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Encephalitis among cree children in northern Quebec.

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ORIGINAL ARTICLES
Encephahtis Among Cree CMdren
in Northern Quebec
Deborah N. Black, MD, FRCP(C),*ft Gordon V. Watters, MD, FRCP(C),t Eva Andermann, MD, PhD,"
Charles Dumont, MD, FRCP(C),ft Michel E. Kabay, PhD,§§ Paige Kaplan, MD, FRCP(C),$
Kathleen Meagher-Villemure, MD,§ Jean Michaud, MD, FRCP(C)," It Gus OGorman, MD, FRCP(C),"
Elena Reece, MD, FAAP,# Christos Tsoukas, MD, FRCP(C),$$ and Mark A. Wainberg, PhD*#
We report a neurological disease among Cree Indian children in a northern Quebec village. The disease manifests as
severe mental retardation, cerebral atrophy with white matter changes and calcifications, and systemic immunological
abnormalities. Eleven cases are known in five families. The familial incidence of cases and the high degree of parental
consanguinity suggest a genetic contribution. We propose that this entity may be caused by an unusual viral infection
in a genetically vulnerable host.
Black DN, Watters GV, Andermann E, Dumont C, Kabay ME, Kaplan P, Meagher-Villemure K, Michaud J,
OGorman G, Reece E, Tsoukas C , Wainberg MA. Encephalitis among Cree children
in northern Quebec. Ann Neurol 1988;24:483-489
The neurological literature contains numerous case reports of familial white matter disease and intracranial
calcifications in children. Some of these cases are familial. However, there are no reports, to our knowledge,
of familial calcific encephalopathy with systemic immunological abnormalities. We report a large kindred
of Cree Indian children in northern Quebec who failed
to thrive in infancy and who have progressive severe
microcephaly, profound mental retardation, quadriplegia, recurrent infections, elevated serum immunoglobulins, and lymphocytic abnormalities affecting
both B and T cells. This "Cree encephalitis," as we
have called it, occurs, together with "Cree leukoencephalopathy" 131, in a highly inbred and closely knit
native community. Both diseases account for over half
of the infant and young child mortality in this village.
Understanding the cause of Cree encephalitis may
shed light on genetic factors governing susceptibility to
viral infection.
Results
The mean age at which these patients came to medical
attention was 2.0 months (range, neonatal to 6
months). In most cases, the mothers had noted abnormalities even earlier. Presenting features, in order of
decreasing frequency, were the following: failure to
thrive, irritability, fever, recurrent infections, develop-
From the 'Department of Neurogenetics, Montreal Neurological
Institute; the Departments of ?Neurology, $Genetics, §Pathology,
"Radiology,* I ~ ~ n o k and
Y , **Microbiology,Montreal Children's
Hospital; HModule du Nord Quebecois and the $$Department of
Immunology, Montreal General Hospital; §§Jinbu Corporation; and
the 'I "Department of Neuropathology, HBpital Ste. Justine, Montreal, Quebec.
mental delay, diarrhea, peculiar cry, arching posture,
hepatosplenomegaly, thrombocytopenia. (Full case histories are available on request.)
Mean (+- SD) 1- and 5-minute Apgar scores for all
patients were, respectively, 8.1 ( k 1.0) and 9.5 (t
0.5). Head circumferences at birth were at the lower
limit of normal for the Cree population [19]. Serial
head circumference measurements showed failure of
head growth from birth.
Neurological abnormalities were usually detected
on the initial evaluation. Subsequent evaluations confirmed the failure to make developmental gains. All
patients were severely retarded, blind, microcephalic,
and spastic.
All patients sustained recurrent bacterial, viral, or
fungal infections. All but 1 patient, whose early history
was unknown, had recurrent pneumonitis or pneumonia. One patient had herpes stomatitis following dental
extraction. A disseminated vesicular eruption developed in 1 patient following a smallpox vaccination.
Four patients had refractory candidal infections of the
mouth, axilla, or groin. Splenomegaly was noted in 5
patients within the first months of life. Patients 10 and
11, fraternal twins, had a Coombs-positive hemolytic
anemia shortly after birth. Severe acrocyanosis caused
chronic ulceration and autoamputation of digits in 1
patient. Death resulted from infection in 10 patients at
Received Jun 8, 1987, and in revised form Jan 7 and Apr 22, 1988.
Accepted for publication Apr 26, 1988.
~ k , de ~
Address correspondence to D~ ~ l ~ service
HBpital HBtel Dieu de Montreal, 3840 St Urbain,
Quebec H2W 1T8 Canada.
~
Copyright 0 1988 by the American Neurological Association 483
~
~
l
A
F i g I . Patient 3 , Axial computed tomography scan through
the posterior fossa at age 15 years. Bilateral symmetrical dense
calcifications can be seen in the dentate nucleus of each cerebellar
hemisphere. Enlargement of the basal cisterns ir also noted.
a median age of 20.6 months (range, 3.5 months to 17
years).
Rudiologicul Findings
Computed tomography (CT) scans or skull roentgenograms in 8 patients showed calcifications in the deep
periventricular nuclei or in the dentate nucleus of the
cerebellum (Figs 1 and 2). Patchy hypodensities of the
hemispheric white matter were also present. Two patients had cerebral atrophy. Progressive white matter
changes and evolving cerebral atrophy were seen on
CT scans of 4 patients.
R
Cerebrospinal Fbid
Cerebrospinal fluid (CSF) white blood cell counts
ranged from 2 to 3,560 cells/m13 (median, 24 cells/
m13). CSF cells were predominantly lymphocytes and
monocytes. Seven bacterial cultures (5 patients) and 6
viral cultures (6 patients) of CSF were negative. Cryptococcus ulbidus grew from the CSF of 1 patient at age
15.
Five patients had elevated concentrations of CSF immunoglobulin (Ig) G, M, or A. In Patients 3 and 6
these elevations corresponded to markedly elevated
serum immunoglobulins. The CSF concentration of
IgG in Patient 3 doubled between 1972 and 1984.
484 Annals of Neurology Vol 24 No 4 October 1988
Fig 2. Patient 10. (A)Supenor ventricular axial computed tomography scan at 14 days of age (gestationalage 36 uleekll
without contrast medium. Multiple periventricular and purenchymal calcifications can be seen. Dgfuse low-density changes are
evident in white matter in the frontal. parietal, and orcipital
lobes. (B) Ventricular axial computed tomography scan without
contrast medium at 5 months of age sbours increased dense
calcijication and enlargement of zwtricular size since the initial
examination. Dgfuse cerebral atropb?. is also .teen.
Cree EncephaIitis: Serum ImmunologicaI Abnormalities
Immune Variable and
Normal Values”
IgG (mg/dl)
550-1,800
IgA (rng/dl)
20-500
IgM (mg/dl)
50-300
Total T cells (%)
68 (rt 18); 76.2 (rt 9.2)
T suppressor lymphocytes (%)
30 ( 2 11); 21.5 (rt 4.3)
T helper lymphocytes (%)
36 (f 13); 56.0 ( 2 3.5)
Ratio T helper-suppressor
2.3 (f 1.1); 2.6 ( 2 0.9)
Total B cells (%)
12.5 (rt 7); 8.6 ( 2 3.2)
Rheumatoid factor
Antinuclear antibodies
Circulating immune complexes
by Clq Binding (% above
control)
Coombs’ direct test
Patient No. (age)
3 (16 yr)
4 (5 yr)
4 (7 yr)
6 (2 mo)
7 (2 yr)
10 (3 wk)
10 ( 5 mo)
11 (3 wk)
11 (5 mo)
3,100
2,500
3,366
1,800
1,700
430
1,400
515
1,960
590
190
275
42
200
0
73
0
73
170
2 60
270
470
2 10
87
420
50
69
69
56
74
80
38
73
39
17
34
5
24
42
22
18
13
13
38
37
31
36
31
44
21
30
26
2.24
1.09
6.20
1.50
0.74
2.00
1.17
2.31
2.00
21
27
7
32
37
10
40
13
22
1:1,800
1:3,200
Neg
Neg
Neg
33
Neg
Neg
Neg
1:80
53
33
loob
Pos
Neg
>YO0
Pos
Neg
Neg
Pos
Pos
“Where more than one normal value appears, the first normal value (mean 5 SD) was standardized for the Cree population, all ages (n
The second normal value (mean f SD) was standardized for children 2 years old and younger at the Montreal Children’s Hospital.
bHigh for age.
Oligoclonal bands were positive in the CSF of Patient
3 and in Patient 11 at birth. Enzyme-linked immunosorbent assay (ELISA) of CSF for antibody to
cytomegalovirus (CMV) was negative in Patient 3.
Other Laboratoty Studies
Other laboratory findings included mild to moderate
elevations of hepatic enzymes (serum glutamic-pyruvic
transaminase, serum glutamic-oxaloacetic transaminase, alkaline phosphatase, lactic dehydrogenase) in 4
of 5 patients tested, and nonspecific elevations of urine
dicarboxylic and 8- and 9-carbon fatty acid metabolites
in 1 patient. Normal values were obtained for serum
protein (4 patients), blood urea nitrogen and creatinine
(4 patients), glucose (4 patients), calcium (7 patients),
uric acid (2 patients), inorganic phosphate (6 patients),
electrolytes ( 5 patients), magnesium (1 patient), urine
amino acids and mucopolysaccharides ( 3 patients), and
urine oligosaccharides (2 patients). In 1 patient, gas
chromatographic analysis of fatty acid composition in
cultured skin fibroblasts was normal.
Immunological and Virological Findings
Patients 3 , 4 , 6, 7, 10, and 11 had polyclonal hypergammaglobulinemia of the IgG, IgM, or IgA class
(Table). IgG, IgM, and IgA rose shatply in Patients 10
and 11 after birth. The number of T helper cells
=
108).
tended to be below normal for age, and progressive
depletion of T helper cells was observed in children
who underwent serial studies. Some had a relative increase in the number of T suppressor or B lymphocytes and evidence of other autoimmune abnormalities
(see Table). There were minor decreases in total complement levels in some patients. Lymphocyte mitogen
responses were normal. Three patients had depressed
neutrophil chemotaxis; one showed normal values. Patients 10 and l l had a Coombs-positive hemolytic
anemia requiring transfusion shortly after birth.
Patients 3, 4 , and 7 had markedly elevated antibody
titers to CMV or Epstein-Barr virus (EBV), and CMV
was recovered from the urine of Patients 4 and 7,
indicating chronic active infection with these agents.
Screening for human T-lymphotropic virus type I
(HTLV-I) was negative in these patients. The remaining patients had consistently negative tests for CMV
and EBV, and screening for herpes simplex, Toxoplasma, rubella, varicella-zoster, coxsackie virus, and
echovirus was also negative. Viral cultures of brain and
peripheral organs in Patients 5 and 6 (post mortem)
and of cord blood, placenta, CSF, urine, and respiratory secretions in Patients 10 and 11 were negative.
ELISA of serum for antibody to human immunodeficiency virus (HIV) showed intense reactivity in Patients 3 , 4 , and 7 ;Western blots were nonconfirmatory
Black et
al:
Cree Encephalitis 485
I
I
lu
1pI
P
Family S
Family K
00
Male Fern&
@@ M
~ ~~~~i~
I ~ deceased
Family C
Family
B
Unknown niwrologlcal disease
unallecled
Male Female allecled
Family P-N
9
=Consangulnlly
St'ilb'r'h
0 Mlscawe
-
Fig 3. Cree encephalitis geneaiogy.
of HIV infection. In Patients 10 and 11, a search for
HIV infection in blood, CSF, and postmortem thymus
(Patient 1I) using cocultivation, reverse transcriptase
assay, and immunohistocytochemical staining uncovered no virus. Immunohistocytochemical staining
of amniotic fluid cells was also negative (Dr Drasko
Pekovic, personal communication). A seroepidemiological survey conducted in April 1984 of 108 individuals of all ages composing the immediate and extended
families of patients failed to disclose evidence of immunological abnormalities, chronic EBV infection, or
antibody to HIV.
Genetics and Epidemiological Findings
The earliest known case of Cree encephalitis in this
study occurred in 1966; the last known pdtients were
born in 1986. The ratio of affected females to affected
males was 6: 5. Karyotypes of 2 patients were normal.
Parental consanguinity was evident in Families B and
C, and all affected families were related within five
generations to each other and also to leukoencephalopathy families {37 by distant kinship ties (Fig 3).
Segregation analysis { 171 of the five affected families
was performed assuming autosomal dominant or recessive transmission and complete or single case ascertainment. Chi-square values were intermediate between
the autosomal dominant and recessive hypotheses (assuming dominant inheritance: complete ascertainment,
x2 = 3.42 E0.l < p < 0.51, single ascertainment, x2 =
2.01 L0.5 < p < 0.91; assuming recessive inheritance:
complete ascertainment, x2 = 7.12 E0.05 < p < 0.17,
single ascertainment, x2 = 4.56 10.1 < p < 0.51).
Case Frequency
From 1966 to 1983, new cases of Cree encephalitis or
Cree leukoencephalopathy f31 occurred at a frequency
of almost 1 new case per year, at a rate of 16.5 cases
per 1,000 live births {6, 71. Of 17 infant and child
deaths in this Cree village between 1975 and 1983 (Dr
486 Annals of Neurology
Vol 24
No 4 October 1988
Elizabeth Robinson, personal communication), 10
(58.8%) of these were of children with encephalitis or
leukoencephalopathy. Between 1982 and 1983 the
only infants or children who died in the village werle 3
children with encephalitis or leukoencephalopathy.
Neurological screening examinations conducted on 5 8
immediate relatives of all patients were normal. No
overlap of encephalitis or leukoencephalopathy cases
occurred within sibships, and no transitional forms between the two diseases were identified.
Pathological Findings
Autopsies were performed on 4 patients. One patient
had bronchopneumonia and gross hyperemia of thymus, spleen, lymph nodes, and liver. Three patients
had bilateral acute and chronic bronchopneumonia
with many foci of chronic interstitial pneumonitis with
lymphoid follicle formation, hyperplasia of T- and Bdependent zones, and desquamation of alveolar lining
cells. Lymphoid tissues throughout the body showed
follicular hyperplasia with striking phagocytic activity.
The spleen, liver, kidneys, bladder, and pancreas contained focal chronic interstitial infiltrates. Steatosis was
seen in the liver. Bone mxrow was normal.
Brain weights ranged from 50 to 92% (mean, 71%)
of normal for age. Multiple concretions were seen in
the deep hemispheric and cerebellar white matter,
periventricular regions, and brainstem on sectioning.
Microscopically, foci of chronic inflammation and
fibrosis involved the leptomeninges of 3 patients (Fig
4A), and similar but less marked changes occurred in 1
patient. Rare microglial nodules and numerous srnall
or confluent vascular calcifications were seen in the
cerebral and cerebellar cortex (Fig 4B). The most
severe changes involved the cerebral and cerebellar
white matter, internal capsules, basal ganglia, thalamus,
brainstem, and cerebellar dentate nuclei. Numerous
calcifications, mainly perivascular (Fig 4C), were associated with a decreased amount of white matter and
chronic inflammatory infiltrates composed of lymp'ho-
A
B
C
Fig 4. (A)Brain. Chronic injammation in the leptomeninges
and underlying subpial gliosis are noted. (Hematoxylin-phloxinesafran; x 10 before 30% reduction.) (B)Brain. A microglial
noduie can be seen in cerebral cortex. (Hematoxylin-phloxinesafran; x 25 before 30% reduction.) (C) Brain. Multiple
calcijcations are noted in vessel wads and in internal capsule
parenchyma. (Holmes’; x 10 before 30% reduction.) (0)
Periuascular chronic inflammatoy inf;(tratein cerebral hemispheric white matter. Note hyperplasia of vascular endothelial
lining. (Hematoxylin-phloxine-safran;
X 2.5 before 30%
reduction.)
cytes, plasma cells, and macrophages (Fig 4D). Blood
vessel walls were frequently calcified or fibrotic, with
endothelial cell hyperplasia. Reactive gliosis and
isolated microglial cells were found in these areas.
Superimposed on these chronic changes, 1 patient also
had rare foci of acute inflammation and necrosis. Immunoperoxidase staining showed some IgG and IgM
positivity in perivascular monocytes in 2 patients. No
inclusion bodies or viral particles were seen by electron microscopy.
The pathological findings were those of a chronic
panmeningoencephalitis with numerous calcifications
and severe vascular changes primarily involving the
white matter.
Discussion
The combination of mental retardation, cerebral white
matter changes, and calcifications has been reported by
previous authors.
Aicardi and Goutisres [ 11reported 8 infants, 3 from
consanguineous marriages, with severe mental retardation, spasticity, dystonia, microcephaly, low-grade CSF
pleocytosis and cerebral atrophy, white matter hypodensities, and basal ganglia calcifications on CT scan.
There was no evidence of viral infection, or of serum
or CSF immunological abnormalities. Two infants had
only white matter changes without calcifications.
Laubenthal and Hallervorden El61 reported 4 children, including 2 siblings, with microcephaly, mental
retardation, spasticity, and athetosis. These children
also showed patchy demyelination and calcification.
Two cases had inflammatory changes of meninges,
Black et al: Cree Encephalitis 487
blood vessels, and the ependyma. Jervis [ 151 reported
two cases with noninflammatory white matter atrophy,
sudanophilia, and scattered calcifications. The condition was ascribed to “an encephalitic process of unknown nature with its concomitant circulatory disturbances” [15]. Also reported 1251 were two siblings
with microcephaly, seizures, and tetraplegia whose
brains showed atrophy, white matter changes, periventricular calcifications, and cerebellar neuronal heterotopia without signs of inflammation or infection.
Calcifications of blood vessels in the basal ganglia,
thalamus, or centrum semiovale may occur in pediatric
patients with the acquired immunodeficiency syndrome (AIDS) with encephalopathy [2, 8}. This calcific vasculopathy, reminiscent of the pathological
changes in our Cree patients, has been ascribed to an
infectious vasculitis, due to either direct MIV infection, deposition of immune complexes, or unidentified
toxic or metabolic factors. Our cases differ from AIDS
cases in the absence of profound T helper lymphocyte
depletion, absence of consistent HIV positivity by
ELISA, and lack of the characteristic pattern of reactivity to HIV membrane antigens by Western blot.
Diagnosis
The combination of panencephdtis and an abnormal
immunological and serological profile distinct from
that of AIDS distinguishes our Cree patients from previously reported cases and from pediatric AIDS cases.
Thus far, no cases have been identified outside this
highly inbred and geographically isolated Cree population. We propose the name Cree encephalitis for this
disease. The major identifying features are as follows:
(1) progressive microcephaly and failure to attain
neurodevelopmental milestones beginning in early infancy; (2) recurrent viral, bacterial, and fungal infections; ( 3 ) cerebral atrophy, white matter attenuation,
and calcifications of basal ganglia, white matter, and/or
cerebellum on CT scan; and (4)polyclonal hypergammaglobulinemia. Corroborative features for the disease include ( 1) splenomegaly, lymphadenopathy; ( 2 )
dystonic posture, acrocyanosis; ( 3 ) CSI; pleocytosis,
elevated CSF immunoglobulins; ( 4 ) chronic active
EBV or CMV infection or persistent viral excretion;
( 5 ) systemic autoimmune abnormalities; and (6) similarly affected siblings. These features mry not be present in all cases but are compatible with the diagnosis if
present. Confirmatory features include chronic meningoencephalitis with attenuation of white matter and
scattered calcifications in white matter, periventricular
nuclei, cerebral and cerebellar cortex; and absence of
cytomegalic cells or intranuclear inclusions.
Cree encephalitis and Cree leukoencephalopathy
[3] have accounted for over half of the infant and child
mortality in this Cree village since 1775; they were
also responsible for the only infant deaths in the village
488
Annals of Neurology
Vol 24
N o 4 October 1988
in 1982 and 1983. The 3 patients living in 1986 required total hospital care at a cost of tens of thousands
of dollars per year.
Although the earliest known case occurred in 1966,
both diseases may have gone undetected earlier. ThLe
traditional nomadism of this native Indian population,
which persisted until the last 10 to 15 years; high
infant mortality; absence of medical records before
1964; and unavailability of immune function studies or
CT scanning may have prevented earlier recognition of
Cree encephalitis and Cree leukoencephalopathy .
Congenital Origin
The presentation of Cree encephalitis at birth or in
early infancy suggests congenital acquisition of the disease. In Patients 10 and 11, C T scans at 2 weeks po’stnatally, equivalent to 36 weeks’ gestational age, alrea-dy
showed dense periventricular Calcifications. At birth,
the head circumferences of our patients were at the
lower limit of normal. This suggests that the cerebral
insult occurred late during the last trimester of gestation, after most intrauterine head growth was completed.
Distinction from Classical lmmunodeficiencies
The immunological profiles of our patients are unlike
those of the known primary immunodeficiency diseases of humoral or cellular immunity [lo}. The immunological abnormalities in our cases are reministcent
of the immune dysfunction caused by infections. For
example, the marked elevation of IgM in Patients 10
and 11 at birth resembles the hyper-lgM syndrome
associated with congenital viral infection in male infants. Abnormalities of neutrophil chemotaxis in 3 of
our patients may reflect virus-related neutrophil dysfunction [ 101.
Distinction from Congenital Herpesvirgs Infections
Our patients appeared unusually susceptible to viral
infections of the herpes group (EBV, CMV) and to
chronic candidiasis, in which cell-mediated immunity
plays an important role 120, 241. The absence of chorioretinitis, hearing loss, multiple congenital abnormalities, and cytomegalic cells at autopsy and the high
incidence of the disease in siblings distinguish our
cases from cases of congenital CMV [22, 231 or EBV
[ 111infection. Antibody titers or cultures of CM‘V and
EBV were consistently negative in 4 siblings whose
mother excreted CMV in her breast milk. Very high
titers of antibody to EBV in 3 other patients probably
reflected postnatally acquired infection.
Multipfe Secondaly Infections
The finding of multiple viral and fungal pathogens in
our patients suggests an immunodeficient state and
multiple secondary infections. For example, chronic
active CMV or EBV infections may increase the number of B and T suppressor lymphocytes and elicit
polyclonal hypergammaglobulinemia, circulating immune complexes, and strikingly elevated serum antibody titers to these viruses [21). Acute CMV infection
may reverse the T helper-suppressor lymphocyte
ratio, suppress mitogen responses and interferon production, and predispose to multiple opportunistic infections [13, 141. EBV-infected B lymphocytes may
secrete a variety of IgM and IgG autoantibodies in
vitro 19, 2 I}. Similar patterns of chronic infection and
secondary autoimmune abnormalites may have occurred in our patients.
Mzlltifactorial Transmission
Polygenetic factors govern host susceptibility to viral
infection [4, 5, 12, IS}. Although the familial occurrence of Cree encephalitis in a highly inbred population suggests that it is a genetic disorder, statistical
analysis was not compatible with either a recessive or
a dominant mode of transmission. A multifactorial
model may explain the observed disease frequency. A
polygenetic background, along with an infectious agent
acting at a specific stage of immunological maturation
in a susceptible host, may be the threshold at which the
disease phenotype becomes evident. Modifying genes
may interact with the disease-susceptibility genes to
influence the final outcome.
Although Cree encephalitis is distinct from pediatric
AIDS, their similarities suggest that a cause of Cree
encephalitis may be sought in a viral agent with shared
tropism for the immune and central nervous systems.
In summary, we propose that a congenital insult in a
genetically vulnerable host causes a chronic panmeningoencephalitis and multiple secondary infections that
contribute to the morbidity and the highly abnormal
serological profile of our patients. Our data are consistent with the hypothesis that the congenital insult may
be viral-possibly retroviral-in origin.
We thank Drs. Francine Gervais and Paul Jolicoeur for viral studies
and Mr John Sampalis for statistical assistance. Drs Cedric Raine,
Dikran Horoupian, and Wayne Moore reviewed the pathology. Dr
Leon Wolfe of the Montreal Neurological Institute performed gas
chromatographic analyses of fatty acids. We thank Drs Jack Ante1
and Paul Jolicoeur for critical review and discussion. The cooperation of the Band Council, physicians, and families of our patients was
essential to this study.
References
~~
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Black D N , Booth F, Watters GV, et al: Leukoencephalopathy
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Black et al: Cree Encephalitis 489
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