Prednisone 80 mg/d
for 6 weeks
Persistent asymptomatic
Case 2 IVIg for 7 courses No benefit Positive
PE for 7 courses Transient improvement
(orthostatic intolerance
and gastrointestinal
function)
Azathioprine
100 mg/d for
2 months
No benefit
MMF 1000 mg twice
a day for 1 year
Progressive clinical
improvement
Case 3 IVIg for 4 courses Improvement of orthostatic
intolerance and bladder
function and resolved
dry eyes
Positive
Case 4 IVIg for 33
courses (2 years)
Transient improvement
(bladder function)
Positive
IVIg with azathioprine
150 mg/d
Stable clinical condition
Case 5 IVIg for 4 courses Improvement of orthostatic
intolerance, resolved
numbness in the feet, and
normal bowel function
Negative
Case 6 Prednisone 100 mg/d No benefit Negative
Cyclophosphamide
for 3 months
No benefit
IVIg for 55 courses
(2.5 years) followed
by MMF 1000 mg
twice a day
Improvement of orthostatic
hypotension, sweating and
somatic impairment, and
normal bladder function

been associated with overactivity of the
sympathetic nervous system, including
tachycardia, sustained hypertension, car-
diac arrhythmia, and blood pressure
fluctuations.
The pathophysiology of GBS-associated
autonomic dysfunction is still unclear.
Small-diameter myelinated or unmy-
elinated nerves, responsible for thermal
sensation, nociception, and autonomic
functions, might be affected in GBS, as
shown by reduction in cutaneous inner-
vation in 55% of patients with demye-
linating GBS using the skin biopsy
technique.40
Autonomic nerve fibers
might be damaged by lymphocytic
infiltrate, neurotoxic cytokines, or cir-
culating autoantibodies that might in-
terfere with noradrenaline synthesis
and synaptic transmission.41
Paraneoplastic autonomic neuropa-
thy. The autonomic nervous system is
frequently affected in patients with
paraneoplastic syndromes. Clinical fea-
tures can resemble GBS, autoimmune
autonomic ganglionopathy, or more
restricted autoimmune forms, including
chronic intestinal pseudoobstruction
and enteric neuropathy. The tumors
most commonly associated are small cell
lung carcinoma, nonYsmall cell lung
carcinoma, gastrointestinal tract malig-
nancies, ovarian carcinoma, breast carci-
noma, Hodgkin lymphoma and non-
Hodgkin lymphoma, and thymoma.42
Paraneoplastic autonomic neuropa-
thy may precede the identification of
the primary tumor and lead to its
recognition, or it may occur following
the diagnosis of cancer. Recognition is
essential as treatment at an earlier
stage provides better outcomes.
The pathophysiology of autoim-
mune paraneoplastic neuropathy is
primarily due to cell-mediated damage
to neurons and axons. This is caused
by cytotoxic T-cellYmediated attack
against neurons, and humoral mecha-
nisms including paraneoplastic anti-
bodies directed against one or more
intracellular onconeuronal antigens
targeting the autonomic nervous system
(antibodies cross-reacting with proteins
expressed in neurons of the central and
peripheral nervous systems).43
Subacuteparaneoplastic panautonomic
neuropathy is indistinguishable from
nonparaneoplastic autoimmune auto-
nomic ganglionopathy, and patients with
a rapidly developing acute/subacute
autonomic neuropathy or multifocal
neurologic disorder should be studied
for the presence of paraneoplastic
antibodies.43
Paraneoplastic autonomic neuro-
pathies are associated with various
overlapping antibodies, including
antineuronal nuclear antibody, type 1
(ANNA-1, or anti-Hu), AChR !-3,
collapsin response mediator protein-5
(CRMP-5), voltage-gated potassium
channel (VGKC), P/Q calcium channel
antibodies, and Purkinje cell antibody-2
(PCA-2). However, negative paraneoplastic
antibody tests cannot exclude a paraneo-
plastic autonomic neuropathy, and con-
tinued tumor surveillance is needed if
suspicion persists.43
Anti-Hu-associated paraneoplastic au-
tonomic and sensory neuropathy has
been reported to be responsive to early
aggressive immunotherapy before
the detection of cancer.44
Intestinal
pseudoobstruction and paraneoplastic
enteric neuropathy could be the
presenting manifestation of small cell
lung carcinoma (25% of positive anti-Hu
patients). Patients present with nausea,
early satiety, bloating, abdominal pain,
intestinal pseudoobstruction, severe
constipation, and weight loss. Gastroin-
testinal function studies and imaging
confirm delayed gastric emptying, dif-
fuse intestinal hypomotility, and absent
or incoordinated motor complexes.
Postmortem samples of the esophagus,
stomach, small bowel, and colon
show neuron and axon degeneration,
KEY POINT
h Recognition of and
availability of testing for
several paraneoplastic
antibodies has
prompted a better
understanding of
immune-mediated
paraneoplastic
disorders, including
potentially treatable
immune-mediated
autonomic
neuropathies.
1383

lymphoplasmacytic infiltration, and
glial cell proliferation within the
myenteric plexus.
Acute cholinergic neuropathy is a
common presentation of Lambert-Eaton
myasthenic syndrome (LEMS), a sub-
acute autoimmune disorder of neuro-
muscular transmission. LEMS is caused
by antibodies directed against presynap-
tic, P/Q voltage-gated calcium channels,
and many cases are paraneoplastic in
nature. Adrenergic failure in the context
of LEMS is less common.
CHRONIC AUTONOMIC
NEUROPATHY
Diabetic Autonomic
Neuropathy
Diabetes mellitus is the most common
cause of somatic and autonomic neu-
ropathy in the developed world. The
pathogenesis is complex, multifactorial,
and still incompletely understood. The
direct effect of hyperglycemia, micro-
vascular injury, oxidative stress, protein
glycosylation, and altered immunologic
state have all been implicated, and
different degrees of involvement may
explain the protean manifestations of
diabetic neuropathies.45
The prevalence of autonomic dys-
function in diabetes mellitus increases
with disease duration, patient age, poor
glycemic control, presence of microvas-
cular complications, hyperlipidemia,
and hypertension (particularly in type
2 diabetes mellitus). The true preva-
lence is unknown, as the reported
numbers in the literature vary widely
owing to patient selection, different
populations, criteria used to define
autonomic neuropathies, and methods
of assessment.45
A reasonable estimate
would place the prevalence between
30% and 40%, but many patients may
have only subclinical or very mild
clinical abnormalities.
The most severe autonomic neu-
ropathy seen in diabetes mellitus is
cardiovascular autonomic neuropathy.
The presence of cardiovascular auto-
nomic neuropathy is an independent
poor prognostic factor; patients with
cardiovascular autonomic neuropathy
have higher mortality (27% to 56% over
5 to 10 years, including sudden death).
The earliest manifestation of cardio-
vascular autonomic neuropathy is usually
an increase in the patient’s resting heart
rate due to loss of vagal innervation,
followed by loss of heart rate modula-
tion, resulting in a fixed heart rate. This
prevents patients from adapting to vary-
ing physiologic demands or stressors
(eg, surgery or infections) and predis-
poses them to malignant arrhythmias
due to sympathovagal imbalance,
prolonged QT, left ventricular dysfunc-
tion, and silent myocardial infarction.
Cardiovascular autonomic neuropathy
prevalence in diabetes mellitus is about
20%, but it can be more than twice as
high in older patients and in those with a
long duration of diabetes mellitus, par-
ticularly in type 2. Dysregulation of
cerebral circulation, reduced coronary
sympathetic mediated vasodilation, loss
of vasomotor reflexes, and diabetic ne-
phropathy often accompany cardiovas-
cular autonomic neuropathy, further
worsening the prognosis.46
Orthostatic hypotension in cardio-
vascular autonomic neuropathy, mainly
due to sympathetic vasomotor dener-
vation resulting in blood pooling in the
splanchnic and peripheral vascular
beds, further limits the patient’s capac-
ity, already hampered by the loss of
heart rate modulation. Orthostatic hy-
potension is reported to occur in 6% to
30% of diabetes mellitus, even if rela-
tively asymptomatic in some patients.
Gastrointestinal symptoms are fre-
quent in diabetic autonomic neuropathy,
with the most problematic being
gastroparesis. A mild degree of delayed
gastric emptying may remain asymptom-
atic, but as severity increases, nausea,
KEY POINTS
h Autonomic involvement
is common in diabetes
mellitus and increases
with disease duration
and severity of
hyperglycemia.
h Cardiovascular
autonomic neuropathy
is an independent factor
portending poor
prognosis with
increased mortality and
risk of sudden death.

early satiety, bloating, belching, and
vomiting appear. Food may remain in
the stomach for many hours or even
days. This has significant implications
for glycemic control as it becomes very
challenging to match insulin require-
ments with the slow, unpredictable
food absorption. The prolonged diges-
tion also worsens the blood pooling in
the splanchnic and mesenteric bed,
aggravating orthostatic hypotension,
if present.47
Constipation is reported in almost
two-thirds of patients with diabetes
mellitus. It is likely the result of degener-
ation of the enteric nervous system and
is worsened by gastroparesis with loss of
gastrocolic reflex. Diarrhea, sometimes
worsened by hypoglycemic medications,
may alternate with constipation. It may
be severe, watery, generally nocturnal,
and difficult to control. Patients may also
experience sphincter dysfunction
resulting in fecal incontinence due to a
combination of reduced rectal sensation
and poor pelvic floor tone (all complica-
tions of diabetic neuropathy).
Neurogenic bladder is extremely
common in diabetes mellitus, particu-
larly in type 1. The symptoms range
from reduced sensation resulting in
increased volume and pressure re-
quired to trigger the micturition reflex,
to reduced detrusor activity that results
in weak flow and incomplete emptying,
to atonic bladder with overdistention
and overflow incontinence.
Erectile dysfunction may be the
presenting symptoms of diabetic au-
tonomic neuropathy in men. Various
factors contribute to it: autonomic
neuropathy, vascular insufficiency
with reduced nitric oxide production
from the endothelium, and subse-
quent psychological factors. Occasion-
ally, retrograde ejaculation (due to
sympathetic dysfunction impairing the
reflex closure of the bladder neck) may
precede erectile dysfunction. In women,
the data are limited, but impaired vaginal
lubrication is often reported.
Sudomotor function is progressively
lost, but patients may report excessive
sweating in the cranial and truncal
regions. This represents compensatory
hyperhidrosis due to loss of sweating
in the lower body. Occasionally,
abnormal sweating (such as gustatory
sweating) may occur in such areas,
possibly because of receptor super-
sensitivity or aberrant regenerating
nerve fibers.47
Besides the chronic forms, acute
forms of diabetic autonomic neuro-
pathy also exist. These may be clini-
cally indistinguishable from seronegative
autoimmune autonomic gangliono-
pathy and require similar therapeutic
strategies. Furthermore, autoimmune
autonomic ganglionopathy may be
superimposed on diabetic autonomic
neuropathy. Treatment-induced neu-
ropathy of diabetes mellitus may
also have autonomic involvement.48
Treatment-induced neuropathy of dia-
betes mellitus is discussed further in
the article ‘‘Small Fiber Neuropathies’’
by Christopher H. Gibbons, MD, FAAN,
in this issue of .
As diabetic autonomic neuropathy
correlates with the severity and dura-
tion of hyperglycemia, and is irrevers-
ible except for the acute forms
mentioned above, the best strategy is
prevention by striving to achieve the
best possible glycemic control. Approx-
imately 30% of patients with impaired
glucose tolerance have abnormal auto-
nomic function tests. In contrast to
diabetic autonomic neuropathy, the
autonomic changes in impaired glucose
tolerance may be reversed through
improvement in metabolic parameters.
Amyloid Neuropathy
Amyloidosis is a disorder caused by the
tissue deposition of misfolded, insoluble
KEY POINTS
h Gastroparesis is the
most problematic
gastrointestinal
symptom in diabetic
autonomic neuropathy
and impacts glycemic
control due to erratic
enteric absorption.
h Patients with diabetes
mellitus are also at
increased risk for
autoimmune autonomic
neuropathies and
treatment-induced
neuropathy of diabetes
mellitus.
1385

beta-pleated proteins. Such deposition
interferes with normal tissue function,
probably through various mechanisms
(eg, ischemic, inflammatory, mechanical,
toxic-metabolic).
Although various proteins can be
responsible, clinical presentations are
relatively similar. Classification is based
on the causative protein biochemistry.
Clinical presentation can be protean.
Primary and familial (mainly
transthyretin [TTR] mutation) amyloid-
osis are the two most common forms,
with significant prevalence variability in
different populations.
Primary amyloidosis is caused by
production and abnormal deposition
of a monoclonal kappa or lambda
(most frequent) light chain. The
diagnosis should be suspected in any
patient who does not have diabetes
mellitus presenting with any of the
following features: cardiomyopathy,
nephrotic syndrome, axonal poly-
radiculoneuropathy, unexplained fatigue,
weight loss, or autonomic dysfunction
(Case 12-2). Other features that may
be present include macroglossia,
easy bruising, and hepatomegaly. Typ-
ical presentation is in the sixth or
seventh decade.
As monoclonal gammopathy of unde-
termined significance is common, in the
presence of documented amyloidosis,
the protein should still be characterized
to exclude a familial form, as manage-
ment differs. The diagnosis can be
challenging because of the variable pre-
sentation. Tissue diagnosis is required,
and combined biopsy of the iliac crest
bone marrow with abdominal subcuta-
neous fat aspiration will identify amyloid
deposits in 85% of patients.49
In cases
where this fails to find amyloid deposits,
biopsy of an affected tissue should be
considered. Treatment with stem cell
transplantation can achieve up to 65%
organ response and 76% hematologic
response. Ten-year survival with stem cell
transplantation is around 40%. Unfortu-
nately, only 20% to 25% of patients are
eligible for stem cell transplantation.
For the remaining patients with primary
amyloidosis, chemotherapy with alkylating
agents, corticosteroids, and other immu-
nomodulatory drugs and proteasome
inhibitors have been used in various
combinations with variable results.49
KEY POINTS
h The clinical presentation
of amyloidosis can be
variable, but the major
determinant of
prognosis is severity of
cardiac involvement.
h Primary amyloidosis due
to monoclonal
gammopathy, and
familial amyloidosis due
to transthyretin
mutation, are the most
common forms of
amyloidosis.
h Stem cell transplant for
primary amyloidosis and
liver transplant for
transthyretin
amyloidosis offer the
best treatment options.
Case 12-2
A 64-year-old previously healthy man presented with a 5-year history of progressive ascending sensory
loss, erectile dysfunction, and diarrhea. He reported occasional orthostatic lightheadedness. The
patient had lost about 50 pounds over 5 years, which he attributed to a change in diet because of the
diarrhea. He denied rash or change in his complexion, body hair, or nails. He also noticed weakness,
particularly in his right hand, with occasional fasciculation and slight atrophy. He showed no cranial
nerve impairment except for symptoms of sicca complex.
His family history was significant for a maternal grandmother and mother with history of concerns of
sensory loss that were not extensively investigated. Examination showed pan-modality sensory loss in the
lower extremities to the level of the trunk, and in the upper extremities in a glove distribution, sensory ataxia,
mild weakness of the right upper limb with mild atrophy, and areflexia.
Extensive blood and urine testing was normal except for a platelet count of 104,000 platelets per 2L, and
serum N-terminal pro b-type natriuretic peptide (NT-pro BNP) level of 3562 pg/mL (normal less than 85 pg/mL).
EMG revealed the presence of an axonal sensorimotor polyradiculoneuropathy and right median
neuropathy at the wrist. There was 22% anhidrosis on thermoregulatory sweat test (TST). Autonomic reflex
screen demonstrated reduced cardiac responses and a flat-top profile of blood pressure on Valsalva maneuver
that did not change with slight tilt, suggestive of heart failure. Fat aspirate was positive for amyloid. Genetic
testing was positive for pathogenic transthyretin (TTR) mutation, consistent with familial amyloidosis.
Continued on page 1387

Familial amyloidoses are autosomal
dominant disorders caused by mutations
in several genes including transthyretin
(TTR), the most common and most likely
to cause autonomic neuropathy, apoli-
poprotein A-I, or gelsolin gene.
More than 100 TTR mutations have
been reported so far, with fewer than 10
being considered nonpathogenic. The
most common mutation associated with
neuropathy is Val30Met in the TTR gene.
Penetrance is variable. Prevalence, age of
onset, and phenotypes vary greatly across
different populations and even within the
same family. Presentation is usually a
length-dependent neuropathy affecting
TABLE 12-7 Autonomic Neuropathies Caused by Infectious Disease: Clinical Features
Infectious
Disease Causative Organism
Sensory and Motor
Involvement Autonomic
HIV Human
immunodeficiency virus
Sensorimotor involvement Usually mild, but more severe in
AIDS patients resulting in orthostatic
hypotension, presyncope,
sweating disturbances, bladder
and bowel dysfunction, impotence
Botulism Anaerobic bacterium
Clostridium botulinum
Sensory: In some patients
thermoalgesic deficits
Motor: Acute neuromuscular
disorder, Guillain-Barrè
syndromeYlike syndrome,
bulbofacial involvement
Mydriasis, xerostomia and
xerophthalmia resulting in
panautonomic manifestations
Chagas
disease
Parasite
Trypanosoma cruzi
Minimal sensorimotor
involvement
Palpitation, syncope, and risk
for sudden death; mild dysmotility
to severe megaesophagus and
megacolon; orthostatic hypotension
plus conduction system and
myocardial damage
Diphtheria Anaerobic bacterium/
Corynebacterium
diphtheriae
Sensory: Impaired vibration
and joint position sense,
sensory ataxia
Motor: Symmetric sensorimotor
neuropathy/cranial involvement
(paralysis of accommodation with
preserved extraocular motility),
diaphragm paralysis
Tachycardia, nodose ganglion of
vagus nerve, bladder dysfunction,
hypotension
Leprosy Aerobic bacterium/
Mycobacterium leprae
Sensory: Decreased sensitivity
to temperature and pain
Motor: Mononeuritis
Loss of sweating, vasomotor
dysfunction, erectile dysfunction,
cardiac autonomic neuropathy
HIV = human immunodeficiency virus; AIDS = acquired immunodeficiency syndrome.
Comment. Amyloidosis can have various manifestations and presentations. Almost universally,
autonomic involvement is present. Weight loss and sensory loss also should raise suspicion. Autonomic
symptoms may present to various specialties (eg, gastroenterology, cardiology, nephrology, or neurology)
based on the most prominent symptoms. It can resemble an axonal polyradiculoneuropathy. Heart rate
variability is often lost early in the course of the disease. The presence of a flat-top profile on autonomic
reflex testing suggests congestive heart failure, supported also by the abnormal NT-pro BNP level.
Continued from page 1386
1387

TABLE
12-8
The
Most
Common
Hereditary
Autonomic
Neuropathies:
Clinical
Features
and
Inheritance
Hereditary
Autonomic
Neuropathy
Onset
Inheritance
Sensory
Motor
Autonomic
Allied
Features
Familial
amyloidosis
Adult
Autosomal
dominant
(AD)
Marked
Modest
Marked
(early
onset)
Systemic
involvement:
cardiomyopathy;
vitreous
opacities;
renal
failure;
weight
loss
Fabry
disease
Late
childhood/
adolescence
X-linked
Marked
Absent
Modest
Fatigue;
hearing
loss;
corneal
opacity;
renal
dysfunction;
skin
(angiokeratomas)
Burning
pain;
loss
of
temperature
perception
Hypohidrosis;
impotence;
gastrointestinal
dysfunction
Allgrove
syndrome
Childhood/
adult
Autosomal
recessive
(AR)
Absent
or
minimal
Modest
Modest
Adrenal
insufficiency
Gastric
atonia;
alacrima;
pupillotonia;
anisocoria;
sudomotor
dysfunction;
orthostatic
hypotension
(adult
onset)
Navajo
Indian
neuropathy
Childhood
AR
Marked
Absent
Modest
Corneal
insensitivity;
painless
fractures;
progressive
arthropathy
Heat
intolerance;
reduced
sweating
Tangier
disease
First
to
seventh
decade
AR
Modest
Modest
Absent
or
minimal
Tonsils,
enlarged
liver,
spleen
and
lymph
nodes;
premature
coronary
artery
disease
Pseudosyringomyelic/
pain
and
temperature
loss
Facial
diplegia
Multiple
endocrine
neoplasia,
type
2b
Variable
AD
Absent
or
minimal
Absent
or
minimal
Minimal
Association
with
neoplasia
(thyroid,
pheochromocytoma,
ganglioneuromas)
gastrointestinal
dysmotility
Mitochondrial
cytopathies
(mitochondrial-
neuro-gastro-
intestinal
encephalomyopathy
[MNGIE])
Variable
AD
Modest
Minimal
Vomiting;
gastrointestinal
dysmotility;
decreased
lacrimation;
vasomotor
disturbances;
hypohidrosis;
orthostatic
hypotension
External
ophthalmoplegia,
ptosis;
retinal
degeneration;
optic
atrophy;
weight
loss;
short
stature;
myopathy;
hearing
loss

predominantly small fibers. As the neu-
ropathy progresses, large fiber involve-
ment occurs with motor and sensory
manifestations. Autonomic symptoms
(loss of sweating, sexual dysfunction,
gastrointestinal symptoms, neurogenic
bladder, and orthostatic hypotension)
are common. Cardiomyopathy, ocular
involvement, and constitutional symp-
toms are also common.
Diagnosis in familial amyloidosis re-
quires confirmation of the presence of
amyloid in tissue, with mass spectrome-
try and DNA confirmation. Diabetes
mellitus, chronic inflammatory demye-
linating polyradiculoneuropathy (CIDP),
alcoholic, and other hereditary forms
may mimic transthyretin-familial amyloid
polyneuropathy (TTR-FAP). Treatment
for TTR-FAP is with liver transplant as
transthyretin is produced in the liver.
Liver transplantation slows or halts
the progression of disease, but reversal
of existing damage does not occur.
However, if significant amyloid accumu-
lation is present pretransplantation, the
disease may still progress due to normal
transthyretindepositiononthe preexistent
deposit. Patients with the Val30Met
TTR mutation have better outcomes
than those with other TTR mutations
(10-year survival posttransplantation
of 74% versus 44%, respectively).
Trials are ongoing to evaluate the
efficacy of certain medications in
preventing the misfolding of the variant
transthyretin and, thus, arrest or slow
disease progression.50
INFECTIOUS DISEASE
Autonomic neuropathies caused by
infectious diseases51
are described
in Table 12-7.
TOXIC AUTONOMIC
NEUROPATHIES
Several naturally occurring environmen-
tal toxins, industrial toxins, and medica-
tions can cause autonomic neuropathy.
Marine toxins are known to affect ion
transport (sodium and calcium in partic-
ular) and attack cell membranes, alter-
ing neurotransmission and intracellular
metabolism, which can result in cell
death and release mediators of inflam-
mation. Aggressive supportive care is
required in all these cases, but morbid-
ity and mortality remain significant. The
box jellyfish is the world’s most venom-
ous marine animal; its venom causes
severe autonomic dysfunction, includ-
ing vasospasm, arrhythmias, and para-
sympathetic failure.51
If instituted early,
treatment with verapamil can be life-
saving. Another type of jellyfish can
cause massive catecholamine release,
resulting in the Irukandji syndrome
(named after the aboriginal Irukandji
people, with symptoms of headache,
muscle pain, tachycardia, hypertension,
nausea,vomiting,abdominalpain,diapho-
resis, and pulmonary edema). Ciguatoxins
are potent sodium channelYactivating
toxins; the initial symptoms are paresthe-
sia, dysesthesia, and pain. Autonomic
features include hypersalivation, brady-
cardia, hypotension, and mydriasis.
IV mannitol may reverse the acute manifes-
tations. Organic solvents, arsenic, mer-
cury, thallium, and other heavy metals,
acrylamide, and the rat poison Vacor
(N-3-pyridylmethyl-N-para-nitrophenyl
urea) can cause autonomic neuropa-
thy. Autonomic neuropathy also may
follow treatment with cytotoxic agents
used in cancer chemotherapy, par-
ticularly with vincristine, which can
induce vagal neuropathy (resulting
in significant gastrointestinal dys-
motility), bladder dysfunction, and
orthostatic hypotension.
HEREDITARY AUTONOMIC
NEUROPATHIES OTHER THAN
FAMILIAL AMYLOIDOSIS
The hereditary autonomic neuropa-
thies are a clinically and genetically
heterogeneous group of disorders,
KEY POINTS
h Autonomic dysfunction
or failure accompanied
by an axonal sensory
greater than motor
neuropathy is almost
universal in amyloidosis.
Its absence should make
physicians question the
diagnosis.
h Several naturally
occurring environmental
and industrial toxins and
medications can cause
autonomic neuropathy.
1389

and most of the causative genes have
now been described (Table 12-3).
Neural degeneration can predomi-
nantly affect the peripheral autonomic
nervous system (eg, Fabry disease) or
affect both peripheral sensory and au-
tonomic nervous systems (eg, heredi-
tary sensory and autonomic neuropathy
[HSAN]). The latter can present with
marked sensory involvement and mini-
mal autonomic dysfunction (HSANI) or
disorders with predominant autonomic
impairment (HSANIII) (Table 12-8
and Table 12-9).
Hereditary Sensory and
Autonomic Neuropathy Type III
Familial dysautonomia, also known as
Riley-Day syndrome or HSANIII, is an
autosomal recessive disorder (muta-
tion in the IKBKAP gene), seen pri-
marily in Ashkenazi Jewish children
(disease frequency of 1 in 3600 live
births). It affects the development and
survival of sensory, sympathetic, and
some parasympathetic neurons, leading to
reduction in neurons in sympathetic
ganglia, intermediolateral gray columns,
dorsal root ganglia, and spinal cord.
TABLE 12-9 The Most Common Hereditary Sensory Autonomic Neuropathies:
Clinical Features and Inheritance
Hereditary
Sensory
Autonomic
Neuropathy
(HSAN) Onset Inheritance Sensory Motor Autonomic Allied Features
HSANI Juvenile to
adult
Autosomal
dominant
Marked Minimal Minimal Foot ulcers or
amputations;
bone deformities
and osteomyelitis;
hearing loss
occurs occasionally
HSANII Childhood Autosomal
recessive (AR)
Marked Minimal Absent or
minimal
Some patients
develop ulcers,
atrophy, and
hyporeflexia
HSANIII/
Familial
dysautonomia
Congenital AR Modest Absent Marked Recurrent
pneumonias;
absence of tears
Decreased
sensitivity
to pain and
temperature
Autonomic
crises
HSANIV Congenital/
childhood
AR Modest Absent Modest Oral self-mutilation;
fingertip biting;
repeated bone
fractures and
joint trauma
Congenital
sensory loss
affecting
perception
of pain and
temperature
Anhidrosis
HSANV Early
childhood
to adult
AR Modest Absent Minimal Charcot joints
and fractures
Congenital
reduced pain
and anhidrosis
Sweating
normal or
reduced

TABLE 12-10 Clinical Criteria in Hereditary Sensory and Autonomic
Neuropathy Type III/Familial Dysautonomia
b Absence of overflow emotional tears
b Absent lingual fungiform papillae
b Depressed patellar reflexes
b Lack of an axon flare following intradermal histamine
b Documentation of Ashkenazi Jewish extraction
TABLE 12-11 Autonomic Function Investigation
Autonomic
Screen Tests
Stimulus/
Mechanism(s)
Normal
Response
Function
Evaluated
Common
Abnormalities
Q-sweat Iontophoresis of
acetylcholine/
axon reflex
Sweat production Postganglionic
sudomotor
Reduction or
loss of sweat
production
Deep
breathing
Rate 6 breaths/min
Lung: stretch
receptors, right heart:
filling pressure
receptors/baroreflex
Heart rate rises
during inspiration,
drops during
expiration, while
blood pressure
does the opposite
Vagal: both afferent
and efferent of sinus
arrhythmia are vagal
Loss of heart
rate variability
Valsalva
maneuver
Expiratory effort
at 40 mm Hg
for 15 seconds/
drop in blood
pressure activating
baroreflex
Blood pressure
initially drops,
then rises; at effort
release, brief drop
in blood pressure
followed by
transient
overshoot
Sympathetic
vasomotor and
cardiomotor,
baroreflex and
cardiovagal
Impaired
vasoconstriction:
loss of blood
pressure recovery
during late
phase II, attenuation
of phase IV,
prolonged
recovery time
Heart rate rises
steadily during
effort, rapidly
drops below
baseline at
release
Reduced Valsalva
ratio
Tilt table test Orthostatic
stress/baroreflex
No major
hemodynamic
changes present
in normal
Sympathetic
vasomotor and
cardiomotor
Orthostatic
hypotension;
inappropriate
postural orthostatic
tachycardia; syncope
Thermoregulatory
sweat test
Rise in core body
temperature/
maintenance of
thermal homeostasis
through heat dissipation
Entire body sweats Entire
thermoregulatory
pathway from
hypothalamus to
sweat glands
Reduction/loss
of sweating;
hyperhidrosis
(focal generalized;
essential or
compensatory)
1391

TABLE 12-11 Autonomic Function Investigation (Continued)
Autonomic
Screen Tests
Stimulus/
Mechanism(s)
Normal
Response
Function
Evaluated
Common
Abnormalities
Serum
catecholamine
measurement
supine and
standing
Orthostatic stress:
10 minutes
of standing;
30 minutes
supine/baroreflex
Norepinephrine (NE)
level: 9100 pg/mL
supine, generally
double with
standing
Humoral response
to orthostasis;
Ganglionic and
postganglionic
pathology: NE level
G100 pg/mL supine, can
double with standing
(inadequate rise
in presence of
orthostatic
hypotension)
Sympathetic
pathway
and adrenal
medulla
Preganglionic
pathology: normal
supine NE level, no or
little change with standing
Postural orthostatic
tachycardia syndrome:
normal or high NE at
baseline, marked rise
(3 times or greater)
with standing often to
9600 pg/mL
TABLE 12-12 Nonpharmacologic Treatment of Orthostatic
Hypotensiona
b Education: Advise on Factors That Influence Blood Pressure
Prolonged standing
Early morning after nocturnal diuresis
Straining during micturition and defecation
Warm environment
Heavy meals (carbohydrate in particular)
Exertion
Alcohol
Drugs with vasoactive effect
b Nonpharmacologic Measures
Head-up tilt at night
Water ingestion/bolus: 250Y500 mL of water
Position and maneuvers to raise blood pressure: physical counter maneuvers
External support to prevent pooling: abdominal binder, compression stocking
a
Modified with permission from Mathias CJ, Bannister R, Oxford University Press.52
B 2013 Oxford
University Press.

Clinical criteria are listed in Table 12-10.
Patients often present with multisystem
involvement, including prominent car-
diovascular (orthostatic hypotension,
hypertensive crisis), sudomotor (hyper-
hidrosis), and neurologic (decreased
TABLE 12-13 Pharmacologic Treatment of Orthostatic Hypotensiona
Predominant Action Dosage
Starting drugs
Fludrocortisone Mineralocorticoid effect: increased
plasma volume; sensitization of
!-adrenoreceptors
Starting with 0.1 mg
and increased up to
0.2mg3times/difresistant
Sympathomimetic
Ephedrine Indirectly acting
sympathomimetic
Starting 15 mg 3 times/d
and maximum of 30 mg
3 times/d
Midodrine Directly acting
sympathomimetic
5 mg 3 times/d and
increasedto10mg3times/d
Droxidopa (dl-threo-3,
4-dihydroxyphenylserine)
Oral synthetic precursor
of norepinephrine
100 mg 3 times/d up to
600 mg 3 times/db
Specific targeting
Octreotide Inhibits release of vasodilator
gut/pancreatic peptides
Starting with 25 2g
3 times/d and
increasedto502g 3 times/d
Acarbose Intestinal !-glucosidase inhibitor 100 mg 20 minutes
before food
Voglibosec
Intestinal !-glucosidase inhibitor 200 2g 10 minutes
before food
Erythropoietind
Stimulates red blood cell production 50 units/kg subcutaneously
3 times/wk
Desmopressin Vasopressin-2 receptors on renal tubules Intranasal form: starting
with 5 2g increased to
40 2g at bedtime
Additional agents
Yohimbine Presynaptic !2-adrenoreceptor antagonist or blocker 5 mg/d
Pyridostigmine Inhibition of acetylcholinesterase/enhancing
sympathetic ganglionic transmission
30 mg 2 times/d or
3 times/d and increased
to 60 mg 3 times/d
Dihydroergotamine Direct action on !-adrenoreceptors 1 mg intramuscularly
1 time/d with maximum
dose 3 mg/d, or
0.0065Y0.013 mg/kg
subcutaneously 1 time/d
in the morning with
maximum 3 mg/d
Caffeine Blockade of adenosine receptors 2Y3 servings/d
Sodium chloride tablets Volume expansion Up to 2 g 3 times/d
a
Modified with permission from Mathias CJ, Bannister R, Oxford University Press.52
B 2013 Oxford University Press.
b
Droxidopa is usually administered 3 times a day: morning, midday, and late afternoon at least 3 hours before sleep.
c
Voglibose is not currently available in the United States.
d
Erythropoietin isnotavailable intheUnitedStatesand is only available as arecombinant form of erythropoietin such asdarbepoetin alfa and epoetin alfa.
1393

deep tendon reflex, decreased pain,
temperature and vibration sensation,
progressive ataxia in adulthood, re-
duced IQ) symptoms and signs. Pa-
tients may also manifest with ocular
(decreased tears, corneal analgesia),
TABLE 12-14 Treatment of Gastrointestinal and Bladder Dysfunction
b Constipation Stepwise Approach
1. Exclude medication effect; exclude pelvic floor dysfunction (amenable to retraining)
2. Trial of dietary fiber
Bran (1 cup/d)
Psyllium (up to 15Y20 g/d)
3. Stool softener: docusate sodium (100 mg 2 times/d)
4. Osmotic laxatives
Polyethylene glycol 3350 (17 g orally daily dissolved in 3 oz of water)
Sorbitol (30Y45 mL [27Y40 g] orally daily)
Lactulose (15Y30 mL [10Y20 g] orally daily)
Milk of magnesia (15Y30 mL 1 or 2 times/d)
5. Stimulant laxatives
Senna
Cascara sagrada
Bisacodyl
Glycerin suppositories
Enemas as rescue agents
6. Secretagogues
Lubiprostone (24 2g 2 times/d)
Linaclotide (145 2g/d)
b Fecal Incontinence
Education: regular bowel habits
Sanitary devices
Pelvic floor strengthening
Surgery
b Bladder Management
Overactive bladder/incontinence
Behavioral: fluid schedules, treat pelvic floor dysfunction, constipation,
timed/prompted voiding, absorbent garments
Antimuscarinic medications
Oxybutynin immediate release tablets (2.5 mg 2 times/d up to 5 mg 4 times/d)
Oxybutynin extended release tablets (5Y10 mg/d up to 30 mg/d)
Oxybutynin patch (3.9 mg/24 hours applied 2 times/week)
Tolterodine immediate release tablets (1Y2 mg 2 times/d)
Tolterodine extended release capsules (2Y4 mg/d)
Solifenacin (5 mg 1Y2 times/d)
Darifenacin (7.5Y15 mg/d)
Fesoterodine (4Y8 mg/d)

gastrointestinal (dysphagia, esophageal
and gastric dysmotility, gastroesopha-
geal reflux, vomiting crisis), pulmonary
(aspiration, insensitivity to hypoxia,
restrictive lung disease), and orthope-
dic involvement (spinal curvature,
avascular necrosis). With the develop-
ment of treatment programs, the
survival of patients with familial dys-
autonomia has improved (50% proba-
bility of reaching 40 years of age). Adult
patients with familial dysautonomia
have a slow progressive peripheral
neuropathy degeneration, a profound
worsening of cardiovascular function
with prominent orthostatic hypoten-
sion, supine hypertension, and occa-
sional bradyarrhythmias.
EVALUATION OF AUTONOMIC
NEUROPATHIES
Standard investigations of autonomic
dysfunction include autonomic testing
and additional specialized studies as
deemed appropriate (Table 12-1,
Table 12-2, Table 12-11).
SYMPTOMATIC TREATMENT OF
AUTONOMIC FAILURE
Treatment of orthostatic hypotension
and bowel and bladder dysfunction is
outlined in Table 12-12, 12-13, and
Table 12-14, while Table 12-5 and
Table 12-6 describe the available
treatment for autoimmune autonomic
ganglionopathy.15,52Y54
CONCLUSION
Autonomic neuropathies are relatively
common conditions, and, because of
the prognostic implications as well as
impact on patient quality of life, they
should be promptly recognized and
treated aggressively. Testing is critical
as other conditions may mimic auto-
nomic neuropathies. Treatment is
symptomatic in many cases, but spe-
cific therapies are also available for
selected autonomic neuropathies.
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