Transcript pptx - Makerere University College of Health Sciences

Progress in the understanding
of Nodding Syndrome
Richard Idro
Makerere University
Uganda
PAANS 2016,
Kampala
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Outline
• Historical perspectives about the disease
• Clinical features
• Interventions and outcomes
• Studies of pathogenesis and an understanding
of the syndrome to date
2
The head nodding syndrome in
Southern Tanzania
Dr Aall Jilek
Described a mysterious disease with
characteristic spells of head drops in
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Tanzania as early as 1962 (Aall, 1962)
4
Burden and affected Countries
A map of Africa showing 3 countries in which NS has been reported
Over 10,000 children
are affected mainly in E
Africa (Uganda,
Tanzania and South
Sudan)
UGANDA
In Uganda, 3320
patients are receiving
treatment in 17 centres
The bright dots mark the areas in South Sudan, Northern Uganda and
southern Tanzania
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Early features
– Initial period of
increasing inattention,
dizzy spells, withdrawal,
poor interest in
environment
– Followed by head
nodding
• While eating or on sight
of food; cool
weather/breeze or
unprovoked
• Increasing frequency and
clusters (usually 1-4 )/day
Subsequent features and
complications
– Development of other seizure types 1-3 years after onset
of symptoms
• Mostly generalized tonic clonic
• Also atypical absence, focal and myoclonic seizures
– Cognitive decline
• Moderate to severe deficits
• Many drop out of school 1-2 years later
• Drooling, Speech difficulties
– Malnutrition
– Growth failure/stunting and delayed sexual development
– Musculoskeletal abnormalities
• Muscular wasting – especially distal
• Deformities of the chest, back, hands, legs(knees) and feet /ankles
Bar graph showing Psychiatric diagnosis in 225
children with nodding syndrome in Uganda
35
30
30
25
25.4
20
16.7
15
10
4.7
5
0
Depression
Post Traumatic
Stress Disorder
Generalised Anxiety Pervasive spectrum
disorder
disorder
Growth failure is associated low levels of IGF
Three siblings: 13 yr old boy with NS and
severe stunting together with his 16 yr
and 17yr old siblings
Serum S-Somatomedin (IGF) levels
and Height for age Z scores in 8
adolescents with nodding syndrome
S-Somatomedin (IGF) level, ng/mL
350
-5.00
300
250
200
150
-4.00
-3.00
-2.00
Height for age Z scores
-1.00
100
0.00
EEG recording in light sleep
Nodding Syndrome: MRI Findings
• Tanzania (17)
– T2 hyper-intensities
– Hippocampus abnormalities
• Uganda (5)
– Cerebral atrophy
• No evidence for meningeal
inflammation, cysts, TB,
ADEM, prion disease…
Uganda – generalized cerebral atrophy
Management of Nodding Syndrome in
Uganda
• Treatment guidelines developed by a
multidisciplinary team of clinicians,
nurses, and therapists
• The goal of treatment is to relieve
symptoms, prevent disability and offer
rehabilitation to improve function.
• Important needs are seizure control,
behavior and psychiatric difficulties,
nursing care, nutritional and
subsequently, physical and cognitive
rehabilitation.
• Sodium valproate as first line anti
epileptic drug
Audit of treatments outcomes one year after
Nodding syndrome,
N=484
Before
Seizure free > 30 days 8 (1.7%)
Other convulsive
epilepsies, N=476
After
P
value
Before
After
P
value
121
(25.0%)
<0.00
1
8
(1.7%)
243
<0.001
(51.1%)
Daily clusters of head
nods, median (IQR)
4
(IQR
3,6)
1
(IQR
0,2)
<0.00
1
Behaviour and
emotional difficulties
327
(67.6%)
133
(27.5%)
<0.00
1
206
(43.3%)
105
<0.001
(22.1%)
Independence in basic
self care
174
(36.0%)
402
(83.1%)
<0.00
1
206
(43.3%)
397
<0.001
(83.4%)
Attending school
107
(22.1%)
193
(39.9%)
<0.00
1
170
(35.7%)
250
<0.001
(52.5%)
Uganda is winning the nodding
syndrome war!
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Studies of the aetiology of nodding
syndrome
• We had several questions?
– Is it caused by a toxin or
chemical in the environment,
water or food eaten in the
area?
– Is it in the genes?
– Is it caused by an infection?
• With support of the CD, we
conducted a series of studies
to answer these questions.
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Is it associated with displacement, war and
toxins?
Is it genetic?
• Nodding syndrome is a new problem in Uganda
so unlikely inherited.
• Exon sequencing of two children
– One from Uganda and one Sudan no genes that are
usually associated with epilepsy.
• No epilepsy genes found in three families
– Studied grand parents, parents, affected and
unaffected children
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Postmortem examinations
First set of brain
specimens – obtained
late
Next ¾ specimens –
high carbon density
material
Similar findings in next
set of brain specimens
Is it due to an infection?
• No association with multiple parasitic infections
studied except the extracranial filarial parasite
Onchocerca volvulus.
• CDC performed exploratory studies for 19 virus
families – none identified
– No evidence of prion disease
Nodding syndrome is associated with
infection by Onchocerca volvulus
Country and area
of study
Test
Cases, n/N Controls,
method
(%
n/N (%
positive) positive)
South Sudan,
Skin snip
29/30
17/34
Amadi, 2001
(96.7%)
(50.0%)
South Sudan, Lui,
Skin snip
35/39
15/31
2001
(89.7%)
(48.4%)
South Sudan, Lui,
Skin snip
12/13
7/16
2002
(92.3%)
(43.8%)
Tanzania,
ELISA
44/51
Mahenge, 2008
(86.3%)
Uganda, Kitgum,
ELISA
37/39
20/41
2009
(94.9%)
(48.8%)
South Sudan, Witto Skin snip
29/38
18/38
and Maridi, 2010
(76.3%)
(47.4%)
Odds ratio
(95% CI)
29 (3.5,
238)
9.3 (2.6,
32.6)
15.4 (1.6,
149)
-
Reference
Tumwine J et al
20129
Tumwine J et al
20129
Tumwine J et al
20129
Winkler A et al
2008
14.4 (2.7, Foltz et al 201318
78)
3.2 (1.2, CDC 201119
8.7)
Where in the northern Uganda are the
patients nodding syndrome found?
GPS locations of patients
with epilepsy in Pader,
Kitgum and Lamwo
districts
GPS locations of patients
with NS in Pader, Kitgum
and Lamwo districts
Map of Lamwo,
Kitgum and Pader
showing black fly
breeding sites
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Pathogenesis
• O.volvulus is endemic in many parts of Africa, Central
and South America but nodding syndrome occurs in
only few localised areas.
• How would it cause brain injury as there is no evidence
of breach of BBB – for direct parenchymal injury.
• In Tanzanian patients, CSF PCR was negative for O.volvulus.
• Hypothesis - Nodding syndrome is an O.volvulus or
wolbachia induced neuro-inflammatory epileptic
encephalopathy with antibodies to these agents cross
reacting with neuron surface proteins.
•
NS is associated with antibodies –
leiomodin and found an association
with
NS
Antibodies against
leiomodin-1 were found in
11/19(58%) cases
• LMOD 1 shares 83%
sequence similarity with a
conserved region of O.
volvulus tropomyosin.
• The antibodies were neurotoxic in mice brain
suggesting cross-reactivity.
– Johnson T et al 2014
The relationship between antibodies to voltage
gated potassium channel (VGKC) complex proteins
and nodding syndrome
• VGKC are key in generation and
propagation of electrical
impulses in the CNS.
• We measured serum antibodies
against VGKC-complex proteins
in 31 patients and 11 sibling
controls:
– 15/31 (48.3%) established cases
of NS tested positive for these
antibodies compared to:
– 1/11(9.1%) controls
Wolbachia and nodding syndrome
• Onchocerca volvulus carries small bacteria called
Wolbachia
• The adult worm depends on this bacteria for
survival and reproduction.
• Ivermectin only kills the young daughter
parasites leaving the mother parasites to
continue reproducing and living for 10-15 years.
• The Wolbachia can be killed with a medicine
called doxycycline and this can lead to the death
of the mother onchocerca.
• We think this can make children with nodding
syndrome improve.
Potential immuno-pathogenic pathways
in the causation of nodding syndrome
Infection of
susceptible
hosts by O.
volvulus
Immune
response
s
Treatment with
Doxycycline may:
1. May cure
patients in early
disease
2. Terminate
progression
3. Improve
symptoms
Antibodies to:
1. Specific O.
Volvulus antigens
2. Novel mutations
in O. Volvulus
3. Specific Wolbachia
super groups
4. Novel mutations
in Wolbachia
Cross – reacting
with host neuron
surface antigens
Nodding
syndrome
Ongoing and planned studies for
2016 - 2019
• R Idro – Uganda (MRC UK)
– Examine if nodding syndrome is an Onchocerca
volvulus/Wolbachia induced neuro-inflammatory
disorder
– Determine if any specific biomarkers
– Determine if doxycycline may be used as treatment.
• Michael Boele – South Sudan (Dutch Govt)
– Pathogen discovery by next generation sequencing
and biomarker study
• Bob Colebunders - DRC, Cameroon, Uganda (EU)
– Epidemiology of River Epilepsy
The Antwerp Group – Study of River
Epilepsy in DR Congo and Cameroon
Slide courtesy of Prof Colebunders
Conclusions
• NS is an ?epidemic neurologic disorder
manifesting as a symptomatic generalized
epilepsy syndrome with encephalopathy
• It may be a neuro-inflammatory disorder
• Symptoms and psychomotor functioning
improve with symptomatic treatments
Acknowledgements
Government of Uganda
WHO Country Office
US Centers for Disease Control
National Institutes of Health
University of Oxford
Waterloo Foundation
Hope for Humans
Medical Research Council, UK
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