motor neuron disease - bmj · disease, and autosomal dominant mndare seen regularly in adult...

86ournalof Neurology, Neurosurgery, and Psychiatry 1994;57:886-896

NEUROLOGICAL MANAGEMENT

Motor neuron disease

P N Leigh, K Ray-Chaudhuri

For neurologists, the management of motorneuron disease (MND) involves prompt andaccurate diagnosis; an understanding of nat-ural history, prognosis, and of the physicaland psychological consequences of the dis-ease for the individual and for carers; famil-iarity with the techniques, philosophies, andethical aspects of symptomatic treatment,rehabilitation medicine and palliative care;and awareness of the new opportunities forresearch into the causes and treatment ofMND and other motor neuron disorders.Because MND is a relatively rare conditionfor most health workers, the neurologist canmake an important contribution to effectivemultidisciplinary management. Underpro-vision of neurology services militates againstthis in the United Kingdom. Nevertheless, anargument can be made that MND be treatedas a "special case" and that health districtsshould develop appropriate models of inter-disciplinary care, not necessarily led, butadvised and supported by, local neurologists.

Definitions and terminologyMND is a progressive disorder in whichdegeneration of upper and lower motor neu-rons leads to progressive weakness of bulbar,limb, thoracic, and abdominal muscles withrelative sparing of oculomotor muscles andsphincter function. Death from ventilatoryfailure usually follows within five years of

onset. Most cases are sporadic (90-95%),whereas 5-10% are familial,1 2 usually withautosomal dominant transmission. Manyother motor system and anterior horn cell dis-orders are recognised (table 1). An unusualform of MND occurs in the Western Pacificassociated with parkinsonism and dementia.3

In the United Kingdom the term MND isused generically to include the complete spec-trum of the disease, including Charcot-typeamyotrophic lateral sclerosis (ALS) with typi-cal upper and lower motor neuron involve-ment, progressive muscular atrophy with onlylower motor neuron involvement, and pro-gressive bulbar palsy with bulbar andpseudobulbar palsy. The relationshipbetween primary lateral sclerosis, in whichprogressive upper motor neuron degenerationis not accompanied by anterior horn celldegeneration, and other forms of MND,remains uncertain. Most cases do notprogress to typical MND.4

Diagnostic criteriaAt a World Federation of Neurology consen-sus conference in 1990 at El Escorial, Spain,research diagnostic criteria for MND weresuggested (table 2). These criteria are basedon clinical evidence of a progressive disorderwith the characteristic combination of upperand lower motor neuron involvement in thesame body regions and with certain exclusion

Table 1 Some rare disorders showing features of anterior horn cell degeneration

Disorder

X-linked recessive bulbar and spinal muscularatrophyHereditary spastic paraparesis with distalamyotrophyJuvenile spinal muscular atrophy of the distal upperextremity"Madras" pattern motor neuron disease

Western Pacific ALS

Adult GM2 gangliosidosis

Azorean disease (Machado-Joseph disease)

Multiple system atrophy and OPCA

Associated neurologicalfeatures Diagnostic pointers

Postural tremor; prominent facial fasciculations Male gender; gynaecomastia; diabetes; infertilityAbsent SAPs; androgen receptor gene mutation

Pes cavus; vibration sense loss; dementia; dystonia Positive family history; early age at onset; slowprogression; ethnic origin (Amish; Tunisian; Lebanese)

Exacerbation of weakness by cold;minipolymyoclonus of fingersSensorineural hearing loss; minipolymyoclonusof fingersParkinsonism; dementia

Intellectual impairment; psychiatric disturbances;ataxia; stutter-dysarthria; pyramidal tract signs;dystonia; dyskinesias; supranuclear ophthalmoplegiaCerebellar syndrome; parkinsonism; supranuclearophthalmoplegia; pseudobulbar palsy; dystonia

Young Japanese males; vasomotor disturbances; benigncourse; structural abnormality of cervical cord

Ethnic origin (southern Indian); young age at onset

Ethnic origin (Guam, Western New Guinea, Kiipeninsula of Japan)Ethnic origin (Ashkenazi Jews)White cell/skin fibroblast hexosaminidase Adeficiency; EM of rectal biopsyEthnic origin (Portuguese; Azorean); family history;diabetes

Orthostatic hypotension; parkinsonism; cerebellar Family history (some cases); infratentorial atrophyataxia; nystagmus; urinary incontinence; on CT or MRIimpotence; dementia; involuntary movements;dysphagia; supranuclear ophthalmoplegia

OPCA = olivopontocerebellar atrophy; SAP = sensory action potential; EM = electron microscopy.

UniversityDepartment ofNeurology, Institute ofPsychiatry and King'sCollege School ofMedicine andDentistry, DeCrespigny Park,London SE5 8AF, UKP N LeighK Ray-ChaudhuriCorrespondence to:Professor P N Leigh

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Table 2 Diagnostic criteria for motor neuron disease(amyotrophic lateral sclerosis, ALS)

The diagnosis of ALS requires the presence of:* LMN signs (including EMG features in clinically

normal muscles)* UMN signs* Progression of the disorderDiagnostic categories:* Definite ALS: UMN plus LMN signs in three regions* Probable ALS: UMN plus LMN signs in two regions

with UMN signs rostral to LMN signs* Possible ALS: UMN plus LMN signs in one region, or

UMN signs in two or three regions, such as inmonomelic ALS, progressive bulbar palsy, andprimary lateral sclerosis

* SuspectedALS: LMN signs in two or three regions, suchas in progressive muscular atrophy, and other motorsyndromes

The diagnosis ofALS requires the absence of:* Sensory signs* Sphincter disturbances* Visual disturbances* Autonomic dysfunction* Parkinson's disease* Alzheimer-type dementia* ALS "mimic" syndromes (see tables 2 and 3)The diagnosis of ALS is supported by:* Fasciculation in one or more regions* Neurogenic change in EMG studies* Normal motor and sensory nerve conduction (distal

motor latencies may be increased)* Absence of conduction block

Regions are defined as follows: brainstem, brachial, thoraxand trunk, crural. UMN = Upper motor neuron; LMN =

lower motor neuron.

criteria. Validation of these criteria is needed,but the predictive power of the definite andprobable categories is high, judged by neuro-

pathological correlations6 and by experiencein clinical trials that have used these cate-gories as inclusion criteria. The diagnosticaccuracy of the category of possible ALSremains to be defined by long term follow up

and neuropathology. Although valuable as

research criteria, the El Escorial criteria donot take account of the vagaries of clinicalpractice; patients with MND sometimes havebladder dysfunction, and dementia andparkinsonism are rare features of otherwisepathologically typical MND7-9 Other disor-ders, such as spondylotic myelopathy, oftencoexist with MND. Thus for clinical ratherthan research purposes the exclusion criteriashould be interpreted flexibly and used toalert clinicians to rare and potentially treat-able disorders.

These research diagnostic criteria havebeen applied to sporadic and familial forms ofMND.5 The familial motor neuron disordersof adult onset are rare and only the milderforms of spinal muscular atrophy, Kennedy'sdisease, and autosomal dominant MND are

seen regularly in adult neurological practice.Nevertheless these disorders offer new possi-bilities for understanding the mechanisms ofmotor neuron degeneration.'01' The diversityand genetic heterogeneity of motor neuron

disorders are exemplified by the WorldFederation of Neurology classification whichincludes 28 autosomal dominant syndromes,37 autosomal recessive syndromes and seven

X-linked syndromes, with an additional 16different types of MND-dementiasyndrome."2

Clinical features and differential diagnosisSYMPTOMS AND SIGNSIn 75% of patients, the first symptoms are in

the limbs; 25% present with bulbar symp-toms.13-'5 The earliest symptom is usuallyasymmetrical weakness of one extremity or,with bulbar onset disease, slurring of speech.The latter is often noted first by family orfriends. Specific symptoms with limb onsetdisease depend on the area involved. In thearms, weakness may start around one shoul-der, and sometimes is noticed after a minorlocal injury, or progresses after what has beenconsidered to be a "frozen shoulder". Distalweakness is often manifest as increasing diffi-culty turning a key in a lock or car ignition,unscrewing bottle tops, holding a pen, orgripping objects. Involvement of arms firstoccurs in about 35% of cases. The diseasebegins in the lumbosacral region of the spinalcord in about 40% of patients. Such patientsbegin to trip or stumble due to a unilateralfoot drop, or may have difficulty rising from achair if weakness starts proximally. Rarelypatients note stiffness and flexor spasms inthe legs, resulting from spasticity. Fatigue isnot a particularly prominent early symptom,but muscle cramps are common, mostly inthe legs where proximal and distal musclesare affected. Fasciculations may attract atten-tion, and cramps and fasciculations some-times precede weakness and wasting byseveral months. Sensory symptoms, usuallyvariable distal paraesthesiae or numbness, arepresent in about 10% of patients and painmay be a prominent symptom in up to 50%ofMND patients with advanced disease.With time, weakness progresses but fascic-

ulations often become less obvious. Almostall patients with limb onset eventuallydevelop bulbar symptoms and, conversely,patients with bulbar onset disease ultimatelydevelop symptoms in the limbs. Orthopnoea,due to diaphragmatic weakness, is common.In bulbar onset disease, dysarthria progressesuntil speech is incomprehensible; manypatients become anarthric. Dysphagia usuallybegins as difficulty clearing a bolus of solids,proceeds to difficulty even with liquifiedfoods and fluids, and eventually becomestotal. Drooling of saliva may be a constantirritation. These symptoms, with limb weak-ness, ultimately render such people depen-dent on others for every form of comfort,sustenance, and care. Fortunately, pressuresores are rare, and urinary and faecal inconti-nence seldom occur.

Although ventilatory muscle weaknessoccurs in almost all patients and, with orwithout pneumonia, is usually responsible fordeath, dyspnoea is not always a prominentsymptom. It may, however, be present earlyin the course of the disease when limb weak-ness is negligible and rarely patients presentwith dyspnoea or even ventilatory failure.The physical signs of MND stem from

upper motor neuron involvement causingweakness, spasticity, hyperreflexia, andBabinski's sign (although the latter is presentonly in 50%)'5 and from lower motor neuroninvolvement causing weakness, muscularatrophy, and fasciculation. Dysphagia anddysarthria may be due to upper or lower



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motor neuron involvement or, in most cases,combined lesions. Emotional lability is usu-ally associated with pseudobulbar palsy and isa sign of upper motor involvement. Bothupper and lower motor neuron signs are oftenevident at presentation in 65% of patients.'4 15Fasciculation can occur in the absence ofother lower motor neuron signs. Ten per centof patients present with lower motor neuronfeatures only, but some develop upper motorneuron signs and only about 5% show thephenotype of progressive muscular atrophythroughout the course of the disease.'5

Objective sensory signs exclude a diagnosisof MND unless there is a clear alternativeexplanation, such as carpal tunnel syndrome.Detailed testing with measurement of, forexample, thermal threshold, may showimpaired sensation, and sural nerve biopsieshave revealed evidence of axonal degenera-tion in some cases of MND.'6 '7 In endstageMND, there may be multisystem involve-ment with degeneration of the spinocerebellartracts, posterior columns, and brainstemreticular formation, although clinically this isof little importance.18

Dementia, which may be associated withparkinsonism, is seen in less than 5% ofpatients,7-9 but subtle cognitive changesindicative of frontal and temporal lobe dys-function can be detected in 25-50% ofpatients, and PET activation studies showmarkedly impaired responses in the medialfrontal region and anterior thalamus in thesepatients.'9 Dementia associated with MND isusually of frontal lobe rather than Alzheimertype, and typically patients present withchanges in conduct and character, althoughmemory impairment may predominate. Afamily history of dementia with or withoutMND, suggestive of autosomal dominanttransmission, is present in some cases.720The Western Pacific ALS-parkinsonism-

dementia complex (PDC) occurs on theisland of Guam, the Kii peninsula in Japanand in parts ofNew Guinea. In this syndromefeatures of ALS coexist with extrapyramidalsigns and dementia. The spinal cord pathol-ogy is that of typical MND, but in additionthere is neurofibrillary degeneration in cere-bral cortex and brainstem, and, to a lesserextent, in the spinal cord.2' Current indica-tions are that ALS on Guam is declining infrequency.

Although in the differential diagnosis ofMND a large number of disorders must beconsidered (tables 1 and 3), in practice thediagnosis is usually straightforward by thetime the patient is referred to a neurologist.

Because the early symptoms may be ill-defined, or may be mistaken for localisedlesions, it is common for patients to bereferred first to rheumatology, orthopaedic,ENT, or psychiatric departments. In the veryelderly, the diagnosis may be especially diffi-cult in the early stages. In 62 consecutivepatients referred with a diagnosis of MND toa research clinic for clinical trials we found sixpatients who were judged not to have MNDincluding two patients with Kennedy's

Table 3 Conditions that should always be considered inthe differential diagnosis ofMND* Cervical spondylotic myelopathy and other cervical and

lumbosacral radiculopathies* Disorders associated with autoimmune processes:

(a) Dysimmune lower motor neuron syndromes(GM,, GDIb and asialo-GM, antibodies)

(b) Monoclonal gammopathy with conductionblock and motor neuropathy

(c) Lymphoma(d) Paraneoplastic syndrome (encephalomyelitis

with anterior horn cell involvement)* Thyrotoxicosis* Hyperparathyroidism* Diabetic "amyotrophy"* Radiation-induced neurogenic disorders* Post-poliomyelitis progressive muscular atrophy* Genetic enzyme defects: hexosaminidase A and (rarely)

B deficiency (particularly in young patients)* Exogenous toxin disorders (lead, mercury, manganese

toxicity)* "Prion" disorders (amyotrophic forms of Creutzfeldt-

Jakob disease)* Certain myopathies, such as inclusion body myositis

syndrome, one with cerebrovascular diseaseand cervical spondylosis, two with motor neu-

ronopathy and multifocal conduction block,and one with inclusion body myositis. It isdifficult to know what the diagnostic errorrate would be in a less selected group of patients.

InvestigationsThe purpose of laboratory investigations is toexclude other diagnoses, and to support thediagnosis of MND. At present there are no

specific biochemical or pathological markersof the disease.

ESSENTIAL INVESTIGATIONSErythrocyte sedimentation rate, haematologi-cal and biochemical screen, chest radiograph,and ECG should be undertaken in allpatients with suspected MND. It is advisableto request antinuclear, thyroid function tests,vitamin B12 and folate levels, VDRL testsand protein electrophoresis. These tests aredone mainly to exclude coincidental diseasethat may influence management, but also toexclude thyroid and parathyroid disordersand autoimmune disorders that may be asso-ciated with motor neuronopathy or atypicalspinal cord syndromes. Serum creatininekinase levels may be elevated, particularly inthose with predominantly lower motor neu-ron involvement and slow progression, butalso in Kennedy's disease. This last can beexcluded by testing for the androgen receptorgene mutation in all male patients wherethere is a suggestion of X-linked inheritance,or lacking a clear family history, where theclinical picture raises the possibility.'022 Thepatient and family should receive appropriatecounselling before testing. Key features ofKennedy's disease are early onset (which canbe in the teens, although it may be as late asthe sixth or seventh decades), slow progres-sion of mainly proximal lower motor neuronweakness associated with facial and tongueweakness and fasciculation, gynaecomastia,and tremor of the hands. Depressed reflexesand reduced sensory nerve action potentialsmay also be potential clues to Kennedy'ssyndrome.



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Electromyography and nerve conductionstudies are important aids to the diagnosis ofMND, and can exclude other neuromusculardisorders such as myopathy and motor neu-ronopathy. In essence, EMG furnishes evi-dence of widespread anterior horn celldamage that cannot be explained on the basisof a localised disease process. Thus it is nec-essary to show denervation and reinnervationoutside the distribution of a single peripheralnerve or nerve root. Although the examina-tion depends largely on analysis of potentialsdetected by concentric needle electrodes,recording of fasciculation potentials usingsurface electrodes is a useful non-invasiveadjunct, allowing many muscles to be exam-ined. Table 4 summarises the criteria used tosupport a diagnosis of MND.2' These criteriacannot always be satisfied in early stages ofMND. Fibrillation potentials are oftenabsent, particularly in patients with slowerdisease progression. Unstable motor unitsand increased jitter are an essential part ofelectrophysiological diagnosis, but are notspecific for MND. Likewise, reduced recruit-ment and large motor unit potentials are non-specific, but in MND larger motor unitamplitudes are seen in relation to diseaseduration than in any other condition. Thebalance between the features of rapidlyadvancing denervation with little reinnerva-tion (frequent fibrillations and fasciculations,highly unstable complex potentials of onlymoderately increased amplitude) and those ofmore slowly progressive disease (scanty fibril-lations, with complex very high amplitude butrelatively stable motor units) differs from caseto case and even between different muscles inone patient. Fasciculations in MND are of alower frequency (0.3 Hz) than in the benignfasciculation syndrome (1 25 Hz). In the lat-ter, fasciculations are not associated withabnormal voluntary motor unit potentials.

Several other points are worth considering.Firstly, motor conduction velocity is seldomlow enough to suggest demyelination,although conduction studies may be unreli-able where the compound muscle actionpotential amplitudes are very low.24 Secondly,a mild reduction in sural nerve action poten-tial amplitude does not exclude the diagnosisof MND. Thirdly, low amplitude of com-pound muscle action potentials and a decre-mental response to repetitive nervestimulation may indicate rapid progression.25Finally, conduction block is not a feature of

Table 4 EMG criteria for diagnosis of motor neurondisease (from ref23, with permission)

* Fibrillation and fasciculation in muscles of the lowerand the upper extremities, or in the extremities andthe head

* Reduction in number and increase in amplitude andduration of motor unit action potentials

* Normal electrical excitability of remaining fibres ofmotor nerves, and motor fibre conduction velocitywithin the normal range in nerves of relativelyunaffected muscles and not less than 70% of theaverage normal value according to age in nerves ofmore severely affected muscles

* Normal excitability and conduction velocity of sensorynerve fibres even in severely affected extremities

typical MND and, when present, raises thepossibility of multifocal motor neuropathy orother demyelinating neuropathy. On theother hand, conduction block is not by itselfdiagnostic of multifocal motor neuronopathy,particularly if it is only present at commonsites of nerve compression. Motor conductionblock should therefore be sought in nervesnot usually liable to pressure palsies.Conduction block implies a greater than 50%reduction in the compound muscle actionpotential amplitude and the negative peakarea following proximal versus distal nervestimulation with less than 15% change in theduration of the negative peak.

Single fibre EMG, macro EMG and cen-tral motor conduction using magnetic stimu-lation are useful techniques for research intomotor system and motor unit physiology.Abnormal jitter and blocking of neuromuscu-lar transmission and increased fibre densitydetected by single fibre EMG reflect earlyreinnervation and collateral sprouting andmay provide evidence of anterior horn celldamage in otherwise normal muscles. Thesetechniques are not mandatory for clinicaldiagnosis and seldom add critical informationbeyond what can be obtained with the moreconventional approaches described above.

DESIRABLE INVESTIGATIONSMany neurologists would now regard MRI asmandatory in patients with possible MND;that is, where there is any possibility that thesigns might be caused by a single lesion.Imaging may be focused on the head, neck,or thoracolumbar region, depending on thepresenting symptoms and signs. MRI notonly helps to exclude common disorders suchas spondylotic myelopathy or neoplasm, butmay reveal extensive corticospinal tractinvolvement with high intensity white matterlesions in the cortex, internal capsule, brain-stem, and spinal cord.2627 Bilateral T2 short-ening in the precentral cortex andhyperintensity of the spinal cord corticospinaltracts at nuclear magnetic resonance imaginghave been reported in MND.28Lumbar puncture with analysis of CSF

should be undertaken in atypical cases but, inmost cases, CSF analysis adds little and inmany centres it is not done routinely. A highprotein level (over 0 75 g/l), the presence ofoligoclonal bands, or increased numbers ofleucocytes, indicate other causes. In a groupof nine patients in whom MND was associ-ated with lymphoma, most had raised CSFprotein, and oligoclonal bands were presentin three.29

OCCASIONAL INVESTIGATIONSA variety of conditions may mimic the clinicalfeatures ofMND (tables 2 and 3), and occa-sionally the following investigations may berelevant: a search for antibodies againstgangliosides30 31 and, occasionally, anti-Huantibodies32; leucocyte or fibroblast hexo-saminidase A and B activity; HIV andHTLV1 assay; blood lead and 24-hoururinary lead excretion.



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SPECT studies may show reduced cerebralblood flow in the frontal regions in patientswith MND and dementia9 but thisinvestigation is not helpful in most cases ofMND.

Familial MND cases may now be screenedfor point mutations in the Cu/Zn superoxidedismutase (SOD 1) gene on the long arm ofchromosome 21 (21q22.1-22.2), but thisshould not be undertaken without propercounselling."I

Epidemiology, risk factors, andpreventionThe incidence of MND is 1-2 per 100 000and the prevalence is 4-6 per 100 000 inmost parts of the world, except the WesternPacific foci.33 34 In Guam, the incidence ofMND has fallen from 87:100 000 in 1962 to5:100 000 in 1985.21 The incidence of MNDelsewhere may be rising, although this couldbe due to improved ascertainment and demo-graphic factors. The average general prac-titioner might expect to see a new case ofMND only once every 25 years. Most surveyshave found that the incidence of MNDincreases with age to a peak between 60 and70 years.3436 In almost all studies, men aremore commonly affected than women, with aratio of around 1-5:1.34-36 In brief, proven riskfactors for MND include increasing age, malesex, and residence for many years in certainparts of the Western Pacific.

As the cause of MND is unknown, andmodifiable risk factors have yet to be definedwith certainty, there are at present no knownprimary or secondary prevention options.Trauma of many types, exposure to a varietyof toxins (cyanide, lead, aluminium) andfarming, and particularly heavy manual activ-ity are possible, but unproven, risk factors.3436In the small community of Two Rivers inWisconsin, United States, a cluster of sixcases occurring over a period of 7-5 years wasdetected.38 Generally the evidence for cluster-ing is weak. Physical trauma, freshly caughtfish from Lake Michigan, and family historyof cancer were implicated as risk factors inthis group. Previous infection with polio virusis probably not a significant risk factor.39

In the Guam MND-PDC syndrome,consumption of a dietary excitotoxin, /B-N-methylamino-L-alanine (L-BMAA), found incycad flour obtained from false sago palm(Cycas circinalis), has been implicated as acausative factor.40 L-BMAA now seems anunlikely factor, however, as insufficientamounts exist in cooked food to be a neuro-toxin.4'

Mortality for MND has been reported tobe different in various ethnic communities.Asian immigrants (Indian and Pakistani) toEngland have less than half the mortalityfrom MND compared with the general popu-lation of England and Wales. Mortality fromMND may also be low in white SouthAfricans (particularly in the Afrikaans-speak-ing group) and in Mexican patients.42A4

PrognosisKNOWN OUTCOMESMedian survival for all sporadic MNDpatients is about 3 5 years from onset ofsymptoms.'545 In a recent, prospective studyof 229 patients with MND, however,Chancellor et a146 reported that, overall, 50%survival from symptom onset was 2-5 yearsand five year survival was 28%.46 BenignMND or long duration MND is recognised,and comprises about 5% of all cases.'5 Earlyonset (below 50 years) is associated withlonger survival. It has been reported that10-16% of patients with MND may livelonger than 10 years, demonstrating a "resis-tance in MND".47 Tucker et a148 reported fourpatients with an MND-like syndrome whorecovered completely 5-12 months after dis-ease onset.48 Complete recovery in MND hasnot been confirmed in a follow up study of708 cases.'5

Bulbar onset is associated with significantlyreduced survival, median survival being about22 years. It is the single most important indi-cator of poor prognosis. It is rare for peoplepresenting with progressive bulbar palsy tosurvive beyond 5 years. ' Older age andfemale sex are adverse risk factors; progres-sive bulbar palsy occurs with greater fre-quency in women.

Communication and counsellingIncreasingly, the neurologist is part of a mul-tidisciplinary team, and a team approach isprobably most satisfactory for coping with thechanging needs of people with MND.

TELLING THE DIAGNOSISOnce the diagnosis has been established byclinical examination and supported by theappropriate investigations, the patient andspouse or close carer should be informed ofthe diagnosis and should be allowed time toexplore the implications. "Telling" shouldtake place with privacy, and a provisionalplan for early follow up and support shouldbe agreed. Most people register only a frac-tion of the information imparted at suchinterviews, and leaflets can alarm more thanreassure at this early stage. Our practice is toexplain the diagnosis with a chosen carer(usually a spouse) and with our care teamcoordinator present. Follow up is thenarranged within two weeks. Close liaison withthe general practitioner is important. Thepatient is given the local contact telephonenumbers for the MND care team and for theMND Association, who fund regional careadvisers to provide advice and practical sup-port. With the permission of the patient andfamily, we inform the RCA about the newlydiagnosed patient.

In our experience, support of the local andnational MND Association forms a key partof an effective care strategy. Although a fewindividuals prefer not to have contact with theMND Association, most patients benefit fromearly referral.

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SUPPORT AND EXTERNAL AGENCIES: THE ROLEOF THE KEYWORKERModels of care through team work will differaccording to local circumstances, but theconcept that each patient should be allocateda keyworker has much to recommend it. Akeyworker is likely to be a health professionalwho agrees to coordinate the activities of themany services that must work efficientlytogether to support MND patients and theirfamilies. The keyworker might be the generalpractitioner, community occupational orspeech therapist, practice nurse or the hospi-tal based team coordinator.

FOLLOW UP AND SUPPORTPatients may know little about MND or mayhave preconceived and erroneous ideas. Theycan be reassured that generally the intellect,sexual and sphincter functions will remainintact. The patient should be encouraged tolead a normal life for as long as possible, butpractical difficulties should be foreseen sothat appropriate action can be taken to pre-vent crises. Patients may benefit from a visitto a disabled living centre or to a specialisedneurological rehabilitation centre. Referral toa "mobility centre" for advice on driving canbe helpful. This theme of coordinating care tominimise delays in the provision of aids andappliances and other forms of support is fun-damental to the good management of MND.Advice about employment, finance, and fam-ily matters should be available from the teamand from expert counsellors. People withMND often feel abandoned by doctors, butregular outpatient attendances may be of littlevalue unless there is a positive care plan andboth the patient and doctor have a clear ideaof what clinic visits can achieve. Continuedsupport from a keyworker, close links withthe general practitioner, a telephone hotlinefor advice and crisis situations, hospitaladmission for respite care or crises, andaccess to hospice care are all important com-ponents of the management of MND.Depression is common, as are frustration,anger, and irritability, the last most oftendirected against spouse or carer, but alsoagainst health professionals.49

Treatment strategiesTable 5 summarises the various treatmentstried and found wanting in MND but thereare a number of promising strategies thatmight yield treatments to influence the courseof the disease.

TRIALS IN PROGRESSBranched chain amino acidsPlaitakis et aF° reported significant benefit inmaintenance of muscle strength and walkingability in 22 patients with MND treated withbranched chain amino acids (L-leucine/L-isoleucine/L-valine). This trial was based onthe hypothesis that partial glutamate dehy-drogenase deficiency can occur in atypicalMND and forms of multiple system atrophy.Branched chain amino acids activate gluta-

Table S Various therapeutic trials undertaken or inprogress in motor neuron disease

Immunotherapy:SteroidsImmunosuppressionWhole body lymphoid irradiationPlasma exchangeInterferon

Vitamin and anti-free radical therapy:Vitamin EVitamin B12SelegilineN-acetylcysteine

Miscellaneous:Chelating agentsThyrotrophin releasing hormoneLevodopaAmantadineGuanidineNaloxoneCytosine arabinosideBovine gangliosidesTestosteronePancreatic extracts

Agents thought to modulate glutaminergic transmission:DextromethorphanLamotrigineBranched chain amino acidsRiluzole

Current trials:RiluzoleN-acetylcysteineBranched chain amino acidsMotor neuron neurotrophic factors:(a) Ciliary neurotrophic factor(b) Insulin-like growth factor 1(c) Brain-derived neurotrophic factor

mate dehydrogenase and may modify gluta-mate metabolism and glutaminergic transmis-sion. A double blind, placebo controlled trialinvolving 126 patients found a higher mortal-ity in the group randomised to active treat-ment, but patients in this group were slightlyolder than the placebo group, and had alower forced vital capacity.5' A multicentre,double blind, placebo controlled trial ofbranched chain amino acids involving over400 patients has now been completed inEurope and the results are awaited.

Glutamate inhibitionInhibition of glutamate has been tried withdextromethorphan, lamotrigine, MK-801,and, more recently, riluzole.5' Riluzole modu-lates glutaminergic transmissions by presy-naptic inhibition of glutamate release andpostsynaptic interference with the effects ofexcitatory amino acids. Riluzole may also actby blocking voltage dependent sodiumchannels and the guanylate cyclase linkedsecond messenger system.5354 Bensimon et aP'reported the results of a prospective, ran-domised, double blind, placebo controlledtrial of riluzole in 155 patients with definite orprobable MND. The primary endpoints weresurvival and rates of change of functional sta-tus and, at the end of one year, survival wassignificantly prolonged in the riluzole group(74%) compared with the placebo group(58%). The apparent effect of riluzole wasgreater in patients with bulbar onset com-pared with limb onset MND. In those withbulbar onset, the survival rate of 12 monthswas 73% with riluzole compared with 35%with placebo (p = 0-014), whereas in thepatients with limb onset the difference wasnot significant. Decline in muscle strengthwas significantly slower in the riluzole group



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as a whole compared with placebo. Althoughrandomisation was stratified according to thesite of onset of the disease (bulbar v limbonset, by first symptoms), the numbers in thebulbar onset group were small (32; 17placebo and 15 riluzole), and there wereminor advantages for the riluzole group interms of age and bulbar function scores,although these differences were not statisti-cally significant. Twenty four of the 155patients randomised did not meet all theentry criteria, but nonetheless all were consid-ered to have ALS and were included in theanalysis. Withdrawals due to adverse drugreactions were more common in the riluzolethan the placebo group. These results cannotbe taken as proof of the efficacy of riluzole,and it is not clear why patients with bulbaronset should respond better than those withlimb onset although such patients mightreceive the drug earlier in the course of lowermotor neuron degeneration. On the otherhand, ventilatory function was worse in thesesubjects than in those with limb onset dis-ease. Only a larger trial can answer thesequestions, and a multicentre trial of riluzolein Europe and North America is now under-way and has recruited over 950 patients.

N-AcetylcysteineN-Acetylcysteine (NAC) is a free radicalscavenger and is a direct and indirect pre-cursor of glutathione, a major intracellularoxidant defence system. Louwerse et al55reported the results of a randomised, doubleblind, placebo controlled trial in 110 patientswith MND.55 After one year, the treatedgroup showed a 29% (non-significant) reduc-tion in mortality in MND of spinal onset butnot of bulbar onset.

Neurotrophic factorsCiliary neurotrophic factor is a neuroactivecytokine made in Schwann cells of peripheralnerves which initiates repair processes. Itpromotes survival of rat and human motorneurons in tissue culture, promotes sproutingof motor axon terminals, and slows progres-sion in murine models of motor neurondegeneration.56 Recombinant human ciliaryneurotrophic factor is being tested in subjectswith MND. Systemic side effects due to thecytokine-like actions of the factor are likely tobe problematic.7Insulin-like growth factor is a 70 amino acidpolypeptide which mediates the action ofgrowth hormone. It enhances motor neuronsprouting in vivo and increases muscle end-plate size in rats.5859 Multicentre trials arenow underway.Brain derived neurotrophic factor enhances thesurvival of motor neurons following axotomyand can rescue motor neurons from deathduring development.606' Trials of recombin-ant human factor have started in North America.

FUTURE PROSPECTS

Although multifocal motor neuropathies may

respond to immunosuppressive treatment,including intravenous infusion of immuneglobulin,62 aggressive immunomodulationdoes not improve MND proper.63 If antibod-ies against calcium channels64 65 are found toplay a part in pathogenesis, there may be fur-ther attempts to treat MND as an autoim-mune disorder, but present indications arethat this approach has failed. Future strate-gies for neuroprotection in MND are likely tofocus on new glutamate antagonists, agentsprotecting against free radical damage, neu-rotrophic factors, and on combinations ofthese.A major difficulty with the human recom-

binant neurotrophic factors is that they haveto be administered by subcutaneous, intra-venous or even intrathecal routes, and accessto the brain and spinal cord is limited. Thusresearch is likely to focus on signal transduc-tion mechanisms to identify compounds thatactivate intracellular systems that respond toneurotrophic factors.

SUPPORTIVE TREATMENT AND TREATMENT OFCOMPLICATIONSDysarthria and communication problemsDysarthria occurs in most patients beforedeath.66 In a hospice setting, only 25% hadnormal speech on admission.67 66 Early referralto a speech therapist and access to a commu-nication aids centre are important.Management measures include encouragingthe patient to decrease the speed of speech.Application of local ice, or use of baclofen,may help to reduce tongue spasticity. Othermeasures include a palatal loop or palatal lift(for hypernasality caused by nasal escape ofair). For patients with anarthria, communica-tion aids may be useful. These include com-puterised type-in speech devices (CanonCommunicator), and Lightwriters orMemowriter (equipped with memory). Incases of severe physical impairment, scanningaids such as the Possum Communicator, inwhich a switch operated cursor light orpointer identifies each item, letter or symbol,can be invaluable.

SalivationDrooling or salivary dribbling is often a prob-lem in people with severe bulbar symptoms.Two to three litres of saliva are produced andswallowed each day normally.69 Loss of auto-matic swallowing and of erect head posturecause drooling of saliva and persistent drib-bling is a major source of distress to patients.Family and friends should be aware that drib-bling is not a sign of mental impairment.Helpful interventions include neck supportand correction of the head position; treat-ment of mouth infections (usually fungal);and application of local ice in the mouth. Thelip seal may be strengthened by simple lipexercises (closing lips against finger resis-tance). Anticholinergic drugs, includingatropine or more usually hyoscine hydrobro-mide elixir or skin patches, may prove effec-



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tive. Amitriptyline is sometimes helpful, andhas the added benefit of improving sleep andmood. Portable suction devices are available,as well as cosmetic assistance to trigger auto-matic swallowing. Surgical measures may bebeneficial, such as transtympanic neurectomy(section of chorda tympani in the middleear),70 and salivary irradiation or denervation.

SwallowingDysphagia is a major problem in 50-70% ofpatients with MND, and may lead tochoking, dehydration, weight loss, salivarydribbling, and aspiration pneumonia.7'Investigation of dysphagia in MND mayinclude cine-videofluoroscopy, which involvesswallowing a barium suspension of varyingconsistency, and analysis of the various stagesof swallowing. Patients should be encouragedto eat where they feel relaxed and comfort-able, as slowness of eating and dribbling maycause severe social embarrassment. It may bepossible to improve head posture and headsupport, as well as lip closure. Again, applica-tion of ice in the mouth may reduce spasticityof the tongue. Dietary measures may includeavoidance of food and drink which precipitatecoughing and choking, such as highly spicedfoods or spirits. Dairy foods (milk and cream)or proprietary thickeners may increase vol-ume and tenacity of mouth secretions.66 If theautomatic swallow reflex becomes depressedin MND, it may be triggered by chewingsweets or gum.Some drugs may help with swallowing

problems: baclofen reduces spasticity and issometimes helpful in doses up to 80-90 mg.L-threonine may help. Anticholinesterasedrugs, however, are usually unhelpful, andincrease salivation. Division of the fibres ofthe cricopharyngeus muscle may help in casesof cricopharyngeal spasm due to demon-strable pseudobulbar incoordination. Post-operative mortality appears to be high (6%-30%) in some published series and thisprocedure is not widely practised.Nasogastric feeding may be useful for tempo-rary feeding when dysphagia is made worseby oral or upper respiratory tract infection.The definitive procedure is percutaneous

endoscopic gastrostomy (PEG). PEG is help-ful in patients with advanced dysphagia, andinvolves the placement of a small borecatheter inserted under local anaesthesia.7172It is helpful to broach the idea relatively earlyin the course of the disease in people withbulbar onset. PEG requires careful dieteticadvice on caloric and nutritional intake andfood selection. Indications for PEG includesevere dehydration, frequent choking, aspira-tion pneumonia, progressive weight loss, andexhaustion due to laboured feeding. PEG isparticularly helpful in patients with severebulbar symptoms but with relatively goodlimb function. It relieves the burden oflaboured attempts to take adequate nourish-ment and often improves wellbeing and qual-ity of life, at least for some months. Theoption of PEG should be discussed withpatients and carers early rather than late in

the disease. For patients who refuse PEG, butwho can swallow some fluids, oral morphineelixir given four hourly or 12 hourly as a slowrelease preparation relieves hunger and thirstto some extent, and may avoid the need for anasogastric tube.

Choking, principally with fluids, accompa-nies dysphagia and patients are often anxiousthat they will choke to death. In fact, thisrarely happens.6768 A home suction devicemay be helpful, at least to provide reassur-ance. Postural advice-for example, askingpatients to lean forward, can be offered, andit may be necessary to teach carers theHeimlich manoeuvre, so that foreign bodiesmay be dislodged in case of obstruction.

Ventilatory failureMost patients with MND die of ventilatoryfailure, usually complicated by varyingdegrees of aspiration pneumonia. Weaknessof the diaphragm may be an early feature ofthe disease, and orthopnea is a commonsymptom.7374 Respiratory insufficiency is bestmonitored by measuring forced vital capacity,specifically measurements taken while sittingand supine (it usually drops to less than20%). Other measures that may help includerespiratory rate; cough strength, anddiaphragmatic excursion; and ability to countup to 20 in one breath. Chest radiograph isimportant when ventilatory function deterio-rates suddenly, as these patients are at risk forpulmonary embolism and infection. Arterialblood gases are maintained normal or nearnormal until a very late stage in manypatients. Nocturnal oximetry may prove help-ful in evaluating the need for assisted ventila-tion during sleep, but the main indication forassisted ventilation is respiratory insufficiencywith disabling symptoms associated with noc-turnal hypercapnia.The management of respiratory failure

includes regular monitoring of forced vitalcapacity with spirometry, correct positioning,particularly during sleep; frequent turning atnight; and prevention of aspiration andremoval of secretions with a hand operated orelectrical suction machine. Prompt treatmentof bronchitis or pneumonia may forestall ven-tilatory failure. Shortness of breath can some-times be helped by use of a continuouspositive airway pressure device along with ahumidifier. Some patients benefit from acuirass with negative pressure ventilation.73Intermittent positive pressure ventilation mayenable patients to sleep, but requires tra-cheotomy, and should, in our view, be con-sidered only after full discussion with family.Nevertheless, it may be appropriate for somepatients.74 75 Tracheostomy is undertakenmore frequently in North America and partsof continental Europe than in the UnitedKingdom. It is often used as a temporarymeasure to tide people over an infection, butwithout intermittent positive pressure ventila-tion, death almost always follows within a fewweeks. In northern Illinois, only 8-6% ofMND patients chose home ventilation.75Home ventilation is expensive and imposes



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significant burdens on families. Oralmorphine often controls dyspnoea effectivelyand can be titrated to avoid drowsiness; itdoes not necessarily shorten life and cansignificantly reduce distress.

SpasticityThis may be helped by the use of benzo-diazepines, baclofen, or dantrolene. Severecontractures may be helped by surgicallengthening- or division of soft tissues. Thiscan be performed under local or spinalanaesthesia.

PainPain may occur in 45-64% patients withMND and arises from muscle cramps, stiffjoints, spasticity, abdominal colic due to con-stipation, and skin pressure.6876 Pain may becontrolled by correct positioning of thepatient and use of a turning bed at night;physiotherapy (changing position, etc.); anddrugs, including muscle relaxants (benzo-diazepines or baclofen), non-steroidal anti-inflammatory drugs, and opioids (inadvanced stages of the disease).

ConstipationConstipation may occur due to weakness ofpelvic muscles, improper diet, spasticity, anddrugs such as anticholinergics and opioids.Management options include increase ofdietary fibre and maintenance of fluid intake;bulk-forming laxatives such as methyl cellu-lose, and osmotic laxatives such as lactulose;and suppositories and enemas.

Peripheral oedemaDependent pedal oedema occurs in virtuallyall patients with MND. This can be counter-acted by elevation of legs, elastic stockings,and cautious use of diuretics.

Sleep disturbancesDisturbed sleep and poor nights may occurdue to pain, depression and anxiety, immo-bility and sleep apnoea. A suitable bed is ofutmost importance to make the nights morecomfortable for patients. Beds should be ofcorrect height with a firm mattress, and turn-ing beds with powered elevator are an addedadvantage.

Emotional problemsThese include depression and anxiety. Theseproblems can be partially helped by effectivemanagement of the other disabilitiesdescribed above, and by antidepressant drugsin selected cases. Emotional lability mayrespond to imipramine.

FINAL STAGESSevere physical disability may require the useof an electronic scanning device whereby eachitem, letter, or symbol is identified by aswitch operated cursor or pointer. ThePossum Communicator is such a device, andenvironmental control devices operated bythe same method are available. Sophisticated

communication aids are available, and withthis and support from home care teams,many people with MND can remain at homeuntil death. In the United Kingdom, supportfrom a local hospice is often the key factorthat allows this to happen.

Patients with MND usually die from respi-ratory failure, inhalation and aspiration pneu-monia, or other infections. Pulmonaryembolism is not uncommon. The variousstrategies available to manage these problemshave already been discussed. In the last stageit is important to maintain symptomatic reliefand avoid distress to patient and family as faras practicable. Narcotic analgesics (morphineor diamorphine) are useful, and may be givenas a suppository, intramuscular or subcuta-neous injection, or by continuous subcuta-neous infusion.The consultant and general practitioner

should be available for consultation, and thekeyworker should stay in close contact withthe family. Hospital or hospice admissionshould be offered if appropriate, to ensure thestress-free death of the patient wheneverpossible.

Following the death of the patient, a letterof condolence should be sent to the partneror family, and the spouse should be offeredcounselling if necessary.

Audit issuesProvision for MND support services have notbeen adequately audited in the past. TheRoyal College of Physicians held a consensusconference on the management of chronicneurological disorders in 1990, and identifieda number of areas in the management ofMND which can be audited. These includeaccessibility to specialist care (with informa-tion regarding waiting list period and travel-ling distance for neurological consultation)and multidisciplinary care (counselling, com-munity physiotherapy, speech therapists, dayhospitals, and provision of aids).

Provision should be made for continuingcare (outpatient visit when the patient is seenby the consultant), and for full informationand liaison (information given to patientsabout the MND Association, consultations toexplain properly the diagnosis and its implica-tions, liaison between the hospital neurologyteam and the general practitioner). The roleof the keyworker should be defined. Otherareas of patient care which can be auditedinclude management of symptoms such aspain, dysphagia, salivary drooling, and insom-nia; patient satisfaction with multidisciplinarycare and general practitioner; support servicesfor specialist help with problems such as dys-phagia and availability of PEG; and provisionfor management of respiratory failure, includ-ing assisted ventilation. The figure shows ascheme used for audit of the MND care teamof the MND Care and Research Centre at theMaudsley and King's College Hospitals,London.



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Current position

Symptoms

Days, weeks, months

GP consultation

Weeks, months

Referral letter tohospital

Weeks. months\

OtherConsultant specialistneurologist Weeks, monti

Weeks

Investigations(IP or OP)

?Weeks

Telling (?)Referral to GP

Weeks, months

?Interdisciplinary teamfollow up in

neurology clinic

Weeks, months

Crisis intervention

Comment:Impact of team

Many variables;education of publicmay shorten delays

Reduce delaysby weeks or months

Reduce delaysby weeks or months

hsReduce delays byweeks

Reduce delays andanxiety

Reduce delays andanxiety

Flexibility, continuity,responsivity of care

\

Impact of MNDteam and

MND centre

Symptoms

Days, weeks, months

GP consultation

Days, weeks

Referral letter tohospital

2-4 Weeks

Consultantneurologist

1-4 Weeks

Investigations(usually IP)

0-2 Weeks

"Telling"Referral to team

2-4 Weeks

Care plan agreedKey worker agreedReview by team

Follow up

Within 4 weeks

Pre-emptive action

Better quality of life

Motor neuron disease: a patient's perspective (suggestedframework for audit).

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