Misdiagnosis and missed diagnoses in patients with ALS
CaliforniaLyme
Misdiagnosis and missed diagnoses in patients with ALS
ALS is debilitating and rapidly fatal, with no effective
disease-modifying treatments yet available. An early, accurate
diagnosis-difficult as it may be to achieve-can allow patients to
prepare and plan.
Jacqueline Cristini, PA-C, MMSc
The author works in the Department of Neurology, University of Medicine
& Dentistry of New Jersey, Robert Wood Johnson Medical School, New
Brunswick, NJ. She has indicated no relationships to disclose relating
to the content of this article.
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Amyotrophic lateral sclerosis (ALS), a progressive neuromuscular
condition characterized by weakness, muscle wasting, fasciculations,
and hyperreflexia,1 was described in 1881 by the French neurologist
Jean-Martin Charcot.2 ALS is commonly called Lou Gehrig's disease,
after the famous baseball player who contracted it. Like many with ALS,
Gehrig suffered through several erroneous diagnoses until the Mayo
Clinic provided an accurate one in 1939. He died 2 years later at the
age of 38. Gehrig's famous farewell address, delivered on July 4,
1939, to an emotional crowd at Yankee Stadium in New York City, brought
the disease to the forefront of the American consciousness.
Although the underlying cause of ALS is unknown, the clinical picture
is generally easy to recognize when the disease is fully developed. For
patients, however, that point is usually too late. The earlier symptoms
are recognized, the sooner a diagnosis can be made-and the more
effectively symptoms can be managed and care can be planned. In a
disease as rapidly progressive as ALS, time is of the essence.
Incidence and prevalence
A 1995-1997 prospective study conducted in Ireland revealed that the
annual incidence rate of ALS was 2 in 100,000 people in Ireland and 4
to 6 in 100,000 worldwide, was higher for men, and increased with age
for both sexes. The median age at onset was 65.2 years for men and 67.8
years for women.3 Overall, the prevalence rate increases with advancing
age, reaching a peak at 65 to 69 years for women and 80 to 84 years for
men and declining thereafter.3
The three types of ALS are sporadic (90%-95% of all cases in the United
States), familial (5%-10% of all cases in the United States), and
Guamanian, a type observed in a cluster of cases in Guam in the 1950s.
The average time from symptom onset to established diagnosis is about
12 months. In many instances, during this time patients are
inappropriately referred to other practitioners, and a number of
patients with ALS are initially misdiagnosed. The result is at best a
delay in diagnosis and at worst inappropriate or potentially harmful
management of an incorrectly diagnosed disorder. The issue of a rapid
and accurate diagnosis is important to the patient and family members
because ALS is fatal and, in all but a few patients, progresses rapidly
to complete paralysis and respiratory failure. Death usually occurs
less than 5 years from the onset of symptoms.
Missing the diagnosis
In 1990, international experts in ALS met in a Spanish
palace-monastery, El Escorial. The resultant consensus document on ALS
diagnostic criteria was published in its final version in 19943 (see
Table 1).
Although the essential requirements for a diagnosis of ALS are clearly
defined by the El Escorial criteria, many physicians, including
neurologists, still miss the diagnosis of ALS or diagnose the disease
when the patient has something else instead.4 At present, up to 10% of
diagnoses of ALS are false-positives, and up to 44% may be
false-negatives.5 Among the reasons cited for misdiagnosis are lack of
knowledge and skill on the part of the practitioner and the overall
difficulty of diagnosing ALS. Diagnosis is a considerable challenge, in
part because of the variability of the clinical presentation.
Presenting symptoms The principal symptom of ALS is weakness. This can
occur in any voluntary muscle of the body in a segmental pattern since
the pathology is in spinal cord segments and the weakness occurs in
muscle groups innervated by these segments.6 Patients may present too
early to manifest the widespread abnormalities of ALS, and they may
have a predominantly lower, upper, or bulbar presentation.4 The primary
care provider who first encounters the patient may be unfamiliar with
the disease, which generally begins insidiously with fatigue,
fasciculations, cramps, and mild weakness. Weakness is a very common
complaint. Most patients use "weakness" to imply fatigue, general
illness, or myalgias.7 Another diagnostic dilemma is that neuroimaging
studies may cloud the diagnostic picture.5
Delayed diagnosis There are many reasons diagnosis may be delayed,
including the perception in Western societies that it is generally a
desirable character trait for people to delay seeking help for vague
symptoms and wait until they are unquestionably ill.6 Practical
clinical reasons are also cited for failure to make a timely and
accurate diagnosis. They include the problematic presentation of ALS,
which can be focal or multifocal, and the fact that patients often
present with predominantly lower motor, upper motor, or bulbar
dysfunction when they actually have a generalized neurologic disease.
In addition, the symptoms of ALS may mimic those of other diseases,
including cancer, depression, heart failure, and anemia. In many
instances, fatigue, weakness, or weight loss may be attributed to
depression, especially in the elderly population. Concomitant diseases
of the elderly often mask the diagnosis. If lower neuron signs alone
are evident, the condition is called progressive spinal muscular
atrophy.8
Pathophysiology
ALS affects both upper motor neurons (UMNs) and lower motor neurons
(LMNs) (see Figure 1). Amyotrophic refers to the muscle atrophy that
occurs with the degeneration of the anterior horn cells, which in turn
causes the weakness and fasciculations that signify LMN disease.
Lateral sclerosis refers to the hardness to palpation of the lateral
columns of the spinal cord in autopsy specimens, where gliosis follows
degeneration of the corticospinal tracts.8 These pathologic changes
characterize the sporadic form of ALS that is seen in 95% of patients.6
Motor disease refers to neuronal degeneration confined to the anterior
horn cell and motor neurons on the cerebral cortex. Abdominal reflexes
and bladder function are usually normal in ALS, as are the findings on
sensory examination. Progressive bulbar palsy, characterized by speech
and swallowing dysfunction, may be the initial manifestation of motor
neuron disease.9 Fortunately or unfortunately, depending on one's
perspective, cognition is not affected and patients remain
intellectually intact throughout the usually rapid course of the
disease.
Clinical diagnostic indications of ALS include UMN and LMN signs,
progressive weakness, and an absence of an alternative explanation for
the neurologic signs and symptoms10 (see Table 2). UMN lesions cause
dysfunction of the corticospinal tracts; LMN dysfunction results from
pathology at the level of the anterior horn cell, motor nerve root,
plexus, peripheral nerve, or neuromuscular junction. The pathological
hallmarks of ALS are the degeneration and loss of motor neurons with
astrocytic gliosis.8
History and physical examination
Neurologic history More than 90% of patients report weakness and
fatigue as the initial symptoms, and an important clinical feature of
ALS is the asymmetry of the weakness.6 Pathognomonic of ALS is a limb
with weak, wasted, and fasciculating muscle but normal or overactive
tendon reflexes; this contradiction implies the presence of both UMN
and LMN lesions. Bladder and bowel disturbances are distinctly rare in
ALS, even late in the course.11 Preservation of full extraocular
movements despite progressive weakness of other cranial
nerve-innervated (bulbar) skeletal muscles is a hallmark of ALS,
helping to distinguish it from myasthenia gravis and other neurologic
diseases.11
Examination During the proximal muscle motor examination, the patient
should squat, get up from a chair, rise from a supine to a sitting
position without using the hands, and flex the neck. To test distal
muscle weakness, the patient should grip your fingers, stand on toes
and heels, and maintain an upward gaze for several minutes. The
manifestations of LMN dysfunction, such as muscle weakness and wasting,
combined with increased deep tendon reflexes (a sign of UMN
dysfunction) and a positive Babinski's sign, will further aid the
examiner in diagnosing ALS. A clinical sign of considerable help in
pointing to the diagnosis is the presence of increased tendon reflexes
in muscles already considerably atrophied due to LMN denervation.12
Difficulty in speaking or swallowing is the initial symptom in the
bulbar form of the disease.1
The primary task in diagnosing weakness is to determine whether the
condition is due to a UMN lesion, an LMN lesion, or both-a
distinction that can be based on clinical findings. In order to
determine whether there is pathologic muscle weakness, the clinician
should consider distribution, associated neurologic abnormalities, the
rapidity of the disease, the genetic history, the patient's age, and
whether there is facial paralysis. Muscle weakness can occur as a
result of dysfunction at any level of the central or peripheral nervous
system.13 There is no known genetic defect in ALS, and the mean age at
onset is 60 years.
In a patient with signs of both LMN and UMN dysfunction, muscle
fasciculations usually confirm the diagnosis of ALS11 (see Table 3).
Diseases to be excluded include spinal cord compression from tumors or
cervical spondylosis, hyperparathyroidism, hyperthyroidism, and
multifocal motor neuropathy. Consider stroke if hemiparesis is present
or if the onset of symptoms is abrupt and the patient is elderly or has
a history of hypertension. Motor neuron disease is an important
consideration in painless isolated limb weakness, particularly without
sensory loss.
Differential diagnosis
The clinician must rely on clinical acumen and experience to diagnose
ALS since the symptoms of this disease may mimic those of a number of
non-neurologic conditions. Limb fasciculations may be difficult to
appreciate in a patient who is overweight. When the disorder commences
with wasting of the hand, which is a common presentation, carpal tunnel
syndrome may be wrongly diagnosed and inappropriate decompression
undertaken-thus delaying diagnosis until further deterioration has
occurred.6 Certain features, especially fasciculations of the tongue,
carry high diagnostic specificity and are especially important.6
The differential diagnosis of ALS includes spinal cord tumors,
syringomyelia, cervical spondylosis, Lyme disease,
dermatomyositis/polymyositis (inflammatory myopathies), myasthenia
gravis, hyperthyroidism, and hyperparathyroidism. Spinal cord tumors
can manifest as limb weakness, numbness, and spasticity. Syringomyelia,
also referred to as cord cavitation, is a degeneration of gray and
white matter adjacent to the central canal of the cervical spinal cord;
its etiology is unknown. The typical clinical scenario is segmental
atrophy, areflexia, and loss of pain and temperature appreciation in a
"cape" distribution; usually thoracic kyphoscoliosis is also
present. Cervical spondylosis, a form of degenerative bone disease
causing compression of nerve roots, is very common in the elderly. In
these patients, lateral flexion and rotation of the neck is usually
limited. Spastic paraparesis may also be present.
When taking a history, inquire whether the patient has been in
tick-infested wooded areas. The neurologic manifestations of Lyme
disease include meningitis and polyradiculoneuropathy. Serologic tests
establish the diagnosis of Lyme disease.
Dermatomyositis and polymyositis, idiopathic inflammatory myopathies,
are systemic diseases of unknown cause whose principal manifestation is
muscle weakness. Although they may develop at any age, most cases occur
in childhood and during the fifth and sixth decades of life. Myasthenia
gravis, an autoimmune neuromuscular disorder of insidious onset, can
occur at any age but is common in women during the third decade and in
men in the fifth decade. Involvement of the ocular muscles
distinguishes it from ALS, with ptosis and diplopia being the initial
manifestations in most cases.
Endocrine myopathies such as hyperthyroidism may cause proximal muscle
weakness, and symptoms of hypothyroidism include muscle weakness,
cramps, pain, and "hung up" reflexes. Clinical manifestations of
hyperparathyroidism include proximal muscle weakness and hyperreflexia
reminiscent of ALS, whereas hypoparathyroidism and associated
hypocalcemia may lead to carpopedal spasm and tetany.
Early diagnosis
The diagnosis of ALS is probably often considered but initially
rejected in favor of other potentially more treatable disorders, such
as compressive cervical myelopathy, peripheral neuropathy, or primary
muscular disease.6 However, diagnosing ALS only when widespread
clinical and electromyographic signs are present limits the diagnosis
to patients with relatively advanced disease.10 The benefits of an
early diagnosis of ALS include the right of the patient to know the
truth as soon as possible, the psychological advantage to the patient
and family, and the opportunity to gain admission to ongoing clinical
trials before the disease is advanced, which would make pharmacologic
therapy less effective. In addition, an earlier diagnosis will allow
the patient and family to plan more effectively.
Laboratory and diagnostic testing
The only frequently noted abnormality on screening blood tests in
patients with ALS is elevated creatine kinase values, which occur in
about 70% of patients.6 While the combination of electromyography (EMG)
and nerve conduction studies remains the best technique for confirming
progressive motor neuron dysfunction, it cannot diagnose ALS, which
still requires the clinical presence of UMN dysfunction.11 EMG is the
single most important investigation in suspected early ALS because it
may yield evidence of neurogenic change in a widespread distribution,
even in clinically normal muscles without evidence of peripheral
neuropathy.6
EMG, muscle biopsy, and tests for creatine kinase levels are
indispensable in evaluating neuromuscular weakness. Tests such as MRI
and CT are primarily useful for excluding structural abnormalities. EMG
is used to document denervation and distinguish benign fasciculations
from those caused by ALS.1 Muscle biopsy is a safe diagnostic procedure
that can provide a definitive diagnosis in many neuromuscular
disorders. Normal muscle stained for enzyme activity shows a
checkerboard distribution of two muscle fiber types. With chronic
denervation and reinnervation, as in anterior horn cell disorders and
neuropathies, fiber-type grouping is seen.13 Muscle degeneration causes
the release of creatine kinase into the blood, increasing levels of
this enzyme in the plasma. The creatine kinase level should be
determined before EMG in order to avoid artifactual increases due to
muscle trauma caused by the EMG needle.
Psychological perspectives
Studies done in patients with cancer make it clear that the way the
diagnosis of a fatal disease is communicated can profoundly affect
subsequent emotional status and coping strategies.11 Most patients
receiving a diagnosis of ALS will experience fear, anxiety, and
depression. Suicide can be viewed as a rational solution by patients
who know the toll that ALS can take physically, emotionally, and
financially on themselves and their families.8 It is important to
convey the diagnosis in a confident and forthright manner, marshalling
your best interpersonal skills. For patients, the matter of utmost
importance is what will happen to them, and the response that no one is
absolutely certain may serve as a source of hope and strength for both
patient and clinician. You may add that although there is no known
cause or cure for ALS, the manifestations are treatable, research is
ongoing, and there are new treatments on the horizon. Be certain
patients understand that ALS is a progressive disease but that in rare
cases patients have recovered or their conditions have stablilized. It
is not appropriate, nor in patients' best interests, to cover
statistics and expected survival times. Supply them with materials from
the ALS Association (ALSA) and information about any clinical research
trials they are eligible for.
Management
Once the diagnosis of ALS is established, patients are usually referred
to a neuromuscular disease specialist. Adjunctive treatment will
probably consist of physical and occupational therapy and various
supplemental aids, which eventually become necessary for activities of
daily living. Physical therapy involving passive range-of-motion
exercises is essential to prevent contractures. All attempts should be
made to keep the patient at home and to avoid hospital admissions.
Overall management of patients with ALS can be divided into three
phases: first, when the definitive diagnosis is made; second, when the
patient makes decisions regarding care, particularly regarding
nutritional, ventilatory, and psychiatric support; and, finally, when
the patient is in the phase of extreme disability, which may range from
weeks to years. These phases will overlap somewhat. Patients with ALS
differ from those with other neurologic disease in that ALS does not
affect cognition.11
Early pulmonary function tests (PFTs) are essential in order to
establish a baseline for future reference. Frequently, patients with
ALS have some degree of decreased pulmonary function before the actual
onset of symptoms. This is attributable to the weakness of skeletal
muscles. Patients will often present with dyspnea on exertion or
recumbency.
Riluzole (Rilutek) is currently the only FDA-approved drug for ALS. At
present, there is little definitive evidence that initiating this
treatment early in the course of the disease improves its efficacy.14
In one study, riluzole did not influence the median time in the mild,
severe, or terminal stage of ALS, but compared with placebo it did
slightly shorten the time in the moderate stage.15 It has been said
that the benefits of riluzole are marginal but its side effects are
major.16 The most commonly reported side effects are fatigue, nausea,
and vomiting.
Symptomatic pharmacotherapy may include baclofen, diazepam, or
dantrolene to treat spasticity; lorazepam for relieving severe muscle
fasciculations; and NSAIDs or anticonvulsant agents for pain. One of
the most psychologically debilitating aspects of ALS is drooling.
Atropine and scopolamine are beneficial in suppressing sialorrhea and
decreasing the incidence of saliva aspiration. Tricyclic
antidepressants can also suppress sialorrhea and have useful effects on
mood as well.
Supportive care is the mainstay of treatment and includes occupational
and physical therapy as well as attention to depression and anxiety.
There are biological and ethical imperatives for providing the
diagnosis of ALS as soon as possible and for involving patients and
their families in therapeutic decisions.17
Advance directives should be discussed early and updated regularly.
Eventually, patients will have to make decisions regarding gastrostomy
for nutritional support and tracheostomy for ventilatory support when
respiratory failure ensues. Instill hope in patients by discussing
palliative measures and ongoing research and by putting patients in
touch with advocacy groups.
The ALS Association (www.alsa.org) is the only national not-for-profit
health organization dedicated solely to the fight against ALS. ALSA
covers research, patient and community services, public education, and
advocacy-everything to provide help and hope to those facing the
disease.18 The mission of this organization is to find a cure for ALS
and improve life for those with the disease; they are currently funding
more than 120 research studies worldwide. ALSA has also launched TREAT
ALS (Translational Research Advancing Therapy for ALS), a
groundbreaking program aimed at the rapid discovery and testing of new
therapeutic agents. TREAT ALS is the most comprehensive effort ever
undertaken to focus leading scientists on developing one or more drugs
within the next decade that will prevent, halt, or significantly slow
the course of this devastating disorder.19
A number of clinical trials in the United States are currently
recruiting patients with ALS. Information about them is available
online at www.clinicaltrials.gov and www.alsa.org. One of the drugs
being studied is thalidomide.
Gene therapy may help nerve cells damaged by the disease process by
providing a steady supply of helpful protein to the right places.20 By
the time many patients receive a diagnosis, they have lost 50% of their
motor neurons; the results of studies in animal models, however,
suggest that this is not too late to begin gene therapy. Recently
published research has reported that key genes govern the ability of
developing brain cells to connect properly to the spinal cord. With
this finding, the remaining challenges facing investigators are to
understand how genetic mutations lead to the disease and to develop
effective treatment plans and, perhaps, a cure.
One of the primary goals in ALS research is to find out what leads to
the selective killing of motor neurons-both the UMNs that send
signals from the motor cortex and the LMNs that cause muscle weakness,
deterioration, and eventually the paralysis and respiratory failure
that afflict all patients with the disease.20 In the meantime, there is
much that can be done from the medical, physical, psychiatric, and
social perspectives to help victims of ALS lead more comfortable and
functional lives.
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