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Childhood Guillain-Barr syndrome in Paraguay 1990 to 1991.

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Chddhood Gdain-Barre Syndrome in
Paraguay, 1990 to 1991
David E. Hart, MD,” Laura A. Rojas, MD,? Joana A. Rosirio, MD, MPH,” Humberto Recalde, MD,?
and Gustavo C. Romgn, MD”
~
~
~~~~~
During 1990 to 1991, through a national surveillance program for poliomyelitis, the Paraguayan Ministry of Health
received reports of 50 children with incident acute flaccid paralysis (< 15 years old). On the basis of established
criteria, 37 were diagnosed with Guillain-Barre syndrome. The average annual incidence rate for 1990 to 1991 was
1.1/100,000 children. The clinical course was more benign than reported in other pediatric series. There were low
rates of hospitalization (5796), respiratory compromise (8%), and intubation (5%).The overall severity, however, was
similar to that described in previous reports, with a 3% case-fatality rate and an 81% total recovery rate at 12 months.
Seventy-six percent of patients had symptom onset during January to April, the warmest months of the year. Thirty
percent of patients had definite or possible exposure to organophosphatepesticides, and the peak use coincides with
the peak incidence of Guillain-Barre syndrome. There was no correlation between occurrence of Guillain-Barre
syndrome and prior immunization.
Hart DE, Rojas LA, Rosario JA, Recalde H , Roman GC. Childhood Guillain-Barb syndrome
in Paraguay, 1990 to 1991. Ann Neurol 1994,36353-863
There are few reports on pediatric Guillain-Barre syndrome (GBS), and virtually all describe relatively small
numbers of hospitalized patients in developed countries with temperate climates. However, in the last 5
years, two reports of pediatric GBS in less developed
countries have appeared [ l , 21.
To investigate pediatric GBS in South America, we
examined data collected by the Paraguayan Ministry of
Health (PMH) on all patients less than 15 years old
who were reported to have acute flaccid paralysis
(AFP) during 1990 to 1791.
Patients and Methods
As part of the Pan American Health Organization’s effort
to eradicate poliomyelitis, Paraguay has been systematically
registering children under 15 years old with AFP since 1989.
Public hospitals and primary health care facilities were to
report such children to the PMH within 48 hours of detection. Also, each center was expected to provide a weekly
update regarding the children detected. Compliance with the
latter was enforced by the P M H with phone calls to nonreporting centers.
Children with AFP also were identified through door-todoor vaccination programs and a reciprocal notification agreement between Paraguay and its neighboring countries, Brazil,
Argentina, and Bolivia. These countries notified the PMH of
Paraguayans seeking medical attention within their borders.
Children reported to the PMH were usually examined by
a pediatric neurologist (L. A. R.) within 7 days of notification.
From the “Neuroepidemiology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Healrh,
Berhesda, MD, and +P=%:uayan Ministry of Health, Asuncion, Para$way.
Medical history and physical findings were recorded on standardized forms. Typically, a child was observed in the acute
state and followed periodically for at least 12 months or until
full motor recovery.
To be eligible for this study, children must have been less
than 15 years old at the onset of weakness, and this onset
must have occurred during 1990 or 1991. Fifty children satisfied the inclusion criteria; 32 were below 5 years old. Relevant data for each child were abstracted and then reviewed independently by two neurologists (D. E. H., J. A. R.) for the
identification of GBS according to established criteria 13, 41.
The incidence rate of pediatric GBS for 1990 to 1991 was
determined by averaging the annual incidence rates for 1990
and 1991. Official midyear projections [ 5 ] of children less
than 15 years old for 1990 (1,726,884) and 1991 (1,768,521)
were used as denominators for the annual incidence rates.
The numerators were determined by the number of children
diagnosed with GBS for each year. We also investigated possible age-specific differences in disease patterns and prognosis, using the t test for continuous and x2 test for categoric
variables. p values 5 0.05 were taken as statistically significant.
Results
Demographics
Twenty-two boys and 15 girls (1.5 : 1 male-female ratio) satisfied the diagnostic criteria for GBS. The mean
age at onset was 4 years 2 months (range, 10
months-14 years). The average annual incidence rate
Received Mar 22, 1993, and in revised form May 16, 1994. Accepted for publication May 19, 1994.
Address correspondence tO D~ Hart, upsrate
~~~~~l~~~ Consultants, 319 South Manning Boulevard, Albany, N Y 12208.
Copyright 0 1994 by the American Neurological Association
859
intestinal disorders, and the user rate at major public
hospitals remained stable [ 5 ] .
Risk Fuctors
Twenty children had an illness within 28 days of onset
of weakness; upper respiratory tract infection was the
most frequently reported (60F ). Also reported were
isolated fever (20%!),gastrointestinal disorder (15%),
and mumps ( 5 % ~ ) Ten
. children had definite or possible
exposure to organophosphate insecticides without evidence of acute cholinergic syndrome. Two children
had oral polio vaccination within 7 5 days prior to weakness, but none had polioviruses isolated from stool cultures. However, vaccinal poliovirus I11 was isolated
from the stools of 1 child with no history of oral polio
vaccine immunization. History of contact between this
child and oral polio-vaccinated children was difficult
to ascertain.
I4
12
I0
1990
8
0
1941
6
4
2
FiR 2. DU tribution o/ Gnzllar'n-Bmri. y d ~ o m eca.cec by ?Jzowth
of onset.
for 1990 to 1991 was 1.1/100,000; age-specific rates
ranged from 1.7/100,000 in children less than 4 years
old to 0.1/100,000 in children 10 to 14 years old.
Of the 37 children with GBS, 24 ( 6 5 2 )came from
rural areas. In fact, 12 lived in Concepcih, a rural
province with only 4 q of the total population (Fig 1).
Concepcih has borders with four other rural provinces and with Brazil. The four neighboring provinces,
with 10V of the Paraguayan population, had a combined total of 1 case for the same period. No comparable data were available for Brazil.
Seventy-six percent of children had symptom onset
during January to April, the Paraguayan summer (Fig
2).There was no seasonal increase in the rate of gastro-
860 Annals of Neurology
Vol 36 No
(3
Clinical Informution
Twenty-one children ( 5 7 % ) were hospitalized, some
simply for collection of two stool specimens 2 4 hours
apart. The average hospital stay was 10 days (2-53
days). Three children had breathing difficulties, but
only 2 required intubation (1 for < 24 hours).
Weakness progressed in an ascending pattern in
'95% of the children, and simultaneously in all limbs
in 5 % ; the average time to reach the nadir was 7 days
(range, 2-1 2 days). After excluding 5 children under
2 years old because of an inability to fully communicate
symptoms, the most frequent presenting sign or symptom was weakness (24/32), followed by paresthesias
(8132).During the clinical course, 6274 (23137) of the
children mentioned paresthesias and hyperesthesias, although these symptoms could not be confirmed by
examination.
Exuminution
Thirty-five children were observed in the acute stage:
18 were unable to walk, 10 walked with assistance,
4 walked independently, and 3 were pretoddlers.
Strength was graded by the MRC scale, and weakness
was always found to be more pronounced in the lower
limbs and distally. Cranial nerve weakness was present
in 12 children; of these, 8 had facial and bulbar weakness, 3 had bulbar weakness alone, and 1 had facial
weakness alone. Twenty-four children exhibited autonomic changes: sudomotor (92%), vasomotor (skin
coloration and/or blood pressure fluctuation in 58% ),
constipation (46% ), tachycardia ( 1757), and bladder
paralysis (8v). We investigated possible clinical differences berween children younger than 5 and those 5
years or older. There was no significant difference in
the distribution or severity of peripheral muscle weakness and pattern of cranial nerve involvement (bulbar,
p = 0.53; facial, p = 0.75). We did not find a correla-
December 1004
Dijtribution of Childrevi by Cerebrospinul Fluid Protein L e d
Ver-sus Age and Awrage Interml Betrueen Sylriptom Onset and
Lumbar- Puncture
Age (yr)
Protein Level (mgidl)
<5
2 5
45
25-44
5 24
4
5
2
Interval
(days)
from the hospital by her parents on the second day of
her illness and died 13 days later. A 3-year-old boy
died during the course of a meningoencephalitis, 4
months after GBS onset. H e had shown moderate protracted weakness at his 2-month visit.
Laboratmy Studies
Nerve conduction testing was performed on 31 children; l child died prior to testing, and for 5 others
their families refused the examination. The mean interval between symptom onset and the examination was
2 8 days. Ninety percent of children had slowed motor
conduction velocities (defined as < 6095 of normal)
with a mean value of 17% of normal for the slowest
nerve examined in each child. F waves were tested in
30 children; they were prolonged in 11 and absent in
19. Lumbar puncture was performed in 14 children,
with a mean interval of 6 days from the onset of symptoms. Cerebrospinal fluid (CSF) protein levels were
elevated in 9 patients (range, 10-192 mg/dl) (Table).
N o child had polymorphonuclear pleocytosis. Nineteen children had stool cultures that tested positive for
enterovirus. Of these, 4 had echoviruses, 1 had vaccinal
poliovirus, and 14 had unspecified nonpolio enterovirus.
Discussion
Patients and Methods
T o our knowledge, this is the first nationwide study of
pediatric GBS in a South American country. Adherence to the program was said (PMH) to be high. This
perceived success could be explained by several factors: the small size of the country and its population,
social stability during 1990 to 1991, low number of
pediatric neurologists (three), and a strong commitment from the PMH to the program. Although the
case-finding process was regarded as effective, we acknowledge three possible mechanisms of underreporting:
1. Children with GBS who were treated with folkloric medicine or received no medical attention would
not have entered the reporting system. This would
have affected predominantly children with very mild
or very severe disease. However, the observed mortality and recovery rates are comparable to those reported
elsewhere, suggesting no significant loss in either
group.
2. Children diagnosed with AFP in a participating
center but not reported to the central office could have
been excluded. This possibility was minimized by the
design of the registry, including its compliance mechanisms. Also, all three pediatric neurologists were highly
committed to the program.
3 . Children with Miller-Fisher syndrome, pure sensory or autonomic variants of GBS, could have been
excluded. These subtypes have accounted for as much
as 5% of patients in some series [b, 73. There were
several children with the Miller-Fisher variant in the
registry, but their symptoms had initiated before the
period of this study.
Outcome
Twenty-seven percent of children were fully recovered
by their 2-month visit; 73%, by their 6-month visit;
and 81%, by their 12-month visit. The mean recovery
time was 120 days. At the 2-month visit, 9 children
had atrophy in the small hand muscles and the distal
leg muscles (predominantly ankle dorsiflexors). The atrophy was resolved at the 12-month visit in 6 of these
children. At the 12-month visit, all patients ambulatory
at baseline were again walking independently (n = 32);
5 of these patients had mild persistent motor deficits.
Two children died but only one death was believed to
be directly related to GBS (case-fatality rate, 3%'). The
GBS-related death pertained to a 3-year-old girl with
bulbar and autonomic dysfunction. She was removed
Demographics
The incidence of GBS in childhood has not been well
studied. A single population-based report indicated a
stable incidence across age [7), whereas several large
series of predominantly adult patients suggested a
higher incidence in younger children 18- 101. Our data
show a pronounced shift in incidence with age, dropping from a rate of 1.7/100,000 in children up to 4
years old to 0.1/100,000 in those aged 10 to 14 years.
This finding might result from differential exposure
across age groups to precipitants of the syndrome (e.g.,
toxins, infections) or from differential susceptibility of
the myelin to such insults. In fact, the latter hypothesis
is supported by two previous accounts: In one, the
author [lo] reported an increased incidence of bulbar
2
3
7
5
6
tion between bulbar weakness and respiratory impairment ( p = 0.14). Sensory complaints were reported
more often by children 5 years or older ( p = 0.009).
The time to recovery was similar in the two age groups
(mean, 116 days for children < 5 years and 123 days
for those 2 5 years; p = 0.74). By 12 months, both
groups showed similar levels of recuperation ( p =
0.46).
Hart et al: Childhood GBS in Paraguay 861
involvement and respiratory compromise in children
less than 5 years old (vs those 2 5 years old), and in
another [61 significantly slower motor/sensory nerve
conduction velocities were found in children 10 years
or younger compared to those older than 10 years.
In children, the incidence of GBS may decrease with
age, while in adults it shows the opposite pattern [7,
101. Features common to both extremes of the life
span (e.g., immunological status, vulnerability of myelin) might lead to increased susceptibility to GBS.
Risk Factors
The clustering of patients in Concepcion could be related to the use of organophosphate pesticides in the
cotton fields. Farmers use great amounts of these pesticides, often in concentrated form, and empty containers
serve as toys. Also, the maximum usage of organophosphates occurs during the summer (December-March).
Since retrospective measurements of exposure to organophosphates are virtually impossible, we tried to
determine the availability of these pesticides in Paraguay. Although official data are lacking, a watchdog
organization, Altervida, reported that the cotton industry alone spent approximately $6.7 million (U.S.) on
organophosphate pesticides in 1991; 35% of that
spending was on monocrotophos. Four children were
excluded from this study because of definite exposure
to this product and presentation with concurrent acute
cholinergic syndrome. Their clinical course, however,
was similar to that of the children included. Altervida
also estimated that half of the pesticides used in Paraguay were obtained unofficially.
Contrary to previous reports of high incidence of
GBS in colder months [S, 9, 111, Paraguay had 7657
of its cases occurring during summertime (Fig 2). We
were unable to correlate this summertime peak of GBS
with gastrointestinal disorders; also, the user rate at the
major public hospitals was stable year-round, suggesting no significant increase in the incidence of acute
illnesses during the summer [ 5 ] . A similar seasonal occurrence of AFP in children was reported in China
[l2]. However, while the Chinese children showed a
pattern of motor axonal neuropathy [13], the Paraguayan children demonstrated predominantly demyelination on their electrophysiological studies.
The 5% intubation rate in our study is near the low
end of the range (4-22p) reported in childhood series
using defined diagnostic criteria 114- IS]. Access to
mechanical ventilation could have biased this result;
however, there are two observations against such a
bias: (1) a high rate of complete recovery (81%) at the
12-month visit and (2) a low case-fatality rate ( 3 % ) ,
suggesting that the children did not require more aggressive care than what was available to them. Considering that 65% of the children with GBS lived in rural
areas where rehabilitation services were virtually nonexistent, full recovery corresponded to the natural evolution of the syndrome. The benign course of these
children is also clinically consistent with the low rates
observed for hospitalization, intubation, and case fatality.
Despite a clinical course that is more benign than
generally described, children with GBS in Paraguay
appear to be similar to those in other countries in terms
of clinical features, CSF changes, and clinical neurophysiological manifestations. In Paraguay, the observed
measures of disease frequency (incidence) and severity
(rate of recovery, case fatality) are similar to those reported previously. There are three possible explanations for the observed difference in clinical course: (1)
Significant underreporting of children with severe disease may result in a cohort with predominantly mild
and moderate GBS. If a significant number of cases of
fulminant disease had developed, so that children died
before reaching medical care, it is likely that the medical community or other health care workers would be
aware of them. (2) Exposure to organophosphates or
other toxins may cause a more benign clinical syndrome otherwise indistinguishable from “classic GBS,”
with geographic and temporal clustering related to usage patterns. Further studies are required to explore
this hypothesis. (3) The disease process indeed follows
a more benign course in Paraguayan children.
We wish to thank the Paraguayan Ministry of Health and the Pan
American Health Organization for providing access to the Paraguayan section of the Expanded Program of Immunizations for South
America.
Clinical Infomation and Outcome
The clinical course of the Paraguayan children was predominantly benign. Only 2 1 ( 5 7 2 ) were hospitalized,
some simply for laboratory tests. Hospitalization solely
for testing was more likely to have occurred for the 6
children whose hospital stays were 3 days or less. All
6 were from isolated rural areas. It is quite possible
that the number of children who really required hospitalization for their clinical condition could have been
as low as 15 (41%).
862 Annals of Neurology Vol 36 No 6 December 1994
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Hart et al: Childhood GBS in Paraguay
863
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