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

• Modified from regions

used in El Escorial criteria

• Additional nutritional and

respiratory failure criteria

– Defined rules – Still works if loosely defined

• Highest stage wins

Bulbar Upper limbs Lower limbs

Roche, Brain 2012

Stage 5: Death Stage 5: Death Stage 4: Nutritional or respiratory failure Stage 4: Nutritional or respiratory failure

Stage 4a: Nutritional failure Stage 4b: Respiratory failure

Stage 3: Third region involved Stage 3: Third region involved Stage 2: Second region involved Stage 2: Second region involved Stage 1: First region involved Stage 1: First region involved

Q1-3 Bulbar region involved Q4

• r

5a Upper limbs involved Q8 Lower limbs involved Q5b Nutritional failure Q10 Respiratory failure Q12 Any lost Any lost Any lost Any score Score = 0 Any lost

Stage 4a Stage 4b Count regions = Stage

Mapping ALSFRS to King’s Stage

Balendra, ALS and FTD 2014

1 2 3

Q1-3 Bulbar region involved Q4

• r

5a Upper limbs involved Q8 Lower limbs involved Q5b Nutritional failure Q10 Respiratory failure Q12 Any lost Any lost Any lost Any score Score = 0 Any lost

Stage 4a Stage 4b Count regions = Stage

Mapping ALSFRS to King’s Stage

Balendra, ALS and FTD 2014

1 2 3

Q1-3 Bulbar region involved Q4

• r

5a Upper limbs involved Q8 Lower limbs involved Q5b Nutritional failure Q10 Respiratory failure Q12 Any lost Any lost Any lost Any score Score = 0 Any lost

Stage 4a Stage 4b Count regions = Stage

Mapping ALSFRS to King’s Stage

Balendra, ALS and FTD 2014

92% correlation with actual stage 1 2 3

N = 103 scores Data from King’s College Hospital Motor Nerve Clinic

Disease proportion completed

Roche, Brain 2012

Disease proportion completed

Roche, Brain 2012

Data from King’s College Hospital Motor Nerve Clinic

N = 1471 patients

Left censored data Patients seen after diagnosis

Disease proportion completed

Roche, Brain 2012

Data from King’s College Hospital Motor Nerve Clinic

N = 1471 patients

Survival from last recorded stage

Stage 1 Stage 2 Stage 3 Stages 4a and 4b

Face validity = behaves as expected

1 2 3 4 5 No change 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%

Stage transition probability

Balendra, JNNP 2013

Data from LiCALS (N = 214) and Trophos (N = 511) trials

To

From Face validity = behaves as expected Content validity = consistent across studies

Duration in each health state

• Median

9.4 months (IQR 4.2-16.5)

• Bulbar onset 3 to 4a

shorter than for limb

• nset

P = 0.0006

• Bulbar onset 4a to 5

longer than for limb onset

P = 0.0003

Stage Duration (months) IQR 1 18.4

13.6-26.4

2 4.8

2.8-7.9

3 – 4a 7.9

3.9-11.2

3 – 4b 6.0

3.2-10.8

4a 5.9

2.6-9.9

4b 3.2

1.6-5.8 Balendra, JNNP 2013

Data from LiCALS (N = 214) and Trophos (N = 511) trials

Duration in each health state

Balendra, JNNP 2013

Data from LiCALS (N = 214) and Trophos (N = 511) trials N = 725 430 436 302 260 Death

*** *** *** ***

1 2 3 4a 4b

Balendra, unpublished

Health utility by stage

1

Data from LiCALS (N = 214) trial

Jones, ALS and FTD 2013

Error bars are 95% CIs

0.05 0.1 0.15 0.2 0.25 0.3 0.35 0.4

2 3 4 0.12 0.24 0.38 0.12 0.26 0.14

Negative change in utility

Jones, ALS and FTD 2013

Every comparison P < 0.001 Data from LiCALS (N = 214) trial

Depression score by stage

1 Jones, ALS and FTD 2013

Data from LiCALS (N = 214) trial Error bars are 95% CIs

Cognitive impairment and King’s clinical stage

Trojsi, ALS and FTD 2016

Independent validation King’s staging South Korea time to stage data

10 20 30 40 50 60 1 2 3 4

2 3 4

months

Independent data set Oh, ALS and FTD 2015 Error bars are +/-SD

Socioeconomic costs of ALS by stage

Oh, ALS and FTD 2015

Independent validation King’s staging NFL dataset ALSFRSr data

12 24 36 48

ALSFRSr score

Stage 1 2-3 4

Puentes F, JNNP 2014

Independent data set Error bars are +/-SD

NFL antibodies in plasma in ALS

Stage 1 Stages 2 and 3 Stage 4

er Puentes F, JNNP 2014

Independent data set

Respiratory or nutritional failure? Stage 4 How many regions involved? Stage 1, 2 or 3

Very simple process

Yes No Count

Respiratory or nutritional failure? Stage 4 How many regions involved? Stage 1, 2 or 3

Very simple process

Yes No Count

Respiratory failure defined by NICE guideline

• SNIP

No symptoms <40cm H2O or decrease > 10cm H2O in 3 mths Symptoms < 65cm H2O (♂) < 55cm H2O (♀)

• FVC:

No symptoms <50% predicted. Symptoms <80% predicted.

• Oximetry measures:

SpO2 at 94% or lower, AND pCO2 >6kPa or > 5 dips /hr on overnight oximetry

• Symptoms of

neuromuscular respiratory failure

– Orthopnoea – Breathless on exertion – Excessive daytime sleepiness

Nutritional failure defined by weight loss and dysphagia

• 10% weight loss

compared with premorbid

• Feeding failure

Respiratory or nutritional failure? Stage 4 How many regions involved? Stage 1, 2 or 3

Very simple process

Yes No Count

Stages 1 to 3

Count regions = Stage 1 2 3

Bulbar symptoms or signs

Upper limbs

Upper limb symptoms or signs

Bulbar Lower limbs

Lower limb symptoms or signs

Stages 1 to 3

Count regions = Stage 1 2 3

Bulbar symptoms or signs

Upper limbs

Upper limb symptoms or signs

Bulbar Lower limbs

Lower limb symptoms or signs

If a region is obviously involved, no need to examine

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

Ashley Jones Rubika Balendra