Causes of chronic neuropathies: a single-center experience

Abstract

Objectives
Chronic neuropathies are a common cause of neurological disability worldwide. However, few reports have evaluated, in real life, the prevalence of the several conditions which can cause it.

Patients and methods
The authors reviewed informatic database for outpatient office to confirm identification of chronic neuropathy in a 3-year interval period.

Results
Among the 100 selected patients with chronic neuropathies, almost one fifth (19%) remained idiopathic. The most common etiologies were diabetes (17%), dysimmune neuropathies (38%), and vitamin B12 deficiency (9%). In the “dysimmune neuropathies” group, we distinguished various etiologies, including dysimmune neuropathies associated or not with systemic autoimmune diseases (7 and 3%, respectively), chronic inflammatory polyneuropathy (CIDP) (8%), multifocal motor neuropathy (MMN) (3%), paraproteinemic (8%), celiac disease-related (6%), and paraneoplastic (3%) neuropathies.

Conclusions
In this report from a single neurological center, treatable causes of chronic neuropathies, such as dysimmune neuropathies, including CIDP, and celiac disease-associated neuropathy, were common. These findings suggest the utility of routine screening with blood testing for dysimmune neuropathy and celiac disease for all patients presenting with idiopathic chronic polyneuropathy in whom primary diagnostic testings had failed to identify an etiology for the disease.

Significance
Our results indicate that patients with peripheral neuropathy could receive a benefit from being evaluated routinely in a specialized neurological center, as many of the conditions that were discovered represented potentially treatable causes of neuropathy.

Full text

1 23
Neurological Sciences
ISSN 1590-1874
Neurol Sci
DOI 10.1007/s10072-019-03899-z
Causes of chronic neuropathies: a single-
center experience
Lorenzo Ricci, Marco Luigetti, Lucia
Florio, Fioravante Capone & Vincenzo
Di Lazzaro

1 23
Your article is protected by copyright and all
rights are held exclusively by Fondazione
Società Italiana di Neurologia. This e-offprint
is for personal use only and shall not be self-
archived in electronic repositories. If you wish
to self-archive your article, please use the
accepted manuscript version for posting on
your own website. You may further deposit
the accepted manuscript version in any
repository, provided it is only made publicly
available 12 months after official publication
or later and provided acknowledgement is
given to the original source of publication
and a link is inserted to the published article
on Springer's website. The link must be
accompanied by the following text: "The final
publication is available at link.springer.com”.

ORIGINAL ARTICLE
Causes of chronic neuropathies: a single-center experience
Lorenzo Ricci
1
&Marco Luigetti
2,3
&Lucia Florio
1
&Fioravante Capone
1
&Vincenzo Di Lazzaro
1
Received: 16 July 2018 /Accepted: 12 April 2019
#Fondazione Società Italiana di Neurologia 2019
Abstract
Objectives Chronic neuropathies are a common cause of neurological disability worldwide. However, few reports have evalu-
ated, in real life, the prevalence of the several conditions which can cause it.
Patients and methods The authors reviewed informatic database for outpatient office to confirm identification of chronic
neuropathy in a 3-year interval period.
Results Among the 100 selected patients with chronic neuropathies, almost one fifth (19%) remained idiopathic. The most
common etiologies were diabetes (17%), dysimmune neuropathies (38%), and vitamin B12 deficiency (9%). In the Bdysimmune
neuropathies^group, we distinguished various etiologies, including dysimmune neuropathies associated or not with systemic
autoimmune diseases (7 and 3%, respectively), chronic inflammatory polyneuropathy (CIDP) (8%), multifocal motor neuropathy
(MMN) (3%), paraproteinemic (8%), celiac disease-related (6%), and paraneoplastic (3%) neuropathies.
Conclusions In this report from a single neurological center, treatable causes of chronic neuropathies, such as dysimmune
neuropathies, including CIDP, and celiac disease-associated neuropathy, were common. These findings suggest the utility of
routine screening with blood testing for dysimmune neuropathy and celiac disease for all patients presenting with idiopathic
chronic polyneuropathy in whom primary diagnostic testings had failed to identify an etiology for the disease.
Significance Our results indicate that patients with peripheral neuropathy could receive a benefit from being evaluated routinely
in a specialized neurological center, as many of the conditions that were discovered represented potentially treatable causes of
neuropathy.
Keywords Chronic neuropathies .Diabetes .CIDP .Celiac disease
Introduction
Chronic neuropathies have a high prevalence among the gen-
eral population: disorders of the peripheral nervous system
account for 1.5 million visits to neurologists annually, with
an estimated prevalence of 2 to 7% in the entire population,
which increases at a rate of more than 10% in the elderly
population [1–4].
The diagnostic workup for the identification of the causes
of neuropathies requires the use of different tests of increasing
complexity. Usually, a first-level evaluation (fasting glucose
test, vitamin B12 dosage, serum protein electrophoresis, thy-
roid screening, and glucose tolerance tests) is performed in
primary neurological centers whilst patients are referred to
specialized centers for further evaluations (blood testing for
autoimmune or paraneoplastic conditions, genetic tests, skin
or nerve biopsy, ultrasound, or magnetic resonance of periph-
eral nerves) [5]. Although data exist about the main epidemi-
ological stratification of patients after a first diagnostic evalu-
ation by primary care physicians [1–5], few reports have eval-
uated the epidemiology and classification of chronic neurop-
athies on the basis of secondary diagnostic tests in specialized
centers [6,7].
The aim of this study was to report data obtained by a
single tertiary neurological center in the classification of dif-
ferent possible etiologies of chronic neuropathies and to com-
pare them with available literature data.
*Lorenzo Ricci
Ricci.lorenzo90@gmail.com; lorenzo.ricci@unicampus.it
1
Unit of Neurology, Neurobiology, Department of Medicine,
University Campus Bio-Medico of Rome, via Álvaro del Portillo, 21,
00128 Rome, Italy
2
IRCCS, UOC Neurologia, Fondazione Policlinico Universitario
Agostino Gemelli, Rome, Italy
3
Università Cattolica del Sacro Cuore, Sede di Roma, Rome, Italy
Neurological Sciences
https://doi.org/10.1007/s10072-019-03899-z
Author's personal copy

Patients and methods
We performed a retrospective study adopting a previously
validated [8] neuropathy case-capture method that involves
screening all new patient visits for International
Classification of Diseases, Ninth Revision (ICD-9) neuropa-
thy symptoms and diagnostic codes (250.60, 356.0-356.2,
356.4, 356.8, 356.9, 357.1-357.7, 357.82, 357.89, 357.9,
729.5 [pain in the limb], and 782.0 [disturbance of skin sen-
sation]) using our informatic database of the outpatient office
(MedArchiver vers. 8.7.9.9), to confirm that the patients met
our peripheral neuropathy definition. Our study was approved
by the local Ethics Committee. No informed consent was re-
quired. The case-capture method was used from January 1,
2013, through March 31, 2015. All patients were visited in
the outward ambulatory for neuromuscular diseases.
Information abstracted included demographic characteristics,
clinical characteristics (time since symptom onset, family his-
tory of neuropathy, pain, weakness on examination, and the
signs of an atypical presentation, including relapsing appear-
ance; asymmetry; non-length dependent; motor predominant;
and prominent autonomic features), and all diagnostic tests
ordered during the visit.
We also performed a neurophysiological examination,
which is part ofthe routine diagnostic workup for neuropathy.
Motor nerve conduction studies (NCSs) of the ulnar, peroneal,
and tibial nerves were performed using standard techniques
[9–11]. All studies were performed in a warm room and skin
temperature was > 32 °C; if needed, an infraredlamp was used
to warm the studied segment. Distal motor latency was mea-
sured at the onset of the compound muscle action potential,
and the low- and high-frequency filters were set at 20 Hz and
10 kHz. Sensory NCSs of sural and radial nerves were per-
formed using standard techniques [11–14]. For the sural nerve
antidromic stimulation was used, whilst the orthodromic
method was performed for sensory NCSs of the upper limbs.
Sensory nerve action potential amplitude and nerve conduc-
tion velocity were measured as previously described [15–18].
Neuropathy was defined as (a) sensory axonal with a reduc-
tion of sensory nerve action potential amplitude at least in the
sural nerve bilaterally or in more sensory nerves, (b) motor
axonal with a reduction of the compound muscle action po-
tential amplitude at least in the tibial nerve bilaterally or in
more motor nerves, and (c) sensory-motor axonal in the pres-
ence of axonal involvement of both motor and sensory nerves.
Finally, demyelinating neuropathy was diagnosed according
to electrophysiological criteria for definite chronic inflamma-
tory demyelinating neuropathy (motor distal latency prolon-
gation, reduction of motor conduction velocity, prolongation
or absence of F-wave latency, conduction blocks or excessive
temporal dispersion) [14].
All patients were screened with laboratory testing for pri-
mary evaluation of chronic neuropathy including fasting
glucose, vitamin B12, serum protein electrophoresis, glucose
tolerance test, and thyroid hormone levels [15]. Patients with
electrophoresis findings suggestive of paraproteinemia
underwent secondary analysis with serum immunofixation.
Moreover, we proposed to all patients with negative results
on primary screening test, according to neurophysiological
sub-set, secondary laboratory evaluations for the detection of
autoantibodies against peripheral nervous system antigens,
including anti-myelin and anti-axon antibodies; anti-MAG
and anti-SGPG antibodies (IgM); anti-ganglioside GM1,
GQ1b, and GD1b antibodies (IgM and IgG), onconeural an-
tibodies (anti-Hu, Yo, Ri, Amphipysine, Cv2, MA1, MA2/
TA, GAD-65 antibodies); celiac disease screening antibodies
(anti-tissue transglutaminase (tTG), anti-endomysial antibod-
ies and antigliadin IgA and IgG antibodies assays); and auto-
antibodies for systemic connective tissue diseases and vascu-
litis (anti DS-DNA, anti Sm, anti U1 RNP, anti-Ro/SSA, anti-
La/SSB, anti-citrullinated peptides, p-ANCA, c-ANCA anti-
bodies, cryoglobulinemia testing), and laboratory evaluation
for infective causes of neuropathy (HBV, HCV, Lyme disease
serology). Selected patients with negative results underwent
CSF examination by lumbar puncture, with analysis for pro-
tein level and white cells’count. Selected patients with high
clinical suspicion for paraneoplastic neuropathy performed
cancer screening with high-resolution contrast-enhanced CT
scans of the chest, abdomen, and pelvis. Patient that were lost
to follow-up were excluded by the study.
Results
We identified100 patients with chronic peripheral neuropathy
based on electrophysiological studies and clinical examination
(including distal symmetric polyneuropathy and neuropathies
with a clinical asymmetrical pattern or proximal involvement).
The age range was 25–90 (mean 69 ± 12.7) years. The gender
distribution was 66% men and 34% women.The demographic
and clinical features are described in Table 1.
The majority of our patients (around 60%) had not been
evaluated by neurologists before referring to our center.
A specific etiology for the neuropathy was identified in 81
patients (81%). The frequencies of the different etiologies are
described in Table 2.
The most common cause was the diabetes mellitus (17%,
mean level of Hb1Ac; 6.9%, mean level of fasting plasma
glucose; 135 mg/dL). Eleven (11%) of these fulfilled the
American Diabetes Association criteria for the diagnosis of
diabetes, and six (6%) had altered glucose metabolism (im-
paired glucose tolerance (IGT)) based on the same criteria
[19]. Ten patients (10%) were under treatment with anti-
diabetic medications (oral hypoglycemic agents or insulin).
Typical clinical features of these patients included not only
distal painful symmetrical sensory polyneuropathy (82.3%),
Neurol Sci
Author's personal copy

but also a significantly high rate of patients with gait instabil-
ity and positive Romberg test (58.8%); electrodiagnostic tests
revealed more commonly a sensory axonal neuropathy
(84.8%).
In our study, we obtained a meaningful number of
dysimmune neuropathies, with results similar to the report
by Hanewinckel et al. [2]. We have further sub-categorized
the group of Bdysimmune neuropathies^allowing for a
comprehensive inclusion of all the kind of neuropathies that
share a common pathophysiological dysimmune trigger that
has included CIDP (8%), dysimmune neuropathies other than
CIDP, associated or not with systemic autoimmune diseases
(7% and 3%, respectively), paraproteinemia-related neuropa-
thy (8%), celiac disease-related neuropathy (6%), multifocal
motor neuropathy (MMN) (3%), and paraneoplastic neuropa-
thy (Table 2).
Eight patients (8%) were found to have chronic inflamma-
tory demyelinating neuropathy (CIDP). The diagnosis was
based on clinical features, typical nerve conduction study pa-
rameters, cerebrospinal fluid (CSF) protein assessment, and
exclusion of other causes [14,17]. In the CIDP group, two
patients showed the typical presentation consisting of proxi-
mal and distal symmetrical motor weakness whilst the other
five patients presented asymmetrical distal and proximal mo-
tor weakness: a variant of CIDP known as multifocal acquired
demyelinating sensory-motor neuropathy (MADSAM) or
Lewis-Sumner syndrome [18,20]. In addition to motor weak-
ness, neurological examination revealed sensory deficits and
ataxia in three patients and decreased deep tendon reflexes in
five patients. One patient presented high titers (> 1:100) anti-
GQ1b antibodies; on neurological examination, this patient
presented cranial nerve involvement (dysarthria) and large
fiber sensory neuropathy with gait instability and ataxia (a
clinical scenario compatible with a diagnosis of chronic ataxic
neuropathy with anti-disialosyl antibodies, CANOMAD
[21]).
Ten patients presented dysimmune neuropathies other than
CIDP associated or not with systemic autoimmune disease
(7% and 3%, respectively). Among patients with systemic
Table 2 Causes of peripheral
neuropathy after initial diagnostic
testing
Cause of peripheral neuropathy Number of patients Percent
Idiopathic 19 19%
Diabetes mellitus 17 17%
Vitamin B12 deficiency 9 9%
Dysimmune neuropathies
Associated or not with autoimmune
disease (other than CIDP)
7 +3 associated with autoimmune disease
(1 vasculitis, 2 connective tissue diseases)
7% + 3%
CIDP 8 8%
Paraproteinemia-related neuropathy 8 8%
Celiac disease 6 6%
Multifocal motor neuropathy (MMN) 3 3%
Paraneoplastic neuropathy 3 3%
Hypothyroidism 6 6%
Toxic causes 4 4%
Genetic polyneuropathy 3 3%
Infective causes 2 2%
Alcohol 1 1%
Chronic kidney disease 1 1%
Total 100
Table 1 Demographic characteristics and clinical features of patients
with distal polyneuropathy
Variable No. (%) of 100 patients
Age mean (SD), years 68.5 (12.7)
Male sex 66 (66)
Smokers 18 (18)
Symmetric involvement 76 (76)
Motor deficit 66 (66)
Abnormal sensory examination 65 (65)
Neuropathic symptoms 51 (51)
Decreased reflexes 61 (61)
Gait instability 45 (45)
Axonal neuropathies 75 (75)
Demyelinating neuropathies 13 (13)
Distal symmetric polyneuropathy 76 (76)
Multineuropathy 24 (24)
Sensory neuronopathy 23 (23)
Sensory-motor axonal neuropathy 29 (29)
Motor axonal neuropathy 14 (14)
Disease duration mean (SD), years 4.9 (5.8)
Neurol Sci
Author's personal copy

autoimmune diseases, connective tissue disease was consid-
ered the cause of dysimmune neuropathy in two patients (2%);
one patient had rheumatoid arthritis whilst the second present-
ed Sjögren disease. Finally, vasculitis was the origin of
dysimmune neuropathy in one patient (1%). This patient
was affected by non-length dependent sensory-motor axonal
neuropathy, positivity for antineutrophil cytoplasmatic auto-
antibodies, and systemic vasculitis.
In the other seven patients (7%), a probable dysimmune
neuropathy (other than CIDP) was diagnosed. This character-
ization was based either on the presence of specific autoanti-
bodies associated with connective tissue diseases or vasculit-
ides on patient’s serum analysis or mononeuritis multiplex
pattern on nerve conduction studies, association with systemic
autoimmune diseases, or elevated protein level on CSF exam-
ination with normal white cell count (albuminocytologic dis-
sociation) and clinical improvement after immune therapy
[14,16]. The majority of these patients (70%) improved after
immune therapy. The remaining three patients showed absent
or poor response to immune-modulating agents (intravenous
glucocorticoids, intravenous immunoglobulin (IVIG)). In one
patient (10% of this group), we discovered the occurrence of
anti-gangliosides antibodies on serum analysis. The patient
presented, as collateral finding, high titer (> 1:100) anti-
GD1a antibodies and symmetrical distal sensory-motor neu-
ropathy with axonal features on NCS and distal motor weak-
ness. One patient presented low-titer autoantibodies against
unspecified peripheral nervous system antigens on serum
analysis. The clinical and neurophysiological features were
consistent with a motor axonal neuropathy presenting with
distal symmetrical motor weakness.
Celiac disease was diagnosed after the onset of peripheral
neuropathy in six patients (6%) by means of celiac disease
antibodies positivity on serum analysis (anti-tissue
transglutaminase (tTG), anti-endomysial antibodies, and
antigliadin IgA and IgG antibodies), presented in five patients
out of six, and/or typical small bowel biopsy (which was di-
agnostic in four patients out of six) [22]. The majority of these
patients presented axonal sensory-motor distal symmetric
polyneuropathy. Neuropathic symptomswere observed in just
one patient, whilst sensory ataxia and gait instability were
seen in four patients. All of them (six patients, 100%) greatly
improved with the introduction of a gluten-free diet.
Paraproteinemic component was identified on serum elec-
trophoresis and immunofixation in eight patients (8%) and
was considered the cause of the neuropathy in these groups.
Six patients (6%) presented a monoclonal gammopathy of
undetermined significance (MGUS). Among them, three pa-
tients presented IgM monoclonal component on serum analy-
sis (two patients IgM-kappa, one patient IgM-lambda) and
two patients presented IgG-kappa monoclonal component
whilst the last patient had IgA-kappa monoclonal component.
The majority of these patients presented a sensory-motor
distal polyneuropathy with symmetrical involvement and
mixed electrophysiological features (axonal and demyelinat-
ing) on NCS. Anti-MAG antibodies were identified in one
patient with IgM monoclonal component.
All patients with MGUS performed fat aspirate in order to
exclude AL amyloidosis, and they all showed negative results
for amyloid deposition.
Two patients had Waldenstrom macroglobulinemia. High
titers anti-MAG and anti-GD2 antibodies were identified in
one patient. This patient was treated with rituximab without
clinical recovery. The other patient had a history of kidneyand
colon cancer which underwent surgical excision.
Three patients (3%) presented multifocal motor neuropathy
(MMN). All of them had high titers (> 1:100) anti-GM1 anti-
bodies on serum analysis and asymmetrical multifocal motor
involvement without a sensory deficit. However, no conduc-
tion blocks were observed in these patients. Two of these
patients also presented other high titers’anti-ganglioside anti-
bodies on serum analysis (anti-GD1b).
Paraneoplastic neuropathy was found as the cause of neu-
ropathy in three patients(3%). Twopatients presented sensory
axonal neuropathy which improved after surgical treatment of
lung adenocarcinoma. The last patient was affected by non-
Hodgkin lymphoma which caused sensory-motor axonal
polyneuropathy and did not improve after chemotherapy for
the neoplastic disorder.
Vitamin B12 deficit was observed as the cause of neurop-
athy in nine patients (9%, vitamin B12 levels < 200 pg/ml in
all patients); most of them (eight patients out of nine) im-
proved after vitamin replacement. Typical electrophysiologi-
cal findings were consistent with axonal large fiber sensory-
motor symmetrical polyneuropathy.
In six patients (6%), hypothyroidism was found (TSH
levels > 3.75 μUI/mL, fT4 levels < 9.8 pmol/L; fT3 levels <
4.29 pmol/L in all patients), and this was considered the cause
of neuropathy. Most of them presented axonal sensory-motor
polyneuropathy with symmetrical involvement and neuro-
pathic pain symptoms with improvement after hormonal re-
placement therapy.
Toxic neuropathy was diagnosed in fourpatients (4%). One
patient developed distal symmetrical sensory-motor neuropa-
thy after treatment with vincristine for Hodgkin lymphoma.
One patient presented asymmetrical demyelinating sensory-
motor neuropathy after treatment with amiodarone. The last
two patients had a history of professional-related toxic expo-
sure. One patient developed symmetrical sensory distal axonal
polyneuropathy after several years of exposure to an industrial
solvent (flugene; 1,1,2-trichloro-1,2,2-trifluoroethane) [23].
The second patient worked as an anesthesiologist and devel-
oped sensory-motor axonal polyneuropathy years after profes-
sional exposure to volatile anesthesia (trichloroethylene, ni-
trous oxide, halogenated hydrocarbons) [24], no other possi-
ble explanation for peripheral neuropathy was discovered,and
Neurol Sci
Author's personal copy

a presumptive diagnosis of occupational-related neuropathy
was made [25].
The cause of polyneuropathy was thought to be genetic in
three patients (3%) because of family history and age of pre-
sentation although genetic testing was not performed. They
both showed axonal sensory-motor neuropathy with promi-
nent neuropathic pain symptoms.
Other causes of neuropathy were alcohol toxicity (1%),
chronic kidney disease (1%), and infections (Lyme disease
1%, HBV infection 1%).
The etiology remained unknown in 19 patients (19%); this
result was in agreement with other studies [2,3,7,26,27]. In
the idiopathic group, the majority of patients (15 patients,
78.9%), presented an axonal neuropathy on electrodiagnostic
studies, whilst four patients (21% of this group) presented
mixed axonal and demyelinating features on NCS. The clini-
cal features were consistent with distal symmetric
polyneuropathy in all 19 patients (100%). An abnormal sen-
sory examination was observed in nine patients (47.3%)
whilst nine patients (47.3%) reported neuropathic symptoms
(extremity pain and dysesthesia). Decreased reflexes were
confirmed on neurological examination in nine patients
(47.3%). Three patients (15.8%) presented gait instability
and a positive Romberg test on physical examination.
Discussion
Chronic neuropathy is a common cause of neurological dis-
ability worldwide; however, few reports exist that testify the
prevalence of the several conditions which can cause neurop-
athy in adult population after secondary diagnostic test in spe-
cialized neurological centers [6,7]. Besides, most of those
results were based on studies from the 1980s and 1990s [26,
27]. Since then, new clinical entities have been characterized
and we have assisted to a remarkable boost in the arsenal of
screening tests for patients with neuropathy.
Among our patients, we confirmed chronic idiopathic neu-
ropathy in almost one fifth of patients presenting for evalua-
tion of peripheral neuropathy (19%), with a similar rate to
previous reports in the literature [2,7,26,27].
Diabetic neuropathy is universally recognized as the most
common cause of peripheral neuropathy and neuropathic pain
worldwide, with a lifetime incidence of 45% in patients with
type 2 diabetes mellitus and 55% for type 1 diabetes mellitus
[29]. Our study showed a compatible result, and diabetic neu-
ropathy was confirmed to be the most frequent cause of neu-
ropathy in our group (17%).
We have observed a significative number of patient with
dysimmune neuropathies, who were further sub-categorized
according to different etiologies (Table 2).
Chronic inflammatory demyelinating neuropathy (CIDP)
is the most common type of immune neuropathy [30]. No
reliable biomarker exists by which to diagnose CIDP [30]
whilst electrodiagnostic criteria, such as those proposed by
the European Federation of Neurological Societies and the
Peripheral Nerve Society, are valuable resources when diag-
nosing the disease [14]. Although the diagnostic tests used
within these criteria are useful, they support rather than defin-
itively confirm the diagnosis of CIDP [31]. Other dysimmune
neuropathies include axonal polyneuropathy causedby vascu-
litis, paraproteinemias, other systemic diseases, and other
dysimmune neuropathies associated with anti-ganglioside
and anti-peripheral nerve antibodies; this group accounts for
a significative portion of this case series.
The search for autoantibodies in CIDP and chronic
dysimmune neuropathies has recently been boosted with the
description of antibodies targeting the node of Ranvier in this
subgroup of patients [32]. In our study, the investigation for
anti-ganglioside and anti-peripheral nerve antigen detection
helped to suggest the diagnosis in eight patients previously
considered as affected by idiopathic chronic neuropathy.
Up to 23% of patients with established celiac disease have
neurophysiologic evidence of a peripheral neuropathy [33].
Gluten neuropathy is defined as otherwise idiopathic neurop-
athy with typical small bowel biopsy findings or serologic
evidence of gluten-related antibodies and clinical improve-
ment after a gluten-free diet. The commonest types are sym-
metric sensorimotor axonal peripheral neuropathy and senso-
ry ganglionopathy [34,35]. Our study showed an interesting
high rate of celiac disease-related neuropathies (6%), at a
higher rate than in the report by Farhad et al. (1.4%) [7].
Other causes of neuropathy secondary to malabsorption (vita-
min B12, B6, and B1 deficiency) were excluded in these pa-
tients. This high rate can be due to the systematic research for
gluten-related antibodies in our group, especially in those pre-
senting with suggestive clinical features (sensory ataxia or
symmetric sensorimotor axonal peripheral neuropathy).
Paraproteinemia is a known cause of neuropathy [10,36].
It was also a common cause of neuropathy in our patients.
Serum protein electrophoresis was regularly performed in
our group of patients as an essential component of the diag-
nostic workup, as MGUS is considered to be a pre-malignant
lymphoplasmacytic proliferative disorder. Two patients either
with IgM monoclonal gammopathy of undetermined signifi-
cance and Wäldenstrom’s macroglobulinemia had anti-MAG
antibodies on serum analysis. The clinical syndrome associat-
ed with anti-MAG antibodies is the distal acquired demyelin-
ating symmetrical (DADS) sensory-motor neuropathy, an en-
tity distinct from classical CIDP [37]. We observed three pa-
tients who presented non-IgM MGUS associated
polyneuropathy. In this subgroup of patients, we decided to
ascribe a causative role to the monoclonal component on the
basis of supportive clinical features (time to peak of the neu-
ropathy > 2 years, chronic slowly progressive course without
relapsing or remitting periods, demyelinating features on
Neurol Sci
Author's personal copy

NCSs) [36] and exclusion of other possible etiologic explana-
tions, although the diagnosis remained presumptive since the
clinical correlation of non-IgM MGUS and peripheral neurop-
athy is still controversial [38].
In our study, we identify three patients with paraneoplastic
neuropathies. Paraneoplastic neurologic diseases are rare
neuroimmunologic disorders that occur in patients with cancer
[39]. Peripheral neuropathy represents one of the more com-
mon presentations [40]. Although these are rare diseases, clin-
ical suspicion and appropriate diagnostic testing are extremely
important because paraneoplastic syndrome can precede the
identification of neoplasia. A definite diagnosis of a
paraneoplastic neuropathy requires a distinct clinical presen-
tation in the context of a well-characterized paraneoplastic
autoantibody or contemporaneous diagnosis of cancer [41].
None of our patients showed paraneoplastic autoantibodies
in serum analysis; however, all of them presented a simulta-
neous diagnosis of cancer, and the peripheral nerve symptom-
atology improved after cancer treatment. We showed a sur-
prisingly high rate of paraneoplastic neuropathies in compar-
ison to other reports [7]. This result is probably due to the
regular evaluation for onconeural antibodies in patients with
clinical suspicion for paraneoplastic disorder (constitutional
symptoms or cancer risk factors) and suggestion for HR CT
of the thorax, pelvis, and abdomen in this subgroup of patient,
as paraneoplastic disorder usually appear prior to formal diag-
nosis of cancer and early recognition could have a dramatic
effect on cancer prognosis.
Hypothyroidism and vitamin B12 deficit were also com-
mon causes of neuropathy in our study, with rates slightly
inferior to other reports (6% for hypothyroidism and 9% for
vitamin deficiency in our report versus 9% for hypothyroid-
ism and 17% for vitamin deficiency in the Hanewinckel report
[2]). This discrepancy could be due to the fact that these
causes of neuropathy are more likely to be diagnosed by gen-
eral practitioners and general neurologists, with lesser need for
specialist neurological evaluation in a tertiary center for
neuropathies.
We observed three patients with a suspected genetic cause
of neuropathy. This rate is not as prevalent as in other reports
described in the literature. The explanation could possibly be
related to a diagnosis extrapolated by family history or skeletal
leg abnormalities rather than confirmatory genetic testing in
earlier studies [1–4]. The actual more diffuse use of screening
genetic tests for hereditary neuropathy in pediatric tertiary
referring centers may haveallowed for a diagnosis to be made
before the adult age. Moreover, since our center is more ex-
perienced in the diagnosis and management of acquired and
dysimmune neuropathies, we could not exclude a selection
bias towards the population of patients with genetic
neuropathies.
We could not exclude the possibility of TTR amyloidosis-
related neuropathy diagnosis among patients with chronic
idiopathic axonal neuropathy since TTR-related neuropathy
is an often under-recognized condition with a sneaky presen-
tation, and it frequently shows unspecific clinical manifesta-
tions [28].
Other causes of neuropathy, although not common in our
study, were toxic neuropathies and infective causes of
neuropathy.
In this report from a single tertiary neurological center,
potentially treatable causes of neuropathy, such as dysimmune
neuropathy, including CIDP and celiac disease-associated
neuropathy, and vitamin deficiencies were common. These
findings could raise the possibility to suggest routine screen-
ing with blood testing for dysimmune neuropathy (anti-
gangliosides antibodies) and celiac disease for all patients pre-
senting with idiopathic chronic polyneuropathy in whom pri-
mary diagnostic testings had failed to identify an etiology for
the disease, offering a chance of effective and safe
therapeutical options for these patients.
Compliance with ethical standards
Ethical Publication statement We confirm that we have read the
Journal’s position on issues involved in ethical publication and affirm that
this report is consistent with those guidelines.
Conflict of interest The authors declare that they have no conflict of
interests.
Abbreviations CD, celiac disease; CIDP, chronic inflammatory demy-
elinating polyneuropathy; CMAP, compound muscle action potential;
CSF, cerebrospinal fluid; DML, distal motor latency; GBS, Guillain-
Barrè syndrome; HR CT, high-resolution computed tomography;
MCV, motor conduction velocity; MGUS, monoclonal gammopathy of
undetermined significance; SCV, sensory conduction velocity; SNAP,
Sensory nerve action potential
References
1. McLeod JG, Tuck RR, Pollard JD, Cameron J, Walsh JC (1984)
Chronic polyneuropathy of undetermined cause. J Neurol
Neurosurg Psychiatry 47:530–535
2. Hanewinckel R, Drenthen J, van Oijen M, Hofman A, van Doorn
PA, Ikram MA (2016) Prevalence of polyneuropathy in the general
middle-aged and elderly population. Neurology 87:1892–1898
3. Pasnoor M, Nascimento OJM, Trivedi J, Wolfe GI, Nations S,
Herbelin L, de Freitas MG, Quintanilha G, Khan S, Dimachkie
M, Barohn R (2013) North America and South America (NA-SA)
neuropathy project. Int J Neurosci 123:563–567
4. Hughes RA (1995) Epidemiology of peripheral neuropathy [edito-
rial]. Curr Opin Neurol 8:335–338
5. Pasnoor M, Dimachkie MM, Barohn RJ (2013) Cryptogenic sen-
sory polyneuropathy. Neurol Clin 31:463–476
6. Callaghan BC et al (2014) Role ofneurologists and diagnostic tests
on the management of distal symmetric polyneuropathy. JAMA
Neurol 48104:1–7
7. Farhad K, Traub R,Ruzhansky KM, Brannagan TH (2016) Causes
of neuropathy in patients referred as ‘idiopathic neuropathy’.
Muscle Nerve 53:856–861. https://doi.org/10.1002/mus.24969
Neurol Sci
Author's personal copy

8. Callaghan B, Kerber K, Longoria R, Feldman E, Lisabeth L (2012)
Capturing cases of distal symmetric polyneuropathy in a commu-
nity. Muscle Nerve 46:943–947
9. Kimura J (1989) Electrodiagnosis in disease of the nerve and mus-
cle: principles and practice
10. Luigetti M, Padua L, Mazza S, Rossini PM, Sabatelli M, Lo
Monaco M (2013) Clinical-neurophysiological correlations in a
series of patients with IgM-related neuropathy. Clin Neurophysiol
124:1899–1903
11. Luigetti M, Sauchelli D, Primiano G, Cuccagna C, Bernardo D, Lo
Monaco M, Servidei S (2016) Peripheral neuropathy is a common
manifestation of mitochondrial diseases: asingle-centre experience.
Eur J Neurol 23:1020–1027
12. Merolli A, Luigetti M, Modoni A, Masciullo M, Lucia Mereu M,
Lo Monaco M (2013) Persistence of abnormal electrophysiological
findings after carpal tunnel release. J Reconstr Microsurg 29:511–
516
13. Luigetti M, Quaranta D, Modoni A, Mereu ML, Lo Monaco M
(2012) Nerve conduction studies of the sural nerve: normative data
from a single-center experience. Clin Neurophysiol 123:1891–1892
14. Joint Task Force of the EFNS and the PNS (2010) European
Federation of Neurological Societies/Peripheral Nerve Society
Guideline on management of chronic inflammatory demyelinating
polyradiculoneuropathy: report of a joint task force of the European
Federation of Neurological Societies and the Peripher. J Peripher
Nerv Syst 15:1–9
15. England JD, Gronseth GS, Franklin G, Carter GT, Kinsella LJ,
Cohen JA, Asbury AK, Szigeti K, Lupski JR, Latov N, Lewis
RA, Low PA, Fisher MA, Herrmann DN, Howard JF Jr, Lauria
G, Miller RG, Polydefkis M, Sumner AJ, American Academy of
Neurology (2009) Practice parameter: evaluation of distal symmet-
ric polyneuropathy: role of laboratory and genetic testing (an
evidence-based review): report of the American Academy of
Neurology, American Association of Neuromuscular and
Electrodiagnostic Medicine, and Am. Neurology 72:185–192
16. Karam C, Tramontozzi LA (2016) Rapid screening for inflamma-
tory neuropathies by standardized clinical criteria. Neurol Clin Pract
6:384–388
17. Rajabally YA, Nicolas G, Piéret F, Bouche P, Van Den Bergh PYK
(2009) Validity of diagnostic criteria for chronic inflammatory de-
myelinating polyneuropathy: a multicentre European study. J
Neurol Neurosurg Psychiatry 80:1364–1368
18. Lewis RA, Sumner AJ, Brown MJ, A A (1982) Multifocal demy-
elinating neuropathy with persistent conduction block. Neurology
32:958–964
19. American Diabetes Association (2012) Standardsof medical care in
diabetes—2012. Diabetes Care 35(suppl 1):S12
20. Saperstein DS, Katz JS, Amato AA, Barohn RJ (2001) Clinical
spectrum of chronic acquired demyelinating polyneuropathies.
Muscle Nerve 24:311–324
21. Willison HJ et al (2001) The clinical and laboratory features of
chronic sensory ataxic neuropathy with anti-disialosyl IgM antibod-
ies. Brain 124:1968–1977
22. Rubio-Tapia A, Hill ID, Kelly CP, Calderwood AH, Murray JA
(2013) ACG clinical guidelines: diagnosis and management of ce-
liac disease. Am J Gastroenterol 108:656–676
23. Raffi GB, Violante FS (1981) Is freon 113 neurotoxic? A case
report. Int Arch Occup Environ Health 49:125–127
24. Sharp CW & Rosenberg NL (1992) Volatile Substances Subst Abus
AComprTextb303–327
25. Kestenberg SH, Young ER (1988) Potential problems associated
with occupational exposure to nitrous oxide. Dent Assoc 54:277–
286
26. Barohn RJ (1998) Approach to peripheral neuropathy and
neuronopathy. Semin Neurol 18:7–18
27. Dyck PJ, Oviatt KF, Lambert EH (1981) Intensive evaluation of
feferred unclassdied neuropahes yields improved diagnosis. Ann
Neurol 10:222–226
28. Luigetti M, Conte A, Del A, Giulia G (2013) TTR-related amyloid
neuropathy: clinical, electrophysiological and pathological findings
in 15 unrelated patients. Neurol Sci 34:1057–1063. https://doi.org/
10.1007/s10072-012-1105-y
29. Zilliox L, Russell JW (2011) Treatment of diabetic sensory
polyneuropathy. Curr Treat Options Neurol 13:143–159
30. Latov N (2014) Diagnosis and treatment of chronic acquired demy-
elinating polyneuropathies. Nat Rev Neurol 10:435–446
31. Brannagan TH (2011) Current diagnosis of CIDP: the need for
biomarkers. J Peripher Nerv Syst 16:3–13
32. Querol L, Illa I (2015) Paranodal and other autoantibodies in chron-
ic inflammatory neuropathies. Curr Opin Neurol 28:474–479
33. Luostarinen L, Himanen SL, Luostarinen M, Collin P, Pirttilä T
(2003) Neuromuscular and sensory disturbances in patients with
well treated coeliac disease. J Neurol Neurosurg Psychiatry 74:
490–494
34. Hadjivassiliou M, Sanders DS, Grünewald RA, Woodroofe N,
Boscolo S, Aeschlimann D (2010) Gluten sensitivity: from gut to
brain. Lancet Neurol 9:318–330
35. Hadjivassiliou M, Sanders DS, Gru RA (2010) Sensory
ganglionopathy due to gluten sensitivity. Neurology 75(11):
1003–1008
36. Ramchandren S, Lewis RA (2009) Monoclonal gammopathy and
neuropathy. Curr Opin Neurol 22:480–485
37. Katz JS, Saperstein DS, Gronseth G, Amato AA, Barohn RJ (2000)
Distal acquired demyelinating symmetric (DADS) neuropathy.
Neurology 54:615–620
38. Notermans NC, Franssen H, Eurelings M, Van Der Graaf Y, Wokke
JHJ (2000) Diagnostic criteria for demyelinating polyneuropathy
associated with monoclonal gammopathy. Muscle Nerve 23:73–79
39. Darnell RB, Posner JB (2003) Mechanisms of disease:
paraneoplastic syndromes involving the nervous system. Nejm
349:1543–1554
40. Gundogdu B, Rosenfeld M. R. & Rudnicki SA (2013)
Paraneoplastic neuromuscular disorders. Neuromuscul Disord
Clin Pract 1501–1514. doi:https://doi.org/10.1007/978-1-4614-
6567-6_75
41. Graus F, Delattre JY, Antoine JC, Dalmau J, Giometto B, Grisold
W, Honnorat J, Smitt PS, Vedeler Ch, Verschuuren JJ, Vincent A,
Voltz R (2004) Recommended diagnostic criteria for paraneoplastic
neurological syndromes. J Neurol Neurosurg Psychiatry 75:1135–
1140
Publisher’snoteSpringer Nature remains neutral with regard to
jurisdictional claims in published maps and institutional affiliations.
Neurol Sci
Author's personal copy