THERAPY IN PRACTICE CNS Drugs 2011; 25 (1): 1-15

1172-7047/11/0001-0001/$49.95/0
ª 2011 Adis Data Information 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
1. Introduction ............................................................................................................................................................ 2
2. Manifestations and Diagnosis .............................................................................................................................. 3
3. Management ......................................................................................................................................................... 4
3.1 Specific Therapy: Riluzole ............................................................................................................................. 4
3.2 Multidisciplinary Care .................................................................................................................................... 5
3.3 Nutrition ........................................................................................................................................................... 5
3.4 Respiration ...................................................................................................................................................... 6
4. Symptomatic Treatment ....................................................................................................................................... 6
4.1 Cognitive Decline and Depression ............................................................................................................. 6
4.2 Emotional Lability/Pseudobulbar Affect .................................................................................................... 8
4.3 Sialorrhoea ...................................................................................................................................................... 8
4.4 Spasticity ......................................................................................................................................................... 8
4.5 Urinary Urgency .............................................................................................................................................. 9
4.6 Impaired Sleep ............................................................................................................................................... 9
4.7 Fatigue............................................................................................................................................................. 9
4.8 Constipation ................................................................................................................................................. 10
4.9 Pain 10
4.10 Palliative Care and Hospice .................................................................................................................... 10
5. Novel Therapies.................................................................................................................................................... 11
6. Conclusions........................................................................................................................................................... 12

Abstract Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative

disease associated with a life expectancy of approximately 3 years after symp-
tom 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 ma-
jority 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 dis-
ease onset, including mitochondrial dysfunction, protein aggregation, gener-
ation 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.
2 Gordon

The diagnosis is based on the history and examination showing progres-

sive 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 neu -
roprotective agents, both pharmacological and nonpharmacological treat-
ments are directed at maintaining quality of life and prolonging life to the
greatest extent possible. Riluzole, ventilatory support for those with respi -
ratory insufficiency, gastrostomy for those with dysphagia and multi-
disciplinary 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 Between 5% and 10% of cases are inherited (fa-

Amyotrophic lateral sclerosis (ALS) is con-
sidered a complex genetic disorder, in which mul-
tiple 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 contribu-
tion 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 100 000/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 exam-
ined in sALS. Accepted risks include age, with most
cases occurring between 55 and 65 years, male sex
and likely cigarette smoking.[2-6] Physical stress, ex-
posure to pesticides and athleticism are possible
contributors, but the associations are small and in-
consistently reproducible.[7,8] It could be that risks
have not yet been examined in correct sequence, for
example, if they interact over a lifetime, or that sci-
ence has not yet developed an awareness of the
important risks.
milial 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 (SOD1) gene,[9] which
normally reduces oxidative stress by converting
superoxide anions to hydrogen peroxide. The mech-
anisms by which mutant SOD1 is toxic to motor
neurons are poorly understood. After discovery of
the gene, an animal model was created that has con-
tributed to improved understanding of cellular pro-
cesses that occur, at least in this genetic form of
ALS, after the disease process has begun.[10] Other
rare genetic loci have been labelled ALS1 through
ALS10, ALS with frontotemporal dementia (ALS-
FTD) and ALS-FTD with Parkinson’s disease (ALS-
FTDP).[9] Mutations infused in sarcoma (FUS)
genes account for approximately 5% of fALS.[11]
Co-segregation of ALS with other neurode-
generative disorders in families suggests common
genetic risks,[12] but genome-wide association
studies have demonstrated that there is no single
gene that accounts for most sALS. [13] TAR DNA
binding protein (TDP-43), a ubiquitously ex-
pressed nuclear protein that regulates messenger
RNA transcription and splicing, is found in in-
clusions of ALS and most forms of FTD.[14]

ª 2011 Adis Data Information BV. All rights reserved. CNS Drugs 2011; 25 (1)
Amyotrophic Lateral Sclerosis
Mutations in the TDP gene have been identified
in some patients with sALS or fALS, [15] suggest-
ing a possible pathogenic link, but the inclusions
have also been identified in other conditions, so
their true role is still unknown. [16]
Once the disease is initiated, a cascade of cel-
lular events occurs, including oxidative stress,
glutamate-induced excitotoxicity, intracellular pro-
tein aggregation, mitochondrial dysfunction, growth
factor deficiency, abnormal axonal transport and
caspase enzyme activation.[17] Nerve cells appear to
eventually die through caspase enzyme-mediated
apoptotic or inflammatory pathways. Current clin-
ical 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 harmful.[18]
Clinical trials are difficult to conduct in ALS
because there are, as yet, no biomarkers of dis-
ease progression; trials use clinical outcome mea-
sures 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 chal-
lenging 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 pos-
sible, which, in the past at least, has prompted
investigators and pharmaceutical companies to
sometimes minimize the role of early-phase dos-
age-selection trials and move quickly to large
phase III trials.
It is likely that better treatments and pre-
ventative measures will be ascertained after the
causes of ALS are found. In the meantime, treat-
ment 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 palli-
ative 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.
ª 2011 Adis Data Information BV. All rights reserved.
3
2. Manifestations and Diagnosis
ALS begins with limb weakness in about 65%
of patients.[19] Foot drop, difficulty walking, loss
of hand dexterity or shoulder weakness are typi-
cal 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. Even-
tually, 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, dehy-
dration, malnutrition with weight loss and aspira-
tion. Weakness of the axial musculature leads to
head drop and kyphosis, which can cause pain, im-
balance 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 ap-
proximately 15% develop overt dementia, most
often FTD.[20] 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 medi-
cal treatments and to shorter survival.[21]
Emotional lability, or pseudobulbar affect,
due to loss of normal inhibition of laughter and
crying, which depend on neural pathways medi-
ating emotion, respiration, vocalization and fa-
cial movements, may be associated with UMN
degeneration.[22]
Depression and anxiety can be prominent fea-
tures at all stages of the disease. Anxiety can ac-
company 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)
4 Gordon
contractures or bedsores. The psychological and
physical discomfort that arises from the inability
to move can be profound.[23] 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 symp-
toms usually occur later in the disease course.
Symptoms include orthopnoea, morning head-
aches and weakened cough. Patients develop dys-
pnoea 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 ex-
amination 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 Ken-
nedy’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 cer-
vical spondylosis. The El Escorial criteria, devel-
oped in 1990 and revised in 1998 to standardize the
diagnosis for clinical research, can be applied.[24]
Transcranial magnetic stimulation and magnetic
resonance spectroscopy examine the UMN,[25] but
are often limited to large centres or research proto-
cols. Spinal fluid is analysed only when the disorder
is atypical, or if a secondary cause, such as carcino-
matous meningitis or infection, is suspected. In the
hands of an experienced ALS specialist and elec-
tromyographer, 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 year.[26]
ª 2011 Adis Data Information BV. All rights reserved.
Practice guidelines[27,28] suggest that the diag-
nosis 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. [27] The neurol-
ogist 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 discus-
sion of ongoing research into better treatments
conveys hope.[29]
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,[30] and more controlled
trials are needed.
3. Management
3.1 Specific Therapy: Riluzole
Excess glutamate, an excitatory neurotrans-
mitter, may be associated with neurodegener-
ation. 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.[31,32] 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 phy-
sicians.[33] The Cochrane Library conducted a
meta-analysis of three published trials, which in-
cluded a total of 876 riluzole-treated and 406
placebo-treated patients.[34] The meta-analysis
indicated that riluzole 100 mg/day prolongs sur-
vival 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,[35] including in the elderly and
those with advanced disease.[36] The most com-
mon adverse effects are fatigue, somnolence, nau-
sea, 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 re-
sulting from different rates of metabolism.[37] Ad-
verse effects tend to be more frequent in those
with high serum concentrations. Dose adjust-
ment based on serum concentrations is one ap-
proach to optimizing treatment, but is rarely used
in practice.
More than half of US patients[38] and nearly all
patients in Europe, where the health systems cover
the cost,[39] take riluzole. The Canadian health
system does not pay for riluzole, but many pa-
tients 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.[40] Most large
centres currently use a multidisciplinary ap-
proach to care,[41] and some data suggest that
patients cared for at multidisciplinary clinics may
survive longer.[26] Patients are evaluated fre-
quently so that impending problems are detected
and treated early. The care plan is centred on the
patient’s decisions, focusing on support and edu-
cation. The neurologist and allied health team
provide information to help in treatment deci-
sions; discussions include advanced directives,
and means to aid in nutritional and respiratory
care.[41] The neurologist also explains clinical and
scientific advances in the field. While all specialty
care can be obtained through regular consulta-
tion, patients and families benefit from having
questions addressed by professionals from differ-
ent 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
ª 2011 Adis Data Information BV. All rights reserved.
5
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 multi-
disciplinary clinic, a social worker assists with
health insurance coverage and disability pay-
ments, a pulmonologist treats respiratory prob-
lems, a gastroenterologist is consulted for enteral
feeding and gastrostomy placement and an or-
thotist 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 clin-
ic,[41] ensuring that home care, palliative care and
hospice are used effectively. Important non-
pharmacological therapies include: communication
devices and voice amplifiers; gaze communication
technology; assistive devices such as canes, or-
thoses, walkers and wheelchairs; home adapta-
tions; 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. [42] Mon-
itoring weight is the simplest way to assess caloric
balance. A speech therapist’s examination pro-
vides information about risk of aspiration, ability
to maintain adequate nutrition and compensa-
tory strategies. Management includes modifica-
tion of diet consistency, postural changes such as
the chin tuck, and enteral feeding via a percuta-
neous endoscopic gastrostomy for those with
symptomatic dysphagia or weight loss.[43] 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 H2 O. Radio-
logically inserted gastrostomy can be done when
respiratory compromise is present, and patients
can use non-invasive ventilation during the
procedure.
CNS Drugs 2011; 25 (1)
6 Gordon
3.4 Respiration
Symptoms of respiratory muscle weakness in-
clude dyspnoea, orthopnoea, sleep fragmentation,
morning 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;[43] a
reduction of MIP to <60 cm H2O is a predictor of
reduced survival. SNIP, a noninvasive measure of
inspiratory pressure, estimates intrathoracic pres-
sure and may provide an early marker of respira-
tory muscle weakness. It decreases predictably
over time in ALS patients, predicts survival and
may better reflect hypercapnoea than VC or MIP.
A transcutaneous carbon dioxide sensor can also
be used.[44]
Nocturnal noninvasive positive-pressure ven-
tilation (NIPPV) has become the standard treatment
for ALS patients with respiratory insufficiency.[41]
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.[45] 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 <60 cm H20.[43] NIPPV extends surviv-
al, particularly in those compliant at least 4 hours
per day, enhances quality of life[46] and may improve
cognition.[47] In general, oxygen is not prescribed
without NIPPV so as not to risk inhibition of respi-
ratory drive in the setting of elevated serum carbon
dioxide levels. Theoretically, using NIPPV can re-
duce energy loss from overworked respiratory mus-
cles, and so may have dual benefits of supporting
respiration and reducing calorie expenditure.
Invasive ventilation is instituted when long-
term survival is the goal. Tracheostomy, ulti-
mately chosen by fewer than 5% of patients,[48] is
expensive[48] and requires 24-hour supervision.
Great emotional and physical burden is placed on
ª 2011 Adis Data Information BV. All rights reserved.
caregivers; a reason that some patients refuse
tracheostomy. Some patients, who are unable to
decide for or against tracheostomy, receive me-
chanical ventilation on an emergency basis due to
respiratory failure. Inadvertent performance of
tracheostomy is usually permanent,[49] and may
lead to nursing home placement if home re-
courses 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 anxio-
lytics 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
insufflator-exsufflator, and use of a suction ma-
chine to remove oropharyngeal secretions. [41]
Mucolytics, expectorants, theophylline, antibac-
terials and oxygen may help to relieve symptoms.
Pneumovax® immunization and yearly influenza
immunizations help reduce pulmonary infec-
tion.[43] High-frequency chest wall oscillation
may help clear airways.[50]
4. Symptomatic Treatment
The following sections outline the use of stan-
dard therapies that are used to combat symp-
toms 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 dis-
orders, some are used off-label for ALS, and most
are used based on clinical experience rather than
solid clinical trial data. Future trials of symptom-
atic 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 person-
ality change, irritability, obsessions, poor insight
and impairments in language.[51] Patients with
dementia are less compliant with interventions,
and probably have shorter survival.[21] No thera-
py has been shown to slow the progression of
dementia in ALS. Symptoms of disinhibition can
CNS Drugs 2011; 25 (1)
Amyotrophic Lateral Sclerosis 7

Table I. Symptomatic treatments used in patients with amyotrophic Table I. Contd

lateral sclerosis Medication Dosage
Medication Dosage Cramps
Sialorrhoea
Vitamin E 400 IU tid
Amitriptyline 12.5–125 mg qhs
Phenytoin 300 mg qhs
Atropine sulphate 0.4 mg q4–6h
Diazepam 2–10 mg tid
1–2 ophthalmic drops SL q4–6h
Urinary urgency
Glycopyrrolate 1–2 mg tid
Oxybutynin 2.5–5 mg bid
Hyoscyamine sulphate 0.125–0.25 mg q4h
Diphenhydramine 25–50 mg tid Amitriptyline 12.5–75 mg qhs

Scopolamine transdermal patch 0.5 mg behind ear q72h Tolterodine 1–2 mg bid

Emotional lability/ Oxybutynin patches 3.9 mg od

pseudobulbar affect
Impaired sleep
Dextromethorphan/quinidine 20 mg/10 mg bid
Zolpidem 5–10 mg qhs
Amitriptyline 12.5–125 mg qhs
Zaleplon 5–10 mg qhs
SSRI antidepressants 20–100 mg od
Amitriptyline 12.5–125 mg qhs
Mirtazapine 15–30 mg qhs
Mirtazapine 10–30 mg qhs
Venlafaxine 37.5–75 mg bid–tid
Temazepam 7.5–30 mg qhs
Fatigue
Amantadine 100 mg qAM, qnoon Diphenhydramine 25–50 mg qhs

Modafinil 100–200 mg qAM Chloral hydrate 500–1000 mg qhs

Pemoline 18.75–93.75 mg od Constipation

Bupropion SR 150–450 mg od Docusate 240 mg od
Fluoxetine 20–80 mg od Magnesium hydroxide 30–60 mL prn
Venlafaxine 75–225 mg od Bisacodyl 10–15 mL prn
Methylphenidate 10 mg bid-tid Lactulose 15–30 mg od
Pyridostigmine 60 mg tid
Magnesium citrate 75–150 mL bid
Depression bid = twice daily; IU = international units; od = once daily; prn = as
Mirtazapine 15–30 mg qhs needed; qAM = every morning; qhs = every day at bedtime; qid =
four times daily; qnoon = every day at noon; qxh = every x hours;
SSRI antidepressants 20–100 mg od
SL = sublingual; SR = slow release; SSRI = selective serotonin
TCAs 20–150 mg od reuptake inhibitor; TCAs = tricyclic antidepressants; tid = three times
Venlafaxine 37.5–75 mg od daily.

Anxiety
Diazepam 2–10 mg tid
Lorazepam 0.5–2 mg bid–tid be relieved with behaviour modification, and
Buspirone 10 mg tid atypical antipsychotics such as olanzapine or
SSRI antidepressants 10–100 mg od quetiapine, AEDs such as carbamazepine or val-
Mirtazapine 15–30 mg qhs
proic acid and selective serotonin reuptake inhib-
itors (SSRIs) in standard doses.
Spasticity
Depression and anxiety can occur in ALS and
Baclofen 10–60 mg tid
may impair quality of life for patients and care-
Dantrolene 25–100 mg tid–qid
givers.[52] Depression occurs in at least 10% of
Tizanidine 2–9 mg qid
patients, but does not appear to increase with ad-
Benzodiazepines 2–10 mg tid vancing disease.[53] Psychotherapy, tricyclic anti-
Continued depressants (TCAs) such as amitriptyline (which
may also help with insomnia, drooling and

ª 2011 Adis Data Information BV. All rights reserved. CNS Drugs 2011; 25 (1)
8 Gordon
emotional lability), SSRIs or other antidepressant
medications in standard doses may be helpful.
Benzodiazepines, SSRIs, buspirone and mirtaza-
pine 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 provoca-
tion, and often inappropriate to the context of the
situation. The symptoms can limit social interac-
tions and quality of life. A combination of dextro-
methorphan hydrobromide (30 mg) and quinidine
sulphate (30 mg), which acts to prolong the half-
life of dextromethorphan by inhibiting its metab-
olism, is effective,[54] reducing emotional lability
and improving quality of life, and a formulation
combining dextromethorphan 20 mg and quini-
dine 10 mg has been approved by the US FDA for
this indication. SSRIs, TCAs, mirtazapine and
venlafaxine might also be beneficial.[55]
4.3 Sialorrhoea
Sialorrhoea in ALS is caused by dysphagia,
rather than increased saliva production, and af-
fects 50% of patients.[51] Sialorrhoea is socially
embarrassing and excess saliva can lead to as-
piration pneumonia. Pharmacological and non-
pharmacological interventions can help. Suction
machines and in-exsufflator or cough-assist de-
vices are nonpharmacological approaches. Anticho-
linergic medications are initial pharmacological
therapy, but the response can be inadequate and
adverse effects are common, including constipation,
fatigue, urinary retention, blurred vision, tachy-
cardia, orthostatic hypotension, confusion and diz-
ziness. Anticholinergic medications are relatively
contraindicated in patients with glaucoma, prostatic
hypertrophy and cardiac conduction disorders. Con-
comitant use of a stool softener may be helpful for
those with constipation. Adverse effects may be less
common with sublingual forms, such as hyoscy-
amine sulphate, than with the oral medications.
Sialorrhoea associated with mealtimes or a
particular time of day can be treated with hyoscy-
amine because of its transient effect. Transdermal
ª 2011 Adis Data Information BV. All rights reserved.
scopolamine, oral glycopyrrolate or TCA medi-
cations provide a more continuous effect. [55]
Patients who have difficulty swallowing medica-
tions 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.[56] 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,[57] but con-
trolled trials are needed.
Thick mucous secretions can result from treat-
ment of sialorrhoea or inadequate water intake.
Patients report a sensation of something caught
in the back of the throat. Pharmacological treat-
ments include high-dose guaifenesin, nebulized
acetylcysteine, nebulized saline or b-adrenoceptor
antagonists (b-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.[58]
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-exsufflation[59] and chest
wall oscillation therapy might also improve clear-
ance of upper airway secretions.[50]
4.4 Spasticity
Spasticity is caused by loss of the normal in-
hibition 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 180 mg/day and
responses vary. Adverse effects include fatigue,
sedation and a sense of looseness or weakness.[55]
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.[55]
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 2011; 25 (1)
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 anti-
spasticity 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.[60]
If the maximum tolerated dose of oral medi-
cations is not effective, intrathecal baclofen can
be tried. Botulinum toxin injections reduce spas-
ticity in other conditions, but have not yet been
formally studied in ALS. The risk of muscle pa-
ralysis 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.[55] Antacids and proton pump
inhibitors can help reduce symptoms due to reflux.
Some patients develop jaw quivering or clench-
ing due to UMN degeneration. Treatment with ben-
zodiazepines 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 in-
fection or prostatism should be excluded before
initiating pharmacotherapy. If no other cause can
be identified, a trial of a spasmolytic agent is in-
ª 2011 Adis Data Information BV. All rights reserved.
9
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 amitriptyline 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, diffi-
culty repositioning in bed, pain, anxiety and
depression.[61] Sleeplessness leads to daytime fa-
tigue, weakness, worsening respiratory compro-
mise and depression. Physical measures such as a
power hospital bed and alternating pressure mat-
tress can enhance mobility and comfort. NIPPV
can improve respiration and sleep quality. Anti-
depressant 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 medica-
tions or chloral hydrate are also sedating. Alter-
native agents, such as melatonin, passionflower,
lavender and hops, have been effective for some
patients, but their benefits are untested.[55]
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.[41] Energy conservation is a simple
treatment. Riluzole, which has fatigue as an
adverse effect, can be stopped.[51] Nocturnal res-
piratory insufficiency is treated with NIPPV. Off-
label use of pyridostigmine can reduce symptoms
of weakness by enhancing neuromuscular junc-
tion transmission. Methylphenidate can also provide
benefit in selected patients. Adverse effects include
CNS Drugs 2011; 25 (1)
10
anorexia, restlessness, anxiety or palpitations. Mo-
dafinil can also be tried,[62] and amantadine, pemo-
line, bupropion, SSRIs and venlafaxine have been
helpful for some patients.
4.8 Constipation
Constipation results from immobility, medica-
tion adverse effects (especially with anticholin-
ergic and narcotic agents) and inadequate fluid
intake. In the later stages of ALS, abdominal wall
muscle weakness contributes. Management in-
cludes the use of stool softeners such as docusate
or senna leaf extract. Increasing fluid intake and
substituting medications with fewer anticholin-
ergic 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 ur-
gent situations.
4.9 Pain
Immobility, emotional distress, muscle spasms,
cramps, oedema or the illness itself may all cause
pain. Identification of the precipitants 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, ben-
zodiazepines and opioids, which are generally
safe but can cause constipation, respiratory de-
pression 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, [63]
and anti-spasticity agents such as baclofen. [30]
For those who are bothered by fasciculation, gab-
apentin or anti-spasticity agents can be tried.[30]
4.10 Palliative Care and Hospice
All of ALS care is currently palliative. Pallia-
tion at the end of life is a time when particular
care is needed to avoid physical suffering. [64] The
ª 2011 Adis Data Information BV. All rights reserved.
Gordon
transition to this phase is less abrupt if contin-
uous palliative care has been provided from the
outset. Around 60% of ALS patients die within
24 hours of deterioration in their clinical condi-
tion and some die suddenly. Advance directives
can help prevent invasive ventilation being in-
stituted 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 treat-
ing pain, breathlessness and nocturnal discomfort
long before the terminal phase of the illness. [65]
Fentanyl transdermal patches, 12.5–100 mg/hour,
worn for 72 hours can be used alone or in con-
junction 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 of-
ten unnecessary. Constipation is a common ad-
verse 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 un-
changed toward the end of life. In those who
require non-oral administration, subcutaneous,
intravenous, rectal or transdermal dosing is pos-
sible, but requires recalculation of the equivalent
dose.[64] NSAIDs, if previously effective, can be
administered by suppository.
Anxiolytics are helpful for symptoms of anxi-
ety and restlessness, and a benzodiazepine is often
used in combination with morphine.[66] Benzodi-
azepines and morphine are also used to prevent
any distress that might occur during ventilator
withdrawal when a patient, family and profes-
sionals agree that life is being prolonged by as-
sisted ventilation to a degree that is intolerable.[67]
It may not be possible to stop noisy breathing;
the first step in management is to explain to the pa-
tient’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 anti-
CNS 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.[68]
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 dis-
ability and serious illness. Hospice teams provide
adequate symptom management and also coun-
selling and emotional support for patients, fami-
lies 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 pa-
tients uncomfortable dying at home.
5. Novel Therapies
An important element of ALS care is partici-
pation 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 month-
ly 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 un-
derstand 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.[69] 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 oth-
er available investigational agents. During clin-
ical trials, it is important to monitor adherence
and to implement effective adherence-improving
strategies.[70]
A number of potentially neuroprotective agents
and new treatment modalities are being tried. One
ª 2011 Adis Data Information BV. All rights reserved.
11
preliminary study showed a positive effect of lith-
ium carbonate in an ALS mouse model, and
possible improvement in 16 patients given the
drug.[71] The mechanism of lithium in ALS is un-
known, 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
continue.[72]
Ceftriaxone, a semi-synthetic, third-generation,
cephalosporin antibacterial, was selected for study
after an NIH-driven high-throughput screen ini-
tiative of 1040 available medications, and a positive
mouse study.[73] 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 as-
sessed the safety of the drug given over 20 weeks.
The third stage, which began in early 2009, will de-
termine 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. [74] In the
futility study, slopes of decline in functional scores
showed non-significant reductions during treat-
ment. High doses of pramipexole were well toler-
ated 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 pro-
teins, which serves as an intracellular chaperone and
appears to have antiapoptotic properties, is also
under study. Molecular chaperone proteins are crit-
ical in the cellular response to stress and protein
misfolding. The drug increased the lifespan in ALS
mice,[75] but after completion of early-phase safety
trials, a large trial in sALS was terminated, appar-
ently because of the need for additional preclinical
toxicology studies. Because SOD1 mutations might
reduce the availability of molecular chaperones, and
weaken their response to cellular stress, a separate
CNS Drugs 2011; 25 (1)
12
study in patients with SOD1 mutation-positive
fALS is planned at two centres.
Talampanel delays mitochondrial vacuoliza-
tion in motor neurons of mice. After an initial
safety and tolerability study in humans, a ran-
domized, controlled, phase III trial is planned. [76]
The primary outcome measure will be change in
functional scores over 52 weeks. Subjects will re-
ceive talampanel 50 mg three times per day, ta-
lampanel 25 mg three times per day or placebo.
AEOL 10150, a manganese porphyrin that
scavenges peroxynitrite and other deleterious oxi-
dized species, is in early-phase clinical trials.
Edaravone (MCI-186), another free radical sca-
venger with potential effects on mitochondrial
function, is also being studied. A double-blind,
placebo-controlled trial of edaravone is ongoing
in Japan, after an initial phase II trial.[77] The pri-
mary outcome measure of the larger study is func-
tional decline over 36 weeks. Trials are planned in
the US.
Sodium phenylbutyrate and valproic acid are
histone deacetylase inhibitors that may promote
transcriptional activation of antiapoptotic genes.
A safety and dose ranging trial of sodium phenyl-
butyrate has been completed, and an efficacy trial
is planned.[78]
Olesoxime (cholest-4-en-3-one, oxime; TRO
19622), identified via high-throughput screening,
binds to the mitochondrial permeability transi-
tion pore.[79] A phase II/III trial is under way.
Vaccines strategies are being tried to remove
aggregated SOD1 protein in fALS, but further
research is needed in animals before human
trials.[80] Methods to reduce the production of
abnormal SOD1 using RNA interference [81] and
antisense oligonucleotides[82] are also under study.
Trials are planned, but research continues in ani-
mal models.
Stem cell therapies are also being tested. At the
time of this writing, multiple centres are testing
the safety of different approaches to stem cell in-
jections in ALS. Most of the trials are testing the
safety of intraspinal infusions in small numbers
of patients and not efficacy of the procedures yet.
Studies of symptomatic therapies include elec-
trical diaphragmatic pacemaker placement and
tetrahydrocannabinol to treat cramps.
ª 2011 Adis Data Information BV. All rights reserved.
Gordon
6. Conclusions
ALS is still an incurable disease, but progress
has been made, both in terms of understanding
the underlying pathophysiology and in helping
patients manage the numerous symptoms that
arise. European researchers and the American
Academy of Neurology have published and re-
vised[43,51] practice guidelines on the symptomatic
care of ALS patients. Many therapies can im-
prove quality of life, and some appear to extend
survival. Gastrostomy and NIPPV likely improve
outcome for those with poor nutrition and res-
piratory insufficiency. Depression and anxiety are
common, but are highly treatable. The multi-
disciplinary clinic, where patients have access to
specialists trained to provide assistive devices,
speech aids and home modifications, has become
the standard of care at most large centres. By
participating in clinical research, patients not only
receive increased attention from the ALS team,
but also contribute to the ongoing effort to find
better treatments and refine current therapy. Pal-
liative care, particularly at the end of life, is one
important means to relieving suffering. Once clear
aetiologies are determined for ALS, therapies that
truly impact disease progression will surely fol-
low, but until then, symptomatic therapies and
palliative care help patients meet the challenges of
ALS with dignity and comfort.
Acknowledgements
No sources of funding were used to prepare this article.
The author has no conflicts of interest that are directly rel-
evant to the content of this article.
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Correspondence: Dr Paul H. Gordon, MD, Fédération des
Maladies du Système Nerveux, Centre référent maladie
rare SLA, Hôpital de la Pitié-Salpêtrière, 47-83, Boulevard
de l’Hôpital, 75651 Paris, France.
E-mail: paul.gordon@psl.aphp.fr
CNS Drugs 2011; 25 (1)