REVIEW ARTICLE

Autonomic Peripheral
Neuropathy

C O N T I N UU M A UD I O
I NT E R V I E W A V AI L A B L E
ONLINE
By Roy Freeman, MBChB

ABSTRACT
Downloaded from http://journals.lww.com/continuum by GAFzbzO5Rnuw5hUjXaSZOw3ZbwlBiJCiZWVyY1bKIJk1mE7IppdHFnp0wxHNkA2hKF9c+EYn+glqRv7BKCFCTU4ZFoj3z1AlcBu5tOBBrKGk86StJP7BZnc8huvopgha on 05/10/2022

PURPOSE OF REVIEW: This article provides a summary of the autonomic

neuropathies, including neuropathies associated with diabetes mellitus,
neuropathies due to amyloid deposition, immune-mediated autonomic
CITE AS:
C O N T I N U U M ( M I N N E AP M I N N ) neuropathies (including those associated with a paraneoplastic syndrome),
2020;26(1, AUTONOMIC DISORDERS): inherited autonomic neuropathies, and toxic autonomic neuropathies. The
58–71.
presenting features, diagnostic investigations, and natural history of these
Address correspondence to
neuropathies are discussed.
Dr Roy Freeman, Center for
Autonomic and Peripheral Nerve
Disorders, Department of
RECENT FINDINGS:Recent findings in autonomic peripheral neuropathy
Neurology, Beth Israel include data on the epidemiology and atypical presentations of diabetic
Deaconess Medical Center, autonomic neuropathy, treatment-induced neuropathy of diabetes
1 Deaconess Rd, Boston, MA
02215, rfreeman@bidmc. mellitus, the presentation of immune-mediated neuropathies, and
harvard.edu. advances in hereditary neuropathy associated with amyloidosis and other
hereditary neuropathies.
RELATIONSHIP DISCLOSURE:
Dr Freeman has received
personal compensation and/or
SUMMARY: Knowledge and recognition of the clinical features of the
stock options for serving on
scientific advisory boards of autonomic neuropathies, combined with appropriate laboratory and
Abide Therapeutics; Applied electrophysiologic testing, will facilitate accurate diagnosis and management.
Therapeutics, Inc; Aptinyx, Inc;
Astellas Pharma; Biogen;
Biohaven Pharmaceuticals;
Chromocell; Cutaneous INTRODUCTION
Neurodiagnostics, LLC; GW

Pharmaceuticals, plc; Ironwood
Pharmaceuticals; Lundbeck;
Mundipharma; NeuroBo
Pharmaceuticals; Novartis;
Pfizer, Inc; Regenacy
Pharmaceuticals; Spinifex
Pharmaceuticals; Theravance
Biopharma; Toray Medical Co,
Ltd; and Vertex Pharmaceuticals.
Dr Freeman has received
personal compensation for
serving as editor-in-chief of
Autonomic Neuroscience: Basic
& Clinical.
UNLABELED USE OF
PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
Dr Freeman reports no
disclosure.
© 2020 American Academy
of Neurology.
T
he autonomic nerve fibers, which are small and lightly myelinated
or unmyelinated, innervate organs and structures involved in
cardiovascular, gastrointestinal, urogenital, thermoregulatory,
sudomotor, pupillary, and immune function. Autonomic symptoms
may be a prominent manifestation in peripheral neuropathies that
selectively or predominantly target these autonomic nerves or may be less
prominent or even subclinical in generalized peripheral neuropathies. Some
peripheral neuropathies may have focal or segmental autonomic manifestations.1
A detailed autonomic history and clinical examination is obligatory in all
patients with peripheral neuropathy, but because autonomic symptoms may be
nonspecific, objective support is often required. Standard neurophysiologic
studies are unable to assess these small unmyelinated or lightly myelinated
nerves as they have a high threshold to electrical stimulation and the evoked
action potentials are small. To counter these challenges, a battery of tests of the
autonomic nervous system has been developed that includes autonomic reflex
assessments, measurement of plasma catecholamines, structural studies of
cutaneous autonomic innervation, and direct measurement of sympathetic nerve
activity. These studies help support a diagnosis of an autonomic neuropathy,

58 FEBRUARY 2020

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define the severity of autonomic dysfunction, and monitor the clinical progression.2 KEY POINT
For more information on testing for autonomic disorders, refer to the article
● A generalized autonomic
“Autonomic History, Examination, and Laboratory Evaluation” by William P. neuropathy typically occurs
Cheshire Jr, MD, FAAN,3 in this issue of Continuum. in the setting of a
generalized diabetic
DIABETIC AUTONOMIC NEUROPATHY polyneuropathy but may
occur in isolation.
The prevalence of diabetes mellitus continues to increase throughout the world.
The Centers for Disease Control and Prevention (CDC) estimates that
30.3 million individuals in the United States have diabetes mellitus (9.3% of the
population), and the prevalence of prediabetes based on fasting glucose or
hemoglobin A1c level is estimated as 84.1 million individuals (33.9% of US adults
aged 18 years or older). In adults aged 65 years or older, nearly half (48.3%) have
prediabetes.4 Worldwide figures are similar: an estimated 425 million adults
(9.0% of the population) have diabetes mellitus.5
The prevalence of peripheral neuropathy and autonomic neuropathy in
diabetes mellitus reflects those numbers. The prevalence of neuropathy is
dependent on the criteria used for diagnosis and the population being studied.
For example, in a cross-sectional community-based population study in Oxford,
England, the prevalence of autonomic neuropathy was 16.7%.6 In this study,
autonomic neuropathy was defined by the presence of one or more abnormal
heart rate variability test results. In a longitudinal, community-based study of
133 patients with newly diagnosed type 2 diabetes mellitus,7 parasympathetic
dysfunction as defined by heart rate variability test abnormalities was present in
4.9% of subjects at the start of the study and in 65% after 10 years of follow-up. In
this study, sympathetic nervous system dysfunction, defined by a systolic blood
pressure fall greater than 30 mm Hg, was present in 24.4% of patients after
10 years of follow-up. In a large study of 557 patients with newly diagnosed type 2
diabetes mellitus, the prevalence of early autonomic neuropathy was 15.3% and
the prevalence of confirmed autonomic neuropathy was 1.8%; no individuals had
severe autonomic neuropathy.7 Two of 557 patients had orthostatic hypotension.
This study defined early cardiac autonomic neuropathy as the presence of one
abnormal or two borderline heart rate tests, confirmed cardiac autonomic
neuropathy as two or more abnormal tests, and severe cardiac autonomic
neuropathy as orthostatic hypotension with two or more abnormal tests.8
Several peripheral neuropathy subtypes cause autonomic dysfunction in
diabetes mellitus, including generalized diabetic autonomic neuropathy,
autonomic neuropathy associated with the prediabetic state,9 and treatment-
induced neuropathy.10 Autonomic impairment also occurs during and after
hypoglycemia.11,12 These autonomic neuropathies are among the major contributors
to the mortality and morbidity associated with diabetes mellitus.13 This article
discusses generalized autonomic neuropathy and treatment-induced neuropathy of
diabetes mellitus. Other autonomic neuropathies associated with diabetes mellitus
include autonomic neuropathy of prediabetes and hypoglycemia-associated
autonomic failure. The interested reader is referred to a review in which all
diabetic autonomic neuropathies are discussed in greater detail.13

Generalized Diabetic Autonomic Neuropathy

Autonomic dysfunction with a generalized diabetic autonomic neuropathy
progresses gradually and may affect cardiovascular, gastrointestinal, urogenital,
sudomotor, and pupillomotor functions; it is usually gradual and progressive.

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AUTONOMIC PERIPHERAL NEUROPATHY

Diabetic cardiovascular autonomic neuropathy results in much of the

morbidity and mortality of diabetes mellitus. Orthostatic hypotension14 occurs
due to impaired vasoconstriction in dependent areas in response to postural
change. Diminished cardiac output, particularly in association with exercise, may
also play a role in the presentation of this disorder.
Several gastrointestinal syndromes occur.15 The underlying pathogenesis is
multifactorial and includes abnormalities in the extrinsic innervation of the
gastrointestinal tract and the intrinsic enteric nervous system combined with
unique site-specific mechanisms. Hyperglycemia may also impair
gastrointestinal function and alter sensory perception. For example, increases in
blood glucose concentration, even within the physiologic postprandial range
(approximately 140 mg/dL), may slow gastric emptying.16 Medications,
including metformin, the α-glucosidase inhibitors (eg, acarbose), the
glucagonlike peptide-1 receptor agonists, sugar alcohols (eg, sorbitol), and the
amylin analogue pramlintide, may produce gastrointestinal symptoms that
mimic autonomic dysfunction. These should be considered in patients presenting
with symptoms referable to the gastrointestinal tract.
Esophageal symptoms are common and include reflux, regurgitation, and
dysphagia, which may result in an increase in the incidence of Barrett esophagus
in patients with diabetes mellitus.15 Diabetic gastroparesis is present in up to 50%
of individuals with diabetes mellitus. Symptoms include nausea, postprandial
vomiting, bloating, abdominal distension and pain, belching, loss of appetite, and
early satiety. The pathophysiologic mechanisms underlying these symptoms
include impaired gastric emptying, impaired gastric accommodation, visceral
hypersensitivity, and gastric dysrhythmia.17 Many patients, however, are
asymptomatic despite documented impaired gastric motility.15
Constipation is a frequently reported gastrointestinal autonomic symptom
and may be found in up to 50% of individuals with diabetes mellitus.18 Diarrhea
and other lower gastrointestinal tract symptoms also occur frequently in
individuals with diabetes mellitus.19 Fecal incontinence due to anal sphincter
incompetence or reduced rectal sensation may occur and may be exacerbated by

CASE 4-1 A 30-year-old woman with type 1 diabetes mellitus diagnosed at 15 years
of age presented with a 2-week history of orthostatic lightheadedness,
diarrhea, and severe distal pain in her arms and legs.
On examination, she had a resting tachycardia with orthostatic
hypotension and postural tachycardia. Sensory examination revealed
impaired pain and temperature sensation to her knees with hyperalgesia
and allodynia.
Her hemoglobin A1c was 6.5%. Three months previously, her hemoglobin
A1c was 18%.

COMMENT The subacute onset of a painful sensory and autonomic neuropathy in

association with a rapid decrease in hemoglobin A1c is the typical
presentation of treatment-induced neuropathy of diabetes mellitus.

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diarrhea. Small intestinal bacterial overgrowth, a consequence of slow intestinal KEY POINT
transit, may be an additional cause of diarrhea.15
● Treatment-induced
Voiding dysfunction is a common complication in diabetes mellitus and occurs neuropathy of diabetes
in more than 80% of patients.20–22 Symptoms include frequency, nocturia, mellitus should be
urinary retention, and incontinence. Urodynamic studies may show bladder considered when a patient
overactivity or hypoactivity. The underlying pathophysiologic mechanisms with diabetes mellitus
presents with the sudden
include afferent and efferent autonomic nerve dysfunction, somatosensory
onset of pain and autonomic
nerve dysfunction, bladder smooth muscle dysfunction, and abnormalities of the dysfunction. This is a
urothelium.21 Mechanism-based therapy may require urodynamic studies. reversible diabetic
Erectile failure is present in up to 75% of men with diabetes mellitus19 and may peripheral neuropathy.
be the earliest symptom of diabetic autonomic neuropathy; it is significantly
associated with an increased incidence of cardiovascular disease.19,23 Ejaculatory
failure is a concomitant manifestation of urogenital neuropathy and may be
accompanied by retrograde ejaculation due to impaired bladder neck closure
during ejaculation.24,25 Few controlled studies of sexual function and genital
autonomic neuropathy in female patients with diabetes mellitus exist. In a
controlled study of 120 patients with type 1 diabetes mellitus, impaired vaginal
lubrication was significantly different in the patients with diabetes mellitus
compared to controls.26
Sudomotor dysfunction manifestations include impaired sweating in a
stocking-glove distribution that can extend to the upper aspects of the limbs and
anterior abdomen27 and gustatory sweating that appears over the face, head,
neck, shoulders, and chest after eating spicy and other foods.28

Treatment-induced Neuropathy of Diabetes Mellitus

Treatment-induced neuropathy is associated with rapidly instituted glycemic
control, typically with a high pretreatment hemoglobin A1c. Reports have
described treatment-induced neuropathy in individuals with type 1 and type 2
diabetes mellitus treated with oral hypoglycemic agents or insulin.10 Autonomic
dysfunction and pain are the cardinal features of this neuropathy and are more
common and severe than in patients with generalized diabetic peripheral
neuropathy. Autonomic manifestations improve over time, particularly in
individuals with type 1 diabetes mellitus. Progression of nephropathy and
retinopathy may occur concomitantly with the onset of treatment-induced
neuropathy. The underlying pathophysiology of treatment-induced neuropathy
and the exacerbation of the retinopathy and nephropathy is not known
(CASE 4-1).

IMMUNE-MEDIATED AUTONOMIC NEUROPATHIES

AND GANGLIONOPATHIES
Typically, immune-mediated autonomic neuropathies are characterized by an
acute or subacute presentation. In many patients, an antecedent event is
identified. Autonomic signs and symptoms may involve both the sympathetic
and parasympathetic divisions of the autonomic nervous system and occur in
varying combinations. Autonomic features include orthostatic hypotension,
sudomotor impairment, gastrointestinal dysmotility, bladder atony, impotence,
secretomotor paralysis, and blurring of vision associated with tonic pupils.29
Sensory manifestation may be a prominent concomitant feature in some
patients.30 Other features include pain, coughing episodes, psychiatric
symptoms, sleep apnea, and aspiration. Acute autonomic and sensory

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AUTONOMIC PERIPHERAL NEUROPATHY

neuropathy is a rare disorder.31 This disorder differs from autoimmune

autonomic ganglionopathy by the presence of various degrees of sensory
impairment. Sensory loss may affect all modalities; may affect the face,
scalp, and trunk; and may be asymmetric and segmental. MRI of the spinal
cord may reveal high-intensity abnormalities in the posterior column on
T2-weighted gradient recalled echo (GRE) images in patients with sensory
ataxia.30
Autoimmune autonomic ganglionopathy due to ganglionic antibodies is
the paradigmatic autoimmune autonomic disorder. The majority of patients
with autoimmune autonomic ganglionopathy have autoantibodies directed
against the α3 subunit of the ganglionic nicotinic acetylcholine receptors.32
Patients typically present with a subacute autonomic neuropathy that can
progress to pandysautonomia.32 The typical clinical findings in autoimmune
autonomic neuropathy include xerostomia, xerophthalmia, orthostatic
hypotension with impaired heart rate response to orthostatic and other stresses,
impaired pupillary response to light and accommodation, gastrointestinal
dysmotility, and urinary retention.33 The presentation is heterogeneous; patients
with higher antibody titers tend to have widespread dysautonomia, whereas
those with lower antibody levels have a more focal or restricted presentation.34
Malignancies such as small cell lung carcinoma, thymoma, bladder carcinoma,
and rectal carcinoma have been associated with the antibodies and phenotypic
presentation.35 Ganglionic antibodies have been reported in patients with the
clinical phenotype of pure autonomic failure.36 Almost 50% of cases with a
subacute presentation are seronegative.32 For more information about
autoimmune autonomic ganglionopathy, refer to the article “Autoimmune
Autonomic Disorders” by Steven Vernino, MD, PhD, FAAS, FAAN,37 in this
issue of Continuum.
The anti-Hu antibody (also known as antineuronal nuclear antibody type 1
[ANNA-1]) is the most common antibody associated with paraneoplastic
syndromes; it characteristically occurs in patients with small cell lung carcinoma,
although it may be seen in patients with other malignancies too.38,39 The
autonomic manifestations may occur in the setting of a widespread
paraneoplastic syndrome. Purkinje cell antibody type 2 (PCA-2)40 and antibodies
to the neuronal cytoplasmic protein collapsin response mediator protein-5
(CRMP-5),41 P/Q voltage-gated calcium channel, voltage-gated potassium channel
complex, and N-methyl-D-aspartate (NMDA) receptor are other antibodies
associated with paraneoplastic syndromes.42,43
An acute or subacute autonomic neuropathy may occur in association with
connective tissue disease. Among these, Sjögren syndrome is the most commonly
reported associated disorder.44 Other collagen vascular disorders that may have
autonomic manifestations include rheumatoid arthritis,45 systemic lupus
erythematosus,45 and mixed connective tissue disease.
The dysautonomia associated with Lambert-Eaton myasthenic syndrome
usually includes prominent cholinergic dysfunction, such as dry mouth, erectile
failure, constipation, blurred vision, and impaired sweating.46 Autonomic test
abnormalities include poorly responsive pupils and sudomotor and secretomotor
failure consistent with cholinergic dysfunction. Adrenergic abnormalities may be
seen in some patients. Antibodies directed against presynaptic P/Q type
voltage-gated calcium channels that impair acetylcholine release may be
detectable. Autonomic dysfunction rarely accompanies myasthenia gravis. In

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42% of these patients, antibodies against neuronal ganglionic nicotinic KEY POINT
acetylcholine receptors are detectable.47
● Prominent autonomic
Autonomic manifestations occur frequently in Guillain-Barré syndrome, features do not occur in
although they are usually overshadowed by the motor features of the disorder. chronic inflammatory
Dysautonomia may be more prominent in patients with respiratory failure, demyelinating
severe motor deficits, and the axonal variant of Guillain-Barré syndrome.48–50 polyradiculoneuropathy
(CIDP), and when patients
Occasionally, autonomic features are the presenting feature of the syndrome.51
present with such features,
In contrast, autonomic manifestations of chronic inflammatory demyelinating alternative diagnoses should
polyradiculoneuropathy (CIDP) are typically subclinical and require autonomic be considered. The
testing for detection.52 The presence of prominent autonomic features, cardiac peripheral neuropathy
associated with hereditary
hypertrophy, gastrointestinal problems, inexplicable weight loss, carpal tunnel
amyloidosis is sometimes
syndrome, renal impairment, or ocular disease in a patient with CIDP are red misdiagnosed as CIDP,
flags suggesting that alternative diagnoses should be sought, in particular particularly in nonendemic
hereditary amyloidosis, which is frequently misdiagnosed as CIDP.53–55 areas.

AMYLOID NEUROPATHY
Amyloidosis is a generic term used to describe the deposition of insoluble,
low-molecular-weight fibrillar proteins in a beta-pleated sheet configuration
within the extracellular space of various tissues and organs. Amyloid fibrils are
rigid, linear, and nonbranching. They measure approximately 7.5 nm to 10 nm
in width. The structure of the beta-pleated sheet permits Congo red stain
binding, which emits a characteristic apple-green birefringence. Both primary
immunoglobulin light chain (AL) amyloidosis and hereditary transthyretin
amyloidosis with neuropathy (also known as familial amyloid polyneuropathy)
may result in a peripheral neuropathy.

Primary (AL) Amyloidosis

Outside the areas endemic for hereditary transthyretin amyloidosis, primary
(AL) amyloidosis is the most common form of amyloidosis in the Western world.
In the United States, 4500 new cases occur each year. In this disorder, a
monoclonal population of bone marrow plasma cells produce kappa or lambda
type immunoglobulin light chains or light chain fragments. These aggregate and
deposit as amyloid.56–58 AL amyloidosis may be preceded by an increase in serum
levels of free light chains.
The characteristic presentation is nonspecific symptoms such as weight loss
and fatigue accompanied by more specific features such as hepatomegaly,
macroglossia, cutaneous ecchymoses, nonischemic cardiomyopathy with
hypertrophy on echocardiogram, and nondiabetic nephrotic-range proteinuria.56
Autonomic involvement of the cardiovascular, gastrointestinal, and urogenital
systems is common. The most common presentation may be autonomic
dysfunction accompanied by pain and a length-dependent generalized
polyneuropathy.59 Evaluation of AL amyloidosis is by immunofixation
electrophoresis of serum and urine and serum free light chain assay. If normal,
AL amyloidosis is unlikely. If positive, the diagnosis should be confirmed
pathologically by bone marrow, fat aspirate, or lip biopsy.56
Treatment with melphalan and corticosteroids (dexamethasone or
prednisolone) was first introduced almost 50 years ago. This treatment improves
survival, particularly when associated with a reduction in serum or urine
monoclonal protein. Stem cell transplantation may improve survival further,
although this therapy is not suitable for all patients.56 Newer chemotherapy

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AUTONOMIC PERIPHERAL NEUROPATHY

regimens include the immunomodulating drugs thalidomide and lenalidomide;

the proteasome inhibitor bortezomib, combined with alkylating agents such
as melphalan and cyclophosphamide, may improve survival further.56,60 A
neurotoxic side effect of these drugs is a small fiber and autonomic neuropathy.61

Hereditary Transthyretin Amyloidosis

Hereditary transthyretin amyloidosis with neuropathy is a manifestation of
hereditary transthyretin amyloidosis, a progressive, debilitating, multisystem,
life-threatening disease caused by the deposition of misfolded transthyretin in
tissues throughout the body. The exact prevalence of hereditary transthyretin
amyloidosis is not known; estimates suggest a worldwide prevalence of 50,000,
with an estimated prevalence of hereditary transthyretin amyloidosis with
neuropathy of approximately 10,000.
The hereditary amyloidoses are autosomal dominant inherited diseases in
which the amyloid precursor is a mutant protein. Mutant transthyretin is a
14-kDa 127 amino acid polypeptide that serves as the transport protein for
thyroxine and retinol-binding protein; it is the most common cause of hereditary
amyloidosis. It is encoded by a single gene on chromosome 18. Hereditary
amyloidosis is associated with more than 120 mutations of the TTR gene.62,63 The
most commonly observed mutation is a substitution of methionine for valine at
position 30 (Val30Met).64,65 This is the predominant variant found in Portugal,
Brazil, and Sweden. Other TTR variants are seen in Japan, Europe, and the
Americas. Less frequently, hereditary amyloidosis is caused by mutations in the
genes encoding for apolipoprotein A-I, fibrinogen Aα, lysozyme, and gelsolin.66
Hereditary transthyretin amyloidosis typically has an insidious onset in the
third to fifth decades. Autonomic manifestations are prominent and may be the
presenting feature of the neuropathy. These include orthostatic intolerance;
upper gastrointestinal symptoms such as nausea, bloating, and early satiety; lower
gastrointestinal symptoms such as constipation, diarrhea, and fecal incontinence;
bladder disturbances; and erectile failure.59 Sensory symptoms such as numbness,
pain, paresthesia, and dysesthesia also occur early in the disease course.
Phenotypic differences exist, even among individuals carrying the same
mutation. These differences depend in part on geographic location. A spectrum
of clinical presentations exist that are only partly related to the mutation. In some
regions, for example, the clinical phenotype of patients with Val30Met
hereditary transthyretin amyloidosis may differ from those seen in Portugal. The
sporadic Japanese patients with hereditary transthyretin amyloidosis outside the
endemic foci exemplify the phenotypic diversity. These patients are older at
presentation; the initial symptom is lower extremity paresthesia, and autonomic
features are mild with prominent large fiber sensory loss. The male to female
ratio is high (>10:1), and the penetrance very low.54,67,68
A pathogenic mutation can be detected in hereditary transthyretin
amyloidosis by TTR gene sequencing. Pathologic confirmation requires
histologic confirmation of amyloid deposition. Recent reports suggest that the
skin biopsy technique may detect cutaneous amyloid deposition.69 Mass
spectrometry–based proteomics is of growing importance in the diagnosis and
typing of AL and hereditary amyloidoses. This technique shows high specificity
but limited sensitivity in the diagnosis of transthyretin amyloidosis.70
Preliminary reports suggest that magnetic resonance neurography may
contribute to the diagnosis too.71

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 Orthotopic liver transplant, which removes the principal source of variant KEY POINTS
transthyretin and reduces circulating transthyretin by up to 90%, was the initial
● The peripheral
treatment for hereditary amyloidosis. Data from multiple centers show that this neuropathy associated with
intervention improves neurophysiologic measures, nerve morphology, and hereditary transthyretin
survival.72 However, pharmacotherapeutic interventions that inhibit amyloidosis has a
amyloidogenesis are available. Two RNA-targeted interventions have shown heterogeneous
presentation, even within
efficacy in clinical trials.73,74 Both bind to the 3′ untranslated region of TTR
families in endemic areas.
mRNA and thus avoid mutations in the coding region. Patisiran, a small
interfering RNA delivered as an IV infusion every 3 weeks, and inotersen, an ● When autonomic features
antisense oligonucleotide administered subcutaneously 3 times a week on occur in combination with
alternate days in the first week and then once weekly for 64 weeks, have received peripheral nerve excitability
and neuropsychiatric
regulatory approval by the US Food and Drug Administration (FDA). Other features such insomnia,
pharmacologic interventions include the mutant transthyretin stabilizers agitation, hallucinations, and
tafamidis75 and diflunisal.76 memory loss, antibodies to
the voltage-gated potassium
channel complex protein
PERIPHERAL AUTONOMIC CHANNELOPATHIES should be considered.
Autonomic manifestations may be present in patients with small fiber
neuropathies associated with ion channel mutations. Several reports have ● Among the hereditary
drawn attention to the presence of gain-of-function variants in the genes sensory and autonomic
neuropathies (HSANs),
encoding sodium channels NaV1.7 (SCN9A),77–79 NaV1.8 (SCN10A),80,81 and
autonomic manifestations
NaV1.9 (SCN11A),82 in some patients with small fiber neuropathy. These are most prominent in HSAN
voltage-gated sodium channel isoforms are preferentially expressed on III (also known as Riley-Day
sensory neurons. Proexcitatory changes in channel physiology and syndrome or familial
dysautonomia). HSAN III is
consequent hyperexcitability are seen on functional analyses of these
caused by homozygous
mutations.77 mutations in the ELP1 gene.
Autonomic features, including dry mouth and eyes, reduced urinary
sensation, hesitation, orthostatic dizziness, hyperhidrosis, palpitations, and ● Chemotherapeutic agents
alternating constipation and diarrhea, were present in some patients harboring are the most common cause
of a toxic autonomic
the SCN9A mutation.77 Similar, although less prominent, clinical manifestations neuropathy. Predisposing
have been reported in patients harboring mutations in the genes encoding factors to a chemotherapy-
Nav 1.8 (SCN10A) and Nav1.9 (SCN11A) mutations.80,81 induced peripheral
Similarly, autonomic manifestions are a frequent accompaniment to neuropathy include genetic
factors and an underlying
antibodies to the voltage-gated potassium channel complex, in particular, clinical or subclinical
contactin-associated proteinlike 2 (CASPR2) and leucine-rich glioma peripheral neuropathy.
inactivated protein 1 (LGI1).83–85 In a series of 29 patients with Morvan
syndrome, autonomic manifestations were a common accompaniment to the
neuromyotonia and neuropsychiatric features. Autonomic features included
orthostatic hypotension, tachycardia, hyperhidrosis, sialorrhea, and urinary
incontinence (CASE 4-2).

HEREDITARY AUTONOMIC NEUROPATHIES

Autonomic manifestations occur to a varying degree in the inherited autonomic
neuropathies. These inherited neuropathies include a diverse group of disorders
classified as the hereditary sensory and autonomic neuropathies (HSANs).
HSAN I is an autosomal dominant hereditary sensory radiculoneuropathy that
presents in the second decade. Causative mutations have been identified in five
genes (SPTLC1, SPTLC2, ATL1, RAB7A, and DNMT1).86 HSAN II, also known as
congenital sensory neuropathy, is an autosomal recessive or sporadic disorder
that presents in infancy or early childhood. Mutations in WNK1, RETREG1, and
KIF1A have been associated with HSAN II.86

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AUTONOMIC PERIPHERAL NEUROPATHY

HSAN III (also known as Riley-Day syndrome or familial dysautonomia), a

rare autosomal recessive disorder seen primarily in children of Ashkenazi Jewish
descent, has prominent autonomic manifestations. The incidence of familial
dysautonomia is 1 in 3700 live births among Ashkenazi Jews, and the carrier
frequency is 1 in 32 individuals.87
HSAN III is caused by homozygous mutations in the ELP1 gene, which
encodes elongator complex protein 1 (ELP1, also known as IκB kinase
complex–associated protein).88 HSAN III presents in infancy. Abnormal
development of primary sensory nerves underlies the disorder, resulting in
reduced pain and temperature sensation, absent deep tendon reflexes, and gait
ataxia.89 Impaired mechanosensory and chemosensory neuronal development
results in baroreflex and chemoreflex dysfunction, leading to orthostatic
hypotension, paroxysmal hypertension, and abnormal control of cardiovascular
function and ventilatory responses to hypoxia and hypercapnia.87,90 Other
clinical manifestations include absence of tears, hypoactive corneal reflexes, and
absence of lingual fungiform papillae. Poor sucking and feeding, esophageal
reflux with vomiting and aspiration, and swallowing dyscoordination may be the
first clinical manifestations.87
HSAN IV (also known as congenital insensitivity to pain with anhidrosis
[CIPA] or hereditary sensory neuropathy with anhidrosis) is the second most
common HSAN. This autosomal recessive disorder manifests in the first months
of life. Features include insensitivity to pain, anhidrosis, episodes of unexplained
fever, and intellectual and motor developmental delay. Missense, nonsense,
frameshift, and splice-site loss-of-function mutations in the NTRK1 (TRKA)
gene are associated with this disorder. In humans, this gene encodes a high-
affinity tyrosine kinase receptor for nerve growth factor (NGF).91 HSAN V is
caused by a homozygous missense or frameshift mutation in NGF, which encodes
β-NGF. The clinical presentation is characterized by loss of pain perception and
consequent acral ulceration, painless fractures, and other trophic injuries.92

CASE 4-2 A 45-year-old man presented with a 3-month history of orthostatic

hypotension, hyperhidrosis, and muscle cramps. He reported a 13.6-kg
(30-lb) weight loss, insomnia, and confusion.
On examination, he was disoriented and showed executive function
impairment. He had orthostatic hypotension with inadequate
compensatory tachycardia. Myokymia was visible in his calves. Distal
sensory loss was present, with hyperalgesia and allodynia.
Screening laboratory testing was normal. Nerve conduction studies
and EMG showed peripheral nerve hyperexcitability and myokymia. CT of
the chest and abdomen was normal. Antibodies to the voltage-gated
potassium channel–related protein contactin-associated proteinlike 2
(CASPR2) were elevated.

COMMENT This case shows the presentation of a patient with Morvan syndrome. The
combination of peripheral and central nervous system manifestations with
elevated CASPR2 antibodies is characteristic of the disorder.

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 Other inherited disorders associated with autonomic dysfunction include Fabry
disease (also known as angiokeratoma corporis diffusum)93 and Allgrove syndrome.94

TOXIC NEUROPATHIES
A number of iatrogenic, industrial, and environmental toxins are implicated in
autonomic neuropathies (TABLE 4-1). Chemotherapeutic agents are the most
common iatrogenic cause. Clinically evident dysautonomia occurs with the vinca
alkaloids; platinum derivatives; taxanes; proteasome inhibitors such as bortezomib;
immunomodulatory agents such as thalidomide, lenalidomide, and pomalidomide;
the epothilones; doxorubicin; and cytosine arabinoside.61,95 Chemotherapeutic
agents are the most common cause of a toxic autonomic neuropathy. Predisposing
factors to a chemotherapy-induced peripheral neuropathy include genetic factors
and an underlying clinical or subclinical peripheral neuropathy.
In addition, industrial, environmental, and marine toxins may cause an
autonomic neuropathy. These include organic solvents, arsenic, mercury, other
heavy metals, industrial-use acrylamide, and thallium.96 Marine toxins such as
ciguatera may affect ion transport, induce channels or pores in neural and
muscular cellular membranes, alter intracellular membranes of organelles, and
release mediators of inflammation.97

Some Toxic Neuropathies TABLE 4-1

Organic Solvents (eg, n-Hexane)

Acrylamide
Heavy Metals (eg, Lead, Arsenic, Thallium, Mercury)
N-3-Pyridylmethyl-N′-p-Nitrophenyl Urea Rat Poison (of Historic Relevance)
Iatrogenic
◆ Chemotherapeutic agents
◇ Vinca alkaloids
◇ Platinum derivatives
◇ Taxanes
◇ Epothilones
◇ Bortezomib
◇ Thalidomide, lenalidomide, pomalidomide
◇ Doxorubicin
◇ Cytosine arabinoside
◆ Other medications
◇ Perhexiline maleate
◇ Amiodarone
◇ Pentamidine
◇ Gold
◇ Podophyllin
Marine Toxins (eg, Ciguatera)

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AUTONOMIC PERIPHERAL NEUROPATHY

CONCLUSION
Autonomic neuropathies are highly prevalent and result in diverse clinical
manifestations that affect the cardiovascular, urogenital, gastrointestinal, and
sudomotor systems. Many peripheral neuropathies also have subclinical
autonomic manifestations. Knowledge and recognition of the clinical features of
the autonomic neuropathies combined with the appropriate laboratory and
electrophysiologic testing will facilitate accurate diagnosis. The availability of
effective treatments for some of these neuropathies, for example, the
immune-mediated neuropathies and those associated with hereditary
transthyretin amyloidosis, has given added impetus to clinical recognition and
accurate diagnosis.

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