Kings Staging Ammar Al-Chalabi ENCALS Training for TRICALS Milan, - PowerPoint PPT Presentation

King’s Staging Ammar Al-Chalabi ENCALS Training for TRICALS Milan, 21-22 May 2016 ammar.al-chalabi@kcl.ac.uk

Staging systems • ALS staging systems proposed – Rehabilitation based scale • Sinaki M, Mayo Clin Proc 1978 – ALS Severity Scale • Hillel AD, Neuroepidemiology 1989 – Riluzole system • Riviere M, Arch Neurol 1998 – Xaliproden system • Lacomblez L, ALS and other MND 2004 – King’s Staging • Roche JC, Brain 2012 – ALS Dashboard • Bravver E, Neurology 2013 – MiToS • Chiò A, JNNP 2015 – Japanese Severity Scale • Japan intractable diseases information center. http://www.nanbyou.or.jp/entry /52

Rationale for a staging system • Objective indication of disease progression • Guides treatment • Health economics • End point in trials

King’s method • Based on neurological regions Bulbar • Modified from regions used in El Escorial criteria Upper limbs • Additional nutritional and respiratory failure criteria – Defined rules Lower limbs – Still works if loosely defined • Highest stage wins

Stage 1: First region involved Stage 1: First region involved Stage 2: Second region involved Stage 2: Second region involved Stage 3: Third region involved Stage 3: Third region involved Stage 4: Nutritional or respiratory failure Stage 4: Nutritional or respiratory failure Stage 4a: Nutritional failure Stage 4b: Respiratory failure Stage 5: Death Stage 5: Death Roche, Brain 2012

Mapping ALSFRS to King’s Stage Bulbar region Any lost Q1-3 involved 1 Q4 Any lost Upper limbs Count regions = Stage 2 or involved 5a 3 Any lost Lower limbs Q8 involved Nutritional Any score Stage 4a Q5b failure Respiratory Stage 4b Score = 0 Q10 failure Any lost Q12 Balendra, ALS and FTD 2014

Mapping ALSFRS to King’s Stage Bulbar region Any lost Q1-3 involved 1 Q4 Any lost Upper limbs Count regions = Stage 2 or involved 5a 3 Any lost Lower limbs Q8 involved Nutritional Any score Stage 4a Q5b failure Respiratory Stage 4b Score = 0 Q10 failure Any lost Q12 Balendra, ALS and FTD 2014

Mapping ALSFRS to King’s Stage 92% correlation with actual stage Bulbar region Any lost Q1-3 involved N = 103 scores 1 Q4 Any lost Upper limbs Count regions = Stage 2 or involved 5a 3 Any lost Lower limbs Q8 involved Nutritional Any score Stage 4a Q5b failure Respiratory Stage 4b Score = 0 Q10 failure Data from King’s College Any lost Hospital Motor Nerve Clinic Q12 Balendra, ALS and FTD 2014

Disease proportion completed Roche, Brain 2012

Disease proportion completed N = 1471 patients Roche, Brain 2012 Data from King’s College Hospital Motor Nerve Clinic

Left censored data Patients seen after diagnosis Disease proportion completed N = 1471 patients Roche, Brain 2012 Data from King’s College Hospital Motor Nerve Clinic

Survival from last recorded stage Face validity = behaves as expected Stage 1 Stage 2 Stages 4a and 4b Stage 3

Stage transition probability To 1 2 3 4 5 No change From 1 N/A 59.3% 31.9% 4.6% 1.0% 3.3% 2 0% N/A 54.0% 17.0% 5.3% 23.7% 3 0% 0% N/A 42.3% 19.0% 38.7% 4 0% 0% 0% N/A 47.0% 53.0% Face validity = behaves as expected Content validity = consistent across studies Balendra, JNNP 2013 Data from LiCALS ( N = 214) and Trophos (N = 511) trials

Duration in each health state • Median Stage Duration IQR (months) 9.4 months (IQR 4.2-16.5) 1 18.4 13.6-26.4 • Bulbar onset 3 to 4a 2 4.8 2.8-7.9 shorter than for limb 3 – 4a 7.9 3.9-11.2 onset 3 – 4b 6.0 3.2-10.8 P = 0.0006 • Bulbar onset 4a to 5 4a 5.9 2.6-9.9 longer than for limb onset 4b 3.2 1.6-5.8 P = 0.0003 Balendra, JNNP 2013 Data from LiCALS ( N = 214) and Trophos (N = 511) trials

Duration in each health state N = 725 430 436 302 260 Death Balendra, JNNP 2013 Data from LiCALS ( N = 214) and Trophos (N = 511) trials

*** *** *** *** 1 2 3 4a 4b Balendra, unpublished

Health utility by stage 1 Error bars are 95% CIs Jones, ALS and FTD 2013 Data from LiCALS (N = 214) trial

Negative change in utility 0.4 Every comparison P < 0.001 0.35 0.38 0.3 0.25 0.26 0.2 0.24 0.15 0.12 0.12 0.1 0.14 0.05 0 2 3 4 Data from LiCALS (N = 214) trial Jones, ALS and FTD 2013

Depression score by stage 1 Error bars are 95% CIs Jones, ALS and FTD 2013 Data from LiCALS (N = 214) trial

Cognitive impairment and King’s clinical stage Trojsi, ALS and FTD 2016

Independent validation King’s staging South Korea time to stage data 60 Error bars are +/-SD 50 40 months 30 20 10 0 2 3 4 0 1 2 3 4 Independent data set Oh, ALS and FTD 2015

Socioeconomic costs of ALS by stage Oh, ALS and FTD 2015

Independent validation King’s staging NFL dataset ALSFRSr data 48 Error bars are +/-SD 36 ALSFRSr score 24 12 1 2-3 4 0 Stage Puentes F, JNNP 2014 Independent data set

NFL antibodies in plasma in ALS er Stage 1 Stages 2 and 3 Stage 4 Puentes F, JNNP 2014 Independent data set

Very simple process Respiratory or Yes nutritional Stage 4 failure? No Count How many regions involved? Stage 1, 2 or 3

Very simple process Respiratory or Yes nutritional Stage 4 failure? No Count How many regions involved? Stage 1, 2 or 3

Respiratory failure defined by NICE guideline • • Symptoms of SNIP No symptoms neuromuscular <40cm H 2 O or decrease > 10cm H 2 O in 3 mths Symptoms respiratory failure < 65cm H 2 O ( ♂ ) – Orthopnoea < 55cm H 2 O ( ♀) – Breathless on exertion • FVC: No symptoms – Excessive daytime <50% predicted. sleepiness Symptoms <80% predicted. • Oximetry measures: SpO 2 at 94% or lower, AND pCO 2 >6kPa or > 5 dips /hr on overnight oximetry

Nutritional failure defined by weight loss and dysphagia • 10% weight loss compared with premorbid • Feeding failure

Very simple process Respiratory or Yes nutritional Stage 4 failure? No Count How many regions involved? Stage 1, 2 or 3

Stages 1 to 3 Bulbar Bulbar symptoms or signs 1 Upper limb Count regions = Stage Upper limbs 2 symptoms or signs 3 Lower limb symptoms or signs Lower limbs

Stages 1 to 3 Bulbar Bulbar symptoms or If a region is obviously involved, signs no need to examine 1 Upper limb Count regions = Stage Upper limbs 2 symptoms or signs 3 Lower limb symptoms or signs Lower limbs

Bulbar and limb symptoms and signs • Symptoms – Bulbar • Slurred speech • Swallowing difficulty • Hoarse voice – Upper limbs • Weakness • Difficulty with keys, zips, locks, buttons – Lower limbs • Weakness • Foot drop, tripping • Stiff leg or legs

Bulbar signs • Slurring dysarthria • Sialorrhoea • Small, wasted tongue • Fasciculation • Slow to move (spastic) • Brisk jaw jerk

Upper limb signs • Weakness • Wasting • Increase or decrease in tone • Loss of reflexes • Brisk reflexes – Pectoral jerks – Finger jerks – Hoffman’s sign

Lower limb signs • Weakness • Wasting • Increase or decrease in tone • Loss of reflexes • Brisk reflexes – Crossed adductor reflex – Ankle clonus

Conclusions • King’s clinical staging is validated in several studies • Behaves as expected in clinic populations and trial populations • Shows some good statistical properties • Balanced throughout disease course

Rubika Balendra Ashley Jones