Journal of Pediatric Rehabilitation Medicine: An Interdisciplinary Approach 6 (2013) 241–244 DOI 10.3233/PRM-140258 IOS Press

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Severity of disability in patients with cerebral palsy secondary to symptomatic congenital cytomegalovirus encephalopathy Nathan A. Camerona, Mark E. Gormley Jr.a,b and Supreet Deshpandea,b,∗ a

Gillette Children’s Specialty Healthcare, St. Paul, MN, USA Deptartment of Physical Medicine and Rehabilitation, University of Minnesota School of Medicine, Minneapolis, MN, USA

b

Accepted 17 October 2013

Abstract. PURPOSE: Cytomegalovirus (CMV) is a leading cause of congenital encephalopathy and cerebral palsy (CP). In this study we report the severity of disability in individuals who developed CP secondary to symptomatic congenital CMV encephalopathy. METHODS: The medical records of patients with CP secondary to symptomatic congenital CMV encephalopathy diagnosed from 1995 to 2011 were retrospectively reviewed. Gross Motor Functional Classification Scale (GMFCS) level, language function, and swallowing function were collected. RESULTS: Twenty-three patients were found. Of those 23 patients, 83% (19/23) were at a GMFCS level IV or V, 9% (2/23) each GMFCS level II or III and none (0%) at GMFCS I. Eighteen patients were non-verbal, 3 had minimal to moderate verbal skills and 2 had no verbal impairment. Eighteen patients also had severe dysphagia requiring gastrostomy tube (GT) feedings, and 5 ate orally. There was a strong correlation between the severity of GMFCS and having a gastrostomy tube (p < 0.0006) and GMFCS and verbal skills (p < 0.0023). CONCLUSION: This study shows that patients with CP secondary to symptomatic congenital cytomegalovirus encephalopathy have a very high risk of having severe physical and cognitive disabilities. This information can help healthcare providers and caregivers plan for the potential long-term medical, rehabilitation, and financial needs of this group of patients. Keywords: Cerebral palsy, cytomegalovirus, encephalopathy, gross motor function classification system

1. Introduction Cytomegalovirus (CMV) is a herpes virus that infects one in 150 live-born children born in the United States [1]. Approximately 45% of the general population is seropositive for asymptomatic CMV [2]. However, approximately one in 750 live-born children, or 5,500 each year, is born with permanent disabilities from CMV [3]. ∗ Corresponding author: Supreet Deshpande, Gillette Children’s Specialty Healthcare 200 University Avenue East. St. Paul, MN 55101, USA. Tel.: +1 651 229 3819; Fax: +1 651 265 7443; E-mail: [email protected].

CMV is most commonly spread by close contact with the bodily fluids of a person who has the virus, which can be present in saliva, tears, semen, urine, cervical secretions, blood, and breast milk [4]. Once infected, a person usually harbors the virus in a dormant phase [5]. Congenital CMV infection occurs when a newly infected or previously infected pregnant mother transmits the virus to her fetus. Approximately 90% of newborns with congenital CMV infections are asymptomatic, of which only approximately 10% develop mild neurological deficits, mostly sensorineural hearing deficits [6]. Approximately 10% of infants with congenital CMV infections are symptomatic, and of these symptomatic patients 60–80%

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Table 1 Gender, GMFCS level, verbal skills, swallowing skills, and diagnostic criteria of patients with CP from symptomatic congenital CMV encephalopathy Gender Male Male Female Female Female Male Female Male Male Male Female Female Female Male Male Female Male Female Female Female Female Female Male*34wk

GMFCS 5 5 5 5 5 5 5 5 5 5 4 3 5 2 5 5 5 5 2 3 5 5 5

Speech development Non-verbal Non-verbal Non-verbal Non-verbal Non-verbal Single words rarely, non-verbal Non-verbal Non-verbal Non-verbal Non-verbal Minimally verbal Moderately verbal Non-verbal Verbal Verbal Non-verbal Non-verbal Non-verbal Verbal Minimally verbal Non-verbal Verbal Non-verbal

Trouble swallowing Gastrostomy Gastrostomy Gastrostomy Gastrostomy Pureed Gastrostomy Gastrostomy Gastrostomy Gastrostomy Gastrostomy Gastrostomy None Gastrostomy None Gastrostomy Gastrostomy Gastrostomy Gastrostomy None None Gastrostomy Gastrostomy Gastrostomy

Diagnosis Sero pos Sero pos Amnio pos Neonate dx Neonate dx Neonate dx Sero pos Igm pos, PCR pos Neonate dx Neonate dx Sero pos Igm, urine cx pos Neonate dx CMV cx pos Neonate dx CMV cx pos Intrautero CMV Intrautero CMV Neonate dx Intrautero CMV PCR pos Sero pos Igg pos, igm equivocal

CMV serologic titers positive: sero pos, Polymerase chain reaction for CMV DNA: PCR pos, Neonatal diagnosis; neonate dx, Amniocentesis culture positive: amnio pos, IgM titer positive: IgM pos, Urine culture positive: Urine cx pos, Intrauterine exposure to acute maternal CMV infection: intrautero CMV.

will develop encephalopathy, which can result in cerebral palsy (CP) [3,7,8]. Symptomatic congenital CMV infections usually only occur from viral transmissions from mothers with a primary CMV infection in the first trimester of pregnancy, not from a recurrent or reactivated CMV infection [9]. Although the frequency of encephalopathy or cerebral palsy in children with symptomatic congenital CMV infections has been reported, the severity of functional impairments in these children has not previously been reported. The purpose of this study is to report the severity of functional deficits in children with cerebral palsy secondary to symptomatic congenital CMV encephalopathy treated at our large pediatric rehabilitation hospital.

2. Patients and methods After IRB review and approval, the medical records of all patients with cerebral palsy secondary to congenital CMV encephalopathy treated at our specialty hospital for children with disabilities from 1995 to 2011 were retrospectively reviewed. All patients were diagnosed with cerebral palsy given their history of perinatal encephalopathy, MRI brain changes, and

physical deficits. Patients were diagnosed with symptomatic congenital CMV encephalopathy based on review of past medical records. Since many of these patients were diagnosed outside of our facility, laboratory records were not always available, so their summaries were instead obtained from the clinician’s notes. A summary of the best available data is included in Table 1. Many patients were diagnosed with congenital CMV in the neonatal period supported by strong documentation and clinical evidence. These patients were included in our study even if we could not locate documented laboratory studies. Patients whose documented laboratory studies could not be found but had strong documentation of a symptomatic congenital CMV encephalopathy diagnosis are classified as neonatal diagnoses in Table 1. All patients with a speculative or retrospectively presumed diagnosis of congenital CMV infection were excluded from this study. A diagnosis of congenital CMV was considered speculative if no positive laboratory results of CMV were found in the perinatal period, and documented clinical evidence was weak. Language function, swallowing function, and the level of gross motor disability were collected. Each patient’s gross motor disability was described using the Gross Motor Function Classification System

N.A. Cameron et al. / Severity of disability in patients with cerebral palsy secondary

(GMFCS) (see Table 1). A patient classified as a GMFCS level I walks without limitations; level II walks with limitations but without the use of assistive devices; level III walks using a hand-held device such as a walker or crutches; level IV has independent mobility using a manual or electric wheelchair; and level V is dependent on the assistance of others for their mobility [10]. The GMFCS level was determined by either the level reported in the clinical documentation or extrapolated from the gross motor function documented in the clinical notes. We excluded from the study patients without clearly documented gross motor functional skills. Verbal and swallowing functions were determined by parental and therapist report. Standardized reports were not used to determine the verbal and swallowing functions but were extrapolated from reading the notes and using best clinical judgment.

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Table 2 Severity of GMFCS in patients fed via gastrostomy feeding tubes (GT) versus orally GMFCS GMFCS vs. GT feeds GT No GT

I, II, III

IV, V

0 4

18 1

Table 3 Severity of GMFCS (gross motor function classification system level) compared based on the patients’ observed verbal skills GMFCS I, II, III IV, V GMFCS vs. verbal skills  minimally verbal  moderately verbal

1 3

19 0

3. Results Twenty-three patients (13 female, 10 male) with a diagnosis of cerebral palsy secondary to symptomatic congenital CMV encephalopathy were found in the hospital’s database (Table 1). Of those 23 patients, none (0%) were were classified as Gross Motor Functional Classification Scale level I, two (9%) were GMFCS level II, two (9%) were GMFCS level III, one (4%) was GMFCS level IV, and 18 (78%) were GMFCS level V, for an average GMFCS of 4.52 (Fig. 1). There was an 83% chance that a patient with CP secondary to symptomatic congenital CMV encephalopathy would have a GMFCS level of IV or V (19/23). Twenty-two patients were born at or near term, and one patient (pt. 23) was born at 34 weeks gestation. Eighteen patients were non-verbal, three had minimal verbal skills (only able to gesture or say a few single words), and one had moderate verbal skills (only able to communicate in short phrases and with significant cognitive impairments). The two patients who had good verbal skills with minimal or no verbal skill impairments were the two patients functioning at a GMFCS level II. Eighteen patients had severe dysphagia requiring gastrostomy tube feedings, one ate a pureed or soft diet, and four could tolerate a regular diet. The one patient who ate a pureed diet was a GMFCS V. The patients were divided into a more severe group (GMFCS IV or V) and a less severe group (GMFCS I, II, or III) to assess a correlation between GMFCS level and co-morbidities. There was a statistically significant relationship between the severity of GMFCS and having

Fig. 1. Number of subjects observed at each GMFCS level.

a gastrostomy tube (GT) (Table 2) (Fisher’s Exact Test: p < 0.0006), and GMFCS and verbal skills (Table 3) (Fisher’s Exact Test: p < 0.0023).

4. Discussion The data gathered in this study shows that an infant with CP due to symptomatic congenital CMV encephalopathy is very likely to have severe functional deficits, dysphagia, and cognitive deficits. Of the twenty-three subjects in our study, 78% were classified with a GMFCS level of V, indicating that the majority of these infants developed gross motor disabilities on the more severe end of the spectrum. Infants with asymptomatic congenital CMV infections are very unlikely to develop CP, but infants with symptomatic congenital CMV encephalopathy have a very high risk of developing severe long-term functional deficits. The degree of functional deficits in this population is not evenly distributed across the GMFCS spectrum.

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The number of infants in our study is relatively low, as this study focused on those patients with a known diagnosis of symptomatic congenital CMV encephalopathy. We may have treated only the most severely impaired children with CP due to symptomatic congenital CMV encephalopathy, but our pediatric specialty hospital treats a broad spectrum of children with CP, and it is very likely that we would have also treated children with milder CP due to symptomatic congenital CMV infections if they were in our catchment area. We may also have treated patients at our hospital who had mild CP from asymptomatic congenital CMV infections who were not diagnosed with CMV infections in the neonatal period. Their encephalopathy may have been too mild to be detected at that time. This study is representative of children with CP secondary to congenital CMV encephalopathy that had a severe enough presentation at birth to lead to CMV testing and therefore a congenital CMV diagnosis. Children diagnosed in the neonatal period with congenital CMV because of symptoms of congenital CMV such as jaundice or splenomegaly but not encephalopathy were not captured in this study unless they were treated for CP at our hospital. Our data also shows that an infant with CP due to a symptomatic congenital CMV encephalopathy is very likely to have severe swallowing and cognitive deficits. Because symptomatic congenital CMV infections often cause a generalized encephalopathy, unlike more localized encephalopathies from vascular injuries, children with severe gross motor functional deficits from CMV infections will likely have global functional deficits including severe swallowing and cognitive impairments. Children with more localized encephalopathies can have significant motor impairments with relatively well-preserved swallowing and verbal skills. Because of these global deficits, patients with congenital CMV encephalopathies are likely to be dependent for all care.

5. Conclusion This study shows that patients who have been diagnosed with cerebral palsy secondary to congenital cytomegalovirus encephalopathy have a very high risk of developing severe physical and cognitive disabilities. These children are likely to be dependent for all care and mobility, non-communicative, and fed a modified diet orally or through a gastrostomy tube. Although

our study has a relatively small sample size, our hospital treats a wide spectrum of children with disabilities and there is no reason to assume that this group is not representative of patients with CP secondary to symptomatic congenital CMV encephalopathy. Healthcare providers, family members, and other caregivers can better plan for the potential long-term medical, rehabilitation, and financial needs of patients with a history of severe congenital CMV encephalopathy by knowing their risks of long-term functional deficits. A larger prospective study of infants with congenital CMV infections, which includes auditory testing, could provide a better understanding of the potential needs of this patient population.

Conflict of interest The authors report no conflict of interest.

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Severity of disability in patients with cerebral palsy secondary to symptomatic congenital cytomegalovirus encephalopathy.

Cytomegalovirus (CMV) is a leading cause of congenital encephalopathy and cerebral palsy (CP). In this study we report the severity of disability in i...
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