Congenital CNS infections ( including Zika virus infections ): Lessons Learned

Topic: Congenital CNS infections ( including Zika virus infections ): Lessons Learned

When: July 24, 2021

Speaker: Vanessa van der Linden

Vanessa van der Linden: Good morning to everyone, and I'd like to thank you, the invitation to be here and talking a little about congenital infection and Congenital Zika Virus Syndrome, especially Congenital Zika Virus Syndrome.

Vanessa van der Linden: This is my disclosure. The mother, or the pregnancy, could suffer from virus different agents or pathogens during the pregnancy, but not all are able to cross the placenta and to cause infections to the fetus. In 1970, we called TORCH, the main disease that can cause congenital infections, especially Toxoplasmosis, rubella, CMV and herpes virus. But since then it change a little, some viruses disappear, like rubella. That disappears in the countries that started compulsory immunization against the virus.

Vanessa van der Linden: And more recently, we recognized pathogens like Zika virus, that was also possible to develop a congenital infection. It's a very important to study and to understand better these diseases, because congenital and perinatal infections represent the major causes of permanent disability among children.

Vanessa van der Linden: The pathogenesis of the involvement of the fetus, of the symptoms in the fetus related to congenital and perinatal infections are related with two factors. First one, the infections and inflammation of the placenta. And it will lead to placenta disfunction, and because of that, there will be intrauterine growth retardation. But also because of the virus that are able to cross the placenta and to infect the fetus. Initially by hematogenous dissemination goes to central nervous system and in the central nervous system can cause neuronal cell death, impairment of the neuronal migration, microcephaly, intracranial calcifications and development of brain defects.

Vanessa van der Linden: There are several factors that can influence the presence or not of the consequences of the neuro-development during congenital infections, including the tropism of the virus, of the agent, not only virus, of the agents for the central nervous system. The immune status of the woman pregnant and the time of the maternal infection.

Vanessa van der Linden: The same factors, problems are related with the discordant clinical outcomes of Congenital Zika Virus and the other infections in twin pregnancy. We have a lot of cases reported of twin pregnancy where one fetus were affected and another one not. So probably, we don't yet, we have only theory about this, but probably it's related with the immune response of the mother, related with the genetic of the baby, and related with the ambiental factors also.

Vanessa van der Linden: Regards to the epidemiological status of these main diseases, these main congenital infections, the most frequent is CMV congenital infections. CMV is the most common congenital cause of permanent deafness in many regions of the world. The infections estimated incidences in developed countries ranges to 0.6% to 0.7% of all live births, with approximately 60,000 neonates born every year with congenital CMV infections culminated in the United States and in Europe.

Vanessa van der Linden: When the mother has the infection by CMV, confirmed infection by CMV, in her primary infection, her first infection, the risk for transmitting the infection for the fetus are around 40% of the case. But only 10% of the cases has symptomatic disease. 90% of the patients have the asymptomatic disease.

Vanessa van der Linden: Congenital toxoplasmosis is less frequent, but is also frequent in around one per 1,000 or to one per 10,000 live-born infants. And the risk for the fetus infected when the mother are confirmed infection by toxoplasmosis in the beginning of the pregnancy is around five to 25%, but in the end of the pregnancy, it's around 90% of the case.

Vanessa van der Linden: In the United States, probably there 400 to 4,000 cases of congenital toxoplasmosis by year. Congenital Zika Virus is different because it occur like epidemic. So we are going to have a lot of cases in the same time and then the incidence will decrease and we'll have only few cases. The risk for the fetus to have infection by Zika when the mother confirmed the infections is around 50% of the case.

Vanessa van der Linden: Here's the table. This table bring the data for my city. For we understand that during the epidemic phase we have a lot of cases, especially between 2015 and 2016, but in the last two years we didn't have one confirmed case for Congenital Zika Virus, only suspections or cases that are doing investigation.

Vanessa van der Linden: Regards to the manifestations of the congenital infections, there are some clinical patterns that are similar between them. But there are some aspects that are more frequent in some diseases, like involvement of the liver with hepatosplenmegaly or cholestasis, is more frequent in CMV and toxoplasmosis. And the involvement of the brain, CMV, toxoplasmosis and Zika Virus are able to infect and to cause damage.

Vanessa van der Linden: Microcephaly is more frequent in CMV and the Zika Virus. And ocular abnormalities is more frequent in toxoplasmosis and Zika Virus.

Vanessa van der Linden: The brain images is very important to analyze it, to understand, because it's the pattern of the brain image that will suggest the diagnosis of congenital infections. So it's important we know these pattern to understand better for make the diagnosis. There are some genetic disease that has a similar pattern of congenital infections so it's important we know that when we try to give the diagnosis we analyze all the infections congenital are negative, we need to think also in some genetic disease.

Vanessa van der Linden: All the congenital infections are able to cause calcifications, but the pattern is different between them, so it's important to understand better the pattern of calcifications in brain images. The involvement of cortical development and the malformation of cortical development is more frequent in CMV and Congenital Zika Virus. And the involvement of white matter is more frequent in CMV, especially in the babies that had the infections in the end of the pregnancy.

Vanessa van der Linden: In CMV, there is a neurotropism by the virus, by some areas of the brain, especially in ependyma in the germinal matrix, and because of that the pattern of calcifications is in the periventricular area. And we have also, because of that, abnormalities in migrational, in cortical brain development. Loss of brain volume in some patients, we have a pattern of vaculopathy, especially in the patients that had the CMV in the end of the pregnancy.

Vanessa van der Linden: This is the CT scan of the patients with CMV. The pattern of periventricular calcifications is typical with CMV, associated with malformation of cortical development.

Vanessa van der Linden: The patients that have the [inaudible 00:10:36] CMV, the infections of the fetus in the end of the pregnancy, the pattern is a combination of periventricular calcifications, but less intense that in the beginning of the pregnancy. Associated with white matter abnormalities and anterior temporal cyst areas.

Vanessa van der Linden: In toxoplasmosis, there are more destruction or inflammatory processes than malformations of the brain. And the calcifications are scattered in parenchymal and also frequent in basal ganglia. And another pattern that we can find is a presence of hydrocephalus.

Vanessa van der Linden: The patients with Congenital Zika Virus, the virus has a particular tropism by the neuroprogenitor cortical cells. Because of that, the infections is before the formation of the cortex. Because of that the cortex of the patients with Congenital Zika Virus, there is a malformation of the cortex, so all of my patients has some degree of malformation of cortical development.

Vanessa van der Linden: And this is the pattern typical of the Congenital Zika Virus. And the calcifications is inside of the neuron, and because of that we are going to find a typical pattern of calcifications in cortical area, especially in transition between cortical and white matter, but also in the basal ganglia and in the posterior fossa. We have some patients with malformation of posterior fossa, cerebellar hemisphere and some patients including with pattern of Dandy-Walker malformation.

Vanessa van der Linden: We can see here, in these two figures, the different presentation of the disease. In the beginning, very severe patients, in the end, patients with mild presentation, mild symptoms. And of course, we have less involvement of the brain, but all of them have some degree of malformation of cortical development. And most of them, not all, but most of them have some degree of calcification, especially when the patient is less severe in high corticality.

Vanessa van der Linden: The MRI is better to understand the involvement of cortex, of malformation of cortical development ranges to very severe cases to mild cases. In the mild cases, the malformation of cortical development sometimes is only in frontal area, or frontal temporal area.

Vanessa van der Linden: Visual impairment and hearing loss are also frequent in patients with congenital infections. And again, to the visual involvement, ocular abnormalities, we can find in most of the congenital infections, but is more frequent and more typical in patients with toxoplasmosis. The special pattern is act in the choroiditis in the toxoplasmosis. In Congenital Zika Virus that we can find chorioretinal atrophy, but in the others, ocular abnormality.

Vanessa van der Linden: Here we can see a photo of congenital toxoplasmosis. It occur in the first photo, it occur in around 70% to 80% of cases. It's more frequent in toxoplasmosis. In Congenital Zika Virus it occurs in between 30% to 40% of cases.

Vanessa van der Linden: Regarding to the deafness, to the sensorineural hearing loss in CMV, congenital CMV, is the most frequent congenital infection that present hearing loss. And CMV is non-genetic cause of permanent deafness. And the damage to the hearing could occur after birth, during the first years of life. So, hearing loss in patients with congenital infection by CMV were found in 21% of the asymptomatic cases, and 32% of symptomatic congenital infections in infants.

Vanessa van der Linden: Patients with Congenital Zika Syndrome also could present hearing loss, but it's less frequent. Around seven percent of the patients.

Vanessa van der Linden: Now I will try to focus more in Congenital Zika Syndrome, and try to correlate some symptoms with other congenital infections. So the dysmorphic features, the neurological features, radiological, arthrogryposis, more in detail. Congenital Zika Virus is a spectrum that range to asymptomatic patients to very severe patients. Now probably we understand better the very severe cases, the patients that it's possible to make the diagnosis at birth. So the patient that have a severe microcephaly or have some degree of microcephaly. We don't know the consequence of the baby, we don't know the consequence of the virus during all pregnancy and if there is any other cases with less involvement or less symptoms. So probably we know only the tip of the iceberg.

Vanessa van der Linden: This is the first paper that described the pattern of the brain images, especially the pattern of cortical malformation and the calcifications. But we are talking about the clinical aspects of the disease.

Vanessa van der Linden: So firstly, the appearance of the patients at birth. They present with some dysmorphic features that we call fetal brain disruption sequencing. Characterized by craniofacial disproportion, head scalp skin, and occipital bone prominence that is possible to see in half of patients. In 50% of the patients.

Vanessa van der Linden: This pattern of sequencing was described before Congenital Zika Virus, but it was very rare. Only before Congenital Zika Virus had the only 20 cases in the early data, and it becomes more frequent related with Congenital Zika Syndrome.

Vanessa van der Linden: The epilepsy is one of the most problem, especially for pediatric neurologists that follow up the patients with Zika, because the prevalence is too high. We published the first paper about the epilepsy in the Congenital Zika Syndrome to describe the first years of the patients. The prevalence of epilepsy was very high. If you compare with other causes of cerebral palsy, the prevalence of epilepsy in the first quarter, for the first years of life was 60% of patients. Most of paper talking about 30% to 40% of patients of cerebral palsy could present epilepsy. So in Congenital Zika Virus it's higher. In most of them, the beginning of the seizures were in the first months of life.

Vanessa van der Linden: The typical pattern of the patients, the EEG pattern was multifocal epileptic discharge and focal epileptic discharge. Focal was more frequent, and less frequent generalized discharge in each side was only in a few cases. Even with the pattern of seizures characterized by spasms in clusters.

Vanessa van der Linden: We reanalyze the patients at two years of age, and the prevalence was higher. Around 80% of patients. And we publish this paper last year, to analyze the follow-up, the pattern at four years of age that evolved to continuous epilepsy discharge, there is a link. Sometimes symmetrical, sometimes asymmetrical with the predominance in one hemisphere. We analyze 55 patients. Their prevalence of epilepsy was more than 90% of patients. Very, very high. Higher than before. In 40% of patients present this pattern of continuous or almost continuous spikes or sharp wave during their sleep, activated by their sleep. In the core, more than 85% of record.

Vanessa van der Linden: The symmetrical distribution occurring in most of the patients, around eight percent of patients, CMV less than 20% was predominant in one hemisphere.

Vanessa van der Linden: So epilepsy is a big problem for pediatric neurologists or pediatricians that care and follow-up the patients of Congenital Zika Syndrome, because most of them have hypsarrhythmic epilepsy. I find only a few papers that describe the epilepsy in another congenital infections. Some papers show that in CMV the prevalence of the epilepsy ranges to 10% to 50% of the cases. This paper brings the prevalence of 37%. In this paper, the typical pattern, the more frequent pattern of EEG was multifocal discharges similar to the patients to the first paper that we publish in the first years of life of patients with Congenital Zika Virus.

Vanessa van der Linden: Other big problems in patients with Congenital Zika Virus is the motor functions. All my patients, I can't say that all patients with Congenital Zika Virus Syndrome will something of motor involvement, but all of my patients, 100% of my patients present some degree of motor function involvement.

Vanessa van der Linden: This is a paper that correlated Congenital Zika Syndrome with cerebral palsy. For high frequency or 100% of patients, like my patients, present some degree of spasticity.

Vanessa van der Linden: At two years of age, we decided to analyze the patients with scale, GMFM, to understand better the level or the motor involvement of my patients with Congenital Zika Syndrome. This is a graph that we can analyze the GMFM correlated with the level of cerebral palsy. So when the patient match 20, the level of cerebral palsy is level five, when the patient doesn't have the head control. Level 5 doesn't have level control.

Vanessa van der Linden: So if we understand a little about the GMFM and understand this graph, it's possible to understand that the patients with ... my patients have severe motor involvement, because the model of the punctuation of GMFM was one. Most of the patients more to 81. And the median was four, and we have only seven percent of patients that match 20% or over. Over that 20% means there's a scale. So most of the patients are too severe.

Vanessa van der Linden: I have only two patients with independent gait, and two patients with better cognition that it was possible to analyze better including with tests, and we are going to proceed with these tests now at five years of age. And six patients that it was possible to make diagnosis of autism disorders.

Vanessa van der Linden: This is a paper that also correlated one of the most important features of patients with Congenital Zika Virus, motor abnormalities and epilepsy.

Vanessa van der Linden: Most of the patients presented pyramidal signs. 100% of the patients, but we have some patients with important involvement of extrapyramidal symptoms with dystonic posture, especially in the upper limbs. But we have also mild cases like this patient. She has cerebral palsy but also associated with cognitive disability and he was classified like cerebral palsy diplegia spasticity with predominance of left side.

Vanessa van der Linden: But we have also patients with a good cognitive profile, without cognitive disability. Now we are going to proceed with neurological with scales to analyze the cognitive of these patients. But this patient, she has good cognitive development but with more disability. More important, he has a pattern of diplegic spastic cerebral palsy.

Vanessa van der Linden: Three of my patients underwent selective dorsal rhizotomy, because we try medications to improve the spasticity without success, especially in the upper limbs, and then we decided to indicate the rhizotomy. Until now, we have a good response. So this is the patients before the rhizotomy. And here after surgery. The importance to reduce the spasticity is to reduce the comorbidity in mobility, because most of these patients evolve to orthopedic deformity during their life. Sometimes are necessary to proceed with a lot of orthopedic surgery, and if we can reduce the spasticity we can reduce the need of surgery in the future.

Vanessa van der Linden: Dysphagia is another point, but related also with motor involvement, motor involvement of oral motor function. And there we have a higher prevalence of dysphagia in our first analysis at two years of age. We found 92% of patients with some degree of dysphagia, and most of them, 60% of them had severe dysphagia, and at that time, 90 patients had tube feeding or gastrostomy. We started to analyze the patients now at five years of age. I analyzed 43 patients and then 41 patients had gastrostomy. So the need of gastrostomy increased in the last three years.

Vanessa van der Linden: Autism was possible to associate with these patients in five percent. It's more than the general population that is around one to two percent of the population. There is some paper that describe this possibility.

Vanessa van der Linden: But it is difficult to analyze it, probably if the patients didn't have so severe motor involvement or eye involvement or cognitive involvement, because some patients it's not possible to analyze the motor and cognitive impairment. Around 70% patients had no eye contact or poor eye contact with severe motor and cognitive involvement. And you have only around 30% of the patients with better eye contact and it was possible to assess the cognitive and behavior of these patients, and was possible to make the diagnosis of autism in these six patients.

Vanessa van der Linden: Congenital Zika Syndrome was also associated with arthrogryposis. It's interesting because before Zika Virus we don't listen a lot about arthrogryposis in congenital infections. We found one or other papers with case reports, but it's not usual to see this description, but it was very frequent in the beginning, and now around 10% of patients presented arthrogryposis.

Vanessa van der Linden: We published the first paper about this. In this paper we described the involvement motor neurons, so we believe that including the MRI it's possible to see the reduction of the anterior horn and the reduction, the spine. We proceed with electromyography analysis in that confirmed the involvement of lower motor neuron. So, if we know about the physiopathology and the tropism of the virus by the progenitor neuronal cells, it's clear that the virus infects the progenitor neuronal cells that will immigrate to form the upper motor neuron and lower motor neuron. So because of that some patients have also involvement of spine, and most of them could present symptoms of arthrogryposis.

Vanessa van der Linden: Patients with arthrogryposis could have involvement of the thorax and some of them have had thoracic deformities with respiratory problems. Including some patients with involvement of the diaphragm with diaphragmatic paralysis. Usually for the patient to be alive unilateral not bilateral.

Vanessa van der Linden: The cause of diaphragmatic paralysis is for the same cause as arthrogryposis because of the involvement of motor neuron that go to invert the diaphragm.

Vanessa van der Linden: And most of these patients the presentation is like neurological disorders with hypoventilation. In some of them are necessary to use non-invasive ventilation because if it's not occur during the infections, they present more [inaudible 00:33:56] respiratory infections and a higher risk to need a tracheostomy.

Vanessa van der Linden: This is the paper that bring these datas about the pathology and show the involvement of the spine with the anterior horn. But I found only a few papers related other congenital infections with arthrogryposis. I find this paper correlated arthrogryposis with cytomegalovirus, but it's not clear the physiopathology of the arthrogryposis in CMV.

Vanessa van der Linden: Hydrocephaly was another surprise in patients with Congenital Zika Syndrome. It was prevalent in 16% of the patients. We publish a paper with the main pattern of hydrocephalus in these patients. 75% of the patients with hydrocephaly presented some degree or some involvement of cerebellum or brainstem hypoplasia of cerebellum or brainstem. So probably the malformation of posterior fossa are related with the evolution for hydrocephaly.

Vanessa van der Linden: But not all patients has an abnormal posterior fossa. We have some patients with normal brainstem and cerebellum. But most of the patients has communicating hydrocephaly not obstruction. Different from patients with toxoplasmosis.

Vanessa van der Linden: Hydrocephalus in toxoplasmosis very frequent. This paper brings the prevalence of 31% of patients, but different for patients of Congenital Zika Syndrome in the hydrocephalus is secondary to aqueductal or foraminal obstruction, we related it to inflammation, to inflammatory processes. But I have also some patients with communicating hydrocephalus.

Vanessa van der Linden: I'd like to thank you, and I'd like to thank my group. I work with a big team in Recife. It's impossible to make this work without a team. And also with other doctors from other states including my brother, Hélio van der Linden, that we work together, collaborate with to understand better this disease. And, of course, I'd like to thank my patients and their families that become possible to do this work. And thank you for your attention.

Biju Hameed: Fantastic. Thanks very much, Dr Vanessa for that talk. It's so fascinating to see how more information that's coming in recent years on the longterm prognosis and management. There are quite a number of questions, mostly related to Zika and CMV. If you could take the Zika first. So, some of the questions are ... So, as you said, it comes in epidemics. Then you suddenly have loads and loads of infections and suddenly, as you said, in the last two years, you haven't seen any. What is the reason for this tremendous drop in congenital Zika infections? This was a question from Manjit Walia from India.

Vanessa van der Linden: Probably related with the immunity. Since the beginning when we don't have relation with microcephaly, Zika were the same. There is a lot of cases and then the dissemination is too fast, and most of the people of the regions have the disease at the same time. And then most of them have immunity and like disappear, or we have only some cases for the people that don't have infections during that time. With the microcephaly it's the same. Most of the people of my city now probably have immunity. Regard to the microcephaly in congenital infection, we see that only 15% of the mothers that have Zika, confirmed Zika, only 15% of the babies will have the disease. Most of them, the mother had the disease. So we need a lot of cases at the same time to have the number that we had during the outbreak.

Vanessa van der Linden: Okay, so we are not sure about everything, but probably it's related with the immunity and the way that the virus has spread fast in the region.

Biju Hameed: And that aspect, what is the prospects completely eradicating the condition? What is the prospect for making Zika disappear altogether?

Vanessa van der Linden: We don't know. Here in my city ... I don't work with epidemiology, I work only with the babies with Congenital Zika Syndrome, and especially with the babies with the disease, because there are some other researchers and doctors that work with the babies that follow up the babies that the mother has Zika, they have IgM positive in the beginning, and the baby are asymptomatic. So I don't follow up this kind of patient. Because of that there is a different, maybe depending on the cohort, we are going to have different symptoms and different presentation of the symptoms of the babies.

Vanessa van der Linden: In my city, I analyze all the new cases. All the new cases, they make an appointment with me and I follow up this baby until confirmed or not confirmed. We have some suspected cases in the last two years, but in the last two years we didn't confirm one case. So we have since 2020 we don't have a confirmed case in my city. And probably we still have Zika in adults, confirmed here in Recife, but probably we need to have a lot of cases to have one baby with microcephaly, because probably most of the babies born without symptoms, even with the mother that had Zika during the pregnancy. But we are not sure about all the questions related with this.

Biju Hameed: was one of the questions of Dr Malinee from Malaysia, how long after Zika?

Vanessa van der Linden: I don't understand.

Biju Hameed: How long do the antibodies remain in the blood?

Vanessa van der Linden: We analyze some patients because the antibodies more positive IgM in babies in CSF. So we analyze some patients in the first month of life, the correlations between CSF and sample of the blood is the same, is similar, but after one month, after 30 days of life, the positive of serum of blood decrease a lot, and in most of the patients we only find positive IgM in the CSF. So it's difficult because it's not possible to collect CSF by the life the patients and to try to understand how long it will be positive. I have the experience with the babies that had hydrocephaly. We had a lot of cases, about 10% of the patients had hydrocephaly, and we analyze the CSF of these patients because we collect it during the surgery.

Vanessa van der Linden: So we have only one of my patients that were negative IgM in CSF. Even at two years of age, the last one was not in two years, the last was at 18 months of age that we collected. We have one patient that the diagnosis in this surgery was at two years of age, was our last patient that develop the hydrocephaly. But we analyze all the patients, and I think that three or four patients at 18 months of age and IgM continues positive. So probably in CSF if you have some patients after two or three months of age, it's better to collect the CSF to analyze to IgM for Zika.

Vanessa van der Linden: Four patients are [crosstalk 00:44:08] regard the IgG, it's difficult because in epidemic area, the baby can have Zika after that, and there is the antibody of the mother. So we proceed with PRND to analyze and to exclude the IgG of the mother. And we need to do this after one year of age to exclude the mother's antibody and to analyze. But it's not the best way to give the diagnosis, because like CMV, the baby could have Zika after birth, so it's not possible to confirm 100% that this IgG is related with the congenital infection or other infection.

Biju Hameed: That's true, yeah. In fact, there were questions about diagnosing Zika in late childhood. When you are faced with the child with microcephaly and you haven't got an answer from genetics or else.

Vanessa van der Linden: We have some patients that starts to follow up with me after five months of age and a half percent of the patients remains ... the pattern of brain MRI and brain in the CT scan it's not possible to confirm 100% that it's Zika but for me it's different from CMV, the calcifications in cortical area. And so sometimes the pattern of CT scan and the MRI can show, then we can confirm the diagnosis but not to confirm it probably the diagnosis. But we have a lot of patients that even after five months of age, the IgM was positive in CSF, not in blood, but in CSF.

Biju Hameed: But also it is quite possible that you could have just microcephaly and no calcifications, isn't it?

Vanessa van der Linden: In my cases not. We have some paper that analyze all the babies that were born during the outbreak, and some papers describe the microcephaly without abnormal MRI and CT scan. For me it's not possible to confirm, because we have a lot of patients asymptomatic for Zika and they can have microcephaly for other cause, like other perinatal problems. So for me, I don't know if it's possible. I'm not sure about that. But it's difficult. When you think about Zika, the virus infects the progenitor neuronal cells. So because of that, the main problem with Zika is the malformation of cortical development. Because of that we have the high prevalence of epilepsy, because the problem is in a neuron. And for me it's difficult to understand only the reduction of neuronal proliferation without abnormal migration. I don't know if it's possible.

Vanessa van der Linden: So we have microcephaly for other causes. We need to analyze better these patients, but I'm not sure if there is case of Congenital Zika Syndrome only with microcephaly without other aspects of the disease. It's my opinion, it's not-

Biju Hameed: That's interesting, yeah. So the fact that the neural progenitor cells are affected involving the migrational abnormalities, and it makes sense with the incidence of epilepsy in these children as well, isn't it?

Biju Hameed: We were talking about this earlier today, but in terms of the management of epilepsy, you said it was difficult to treat epilepsy that these children have, and you were talking about your experience with Cannabidiol. Would you be able to elaborate it on further, about your experience with Cannabidiol?

Vanessa van der Linden: For me, I follow up around 100 patients with Congenital Zika Syndrome. And the worst for me is the epilepsy. The prevalence is too high. Most of them now are evolved to spike wave continuous. For me it was a surprise. It's different. It's similar when I saw the EEG of 10 patients is very similar, but we have some patients with a bad EEG, but we found without the seizures. And we have babies that the EEG is not so bad and the seizure is too severe.

Vanessa van der Linden: So most of the patients need more than two or three drugs to try to control. I talk a lot with the mothers and sometimes when the baby have only, the baby not the kids because they are grown, have only one or two seizures during the day or during the week, and it's not interfere with their life. I stopped trying new medications, so we need to ... it's similar with the other encephalopathies with epilepsy. In the beginning the best response for most of the patients with levetiracetam. In Brazil, we only have had levetiracetam after 2015, and the levetiracetam arrives in Brazil at the time of the outbreak of Zika, it was great. We have some patients with a good response to valproate. But we have a lot of patients that you try a lot of drugs without response, and in some them I try Cannabidiol, and they have a good response. But they improve with Cannabidiol but was not possible to reduce the other drugs. So even with Cannabidiol, I need to maintain the other drugs.

Vanessa van der Linden: I try also ketogenic diet for some patients, but it was not good for my patients. I don't have success for improvement of the seizures. But we have around three or four patients that only reduce or control the seizures after Cannabidiol. With the doses similar that we saw in the papers, between three and 10 milligrams per kilo per day.

Biju Hameed: And just like in CMV, in terms of the malformations that you see. Obviously, it depends on what trimester the infection has happened, isn't it? That's true in Zika as well?

Vanessa van der Linden: Yes. Every baby that ... because sometimes it's very similar. I said to you in the beginning, last year I had a case that I swear this is Zika because it's similar, the baby has arthrogryposis and never seen before in my experience babies with CMV and arthrogryposis. Most of the patients with congenital infections, pattern of congenital infections in brain MRI or in brain CT scan, we confirmed Zika for patients with arthrogryposis. But last year, I saw one baby with arthrogryposis in Zika, in CMV, sorry, in CMV. But sometimes the pattern of CT scans is very difficult to differentiate between Zika and CMV, and always when you think about CMV we need to test Zika, and when you think about Zika we need to test CMV.

Vanessa van der Linden: I think the disease is more closer and more similar to Zika. And, of course, because we have ... we normalize a lot of cases at the same time, it's better to understand the epilepsy in these patients. I look for a paper that talking about epilepsy in CMV, we don't have a lot of information about the follow up of CMV and epilepsy. But I have some patients with CMV and the pattern of EEG in the beginning, I don't see the pattern of continuous spike wave during the sleeping patients with CMV. But the pattern in the beginning with multifocal discharge, I don't see a lot of patients with hypsarrhythmic pattern in CMV and Zika. So are similar. But we don't have a lot of studies about epilepsy in CMV.

Biju Hameed: Absolutely. I was quite surprised by that slide, because one would have thought that there would be hundreds of papers on that, given how common. Which is one of the most different aspects of management in these children, but very few papers like you said.

Biju Hameed: And also same thing with motor disability as well, isn't it? And it is mainly spasticity that you see, and not much dystonia. Even though basal ganglia could be involved.

Vanessa van der Linden: Yes. In the beginning, now I think differently than two years ago. In the beginning I saw a lot of pattern of movement in the beginning of the life of these patients that looked like dystonia. Included, I talk a lot in my presentations, that sometimes in the first two months of life it's not usual to see a motor pattern of dystonia, but they have movement similar to dystonia. I don't know if it was because the persistence of the archaical reflex, so they asymmetric posturing. But now after some years, the spasticity is more important than dystonia.

Vanessa van der Linden: They have a mix. Most of the patients have also dystonia and dispasticity, but now the spasticity, I think that's more important than dystonia. Especially in the lower limbs. The problem with is because the [autopathic 00:54:55] problems the prevalence is too high. A lot of patients evolved to hip dysplasia and to hip subluxation, I forgot the name in English, but-

Biju Hameed: Subluxation.

Vanessa van der Linden: So, the problem with these patients in the beginning, the most problem with these patients is the irritability, then epilepsy, probably the irritability is related with epilepsy because maybe in the beginning it was not easy to understand that the irritability was probably because of the epilepsy. But now we have the two big problem with these patients, is epilepsy and also the motor involvement with the orthopedic problems. And I am showed in my talk, we proceeded with rhizotomy in two patients and I like the result, but it was in the last two months. It's too early to understand better the result of this. And we only indicate rhizotomy for the patients with only the presence of spasticity, not with dystonia, because they can worst a lot when the dystonia is most important in the pictures of the patient.

Biju Hameed: And, of course, you mentioned the dysphagia as well, isn't it? All these children seem to have dysphagia as well, and ending up in gastrostomy.

Vanessa van der Linden: Like epilepsy, dysphagia is the same. I started analyze of the patients with five years of age, and every year we increase the number of patients that underwent gastrostomy, because of the weight or because of the respiratory problems.

Biju Hameed: There was a question earlier. In terms of the subacute worsening of the infection by another virus, have you ever come across a double hit? Somebody who is having both CMV and Zika? Or is that not possible?

Vanessa van der Linden: Yes. I had two patients that was positive for CMV and for Zika. In all patients, the pictures of the brain images is typical of Zika. In another patient, it was mixed. The patient has periventricular calcifications, the cystic area in the white matter, but also the pattern of calcifications in cortical area. So when I look to the CT scan of these patients, I said, oh there is something that looks like CMV, and the baby was positive for CMV and also for Zika. Both patients didn't present hearing loss. That is very frequent in patients with CMV. Because different from Zika, most of the patients with microcephaly in Zika have motor disability as a main problem, but the patients with CMV, sometimes we can see microcephaly with mental retardation in terms of ability, but the motor involvement's not so important. And we have a lot of patients only with deafness and different from Zika. But we have two patients that was positive for both, and there is difficult to understand if the problem was Zika or CMV.

Biju Hameed: Interesting. There's a question from one of my colleagues, Sunil Pullaperuma from London. So obviously with the CMV we have now antiviral drugs which we use. What's the current situation with Zika and antiviral drugs?

Vanessa van der Linden: For drugs specifically for Zika, we don't have. Only symptomatic treatment. We don't have. Even in the pregnancy or after the birth. In Zika, it's different from CMV. We analyze the patients, follow up is around five years, and it's not progressive like CMV that we can we have surprises after some years, of like deafness that could occur after the birth. Zika doesn't look like a disease that will be progressive. I think that baby born with the sequelae, like a scar, but not progressive.

Biju Hameed: Someone had asked that question. Is there any chance that Zika could be a progressive illness? So the answer is no.

Vanessa van der Linden: No. My opinion. There is another question about asymptomatic patients that could present disability to learning. I don't know. I think that it's a possibility. We have a lot of cases at the same time. It's easy to make a diagnosis of Zika in patients with microcephaly, but there is a group of doctors or researchers that follow up babies that are born from mothers with confirmed Zika during the pregnancy. And they will follow up these patients until the time that it was possible to analyze the learning disability. But I don't have patients with this pattern. I'm not part of this group of the follow up of these babies. And I think that we don't have response for this question yet. Maybe in some years we are going to understand better.

Vanessa van der Linden: And it's difficult because autism. A lot of people and mothers ask me about autism for the babies that was born at that time, but autism is so prevalent that it's difficult to-

Biju Hameed: Make the connection. Yeah, true.

Vanessa van der Linden: It's difficult if they after two or three years of age with normal brain image. When the mothers refer to have Zika in the pregnancy without diagnosis or with the diagnosis, usually I don't use brain images for babies that have only autism, but in these cases, I prefer to ask for the brain images for these patients. But I never saw patients with only autism or only learning disabilities with abnormal brain image. So it's difficult to understand this, and to have this connection. The connection between this.

Biju Hameed: I know, I've got a patient as well. Mum, when she was pregnant had spent some time in Brazil and then moved to London, and the girl's got microcephaly, just microcephaly, and she's adamant that it is because of Zika. It's interesting. So much we have learned and yet there is more to learn. If you've got time for just a couple of more questions, Vanessa. One of my friends, Dr Narayan Saha from Bangladesh has got a question on CMV, about diagnosing CMV in later childhood. I think Dr Saha mentioned one and a half years of age. What would be your approach in terms of diagnosing CMV in retrospect?

Vanessa van der Linden: We can make the diagnosis, because of the brain image correlated with the ... we know that CMV remains positive in urine and in serum by more than one year. And we need to correlate the symptoms [crosstalk 01:03:08], but for have sure about the CMV we need to proceed with the exams in the first month, or at least the first three months of age of the patients.

Biju Hameed: That's really early.

Vanessa van der Linden: And the treatment ... I'm not infectiologist, but the treatment for CMV, the best I saw-

Biju Hameed: It was a question of optimal age of starting valganciclovir in baby with CMV.

Vanessa van der Linden: We only treat the symptomatic patients. The asymptomatic patients we follow up until 10 years of age because of the deafness problem. But we only treat when it has some symptoms, even in the lab, not necessarily with the symptoms signs, but symptoms in the exams of the lab. But the better time is in the first months of age, especially in the first two weeks of age, to reduce the risk for develop the consequence of CMV.

Biju Hameed: Fantastic. Thanks very much, Vanessa. Now, as we were talking earlier, there is currently an outbreak in South India, in Kerala, a small outbreak, and I'm sure there are quite a few physicians from there in the group, in the audience today. And I'm sure they would be happy to get in touch with you if any questions. It's happening now. There is a current outbreak of Zika in Kerala.

Vanessa van der Linden: Now, after five years, it's easy to say that there are different phases to follow up the patients with Zika. In the beginning, it's the irritability and the swallow problems, and we don't know about this in that time, about the epilepsy, and a lot of the patients that started with the irritability and just try other treatment, now we know that it was epilepsy. And now another phase is the patients are calm without irritability, but epilepsy is my big problem with these patients and also the cerebral palsy of these patients.

Biju Hameed: Fantastic. I'm really sorry we went over by 10 minutes. I'm really sorry for keeping you this long, but fantastic. Thanks very much, Vanessa. Thank you.

Vanessa van der Linden: Thank you.

Biju Hameed: And thanks everyone for joining in today. And in three weeks time in August 14th we have another session. And this is a debate style session on dietary therapies in epilepsy. So until then, see you.

Vanessa van der Linden: See you, bye.

Biju Hameed: Bye.