Download Amyotrophic Lateral Sclerosis

CNS Drugs 2O11.-25(1): 1-16
1172-7047/11/CX)01-OCI01/S49.96/0
THERAPY IN PRACTICE
© 2011 Adb Dota Intormatlon BV. All rights reserved.
Amyotrophic Lateral Sclerosis
Pathophysiology, Diagnosis and Management
Paul H. Gordon
Fédération des Maladies du Système Nerveux, Assistance Publique - Hôpitaux de Paris, Hôpital de la
Pitié-Salpêtrière, Paris, France
Contents
Abstract
1. Introduction
2. Manifestations and Diagnosis
3. tVlanagement
3.1 .Speoiflo Ttierapy: Riluzole
3.2 Multidisciplinary Care
3.3 Nutrition
3.4 Respiration
4. Symptomatic Treatment
4.1 Cognitive Decline and Depression
4.2 Emotional Labiiity/Pseudobuibar Affect
4.3 Sialorrhoea
4.4 Spasticity
4.5 Urinary Urgency
4.6 Impaired Sieep
4.7 Fatigue
4.8 Constipation
4.9 Pain
4.10 Palliative Care and Hospice
5. Novel Therapies
6. Conclusions
Abstract
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Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative
disease associated with a life expectancy of approximately 3 years after symptom onset, but the range of survival extends from a few months for some to
decades for approximately 5% of patients. There is no clear cause in the majority of cases and just one medication, riluzole, has been shown to modestly
prolong survival.
Research has identified some of the cellular processes that occur after disease onset, including mitochondrial dysfunction, protein aggregation, generation of free radicals, excitotoxicity, inflammation and apoptosis, but for
most patients the underlying cause is unknown. While ALS is considered to
be a complex genetic disorder in which multiple genes in combination with
environmental exposures combine to render a person susceptible, few genetic
or environmental risks have been discovered to date.
Gordon
The diagnosis is based on the history and examination showing progressive upper and lower motor neuron findings. The electromyogram can
help confirm the diagnosis, and additional tests are used to exclude other
conditions.
Published practice parameters guide the care of patients with ALS. Until
the elucidation of aetiologies leads to the development of more robust neuroprotective agents, both pharmacological and nonpharmacological treatments are directed at maintaining quality of life and prolonging life to the
greatest extent possible. Riluzole, ventilatory support for those with respiratory insufficiency, gastrostomy for those with dysphagia and multidisciplinary care may help extend life. The off-label use of many symptomatic
agents can have a meaningful impact for those with the illness. Palliative care
ensures dignity toward the end stages of the disease.
Clinical trials currently aim to slow disease progression by testing drugs
that impact one or more of the processes that are initiated after disease onset.
Novel therapies currently in trials include potential neuroprotective agents
with differing mechanisms of action, vaccine therapies, stem cell injections
and diaphragmatic pacing.
1. introduction
Amyotrophic lateral sclerosis (ALS) is considered a complex genetic disorder, in which multiple genetic and environmental factors combine
to cause the disease, with the contribution of any
single factor being small. There is currently very
little evidence, however, to support the contribution of any major genetic or environmental risk
factor in most cases of sporadic ALS (sALS). The
causes of ALS have proved difficult to identify, in
part because the disease is rare, with an incidence
of approximately 2 per 100000/year in Western
countries,!'1 but also because the nerve cells are
hidden and ephemeral, and antecedents may act
in sequence over decades, so that once the illness
develops, the aetiology might be long since past.
Many environmental factors have been examined in s ALS. Accepted risks include age, with most
cases occurring between 55 and 65 years, male sex
and likely cigarette smoking.'^'^^ Physical stress, exposure to pesticides and athleticism are possible
contributors, but the associations are small and inconsistently reproducible.I^'^1 It could be that risks
have not yet been examined in correct sequence, for
example, if they interact over a lifetime, or that science has not yet developed an awareness of the
important risks.
© 2011 Adis Data Information BV. All rights reserved.
Between 5% and 10% of cases are inherited (familial ALS; fALS) as a Mendelian trait, usually
autosomal dominant, of which 15-20% are due to
one of more than 100 mutations in the Cu-Zn
Superoxide dismutase type 1 (SODl) gene,'^' which
normally reduces oxidative stress by converting
Superoxide anions to hydrogen peroxide. The mechanisms by which mutant SOD] is toxic to motor
neurons are poorly understood. After discovery of
the gene, an animal model was created that has contributed to improved understanding of cellular processes that occur, at least in this genetic form of
ALS, after the disease process has begun.['°l Other
rare genetic loci have been labelled ALSl through
ALS 10, ALS with frontotemporal dementia (ALSFTD) and ALS-FTD with Parkinson's disease
{ALS-FTDP)P^ Mutations infused in sarcoma
{FUS) genes account for approximately 5% of
Co-segregation of ALS with other neurodegenerative disorders in families suggests common
genetic risks,f'^l but genome-wide association
studies have demonstrated that there is no single
gene that accounts for most sALS."^' TAR DNA
binding protein (TDP-43), a ubiquitously expressed nuclear protein that regulates messenger
RNA transcription and splicing, is found in inclusions of ALS and most forms of
CNS Drugs 2011:25(1)
Amyotrophic Lateral Sclerosis
Mutations in the TDP gene have been identified
in some patients with sALS or fALS,^'^' suggesting a possible pathogenic link, but the inclusions
have also been identified in other conditions, so
their true role is still unknown.''^'
Once the disease is initiated, a cascade of cellular events occurs, including oxidative stress,
glutamate-induced excitotoxicity, intracellular protein aggregation, mitochondrial dysfunction, growth
factor deficiency, abnormal axonal transport and
caspase enzyme activation.t'^ Nerve cells appear to
eventually die through caspase enzyme-mediated
apoptotic or inflammatory pathways. Current clinical trials test drugs that may interfere with these
downstream pathways, but only one drug has been
shown to modestly prolong survival, and most trials
have been negative or shown the agent under study
to be harmfulJ'^i
Clinical trials are difficult to conduct in ALS
because there are, as yet, no biomarkers of disease progression; trials use clinical outcome measures and must be large and of long duration in
order to reliably detect changes. Dosage selection
is especially important so that correct dosages of
medications are tested for efficacy, but it is challenging to determine the most effective dosage for
neuroprotection outside of a large efficacy trial.
Additionally, there is great pressure within the
field to identify new therapies as quickly as possible, which, in the past at least, has prompted
investigators and pharmaceutical companies to
sometimes minimize the role of early-phase dosage-selection trials and move quickly to large
phase III trials.
It is likely that better treatments and preventative measures will be ascertained after the
causes of ALS are found. In the meantime, treatment is aimed at maintaining quality of life and
prolonging life to the greatest extent possible,
through multi-disciplinary clinics, management of
nutrition and respiratory insufficiency, off-label
use of medications to control symptoms and palliative care. Ongoing basic and clinical research
aims to gain a better understanding of the disease.
The purpose of the current article is to give an
overview of the manifestations and diagnosis of
ALS, and to describe the current approach to
treatment.
© 2011 Adis Data Information BV. All rigtits reserved.
2. Manifestations and Diagnosis
ALS begins with limb weakness in about 65%
of patients.t"! Foot drop, difficulty walking, loss
of hand dexterity or shoulder weakness are typical early symptoms. Approximately one-third of
the time, weakness begins in bulbar muscles,
usually with dysarthria followed by dysphagia.
Symptoms due to lower motor neuron (LMN)
degeneration, including weakness, atrophy, cramps
and fasciculation, often eclipse those associated
with upper motor neuron (UMN) disease. Eventually, limb function is lost, leading to dependence
on caregivers; walking and standing, as well as
bearing weight for transfers, become impossible.
Falls are common.
With time, some patients become anarthric.
Swallowing problems can lead to drooling, dehydration, malnutrition with weight loss and aspiration. Weakness of the axial musculature leads to
head drop and kyphosis, which can cause pain, imbalance due to change in the centre of gravity and
problems with activities such as eating and driving.
Sphincter and sensory function are often spared.
Cognition is impaired in 25-50% of patients
who receive neuropsychological tests, and approximately 15% develop overt dementia, most
often FTD.[^°1 The cognitive abnormalities lead
to changes in personality, language, judgement,
decision making or affect. The associated abulia
and reduced judgement can render patients less
able to participate in decisions about their medical treatments and to shorter survival.'^''
Emotional lability, or pseudobulbar affect,
due to loss of normal inhibition of laughter and
crying, which depend on neural pathways mediating emotion, respiration, vocalization and facial movements, may be associated with UMN
Depression and anxiety can be prominent features at all stages of the disease. Anxiety can accompany symptoms of respiratory insufficiency,
and depression may lead to reduced appetite,
poor sleep, hopelessness and impaired ability to
make decisions.
ALS is usually described as causing painless
weakness, but pain can occur, resulting from loss
of mobility, the inability to turn in bed, joint
CNS Drugs 2011:25(1)
Gordon
contractures or bedsores. The psychological and
physical discomfort that arises from the inability
to move can be profound.'^^' Occasionally, pain
seems to be a feature of the disease itself, possibly
related to degeneration of sensory tracts or nuclei.
Cramps can also be painful and may interfere
with sleep or physical activity.
Shortness of breath or other respiratory symptoms usually occur later in the disease course.
Symptoms include orthopnoea, morning headaches and weakened cough. Patients develop dyspnoea on exertion and eventually during inactivity.
Respiratory failure and pulmonary complications
of bulbar weakness, such as aspiration pneumonia,
are the most common causes of death.
The diagnosis is based on the history and examination that shows progressive UMN and LMN
findings. An electromyogram, done in three limbs,
and bulbar as well as paraspinal muscles, confirms
the presence of widespread LMN disease, and helps
to exclude potential mimicking disorders such as
multi-focal motor neuropathy with conduction
block. A sensory neuropathy detected by nerve
conduction studies suggests the possibility of Kennedy's disease (X-linked bulbo-spinal atrophy), but
sensory loss can rarely be a feature of typical ALS.
Brain and cervical spine MRI are done to exclude
other conditions that affect the UMN, such as cervical spondylosis. The El Escorial criteria, developed in 1990 and revised in 1998 to standardize the
diagnosis for clinical research, can be applied.'^'*'
Transcranial magnetic stimulation and magnetic
resonance spectroscopy examine the UMN,'^^' but
are often limited to large centres or research protocols. Spinal fluid is analysed only when the disorder
is atypical, or if a secondary cause, such as carcinomatous meningitis or infection, is suspected. In the
hands of an experienced ALS specialist and electromyographer, the diagnosis is correct more than
95% of the time. Patients with both UMN and
LMN disease are labelled as having ALS, those
with only LMN signs are diagnosed as having
progressive muscular atrophy and those with only
UMN signs for 4 years or longer as having primary
lateral sclerosis. Genetic testing is not a routine part
of the evaluation unless there is a family history of
the disorder. The progression is insidious and time
to diagnosis is often more than 1
© 2011 Adis Data information BV. Aii rigtits reserved.
Practice guidelines'^^'^^' suggest that the diagnosis should be given in person, not by telephone,
with family or friends present to give support,
and that a follow-up appointment be scheduled
soon afterward. The process of breaking the news
may require 45 minutes or longer.'^^' The neurologist usually summarizes the main points of the
discussion verbally or in writing and proposes a
plan of care before the patient leaves the office.
Patients are also informed about ALS resources,
including patient advocacy groups, and a discussion of ongoing research into better treatments
conveys hope.'^^'
While ALS is an incurable disease, many
symptoms are amenable to supportive therapies,
some of which may even improve the disease
course. Unfortunately, there are few controlled
trials of symptom management. As a result, the
selection of therapies is still based largely upon
physician experience. Practice parameters outline
common strategies, but there is a wide variety of
management practices,'^"' and more controlled
trials are needed.
3. Management
3.1 Specific Therapy: Riiuzoie
Excess glutamate, an excitatory neurotransmitter, may be associated with neurodegeneration. Riluzole, first developed as an antiepileptic
drug (AED), inhibits the presynaptic release of
glutamate, but its exact mechanism in ALS is
unknown. Riluzole is currently the only drug
approved to slow the course of ALS. In two
randomized, controlled trials, riluzole prolonged
survival by approximately 4 months.'^''^^' The
first trial showed mild slowing in deterioration of
strength, but neither study showed improvements
in quality of life. The small beneficial effect was
not apparent to patients, family members or physicians.'^^' The Cochrane Library conducted a
meta-analysis of three published trials, which included a total of 876 riluzole-treated and 406
placebo-treated patients.'^'*' The meta-analysis
indicated that riluzole lOOmg/day prolongs survival by approximately 11%, or about 2 months.
CNS Drugs 2011; 25(1)
Amyotrophic Lateral Sclerosis
The long-term safety of riluzole therapy has
been established,'-'^' including in the elderly and
those with advanced disease.'^^' The most common adverse effects are fatigue, somnolence, nausea, diarrhoea and dizziness. Liver enzyme level
elevation can occur, but rarely to levels that are
clinically meaningful. Serum concentrations of
riluzole vary between individuals, probably resulting from different rates of metabolism.'^^' Adverse effects tend to be more frequent in those
with high serum concentrations. Dose adjustment based on serum concentrations is one approach to optimizing treatment, but is rarely used
in practice.
More than half of US patients'^^' and nearly all
patients in Europe, where the health systems cover
the cost,'^'' take riluzole. The Canadian health
system does not pay for riluzole, but many patients there are provided with the drug based on
compassionate use.
3.2 Multidisciplinary Care
The care of patients is challenging because
ALS is progressive and terminal, and there are, as
yet, no truly effective treatments.''*^' Most large
centres currently use a multidisciplinary approach to care,''*'' and some data suggest that
patients cared for at multidisciplinary clinics may
survive longerP^' Patients are evaluated frequently so that impending problems are detected
and treated early. The care plan is centred on the
patient's decisions, focusing on support and education. The neurologist and allied health team
provide information to help in treatment decisions; discussions include advanced directives,
and means to aid in nutritional and respiratory
care.''"' The neurologist also explains clinical and
scientific advances in thefield.While all specialty
care can be obtained through regular consultation, patients and families benefit from having
questions addressed by professionals from different disciplines in one visit to a multidisciplinary
clinic, which conserves energy and time.
The neurologist is responsible for patient care,
an ALS nurse provides nursing care, physical
therapists evaluate limb strength, occupational
therapists address the skilled motor functions
© 2011 AdIs Data Information BV. Ali rights reserved.
that enable patients to engage in activities of daily
living, a dietitian assesses nutritional status, a
speech pathologist evaluates bulbar function and
a respiratory therapist aids in treating respiratory
symptoms. Either in or outside of the multidisciplinary clinic, a social worker assists with
health insurance coverage and disability payments, a pulmonologist treats respiratory problems, a gastroenterologist is consulted for enterai
feeding and gastrostomy placement and an orthotist fits braces for those with focal weakness.
A psychiatrist or psychologist treats symptoms
related to depression and anxiety. The ALS team
also directs patients to services outside the clinic,''*'' ensuring that home care, palliative care and
hospice are used effectively. Important nonpharmacological therapies include: communication
devices and voice amplifiers; gaze communication
technology; assistive devices such as canes, orthoses, walkers and wheelchairs; home adaptations; and exercise. Until stronger neuroprotective
agents are identified, the goal of multidisciplinary
care is to help patients achieve the highest quality
of life possible throughout the course of the
disease.
3.3 Nutrition
Poor nutrition, a predictor of survival, can
result from dysphagia, arm weakness limiting the
ability to eat, and hypermetabolism.''*^' Monitoring weight is the simplest way to assess caloric
balance. A speech therapist's examination provides information about risk of aspiration, ability
to maintain adequate nutrition and compensatory strategies. Management includes modification of diet consistency, postural changes such as
the chin tuck, and enterai feeding via a percutaneous endoscopie gastrostomy for those with
symptomatic dysphagia or weight loss.'"*^' There
may be lower morbidity if the procedure is
done when the vital capacity (VC) is >50% of
predicted and before sniff nasal inspiratory
pressure (SNIP) falls below 40 cm H2O. Radiologically inserted gastrostomy can be done when
respiratory compromise is present, and patients
can use non-invasive ventilation during the
procedure.
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Gordon
3.4 Respiration
Symptoms of respiratory muscle weakness include dyspnoea, orthopnoea, sleep fragmentation,
moming headaches and daytime fatigue. Bulbar
weakness and weakened cough can lead to excess
secretions and poor airway clearance, which can
cause aspiration and pneumonia. The history,
physical examination, overnight pulse oximetry
and VC are standard assessments and are done
serially, typically every 3 months. The maximal
inspiratory and expiratory pressures (MIP and
MEP) are also often reduced in ALS patients and
correlate with respiratory muscle weakness;^''^' a
reduction of MIP to <60 cm H2O is a predictor of
reduced survival. SNIP, a noninvasive measure of
inspiratory pressure, estimates intrathoracic pressure and may provide an early marker of respiratory muscle weakness. It decreases predictably
over time in ALS patients, predicts survival and
may better refiect hypercapnoea than VC or MIP.
A transcutaneous carbon dioxide sensor can also
be
Nocturnal noninvasive positive-pressure ventilation (NTPPV) has become the standard treatment
for ALS patients with respiratory insufficiency.t'*'^
The bi-level intermittent positive-pressure ventilator
imitates physiological function; it is triggered by the
patient's inspiratory efforts, reduces the work of
breathing and improves gas exchange and sleep
quality.t"*^ Patients are counselled on the use of
NIPPV with the onset of respiratory symptoms,
when the VC drops to 50% of predicted, or when the
MIP falls to <60cm HjO.f'^^i NIPPV extends survival, particularly in those compliant at least 4 hours
per day, enhances quality of life!''*] and may improve
cognition.!'*^ In general, oxygen is not prescribed
without NIPPV so as not to risk inhibition of respiratory drive in the setting of elevated serum carbon
dioxide levels. Theoretically, using NIPPV can reduce energy loss from overworked respiratory muscles, and so may have dual benefits of supporting
respiration and reducing calorie expenditure.
Invasive ventilation is instituted when longterm survival is the goal. Tracheostomy, ultimately chosen by fewer than 5% of patients,^'**! is
expensivef'*^^ and requires 24-hour supervision.
Great emotional and physical burden is placed on
© 2011 Adis Data Intormation BV. All rights reserved.
caregivers; a reason that some patients refuse
tracheostomy. Some patients, who are unable to
decide for or against tracheostomy, receive mechanical ventilation on an emergency basis due to
respiratory failure. Inadvertent performance of
tracheostomy is usually permanent,''*^' and may
lead to nursing home placement if home recourses are inadequate. Patients may choose to
withdrawal respiratory support, a decision that is
considered ethical when the treating physician
prescribes adequate dosages of opiates and anxiolytics to avoid suffering when the ventilator is
turned off.
Interventions that facilitate the clearance of
secretions consist of air stacking, assisted cough,
either manually or mechanically through an
insuffiator-exsufflator, and use of a suction machine to remove oropharyngeal secretions.t'"'
Mucolytics, expectorants, theophylline, antibacterials and oxygen may help to relieve symptoms.
Pneumovax® immunization and yearly influenza
immunizations help reduce pulmonary infection.t'*^' High-frequency chest wall oscillation
may help clear airways.'^^l
4. Symptomatic Treatment
The following sections outline the use of standard therapies that are used to combat symptoms of ALS (table I). Few of the therapies have
been tested in clinical trials in ALS. Some are
approved for treating the symptoms in other disorders, some are used off-label for ALS, and most
are used based on clinical experience rather than
solid clinical trial data. Future trials of symptomatic agents may help refine which therapies are
most helpful in ALS.
4.1 Cognitive Decline and Depression
Cognitive symptoms in ALS are usually due to
frontotemporal impairment and include personality change, irritability, obsessions, poor insight
and impairments in language.t^'' Patients with
dementia are less compliant with interventions,
and probably have shorter survival.f^'l No therapy has been shown to slow the progression of
dementia in ALS. Symptoms of disinhibition can
CNS Drugs 2011; 25(1)
Amyotrophic Lateral Sclerosis
Table I. Symptomatic treatments used in patients with amyotrophic
iateral sclerosis
Table I. Contd
Medication
Cramps
Dosage
Slalorrhoea
Amitriptyiine
12.5-125 mgqhs
Atropine suiphate
0.4 mg q4-6h
1-2 ophthaimic drops SL q4-6h
Glycopyrrolate
Hyoscyamine suiphate
Medication
Dosage
Vitamin E
400 iU tid
Phenytoin
300 mg qhs
Diazepam
2-10mgtid
Urinary urgency
1-2 mg tid
0.125-0.25 mgq4h
Oxybutynin
2.5-5 mg bid
12.5-75 mgqhs
Diphenhydramine
25-50 mg tid
Amitriptyiine
Scopoiamine transdermal patch
0.5 mg behind ear q72h
Toiterodine
1-2 mg bid
Oxybutynin patches
3.9 mgod
Emotional lability/
pseudobulbar affect
impaired sleep
Dextromethorphan/quinidine
20mg/10mgbid
Amitriptyiine
12.5-125 mgqhs
SSRI antidepressants
20-100mgod
MIrtazapine
15-30 mgqhs
Venlafaxine
37.5-75 mgbid-tid
Fatigue
Zoipidem
5-10 mgqhs
Zaieplon
5-10 mgqhs
Amitriptyiine
12.5-125 mgqhs
Mirtazapine
10-30 mgqhs
Temazepam
7.5-30 mg qhs
Amantadine
lOOmgqAM, qnoon
Diphenhydramine
25-50 mg qhs
Modafinii
100-200 mgqAM
Chioral hydrate
500-1000 mgqhs
Pemoline
18.75-93.75 mgod
Constipation
Bupropion SR
150-450 mgod
Docusate
240 mg od
Fiuoxetine
20-60 mg od
Magnesium hydroxide
30-60 mL prn
Venlafaxine
75-225 mg od
Bisacodyi
10-15mLprn
Methylphenidate
10 mgbid-tid
Pyridostigmine
60 mg tid
Depression
Mirtazapine
15-30 mgqhs
SSRi antidepressants
20-100 mgod
TCAs
20-150 mgod
Veniafaxine
37.5-75 mg od
Lactuiose
15-30 mgod
Magnesium citrate
75-150 mL bid
bld=twice daiiy; iU = internationai units; od==once daiiy; prn^^as
needed; qAM = every morning; qhs = every day at bedtime; qid =
four times daiiy; qnoon-every day at noon; q>iti=every x hours;
SL-subiinguai; SR= siow release; SSRI = seiective serotonin
reuptake inhibitor; TCAs=tricyciic antidepressants; tid = three times
daiiy.
Anxiety
Diazepam
2-10mgtid
Lorazepam
0.5-2 mg bid-tid
Buspirone
lOmgtid
SSRi antidepressants
10-100 mgod
Mirtazapine
15-30 mgqhs
Spasticity
Bacioten
10-60 mg tid
Dantroiene
25-100mgtid-qid
Tizanidine
2-9 mg qid
Benzodiazepines
2-10mgtid
Continued
© 2011 Adis Data information BV. Aii rights reserved.
be relieved with behaviour modification, and
atypical antipsychotics such as olanzapine or
quetiapine, AEDs such as carbamazepine or valproic acid and selective serotonin reuptake inhibitors (SSRIs) in standard doses.
Depression and anxiety can occur in ALS and
may impair quality of life for patients and caregivers.'^^' Depression occurs in at least 10% of
patients, but does not appear to increase with advancing disease.'^-'! Psychotherapy, tricyciic antidepressants (TCAs) such as amitriptyiine (which
may also help with insomnia, drooling and
CNS Dajgs 2011; 25(1)
Gordon
emotional lability), SSRIs or other antidepressant
medications in standard doses may be helpful.
Benzodiazepines, SSRIs, buspirone and mirtazapine are used to treat anxiety, after ensuring
that symptoms of respiratory insufficiency are
adequately controlled.
4.2 Emotional Lability/Pseudobulbar Affect
Features of emotional lability are uncontrolled
laughter or crying, often with minimal provocation, and often inappropriate to the context of the
situation. The symptoms can limit social interactions and quality of life. A combination of dextromethorphan hydrobromide (30 mg) and quinidine
sulphate (30 mg), which acts to prolong the halflife of dextromethorphan by inhibiting its metabolism, is effective,'^'*' reducing emotional lability
and improving quality of life, and a formulation
combining dextromethorphan 20 mg and quinidine 10 mg has been approved by the US FDA for
this indication. SSRIs, TCAs, mirtazapine and
venlafaxine might also be beneficial.'^^1
4.3 Sialorrhoea
Sialorrhoea in ALS is caused by dysphagia,
rather than increased saliva production, and affects 50% of patients.'^'' Sialorrhoea is socially
embarrassing and excess saliva can lead to aspiration pneumonia. Pharmacological and nonpharmacological interventions can help. Suction
machines and in-exsuffiator or cough-assist devices are nonpharmacological approaches. Anticholinergic medications are initial pharmacological
therapy, but the response can be inadequate and
adverse effects are common, including constipation,
fatigue, urinary retention, blurred vision, tachycardia, orthostatic hypotension, confusion and dizziness. Anticholinergic medications are relatively
contraindicated in patients with glaucoma, prostatic
hypertrophy and cardiac conduction disorders. Concomitant use of a stool softener may be helpful for
those with constipation. Adverse effects may be less
common with sublingual forms, such as hyoscyamine sulphate, than with the oral medications.
Sialorrhoea associated with mealtimes or a
particular time of day can be treated with hyoscyamine because of its transient effect. Transdermal
© 2011 Adis Data Intormation BV. All rights resen/ed.
scopolamine, oral glycopyrrolate or TCA medications provide a more continuous effect.'^^'
Patients who have difficulty swallowing medications can use sublingual, transdermal or liquid forms
that can be administered through a gastrostomy.
Injections of botulinum toxin into the salivary
glands can also reduce sialorrhoea by blocking
neural stimulation of the salivary glands.'^^' While
there were few adverse events in clinical trials,
worsening of dysphagia and chewing difficulties
have been reported. Radiotherapy of the salivary
glands has also been tried in ALS,'^^' but controlled trials are needed.
Thick mucous secretions can result from treatment of sialorrhoea or inadequate water intake.
Patients report a sensation of something caught
in the back of the throat. Pharmacological treatments include high-dose guaifenesin, nebulized
acetylcysteine, nebulized saline or ß-adrenoceptor
antagonists (ß-blockers) such as propranolol.
A survey of alternative measures reported that
dark grape juice, papaya tablets, sugar-free citrus
lozenges and grape-seed oil can also be helpful.'^^1
Reduction of alcohol, caffeine and dairy products
along with increased fluid intake may also help.
Some find a cool mist humidifier to be helpful.
Mechanical insufflation-exsufïlation'^^' and chest
wall oscillation therapy might also improve clearance of upper airway secretions.'^'''
4.4 Spasticity
Spasticity is caused by loss of the normal inhibition from descending UMNs. Baclofen, a
GABA analogue that facilitates motor neuron
inhibition, may be beneficial to some patients.
Dosing begins at 10 mg one to three times per day
and increases by 10 mg every 3-5 days. Maximum
tolerated doses range from 30 to 180mg/day and
responses vary. Adverse effects include fatigue,
sedation and a sense of looseness or weakness.'^^'
Dantrolene sodium, which acts by blocking
calcium release from the sarcoplasmic reticulum,
reduces both rigidity and spasticity. There may be
a synergistic effect when used with baclofen.'^^'
Dosing is initiated at 25 mg three times per day,
with a maximum dose of 100 mg four times daily.
Liver function is checked regularly.
CNS Drugs 201I;25(l)
Amyotrophic Lateral Sclerosis
Tizanidine, an a2-adrenergic agonist, reduces
rigidity and spasticity by inhibiting excitatory
interneurons in the spinal cord, and can be used
as monotherapy or in conjunction with other antispasticity medications. Initial doses of 2-4 mg/day
are increased to 36 mg/day in divided doses.
Adverse effects are similar to those with baclofen
and are minimized by slow dose titration.
Benzodiazepines can reduce spasms and cramps
that accompany spasticity. The use of these drugs
is weighed against the potential for sedation and
respiratory suppression. Stretching exercises can
also reduce spasms and cramping.'^"'
If the maximum tolerated dose of oral medications is not effective, intrathecal baclofen can
be tried. Botulinum toxin injections reduce spasticity in other conditions, but have not yet been
formally studied in ALS. The risk of muscle paralysis may limit their use in large muscle groups
in ALS.
Laryngospasm, related to spasticity, is due to
hyper-adduction of the vocal cords, and usually
follows aspiration of liquids or saliva, or acid
reflux. It typically resolves spontaneously within
several seconds, and is lessened by repeated
swallowing while breathing through the nose. If
the episodes occur frequently, treatment with a
few drops of sublingual liquid lorazepam can
abort the attacks.'^^' Antacids and proton pump
inhibitors can help reduce symptoms due to reflux.
Some patients develop jaw quivering or clenching due to UMN degeneration. Treatment with benzodiazepines such as clonazepam, diazepam or
lorazepam can be helpful. Botulinum toxin injected
at two sites within the masseter muscles may also be
effective.
4.5 Urinary Urgency
Urinary urgency or incontinence can occur in
ALS, especially in those with leg spasticity, and
are compounded by impaired mobility and the
fear of not being able to reach the toilet in time.
The likely aetiology is spasm of the urinary
sphincter or detrussor muscle. Urinary tract infection or prostatism should be excluded before
initiating pharmacotherapy. If no other cause can
be identified, a trial of a spasmolytic agent is in© 2011 Adis Data Information BV. All rights reserved.
dicated. Oxybutynin is inexpensive and can be
crushed and put through a gastrostomy tube. An
extended-release form that is administered once
daily is also available, but cannot be crushed.
Tolterodine tartrate is prescribed twice daily.
Oxybutynin patches can be used along with oral
tablets for those with refractory symptoms. The
anticholinergic properties of amitriptyiine make
it an alternative for some patients. A voiding
schedule in which patients attempt to urinate
every 2-3 hours regardless of whether they have
an urge or not can help reduce accidents.
4.6 Impaired Sleep
Poor sleep in patients with ALS has numerous
causes, including respiratory insufficiency, difficulty repositioning in bed, pain, anxiety and
depression.'^'' Sleeplessness leads to daytime fatigue, weakness, worsening respiratory compromise and depression. Physical measures such as a
power hospital bed and alternating pressure mattress can enhance mobility and comfort. NIPPV
can improve respiration and sleep quality. Antidepressant medications may relieve depression
and promote sleep. Mirtazapine and the TCAs
are especially helpful. Anxiolytic medications
such as benzodiazepines can be helpful when used
selectively. Zolpidem tartrate, or other similar
non-benzodiazepine sleep aids, carries a low risk
of respiratory depression. Antihistamine medications or chloral hydrate are also sedating. Alternative agents, such as melatonin, passionfiower,
lavender and hops, have been effective for some
patients, but their benefits are untested.'^^'
4.7 Fatigue
Fatigue, which is common in ALS, can be
caused by over-expenditure of physical energy,
stress or depression, poor sleep and medication
side effects.'""' Energy conservation is a simple
treatment. Riluzole, which has fatigue as an
adverse effect, can be stopped.'^'' Nocturnal respiratory insufficiency is treated with NIPPV. Offlabel use of pyridostigmine can reduce symptoms
of weakness by enhancing neuromuscular junction transmission. Methylphenidate can also provide
benefit in selected patients. Adverse efTects include
CNS Drugs 2011;25(l)
10
Cordon
anorexia, restlessness, anxiety or palpitations. Modafinil can also be tried,'^^' and amantadine, pemoline, bupropion, SSRIs and venlafaxine have been
helpful for some patients.
4.8 Constipation
Constipation results from immobility, medication adverse effects (especially with anticholinergic and narcotic agents) and inadequate fluid
intake. In the later stages of ALS, abdominal wall
muscle weakness contributes. Management includes the use of stool softeners such as docusate
or senna leaf extract. Increasing fluid intake and
substituting medications with fewer anticholinergic effects is helpful. Increasing dietary fibre in
the form of prunes, fruit juices, apple sauce and
bran is important. Milk of magnesia or bisacodyl
tablets can be added to the regimen. Lactulose
can be administered through a gastrostomy tube,
and enemas or magnesium citrate are used in urgent situations.
4.9 Pain
Immobility, emotional distress, muscle spasms,
cramps, oedema or the illness itself may all cause
pain. Identification of the précipitants leading to
pain is the first priority. Medication can often
be avoided through physical therapy, stretching
and range of motion exercises, massage and limb
elevation, as well as a support hose to reduce
oedema.
Medical management includes NSAIDs, benzodiazepines and opioids, which are generally
safe but can cause constipation, respiratory depression in high doses and tolerance. Liberal use
of narcotics and anxiolytics to prevent suffering is
often necessary at the end stages of the illness.
Cramps can be reduced by vitamins E and C,'^^'
and anti-spasticity agents such as baclofen.'-'^'
For those who are bothered by fasciculation, gabapentin or anti-spasticity agents can be tried.'^*''
4.10 Palliative Care and Hospice
All of ALS care is currently palliative. Palliation at the end of life is a time when particular
care is needed to avoid physical suffering.'^' The
© 2011 Adis Data Information BV. Aii rigtits reserved.
transition to this phase is less abrupt if continuous palliative care has been provided from the
outset. Around 60% of ALS patients die within
24 hours of deterioration in their clinical condition and some die suddenly. Advance directives
can help prevent invasive ventilation being instituted in a crisis, but the key to good care is
ongoing and open communication between the
patient and the healthcare team.
Anticipating symptoms before they occur is
crucial. Medications, including opioids, sedatives
and anticholinergic agents, can be prescribed in
the home under the direction of the neurologist
and hospice team. Morphine is effective for treating pain, breathlessness and nocturnal discomfort
long before the terminal phase of the illness.'^^
Fentanyl transdermal patches, 12.5-100 ng/hour,
worn for 72 hours can be used alone or in conjunction with morphine. It is best to start with low
doses of morphine, typically 5 mg every 4-6 hours
and to titrate slowly. Doses can be increased to
control new symptoms, but dose escalation is often unnecessary. Constipation is a common adverse effect and needs to be treated concurrently.
There is no evidence that opioids shorten life, but
relief of distress is the goal, and some sedation
may be necessary.
In patients with gastrostomy, the route of
administration of medications can remain unchanged toward the end of life. In those who
require non-oral administration, subcutaneous,
intravenous, rectal or transdermal dosing is possible, but requires recalculation ofthe equivalent
dose.'^' NSAIDs, if previously effective, can be
administered by suppository.
Anxiolytics are helpful for symptoms of anxiety and restlessness, and a benzodiazepine is often
used in combination with morphine.'^^' Benzodiazepines and morphine are also used to prevent
any distress that might occur during ventilator
withdrawal when a patient, family and professionals agree that life is being prolonged by assisted ventilation to a degree that is intolerable.'^'^'
It may not be possible to stop noisy breathing;
thefirststep in management is to explain to the patient's family the causes of noisy breathing, and to
reassure them that the patient is not aware of the
sounds. Atropine tends to be arousing, but other antiCNS Drugs 2011:25(1)
Amyotrophic Lateral Sclerosis
cholinergic medications are used to control rattly
breathing in those with reduced ability to cough or
unsuccessful treatment of a lung infection.'^!
The quality of a patient's dying is a powerful
memory for those left behind and good care at
this time shapes public attitudes towards disability and serious illness. Hospice teams provide
adequate symptom management and also counselling and emotional support for patients, families and caregivers. Palliation at the end of life is
usually done at home, but inpatient palliative
care teams and suites can be used for those patients uncomfortable dying at home.
5. Novel Iherapies
An important element of ALS care is participation in research. According to the website for
the National Institutes of Health (NIH) [www.
clinicaltrials.gov], at the time of this article, there
were more than 100 clinical research studies in
ALS. Clinical trials offer patients the chance to
share in the search for better treatments and to
have successive evaluations by the ALS team.
These assessments, which may occur on a monthly basis depending on the study, provide a level of
attention that could not be had otherwise. The
patients usually meet with the neurologist, nurse
and physical therapist during the research visit,
and new problems are treated.
The psychological benefit of participating in
research can be great, but patients must also understand the goal of obtaining accurate data so
that a trial's conclusions will be valid. For this
reason, investigators must explain the importance
of compliance and the purpose of research to
patients before they enrol.'^^1 Patients are prone
to drop out if benefits do not occur or adverse
effects develop. They may lose interest in the trial
as their disease advances, they may drop out to
participate in another study or they may use other available investigational agents. During clinical trials, it is important to monitor adherence
and to implement effective adherence-improving
strategies.'™!
A number of potentially neuroprotective agents
and new treatment modalities are being tried. One
© 2011 Adis Data information BV. Ailrightsreserved.
11
preliminary study showed a positive effect of lithium carbonate in an ALS mouse model, and
possible improvement in 16 patients given the
drug.'^'l The mechanism of lithium in ALS is unknown, but it might act through ameliorating
excitotoxicity. Another phase II trial is ongoing,
but a small efficacy trial was terminated following
enrolment of 84 patients after the data and safety
monitoring board deemed it statistically futile to
Ceftriaxone, a semi-synthetic, third-generation,
cephalosporin antibacterial, was selected for study
after an NIH-driven high-throughput screen initiative of 1040 available medications, and a positive
mouse study.'^^' Ceftriaxone appears to possess
antiexcitotoxic properties. A phase III trial is being
conducted in 600 participants for at least 12 months,
with survival as the primary outcome measure. The
study consists of three stages, of which two have
been completed. The first stage examined CSF
concentrations of ceftriaxone. The second stage assessed the safety of the drug given over 20 weeks.
The third stage, which began in early 2009, will determine whether intravenous ceftriaxone is effective
in slowing the disease course.
Pramipexole, which may possess antioxidant
properties, has been tested in an early-phase safety
trial, and a futility design phase II study.'^"*! In the
futility study, slopes of decline in functional scores
showed non-significant reductions during treatment. High doses of pramipexole were well tolerated and larger studies are planned. Memantine,
a glutamate antagonist, is being studied in a
phase II randomized, controlled, dose-ranging
trial, using functional endpoints. Several different
trials are under way to assess safety and efficacy.
Arimoclomol, a coinducer of heat shock proteins, which serves as an intracellular chaperone and
appears to have antiapoptotic properties, is also
under study. Molecular chaperone proteins are critical in the cellular response to stress and protein
misfolding. The drug increased the lifespan in ALS
mice,'^^' but after completion of early-phase safety
trials, a large trial in sALS was terminated, apparently because of the need for additional preclinical
toxicology studies. Because SODl mutations might
reduce the availability of molecular chaperones, and
weaken their response to cellular stress, a separate
CNS Drugs 2011:25(1)
12
Gordon
Study in patients with SODl mutation-positive
6. Conclusions
fALS is planned at two centres.
ALS is still an incurable disease, but progress
Talampanel delays mitochondrial vacuolization in motor neurons of mice. After an initial has been made, both in terms of understanding
safety and tolerability study in humans, a ran- the underlying pathophysiology and in helping
domized, controlled, phase III trial is planned.'^^' patients manage the numerous symptoms that
The primary outcome measure will be change in arise. European researchers and the American
functional scores over 52 weeks. Subjects will re- Academy of Neurology have published and receive talampanel 50 mg three times per day, ta- vised''*-''^'' practice guidelines on the symptomatic
care of ALS patients. Many therapies can imlampanel 25 mg three times per day or placebo.
AEOL 10150, a manganese porphyrin that prove quality of life, aiid some appear to extend
scavenges peroxynitrite and other deleterious oxi- survival. Gastrostomy and NIPPV likely improve
dized species, is in early-phase clinical trials. outcome for those with poor nutrition and resEdaravone (MCI-186), another free radical sca- piratory insufficiency. Depression and anxiety are
venger with potential effects on mitochondrial common, but are highly treatable. The multifunction, is also being studied. A double-blind, disciplinary clinic, where patients have access to
placebo-controlled trial of edaravone is ongoing specialists trained to provide assistive devices,
in Japan, after an initial phase II trial.'^^' The pri- speech aids and home modifications, has become
mary outcome measure of the larger study is func- the standard of care at most large centres. By
tional decline over 36 weeks. Trials are planned in participating in clinical research, patients not only
receive increased attention from the ALS team,
the US.
Sodium phenylbutyrate and valproic acid are but also contribute to the ongoing effort to find
histone deacetylase inhibitors that may promote better treatments and refine current therapy. Paltranscriptional activation of antiapoptotic genes. liative care, particularly at the end of life, is one
A safety and dose ranging trial of sodium phenyl- important means to relieving suffering. Once clear
butyrate has been completed, and an efficacy trial aetiologies are determined for ALS, therapies that
truly impact disease progression will surely folis planned.'^^'
Olesoxime (cholest-4-en-3-one, oxime; TRO low, but until then, symptomatic therapies and
19622), identified via high-throughput screening, palliative care help patients meet the challenges of
binds to the mitochondrial permeability transi- ALS with dignity and comfort.
tion pore.t'''' A phase Will trial is under way.
Vaccines strategies are being tried to remove
aggregated SODl protein in fALS, but further
Acknowledgements
research is needed in animals before human
trials.'^"' Methods to reduce the production of
No sources of funding were used to prepare this article.
abnormal SODl using RNA interference'*'' and The author has no conflicts of interest that are directly relantisense oligonucleotides'^^' are also under study. evant to the content of this article.
Trials are planned, but research continues in animal models.
Stem cell therapies are also being tested. At the
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Correspondence: Dr Paul H. Gordon, MD, Fédération des
Maladies du Système Nerveux, Centre réfèrent maladie
rare SLA, Hôpital de la Pitié-Salpêtrière, 47-83, Boulevard
de l'Hôpital, 75651 Paris, France.
E-mail: [email protected]
CNS Drugs 2011:25(1)
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