Dr Giacomo Garone (Paediatric Neurologist, Rome, Italy) discusses data from Italy and current practices.

Transcript

[Nadine]

And the charity is really excited to welcome our first Italian speaker and the lovely Doctor Garone from Rome is going to present on Sydenham’s Chorea and their experience over in Italy, so over to you please.

[Dr Garone]
I hope you can see my screen and you can hear me. OK, so good morning again and thank you very much for your kind invitation. And I I’ve been asked to talk about the Italian approaches to Sydenham’s Chorea. So I will try to make an overview of the data available about the management of this condition in my country.

As you know Sydenham’s Chorea is a condition that is diagnosed on clinical grounds and as a part of acute rheumatic fever, and its diagnosis requires clinical diagnosis of rheumatic fever, according to Jones criteria and Jones criteria are different, according to the expected incidence of this condition in a specific geographic area. So it is critical to know the exact frequency of Sydenham’s Chorea in acute rheumatic fever in each country to know which clinical criteria should be applied to answer an accurate diagnosis.

However there are just few studies investigating this topic in Italy and they are quite recent but referring to two different periods of time, and as you can see in this table, most of them reported an incidence of acute rheumatic fever that was above the threshold for considering the regions investigated as an intermediate or high risk country. So according to available evidence, Italy should be considered an intermediate risk country, where the less strict high risk criteria should be applied to avoid under diagnosis of Sydenham’s Chorea and Acute rheumatic fever in general.

However, the incidence of Sydenham’s Chorea was highly different in these studies and chorea was found to occur in a very variable proportion of these cases, from 5 to 33% of the children diagnosed with acute rheumatic fever. However the question is if this data is actually reliable, if we can trust this data.

All incidence rates in these studies have been retrospectively estimated and no surveillance studies have been conducted, different from the UK, and population studies were relatively small and each study referred to small provinces or regions which were geographically scattered and with total lack of knowledge from a very large part of Italy, such as southern and insular Italy. And also the studies from the largest populations of Italian territory were based on discharge diagnosis, with no information on what diagnostic criteria were used, or whether the diagnosis was correct or not.

So one point is that the epidemiology of our rheumatic fever and Sydenham’s Chorea is almost unknown but how frequent is Sydenham’s Chorea as a neurological emergency, as a presentation in the emergency department or to acute neurology services?

In a retrospective study of children admitted to six paediatric emergency rooms over two years, we found that 36 cases of Sydenham’s Chorea were diagnosed, accounting for 14% of all children with hyperkinetic movement disorders, and according to this study, Sydenham’s Chorea was the second most common cause of acutely presenting movement disorders, after primary tic disorders.

In other countries similar studies have reported very different results with a lower frequency of Sydenham’s chorea among children with acute movement disorders. However, it should be noticed that the studies have been conducted in different settings, more specialized settings than emergency departments, such as child neurology services or paediatric movement disorder clinics.

So one explanation can be that not all children with Sydenham’s Chorea are referred to these highly specialized services and in most of the cases, they are treated by general paediatricians or rheumatologists, and they are not referred to movement disorder specialists or to child neurologists.

The information that we have about the clinical presentation and management of Sydenham’s Chorea in Italy are largely due to this larger prospective multicentre cohort that has been recently published, and that was recruited from 16 Italian centres, who collected information about 171 cases of Sydenham’s Chorea, which provided very useful information about clinical practice in Italy.

The authors found that body distribution of Chorea was generalized [rather than hemichorea, or one sided] in most of the cases, and that carditis was highly prevalent in this cohort.

And about treatment choice, regimens used, this cohort demonstrated how Italian centres are prone to using immunomodulatory treatments in Sydenham’s chorea with a frequency that is much higher than what has been observed in other countries, such as the UK. As you can see, about 40% of the patients receive corticosteroids alone, and another 40% of patients are treated with a combination of corticosteroids and symptomatic agents, and only a minority of patients are treated with symptomatic treatment alone or receive no specific treatment apart from antibiotic prophylaxis.

Symptomatic treatment choices also were extremely variable. There was no specific clear difference in the use of anti-seizure medications or dopamine receptor blocking agents.

But a lot of molecules have been prescribed and also molecules that are not usually listed as anti choreic agents, suggesting that perhaps the confidence of each specific physician is the most important factor in the choice of the of the molecule rather than expert recommendations .

Corticosteroids use in Sydenham’s Chorea is one of the most controversial topics in the management of this condition. But we can say that Italian physicians are quite prone to prescribe these drugs to their patients as testified by many studies reporting their experience from Italian centres.

As you can see there are many retrospective case series that have been published in the past, also in recent years, reporting the various steroid regimens used in this condition with some judgment about their good efficacy that however was not based on high quality evidence.

So to summarize, we can say that Italian physicians are very prone to prescribe corticosteroids. More than 70% of  Italian patients with Sydenham’s Chorea receive steroids, even if evidence supporting this regimen is limited and of low quality and also the regimen choice is highly dependent on physicians’ experience and background.

Clinical presentation of Sydenham’s Chorea in Italy is really heterogenous but one important finding from this cohort is the high prevalence of non-motor symptoms, including neuropsychiatric disorders that have been reported in about half of the of the children at disease onset and this is similar to the results we saw earlier from the UK with a high prevalence of mood disorder and anxiety.

Another important factor that I would like to highlight is the relapse risk. It is usually said that Sydenham’s Chorea is a monophasic disease, but this is not true for about 10% of the patients, according to our findings, with many children who experience relapse of Chorea, mostly in the first months after onset.

This data should be interpreted cautiously. It seems that an older age at onset [older than 8] and the need for treatment with symptomatic drugs increase the risk for a relapse. However, this data is based on the retrospective investigation and is not exactly reliable. However our approach to diagnosis and management of Sydenham’s Chorea in our institutions is based on clinical assessment through the demonstration of Jones criteria for acute rheumatic fever and thorough investigations which are useful to rule out alternative causes of chorea. As a rule, we suggest for every child with new onset chorea of unknown cause, a brain MRI and auto immune assessment [C3/4, ANA, anti-dsDNA, ENA, antiphospholipid panel, lupus anticoagulant] to exclude other, potentially treatable causes of Chorea such as anti phospholipid syndrome, and also rare, but treatable, inherited disorders that may present with acute or subacute chorea such as Wilson disease. So we usually perform in every child referred with chorea plasma ceruloplasmin.

And also we suggest further investigations if Jones criteria are not fulfilled, so a positive and certain diagnosis of rheumatic fever cannot be made, in these cases lumbar puncture and screening for autoimmune and viral encephalitis or for inborn error of metabolism is required.

About treatment in our institutions, we usually treat patients with steroids at presentation, at disease onset, with oral Prednisolone in mild cases, or with a cycle of intravenous methylprednisolone in severe or moderate cases, and we usually consider symptomatic treatment as an add on therapy, to be reserved for patients with a poor or slow recovery with immunomodulatory treatment and moderate to severe disability related to the movement disorder.

In in terms of the treatment of relapses, we usually suggest you reconsider diagnosis in every child who presents with a relapse of chorea, with performing another brain MRI and re-assessing for autoimmune conditions. But again, we usually treat relapses of Sydenham’s chorea with corticosteroids. If the last steroid cycle was earlier than six months at the time of the relapse, or if already 2 cycles of steroids have been performed, we usually treat patients with intravenous immunoglobulins.

This is just one explanatory case that I would like to share with you of a young girl who was admitted in May 2020 at our emergency department for left sided involuntary movements with subacute onset, generalized in the following days, with progressive worsening leading to speech difficulties and gait disorder.

Neurological examination demonstrated bilateral chorea with moderate to severe impairment. And I her general examination showed a systolic heart murmur.

Clinical investigation demonstrated echocardiographic signs of rheumatic heart disease.

Brain MRI was normal and anti-streptolysin titre was elevated. So a diagnosis of Sydenham’s chorea was mad, and screening for alternative causes was negative

So she was treated, as I said before, with methylprednisolone and short treatment with haloperidol was added because of the severity of the presentation, and she was also treated, of course, with antibiotic prophylaxis and [20mg/kg daily for 5 days, followed by oral prednisolone tapered within 1 month], with symptomatic treatment [enalapril] for her rheumatic heart disease.

However, despite fast improvement in the following weeks, she experienced a relapse about three months after onset that was treated with intravenous immunoglobulins due to recent steroid treatment.

And she recovered. But she suffered from another relapse a few months after that, she was again treated with intravenous immunoglobulin, this time in addition to methyl Prednisolone, because the symptoms were highly disabling.

And she experienced a third relapse about ten months after the second episode that was effectively treated with intravenous immunoglobulins.

So many questions are still open at this at this point.

We don’t know exactly which are the correct application to immunomodulatory treatments including steroids and intravenous immunoglobulins.

We do not know yet what are the optimal steroid regimens in terms of type of molecules and duration of the treatment, and the same is true for intravenous immunoglobulins, we don’t know yet if repeated cycles effectively prevent relapses, and how long these cycles should be.

There is also poor knowledge about the most effective symptomatic treatment, which molecules have the best safety and efficacy profiles? Also considering the risk for neuropsychiatric associated side effects.

And another important open question is relevance and frequency of residual motor and non-motor symptoms in patients who experienced Sydenham’s chorea in the past and recovered.

So just to conclude that we in Italy see Sydenham’s chorea and acute rheumatic fever are poorly studied. We do not have a reliable data about their epidemiology.

Sydenham’s chorea assessment and treatment are highly heterogenous even within centres, so patients treated in the same centre frequently receive different treatments, and there is a strong propensity in Italy towards steroid treatment and immunomodulatory treatment in general.

The awareness about psychiatric comorbidities and non motor features is increasing, but they are likely underestimated, and undertreated, and under-recognized, so we do really need surveillance studies, one surveillance study, and some attempt to standardize our clinical practice in terms of diagnostic and theoretic protocols in order to answer reliable evaluation of potential pitfalls in our clinical practice.

Thank you very much for for your attention, and for your invitation again.

 [Adrian]
As I said at the start of the meeting your own Italian data shows that treatment with steroids and IVIG doesn’t actually make any difference, either to the functional outcome or to relapses, but yet you’re still doing it – is that because you feel that there is some other benefit that is not seen in the data or for some other reason?

[Dr Garone]

I think most of the papers suggest that steroids are not effective in in preventing relapses or in reducing the residual symptoms, but that steroids may be helpful in achieving faster recovery, probably this is the only benefit that has some poor evidence, but still some evidence.

I’m not sure this is the right way of thinking about treatment of these conditions. There are so many things that we do not know yet.  But I think this can be an actual goal of treatment, so achieving a fast recovery, and some data from the past suggest that steroids are helpful in achieving this goal.

However, it should be demonstrated with studies with more quality, but I’m not sure that this is feasible in the short term.

In terms of treatment with immunoglobulins,  the evidence is still poor, but in our experience it is extremely helpful.  It is usually reserved for patients who have relapses or severe symptoms, but empiric experience seems to suggest that they can be helpful. I don’t know what your opinion is about this?

[Adrian]
Thank you. I’ll pass you over to Michael first, but Dr Michael Eyre will shortly be showing some data that steroids maybe do help with reducing relapses in the future.

[Michael]
Yeah, I was very interested in your data on relapses because the rate of relapse is, I think we saw clinically and from other research, seems relatively low in Italy compared with other experience. And I just wonder whether the steroid treatments that you’re routinely using could be responsible or whether it’s something to do with methodology of the retrospective reviews, which is simply missing relapses because they don’t go back to the neurology centres.

They maybe get managed elsewhere, I don’t know what you think about that?

[Dr Garone]
I think both options are possible. I think there is a bias due to the retrospective nature of the studies and I think some relapses have been missed. This is very likely, but it is also possible that a wide use of immunomodulatory treatments, also prolonged immunomodulatory treatment (because many centres prescribed very long steroid treatment) might have some influence on the rate of relapse.  The problem in my opinion is that we lack a clear definition of relapse for Sydenham’s Chorea, because in my experience, many patients do not have a full recovery after chorea, some mild, very mild and not disabling symptoms persist, and it’s sometimes difficult to see if it is a true relapse of the main disease or a fluctuating course of mild symptoms. I’m referring to, for example, young female patients that have disease onset before puberty and who experience an aggravation of symptoms with puberty, or one day start taking oestrogens for contraception, and this is a relapse?. This is immune mediated? I don’t know. I  don’t think so. But this is another topic.

 Also, timing of relapse is an open question. So if you relapse, so called, after three months, during tapering of the steroid, is this a relapse or not? I’m not sure about this definition and this retrospective cohort does not help in clarifying these points. And this is a major pitfall in our understanding of this condition.

[Nadine]
I think that’s really interesting. I think we found the same within the Scottish study around just understanding that word “relapse” and what families felt that word meant because quite often it was the extremes in the presentation and the behaviour. And when you unpicked it to get the actual physical symptoms of the chorea, I think there was only one of our cases that had current chorea at the time. But it’s families’ perception of what actually Sydenham’s Chorea is, and what’s important for them, and what’s important in the treatment they receive from the professionals around that understanding of the word relapse as well. So it is a really interesting point.

 [Oana]
I am aware that part of one of the slides at the end, one of your questions was already around the assessment of non motor symptoms. So when I think in the psychological or neuropsychological sense, so talking about the emotional lability and everything, so I’m quite aware that was already part of your questions. I was reflecting on the case study of the 12 year old girl you said that she had I think a full, comprehensive neuropsychological, and in my mind instantly I was thinking, is there an assessment tool that you are using? Is it like a questionnaire or did you mean that she was seen by psychologist? Because I think there’s a huge variety, I was curious with that case, what was the assessment? If you have the details.

[Dr Garone]
Usually we perform a standardized neuropsychological assessment at first control after discharge from hospital that encompass some screening for intelligence, like a fluid intelligence test,  number, verbal test and executive functioning.

And then we also administer questioners to investigate neuropsychiatric comorbidities and a trained neuropsychologist performs a structured interview for psychiatric symptoms. And then we, according with the results we continue the follow up so I should say that we do not repeat on a regular basis this overall assessment, but just according with symptoms and result of the first assessment and probably we should repeat the same full assessment at regular intervals.But in most of the cases we are not able  to do it on a regular basis.

And in my experience non motor symptoms in the course of the disease become the most disabling and important part of the disease, and I think they are really under investigated and I’m not sure that the data that I showed suggesting a gradual decrease of neuropsychiatric symptoms along with the disease course is actually what occurs in most of the patients, I’m not sure.

[Oana]

Well, thank you it’s just one of the things I’m curious about and I don’t know if there is any data suggesting it, there might be from listening to young people’s stories, I was reflecting again on Callum’s story, about some difficulties being present before the actual onset of chorea, and part of me is thinking, could it be the emotional lability, most subtle changes, emotional changes before we actually see the striking features of the chorea? But that’s just something I’m curious about.

[Dr Garone]
I totally agree, and this is a another major pitfall in this practice. So we usually lack any baseline evaluation before onset of motor symptoms. And I agree that in many cases people come to consultation and parents report that some hyperactivity or attention deficit or emotional liability was always part of the picture of their child, and you don’t know to what extent you can ascribe symptoms to the Sydenham’s Chorea or not.

[Nadine]
It’s very  interesting because the Scottish study was exactly the same and we used the KiddiSize???? but we started with the timeline and it was a timeline leading up from birth till now and the symptoms that definitely came out were the spikes and emotional presentation, but separation anxiety, just not being able to be separate from the parent, and then the rapid decline in school, most of them had a real drop in their ability in school and it’s how you assess and judge that, you know, was that part of normal development? Would that have happened anyway, or is it linked to the Sydenham’s? And it’s a really important point. But ours again was just a small study. But in that study you could clearly see, I think the separation anxiety, the ADHD and the emotional resilience of the child.

[Ulrika]

We were part of a study in Sweden for IVIG because they thought Rebecca had PANDAS to begin with and we’ve seen remarkable results actually with IVIG. But my question is we have only received like short spouts of steroids.

Do you think steroids should be part of the treatment? Or could you only get IVIG, because this time she has had two relapses. And this relapse she has had six IVIG treatments and she has improved, but she’s not fully recovered. So I’m just wondering.

[Nadine]
Did you feel the side effects from the treatment?

[Ulrika]
We had really horrible side effects to begin with. Actually, the first I think 7 treatments, 8 treatments, possibly. But the last few treatments we’ve had no real side effects. She had a treatment yesterday, actually, so that’s why I’m at home with her right now.

[Dr Garone]
I’m not sure if I correctly understood the question, is it about treatment of Sydenham’s Chorea or about PANDAS?

[Ulrika]
 They have now decided she has Sydenham’s Chorea. So because it’s really rare in Sweden and I’m not sure, you know, it’s difficult to get treatment, correct treatment, I guess. And so I’m just wondering if you would recommend steroids as well, because we’ve had a week of steroids and it hasn’t really made much difference.

[Dr Garone]
I think nobody can answer this question with an evidence based approach.

 What I can say is that, in Italy, steroids are widely used for this indication even though they lack any recommendations, specific recommendation or guideline supporting this practice, so we can’t say if they are actually effective but we use them in many cases.

In my opinion, that can be part of the treatment of children with Sydenham’s Chorea but there are also a lot of side effects that should be cautiously taken into account before deciding which treatment is appropriate.

And usually I don’t think they are more effective than intravenous immunoglobulins. This is not however studied, and there is no evidence that can be used  to answer this question in a  a proper way. This is the problem.