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\begin{document}

\title{Refining the video head-impulse test diagnostic accuracy - a
retrospective case-control study.}



\author[1]{Nabil Faranesh}%
\author[1]{KHALDOON Abo-Saleh}%
\author[1]{Margalith Kaminer}%
\author[2]{Avi Shupak}%
\affil[1]{LIN Medical Center}%
\affil[2]{Technion Israel Institute of Technology The Ruth and Bruce Rappaport Faculty of Medicine}%


\vspace{-1em}



  
  \date{June 16, 2024}


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\selectlanguage{english}
\begin{abstract}
Abstract Objective: To appraise the added benefit of refixation saccades
(RS) towards the improvement of the video head-impulse test (vHIT)
diagnostic accuracy in cases of suspected left horizontal semicircular
canal dysfunction. Study Design: Case-control. Setting: Tertiary
referral center. Participants: Twenty patients with a final diagnosis of
left horizontal semicircular canal dysfunction and 20 patients for whom
vestibular dysfunction was ruled out. Intervention: vHIT recordings of
40 patients with left horizontal semicircular canal (LHSCC)
vestibulo-ocular reflex (VOR) gain \textless{}0.8. Main outcome
measures: LHSCC VOR gain; Presence of RS and their frequency, latency,
and velocity characteristics. Results: Gain values \textgreater{} 0.72
were found in all patients with no vestibular disease and in 4 (20\%)
patients having vestibulopathy. Significantly higher average left-sided
RS velocity and frequency were found among the vestibular patients. VOR
gain \textless{} 0.72 was found to be highly specific for the diagnosis
of vestibular dysfunction. However, for gain values in the range of
0.72-0.79 the presence of RS with frequency \textgreater{} 80\% largely
improved vHIT diagnostic accuracy. CONCLUSIONS: Although VOR
gain\textless{}0.8 is considered to reflect dysfunction a significant
false positive rate for left-sided horizontal vHIT was found for gains
in the range of 0.72-0.79. The presence of RS with frequency
\textgreater{}80\% could improve vHIT diagnostic ability in these
patients. Key words: video head impulse test, re-fixation saccades,
peripheral vestibular pathology, gain asymmetry in vHIT, lateral
semicircular canal hypofunction, saccadic frequency, corrective saccade
velocity%
\end{abstract}%



\sloppy


\textbf{Abstract}

\textbf{Objective:} To appraise the added benefit of refixation saccades
(RS) towards the improvement of the video head-impulse test (vHIT)
diagnostic accuracy in cases of suspected left horizontal semicircular
canal dysfunction.

\textbf{Study Design:} Case-control.

\textbf{Setting:} Tertiary referral center.

\textbf{Patients:} Twenty patients with a final diagnosis of left
horizontal semicircular canal dysfunction and 20 patients for whom
vestibular dysfunction was ruled out.

\textbf{Intervention:} vHIT recordings of 40 patients with left
horizontal semicircular canal (LHSCC) vestibulo-ocular reflex (VOR) gain
\textless{}0.8.

\textbf{Main outcome measures:} LHSCC VOR gain; Presence of RS and their
frequency, latency, and velocity characteristics.

\textbf{Results:} Gain values \textgreater{} 0.72 were found in all
patients with no vestibular disease and in 4 (20\%) patients having
vestibulopathy. Significantly higher average left-sided RS velocity and
frequency were found among the vestibular patients. VOR gain \textless{}
0.72 was found to be highly specific for the diagnosis of vestibular
dysfunction. However, for gain values in the range of 0.72-0.79 the
presence of RS with frequency \textgreater{} 80\% largely improved vHIT
diagnostic accuracy.

\textbf{CONCLUSIONS:} Although VOR gain\textless{}0.8 is considered to
reflect dysfunction a significant false positive rate for left-sided
horizontal vHIT was found for gains in the range of 0.72-0.79. The
presence of RS with frequency \textgreater{}80\% could improve vHIT
diagnostic ability in these patients.

\textbf{Key words:} video head impulse test, re-fixation saccades,
peripheral vestibular pathology, gain asymmetry in vHIT, lateral
semicircular canal hypofunction, saccadic frequency, corrective saccade
velocity

\textbf{Key points}

\begin{enumerate}
\tightlist
\item
  The video head impulse test (vHIT) is widely employed for the
  evaluation of the semicircular canals (SCC) function in velocities and
  frequencies relevant to daily activities.
\item
  Current clinical practice considers the vHIT registered
  vestibulo-ocular reflex (VOR) gain, as the primary measure for SCC
  function while the role of the recorded re-fixation saccades (RS) is
  still under evaluation.
\item
  Difficulty in the interpretation of borderline vHIT gain results stems
  from the inherited differences in gain values being larger for the
  adductive eye.
\item
  Employing the widely used Otometrics - Natus ICS Impulse device
  (Taastrup, Denmark), in which the camera captures the right eye
  movements alone, we found that when borderline gain values of 0.72-0.8
  are recorded for the left-word impulses raising the possibility of
  left canal dysfunction, the presence of RS with frequency
  \textgreater{}80\% largely improve the diagnostic accuracy of
  vestibular pathology.
\item
  Based on our results we recommend careful re-consideration of the vHIT
  test results implications when left-sided VOR gain values \textless{}
  0.8 are recorded. Gain \textless{} 0.72 is highly specific for the
  diagnosis of vestibular dysfunction. However, for gain values in the
  range of 0.72-0.79 the presence of RS with frequency \textgreater{}
  80\% would largely improve the diagnostic accuracy
\end{enumerate}

\textbf{Introduction}

The bed-side head impulse test was formulated in 1988 as a measure of
the lateral semicircular canal function (1). For this test pathological
response is based on the detection of re-fixation saccades (RS) that
compensate for the low gain of the failing vestibulo-ocular reflex
(VOR). In 2009 the video head impulse test (vHIT) was introduced (2).
This technology, which is based on the capturing of eye-movements at a
frequency of around 250 Hz, enables the quantification of the VOR gain
and the recording of RS both during the head movement and following it
(''covert'' and ''overt'' RS respectively). The RS parameters of
latency, frequency, and velocity are provided by the commercially
available vHIT systems (3). However, current clinical practice considers
the VOR gain, for which norms and pathological values have been
published, as the primary measure for semicircular canal function while
the role of the registered RS is still under evaluation (4-7).

It was found that the RS velocity increases with decreasing gain (8,9).
Also, in a group of dizzy patients with normal VOR gains the frequency
of the RS was reported to increase with age (8). Several previous
studies have examined the possible role of RS parameters in addition to
the VOR gain towards the diagnosis of canal dysfunction. High velocity
RS were demonstrated together with improved gain values among patients
recovering from vestibular neuritis supporting the possible diagnostic
value of RS in addition to the gain criterion (10). Overt but not covert
RS were frequently recorded in asymptomatic older patients (9,11)
differentiated from those found in unilateral semicircular canal
dysfunction by their lower frequency and slower peak velocity. The
combination of gain values \textless{}0.78 and RS frequency
\textgreater{} 82\% was recently suggested to improve diagnostic
accuracy over the low gain parameter alone (9). Others even assert that
the interpretation of vHIT results should first rely on the occurrence
of RS and only second on the gain values (12). Another study proposed
that the presence of RS albeit normal gain values indicate the existence
of peripheral vestibulopathy and localizes the side of the lesion (13).
For the recently introduced protocol of suppressive head impulse
(SHIMP), the amplitude of anti-compensatory saccades was suggested as an
indicator of residual semicircular canal function (14).

When mono-ocular eye movements registration is employed, the horizontal
vHIT gain values were found to vary according to the side of the eye
against which the recording camera is placed. Higher gains and longer
saccade latencies were found for rightward impulses when the right eye
movements only were captured (4,6,9,11,15).

\emph{Study Objectives}

The purpose of the study was to appraise the added benefit of RS
parameters alongside the VOR gain values towards the improvement of the
vHIT diagnostic accuracy. Specifically, the horizontal vHIT (hvHIT)
results of patients with leftward VOR gain values \textless{}0.8,
currently defined as pathological (2,4,5,6,7,16), which was registered
by right eye position of the testing system camera, were retrospectively
evaluated for the presence of RS. The contribution of low VOR gain
values with and without the addition of RS findings to the patients'
final diagnosis of left vestibular dysfunction was analyzed. The focus
of our study was on the diagnosis of left horizontal canal dysfunction
as the mono-ocular right eye placement of the recording camera, might
introduce potential bias of lower leftwards VOR gain values
(4,6,9,11,15).

\textbf{Materials and Methods}

\emph{Study subjects and ethics statement}

The hvHIT recordings of 40 dizzy patients with left sided horizontal
canal VOR gains \textless{}0.8 were retrospectively re-evaluated for the
presence of RS. The study groups included 20 patients with a final
diagnosis of left horizontal semicircular canal vestibular dysfunction
(VD) secondary to vestibular neuritis, vestibular schwannoma and
unilateral intra-tympanic gentamicin-induced vestibulopathy and 20
patients for whom vestibular disease was ruled out (NVD). The diagnosis
of left vestibular disease was based on the cumulative data of the
patient's history, bedside otoneurological examination findings,
videonystagmography caloric test results, vHIT findings and imaging
results. The NVD subjects had non-specific complaint of dizziness,
history that was not typical for vestibular disease, normal bed-side
otoneurological examination as well as videonystagmography and imaging
studies results. Also, no persistent postural perceptual dizziness
(PPPD) nor vestibular migraine cases were included in the NVD group. The
contribution of the VOR gain values, RS latency, frequency, and velocity
parameters towards the prediction of left vestibular dysfunction was
assessed. The study protocol was approved, and an exempt was granted
from informed consent procedure by the institutional committee for human
experiments (identifying data removed to comply with the instruction to
authors)

\emph{Study set-up and paradigm}

All hvHIT examinations were carried out by the same experienced
right-handed examiner (M.K.) employing the Otometrics - Natus ICS
Impulse device (Taastrup, Denmark) in which the camera captures the
right eye movements alone. For the vHIT system used the VOR gain is
calculated as the whole area under the curve of the velocity over time
recordings of the eye movement divided by that of the head.
Physiologically occurring microsaccades characterized by eye movements
smaller than 15 minutes of arch with velocity \textless{} 50 deg/sec are
screened out by the vHIT system (17). The vHIT test was carried out as
has been previously described for the Otometrics - Natus ICS Impulse
system (16). For each participant 20 repetitions of the head impulse
were randomly carried out to the left and right sides.

The outcome measures for the hvHIT were the horizontal canal VOR gain;
percentage of gain asymmetry ((rightward gain -- leftward gain /
rightward gain + leftward gain)*100), head velocity (degrees/sec), RS
velocity (degrees/sec), RS latency (msec), and RS frequency ((number of
corrective saccades / number of eligible head thrusts) * 100).

\emph{Establishing our laboratory norms for the horizontal vHIT gains.}

42 healthy subjects with no vestibular complaints and normal
otoneurological examination had vHIT testing of the horizontal
semicircular canals employing the Otometrics - Natus ICS Impulse device
(Taastrup, Denmark). All the examinations were carried out by the same
experienced right-handed examiner (M.K.). The gain values obtained had
normal distribution averaging 0.88\emph{+} 0.08 (mean \emph{+} standard
deviation) for the left horizontal semicircular canal and 1\emph{+} 0.14
(mean \emph{+} standard deviation) for the right semicircular canal.
Taking into consideration normal range within mean \emph{+} 2 standard
deviations, the calculated normal ranges for the hvHIT gains are 0.72 --
1.04 and 0.72 -- 1.28 for the left and right side respectively.

\emph{Statistical analysis}

Leftward hvHIT gain values, percentage of gain asymmetry, head velocity,
RS velocity, latency, and frequency were compared between the VD and NVD
groups by the Student unpaired two-tailed test or the non-parametric
Mann--Whitney test. Within subjects rightward and leftward head
velocities and VOR gains were compared by the Student paired two-tailed
test or the non-parametric Wilcoxon matched-pairs signed-ranks test.
Data sets were tested for normal distribution by the Shapiro--Wilk
normality test and the appropriate statistical tests were accordingly
used. Proportions of the cut-off gain values, presence of RS, detection
of RS with specific velocity and frequency characteristics, and their
combinations were compared between the groups employing the Fisher's
exact test. Sensitivity, specificity, positive and negative predictive
values towards the prediction of VD were calculated for the various
outcome measures and their combinations. P-values \textless{}0.05 were
considered statistically significant. Statistical analysis was performed
using the GraphPad InStat version 3.06 software (San Diego, CA, USA).

\textbf{Results}

The VD and NVD groups each included 11 men and 9 women. The mean
subjects' age of the VD group participants was 56.45\emph{+} 16.64 years
(mean \emph{+} standard deviation) and did not significantly differ from
that of the NVD group which was 50.75\emph{+} 14.58 years (unpaired
t-test). The final diagnosis of the 20 patients included in the VD group
was vestibular neuritis in 17, vestibular schwannoma in 2 and
intra-tympanic gentamicin- induced vestibulopathy in 1 patient. The
diagnosis of vestibular neuritis was reached only if all the following
symptoms and signs were present: acute onset of prolonged severe
rotatory vertigo, the presence of spontaneous nystagmus and postural
imbalance, and documentation of unilateral reduced caloric response
(caloric lateralization \textgreater{} 25\%) on the caloric study of
videonystagmography.

For the NVD group the average rightward hvHIT gain was 0.93\emph{+} 0.1
(95\% CI 0.88-0.98) and the leftward gain 0.75\emph{+} 0.02 (95\% CI
0.74-0.77). The difference was of statistical significance
(p\textless{}0.0001; Wilcoxon matched-pairs signed-ranks test).

The rightward and leftward head velocity values did not significantly
differ reaching 210\emph{+} 31.3 (95\% CI 195.7-224.9) and 213.9+33.8
(95\% CI 198.1-229.7) deg/sec respectively (Paired t-test).

No significant difference was found between the leftward head velocities
of the VD and NVD groups registered as 207.3\emph{+} 33.2 (95\% CI
191.8-222.8) and 213.9\emph{+} 33.8 (95\% CI 198.1-229.7) respectively
(Unpaired t-test).

The average left hvHIT gain of the VD group was significantly lower as
compared to the NVD group (0.445\emph{+} 0.23 vs. 0.757\emph{+} 0.024;
p\textless{}0.0001, unpaired t-test; Fig. 1) and the gain asymmetry
average, where higher gains were recorded for the rightward stimuli, was
significantly larger (39.2\emph{+} 24.11\% vs. 18.12\emph{+} 9.05\%;
p\textless{}0.002, unpaired t-test; Fig. 2).

As detailed in section \emph{2.3} the calculated normal range in our
laboratory for the right hvHIT gain is 0.72-1.28 and 0.72-1.04 for the
left hvHIT gain.

Gain values \emph{\textgreater{}} 0.72 were found in all NVD patients
and in 4 (20\%) patients of the VD group (p\textless{}0.0001; Fisher's
exact test).

Significantly higher left-sided RS velocity and frequency were found in
the VD group (221.35\emph{+} 89.18 vs. 131\emph{+} 42.93 degrees/sec;
p\textless{}0.0002 and 83.2\emph{+} 33.2\% vs. 24.15\emph{+} 29.8\%;
p\textless{}0.0001, Mann--Whitney test respectively; Fig. 3, Fig. 4). No
differences between the groups were found in the RS latency
(196.71\emph{+} 52.13 vs. 250.82\emph{+} 114.78 msec for the VD and NVD
groups respectively. Not significant by unpaired t-test, Welch corrected
for different standard deviations).

RS were detected in 19 (95\%) of the VD patients and 12 (60\%) of the
NVD group (p\textless{}0.02; Fisher's exact test).

Among the 19 VD patients in whom RS were detected 17 (89\%) had RS
frequency \textgreater{} 80\%, while in all the 12 NVD patients having
RS the frequency value was \textless{} 80\% (p\textless{}0.0001 Fisher's
exact test).

RS velocity was higher than 150 deg/sec in 17 of the 19 VD patients
(89\%) and in only 3 of the 12 NVD patients (25\%) having RS
(p\textless{}0.0004 Fisher's exact test).

17 of the VD group out of 19 (89\%) and 1 of the NVD group out of 12
(8\%) had RS with both frequency \textgreater{} 80\% and velocity
\textgreater{} 150 deg/sec (p\textless{}0.0001 Fisher's exact test).

15 of the VD group participants (75\%) had gain values \textless{} 0.72
and RS frequency \textgreater{} 80\% while in none of the NVD group such
association was recorded (p\textless{}0.0001 Fisher's exact test).

15 of the VD group (75\%) and 3 NVD group participants (15\%) presented
with gain values \textless{} 0.72 and saccade velocity \textgreater{}
150 deg/sec (p\textless{}0.0004 Fisher's exact test).

The combination of gain values \textless{} 0.72, saccade frequency
\textgreater{} 80\% and saccade velocity \textgreater{} 150 deg/se was
found in 15 (75\%) of the VD group and none of the NVD group
(p\textless{}0.0001 Fisher's exact test).

The sensitivity, specificity, positive predictive value and negative
predictive value of the following outcome measures towards the
prediction of VD are detailed in Table 1.

\textbf{Discussion}

vHIT systems employing mono-ocular eye movements recording have an
inherited right-left imbalance regarding the horizontal semicircular
canal gain values depending on the location of the camera. A study
including 212 healthy subjects from all ages showed a mean 9.1\% gain
value difference in favor of the right side in all age groups while
using right eye recording system (6). Another recent study of
commercially available vHIT systems reported on 5\% rightward gain bias
when the right eye movements only were captured (18). While using
scleral search coils for accurate binocular eye movements recording it
was found that the horizontal VOR gain for the adducting eye exceeded
the gain of the abducting eye by an average of 15.3\% (19). Several
explanations have been offered for this right-left imbalance; a longer
neural pathways (trisynaptic) for the adducting medial rectus, compared
to the shorter (disynaptic) pathway of the abducting lateral rectus when
the system camera captures the right eye movements alone (6,19).
Alternatively, the higher gain might stem from the relative decrease in
head velocity while a right-handed examiner uses his weaker left hand
for the conduction of the rightward head thrust. Others have attributed
the rightward higher gain to asymmetry in the maximal active force of
the medial rectus when compared to the lateral rectus muscle which is
about 26\% greater for the adducting muscle (4,20).

Although we have found in the NVD group a significant gain difference in
favour of the rightward head impulse which was conducted by a
right-handed examiner, the head velocities to both sides were
comparable. Thus, for our study the higher right-sided gain is not
explained by possible examiner-related factors.

The reported bias in favour of lower left hvHIT gain when right eye
movements alone are recorded, that is also supported by our results in
the NVD group, might introduce false-positive results of left sided
vestibulopathy especially when the VOR gain is used as the sole
diagnostic criterion. In the current study we evaluated the added
benefit of RS in reaching a final diagnosis of left horizontal
semicircular canal hypofunction in using the right mono-ocular ICS
impulse vHIT system.

The recommended published VOR gain cut-off value discriminating normal
and pathological horizontal semicircular canal function is 0.8
(2,4-7,16). Based on our laboratory norms we have looked at a cut-off
value of 0.72. Significantly lower average left-side VOR gain and higher
gain asymmetry were found for the VD group, and all the NVD group
participants had left hvHIT gain \emph{\textgreater{}} 0.72. Still the
sensitivity of gain \textless{}0.72 alone towards the diagnosis of VD
was only 80\%.

The existence of RS has been previously reported in healthy subjects,
with increased frequency and velocity with higher age and lower gain
values (6,21). In our study the mere presence of RS had 100\%
sensitivity but only 40\% towards the diagnosis of VD. A recent research
has suggested RS frequency of 80\% as a parameter for their consistency
(13). Adding the restriction parameter of RS frequency\textgreater{}80\%
increased the hvHIT specificity to 100\% with 89\% sensitivity.

Various RS velocity criteria have been proposed to distinguish normal vs
pathological vestibular function. These include critical RS velocity of
50 (13), 100 (21), 133 (22) and 135 deg/sec (9).

Although RS average velocity was significantly higher in the VD group
and significantly higher proportion of VD patients demonstrated RS with
velocity \textgreater{} 150 degrees/sec, this RS velocity criterion
alone or adding it to the RS frequency \textgreater{}80\% parameter did
not improve the vHIT prediction values.

Based on our results we recommend careful re-consideration of the hvHIT
test results implications when left-sided VOR gain values \textless{}
0.8 are recorded. Gain \textless{} 0.72 is highly specific for the
diagnosis of vestibular dysfunction. However, for gain values in the
range of 0.72-0.79 the presence of RS with frequency \textgreater{} 80\%
would largely improve the hvHIT diagnostic accuracy (Fig. 5).

Our study limitations include its retrospective nature and the
relatively small size of the cohort included. Although vestibular
disease was ruled out in our NVD subjects, the ideal control group
should have been comprised of healthy subjects with no complaint of
dizziness, which we found difficult to recruit. Most (85\%) of the VD
group have suffered from vestibular neuritis. Still, the inclusion of
other diagnoses might have introduced some disparity in our results.

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\textbf{Figure legends}

Fig. 1

Box plot of the VOR gain values of patients with a final diagnosis of
vestibular dysfunction and those with no vestibular disease. The
boundary of the box closest to zero indicates the 25th percentile, the
solid line within the box marks the median, the dashed line marks the
mean, and the boundary of the box farthest from zero indicates the 75th
percentile. Whiskers above and below the box indicate the 90th and 10th
percentiles. Circles above and below the 90th and 10th percentiles mark
outlying data points.

Fig. 2

Box plot of the VOR gain values left-right asymmetry of patients with a
final diagnosis of vestibular dysfunction and those with no vestibular
disease.

Fig. 3

Box plot of re-fixation saccades velocity of patients with a final
diagnosis of vestibular dysfunction and those with no vestibular
disease.

Fig. 4

Box plot of re-fixation saccades frequency of patients with a final
diagnosis of vestibular dysfunction and those with no vestibular
disease.

Fig. 5

Decision algorithm for horizontal semicircular dysfunction incorporating
vHIT gain and re-fixating saccades parameters.

\textbf{Hosted file}

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