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Amyotrophic lateral sclerosis Part 1.

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NEUROLOGICAL PROGRESS
Amyotrophc Lateral Sclerosis:
Part 1. Clinical Features, Pathology,
and E h c d Issues in Management*
Rup Tandan, MD, MRCP, and Walter G. Bradley, DM, FRCP
Amyotrophic lateral sclerosis (ALS) is a progressive degenerative disease of the motor system in adults that occurs in
sporadic, familial, and Western Pacific forms. Involvement of non-motor pathways has been increasingly recognized,
both clinically and pathologically. Although the usual course is relentlessly progressive with death in half the cases
within three years from onset, it can sometimes be protracted. Degeneration and loss of large motor neurons in the
cerebral cortex, brainstem, and cervical and lumbar spinal cord are characteristic. Marked reduction in the number of
large myelinated fibers is notable in the cervical and lumbar ventral roots. Peripheral nerves show reduced numbers of
large myelinated fibers, acute axonal degeneration at all levels, and distal axonal atrophy. Motor end-plates reveal small
or absent nerve terminals. Subclinical non-motor system involvement includes neuronal loss in Clarke’s nucleus and
dorsal r m t ganglia, degeneration of non-motor tracts in the spinal cord, loss of receptors in the dorsal horns of the
spinal cord, and myelinated fiber loss with segmental demyelination in sensory and mixed nerves. The serious implications of the diagnosis of ALS make it mandatory to exclude similar potentially treatable disorders. Management should
be multidisciplinary, and discussions with the patient and family members should be frank and frequent. Discussions
about ventilatory support should take place early in the disease so that death from respiratory failure can be prevented,
when that is desired, and conversely to obviate the discontent and anger that accompany involuntary life on a
ventilator.
Tandan R, Bradley WG: Amyotrophic lateral sclerosis:
Part 1. Clinical features, pathology, and ethical issues in management.
Ann Neurol 18:271-280, 1985
The degenerative diseases involving large motor
neurons of the brain and spinal cord constitute a
heterogeneous group of crippling disorders that span
all ages and exhibit protean manifestations (Table).
The motor neuron diseases were originally described
over a century ago 131 and have been the subject of
several reviews in the last two decades 191, 121).
Some of these diseases are inherited while in others
familial occurrence is rare. In the vast majority of
these disorders no underlying biochemical defect has
been recognized (though see [64j). The lower motor
neurons (LMNs) of the brainstem or spinal cord, or
both, are predominantly involved in some (such as hereditary spinal muscular atrophy and progressive bulbar palsy); the upper motor neurons (UMNs) are
primarily affected in others (primary lateral sclerosis);
in yet others, both UMN and LMN involvement occurs (amyotrophic lateral sclerosis [ALS]).
This review will emphasize recent advances in the
pathology, etiology, and management of ALS (also re-
ferred to as motor neuron disease in Great Britain and as
Charcot’s diseuse in France) and will concentrate on
publications that have come out in the 6 years since
our last review 197). (The second part of this review
will appear in the October issue of the Annals and will
consider the etiopathogenesis of ALS.) We will give
only limited attention to ALS and other MNDs found
in the high-incidence foci in Guam and other Mariana
islands {112, 113, 1541, the Kii peninsula of Japan
C743, West New Guinea [391, Groote Eylandt and the
adjacent Australian mainland [72), and the Viluisk region of eastern Siberia 1381.
Our review is particularly timely as there has been a
great upsurge in public awareness about ALS because a
number of public figures have recently been afflicted
by it. This public interest has bolstered the efforts of
the three U.S. national bodies (the ALS Society of
America, National ALS Foundation, and Muscular
Dystrophy Association) that are involved with the support of ALS patients and research. There are also na-
From the Department of Neurology, University of Vermont College of Medicine, Burlington, VT 05401.
Address reprint requests to Dr Bradley.
*Part 2 will appear in the October issue of the Annah.
Received Nov 26, 1984, and in revised form Mar 28, 1985. Accepted for publication Mar 28, 1985.
271
Motor
Neuron Diseases
Ink i t e d
Spinal muscular atrophy
Type I: infantile (Werdnig-Hoffmann disease)
Type 11: late (benign) infantile
Type 111: juvenile (Kugelberg-Welander disease)
Type IV: adult
Limb girdle
Facioscapulohumeral
Scapuloperoneal
Peroneal
Ophthalmoplegia plus
Other
Hexosaminidase deficiency
Familial ALS
Fazio-Londe disease
ALS-like syndrome (hexosaminidase deficiency)
Acquired
Acute: Acute anterior poliomyelitis-polio,
coxsackie,
other enteroviruses
Chronic
ALS
AHC degeneration in:
Spinocerebellar degeneration
Creutzfeldt-Jakob disease
Huntington’s disease
Parkinsonism
Shy-Drager syndrome
Joseph‘s disease
Neoplasms
Other
ALS = amyotrophic lateral sclerosis; ,4HC = anterior horn cell.
tional organizations in Great Rritain, West Germany,
Sweden, Switzerland, the Netherlands, Italy, Denmark, Canada, Mexico, and Australia.
Classification and Clinical Features of ALS
ALS is a progressive degenerative disease of adults that
occurs in sporadic, familial, and Western Pacific forms,
all of which are quite similar in presentation. Clinically
the disease is almost confined to the motor system with
sparing of the extraocular muscles and sphincters 1921.
The degree of UMN and LMN involvement in limb
and bulbar muscles allows identification of distinct syndromes, particularly early in the disease 197, 121).
Some observers consider such distinction unjustified
11011. The disease may predominantly affect the
LMNs of the limb or bulbar muscles (progressive
muscular atrophy or progressive bulbar palsy) or
the UMNs (primary lateral sclerosis or progressive
pseudobulbar palsy).
Although the usual course of ALS is relentlessly
progressive, with death by three years in 50% of patients 1951, in some patients it can be unusually prolonged or benign 148, 95, 104}, stabilize after several
years of progression 11041, or rarely reverse 110, 1201.
Cases with later onset and those with predominantly
bulbar or pseudobulbar syndromes 122, 95, 1201 dis272
Annals of Neurology
play a rapid course, though results from a recent study
disagree with these observations 1681.
Recent reports emphasize that ALS may involve
parts of the central and peripheral nervous systems
outside the UMNs and LMNs. Dementia has been
reported in up to 5% of sporadic I1511 and familial
152, 551 cases of ALS. About 5 to 10% of ALS patients are reported to have difficulty with grammatical
speech or spelling 11467, though this has never been
systematically studied. The cases of subacute spongiform encephalopathy (Creutzfeldt-Jakob disease)
with amyotrophy may well have a closer resemblance
to ALS, as they appear not to be transmissible to
nonhuman primates 11221.
Defective eye movements detected by electrooculography 183, 1011, impaired visual scanning 1881,
abnormalities of Bell’s phenomenon 1331, nystagmus
1791, and ophthalmoplegia 1531 have all been found in
ALS patients, albeit rarely.
Although many patients report initial sensory symptoms 192, 1481, elaborate computer-assisted examination may be required to detect sensory threshold
abnormalities 127, 931. Bladder, bowel, and other autonomic dysfunctions are unusual in ALS even late in
the disease 192, 120). Unaffected sphincter functions
correlate with histological preservation of “group X
cells of the nucleus of Onufrowicz in the sacral spinal
cord, and of the external anal sphincter muscle 1851.
Epidemiology
The average worldwide annual incidence rates for ALS
range between 0.4 and 1.8 per 100,000 population
1671 and the prevalence rates range between 4 and 6
per 100,000 population, with an overall male predominance 178). Low incidence rates reported from some
regions 175, 1081 may reflect incomplete case ascertainment 178) and not necessarily a local “resistance”
to ALS. The reported high incidence of ALS among
Filipinos in Hawaii 1871 is no longer evident after age
adjustment of the population 1781. The annual average
death rate worldwide is fairly uniform at 1 per 100,000
population 1771.
With data compiled from cases of sporadic ALS in
ten epidemiological studies conducted in the U.S. and
Europe, the mean ages at onset and death were estimated to be 56 years and 59 years, respectively, male
to female ratio was 2 :1, and mean disease duration was
2.5 years [591. Pooled data for familial ALS, also from
ten studies, revealed a mean age of onset of 45.1 years,
male to female ratio of 1.2 : 1, and median disease duration of 1.5 years 1291. This confirms prior observations E591 of earlier onset, lesser male preponderance,
and shorter duration in the familial compared with the
sporadic type of ALS. An overall earlier age of onset
but longer disease duration is usual among patients
from high-risk foci in Guam 1112, 1131, the Kii penin-
Vol 18 No 3 September 1985
sula of Japan 1741, West New Guinea 1391, and the
Viluisk region of eastern Siberia 1381, and also in
Chamorro migrants from Guam 1413.
Several series have reported increasing age-specific
rates for ALS up to the sixth or seventh decades, with
generally a decline thereafter 177, 1771. However, the
recent small series reported from the Mayo Clinic
1681, in which ascertainment in older cases may have
been more complete, indicated that the age-specific
incidence rate rises progressively with increasing age.
This suggests that ALS is truly a disease of aging.
Laboratory Investigations
The lack of a specific biochemical marker for ALS
often makes diagnosis difficult early in the disease.
Electrophysiological, radiological, biochemical, immunological, and histopathological studies may be
needed to make the diagnosis of ALS, and to help
differentiate clinically similar disorders.
Electrophysiological evidence of denervation with
reinnervation in muscles from two or more extremities, outside the distribution of a single peripheral
nerve or nerve root in each extremity, is usually seen
in ALS. Fasciculations in ALS characteristically have a
slower rate (0.3 Hz) than those in the benign fasciculation syndrome (1.25 Hz 1142)). Decremental responses to repetitive nerve stimulation 1247, signifying
impaired transmission through immature neuromuscular junctions 11361, correlate with rapidly progressive
disease and with the degree of atrophy in the muscles
tested [8}. Increased fiber density and abnormal jitter,
which indicate collateral sprouting and uncertain impulse transmission, can be detected early by singlefiber electromyography (SFEMG). These changes are
most pronounced in rapidly and severely weakened
atrophic muscles. However, they are also noted in all
patients with predominant UMN symptoms 11361. Increased fiber density and abnormal jitter are recorded
in some clinically normal muscles too, indicating that
the disease must be diffuse from the onset [136) despite focal features. There is, though, an increased susceptibility of the lower cervical and upper thoracic
myotomes, as evidenced by the frequent presence of
wasting of the intrinsic hand muscles and by early involvement of these myotomes revealed by SFEMG
analysis [138). Normal or only mildly inceased fiber
density with increased jitter suggests rapidly progressive and mild involvement 11361.
Mild to moderate elevation of serum creatine kinase
activity is observed in 35 to 100% of ALS patients and
correlates with axial muscle weakness at presentation
and with muscle atrophy, but not with the duration or
rate of progression of the disease C511. Increased
creatine kinase (MB) isoenzyme, traditionally considered to be the cardiac isoenzyme, has recently been
described in more than half of ALS patients and its
presence has been correlated with the occurrence of
alkaline phosphatase-positive (regenerating) fibers in
muscle biopsy specimens 1731. Muscle fiber degeneration and regeneration are uncommon in ALS and may
be indicative of a more slowly progressive disease.
Differential Diagnosis
The dire implications associated with the diagnosis of
ALS make it essential to discover potentially treatable
disorders that can imitate ALS. Combinations of
UMN and LMN involvement can characterize cervical
spondylotic myeloradiculopathy 1104, 1371, tumors
and anomalies of the region of the foramen magnum
130,431, tumors of the cervical or high thoracic spinal
cord 194, 1041, syringomyelia [37), familial spastic
paraplegia with distal amyotrophy [99], thyrotoxicosis
1401, exposure to inorganic or organic mercury 111,
and lead intoxication [lo].
Pronounced LMN disease with amyotrophy necessitates differentiation from the spinal muscular atrophies
149, 1141, polymyositis [1041, diabetic amyotrophy
1191, post-polio syndrome 121, monomelic atrophy
11261, neuronal Charcot-Marie-Tooth disease 12 5),
chronic inflammatory polyradiculoneuropathy 1261,
and amyotrophy in multisystem genetic disorders
11191.
Cramps and fasciculations, both characteristically
seen in ALS 11041, also occur in several “benign” conditions such as recovered poliomyelitis 154, 961, myelitis 1361, and the muscle pain-fasciculation syndrome 1601. Abnormal fatigue, which is an early and
often overlooked symptom in ALS, needs to be differentiated from myasthenia gravis and the LambertEaton syndrome 11041. The report by Tyler 11461of a
case of typical myasthenia gravis of several years duration becoming refractory to anticholinesterase drugs
and developing into typical motor neuron disease may
be a chance occurrence of two diseases.
Pathology
The Central Nervous System
The pathological changes within the central nervous
system have been extensively reviewed at the light microscopy level in sporadic, familial, and Guamanian
types of ALS, and less extensively examined using
electronmicroscopy 120, 57, 61). Motor neurons of
the brainstem and spinal cord show simple atrophy,
shrinkage, and intracytoplasmic lipofuscin accumulation leading to cell loss with astrocytic gliosis 1571.
Intracytoplasmic inclusions (Bunina bodies) and ghost
cells are very frequent, but vacuolation of the motor
neurons, central chromatolysis, and neuronophagia are
rarely seen, except in rapidly progressive disease 157).
Several other varieties of neuronal inclusions, some
considered to represent aging 1561, are occasionally
encountered 1201 not only in anterior horn cells but
Neurological Progress: Tandan and Bradley: ALS: Part I
273
also in the dorsal motor nucleus of cranial nerve X and
the dorsal root ganglia, neuronal populations which are
not markedly involved in typical ALS. In patients with
prominent UMN signs there is severe depletion or
loss of Betz’s cells and large pyramidal neurons from
the fifth layer of the motor cortex, and widespread
degeneration of the corticospinal tracts 1611. The posterior columns are generally uninvolved in sporadic
ALS 1801, though significant degeneration in the
neurons of Clarke’s nucleus [6} and in the spinocerebellar tracts 153 has been recognized. In familial ALS
there is evidence of at least three pathological types
I581, and involvement of the posterior columns,
Clarke’s nucleus, and spinocerebellar tracts is encountered in over 50% of cases 1291.
Alzheimer-type neurofibrillary tangles (571, Lewy
bodies 11401, and pathological features similar to those
seen in Pick‘s disease (141 have been reported in rare
cases. Proximal axonal spheroids filled with 10 nm
neurofilaments, which were considered to be rare
when first described 1171, may occur in up to 60% of
ALS cases [23}.
Quantitative studies have shown a significant reduction in the number of large motor neurons in the cervical 11447 and lumbar 1691 spinal cord, with a parallel
decrease in the corresponding populations of large myelinated fibers in the ventral root. The number of residual large cervical El441 and lumbar 11333 motor
neurons correlates with muscle strength and atrophy in
the corresponding limbs, and with the duration of
symptoms [133]. Loss of small motor neurons in the
cervical cord of some patients with ALS 11441 also
suggests involvement of gamma motor neurons,
though this is disputed 169, 7 1, 1391. A 36% reduction of neurons in Clarke’s nucleus [61 probably
underlies the “dying b ack change in the distal spinocerebellar tract seen in some cases [18].
The oculomotor nucleus complex shows pathological changes even in ALS patients not exhibiting
ophthalmoparesis f61, 841. However, quantitative
analysis of fibers in roots of cranial nerves 111, IV, and
VI has not shown a substantial abnormahty 1132).
Marked brainstem gliosis in the vicinity of extraocular
nuclei occurs in patients with external ophthalmoplegia
1531.
The Peripheral Newoas System
Quantitative analysis of the changes in the spinal roots,
peripheral nerves, and motor endplates in ALS has
been done recently. Several morphometric srudies
have confirmed an earlier nonquantitated report 176)
and a later histographic finding 11521 of a marked reduction in the numbers of large myelinated fibers in
ventral roots in ALS (47, 131, 1321. A substantid
decrease in the fascicular area of the cervical C131,
1321 and lumbar 1132) ventral root and in the num-
bers of total myelinated fibers 147, 132) and large myelinated fibers [47, 69, 131, 1327 has been reported
but there is negligible thoracic and sacral involvement
1132). The quantitative changes are most striking in
the cervical region f1311 and correlate with strength
in corresponding myotomes 1131, 132). Smallerdiameter myelinated fibers (probably gamma efferents)
and thinly myelinated fibers (probably autonomic preganglionic fibers) are well preserved E131, 132). The
above changes, along with reduced numbers of large
motor neurons of the cervical and lumbar spinal cord,
verify the selective vulnerability of alpha motor
neurons in ALS 169, 152).
Teased-fiber preparations of ALS ventral roots have
demonstrated an abnormal number of fibers undergoing axonal degeneration 147, 131, 1323 and a lesser
increase of fibers with active segmental demyelination
147, 1311. The latter suggests secondary Schwann-cell
involvement at the ventral root level and explains the
decreased proximal conduction velocity recorded in
some patients. Regenerating fibers with uniformly
short myelinated segments are rare 147, 1311, though
increased numbers of small myelinated fibers and a
reduced myelin lamellae-to-axonal
circumference
ratio seen in some patients might suggest regeneration
in the ventral roots. We have reported an increase in
small-diameter fibers in ALS phrenic nerves 1121, similarly indicating axonal regeneration.
Light microscopic, ultrastructural El 531, and morphometric studies 197 have demonstrated motor endplate involvement in ALS muscle biopsy specimens.
Decreased numbers of motor axons, degenerating
and atrophic axons, some axonal sprouts, thickened
and multilayered Schwann-cell basement membranes,
and banded structures with a periodicity of 120 to 130
nm continuous with the Schwann-cell basement membrane have all been observed f47. In recent ultrastructurd studies, Tsujihata and associates {143] demonstrated many endplates with small axon terminals and
an absence of nerve terminals in 34% of ALS motor
endplates (as compared with 10% of controls), but
with preserved postsynaptic folds and junctional
acetylcholine receptors. These features probably represent degeneration and regeneration in distal motor
nerves.
Recent studies by our group on phrenic nerves obtained post mortem 112) clarified the controversy over
whether the degeneration in ALS is a neuronopathy
[135], a focal proximal axonopathy [17, 451, or a “dying b a c k change 118, 1341. Numbers of total myelinated fibers from all levels of ALS phrenic nerve were
reduced to 70% of controls and large myelinated
fibers to 33% of controls, while small myelinated
fibers were increased to 120% of controls. There were
15% fewer myelinated fibers of all ages and 18%
fewer large myelinated fibers distally as compared with
274 Annals of Neurology Vol 18 NO 3 September I985
proximally in ALS phrenic nerves. Acute axonal degeneration in teased-fiber preparations was rhore frequent in ALS than in control nerves and occurred
equally at the proximal and distal levels; regenerating
fibers were absent in ALS nerves. The myelin lamellae-to-axonal circumference ratio was increased by
34% in distal ALS phrenic nerve fibers compared with
controls. Choline acetyltransferase activity in ALS
nerves was reduced to 20% of control values, and that
of acetylcholinesterase to about 45%, with considerably less activity distally. These data indicate that ALS
is predominantly a neuronopathy, as evidenced by considerable loss of large myelinated fibers from all levels
of the nerve and by quantitatively similar acute axonal
degeneration at the proximal and distal levels. In addition, the 18% reduction in large myelinated fibers distally suggests some “dying b ack change, and the distal
increase in myelin lamellae-to-axonal circumference
ratio indicates axonal atrophy. A decrease in choline
acetyltransferase activity does not precede motor
neuron degeneration, as it paralleled reduction in
numbers of large myelinated fibers.
Pathological evidence of non-motor system involvement in ALS is well established. The number of large
neurons in the L5 dorsal root ganghon is reduced in
ALS to 46% of control values, and that of large dorsal
root axons is reduced to 73% of control values (691.
Other evidence of non-motor system involvement in
ALS is provided by decreased numbers of large myelinated fibers and more frequent degenerating fibers
in sensory nerves 127, 1411, increased frequency of
segmental demyelination (27) and of remyelination
after segmental demyelination in sensory or mixed
nerves 1271, degeneration of non-motor tracts in the
spinal cord [6, 16, 62, 801, and loss of choline acetyltransferase activity 142) and muscarinic cholinergic receptors 1150) in the dorsal horns of the spinal cord.
Our recent studies of sural and common peroneal
nerves from ALS patients C12) showed a considerable
reduction in total myelinated fiber numbers. A substantially increased number of denervated Remak’s cell
processes in ALS surd and common peroneal nerves
suggested degeneration of unmyelinated nerve fibers.
and the need for equipment or community services is
most important.
There are several features that determine the course
and duration of the disease; the prognosis becomes
increasingly benign, in the following order, in the presence of: predominant bulbar symptoms and signs, respiratory insufficiency, UMN involvement, and muscular atrophy. Between 14 and 39% of patients live for
5 years 168, 95, 1181, about 10% live up to 10 years
1921, and a few live for 20 years or more following
onset of symptoms. There are many patients who lead
extremely productive lives despite the disease.
Through active participation in a rehabilitation program C631, patients can learn about range of motion
and isometric exercises and the avoidance of fatigue,
and this helps to identify the need for corrective or
supportive orthotic devices. This is essential to help
the patient maintain optimal function. Speech therapy
in patients with mild dysarthria helps “speech conservation.” Patients with nasal air loss or hypernasal resonance can benefit from aids such as palatal lifts and
nasopharyngeal obturators, or can undergo procedures
such as pharyngeal flaps and Teflon injections into the
nasopharynx 128, 891 to narrow or block mechanically
the nasopharyngeal isthmus. Patients with unintelligible speech or anarthria can use an alternative communication system (147).
Dysphagia, resulting from either pharyngeal dysfunction [ll] or esophageal dysmotility (1301, predisposes to repeated aspiration and may benefit from
cricopharyngeal myotomy 1811. In our experience,
pseudobulbar dyscoordination appears to be the type
of ALS most likely to benefit. In some patients cervical
esophagostomy (1 101, feeding gastrostomy, or jejunostomy 11l l 1 may be required. Suboptimal nutritional intake is very common and may account for the
cachexia [lo31 seen in ALS patients with established
disease and the associated crescendo deterioration.
Muscle wasting generally has a multifactorial cause 190,
129). Estimation of caloric and nutrient intake and requirement, monitoring of deglutition (149) and gastrointestinal function, and advice on modified foods are
all of paramount importance in dietary management.
Management
A multidisciplinary approach to the care of an ALS
patient is required. At the initial interview a frank discussion of the diagnosis by a team of compassionate
personnel may help allay some anxiety in the patient
and relatives. An initial denial of the disease by the
patient and relatives is not unusual. The depression
that follows is generally amenable to psychological support by the treating physician, but may need more
formal psychotherapy or antidepressant medications.
A periodic review by home care personnel of family
and psychosocial problems, imminent crisis situations,
Respiratory Failure in ALS:
Ethical Considerations
Although early deterioration of respiratory function in
ALS is invariably gradual, an accelerated decline occurs
during the 12 to 15 months preceding death (341 and
terminal respiratory failure usually is rapid. Rarely patients present with exemonal dyspnea or respiratory
failure while still ambulatory (109, 128) but with
minimal non-respiratory muscle involvement. Early
diaphragmatic paralysis from preferential degeneration
of phrenic motor neurons in the cervical cord probably
accounts for such a presentation 1109). An abnormal
Neurological Progress: Tandan and Bradley: ALS: Part I
275
maximum expiratory pressure accurately detects early
respiratory muscle involvement 1447. Forced vital capacity below 50% of that predicted increases the likelihood of the development of respiratory failure 1461
from precipitating events such as aspiration pneumonia, atelectasis, and heart failure. Inspiratory muscle
training considerably improves respiratory function in
patients with ventilatory insufficiency caused by chest
wall and diaphragmatic weakness 1861.
The management of respiratory failure in ALS patients has recently focused on home care ventilation
and nursing 182, 1271. Most patients who require ventilatory support need it permanently. Assisted ventilation in a disease which ultimately leads to complete
paralysis in the majority of patients, and which rarely
stabilizes, raises several bioethical, legal, and psychosocial considerations. It is imperative that discussion with
patients and relatives about ventilatory care and the
above issues be candid and sympathetic, and take place
early in the disease so as to help the patient decide
whether to accept ventilatory assistance when that becomes necessary.
When patients request life support for respiratory
failure, it is essential to make emergency treatment
efficient and to consider prophylactic respiratory support. On the other hand, patients who have been denied the opportunity of making active decisions based
on early discussions may exhibit extreme discontent
and anger about an involuntary life on a ventilator.
Present-day legal, ethical, and moral dictates probably
prevent “switching off” the ventilator unless brain
death has occurred (however, see {7}). Though the
wishes of a competent patient should be respected relatives of patients requesting respiratory support should
be made aware of the level of commitment required,
especially for home ventilation. This is essential for
maintaining harmony within the family unit, which in
turn bolsters psychological mechanisms and facilitates
social interaction between patients and their care givers. If a patient decides against respiratory support, a
statement to that effect must be conspicuous in the
medical records.
The long-term problems and limitations and some
advantages of home ventilation using portable ventilators have been discussed recently 182, 1271. Some
aspects needing attention include ventilator maintenance, respiratory toilet, respiratory therapy and postural drainage, general nursing needs, and social service help. Carefully planned home ventilatory support
has distinct financial, emotional, and psychological advantages over long-term hospital care, and is available
through judicious use of health resource personnel.
Therapeutic Trials in ALS
Most earlier therapeutic trials in ALS have been inadequate by virtue of being nonrandomized and non276
Annals of Neurology
Vol 18 No 3
blinded 1351. Careful selection of the experimental design, an adequate number of well-matched patients and
controls, and valid and reliable measurement criteria
are essential to evaluate the efficacy of any treatment
modality 11231. Tyler 11451, however, has emphasized
the pitfalls of a double-blind study in a progressive
disease such as ALS in which moral and ethical issues
are bound to be violated.
Agents that have been unsuccessful in uncontrolled
trials 1357 include vitamins E, D, and BIZ; penicillamine 121) and other chelating agents; amitriptyline
and L-dopa; pancreatic extract; the antiviral agents
amantadine 23 1, 1001, isoprinosine, idoxuridine, and
guanidine; the supravital dye trypan red; securinine (a
central nervous system stimulant); and modified neurotoxin 11161. Randomized trials 1351 with modified
neurotoxin and the antiviral compounds isoprinosine, amantadine, and tilerone have also shown that
these substances are of no benefit in ALS. Other
series, mostly small and uncontrolled, have reported
no improvement with transfer factor 1651 or interferon 11151, phthalazinol (a cyclic adenosine monophosphate phosphodiesterase inhibitor) 1151, lecithin
1701, testosterone 1661, and naloxone 11241. Plasma
exchange has generally been ineffective in ALS 1107,
1251, though Norris and associates [lo21 reported improvement in some of their patients. Olarte and colleagues were unable to demonstrate benefit in controlled studies with transfer factor El061 or levamisole
Cl051. Bovine brain gangliosides (Cronassial), which
promote axonal sprouting, failed to be of benefit in
ALS patients in two recent placebo-controlled studies
when used for 6 months in a daily dose of 40 mg 113,
501.
Thyrotropin-releasing hormone (TRH) has most recently been shown to produce transient improvement
in UMN and LMN functions in about 50% of ALS
patients when given either in increasing doses by intravenous infusion over 1 to 5 hours, or as a single-bolus
intrathecal injection 132, 98). Benefit was greater in
males and occurred earlier by the intravenous route
and before peak spinal fluid levels were attained. The
exact mechanism of action of TRH is unknown, but
Engel and associates 132) postulate that exogenous
TRH may correct a deficiency of endogenous hormone, produce a neurotransmitter-like trophic influence on affected LMNs, and reduce excessive activity at the segmental or suprasegmental levels (UMNs).
However, whether TRH will have any long-term effect on the clinical course of ALS still remains to be
determined.
Several other agents are currently being evaluated
in the treatment of ALS, and these include cyclophosphamide, bromocriptine, octacosanol, and P-melanocyte-stimulating hormone. Therapeutic trials are
warranted with other agents (such as the ACTH4-lo
September 1985
sequence) that are likely to facilitate axonal sprouting
and reinnervation. Perhaps a higher dose (100 mg or
more daily) and possibly intrathecal use of Cronassial
or different routes of administration (subcutaneous
and intrathecal) of interferon are some forms of therapy worthy of trial.
The authors thank Donna Provost, Peggy Gelinas, and Lynn Hoepner for secretarial help with preparation of this manuscript.
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