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Date: September 16th, 2022

Reference: Gerlier C, et al.  Differentiating central from peripheral causes of acute vertigo in an emergency setting with the HINTS, STANDING and ABCD2 tests: A diagnostic cohort study. AEM 2021

Guest Skeptic: Dr. Peter Johns has been practicing emergency medicine since 1985 and has been passionate about vertigo education for the last two decades.  He co-authored the Vertigo chapter in the current edition of Tintinalli’s emergency medicine textbook and has a YouTube channel about vertigo with over 16,000 subscribers and five million views.

Case: This is a real case seen by Peter and you can see the actual exam findings in a video on his YouTube channel.

A 70-year-old woman wakes up with dizziness and presents to the emergency department (ED) later that day.  She’s vomited twice, and describes her dizziness as a constant spinning sensation, which gets worse when she moves her head.  She has some unsteadiness but can walk unaided.  She has no other neurologic symptoms.  In particular, she denies any new significant headache or neck pain, or focal weakness or paresthesia, dysarthria, diplopia, dysmetria, dysphagia or dysphonia, (the so-called Dangerous D’s).  When you examine her, and she is looking straight ahead, you observe that she has horizontal and slight torsional nystagmus beating towards her left ear. That means that the fast component of the nystagmus is horizontal, to the left, and there is a slight rotation with the upper pole of the eyes beating towards the left as well.

Background: We have looked at acute vestibular syndrome (AVS) on the SGEM with Dr. Mary McLean who was the guest skeptic on SGEM #310. The bottom line from that episode was that:

Dr. Mary McLean

“the available evidence does not support the use of the HINTS examination alone by emergency physicians in patients with isolated vertigo or AVS to rule out a posterior stroke.”

In that episode, the case patient was told they would be admitted to the hospital to have a neurologist do the HINTS exam and decide if an MRI was necessary.

But the question remains: can emergency physicians be taught how to use the HINTS exam to make clinical decisions?

This is a difficult task, in part because vertigo education for emergency physicians has historically contained lots of  misinformation.  If there’s one thing we learned from the current pandemic, it is that misinformation is easier to spread than to correct.

The tsunami of misinformation around COVID-19 has been coined the “infodemic”. We talked about this with Simon Carley on an SGEM Xtra and he emphasized “principles EBM are even more important now than in any time in our career”.

There is a great quote by Thomas Francklin in 1787 about misinformation that rings true over two-hundred years later in the age of social media. He said: “Falsehoods will fly, as it were, on the wings of the wind, and carry its tale to every corner of the earth; whilst truth lags behind; her steps, though sure, are slow and solemn.”

There is quote from another famous Franklin, Ben, which is apropos to the HINTS exam. “You will observe with concern how long a useful truth may be known, and exist, before it is generally received and practiced on.”

Myths & Misinformation about Dizziness:

  • Myth: Asking what they mean by dizzy is the most important question to ask a dizzy patient.
    • In fact, the patient’s description of the sensation of their dizziness cannot be used to generate a reliable differential diagnosis.
  • Myth: Tables of central vs peripheral characteristics of vertigo are helpful.
    • Let us just say they are not.  You can watch my YouTube video about this for more info.
  • Myth: If it gets worse when you move your head, that means it’s a peripheral cause.
    • All vertigo gets worse when you move your head. If it does not, it probably is not vertigo.
  • Myth: A CT or CTA will prevent you from sending home a stroke presenting with dizziness.
    • Nope. CT has very poor sensitivity for stroke.
  • Myth: Hearing loss only happens in peripheral causes.
    • In fact, an AICA stroke, (anterior, inferior cerebellar artery) can cause hearing loss.
  • Myth: If you see any vertical nystagmus, it must be a central cause.
    • In fact, the most common cause of nystagmus is BPPV, and vertical upward nystagmus is an expected finding. Spontaneous vertical nystagmus, (nystagmus you see when the patient is just sitting or lying there) is central.

There are a lot of dogmas and myths in medicine. We have discussed some of them on the SGEM including SGEM#9, SGEM#63, and SGEM Xtra: Dogmalysis 2021. 

It is no wonder emergency physicians struggle with dizzy patients when what we were taught for decades is often not very helpful. Added to these myths is the fact that some cerebellar strokes appear very similar to vestibular neuritis.  Poor understanding of vertigo leads to fear and avoidance of seeing these kinds of patients, which leads to continued poor knowledge, more avoidance and so on.  I call this the Vertigo Vicious Cycle of Vexation.  And most emergency physicians are caught in that cycle.

The problem, as illustrated by the case, is that most of the patients with AVS (constant vertigo, which is worse with head movement, nausea/vomiting, difficulty walking, AND nystagmus) have vestibular neuritis (VN).  But some will be have a posterior circulation stroke (PCS).

There are other rarer causes of AVS but, functionally, the differential diagnosis in AVS is VN vs stroke.  Many, but not all, patients with PCS will have other central features.

It would be unusual for a patient with VN to have a new significant headache or neck pain, which are red flags for a cerebellar hemorrhage or vertebral artery dissection. Other concerning features would include focal weakness or paresthesia, or diplopia, dysarthria, dysmetria, dysphagia, dysphonia, or spontaneous vertical nystagmus or the inability to walk unaided.

Any of those features in a patient with vertigo and nystagmus at rest should make you very concerned that your patient is having a stroke.  The first line of defence against missing a PCS should therefore be screening for thee central features, and NOT the HINTS exam.  If you find any of those central features, work them up for stroke.

What do we do with the majority of patients who have AVS but, none of those central features, like in the case scenario? Do we just say: “no neuro findings, must be VN, and send them home” or do we get an MRI in them all?

Since most patient with AVS (again with nystagmus) have VN, the cost and availability of MRI for this indication becomes a real practical issue.   In addition, MRIs done within the first 24 hours of onset can miss approximately 20% of PCS. (Shah et al AEM 2022).

Should we admit all of these dizzy patients for two or three days and get an MRI? Some well-funded systems do that, but most systems are simply unable to afford such practices.

Therefore, there is a great need for a clinical test with excellent negative predictive value to rule out stroke in these low risk AVS patients with no central features.

The key phrase is in “expert hands”. David Newman-Toker is an MD, PhD and Professor of Neurology, Ophthalmology, & Otolaryngology. This leads back to the question of can the HINTS exam be correctly applied and interpreted in the hands of an emergency physician? The SRMA by Ohle et al AEM 2020 suggested they cannot. In the one study that included a specially trained emergency physician, the diagnostic accuracy of the HINTS exam was not impressive: sensitivity was 83% and specificity was 44%.

In Kerber’s 2015 study, there was only one emergency physician amongst the three physicians using the HINTS exam.  The HINTS should be seen as an extra safety measure to ensure we aren’t missing a stroke in patients suffering with what is most likely vestibular neuritis. It is very important to stress that the HINTS exam should not be viewed as a stand-alone test on all patients presenting with vertigo.

The HINTS exam must also be applied in the correct clinical situation. In a retrospective chart review of 2,309 patients presenting with dizziness, the HINTS exam was misapplied 97% of the time. (Dmitriew et al AEM 2021).

This study showed the drawbacks of applying a new, somewhat sophisticated bedside examination technique without training.  If you just handed out ultrasound machines in the 1990’s without training, you’d be getting similar bad results. Again, HINTS should only be used in patients with significant, constant vertigo AND spontaneous nystagmus who don’t have the central features we already described.

The HINTS exam consists of three bedside tests: assessment of nystagmus, test of skew, and the head impulse test.

The HINTS “plus” exam is HINTS with the addition of a bedside test of hearing (the finger rub test) to help pick up an AICA stroke. An anterior inferior cerebellar artery stroke can present with the other HINTS exam findings identical to vestibular neuritis, as the AICA stroke produces an infarct of the organs of balance and hearing as well as part of the cerebellum.  So, a new hearing loss in a patient who presents with vertigo and findings consistent with a vestibular neuritis in that same ear signals a potential AICA stroke.  The bedside test of hearing can pick up these AICA strokes and make the negative predictive value for HINTS even higher.

The questions remain: how much training is required to use the HINTS exam in clinical decisions, and how should it be taught? And, if you decide to not use the HINTS exam, what are you using to evaluate these patients in its place?

The paper we will discuss compares the HINTS exam to the STANDING protocol.  STANDING is an algorithm by Dr. Vanni et al. published in Frontiers in Neurology 2017.

The STANDING algorithm assesses patients with acute onset of vertigo or imbalance. They were evaluated by six emergency physicians whose training was fairly significant, with six hours of lectures and hands on training, plus ten proctored examinations.  The physicians looked at the type of nystagmus, the results of the Head Impulse Test (HIT), performed an assessment of the patient’s ability to stand or walk, and considered the results of positional testing to look for benign paroxysmal positional vertigo (BPPV).  This study showed that STANDING had a 99% negative predictive value for stroke, making it a good protocol to allow you to send home the majority of patients with VN.

However, the test of skew, one of the components of the HINTS exam, was not a part of this algorithm, which is why STANDING was not included in the SRMA of HINTS by Ohle et al AEM 2020. In fact, the five studies in that meta-analysis of HINTS, there was only one emergency physician included. In STANDING, there were six ED physicians.

STANDING, with its six trained emergency physicians, showed that the HIT exam could be taught to emergency physicians and be used to rule out stroke.  The HIT is the most important part of the HINTS exam because the diagnosis in AVS is mostly VN and some strokes.  Patients with VN in the first couple of days will have spontaneous nystagmus and an abnormal HIT.  But the HIT is also the most controversial aspect of the HINTS exam, with some emergency physicians arguing that it is too difficult to learn and interpret.  However, sometimes useful things take a fair bit of training to learn how to use properly (ex point of care ultrasound).  Others have suggested the HIT could potentially harm a patient, which has never been shown to be the case.

The STANDING study was also the first ever published study that specifically trained emergency physicians how to perform and interpret the supine roll test, which is how you diagnose the less common horizontal canal BPPV, as well as the Dix-Hallpike test to diagnose the more common variety of BPPV:  posterior canal BPPV.

Since the STANDING study included all patients with vertigo or imbalance, and not just those with nystagmus, they found that half the patients had BPPV of which 40% of those had horizontal canal BPPV.

Horizontal canal BPPV is not well known to emergency physicians and is probably one of the reasons that there has been a low uptake of the Epley maneuver for BPPV despite it being around for 30 years, very easy to do, and highly effective.  But the Epley maneuver doesn’t treat horizontal canal BPPV.  If 40% of your BPPV patients don’t respond to the Epley maneuver, you probably are going to stop doing it.

You can watch a short YouTube video showing how to use the supine roll test and the Gufoni maneuver to diagnose and treat horizontal canal BPPV.

Clinical Question: Can emergency physicians learn and properly use vertigo protocols to assess patients with acute vestibular syndrome, and is one protocol better than others?

Reference: Gerlier C, et al.  Differentiating central from peripheral causes of acute vertigo in an emergency setting with the HINTS, STANDING and ABCD2 tests: A diagnostic cohort study. AEM 2021

  • Population: Patients presenting with isolated vertigo and unsteadiness in the ED. Very importantly, nystagmus was NOT an inclusion criterion.
    • Excluded: Patients without symptoms at the time of examination. This was an attempt to prevent patients with BPPV from being entered in the study, as those patients don’t generally complain of symptoms at rest.  They also excluded  those with “frank localizing neurological signs”.
  • Index Test: HINTS exam, STANDING protocol and ABCD2 score . Nine senior emergency physicians received six hours of training in both the HINTS and STANDING protocols. That included the Dix-Hallpike test and supine roll test to look for both posterior canal and horizontal canal BPPV.  They also looked at the ABCD2 score of these patients.  STANDING doesn’t include the test of skew, but it adds testing of gait and testing for BPPV.
  • Comparison: MRI 48 to 72 hours after symptoms onset in hospitalized patients if it wasn’t already performed in the ED. CTA was used in patients with a contraindication for MRI. An examination by an otologist was arranged to reassess MRI results and to further identify peripheral etiologies like BPPV.
  • Outcome:
    • Primary Outcome: Diagnostic accuracy (sensitivity and specificity) of the HINTS exam to diagnose a central cause of isolated vertigo.
    • Secondary Outcomes: Comparing the accuracy between the HINTS examination, the STANDING algorithm, and the ABCD2 score. The perceptions of the trained emergency physicians on the use and the interpretation of HINTS and STANDING examinations.
  • Type of Study: Single-centre, prospective diagnostic cohort study

Authors’ Conclusions: “In the hands of EPs, HINTS and STANDING tests outperformed ABCD2 in identifying central causes of vertigo.  For diagnosing peripheral disorder, the STANDING algorithm is more specific than the HINTS test.  HINTS and STANDING could be useful tools saving both time and costs related to unnecessary neuroimaging use.”

Quality Checklist for A Diagnostic Study:

  1. The clinical problem is well defined. Unsure
  2. The study population represents the target population that would normally be tested for the condition (ie no spectrum bias). Unsure
  3. The study population included or focused on those in the ED. Yes
  4. The study patients were recruited consecutively (ie no selection bias). No
  5. The diagnostic evaluation was sufficiently comprehensive and applied equally to all patients (ie no evidence of verification bias) Yes
  6. All diagnostic criteria were explicit, valid and reproducible (ie no incorporation bias) Yes
  7. The reference standard was appropriate (ie no imperfect gold-standard bias) Unsure
  8. All undiagnosed patients underwent sufficiently long and comprehensive follow-up (ie no double gold-standard bias) Yes
  9. The likelihood ratio(s) of the test(s) in question is presented or can be calculated from the information provided. Yes
  10. The precision of the measure of diagnostic performance is satisfactory Yes
  11. Conflicts of interest. None declared

Results: Over 1% (660/63,407) of ED patients presented with dizziness in this study. Half were excluded from the cohort because a trained emergency physician was not available giving a total of 330 patients included in the final cohort. The mean age of patients was 60 years and close to two-thirds were female. Those ultimately diagnosed with central vertigo were 14 years older and more likely to be male compared to those diagnosed with peripheral vertigo. There were many other statistical differences between the two groups detailed in Table 1 of the publication.

Key Result: In these nine trained emergency physicians, the HINTS exam, and the STANDING algorithm outperformed ABCD2 in diagnosing central causes of vertigo.

  • Primary Outcome: Diagnostic accuracy (sensitivity and specificity) of the HINTS exam to diagnose a central cause of isolated vertigo
    • Sensitivity of 96.7% (95% CI; 89.0 to 99.3)
    • Specificity of 67.4% (95% CI; 61.2 to 73.0)
  • Secondary Outcomes: Table 2 shows the diagnostic accuracy including sensitivity, specificity, PPV, NPV and likelihood ratios

The HINTS exam and STANDING protocol had an impressive negative predictive value to rule out a stroke, 99.4% and 98.3% respectively. Out of 300 patients evaluated, HINTS missed one stroke, and STANDING missed 3 strokes.

Figure 2 shows the confidence of trained emergency physicians using the clinical tests and perceptions about their impact in routine practice. The 5-point scale was defined by a minimum agreement of 1 (strongly disagree) and a maximum agreement of 5 (strongly agree).

They generally found it not difficult to perform HINTS, but two out of nine trained physicians still did not feel confident in the interpretation of the HIT. They also found using the Frenzel glass to interpret nystagmus the most challenging.

1) Consecutive Patients: These were not consecutive patients. Half of the patients were not included in the cohort because the emergency physician was not available. A lack of additional information makes it difficult to know if these dizzy patients were similar to the included dizzy patients.

2) Specificity (True Negatives): The authors claim that the HINTS exam was less specific than STANDING, that they had more false positive results with HINTS. But this is because more patients with BPPV were classified by HINTS as a central cause, and that’s because they had a normal HIT.  The HINTS exam was never designed to be tested on patients with BPPV.  Patients with BPPV do not have a reason to have an abnormal HIT, because they don’t have the vestibular nerve problem that would be seen by the abnormal HIT which is seen in all cases of vestibular neuritis.

3) Gold Standard: Ten percent of the cohort did not receive an MRI which is considered the gold standard test. This could have introduced some potential bias into the final diagnostic accuracy metrics.

When the MRI is performed is also a concern. Evidence suggests up to 20% of cases can be missed if the MRI is performed early. It is unclear from Figure 1 exactly when this reference standard test was done. The authors do mention in the discussion that they did not repeat an MRI in 8% of patients who received their MRI within 24 hours of symptoms onset.

For more on biases in diagnostic studies and understanding the direction of these biases please see the excellent article by Kohn et al AEM 2013.

4) Benign Paroxysmal Positional Vertigo (BPPV): The odd thing is that this study claims that 72% (66/90) of the patients with BPPV had a true overall HINTS peripheral result. This is hard to understand because the only way to have an overall HINTS peripheral result is to have an abnormal HIT and BPPV patients shouldn’t have one.  The author was contacted to ask how this could have occurred and she did not have a good answer.

If they had successfully excluded BPPV patients from their study, as was their intent, then the specificity of HINTS would have been much better.  This is because they wouldn’t have had any false positive with HINTS from the many BPPV patients.

So why did they have so many BPPV patients in this study, when they didn’t want them to be included.  First, BPPV is the most common cause of vertigo and many patients with BPPV endorse a baseline dizziness even when they are still.  A careful history can usually distinguish the brief intense episodes of BPPV with a minimal baseline “off” feeling, from the very significant amount of constant dizziness/vertigo experienced by those with true AVS, who are suffering from VN or stroke.  So, when they asked the patients if they were still dizzy, many BPPV patients said yes.

Secondly, and most importantly, they didn’t require their patients to have spontaneous nystagmus as an inclusion criterion.  Patients with BPPV almost never have spontaneous nystagmus.  So, if they had used the strict definition of AVS as having significant constant dizziness AND spontaneous nystagmus, they would have eliminated almost all the patients with BPPV.

5) Confidence Intervals: The sensitivity for the HINTS exam in detecting all-causes of central vertigo was high at 96.7%. However, the lower end of the 95% confidence interval was 89% suggesting over 10% of central causes of vertigo could be potentially missed.

The point estimate for the negative predictive value for the HINTS exam was better at 99.4% for diagnosing stroke. The lower end of the 95% confidence interval for this metric was 96.6% suggesting over 3% of strokes could be missed. Whether that is an acceptable miss rate would depend on your practice environment.

The negative likelihood ratio for diagnosing a stroke with the HINTS exam, which is independent of prevalence, was 0.03. This is less than the 0.1 that has been traditionally used to rule out a diagnosis. However, the 95% confidence interval does go to 0.2. Again, it depends on where you practice if this is a reasonable miss rate.

Questions for Dr. Peter (Dizzy) Johns

1) Is it possible to train emergency physicians to do the HINTS exam?

If you include the six emergency physicians trained in the original STANDING study and nine trained in this study by Gerlier, that is 15 emergency physicians who were able to use the head impulse as part of a diagnostic algorithm and to reliably rule out stroke in patients with acute dizziness.  I have trained many myself. Yesterday, I taught a 4th year medical student how to perform the HINTS exam and, after only a couple of minutes, his technique for performing the HIT was much better than when he started.  So, the question is not any more if it is possible, but how best to train physicians, and what percentage of emergency physicians who are trained will be able to use this effectively in clinical practice?  Will there be 100% uptake?  Of course not, there isn’t 100% uptake in any clinical practice advance, no matter how easy or effective it might be.  But what’s the alternative?  Admit them all for three days and MRI them all?  That approach can not be used in every clinical scenario where dizzy patients present themselves.  But the HINTS exam by trained physicians can.

2) Should you do the HINTS exam first?

No, the HINTS exam should only be performed on a dizzy patient WITH nystagmus after first carefully screening them for the central features as I have described.  If you use HINTS this way, I think it can save time and precious MRI resources as Gerlier suggests.

But we are facing a huge problem with indication creep with respect to people suggesting doing HINTS on those without nystagmus.  For instance, Jonathan Edlow, a giant in vertigo education of emergency physicians, says you can do the HIT on patients without nystagmus, but you can not rely on the result.  Makes no sense to me.

It gets worse.  I have looked at the brand-new Rosen’s Emergency Medicine textbook chapter on vertigo, and it has in figure 15.3 an algorithm that says if you have “persistent symptoms” you should be subjected to the components of the HINTS exam as well as screened for central features, and if the HIT is normal, you need an MRI and neurology consult.  As Gerlier’s study just showed, not including nystagmus as an indication for HINTS makes you perform HINTS on the many patients with BPPV, and many false positive results, and the value of HINTS is degraded to the point where it’s no long a useful test.

No nystagmus, no HINTS for you!

4) When can you start using the HINTS exam in clinical practice?

I personally think that if you can check the following boxes, you can use it clinically.

  • You know the indication for the HINTS exam which means constant vertigo AND nystagmus, and the patients screen negative for the central features
  • Can describe the central and peripheral results of the three components of the exam without using notes
  • You have had a vertigo interested clinician (vertigo champion) observed you performing the HINTS exam, and they approve your technique
  • You have been able to record an abnormal HIT on your phone’s camera, which was verified to be an abnormal HIT by a vertigo champion,

Then you can start using it to make clinical decisions. If you do the HINTS exam on a patient, and you’re not sure whether there is an abnormal HIT or skew, be cautious and call it a central result.  But with experience, you will became more confident, you will end up sending home a lot of vestibular neuritis patients’ safety and quickly without imaging.

For all those patients with very little or no dizziness at rest and no nystagmus you should perform the Dix-Hallpike and the supine roll test to pick the BPPV patients, both posterior canal and horizontal canal.

5) Local Champion

Having local ultrasound champions was a big factor in the development of bedside, point of care ultrasound throughout the world. Unfortunately, there are not a lot of vertigo champions in emergency medicine, but I believe there can be.

I am currently winding down my clinical practice after 37 years of working in the ED trenches and I am looking forward to having the time to reach out and give in person hands-on vertigo workshops locally and abroad.  I can also critique the technique of the HIT virtually, but in person is better.  If you want me to visit your hospital and teach your residents or faculty, send me an email at peterjohns84@gmail.com and let’s nurture more people to become vertigo champions so we can stop  the Vertigo Vicious cycle of Vexation, and help our patients.

6) What about the patient who is constantly dizzy with no nystagmus?

A lot of people ask me that question and I think the answer is found in a study by Machner et al Journal of Neurology 2020.  He found that patients who were dizzy in the ED and had an objective finding of difficulty with standing or walking but did not have nystagmus had a high risk of stroke. He called this the Acute Imbalance Syndrome, and when he performed delayed MRIs on them all, a third had acute lesions of their MRI, and if their ABCD2 score was 4 or more, half had MRI abnormalities.

So, worry about patients with an acute objective change in balance, dizzy, but no nystagmus.  BPPV patients rarely if ever have an objective change in their balance once their brief episode of dizziness settles down.

Comment on Authors’ Conclusion Compared to SGEM Conclusion: We generally agree with the authors’ conclusions.

SGEM Bottom Line: This study shows that emergency physicians can use the HINTS exam to rule out stroke on patients with constant vertigo AND nystagmus, who screen negative for central features of vertigo, and have an overall HINTS peripheral result.

Case Resolution: You perform the HINTS exam. The patient’s nystagmus does not change direction with gaze, it always beats to the left, there is no vertical skew deviation seen with the alternate cover test, and there is an abnormal catch-up saccade seen during the head impulse test when her head is turned rapidly to the right.  This is an overall HINTS peripheral result, so she likely is suffering from vestibular neuritis affecting her right ear.  She also has no new hearing loss when tested with the finger rub test.  If there was, it would be concerning for an AICA stroke.  As it was normal, she was discharged home and when seen in follow up a week later at the local Rapid Access Dizzy clinic run by a vertigo interested ENT surgeon and neurologist, her symptoms had completely resolved.  Again, her findings can be seen in my YouTube video.

Clinical Application: Given that an early MRI can miss 20% of strokes in dizzy patients, and the lack of 24-hour MRI availability throughout the world, more education about the HINTS exam is warranted to save time and money in these patients. Emergency physicians can be taught how to use the HINTS exam to safely discharge patients with constant vertigo and nystagmus and no central features.

Dr. Peter Johns

What Do I Tell the Patient. I would tell a patient with constant dizziness and nystagmus with no central features and an overall HINTS peripheral exam that their dizziness is caused by a problem with the nerve that carries information about balance from their ear to their brain, and that it’s very unlikely to be a serious cause such as a stroke.  They are safe to recuperate at home, using anti-nausea medications for nausea for two or three days only.   It is also been shown that vestibular physiotherapy can be useful to help the recovery of vestibular neuritis, so you can offer to make a referral for your patient.

Keener Kontest: Last weeks’ winner was Caleb Herrick. He knew naloxone is included in suboxone to deter IV use.

Listen to the podcast this week to hear the keener contest question. If you are the first person to email the correct answer to TheSGEM@gmail.com with “keener” in the subject line you will receive a cool skeptical prize.

Remember to be skeptical of anything you learn, even if you heard it on the Skeptics’ Guide to Emergency Medicine.