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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