CHAPTER XII
AMYOTROPHIC LATERAL SCLEROSIS (ALS)
Presenting complaints in patients with suspected ALS
 Muscle weakness (usually focal but may be multifocal)
 Bulbar symptoms (dysarthia, dysphagia, drooling)
 Spinal symptoms (weakness in an arm or leg)
 Respiratory symptoms (exertional dyspnea)
 Fatigue
 Weight loss
Differentiation between UMN & LMN ALS
UMN syndrome
Loss of dexterity
Loss of muscle strength
Spasticity
Pathologic reflexes
Flexor spasms
Psuedobulbar signs
LMN syndrome
Loss of muscle strength
Muscle atrophy
Hyporeflexia
Fasciculations
Muscle cramps
El Escorial World Federation of Neurology Diagnostic Criteria for ALS
The diagnosis of ALS requires the presence of:
 Signs of lower motor neuron (LMN) degeneration by clinical, electrophysiologic, or
neuropathologic examination
 Signs of upper motor neuron (UMN) degeneration by clinical examination
 Progressive spread of signs within a region or to other regions with the absence of:
Electrophysiologic evidence of other disease processes that might explain the signs
of LMN &/or UMN degeneration
Neuroimaging evidence of other disease processes that might explain the observed
clinical & electrophysiologic signs
El Escorial Revised Criteria for the Diagnosis of ALS
Definite ALS
UMN signs & LMN signs in 3 regions
Probable ALS
UMN signs & LMN signs in 2 regions with at least some UMN signs rostral to LMN
signs
Possible ALS
UMN signs & LMN signs in I region (together), or
UMN signs in 2 or more regions, or
UMN & LMN signs in 2 regions with no UMN rostral to LMN signs
Probable ALS - Laboratory Supported
UMN signs in I or more regions & LMN signs defined by EMG criteria in at least 2
regions
339
El Escorial & Airlie House Diagnostic Criteria for Diagnosis of ALS
1. The presence of
a. Evidence of LMN degeneration by clinical, electrophysiological or neuropathologycal examination
b. Evidence of UMN degeneration by clinical examination; &
c. Progression of the motor syndrome within a region or to other regions, as
determined by history or examination; &,
2. The absence of
a. Electrophysiological & pathological evidence of other disease processes that might
explain the signs of LMN or UMN degeneration; &,
b. Neuroimaging evidence of other disease processes that might explain the observed
clinical & electrophysiological signs.
Categories of Diagnostic Certainty
El Escorial Criteria
Definite ALS: UMN & LMN signs in three regions.
Probable ALS: UMN & LMN signs in at least two regions with UMN signs rostral to
(above) LMN signs.
Possible ALS: UMN & LMN signs in one region, UMN signs alone in two or more regions,
or LMN signs above UMN signs.
Suspected ALS: LMN signs only in two or more regions.
Airlie House Criteria
Clinically Definite ALS: Clinical evidence alone of UMN & LMN signs in 3 regions.
Clinically Probable ALS: Clinical evidence alone of UMN & LMN signs in at least two
regions with some UMN signs rostral to (above) the LMN signs.
Clinically Probable - Laboratory-supported ALS: clinical signs of UMN & LMN
dysfunction are in only one region, or UMN signs alone in one region with LMN signs
defined by EMG criteria in at least two limbs, together with proper application of
neuroimaging & clinical laboratory protocols to exclude other causes.
Possible ALS: Clinical signs of UMN & LMN dysfunction in only one region, or UMN signs
alone in 2 or more regions; or LMN signs rostral to UMN signs & the diagnosis of Clinically
Probable - Lab - supported ALS cannot be, proven.
Suspected ALS: This category is deleted from the revised El Escorial Criteria.
Diseases which comprise the spectrum of motor neurone disease (MND)
 ALS/MND
 Progressive spinal muscular atrophy (PSMA)
 Primary lateral sclerosis (PLS)
 Segmental spinal muscular atrophy
 Focal spinal muscular atrophy
 Distal spinal muscular atrophy
 Multifocal motor neuropathy (MMN)
 Kennedy's disease (progressive X-linked bulbospinal muscular atrophy)
 Brown-Vialetto-Van Laere syndrome (pontobulbar palsy, with sensorineural deafness)
 SMN gene-linked spinal muscular atrophy, (SMA)
 Adult onset progressive, familial SMA
 Hereditary spastic paraplegia (HSP, Strumpell's disease)
 Fazio-Londe syndrome (infantile progressive bulbar palsy)
340

Other forms (miscellaneous: toxic e.g. lead amyotrophy & axonal polyneuropathy
caused by organophosphates, radiation myelopathy, postpoliosyndrome)
The Lambert criteria for the electrophysiological confirmation of ALS
1. Normal sensory NCS
2. Motor NCS: CVs that are normal when recording from relatively unaffected muscles &
are not less than 70% of the age-based average normal value when recording from
severely affected muscles
3. Fibrillation & fasciculation potentials in muscles of the upper & lower extremities or in
the muscles of the extremities & the head
4. MUPs which are reduced in number & increased in duration & amplitude
*MUP: motor unit potentials, NCS: nerve conduction studies
Essential diagnostic tests prior to diagnosis of ALS
Routine Hematology & Biochemistry
 Serum Calcium & Phosphate
 Thyroid Function Tests
 Serum protein electrophoresis (SPEP) & Urine protein electrophoresis (UPEP)
Lumbar Puncture
 Analysis for trinucleotide expansion within the androgen receptor gene (in males with
lower motor neurone syndrome of bulbar & proximal musculature)
Neuroimaging
 MRI brain (in patients with predominantly upper motor neurone signs)
 MRI spine (in patients with upper motor neurone signs caudal to lower motor neurone
signs, & no bulbar features)
Neurophysiology
 Extensive nerve conduction studies (in patients with predominantly lower motor
neurone signs)
 EMG of 4 limbs & bulbar musculature
Muscle biopsy (if EMG is atypical or unusual myopathy is suspected)
 Hexosaminidase A & B activity (in susceptible Ashkenazi Jewish population)
 Very long chain fatty acids (in patients with positive family history & predominantly
upper motor neuron signs)
Clinical features that should lead to re-consideration of the diagnosis of ALS
Failure to progress
 History of poliomyelitis
 Family history with no affected females & no male to male transmission
 Symmetrical Signs
 Pure upper or pure lower motor neurone syndrome
 UMN signs caudal to LMN signs, with no bulbar involvement
 Development of sensory signs
 Development of sphincter disturbances
341
Clinical features of ALS mimic syndrome patients (n = 33) in comparison to ALS
patients (n = 404) enrolled on the Irish ALS Register, 1993 - 1997
Age at onset (yrs):
Median
Range
Time
from
onset
of
symptoms (yrs):
Median
Range
Time
from
onset
of
symptoms to re-diagnosis
(yrs):
Median
Range
Site of onset:
Lower limb onset
Upper limb onset
Both upper & lower limbs
Bulbar onset
(Including
patients
with
simultaneous limb & bulbar
onset)
ALS Mimic syndromes
Males
Females
(n = 25)
(n = 8)
50.8
57.0
22.0 - 70.4
19.5 85.8
All (n =33)
1.0
0.1 - 6.5
5.2
0.6 - 22.2
18 (54.5%)
10 (30.3%)
2 (6.1%)
3 (9.1%)
ALS
Males
Females
(n = 241)
(n = 163)
65.4
60.8
13.2 - 93.1
29.7 - 91.2
All (n = 404)
0.7
0.1 - 16.0
N/A
N/A
117 (28.9%)
77 (19.1%)
44 (10.9%)
166 (41.1%)
Revised diagnoses of 33 patients with ALS syndromes referred to the Irish ALS
Register, 1993 – 1997.
Final diagnosis
o Multi-focal motor neuropathy
o Kennedy's disease
o Motor neuropathy
o Non-compressive myelopathy
o Spino-muscular atrophy (SMA)
o Cervical spondylotic myelopathy
o Post-polio syndrome
o ALS plus dementia
o Multiple sclerosis (MS)
o Thyroid disease
o Pancoast's syndrome
o Uncertain
Total number of ALS Mimic patients
N
6
4
4
3
2
1
1
1
1
1
1
8
33
342
Loci & Genes underlying Familial ALS (FALS)
Familial ALS
Dominant
Chromosomal locus
Gene
21q
9q34
9q21-22
11
SOD1
17q
tau
NFH
Xp11-q12
21q
15q12
2q33-35
SOD1 = Superoxide dismutase
Recessive
SOD1
Remarks
Juvenile onset
With dementia
Transmission uncertain
Frontotemporal dementia with
amyotrophy
D90A only
Diseases Mistaken for ALS
 Benign fasciculations
 Parkinson's disease (PD)
 Kennedy's disease (X-linked bulbospinal muscle atrophy)
 Brainstem stroke
 Lumbosacral stenosis
 Cervical myelopathy
 Carpal tunnel syndrome (CTS)
 Brachial plexopathy
 Neuropathy
Prognosis of ALS: Spinal Onset Versus Bulbar Onset
Investigator
Spinal onset
Tysnes et al.(1991)*
37%
Rosen et al (1978)*
44%
Jokelainen et al. (1977) ‡
34 months
Kristensen et al. (1977) ‡
36 months
Gubbay et al. (1985) ‡
38 months
Mackay et al. ‡
36/33 months
Tysnes et al (1994) ‡
26 months
*Five - year survival rate.
† Statistically significant differences (P< 0.01).
‡ Mean duration of disease.
§ Data represent spastic / paretic forms.
343
Bulbar onset
9% †
14% †
25 months 24
24 months
26 months
24 / 17 months§
12 months
Core membership of the MND Care Team (the King's model)
Team member
Team & care coordinator
Main Roles
Integrates & facilitates care plan; out-reach
to regional teams; education; administration
of MND Centre; advice on benefits; liaison
with support group (e.g., MND Association)
Nurse specialist
Advice on PEG, RIG, NIPPV; follow-up of
patients after admission to wards; out-reach
to patients & community services
Speech & language therapist
Advice on communication, communication
aids, swallowing, PEG & RIG
Dietician
Advice on nutrition, PEG, RIG
Physiotherapist
Advice on physical therapy, aids &
appliances, referral to orthotist
Occupational therapist
Advice on activities of daily living, aids &
appliances, modifications to home, social
support; referral to orthotist
Respiratory physician
Assessment of ventilatory function; advice
on NIPPV, tracheostomy
Counseling team
Psychological counseling & support; family
therapy; bereavement support
Neurologist
Diagnosis, treatment (e.g., riluzole);
symptom control; palliative care; integration
of medical & social aspects of care; review
of diagnosis
Neurogeneticist
Genetic counseling for familial MND &,
genetic testing
MND Association
Information, equipment, advice on local
services, benefits & rights, local volunteers;
advocacy at personal, local & national levels
Gastroeneterologist / radiologist
Placement of PEG, RIG
Neuropsychologist
Assessment of cognitive function & Care of
cognitively impaired patients
Clinical Neurophysiologist
EMG & nerve conduction studies
Primary care physician
Prescription & monitoring of drugs;
coordination of care locally; symptom
control; liaison with hospice/palliative care
team
Palliative care physician
Assessment of need for home care, respite
care &/or hospice care; symptom control;
terminal care.
PEG = Percutaneous endoscopic gastrostomy/gastrojujonostomy
RIG = Radiologically inserted gastrostomy
MND = Motor neurone disease
NIPPV = Non-invasive positive pressure ventilation
EMG = Electromyography
344
Patient - Specific Problems to be addressed in a Comprehensive Treatment Plan for
ALS






Speech / communication
Swallowing / salivation
Sleep / fatigue
Respiration
Activities of daily living
Ambulation
Instruments & devices used to enhance speech & communication
 "Low tech" (e.g., paper/pencil, erasable pad)
 Communication board
 Typed communications
 Crespeaker (converts single words to speech)
 "Higher tech" instruments (e.g., Light Writer); anticipates word endings.
 Personal computers:
 Access to the internet
 Environmental controls
 Single letter or phrase through scanning & microswitches
 Voice preservation
 TDD (telecommunication device for the deaf); essential for anarthric patients
General recommendations to enhance swallowing
 Assessment by speech pathologist
 Body weights at every visit
 Nutritional supplements for protein & caloric maintenance
 Thickeners for thin liquids
 Feeding tubes
Causes & mechanisms of weight loss & malnutrition in MND
Difficulty
Bulbar dysfunction
Weakness of jaw muscles
Weakness/dysphagia
(Eating slowly in company)
Upper limb weakness
Loss of appetite
‘MND cachexia‘
Main contributing factors
Weakness of muscles of deglutition.
Aspiration during swallowing
Spasticity of muscles of deglutition
Difficulty chewing
Social embarrassment
Inability to eat unaided
Hypoventilation & respiratory failure;
riluzole; depression
Uncertain:? Hypermetabolic state
The management of nutrition in MND comprises:
 Assessment & monitoring of dietary intake in relation to the energy, fluid, vitamin &
mineral needs of the patient
 Advice on maintaining a healthy diet
 Monitoring of weight & anthropometric measures
345


Assessment of the need for & timing of percutaneous endoscopic gastrostomy /
gastrojejunostomy (PEG) or radiologically inserted gastrostomy (RIG)
Advice on PEG or RIG feeding &care of feeding tubes
Advantages & disadvantages of PEG, RIG, & NGT Hydration & Nutrition in MND
patients
Procedure
PEG
RIG
NGT
Advantages
Standardized procedure for MND
patients; risks & benefits
well-documented; tubes widely
available & standardized
Only fine-bore NGT tube required
(for introduction of Barium & air);
sedation optional; seems to be
tolerated well by patients with VC <
50%; can be used with NIPPV
Minor, non-invasive procedure;
possible to place in virtually all
patients; good for maintaining
hydration & avoiding IV
fluids/feeding
Disadvantages
Requires sedation, introduction of
endoscope tube, recumbency. Not
recommended if VC < 50%; requires
admission to hospital (2-5 days)
Not yet standardized for MND
(different tubes for PEG); requires T fasteners to hold stomach wall in place;
sutures require removal at 10-14 days.
Requires admission to hospital (2-5
days)
Nasopharyngeal discomfort, pain or
even ulceration; intrusive & unsightly
for active patients; narrow diameter
limits feeding
Benefits & Risks of Gastrostomy
Benefits
 Relatively easy insertion with local anesthesia
 Flexible dietary choices / delivery modes
 Bolus / continuous infusion
 Pureed / commercial liquid diet
 Diet administered in “normal meal time”
 Lower risk of cramps / diarrhea than with jejunostomy
Risks & other considerations
 Possible regurgitation / aspiration
 Requires patient's head to be elevated after feeding
Pharmacologic Management of Excessive Salivation
Medication
Amitriptyline (Tryptizol)
Glyopyrrolate
Imipramine (Tofranil)
Methantheline
Methylphenidate (Ritalin)
Propantheline (Probanthene)
Trihexphenidyl (artane)
Dosing schedule*
10 mg hs or am and hs
1-2 mg q4h
50-200 mg hs
50-100 mg q4h
10-20 mg q6h
15-30 mg q4h
2-10 mg q4th
*Usual adult dosage used as needed (prn)
346
Symptoms & Signs of Respiratory Insufficiency in MND
Symptoms
Orthopnoea
Dyspnoea on exertion or talking
Disturbed night time sleep
Excessive daytime sleepiness
Fatigue
Anorexia
Depression
Poor concentration &/or memory
Morning headache
Signs
Increased respiratory rate
Use of accessory muscles
Paradoxical movement of abdomen
Decreased chest movement
Sweating
Hyperdynamic circulation
Weight loss
Respiratory Management of Patients with ALS
 Discuss respiratory complications & management options early in disease course
 Encourage patient / family involvement in major treatment decisions (including periodic
review of "code status")
 Meticulous pulmonary toilet
 Pneumococcal / influenza vaccines
 Aggressive treatment of respiratory infections
 Maintenance of adequate nutritional status
 Regular monitoring of vital signs / measurement of FVC at every clinic visit
 Instruction concerning techniques to avoid aspiration
 Resistive inspiratory training
 Home use of noninvasive ventilatory assistive devices (e.g., IPPB, CPAP, BiPAP, chest
cuirass)
 Tracheostomy & mechanical ventilation
 Pharmacologic management: Low-dose theophylline to increase respiratory muscle
strength after resistive breathing; diuretics for fluid overload; nebulizer breathing
treatments (e.g. Albuterol) to loosen secretions
Current criteria for considering assisted ventilation:
Patients should have
1. Symptoms relating to respiratory muscle weakness
2. Symptoms suggesting nocturnal hypoventilation
3. Evidence of respiratory muscle weakness
4. Evidence of nocturnal hypoventilation (abnormal polysomnography)
Measures for Assisting in Activities of Daily Living



Home visit at selected times
Bathing
 Grab bars
 Chair / bench
 Handheld shower
Toileting
 Raised toilet seat
 Grab bars
347




Dressing
 Assistive devices for buttons / zippers
 Casual, loose-fitting clothing with elastic waistbands
Feeding
 Large - handled utensils
 Alternative food preparation (e.g., purees)
Grasping
 Large handles
 “Reachers”
Home management
 Assistances with shopping, household chores
Interventions for Various Other Problems & Complications of ALS
 Head control
Neck brace
 Rotator cuff tendinitis / impingement
Range -of- motion exercises
NSAIDs (nonsteroidal antiinflammatory drugs)
Proper lifting by caregivers
 Painful cramps
Quinine
Diazepam (Valium)
Phenytoin (Epanutin)
 Other pains
Treat symptomatically
 Spasticity
Baclofen (Lioresal) (orally or via implantable pump)
 Pseudobulbar affect
Tricyclic antidepressants (TCAs)
SSRIs (selctive serotonin reuptake inhibitors)
Airlie House Guidelines
(ALS Clinical Trials Guidelines)
Diagnosis
Inclusion criteria
Exclusion criteria
Primary & secondary
disease end points
Should conform to World Federation of Neurology El
Escorial Criteria
Sporadic & familial ALS patients can be entered,
depending on trial
18-65 years old
Evidence of disease progression during the 6 - month
period from onset of symptoms, but not more than 5 years
Significant sensory abnormalities, dementia, other
neurologic disease, uncompansated medical illness,
substance abuse, psychiatric illness; non investigational
drugs concurrently
Death or ventilator dependence, change in muscle strength
Control arm; quality -of- life assessment, detailed
statistical analysis
348
Compassionate release /
treatment indications
Information release
Commercial concerns
Should be used only when assessment of therapeutic
efficacy of drug is not compromised
Phase of trial
Independent data safety
monitoring board
Phase I, II, III
Include physicians & biostaticians
Define at start of trial
Should not distort conduct of trial
Proposed Measurements for Substrates Involved in the Pathology & Functional
Deficits in Patients with ALS
Domain
Pathology
Substrate
Motor neuron changes
Motor neuron loss
Corticospinal tract
degeneration
Strength loss
Breathing
Measurement (s)
Ubiquitin-positive motor neurons
Neurofilament-positive motor neurons
Glial fibrillary acidic protein-positive corticospinal
tract staining
MVIC (tongue, limbs); inspiratory & expiratory
Impairment
force (diaphragm)
Respiratory rate; FVC; SVC; PIF
Spasticity
Ashworth spasticity scale
Fine coordination
Alternate motion rates;
Finger kinematics; motor performance tests;
pegboard test
Speech
Intelligibility test, Frenshay test, ALSFRS
Disability
Swallowing
Deglutition measurements by videofluroscopy or
timing; ALSFRS
Breathing
ALSFRS
Limb
ALSFRS
Loss of independence
Sickness Impact Profile, Short Form 36
Handicap
Death
Survival
ALSFRS = ALS functional rating scale;
FVC = Forced vital capacity;
MVIC = maximal voluntary isometric contraction;
PIF = Peak inspiratory flow;
SVC = Slow vital capacity
Reasons for Performing EMG in ALS
 To ascertain findings that confirm LMN degeneration in regions with clinically
identified involvement
 To identify LMN degeneration in clinically uninvolved regions
 To exclude other disorders
 EMG examinations should be performed in at least 2 muscles of different roots, cranial
nerves or peripheral nerves & at least 2 or more of the 4 regions of involvement (bulbar,
cervical, thoracic, lumbo sacral).
The diagnosis of ALS is supported by the following EMG findings:
 Reduced recruitment (firing rate > 10 Hz)
 Large motor unit action potentials
 Fibrillation potentials
 Unstable, large motor unit action potentials
 Reduced motor unit action potentials
349

Reduced motor unit number estimates (MUNE) & increased macro-EMG unit action
potentials
Other Diagnostic Tests Performed in ALS
The following diagnostic tests are not mandatory but can be used primarily to rule out other
similar diseases, & secondarily as confirmatory tests
 Neuroimaging
 Ascertain findings that may exclude other disease processes
 Muscle biopsy
 Ascertain acute & chronic denervation
 Identify LMN degeneration in clinically uninvolved regions
 Laboratory tests
 CBC & serum chemistry panel
 Endocrine function tests (especially thyroid function tests)
 Heavy metals (do not perform unless there has been a definite history of exposure)
 GM1 antibodies (helpful when positive if patient has multifocal motor neuropathy)
Therapeutic Agents in ALS
Drug class
Agents
Status
Riluzole (Rilutek)
Approved
Gabapentin (Neurontin)
Phase III (approved as an AED)
Vitamin E
Preclinical
Antioxidant
CT-I
Preclinical
Neurotrophic factors
IGF-I
Phase III
GDNF
Phse I
NT-3
Preclinical
NT-4
Preclinical
Axokine
Preclinical
ACT
Preclinical
Protease inhibitor
PN-I
Preclinical
ACT = µ1-antichymotrypsin; BDNF = brain-derived neurotrophic factor; CT-I =
cardiotrophin-I; IGF-I = insulin-like growth factor-I; GDNF = glial-derived neurotrophic
factor; NT-3 = neurotrophic factor-3; NT-4 = neurotrophic factor-4; PN-I = protease nexin-I
Antiglutamate
Drug Treatment:
Riluzole (Rilutek)
Is it a useful drug in MND?
 Riluzole is a benzothiazole derivative with complex effects on glutamate
neurotransmission including inhibition of presynaptic glutamate release
Mechanisms of action of riluzole
Effect
o Blockade of presynatic glutamate
release
o
NMDA receptor antagonism
Mechanism
 Uncertain: ? effects on Na+ channels;
activation of G-protein linked signal
transduction
 Direct, non-competitive receptor blockade
350
o
o
o
Inhibition of glutamate evoked Ca
2+ entry
Prevention of neuronal
depolarization
? Inhibition of apoptosis
 Activation of G-protein mediated signal
transduction
 Inactivation of neuronal Na+ Channels
 Inhibition of stress-activated protein kinase
(SAPkinase)
Symptomatic Treatment of ALS
Symptoms
Weakness/ ambulation
Exercise
Activities of daily living
Cramping
Spasticity
Pain
Dysphagia/ swallowing/
weight loss
Salivation
Loss of speaking
Assessment
Anticipate need for &
Introduce early; keep
patients ambulatory as
long as possible
(independence)
Controversial; may be
of benefit in ALS; use
strength testing as guide
Home visits for
assessment
May cause sleep
disturbance
Not usually a major
problem
May cause sleep
disturbance
Speech pathologist;
malnutrition can
accelerate course of ALS
Can result in
laryngospasm or severe
coughing
Speech &
communication
Depression/insomnia
May cause sleep
disturbance
Sleep disturbance
May be related to leg
movements or to
myoclonus or apneas;
do pulse oximetry or
sleep study
351
Treatment
Physical therapy, orthopedic &
assistive devices, canes, walkers,
specialized wheelchairs
Exercise in grade 4 or 5 muscles
only
Safety devices for bath & toilet,
dressing & feeding
Assistive devices
Quinine (Lioresal), diazepam,
phenytoin
Baclofen
Analgesics, opiates,
Transcutaneous electical nerve
stimulation (TENS)
Blenderized food, supplements,
feeding tube, percutaneous
gastrostomy (PEG)
Suction machines; amitriptyline or
atropine
Paper & pencil, specialized voice
ability synthesizers, Etran
communications board, TDD
(telecommunication device for the
deaf), microcomputer-based
instruments
Antidepressants (offer universally),
anxiolytics, electrically powered
adjustable bed
Clonazepam or Sinemet CR;
ventilatory assistance (BiPAP or
nasal CPAP)
Respiratory/pulmonary
weakness
Measure FVC every
visit; ventilator
education
Infections
From decreased
bronchial clearance of
secretions
Anticipate need; sooner
if needs are present
Hospice
Antisecretory agents, cough
medication, tracheostomy; BiPAP,
CPAP, chest cuirass volume
ventilators
Antibiotics; prophylactic vaccines
(pneumococcal, influenza)
Some common symptoms in ALS & their treatment
Symptoms
Cramps
Cause
? Changes in motor neurone
Na+ channel function
Treatment
Quinine sulphate 200m bid
Carbamazepine (Tegretol)
Phenytoin (Epanutin)
Magnesium
Verapamil
Corticospinal tract damage
Baclofen 10-80mg daily
Spasticity
Tizanidine 6-24mg daily
Dantrolene 25-100mg daily
Intrathecal baclofen
Memantine 10-60mg daily
Bulbar weakness
Atropine eye drops
Sialorrhoea
sub-lingual
Atropine 0.25-0.75 mg tds
(tabs/liquid)
Benztropine (tabs/liquid)
Benzhexol (tabs)
Hyoscine (tabs/transdermal
patches)
Amitriptyline (Tryptizol)
(tabs/liquid)
Glycopyrrolate (liquid:
sc/im/via PEG)
Salivary gland irradiation
Transtympanic neurectomy
(?)
Botox injection to salivary
glands (?)
Pseudobulbar syndrome
Amitriptyline (Tryptizol)
Emotional
SSRIs (e.g., citalopram,
Lability
fluvoxamine)
Agents Approved or Under Investigation for the Treatment of ALS
 Glutamate antagonists
 Riluzole (approved for the treatment of ALS)
 Gabapentin (commercially available for treatment of seizure disorders)
 Neurotrophic factors
352

Insulin-like growth factor-1 (IGF-1)
Glial-derived neurotrophic factor (GDNF)
 Cardiotrophin-I (CT-1)
 Neurotrophin-3, neurotrophin-4 (NT-3, NT-4)
Protease inhibitors


1Antichymotrypsin (ACT)
Protease-nexin-1 (PN-1)
Antioxidants
 Vitamin E



Conclusions
1. People affected by MD (ALS) are best served by a multi-professional team approach that
is 'user-centred'. New models of user-involvement are being developed.
2. Riluzole is associated with improved survival at 12 & 18 months, but the survival gain
(estimated at 2-3 months at 18 months) beyond 18 months is unknown. Riluzole is safe
& well-tolerated.
3. Recent trials of neurotrophic factors (e.g., subcutaneous & intrathecal BDNF) & related
agents have been essentially negative.
4. PEG is associated with prolonged survival & improved nutrition but is hazardous in
patients with VC <50% predicted. RIG may offer advantages over PEG in patients with
low VC (<50%).
5. New evidence suggests that both survival & QL is improved by non-invasive positive
pressure ventilation (NIPPV) but as yet there are no agreed criteria for initiating NIPPV.
Currently 10-20% of patients in Europe have NIPPV but this varies widely in different
centers.
6. Palliative care encompasses the entire course of MND, not only the final phase.
Symptom control is important at all stages.
7. Advance directives are seldom but increasingly used in Europe. Ethical concerns about
end of life decisions (e.g., ceasing ventilatory support: physician assisted suicide) are
under debate.
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