Diabetes and Metabolic Disorders and The Peripheral Nervous System

Diabetes and Metabolic REVIEW ARTICLE

Disorders and the C O N T I N U UM A U D I O
I NT E R V I E W A V A I L AB L E
ONLINE
Peripheral Nervous
System
By Christopher H. Gibbons, MD, MMSc, FAAN
ABSTRACT
PURPOSE OF REVIEW: This
article provides an up-to-date review of the
manifestations of neuropathy seen in the setting of diabetes and other
metabolic disorders.
RECENT FINDINGS: Although a number of metabolic disorders cause or are

associated with peripheral neuropathy, the neuropathies associated with CITE AS:
glucose dysregulation make up the vast majority of cases. Recent CONTINUUM (MINNEAP MINN)
2020;26(5, PERIPHERAL NERVE AND
investigations have determined major differences in the neuropathies
MOTOR NEURON DISORDERS):
associated with type 1 and type 2 diabetes. Neuropathy in type 1 diabetes is 1161–1183.
closely linked to glycemic control, whereas neuropathy in type 2 diabetes
is linked to dyslipidemia, central obesity, hypertension, insulin resistance, Address correspondence to
Dr Christopher Gibbons, Center
and glucose control. Although length-dependent axonal distal symmetric for Autonomic and Peripheral
polyneuropathy is the most common clinical presentation, diabetes is also Nerve Disorders, Beth Israel
associated with acute, asymmetric, painless, and autonomic neuropathies. Deaconess Medical Center,
1 Deaconess Rd, Palmer 111,
Boston, MA 02215,
SUMMARY: The prevalence of diabetes and metabolic syndrome is increasing cgibbons@bidmc.harvard.edu.
across the globe. The need to recognize and treat the wide array of clinical
RELATIONSHIP DISCLOSURE:
manifestations of neuropathy detected in individuals with metabolic Dr Gibbons has received
disorders will continue to grow. As a consequence, an increasing number personal compensation for
serving as a scientific advisor for
of well-trained physicians who can manage these patients is needed. At Lundbeck and Theravance
present, treatment is largely focused on prevention and symptomatic Biopharma and as an associate
management. Investments into funding for both basic and clinical science editor for Autonomic
Neuroscience: Basic and
are necessary to bring novel therapeutic interventions into clinical practice. Clinical, research/grant support
from Grifols, and publishing
royalties from UpToDate, Inc.
Dr Gibbons has held stock/
INTRODUCTION stock options in Cutaneous
D
iabetes includes a group of disorders of abnormal carbohydrate Neurodiagnostics, LLC, and has
given expert medical testimony.
metabolism that result in hyperglycemia due to a range of conditions
that include impaired insulin secretion or insulin resistance, or both.1 UNLABELED USE OF
Type 2 diabetes is the most common form of diabetes (>90%) and is PRODUCTS/INVESTIGATIONAL
USE DISCLOSURE:
characterized by increased insulin secretion in the setting of Dr Gibbons reports no
increasing peripheral insulin resistance. In contrast, type 1 diabetes is seen in 5% disclosure.
to 10% of cases of diabetes and is due to the autoimmune destruction of pancreatic
beta cells with subsequent insulin deficiency.1 Diagnostic criteria for type 1 and © 2020 American Academy
type 2 diabetes are reviewed in TABLE 2-1.2 It should be noted that a number of of Neurology.
CONTINUUMJOURNAL.COM 1161
Copyright © American Academy of Neurology. Unauthorized reproduction of this article is prohibited.

DIABETES AND METABOLIC DISORDERS
other forms of diabetes exist, including genetic defects in pancreatic beta cell
function, genetic defects in insulin activity, diseases that cause pancreatic
damage, endocrinopathies with diabetes as a component, chemical toxicities,
infections, immune-mediated disorders, and other genetic diseases.1 At present,
approximately 425 million people worldwide have a diagnosis of diabetes.3
OVERVIEW AND EPIDEMIOLOGY OF DIABETIC NEUROPATHIES

Neuropathy is one of the most prevalent, debilitating, and costly complications
of diabetes. More than 400 million people worldwide have diabetes, including
nearly 10% of Americans, highlighting the major potential health impacts both
individually and as a society.4 Diabetic neuropathy is one of the more challenging
disorders to recognize and treat because of the myriad clinical manifestations
that can occur. Because of the heterogeneity in symptoms and signs of
neuropathy, it is critical to define the potential involvement of neuropathy across
the nervous system and to understand the different pathophysiologic mechanisms
that may be involved across the types of diabetes and types of neuropathy.4–6
To distill this information into a digestible format, this article begins with a
general discussion of the pathophysiology of diabetes and neuropathy, with
subsequent sections focusing on the unique clinical manifestations of different
forms of neuropathy with attention to how a clinician can recognize and manage
each form. Uremic neuropathy is discussed separately.
Diabetic neuropathies encompass a broad range of conditions. The
neuropathies associated with diabetes generally fall into five categories:
u Length-dependent axonal polyneuropathy, the most common form; may be characterized

by differential injury to small-diameter unmyelinated axons, large myelinated axons, or both
u Acute diabetic neuropathies, including both radiculoplexus and treatment-induced
neuropathies
u Mononeuropathies involving individual cranial or peripheral nerves
u Autonomic neuropathies, which cause a range of symptoms depending on the end organ
involved
u An increase in risk for chronic inflammatory demyelinating polyradiculoneuropathy (CIDP)4–6
TABLE 2-1 American Diabetes Association Criteria for the Diagnosis of Diabetesa
Test Result
Fasting plasma glucose (FPG) Diabetes: FPG values ≥126 mg/dL (7.0 mmol/L)
Prediabetes: FPG values 100–125 mg/dL (5.6–6.9 mmol/L)
2-Hour oral glucose tolerance test Diabetes: 2-hour plasma glucose values of ≥200 mg/dL (11.1 mmol/L) during a 75-g
(OGTT) OGTT
Prediabetes: 2-hour plasma glucose values of 140–199 mg/dL (7.8–11.0 mmol/L) during
a 75-g OGTT
Glycosylated hemoglobin (A1c) Diabetes: A1c values ≥6.5% (48 mmol/mol)
Prediabetes: A1c values 5.7 to <6.5% (39–48 mmol/mol)
a
Data from the American Diabetes Association.2
1162 OCTOBER 2020

The epidemiologic data describing the neuropathies in diabetes are KEY POINTS
challenging to interpret, largely because of the varied clinical manifestations
● A number of
and the tendency for studies to investigate a particular neuropathy of interest manifestations of
(eg, length-dependent axonal neuropathy, cardiovascular autonomic neuropathy are seen in
neuropathy, or gastrointestinal autonomic neuropathy). Specific details of diabetes, including
epidemiology are provided within each of the neuropathy subsections of this length-dependent
neuropathy, acute
article, although several overarching themes are seen. It is important to
generalized or focal
recognize that both type 1 and type 2 diabetes carry a high risk of neuropathy neuropathies,
development, but they are distinct disorders.6 The underlying pathophysiology mononeuropathies, and
of neuropathy is different between the two. Neuropathy related to type 1 autonomic neuropathies.
diabetes is directly linked to glycemic control. Extensive literature has
● The risk of neuropathy in
established the clear connection between hyperglycemia and neuropathy type 1 diabetes is primarily
development in individuals with type 1 diabetes and that aggressive glycemic linked to glucose control,
control will reduce the risk of neuropathy development in the short term and whereas the risks of
carry significant long-term benefit.6 Optimal glycemic control in type 1 diabetes neuropathy in type 2
diabetes include glucose
reduces the relative risk of neuropathy development by 78%.4 In contrast, control, hyperlipidemia,
although still an important risk factor, hyperglycemia is much less important hypertension, abdominal
in the pathogenesis of neuropathy in type 2 diabetes. In type 2 diabetes, intensive obesity, low levels of
glycemic control only reduces the risk of neuropathy by 5% to 9%.4 Increasing high-density lipoproteins,
and tobacco use.
evidence indicates that individual components of the metabolic syndrome,
including hypertriglyceridemia, hypertension, abdominal obesity, low levels of ● Approximately half of
high-density lipoproteins, and tobacco use, are important determinants of patients with diabetic
neuropathy risk and progression.5,6 neuropathy have
neuropathic pain; however,
Type 1 diabetes accounts for approximately 5% to 10% of total cases of
it is important to recognize
neuropathy, although that number is decreasing over time as the magnitude of that the absence of pain
the public health epidemic of type 2 diabetes continues to grow. The does not rule out a
prevalence of neuropathy in the population of individuals with diabetes is neuropathy.
similar between those with type 1 and type 2 diabetes, ranging from 10% to
● Small unmyelinated axons
50% depending on how neuropathy is defined, although the onset is much are affected earlier than
earlier in disease duration in those with type 2 diabetes.4 The prevalence of large fibers in most cases of
neuropathy in a cohort of individuals with well-controlled type 2 diabetes axonal neuropathy in type 2
increased from 8% to 42% over 10 years; in contrast, in a cohort of individuals diabetes, so an examination
should always include
with poorly controlled type 2 diabetes, the prevalence of neuropathy increased testing for signs of small
from 0% to 68% over 4 years. fiber dysfunction (thermal or
Pain is a common comorbidity in diabetic neuropathy, seen in approximately pain sensation) as well as
30% of cases. Pain varies across the neuropathy phenotype but is most often large fiber function
(reflexes, vibration
seen in length-dependent and acute neuropathies. Risk factors for the
detection).
development of neuropathic pain in diabetic neuropathy are poorly understood,
but female sex and more advanced neuropathy are recognized risk factors.
Metabolic risk factors for pain include poor glycemic control, impaired renal
function, and elevated body mass index. For more information on the treatment
of neuropathic pain, refer to the article “Management of Neuropathic Pain in
Polyneuropathy” by Amanda C. Peltier, MD, MS, and Derek Wood, MD,7 in this
issue of Continuum.
DISTAL SYMMETRIC POLYNEUROPATHY OF DIABETES

Distal symmetric polyneuropathy (DSPN) is the most common clinical
presentation of neuropathy in diabetes. Accounting for roughly 50% to 75% of
cases of diabetic neuropathy,4 DSPN is the classic chronic and length-dependent
neuropathy associated with diabetes. Increasing evidence indicates that early

DSPN in type 2 diabetes (or even prediabetes) preferentially involves small

unmyelinated axons, frequently causing neuropathic pain, and gradually
progresses to more involvement of large myelinated axons over time.8
Longitudinal information gathered from DCCT (the Diabetes Control and
Complications Trial) and the EDIC (Epidemiology of Diabetes Interventions
and Complications) study show that approximately 20% of individuals with
type 1 diabetes develop DSPN after 20 years of diabetes and that glycemic control
is the major modifiable risk factor for disease progression.9 In contrast, 15% or
more of patients with type 2 diabetes have DSPN at the time of diagnosis,
a number that increases to 50% over 10 years.4 The risk factors for disease
progression in type 2 diabetes include glucose control, tobacco use, weight,
and lipid levels.4,6
The diagnosis of DSPN in diabetes is based on history, clinical examination
findings, and nerve conduction studies in select cases. The appropriate clinical
CASE 2-1 A 47-year-old woman with an 8-year history of type 2 diabetes and
chronically elevated glucose levels, with hemoglobin A1c values in the 8%
to 9% range, presented to her primary care doctor with an infection in the
bottom of her right great toe, with osteomyelitis. She did not routinely
seek preventive care and had not noticed the injury, so it was fairly
advanced by the time she sought medical attention. She was referred for
a neurologic consultation for evaluation of an acute asymmetric neuropathy
(the ulcer occurred only in the right foot, and she had never reported
neuropathy symptoms). She reported no symptoms of pain in either foot
and had not noticed anything wrong with her feet until she found the injury
on her toe. Upon direct questioning, she said she had not noticed the
sensation of the cold tile bathroom floor on her feet in many years.
On examination, she had normal strength, except for 4/5 strength at the
extensor hallucis longus bilaterally. She had reduced patellar and absent
ankle reflexes. Sensory examination revealed absent vibration, pinprick,
and temperature sensation at the great toes, with a graded increase in
sensation to the midshin of both legs. She had reduced proprioception in
the toes and reduced light touch in the feet. She also had loss of hair and
venous stasis changes in the lower limbs.
COMMENT This is a typical clinical presentation for a patient with a painless

length-dependent distal symmetric polyneuropathy in the setting of
diabetes. It is critical to screen patients with diabetes annually by history
and examination for evidence of neuropathy to detect the development of
neuropathy in a timely manner. In this case, education about foot care and
safety is critical, as is more aggressive treatment of glucose, lipids, and
blood pressure. Now that the patient is aware of the risks, she is more likely
to take an active role in her health care. Unfortunately, established distal
symmetric polyneuropathy is irreversible, so it is important to prevent
further neuropathy progression by aggressively addressing all modifiable
risk factors.
1164 OCTOBER 2020

evaluation for DSPN includes, but is not limited to, examination of muscle KEY POINTS
strength, deep tendon reflexes, and sensation (vibration, proprioception,
● The presence of atypical
thermal, pain, and light touch sensation). The presence of atypical features such features in a patient with
as significant asymmetry, an acute onset, or early motor involvement suggests a suspected distal symmetric
different neuropathy type or diagnosis and should prompt further diagnostic polyneuropathy, such as a
evaluation, including nerve conduction studies and EMG. Although DSPN is significant asymmetry, an
acute onset, or early motor
generally symmetric (by definition), symptoms may initially be reported in one
involvement, suggests a
limb and then gradually evolve into a symmetric pattern over time. However, a different neuropathy type or
significant asymmetry on neurologic examination is unusual and should prompt diagnosis and should
additional testing.4–6 prompt further diagnostic
evaluation, including nerve
The clinical features of the neuropathy typically reflect the underlying
conduction studies and
pathophysiology. The “dying back” neuropathy that occurs in the setting of EMG.
length-dependent axonal dysfunction due to metabolic disturbance presents as
numbness and positive sensory symptoms (paresthesia or neuropathic pain) in ● Nerve conduction studies
the most distal parts of the body first (eg, the feet) and then progresses up the leg and EMG are not required as
part of the routine diagnosis
as more proximal nerve fibers are damaged. Some patients present with pain in of distal symmetric
the distribution of the neuropathy (approximately 25% to 35%), whereas other polyneuropathy in diabetes
patients are asymptomatic (CASE 2-1). Unless routine neuropathy screening of unless atypical features are
patients with diabetes occurs, many patients may progress to an advanced present.
neuropathy and present with a complication (foot ulcer or injury) that could
● The diagnosis of distal
have been avoided. Patients with neuropathic pain in the setting of DSPN symmetric polyneuropathy
typically present much earlier in the disease course than those without pain. The provides a valuable
diagnosis of DSPN in diabetes can be classified as small fiber predominant, large opportunity to educate
patients on the health
fiber predominant, or mixed, depending on the combination of clinical
benefits of addressing risk
symptoms and signs.4–6 factors associated with
Although nerve conduction studies and EMG have traditionally been a neuropathy (glucose
component of the diagnosis of neuropathy, recent studies have questioned control, hyperlipidemia,
whether these results have changed clinical management.10 Neurophysiologic hypertension, tobacco use),
advocate for exercise, and
testing should be performed in individuals with atypical clinical presentations, in counsel on the importance
which the differential diagnosis still includes radicular, entrapment, or of proper foot care.
demyelinating neuropathies.
The management of DSPN in diabetes largely involves education about the
underlying problem. In many individuals, neuropathy may be the first
complication of diabetes, and this can be a wake-up call to the consequences
of unmanaged risk factors. The initial diagnosis of neuropathy offers an
opportunity to educate patients (and their treating physicians) about the need
to improve glycemic control, to more aggressively manage lipids and blood
pressure, and to counsel on tobacco cessation (in both type 1 and type 2
diabetes). Advocating for an increase in exercise is also a critical component
to successful treatment. Finally, all patients with DSPN should be counseled
on foot care to reduce the risk of foot ulceration or amputation. All patients
with diabetes should have protective sensation evaluated using a 10-gram
monofilament by applying the filament to the great toe until the filament
bends (FIGURE 2-1).11 Those unable to detect 7 of 10 applications are at
significantly elevated risk for painless injury and should be referred for
appropriate podiatric foot care. Patients should always wear hard-soled shoes
(to prevent stepping on something sharp or inadvertently injuring an
insensate foot), should make sure to check their feet at least once daily, and
should have a very low threshold for seeking medical attention in the setting
of a foot injury.

NEUROPATHY ASSOCIATED
WITH METABOLIC
SYNDROME AND
PREDIABETES
Prediabetes (impaired fasting
glucose or impaired glucose
tolerance) may precede the
diagnosis of type 2 diabetes by
several years. The American
Diabetes Association’s definition
of prediabetes is a hemoglobin
A1c level of 5.7% to 6.4%.12
Metabolic syndrome consists of
five components: glucose
dysregulation due to insulin
resistance (which includes the
diagnosis of prediabetes or
diabetes), elevated serum
triglycerides, reduced
high-density lipoprotein level,
central obesity, and
hypertension. In general, the
presence of three of the five
components of metabolic
syndrome is required for
diagnosis.12
At present, it is estimated
that more than 1 in 3 adults in
the United States and almost
1 billion people worldwide have
prediabetes.3,13 The prevalence of
FIGURE 2-1
The proper technique for testing pressure
neuropathy in prediabetes is
perception with the 10-gram monofilament. approximately 10%, and among
Patients should close their eyes while being individuals with otherwise
tested. The monofilament is placed perpendicular “idiopathic” neuropathy, the
to the skin (A) and pressure applied until the
monofilament bends (B). The monofilament
presence of prediabetes is
should be held in the bent position for 1 second approximately 25%.14,15 A
and then released. Testing sites include the first, growing body of literature links
third, and fifth metatarsal heads and the plantar metabolic syndrome with DSPN
surface of the distal hallux on each foot (C). Loss
risk. In many cases, a diagnosis
of ability to detect the monofilament at one or
more sites indicates neuropathy with a high risk of of DSPN can be made at the
foot ulceration. time of diagnosis of type 2
diabetes, strongly supporting
the evidence of ongoing
neuropathy development in the preceding years.12 The clinical manifestations
of DSPN in the setting of prediabetes and metabolic syndrome largely mirror
the clinical presentation of DSPN in type 2 diabetes, albeit at an earlier stage of
neuropathy severity. In most cases, patients have a length-dependent axonal
neuropathy that selectively targets small-diameter unmyelinated axons.
Clinically, this may present with small fiber sensory neuropathy that may be
1166 OCTOBER 2020

either painful or painless (CASE 2-2). A smaller number of patients may KEY POINT
present with autonomic dysfunction, primarily manifesting as reduced
● The risks associated with
cardiovagal function with a resting tachycardia and reduced exercise neuropathy development
tolerance. The reason that small unmyelinated fibers are more prone to exist in the prediabetes
damage has not been fully identified. state. The individual
components of the
metabolic syndrome,
PATHOPHYSIOLOGY OF DIABETIC NEUROPATHY
including glucose
At present, our understanding of the pathophysiology of diabetic neuropathy dysregulation/insulin
is incomplete, and the etiology is most likely multifactorial. Several putative resistance, dyslipidemia
mechanisms involving derangements of normal metabolic homeostasis, (hypertriglyceridemia and
low high-density lipoprotein
autoimmunity, and microvascular insufficiency have been implicated. The
level), central obesity, and
metabolic mechanisms that have been identified include the accumulation of hypertension, all contribute
glycation end products, oxidative and nitrosative stress, abnormal flux in to the risk of developing
calcium regulation, increased polyol pathway function, and mitochondrial distal symmetric
dysfunction. At the root of these metabolic derangements is inflammatory polyneuropathy.
stress on the system that has been linked to the growing role of dyslipidemia in
the development of neuropathy (particularly in type 2 diabetes) in addition to
hyperglycemia.5 Hyperglycemia and hyperlipidemia cause a combination of
inflammation, mitochondrial dysfunction, and oxidative stress that all result
in neuronal dysfunction, impaired axonal transport, and ultimately axonal
damage.6 Other potential pathways that contribute to neuropathy
development include the metabolism of sphingolipids into toxic
deoxysphingolipids.20 These various pathophysiologic mechanisms are
associated with damage to both peripheral sensory and autonomic neurons as
well as the supporting glial cells.5,6,19 For more complete information on the
pathophysiologic mechanism underlying the development of neuropathy,
several recent reviews of the pathophysiology of diabetic neuropathy have
been published.5,6,19
TREATMENT OF NEUROPATHIES IN DIABETES AND PREDIABETES

To date, no disease-modifying therapies have been approved for diabetic
neuropathy (or prediabetes-associated neuropathy). A string of significant
pharmaceutical failures in diabetic neuropathy has hampered further drug
development.21 However, treatment of modifiable risk factors has been shown to
limit disease progression in most patients.22 The major goals of care therefore
include reduction of modifiable risk factors such as hyperglycemia,
hyperlipidemia, hypertension, obesity, and tobacco use. The optimal types of
exercise and specific dietary recommendations that might improve outcomes are
not known at this time.
Dietary supplements have often been touted as effective treatments for
diabetic neuropathy. α-Lipoic acid has been investigated in a number of clinical
trials of diabetic neuropathy23; however, the benefits have been limited to
symptomatic relief, and it has not been shown to have any impact on disease
modification.24 Other dietary therapeutic interventions have been suggested but
have not demonstrated efficacy in clinical trials.
ACUTE DIABETIC NEUROPATHIES

The onset of an acute neuropathy in the setting of diabetes should suggest a small
number of potential causes. An asymmetric painful motor neuropathy often
suggests a lumbosacral radiculoplexus neuropathy (also known as diabetic

amyotrophy), whereas a length-dependent or generalized painful small fiber and

autonomic neuropathy might suggest complications of a rapid change in glucose
levels (treatment-induced neuropathy of diabetes).
Diabetic Lumbosacral Radiculoplexus Neuropathy

Commonly referred to as diabetic amyotrophy, diabetic lumbosacral
radiculoplexus neuropathy is a monophasic neuropathy that typically presents
over weeks to months, initially with asymmetric lower extremity pain, weakness,
and atrophy, often more prominent proximally.25 Although diabetic lumbosacral
radiculoplexus neuropathy has not been well studied due to its rarity and the
frequent delay in diagnosis, a 2019 study found the incidence to be approximately
CASE 2-2 A 53-year-old man presented for evaluation of a 4-month history of

painful tingling and lancinating pain in his toes, particularly at night. He
had been relatively healthy, with some mild hypertension and
hyperlipidemia.
On examination, his body mass index (BMI) was 31.3 kg/m2. He had
normal strength, reflexes, and coordination. Sensory examination
revealed intact proprioception, mildly decreased sensation to vibration
using a 128-Hz tuning fork (8 seconds at the great toes), and diminished
temperature and pinprick sensation in the feet. He also had some
thickened dry skin along the soles of the feet.
The clinical history and examination were consistent with small fiber
distal symmetric polyneuropathy. An initial laboratory workup showed
hemoglobin A1c of 5.9% and elevated total cholesterol (209 mg/dL) and
triglycerides (317 mg/dL). A 3-mm punch skin biopsy from the distal leg
demonstrated reduced intraepidermal nerve fiber density (FIGURE 2-2).
COMMENT This case illustrates a typical clinical presentation for a patient with a
painful small fiber distal symmetric polyneuropathy in the setting of
prediabetes and metabolic syndrome. Treatment should include exercise
and diet, with a goal of reducing insulin resistance and hyperglycemia. To
date, exercise programs that focus on cardiovascular exercise or a
combination of cardiovascular and resistance training exercises have
shown benefit in metabolic parameters and might reduce neuropathy
progression.16,17 Several small exercise studies have shown improvements
in pain and balance, although maintaining a long-term exercise program is a
significant hurdle.17,18 With obesity as a major risk factor for neuropathy
progression, a focus on weight loss has been of interest. To date, no
specific recommendations for dietary changes have been linked to
successful disease modification. Ongoing clinical trials with medical and
surgical weight loss are under way to determine potential impacts on
neuropathy progression.19 Close monitoring is needed for possible
progression to diabetes. Aggressive treatment of hyperlipidemia is also
recommended. Treatment of neuropathic pain should be considered if this
patient’s discomfort interferes with his activities of daily living.
1168 OCTOBER 2020

4.2 per 100,000 per year, suggesting that it is more common than other
immune-mediated neuropathies such as CIDP.26
Diabetic lumbosacral radiculoplexus neuropathy is most common in
middle-aged patients with type 2 diabetes and is more common in men than in
women. It is often associated with weight loss. The clinical presentation is
characterized by the relatively acute onset of severe unilateral burning pain in the
hip, thigh, or back that often spreads to the entire limb and contralaterally. After
the onset of pain, proximal weakness develops that can be quite debilitating.
Most patients require assistance with ambulation and aggressive pain
management.25,27 Sensory loss is not typically a major component of this process.
Neurophysiologic testing can be helpful in confirming involvement of the
FIGURE 2-2
Small fiber neuropathy. A punch skin biopsy is stained with protein gene product 9.5
(PGP 9.5), an axonal marker. A, No small unmyelinated nerve fibers are seen entering the
epidermal layers (the epidermis is the red tissue at the top). B, The usual appearance of a
normal skin biopsy, in which nerve fibers (green) pierce the epidermal layer.

lumbosacral roots, plexus, and nerves. Diabetic lumbosacral radiculoplexus

neuropathy may progress over months (in some cases as long as 18 months), with
another 12 to 24 months required for recovery. Unfortunately, recovery is
typically incomplete. Less commonly, patients may present with a symmetric
motor-only form.26,28
CASE 2-3 A 28-year-old woman with a 14-year history of type 1 diabetes with
historically poor glycemic control (hemoglobin A1c values in the 10% to 14%
range) but no symptoms of neuropathy and no other complications of
diabetes presented to the hospital with diabetic ketoacidosis due to a
urinary tract infection. Her family and providers met with her while she
was admitted to the hospital to encourage improved glucose control. She
started taking her insulin as prescribed after discharge from the hospital,
and her daily glucose readings improved.
Three weeks later, she presented to her primary care doctor with
severe burning pain in her hands and her legs with no associated
weakness or numbness. She had severe contact allodynia and
hyperalgesia in the distribution of the pain. Nerve conduction studies and
EMG ordered by her primary care physician were normal and she was
referred for a neurologic consultation.
At the time of her neurologic evaluation 6 weeks after hospitalization,
her hemoglobin A1c had decreased from 12.2% to 8.1%. On examination,
she had findings consistent with a length-dependent small fiber
neuropathy. She had normal strength, reflexes, and normal sensation to
vibration and proprioception. She had allodynia to light touch and
diminished pinprick and temperature sensation in her legs distally up to
midthigh and distally in her arms up to midforearm with areas of
hyperalgesia. Skin biopsies confirmed a severe small fiber neuropathy
with absent fibers at the distal leg, severely reduced at the distal thigh
but normal at the proximal thigh.
She was prescribed a tricyclic antidepressant, gabapentin, and an
agent for breakthrough pain. She had also developed proliferative
retinopathy during this time and required ophthalmologic intervention.
COMMENT Treatment-induced neuropathy of diabetes is seen in individuals with rapid

glycemic control on the background of chronic hyperglycemia. The severity
of the syndrome typically reflects the magnitude of change in the glucose
control. Treatment of the neuropathic pain can be challenging and typically
requires polypharmacy. As noted in this case, it may involve other
microvascular tissue beds, such as the eye and kidney, and both should be
monitored for disease progression. Diabetic anorexia, or diabulimia, is an
eating disorder characterized by the withholding of insulin to lose weight in
individuals with type 1 diabetes. It is a significant risk factor for
treatment-induced neuropathy and carries a very high morbidity and
mortality.32,33
1170 OCTOBER 2020

Unlike DSPN, diabetic lumbosacral radiculoplexus neuropathy is not directly KEY POINTS
related to hyperglycemia or metabolic syndrome. Pathologic data suggest it is
● The acute to subacute
caused by a microvasculitis resulting in ischemic nerve injury. Unlike patients onset of pain and weakness
with DSPN, patients with diabetic lumbosacral radiculoplexus neuropathy have in the hip and leg of an
generally better-than-average glycemic control. Despite the evidence of an individual with diabetes
immune basis, limited data are available regarding the potential efficacy of should raise suspicion for
diabetic lumbosacral
immunomodulatory treatment. A small randomized trial suggested that IV
radiculoplexus neuropathy.
methylprednisolone may help with neuropathic pain associated with diabetic Early recognition and
lumbosacral radiculoplexus neuropathy.29,30 Clinical trials are challenging intervention with IV
because patients with diabetic lumbosacral radiculoplexus neuropathy are often corticosteroids may improve
neuropathic pain and reduce
not appropriately diagnosed in the acute setting before the development of
the associated morbidity.
significant axonal injury. Although speculative, it is likely that early diagnosis
and prompt treatment could be of benefit. ● Treatment-induced
neuropathy of diabetes
Treatment-Induced Neuropathy of Diabetes should be suspected in an
individual with diabetes who
Previously known as insulin neuritis, or acute painful neuropathy, presents with the acute to
treatment-induced neuropathy of diabetes develops suddenly following rapid subacute onset of
improvement in glycemic control in the setting of chronic hyperglycemia. neuropathic pain in a
Treatment-induced neuropathy of diabetes may also be related to diabetic symmetric pattern that is
accompanied by
neuropathic cachexia, a disorder with overlapping clinical features, and is also predominantly small fiber
associated with weight loss.31 Treatment-induced neuropathy of diabetes is findings. A significant
characterized by the acute onset of neuropathic pain in a length-dependent or improvement in glycemic
generalized distribution, often with accompanying autonomic symptoms. The control that precedes the
development of pain is the
neuropathy predominantly involves small fiber sensory and autonomic nerve
clue to the diagnosis.
fibers (CASE 2-3). Treatment-induced neuropathy of diabetes is most
commonly seen after a significant treatment change in individuals with type 1
diabetes who have had chronic hyperglycemia or in individuals with newly
discovered type 2 diabetes with an unknown period of hyperglycemia
combined with an aggressive lowering of the hemoglobin A1c. Symptoms
typically begin 2 to 6 weeks after the change in glucose control, and
neuropathic pain can be very severe. Autonomic symptoms are sometimes
prominent, including orthostatic intolerance or hypotension, hyperhidrosis or
anhidrosis, early satiety, and erectile dysfunction, but they are frequently
overlooked given the severity of the neuropathic pain.31
Although the exact mechanism of treatment-induced neuropathy of diabetes
is unknown, one theory includes a relative hypoglycemic state resulting in
inadequate energy production by mitochondria and energy failure. Other
suspected mechanisms include an increase in proinflammatory cytokines and
resulting nerve fiber damage. Irrespective of the underlying mechanism,
longitudinal data suggest that complications associated with treatment-induced
neuropathy of diabetes can be profound if glycemic control is destabilized.34
Diabetic anorexia, also reported as diabulimia, is an eating disorder in
individuals with type 1 diabetes characterized by the withholding of insulin to
lose weight. Diabulemia is a significant risk factor for treatment-induced
neuropathy of diabetes and carries a very high rate of morbidity and mortality.
The severity of neuropathy in treatment-induced neuropathy of diabetes is
tied to the magnitude and rate of the change in hemoglobin A1c. Individuals
with the largest changes in glucose control have the largest region of body
involvement, the most severe pain, and the greatest symptoms of autonomic
dysfunction (FIGURE 2-3).

FIGURE 2-3
Treatment-induced neuropathy of diabetes. In this figure, the decline in the hemoglobin A1c is
shown along the x-axis, with the absolute risk of developing neuropathy shown along the
y-axis. With a greater change in the hemoglobin A1c, the risk of developing treatment-induced
neuropathy of diabetes increases. In addition, the clinical manifestations of neuropathy
tend to worsen, covering larger regions of the body with the larger change in hemoglobin A1c.
The red areas of the body are regularly involved, whereas the gray areas are sometimes
involved. With a modest change in the hemoglobin A1c of 2% to 3%, a distal small fiber
neuropathy may be the only manifestation.
In addition to the development of neuropathy, individuals who develop

treatment-induced neuropathy of diabetes also frequently have renal and retinal
involvement simultaneously, suggesting this is a diffuse microvascular process.
The majority of individuals with treatment-induced neuropathy of diabetes have
significant progression of proliferative retinopathy over a period of 12 months.
Renal function may decline, although increased microalbuminuria is the most
common manifestation.34,35
One of the most interesting findings in treatment-induced neuropathy of
diabetes is that a degree of neuropathy reversibility exists in some individuals
with type 1 diabetes. Although the neuropathy may not entirely resolve, in some
individuals with stable glucose control over several years, a trend in
improvement in nerve fiber density is noted by skin biopsy, neuropathy severity
as noted by examination score, and neuropathy pain scores. In contrast, in
patients with treatment-induced neuropathy of diabetes who continue to have
labile glycemic control with periods of poor control punctuated by significant
improvement in hemoglobin A1c, the neuropathy can be severe and
progressive.31,34 Unfortunately, because of the relatively small number of studies
on the topic, no clear consensus exists on how best to prevent or treat
treatment-induced neuropathy of diabetes. Based on the author’s experience
with the largest published cohort of individuals with treatment-induced
neuropathy of diabetes, avoiding dramatic improvements in hemoglobin A1c
1172 OCTOBER 2020

levels in individuals with chronic hyperglycemia is recommended (limiting KEY POINT
change to 1% reduction in the hemoglobin A1c per month). Management of
● The earliest clinical
treatment-induced neuropathy of diabetes should focus on managing manifestation of a diabetic
symptomatic pain while encouraging glucose stabilization at the current autonomic neuropathy is a
hemoglobin A1c level until symptoms begin to improve. resting tachycardia.
FOCAL NEUROPATHIES
Entrapment neuropathies, including median mononeuropathy at the wrist
(carpal tunnel syndrome), ulnar mononeuropathy at the elbow (cubital tunnel
syndrome), and fibular (peroneal) mononeuropathy at the fibular head are more
prevalent in individuals with diabetes when compared to the general
population.36 The clinical characteristics and electrodiagnostic features of the
entrapment neuropathies do not differ in diabetes, although they can be more
challenging to diagnose in the setting of an ongoing axonal neuropathy due to
diabetes.
AUTONOMIC NEUROPATHIES
Autonomic neuropathies encompass a diverse spectrum of clinical
manifestations because of the different organ systems involved. A major
difficulty in providing estimates of the prevalence of diabetic autonomic
neuropathy is the tendency to report autonomic dysfunction as it relates to the
organ system of interest. As a typical example, cardiovascular autonomic
neuropathy is a commonly measured study outcome in diabetes trials, but the
cardiovascular autonomic neuropathy results do not inform the investigator
about the presence or absence of gastrointestinal autonomic neuropathy (or any
other organ system involvement). Thus, rates of autonomic neuropathy may
range from less than 5% to greater than 70% depending on the organ system
studied and the testing paradigm employed. However, it is clear that
uncontrolled hyperglycemia over longer periods of time results in clinically
meaningful dysfunction of the autonomic nervous system.37
Diabetic Cardiovascular Autonomic Neuropathy

Diabetic cardiovascular autonomic neuropathy is of major clinical concern
because it is associated with a significant increase in both morbidity and
mortality.38 The clinical manifestations of cardiovascular autonomic neuropathy
may range from an increased resting heart rate to diminished heart rate response
to physiologic stress.4 As cardiovascular autonomic neuropathy becomes more
severe, orthostatic hypotension (defined as a fall in blood pressure of >20 mm Hg
systolic and 10 mm Hg diastolic) develops, which is the most severe and
debilitating form of cardiovascular autonomic neuropathy.37 The autonomic
dysfunction in cardiovascular autonomic neuropathy is due to denervation of the
vagus nerve, causing impaired heart rate variability and an increase in resting
heart rate and damage to peripheral efferent sympathetic vasomotor nerves that
control vasoconstriction, resulting in orthostatic hypotension. The end result of
cardiovascular autonomic neuropathy is diminished cardiac output, particularly
in association with exercise.39
The association between cardiovascular autonomic neuropathy in diabetes
and an increased rate of mortality is very high.40 Patients with diabetes who have
orthostatic hypotension in the setting of cardiovascular autonomic neuropathy
have a 5- to 10-year mortality range between 27% and 56%.4,6,37 The proposed

mechanisms for the increase in mortality include an absent or reduced

perception of myocardial ischemia, impaired hemodynamic response to
physiologic stressors (including surgery, infection, and anesthesia), QT interval
dispersion (the difference between maximum and minimum QT interval)
causing arrhythmias, imbalance between the sympathetic and parasympathetic
nervous system, and localized areas of myocardial ischemia with sympathetic
denervation and reinnervation.41
A number of treatments exist for the specific symptoms associated with
cardiovascular autonomic neuropathy. However, at present, no treatment
exists for the underlying disease, and no evidence has shown that symptomatic
therapy reduces the associated morbidity and mortality. As a consequence, the
primary goal is prevention of disease development and progression with
glycemic control and aggressive management of other features of metabolic
syndrome. A number of medications may cause or exacerbate orthostatic
hypotension, and they should be removed in the setting of orthostatic
hypotension (TABLE 2-2).
Gastrointestinal Autonomic Neuropathies in Diabetes

Gastrointestinal complications of diabetes include disorders of motility (slow or
fast transit) and the accompanying symptoms.
GASTROPARESIS. Gastroparesis is one of the most feared and challenging medical

complications of diabetes. Gastroparesis causes delayed transit of food (solids or
liquids) from the stomach into the small intestine; it is present in up to 50% of
individuals with diabetes.42–45 Many patients report postprandial fullness,
nausea, bloating, or vomiting, although some patients may be asymptomatic.
One of the more challenging aspects of gastroparesis is that it further complicates
glycemic control by causing a mismatch between glucose absorption and
administration of insulin. If insulin is taken with meals, delayed food absorption
can result in hypoglycemia with hyperglycemia later in the day. This mismatch
between food intake and insulin timing due to the gastroparesis results in a
TABLE 2-2 Impact of Medications and Other Agents on Autonomic Function
Autonomic Symptoms/Signs Potentially Causative Agents
Orthostatic hypotension Antidepressants, antihypertensive medications, α1-adrenoreceptor antagonists,

antiparkinsonian dopaminergic agents
Gastroparesis Opioids, clonidine, tricyclic antidepressants, calcium channel blockers, dopamine

agonists, muscarinic cholinergic receptor antagonists, glucagonlike peptide 1 (GLP-1)
agonists, phenothiazines, cyclosporine
Constipation Calcium channel antagonists, opioids, anticholinergic medications
Diabetic diarrhea Metformin, sorbitol-containing foods
Bladder dysfunction Anticholinergic agents, tricyclic antidepressants, calcium channel antagonists (impair
detrusor activity); α1-adrenoreceptor agonists (increase urethral sphincter tone),
α1-adrenoreceptor antagonists (decrease urethral sphincter tone)
Sexual dysfunction Antidepressants, antihypertensive medications, statins, antihistamines
1174 OCTOBER 2020

vicious cycle of worsening diabetes control resulting in more severe KEY POINTS
gastroparesis.
● Cardiovascular autonomic
Although symptoms of postprandial fullness are commonly noted in individuals neuropathy (particularly
with gastroparesis, objective assessment of gastroparesis severity is recommended. with orthostatic
The recommended diagnostic testing for gastroparesis is a gastric-emptying hypotension) is associated
study with scintigraphy. After a solid meal, 37% to 90% of food normally remains with significantly increased
mortality risk in patients
in the stomach after 1 hour. After 2 hours, this is reduced to 30% to 60%, and
with diabetes, with 5- to
typically 10% or less of food remains in the stomach after 4 hours. Food 10-year mortality rates
remaining in the stomach longer than expected suggests impaired gastric greater than 50%.
emptying (although certain medications can alter gastric emptying and should be
noted). Other causes for delayed gastric emptying should also be considered, ● Gastroparesis is a
common and disabling
including peptic ulcer, gastric obstruction, or other structural disorders. manifestation of diabetic
It should also be noted that although autonomic neuropathy plays an autonomic neuropathy, but
important role in the pathophysiology of gastroparesis, a separate and potentially the potential for
reversible component is directly related to hyperglycemia.46–48 Thus, if glucose symptomatic improvement
exists with better glycemic
control stabilizes, an improvement in gastroparesis may be seen that is not due to control.
any change in autonomic function.
Treatments for gastroparesis may require collaboration with a gastric motility ● Constipation may be a
expert. The first-line approach involves having patients eat smaller, more manifestation of diabetic
autonomic neuropathy but is
frequent meals. However, this strategy can further complicate glycemic control.
also frequently due to
Avoiding dietary fiber and fat is recommended. Removal of any offending medication. A careful review
medications (such as opioids, clonidine, tricyclic antidepressants, calcium of both prescribed and
channel blockers, dopamine agonists, muscarinic cholinergic receptor over-the-counter
medications may identify
antagonists, glucagonlike peptide 1 [GLP-1] agonists, phenothiazines, and
potential opportunities to
cyclosporine) should always be attempted (TABLE 2-2).49,50 Metoclopramide is improve symptoms.
the only US Food and Drug Administration (FDA)–approved agent for the
treatment of gastroparesis.46–48 However, it carries a host of serious
extrapyramidal side effects that limit its use, and duration of therapy beyond
5 days is not recommended.
CONSTIPATION. Although constipation is a common symptom in the general

population, it is particularly prevalent in diabetes, with up to 60% of patients
affected.51 Autonomic dysfunction can be due to several potential mechanisms,
but numerous potential medication effects can cause constipation in individuals
with diabetes. The patient’s medication list should be closely investigated, with
particular attention paid to the use of calcium channel antagonists, opioids, and
anticholinergic medications (TABLE 2-2).51 Constipation can be a challenge,
particularly if it occurs with gastroparesis because high-fiber diets and bulking
agents are contraindicated in gastroparesis.
DIARRHEA. Diabetic diarrhea is associated with autonomic neuropathy of the

gastrointestinal system, although the pathogenesis is frequently multifactorial.
Diabetic diarrhea is a disconcerting problem for people because it is typically a
profuse and watery diarrhea that usually presents during sleep. It is more
common in individuals with type 1 diabetes52 and is often associated with fecal
incontinence. Diabetic diarrhea may be reported in up to 20% of individuals with
diabetes. It may alternate with constipation or may persist as diarrhea for hours
at a time. Although the diagnosis in this case is typically made by history,
gastric-emptying studies may show either rapid or slow transit times and
therefore are not particularly helpful. Bacterial overgrowth is a common

comorbid complication. The differential diagnosis of diabetic diarrhea is

medication side effect (particularly metformin therapy in type 2 diabetes), foods
containing sorbitol (TABLE 2-2), exocrine pancreatic insufficiency, celiac disease,
or dysfunction of the bile salt metabolism pathway.37,52 Treatment focuses on
agents that reduce peristalsis, prolong transit time, and reduce fecal volume,
including loperamide, codeine, combination diphenoxylate and atropine, or
tincture of opium.53
Diabetic Urogenital Autonomic Neuropathy

Sexual dysfunction and bladder dysfunction are common urogenital
complications of diabetic autonomic neuropathy.
BLADDER DYSFUNCTION. In individuals with diabetes, involvement of the

bladder may occur as part of a progressive autonomic neuropathy and may result
in symptoms such as urinary frequency, urinary urgency, nocturia, and urinary
incontinence.52 Bladder symptoms are reported in up to 50% of individuals with
diabetes. However, objective evidence of bladder dysfunction may be seen in up
to 87% of individuals with type 1 diabetes. Bladder dysfunction may be a
consequence of damage to the autonomic and sensory afferent and efferent
fibers or of damage to the smooth muscle of the bladder or urothelial cell layer.
An overlap exists between symptoms linked to autonomic neuropathy and
urogenital symptoms attributed to central nervous system involvement, and
individuals with diabetes have risks for both.
One of the initial symptoms of autonomic neuropathy involving the bladder is
impaired sensation of fullness and dysfunction of the micturition reflex. As
neuropathy severity increases, detrusor activity is impaired, resulting in
increasing postvoid residuals, diminished urinary flow rates, and, ultimately,
urinary retention. With increasing retention, increasing bladder distention
eventually leads to urinary retention with overflow incontinence.37,52
Medications are a common cause of bladder dysfunction and should be
considered in the differential diagnosis of bladder dysfunction in diabetes.
Medications that impair detrusor activity include anticholinergic agents, tricyclic
antidepressants, and calcium channel antagonists (TABLE 2-2). Medications that
decrease urethral sphincter tone include the α1-adrenoreceptor antagonists,
which can cause urinary leakage; conversely α1-adrenoreceptor agonists can
increase urethral sphincter tone and result in urinary retention.37,52
The initial evaluation of a patient with diabetes with symptoms of urinary
dysfunction should include a review of medications for potential side effects
(TABLE 2-2), followed by a postvoid residual measurement by ultrasound. In
more complicated situations (ie, recurrent urinary tract infection or symptoms
suggestive of bladder outlet obstruction), a formal urodynamic study and
evaluation by urology are appropriate.
SEXUAL DYSFUNCTION. Diabetic autonomic neuropathy is a frequent cause of

sexual dysfunction in men and women. In women with diabetes, a reduction in
the vascular release of nitric oxide results in decreased vaginal relaxation and
painful intercourse.54 Diabetic neuropathy also leads to dysfunction of vaginal
exocrine glands, resulting in dryness and tissue irritation, further compounding
painful intercourse.55 As noted in a 2019 meta-analysis, the frequency of sexual
dysfunction in women was approximately 70% in women with type 2 diabetes, a
1176 OCTOBER 2020

twofold increase over age-matched women without diabetes.56 As with men, KEY POINTS
psychological factors also play a role in sexual function in women with diabetes,
● Diabetic diarrhea is often
and multifaceted clinical care addressing both physical and psychological factors profuse and watery; it
is necessary.55,56 frequently occurs at night
Erectile dysfunction is highly prevalent in men with diabetes, noted in up to with fecal incontinence.
75% of male patients.52 Although erectile dysfunction may be an early Medications should be
reviewed carefully because
manifestation of autonomic dysfunction, the underlying pathophysiology is a
identification and removal
combination of vascular, neurologic, and psychological factors. Medication side of offending medications
effects are also in the differential diagnosis for sexual dysfunction, and offending may improve symptoms.
medications should be removed, if possible (TABLE 2-2). One characteristic
feature of neurogenic and vascular erectile dysfunction is the gradual ● Bladder dysfunction is
common in diabetes and
decrease of morning erections combined with erectile failure during sexual often related to medication
stimulation; in contrast, erectile dysfunction associated with psychological side effects. As with other
onset is generally of more sudden onset, and morning erections are maintained. diabetic autonomic
In some cases of diabetic sympathetic nervous system dysfunction, neuropathies, offending
medications should be
ejaculatory failure may precede erectile dysfunction. Sympathetic nervous removed as the initial step in
system dysfunction can also lead to retrograde ejaculation due to impaired management.
bladder neck closure.57 Although a number of medications exist to treat
erectile dysfunction, they become less effective as neuropathy and vascular ● Sexual dysfunction is
common in both men and
disease worsen.
women with diabetes and
frequently is due to a
Sudomotor Function combination of
Sweat glands contain sympathetic cholinergic innervation and are necessary for psychological and physical
factors, both of which
proper homeostatic thermoregulation as well as skin health. Damage to
should be addressed.
sympathetic cholinergic nerves in a length-dependent fashion is a common
finding in individuals with diabetic neuropathy.52 The pattern of sudomotor ● Neuropathy involving the
dysfunction matches the distribution of the sensory neuropathy, typically sympathetic cholinergic
presenting in a stocking-and-glove distribution. Interestingly, patients do not nerves results in a
length-dependent region of
present with symptoms related to distal anhidrosis but instead report proximal anhidrosis, but patients
hyperhidrosis. The loss of distal sweating causes a compensatory proximal typically present with
hyperhidrosis to maintain thermoregulation; therefore, patients feel that they are complaints of proximal
sweating too much over their head and trunk. Management of this condition is hyperhidrosis.
challenging because sweat reduction can lead to hyperthermia, so treatments
focus on nonpharmacologic thermoregulation. Another classic finding in diabetic
neuropathy, although less common than distal anhidrosis, is gustatory sweating.
Sweat will appear over the face, head, neck, shoulders, and chest after eating;
although it is presumed to be related to nerve injury and aberrant reinnervation,
the pathophysiology has not been fully elucidated. Typical treatments range from
topical anticholinergic or aluminum-based agents to botulinum toxin
injections.58
Sudomotor dysfunction may present as the earliest clinical manifestation of
neuropathy and can be detected in very early diabetic neuropathy and in the
prediabetic/metabolic syndrome state. Clinical testing for sudomotor
dysfunction may involve different neurophysiologic tests of sweat function,
including the quantitative sudomotor axon reflex test (QSART),
thermoregulatory sweat testing, or other tests of sweat function. Testing
abnormalities must be differentiated from medication side effects, and without
proper thermal and humidity control, testing may be unreliable. It should be
noted that devices using electrochemical skin conductance that have been
heavily marketed for testing sweat function in neuropathy have had questions

raised about their utility because of serious problems in data reporting that
question the reliability and reproducibility of the results.59
Hypoglycemia-associated Autonomic Failure

Hypoglycemia-associated autonomic failure is a serious complication of
aggressive glycemic control. With a fall in glucose levels, the autonomic nervous
system is activated, including the sympathetic, parasympathetic, and
sympathoadrenal divisions. This results in a decrease in insulin secretion and an
increase in circulating glucagon, epinephrine, norepinephrine, pancreatic
polypeptide, cortisol, and growth hormone. With the fluctuation in hormone
levels, symptoms of autonomic activation are noted, including tremor,
palpitations, anxiety, diaphoresis, hunger, and paresthesia. With progressive
hypoglycemia, neuronal function declines and symptoms such as fatigue,
weakness, and dizziness occur, which progress to cognitive and behavioral
symptoms and finally to seizures in severe hypoglycemia.
A number of studies have identified an association between strict glycemic
control and a decreased counterregulatory response to hypoglycemia. As a result
of this diminished counterregulatory response, the perception of symptoms
associated with hypoglycemia is diminished, resulting in a lower threshold of
glucose at which future symptoms will occur. As the number of hypoglycemic
episodes increases, a vicious cycle of more severe and more frequent
hypoglycemia then develops.
A number of large longitudinal studies show that better glycemic control leads
to a reduction in the incidence of neuropathy, retinopathy, and nephropathy in
individuals with type 1 diabetes. However, in type 2 diabetes, the relationship
between glycemic control and the development of complications is not as clear.
A strong association exists between tight glycemic control and an increased
incidence of severe iatrogenic hypoglycemia. More recent studies have noted an
association between intensive glycemic control, hypoglycemic events, and an
increased rate of mortality. Although hypoglycemia has not been confirmed as
the cause of the increase in mortality in these studies, evidence was sufficient to
stop these ongoing trials prematurely.
Hypoglycemia and Cardiovascular Autonomic Function

During periods of recurrent hypoglycemia, the production of stimulating
hormones (eg, epinephrine, glucagon, adrenocorticotropic hormone [ACTH])
that result in the symptoms of hypoglycemia is decreased, thereby blunting the
responses to future episodes of hypoglycemia. In exposure to mild experimental
hypoglycemia in a controlled setting, cardiac vagal baroreflex sensitivity and
sympathetic adrenergic response to hypotension and orthostatic stress are
decreased.60 These changes in cardiovascular autonomic function persist for at
least 16 hours. These findings have direct clinical implications for patients with
diabetes who may have episodes of hypoglycemia. Recurrent episodes of
hypoglycemia lead to a blunted baroreflex response and may impair vagal
protection against arrhythmia and sudden death. Impaired parasympathetic
function (ie, cardiac vagal control) is also linked to higher mortality after
myocardial infarction.
Several studies have also linked hypoglycemia to abnormal cardiac
repolarization, manifesting as QT interval prolongation and QT dispersion on
ECG. It is unclear whether spontaneous hypoglycemia in individuals with
1178 OCTOBER 2020

diabetes results in the same degree of QT interval prolongation (although KEY POINTS
increases in up to 45 milliseconds have been reported in the setting of
● Recurrent hypoglycemia
spontaneous hypoglycemia). The potential pathophysiologic mechanisms blunts future autonomic
underlying the acute alterations in cardiac repolarization are not known. responses to low levels of
The long-term effects of hypoglycemia on nerve fiber structure and function glucose, creating a vicious
need to be more clearly identified, particularly as they relate to aggressive cycle of recurrent
hypoglycemia because of
glycemic control. At present, individuals with diabetes must walk a fine line
the body’s inability to sense
between the increased risk of complications with hyperglycemia and the low glucose levels.
increased risk of mortality with hypoglycemia.
● Recurrent hypoglycemia
DIABETES AND CHRONIC INFLAMMATORY DEMYELINATING is associated with an
increase in cardiovascular
POLYRADICULONEUROPATHY mortality, although the
CIDP is a heterogeneous immune-mediated condition of the peripheral nervous exact mechanism for the
system that may present in a progressive or relapsing-remitting fashion. CIDP increase in mortality is still
typically presents with the symmetric onset of proximal and distal sensory and under investigation.
motor symptoms. However, almost half of patients may present with an atypical ● It is controversial whether
disease with either focal or multifocal manifestations or more isolated motor or chronic inflammatory
sensory symptoms. CIDP is important to recognize because it is responsive to demyelinating
immunomodulatory treatment. The diagnosis of CIDP is based on a combination polyradiculoneuropathy
(CIDP) occurs more
of clinical features, supportive laboratory tests, and electrodiagnostic criteria. For
frequently in individuals
more information on CIDP, refer to the article “Chronic Inflammatory with diabetes; however,
Demyelinating Polyradiculoneuropathy and Its Variants” by Kelly Gwathmey, CIDP is widely
MD,61 in this issue of Continuum. overdiagnosed. A diagnosis
of CIDP in a patient with
A significant diagnostic dilemma exists in some patients with diabetes because
diabetes should be based on
of the overlapping clinical, electrodiagnostic, and laboratory features.62 typical clinical features, not
Individuals with significant axonal neuropathy in diabetes may have reduced on nerve conduction study
conduction velocities and elevated CSF protein. As a consequence, a debate is findings alone.
ongoing about whether an increased incidence of CIDP exists in patients with
diabetes. Some investigators argue that the numbers of patients with CIDP are
greater than that seen in the general population62; however, other investigators
suggest that the overlapping clinical, laboratory, and electrodiagnostic features
simply create an increased risk of misdiagnosis.63
A 2016 review of the literature reported that the prevalence of CIDP in
patients with diabetes was 9 times higher than in the general population.62 A
summary of the evidence for and against an association between CIDP and
diabetes has not provided a clear answer at this stage.63 A 2018 study examining
the utility of peripheral nerve ultrasound to distinguish between CIDP and
diabetic peripheral neuropathy demonstrated that individuals with CIDP had
larger cross-sectional nerve areas, a finding that might be valuable in
distinguishing between the two disorders.64 Future studies are required to
determine the relevance of this finding in clinical practice.
In clinical practice, a number of potential reasons to distinguish these
disorders exist, but the use of immunomodulatory therapy in a population of
individuals who will not benefit and could have complications from it is the
primary reason to ensure an accurate diagnosis. At present, motor nerve
conduction velocities less than 70% of the lower limit of normal, distal motor
latencies of greater than 150% of the upper limit of normal, and conduction block
in multiple nerves is highly specific for CIDP when detected within multiple
nerves.63 It is critical to remember that CIDP is a clinical diagnosis based on the
presence of proximal and distal weakness with areflexia. CIDP is widely

KEY POINTS overdiagnosed, in part because of overinterpretation of nerve conduction study

findings.65 In summary, there are no specific recommendations for the diagnosis
● Uremia is linked to an
increased risk of
and management of CIDP in diabetes, except that clear criteria should be
length-dependent followed to help confirm the individual diagnoses.
neuropathy but may improve
with dialysis or kidney UREMIA
transplantation.
Similar to the neuropathies seen in diabetes, neuropathy associated with uremia
● An acute optic may present with a variety of clinical manifestations, including a length-
neuropathy may also be dependent axonal neuropathy that is, in some cases, associated with slowed
seen in uremia and should be motor nerve conduction velocities in the demyelinating range. Typically seen
treated with hemodialysis with very low glomerular filtration rates, the clinical features typically suggest a
and corticosteroids.
slowly progressive length-dependent axonal neuropathy. Symptoms often
include paresthesia, burning pain, and cramps. Findings on neurologic examination
typically include reduced small and large fiber function, with motor weakness in
more advanced disease. In some cases, symptoms may improve with either kidney
transplantation or dialysis. Nerve conduction velocities often improve
posttransplantation, although there is minimal improvement in axon loss.66
One of the more unique clinical manifestations of uremic neuropathy is an
acute optic neuropathy. The pathophysiology of this manifestation is not well
understood, but it may be related to the accumulation of specific toxins in the
setting of uremia. Although data are relatively limited, treatment
recommendations include hemodialysis and the use of corticosteroids.67
CONCLUSION
Neuropathies associated with metabolic disorders are common. Diabetes and the
individual components of the metabolic syndrome make up the overwhelming
majority of all cases of neuropathy. The increasing frequency with which
diabetes and metabolic syndrome are detected in individuals around the world
suggests that an enormous number of individuals will develop neuropathy over
the next few decades. This will result in an increasing strain on health care
systems and the need for individuals who are able to effectively manage these
conditions. The neuropathies associated with diabetes include diverse clinical
manifestations that encompass chronic length-dependent axonal, focal, acute
focal, acute generalized, and autonomic neuropathies. The increasing prevalence
of diabetes and metabolic syndrome will cause even the rare manifestations of
diabetic neuropathy to be seen more regularly. The need for individuals with
expertise in this area should be a major focus for training across health care
systems. Funding of both basic and clinical investigations into treatments for
diabetic neuropathy is of critical importance given the impending influx of
diabetic neuropathies in aging populations.
USEFUL WEBSITES
INTERNATIONAL DIABETES FEDERATION IDF DIABETES AMERICAN DIABETES ASSOCIATION DIABETESPRO
ATLAS 9TH EDITION The American Diabetes Association’s DiabetesPro
The IDF Diabetes Atlas is an excellent resource for website provides practice guidelines resources,
information about the global impact of diabetes including standards of medical care in diabetes, and
with details about complications at a regional level. opportunities for continuing education.
diabetesatlas.org professional.diabetes.org/content-page/practice-
guidelines-resources
1180 OCTOBER 2020

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Diabetes and Metabolic Disorders and The Peripheral Nervous System

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Diabetes and Metabolic REVIEW ARTICLE

RECENT FINDINGS: Although a number of metabolic disorders cause or are

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OVERVIEW AND EPIDEMIOLOGY OF DIABETIC NEUROPATHIES

u Length-dependent axonal polyneuropathy, the most common form; may be characterized

Prediabetes: FPG values 100–125 mg/dL (5.6–6.9 mmol/L)

Glycosylated hemoglobin (A1c) Diabetes: A1c values ≥6.5% (48 mmol/mol)

Prediabetes: A1c values 5.7 to <6.5% (39–48 mmol/mol)

1162 OCTOBER 2020

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DISTAL SYMMETRIC POLYNEUROPATHY OF DIABETES

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DSPN in type 2 diabetes (or even prediabetes) preferentially involves small

COMMENT This is a typical clinical presentation for a patient with a painless

1164 OCTOBER 2020

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1166 OCTOBER 2020

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TREATMENT OF NEUROPATHIES IN DIABETES AND PREDIABETES

ACUTE DIABETIC NEUROPATHIES

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amyotrophy), whereas a length-dependent or generalized painful small fiber and

Diabetic Lumbosacral Radiculoplexus Neuropathy

CASE 2-2 A 53-year-old man presented for evaluation of a 4-month history of

1168 OCTOBER 2020

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lumbosacral roots, plexus, and nerves. Diabetic lumbosacral radiculoplexus

COMMENT Treatment-induced neuropathy of diabetes is seen in individuals with rapid

1170 OCTOBER 2020

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In addition to the development of neuropathy, individuals who develop

1172 OCTOBER 2020

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Diabetic Cardiovascular Autonomic Neuropathy

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mechanisms for the increase in mortality include an absent or reduced

Gastrointestinal Autonomic Neuropathies in Diabetes

GASTROPARESIS. Gastroparesis is one of the most feared and challenging medical

TABLE 2-2 Impact of Medications and Other Agents on Autonomic Function

Autonomic Symptoms/Signs Potentially Causative Agents

Orthostatic hypotension Antidepressants, antihypertensive medications, α1-adrenoreceptor antagonists,

Gastroparesis Opioids, clonidine, tricyclic antidepressants, calcium channel blockers, dopamine

Constipation Calcium channel antagonists, opioids, anticholinergic medications

Diabetic diarrhea Metformin, sorbitol-containing foods

Sexual dysfunction Antidepressants, antihypertensive medications, statins, antihistamines

1174 OCTOBER 2020

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CONSTIPATION. Although constipation is a common symptom in the general

DIARRHEA. Diabetic diarrhea is associated with autonomic neuropathy of the

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comorbid complication. The differential diagnosis of diabetic diarrhea is

Diabetic Urogenital Autonomic Neuropathy

BLADDER DYSFUNCTION. In individuals with diabetes, involvement of the

SEXUAL DYSFUNCTION. Diabetic autonomic neuropathy is a frequent cause of

1176 OCTOBER 2020

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Hypoglycemia-associated Autonomic Failure

Hypoglycemia and Cardiovascular Autonomic Function

1178 OCTOBER 2020