Quantitative Sensory Testing
11
Pariwat Thaisetthawatkul
Basic Principles in Sensory Physiology
The sensory system integrates and perceives sensory stimuli
from the outside world. The sensory perception starts with a
physical stimulus reacting on a sensory receptor. The recep-
tor has an intrinsic mechanism to transform the physical
stimulus into a nerve impulse. The nerve impulse reaches the
central sensory system for integration and interpretation and
becoming a perception. The modality of sensory perception
is determined by the type of sensory stimuli and their specific
receptors mediating nerve impulses along specific nerve
fibers. There are five modalities of somatosensory system:
vibration, touch, proprioception, pain, and temperature
senses. These modalities are determined by specific recep-
tors to mediate each type of sensory perception. There are
three types of sensory receptors in the somatosensory sys-
tem: mechanoreceptors, thermoreceptors, and nociceptors.
The mechanoreceptors mediate vibration, touch, propriocep-
tion, and joint position senses. The nociceptors mediate pain,
and the thermoreceptors mediate temperature senses. Each
specific type of sense is mediated through a specific receptor.
Most receptors are located in the skin with less or no hair
(glabrous skin). The mechanoreceptors have two types of
adaptation (decrease firing potentials with time even with
constant stimuli): rapidly adapting (Pacinian and Meissner’s
corpuscles and most hair follicle receptors) and slowly adapt-
ing (Merkels discs and Ruffini end organs). Rapidly adapting
mechanoreceptors responds best to rapidly changing stimuli
such as swift movement (touch) or rapidly changing stimuli
P. Thaisetthawatkul, MD
Department of Neurological Sciences,
University of Nebraska Medical Center,
982045 Nebraska Medical Center, Omaha,
NE 68198–2045, USA
e-mail: pthaiset@unmc.edu
B. Katirji et al. (eds.), Neuromuscular Disorders in Clinical Practice,
DOI 10.1007/978-1-4614-6567-6_11, © Springer Science+Business Media New York 2014
in sinusoidal wave forms (vibration). Slowly adapting
mechanoreceptors respond better to continuous stimuli such
as prolonged stretch or pressure [1]. Each of these receptors
responds best to specific ranges of stimuli. For example,
Pacinian corpuscles respond best to vibration stimuli with
frequency range of 60–400 Hz, while Meissner’s corpuscles
are more sensitive to midrange stimuli of 20–50 Hz and
Merkel discs to very low frequency of 5–15 Hz [2]. Because
of these, humans are most sensitive to vibration at frequen-
cies of 200–250 Hz, and vibration stimuli whose frequencies
fall out of these ranges need higher intensity to be felt. Also,
a sensory stimulus is felt best within the receptive field (the
area where the density of the receptors is highest) of that
particular modality. Proprioception sense is mediated through
receptors outside the skin including muscle spindles, Golgi
tendon organs, and receptors within the joint capsules.
Thermoreceptors respond to changes in skin temperatures,
resulting from the external temperature touching the skin,
from baseline temperature, usually at 34 °C. Cool receptors
respond most at 25 °C and stop responding at 5 °C, below
which the cold nociceptors start responding. Warm receptors
are most active at 45 °C, above which heat nociceptors start
responding [2]. There are three types of nociceptors: mechan-
ical, thermal, and polymodal. The mechanical nociceptors
respond to painful tactile stimuli, often associated with tissue
damage, and the thermal nociceptors respond to extreme
changes in skin temperatures (<5 °C or >45 °C). Polymodal
nociceptors respond to destructive mechanical, thermal, and
chemical stimuli [2]. Not only the sensory modality depends
on the sensory receptors, but also its nerve impulse is con-
ducted via specific types of nerve fibers. Vibration, touch,
and proprioception senses are conveyed through fast-
conducting, large-diameter, myelinated (Aa or Ab) nerve fibers
while temperature and pain sensations are conveyed through
slow-conducting, small-diameter, myelinated (Ad) or unmyeli-
nated (C) nerve fibers. The first group of the nerve fibers is
often called “large fibers” and the latter “small fibers.”
223
224
Sensory Evaluation in Clinical Neurology
The examination of the sensory system is a very important
part of clinical neurology. The results can confirm the pres-
ence, determine the localization, identify the cause, and
grade the severity of the neurologic problem. Because the
sensory system is organized by different modalities as men-
tioned above, the clinical exam is usually performed to check
on each modality separately by utilizing different tools that
can give different type of stimuli aimed to stimulate each
type of sensory receptors. A tuning fork is commonly used to
check on the vibration sense. The frequency of the tuning
forks can vary from 64 to 165 Hz [3, 4]. However, the most
commonly used frequency of a tuning fork is 128 Hz [5].
The method can be all-or-none response, where the subject
reports whether he or she feels the vibration sense, or graded
response, where the duration of the feeling of vibration is
recorded, or comparative, where the sensation on one side is
compared to the other corresponding side. Some type of tun-
ing fork can be used quantitatively such as Rydel-Seiffer
type [6]. The touch sense is checked on by swift touch on the
skin by a cotton wool, tissue, or even a finger. Quantitative
assessment of touch sense can be considered by using
Semmes-Weinstein monofilaments [7]. This is noninvasive,
rapid, and low-cost test that can be used in a clinical exam
room. The filament is applied to the skin until it bends, and
the patient will acknowledge each time he or she senses the
monofilament. The touch threshold is determined by which
filament can be sensed. The use of the filaments has been
adopted widely. It is considered by some authors to be a good
screening method to identify diabetic patients who are at risk
of developing foot ulcers and having peripheral neuropathy
[8, 9]. Pain sensation is tested most commonly by using a
sharp object such as a safety pin, and temperature sense can
be checked by using a warm or cold flask containing warm or
cold water.
Even though routine sensory exams are used widely in
clinical practice, the methods mentioned above are not usu-
ally quantifiable or, at most, semiquantitative. The intensity
of stimuli and the methods of delivery of stimuli differ
significantly between each test performance. In day-to-day
experience, interobserver and intraobserver variability in
routine sensory exam is frequently observed and makes the
results of the exam not reproducible. Besides, different insti-
tutions may adopt a different approach for the assessment of
the same sensory evaluation. A tuning fork has also been
shown to overestimate vibration assessment compared to a
more quantitative assessment [10]. Quantitative method of
bedside sensory assessment such as the use of 64-Hz Rydel-
Seiffer tuning fork may have a good correlation with sensory
nerve action potential amplitudes on nerve conduction stud-
ies [3]. However, the use of Semmes-Weinstein monofilaments
has been more controversial. It can be more or less specific
P. Thaisetthawatkul
for the diagnosis of peripheral neuropathy based on nerve
conduction study [11, 12]. Moreover, if sensory assessment
is used as an end point in a clinical trial, there will be a need
for a more validated, gender- and age-control, quantifiable,
and sensitive technique.
Method of Automated Quantitative
Sensory Testing
An automated system to evaluate the sensory function has
been designed. The concept of the system is to deliver each
sensory stimulus, including touch-pressure, vibration, ther-
mal, and heat-pain sensory stimuli, in a quantifiable and
reproducible manner [13]. The system requires an apparatus
that can deliver specific type of sensory stimuli in a method
that is best time-efficient and accurate and employ the best
method of presentation of stimuli to the subjects. At the same
time, the method should be able to score the result by defining
the threshold of each sensation and establishing normal val-
ues and validating them to a large number of normal subjects
and adjusting them according to age, gender, and test site. In
general, these methods will be categorized into the follow-
ing: presentation of stimulus, subject’s response, and method
of threshold determination [14].
Presentation of Stimulus
There are two methods of the presentation of stimulus:
method of limits and method of levels. In method of limits,
the stimulus increases (such as in warm stimuli) or decreases
(such as in cool stimuli) until the subject starts feeling the
appearance or disappearance of stimuli, in which case, the
subject will press a response key and that will stop the stimu-
lation. This type of stimuli is also called dynamic stimuli
[15]. The sensory threshold (appearance threshold) is the
intensity of the stimulus at which the subject acknowledges
the feeling. A good example of how dynamic stimuli work is
to look at the Marstock method demonstrated by Verdugo
and Ochoa [16]. This method delivers hot and cold stimuli
by changing the direction and intensity of electrical currents
applied to a thermostimulator. A thermostimulator creates
changes in the temperature of a thermode attached to the
skin. Incoming currents cause increase in the skin tempera-
ture and outgoing currents decrease in the temperature. Heat
ramp is kept from 5 to 50 °C to prevent tissue damage and
damage to the thermode itself, in which case, the direction of
the currents is automatically reversed when those tempera-
ture limits are reached. Baseline skin temperature is kept at
32 °C. This method can evaluate warm and cool threshold
(when the subjects start to feel the first change in skin tem-
perature) and heat-pain and cold-pain threshold (when the
11 Quantitative Sensory Testing
feeling of pain starts). Thresholds are expressed in the physi-
cal unit (temperature) at which the subjects acknowledge the
change. An advantage of using dynamic stimuli is that this
method is time-saving. However, the subject’s response
always includes reaction time which makes the subject over-
estimate the sensory threshold. To overcome issues on reac-
tion time, trapezoid-shaped stimuli are recommended instead
of the usual triangular-shaped stimuli [17]. Besides, the sen-
sory threshold determined by this method can be affected by
“learning effects” [18].
In the method of levels, the changes in the level of sen-
sory stimuli happen in a stepwise manner. In each step, the
stimulus is given with predetermined intensity and duration
depending on the stimulus “step.” The step is usually num-
bered from small to large with corresponding low and high
level of stimulus, respectively. The duration and intensity of
the stimulus at each step is quantified and reproducible. The
intensity or duration of the stimulus at the next level depends
on the response of the subject to the preceding stimulus.
This method is reaction-time exclusive and, therefore, mini-
mizes test response variability. However, it is more time-
consuming. This type of the stimuli is called static stimuli
[15]. The sensory threshold is the intensity level that is per-
ceived by the subject 50 % of the time. Compared to static
stimuli, using dynamic stimuli tends to overestimate sensory
threshold, especially fast- and high-intensity stimuli, and
also creates a sense of “expectation.” These effects have
been shown in vibration [19], temperature, and heat-pain
testing [20]. To deliver static stimuli, a good example is to
look at the use of Computerized Assessment of Sensory
Examination (CASE IV®; WR Medical) QST equipment
[21]. There are two methods or algorithms to deliver static
stimuli: a forced-choice technique [19] and a 4-2-1 stepping
algorithms [22]. For either technique, a subject sits in front
of a visual cuing device and will be let alert of a time period
when the stimuli may be delivered (yellow light = get ready,
green light = test in progress). In general, the time period
when the stimuli may be delivered will be displayed in num-
ber 1 or 2. The stimuli are delivered randomly. Null stimuli
are used only in 4-2-1 stepping algorithms. Null stimuli are
delivered randomly in between to assure alertness and atten-
tiveness of the subject. When and how many the null stimuli
are delivered are unknown to the subject. The subject is, by
that time, already attached to either vibration or thermal
transducers depending on which modality of sensation is
being tested. In a force-choice technique, the subject is
forced to acknowledge at which time period (1 or 2) the
stimuli are present after the last (2) period indicator appears
in the visual cue. Even if the subject is not sure, he or she
will still have to choose a “most likely” time period in which
the stimuli might be. Null stimuli are not used in forced-
choice method. The stimulus will never be delivered in both
periods, only in period 1 or 2. Because the subject will have
225
a 50 % chance of guessing where the stimulus is, a sensory
threshold determined by a forced-choice method is set as the
stimulus level at which a subject is correct 75 % of the time.
In a 4-2-1 stepping algorithms, the subject acknowledges the
presence of each stimulus at the time right when he or she
feels it (in either 1 or 2 time period). The subject acknowl-
edges the response by pressing a response key (yes = felt, no
= not felt). The advantage of using a force-choice technique
is that it eliminates the indecisiveness (slow reaction) from
the subject and can help in discriminating “internal” sensa-
tion (if this sensation is there already) from external stimuli.
The disadvantage of the force-choice technique is that it is
more time-consuming and requires more understanding of
the test and more attention from the subject. It is also easier
for a subject to make mistakes in forced-choice methods. If
done right, the thresholds estimated from 4-2-1 stepping
algorithms are comparable to those from a forced-choice
method [22].
In CASE IV, the magnitude of stimulus is measured not in
physical units (displacement or temperature) but in a unit
called JND (just-noticeable difference). One JND unit is the
minimal difference of the intensity between two stimuli to
make a subject feel different during the stimulation. The sen-
sory perception is governed by psychophysical laws [23].
According to psychophysical laws, the relationship between
the sensory perception and stimulus strength is not linear but
exponential. Therefore, it is more accurate if the stimulus
strength is expressed as JND, not physical units, when the
numerical value of threshold is used for statistical calcula-
tion [4].
In delivering static stimuli (both vibration and thermal)
with CASE IV, the magnitude of each step of stimuli has
been discretely defined and set up as 25 JND steps(ranging
from step 1 JND (smallest magnitude) to step 25 JND (larg-
est magnitude)) [21]. For vibration testing, the stimulus is
created from a stimulating probe, which is placed over the
skin. This probe is part of a vibration stimulator set at pre-
cisely 125 Hz of vibration and has displacement between
0.1 and 576 mm [21]. In CASE IV, step 1 is defined as dis-
placement of <1 mm and step 25 as 315 mm [4]. A 30-g
preload weight is used to balance the movement so that
there is no non-stimulus vibration. In vibration testing, the
stimulus is shaped into sinusoidal curves wrapped in an
exponential envelope. For thermal testing, a thermode is
placed over the skin. This thermode provides a ramp of
increasing (heat) or decreasing (cool) temperatures in a pre-
cise manner. The shape of the stimulus is either triangular or
trapezoid. The lowest temperature is set at 10 °C and the
highest 50 °C [4]. If more strength of stimulus is required
for a higher or lower JND step after the highest or lowest
temperature has been reached, the duration of the stimulus
can be kept longer to increase the strength without causing
tissue damage.
226
25
Stimulus magnitude (JND)
20
15
10
0
1 2 3 4 5 6
Fig. 11.1 Forced-choice algorithm. The diagram illustrates the
sequence of a force-choice technique on vibration threshold testing
performed on a subject using CASE IV device. The test was done at the
fingertip of the left index finger. The test starts with JND 13. The ●
represents success. The ○ represents failure. Success is defined as
correct identification of a stimulus pair six of seven times or five of the
first six times and seven times incorrect and the eighth and ninth time
correct according to Dyck et al. [4]. Step 1(●, JND 13) = ssssss, step 2
Subject Response and Method
of Threshold Determination
Either in forced-choice or 4-2-1 algorithms, the test usually
starts with an intermediate JND step (step 13) delivered to
the subject. The next level of JND delivered depends on the
response from the subject. In general, the stimulus delivery
follows the rule of up-down transformed rule described by
Wetherill [24]. This rule dictates that every step of “felt”
stimulus will be followed by the next stimulus of lesser
strength until the subject no longer feels. Then, the next step
will be of a stimulus of increasing strength (up-turnaround
point). Similarly, every “not felt” stimulus will be followed
by the next stimulus of greater strength until the subject starts
to feel. Then, the next step will be of stimulus of lesser
strength (down- turnaround point). In forced-choice algo-
rithms, step 13 will be followed by larger or smaller steps
depending on the response of the subject and the rule
described by Dyck et al. [4]. At each stimulus level, the sub-
ject will be tested up to eight times before the next level of
stimulus is given. If the subject answers correctly, the next
stimulus level will be decreased. If the stimulus is identified
incorrectly, the next stimulus level will be increased. The
threshold is determined from the mean JND at the last six
turnarounds. The sequence of testing results is shown in
Fig. 11.1. In 4-2-1 stepping algorithms, the stimuli are simi-
larly divided into 25 discrete JND steps. In this algorithm,
null stimuli will be given randomly with the real stimuli.
After the initial step (13), the next stimulus will depend on
the subject’s response and follow the rule above. The stimu-
lus level will be changed by 4, 2, and then a sequence of 1
P. Thaisetthawatkul
7 8 9 10 11 12 13 14 15 16 17 18 19 20
Trial number
(○, JND 9) = sfssf, step 3 (●, JND 13) = ssssss, step 4 (●, JND 11) = ssssss,
step 5 (●, JND 10) = ssssss, step 6 (○, JND 9) = ff, step 7 (●, JND
12) = ssssss, step 8 (●, JND 11) = fssssss, step 9 (○, JND10) = ff, step 10
(●, JND11) = ssssfss, step 11 (○, JND10) = ff, step 12 (●, JND11) = sfsssss.
The changes in stimulus level follow 4-2-1 rules. Null stimulus is not
given in forced-choice algorithm. In this subject, the vibration detection
threshold is 10.5 JND and 92nd percentile
JND step change. Again, the threshold is determined by the
mean JND at the last six turnarounds. The sequences of test-
ing result are shown in Fig. 11.2. In 4-2-1 algorithms, if a
subject gives affirmative responses to two or more of null
stimuli, the test is not considered valid and needs to be
retested, and if this happens again for two more subsequent
occasions in the same subject, a forced-choice technique is
recommended. If step 25 is not repeatedly felt (at least three
times), the subject is considered “insensitive” (Fig. 11.3),
and if step 1 is recurrently felt (at least three times), the sub-
ject is considered “hypersensitive.” Some responses are not
considered legitimate. For example, if the subject identified
the same level of stimuli as “felt” one time and “not felt”
another time, the subject may have not paid enough attention
to the test. One possibility is that the subject fell asleep or
his/her mind was occupied by other issues, not the test at
hand (Fig. 11.4). In this case, the test needs to be repeated or
switched to the force-choice technique.
Forced-choice and 4-2-1 stepping algorithms are not used
in testing heat-pain threshold. These algorithms can produce
overstimulation and cause tissue damage in this category of
sensation test [25]. Instead, the method employs a series of
non-repeating heat ramps of increasing level to stimulate
pain sensation with null stimuli [25]. In CASE IV, the subject
will be presented with a visual analog pain scale with pain
level ranging from 1(least) to 10 (most), with 0 level indicat-
ing no discomfort or pain. At the level 0, the subject may feel
only warm or hot feeling but still no pain feeling. When the
subject starts feeling pain (minimal), the subject will choose
level 1 and will report this to the operator. When the subject
feels that he or she no longer wants the thermal stimulus to
11 Quantitative Sensory Testing 227

25

Stimulus magnitude (JND)

20

15

10

0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Trial number

Fig. 11.2 4-2-1 stepping algorithm with null stimuli. The diagram graph represents “not felt.” The ○ on the trial number axis represents
illustrates the sequence of a 4-2-1 stepping algorithm on vibration null stimuli. Please note that the changes in the stimulus level follow
threshold testing performed by the same subject as in Fig. 11.1 using 4-2-1 stepping rule described in the text. In this subject, the vibration
CASE IV device. The test was done at the fingertip of the left index detection threshold is 9.8 JND and 89th percentile
finger. The test starts with JND 13. The ● represents “felt.” The ○ on the

Fig. 11.3 Vibration insensitivity. 25

The diagram illustrates the
sequence of a 4-2-1 stepping
Stimulus magnitude (JND)

algorithm on vibration threshold 20

testing performed by another
subject using CASE IV device.
15
The ○ represents “not felt” as
mentioned under Fig. 11.2. In this
subject, the vibration sensate was 10
not felt even though the stimulus
level was raised to JND 25. When
the subject did not feel JND 25 5
level for three consecutive times,
the test was terminated and the
subject was declared “vibration 0
insensitive” 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
Trial number

25
Stimulus magnitude (JND)

20
Fig. 11.4 Unacceptable result of
testing. The diagram illustrates
the sequence of a 4-2-1 stepping 15
algorithm on vibration threshold
testing performed by a subject
using CASE IV device. In this 10
subject, the step 6 (JND 23) was
felt. However, subsequent steps
with JND 23 or higher were not 5
felt. With a pattern like this one,
the threshold cannot be
0
determined, and the test should be
repeated. The ● represents “felt.” 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
The ○ represents “not felt” Trial number
228
Fig. 11.5 Non-repeating
heat-pain algorithm with null
stimuli [4]. The diagram illustrates
the sequence of steps to determine
Patient response [0 10 ]
HP threshold by a subject using
CASE IV device. The test starts
with JND 13. The ● represents
“pain feeling.” The ○ represents
“warm feeling only.” The □
represents HP 0.5 and HP 5.0. The
difference between HP 5.0 and HP
0.5 is HP 5.0-0.5. In this subject,
HP 0.5 =18.8 JND (12th
percentile), HP 5.0 = 22.5 JND
(47th percentile), and HP
5.0-0.5 = 3.7 JND (88th percentile)
Fig. 11.6 Heat-pain
hypersensitivity. The diagram
illustrates the sequence of steps to
determine HP threshold by a
Patient response [0 10]
subject using CASE IV device.
The test starts with JND 13. In this
subject, HP 0.5 = 23.2 JND (97th
percentile), HP 5.0 = 23.9 JND
(75th percentile), and HP
5.0-0.5 = 0.7 JND (1st percentile).
The ● represents “pain feeling.”
The ○ represents “warm feeling.”
The □ represents HP 0.5 and
HP 5.0
increase, the subject will report level 10 (most discomfort).
Because heat-pain threshold is the thermal level at which the
subject feels pain 50 % of the time, the levels 0.5 (HP 0.5)
and 5 (HP 5.0) are used for threshold description [25]. The
sequence of test results is shown in Fig. 11.5. HP 0.5 is con-
sidered to be the heat-pain threshold, and HP 5.0 is the inter-
mediate pain level. The difference between the threshold (HP
0.5) and the intermediate step (HP 5.0) is named HP 5.0-0.5.
HP 5.0-0.5 indicates tolerability of a subject to increasing
pain stimulus. In heat-pain testing, not only elevated thresh-
olds (hypoalgesia) but also decreased thresholds (hyperalge-
sia) can be established (Fig. 11.6). Using this method, only
erythema of the skin can happen, but tissue damage (burns)
is not expected.
When performing automated quantitative sensory testing,
vibration threshold estimation is usually done first, followed
by thermal (cool and warm), then heat-pain threshold esti-
mation the last. In all these tests, normal values controlled
for age, gender, test sites, methods of tests, and stimulus pre-
sentation are available [4]. The threshold is usually reported
in percentile value compared to the results obtained from
normal populations. Elevated thresholds are considered when
P. Thaisetthawatkul
10
8
6
4
2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Stimulus magnitude (JND)
10
8
6
4
2
0
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30
Stimulus magnitude (JND)
the thresholds obtained are >95th percentile compared to
normal population. In evaluating heat-pain sensation,
decreased thresholds or hypoalgesia is considered when the
thresholds are <5th percentile. However, for more restricted
criteria, especially for a research purpose, the cutoff points
of >97.5th or >99th and <2.5th or <1st percentile may be
considered [26]. Normal values for different type of equip-
ment may not be applicable to CASE IV and have been
established [27]. Normal values for children and adolescents
are also available for a different type of equipment [28].
Cautions need to be taken on choosing normal values because
this may change according to type of equipment, test meth-
ods chosen, and stimulus types.
Limitations of Quantitative Sensory Testing
Even though quantitative sensory testing (QST) is very help-
ful for the reasons mentioned above, the technique has some
disadvantages or shortfalls. First of all, QST requires a spe-
cial equipment and needs to be done in a quiet environment
without distraction such as in a separate, quite room. The
11 Quantitative Sensory Testing
subject needs to be alert, pay attention to the instructions,
cooperative, and follows the testing protocol closely until the
test ends. If the subject becomes drowsy, falls asleep, or is
under influence of psychotropic drugs, the test results may
deviate. However, a small dose of simple analgesics does not
affect the test outcome [29]. Secondly, QST cannot differen-
tiate between peripheral and central causes of sensory
deficits. QST by itself has no anatomical-localizing value
apart from telling which fiber types (large, small, or both) are
involved. For example, QST is used to evaluate central pain
syndrome after stroke [30]. Thirdly, the subject may deliber-
ately alter the results, especially in a medicolegal case, so
that they appear abnormal or more abnormal than what really
is [31]. Fourthly, because it is a psychophysical testing, the
response is always subjective.
Clinical Applications of QST
Because QST is a standardized, quantified, reproducible sen-
sory testing with validated normal values, the use of QST has
been adopted in many clinical situations [32]. QST can be
used in establishing a diagnosis, quantifying severity, identi-
fying fiber type involved, following up a patient after the use
of medications or other treatment intervention, and follow-
ing up the subjects participating in a research project if the
research project uses QST as an end point [33]. In establish-
ing the diagnosis of peripheral neuropathy, one has to keep in
mind that an abnormal QST result is not by itself diagnostic
of peripheral neuropathy but QST is a helpful tool when used
in combination with another diagnostic test in defining the
diagnosis of peripheral neuropathy.
The Role of QST in Generalized
Peripheral Polyneuropathy
QST has been used mostly to evaluate generalized polyneu-
ropathy. Diabetic distal sensorimotor polyneuropathy is the
most common neuropathy that uses QST as a diagnostic and
evaluating tool. QST assessing vibration and cooling thresh-
old has been incorporated into diagnostic criteria to diagnose
diabetic neuropathy in a large longitudinal study [34]. On
long-term follow-up, it has been shown that vibration detec-
tion threshold was a good measure showing the worsening of
diabetic neuropathy even though monotone worsening was
better shown by the neuropathy impairment composite score
of the lower limbs [35]. In diabetic patients without
polyneuropathy, however, QST showed no monotone wors-
ening toward the development of neuropathy, compared to a
composite score from the nerve conduction study attributes
[36]. The abnormalities in the patterns of QST, especially
229
vibration (VDT), cooling (CDT), and heat-pain (HP 0.5 and
HP 5.0) detection thresholds, correlate with the severity of
diabetic polyneuropathy [37]. When using ³97.5th percen-
tiles as abnormal, patients with diabetic polyneuropathy who
have abnormal VDT, CDT, HP 0.5, and HP 5.0 have more
severe symptoms. HP 5.0-0.5, which indicates pain-stimulus
response slope, if it is in the £2.5th percentile or suggests
hyperalgeisa, was also correlated with the severity of dia-
betic polyneuropathy [37]. The use of QST has been accepted
as a method of assessment of response to treatment in clini-
cal trials on polyneuropathy [38]. In a clinical trial evaluat-
ing recombinant human nerve growth factor in patients with
diabetic polyneuropathy, QST assessing CDT and HP 5.0
were used as a second end point to indicate the effect of the
treatment and placebo on the studied subjects [39]. Likewise,
QST was also used as a secondary end point in clinical trials
assessing the use of antioxidant, alpha lipoic acid [40, 41],
and aldose reductase inhibitor [42] in diabetic polyneuropa-
thy. However, the centers participating in a clinical trial have
to use the same QST device because different devices do not
share the same normal values and the results may not be
comparable [43]. When QST is used in that manner, the
results are found to be reproducible [44].
The other common clinical application of QST is to assess
and diagnose small fiber neuropathy (SFN). SFN is a very
common sensory neuropathy seen in clinical practice.
A patient is suspected to have SFN when one presents with
positive sensory and pain symptoms but routine electrophys-
iologic studies are normal or minimally abnormal [45]. The
diagnosis is based on demonstration of abnormal small fiber
nerve functions and/or pathology [46]. Because QST can
evaluate each modality of sensory function separately, QST
has a role in diagnosis of SFN when abnormality is seen in
cooling, warm, or heat-pain detection threshold while vibra-
tion detection threshold is normal [47]. The other diagnostic
tools for SFN include skin biopsy to study intraepidermal
nerve fiber density [48] and the assessment of sweat output
by quantitative sudomotor axon reflex testing (QSART) or
thermoregulatory sweat test [49]. In a large study on painful
sensory neuropathy, the sensitivity of QST (abnormal cool-
ing threshold) in diagnosing SFN was about 72 %, ranked
between skin biopsy and QSART [50]. In the other study, the
sensitivity of QST in SFN was up to 100 % [51]. In most
cases, abnormal VDT can be allowed due to mild coexisting
involvement of large fiber nerves [50]. QST abnormalities do
not predict pain symptoms in sensory neuropathy [52, 53]
suggesting that the mechanism of pain symptoms in sensory
neuropathy, especially SFN, may have other associated
mechanisms rather than small fiber dysfunction alone [54].
Assessment of sensory abnormalities by utilizing QST
has been commonly used in cancer and chemotherapy
researches to identify cancer subjects who have abnormal
230
sensation at baseline before, during, or after chemotherapy
[55–59]. In some of these studies, QST alone was performed
either to screen the patients before chemotherapy or to fol-
low up on the patients after chemotherapy, especially when
they developed neuropathic symptoms. However, without a
gold standard of the nerve conduction studies, the validity of
QST alone as a test to identify peripheral neuropathy is in
doubt. Besides, the methods and devices of QST in these
studies were different making comparison between studies
impossible. In a study on subclinical peripheral neuropathy
in colorectal cancer, touch detection was done by Semmes-
Weinstein monofilament and BUMPS device while thermal
detection was done by heat ramps with dynamic stimuli [59].
Another study on neurotoxicity of paclitaxel in patients with
breast cancer used handheld biothesiometer to assess vibra-
tion threshold [58]. In a study on suramin-induced neuropa-
thy after the use of the agent to treat prostate cancer, QST by
CASE IV was incorporated into Total Neuropathy Score to
categorize the patients along with standard electrophysiolog-
ical studies and other clinical assessment [60]. In that study,
QST showed good correlation with the presence of periph-
eral neuropathy after the treatment [60].
In diseases that have high prevalence of SFN, such as
human immune deficiency (HIV)-associated sensory neu-
ropathy and Fabry disease, QST has been widely used to
assess and diagnose SFN. Heat-pain threshold (HP 0.5) and
epidermal nerve swelling seen from skin biopsy were found
to predict the development of HIV distal sensory neuropathy
[61]. There was also a good correlation between the swelling
of the intraepidermal nerves and HP 0.5 and HP 5.0 [62]. In
a study with a longer follow-up, an abnormal CDT, HP 0.5,
and leg intraepidermal nerve fiber density were found to pre-
dict transition to symptomatic HIV distal sensory neuropa-
thy [62]. QST has been shown to add significantly to the
research diagnosis of HIV-associated sensory neuropathy
[63]. QST was included in a study on an antiretroviral medi-
cation, 2¢,3¢ dideoxycytidine (ddC), and its role in sensory
neuropathy in HIV patients [64]. In this study, abnormal
vibration detection threshold was found to precede the occur-
rence of clinical symptoms. Fabry disease is an X-linked
metabolic disease caused by deficiency of alpha-galactosi-
dase resulting in accumulation of galactosyl conjugates,
especially globotriaosylceramide, in vascular endothelial
cells in various organs. QST has an important role in identi-
fying SFN related to this disorder [65]. QST was one of the
outcome measures in a clinical trial assessing enzyme
replacement therapy in Fabry disease, showing significant
reduction in warm and cooling detection threshold after
3 years of treatment [66].
QST has also been used in the assessment of abnormal
sensibility in many other disorders that cause predominantly
sensory neuropathy or SFN such as uremia [67], leprosy
[68], familial dysautonomia [69], and hypothyroidism [70].
P. Thaisetthawatkul
The Role of QST in Focal Peripheral Neuropathy
(Such as Carpal Tunnel Syndrome)
Because of its noninvasiveness, QST has been tried to iden-
tify cases of entrapment neuropathy, especially carpal tunnel
syndrome. If QST is going to be helpful in carpal tunnel syn-
drome, the sensory threshold at the tip of the second digit
should be higher than the fifth digit, and the sensitivity of
abnormal QST should be at least equal to or, better, higher
than the nerve conduction study that is already the gold stan-
dard diagnostic test for carpal tunnel syndrome. However,
many studies that were done to look at these particular issues
failed to support the use of QST as a diagnostic test for car-
pal tunnel syndrome. One study looked at vibration thresh-
old at the second and fifth finger tips on 28 affected limbs in
17 patients with carpal tunnel syndrome [71]. The VDT was
compared to the standard nerve conduction studies. Even
though there was a good correlation between elevated VDT
at the second digit and abnormal nerve conduction study
indicating a median mononeuropathy across the wrist, con-
comitant elevation of vibration threshold was found in 36 %
of the patients [71]. Another study looked at thermal (hot and
cold) threshold using automated force-choice procedure at
the second and fifth finger tips on 24 patients with carpal tun-
nel syndrome and 25 controls [72]. Again, the thermal
threshold detection was compared to the standard nerve con-
duction studies. Abnormal thermal (both hot and cold)
threshold was found to correlate well with the nerve conduc-
tion studies. However, abnormal thermal threshold, espe-
cially cold threshold, was found frequently on the fifth digit
[72]. The sensitivity of abnormal vibration and thermal
threshold in carpal tunnel syndrome was unacceptably low
[73], especially when compared to the nerve conduction
studies [74]. Similar findings were found in a large study
using vibrometry and electrophysiologic testing in 130 fac-
tory workers for carpal tunnel syndrome [75]. In a large
study using vibrometry with different frequency to screen for
carpal tunnel syndrome compared to the nerve conduction
study in 169 industrial workers, vibration threshold was
found to correlate poorly with the nerve conduction studies
when the carpal tunnel syndrome was mild or early thus pre-
cluding a vibrometer as a good screening method [76].
The Role of QST in Central
Nervous System Disease
The role of QST in diseases of the central nervous system is
limited. Neuroimaging studies such as magnetic resonance
imaging study or computerized tomography scan and
electrophysiologic studies such as somatosensory evoked
potential study already are efficient in demonstrating a lesion
within or detecting objective physiologic changes in the
11 Quantitative Sensory Testing
central nervous system, respectively. QST is not usually used
to diagnose central nervous system diseases. However, QST
has an advantage of detecting functional abnormalities in
spinothalamic- or posterior column-specific modality of sen-
sory system separately. So, its use has been limited to study
sensory abnormality in the central nervous system pertaining
to specific modality of sensory function. QST has been used
to study sensorimotor dysfunction in patients with multiple
sclerosis correlated with magnetization transfer imaging of
the spinal cord [77]. QST was also used in the study of the
mechanism of central pain in patients with syringomyelia
[78] and stroke [79]. The other use of QST in central nervous
system diseases can be demonstrated by the use of QST in
studying sexual dysfunction in female patients with multiple
sclerosis [80] and the use of QST in studying recovery of
sensory symptoms in acute stroke [81].
Acknowledgment The author wants to thank Ken Maurer, manager of
the neurophysiology laboratory at the Nebraska Medical Center, and
Debi Kibbee, research assistant at the Department of Neurological
Sciences, University of Nebraska Medical Center, for their contribution
to all the figures.
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