Transcript Part - time MSc course Epidemiology & Statistics Module

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Neurobehavioural testing
Welding & Parkinson’s Disease
Is there evidence of a link?
Prof. Craig Jackson
Head of Psychology
BCU
Parkinson’s Disease
Neurological Condition
James Parkinson
Cell atrophy in substantia nigra
Cardinal Symptoms
Tremor (initial symptom in 70% cases)
Slowness
Stiffness of movement (bradykineasia)
Postural instability
Usual onset in mid-late 50s ( 1 in 20 diagnosed <40 years)
Mostly male
1 case per 500 in UK
Introduction
Parkinson's disease (also known as Parkinson disease or PD)
Degenerative disorder of the CNS
Impairs the sufferer's motor skills and speech.
Belongs to a group of conditions called movement disorders.
Primary Symptoms
Muscle rigidity
Tremor
Slowing of physical movement (bradykinesia)
Loss of physical movement (akinesia)
Dopamine
Symptoms result from decreased stimulation of the motor cortex by the basal
ganglia
caused by insufficient formation and action of dopamine
produced in the dopaminergic neurons
Secondary symptoms may include:
high level cognitive dysfunction
subtle language problems.
PD is both chronic and progressive.
Dopaminergic Pathways
Dopamine
Symptoms result from the loss of dopamine-secreting (dopaminergic) cells
Subsequent loss of melanin (secreted by the same cells) in the substantia
nigra
These neurons project to the striatum and their loss leads to alterations in
the activity of the neural circuits within the basal ganglia that regulate
movement
Essentially an inhibition of the direct pathway and excitation of the
indirect pathway
Dopamine Pathways
Four major dopamine pathways;
nigrostriatal pathway
mesocortical
volition and emotional responsiveness
mesolimbic desire,
initiative, and reward
Tuberoinfundibular
sensory processes and maternal behaviour
Disruption of dopamine along the non-striatal pathways explains much of the
neuropsychiatric pathology sometimes associated with Parkinson's Disease.
Head Injury
Previous episodes of head injury are reported more frequently by PD
sufferers than by non PD sufferers in the population
Those with head injury 4 times more likely to develop PD than those who
have never suffered a head injury - Bower et al. 2003
Risk of developing PD increases X 8 head trauma requiring hospitalization
Increases X 11severe head injury.
However, since head trauma is rare, the contribution to PD incidence in the
general population is minimal. T
Recall Bias? ? ?
Drug Inducement
Antipsychotic medication, used to treat / manage psychoses and
schizophrenia can induce PD symptoms
Lowering dopaminergic activity
Due to feedback inhibition, L-dopa can also eventually cause the symptoms
of Parkinson's disease that it initially relieves
Dopamine agonists can also eventually contribute to Parkinson's disease
symptoms by decreasing the sensitivity of dopamine receptors.
Pallidotomy
Surgery was common
Liq Nit
80 Celcius for 6 sec
Immediate benefits
Limited duration?
Declined since LevoDopa
Surgery more popular again for
drug-resistant PD
Deep Brain Stimulation
LevoDopa
The most widely used form of treatment is L-dopa
Various formats.
L-dopa is transformed into dopamine in the dopaminergic neurons
Done by L-aromatic amino acid decarboxylase (often known by its former
name dopa-decarboxylase).
Only 1-5% of L-DOPA enters the dopaminergic neurons.
The remaining L-DOPA is metabolised to dopamine elsewhere,
Causes a wide variety of side effects.
LevoDopa
Due to feedback inhibition, L-dopa results in a reduction in the endogenous
formation of L-dopa, and so eventually becomes counterproductive
Carbidopa and Benserazide are dopa decarboxylase inhibitors
They help to prevent the metabolism of L-dopa before it reaches the
dopaminergic neurons and are generally given as combination preparations
e.g.
Carbidopa / Levodopa (co-careldopa) (e.g. Sinemet, Parcopa)
Benserazide / Levodopa (co-beneldopa) (e.g. Madopar).
Stalevo
New Treatments
Gene Therapy
Neuroprotective Treatment
Neural Transplants
Nutrient Therapy
Qigong
Parkinsonism
PD is the most common cause of Parkinsonism
A group of similar symptoms.
PD is also called "primary parkinsonism" or "idiopathic PD"
"idiopathic" - of no known cause
Most forms of parkinsonism are idiopathic, there are some cases where the
symptoms may result from:
genetic mutation
drugs
other medical complications
toxicity
head injury
Manganism
James Couper 1837
Extreme manifestation of PD
Excessive manganese poisoning
Farmers
Miners
Steel workers
Battery manufacturing
Symptoms
Parkinsonian Features
Dystonia
Gait (Cock’s walk)
Locuria manganica (manganese madness)
Introduction
Current Problem in USA
Steel Welding
Parkinson’s Disease
Neurobehavioural Testing
Systematic Review
Conclusion
Litigation
October 1st 2004
Larry Elam versus A.O. Smith
Elam, former welder, aged 65
Developed PD
Lifetime welder
Wins £1M from Welding Rod
Manufacturers
Current Problem in USA
March 25th 2005
Fed Judge Kathleen O’Malley
“Valid scientific evidence supports the conclusion that
manganese exposure is connected to dangerous side
effects.”
February 27th 2006
Fed Judge Kathleen O’Malley
Ruled welding can cause serious neurological damage
to welders
Out of court settlement for 2 welders, made by welding rod
manufacturing company ($ undisclosed )
Litigation
Welding of Steel
Joins pieces of metal that have been made liquid by heat
Metal pieces to be joined and a filler metal (rod) coming from a consumable
Heat produced as electricity passes from one conductor to another
Temperatures >4000 oC in the arc
At least 80 different types of welding processes
365,000 welders in USA
1,000,000 full time welders globally
5,000,000 paid welders globally
Neurobehavioural Testing
Study of specific human functioning
Performance across several domains:
Cognition
Motor Skills
Reaction Time
Coordination
Visuospatial
Reasoning
Mostly computerised
Portable
Relatively cheap
Memory
Attention
General
The Current Situation
1) Manganese Overload = Parkinson’s Disease
2) Welding Work = High Manganese Exposure
Therefore . . .
“Neurobehavioural testing
is used
to identify or screen workers
with
early symptoms
of
Parkinson’s disease”
Could this be a flawed assumption?
Systematic Review of the Literature
Three Objectives
1)
Is there any evidence of occupational manganese exposure impairing
neurobehavioural performance?
2)
Which tests (domains) are best at demonstrating such impaired performance?
3)
What is the smallest level of Mn exposure associated with test impairment?
Systematic Review of the Literature
16 Databases Searched
Medline & Pubmed
HSE Line
CISDOC
NIOSHTIC & NIOSHTIC2
PsychoInfo
Excerpta Medica
Toxfile
Embase
SciSearch
Biosis Previews
Web of Science
Web of knowledge
Science Citation Index
Social Science Citation Index
Systematic Review of the Literature
Search Terms
Cognition disorder
Neurobehavioral / Neurobehavioural (deficit / impairment)
Neurological
Neuromotor
Neuropsychiatric
Neuropsychological (test(ing))
Neurotoxicology
Neurotoxic
Manganese
Manganate
Manganese alloy / dioxide / dust / ore / oxide
Steel
Welding
Welders
Limitations:
Human
English Language
1970-2006
Systematic Review of the Literature
The Better Quality Studies
EU Guidelines for qualitative evaluation of neurobehavioural studies (1997)
1. Population of an adequate size relative to the number of tests used
2. Subject selection method which avoids bias for the exposed group
3. Subject selection method which avoids bias for the control group
4. Pre-stated exclusion/inclusion criteria for study participants
5. High response rate for the exposed group (usually > 60%)
6. High response rate for the control group (usually > 60%) where applicable
7. Control or adjustment for important confounders / modifiers of performance
8. Inclusion of quantitative or semi-quantitative assessment of long-term exposure
9. Control for recent exposure (where applicable)
10. An indication of the standardization of testing conditions
After application of Quality Criteria, only 12 studies were of “Better Quality”
Expected Neurobehavioural Differences
exposed
controls
poorer
slower
poorer
poorer
slower
poorer
poorer
Cognition
Motor Skills
Memory
Reaction Time
Coordination
Attention
Visuospatial
Reasoning
better
faster
better
better
faster
better
better
Locuria Manganica Indeed
Very serious implications for litigants and defendants in USA
Currently huge numbers of plaintiffs filing cases in USA
Share prices dropped globally e.g. BOC
Major concern to US Dept of Defense / USAMRC – currently funding research
Serious concern to International Manganese Institute
Serious concern to International Institute of Welding