The heterogeneity of MND:Patterns, within the puzzle.
Dr Thanuja Dharmadasa
Neurologist (MBBS, FRACP)
Brain and Mind Centre, University of Sydney
Diagnosis? Prognosis?
Treatment?
“many diseases?”“one disease?”
Overview clinical
genetic
mechanistic
Clinical heterogeneity:
Dharmadasa et al, Med J Aust 2017; 206 (8):357-362 Kiernan MC et al, The Lancet 2011; 377 (9769): 942-955
Upper Motor Neurones
Lower Motor Neurones
Clinical heterogeneity:
Dharmadasa et al, Med J Aust 2017; 206 (8):357-362 Kiernan MC et al, The Lancet 2011; 377 (9769): 942-955
Clinical heterogeneity:
phenotype
/ˈfiːnə(ʊ)tʌɪp/
noun
the set of observable characteristics of an individual (e.g. appearance,
behaviour etc)
Clinical heterogeneity:
LMN UMN
(i) Site-of-onset
(ii) Mix of UMN and LMN involvement
Clinical heterogeneity:
(i) Site-of-onset
(ii) Mix of UMN and LMN involvement
(iii)Rate of disease progression
Swinnen, B. & Robberecht, W. Nat. Rev. Neurol. 10, 661–670 (2014); published online 14 October 2014;
1) ALS- 70% of cases, - classically limb-onset (~80%)- ~20% of patients bulbar onset- combination of UMN&LMN signs
LMN UMN
Contributors to disease heterogeneity:
1. Clinical variability→motor phenotypes
2) Progressive bulbar palsy- 4-8% of cases- Localised to bulbar >6 months- Limb strength ~preserved
LMN UMN
Contributors to disease heterogeneity:
1. Clinical variability→motor phenotypes
3) Progressive muscular atrophy (PMA)- 5% of cases- Pure LMN signs >12 mths- “Flail limb”- either the arm or leg
LMN UMN
Contributors to disease heterogeneity:
1. Clinical variability→motor phenotypes
4) Primary Lateral Sclerosis- 1-3% of cases- Pure UMN signs for >3-5 years- Lower-limb onset (typical)
LMN UMN
Contributors to disease heterogeneity:
1. Clinical variability→motor phenotypes
• Balance, coordination• C9orf72 and ATXN mutations• Basal ganglia involvement• Rigidity, slowness, instability
Dharmadasa et al, Handbook in Clinical Neurology; Elsevier 2017
• Heart rate, BP regulation (50%)• Urinary, gastrointestinal• UMN predominant phenotypes
Contributors to disease heterogeneity:
1. Clinical variability- non-motor systems
• ~20% of patients (inc. pain)
Impact of heterogeneity:
Diagnosis delayed
LMN UMN
No diagnostic test for MNDDiagnostic delay is ~14-20 months on average
Vucic S. ACNR 2014;14(5):27-29
Impact of heterogeneity:
Prognosis affected
LMN UMN
Impact of heterogeneity:
Prognosis affected
LMN UMN
2. Motor systems interaction? - Dying forward?- Dying backwards?- Independently?
Impact of heterogeneity:
How does the disease progress?
Neurophysiology
Transcranial Magnetic Stimulation (TMS)
Looking for UMN changes
Novel techniquesCortical hyperexcitability in the brain
Novel techniquesCortical hyperexcitability in the brain
1. An early pathogenic mechanism (Vucic and Kiernan, 2006)
2. Differentiates ALS from mimics (Vucic et al, 2011; Menon et al 2015)
1. Cortical hyperexcitabiltiy is a global phenomonen
2. Changes correspond to the clinically affected side
Clinical change Central dysfunction
**
Novel techniquesCortical excitability
Cortical hyperexcitability is a common finding
1. Disease implications:- Applicable clinical biomarkers- Earlier diagnosis- Prognostic clarification- Prediction of likely trajectory
2. Cortical ‘hot spots’ to target- The “critical trigger” points
3. Trials• Essential to think about clinical
heterogeneity
4. PRECISION MEDICINE
• Supervisors
• Collaborators and colleagues
• Forefront Neurology Clinic,
Brain and Mind Centre, University of Sydney
• Funding • University of Sydney
• MNDRIA
• Yugilbar Foundation
• Rotary Health Australia