Review of Long -term Health Implications of Congenital Rubella Syndrome
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- Bu səhifədəki naviqasiya:
- 1.0 Congenital Rubella Syndrome
- 4.0 Late Manifestations of Congenital Rubella Syndrome.
- 4.1 Overview of Australian, American and Canadian Projects before 2000
- 4.1.4 Canadian Study
- 5.0 Other Studies
- 5.2 Japan
- 5.3 Oman
- 5.4 Denmark
- 5.5 The Netherlands
Literature Review of Long –Term Health Implications of Congenital Rubella Syndrome Susannah Barnett 1.0 Congenital Rubella SyndromeRubella infection was first recorded in the mid Eighteenth Century by Henry Veale although at the time the condition was referred to by its German name of ‘Rotheln’ (Veale, 1866; Miller, 1991). Whilst rarely a serious infection in children and adults, it is now well known to have potentially devastating consequences on the developing embryo if contracted by pregnant women in the early stages of pregnancy. Gregg (1941) an Australian Ophthalmologist, first identified the evidence of pregnant mothers with rubella transmitting congenital defects to their new born infants. Initially high incidences of cataracts were noted where mothers had contracted rubella during the first trimester of pregnancy (Forrest et al, 2002). Gregg’s early observations included the fact that low birth weight was also a common feature of affected infants (Gregg, 1941). After Gregg, others began to observe additional defects seen as resulting from in-vitro rubella infection. South and Sever (1985) used the term ‘Congenital Rubella Syndrome’ to denote a combination of cardiac, ocular and hearing defects. Others, for example Swan et al (1946),suggested that additional defects such as deafness, low birth weight and failure to thrive, and signs of meningitis with central nervous system damage, should be added to the list of effects caused by the rubella virus (Swan et al 1946). Duszak (2009) discusses an unusual pigmentary retinopathy, termed salt and pepper retinopathy, that was first identified by Gregg (1941) and also reports failure to thrive as being associated with exposure. More recent descriptions of Congenital Rubella Syndrome (CRS) also list congenital anomalies such as micropthalmia, transient corneal clouding, Patent Ductus Arteriosus (PDA), mental retardation, low birth weight and feeding difficulties (Armstrong and O’Donnell 2004). Whilst foetal infection can occur at any stage of pregnancy, Duszak (2009) describes the rubella virus as infecting and replicating in the placenta and he argues that the outcome of foetal infection is dependent on the gestational timing of the maternal rubella as the risk of foetal infection varies according to the time of onset of maternal infection. Miller (1991) reports that infection rates of infants are highest during the 1st trimester (81% overall with 100% infection rate in weeks 1 – 10) declining to a minimum of 25% at the end of the 2nd trimester, and rising back to 100% in the last month. However it is important to note that even though a mother might become infected with the rubella virus this does not automatically assume defects in the infant will occur (Frij, South & Saver 1988).The widely accepted relationship between gestational age at the time of rubella in pregnancy and clinical manifestations of CRS is shown below.
Certain neurological deficits are also widely associated with CRS. These include difficulty in shifting task, sudden shifts in mood, over reaction to minor stimuli, repetition or prolongation of a particular act (O’ Donnell, 1995, Vernon 1967, O'Dea and Mayhall 1988, Munroe, 1999, Desmond et al 1978, Nicholas 2000). These types of behavioural disturbance observed in individuals with CRS are considered to be associated with frontal lobe brain damage (Gardner, 1994). Nicholas (2000) found abnormalities in cerebral blood cells, as well as retardation in the myelinisation process within the brain (Rorke & Spiro (1967) in Armstrong & O’Donnell 2004). Autistic-like behaviour is often reported in children with CRS (Chess 1977) but according to Van Dijk (1991) there is no biologically conditioned link between rubella and autism. The ritualistic behaviours demonstrated by children with CRS are not manifestations of autism he argues, but rather a consequence of sensory deprivation (Van Dijk, 1982). The World Health Organisation (2003) divides cases of CRS into 4 categories:
Cataract; diminished vision; Nystagmus, squint, Microphthalmos, Congenital Glaucoma;
2. Clinically Confirmed CRS Where a qualified physician detects two or more of the complications in section A or one from section A and one from section B below: A: Cataracts, Congenital Glaucoma, Congenital Heart Disease, Hearing Impairment, Pigmentary Retinopathy B: Purpura (rash), Splenomegaly, Mental retardation, Meningoencephalitis, radiolucent bone disease, jaundice with onset within 24hrs after birth.
2.0 Epidemiology of CRSThe rubella virus itself was identified in 1962, by two groups of independent investigators, one in Boston, Massachusetts, and the other in Washington, DC. (Armstrong & O’Donnell, 2004, Banatvala & Brown, 2004). Since the discovery of the rubella virus epidemics have occurred at six to nine year intervals and major pandemics have occurred every ten to thirty years. The last major worldwide pandemic occurred in 1963-64, in the United States, Canada and Europe, with significant impact on the UK. Further severe epidemics occurred in the UK in 1978, 1979, 1983 (Banatvala & Brown, 2004). It is estimated that 30,000 babies were born in the USA with rubella damage in the1964 epidemic (Cooper, 1985). The actual total number of affected infants born in the U.K. is unknown but before the rubella vaccine was introduced for schoolgirls in 1970, about 200-300 babies were born with congenital rubella defects annually in England and Wales, with many more in the epidemic years (Tookey, 1999). Although the frequency of CRS reduced in the developed world after the introduction of immunization, the current study does not focus on immunization issues. Even though the incidence has reduced, individuals who were exposed to the virus before immunisation are facing ongoing health compromise. It is also important to note that as a result of the lack of total vaccination across the globe, the rubella virus is still in circulation and the World Health Organization records that there are still more than 100,000 confirmed cases each year (Banatvala & Brown, 2004). Rubella epidemics are still prevalent in the developing world and Duszak (2009) estimates that 238,000 children worldwide are born with CRS worldwide, mostly in developing countries. Some small localised epidemics are also evidenced within specific communities. In America during the 1990’s, mini-outbreaks of rubella were documented in California, in the Amish Community, and at a meat packing plant in Iowa. These cases have occurred in populations that have not routinely received rubella vaccines (Armstrong & O’Donnell, 2004). 3.0 PathogenesisIn the 1940’s Gregg’s work was considered revolutionary as at that time the placenta was considered an absolute barrier to infectious agents. Gregg’s observations were the first record of the teratogenic effect of a viral infection. The significance of rubella derives from its teratogenic origins. Rubella is a togavirus of the genus Rubivirus (Duszak 2009). The mechanisms by which the rubella virus causes fetal damage are not however fully understood (South & Sever, 1985; Frij, South & Sever, 1988; Cherry (ed) 1981; Reye 1974) but it is thought that the virus embeds itself in internal organs and is therefore able to colonise areas of the body for much longer than a virus that is easily shed. Before the development of the maternal immune response, the virus spreads through the mother’s bloodstream and may affect multiple tissues, including the placenta. As a result of placental damage, the virus can then cross the placenta to the foetus. Once the placenta has been infected, the foetus undergoes cellular deficiencies that cause disturbances of organogenesis during the critical first 12 weeks of development. During the 2nd trimester onwards infection in the placenta is thought to carry a lower risk of fetal damage. Duszak (2009) goes on to describe the manifestations of Congenital Rubella Syndrome that result from tissue destruction and scarring. This may occur from viral persistence as developing immune system mechanisms such as autoimmunity may not be sufficient to cope with rubella, resulting in defective cytotoxic cell function. Armstrong and O’Donnell (2004) likewise offer a description of how the virus results in such ongoing damage. Firstly, the virus reduces cell division in the developing embryo or foetus, resulting in incomplete, delayed, or defective growth in major organs. An attack during the critical first trimester of development can therefore affect virtually every developing organ. Secondly, blood vessels that routinely carry oxygen are frequently obliterated causing vast hypoxic damage. Chromosomal injury and ongoing cellular destruction are also common phenomena. Rubella-specific immune complexes caused by the rubella virus may manifest as one of several immune-mediated conditions, including seizures, thyroid dysfunction, glaucoma and Type 2 diabetes mellitus. These conditions are commonly known as the ‘Late Manifestations of Congenital Rubella Syndrome’ (Armstrong & O’Donnell, 2004). Banatvala and Brown (2004) similarly describe foetal damage as being multifactorial - a combination of virus-induced cellular damage and the effect of the virus on dividing cells. In the UK, Best (2009) studied a cohort of 307 infants born to mothers between 1976 and1989. Congenital defects occurred in 85% of cases infected during the first weeks of pregnancy, with multiple defects most likely to occur in those infected in the first 8 weeks. After 12 weeks gestation, the risk to the foetus declines rapidly, with only rare cases of deafness reported from exposure at 17-18 weeks gestation. Best’s findings are summarized in the following table. Risk of congenital infection and congenital defects after maternal rubella at successive stages of pregnancy
Spontaneous abortion may occur may occur in up to 20% of cases where rubella occurs in the first 8 weeks of pregnancy (Best 2009). Accurate clinical diagnosis of CRS is based on the detection of rubella-specific immunoglobulin IgM and IgG after maternal antibodies have declined. However rubella-specific IgM is generally lost in infants with CRS by six months of age. (Vijayalakshmi et al 2007). It is likely that some of the current sample may therefore be people who do not ‘fit’ the WHO classification of CRS or who at the time of their birth were not given a laboratory tested confirmation of CRS.
The concept of 'late manifestations’ of congenital rubella syndrome was first used by South & Sever (1985). It was intended to denote the appearance of additional defects not present at birth, or damage that continued after birth with the degeneration of faculties, or the emergence of fresh difficulties at later stages of development. 'Late emerging difficulties' or ‘delayed manifestations’ and other similar terms are also used by researchers. However some caution should be attached to these terms as there is no clear definition as to what is meant by 'late'. Some researchers report 'late’ manifestations as defects occurring in the months immediately following birth (Merth et al (1987) in Munroe 1999) whilst others focus on difficulties that emerge in adolescence and adulthood (Desmond et al 1985). It is also the case that some features of the normal development of a child would not be expected to be clinically observed or diagnosed in a newborn so delays in such developments would not be evident in the first few months. Best (2009) describes congenital rubella syndrome as a progressive disease due to persistent virus infection and defects in the infant’s immune response. Existing manifestations, such as deafness and CNS disease, may progress and some abnormalities may not be detected until the second year of life or even later. These include hearing loss, visual loss, developmental delay, diabetes mellitus, behavioural and educational difficulties and progressive pan encephalitis (Best 2009). Duszak (2009) concludes that 'congenital rubella should be viewed as a chronic disease capable of producing ongoing vital organ damage throughout life’ (p39). He cites the ‘late-onset’ manifestations as being insulin-dependent diabetes (at 50 times the rate in the general population), thyroid dysfunction and a rare neurodegenerative disorder, pancephalitis. It is not clear however what age range is denoted by his use of the term ‘late-onset’.
The Sense study (2012) concerns itself with the experiences of people with congenital rubella syndrome within the U.K. Although Brown (1989) conducted an anecdotal study of the experiences of people with CRS, no subsequent work within the U.K. has been identified. The Sense study was therefore undertaken within the context of studies completed in other Western countries. There are significant differences in these studies, and these will be noted, however they provided the Sense study with a starting point. Research from Australia, America and Canada will be reviewed. The American and Canadian studies are particularly important in that they provide examples of the survey design which was adapted for the Sense study. Other smaller scale studies looking at the incidence of particular manifestations are also noted. In more recent years, other European countries such as Denmark and Norway have also undertaken research and each of these countries has attempted to look at the 'late manifestation' issue. (The Netherlands is also known to have undertaken research but no publication of the outcomes has been identified to date.) 4.1 Overview of Australian, American and Canadian Projects before 2000Research Comparisons
The three studies detailed above are clearly useful, but are not comparable in terms of sampling. It should also be noted that, particularly in the case of the American and Canadian research, responses were based on anecdotal evidence rather than medical evidence. However from other independent research (cited as comparisons below) some similarities and overlaps can be identified. 4.1.2 Australian StudyGregg’s (1941) original observations of the connection between the rubella virus, pregnancy and consequent effect of fetus development emerged from a very early group of affected infants born between 1939 -1944. His sample group was reviewed in 1967 and 1991 and of the original sample of 50 participants, 32 agreed to be involved again in 2000. The following table provides a summary of the 2000 review.
The Australian study was the first research that looked at CRS and its effects on people by identifying the early manifestations and following the same group to record what happened later. Research in other countries then followed. 4.1.3 American StudyThe American research led by O’Donnell at the Helen Keller National Centre (HKNC) was a response to concerns voiced by parents/care givers about long-term changes seen in individuals with CRS. The research was carried out in two phases: Phase 1: 1989 – 1990 (39 interviews by phone), Phase 2: 1990 – 1991 (large scale survey mailing – 88 people). This covered a much wider range of medical conditions than the initial Australian work. The results from the sample group are reported as is wider work achieved by others, which bears a relationship to the particular disorder in question.
92% of respondents had little or no hearing at time of survey and 1 person reported acquiring hearing loss at age 10. Other related research “Long term follow-up of these children indicates that almost all eventually show signs of some neurological damage, the most common being sensori- neural hearing loss, which approached 93% at seven to nine years of age” Waxham & Wolinsky 1994 (p.11) “… the hearing defect may become progressively worse after the first year of life. There have also been cases in which children with CRS, for whom audiograms and speech patterns are normal suddenly develop mild-to –profound sensor neural hearing loss. The latest age … is ten years” Sever, South and Shaver 1985 (p.8)
“Glaucoma with late onset was reported by Boger in 13 patients with CRS. The diagnosis was made when the patients were between 2 and 22 years of age…” (Sever, South and Shaver 1985) Cardiac Problems 52% of the respondents indicated the presence of a heart condition (Including Patent Ductus, Atrial or Ventral Septral Defects, Pulmonary Stenosus) Other Research “van Dijk, citing Menser, Dodds and Harley (1967), states that of 50 high functioning persons born with CRS in 1940, twenty-five years later – three were found with systemic arterial hypertension” (Van Dijk, 1990) Endocrine System Difficulties Diabetes 5 out of 88 respondents were diabetic (6%) and although this percentage is lower than that recorded by other studies, it is 20 times higher than the incidence of diabetes in the general population of the U.S. Other Research “The most frequent delayed manifestation of CRS is diabetes mellitus. Studies reported by Menser et al of patients from the rubella epidemic in 1941 in Sydney, Australia showed that 9 (20%) of 45 patients had overt or latent diabetes by the time they were35 years old. An additional nine had abnormal insulin response…. The high prevalence of diabetes in this small number of patients is remarkable, since diabetes develops in the general population in only 0.1% of individuals younger than 30 years of age.” (Sever, South and Shaver, 1985, p.166) ‘Research from the Maryland School for the Deaf (1980) and previous findings from Australia indicated that diabetes mellitus is starting to appear among rubella deaf teenagers at an alarming rate of 15 – 40%’. (Vernon, Grieve, Shaver 1980) “Hypothyroidism, hyperthyroidism, and thyroiditis have all been reported as delayed manifestations of CRS…. Thyroid dysfunction has been identified in 5% of patients with CRS in one study” (Sever, South and Shaver 1985, p167) Degenerative Conditions Detailed descriptions of changes occurring in individuals with CRS were given by some of the respondents: “Over the past four years (our son) has gradually lost his ability to walk, In the past year, he cannot stand by himself no walk at all without totally leaning on another… (He) was always very hyper…. He is also very aggressive. He still butts his head quite often and pinches if he is near us. We were recently told that (he) is on a down-hill slide and will eventually lose all control, including muscles; swallowing etc…The doctor does not know another patient with (this) condition. The doctor advised us to remodel our house to accommodate a wheelchair. Do you know how long the time between wheelchair and bed?” (O’Donnell, 1991) Another mother reported about her 26 year old daughter: “When (she) began her weight gain in 1982, almost overnight after being so thin since birth, I felt we had a problem. Along with this extreme weight gain, she began tantrums etc, her behaviour became so aggressive, and I could not handle her... Hirsuitism was also diagnosed. Ever since 1982, there has been one thing and then another. Diabetes was diagnosed 1988. Losing control of bowel and bladder (what appears to be faster ageing on inside than outside) Eyesight declining due to Congenital Glaucoma…. On the other side of the coin we have seen the most miraculous advancement in her mental abilities. This has been since 1988. It is almost scary sometimes because she has these conversations with you that are so adult and completely normal. (She) talks with wisdom and great reasoning” (O’Donnell, 1991) It is also recognized that there is a degenerative condition called Progressive Rubella Panencephalitis that is very rare and does not fit the descriptions above (Sever, South & Shaver, 1985). There have been only 9 well documented cases, so far only affecting males. In this condition neurological deterioration is seen between the ages of 8 & 19 years. Behaviours and seizures become apparent. The condition can affect all limbs and causes particular problems with walking and all known cases have been fatal. Esophageal / Gastrointestinal Difficulties Reports of gagging and vomiting were reported: “In the past year we have had some strange behaviours come and go with our daughter. Your late onset manifestations of CRS (document) was very insightful as (she) is definitely experiencing changes, whether physical or emotional is anyone’s guess. She has had some weight loss, a decrease in appetite with intermittent crying spells at times, and when crying she does a strange throat sound prior to this – then just sobs. During these times she gags violently as if to vomit but doesn’t. She has had most exams done – blood test, urine, complete dental checks under anesthesia and we have found no obvious physical ailment” (p.10) “The doctors are unable to determine the cause of her recurring vomiting (every 3 – 9 weeks for the past six years)” Behavioural difficulties The HKNC survey includes some details about the behaviour of people with CRS and whether this had changed over the past year in question. Behaviours such as Self-stimulization, tantrums, self-injury and aggression were all reported by the respondents but the general trend suggests that these behaviours decreased or remained the same over the year recorded. This is interesting because the concept of ‘late manifestations’, is usually associated with things getting worse – however some caution is attached to these results as there is no information on earlier changes or other things which have influenced behaviour change e.g. an individual may have moved house which consequently had an effect on his/her behaviour. Summary The American results may at first glance present a depressing picture of the long term experiences of this group of people however it is important to remember that almost a third of the sample group indicated no signs at all of any late emerging medical problems. There is also great variation in the number/ nature of late manifestations experienced. These ranged from a person who ‘only’ developed glaucoma to a person who had developed every known late manifestation on the list. Equally the probability of any one person developing a particular condition is unknown, as is the time frame in which these conditions emerge. As with each of the studies from respective countries, the CRS population will also be susceptible to the same illnesses as the general population. It is also recognized that people with CRS may have very significant changes in their medical condition, but may be very limited in the ways they can express these changes meaningfully and this may lead to under-identification of conditions that are in fact late manifestations.
4.1.4 Canadian Study
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