This study investigated peripheral neuropathy in vitamin B12 deficient patients with megaloblastic anemia using dorsal sural nerve conduction studies and tibial sensory-evoked potentials. Dorsal sural nerve responses were absent in over half of patients but only one third had abnormalities on conventional nerve conduction studies. Patients with recordable dorsal sural nerves had prolonged latencies, reduced amplitudes, and slower conduction velocities compared to controls, suggesting dorsal sural nerve conduction is more sensitive for detecting early neuropathy. Over 70% of patients showed evidence of myelopathy on tibial sensory-evoked potentials and neurological examination.
La conduzione del nervo surale dorsale in pazienti con carenza di vitamina B12 associata ad anemia megaloblastica
1. Journal of the Peripheral Nervous System 11:247–252 (2006)
RESEARCH REPORT
Dorsal sural nerve conduction study in vitamin B12
deficiency with megaloblastic anemia
BurhanTurgut1, NildaTurgut2 , Seval Akpinar1, Kemal Balci2 , Gu lsu m E. Pamuk1,
« «
EmreTekgu ndu z1, and Muzaffer Demir1
« «
1Department of Medicine, Division of Hematology; and 2Department of Neurology, Trakya Medical Faculty,
University of Trakya, Edirne, Turkey
Abstract Peripheral neuropathy is frequently observed in B12 deficiency. In spite of
this, there is little knowledge about peripheral neuropathy in B12 deficiency because the
severity of clinical involvement of the central nervous system clearly outweighs signs and
symptoms due to peripheral nervous system involvement. We primarily investigated
peripheral neuropathy with dorsal sural conduction study, which is a new method for
detection of early peripheral neuropathy, in B12 deficiency with megaloblastic anemia.
Conventional nerve conduction studies and tibial sensory-evoked potential (SEP) recording
were also performed. Twenty-eight B12-deficient patients (15 male, 13 female, mean age
65.8 years) with megaloblastic anemia and 18 age- and sex-matched controls were
included in the study. Although dorsal sural sensory nerve action potentials (SNAPs) were
not recorded in 15 (54%) of 28 patients, only 9 (32%) of them were found to have poly-
neuropathy by conventional conduction studies. Furthermore, patients with dorsal sural
SNAP had mean lower amplitude, mean longer latency, and slower velocity response
when compared with controls. Twenty patients (71%) were diagnosed as having myelop-
athy by the combination of tibial SEP and neurological findings. Two patients whose dor-
sal sural SNAPs were not recorded had normal tibial SEP responses; therefore, these
patients were considered to have isolated peripheral neuropathy. As a result, we conclude
that dorsal sural nerve conduction study is a reliable method for detection of early periph-
eral neuropathy in B12 deficiency.
Key words: B12 deficiency, dorsal sural nerve, peripheral neuropathy, SEP
Introduction the central nervous system (Carmel, 2003). Peripheral
nerves, however, tend to show axonal degeneration
Vitamin B12 deficiency is a systemic disease that
without demyelination (McCombe and McLeod,
often affects the nervous system. It may cause
1984; Tomoda et al., 1988). Peripheral neuropathy,
peripheral neuropathy and lesions in the posterior and
which is usually sensory, may be sensorimotor
lateral columns of the spinal cord and in the cerebrum
(Hemmer et al., 1998), and posterior column damage
(Toh et al., 1997). Demyelination with subsequent
is often hard to differentiate clinically (Steiner et al.,
axonal disruption and gliosis can affect all parts of
1988; Healton et al., 1991).
In peripheral neuropathies, the most distal sen-
sory fibers of the lower extremities are generally first
Address correspondence to: Burhan Turgut, MD, Department of affected, but these nerves cannot be evaluated by
Hematology, Trakya Medical Faculty, University of Trakya, 22030
Edirne, Turkey. Tel: þ90 532 433 36 76; Fax: þ90 284 235 76 52; sural and superficial peroneal conduction studies, which
E-mail: burhanturgut@trakya.edu.tr are used routinely for the diagnosis of polyneuropathy
ª 2006 Peripheral Nerve Society 247 Blackwell Publishing
2. Turgut et al. Journal of the Peripheral Nervous System 11:247–252 (2006)
(Killian and Foreman, 2001). Dorsal sural nerve of the and stimulation was delivered at the wrist and at the
foot is the most distal sensory nerve. It has been elbow. Tibial and common peroneal nerve CMAPs
reported that dorsal sural nerve conduction study is were recorded from the abductor hallucis and exten-
a sensitive marker of peripheral neuropathies that sor digitorum brevis muscles, and stimulation was
may show abnormalities before they are found in delivered at the ankle and at the poplitea for tibial
proximal sural nerve (Lee et al., 1992; Killian and nerve and at the fibula head for the peroneal nerve.
Foreman, 2001; Turgut et al., 2004). Median and ulnar sensory nerve action potentials
In this study, we investigated peripheral neuropa- (SNAPs) were recorded with ring electrodes from digit
thy by dorsal sural nerve conduction studies in addition 2 and digit 5, and stimulation was applied at the wrist.
to conventional conduction studies in B12-deficient Sural antidromic sensory nerve conduction studies
patients with megaloblastic anemia. Also, because were performed by recording the SNAP posterior to
posterior column involvement is the most frequently the lateral malleolus. Stimulation was carried out 14
reported and complicated neuropathy in B12 defi- cm proximally in the midcalf (Oh, 1993).
ciency, tibial sensory-evoked potentials (SEPs) were Filter settings were 20–2,000 Hz bandpass for
studied in all patients. sensory nerve studies, and 2–10,000 Hz bandpass for
motor nerve studies. An average was used for the
sensory nerve recording, and the mean number of
averages required to clearly define the potential was
Materials and Methods 8. The averaging was repeated to confirm the repro-
ducibility, if necessary. In patients whose sensory
Subjects nerve response could not be obtained, the averaging
The study was carried out between December was repeated at least three to five times. Limb tem-
2004 and October 2005. Twenty-eight consecutive perature was maintained between 31 and 34°C in all
patients and 18 healthy age- and sex-matched con- subjects. Polyneuropathy was diagnosed on the basis
trols were included in the study. Informed consent of abnormal nerve conduction studies when abnor-
was obtained from each subject. The patients met all malities were found in two or more nerves (Feldman
the following criteria: the presence of megaloblastic et al., 1994).
anemia with characteristic features such as macroova-
locytosis and hypersegmentation and evidence of Dorsal sural nerve recording
cobalamin deficiency based on a low serum cobalamin Surface bar recording electrodes (Teca Corp.)
level (,200 ng/l). were used to test dorsal sural nerve SNAP. A record-
All the patients underwent detailed general and ing electrode was placed over the lateral dorsal sur-
neurological examination. Routine blood chemistry, face of the foot, with the distal electrode at the origin
complete blood cell count, vitamin B12 analysis, and of digits 4 and 5 and the proximal active electrode
folate serum concentration analysis were performed 3 cm from the distal electrode. The stimulation site
in all patients. Blood smears were examined by was posterior to the lateral malleolus, with the cathode
a hematologist. They also had no history of folate placed 14 cm proximal from the recording electrode.
deficiency and other spinal cord or peripheral nerve A ground electrode was placed on the dorsum of the
diseases. Patients with carpal tunnel syndrome, foot equidistant between the recording and the stimu-
radiculopathy, plexopathy, and mononeuropathy were lating electrodes. Low filters were set at 20 Hz and
excluded from the study. Diabetes mellitus, uremia, high filters at 2 kHz. Sweep speed was 1 ms per divi-
alcohol abuse, drug use, and other possible causes sion, sensitivity was adjusted between 5 and 20 mV
of polyneuropathy were excluded by blood chemistry per division, and stimulus duration was 0.2 ms at
analysis and history of the patients. a stimulus rate of 0.5 Hz. At least eight potentials
were averaged to record an appropriate response,
Electrophysiological investigations and the averaging was repeated if necessary. Distal
Conventional motor and sensory nerve latency was measured from stimulus onset to the
conduction studies negative peak of the SNAP. SNAP amplitudes were
In all patients and control subjects, left median, measured from baseline to peak (Killian and Foreman,
ulnar, common peroneal and tibial motor nerves and 2001). A representative figure demonstrating sural and
left median, ulnar, sural sensory nerves were studied dorsal sural nerves action potentials is shown in Fig. 1.
with a Medelec Synergy electromyography machine.
Median and ulnar nerve compound muscle action Tibial somatosensory-evoked potential recording
potentials (CMAPs) were recorded from the abductor The active electrode was placed at the Cz0 (2 cm
pollicis brevis and the abductor digiti minimi muscles, posterior to Cz). The reference electrode was placed
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3. Turgut et al. Journal of the Peripheral Nervous System 11:247–252 (2006)
Results
Clinical evaluations
Clinical and laboratory data of the patients are
shown in Table 1. All the patients had a B12 serum
level less than 200 pg/ml and obvious megaloblastic
anemia. We did not perform a schilling test or intrinsic
factor antibody test for diagnosis of pernicious anemia,
but eight patients underwent endoscopy and all
had type A atrophic gastritis. Moreover, gastrectomy,
malabsorption syndromes, vegetarianism, and other
rare causes of B12 deficiency were absent in all the
patients; therefore, the diagnosis of pernicious anemia
in our patients had a high probability.
Electrophysiological findings
The results of conventional nerve conduction
studies of the patients and control subjects are
shown in Table 2. Conventional nerve conduction
was impaired in 9 (32%) of 28 patients; 4 patients had
axonal sensory polyneuropathy, 4 had axonal sensori-
motor polyneuropathy, and 1 had mixed (axonal and
demyelinating) sensorimotor polyneuropathy.
Dorsal sural nerve conduction studies
Figure 1 The top traces show the sensory-evoked poten-
. The patients and control subjects underwent dor-
tial (SEP) from sural nerve and the bottom traces show the sal sural nerve conduction studies. Dorsal sural nerve
SEP from dorsal sural nerve of a control subject. was recordable bilaterally in all the control subjects.
Dorsal sural nerve SNAPs were bilaterally absent in
at Fpz0 (2 cm behind Fp). The ground electrode was 15 (54%) of 28 patients, and 9 of them had impaired
placed as close to the first pair of recording electrodes. conventional conduction abnormalities simultaneously.
With the patient in the supine position, surface stimu- In the other 13 (46%) patients, the mean distal latency
lating electrodes were placed behind the medial mal- of the dorsal sural nerve response was longer (p ¼
leolus. The exact point of stimulation was identified 0.003), mean amplitude was lower (p ¼ 0.008), and
by measuring 1 cm behind and 1 cm below the navic- mean velocity response was slower (p ¼ 0.001) than
ular tubercle (medial side of the foot). This point ap- those of 18 healthy controls (Table 3). However, the
proximates the middle of the belly of the abductor
hallucis muscle. Next, measure 8 cm proximal to this
point, following the course of the tibial nerve 1 cm Table 1 Clinical and laboratory characteristics of the patients.
.
posterior to the medial malleolus. The electrode at
this point was the anode. The cathode was placed Number of the patients (N) 28
Age (years), median (range) 66 (39^91)
4 cm proximal to the anode. Analysis time was 50–100 Gender (N), F/M 15/13
ms, gain was 10 mV, frequency bandwith was 0–2,000 Neurological findings, N (%)
Hz. The N35 and P40 latencies were evaluated (Delisa Abnormal vibration or proprioception 15 (54)
Abnormal pinprick sensation 6 (21)
et al., 1994). Gait disturbance 9 (32)
Loss of deep tendon reflexes 3 (10)
Pyramidal tract finding 1 (3,6)
Statistical analysis Mental impairment 1 (3,6)
Hemoglobulin (g/dl), mean Æ SD 7.57 Æ 2.44
Statistical analysis was performed using SPSS WBC (ml), mean Æ SD 4,515 Æ 1,825
software (SPSS, Inc.). Mann–Whitney U test was used Platelet (ml), mean Æ SD 123,892 Æ 79,017
MCV (fl), mean Æ SD 110.1 Æ23.9
for comparing groups. Relationships between cate- Serum vitamin B12 (pg/ml), mean Æ SD 109.6 Æ 21.5
gorical variables were compared using the chi-square Serum folate (ng/ml), mean Æ SD 7.98 Æ 4.11
test. Coefficients of correlation (r) were calculated LDH (U/l), mean Æ SD 2,121 Æ2,295
using the Spearman’s rank test. The level of signifi- LDH, lactate dehydrogenase; MCV, mean cell volume; WBC, white
cance in all statistical analysis was set at p , 0.05. blood cell.
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4. Turgut et al. Journal of the Peripheral Nervous System 11:247–252 (2006)
Table 2. The results of action potentials in patients with B12 deficiency who had normal conventional electrophysiological studies
and control subjects.*
B12-deficient patients with normal conventional
conduction studies (n ¼ 19) Control subjects (n ¼ 18)
Nerves Latency (ms) Amplitude (mV) Velocity (m/s) Latency (ms) Amplitude (mV) Velocity (m/s)
Median (s) 3.31 Æ 0.40 20.2 Æ 9.50 54.1 Æ 6.08 2.97 Æ 0.24 23.1 Æ7.71 53.5 Æ 4.27
Ulnar (s) 2.82 Æ 0.31 18.8 Æ 8.89 53.5 Æ 4.27 2.46 Æ 0.22 22.8 Æ 7.92 63.9 Æ 5.85
Tibial 4.22 Æ 0.83 9.31 Æ3.97 44.9 Æ 3.01 4.14 Æ 0.63 7.63 Æ 2.45 48.8 Æ 3.98
Median (m) 3.52 Æ 0.43 7.86 Æ 2.64 53.7 Æ 3.61 3.32 Æ 0.37 7.53 Æ 2.14 59.1 Æ 4.54
Ulnar (m) 2.60 Æ 0.33 9.78 Æ 2.04 66.2 Æ 5.37 2.27 Æ 0.22 9.38 Æ 2.28 70.6 Æ 7.16
C. Peroneal 4.37 Æ 0.67 4.02 Æ 1.67 48.4 Æ 4.96 3.68 Æ 0.76 4.28 Æ 1.92 54.1 Æ 5.71
Sural 2.89 Æ 0.81 13.3 Æ 5.71 49.2 Æ 7.66 2.68 Æ 0.63 12.4 Æ 4.39 55.9 Æ 12.7
*The values are expressed as mean Æ SD.
action potentials of sural nerve did not differ between patients had unsteady walking with positive Romberg’s
the same patients and the control subjects (Table 3). test, and SEP was abnormal (6 absent, 3 delayed) in
all. Spasticity was evident in the lower limbs of a
Tibial SEPs patient with extensor plantar response. No motor deficit
Tibial SEPs were abnormal in 20 (71%) of 28 was found in any of these patients.
patients with delayed (14 patients) or absent (6 patients)
responses. Nine patients were found to have neuro- Correlation analysis
pathy by conventional conduction studies, and they There was no difference between female and
had impaired tibial SEP simultaneously. Three patients male patients for all the electrophysiological studies.
who had no SEP response had severe tibial nerve con- There was no correlation between all the electrophys-
duction impairment, so impaired SEPs may be associ- iological findings and serum vitamin B12 and folate
ated with severe motor neuropathy, but they had the levels, hemoglobin level, mean cell volume, leuko-
clinical finding of myelopathy. Two patients whose cyte and platelet counts, and lactate dehydrogenase
dorsal sural SNAPs were absent had normal SEP level.
responses and seven patients with abnormal SEP
responses had dorsal sural SNAPs. Tibial SEPs results
are shown in Table 4.
Six patients had stocking/glove type sensory loss, Discussion
and all of them had sensory or sensorimotor polyneuro- There is a wide range of neurological disturbances
pathy. Three patients with sensorimotor polyneuro- in patients with B12 deficiency including myelopathy,
pathy had absent deep tendon reflexes. However, the peripheral neuropathy, altered mental status, and
other three patients with polyneuropathy had no sen- optic neuropathy (Healton et al., 1991; Pandey et al.,
sory loss and abnormality of deep tendon reflexes. 2004). It is difficult to distinguish findings due to the
Of 20 patients with abnormal SEP responses, 15 involvement of the central nervous system from
had abnormal vibration or proprioception, and nine those due to peripheral nervous system dysfunction
(Roos, 1978; Healton et al., 1991; Shevell and Rosen-
blatt, 1992), and there are no commonly accepted
Table 3. The results of sural and dorsal sural nerve action inclusion criteria in studies that investigated neurologi-
potentials of patients whose dorsal nerve was recordable and
the comparison of these results with controls.* cal disturbances because there are no exact criteria
for the diagnosis of B12 deficiency. For this reason,
Patients Controls the frequency of peripheral neuropathy in vitamin B12
Nerves (n ¼ 13) (n ¼ 18) p
deficiency sharply differs among studies. This study
Dorsal sural included B12-deficient patients with overt megaloblas-
Amplitude (mV) 4.78 Æ 1.62 6.99 Æ 2.24 0.008 tic anemia; the cause of B12 deficiency was perni-
Velocity (m/s) 34.5 Æ 6.22 46.8 Æ 11.2 0.001
Latency (ms) 3.89 Æ 0.70 3.09 Æ 0.59 0.003
cious anemia with high probability. We primarily
Sural investigated peripheral neuropathy in these patients
Amplitude (mV) 14.1 Æ 5.68 12.4 Æ 4.39 0.70 by dorsal sural nerve conduction studies, in addition to
Velocity (m/s) 50.3 Æ 8.33 55.9 Æ 12.7 0.17 conventional electrophysiological studies. Dorsal sural
Latency (ms) 2.86 Æ 0.77 2.68 Æ 0.63 0.37
SNAPs were not recorded in 54% of the patients.
*The values are expressed as mean Æ SD. Only 32% of patients were diagnosed as having
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5. Turgut et al. Journal of the Peripheral Nervous System 11:247–252 (2006)
Table 4. The results of tibial SEP studies.*
No Delayed
P40 N35 N50 response response
SEP right (n ¼ 28) 46.2 Æ 7.6 40.1 Æ7.27 54.4 Æ 6.32 6 patients 14 patients
SEP left (n ¼ 28) 47.1 Æ 8.09 40.0 Æ 7.25 58.7 Æ 11.4 6 patients 14 patients
SEP, sensory-evoked potential.
*The values are expressed as mean Æ SD.
polyneuropathy by conventional conduction studies. that 4 patients had isolated neuropathy on the basis
Furthermore, when compared with normal in- of clinicoelectrophysiological profiles of 40 patients with
dividuals, patients with recordable dorsal sural SNAPs B12 deficiency.
had lower mean amplitude, slower mean velocity, There are a few studies proposing a correlation
and longer mean latency. It was reported that there between clinicolaboratory findings and neurological
was high variability in dorsal sural SNAPs in normal in- findings in B12 deficiency. It has been reported that
dividuals, and standard cutoff values for dorsal sural the severity of neurological abnormalities increases
SNAPs for adults were not designated in the literature with increasing hematocrit levels (Healton et al.,
(Killian and Foreman, 2001). For this reason, we did 1991; Savage and Lindenbaum, 1995). In another
not use the quantitative values of the action poten- study, serum vitamin B12 level was found to correlate
tials of dorsal sural nerve to diagnose peripheral well with sural SNAP and prolonged tibial SEP res-
neuropathy. ponses (Puri et al., 2005). In spite of this, we did not
Dorsal sural nerve conduction study is described find any correlation between electrophysiological find-
as a new method providing an opportunity for the ings and clinicolaboratory findings. The studies that
evaluation of most distal nerves of lower extremities reported an inverse correlation between hematocrit
that are usually first affected in peripheral neuropathy and the severity of neurologic findings included
(Lee et al., 1992; Killian and Foreman, 2001). In dia- patients without anemia or mild anemia. Even in the
betic children, this method is reliable to show sub- study of Healton et al. (1991), this correlation was
clinical neuropathy (Turgut et al., 2004). Our results reported only in patients with normal hematocrit level.
demonstrated that dorsal sural SNAP can aid to diag- Discordance between these studies and our study
nose the peripheral neuropathy component of neuro- can be explained by the fact that we included only
logical disturbances of B12 deficiency. patients with overt anemia. Exact reasons for the
Myelopathic presentation has been reported to inverse correlation between hematocrit and the
be more common than peripheral neuropathy in B12 neurologic involvement are not known. Recently,
deficiency (Misra et al., 2003). Furthermore, it is con- Carmel et al. (2003) showed significant differences in
troversial whether polyneuropathy may be present in homocysteine metabolism among patients with B12
the absence of myelopathy (Saperstein et al., 2003). deficiency. They found that patients with B12 defi-
In concordance with the literature, most of our pa- ciency who had neurologic defects had higher folate,
tients presented with myelopathy. With clinical evalu- S-adenosylmethionine, cysteine, and cysteinylglycine
ations and SEP studies, we found that 71% of our levels than neurologically unaffected patients and that
patients had posterior tract damage. Myelopathy low S-adenosylmethionine and glutathione levels
predominantly affects the posterior columns followed were independent predictors of anemia.
by the anterolateral and anterior tracts (Hemmer As a result, with dorsal sural SNAP, most of the
et al., 1998). We did not measure motor-evoked po- B12-deficient patients with megaloblastic anemia can
tentials of our patients, but the presence of signs of be detected to have peripheral neuropathy. On the
central motor pathway damage in only one patient on other hand, in concordance with previous studies,
neurological examination made us think that damage dorsal tract involvement is more common than
to the pyramidal tract was not frequent in B12 defi- neuropathy in B12 deficiency.
ciency as previously reported (Hemmer et al., 1998).
Two patients with peripheral neuropathy diagnosed
with dorsal sural nerve conduction study did not have
myelopathy; this observation demonstrated that iso-
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