Neurol Clin 25 (2007) 277–301

Autonomic Peripheral Neuropathy

Roy Freeman, MD
Department of Neurology, Harvard Medical School, Center for Autonomic
and Peripheral Nerve Disorders, Beth Israel Deaconess Medical Center,
One Deaconess Road, Boston, MA 02215, USA

Most generalized peripheral polyneuropathies are accompanied by clini-

cal or subclinical autonomic dysfunction. There is a group of peripheral
neuropathies in which the small or unmyelinated fibers are selectively tar-
geted [1]. In these neuropathies, autonomic dysfunction is the most promi-
nent manifestation. The autonomic nervous system innervates viscera,
vascular smooth muscle, endocrine and exocrine glands, the immune system,
and soft tissues, and the associated signs and symptoms include impairment
of cardiovascular, gastrointestinal, urogenital, thermoregulatory, pseudo-
motor, and pupillomotor autonomic function. A list of common peripheral
neuropathies with autonomic manifestations is found in Box 1.

Diabetic autonomic neuropathy

Diabetes mellitus is the most common cause of autonomic neuropathy in
the developed world [2,3]. This topic has been covered in detail in several re-
cent reviews [4,5]. Diabetic cardiovascular autonomic neuropathy often
manifests initially as an increased resting heart rate caused by a cardiac va-
gal neuropathy. As the autonomic neuropathy progresses, cardiac sympa-
thetic fibers are involved and the resting tachycardia is replaced with
a slowed, and ultimately fixed, heart rate [6–8]. Orthostatic hypotension oc-
curs in diabetes as a consequence of efferent sympathetic vasomotor dener-
vation, causing reduced vasoconstriction of the splanchnic and other
peripheral vascular beds [9]. There is an increase in overall mortality and
sudden death in patients with diabetic autonomic neuropathy [10–17]. In
a meta-analysis of 15 studies, a significant association between cardiovascu-
lar autonomic neuropathy and subsequent mortality was observed. There
was a pooled relative risk of 2.14 (95% confidence interval 1.83–2.51;
P ! 0.0001). The relative risk was stronger for studies for which two or

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278 FREEMAN

Box 1. Autonomic peripheral neuropathies

Diabetes
Amyloidosis
Guillain-Barré syndrome
Acute and subacute autonomic neuropathies
Immune-mediated and paraneoplastic neuropathies
Paraneoplastic neuropathies
Connective tissue diseases
Sjögren’s syndrome
Systemic lupus erythematosus
Rheumatoid arthritis
Mixed connective tissue disease
Hereditary neuropathies
Hereditary sensory and autonomic neuropathies
Fabry’s disease
Allgrove syndrome
Navajo Indian neuropathy
Tangier disease
Multiple endocrine neoplasia, type 2b
Infectious diseases
Chagas disease
HIV neuropathy
Botulism
Leprosy
Diphtheria
Toxic neuropathies
Organic solvents
Acrylamide
Heavy metals
Vacor
Vincristine
Cisplatinum
Taxol
Doxorubicin
Cytosine arabinoside
Perhexiline maleate
Amiodarone
Pentamidine
Gold
Podophyllin
Marine toxins
 AUTONOMIC PERIPHERAL NEUROPATHY 279

more measures were used to define cardiac autonomic neuropathy. The

stronger association observed in studies defining cardiac autonomic neurop-
athy by the presence of two or more abnormalities may be caused by more
severe autonomic dysfunction in these subjects or a higher frequency of
other comorbid complications that contributed to their higher mortality
risk [18].
Symptoms of bladder dysfunction are observed in up to 50% of patients
who have diabetes [19–21]. The earliest manifestation is impaired bladder
sensation that increases the threshold for initiating the micturition reflex.
A decrease in detrusor activity follows, which causes incomplete bladder
emptying, an increased postvoid residual, decreased peak urinary flow
rate, bladder overdistension, and ultimately, urinary retention and overflow
incontinence [22,23].
Erectile failure affects up to 75% of men who have diabetes and may be
the earliest symptom of diabetic autonomic neuropathy [24–28]. Vascular
and psychogenic causes also may contribute to this symptom. In vitro stud-
ies of isolated corpus cavernosum tissue from men who have diabetes sug-
gest that the erectile failure is caused by impairment in autonomic and
endothelial-dependent nitric oxide–mediated relaxation of corpus caverno-
sum smooth muscle [29]. Ejaculatory failure caused by sympathetic nervous
system dysfunction may precede the appearance of erectile dysfunction, al-
though erectile failure can occur with retained ability to ejaculate and expe-
rience orgasm. There are few studies of genital autonomic neuropathy in
women who have diabetes [30]. Reduced vaginal lubrication is a commonly
reported symptom [31].
Autonomic dysfunction occurs throughout the gastrointestinal tract and
produces several specific clinical syndromes [32,33]. Diabetic gastroparesisd
delayed gastric emptying of solids or liquidsdis present in up to 50% of
individuals who have diabetes [34–36]. Gastroparesis may manifest as nau-
sea, postprandial vomiting, bloating, belching, loss of appetite, and early sa-
tiety. Many patients, however, are asymptomatic despite impaired gastric
motility [33]. Gastroparesis often impairs the establishment of adequate
glycemic control. Dysfunction of the vagus nerve and intrinsic enteric
autonomic nerves may play a role in this disorder. Recent studies have im-
plicated hyperglycemia as a cause of reversible impairment in gastric and
small intestinal motility during fasting and after food intake [37,38].
Constipation is the most frequently reported gastrointestinal autonomic
symptom and is found in up to 60% of persons who have diabetes [39–41].
Diabetic diarrhea and other lower gastrointestinal tract symptoms also
may occur. The diarrhea is profuse and watery and typically occurs at
night. The diarrhea can last for hours or days and frequently alternates
with constipation. In individuals who have type 2 diabetes, metformin ther-
apy is a common cause of diarrhea [42]. Fecal incontinence caused by anal
sphincter incompetence or reduced rectal sensation is often exacerbated by
diarrhea [43,44].
280 FREEMAN

Diabetic autonomic neuropathy initially results in a loss of thermoregu-

latory sweating in a glove and stocking distribution that can extend to the
upper aspects of the limbs and anterior abdomen, conforming to the well-
recognized length dependency of diabetic neuropathy [45]. Hyperhidrosis
also may accompany diabetic autonomic neuropathy. Gustatory sweating,
an abnormal production of sweating that appears over the face, head,
neck, shoulders, and chest after eating even nonspicy foods, is observed oc-
casionally. The pathophysiology of this phenomenon, which suggests aber-
rant reinnervation, is not fully elucidated [46].
Preliminary evidence indicates that impaired glucose tolerance is associ-
ated with and may be the direct cause of a peripheral neuropathy that pre-
dominantly affects small nerve fibers. The prevalence of this association is
unknown. There are few community-based epidemiologic studies of this dis-
order, and the evidence is mainly derived from studies in tertiary care cen-
ters. Sudomotor abnormalities are a prominent manifestation of this
neuropathy [47–51]. An open label diet and exercise program based on
the Diabetes Prevention Program improved the metabolic parameters (in-
cluding weight, lipids, and 2-hour glucose levels) and measures of small fiber
structure and function. After 1 year of treatment there was a significant im-
provement in proximal intraepidermal nerve fiber density. The change in in-
traepidermal nerve fiber density correlated with pain scores. There also was
a significant improvement in foot sweat volume measured by quantitative
sudomotor axon reflex test (QSART) [49].

Amyloid neuropathy
Amyloidosis is caused by the deposition of insoluble fibrillar proteins in
a beta-pleated sheet configuration within the extracellular space of various tis-
sues and organs. Various amyloidogenic proteins have been associated with
amyloidosis. The current classification of the systemic amyloidoses is based
on the biochemistry of the precursor protein [52,53]. Although the fibril pre-
cursor proteins differ, there are strong similarities between the clinical presen-
tations and pathology of the neuropathies associated with the different
amyloidoses. Autonomic dysfunction frequently accompanies the polyneur-
opathy of primary ([AL] immunoglobulin light chain associated) and heredi-
tary amyloidosis (familial amyloid polyneuropathy [FAP]) but in contrast is
not common in secondary (amyloid A protein-associated) amyloidosis [52,53].
Patients who have amyloid neuropathy typically present with distal sen-
sory symptoms, such as numbness, pain, paresthesias, and dysesthesias, al-
though the autonomic manifestations occasionally may be the presenting
feature of the neuropathy. On examination, there are signs of a sensorimotor
polyneuropathy that predominantly involves the small fibers that mediate
nociceptive and thermal sensation. Touch-pressure, position, and vibration
perception are typically less severely impaired, particularly in patients who
have FAP. Weakness is not a prominent feature and usually occurs later
 AUTONOMIC PERIPHERAL NEUROPATHY 281

in the course of the disease. Painless, trophic ulcers may occur because of
sensory loss and autonomic dysfunction. Characteristic autonomic signs
and symptoms include postural hypotension, early satiety, diarrhea, consti-
pation, fecal incontinence, disturbances in bladder function, pupillary ab-
normalities, and erectile failure. These autonomic manifestations are
similar to those described with diabetic autonomic neuropathy. Sick sinus
syndrome and A-V conduction deficits also are frequently present. Tests re-
sults for assessing cardiac vagal function are often abnormal [54].
Amyloid neuropathy is characterized pathologically by the deposition of
insoluble beta-fibrillar proteins in the epi-, peri-, and endoneurium, the
perineuronal tissues, and the neural vasculature. Ischemic, infiltrative, in-
flammatory, and toxic-metabolic factors have been implicated in the patho-
genesis of the peripheral neuropathy, which remains unresolved [54].
The pathogenesis of amyloid peripheral neuropathy is unresolved [54].
Proposed pathogenic processes include ischemia caused by obliteration of
small arteries and arterioles of nerves by amyloid deposits [55–57], infiltra-
tion and compression of peripheral nerves, dorsal nerve root ganglia, or au-
tonomic ganglia by amyloid [56–58], inflammation, and toxic-metabolic
factors, including oxidative stress [59,60].
Amyloidosis can be diagnosed by subcutaneous fat pad aspiration, gingi-
val biopsy, or biopsy of rectal (and other gastrointestinal tract) mucosa.
Nerve biopsy may be less sensitive because of the focal distribution of the
amyloid deposits [61]. Amyloid deposits have a homogeneous, eosinophilic
appearance on light microscopy and reveal a characteristic yellow-green bi-
refringence when viewed under polarized light with Congo red staining.
Primary (AL) amyloidosis is the most common form of amyloidosis in
the Western world. This disorder is a plasma cell dyscrasia in which a mono-
clonal population of bone marrow cells produces monoclonal immunoglob-
ulin light chains or light-chain fragments that deposit as amyloid [62].
Symptoms typically appear in the sixth or seventh decade. Patients usually
present with weight loss and fatigue. Peripheral neuropathy, which may be
the presenting feature of the disease or an incidental finding, is present in up
to 20% of patients who have AL [58]. Autonomic involvement of the cardio-
vascular, gastrointestinal, and urogenital systems is common [52,58,63].
Other systemic features include hepatomegaly, macroglossia, cutaneous ec-
chymoses, cardiomyopathy, and nephrotic range proteinuria. Immunofixa-
tion electrophoresis of serum or urine detects immunoglobulins or light
chains in 90% of patients who have AL amyloidosis [62].
The median survival of patients who have AL amyloid neuropathy ranges
from 13 to 35 months, with a 3-year survival rate of 38% to 50%. The prog-
nosis for patients who have heart failure is considerably worse [64,65].
Treatment with melphalan and prednisone improves survival, particularly
when associated with a reduction in serum or urine monoclonal protein
[64,65]. Stem cell transplantation in carefully selected patients may improve
survival further [66].
282 FREEMAN

FAP is a manifestation of hereditary generalized amyloidosis. This disor-

der was first reported in Portugal in 1952 [67]. The hereditary amyloidoses
are autosomal dominantly inherited diseases in which the amyloid precursor
is a mutant protein. Mutant transthyretin (TTR), previously called prealbu-
min, a 14-kDa protein that serves as the transport protein for thyroxine and
retinol-binding protein, is the most common cause of hereditary amyloid-
osis. It is encoded by a single gene on chromosome 18. The most commonly
observed mutation is a substitution of methionine for valine at position 30
(Met-Val 30) [68,69]. This disorder, which encompasses what was previously
called FAP I (Portuguese or Andrade amyloidosis) [67] and FAP II (Indi-
ana-Swiss or Rukavina amyloidosis) [70,71], has been associated with
more than 100 single or double mutations or deletions of the TTR gene [72].
TTR amyloidosis typically presents in the third to fifth decade. Charac-
teristic features include prominent dysautonomia that accompanies a painful
sensorimotor neuropathy, carpal tunnel syndrome, vitreous opacities, ne-
phropathy, and cardiomyopathy. Sensory neuropathy and gastrointestinal
symptoms are the most frequent initial symptoms. Death occurs 5 to 15
years after the appearance of symptoms [53,72]. The clinical phenotype is
variable, however, and depends on the position and nature of the amino
acid substitution. Variant presentations include late onset [73], isolated car-
pal tunnel syndrome, and a distal sensory or sensorimotor neuropathy with-
out autonomic dysfunction [70,71]. Clusters of hereditary amyloidosis
caused by mutant TTR have been found in Portugal, Japan, Sweden, United
States, Spain, Finland, Ireland, France, and Germany [53,72].
A late-onset, seemingly sporadic FAP (TTR Met 30) has been documented
in Portugal and Japan. Patients in the sixth decade or older typically present
with lower extremity paresthesias. The autonomic features are mild and not
incapacitating. This disorder has an autosomal dominant pattern of inheri-
tance with low penetrance. There is a high male/female ratio (10.7:1) [73].
FAP is also rarely caused by mutations in other proteins besides TTR.
FAP rarely may be caused by mutations in the genes encoding for apolipo-
protein-A1, fibrinogen Aa, lysozyme, and gelsolin [52]. A recent report
documented that almost 10% of patients with sporadic amyloidosis, pre-
sumed to be primary (AL) amyloidosis, actually had hereditary amyloidosis.
In more than half of these patients, neuropathy was the dominant clinical
presentation. These results suggest that hereditary amyloidosis may occur
more frequently than previously suspected. Given the different prognoses
and therapies for the two conditions, these findings emphasize the impor-
tance of genetic testing in patients with amyloidosis who do not have a path-
ologically confirmed diagnosis of AL disease. A low-grade monoclonal
gammopathy was present in 24% of patients who were found later to
have hereditary amyloidosis [74].
Because most of the mutated amyloidogenic TTR is secreted by the liver,
orthotopic liver transplant is the most effective treatment for hereditary am-
yloidosis. Liver transplant removes the principal source of variant TTR and
 AUTONOMIC PERIPHERAL NEUROPATHY 283

reduces circulating TTR by up to 90%. In appropriately selected patients,

liver transplant improves neurophysiologic measures, nerve morphology,
and survival [75,76]. Although the extent of the benefits of liver transplan-
tation on the sensorimotor peripheral neuropathy is unresolved [76,77],
the features of an established autonomic neuropathy do not seem to im-
prove significantly with this intervention [76,78,79]. Similarly, conduction
system abnormalities and arrhythmias seem to progress despite liver trans-
plantation [79]. Pharmacotherapeutic interventions that inhibit amyloido-
genesis eventually may replace liver transplant [80].

Acute and subacute autonomic neuropathies

Guillain-Barre´ syndrome
Guillain-Barré syndrome (acute inflammatory demyelinating polyradicu-
loneuropathy) is a monophasic illness of immune etiology that presents as
an acutely evolving sensorimotor polyneuropathy of varying severity. Auto-
nomic manifestations such as sinus tachycardia, sinus pauses and other
tachy- and bradyarrhythmias, blood pressure lability, bowel and bladder
dysfunction, pupillomotor disturbances, sudomotor dysfunction, and vaso-
motor abnormalities frequently accompany Guillain-Barré syndrome
[81,82]. Autonomic manifestations, which occasionally may be the present-
ing feature of Guillain-Barré syndrome [83], may be more prominent in pa-
tients with respiratory failure, severe motor deficits, and the axonal variant
of Guillain-Barré syndrome [84–86]. The autonomic features can result in
significant mortality and morbidity in some patients, although they are usu-
ally overshadowed by the motor features of the disorder.

Acute and subacute autonomic neuropathies

Autonomic manifestations may be the sole or predominant feature of an
acute or subacute peripheral neuropathy [87]. Although acute or subacute
autonomic neuropathy is usually immune-mediated or paraneoplastic, the
differential diagnosis includes botulism, porphyria [88], and some toxic neu-
ropathies (see later discussion). The hallmark of these autonomic neuropa-
thies is the acute or subacute presentation, in varying combinations, of
orthostatic hypotension, anhidrosis, constipation, bladder atony, impo-
tence, secretomotor paralysis, and blurring of vision associated with tonic
pupils. Mild sensorimotor manifestations may accompany the autonomic
manifestations but are not the predominant aspect of the presentation.
The autonomic features of this disorder may involve the sympathetic and
parasympathetic divisions of the autonomic nervous system (pandysautono-
mia) [89] or the sympathetic or parasympathetic nervous system alone (also
called cholinergic dysautonomia) [90]. Only 40% of cases recover fully to
premorbid status. Autonomic testing in the recovery phase of illness in these
284 FREEMAN

patients often shows evidence of persisting subclinical autonomic dysfunc-

tion [87].
Acute dysautonomia has been described in association with infectious
mononucleosis or Epstein Barr virus [91,92], streptococcus [93], Coxsackie
B virus [94], rubella [95], and herpes simplex virus [96] infections in addition
to other nondiagnosed viral syndromes. Associations with malignancies
[97,98] (see later discussion) and connective tissue diseases have been de-
scribed in other cases [99,100]. Lending further support to the likelihood
that some of these cases are immune mediated, a positive therapeutic re-
sponse to intravenous immunoglobulin has been reported in uncontrolled
case studies [101,102].
An acute case of subacute autonomic neuropathy may occur in associa-
tion with connective tissue disease, including Sjögren’s syndrome [103],
rheumatoid arthritis [104], systemic lupus erythematosus [99,100], and
mixed connective tissue disease. No specific autoantibodies have been asso-
ciated with the dysautonomia in connective tissue diseases.

Immune-mediated and paraneoplastic autonomic neuropathies

(specific autoantibody-associated autonomic neuropathies)
Autonomic dysfunction has been associated with the presence of specific
autoantibodies (Box 2). The subacute appearance of autonomic symptoms,
including orthostatic hypotension, pupillomotor dysfunction, sudomotor
dysfunction, constipation, urinary retention, impotence, and xerophthalmia,
has been associated with the presence of anti-Hu antibodies (also known as
Type 1 antineuronal nuclear antibody, ANNA-1) in patients with malignan-
cies, especially small-cell lung cancer. Other associated malignancies include
non–small-cell lung cancer and malignancies of the gastrointestinal tract,
prostate, breast, bladder, kidney, pancreas, testicle, and ovary [105–108].
Dysautonomia may be an isolated manifestation of a paraneoplastic disor-
der or part of a generalized paraneoplastic syndrome that includes a sensory
neuronopathy, limbic and brainstem encephalitis, encephalomyelitis,

Box 2. Specific antibodies associated with autonomic

neuropathies
Anti-Hu antibodies (Type 1 anti-neuronal nuclear antibody,
ANNA-1)
Purkinje cell antibodies Type 2 (PCA-2)
Collapsing response mediator protein-5 (CRMP-5)
Neuronal nicotinic acetylcholine receptor antibodies
P/Q-type Ca2 + channel antibodies
Acetylcholine receptor antibodies
 AUTONOMIC PERIPHERAL NEUROPATHY 285

cerebellar degeneration, and a sensorimotor peripheral neuropathy. Other

autoantibodies that are associated with a paraneoplastic autonomic neurop-
athy include Purkinje cell cytoplasmic antibodies Type 2 (PCA-2) [109] and
antibodies to the neuron cytoplasmic protein, collapsin response-mediator
protein-5 (CRMP-5) [110].
Patients who have autoantibodies to ganglionic acetylcholine receptors
typically present with a subacute autonomic neuropathy with progression
to panautonomic failure [111]. Based on studies in animals, these antibodies
impair ganglionic synaptic transmission by depleting acetylcholine receptors
on the ganglionic neuron [112]. The typical clinical findings in autoimmune
autonomic neuropathy include dry eyes and mouth, fixed heart rate, im-
paired pupillary response to light and accommodation, gastrointestinal dys-
motility, and urinary retention [111,113,114]. Orthostatic hypotension can
be the most incapacitating feature, with frequent syncopal episodes and re-
strictions on activities of daily living. Laboratory studies reveal substantially
reduced levels of plasma catecholamines [112]. Some [115], but not all [116],
patients respond to plasmapheresis and immune modulation. Malignancies
associated with these antibodies include small-cell lung carcinoma, thy-
moma, bladder carcinoma, and rectal carcinoma. These antibodies may
be present in patients with the clinical phenotype of pure autonomic failure
[117]. When cholinergic features are prominent, the diagnosis of an immune-
mediated autonomic neuropathy should be entertained [113].
Celiac disease (gluten-sensitive enteropathy) is the most common mani-
festation of gluten sensitivity; however, diverse manifestations may accom-
pany the disorder [118,119]. Several recent reports have drawn attention to
the association between gluten sensitivity with elevated antigliadin anti-
bodies and neurologic disorders [118,119], although given the high percent-
age of antigliadin antibodies in the general population (6%–12%), the
etiologic significance of this association is uncertain in most patients
[120,121]. We have documented that 2.4% of patients referred for auto-
nomic testing had biopsy-proven celiac disease and dysautonomia [122],
a frequency of celiac disease similar to that reported in idiopathic peripheral
neuropathy [119]. In these patients, nausea, which was postural in nature,
was the primary symptom for referral. Other reported autonomic symptoms
included lightheadedness, palpitations, fatigue, presyncope, and syncope.
Autonomic test results revealed abnormalities in sympathetic and parasym-
pathetic nervous system function [122]. Esophageal dysmotility and subclin-
ical abnormalities of cardiovascular reflexes, which were present in 19% of
patients, also have been reported in patients who have celiac disease [123].

Hereditary autonomic neuropathies

The hereditary autonomic neuropathies are a heterogeneous group of dis-
orders, some of which have significant involvement of autonomic fibers (see
Box 1) [124–127]. Autonomic features are most prominent in the hereditary
286 FREEMAN

sensory and autonomic neuropathies (HSAN) and Fabry’s disease [124–

127]. Other hereditary autonomic neuropathies include Allgrove syndrome
[128], Tangier disease [129–131], a sensory and autonomic neuropathy
with arthropathy that is present in Navajo children [132,133], and multiple
endocrine neoplasia, type 2b [134]. HSANs are characterized by prominent
sensory loss without motor involvement and by often striking dysautono-
mia. The axon reflex-mediated vasomotor response (the flare) after intrader-
mal histamine is absent in all HSAN.

Hereditary sensory and autonomic neuropathy type I

HSAN type I is an autosomal dominant, hereditary sensory radiculo-
neuropathy that presents in the second decade. Patients who have this dis-
order present with distal pain that is associated with sensory loss that
predominantly involves nociceptive and thermal perception while relatively
sparing touch-pressure sensation and proprioception. The sensory loss prog-
resses gradually and is accompanied by anhidrosis, trophic ulcers, acral in-
juries, stress fractures, and osteomyelitis [125,126]. HSAN type I has been
associated with a mutation in the SPTLC1 gene on chromosome 9q22.1-
q22.3 that encodes for subunit 1 of serine palmitoyltransferasedthe rate
limiting enzyme for the synthesis of the sphingolipids, ceramide, and sphin-
gomyelin [135,136]. A variant of this disorder, associated with chronic
cough and gastroesophageal reflux, has been mapped to a locus on chromo-
some 3p22-p24 [137].

Hereditary sensory and autonomic neuropathy type II

HSAN type II (congenital sensory neuropathy or Morvan’s disease) is an
autosomal recessive or sporadic disorder that presents in infancy or early
childhood. This disorder is associated with profound sensory loss that in-
volves large and small fiber modalities (pain and temperature perception
and proprioception). Marked hypotonia and decreased deep tendon reflexes
are common [127]. Trophic changes are present in the upper and lower ex-
tremities. Painless fractures may occur. Autonomic features include episodic
hyperhidrosis, tonic pupils, constipation, and apneic episodes [125,126].
Tearing may be delayed but is eventually normal. Sural nerve biopsy reveals
depletion of large and small myelinated fibers but only slightly decreased
number of unmyelinated fibers. This disorder has been associated with a mu-
tation on a gene, HSN2, with a locus that maps to chromosome 12p13.33
[138].

Hereditary sensory and autonomic neuropathy type III

Autonomic manifestations are prominent in HSAN type III (Riley-Day
syndrome or familial dysautonomia). This autosomal recessive disorder is
 AUTONOMIC PERIPHERAL NEUROPATHY 287

seen primarily in Ashkenazi Jewish children. The incidence of familial dys-

autonomia is 1 in 3700 live births among Ashkenazi Jews, and the carrier
frequency is 1 in 32 individuals [139,140]. The defective gene that causes fa-
milial dysautonomia has been mapped to the long arm of chromosome 9
(9q31) [141]. Most (99.5%) patients who have familial dysautonomia have
a single, splicing mutation in the I-kappa B kinase associated protein (IKB-
KAP) gene that results in tissue-specific expression of a truncated IKAP
protein [142].
HSAN III presents in infancy. The clinical features of this disease include
insensitivity to pain and temperature stimuli but sparing visceral pain, ab-
sence of tears (alacrima), hypoactive corneal and tendon reflexes, and ab-
sence of lingual fungiform papillae. Poor suck and feeding, esophageal
reflux with vomiting and aspiration, and swallowing dyscoordination may
be the first clinical manifestations [140,143]. Autonomic disturbances may
be prominent at any point in the disease. Autonomic manifestations include
episodic hyperhidrosis, vasomotor instability with defective temperature
homeostasis, breath-holding episodes, protracted episodes of vomiting,
postural hypotension, hypertensive crises, and supersensitivity to cholinergic
and adrenergic agents.

Hereditary sensory and autonomic neuropathy type IV

HSAN type IV (congenital insensitivity to pain with anhidrosis, anhi-
drotic sensory neuropathy), the second most common HSAN, is an autoso-
mal recessive disorder that manifests in the first months of life with
insensitivity to pain, anhidrosis, episodes of unexplained fever, and mental
and motor developmental retardation [127]. The skin appears thick, hyper-
keratotic, and callused because of the anhidrosis. Virtual absence of unmy-
elinated fibers has been noted in peripheral nerves [144,145]. Skin biopsy
morphology of patients who have HSAN IV reveals deficient C and A delta
fibers in the epidermis and absent or hypoplastic dermal sweat glands with-
out innervation [146,147]. Intradermal injection or iontophoresis of cholin-
ergic agonists, such as acetylcholine or methacholine, does not produce
direct sweat gland–stimulated or axon reflex–mediated sweating [148].
Frame-shift, splice, and missense mutations have been documented in the
NTRK1 (TRKA) gene located on chromosome 1 (1q21-q22). This gene en-
codes for neurotrophic tyrosine kinase receptor type I, which is autophos-
phorylated in response to nerve growth factor [149].

Hereditary sensory and autonomic neuropathy type V

This rare disorder presents in infancy with loss of pain perception that
leads to acral ulcers, painless fractures, and other trophic injuries. Sudomo-
tor abnormalities are present [150]. A mutation in the NTRK1 gene also
may be responsible for this neuropathy [151].
288 FREEMAN

Fabry’s disease
Fabry’s disease, or angiokeratoma corporis diffusum, is an X-linked, re-
cessively inherited disorder that is associated with deficiency of the enzyme
alpha-galactosidase A (ceramide trihexosidase). The enzyme deficiency re-
sults in the accumulation of ceramide trihexoside and other neutral glyco-
sphingolipids in homozygotes. There is extensive lipid deposition in
various tissues, including the skin, nervous system, vascular endothelium,
kidney, cardiovascular system, and eye [152]. The neurologic manifestations
of this disorder are caused by the deposition of glycolipids in autonomic and
dorsal root ganglia, perineurial cells, and unmyelinated and myelinated
axons [153–155].
The autonomic manifestations include hypo- or anhidrosis, reduced sa-
liva and tear formation, impaired cutaneous flare response to scratch and
histamine, and disordered intestinal motility. Gastrointestinal symptoms
may be as severe as their sensory complaints. The generalized presentation
of the anhidrosis has suggested that sweat gland dysfunction, perhaps
caused by intracytoplasmic inclusions in the eccrine glands, may play
a role in the anhidrosis [156]. Sural nerve biopsies studies have demonstrated
degeneration and loss of unmyelinated fibers [153–155]. Skin biopsies show
decreased intraepidermal small nerve fibers [157]. Fabry’s disease can be di-
agnosed by assaying the enzyme alpha-galactosidase A in leukocytes or skin
fibroblasts [158].
Enzyme replacement therapy leads to a modest improvement in the clin-
ical manifestations of the small-fiber neuropathy associated with this dis-
order. QSART testing may even normalize in some patients; however, no
evidence indicates that these functional changes are associated with im-
provement in intraepidermal innervation [159,160].

Allgrove’s syndrome
Allgrove’s syndrome is an autosomal recessive disorder characterized by
achalasia, alacrima, autonomic impairment, and adrenocorticotropin hor-
mone (ACTH) insensitivity and progressive neurologic dysfunction. Af-
fected individuals have between two and four of these relatively common
symptoms occurring in varying combinations. Because these are relatively
common clinical conditions, individuals with this syndrome may be undiag-
nosed [128]. The pattern of inheritance is autosomal recessive. Most cases of
Allgrove’s syndrome have no family history. A locus on chromosome 12q13
has been identified using genetic linkage analysis in a small number of fam-
ilies [128]. The disorder rarely may be unrecognized until adulthood [161].

Other hereditary autonomic neuropathies

Autonomic neuropathies are associated with several other hereditary
disorders, including Tangier disease [129–131], a sensory and autonomic
 AUTONOMIC PERIPHERAL NEUROPATHY 289

neuropathy with arthropathy that is present in Navajo children [132,133],

and multiple endocrine neoplasia, type 2b [134].

Autonomic neuropathy caused by infectious diseases

The peripheral neuropathies associated with several infectious diseases
have prominent accompanying autonomic manifestations.

Botulism
Botulism is an acute neuromuscular disorder caused by the binding of
a neurotoxin from the anaerobic bacterium, Clostridium botulinum, to the
presynaptic nerve terminal, preventing acetylcholine release [162]. The ill-
ness begins with gastrointestinal manifestations, followed by autonomic
symptoms and a descending paralysis that spreads from the extraocular
and bulbar muscles to the limbs [163–166]. Autonomic symptoms result
from cholinergic dysfunction and include constipation, blurred vision, uri-
nary hesitancy and retention, and dry mouth and eyes. Dilated pupils,
with poor response to light and accommodation, are characteristic auto-
nomic signs. Orthostatic hypotension also may be present. Autonomic
symptoms may occur in botulism, even in the absence of the characteristic
motor and cranial nerve abnormalities [163–165]. Among toxigenic strains
of C botulinum, types A, B, and E account for most human cases [162].
Bowel and bladder symptoms often persist after resolution of the infec-
tion. Diagnosis is based on the clinical and electrophysiologic findings and
is verified by demonstrating neurotoxin in the serum, stool, or contaminated
food or by culturing C botulinum from the stool. Botulism may manifest as
a subacute cholinergic disturbance without associated clinical or electro-
myographic evidence of motor-endplate pathology [167,168]. Treatment in-
volves eliminating sources of toxin. Intravenous trivalent equine antitoxin
can prevent progression and reduce mortality, which remains at approxi-
mately 5% to 15%. Case studies of patients with the subacute onset of cho-
linergic disturbance without associated clinical or electromyographic
evidence of motor-endplate pathology [167] underscore that dysautonomia
may occur in botulism without the typical motor abnormalities [168].

HIV infection
Autonomic dysfunction may occur in patients with HIV infection. Al-
though autonomic dysfunction seems to occur more frequently and with
greater severity in patients who have AIDS, several reports suggest that se-
ropositive patients and patients in the early stages of infection exhibit evi-
dence of dysautonomia. The severity of autonomic dysfunction seems to
constitute a continuum from the early to later stages of HIV infection
[169–172]. In addition to direct virus effects and virus host interactions,
toxins, medications, vitamin deficiency, and malnutrition may play a role
290 FREEMAN

in the manifestations of this syndrome in the later stages of illness. The

symptoms of dysautonomia have included orthostatic hypotension, syn-
cope, presyncope, sweating disturbances, bladder and bowel dysfunction,
and impotence [169]. Autonomic testing reveals sympathetic and parasym-
pathetic nervous system abnormalities [169,173].

Chagas’ disease
Chagas’ disease, which is caused by a parasitic infection by the protozoan
Trypanosoma cruzi, is found predominantly in Latin America. Because of
immigration patterns, there is an increasing incidence of Chagas’ disease
in the United States, and the autonomic manifestations of this disease
should be considered in the differential diagnosis of dysautonomia in non-
endemic areas. Vectorial transmission is the most common mode of infec-
tion in Latin America, whereas in nonendemic areas, transmission via blood
transfusions is more common [174].
Clinical manifestations occur in two stages, the acute and chronic phases
of the disease, which are separated by an indeterminate phase. Acute infec-
tion is characterized by fevers, myalgias, and sweating. Congestive heart
failure may be present. Autonomic abnormalities occur in the chronic phase
of the disease and are characterized by severe gastrointestinal and cardiovas-
cular dysfunction. Gastrointestinal complaints include dysphagia, sialorrhea
and constipation; reduced bowel motility, megaesophagus, and megacolon
are the most frequent gastrointestinal findings. These abnormalities are
caused by denervation of the intrinsic enteric neurons of the submucosal
(Meissner) and myenteric (Auerbach) plexuses [175–177]. Cardiovascular
manifestations include impaired blood pressure response to standing, resting
bradycardia, conduction system abnormalities, arrhythmias, cardiomegaly,
and cardiac failure [178–183]. The pathogenesis of the autonomic dysfunc-
tion is unresolved and may be caused by direct neural injury during the
acute illness, an immune-mediated response, or both.

Leprosy
Autonomic dysfunction is observed in patients with leprous neuropathy
caused by infection by the acid-fast bacillus Mycobacterium leprae. Focal
anhidrosis, which is the best documented autonomic abnormality, occurs
in association with impaired pain and temperature perception in the cooler
regions of the body. These are the earliest neurologic manifestations of lep-
rosy and correlate with the loss of cutaneous innervation [184]. More gener-
alized autonomic symptoms, such as syncope, gustatory sweating, and
erectile dysfunction, also may occur [185].

Diphtheria
A toxin-mediated sensorimotor neuropathy occurs some weeks after pha-
ryngeal or cutaneous diphtheria. Early palatal paralysis in the disease is
 AUTONOMIC PERIPHERAL NEUROPATHY 291

probably a direct effect of diphtheria toxin but can occur at any time be-
tween the first and seventh weeks after infection [186,187]. Accommodation
paralysis, with preserved light responses, is an early manifestation in 10% to
50% of cases [186]. The sparing of the light reflex is a clinical feature that
distinguishes diphtheritic from botulism-related pupillary changes. Tempo-
rary loss of bladder or bowel control has been reported. Resting tachycardia
and an often serious myocarditis are other features. Abnormalities on tests
of cardiac vagal function have been documented [187,188].

Toxic neuropathies
Several industrial and environmental toxins and medications can cause
autonomic neuropathy (see Box 1). Autonomic neuropathy has been re-
ported in individuals exposed to organic solvents [189,190], arsenic [191],
mercury [192], other heavy metals [193], industrial-use acrylamide [194],
thallium [192,195], and the rat poison, Vacor (N-3-pyridylmethyl-N’-para-
nitrophenyl urea) [196].
Autonomic neuropathy also may follow treatment with cytotoxic agents
used in cancer chemotherapy. Clinically evident dysautonomia occurs most
consistently with the vinca-alkaloid, vincristine [197,198]. Autonomic ab-
normalities are also observed in patients treated with cisplatin [199–202]
and paclitaxel [203–206]. There are interindividual differences in susceptibil-
ity to chemotherapy-induced peripheral neuropathies; however, patients
with pre-existing peripheral nerve injury caused by diabetes mellitus, etha-
nol, and inherited and other peripheral neuropathies may show a greater
predisposition to the development of chemotherapy-induced neurotoxicity.
Other medications that may cause autonomic dysfunction include the
anti-arrhythmic agent, amiodarone [207], the coronary vasodilator, perhexi-
line [208], and pentamidine [209].
Marine toxins may affect ion transport, induce channels or pores in neu-
ral and muscular cellular membranes, alter intracellular membranes of
organelles, and release mediators of inflammation. The box jellyfish, partic-
ularly Chironex fleckeri, which is in the Indo-Pacific region, is the world’s
most venomous marine animal and causes severe sympathetic and parasym-
pathetic nervous system dysfunction in exposed patients [210]. Ciguatera
poisoning is the most prevalent marine toxic exposure. Ciguatoxins are po-
tent heat stable, non-protein, lipophilic sodium channel activator toxins that
bind to the voltage sensitive sodium channel. The toxin is stored in the vis-
cera of fish that have eaten the photosynthetic dinoflagellate and is progres-
sively concentrated upwards along the food chain. The initial manifestations
are characteristically sensory and include paresthesias, dysesthesias, and
pain. Autonomic features may be prominent, including hypersalivation, bra-
dycardia, hypotension, mydriasis, and meiosis [210–212]. Intravenous man-
nitol may reverse the acute sensory and autonomic features of ciguatera
toxicity [212].
292 FREEMAN

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