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Original Articles

Acute Combined Central and Peripheral

Nervous System Demyelination in ChildrenTanja Adamovic, MD*, Emilie M. Riou, MD†, Genevieve Bernard, MD, MSc†,

Michel Vanasse, MD‡, Jean-Claude Decarie, MD§, Chantal Poulin, MD†,and France Gauvin, MD, MSc*

Reports of acute combined central and peripheral ner-vous system acquired inflammatory demyelination arerare in children. This study aimed to (1) define the clin-ical features and prognoses of patients with this entity;and (2) compare these patients with children presentingisolated acute central or peripheral nervous systemdemyelination. A retrospective chart review of 523children with central or peripheral nervous systemdemyelination hospitalized between 1993-2006 wasundertaken. Among these, 93 fulfilled criteria (clinicalfeatures and positive magnetic resonance imaging orelectromyography/nerve conduction studies) for eitheracute central (n = 37; 39.8%) or peripheral (n = 43;46%) nervous system demyelination, or a combinationof the two (n = 13; 14%). Significant differences betweengroups were evident for age (median, 10 versus 7 versus11 years, respectively; P = 0.047), admission to pediatricintensive care unit (8% versus 30% versus 58%, respec-tively; P = 0.001), length of hospital stay (median, 8 ver-sus 9 versus 29 days, respectively; P < 0.001), treatmentwith steroids (52% versus 7% versus 75%, respec-tively; P < 0.001) and immunoglobulins (11% versus81% versus 75%, respectively; P < 0.001), and poorevolution (3% versus 12% versus 54%, respectively;P = 0.002). This entity in children is not rare, and hasa poorer outcome than isolated central or peripheralnervous system demyelination. Assessment is neededfor a better understanding of risk factors, etiologies,management, and prognosis. � 2008 by Elsevier Inc.All rights reserved.

Adamovic T, Riou EM, Bernard G, Vanasse M, Decarie

J-C, Poulin C, Gauvin F. Acute combined central and pe-

ripheral nervous system demyelination in children. Pediatr

Neurol 2008;39:307-316.

Introduction

Acquired inflammatory demyelinating diseases of the

central nervous system constitute a heterogeneous group

of disorders thought to be of autoimmune origin [1-3], in-

cluding acute disseminated encephalomyelitis, acute hem-

orrhagic leukoencephalitis, Devic’s disease, multiple

sclerosis, transverse myelitis, and clinically isolated syn-

dromes such as optic neuritis.

Acquired inflammatory demyelination of the peripheral

nervous system is also thought to be of autoimmune origin

[3], and can present acutely as the heterogeneous entity

known as Guillain-Barre syndrome or in a more protracted,

sometimes relapsing course, known as chronic inflamma-

tory demyelinating polyradiculoneuropathy.

Combined or sequential inflammatory demyelination of

the central nervous system and peripheral nervous system

in the same patient is thought to result from the same path-

ogenic mechanism [4-6]. Combined acute central nervous

system and peripheral nervous system inflammatory demy-

elination in adults [7-11] and children [7,10-14] was de-

scribed. One study suggests that this association is not

unusual in adults and carries an increased risk of poor neu-

rologic outcome [15]. Aside from case reports, only one ret-

rospective pediatric study discussed this combination,

specifically the combination of myelitis and polyradiculo-

neuritis [11].

The primary objective of our study was to describe the

clinical features and prognoses of a cohort with acute

From the *Paediatric Intensive Care Unit, Department of Paediatrics,Sainte-Justine Hospital, Universite de Montreal, Montreal, Quebec, Can-ada; †Division of Neurology, Department of Pediatrics, Montreal Children’sHospital, McGill University, Montreal, Quebec, Canada; and ‡Division ofNeurology, Department of Pediatrics, and §Department of Radiology,Sainte-Justine Hospital, Universite de Montreal, Montreal, Quebec, Canada.

Communications should be addressed to:Dr. Gauvin; Intensive Care Section (#3406), Sainte-Justine Hospital;3175 Cote Ste.-Catherine; Montreal, Quebec H3T 1C5, Canada.E-mail: france_gauvin@ssss.gouv.qc.caReceived May 7, 2008; accepted July 30, 2008.

� 2008 by Elsevier Inc. All rights reserved.doi:10.1016/j.pediatrneurol.2008.07.022 � 0887-8994/08/$—see front matter

Adamovic et al: CNS and PNS Demyelination 307

Author's personal copy

combined central nervous system and peripheral nervous

system demyelination in our population of children with

acquired inflammatory demyelinating diseases. Our sec-

ondary objective was to compare these patients with chil-

dren presenting with isolated central nervous system or

peripheral nervous system demyelination.

Methods

This retrospective epidemiologic study was conducted simultaneously

in two pediatric tertiary-care, university-affiliated hospitals (Sainte-Justine

University Hospital and Montreal Children’s Hospital), and covered a 13-

year period.

Recruitment of subjects was based on a systematic search of intrahospi-

tal chart databases for all patients diagnosed with central nervous system or

peripheral nervous system demyelinating syndromes between January

1993 and April 2006. To ensure optimal recruitment, the database was

searched for 18 different diagnostic terms related to demyelinating diseases

(Fig 1), and each retrieved chart was reviewed. Patients presenting the fol-

lowing criteria were excluded: (1) age >18 years; (2) disease not associated

with demyelination; (3) demyelination not associated with immune or in-

flammatory mechanism, as confirmed by laboratory or clinical criteria;

(4) isolated optic neuritis; and (5) absence of magnetic resonance imaging

or electromyography and nerve conduction studies to confirm demyelin-

ation. Patients with isolated optic neuritis were excluded from the study be-

cause of nonsystematic evaluation by magnetic resonance imaging, and

difficulty distinguishing between this entity and other causes of optic neu-

ropathy in children [16]. Finally, patients who fulfilled the predefined cri-

teria (Table 1) for one of the following diagnoses were included in the

study: acute disseminated encephalomyelitis, transverse myelitis, multiple

sclerosis, Guillain-Barre syndrome, and chronic inflammatory demyelinat-

ing polyradiculoneuropathy. Patients with Devic’s disease, because of the

rarity of this disorder in children, were included in the transverse myelitis

group. Positive magnetic resonance imaging findings were mandatory for

a diagnosis of central nervous system demyelination, and a positive electro-

myography/nerve conduction study was mandatory for a diagnosis of

peripheral nervous system demyelination. Definitions of central and

peripheral nervous system demyelinating inflammatory disorders were in

accordance with the literature available at the time of the study [17-27].

Patients with acute-onset demyelinating disease were further catego-

rized into 3 different groups: (1) patients with isolated acute central nervous

system demyelination (including acute disseminated encephalomyelitis

and transverse myelitis); (2) patients with isolated acute peripheral nervous

system demyelination (Guillain-Barre syndrome); and (3) patients with

acute combined central and peripheral nervous system demyelination. Pa-

tients with chronic inflammatory diseases were categorized into 2 groups:

(1) multiple sclerosis, and (2) chronic inflammatory demyelinating polyra-

diculoneuropathy.

Clinical data were collected from patient charts, and were recorded in

individual case-report forms. The following information was recorded

for all patients: demographic data, signs at presentation, treatment(s)

used, delay between beginning of signs and introduction of first immuno-

modulatory therapy, admission to pediatric intensive care unit, neurologic

outcome (Expanded Disability Status Scale) [28], length of stay in hospital,

and presence of recurrences. For patients with acute combined central and

peripheral nervous system demyelination, additional data were gathered:

detailed past and family medical histories, detailed neurologic signs on pre-

sentation and during hospitalization, and response to treatment, as assessed

Figure 1. Diagram of reviewed and included cases. CNS = central nervous system; PNS = peripheral nervous system; ADEM = acute disseminatedencephalomyelitis; GBS = Guillain-Barre syndrome; CIDP = chronic inflammatory demyelinating polyneuropathy. 1Key words used to select charts: demy-elinating disease, acute demyelinating encephalomyelitis, multiphasic demyelinating encephalomyelitis, multiple sclerosis, Devic disease, neuromyelitis op-tica, transverse myelitis, Guillain-Barre syndrome, Miller Fisher disease, acute inflammatory demyelinating polyneuropathy, acute inflammatorydemyelinating polyradiculoneuropathy, chronic inflammatory demyelinating polyneuropathy, chronic inflammatory demyelinating polyradiculoneuropathy,acute hemorrhagic leukoencephalitis, acute motor axonal neuropathy, acute motor sensory axonal neuropathy, postinfectious encephalitis, and postinfec-tious encephalomyelitis. 2The transverse myelitis group includes 2 cases of Devic’s syndrome.

308 PEDIATRIC NEUROLOGY Vol. 39 No. 5

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by the neurologist during hospitalization. Neurologic outcome was evalu-

ated at discharge from the hospital and at the last available follow-up neu-

rology visit, using the Expanded Disability Status Scale. A good outcome

was defined as an Expanded Disability Status Scale score from 0-4.5 (no

disability or ambulatory without aid), and poor outcome as an Expanded

Disability Status Scale score from 5-10 (severe disability, restriction to

bed or wheelchair, or death).

Laboratory data were collected, when available, including evidence of

albuminocytologic dissociation (increased protein without an increase in

cell count) or oligoclonal bands in cerebrospinal fluid. For patients with

acute combined central and peripheral nervous system demyelination,

additional laboratory evaluations included acute inflammatory markers,

a hematologic, biochemical, metabolic, and vasculitic workup, and micro-

biology and virologic investigations, when available.

For all patients with a diagnosis of central nervous system demyelin-

ation, the results of brain and spine magnetic resonance imaging were re-

viewed to confirm the presence of acute demyelination. For patients with

acute combined central and peripheral nervous system demyelination,

specific abnormalities on magnetic resonance imaging were detailed by

an experienced pediatric neuroradiologist (J.-C.D.), and recorded on stan-

dardized, individual radiologic case-report forms.

The results of electromyography and nerve conduction studies were ver-

ified by an expert neurologist (M.V.) to confirm the presence of abnormal-

ities in patients with a diagnosis of acute peripheral nervous system

demyelination. For patients with acute combined central and peripheral

nervous system demyelination, detailed abnormalities were recorded.

Nerve conduction velocities were recorded according to standard proce-

dures [27]. Abnormal results were confirmed using established normative

values for the respective age groups [27]. Finally, results of nerve and mus-

cle biopsies were recorded, when available.

Statistical Analysis

Descriptive data were expressed as proportions with percentages for cat-

egorical data, and medians with range for continuous data. Data were com-

pared between patients with acute central nervous system demyelination,

acute peripheral nervous system demyelination, and acute combined cen-

tral and peripheral nervous system demyelination. Comparisons between

groups were performed using the Kruskal-Wallis test for continuous

data, and c2 and Fisher’s exact tests for categorical data. All statistical anal-

yses were performed using SPSS (Statistical Package for the Social Sci-

ences, version 15.0, SPSS, Inc., Chicago, IL). The level of significance

was set at P < 0.05. This research project was approved by the Ethics

Committee of the Sainte-Justine Hospital Research Center and the Chart

Archive Department of Montreal Children’s Hospital.

Table 1. Predefined criteria for confirming diagnosis of acute demyelinating encephalomyelitis, transverse myelitis, Guillain-Barre syndrome,

multiple sclerosis, and chronic inflammatory demyelinating polyneuropathy

Diagnostic Criteria Clinical Criteria MRI Criteria EMG/NCS Criteria

ADEM Acute or subacute onset;

polysymptomatic presentation

including encephalopathy; no history

of neurologic signs suggestive of earlier

demyelinating episode [17,18]

Multifocal, hyperintense

lesions on T2-weighted/

fluid-attenuated inversion recovery

brain-spinal imaging studies [19]

Acute transverse

myelitis

Acute or subacute onset;

sensory and motor deficits

(sometimes autonomic) under site

of medullar lesion; evidence of

inflammation within spinal cord

(MRI or CSF) [20]

High signal intensity lesion

on T2-weighted sequences [20]

with possible rostral-caudal

extent to several spinal

segments [36]; either monofocal

or multifocal [36,37]

Multiple sclerosis Evidence of dissemination in time

and space of demyelinating lesions

according to criteria of McDonald et al.,

and exclusion of all other etiologies

for clinical features [21]

MRI criteria of McDonald et al. [21]

GBS Acute or subacute onset of motor and/or

sensory signs; decreased or absent

reflexes; and/or lumbar puncture revealing

albuminocytologic dissociation [23]

Slowed nerve conduction velocity,

conduction blocks, and/or prolonged

or absent F-waves [27]

CIDP Motor and/or sensory symptoms and

signs in more than one limb;

development over at least 2

months; progressive or

relapsing-remitting course,

with decreased or absent

reflexes; and/or albumino-cytologic

dissociation [24,25]

Slowed conduction velocities, temporal

dispersion, and conduction blocks

[23,24,26]

Abbreviations:

ADEM = Acute disseminated encephalomyelitis

CIDP = Chronic inflammatory demyelinating polyneuropathy

CSF = Cerebrospinal fluid

EMG/NCS = Electromyogram/nerve conduction studies

GBS = Guillain-Barre syndrome

MRI = Magnetic resonance imaging

Adamovic et al: CNS and PNS Demyelination 309

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Results

Between January 1993 and April 2006, 523 patients were

identified in hospital chart databases as eligible. All charts

were reviewed, except for 2 that were lost. Among eligible

patients, 390 patients were excluded according to prede-

fined criteria (Fig 1). The remaining 131 met the inclusion

criteria and were retained for analysis. Thirty-eight patients

presented chronic demyelination (27 with multiple sclero-

sis, and 11 with chronic inflammatory demyelinating poly-

radiculoneuropathy), and 93 patients presented acute

demyelination. Among the latter, 37 presented acute central

nervous system demyelination (25 with acute disseminated

encephalomyelitis, and 12 with transverse myelitis), and 43

presented acute peripheral nervous system demyelination

(Guillain-Barre syndrome). Thirteen patients met the crite-

ria for acute combined central and peripheral nervous

system demyelination.

Patients With Acute Demyelination (Central orPeripheral Nervous System)

Patients with acute demyelination had a median age at

presentation of 7.9 years (range, 1-18 years), and were

mostly boys (61%). When comparing patients with acute

central nervous system demyelination, acute peripheral ner-

vous system demyelination, and acute combined central

and peripheral nervous system demyelination (Table 2),

there were significant differences between the 3 groups

for age, occurrence of disease between 2000-2006, admis-

sion to pediatric intensive care unit, length of hospital

stay, presence of albuminocytologic dissociation in cere-

brospinal fluid, use of steroids, use of immunoglobulins,

and poor neurologic outcome at discharge and at last fol-

low-up. No significant differences were evident for sex,

presence and type of previous chronic disease, season of oc-

currence, presence of neurologic or constitutional signs on

admission, number of recurrences, and delay between initial

signs and therapy.

Patients With Acute Combined Central and PeripheralNervous System Demyelination

Patients with acute combined central and peripheral ner-

vous system demyelination are detailed in Table 3. Most

presented during the winter (46%), and were diagnosed be-

tween 2000 and 2006 (85%). The disease occurred within 3

weeks of an infectious prodrome in 11 patients (85%). Pro-

dromes consisted of isolated fever (27%), flu-like illness

(27%), malaise/fatigue (18%), gastroenteritis (18%), or up-

per respiratory-tract infection (9%). The family history was

negative for demyelinating diseases in all patients. Most pa-

tients exhibited both neurologic and constitutional signs on

presentation (62%). Median time to maximal neurologic

deficit was of 6.8 days from the onset of neurologic signs.

The most common presenting complaints consisted of

weakness (85%), walking difficulties (85%), sensory distur-

bances (46%), and decreased level of consciousness (23%).

Most patients (9/13; 69%) first presented signs of central

nervous system demyelination, whereas a few patients (4/

13; 31%) first presented signs of peripheral nervous system

demyelination. The time interval until both central and pe-

ripheral nervous system demyelinations were coexpressed

varied from 1-16 days. Only 3 patients manifested seizures

during hospitalization (Table 3). One patient presented at

admission with generalized tonic-clonic status (patient 2),

another had partial motor seizures in the early phase of

the disease (patient 4), and for a third patient, seizures

were the presenting signs of a first relapse of acute dissem-

inated encephalomyelitis (patient 3).

Results of laboratory examinations were normal, except

for an elevated sedimentation rate in 8 of 10 patients in

whom this test was performed (median, 24 mm/hour; range,

14-62 mm/hour). A cerebrospinal fluid examination was

performed in 89% of patient with central nervous system

demyelination, in 91% of patients with peripheral nervous

system demyelination, and in 100% of patients with com-

bined central and peripheral nervous system demyelination

(Table 2). Cerebrospinal fluid examination indicated a me-

dian cerebrospinal fluid leukocyte concentration of 4 cells/

mm3 (range, 0-60 cells/mm3), with lymphocytic or mono-

cytic predominance (55%) and a median protein level of 0.8

g/L (range, 0.2-2.9 g/L). Albuminocytologic dissociation

was detected in 3 patients (23%). Oligoclonal bands in ce-

rebrospinal fluid were tested in only 4 of 13 patients, and in

all of them were negative. Microbiology revealed serologic

evidence of recent infection in 6 patients (Table 3).

Magnetic resonance imaging indicated isolated brain de-

myelination in 6 (46%) patients, isolated spinal cord demy-

elination in 4 (31%) patients, and combined brain and

spinal-cord demyelination in 3 (23%) patients. Magnetic

resonance imaging of the brain demonstrated an average

of 12 lesions per patient, and was characterized by multifo-

cal areas of high signal intensity mainly in the supratentorial

white matter, along with frequent involvement of the deep

gray matter (Table 4). Most of the lesions were large, asym-

metrical, and confluent, with mild mass effect and occa-

sional contrast enhancement. Similarly, spinal magnetic

resonance imaging revealed large and confluent lesions.

In 2 patients, results of the first magnetic resonance imaging

were normal, and demyelination was evident only on subse-

quent magnetic resonance imaging, performed 16 and 22

days after the initial presentation.

The results of electromyography and nerve conduction

studies are detailed in Table 4. These revealed a predomi-

nantly axonal pattern in 6 patients, and a predominantly de-

myelinating pattern in 5. In the 2 other patients, it was

impossible to conclude whether the involvement was pri-

marily axonal or demyelinating.

Only 1 patient underwent sural-nerve and muscle biop-

sies, which indicated mild axonal neuropathic abnormalities

and myopathic changes. These invasive procedures were

rarely performed, an indication that they are not routinely

used in the diagnosis of demyelinating diseases.

310 PEDIATRIC NEUROLOGY Vol. 39 No. 5

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Table 2. Characteristics of patients with acute demyelination

Variable

Acute CNS

Demyelination

(n = 37)

Acute PNS

Demyelination

(n = 43)

Acute Combined

CNS and PNS

Demyelination

(n = 13) P Value

Sex (male) 25 (67.6%) 24 (55.8%) 8 (61.5%) 0.047

Age (yr) 9.6 (1-17) 6.7 (1-18) 11.5 (1-17) 0.06

Previous chronic disease 9 (24.3%) 11 (25.6%) 2 (15.4%) 0.75

Type of chronic disease 0.09

Neurologic 3 (33.3%) 3 (27.3%) 2 (100%)

Immunologic 3 (33.3%) 0 0

Respiratory 3 (33.3%) 5 (45.5%) 0

Other 0 3 (27.3%) 0

Year of beginning of signs 0.03

1993-1999 19 (51.4%) 24 (55.8%) 2 (15.4%)

2000-2006 18 (48.6%) 19 (44.2%) 11 (84.6%)

Season of presentation 0.75

Summer 8 (21.6%) 9 (20.9%) 1 (7.7)

Fall 8 (21.6%) 11 (25.6%) 3 (23.1%)

Winter 13 (35.1%) 10 (23.3%) 6 (46.2%)

Spring 8 (21.6%) 13 (30.2%) 3 (23.1%)

Signs on admission 0.13

Neurologic 19 (51.4%) 29 (67.4%) 5 (38.5%)

Constitutional 1 (2.7%) 0 0

Both 17 (45.9%) 14 (32.6%) 8 (61.5%)

Hospital length of stay (days) 8.0 (0-37) 9.0 (1-59) 29 (9-905) <0.001

PICU admission 3 (8.1%) 13 (30.2%) 7 (58.3%) 0.001

PICU length of stay (days) 2.0 (1-15) 5.0 (1-20) 43.0 (2-638) 0.08

Time between beginning of signs and treatment (days) 5 (0-380) 6.0 (0-42) 9.0 (0-14) 0.93

Treatment

Steroids 19 (51.4%) 3 (7%) 9 (75%) <0.001

Immunoglobulins 4 (10.8%) 35 (81.4%) 9 (75%) <0.001

Plasmapheresis 0 1 (2.3%) 1 (8.3%) 0.23

Other immunomodulatory agent 0 1 (2.3%) 2 (16.7%) 0.02

Lumbar puncture performed 33 (89.2%) 39 (90.7%) 13 (100%) 0.48

Albuminocytologic dissociation 2 (6.1%) 30 (76.9%) 3 (23.1%) <0.001

WBC in CSF (cells/mm3) 2.5 (0-5) 1.0 (0-8) 4.0 (0-60) 0.47

Proteins in CSF (g/L) 0.5 (0.5-0.6) 1.2 (0.6-3.7) 0.8 (0.2-2.9) 0.07

EDSS score at discharge <0.001

No disability (0-2.5) 19 (52.8%) 11 (25.6%) 1 (7.7%)

Disability, ambulatory without aid (3-4.5) 12 (33.3%) 15 (34.9%) 4 (30.8%)

Severe disability, assisted walk (5-6.5) 4 (11.1%) 8 (18.6%) 1 (7.7%)

Restricted to bed or wheelchair (7-9) 0 9 (20.9%) 6 (46.2%)

Death because of demyelinating disease (10) 1 (2.8%) 0 1 (7.7%)

EDSS score at follow-up 0.002

No disability (0-2.5) 30 (88.2%) 25 (75.8%) 6 (46.2%)

Disability, ambulatory without aid (3-4.5) 3 (8.8%) 4 (12.1%) 0

Severe disability, assisted walking (5-6.5) 0 3 (9.1%) 0

Restricted to bed or wheelchair (7-9) 0 1 (3.0%) 5 (38.5%)

Death because of demyelinating disease (10) 1 (2.9%) 0 2 (15.4%)

Recurrence 5 (13.5%) 3 (7.1%) 2 (15.4%) 0.60

Death 1 (2.8%) 0 2 (15.4%) 0.02

Values are expressed as n (%), or as median (range).

Abbreviations:

CNS = Central nervous system

CS = Corticosteroids

CSF = Cerebrospinal fluid

EDSS = Expanded Disability Status Scale

EMG/NCS = Electromyogram/nerve conducting studies

LOS = Length of stay

MRI = Magnetic resonance imaging

PICU = Pediatric intensive care unit

PNS = Peripheral nervous system

WBC = White blood count

Adamovic et al: CNS and PNS Demyelination 311

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Treatments of patients with acute combined central and

peripheral nervous system demyelination, and responses

to treatment, are detailed in Table 3. Only 6 patients demon-

strated clinical improvement after treatment. Nine patients

were treated with corticosteroids, and among these, 3 re-

ceived 2 distinct courses. A high-dose, short course of intra-

venous methylprednisolone was used in 8 children. Steroids

were the first treatment option in 7 patients. Steroids fol-

lowed a first treatment with intravenous immunoglobulins

in 2 patients (patients 3 and 4), in whom the primary diag-

nosis was Guillain-Barre syndrome. In 6 patients, an oral

steroid taper was given for a median duration of 45 days

(range, 12-135 days). A total of 9 patients received intrave-

nous immunoglobulins. This was the only treatment in 2 pa-

tients (patients 10 and 11) for whom a primary diagnosis of

Guillain-Barre syndrome was rendered, and who exhibited

excellent response to therapy. Plasmapheresis was used in

one patient who did not demonstrate any improvement.

Other immunomodulatory modalities were used in 2 pa-

tients: one patient received anti-thymocyte globulin and

did not show any improvement after therapy, and another

patient received anti-CD20 and did show improvement

after therapy, but ultimately exhibited a poor outcome.

One patient did not receive any drug treatment and showed

improvement. Finally, information about treatment used

was lacking in one patient.

Outcomes of patients with acute combined central and

peripheral nervous system demyelination, as defined by Ex-

panded Disability Status Scale score at discharge and at last

follow-up, are detailed in Table 3. The median follow-up

time was 0.77 years (range, 0.02-9.3 years). Six patients

demonstrated good outcomes (Expanded Disability Status

Scale score, 0-2.5) at most recent follow-up, whereas 7 pa-

tients remained severely disabled, bed or wheelchair bound,

or mechanical ventilator-dependent. Two patients died after

withdrawal of mechanical ventilation. Two patients

Table 3. Demographic and disease features in 13 patients with acute combined CNS and PNS demyelination

Patient

Age

(yr)/

Sex

Signs During

Hospitalization

Delay

Deficit

Possible

Causative

Agent PICU Treatment

Response

to Treatment

EDSS

Discharge/Last

Follow-Up

Duration

of Follow-Up

(yr)

Relapse/Lag

Time to

Relapse

1 5/M Hemiparesis, CNP 11 No None n/a 3-4.5/0-2.5 0.02 No

2 13/M Psychiatric signs,

seizures, AC,

autonomic disorder,

CNP, decerebration,

abnormal LMNF,

extrapyramidal

12 B. henselae Yes CS

IVIG

CS 2nd course

D

I

I

3-4.5/0-2.5 0.32 No

3 6/F Quadriparesis,

psychiatric signs, AC,

BP, abnormal LMNF,

CNP, ON

6 Yes IVIG

CS

Anti-CD20

NR

NR

I

7-9/10 1.67 Yes/2 yr

4 15/F Paraparesis, psychiatric

signs, seizures, AC,

autonomic disorder,

BP, CNP, ON,

abnormal LMNF,

cerebellar signs

16 HHV7 Yes IVIG

CS

PF

ATG

CS 2nd course

D

NR

NR

NR

NR

7-9/7-9 0.36 No

5 12/M Paraparesis, sensory

level L4, psychiatric

signs, objective

weakness

2 No CS NR 7-9/7-9 5.78 No

6 17/F Quadriparesis, AC,

abnormal LMNF, BP,

CNP, objective

weakness

Mycoplasma

pneumoniae

Yes CS

IVIG

CS 2nd course

NR

NR

NR

7-9/7-9 1.63 No

7 8/M Paraparesis and brachial

monoparesis, BP, ON,

objective weakness,

sensory level T4

Borrelia

burgdorferi

n/d n/a n/a 7-9/7-9 9.32 No

8 12/F Paraparesis, objective

weakness, sensory

level T10

0 No CS

IVIG

NR

NR

7-9/7-9 4.22 No

9 1/M Quadriparesis,

fluctuating level of

consciousness,

psychiatric signs,

objective weakness

1 Yes CS

IVIG

NR

NR

10 No

312 PEDIATRIC NEUROLOGY Vol. 39 No. 5

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experienced relapses in the forms of recurrent (patient 13)

or multiphasic (patient 3) acute disseminated encephalomy-

elitis. Patient 13, with recurrent acute disseminated enceph-

alomyelitis, experienced one relapse 8 months after

discharge, and the signs were identical to the original man-

ifestations of the disease. Patient 3 exhibited 2 relapses

more than 2 years after the beginning of the disease, pre-

senting with different signs compared with the original pre-

sentation (seizures and aphasia), and this patient manifested

a progression of previously nonresolved demyelinating le-

sions on magnetic resonance imaging.

Discussion

Despite several case reports on acute combined central

and peripheral nervous system demyelination [7-

9,13,14,29], there have been no clear definitions or even

clear recognitions of this entity in the literature. One prospec-

tive study [15] discussed this entity in 60 adults with postin-

fectious central nervous system demyelinating disease, and

indicated that 44% of patients exhibited simultaneous pe-

ripheral nervous system involvement in the form of polyra-

diculoneuropathy (clinically obvious in 38% of them).

We observed 13 patients with severe acute combined

central and peripheral nervous system demyelination over

a 13-year period, and found that they accounted for 14%

of children with acute acquired demyelination in our popu-

lation. Compared with previously described pediatric pa-

tients with classic acute disseminated encephalomyelitis

[17,19,30,31], our patients with acute combined central

and peripheral nervous system demyelination were older.

Most presented during the winter, with both constitutional

and neurologic signs at admission. The onset of neurologic

disturbance was preceded by an infectious prodrome in

84.6% of patients, which is somewhat higher than what

was reported in pediatric classic acute disseminated enceph-

alomyelitis (72-77%) [17,19,30,31]. However, the sus-

pected infectious agent could only be identified in 38.5%

of our patients. Similar to patients with classic acute dis-

seminated encephalomyelitis, our patients with acute com-

bined central and peripheral nervous system demyelination

manifested a wide variability of multifocal neurologic def-

icits, mostly exhibiting signs of encephalopathy or spinal-

cord dysfunction.

One interesting epidemiologic finding in our study is the

temporal clustering of patients, with 84.6% of acute com-

bined central and peripheral nervous system demyelination

patients presenting during the last 6 years of the study period.

This type of time clustering was not previously observed or

evaluated. In fact, the cause of the increased prevalence of

combined central and peripheral nervous system demyelin-

ation in the last 6 years is not understood. A possible hypoth-

esis is that this entity is more frequent than before; this

would need to be evaluated in a prospective study. Another

Table 3. Continued

Patient

Age

(yr)/

Sex

Signs During

Hospitalization

Delay

Deficit

Possible

Causative

Agent PICU Treatment

Response

to Treatment

EDSS

Discharge/Last

Follow-Up

Duration

of Follow-Up

(yr)

Relapse/Lag

Time to

Relapse

10 12/M Objective severe

weakness, autonomic

instability, CNP,

psychomotor slowing

Yes IVIG I 3-4.5/0-2.5 0.11 No

11 17/M Objective weakness and

sensory disturbances,

mild autonomic

instability, CNP, optic

nerve disc edema

13 Yes IVIG I 0-2.5/0-2.5 0.19 No

12 11/M Objective weakness,

sensory level T5, AC,

paraparesis

0 No CS

IVIG

MI

I

5-6.5/0-2.5 0.31 No

13 5/F AC, objective weakness,

ataxia

EBV No CS

CS

I

I

3-4.5/0-2.5 1.17 Yes/8 months

Abbreviations:

AC = Altered consciousness

AP = Airway protection

BP = Bulbar palsy

CNP = Cranial nerve palsies

CNS = Central nervous system

CS = Corticosteroids

D = Deterioration

Delay deficit = Delay between beginning of signs and maximal neurologic deficit

EDSS = Expanded Disability Status Scale

F = Female

I = Improvement

LMNF = Lower motor neuron findings

M = Male

MI = Mild improvement

MW = Muscle weakness

n/a = Not applicable

n/d = No data

NR = No response

ON = Optic neuritis

PNS = Peripheral nervous system

Adamovic et al: CNS and PNS Demyelination 313

Author's personal copy

plausible hypothesis involves increased detection of the en-

tity because of enhanced awareness and increased systematic

neuroimaging and electromyography/nerve conduction stud-

ies in patients with demyelinating diseases. In our study,

although magnetic resonance imaging was performed in all

patients with acute central nervous system demyelination

and with acute combined central and peripheral nervous sys-

tem demyelination, this test was performed in only 9 patients

(20.9%) with isolated peripheral nervous system demyelin-

ation. Similarly, electromyography/nerve conduction studies

were performed in all patients with acute peripheral nervous

system demyelination and with acute combined central and

peripheral nervous system demyelination, but in only 2 pa-

tients with isolated acute central nervous system demyelin-

ation (5%). Further studies using systematic magnetic

resonance imaging and electromyography/nerve conduction

studies in all patients with demyelinating diseases will be

necessary to verify this hypothesis.

Another notable finding of our study is the poor neuro-

logic evolution and final outcome of 7 (54%) patients

with acute combined central and peripheral nervous system

demyelination. Classic acute disseminated encephalomyeli-

tis is typically a disease characterized by a good evolution

and excellent neurologic outcome [17,19,30,31], although

cases with residual neurologic and cognitive deficit [32]

and even death [33,34] are rarely observed. The same ap-

plies to Guillain-Barre syndrome in the pediatric population

[35]. A pediatric study on transverse myelitis demonstrated

an overall poor outcome, with 40% of children permanently

wheelchair-dependent as a result of the disease [36]. On the

contrary, in our study, we observed excellent functional

outcomes in patients with isolated transverse myelitis,

whereas 7 of 13 patients with acute combined central and

peripheral nervous system demyelination displayed signif-

icantly poorer outcomes. Functional impairment at clinical

onset was not correlated with response to therapy and final

outcome in our cohort. The reason for the worse neurologic

outcome is unclear. Further prospective studies are neces-

sary to identify causes and risk factors of poor neurologic

outcomes in these patients.

The primary therapy in our cohort of patients was chosen

according to the first-appearing or more severe symptom-

atology. Corticosteroids were used for central nervous sys-

tem demyelination, and intravenous immunoglobulins were

used for peripheral nervous system demyelination. In case

of treatment failure or progression of the disease, the alter-

nate therapy was tried. Both therapies failed to produce sig-

nificant benefits in 39% of patients. Two patients were

additionally treated with other immunomodulatory treat-

ments, including plasmapheresis, anti-CD20, and anti-thy-

mocyte globulin, with no significant effect on outcome.

This result suggests that optimal therapeutic options for

acute combined central and peripheral nervous system de-

myelination are still uncertain, and the question of which

treatment to use first remains unanswered. A study of this

entity in adults [15] suggests that intravenous immunoglob-

ulins should be the first-line therapy in patients with both

central and peripheral nervous system involvement, be-

cause it produced better results than steroids.

This study systematically describes epidemiologic and

clinical characteristics of children with severe acute com-

bined central and peripheral nervous system inflammatory

demyelination in 2 pediatric tertiary-care hospitals. We

used broad criteria for eligibility, to include as many poten-

tial subjects as possible. Although consensus definitions for

pediatric multiple sclerosis and related disorders, as re-

cently proposed by the International Pediatric Multiple

Sclerosis Study Group [37], were not available at the time

of the study, the criteria used here were concordant with

Table 4. Detailed abnormal results of confirmatory tests in 13

patients with acute combined CNS and PNS demyelination, with

demyelination according to brain and spinal magnetic resonance

imaging, as well as anomalies evident on nerve conduction studies

and electromyography

Results of MRI* Patients, n (%)

Cerebral demyelination 9 (69%)

Supratentorial lesions 9 (69%)

Subcortical white matter 8 (62%)

Paraventricular white matter 4 (31%)

Supratentorial cortex 3 (23%)

Basal ganglia 3 (23%)

Thalami 2 (15%)

Infratentorial demyelinating lesions 5 (39%)

Brainstem 4 (31%)

Cerebellum 2 (15%)

Spinal cord demyelination 7 (54%)

Cervical spine 1 (14%)

Cervico-thoracic 4 (57%)

Thoraco-lumbar 2 (29%)

Enhancement of ventral and dorsal roots,

and/or cauda equina

3 (23%)

Results of NCS/EMG†

Abnormal motor NCS 13 (100%)

Prolonged distal latencies 4 (31%)

Decreased conduction velocities 2 (15%)

Conduction blocks 1 (8%)

Decreased amplitudes (or absence of response) 8 (62%)

Absence or prolonged F-waves 3 (23%)

Abnormal sensory NCS 6 (60%)

Decreased conduction velocities 3 (30%)

Absence of response 3 (30%)

Abnormal EMG 9 (90%)

Active denervation 8 (80%)

Chronic denervation 4 (40%)

*Cerebral MRI was performed in 12 patients; spinal MRI was

performed in 13 patients.

†Motor nerve conduction was performed in 13 patients, sensory nerve

conduction was performed in 10 patients, and electromyography was

performed in 10 patients.

Abbreviations:

CNS = Central nervous system

EMG = Electromyography

MRI = Magnetic resonance imaging

NCS = Nerve conduction studies

PNS = Peripheral nervous system

314 PEDIATRIC NEUROLOGY Vol. 39 No. 5

Author's personal copy

those recent definitions. Classification of patients was per-

formed in a rigorous manner. All diagnoses were supported

by at least one objective examination, in the form of mag-

netic resonance imaging and/or electromyography/nerve

conduction studies. Finally, this study covered a 13-year

period, which allowed the findings to be representative

and accounted for possible seasonal and annual variations.

However, this study has the limitations inherent in any

retrospective study. Specific risk factors for acute combined

central and peripheral nervous system demyelination could

not be established, because of the small sample size of pa-

tients with this rare entity. A larger prospective study, in-

volving several pediatric centers, is needed to identify

those risk factors. The prevalence of acute combined central

and peripheral nervous system demyelination was probably

underestimated, because most of the patients with acute iso-

lated central nervous system and acute isolated peripheral

nervous system demyelination were not systematically

evaluated for possible associated involvement (magnetic

resonance imaging and/or electromyography/nerve conduc-

tion studies). Some patients with mild involvement were

possibly overlooked because these investigations were not

undertaken. Hence, a potential to bias the apparent out-

comes of patients with acute combined central and periph-

eral nervous system demyelination is possible. In other

words, a selection bias based on the necessity for confirma-

tory tests (magnetic resonance imaging and electromyogra-

phy/nerve conduction studies) in this cohort of patients

could explain the severity of disease seen in this cohort

and the associated poor neurologic outcomes. This could

partly explain the worse prognosis of this subgroup, and

the relatively small number of patients found, compared

with previously reported adult series [15].

Furthermore, it is possible that in some patients, investi-

gations were obtained too early in the evolution of the dis-

ease, and thus failed to demonstrate demyelination. A lag of

a few weeks between the beginning of neurologic signs and

magnetic resonance imaging confirmation of demyelination

was reported previously in acute disseminated encephalo-

myelitis [38].

In conclusion, acute combined central and peripheral ner-

vous system demyelination is not as rare as previously

thought in the pediatric population. Although isolated cen-

tral nervous system or peripheral nervous system demyelin-

ation usually portends a good prognosis, the combination of

these two diseases may have, in some patients, a poorer

prognosis. Systematic assessment of this entity, using mag-

netic resonance imaging and electromyography/nerve con-

duction studies, is important. Further studies are necessary

to clarify its incidence, risk factors, potential etiologies,

optimal management, and prognosis.

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