10.14639/0392-100X-N1975
Objective. To relate clinically the duration of spontaneous nystagmus and hyperventilationinduced nystagmus (HVIN) to vascular or inflammatory aetiology of acute unilateral vestibulopathy observed in a very early stage.Methods. This is a retrospective study on 198 patients with acute unilateral vestibulopathy.Results. In the short-lasting nystagmus group (spontaneous nystagmus &lt; 48 h), mean age and cardiovascular risk were significantly higher; the rates of negative HVIN and paretic HVIN were 41.7% and 58.3%, respectively. In the long-lasting nystagmus group (spontaneous nystagmus &gt; 48 h), mean age and vascular risk were lower; HVIN was absent in 12.6% of the cases, HVIN excitatory patterns were observed in 40.3% of cases and a paretic pattern in 47.1%.Conclusions. A vascular aetiology should be considered the most likely in patients with spontaneous nystagmus &lt; 48 hours: all patients were &gt; 60 years old, cardiovascular risk was higher and HVIN was always absent or paretic. In the group with nystagmus &gt; 48 hours, similarly, data indicate a higher incidence of paretic HVIN in older patients and higher vascular risk, even if the data does not allow us to lean clearly towards one of the two aetiological hypotheses.
text/xml
1827-675X
1975
en
Maria Grazia Melillo
http://creativecommons.org/licenses/by-nc-nd/4.0
ACTA Otorhinolaryngologica Italica
hyperventilation-induced nystagmus
Can hyperventilation test and duration of spontaneous nystagmus help differentiate between vascular and inflammatory aetiology of acute unilateral vestibular deficit?
Text.Serial.Journal
https://www.actaitalica.it/
42
Vestibology
2022-12-29
2021-12-20
2022-12-29
2023-01-16
560-568
1
Maria Grazia Melillo
2022/12/29
10.14639/0392-100X-N1975
560
Department of Audiology and Phoniatrics, AO “San Pio” Benevento, Italy
1827-675X
hyperventilation-induced nystagmus
en
568
Can hyperventilation test and duration of spontaneous nystagmus help differentiate between vascular and inflammatory aetiology of acute unilateral vestibular deficit?
https://www.actaitalica.it/article/download/1975/896
42
ACTA OTORHINOLARYNGOLOGICA ITALICA 2022;42:560-568; doi: 10.14639/0392-100X-N1975




Vestibology


Can hyperventilation test and duration of spontaneous
nystagmus help differentiate between vascular
and inflammatory aetiology of acute unilateral
vestibular deficit?
Possono il test di iperventilazione e la durata del nistagmo spontaneo aiutare
a differenziare l’eziologia vascolare da quella infiammatoria del deficit vestibolare
unilaterale acuto?
Luigi Califano, Giulia Locatelli, Maria Grazia Melillo
Department of Audiology and Phoniatrics, AO “San Pio” Benevento, Italy


SUMMARY
Objective. To relate clinically the duration of spontaneous nystagmus and hyperventilation-
induced nystagmus (HVIN) to vascular or inflammatory aetiology of acute unilateral vesti-
bulopathy observed in a very early stage.
Methods. This is a retrospective study on 198 patients with acute unilateral vestibulopathy.
Results. In the short-lasting nystagmus group (spontaneous nystagmus < 48 h), mean age and
cardiovascular risk were significantly higher; the rates of negative HVIN and paretic HVIN were
41.7% and 58.3%, respectively. In the long-lasting nystagmus group (spontaneous nystagmus
> 48 h), mean age and vascular risk were lower; HVIN was absent in 12.6% of the cases, HVIN
excitatory patterns were observed in 40.3% of cases and a paretic pattern in 47.1%.
Conclusions. A vascular aetiology should be considered the most likely in patients with
spontaneous nystagmus < 48 hours: all patients were > 60 years old, cardiovascular risk
was higher and HVIN was always absent or paretic. In the group with nystagmus > 48                Received: December 20, 2021
hours, similarly, data indicate a higher incidence of paretic HVIN in older patients and          Accepted: July 29, 2022
higher vascular risk, even if the data does not allow us to lean clearly towards one of the
two aetiological hypotheses.                                                                      Correspondence
KEY WORDS: acute unilateral vestibulopathy, hyperventilation test, vestibular bed-side            Luigi Califano
                                                                                                  AO “San Pio” Benevento, Department of Audiology
examination, vestibular neuritis, hyperventilation-induced nystagmus
                                                                                                  and Phoniatrics, via A. Lepore A4 bis, 82100
                                                                                                  Benevento, Italy
RIASSUNTO                                                                                         E-mail: luigi.califano@tin.it
Obiettivi. Correlare la durata del nistagmo spontaneo e i pattern del nistagmo da iper-
ventilazione (HVIN) alla eziologia infiammatoria o vascolare della vestibulopatia acuta             How to cite this article: Califano L, Locatelli
monolaterale (VAM), osservato in uno stadio molto precoce.                                          G, Melillo MG. Can hyperventilation test
Metodi. Studio retrospettivo. Inclusi 198 pazienti con VAM.                                         and duration of spontaneous nystagmus help
Risultati. Nel gruppo con durata del nistagmo spontaneo < 48 ore, l’età media dei pazien-           differentiate between vascular and inflammatory
ti e il rischio cardiovascolare erano significativamente più alti; HVIN negativo e pattern          aetiology of acute unilateral vestibular deficit?
paretico sono stati osservati nel 41,7% e 58,3% rispettivamente. Nel gruppo con nistagmo            Acta Otorhinolaryngol Ital 2022;42:560-568.
spontaneo > 48 ore l’età e il grado di rischio cardiovascolare erano più bassi; l’HVIN              https://doi.org/10.14639/0392-100X-N1975
negativo era presente nel 12,6% dei casi, i pattern eccitatori nel 40,3% dei casi, il pattern
                                                                                                  © Società Italiana di Otorinolaringoiatria
paretico nel 47,1%.                                                                               e Chirurgia Cervico-Facciale
Conclusioni. L’eziologia vascolare appare più probabile nel gruppo con durata del nistag-
mo spontaneo < 48 ore, in cui tutti i pazienti avevano più di 60 anni, il rischio cardiova-
                                                                                                                 OPEN ACCESS
scolare era più alto e l’HVIN o assente o con pattern paretico. Nel gruppo con durata del
nistagmo> 48 ore i dati indicano ugualmente una maggiore incidenza del pattern paretico           This is an open access article distributed in accordance with
                                                                                                  the CC-BY-NC-ND (Creative Commons Attribution-Non-
nei pazienti più anziani e più alto rischio cardiovascolare, ma la maggiore dispersione dei       Commercial-NoDerivatives 4.0 International) license. The
dati non fa propendere verso l’una o l’altra delle due ipotesi eziologiche.                       article can be used by giving appropriate credit and mentio-
                                                                                                  ning the license, but only for non-commercial purposes and
PAROLE CHIAVE: vestibulopatia acuta unilaterale, test di iperventilazione, bed-side               only in the original version. For further information: https://
examination vestibulare, neurite vestibolare, nistagmo evocato da iperventilazione                creativecommons.org/licenses/by-nc-nd/4.0/deed.en




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Introduction                                                       Table I. Hyperventilation-induced nystagmus (HVIN) patterns in acute unilat-
                                                                   eral vestibulopathy.
Acute unilateral vestibulopathy (AUV) is one of the most            HVIN absent                     No effect on spontaneous nystagmus
frequent causes of acute vertigo, with an annual incidence          Paretic HVIN                   Spontaneous nystagmus is temporarily
between 3.5 and 15.5 cases/100,000 and a maximum be-                                                              enhanced
tween 30 and 60 years without significant gender differ-            Excitatory HVIN            Spontaneous nystagmus is temporarily reduced
ences 1. In the most frequent form 2, cochlear symptoms                                                          or inhibited
are missing; they may however be present in the case of             Strongly excitatory HVIN Spontaneous nystagmus is temporarily reversed
complete cochlear-labyrinthine infarction or specific her-
petic aetiology (Ramsay-Hunt syndrome) 3.
The superior division of the vestibular nerve is the most          affecting the acid-base balance. These metabolic modifica-
frequently affected 4; the superior and inferior branches are      tions have an excitatory effect on nervous tissue 12.
sometimes both injured, and much more rarely only the in-          In spinocerebellar ataxia type 6, hyperventilation causes fur-
ferior one is impaired 5. The reactivation of a latent herpes      ther functional deficit of Ca2+ α1A -voltage-dependent chan-
simplex virus type 1 infection is the most probable cause,         nels through variations of pH and extracellular Ca2+ 12. This
although it is not definitely proven 1. Vascular damage to         clinical model predicts how HVT can act on nystagmus ei-
inner ear structures is also a possible cause. Because of the      ther in the case of primitive cerebellar dysfunctions or when
overlap between the distribution of the superior vestibular        the normal cerebellar inhibitory action had previously par-
nerve and the anterior vestibular artery, the two aetiologies      tially compensated a vestibular deficit. HVT can disrupt the
are clinically indistinguishable. The utriculus, lateral and       central compensation of a peripheral vestibular asymmetry,
anterior semicircular canals are usually involved in either        as seen by the appearance or accentuation of paretic nystag-
viral superior vestibular neuritis or ischaemia of the ante-       mus (fast phases towards the healthy side), respectively, in
rior vestibular artery. A recent review by Simoes et al. iden-     eighth cranial nerve schwannomas and AUV 14-17.
tified important gaps in the literature regarding the explora-     Several HVIN patterns have been described in AUV 15
tion of a vascular aetiology of AUV and no studies were            (Tab. I): 1) HVIN absent: no effect on spontaneous nystag-
identified regarding the risk of future vascular events 6.         mus; 2) paretic pattern, which temporarily reinforces spon-
Immuno-related disorders, demyelinating lesions of the             taneous nystagmus; 3) excitatory pattern, which temporarily
root-entry zone of the eighth cranial nerve, metastasis and        inhibits spontaneous nystagmus; 4) strongly excitatory pat-
thiamine deficiency are considered much rarer aetiologies          tern, which temporarily reverses spontaneous nystagmus.
of AUV.                                                            In the case of AUV, HVIN excitatory patterns can be
Spontaneous unidirectional nystagmus is the main sign of           caused by: a) increase of neuronal excitability of a par-
AUV. It usually lasts more than 7-10 days, but its duration        tially damaged receptor which would determine transient
is sometimes limited to hours or a few days. After about one       up-regulation of the central mechanisms of compensation;
month, most patients no longer show spontaneous nystag-            b) modification of the thresholds of membrane channels; c)
mus, due to either peripheral recovery or central compen-          transient improvement of neural conduction in partially and
sation, even if some clinical and instrumental signs of the        transiently microdemyelinated areas that could have been
deficit may persist for many years 7. The “HINTS” protocol         caused by impairment of the blood-nerve barrier due to,
provides a high diagnostic sensitivity in identifying periph-      for example, the diffusion of gadolinium in the vestibular
eral forms vs central forms in the acute stage of the disease 8.   nerve in some cases of vestibular neuritis 18.
Spontaneous nystagmus is “modulated” by clinical tests:            Excitatory patterns are observed in the early stages of AUV
head shaking test, vibratory test, hyperventilation test           and disappear within a few days, and then replaced by the
(HVT) and lateral decubitus. On the affected side, the head        paretic pattern when, with all probability, the blood-nerve
impulse test (HIT) evokes catch-up saccades 9, and the             barrier has reestablished itself. The paretic pattern decreas-
caloric test shows labyrinthine hyporeflexia/areflexia; on         es over time, even if it may be observed even months later,
video-HIT (v-HIT) impaired gains of the vestibulo-ocular           in a now-compensated clinical phase. The HVIN patterns
reflex (VOR) of lateral and superior semicircular canals are       observed in the acute phase have no predictive significance
seen, and catch-up saccades are evident 10.                        for mid- or long-term prognosis 15.
HVT is “the only test that unmasks unilateral vestibular dis-      The questions are:
ease without testing the dynamic properties of the vestibule-      1. Why does HVIN have two opposite behaviours in AUV –
ocular reflex” 11. Hyperventilation causes hypocapnia, intra-         paretic vs excitatory – whereas the other tests unambigu-
cellular alkalosis, lowering of plasmatic and liquoral Ca2+,          ously point out the side of the acute vestibular loss?



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2. Why is the duration of spontaneous nystagmus in any          the impaired side provoke the so-called “uphill nystag-
   individuals significantly shorter than in the majority of    mus”, considered a sign of peripheral deficit 20.
   other cases?                                                 SBIWCT works by inhibiting both labyrinths; in the case
The study had two main objectives. 1) to highlight if, in       of a peripheral lesion, it breaks down vestibular asym-
AUV observed between the first and the fifth day from its       metry. Thus, it suppresses or sometimes reverses spon-
onset, there was a relationship between HVIN patterns,          taneous nystagmus due to its prevailing inhibitory action
age and vascular risk, and if this relationship mattered or     on the healthy labyrinth. Conversely, in central diseases,
did not in identifying the cause – inflammatory vs ischae-      SBIWCT does not modify spontaneous nystagmus be-
mic – of the disease; 2) to evaluate whether the duration       cause the vestibular asymmetry remains unchanged. We
of spontaneous nystagmus more or less than 48 hours cor-        previously classified HVIN patterns 15 as absent, paretic,
related with age and degree of vascular risk and examine        excitatory, and strongly excitatory. For the current study,
the behavior of HVIN in both groups.                            we merged excitatory and strongly excitatory patterns as
                                                                expressions of the same pathophysiological mechanism.
Materials and methods                                           HVT was carried out for 60 seconds, and monitored
                                                                through “sidestream” capnography 21 to ensure that pa-
The study includes 198 patients diagnosed with AUV              tients performed the test correctly, estimating PaCO2 val-
observed between one and three days after symptom on-           ues. In a previous study, we identified a PaCO2 value of
set, without concomitant acute cochlear suffering, from         approximately 16 mm Hg as appropriate for acting on an
January 2016 to March 2019. During the same period, we          impaired vestibular system 17. It should be specified that
suspected a central vestibular mimic in other 26 patients,      the instrumental monitoring of HVT, which we used to
who were not included in the study, with a similar clini-       more objectively report the data of our study, is not neces-
cal scenario of acute vertigo (spontaneous nystagmus, un-       sary for a bedside setting. The operator has only to ensure
steadiness, ataxia).                                            that respiratory acts are enough deep and rhythmic, with a
All patients underwent vestibular bedside examination           60-second duration. We repeated vestibular examinations
using infrared videonystagmoscopy. Our first observa-           daily until patients were discharged between the 3rd and
tion was primarily aimed at ruling out a central disease        10th day; non-hospitalised patients were checked after 3,
as the possible cause of acute vertigo. In sitting position:    7 and 10 days from the first observation. We scheduled
observation of spontaneous nystagmus – gaze in primary          a further follow-up examination at about 30 days for all
position, to the left, to the right, upward, downward –; un-    patients.
der closed eyelids, research for gaze lateropulsion 19; head    In all, 175 of the 198 patients underwent brain MRI,
pitching test; head shaking test (HST); vibratory test;         from 3 to 30 days from the onset of disease. In no case
HVT; head impulse test; evaluation of the skew deviation.       lesions of the VIII cranial nerve of pontocerebellar angle,
In supine position: observation of nystagmus (supine, right     demyelinating lesions, or signs of recent acute vascular
lateral decubitus, left lateral decubitus); simultaneous bin-   accidents were observed, which would have been exclu-
aural caloric test using ice water, 5 ml for ear, about 5°C.    sion criteria. In no case gadolinium enhancement of the
At the first examination, we performed v-HIT in 67 cases,       VIII cranial nerve was observed.
preferentially in older and higher vascular risk patients,      Patients were subdivided into two groups: a) spontaneous
and bithermal caloric test (30° and 44°C) in 34 patients.       nystagmus < 48 hours; b) spontaneous nystagmus > 48
All patients during the successive observations underwent       hours. We chose the cut-off value of 48 hours because
v-HIT. The differential diagnosis between peripheral and        the duration of spontaneous nystagmus in AUV is usually
central diseases was based on the HINTS protocol, in ad-        longer, and it might be a good indicator of a self-limiting
dition to the simultaneous binaural ice water caloric test      lesion of the vestibular system. Vascular risk was assessed
(SBIWCT) plus v-HIT when performed. We considered               using the “Global Cardiovascular Risk - Heart Project”
as signs of peripheral lesions: unidirectional horizontal-      Calculator of the Italian Istituto Superiore di Sanità 22
torsional nystagmus, catch-up saccades on head impulse          (Fig. 1 and Tab. II). As established in the Heart Project,
test and moderate ocular hypotropia towards the side of         patients with previous acute vascular events in their per-
the nystagmus slow phase direction, inhibition/reversal of      sonal medical history were considered at the maximum
the spontaneous nystagmus after SBIWCT; on v-HIT, the           risk (grade VI). For our study, we merged low-moderate
presence of semicircular canals impairment and catch-up         risk (grades I, II, III) and moderate-high-very high-risk
saccades on the affected side. Nystagmus with fast phases       categories (grades IV, V, VI), obtaining only two class-
towards the healthy side and vertical ocular hypotropia on      es of risk: “lowest class” and “highest class”. Statistical



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Table II. Personal data and risk factors considered in the Istituto Superiore di Sanità.
 “Heart Project calculator”                                                                        Male/female
 Age                                                                                                 35-69 years old
 Smoking                                                                              People who smoke regularly every day, even
                                                                             a single cigarette, or have stopped less than 12 months ago
 Systolic pressure                                                                                 Expressed in mmHg
 Diastolic pressure                                                                                Expressed in mmHg
 Total cholesterolaemia                                                                            Expressed in mg/dl
 HDL cholesterolaemia                                                                              Expressed in mg/dl
 Diabetes                                                                             Diagnosis or two successive determinations
                                                                             of fasting blood glucose greater than or equal to 126 mg/dl
 Hypertension                                                                     People who regularly take anti-hypertensive drugs



                                                                                    The age difference between patients with positive HVIN
                                                                                    and those with negative HVIN, respectively 58.1 +/- 12.82
                                                                                    years vs 65.2 +/- 12.96 years, was statistically significant
                                                                                    (p = 0.0042). Furthermore, patients with paretic HVIN
                                                                                    had a significantly higher mean age than patients with
                                                                                    excitatory HVIN, respectively 66.01 +/- 12.35 years vs
                                                                                    47.4 +/- 11.76 years (p < 0.0001).
                                                                                    We observed the paretic pattern in 14/24 patients with
Figure 1. Grading of ten-year cardiovascular risk (modified from Progetto           spontaneous nystagmus < 48 hours (58.3%), while in the
Cuore, ISS).                                                                        remaining 10 cases (41.7%) HVT did not modify the spon-
                                                                                    taneous nystagmus. In patients with spontaneous nystag-
                                                                                    mus > 48 hours, a paretic pattern was observed in 82/174
analysis was performed with Unpaired T-test, Fisher’s                               cases (47.1%), excitatory patterns in 70 cases (40.3%)
exact test and Chi-square test, and significance level set                          and HVIN was absent in 22 cases (12.6%) (Tab. III). In
at 0.05 with 95% confidence interval. Analyses were per-                            this subgroup, the difference in the mean age between pa-
formed using Graph pad Quick Calcs software (multivari-                             tients with paretic HVIN (63.7 +/- 10.02 years) and those
ate analysis).                                                                      with HVIN excitatory patterns (46.7 +/- 13.88 years) was
                                                                                    also significant (p < 0.0001).
Results                                                                             Comparing the two subgroups, the differences between
                                                                                    the presence/absence of HVIN and presence of the paretic
There were 198 patients, 111 males and 87 females, with                             pattern vs excitatory patterns were both significant (re-
a mean age of 57.7 +/- 15.67 years (range 18-86 years).                             spectively: p < 0.001; p < 0.0001); the absence of HVIN
Twenty-four patients had spontaneous nystagmus for less                             and the paretic pattern were more frequent in the group
than 48 hours after symptom onset (range 10-45 hours), and                          with spontaneous nystagmus < 48 hours. In the subgroup
174 patients for more than 48 hours. Based on the HINTS                             with spontaneous nystagmus < 48 hours, 21/24 patients
protocol, plus v-HIT and SBIWCT, we clinically excluded                             (87.5%) were older than 65 years, which is the conven-
or considered very improbable a central mimic in all. Ad-                           tional age to distinguish between “young” and “elderly”
ditionally, vestibular Menière crisis and acute migraine re-                        patients (range 60-89 years), whereas in the subgroup
lated vertigo were considered clinically highly unlikely.                           with spontaneous nystagmus > 48 hours only 56/174 pa-
Patients with spontaneous nystagmus duration < 48 hours                             tients (32.2%) were over 65 years (range 19-78 years),
had a significantly higher mean age than those with spon-                           with a significant difference (p < 0.0001). In the subgroup
taneous nystagmus duration > 48 hours (76 +/- 9.43 years                            with nystagmus > 48 hours, excitatory patterns showed
vs 56.03 +/- 12.58 years; p < 0.0001).                                              a higher incidence in the “lowest risk class” – 60/135
HVIN was evoked in 166/198 patients (83.8%): a paret-                               cases (44.4%) – vs 10/39 cases (25.6%) in the “highest
ic pattern was seen in 96 cases (48.5%) and excitatory                              risk class”. The paretic pattern was found in 54/135 indi-
patterns in 70 cases (35.3%), while HVIN was absent in                              viduals (40%) in the “lowest risk class” and 25/39 cases
32 patients (16.2%).                                                                (64.1%) in the “highest risk class”. Paretic/absent HVIN



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L. Califano et al.




Table III. Distribution of HVIN patterns in relation to cardiovascular risk and duration of spontaneous nystagmus.
                                                                                                             HVIN PATTERN
 Spontaneous nystagmus                                 Risk                             Paretic             Excitatory/strongly excitatory               HVIN absent
 > 48 hours (174 cases)                                                               82 (47.1%)                        70 (40.3%)                        22 (12.6%)
                                          Grades I-III Class (135 cases)               54 (40%)                         60 (44.4%)                        21(15.6%)
                                          Grades IV-VI Class (39 cases)               25 (64.1%)                        10 (25.6%)                         4 (10.3%)
 < 48 hours (24 cases)                                                                14 (58.3%)                             0                            10 (41.7%)
                                            Grades I-III Class (1 case)                1 (100%)                              0                                 0
                                          Grades IV-VI Class (23 cases)               13 (56.5%)                             0                            10 (43.5%)



Table. IV. Synopsis of clinical data at the first observation.
                                                                                   Nystagmus > 48 h                                      Nystagmus < 48 h
 HSIN towards the healthy side                                                       172/174 (98.9%)                                        21/24 (87.5%)
 VIN towards the healthy side                                                           174/174                                                 24/24
 HVIN                                                                                152/174 (87.4%)                                        14/24 (58.3%)
 Caloric hypo/areflexia on the affected side                                              24/24                                                 10/10
 HIT: Saccades on the affected side                                                   167/174 (96%)                                         22/24 (91.7%)
 V-HIT: Overt-saccades on the affected side                                               47/47                                                 20/20
Note: HSIN: Head-Shaking Induced Nystagmus; VIN: Vibration-induced Nystagmus; HVIN: Hyperventilation-induced nystagmus; HIT: Head Impulse Test: V-HIT: Video Head Impulse Test.



patterns were more frequent in the “highest risk class”                                      anticompensatory saccades: still reduced but more ef-
(29/39 cases: 74.4%), and excitatory patterns in the “low-                                   ficient (Fig. 2);
est risk class” (60/135 cases: 44.4%) (p < 0.001). In the                                 2. Female, 32 years old. Acute vertigo for two days. Car-
“lowest risk class”, the difference between the incidences                                   diovascular risk: Heart Project class I. 3rd grade unidi-
of paretic/absent HVIN vs excitatory patterns was not sig-                                   rectional left beating spontaneous nystagmus; strongly
nificant (p = 0.088), whereas in the “highest risk class”,                                   excitatory HVIN; v-HIT: a) HIMP. Right lateral canal
paretic/absent HVIN was significantly more frequent than                                     VOR gain: 0.15; right anterior canal VOR gain: 0.24;
excitatory patterns (p < 0.001).                                                             b) SHIMP. Right lateral canal VOR gain: 0.08; anti-
In the subgroup with spontaneous nystagmus < 48 hours,                                       compensatory saccades: absent on the right side. Ten
all patients except one were in the “highest risk class”                                     days after onset: 2nd grade unidirectional left beating
and, as already said, we observed only either absent HVIN                                    spontaneous nystagmus; excitatory HVIN; v-HIT: a)
(43.5%) or paretic HVIN (56.5%) (Tab. III).                                                  HIMP. Right lateral canal VOR gain: 0.23; right an-
Clinical data at the first observation are reported in Ta-                                   terior canal VOR gain: 0.24; b) SHIMP: right lateral
ble IV.                                                                                      canal VOR gain: 0.23; anticompensatory saccades: still
                                                                                             absent on the right side (Fig. 3).
Two illustrative cases
1. Male, 64 years old. Acute vertigo for one day. Cardio-
                                                                                          Discussion
   vascular risk: Heart Project class IV. 3rd grade unidi-
   rectional right beating spontaneous nystagmus; paretic                                 AUV is characterised by the sudden onset of vertigo with
   HVIN; v-HIT: a) head impulse test (HIMP). Left later-                                  neurovegetative symptoms. Spontaneous nystagmus is the
   al canal VOR gain: 0.41; left anterior canal VOR gain:                                 expression of the acute imbalance between the two ves-
   0.16; b) Suppression HIMP (SHIMP). Left lateral canal                                  tibular hemi-systems. A viral aetiology is considered the
   VOR gain: 0.28; anticompensatory saccades: present                                     most plausible cause; at the same time, a vascular cause is
   but reduced on the left side. At two days from onset:                                  possible due to the characteristics of labyrinthine terminal
   spontaneous nystagmus no longer present; right beat-                                   blood flow. In the case of damage to one of the two factors,
   ing vibration induced nystagmus; v-HIT: a) HIMP. Left                                  the overlap between the distribution of the superior branch
   lateral canal VOR gain: 0.85; left anterior canal VOR                                  of the vestibular nerve and the flow of the anterior vestibu-
   gain: 0.69; b) SHIMP. Left lateral canal VOR gain: 0.8;                                lar artery provokes the same symptoms and signs and does



564
                                                                                                             Ischemic vs inflammatory etiology of AUV




A                                                                             B




Figure 2. V-HIT: a short-lasting spontaneous nystagmus case. Panel A: HIMP and SHIMP at the onset of the disease; Panel B: HIMP and SHIMP 3 days after
the onset of the disease.



A                                                                             B




Figure 3. V-HIT: a long-lasting spontaneous nystagmus case. Panel A: HIMP and SHIMP at the onset of the disease; Panel B: HIMP and SHIMP 10 days after
the onset of the disease.



not allow definition of the aetiology. To date, no test can                  considered the most probable in the younger population,
discriminate between the two hypotheses. Aetiology is pre-                   and a vascular hypothesis is the most probable in older
sumed on an epidemiological basis: a viral hypothesis is                     patients or, independently of age, in individuals with sig-



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L. Califano et al.




nificant vascular risk factors. The attribution to one of the           sidered the most plausible in the group with nystagmus
two possible aetiologies could be pivotal in follow-up.                 < 48 hours: all patients were over 60 years old, had higher
The risk of acute stroke is higher in vertiginous patients              vascular risk, and HVIN was always absent or paretic. In
within the first month from the discharge, even if few pa-              the group with nystagmus lasting > 48 hours, there was
tients (0.93%) experience a major stroke during 6-month                 a higher prevalence of paretic/absent HVIN in older pa-
follow-up 23. Patients with vertigo had a 3.01 fold greater             tients and higher vascular risk, but their greater dispersion
risk for stroke; patients with ≥ 3 cardiovascular risk fac-             did not allow us to lean univocally towards one of the two
tors had a risk of stroke that is increased by 5.51-fold 24.            aetiological hypotheses: the incidences of paretic/absent
ER patients discharged with a diagnosis of vertigo or diz-              HVIN and excitatory patterns were significantly different
ziness had a 2-fold higher risk of developing subsequent                in the “highest risk group” (39 patients), not in the most
vascular events than those without dizziness/vertigo 25.                numerous “lowest risk group” (135 patients).
Consequently, identifying or suspecting a vascular aetiol-              Aetiology is more attributable to: a) younger and low-
ogy of acute vertigo is a decisive task, although a recent              risk patients, presenting HVIN excitatory patterns and
meta-analysis seems to rule out the correlation between                 nystagmus > 48 hours. In these cases, the disease is more
acute vertigo and subsequent vascular accidents 6.                      likely caused by an inflammatory neural process (viral
The direction of the slow phases of the spontaneous nystag-             neuritis) involving the superior branch of the vestibular
mus, usually enhanced by HST and vibratory test, denotes                nerve. Excitatory patterns could be explainable through
the affected side. The head impulse test identifies correc-             a transient improvement of conduction along nerve fib-
tive saccades in the movements towards the affected side.               ers (possibly microdemyelinated areas); b) oldest and
On the impaired side, the eye is usually hypotropic and                 high-risk patients with nystagmus < 48 hours who never
the caloric test shows canal paresis. HIMP denotes VOR                  showed excitatory HVIN patterns. In these cases, the
gain deficit of both lateral and anterior canals and, in the            most likely aetiology is a transient vascular deficit in the
very early stage, the presence of overt catch-up saccades;              district of the superior vestibular artery. In all the oth-
SHIMP shows VOR gain deficit of the lateral canal and ab-               er intermediate situations, the aetiology remains based
sence/reduction of the anti-compensatory saccades *.                    on an epidemiological and presumptive basis, even if
Differently, HVIN patterns do not necessarily correlate                 in these cases HVIN patterns and duration of sponta-
with the side of the lesion: hyperventilation test can ei-              neous nystagmus can guide the diagnosis. Our results
ther enhance the spontaneous nystagmus (paretic pattern)                may be useful in therapeutic choices: steroids may be
or inhibit/reverse it (excitatory patterns). In other words,            the first-line therapy in younger patients, with low vas-
HVIN direction is not related to the side of the lesion but             cular risk and HVIN excitatory patterns, whereas older
to the metabolic mechanisms of action of hyperventilation               patients, with high vascular risk and absent or paretic
test on nystagmus: worsening of central compensation                    HVIN, might be preferentially treated using vascular
mechanisms, transient improvement of nerve conduction                   drugs, such as heparinoids or antiaggregants. It should
along partially demyelinated pathways, hypersensitivity                 be specified that this proposal is purely hypothetical, and
of a partially damaged peripheral receptor due to hyper-                lack defined guidelines. Additionally, if one considers
ventilation-induced changes in calcium and acid-base bal-               such acute distress as a labyrinthine vascular accident,
ance.                                                                   it is worthy of further specific diagnostic investigations
Our study tried to study data on the two most frequent                  in other districts, like the heart and brain. For these pa-
aetiologies of AUV: duration of spontaneous nystagmus                   tients, we recommend careful follow-up.
and HVIN patterns. Both HVIN patterns and the length                    Finally, in the same cohort we obtained similar results
of spontaneous nystagmus correlated with patients’ age                  even when the cut-off time was set at 72 hours. In a more
and degree of vascular risk in a significant way. We ob-                general way, this indicates that in AUV the short duration
served higher mean age, higher vascular risk and paretic/               of spontaneous nystagmus (< 48-72 hours) is a red flag for
absent HVIN more frequently in the short-lasting nystag-                a possible vascular aetiology.
mus group; on the contrary, lower age, lower vascular risk
and excitatory patterns were prevalent in the long-lasting              Conclusions
nystagmus group. A vascular hypothesis should be con-
                                                                        The differential diagnosis between inflammatory and vas-
                                                                        cular aetiologies of AUV remains controversial. In both
*
 We would also prefer “Centriphugal saccades” in SHIMP because, in      cases, the shared suffering of the lateral canal, anterior
our opinion, a physiological mechanism cannot be “anti-compensatory”.   canal and utriculus does not allow specific discriminatory



566
                                                                                                             Ischemic vs inflammatory etiology of AUV




tests. In this perspective, HVT is the only test that can                        view. Acta Otorhinolaryngol Ital 2021;41:401-409. https://doi.
                                                                                 org/10.14639/0392-100X-N1543
be of use, even if only partially. Its pathophysiological
                                                                            7
                                                                                 Mandalà M, Nuti D, Broman AT, et al. Effectiveness of careful bed-
mechanisms interfere with the responses of the vestibu-                          side examination in assessment, diagnosis, and prognosis of vestibu-
lar system, above all nystagmus, through metabolic path-                         lar neuritis. Arch Otolaryngol Head Neck Surg 2008;134:164-169.
ways, and not by acting directly on receptor dynamics,                           https://doi.org/10.1001/archoto.2007.35
as, for example, the caloric test does. Both the diagnosis                  8
                                                                                 Kattah JC, Talkad AV, Wang DZ, et al. HINTS to diagnose stroke
                                                                                 in the acute vestibular syndrome: three step bedside oculomo-
of vascular rather an inflammatory aetiology and propos-                         tor examination more sensitive than early MRI diffusion-weight-
als for different treatment remain purely hypothetical, and                      ed imaging. Stroke 2009;40:3504-3510. https://doi.org/:10.1161/
centred exclusively on clinical criteria. The duration of                        STROKEAHA.109.551234
the spontaneous nystagmus and its modulation by HVT                         9
                                                                                 Halmagyi GM, Curthoys IS. A clinical sign of canal pare-
                                                                                 sis. Arch Neurol 1988;45:737-773. https://doi.org/10.1001/
can be of help in this task, always keeping in mind assess-                      archneur.1988.00520310043015
ment of individual cardiovascular risk.                                     10
                                                                                 Weber KP, Aw ST, Todd MJ, et al. Head impulse test in unilat-
                                                                                 eral vestibular loss: vestibuloocular reflex and catch-up sac-
Conflict of interest statement                                                   cades. Neurology 2008;70:454-463. https://doi.org/10.1212/01.
                                                                                 wnl.0000299117.48935.2e
The authors declare no conflict of interest.
                                                                            11
                                                                                 Bance ML, O’Driscoll M, Patel N, et al. Vestibular disease unmasked
                                                                                 by hyperventilation. Laryngoscope 1998;108:610-614. https://doi.
Funding                                                                          org/10.1097/00005537-199804000-00027
This research did not receive any specific grant from                       12
                                                                                 Davis FA, Becker FO, Michael JA, et al. Effects of intravenous sodi-
funding agencies in the public, commercial, or not-for-                          um bicarbonate, disodium editate (Na2EDTA) and hyperventilation on
                                                                                 visual and oculomotor signs in multiple sclerosis. J Neurol Neurosurg
profit sectors.
                                                                                 Psychiatry 1970;33:723-732. https://doi.org/10.1136/jnnp.33.6.723
                                                                            13
                                                                                 Matsuyama Z, Wakamori M, Mori Y, et al. Direct alteration of the
Author contributions                                                             P/Q-type Ca ++ channel property by poliglutamine expansion in
All authors contributed equally to the design and develop-                       spinocerebellar ataxia 6. J Neurosci 1999;19:RC14. https://doi.
ment of the study.                                                               org/10.1523/JNEUROSCI.19-12-j0004.1999
                                                                            14
                                                                                 Choi KD, Cho HJ, Koo JW, et al. Hyperventilation-induced nystag-
                                                                                 mus in vestibular schwannoma. Neurology 2005;64:2062. https://doi.
Ethical consideration                                                            org/10.1212/01.WNL.0000170969.19299.D7
As a retrospective observational study, it did not require                  15
                                                                                 Califano L, Melillo MG, Vassallo A, et al. Hyperventilation-induced
approval of Ethics Committee. This was done internally as                        Nystagmus in a large series of vestibular patients. Acta Otorhinolar-
part of our routine evaluation, so as to improve our quality                     ingol Ital 2011;3:17-26.
                                                                            16
                                                                                 Choi KD, Kim JS, Kim HJ, et al. Hyperventilation-induced nys-
of care.
                                                                                 tagmus in peripheral vestibulopathy and cerebellopontine angle tu-
The research was conducted ethically, with all study pro-                        mor. Neurology 2007;69:1050-1059. https://doi.org/10.1212/01.
cedures being performed in accordance with the require-                          wnl.0000271378.54381.6a
ments of the World Medical Association’s Declaration of                     17
                                                                                 Califano L, Iorio G, Salafia F, et al. Hyperventilation-induced nys-
                                                                                 tagmus in patients with vestibular schwannoma. Otol Neurotol
Helsinki.
                                                                                 2015;36:303-306. https://doi.org/10.1097/MAO.0000000000000699
                                                                            18
                                                                                 Venkatasamy A, Huynh TT, Wohluter N, et al. Superior vestibular
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