Motor Neurone Disease (MND): An overview Suresh Chhetri MD, FRCP, - PowerPoint PPT Presentation

Motor Neurone Disease (MND): An overview Suresh Chhetri MD, FRCP, FHEA Consultant Neurologist and Co-Director Lancashire and South Cumbria MND care and Research centre Royal Preston Hospital

Declaration of interests Funding from GBT

Amyotrophic lateral sclerosis (ALS) 1881: Jean-Martin Charcot, French neurobiologist and physician.

Amyotrophic lateral sclerosis (ALS) • Amyotrophy: muscle atrophy • Lateral: lateral corticospinal tracts • Sclerosis: scarring or hardening

UMN and LMN pathways Damjanov, I. (Ed.). (2012). Pathology for the health-related professions . Saunders, Elsevier, Missouri, pp. 437

Nomenclature Motor Neurone Disease (Brain, 1962 ) Brain, W. R. Motor Neurone Disease (1962). In W. R. Brain (Ed.), Diseases of the Nervous System. Oxford University Press, London, pp. 531-543.

Lou Gehrig's disease “……for some reason that I do not know, his old power isn’t there . . . He is meeting the ball, time after time, and it isn’t going anywhere….”

Epidemiology • Mean age 55 to 65 years • Incidence: 1.5 - 2.5 cases/100,000/year • Median prevalence: 5.4/100,000 ((IQR 4.06– 7.89) • 5000 individuals with MND in UK Alonso et al. Eur J Neurol, 2009; 16:745-51 Hoppitt T et al. Neuroepidemiology, 2011; 36:19–28 Chio et al. Neuroepidemiology, 2013; 41:118–30

Age groups at symptom onset (n = 340) Chhetri et al. J Clin Neurosci, 2016;24:47-51

Epidemiology • Males > Females (1.5:1) • Lifetime risk : 1 in 350 for men and 1 in 472 for women Alonso et al. Eur J Neurol, 2009; 16:745-51 Hoppitt T et al. Neuroepidemiology, 2011; 36:19–28 Chio et al. Neuroepidemiology, 2013; 41:118–30

Clinical features • Marked phenotypic variability • Progressive weakness and wasting • Limb • Bulbar • Respiratory muscles Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Clinical features - symptoms • Muscle wasting and weakness • Muscle twitching/cramps • Sensory, EOM and sphincters spared Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Clinical features – symptoms • Limb onset : roughly 60% • Muscle weakness and wasting • Cramps • Impaired hand dexterity • Leg weakness/heaviness • Difficulty walking/foot drop Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Clinical features – symptoms • Bulbar onset : 30% (eventually 80%) • Difficulty swallowing • Dysarthria • Sialorrhoea • Females more commonly affected • Respiratory onset: 3 - 5% Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Clinical features – signs • Signs of UMN and/or LMN degeneration • UMN features • Preservation of reflexes in a wasted extremity

Bulbar dysfunction • Pseudobulbar palsy • Spastic dysarthria • Slow and spastic tongue movements • Brisk jaw jerk • Emotional lability • Bulbar palsy • Flaccid dysarthria • Tongue wasting and fasciculations Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Clinical features – signs Tiryaki et al. Continuum. 2014; 20 :1185-1207

Clinical features • Head drop • Progressive hemiplegia (Mills variant) Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Cruel………. “There was no hope in it anywhere along the line, just downhill going, every day a little more downhill . . . [He] just died away by inches, every day a little bit more . . . . Eleanor Gehrig

Split hand syndrome Eisen et al. JNNP, 2012; 83 :399-403

Wasting

Wasting Kiernan et al. Lancet, 2011;377:942-955

“Creeping paralysis”

Variants • Amyotrophic lateral sclerosis • Progressive bulbar palsy • Progressive muscular atrophy • Primary lateral sclerosis • Other rare variants • Familial motor neurone disease Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Progressive muscular atrophy • Pure LMN dysfunction • 2.4 to 7.6% of cases with sporadic MND • Median survival of 48 to 56 months Visser et al. Neurology, 2008; 70 :723-727 Kim et al. Neurology,2009; 73 :1686-1692

Primary Lateral Sclerosis • Progressive pure upper motor syndrome • 1.6 to 4.4% of patients with MND • Patients report stiffness and clumsiness rather than weakness as compared to ALS Gordon et al. Neurology, 2006; 66:647-653 Singer et al. Muscle and Nerve, 2007;35:291-302

Primary Lateral Sclerosis • UMN signs and absence of LMN signs • No evidence of denervation on EMG at 4 years • 77% develop LMN clinical or EMG features • Median survival of 13.1 years and a 10 year survival rate of 71.1% Gordon et al. Neurology, 2006;66:647-653 Singer et al. Muscle and Nerve, 2007;35:291-302 Chio et al. JNNP, 2011; 82 :740-746

Familial MND • 5 to 10% of cases (Renton et al., 2014) • Most cases are autosomal dominant (Renton et al., 2014) Renton et al. Nature Neuroscience, 2014;17:17-23 Brown et al. N Engl J Med. 2017;377:1602

The story of genes Brown et al. N Engl J Med. 2017;377:1602

Aetiology • Remains unknown • Occupation • Physical activity • Alcohol • Environmental toxins • Smoking Ingre et al. Clinical Epidemiology, 2015; 7:181–193

Pathogenesis • Multifactorial • Complex interactions between genetic and molecular pathways

Hardiman et al. Nat Rev Dis Primers. 2017;3:17085

The ‘myths’ Wicks P. Eur J Neurol 2012; 19: 531–32.

Heterogeneity of MND

• Neurodegenerative rather than neuromuscular • Complex multisystem disorder • Marked heterogeneity • Degeneration of motor system unifying feature Curr Opin Neurol. 2017;30:599-607

Prognosis • Median survival varies from 20 to 48 months • 3 and 5 year survival rates: approximately 48% and 24% respectively • About 4% survive longer than 10 years after symptom onset Testa et al , Amyotroph Lateral Scler Other Motor Neuron Disord, 2004; 5 :208-212 Turner et al , JNNP, 2003;, 74 :995-997. Beghi et al. Amyotrophic Lateral Sclerosis, 2011; 12 :1-10

King’s Staging • Stage 1: One region functionally involved (symptom onset) • Stage 2: Two regions functionally involved • Stage 3: Three regions functionally involved • Stage 4: As above + • Nutritional failure/need for gastrostomy (4A) or • Respiratory failure/need for noninvasive ventilation (4B) • Stage 5: Death Roche et al. Brain, 2012:;135: 847–852 Balendra, R. et al. JNNP , 2015; 86:45–49

Milestones • Predictable time points over the disease course • Median of 3–7 months spent at each milestone for stages 2 to 4 Balendra. et al. JNNP 2015; 86 :45–49

Prognostic indicators • Age • Phenotype e.g. bulbar onset • Early respiratory dysfunction • Nutritional status • Executive dysfunction • Rapid progression of symptoms • Short time from symptom onset to diagnosis • Access to MDT Kiernan et al. Lancet, 2011;377:942-955 Hardiman et al. Nat Rev Dis Primers. 2017;3:17085 van Es et al. Lancet 2017; 390: 2084–98

Diagnosis • Clinical (criteria e.g. Revised El Escorial) • No diagnostic test • No Biomarkers • Exclusion of MND mimics • Diagnostic delay of 12 months

Revised El Escorial criteria • Clinically Definite: Mixed signs in 3 regions • Clinically Probable: Mixed sings in 2 regions with some UMN sings rostral to LMN signs • Clinically Probable – Laboratory supported: UMN signs in at least one region with EMG evidence of LMN loss in two regions • Clinically Possible: UMN and LMN signs in one region, or UMN signs in two regions, or UMN and LMN signs in two regions but no UMN rostral to LMN signs Brooks et al. Amyotroph Lateral Scler Other Motor Neuron Disord 2000: 293–99

Treatment • No cure • Symptomatic and supportive • Quality of life

“When [no therapy] avails to ward off the fatal ending, it is still no small portion of [the physician's] art to rid his patient's path of thorns if he cannot make it bloom with roses.” Alfred Stille

Thank you