Idiopathic neuropathy: new paradigms, new promise

Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
REVIEW
Idiopathic neuropathy: new paradigms, new promise
Mike A. Singer1, Steven A. Vernino1, and Gil I. Wolfe2
1Department of Neurology and Neurotherapeutics, University of Texas Southwestern Medical Center, Dallas, TX, USA;
and 2Department of Neurology, Buffalo General Hospital, Buffalo, NY, USA
Abstract Idiopathic neuropathy, now designated as chronic idiopathic axonal polyneu-
ropathy (CIAP), is a major public health problem in the United States. The disorder
affects an estimated 5-8 million Americans, comprising about one-third of patients with
neuropathy, based on data from referral centers. Typically, patients develop symptoms in
the sixth decade or older. The onset is insidious, with numbness, paresthesias, and pain
appearing over months to years. Although strength is generally preserved, the sensory loss
and pain can be disabling. The clinical approach to this condition has evolved in important
ways over the years, enabling improved diagnosis and characterization of this population.
Current work has focused on identifying modifiable risk factors that may be associated
with idiopathic neuropathy. The results may suggest that an underlying mechanism such
as oxidative stress contributes to the development of CIAP.
Key words: chronic idiopathic axonal polyneuropathy, cryptogenic neuropathy, cryptogenic
sensory polyneuropathy, idiopathic neuropathy, metabolic syndrome, obstructive sleep
apnea
Introduction
which we will use here. Although seemingly little
has changed regarding this disorder except the name,
About one in every three patients with neuropathy
in fact, the clinical approach to CIAP has evolved in
leaves their doctor's office without a definite etiologic
important directions, more rapidly in recent years.
diagnosis, despite extensive testing in referral centers
We will review these shifting paradigms, and how
(Smith and Singleton, 2006; Herskovitz et al., 2010).
those changes offer new understanding and potential
This figure is even more remarkable considering that
for treatment for what remains a vexing problem for
it represents some 5-8 million Americans, making
patients as well as clinicians.
idiopathic neuropathy one of the most common chronic
neurologic disorders (Table 1).
A variety of labels have been given to idiopathic
First Paradigm: Improving Recognition
neuropathy in the medical literature, including chronic
of Known Causes
sensory polyneuropathy, chronic polyneuropathy of
undetermined cause, and unclassified peripheral neu-
Although the nervous system had been a subject
ropathy. Currently, the most widely employed term
of study since ancient times, the insight that
disease could originate in the peripheral nerves is
is chronic idiopathic axonal polyneuropathy (CIAP),
comparatively recent, proposed in 1848 by the Irish
physician and polymath Robert Graves (Viets, 1934).
Numerous causes of peripheral neuropathy were
Address correspondence to: Mike A. Singer, MD, Department
subsequently identified, and in 1886 Sir William
of
Neurology
and
Neurotherapeutics,
University
of
Texas
Gowers made the first attempt to categorize these
Southwestern Medical Center, MC 8897, 5323 Harry Hines Blvd.,
Dallas, TX 75390, USA. Tel: +1 214-648-8747; Fax: +1 214-648-
etiologies systematically, in his classic text A Manual
9311; E-mail: mike.singer@utsouthwestern.edu
of Diseases of the Nervous System (Gowers, 1886).
(c) 2012 Peripheral Nerve Society
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Singer et al.
Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
Table 1. Estimated prevalence of various chronic
presentations proposed that their condition repre-
neurologic disorders in the United States.
sented a distinct clinical entity which he termed `late-
Chronic neurologic disorder
Number of patients
life chronic peripheral neuropathy of obscure nature'
(Fisher, 1982). Several major observational studies fol-
Idiopathic neuropathy
5-8 million
lowed, reporting clinical, electrophysiologic, and patho-
(Smith and Singleton, 2006)
logic characteristics of these patients. McLeod and
Alzheimer's disease
2.4-5.1 million
colleagues found the majority of their idiopathic neu-
(National Institute on Aging)
ropathy patients had a mixed sensorimotor polyneu-
Parkinson's disease
500,000
(National Institutes of Health)
ropathy, with a subset having predominantly sensory
Multiple sclerosis
400,000
symptoms (McLeod et al., 1984). Notermans and col-
(National Multiple Sclerosis Society)
leagues, initiating ongoing work that has spanned
Amyotrophic lateral sclerosis
30,000
(ALS Association)
nearly two decades, raised the possibility that CIAP
may consist of two subgroups, one sensorimotor and
Figures for disorders other than idiopathic neuropathy are taken
the other exclusively sensory (Notermans et al., 1993).
from the website of the indicated institution or society.
CIAP initially was thought primarily to affect men,
Table 2. Percentage of idiopathic neuropathy cases in
but as the number of patients studied increased, the
major studies.
proportions of men and women became roughly equiv-
alent. Reporting on 93 patients seen in their clinics, and
Idiopathic neuropathy
taking into account findings in the other studies, Wolfe
Study
cases (%)
and colleagues proposed the first diagnostic criteria for
idiopathic neuropathy, which remain in use (Table 3)
Matthews (1952)
70
Rose (1960)
56
(Wolfe et al., 1999).
Prineas (1970)
38
CIAP typically is a disorder of late adulthood, affect-
Dyck et al. (1981)
24
ing patients in their 50-60s. The onset is insidious,
Fagius (1983)
74
K onig et al. (1984)
14
with symptoms appearing gradually over months to
McLeod et al. (1984)
13
years. Patients experience sensory loss or paresthe-
Corvisier et al. (1987)
11
sias beginning symmetrically in the feet and ascending
Notermans et al. (1993)
10
Wolfe et al. (1999)
23
proximally. Rarely, symptoms will begin in the hands.
Jann et al. (2001)
18
Although coordination may be diminished, strength
Rosenberg and Vermeulen (2004)
6
usually is preserved, in contrast to the hereditary and
De Sousa et al. (2006)
61
immune-mediated neuropathies. Deep tendon reflexes
are absent or reduced, particularly at the ankles (Wolfe
Over the ensuing century, more than 100 distinct
et al., 1999; Traub and Brannagan, 2010).
causes of peripheral neuropathy have been identified
Most commonly, multiple sensory modalities are
(Mauermann and Burns, 2008). Particularly in latter
affected, involving both small and large nerve fibers. A
years, diagnostic approaches have benefited greatly
small proportion of patients show defects only in small-
from the development of electrophysiologic test-
fiber function, with impairment in temperature and pain
ing, improved pathologic and biochemical techniques,
sensation. Patients with sensorimotor manifestations
and growing understanding of immune-mediated and
most commonly experience a feeling of heaviness
hereditary neuropathies. The dominant model guiding
and paresthesias in their limbs, and to a lesser extent
the approach to patients with an initially unclassified
pain and imbalance. In contrast, patients with exclu-
neuropathy was based on more intensive evaluation,
sive involvement of small-caliber fibers primarily report
drawing on these tools as well as on more detailed kin-
pain, paresthesias, and sensory loss (Fig. 1) (McLeod
ship history and assessment (Dyck et al., 1981). This
et al., 1984; Notermans et al., 1993; Gorson and Rop-
paradigm proved quite fruitful, yielding a considerable
per, 1995; Periquet et al., 1999; Wolfe et al., 1999;
decline in the percentage of patients whose neuropa-
Jann et al., 2001; Hughes et al., 2004; Lindh et al.,
thy remained of `unknown etiology' in referral centers
2005). On physical examination, both groups typi-
(Table 2). Nevertheless, many cases remain without a
cally demonstrate loss of vibration sense in the lower
defined etiology.
extremities, as well as diminished perception of pain
and temperature. Ankle reflexes are absent in most
Second Paradigm: Idiopathic
patients with sensorimotor findings, and to a lesser
Neuropathy as a Distinct Disease
extent in patients with exclusive small-fiber involve-
ment (Fig. 1).
In 1982, Fisher described four patients with
Although the two populations may represent
idiopathic neuropathy and based on their similar
distinct disorders, Wolfe and colleagues observed that
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Singer et al.
Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
Table 3. Diagnostic criteria for CIAP (based on Wolfe et al., 1999).
Inclusion criteria
Symptoms
* Loss of sensation (numbness) or altered sensation (tingling, paresthesias, dysesthesias) or pain beginning in the distal
extremities (usually with onset in feet before hands)
* Symptoms present for at least 3 months
* No symptoms of weakness
* Symptoms of gait unsteadiness and autonomic dysfunction are allowed.
Signs
* Sensory signs are present symmetrically in distal limbs and may include any of the following: loss of vibration,
proprioception, light touch, pain (pinprick), or temperature
* Hyporeflexia or areflexia may be present but is not required, even at the ankles
* Minimal weakness or atrophy is allowed in muscles supplying movement to the finger and toes.
Laboratory studies
* Electrophysiology: sensory and motor NCS and needle EMG are often, but not invariably, abnormal; when abnormal,
findings indicate a primarily axonal polyneuropathy
* Quantitative sensory tests: vibration and temperature thresholds are often, but not invariably, abnormal
* Other studies: if NCS/EMG and QST are normal, other studies including skin biopsy to measure epidermal nerve fiber
density and autonomic studies including sudomotor tests (quantitative sudomotor axon reflex test, Silastic imprint
testing, sympathetic skin response) and vasomotor tests (heart rate variability to deep breathing, Valsalva ratio) may
provide evidence of peripheral nerve dysfunction
* Blood and urine tests: these studies should be normal or negative; a monoclonal protein by serum protein electrophoresis
and/or immunofixation electrophoresis is allowable in patients with MGUS
Exclusion criteria
* Any identifiable metabolic, toxic, infectious, systemic, or hereditary disorder known to cause peripheral neuropathy
* NCS abnormalities consistent with demyelination
* If a monoclonal gammopathy is present, the presence of an underlying lymphoproliferative disorder, malignancy, or
amyloidosis
* Weakness on examination other than mild toe and/or finger weakness
EMG, electromyography; MGUS, monoclonal gammopathy of undetermined significance; NCS, nerve conduction study; QST, quantitative
sensory testing.
many of their CIAP patients presenting with only small-
neuropathy, skin biopsy is also performed at a prox-
fiber symptoms and signs nevertheless demonstrated
imal site, generally the thigh. Quantitative sensory
large-fiber sensory, and often motor, abnormalities
testing (QST) has also been used to identify small-fiber
on electrodiagnostic testing (Wolfe et al., 1999). The
involvement in idiopathic neuropathy. Although QST
finding of large-fiber impairment in both groups on
has the benefit of being a non-invasive procedure, it is
laboratory testing suggests that they are part of a
less sensitive than skin biopsy, and has the additional
continuum of the same underlying disease process.
disadvantage of requiring active patient involvement,
Nerve conduction testing in over 75% of patients
thereby providing subjective rather than objective
with CIAP shows abnormalities, most commonly a
results (Devigili et al., 2008). Cerebrospinal fluid (CSF)
examination and sural nerve biopsy generally do not
reduced-amplitude or absent sural sensory response.
contribute helpful information, and are not part of
Notably, abnormalities on needle electromyography
the standard workup of idiopathic neuropathy. CSF
(EMG) examination are observed in a majority of
results typically are normal. Pathologic assessment of
patients, including those without motor symptoms or
the sural nerve in CIAP patients demonstrates non-
deficits on examination (Wolfe et al., 1999).
specific axonal degeneration (Traub and Brannagan,
The most sensitive test to confirm small-fiber
2010).
abnormalities is skin biopsy, with assessment of the
Although the absence of a clear etiologic diagnosis
density and morphology of epidermal nerve fibers.
may be distressing to patients and their families, the
This procedure typically utilizes a small (3 mm) punch
natural history of CIAP offers some reassurance. The
biopsy tool, following injection of local anesthetic, and
typical course for CIAP is one of generally stable
can be completed in minutes during a clinic visit.
symptoms, which may progress slowly over years.
Distal sites routinely biopsied include the dorsum
Patients with an exclusively sensory polyneuropathy
of the foot or the calf. For comparison, as well as
may
reach
a
stable
plateau,
without
further
to distinguish sensory neuronopathy from peripheral
progression. Nearly all CIAP patients retain the ability to
45

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Singer et al.
Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
(A)
Sensorimotor Polyneuropathy
Sensory Polyneuropathy
heaviness
paresthesias
paresthesias
sensory loss
sensory loss
pain
pain
imbalance
0
20
40
60
80
100
0
20
40
60
80
100
Percent
Percent
(B)
Sensorimotor Polyneuropathy
Sensory Polyneuropathy
LE vibratory
LE vibratory
pinprick
pinprick
light touch
light touch
proprioception
proprioception
ankle reflexes
ankle reflexes
LE weakness
LE weakness
hand weakness
hand weakness
0
20
40
60
80
100
0
20
40
60
80
100
Percent
Percent
Figure 1. Chronic idiopathic axonal polyneuropathy (CIAP) patients with various reported presenting symptoms (A) (McLeod
et al., 1984; Notermans et al., 1993; Gorson and Ropper, 1995; Periquet et al., 1999; Wolfe et al., 1999; Jann et al., 2001;
Hughes et al., 2004; Lindh et al., 2005) and examination findings (B) (Notermans et al., 1993; Gorson and Ropper, 1995;
Periquet et al., 1999; Wolfe et al., 1999; De Sousa et al., 2006). CIAP patients were grouped based on whether they had
combined sensorimotor involvement, or exclusively small-fiber sensory involvement. Bars indicate the range of percent of
patients with the corresponding feature in the referenced studies.
walk independently (Wolfe et al., 1999). In addition to
less effective (Wolfe and Trivedi, 2004). There is no
counseling regarding the relatively benign course of the
evidence to support the use of laser light therapy or
disorder, clinicians also should address any problems
magnet-based treatments (Bril et al., 2011).
with fatigue, gait instability, or neuropathic pain.
Physical therapy is not necessary for all patients, but
can be very helpful for those who feel unsteady when
Third Paradigm: Identification
walking or otherwise are at increased risk for falling.
of Modifiable Risk Factors
No clinical trials have yet been undertaken specifi-
Detailed characterization of increasing numbers of
cally for pain in CIAP. Nevertheless, clinicians have suc-
CIAP patients has now enabled investigators to turn
cessfully treated CIAP patients with medications for
their attention to the search for common features that
neuropathic pain proven effective in studies involving
could represent underlying causes of CIAP. Although
patients with neuropathy due diabetes mellitus (Wolfe
to date no consensus exists regarding the pertinence
and Trivedi, 2004). First-line medications include tri-
of potential risk factors, a number of associations
cyclic antidepressants, such as amitriptyline or nor-
have been identified. Data suggest that impaired
triptyline; calcium-channel ligands, such as gabapentin
glucose tolerance (IGT) (Novella et al., 2001; Singleton
or pregabalin; and serotonin-norepinephrine reuptake
et al., 2001), hypertension (Teunissen et al., 2002), and
inhibitors such as venlafaxine or duloxetine. Opiate
dyslipidemia (Teunissen et al., 2002; Hughes et al.,
medications are effective and may be appropriate
2004) contribute to the development of CIAP.
under certain circumstances, but for safety, admin-
IGT, dysplidemia, hypertension, and obesity com-
istration is best guided by pain specialists or other
prise the metabolic syndrome, which is well known to
physicians experienced in their use, particularly in
increase the risk of cerebrovascular and cardiovascu-
the elderly. Medications such as selective serotonin-
lar diseases. Patients with only small-fiber involvement
reuptake inhibitors and anticonvulsants tend to be
also have increased prevalence of metabolic syndrome
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Singer et al.
Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
(Pittenger et al., 2005; Zhou et al., 2011), correlating
in CIAP. In a meta-analysis of 50 studies, compris-
with the severity of the neuropathy (Zhou et al., 2011).
ing nearly 10,000 patients, Vrancken and colleagues
Retrospective analysis of over 120 CIAP patients seen
observed that absent vibration sense at the great toes,
at our institution supports the association of obesity,
as well as absent ankle reflexes, was identified in
IGT, and hypertension, and also indicates a strong
nearly one-quarter of self-reported healthy individu-
association with a new risk factor, obstructive sleep
als >60 years old, but only rarely in healthy younger
apnea (OSA) (Singer et al., manuscript in preparation).
patients (Vrancken et al., 2006). Corresponding results
These findings offer the encouraging prospect that
were obtained from an analysis of nerve conduction
management of risk factors of metabolic syndrome
studies on 3,969 patients determined by neurologists
and OSA, for which effective treatments already exist,
to have a normal neurologic examination: some 24% of
can slow progression or even prevent development of
individuals aged 70-79 years had absent sural sensory
CIAP. A necessary first step, of course, is confirmation
responses, whereas the sural response was absent
of these results in large-scale studies, as well as
in fewer than 1% of normal subjects younger than
demonstration of the benefits of intervention. Such
50 years of age (Rivner et al., 2001). Pathologic analy-
efforts are already underway (Dyck et al., 2007). A
sis of peripheral nerve tissue from patients older than
small interventional study, utilizing diet and exercise
50 without neuropathy showed axonal degeneration,
counseling for 32 patients with IGT, demonstrated
with attempted regeneration (Swallow, 1966; Jacobs
improvements in intraepidermal nerve fiber density,
and Love, 1985). Similarly, skin biopsies demonstrated
as well as glucose and cholesterol levels, body mass
decreased intraepidermal nerve fiber density in clini-
index, and neuropathic pain (Smith et al., 2006).
cally normal individuals older than 60 years, compared
with normal younger subjects (Periquet et al., 1999).
We propose that CIAP may be caused by elevated
levels of ROS resulting from one or more of a
Oxidative Stress: A Fourth Paradigm?
number of comorbid conditions, such as OSA and the
Certainly, CIAP may develop through a variety of
components of metabolic syndrome. The generation
mechanisms that generate a similar phenotype. Some
of ROS, beyond levels produced by normal metabolic
presumed cases of CIAP ultimately may prove to
processes and cell signaling, overwhelms cellular
be due to hereditary factors or another known but
antioxidant systems, damages peripheral nerves, and
previously unrecognized cause. While it is important to
interferes with the ability of nerves to repair injury. As a
be open to these possibilities, the substantial recent
result, susceptible individuals experience `accelerated
progress in CIAP investigation testifies to the value of
aging' of their peripheral nerves. Intriguingly, peripheral
a unifying hypothesis to guide research efforts. Such
neuropathy has been reported as a possibly under-
a unifying hypothesis may be emerging from more
recognized feature of Werner's progeria syndrome
recent observations: increased oxidative stress as a
(Anderson and Haas, 2003).
cause of CIAP.
Effective treatments to counter excess ROS would
Several lines of evidence support this possibility.
require access to appropriate intracellular compart-
First, the risk factors of obesity (Furukawa et al.,
ments, while not interfering with normal cellular signal-
2004), hypertension (Lassegue and Griendling, 2004),
ing dependent on reactive species. Simply increasing
hypercholesterolemia (Stokes and Granger, 2005),
antioxidant intake by dietary modifications or use of
impaired glucose metabolism (Meigs et al., 2007), and
supplements may not be efficacious and could even
OSA (Lavie, 2009) are all associated with oxidative
be harmful.
stress. In addition, experimental studies have shown
that the peripheral nervous system is vulnerable to
Conclusion
damage by oxidative stress (Vincent et al., 2004).
Interestingly,
the
cellular
mechanism
by
which
Despite the many challenges ahead, recent work
peripheral nerves trigger repair of injuries also appears
characterizing the CIAP population provides a solid
to be sensitive to inactivation by reactive oxygen
foundation for optimism on the part of patients and
species (ROS) (H oke, 2006). Therefore, oxidative
clinicians. The paradigm shifts outlined above hopefully
stress not only may damage peripheral nerves directly
will focus greater scientific and public attention on
but also may perpetuate and extend such injuries by
CIAP, and help broaden funding support for further
impairing the ability of nerves to recover.
investigation. With time and continued effort, the era
Oxidative stress is widely thought to cause many
of the `non-diagnosis of idiopathic neuropathy' (Kissel,
physiologic changes that occur with normal human
2006) should finally give way to one in which clinicians
aging (Lane, 2003). A number of peripheral nerve
are empowered to classify and treat this very common
changes documented with aging are also present
neuropathy presentation.
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Singer et al.
Journal of the Peripheral Nervous System 17(Supplement):43-49 (2012)
Disclosure
Jann S, Beretta S, Bramerio M, Defanti CA (2001). Prospective
follow-up study of chronic polyneuropathy of undetermined
The author declares no conflict of interest.
cause. Muscle Nerve 24:1197-1201.
Kissel JT (2006). Peripheral neuropathy with impaired glucose
tolerance:
a
sweet
smell
of
success?
Arch
Neurol
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