Classic Amyotrophic Lateral Sclerosis

ALS is a degenerative, progressive disorder that affects both UMNs and LMNs. Although younger patients may be affected, it occurs most frequently in those 55 to 60 years old, with a slight male predominance. Signs and symptoms of LMN dysfunction include muscle atrophy, weakness, fasciculations, and cramps. UMN dysfunction manifests as stiffness, slowness of movement, spasticity, weakness, pathologic hyperreflexia, and Babinski responses. The presence of both UMN and LMN signs in the same myotome is characteristic of ALS. The mean duration of illness from symptom onset to death is approximately 3 years. However, it is important to remember that about 10% of patients follow a more benign course, surviving for many more years.

ALS is remarkably specific for the motor system. Although detailed pathologic studies have shown some minor loss of sensory fibers, it is distinctly unusual to see sensory complaints or findings on examination. Likewise, there is no disturbance of vision, hearing or the autonomic system. Late in the course, spasticity can affect the bladder, creating symptoms of urinary urgency and frequency. Clinically, an association between abnormalities of cognition and ALS has been recognized in some patients, especially between ALS and Frontotemporal Dementia (FTD). This association is seen in both sporadic and familial forms of ALS and FTD. If patients with classic ALS undergo formal neuropsychological testing, some 40–50% will display some mild evidence of executive dysfunction. FTD develops in approximately 5 to 15% of patients with ALS, and conversely, 10–15% of FTD patients show an associated motor neuron syndrome. Most often, ALS is a regional disease that usually starts in one body segment and progresses to adjacent myotomes. Most cases begin with insidious weakness in either a distal upper or lower extremity. In the upper extremity, the initial presentation can mimic an ulnar neuropathy, especially one at the wrist. In the lower extremity, the presentation is often a progressive foot drop, sometimes misdiagnosed as a peroneal palsy or L5 radiculopathy. As time progresses, symptoms develop in adjacent myotomes of the same limb and then spread to the contralateral limb. Progression continues to other extremities and ultimately to bulbar and respiratory muscles. Death usually results from respiratory insufficiency or from medical complications of prolonged inactivity (pulmonary embolus, sepsis, pneumonia, etc.).

The El Escorial criteria are most often quoted in reaching a diagnosis of ALS. These criteria were set by the World Federation of Neurology meeting in El Escorial, Spain, and published in 1994. They identify four separate body part regions: craniobulbar, cervical, thoracic and lumbosacral. Definite ALS requires that both UMN and LMN signs be seen together in at least three of these regions. Probable ALS requires UMN and LMN signs in two regions, with some UMN signs rostral to the LMN signs. Possible ALS requires UMN and LMN signs in one region or UMN signs in at least two regions. In addition to these criteria, there must be an absence of EDX, pathologic, or radiologic evidence that would support the diagnosis of another disease that may mimic ALS.

Patients with a typical ALS presentation including diffuse atrophy, weakness, fasciculations, and spasticity, in the appropriate age group and clinical setting, are relatively easy to identify. However, not all cases are straightforward, especially when patients present early in the illness with signs and symptoms that are anatomically restricted. In addition, several variants within the spectrum of classic ALS can present diagnostic problems (discussed in the following sections).

Progressive Bulbar Palsy

Patients with progressive bulbar palsy initially develop symptoms restricted to the bulbar muscles. They usually present with a several month history of progressive dysarthria with gagging, choking, and weight loss. The speech disturbance may lead to complete anarthria. These patients are commonly incorrectly diagnosed, and many undergo exhaustive ear, nose, and throat or gastrointestinal evaluations looking for the cause of dysarthria or dysphagia. Occasionally, patients may present with respiratory distress as the result of aspiration. Speech is most commonly slow and spastic with variable flaccid features, depending on the degree of LMN dysfunction. The tongue may be atrophied with fasciculations, accompanied by brisk jaw, gag, and facial reflexes (Figure 27–1). One of the characteristic signs is the “napkin or handkerchief sign.” Because of excessive drooling from bulbofacial weakness, patients often carry a tissue in their hand to frequently clear their mouth and face of saliva. Occasionally the symptoms remain relatively restricted to the bulbar muscles. However, in the vast majority of patients the disorder eventually progresses to involve the limbs, as in typical ALS. Indeed, approximately 25% of patients with ALS will have the bulbar onset form.

FIGURE 27–1 Tongue atrophy.

One of the important findings in ALS is the presence of bulbar muscle weakness. The tongue is commonly affected in ALS. Typical lower motor neuron signs include atrophy, fasciculations and weakness; upper motor neuron dysfunction can also be discerned as difficulty moving the tongue quickly from side to side. In the photo, note the prominent atrophy of the tongue, especially on the left lateral side.

Progressive Muscular Atrophy

Approximately 15% of patients with sporadic motor neuron disease present with a pure LMN syndrome referred to as progressive muscular atrophy. These patients have distal limb wasting and weakness, fasciculations, and cramps, with no sensory symptoms or signs. Reflexes may be present but are generally reduced or absent in weak limbs. The clinical course is commonly long, with slow progression to proximal limb muscles. Bulbar involvement is unusual, occurring very late if at all. Unequivocal UMN dysfunction is not present, although some patients have retained or slightly brisk reflexes that appear inappropriate for the level of limb weakness and atrophy. Of all the ALS variants, progressive muscular atrophy is the one that especially warrants thorough evaluation to exclude other disorders, in particular multifocal motor neuropathy with conduction block (MMNCB, discussed in the section on Differential Diagnosis), which is potentially treatable.

Primary Lateral Sclerosis

Primary lateral sclerosis is a very rare disorder marked by progressive and selective UMN involvement with sparing of the LMNs. It accounts for less than 1% of patients with an acquired motor neuron disorder. The disorder is characterized by spasticity, weakness, pathologically increased reflexes, Babinski signs, and pseudobulbar speech and affect. Atrophy (except due to disuse), fasciculations, or other LMN signs are not seen. The disease commonly presents as a progressive paraplegia or quadriplegia. Occasionally, patients present with progressive bulbar weakness of the spastic type, or hemiplegia. The course tends to be prolonged, with a better prognosis than classic ALS. Some patients may live for decades after the onset of the illness.

Flail Arm and Flail Leg Syndromes

The flail arm (FA) and flail leg (FL) phenotypes have been recognized for over a century, but have recently been studied in more detail. The FA syndrome has gone by many names, including the scapulohumeral variant of progressive muscular atrophy, the hanging arm syndrome, and the man-in-the-barrel syndrome. It presents with progressive weakness and wasting of both upper extremities, is often symmetric, and may affect proximal before distal muscles. However, there is little to no involvement of the lower extremities or bulbar muscles. Males are affected out of proportion to females (ratio 4 : 1). Many patients remain ambulatory for years. In a similar vein, FL syndrome (also known as the pseudopolyneuritic variant of ALS) presents with wasting and weakness of the lower extremities. UMN signs are either absent, subtle or occur late in the course. Unlike FA syndrome, FL syndrome shows no predilection for males over females. FA and FL syndrome often remain restricted to the upper or lower extremities, respectively, typically for 1 to 3 years.

Both the FA and FL presentations have important prognostic implications. Both progress very slowly and have significantly higher 5-year survival rates than classic limb onset ALS (FA: 52%; FL 64%; classic ALS: 20%). By 10 years out, however, the survival rates for FA and FL are similar to classic ALS.

Cervical/Lumbar Stenosis

Degenerative disease of the neck and back is extremely common, especially in older individuals. The combination of cervical and lumbar spondylosis occasionally can mimic ALS, both clinically and in the EMG laboratory. Cervical spondylosis, by itself, is a common cause of gait disturbance in the elderly. Compression in the cervical area can result in a polyradiculopathy involving the cervical nerve roots as well as a myelopathy from direct cord compression. This can create a clinical picture of LMN dysfunction in the upper extremities and UMN dysfunction in the lower extremities (Figure 27–2). If additional compression occurs above the C5 level, UMN signs can be seen in the upper extremities as well. To complicate the situation further, patients with coexistent lumbar stenosis may have additional LMN signs in the lumbosacral myotomes. Taken together, the clinical picture can resemble ALS.

FIGURE 27–2 Cervical spondylosis.

In the differential diagnosis of amyotrophic lateral sclerosis, one of the most important diagnoses to exclude is cervical spondylosis. Compression of the cervical nerve roots (left, arrow) results in a polyradiculopathy while direct cord compression (right, arrow) results in a myelopathy. This can create a clinical picture of lower motor neuron dysfunction in the upper extremities and upper motor neuron dysfunction in the lower extremities. If additional compression occurs above the C5 level, upper motor neuron signs can be seen in the upper extremities as well.

However, several points in the history and on the neurologic examination should raise the question of possible cervical or lumbar (or combined) stenosis. Cervical stenosis often follows a stepwise progression, sometimes associated with periods of improvement. In addition, there is usually some neck or radicular pain, along with limitation of neck motion and sensory symptoms in the arms. Paresthesias and vibratory loss in the lower extremities may occur as a result of posterior column compression. A Romberg sign may be present. Back pain commonly accompanies coexistent lumbar stenosis. Moreover, increased pain or sensory disturbance may develop after walking a distance, which is relieved only by the sitting position.

The signs and symptoms noted above will usually suggest the diagnosis of cervical and lumbar stenosis. However, occasionally a patient with cervical and lumbar stenosis presents with a relatively pure motor syndrome consisting of muscle weakness, atrophy, and spasticity, making the clinical distinction from ALS difficult. It is in these patients that the clinical and EMG evaluation of the bulbar and thoracic paraspinal muscles assumes special significance, because they should never be abnormal in lesions restricted to the cervical or lumbar spine (see Chapter 26).

Multifocal Motor Neuropathy with Conduction Block

An important condition that can mimic the PMA presentation of ALS clinically is demyelinating motor neuropathy. Nearly all peripheral neuropathies have both sensory and motor symptoms and signs; therefore, they are not frequently confused with ALS. Very few neuropathies, however, are purely or predominantly motor. Of those, most are demyelinating and are believed to be immune mediated. Although the exact pathophysiology is not understood, presumably some component of motor nerve or myelin is selectively targeted by the immune system, leading to motor dysfunction. It is in these circumstances that a motor neuropathy may be mistaken for a motor neuronopathy (i.e., motor neuron disease). Although it is quite rare, the motor neuropathy that must be excluded, especially in patients with predominantly LMN dysfunction, is MMNCB (see Chapter 26).

MMNCB usually affects only motor fibers, sparing sensory fibers. It often is slowly progressive and begins distally, like ALS. In addition, fasciculations and cramps are common. Unlike ALS, however, it more commonly affects younger patients (<45 years) and has a strong male predominance (male-to-female ratio of approximately 2 : 1). Several important clues may suggest MMNCB on examination. Often, individual motor nerves are affected out of proportion to adjacent nerves that have the same myotomal innervation (hence, multifocal motor neuropathy). For instance, severe weakness in distal median-innervated muscles with relative sparing of ulnar-innervated muscles might occur in MMNCB, but would be very unusual in ALS, marking the disorder as a motor nerve rather than a motor neuron disorder. Second, muscle weakness may appear out of proportion to muscle atrophy in MMNCB, especially early in the course of the disease, reflecting that demyelination, not axonal loss, is the major underlying pathology. Finally, MMNCB does not result in any UMN dysfunction. Reflexes usually are depressed or normal. Pathologic hyperreflexia, spasticity, and Babinski signs are not seen.

The diagnosis of MMNCB may be suggested by the clinical presentation as well as by elevated titers of antiganglioside antibodies, which occur in more than half of patients. Most often, MMNCB is diagnosed through nerve conduction studies, which show evidence of conduction block along motor fibers, between distal and proximal segments. It is extremely important not to miss this diagnosis because the prognosis for these patients is far better than for patients with ALS. Most patients with MMNCB respond well to immune-modulating therapy, especially treatment with intravenous immunoglobulin.

Inclusion Body Myositis

IBM is an idiopathic inflammatory disorder of muscle that can be confused clinically and sometimes electrically with the PMA variant of ALS. IBM is now the most common inflammatory myopathy in individuals older than 50 years. Clinically, IBM presents as slowly progressive weakness. It is more common in men than in women. Along with proximal muscle weakness, distal muscles are commonly involved. In some patients, the distal muscles are weaker than the proximal ones. Although the distribution of weakness most commonly is symmetric, asymmetric presentations often occur. The disease has a predilection for certain muscles, including the iliopsoas, quadriceps, tibialis anterior, biceps, triceps, and long finger flexors. Prominent muscle atrophy, especially of the quadriceps, is common. Facial and ocular weakness does not occur. However, dysphagia is common. The deep tendon reflexes tend to be depressed or absent early in the course, especially the quadriceps reflex. Patients with IBM and severe distal and proximal weakness and wasting, with depressed reflexes, can easily be mistaken for an LMN disease such as PMA.

Unfortunately, the electrophysiology often complicates the diagnosis of IBM. Prominent fibrillation potentials and positive sharp waves are common. Motor unit action potentials (MUAPs) can be small and short, typical of a myopathy; large and long, suggestive of a neuropathic process; or a combination of both. Although large, long duration MUAPs are classically associated with neuropathic disorders, they are also seen in chronic myopathies, especially in those associated with denervation (i.e., usually myopathies with inflammatory or necrotic features).

One of the key differentiating features between LMN disease and IBM is the presence of fasciculations and cramps. Both fasciculations and cramps are neuropathic phenomena; they are not seen in any myopathy, including IBM. In the absence of fasciculations and cramps in a patient with a LMN syndrome, muscle biopsy sometimes is needed to make the differentiation between a motor neuron disorder and IBM.

Benign Fasciculation Syndrome

Fasciculations are noted in nearly all individuals and are a benign phenomenon. However, because of the well-recognized association of fasciculations and ALS, some people, especially medical personnel or those with a family member with ALS, are more likely to be concerned about fasciculations and bring them to medical attention. The vast majority of persons who experience fasciculations have no neurologic disease. BFS is diagnosed in those individuals who have frequent fasciculations beyond what is normally experienced and have normal neurologic and EMG examinations (except for fasciculations). In some patients with BFS, there may be accompanying fatigue, cramps, and exercise intolerance. In extensive follow-up studies, no patient with BFS developed ALS or any other significant neurologic disorder. It is important to reassure patients with BFS that they have no greater risk of developing motor neuron disease than any other individual.