Published Ahead of Print on February 1, 2019 as 10.1212/WNL.

0000000000006876
ARTICLE CLASS OF EVIDENCE

Amyotrophic lateral sclerosis diagnostic index

Toward a personalized diagnosis of ALS
Nimeshan Geevasinga, PhD, James Howells, PhD, Parvathi Menon, PhD, Mehdi van den Bos, PhD, Correspondence
Kazumoto Shibuya, MD, José Manuel Matamala, MD, Susanna B. Park, PhD, Karen Byth, PhD, Prof. Vucic
Matthew C. Kiernan, DSc, and Steve Vucic, PhD steve.vucic@sydney.edu.au

®
Neurology 2019;92:e536-e547. doi:10.1212/WNL.0000000000006876

Abstract RELATED ARTICLE

Objective Editorial
The aim of the study was to assess the utility of a novel amyotrophic lateral sclerosis (ALS) Upper motor neuron
diagnostic index (ALSDI). assessment and early
diagnosis in ALS: Getting it
Methods right the first time
A prospective multicenter study was undertaken on patients presenting with suspected ALS. Page 255
The reference standard (Awaji criteria) was applied to all patients at recruitment. Patients were
randomly assigned to a training (75%) and a test (25%) cohort. The ALSDI was developed in MORE ONLINE

the training cohort and its diagnostic utility was subsequently assessed in the test cohort.
Class of Evidence
Criteria for rating
Results therapeutic and diagnostic
A total of 407 patients were recruited, with 305 patients subsequently diagnosed with ALS and studies
102 with a non-ALS mimicking disorder. The ALSDI reliably differentiated ALS from neu-
NPub.org/coe
romuscular disorders in the training cohort (area under the curve 0.92, 95% confidence interval
0.89–0.95), with ALSDI ≥4 exhibiting 81.6% sensitivity, 89.6% specificity, and 83.5% diagnostic
accuracy. The ALSDI diagnostic utility was confirmed in the test cohort (area under the curve
0.90, 95% confidence interval 0.84–0.97), with ALSDI ≥4 exhibiting 83.3% sensitivity, 84%
specificity, and 83.5% diagnostic accuracy. In addition, the diagnostic utility of the ALSDI was
confirmed in patients who were Awaji negative at recruitment and in those exhibiting a pre-
dominantly lower motor neuron phenotype.

Conclusion
The ALSDI reliably differentiates ALS from mimicking disorders at an early stage in the disease
process.

Classification of evidence
This study provides Class I evidence that for patients with suspected ALS, the ALSDI distin-
guished ALS from neuromuscular mimicking disorders.

From Westmead Clinical School (N.G., P.M., M.v.d.B., S.V.), Brain and Mind Center (J.H., K.S., J.M.M., S.B.P., M.C.K.), and NHMRC Clinical Trials Centre (K.B.), University of Sydney; and
Westmead Hospital (K.B.), Research and Education Network, Sydney, Australia.

Go to Neurology.org/N for full disclosures. Funding information and disclosures deemed relevant by the authors, if any, are provided at the end of the article.

e536 Copyright © 2019 American Academy of Neurology

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Glossary
ALS = amyotrophic lateral sclerosis; ALSDI = amyotrophic lateral sclerosis diagnostic index; ALSFRS-R = Amyotrophic Lateral
Sclerosis Functional Rating Scale–Revised; AUC = area under the curve; CI = confidence interval; CMAP = compound muscle
action potential; CSP = cortical silent period; ICF = intracortical facilitation; LMN = lower motor neuron; MEP = motor
evoked potential; MRC = Medical Research Council; OR = odds ratio; SICI = short-interval intracortical inhibition; TMS =
transcranial magnetic stimulation; UMN = upper motor neuron.
Amyotrophic lateral sclerosis (ALS) is a progressive neuro-
degenerative disorder of the human motor system, charac-
terized by a progressive loss of upper motor neurons (UMNs)
and lower motor neurons (LMNs) (and interneurons),
resulting in initial dysfunction and later total loss of function
of the aforementioned neurons.1,2 The diagnosis of ALS
remains reliant on identification of concurrent UMN and
LMN signs,3–5 along with evidence of disease progression and
exclusion of neuromuscular mimicking disorders.2,6 In the
absence of a pathognomonic test and a heterogeneous clinical
phenotype, significant diagnostic delays have been reported.7–9
Consequently, institution of appropriate management strategies,
including neuroprotective therapies and recruitment into clinical
trials may be critically delayed, perhaps beyond the putative
therapeutic window period.10,11
A greater understanding of ALS pathophysiology has led to
identification of novel therapeutic approaches,2 and the
consequent need for efficient clinical trial designs. Despite
this need, the diagnostic algorithm remains complex, resulting
in uncertainty in requirements for patient recruitment.
Attempts to develop more efficient ALS diagnostic criteria led
to the first international workshop resulting in the clinically
based El Escorial criteria.3 Subsequently, the neurophysio-
logically based Awaji criteria were developed as an add-on to
the El Escorial diagnostic criteria.5 The Awaji criteria exhibi-
ted greater sensitivity,12–20 but the diagnostic benefits were
most prominent in bulbar-onset ALS.16 Incorporation of the
“clinically probable laboratory-supported” diagnostic cate-
gory, necessitating the identification of UMN and LMN
dysfunction in one region, increased the sensitivity of the
Awaji criteria.21 More recently, a further revision of the El
Escorial criteria was proposed, whereby identification of
UMN and/or LMN signs in one region was considered di-
agnostic.22 Given the reliance of clinical identification of
UMN dysfunction and difficulties in identifying UMN signs
in patients with ALS,23 the sensitivity of these diagnostic
criteria could be enhanced by objective assessment of the
corticomotoneuronal system.
Transcranial magnetic stimulation (TMS) techniques enable
an objective assessment of the UMN functional integrity in
human CNS. Of importance, cortical hyperexcitability was
identified as an early and specific feature in ALS, clearly dif-
ferentiating ALS from neuromuscular mimic disorders.24–26
Separately, cortical hyperexcitability was reported in atyp-
ical ALS phenotypes,27,28 underscoring the importance of
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subclinical UMN dysfunction as a diagnostic biomarker of
ALS. In addition, it has been postulated that cortical hy-
perexcitability is an adverse prognostic biomarker in ALS,29
evolving with disease progression.30 Although TMS di-
agnostic criteria for diagnosis of ALS have been previously
reported,26 these have not been validated in independent
cohorts.31 In addition, the current ALS diagnostic process
is complex, relying on the identification of numerous
clinical and neurophysiologic abnormalities. Consequently,
the aim of the present study was to use multivariable sta-
tistical analysis to develop a diagnostic score for ALS in-
corporating clinical, conventional neurophysiologic and
TMS measures available on recruitment, termed the ALS
diagnostic index (ALSDI), in order to reliably differentiate
ALS from neuromuscular disorders. The ALSDI test was
developed in the randomly selected training cohort and its
performance subsequently assessed in the independent
validation test cohort to minimize potential bias.32
Methods
Study design and patients
In this prospective study undertaken according to the STARD
(Standards for Reporting of Diagnostic Accuracy Studies)
criteria, potential participants were identified following de-
tailed clinical and neurophysiologic assessment at 2 neuro-
muscular centers integrated through Sydney Health Partners,
University of Sydney. Subsequently, patients were consecu-
tively and prospectively recruited in accordance with the in-
clusion criteria. The investigators were blinded at the time of
enrollment to the final diagnosis, which was established after
at least 6 months of follow-up. The investigators that per-
formed TMS testing were blinded to the eventual diagnosis
at TMS assessment. The inclusion criteria were as follows:
(1) pure LMN syndrome, (2) mixed UMN and LMN syn-
drome, or (3) UMN syndrome. Patients were recruited early
in the disease process, with the median duration of disease
onset in the ALS cohort 12 months (interquartile range 7–20
months).
The exclusion criteria included the following: (1) use of psy-
chotropic medications that could potentially affect TMS
measures; (2) acute migraine headache within 4 weeks pre-
ceding assessment; (3) history of other neurologic diseases
including movement disorders, epilepsy, stroke, or TIA; (4) in
situ pacemakers and other cardiac devices, cochlear implants;
(5) history of brain or cerebrovascular surgery; (6) patients
Neurology | Volume 92, Number 6 | February 5, 2019 e537
 taking neurotropic drugs such as baclofen, tizanidine, or Neu-
rontin; and (7) marked wasting of the target muscle precluding
recording of motor evoked potential (MEP) responses. Written
informed consent for the procedures was provided by all partic-
ipants, and the study was approved by both the Western Sydney
Local Health District and South East Sydney Area Health Service
Human Research Ethics Committees.
Procedures
At recruitment, all enrolled patients underwent clinical phe-
notyping, peripheral neurophysiology, and threshold tracking
TMS testing performed by 5 examiners (N.G., P.M., M.v.d.B.,
K.S., J.M.M.) with the necessary technical expertise. Medical
Research Council (MRC) scoring was used to assess the
muscle strength in the upper and lower limbs from the fol-
lowing muscle groups: shoulder abduction, elbow flexion/
extension, wrist dorsiflexion, finger and thumb abduction, hip
flexion, knee extension, and ankle dorsiflexion. Muscle strength
was assessed bilaterally yielding a maximum MRC score of
90 (indicating normal strength). UMN function was clini-
cally assessed using the previously reported UMN score.33
The site of disease onset and disease duration (from symp-
tom onset) was recorded for each patient.
Threshold tracking TMS was applied to all patients according
to a previously reported technique.34 The MEP responses
were recorded over the abductor pollicis brevis muscle. The
reason for selecting the abductor pollicis brevis relates to the
fact that in patients with ALS, cortical hyperexcitability was
most prominent when recorded over this muscle.35 Furthermore,
assessing cortical excitability is time-consuming and as such we
limited the assessment to the most affected upper limb rather
than 4 limbs. The following TMS measures were calculated34:
1. Resting motor threshold, defined as the stimulus
intensity required to produce and maintain a target
MEP response of 0.2 mV (±20%)
2. MEP amplitude, expressed as percentage of compound
muscle action potential (CMAP) response
3. Cortical silent period (CSP) duration (milliseconds)
4. Short-interval intracortical inhibition (SICI) and intra-
cortical facilitation (ICF).

Figure 1 Classification and regression tree for the training cohort

The tree includes the UMN score along with other continuous covariates and categorical variables, including the site of onset and inexcitability status. The
UMN score has replaced some of the other covariates, but it should be noted that this variable was systematically missing more often in the non-ALS group.
The inexcitability status and averaged SICI were of clear value in both the training and test sets. The overall performance in the training cohort was 89.6%.
Adj. = adjusted; ALS = amyotrophic lateral sclerosis; df = degrees of freedom; SICI = short-interval intracortical inhibition; UMN = upper motor neuron.

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Figure 2 Classification and regression tree for the training cohort

The tree includes the UMN score along with the other continuous covariates and the categorical variables site of onset and inexcitability status. The UMN
score has replaced some of the other covariates, but it should be noted that this variable was systematically missing more often in the non-ALS group. The
inexcitability status and averaged SICI were of clear value in both the training and test sets. The overall performance in the test cohort was 86.8%. Adj. =
adjusted; ALS = amyotrophic lateral sclerosis; df = degrees of freedom; SICI = short-interval intracortical inhibition; UMN = upper motor neuron.

In the same sitting, the degree of LMN dysfunction was de-
termined by electrically stimulating the median nerve at the wrist
and recording the peak-peak CMAP amplitude, distal motor
latency, F-wave latency, and frequency. The neurophysiologic
index was determined using a previously reported formula.36
Reference standard
The reference standard was the Awaji diagnostic criteria.5 A
positive reference standard was regarded as classification into
a definite, probable, or possible category based on assessment
at recruitment (first visit).
Statistical methods
The software IBM SPSS Statistics version 23 (IBM Corp.,
Armonk, NY) was used to analyze the data. Continuous
variables were summarized using mean and SD or median and
lower quartile to upper quartile as appropriate. Frequencies or
percentages were used to summarize categorical variables.
Chi-squared tests (or exact permutation tests if appropriate)
were used to test for univariable associations between cate-
gorical variables. Two-tailed tests with a significance level of
5% were used throughout.
Before developing a diagnostic index for ALS at final diagnosis
based on clinical and neurophysiologic measures assessed at
recruitment, SPSS was used to split the dataset at random
in a 3:1 ratio into the training cohort (approximately 75%
of study participants) and the remaining independent test
cohort (approximately 25%). The 3:1 ratio was deemed
optimal to assess the accuracy of the ALSDI based on ad-
vice from the biostatistician (K.B.). The ALSDI was de-
veloped in the training cohort. The receiver operating
characteristic curve for ALSDI in the training cohort was
used to determine an appropriate cutpoint for the index
test. The diagnostic performance of ALSDI was sub-
sequently assessed in the independent test cohort to min-
imize potential bias.32
The primary outcome measure was the diagnostic utility of
ALSDI in differentiating ALS from non-ALS neuromuscular
disorders in the test cohort. The area under the receiver op-
erating characteristic curve (AUC) was used to quantify the
diagnostic utility of ALSDI. Sensitivity, specificity, positive
and negative predictive values, diagnostic odds ratios (ORs),
and accuracy for particular ALSDI cutpoints, together with

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 their 95% confidence intervals (CIs), were calculated for the
training and test cohorts.
Continuous clinical and neurophysiologic variables were each
split into 4 categories based on quartiles before assessing their
univariable association with ALS in the training cohort. The
following variables were assessed: age, sex, onset site, inex-
citable motor cortex status, resting motor threshold, CMAP
amplitude, F-wave latency, central motor conduction time,
MEP amplitude, neurophysiologic index, SICI, ICF, and CSP
duration. All patients in the training set with an “inexcitable”
motor cortex at recruitment were considered to ALS at final
diagnosis. Therefore, it was decided to exclude the “inex-
citable” patients and to identify the independent predictors of
ALS in the training cohort for those with an “excitable” motor
cortex using multiple logistic regression analysis. Measures
associated with ALS at a significance level of p < 0.1 in the
“excitable” subgroup were considered as candidates for in-
clusion in the multivariable model. Multiple logistic re-
gression with backward stepwise variable selection was used
to identify the independent predictors of ALS in the excitable
subgroup of the training cohort. By rounding the B coef-
ficients of the best-fitting logistic regression model to the
nearest integer, a score was assigned to each category of the
independent predictors. These scores were then summed to
produce the ALSDI for “excitable” patients. The ALSDI for
“inexcitable” patients was calculated by adding 1 to the
maximum possible ALSDI of 28 for “excitable” patients. The
ALSDI was then computed for patients in the test cohort
and its diagnostic performance assessed as described ear-
lier. Separately, a sensitivity analysis was conducted using
a classification and regression tree (figure 1 [training co-
hort] and figure 2 [test cohort]) to further explore the
relationship between the variables obtained.
Data availability
Individual deidentified participant data, related documents
such as study protocol, and statistical analysis will be shared
on request from any qualified investigator for 3 years after the
date of publication.
Results
Participants
Between January 1, 2010, and July 1, 2017, we screened
and recruited 407 patients (245 men, 162 women, mean age

Figure 3 Flow diagram for the study

After the study was closed and all patient data had been collated, the dataset was split at random in a 3:1 ratio into the training cohort (approximately 75% of
study participants) and a test cohort (approximately 25%). The index test was developed in the training cohort and its performance then assessed in the
independent test cohort. In this flow diagram, a positive index test was defined as ALSDI ≥4. ALS = amyotrophic lateral sclerosis; ALSDI = amyotrophic lateral
sclerosis diagnostic index.

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58.7 ± 13.6 years) who satisfied the inclusion criteria and
presented consecutively to the neuromuscular clinics (Sydney
Health Partners, University of Sydney, Australia) (figure 3).
In total, 305 patients were eventually diagnosed with ALS
after at least 6 months of follow-up. At recruitment, 87 (29%)
of these patients with ALS were classified as Awaji definite, 83
(27%) Awaji probable, 87 (29%) Awaji possible, and 48
(16%) did not meet the Awaji diagnostic criteria. All patients
classified as Awaji negative progressed to develop ALS and
were Awaji definite or probable at the final assessment.
Twenty-six (6%) of the 407 recruited patients could not un-
dergo TMS testing because of marked wasting of the re-
cording (thenar) muscle. One hundred two patients were
finally diagnosed with a non-ALS neuromuscular mimicking
disorder after extensive investigation and failure of disease
progression after at least 6 months of follow-up (table 1 and
figure 3). They served as pathologic controls. None of the
patients with non-ALS neuromuscular mimicking disorder
were excluded from the analysis. The patients with ALS were
older and exhibited a greater degree of muscle weakness and
more prominent UMN signs (table 1). They were clinically
staged using the ALS Functional Rating Scale–Revised
(ALSFRS-R),37 which disclosed a moderate degree of func-
tional disability at final diagnosis (mean ALSFRS-R score
40.6, SD 6.0).
Table 1 summarizes the age of patients, sex, disease duration,
total MRC score, lower and upper limb MRC scores, and
UMN score at final diagnosis. Age older than 50 years, bulbar-
onset disease, motor cortex inexcitability, prominent UMN
signs, reduced CMAP amplitude, reduced neurophysiologic in-
dex, CSP duration, and SICI, as well as increased MEP amplitude
and ICF at recruitment were all significantly association with
ALS at final diagnosis.
Table 2 discloses the independent predictors (age of patient,
site of disease onset, CMAP amplitude, CSP duration, and
SICI) in the best-fitting multiple logistic regression model
for ALS in the training cohort with an excitable motor cortex.
The scores obtained for the categories of each independent
predictor were derived by rounding the B coefficients to the
nearest integer and are set out in table 3. The novel ALSDI
score was defined as the sum of the scores for each in-
dependent predictor and ranged from 0 (no ALS) to 28
(strongly predictive of ALS). Patients with an inexcitable
motor cortex at recruitment were allocated an ALSDI score
of 29. This ALSDI is the index test. Reduction or absence of
SICI made the largest contribution to the overall ALSDI
score, a fact that is important given that SICI exhibits the
highest interrater reliability of all threshold tracking TMS
measures.38
In the training cohort, the ALSDI showed “excellent” di-
agnostic utility with an AUC of 0.92 (95% CI 0.89–0.95)
(figure 4). An ALSDI ≥4 exhibited a diagnostic OR of 38.2,
sensitivity 81.6%, specificity 89.6%, and diagnostic accuracy
83.5% (table 4), while an ALSDI ≥5 had a diagnostic OR of
154, with sensitivity of 66.9%, specificity 98.7%, and di-
agnostic accuracy 74.7%.
Impressively, the diagnostic utility of the ALSDI was con-
firmed in the independent validation test cohort where the
AUC was 0.90 (95% CI 0.84–0.97) (figure 4B), being com-
parable to that for the training cohort. In the test cohort, an
ALSDI value ≥4 exhibited a diagnostic OR of 26.3, sensitivity
83.3%, specificity 84%, and diagnostic accuracy of 83.5%
(table 4). An ALSDI ≥5 had a diagnostic OR of 59.4, sensi-
tivity 71.2%, specificity 96%, and diagnostic accuracy 78%
(table 4). Of note, the AUC for the ALSDI was greater when

Table 1 Clinical and demographic features of patients with ALS and neuromuscular mimic disorders
Neuromuscular ALS mimic disorders (n = 102) ALS excitable (n = 248) ALS inexcitable (n = 57)

Median 25th % 75th % Median 25th % 75th % Median 25th % 75th %

Age, y 53 40 63 62 54 70 62 48 69

Disease duration, y 48 14 120 184 151 209

MRC sum 90 86 90 82 76 87 84 71 89

MRC upper limb 60 57 60 56 50 60 54 44 60

MRC lower limb 30 30 30 28 24 30 30 28 30

UMN score 0 0 0 10 3 12 13 12 14

Men, % 66 (65) 150 (60) 29 (51)

Women, % 36 (35) 98 (40) 28 (49)

Abbreviations: ALS = amyotrophic lateral sclerosis; MRC = Medical Research Council; UMN = upper motor neuron.
All data are expressed as mean (SD) or median (interquartile range). The neuromuscular mimic disorder group included acquired neuromyotonia syndrome
(26), hereditary spastic paraplegia (12), myopathy (12), Kennedy disease (9), Hirayama disease (8), pure motor chronic inflammatory demyelinating neu-
ropathy (7), multifocal motor neuropathy (7), spinal muscular atrophy (6), FOSMN (facial-onset sensory and motor neuronopathy) syndrome (4), distal
hereditary motor neuronopathy with pyramidal features (3), postpolio syndrome (2), cervical radiculopathy (2), Pompe disease (2), lumbosacral radiculopathy
(1), and lead toxicity (1). A majority of patients classified as “myopathy” were diagnosed with inclusion body myositis (75%). All patients were assessed using
the MRC and UMN scores. The UMN score was not available for 15% of patients without ALS and 2.6% of patients with ALS.

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 Table 2 Best-fitting model for amyotrophic lateral sclerosis in the subgroup of the training cohort with an “excitable”
cortex obtained using multiple logistic regression with backward stepwise variable selection
Measure B coefficient Odds ratio 95% CI p Value

Age at assessment, y

<50R

51.0–60 1.302 3.68 1.319–10.238 0.013a

61–70 1.280 3.60 1.225–10.552 0.020a

>71 1.327 3.77 1.018–13.963 0.047a

Site of disease onset

Bulbar 1.760 5.82 1.586–21.313 0.008a

Limb

Median nerve CMAP amplitude, mV

<5.0 1.411 411 1.376–12.289 0.011a

5.01–7.0 −0.042 0.96 0.351–2.617 0.936

7.01–9.0 0.375 1.46 0.493–4.297 0.497

R
>9.01

CSP duration, ms

≤160.0 2.501 12.20 3.409–43.626 <0.001a

160.1–190.0 1.323 3.76 1.221–11.552 0.021a

190.1–220.0 1.686 5.40 1.907–15.279 0.001a

>220.1R

Mean SICI, %

≤0.0 20.889 >100 <0.001a

0.1–6.0 1.586 4.89 1.681–14.204 0.004a

6.1–12.0 −0.809 0.45 0.187–1.061 0.068

R
>12.1

Abbreviations: CI = confidence interval; CMAP = compound muscle action potential; CSP = cortical silent period; R = reference; SICI = short-interval intracortical
inhibition.
Five independent predictors were identified, namely, age at assessment, site of disease onset, median nerve CMAP amplitude, CSP duration, and mean SICI.
a
Significant.

compared to the Awaji criteria (figure 4C), although the dif-
ference was not significant as indicated by overlapping
95% CIs.
From the above it was determined that the sensitivity and
diagnostic accuracy were higher for both cohorts when an
ALSDI cutpoint of 4 was used. Consequently, in the subgroup
analyses, based on Awaji positive versus negative status at
recruitment, and prominent UMN signs (UMN score >3)
versus paucity of UMN signs (UMN score < 3), we therefore
assessed the diagnostic utility of ALSDI ≥4.
An ALSDI ≥4 exhibited a comparable sensitivity and di-
agnostic accuracy in patients initially classified as Awaji neg-
ative and positive (table 4). Specifically, in patients who were
Awaji negative, ALSDI ≥4 exhibited 79.2% sensitivity, 91.8%
specificity, diagnostic OR 42.3, and 87.2% accuracy compared
to 82.5%, 70.6%, 11.3, and 81.8%, respectively, in patients
who were Awaji positive (table 4). Of note, application of the
index test (ALSDI ≥4) in patients initially classified as Awaji
negative (n = 133) resulted in identification of an extra 38
patients with ALS (29%) at the risk of misclassifying 7 non-
ALS patients as ALS.
The diagnostic utility of the index test (ALSDI ≥4) was also
established in predominantly LMN phenotypes of ALS.
Specifically, ALSDI ≥4 had comparable sensitivity in patients
expressing a paucity of UMN signs (UMN score <3) and in
those with prominent UMN signs (UMN ≥3) (table 4). It
should be stressed that the UMN score was not recorded in
15% of patients without ALS and 2.6% of patients with ALS,
and these patients were excluded from the analysis. Of

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Table 3 The ALSDI was derived by rounding to the
nearest integer the B coefficient values shown in
table 2 for the independent predictors of ALS in
the subgroup of the training cohort with an
“excitable” cortex
Measure
100%, and all of these patients were eventually diagnosed with
ALS. Separately, in patients presenting with limb-onset disease,
the sensitivity of the index test (ALSDI ≥4) was 74.9%
(68.40%–80.6%), specificity 89.8% (82.0%–95.0%), and di-
agnostic OR 26.2 (12.7–54.2) underscoring the utility of ALSDI
≥4 in patients with limb-onset ALS.
Score

Age at assessment, y In total, 279 patients with ALS (68.6%) were receiving rilu-
zole at the time of assessment. Given that riluzole modulates
<50 0
SICI,39,40 a major component of the ALSDI, we assessed
51–60 1 whether riluzole therapy could reduce the diagnostic utility of
61–70 1
the index test ALSDI ≥4. The sensitivity was similar between
patients on riluzole (83.5%, 95% CI 76.0%–89.3%) and off
>71 1 riluzole (81.5%, 95% CI 74.3%–87.4%) therapy, thereby in-
Site of disease onset dicating that treatment status did not influence the diagnostic
potential of the ALSDI ≥4.
Bulbar 2

Limb 0

Median nerve CMAP amplitude, mV Discussion

<5.0 1
In the present study, we established the diagnostic utility of
5.01–7 0 the ALSDI in differentiating ALS from non-ALS disorders at
7.01–9.0 0
an early stage of the disease process. Of note, an ALSDI ≥4,
characterized by age at onset older than 50 years, bulbar-
>9.01 0 onset disease, low median nerve CMAP amplitude (<5 mV),
CSP duration, ms reduced CSP duration, or absent SICI, exhibited high sen-
sitivity, specificity, and diagnostic accuracy. It was impressive
≤160.0 3
that the utility of ALSDI ≥4 was confirmed in patients who
160.1–190.0 1 were Awaji negative and in patients with predominantly
190.1–220.0 1
LMN phenotype, underscoring the diagnostic utility of the
ALSDI in establishing an earlier and more definitive di-
>220.1 0
agnosis of ALS.
Mean SICI, %
An unmet need in management of patients with ALS and re-
≤0.0 21
cruitment into clinical trials pertains to establishing a conclusive
0.1–6.0 2 diagnosis of ALS at an early stage of the disease process. In the
6.1–12.0 0 absence of a pathognomic test, the diagnosis of ALS remains
reliant on identification of concomitant UMN and LMN dys-
>12.1 0
function, along with evidence of disease progression.1,4,6,22
Abbreviations: ALS = amyotrophic lateral sclerosis; ALSDI = amyotrophic Numerous diagnostic criteria were developed to facilitate an
lateral sclerosis diagnostic index; CMAP = compound muscle action poten- earlier diagnosis of ALS.3–5 Application of these diagnostic
tial; CSP = cortical silent period; SICI = short-interval intracortical inhibition.
The scores were summed to produce the ALSDI. An ALSDI score of 0 was not criteria have yielded conflicting findings,12–15,17–19,41–43 a no-
predictive of ALS while a score of 28 was highly predictive. All patients with tion attributed to disease heterogeneity, limitations of con-
an “inexcitable” cortex in the training cohort were diagnosed with ALS. The
ALSDI for “inexcitable” patients was set at 29. sensus diagnostic criteria, and reliance on clinical identification
of UMN dysfunction.23 A recent liberalization of the clinically
based El Escorial criteria22 was shown to increase the diagnostic
interest, the specificity, diagnostic accuracy, and OR, as well sensitivity,42 although reliance on UMN signs potentially lim-
as negative predictive value of the index test were higher in ited the diagnostic utility.
ALS phenotypes with a predominant LMN phenotype (table
4). Consequently, the greater degree of weighting of the Abnormalities of TMS have been well established in ALS,44
ALSDI toward SICI did not seem to bias the ALSDI score’s characterized by features of cortical hyperexcitability or
sensitivity in relation to the degree of UMN or LMN motor cortex inexcitability.24,26 While these cortical ab-
involvement. normalities were again demonstrated in the present ALS
cohort and contributed significantly to the ALSDI, the
In patients exhibiting a wasted thenar muscle (n = 26, 6% of important aspect of the present study was the inclusion of
cohort), thereby precluding TMS assessment and measurement an independent validation test cohort to assess perfor-
of SICI and CSP duration, the sensitivity of ALSDI ≥4 was mance of the ALSDI, thereby providing a more accurate

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 Figure 4 Receiver operator characteristic curves for the ALS diagnostic index
estimate of index test performance in a real-world setting.45
The robust diagnostic performance of ALSDI ≥4 in the
independent test cohort corroborated its diagnostic utility.
It should be stressed that an ALSDI ≥4 exhibited a speci-
ficity of 84%, while an ALSDI ≥5 had a specificity of 96%.
Consequently, ALSDI scores <4 would be less appropriate
for clinical trials.
The present study utilized multivariable statistical analysis to
identify independent biomarkers of UMN dysfunction. In
addition to abnormalities of SICI and motor cortex inex-
citability, reduction of CSP duration was also identified as an
independent diagnostic biomarker of ALS. While CSP re-
duction has been well established in ALS,26–28,46,47 a finding
attributed to dysfunction of long latency inhibitory circuits
acting via GABAB (γ-aminobutyric acid type B) receptors,
the diagnostic utility of this biomarker has not been pre-
viously utilized. In the present study, we demonstrated
a modest diagnostic potential of CSP duration (<160 milli-
seconds), potentially aiding ALS diagnosis in situations in
e544 Neurology | Volume 92, Number 6 | February 5, 2019
Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
Receiver operating characteristic curves
illustrate the excellent diagnostic utility of
the ALSDI in differentiating ALS from
neuromuscular mimicking disorders in (A)
training and (B) independent test cohorts.
(C) The AUC for the Awaji criteria was
smaller compared to the ALSDI for the
entire cohort. ALS = amyotrophic lateral
sclerosis; ALSDI = amyotrophic lateral
sclerosis diagnostic index; AUC = area
under the curve; CI = confidence interval.
which the SICI is normal, as evident in approximately 30% of
patients with ALS.26
Of further relevance, the presenting clinical phenotype, pa-
tient demographics, and site of disease onset are important
considerations in the diagnosis of ALS. Incorporating clinical
and peripheral neurophysiologic measures into the diagnostic
model, along with objective biomarkers of UMN dysfunction,
could potentially enhance the diagnosis of ALS. In the present
study, an ALSDI ≥4, derived by summing age at onset (older
than 50 years), low CMAP amplitude (<5 mV), and bulbar-
onset disease, reliably differentiated ALS from neuromuscular
mimicking disorders. An exclusive reliance on TMS abnor-
malities may preclude the diagnosis of ALS in patients with
severe wasting of the target muscle (approximately 6% of ALS
cohorts).26 Consequently, the ALSDI could potentially en-
able a diagnosis of ALS in cases in which the target muscle is
markedly wasted precluding TMS assessment. ALS diagnosis
may also be delayed in predominantly LMN phenotypes. In
the present study, the utility of the index test ALSDI ≥4 was
Neurology.org/N
Table 4 The diagnostic utility of the ALSDI was assessed in the training (n = 316) and test (n = 91) cohorts as well as an ALS
subgroup
Sensitivity, Specificity, PPV, NPV, Diagnostic Accuracy,
% (95% CI) % (95% CI) % (95% CI) % (95% CI) OR (95% CI) % (95% CI)

Training cohort

Awaji 84.1 (78.9–88.5) 87.0 (77.4–93.6) 95.3 (91.8–97.3) 63.8 (56.5–70.5) 35.4 (16.8–75) 84.8 (80.4–88.6)

ALSDI >4 81.6 (76.1–86.3) 89.6 (80.6–95.4) 96.1 (92.7–97.9) 61.1 (54.3–67.4) 38.2 (17.1–85.2) 83.5 (79.0–87.5)

ALSDI >5 66.9 (60.6–72.9) 98.7 (93–100) 99.4 (95.8–99.9) 49.0 (44.5–53.6) 154 (21–>1,000) 74.7 (69.5–79.4)

Test cohort

Awaji 84.8 (73.9–92.5) 72.0 (50.6–87.9) 88.9 (80.9–93.8) 64.3 (49.2–77.0) 14.4 (4.8–43.4) 81.3 (71.8–88.7)

ALSDI ≥4 83.3 (72.1–91.4) 84.0 (63.9–95.5) 93.2 (84.8–97.1) 65.6 (52.0–77.1) 26.3 (7.5–91.3) 83.5 (74.3–90.5)

ALSDI ≥5 71.2 (58.8–81.7) 96.0 (79.7–99.9) 97.9 (87.3–99.7) 55.8 (46.2–65.1) 59.4 (7.5–>400) 78 (68.1–86.0)

Subgroup analysis

Awaji

Positive 82.5 (77.3–86.9) 70.6 (44.0–89.7) 97.7 (95.3–98.9) 21.1 (15.1–28.6) 11.3 (3.8–33.7) 81.8 (76.7–86.1)

Negative 79.2 (65.0–89.5) 91.8 (83.8–96.6) 84.4 (72.5–91.8) 88.6 (81.7–93.2) 42.3 (15.0–119.9) 87.2 (80.3–92.4)

UMN signs

<3 79.4 (67.3–88.5) 92.8 (83.9–97.6) 90.9 (81.0–95.9) 83.1 (75.1–88.9) 49.2 (16.5–147.3) 86.4 (79.3–91.7)

≥3 82.3 (76.8–86.9) 70.6 (44.0–89.7) 97.5 (94.2–98.9) 22.2 (15.9–30.1) 11.1 (3.7–33.3) 81.3 (76.0–85.6)

Abbreviations: ALS = amyotrophic lateral sclerosis; ALSDI = amyotrophic lateral sclerosis diagnostic index; CI = confidence interval; NPV = negative predictive
value; OR = odds ratio; PPV = positive predictive value; UMN = upper motor neuron.
The diagnostic utility of the ALSDI was assessed in the training and test cohorts as well as an ALS subgroup based on Awaji criteria (positive: definite/probable/
possible; negative) and degree of UMN dysfunction (UMN <3: predominant lower motor neuron phenotype; UMN ≥3: prominent UMN signs).

established in the LMN phenotypes, including patients ini-
tially classified as Awaji negative.
A potential limitation of the ALSDI relates to wider applica-
bility, given that the threshold tracking TMS technique
requires specific technology and expertise. SICI, a major
component of the ALSDI, is derived by utilizing the threshold
tracking TMS technique, which is not commercially available
at present. Of note, commercialization of the threshold
tracking TMS technology is in the final stages with the
prospect of imminent widespread availability. Once available,
multicenter studies incorporating cross-validated study de-
sign would enable further assessment of the diagnostic utility
of the ALSDI in ALS cohorts. It has also been previously
argued that subtle differences in cohort characteristics,26
such as age, functional status, and disease duration, could
have reduced the diagnostic utility of the ALSDI. This
possibility seems unlikely given the robust diagnostic per-
formance of the ALSDI in both the independent validation
test cohort and in subgroups of clinical interest. Separately,
none of the patients recruited in the present study un-
derwent an autopsy and as such the proportion of patients
with LMN syndrome exhibiting pathologic features of ALS,
classified as negative on the ALSDI, could not be precisely
determined.
It could also be argued that the control group did not contain
a sufficient number of “difficult” ALS mimicking patients, and
that experienced clinicians would reliably differentiate such
disorders from ALS. It should be stressed, however, that di-
agnostic delays remain a major limiting factor in the man-
agement of patients with ALS and recruitment into clinical
trials.48 Conditions such as acquired neuromyotonia, Ken-
nedy disease, Hirayama disease, and inclusion body myositis
are “difficult” ALS mimics for both frontline clinicians and
experienced ALS physicians.49 Of importance, these con-
ditions comprised 58% of the non-ALS cohort and were re-
liably differentiated from ALS by the ALSDI, underscoring the
diagnostic potential of the novel index.
An ongoing challenge in the management of patients with
ALS pertains to early and definitive diagnosis of ALS.7 Cur-
rent reliance on consensus criteria that are based on identi-
fying concomitant UMN and LMN dysfunction, and have not
been verified in independent cohorts, could result in signifi-
cant diagnostic delays.16,21 Ultimately, delayed recruitment of
patients with ALS into clinical trials may occur, perhaps be-
yond the therapeutic window period when therapies may be
most effective. The index test (ALSDI ≥4) could enhance ALS
diagnosis, especially in early stages of the disease process or in
atypical phenotypes, and should be used in conjunction with

Neurology.org/N Neurology | Volume 92, Number 6 | February 5, 2019 e545

Copyright © 2019 American Academy of Neurology. Unauthorized reproduction of this article is prohibited.
 the Awaji criteria. Ultimately, this approach may enable in-
creased recruitment into therapeutic trials, at an earlier stage
of the disease process, when neuroprotective agents may be
most efficacious.
Author contributions
N.G.: study design, conducting experiment, data analysis,
writing of manuscript. J.H.: study design, experimentation,
critiquing manuscript. P.M.: conducting experiments, data
analysis, critiquing manuscript. M.v.d.B.: study design, con-
ducting experiments, critiquing manuscript. K.S.: study de-
sign, conducting experiments, critiquing manuscript. J.M.M.:
study design, conducting experiments, critiquing manuscript.
S.B.P.: study design, conducting experiments, critiquing
manuscript. K.B.: study design, statistical analysis, writing and
critiquing manuscript. M.C.K.: study design, critiquing man-
uscript, input in data analysis. S.V.: study and statistical design,
writing and critiquing manuscript, senior author.
Study funding
This study was supported by a research grant from the Motor
Neuron Disease Research Institute of Australia, National
Health and Medical Research Council of Australia (project
grants 510233, 1024915, 1055778) and is gratefully ac-
knowledged. This work was also supported by funding to
Forefront, a collaborative research group dedicated to the
study of frontotemporal dementia and motor neuron disease,
from the National Health and Medical Research Council of
Australia Program Grant (1037746).
Disclosure
N. Geevasinga, J. Howells, P. Menon, M. van den Bos, K.
Shibuya, J.M. Matamala, S.B. Park, K. Byth, and M.C Kiernan
report no disclosures relevant to the manuscript. S. Vucic
received honoraria from Merck Serono Australia. Go to
Neurology.org/N for full disclosures.
Publication history
Received by Neurology April 3, 2018. Accepted in final form September
28, 2018.
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Neurology | Volume 92, Number 6 | February 5, 2019 e547
 Amyotrophic lateral sclerosis diagnostic index: Toward a personalized diagnosis of
ALS
Nimeshan Geevasinga, James Howells, Parvathi Menon, et al.
Neurology published online January 11, 2019
DOI 10.1212/WNL.0000000000006876

This information is current as of January 11, 2019

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