Long-term motor, cognitive and behavioral outcome of acute disseminated encephalomyelitis. – pdf download free anoxia cerebral

Accepted manuscript long-term motor, cognitive and behavioral outcome of acute disseminated encephalomyelitis smadar shilo, MD, orli michaeli, MD, eli shahar, MD, sarit ravid, MD, dr. PII:

S1090-3798(16)00026-X

DOI:

10.1016/j.Ejpn.2016.01.008

Reference:

YEJPN 2004

To appear in:

European journal of paediatric neurology

Received date: 16 november 2015 revised date:

6 january 2016

Accepted date: 23 january 2016

Please cite this article as: shilo S, michaeli O, shahar E, ravid S, long-term motor, cognitive and behavioral outcome of acute disseminated encephalomyelitis, european journal of paediatric neurology (2016), doi: 10.1016/j.Ejpn.2016.01.008.


This is a PDF file of an unedited manuscript that has been accepted for publication.Anoxia cerebral as a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

Children with acute disseminated encephalomyelitis: 1

ACCEPTED MANUSCRIPT long-term motor, cognitive and behavioral outcome of acute disseminated encephalomyelitis

A

RI PT

Smadar shilo mda, orli michaeli mdb, eli shahar mdc, sarit ravid mdc

Department of pediatrics A, ruth children’s hospital, rambam health care campus, haifa,

anoxia cerebral

Israel

Division of hematology-oncology, schneider medical center, petah tikvah, israel

C

Pediatric neurology unit, ruth children’s hospital, rambam health care campus, haifa,

SC

B

M AN U

Israel

Running head: children with acute disseminated encephalomyelitis correspondence to:

TE D

Dr. Sarit ravid pediatric neurology unit

POB 91062

EP

Ruth children’s hospital, rambam health care campus

Haifa 31096, israel

AC C

Tel: 972-4-854-2646

Fax: 972-4-854-2441

E-mail: [email protected] abbreviations: ADEM=acute disseminated encephalomyelitis, ADHD=attention deficit hyperactivity disorder, CBCL=child behavior check list, CI=confidence interval, CNS=central nervous system, EDSS=expanded disability status scale, EEG=electroencephalography, ICU=intensive care unit, IQ=intelligence quotient, MS=multiple sclerosis, OR=odds ratio

anoxia cerebral

Children with acute disseminated encephalomyelitis: 2

ACCEPTED MANUSCRIPT abstract objective: the purpose of this study was to evaluate the long-term motor and neurocognitive outcome of children with acute disseminated encephalomyelitis and to identify prognostic risk factors.

RI PT

Methods: the study included 43 children who were hospitalized due to acute disseminated encephalomyelitis during the years 2002-2012. The children underwent full neurological examinations, along with comprehensive neurocognitive and behavioral assessments.

SC

Results: twenty-six (61%) children had different degrees of neurological sequelae after a mean follow-up of 5.5±3.5 years. The most common residual impairment included attention-

anoxia cerebral

M AN U

Deficit hyperactivity disorder (44%), behavioral problems (32%), and learning disabilities (21%). Five (12%) children had a full-scale IQ of 70 or less, compared to 2.2% in the general population.

Conclusions: neurocognitive sequelae were found even in children who were considered as

TE D

Fully recovered at the time of discharge. Risk factors for severe neurological sequelae were older age at diagnosis and male gender. We suggest neuropsychological testing and long-term follow-up for all children with acute disseminated encephalomyelitis, even in the absence of

EP

Neurological deficits at discharge.

AC C

Key words: children; acute disseminated encephalomyelitis; neurocognitive outcome

Children with acute disseminated encephalomyelitis: 3

anoxia cerebral

ACCEPTED MANUSCRIPT 1. Introduction acute disseminated encephalomyelitis (ADEM) is an acute, usually monophasic, immunemediated inflammatory disorder of the central nervous system, characterized by multifocal neurological signs and symptoms and encephalopathy, along with the presence of multifocal

RI PT

Demyelinating lesions on neuroimaging studies 1. While the etiology is not fully understood, ADEM is commonly preceded by immunization or by viral infection, suggesting an

Autoimmune response to myelin basic protein 2. Although usually monophasic, some children

SC

May develop either recurrent or chronic disease, such as multiple sclerosis.

Data regarding long-term outcome for patients diagnosed with ADEM prior to the steroid era

anoxia cerebral

M AN U

Suggest that spontaneous improvement was seen over several weeks in most children, with 50-70% of patients experiencing full recovery 3,4.

Previous studies on long-term neurologic outcomes in children with ADEM showed complete remission of symptoms in approximately 60-90% of patients 5-7. In the majority of these

TE D

Studies, data were determined by using clinical follow-up assessments at outpatient clinics 8-11 and structured questionnaires 5 that focused mainly on motor sequelae and the possibility of predicting multiple sclerosis. Only a few small case studies used standardized cognitive and

EP

Behavioral tests 12-15. Previously reported neurological sequelae include motor deficits, cognitive and behavioral problems 15,16.Anoxia cerebral up to 30% of patients had a recurrent or multiphasic

AC C

Course 17.

Information regarding prognostic factors of ADEM in children is sparse. One study reported a greater vulnerability to cognitive dysfunction and behavioral problems among ADEM patients diagnosed prior to age five 12. Optic nerve involvements at presentation 18 and antecedent viral infection 5 have also been suggested as indicative of a poor outcome. The aim of the present study was to evaluate the long-term sequelae of ADEM in children and to look for predictors of long-term morbidity. This study is distinctive because it combines

Children with acute disseminated encephalomyelitis: 4

ACCEPTED MANUSCRIPT genuine motor assessment with an objective neurocognitive performance and behavior evaluation in a relatively large group of children.Anoxia cerebral this information can help in offering

RI PT

Guidance, as well as emphasizing important aspects for future follow-up.

2. Materials and methods 2.1 study population

The medical records of children and adolescents, aged one month to 18 years, admitted to

SC

Meyer children’s hospital in haifa, israel, during the years 2002-2012 with a final diagnosis

M AN U

Of ADEM were reviewed. The hospital is the main tertiary center in the north of israel and serves a population of 280,000 children. Patients are referred either directly from pediatricians or pediatric neurologists in this case, or from other smaller medical centers that lack either a pediatric neurologist or a pediatric intensive care unit. The diagnosis of ADEM was based on the international consensus clinical criteria according to the international pediatric multiple

anoxia cerebral

TE D

Sclerosis study group. These include a first polyfocal, clinical CNS event with presumed inflammatory demyelinating cause, encephalopathy that cannot be explained by fever, and

EP

Abnormal typical brain MRI findings during the acute phase (3 months) 19. Children with any underlying neurological, systemic or metabolic diseases were excluded from the study.

AC C

Children eventually diagnosed as having MS, or children that developed a clinical picture suggestive of neuromyelitis optica (devic disease) were not included in the study. All eligible patients were contacted by letter and then by telephone to ask whether they would be willing to participate in the study.

Sixty-one patients fulfilled the criteria for ADEM.Anoxia cerebral of those, five children were eventually diagnosed as having multiple sclerosis and were excluded, eight declined to be assessed, and five could not be located. There was no difference between the children regarding age at onset, gender, and presenting symptoms.

Children with acute disseminated encephalomyelitis: 5

ACCEPTED MANUSCRIPT written informed consent was obtained from the parents during the follow-up meeting. The study was approved by the institutional ethics committee. 2.2 data collection A structured form was used to obtain data from the patients’ hospital records regarding

RI PT

Presenting symptoms and signs, laboratory examinations, EEG and neuroimaging studies, and clinical findings at discharge.Anoxia cerebral outcome at discharge was classified for all subjects. Good

Outcome was defined as having no neurological sequelae. Moderate outcome was defined as

SC

Having minor to moderate sequelae, including altered behavior or clinical signs not affecting functions. Poor outcome was defined as having severe neurological sequelae that impaired

M AN U

Everyday functions.

2.3 clinical, motor and neurocognitive assessment

All the children were interviewed and underwent a thorough neurological examination by a pediatric neurologist during the follow-up visit. A structured questionnaire was used to obtain

TE D

Information from parents regarding comorbid illnesses, medications, behavioral problems, school performance, and ability to perform daily activities.Anoxia cerebral the functional degree of neurologic disability was assessed using the kurtzke functional

EP

Systems and expanded disability status scale (EDSS) 20. The kaufman brief intelligence test 21 was used to assess intelligence. This is a standardized

AC C

Validated test that yields three scores: verbal, nonverbal, and the overall score, known as the IQ composite. The mean age-based standard score for each test is 100 with a standard deviation of 15. Scores lower than 2 standard deviations from mean were considered as retardation. Scores between 1 and 2 standard deviations from mean were considered as borderline intelligence. The diagnosis of attention deficit hyperactivity disorder (ADHD) was based on the diagnostic and statistical manual of mental disorders IV criteria 22.Anoxia cerebral clinical evaluation was performed

Children with acute disseminated encephalomyelitis: 6

ACCEPTED MANUSCRIPT by a pediatric neurologist, using interviews with the parents and child, and examination during the visit. In addition, attention and behavior were measured using the conners’ parents rating scales-revised 23. The parent’s version of the child behavior check list (CBCL) was used to measure social

RI PT

Competency and problematic behavior 24,25. The CBCL rates child behavioral and emotional problems both globally and along the two dimensions of internalizing symptoms and

Externalizing symptoms. Raw scores of each clinical factor were transformed to T scores

SC

Based on published norms, and scores ≥67 were considered as clinical impairment. 2.4 long-term outcome

anoxia cerebral

M AN U

The long-term outcome was classified for all subjects. Good outcome was defined as full recovery with no neurological sequelae. Moderate outcome was defined as having moderate sequelae, including mild to moderate motor impairment (EDSS 1-3.5), ADHD, learning disabilities or seizures affecting function but compatible with independent living. Poor

TE D

Outcome was defined as having severe neurological sequelae that impaired everyday functions, contrary to independent living. 2.5 statistical analysis

EP

Data were summarized as proportions or means and standard deviations. Chi-square analysis was used to test for difference between the distributions of qualitative variables, and student’s

AC C

T-test for difference between quantitative variables.Anoxia cerebral multivariate analyses of the associations between clinical presentation, laboratory examinations, EEG, and long-term outcome were conducted using logistic regressions with odds ratio (OR) and 95% confidence interval (CI). Analyses for the total sample were adjusted for age and gender. The relationship between current EDSS score and that upon discharge was examined with spearman’s rho correlation coefficient. The difference between these two scores was examined with wilcoxon’s test, due

Children with acute disseminated encephalomyelitis: 7

ACCEPTED MANUSCRIPT to their non-normal distribution. For all comparisons and analyses, a p value of 5). Of these, one had spastic paraplegia and urinary incontinence, and two had hemiparesis.Anoxia cerebral

M AN U

Minor motor abnormalities (EDSS score 5)

3 (7)

RI PT

Motor deficit ADHD

19 (44) total score

Behavior

Externalizing behavioral problems (parents’ report)

5 (12)

11 (26) 9 (21)

Epilepsy

M AN U

Learning disabilities

5 (12)

Below average (71-84)

12 (28)

Average or above average (≥85)

26 (60)

Good

17 (39)

TE D

Outcome

3 (7)

Mental retardation (≤70)

Moderate

Overall long-term

7 (16)

SC

Internalizing

(CBCL in clinical range)

Global IQ

8 (19)

21 (49)

(motor deficit 5, ADHD 19, learning disabilities 9, behavioral problems 5, epilepsy 1 )

EP

Poor

5 (12)

Notes

AC C

(motor deficit 3, behavioral problems 3, epilepsy 2, mental retardation 5 )

ADHD=attention deficit hyperactivity disorder, CBCL=child behavior check list

Children with acute disseminated encephalomyelitis: 22

anoxia cerebral

ACCEPTED MANUSCRIPT table 3: prevalence odds ratio for poor prognosis by demographics, clinical presentation, laboratory results, and EEG 95% CI

P

Age at diagnosis

0.81

0.7-0.96

0.024*

Female gender

0.18

0.03-0.8

0.025*

Age/gender

1.54

Ethnicity

0.66

Fever on admission

2.2

Seizure

1.7

Normal EEG admission to ICU EDSS score at discharge

Notes

TE D

Abnormal neurologic examination results at discharge length of hospital stay

0.54

0.14-2.69

0.5

0.44-9.2

0.25

0.3-11.70

0.32

0.2

0.03-1.39

0.104

1.1

0.9-1.2

0.92

0.66

0.11-4.04

0.65

1.6

0.31- 5.9

0.52

0.7

0.07-8.6

0.7

0.7

0.19-3.12

0.6

1.03

0.82-1.30

0.81

0.66

0.25-1.85

0.45

1

0.95-1.05

0.992

M AN U

WBC on admission

Pathologic LP on admission

0.44-5.47

SC

Papilledema on eye examination

Confirmed pathogen

RI PT

OR

anoxia cerebral

EP

WBC=white blood cell count, LP=lumbar puncture, EEG=electroencephalogram, ICU=intensive care unit, EDSS=expanded disability status scale

AC C

*P0.05

Children with acute disseminated encephalomyelitis: 23

ACCEPTED MANUSCRIPT legend to figure

AC C

EP

TE D

M AN U

SC

RI PT

Figure 1: association between outcome at hospital discharge and long-term outcome

AC C

EP

TE D

M AN U

SC

RI PT

ACCEPTED MANUSCRIPT

ACCEPTED MANUSCRIPT highlights •

Attention deficit disorder is comon after childhood ADEM.

Behavioral and learning disabilities are common after childhood ADEM.

Even children who were considered fully recovered may be significantly

Male gender and older age at diagnosis are risk factors for poor outcome.

AC C

EP

TE D

M AN U

anoxia cerebral

SC

RI PT

Affected.