DIFFERENTIAL DIAGNOSIS AND DIAGNOSTIC TESTING

The recommended evaluation for suspected patients is summarized in Table 2. The singular role of testing in ALS is to confirm the diagnosis and confidently eliminate other disorders that may bear clinical resemblance to it and identify other potentially serious and treatable disorders toward which therapy might also be directed. Clinically apparent or occult Hodgkin and non-Hodgkin lymphoma or macroglobulinemia may be the cause of a motor neuron syndrome resembling PSMA or ALS. Motor neuropathy may be clinically indistinguishable from PSMA. Patients with multifocal motor neuropathy resembling ALS-probable UMN signs with or without GM1 antibodies may have overactive or retained tendon reflexes despite weakness, wasting, and twitching (9,10). The importance of making the diagnosis of multifocal motor neuropathy is that such patients respond dramatically to intravenous immunoglobulin (11). There is little rationale for the routine evaluation of antibodies to GM1 gangliosides and myelin-associated glycoprotein in otherwise typical cases of ALS, because they are rarely detected in significant titer to warrant serious consideration of treatment (12).

Disorders that may sometimes be confused with MND but are obvious after an appropriate history and evaluation include post-polio muscular atrophy, postirradiation atrophy or myelitis, myasthenia gravis, inclusion body myositis, and PLS. Patients with PLS complain of stiffness, diminution in fluidity of movement, and imbalance, without muscle twitching or atrophy. Reflexes are hyperactive with pathologic signs of corticospinal tract dysfunction, including Babinski and Hoffmann signs and abnormally active jaw jerk. Pseudobulbar palsy is typical with accompanying slurred speech, inappropriate affect, and hyperactive jaw jerk. EMG does not reveal denervation or fasciculation. The prognosis is one of continued progression of symptoms, but the rate is generally slow. PLS is a diagnosis of exclusion, but recent studies using magnetic resonance spectroscopy suggest that abnormalities in the NAA/creatine ratio in the frontal motor areas correlate with clinical signs of UMN degeneration and corticospinal tract signs. Nevertheless, until diagnostic specificity is proven, all patients should be screened for other causes, such as Chiari malformations, intrinsic lesions of the spinal cord, extrinsic tumors at the foramen magnum, syringomyelia, multiple sclerosis, and human T-cell lymphotropic virus type 1 infection. Therefore, magnetic resonance imaging of the brain and cervical cord, lumbar puncture, and EMG are necessary before the diagnosis is made. Sometimes separation from familial spastic paraparesis is difficult.

Genetic testing for FALS and Kennedy syndrome is indicated in selected situations. In sporadic ALS, it may be useful to screen for an SOD mutation when the family history is vague or incomplete. Kennedy syndrome should be clinically suspected in men with perioral fasciculation limb girdle and bulbar weakness, wasting, twitching, and gynecomastia. Genetic analysis shows more than 40 CAG repeats in the gene for the androgen receptor (13). Creatine kinase and serum gonadotropins may be elevated; however, serum testosterone levels are normal.

PROGNOSIS

The prognosis for an individual patient with ALS cannot be estimated from population studies. Rare patients have had reversible symptoms (14). Poor vital capacity, dysarthria, dysphagia, and four-limb fasciculation are considered poor prognostic findings. Studies regarding the prognosis of patients with progressive muscular atrophy vary. Some show prognosis to be similar to classic ALS, whereas others show a mean survival of 6.5 years. The variation is due to the fact that patients in this group include those with only anterior horn cell degeneration (spinal muscular atrophy), motor neuropathy, and ALS with pathologic involvement of the corticospinal tract without clinical expression. Patients with bulbar palsy also have a variable course with some dying shortly after onset and others having a very prolonged course.

SYMPTOMATIC TREATMENT

Fatigue and insomnia are disabling symptoms at any time in the course of the illness. One possible cause of fatigue is inefficient neuromuscular transmission in degenerating neurons, with symptoms reminiscent of myasthenia gravis. For this reason, some clinicians give pyridostigmine. Polysomnography occasionally shows disrupted sleep patterns due to airway obstruction and weak pharyngeal musculature; because of resultant hypoxemia, frequent awakenings and daytime fatigue results. Nocturnal noninvasive respiratory support is often therapeutic (15). As weakness worsens, physical activity decreases. The degree of exhaustion at the day's end may be less, and small naps during the day may detract from ease of entering sleep. Frequent nocturnal awakenings may cause insomnia. Therefore, proper diagnosis is essential. If falling asleep is deemed the problem, medications to facilitate sleep may be necessary, either trihexiphenidyl or triazolam (0.25 mg hs).

Patients with bulbar weakness have particular difficulty controlling secretions, and long-term control is often difficult to achieve. Amitriptyline is often used because of its anticholinergic properties. Atropine has recently returned to the pharmaceutical market and may also be helpful. As a last resort, some patients have opted for radiation of the parotid glands. However, because of totality of destruction of glandular tissue, excessive dryness is a common and troubling side effect because infection becomes a problem under such circumstances. Cramps and fasciculation can be annoying symptoms but are never disabling. Nocturnal cramps are often the earliest symptom of ALS. Patients with cramps report immediate relief from drinking electrolyte-fortified drinks or use of quinine sulfate, and those with fasciculates generally find clonazepam to be helpful. Spasticity and muscle spasms are most often due to dysfunction of the corticospinal tracts. Therapy is usually through physical therapy and antispasticity agents. These include baclofen and tizanidine. Severely affected patients may require baclofen injected directly into the cerebrospinal fluid, administered through a computer-driven pumping system.

Although formal testing does not reveal excessively prevalent depression, it is a frequent enough complaint that antidepressant therapy is often warranted. It is clear that professional education and emotional support is essential for patients and families affected by ALS. The natural end point of ALS is pulmonary failure. When breathing becomes sufficiently compromised, noninvasive ventilatory support is becoming increasingly helpful. In severely affected patients, tracheostomy and mechanical ventilatory support is the only alternative. Many patients choose not to pursue this therapy because of its dramatic impact on quality of life.

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