Supplement

Problems in shortening the time to con�rmationof ALS diagnosis: lessons from the 1st ConsensusConference, Chicago, May 1998

Benjamin Rix Brooks

ALS and other motor neuron disorders 2000 1 (suppl 1), S3–S7 © 2000 ALS and other motor neuron disorders. All rights reserved. ISSN 1462-8848 S3

Introduction

The goal of the 2nd Consensus Conference on ‘Debatingthe Possibility of Earlier Diagnosis of Patients with AmyotrophicLateral Sclerosis’ at Versailles, France on 30 January 1999,was to develop those themes identi�ed at the 1st Consen-sus Conference on ‘De�ning Optimal Management in ALS:From First Symptoms to Announcement’ at Chicago, USA on 7May 1998.

The themes to be developed were:

� Describing the problems and limitations in currentdiagnostic practices.

� Identifying consequences of early diagnosis on patientmanagement.

� Establishing recommendations to help healthcare per-sonnel achieve the early diagnosis.

� Proposing some solutions for facilitating early diagnosisof ALS.

University of Wisconsin Hospital & ClinicsALS Clinical Research Centerand William S Middleton Memorial Veterans Affairs Medical CenterGreat Lakes Veterans Integrated Service Network(VISN 12),Madison, Wisconsin, USA

Correspondence:Benjamin Rix Brooks, MDProfessor of NeurologyDirector, ALS Clinical Research CenterUniversity of Wisconsin Hospital & Clinics600 Highland Avenue CSC H6-563Madison, WI 53792-5132USATel: +1 608 263 5421Fax: +1 608 263 0412E-mail: Brooks@neurology.wisc.edu

The 2nd Consensus Conference (Ver-sailles) on the early diagnosis of amyo-trophic lateral sclerosis (ALS) developedthemes identi�ed at the 1st ConsensusConference (Chicago) on de�ning optimalmanagement in ALS. These themesincluded describing the problems andlimitations in current diagnostic practices,identifying consequences of early dia-gnosis on patient management, establish-ing recommendations to help healthcarepersonnel achieve the early diagnosis andproposing solutions to facilitate earlydiagnosis of ALS. Lessons from the ISISSurvey and the 1st Consensus Conferencefocused on the variability of the �rst-contact physician, supply factors for spe-cialists and variability of application ofmedical techniques. The recently intro-

duced concept of ‘ALS health states orstages’ was reviewed in terms of ongoingand potential prospective studies. Therelative contribution of neuroimaging orclinical neurophysiological investigationsto accelerating the diagnosis of ALS inclinical practice was debated. The role ofa common ALS knowledge-base amongpatients, initial healthcare providers, dia-gnosing neurologists and con�rmingneurologists was critically appraised withregard to simpli�ed ‘ALS diagnostic algo-rithm’, ‘ten aphorisms in the diagnosis ofALS’ and ‘ALS axioms of referral’. Re�ningthis ALS knowledge-base is required toidentify a minimum dataset required forthe evaluation and diagnosis of ALS.(ALS 2000; 1 (suppl 1): S3–S7).

Keywords: motor neuron disease – practice guideline – neurodegenerative –shared decision making – electrodiagnostic – neuroimaging/neuroradiology

Lessons from the ISIS survey

In order to implement this, the ISIS studies in Europe,North America and South America have been reviewed byDr Chiò,1,2 and ideal times to achieve the diagnosis of ALShave been surveyed from an international perspective, interms of Europe, Asia, North America and South America.The critical messages that can be derived from the studieshave been examined and condensed, into a �nal set ofrecommendations published here and distributed toappropriate healthcare personnel internationally. To helpus in this regard we formulated some questions:

� What simpli�ed diagnostic criteria could be suggestedfor use by the non-specialist, as opposed to the El Esco-rial criteria?3

� What other healthcare professionals should be involvedand when, in terms of the diagnostic process?

� What information is important to give to, or obtainfrom, non-specialist or even specialist non-neurologists,e.g. general practitioners (GPs), orthopaedic surgeons,etc?

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� What sort of laboratory evaluations are useful andwhen?

� What should be offered as psychological counsellingand then what should be the involvement of patientassociations?

� What are the advantages and disadvantages in terms ofearlier diagnoses?

� What should be the frequency of follow-up?� What potential biological markers may be followed,

such as genetic markers, and what is the impact of earlydiagnosis in terms of false-positive and false-negativemisdiagnosis?

Lessons from the 1st ConsensusConference

The lessons learned from the 1st Consensus Conferenceare best summarized with respect to Dr Smithson’s con-cerns regarding the complexities of the problem con-fronting us.4 ALS is obviously a rare condition.Practitioners have an information overload with respect tomany diseases and there may be no best way of changingclinical practice at the entry points of a patient who hassymptoms that are related to ALS (Table 1). We discussedthe ownership of the decision-making process. Should thisbe a mixture, with the patient having some educationalresponsibility? We all identi�ed that we really had toincrease the index of suspicion clinically among GPs.

One of the things learned from the ISIS Survey inEurope, as will be discussed by Dr Chiò, is that the timefrom �rst symptoms to �rst consultation depended some-what on the symptom onset and whether there were fascic-ulations or not.1,2 Overall, the time from �rst symptoms todiagnostic con�rmation was 12–17 months, and it was alittle shorter if there were fasciculations, hence the empha-sis on fasciculations at this Versailles conference. Similaroutcomes were seen in the South American study, but withfasciculations not being that key force accelerating thediagnosis. What was clear was there was a difference acrosscountries in terms of who saw the patient �rst, and in the

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‘Gatekeeper role’Variability of �rst-contact physicianMode of access to secondary care

Supply factorsDensity of specialistsLocation and number of referral unitsRemuneration of specialists and GPs

Vocational/professional trainingVariability of application of medical techniques

Table 1Problems in accelerating the diagnosis of ALS. Modi�ed from Smithson(1999)3

Mild Recent diagnosis, mild de�cit in 1/3 regions (speech,arm, leg)Functionally independent in speech, arm ADL,ambulation

Moderate Mild de�cit in all 3 regions or moderate to severede�cit in 1 region, other 2 regions are normal ormildly affected

Severe Needs assistance in 2 or 3 regions, speech dysarthricand/or patient needs assistance to walk and/or needsassistance with arm ADL

Terminal Non-functional use of at least 2 regions andmoderate or non-functional use of the third region

Death

Table 2ALS health states or stages. Modi�ed from Riviere et al (1998)5

proportion of second opinions sought from the neurolo-gist.

There were also differences among the countries withrespect to the types of tests that were being used. Inparticular, in Northern Europe, there was greater use ofmotor-evoked potentials especially when compared to usein South America and the USA. In South America therewas lesser use of motor-evoked potentials, but a numberof classic neuromuscular electrodiagnostic studies andimaging studies were common across all countries.

ALS health states or stages

The other aspect of early diagnosis which we reviewed inChicago was the concept of health states or stages in ALS.5

This has now become more important following the pre-liminary report at the ALS/MND International Symposiumin Munich, Germany, November, 1998, with respect toriluzole and vitamin E in combination versus riluzole withplacebo vitamin E. This is the �rst report of a prospectivestudy involving the health states or stages of ALS (Table 2).

The ALS health states allow us to look at event-history(time to failure) analysis with respect to entry into theparticular ALS health states or stages. In a retrospectivestudy of the original riluzole clinical trials, the relative riskwith the 95% con�dence limit was below 1 in the moder-ate stage of ALS, suggesting that a potential treatmenteffect may be seen after the earlier stages of the disease(Figure 1). However, the number of patients in the mildstage of ALS was small, and while the trend toward bene�tfrom riluzole seen in the moderate stage was signi�cant,the trend toward a treatment effect with riluzole, in thesevere and terminal stages was not.5 Such studies, employ-ing the ALS Health States or ALS Stages, including therecent report on vitamin E and riluzole, will lead to a

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better understanding of whether the earlier that we candiagnose the disease, the more likely it is that we may beable to see a treatment effect which the patient can per-ceive. At the very least we may, with earlier diagnosis, beable to extend the time that patients spend in the moder-ate stage of ALS before entering the severe and terminalstages of ALS.

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Terminal

Severe

Moderate

Mild

Relative Risk1.510.50

Figure 1ALS health states or stages during riluzole therapy.

Neuroimaging and neurophysiologicalinvestigations

The early application of clinical neurophysiological tech-niques and neuroimaging techniques may serve to acceler-ate the diagnosis of ALS.6 We reviewed the effect ofemploying the neuroimaging information alone comparedwith that of using the clinical neurophysiological informa-tion alone in 36 autopsy-proven ALS patients on the rateof achieving the clinically de�nite ALS diagnosis accordingto the World Federation of Neurology El Escorial criteriafor the diagnosis of ALS (Figure 2). Neuroimaging infor-mation, which provides exclusion of structural or intrinsiclesions that may cause symptoms similar to clinically pos-sible and probable ALS, is an important ally in increasingthe certainty of the diagnosis of ALS early in its course.

ALS knowledge-base

It was clear from our discussion that the diagnosis of ALSrelies on a knowledge-base held by the patient, the initialhealthcare provider, the initial neurologist and thecon�rming neurologist. What kind of preliminary symp-toms would be consistent with wanting to go to a physi-cian? At the level of the physician, what should he/sheknow with respect to the warning signs that are importantfor accelerating evaluation by a neurologist? The same

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00 6 12 18 24 30 36 42 48 54 60 66 72 78

With neuroimaging and EMG (n 5 29)

With neuroimaging, no EMG (n 5 29)

With EMG, no neuroimaging (n 5 9)

No EMG, no neuroimaging (n 5 9)

Time from onset of symptoms (months)

Figure 2Acceleration of the ALS diagnosis by neuroimaging and EMG investigations (with vs without neuroimaging: chi-square = 4.57; p = 0.03). Reproduced withpermission from Brooks BR (1999).6

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would be true at the level of the nurse as well. In theUnited States we are seeing increased general communityawareness of the disease, particularly in certain age groups.We have to look at the whole issue of health education,which has not, until recently, been done.

With the introduction of riluzole we began to realizethat the early diagnosis of ALS was a two-way process. Wehad to educate ourselves as well as the patient supportgroups and patient lay organizations.

Dr Swash presented a simpli�ed scheme with respect tolooking at weakness and wasting as the presenting signand then also being able to recognize that this is truly theALS disease process and not some other process.7 He iden-ti�ed that we should look for characteristic features, partic-ularly fasciculations of the tongue and a combination ofupper and lower motor neuron features, and then a physi-cal examination should be performed.

Other syndromes should be excluded, such as neuro-pathy, multiple sclerosis, syringomyelia, spinal tumourand spondylosis. Neuroimaging studies such as magnetic

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1. The diagnosis must be accurate2. The diagnosis must be expeditious3. Be sensitive in giving information4. Follow-up discussions are essential5. Recognize, discuss, and alleviate fears6. Continuing care is a responsibility7. Anticipate problems: be there8. Maintain work and social structure9. Educate regarding the science and genetic risk of ALS

10. Help plan the process of death

Table 3Ten aphorisms in the diagnosis of ALS. Modi�ed from Swash (1999)7

Healthcare level Role

Initial healthcare provider If foot drop, pinch weakness, speech or swallowing change without pain, look for atrophy and fasciculationsRefer to neurologist

Neurologist Immediate neuroimaging and electrodiagnostic studies to rule out structural disease and con�rm active andchronic denervation in clinically affected and unaffected neuroanatomic regions (brainstem, cervical, thoracic,lumbo-sacral spinal cord)Refer to ALS Centre or second neurologist to con�rm diagnosis

ALS centre Con�rm ALS diagnosis, identify ALS-mimics, ALS-plus, ALS-LAUS (ALS with laboratory abnormalities ofunknown signi�cance)Institute or modify therapy as indicated

Table 41st Consensus Conference: ALS – accelerating the diagnosis: axioms of referral. Modi�ed from Brooks (1999)8

resonance imaging (MRI) or computerized tomography(CT) scan, electromyography (EMG) and appropriateblood studies should be arranged. When these are com-plete there follows the issue of informing the patient andbeginning the process of management. Dr Swashreminded us that we should often review the diagnosis tobe sure we are correct. Dr Swash left us with 10 aphorismsfor the diagnosis of ALS (Table 3).

The diagnosis of ALS must be accurate and it must beexpeditious. We must be sensitive in giving information ofthe diagnosis to the patients, and follow-up discussions areessential. We must recognize and alleviate the fears of thepatient. Continuing care is a responsibility of the persongiving the diagnosis. We must anticipate problems and bethere to discuss them, and they might be different during dif-ferent stages of the disease. Dr Swash identi�ed that we mustmaintain and work on the social structure for the patient.The 9th aphorism was that we must educate in respect to thescience and genetic risk of ALS, and then in the later stages ofthe disease, we must help plan for the process of death.

ALS axioms of referral

We �nished the 1st Consensus Conference brainstorminghow to accelerate the diagnosis. This effort resulted in theALS axioms of referral (Table 4).

Always review the diagnosis

Begin process of managementInform

exclude other syndromes,e.g. neuropathy, MS, syrinx,spinal tumor, spondylosisarrange imaging and EMG,

blood studies

physical examination

neurological disease

weakness & wasting

look for characteristic features,especially fasciculation of the

tongue & combination ofUMN / LMN features

Figure 3ALS diagnosis – an algorithm. Reproduced with permission from Swash(1999)7.

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At the level of the initial healthcare provider – thenurse, the doctor – we felt that foot drop, pinch weaknessof the index �nger and the thumb, or speech or swallow-ing changes without pain, would lead us to look foratrophy and fasciculation. These are the symptomaticelements, which would make someone concerned thathe or she should be evaluated in the healthcare system.We wanted to identify key elements which shouldincrease the diagnostic concern of the healthcare providerleading to the referral of the patient to a neurologist. At thelevel of the neurologist, we felt that neuroimaging andelectrodiagnostic studies should be an immediate consid-eration to rule out structural disease and con�rm activeand chronic denervation in clinically affected, but alsoclinically unaffected, neuroanatomical regions. It is impor-tant to note that all central nervous system regions includ-ing the brainstem, cervical, thoracic, and lumbosacralspinal cord should be evaluated to raise the certainty ofearly diagnosis. Following the af�rming of the diagnosisby these clinical investigations, the patient should bereferred to an ALS centre or a second neurologist tocon�rm the diagnosis.

We felt that the ALS centre specialist or a second neuro-logist would be necessary to look at all the data and toreally con�rm or dispute the diagnosis following theraising of the index of suspicion. The role of the secondneurologist or the ALS centre is to con�rm the ALS diagno-sis, or identify ALS-mimics, ALS-plus syndromes, and,where appropriate, the newly-conceived category of ALSwith laboratory abnormalities of an unknown signi�cance.It is at the second neurologist level or ALS Centre thattherapy is instituted or modi�ed as indicated.8

We tried to de�ne the problem of delays. There is a

delay in the realization of the illness by the patient; in therecognition of there being a neurological disorder byprimary healthcare providers; and in the referral to aninappropriate consultant (orthopaedic surgeon vs neuro-logist). Furthermore, there is a delay owing to the diagnos-tic certainty of the neurologist leading to the need forfurther neuroimaging and electrodiagnostic studies (EMGand nerve conduction studies (NCS)) as well as the naturaltendency to delay telling the patient and the family.

Aims of the 2nd Consensus Conference

Our aim at the 2nd Consensus Conference was to arrive atsome recommendations about a minimum datasetrequired for the evaluation and diagnosis of ALS that,when implemented, may accelerate the diagnosis of ALS.

Acknowledgements

Supported in part by the Muscular Dystrophy Association(MDA) of America (MDA-ALS Clinical Center), NationalInstitute of General Medical Sciences (NIH) University ofWisconsin General Clinical Research Center (M01RR03186) and Department of Veterans Affairs. The 1stConsensus Conference ‘De�ning Optimal Management inALS: From First Symptoms to Announcement’ in Chicago, Illi-nois, USA on 7 May 1998 was supported in part by anunrestricted educational grant from Rhône-Poulenc Rorerto assist the Consensus Meeting and Proceedingsmanuscript.

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3. Smithson WH. Integrating the algorithm into communitypractice. Neurology 1999; 53 (Suppl 5): S63–S66.

4. Brooks BR. El Escorial World Federation of Neurology crite-ria for the diagnosis of amyotrophic lateral sclerosis. Sub-committee on Motor Neuron Diseases/Amyotrophic LateralSclerosis of the World Federation of Neurology ResearchGroup on Neuromuscular Diseases and the El Escorial ‘Clin-

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5. Riviere M, Meininger V, Zeisser P et al. T. An analysis ofextended survival in patients with amyotrophic lateral scler-osis treated with riluzole. Arch Neurol 1998; 55: 526–528.

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8. Brooks BR. De�ning optimal management in ALS: from �rstsymptoms to announcement. Neurology 1999; 53 (8 Suppl5): S1–S3.

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