Amyotrophic Lateral Sclerosis and Its Variants

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 55–60 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%–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 were formerly the 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. However, in 2008, revised criteria for ALS were proposed, known as the Awaji criteria, which are now widely used. One of the major differences between the Awaji and the El Escorial criteria is that active denervation can be demonstrated by either fibrillations and positive waves, or fasciculations. Thus, the presence of fasciculations took on a more prominent role with the Awaji criteria, allowing an earlier diagnosis in many patients. This has allowed more patients access to clinical trials.

Patients with a typical ALS presentation including diffuse atrophy, weakness, fasciculations, and spasticity, and 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 ( Fig. 30.1 ). 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 have the bulbar onset form.

Progressive Muscular Atrophy

Approximately 15% of patients with sporadic motor neuron disease present with a pure LMN syndrome referred to as PMA. 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, PMA 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

PLS 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. The FA syndrome has gone by many names, including the scapulohumeral variant of PMA, 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 or subtle or occur late in the course. Unlike FA syndrome, FL syndrome shows no predilection for males over females. FA and FL syndromes often remain restricted to the upper or lower extremities, respectively, typically for 1–3 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 ( Fig. 30.2 ). 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.

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 earlier 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 32 ).