Motor Neuron Disease
Dirk Bäumer
Wessex Neurological Centre
MND – take home points
There is no diagnostic test for MND – but clinical diagnosis is reliable
Mean survival is 3-4 years, but there are marked differences between patients
Multidisciplinary care makes a difference
What is Motor Neuron Disease?
What is MND? What is ALS? Some terminology
Clinical features
Pathology
What is causing it? Environment vs genetics
Overview of management
What is Motor Neuron Disease?
“upper motor neuron”
corticospinal tract
NEJM 2001
344 (22): 1688
“lower motor neuron”
anterior horn cell
What is ALS (Amyotrophic lateral sclerosis)
Amyotrophy
Lateral sclerosis
muscle loss from denervation
degeneration of the lateral corticospinal tract
(upper motor neuron)
ALS = MND
What is ALS? Charcot’s disease
Jean-Martin Charcot 1874
La sclérose latérale amyotrophique
“lateral sclerosis”
What is ALS? Lou Gehrig’s disease
0.6
Batting average
0.5
0.4
0.3
0.2
0.1
0
1922
1924
1926
1928
1930
1932
Year
1934
1936
1938
1940
What is ALS? Lou Gehrig’s disease
http://www.lougehrig.com/about/bio.html
MND: Clinical features and diagnosis
• Essential: Progressive pure motor
weakness
• Combination of lower motor
neuron and upper motor neuron
dysfunction:
– LMN: weakness, wasting and
fasciculations
– UMN: Stiffness (spasticity),
brisk reflexes, extensor plantar
responses
• Almost always: Focal onset
– Upper limb 30%
– Lower limb 35%
– Bulbar 30%
– Respiratory 1-2%
– Trunk 1-2%
• All this not explained by another
condition
MND: Clinical features and diagnosis
Kiernan et al Lancet 2011
MND: ‘Diagnostic criteria’ and tests
Sensitivity as low as 28%!
NOT used in clinical practice
Clinical
features features and diagnosis
MND:
Clinical
– About 25% of cases
– ‘progressive bulbar palsy’
– Presents with dysarthria and
dysphagia
– Often seen in TIA clinic because of
perceived ‘stroke-like’ onset
– Typically combination of upper motor
neuron (corticobulbar, or
‘pseudobulbar’) and lower motor
neuron bulbar problems
– More common in elderly females
– Generally worse prognosis – but there
are long survivors
Bulbar onset ALS
Clinical
features features and diagnosis
MND:
Clinical
‘Flail arm’ syndrome
• Vulpian-Bernhardt syndrome,
brachial amyotrophic diplegia
or ‘Man-in-the-barrel’
• Usually severe symmetrical
shoulder girdle wasting
Regional variants
‘Flail leg’ syndrome
• ‘Polyneuritic variant’ or MariePatrikios syndrome
• Asymmetric distal leg wasting
• Very few pathological cases
Wijesekera et al 2009
MND:
Clinical features and diagnosis
Clinical features
Primary lateral sclerosis (PLS)
• Rare (2% of all cases)
• Pure upper motor neuron disease
– Stiffness and spasticity
– Progressive ascending tetraparesis
– Spastic dysarthria
• No wasting or fasciculation
• Weakness may take some time to develop
• Survival is prolonged (decades)
• By convention only diagnosed after 5 years of symptoms
• Can look like PSP
Clinical
features features and diagnosis Dementia in MND
MND:
Clinical
•
Frontal or ‘dysexecutive’
syndrome
– Apathy, disinhibition or
stereotypies
– Socially inappropriate behaviour
– Language (rare)
•
•
•
•
Memory, orientation and
visuospatial skills preserved
Emotionality is not always
associated with dementia
Can develop before or after
motor weakness
Dementia up to 15%, cognitive
impairment up to 50%
Clinical
features features and diagnosis Dementia in MND
MND:
Clinical
MND: Differential
diagnosis diagnosis of MND
Differential
In theory…
In practice…
7.3% ‘mimic syndromes’ in 405 clinical diagnoses
Traynor et al Arch Neurol 2000
Differential diagnosis –
cervical spondylotic radiculomyelopathy
What causes MND? Pathology
Olaf Ansorge
What causes MND? Epidemiology
700
Alzheimer’s Disease
1.3/1000
7000
6000
5000
4000
3000
2000
1000
0
60
70
80
90
100
Age
400
300
200
0
40
50
60
70
80
90
Age
Motor Neuron Disease
3/100 000 (lifetime risk 1:300-1:400)
12
Rate per 100,000
500
100
50
14
Parkinson’s Disease
1.6/10 000
600
Incidence per 100,000
Rate per 100,000
10000
9000
8000
10
8
6
Incidence of neurodegenerative disorders
4
2
0
10
20
30
40
50
Age
60
70
80
90
Hirtz et al, NEUROLOGY 2007;68:326-337
What causes MND? Epidemiology
What causes MND? Genetics
5-10% of patients have a family history
Familial disease is indistinguishable from sporadic disease
What is familial ALS? Experts disagree…
What causes MND? Genetics
Genetic disease may appear sporadic in small families and with low penetrance
‘Familial inheritance’ can be seen as a proxy measure of penetrance
Al-Chalabi et al 2011
What causes MND? Genetics
8 fold increase of risk of siblings to develop MND by the age of 85
Absolute risk still very small
What causes MND? Genetics
C9orf72:
• >30% of ‘familial’ ALS cases,
>5% of sporadic ALS cases,
• >25% of familial FTD cases,>5 %
of sporadic FTD cases
How does C9orf72 cause MND?
Loss of C9orf72 function
RNA gain of function
Toxic RAN translation
Differential expression
Somatic mosaicism
Differential methylation
Preferential vulnerability
Does MND spread?
Ravits and La Spada 2009
When does MND start?
Eisen et al 2014
MND classification
and overview Lateral Sclerosis (ALS/MND)
Motor Neuron Disease/Amyotrophic
LMN/UMN
P
h
e
n
o
t
y
p
e
Motor/cognitive
PLS
Spinal/limb
ALS
UMN
predominant
ALS
ALS-FTLD
‘typical’ ALS
FTLD-MND
LMN
predominant
ALS
Neuropathology
SOD1
Bulbar
TDP-43
Respiratory
TDP-43/DPR
Flail arm
FTLD
FUS
Flail leg
PMA
G
e
n
o
t
y
p
e
Region of onset
‘Sporadic ALS’
‘Familial ALS’
High penetrance mutations rare variants
C9orf72
SOD1
TARDBP
FUS
UBQLN2
OPT
ANG
TAF15
EWRS1
‘at risk genotypes’
UNC13A
ELP3
ATXN2
complex models
Liability threshold
model
MND
management - Conveying the diagnosis
Diagnosis
•
•
•
•
•
Are you sure of the diagnosis?
Do you have the knowledge?
Do you have the support structures?
The role of a specialist clinic
20-30% of people initially diagnosed with MND by
non-neurologists do not have it
• The experience of how the diagnosis is given has a
long term impact
MND - prognosis
Turner and Talbot 2013
MND - prognosis
Range 6 months – 20 years
Millul et al Neuroepidemiology 2005
MND
management - talking about prognosis
Prognosis
Motor Neurone Disease
Survival from symptom onset
100%
Range 6 months – 20 years
Mean 3-4 years
50%
5 years
Slide: Kevin Talbot
10 years
15 years
MND - prognosis
Better prognosis
• The rate of change in the first year
• Pure UMN or pure LMN syndromes
• Regional syndromes (upper or lower
limb)
Worse prognosis
• Early diagnosis
• Elderly
• Bulbar onset
• Early respiratory involvement
• Neck weakness
Nakamura et al 2013
MND – management
Riluzole
Mean survival 14.8 months on
Riluzole,
11.8 months off treatment
Well tolerated but need to
monitor LFTs every month for
three months, then every
three-monthly for 9 months
Miller et al Cochrane Review 2008
MND management – the multidisciplinary team
MND management – the multidisciplinary team
JNNP 2015
Thank you!
dirk.baumer@uhs.nhs.uk