Keywords: Polyneuropathies - Epidemiology - Diagnosis - Electrodiagnosis
Palavras-chave: Polineuropatias - Epidemiologia - Diagnóstico - Eletrodiagnóstico
INTRODUCTION
Polyneuropathies are characterized by a symmetrical and diffuse impairment of the
peripheral nervous system, which may affect motor, sensitive or autonomic nerve fibers.
Clinical features vary widely and include muscle weakness and atrophy, paresthesia,
pain, hypoesthesia and autonomic symptoms[1 ],[2 ]. Polyneuropathies have a great heterogeneity of causes. Diabetes mellitus, alcohol
abuse, genetic conditions, nutritional deficiency, drug toxicity, autoimmunity, infection,
and malignancy are some examples[2 ],[3 ]. Worldwide, especially in developed countries, the main etiology of peripheral polyneuropathy
is diabetes mellitus, with a prevalence of 30 to 66%[4 ],[5 ]. Therefore, an etiological diagnosis of polyneuropathy is a challenge that demands
time and financial resources[3 ]. Even with appropriate evaluation, between 20 and 30% of polyneuropathies remain
without a definite cause[1 ],[2 ].
Electrodiagnostic (EDX) testing, which include nerve conduction studies and needle
electromyography, is a method to measure the electrical activity of the peripheral
nervous system that is considered an extension of the neurological exam in the evaluation
of polyneuropathies[3 ],[4 ]. Several publications have discussed the indications of this exam in the diagnosis
of neuropathies[6 ]
-
[8 ]. Unfortunately, EDX testing is not used by all physicians who treat patients with
polyneuropathy. The American Association of Neuromuscular and Electrodiagnostic Medicine
(AANEM) states in its official position in 2017 that EDX testing should be considered
in the following cases: when no cause has been identified; in severe cases; in atypical
presentations; in the presence of signs or symptoms suggestive of another neuromuscular
disease; when there is a positive family history of hereditary neuropathy; or when
there is a history of exposure to toxic substances known to cause polyneuropathy[9 ].
Due to discussions regarding the indication of electrodiagnostic tests and due to
the lack of information related to the epidemiology of polyneuropathies[3 ],[10 ], the aim of this study was to determine the main etiologies of polyneuropathy confirmed
by electrodiagnostic tests within a single specialized tertiary center of Southern
Brazil. The main clinical manifestations, risk factors, and associated electrophysiological
findings are reported.
METHODS
We selected all patients with a clinical suspicion of polyneuropathy (symptoms and
signs) who attended the neuromuscular disorder center at Hospital de Clínicas da Universidade
Federal do Paraná (Curitiba, Brazil) between 2008 and 2017 and who underwent EDX testing.
The diagnosis of polyneuropathy is usually done by the combination of clinical and
electroneurophysiological features[11 ]. In this study, we included patients whose EDX test confirmed polyneuropathy and
excluded patients whose EDX test was normal, with nonspecific electroneurophysiological
findings, or showed another diagnosis, such as radiculopathy, mononeuropathy and multiple
mononeuropathy. [Figure 1 ] shows the criteria used for selecting the patients. The study was approved by the
institution's Ethics Committee (Comitê de Ética em Pesquisa em Seres Humanos).
Figure 1 Flow chart of the study methodology.*EDX tests performed in the investigation of
the same patient. EDX: Electrodiagnostic test.
In our hospital, patients with suspected polyneuropathy are determined by the examination
of the neurologist. Nerve conduction studies and needle electromyography (EMG) are
performed in all patients according to standard protocols[11 ],[12 ]. Reference values of the nerve conduction studies are based on previously published
standard protocols[12 ].
The electrophysiological criterion used for definition of polyneuropathy was an abnormality
in at least one parameter in two or more peripheral nerves of two or more extremities[11 ],[13 ]. All EDX tests were retrospectively reviewed by the authors to verify the fulfillment
of this criterion.
Electrophysiological criteria for axonal polyneuropathies were: reduced amplitude
of sensory nerve action potential (SNAP) and/or compound muscle action potential (CMAP),
with normal or only slightly slowed nerve conduction velocity (NCV), distal motor
latency (DML). and late responses. These findings may be associated with denervation
and/or reinervation signs at EMG. Isolated signs of denervation were also used as
criteria for axonal polyneuropathy[12 ],[14 ]. Criteria for demyelinating polyneuropathies were: prolonged DML (> 130% of the
upper limit of normal), slowed NCV (< 70% of the lower limit of normal), and/or prolonged
or absent late responses (> 130% of the upper limit of normal), with a normal amplitude
of SNAP and CMAP and normal results of EMG[12 ],[14 ]. Polyneuropathies were considered “demyelinating and axonal” when there were demyelinating
findings, but also reduced amplitudes and evidence of denervation, or when there were
axonal criteria but with conduction velocity below 70% of the lower limit of normality[13 ].
Polyneuropathies were classified as motor or sensory if disturbances were present
only in motor or sensitive nerve fibers, respectively. Sensorimotor polyneuropathy
was defined by abnormalities involving motor and sensitive nerve fibers[12 ].
Considering that only patients with electrodiagnostic test compatible with polyneuropathy
were included, this study did not evaluate small fiber polyneuropathies, which have
as a diagnostic criterion a normal EDX test[15 ],[16 ].
A retrospective analysis of medical records was performed, collecting data on symptoms
and signs, risk factors for neuropathy, routine and additional laboratory tests, and
complementary tests. Routine tests included complete blood count, fasting blood glucose,
glycated hemoglobin (Hb1Ac), thyroid stimulating hormone (TSH), vitamin B12, folic
acid, creatinine, urea, alanine aminotransferase (ALT), aspartate aminotransferase
(AST), direct and indirect total bilirubin, albumin, alkaline phosphatase, gamma-glutamyl
transferase, erythrocyte sedimentation rate (ESR), C-reactive protein (CRP), serology
for human immunodeficiency virus (HIV), hepatitis B and C, syphilis, and lymph node
acid-fast bacilli (AFB). Research on antinuclear antibodies (ANA), rheumatoid factor
(RF), anti-Ro and anti-La antibodies, cerebrospinal fluid (CSF) analysis, investigation
of malignancy, and genetic tests were considered additional exams[3 ],[10 ]. Although this was a retrospective study, in which the difficulty of getting information
is to be expected, no patient was excluded because of insufficient data.
The patients were grouped according to the number of polyneuropathy etiologies as
monocausal, multifactorial, or idiopathic. After evaluation of collected variables,
the etiology of the polyneuropathies was determined retrospectively according to the
following diagnostic criteria:
Hereditary: considered in the presence of a confirmatory genetic test or in the presence
of a positive family history and/or highly suggestive clinical condition, when other
causes were excluded[17 ].
Diabetes: considered in individuals with type 1 or type 2 diabetes mellitus using
hypoglycemic agents, and/or in those with fasting glucose greater than or equal to
126 mg/dL or Hb1Ac above or equal to 6.5%, confirmed at two strengths[18 ].
Guillain-Barré syndrome (GBS): diagnosed according to the diagnostic criteria of Asbury
and Cornblath, which include progressive upper and lower limb weakness, global areflexia,
a progressive phase lasting a maximum of 4 weeks, albumin-cytological dissociation
in CSF and nerve conduction changes in EDX testing, whether demyelinating (acute inflammatory
demyelinating polyneuropathy [AIDP]) or axonal (acute motor axonal neuropathy [AMAN]
or acute sensory motor axonal neuropathy [AMSAN]). The GBS variant, Miller-Fischer
syndrome, was diagnosed in the presence of ophthalmoplegia, ataxia, and global areflexia[19 ].
Chronic inflammatory demyelinating polyneuropathy (CIDP): symmetrical progressive
distal and proximal weakness associated with sensory changes in extremities, with
a progressive phase lasting at least 8 weeks, global areflexia or global hyporeflexia,
neurophysiological findings compatible with demyelination, and albumin-cytological
dissociation in CSF. The most common atypical form of CIDP, Lewis-Sumner syndrome,
was considered in the presence of an asymmetrical clinical picture, with predominance
in upper limbs[20 ].
Alcohol: in the presence of reported alcohol abuse, based on the amount and time of
consumption and the absence of another cause that better explained symptoms[21 ].
Vitamin B12 deficiency: serum vitamin B12 level below 350 pg/mL[22 ] was indispensable.
Toxicity (by medication or other substances): considered in the presence of current
or past use of a neurotoxic drug or a history of prolonged contact with a toxic substance,
in addition to finding a temporal relationship between the onset of use/contact and
the onset of symptoms and/or improvement or stabilization of symptoms after withdrawal
of the offending agent[23 ].
Infectious: in the presence of a previous diagnosis of any infectious disease known
to cause polyneuropathy (e.g. leprosy, HIV, hepatitis B and C), current or previous
treatment for any of these infections, and/or laboratory or skin biopsy changes suggestive
of an infectious disease associated with polyneuropathy[24 ].
Vasculitis: presence of a systemic disease known to be associated with vasculitis
and/or in the presence of vascular changes compatible with vasculitis on nerve biopsy[25 ].
Paraneoplastic: considered when primary neoplasia was diagnosed during the investigation,
even without onconeural antibody tests, or in those patients at high risk of having
an associated neoplasia, always in the absence of other causes or risk factors[26 ].
Finally, individuals with no risk factors for polyneuropathy or altered laboratory
tests made up the group of idiopathic polyneuropathies. Those who underwent all routine
laboratory tests were classified as “idiopathic polyneuropathy with complete basic
investigation” [5 ]. On the other hand, if routine examinations were not performed or were only partially
performed and in the absence of any risk factors, polyneuropathy was considered “idiopathic
with incomplete basic investigation”. Individuals with various risk factors for polyneuropathy,
with no clear predominance of either factor, were classified as “multifactorial polyneuropathy”[27 ]. It is important to highlight that we could not define how much each etiologic factor
contributed to the pathophysiology of polyneuropathy. Thus, patients who met this
criterion had a probable multifactorial etiology rather than a definite one.
The above criteria were used retrospectively. That is, the etiological diagnosis previously
defined in the medical record was reviewed, applying the study criteria. However,
the etiology of polyneuropathy was not changed.
The electrophysiological pattern of the EDX test was also used to classify the patients.
Demographic characteristics and main etiologies of polyneuropathy for each electrophysiological
pattern of the selected patients were determined for each group.
From collected data, a descriptive analysis of all variables was performed. Thus,
it was possible to evaluate the frequency of qualitative variables and the symmetry
of the distributions of quantitative variables (normal distribution assessed by the
Shapiro-Wilk test). Quantitative variables were described by median (minimum - maximum
range) because the data did not always have a normal distribution, while qualitative
variables were described by frequency and percentage.
RESULTS
Of 877 EDX tests performed on a clinical suspicion of polyneuropathy, 429 (48.9%)
confirmed this diagnosis. Because some individuals underwent EDX test more than once,
we identified 380 patients whose EDX test was compatible with polyneuropathy. The
sample population was predominantly male (59.5%), with a male-to-female ratio of 3:2.
The median age was 43 years (range 0.3-85). The median time to onset of symptoms before
the first appointment was 2 years (range 0-58).
The risk factors, symptoms, and signs of investigated individuals are shown in [Table 1 ]. The main risk factors were diabetes mellitus (23.2%) and alcoholism (14.2%). The
symptoms reported more often were distal weakness in the lower limbs (65.8%) and paresthesia
(49.2%). The main neurological signs detected were sensory disturbance (72.9%), muscle
weakness (72.9%), and areflexia (61.6%).
Table 1
Distribution of risk factors and neurological symptoms and signs in 380 patients whose
EDX test indicated polyneuropathy.
Variable
n (%)
Risk factor
Diabetes
88 (23.2)
Alcohol abuse
54 (14.2)
Family history
46 (11.8)
Toxic medicationa
43 (11.3)
Hypothyroidism
30 (7.9)
Previous history of malignancy
27 (7.1)
Exposure to toxic substancesb
20 (5.3)
HIV
10 (2.6)
Hepatitisc
10 (2.6)
Neurological symptoms
Distal weakness in the lower limbs
250 (65.8)
Paresthesia
187 (49.2)
Distal weakness in the upper limbs
167 (43.9)
Neuropathic pain
132 (34.7)
Hypoesthesia
84 (22.1)
Allodynia
11 (2.9)
Anesthesia
5 (1.3)
Neurological signs
Sensory disturbance
277 (72.9)
Muscle weakness
277 (72.9)
Areflexia
234 (61.6)
Hyporeflexia
111 (29.2)
Atrophy
93 (24.5)
Sensory ataxia
90 (23.7)
Romberg sign
83 (21.8)
Foot and leg abnormalitiesd
58 (15.3)
Hypotonia
46 (12.1)
n: number of patients who presented each variable; a Cyclosporine, chloroquine, RIPE regimen for tuberculosis, phenytoin, methotrexate,
chemotherapy, radiotherapy, tacrolimus, thalidomide, antiretroviral therapy for HIV,
treatment for leprosy; b Chemical agents (thinner, methylene oxide, lead paint), pesticides, cocaine, and crack;
c Hepatitis B and hepatitis C; d Claw toes, hammer toes, nonspecific deformities of hands and feet, pes cavus, equine
foot, flat foot, leg in champagne bottle. EDX: Electrodiagnostic.
[Table 2 ] summarizes the etiology of the polyneuropathy in the sample population. The majority
of patients (75.2%) had one etiology for polyneuropathy (monocausal group), 11.1%
had two or more concomitant etiologies (multifactorial group), and 13.7% had no etiological
factor identified (idiopathic group).
Table 2
Classification of the study group according to etiology.
Etiology
n (%)
Monocausal polyneuropathies
Inflammatory
90 (23.7)
286 (75.2)
Hereditary
72 (18.9)
Diabetes
41 (10.8)
Vasculitis
17 (4.5)
Toxicitya
17 (4.5)
Alcohol abuse
14 (3.7)
Infectionb
12 (3.2)
Nutritional deficiency c
11 (2.9)
Metabolicd
4 (1.1)
Malignancy
4 (1.1)
Critical illness
4 (1.1)
Multifactorial polyneuropathies
Diabetes and hypothyroidism
6 (1.5)
42 (11.1)
Alcohol abuse and vitamin B12 deficiency
5 (1.3)
Diabetes and vitamin B12 deficiency
4 (1.1)
HIV and antiretroviral therapy
4 (1.1)
Diabetes and toxic medicationa
4 (1.1)
Diabetes and alcohol abuse
3 (0.7)
Alcohol and infectious diseaseb
2 (0.5)
Diabetes and infectious diseaseb
2 (0.5)
Alcohol abuse and toxic medicationa
2 (0.5)
Other combinations
10 (2.6)
Idiopathic polyneuropathies
Complete basic investigation
37 (9.7)
52 (13.7)
Incomplete basic investigation
15 (3.9)
Total
380
n: number of cases for each polyneuropathy etiology; a Toxic medication (chloroquine, stavudine, phenytoin, chemotherapy, radiotherapy, RIPE
regimen for tuberculosis, tacrolimus, thalidomide, antiretroviral therapy for HIV,
treatment for leprosy), contact with pesticides, and contact with chemical agents
(methylene oxide, thinner, lead paint); b HIV or leprosy; c Vitamin B12 deficiency or vitamin E deficiency; d Acute intermittent porphyria or hypothyroidism.
In general, considering the entire sample of the study rather than each group individually,
the five main causes of polyneuropathy confirmed by EDX testing were inflammatory,
hereditary, idiopathic, multifactorial, and diabetic polyneuropathy.
From the group of monocausal polyneuropathies, the three main etiologies were inflammatory,
hereditary, and diabetes. Inflammatory etiology occurred in 23.7% of the patients:
16.3% occurred by GBS (and its variants AMAN, AMSAN, and Miller-Fischer syndrome),
4.7% by CIDP, and 2.6% by other causes (including multifocal motor neuropathy and
Lewis-Sumner syndrome). The median age of patients with GBS was 33 years (range 2-76)
and 46 years (range 2-81) for those with CIDP. In both cases, there was a predominance
of males (74.2% in GBS and 66.7% in CIDP). A hereditary etiology was diagnosed in
18.9% of patients, with a median age of 13 years (range 0.3-75) and a predominance
in males (61.1%). Charcot-Marie-Tooth was the main cause of hereditary polyneuropathy,
corresponding to 10.2% of the total sample. The third most common isolated etiology
was diabetes, accounting for 10.8% of the investigated patients. The median age for
the diabetic etiology was 55 years (range 22-77) and, unlike the first two causes,
there was a predominance in females (56.1%). The frequency of the other etiologies
is shown in [Table 2 ].
Multifactorial polyneuropathy was diagnosed in 42 patients (11.1%). Diabetes was the
most involved etiology, being present in half of the cases. The most frequent combination
was diabetes and hypothyroidism ([Table 2 ]).
In 13.7% of the patients, no etiological cause of peripheral neuropathy was identified,
being classified as idiopathic polyneuropathy, either by complete basic investigation
(9.7%) or incomplete basic investigation (3.9%). The median age was 51.5 years (range
1-85) for idiopathic polyneuropathy with incomplete basic investigation and 45.5 years
(range 15-79) for those with complete basic investigation. In both groups, there was
a similar distribution between male and female individuals.
Considering risk factors, 88 patients had diabetes, 40 of whom developed diabetic
polyneuropathy, 21 multifactorial polyneuropathy, 10 inflammatory polyneuropathy (7
with GBS, 2 with CIDP and 1 with Lewis-Sumner syndrome), and 17 patients presented
with different etiologies. A similar situation occurred with alcohol abuse: 54 patients
had a current or previous history of alcoholism, but only 14 patients were diagnosed
with alcoholic polyneuropathy. Thirteen patients were diagnosed with multifactorial
polyneuropathy, 5 were classified as inflammatory polyneuropathy (4 with GBS and 1
with CIDP), another 5 as hereditary polyneuropathy, and 17 had different etiologies,
as did diabetic patients. The presence of different etiologies occurred because these
patients did not fulfilled the criteria for diabetic or alcoholic polyneuropathy or
because there was a lack of temporal correlation.
[Figure 2 ] shows the frequency of each electrophysiological pattern, as well as median age
and gender distribution. [Figure 3 ] shows the main causes for each electrophysiological pattern. The main electrophysiological
patterns were axonal sensorimotor polyneuropathy (36.1%) and “demyelinating and axonal”
sensorimotor polyneuropathy (27.9%). Individuals with demyelinating polyneuropathies
had a lower median age than those with axonal forms. Compared with demyelinating and
“demyelinating and axonal” patterns, axonal patterns showed greater etiological heterogeneity,
with a predominance of idiopathic and multifactorial polyneuropathy. However, in axonal
motor polyneuropathies, there was a predominance of the inflammatory etiology. Analyzing
demyelinating and “demyelinating and axonal” polyneuropathies, there was a lower number
of etiologies, with a predominance of hereditary and inflammatory polyneuropathies.
Figure 2 Flow chart of polyneuropathies epidemiological profile according to neurophysiological
aspects.n: number of cases of each neurophysiological pattern; EDX: electrodiagnostic
test; [1 ]median age (range minimum - maximum); [2 ]percentage of male patients.
Figure 3 Distribution of different polyneuropathies according to the neurophysiological study.
DISCUSSION
The five main causes of polyneuropathy confirmed by EDX testing were inflammatory,
hereditary, idiopathic, multifactorial, and diabetic polyneuropathy. From these data,
our study indicates that polyneuropathies submitted to electrodiagnostic testing are
those recently advocated by the AANEM in its official position: polyneuropathies that
show a severe, atypical, rapidly progressing course, with predominant motor involvement,
a positive family history, or when no cause is identified despite initial assessment[9 ].
From the EDX tests performed on suspicion of polyneuropathy, 48.9% confirmed this
condition and 17.7% revealed a different diagnosis. This corroborates the fact that
EDX not only confirms polyneuropathy but also detects other associated neuromuscular
diseases and reveals other diagnoses, specially mononeuropathies and radiculopathies.
Ginsberg and Morren recently found similar results[28 ]; the EDX of patients with suspected diabetic polyneuropathy presented an alternative
diagnosis in about 20% of patients, and in 25% of those patients, it detected other
overlapping diseases. Thus, it would be interesting to explore polyneuropathies due
to common causes to better determine the origin of symptoms and the outcome[28 ],[29 ].
In our study, the frequencies of the identified etiologies differ from other studies
conducted in tertiary hospitals[8 ],[30 ]
-
[34 ]. The reason for this probably lies in the fact that our study used a retrospective
design with the objective of identifying the main causes of polyneuropathies confirmed
by electrophysiological study from a specialized center, with the selection of patients
based on EDX. Epidemiological studies are usually prospective, selecting patients
according to symptomatology and risk factors, and only later performing nerve a conduction
study, for which abnormal EDX is not an inclusion criterion[1 ].
Inflammatory polyneuropathy had a frequency of approximately 24%, which is higher
than previously described[8 ],[30 ]
-
[34 ]. The frequency was similar to the results of Rudolph and Farbu, who identified inflammatory
polyneuropathy as the main cause of monocausal polyneuropathy in 24% of individuals[27 ]. GBS (and its variants) and CIDP were the main conditions in this etiological group,
which was characterized by the predominance of demyelinating electrophysiological
alterations[35 ],[36 ]. Axonal motor polyneuropathy was also related to inflammatory polyneuropathy, mainly
due to the diagnosis of one of the GBS variants (e.g., AMAN).
Idiopathic polyneuropathy occurred in 14% of the patients in our sample, a pattern
that is different from some epidemiological studies in specialized hospitals, which
have reported frequencies of 20 to 49%[8 ],[27 ],[30 ],[31 ],[33 ]. The results are similar to Lin et al. and Verghese et al., who demonstrated idiopathic
polyneuropathy frequencies of 12 and 13%, respectively[32 ],[34 ]. Indeed, a decreasing incidence of idiopathic polyneuropathy has already been reported
due to the improvement in the diagnosis of lower prevalence polyneuropathies through
more sophisticated diagnostic guidelines[37 ],[38 ]. In our study, idiopathic polyneuropathy was the main cause of axonal sensory and
axonal sensorimotor polyneuropathies, with a median age of around 50 years, in accordance
with previous literature data[37 ],[38 ].
The frequency of diabetic polyneuropathy (around 11%) was lower than in previous studies,
which reported frequencies ranging from 20 and 50%[1 ],[4 ]. This divergence can be explained by several factors. In addition to the aforementioned
divergence in methodology, most epidemiological studies do not classify polyneuropathies
as multifactorial, as in this study. Of the multifactorial polyneuropathy cases, 50%
presented diabetes as one of the etiological factors. Another explanation for this
lower occurrence is the fact that only patients with severe diabetic polyneuropathy
were referred to our center. Mild and moderate forms of diabetic polyneuropathy, included
in population-based studies, are not usually submitted to EDX tests in our center.
Because this study was conducted in a specialized center, a possible selection bias
of patients in the sample might have occurred, with a predominance of severe polyneuropathies.
Hence, the results cannot be extrapolated to the general population. Another limitation
of this study is the non-inclusion of patients with normal EDX tests. Although the
objective did not include the evaluation of small fiber polyneuropathy, it is known
that patients with a clinical picture of polyneuropathy and normal nerve conduction
studies may present large fiber dysfunction with abnormalities in the EDX test during
the course of the disease[15 ],[16 ]. Thus, it is necessary to consider a possible underestimation of our frequencies.
On the other hand, in the present study, cases of polyneuropathy were submitted to
EDX tests and different etiologies were found in each neurophysiological pattern.
Therefore, when exploring whether the pathophysiology is axonal or demyelinating,
EDX testing guides differential diagnosis of rare and atypical polyneuropathies. Our
results indicate that axonal polyneuropathies result from idiopathic, infectious,
toxic, nutritional deficiency, vasculitic, and metabolic causes, while demyelinating
polyneuropathies have predominantly inflammatory and hereditary causes, in accordance
to the literature[9 ],[39 ] It is important to identify these etiologies because some of them, such as inflammatory
and vasculitic causes, have disease-modifying therapies, including corticosteroids
and immunoglobulin[9 ],[39 ].In conclusion, polyneuropathies in this study were predominantly from inflammatory,
hereditary, idiopathic, multifactorial, and diabetic causes. It is clear that polyneuropathies
confirmed by EDX testing in a specialized center are those that most challenge clinical
reasoning because they are atypical, hereditary, severe, require rapid management,
or because there is no diagnostic clue in the medical history and laboratory tests.
By understanding how neurophysiological patterns correlate with specific etiologies
and that the electrophysiological study can reveal other diagnoses, we can deduce
that EDX testing is useful for the etiological diagnosis of less common polyneuropathies
and contributes to the initiation of correct and early treatment, avoiding inappropriate
treatments, with possible gain in quality of life for the patient.
