Amyotrophic lateral sclerosis (ALS) was recognized as a distinct clinical and neuropathologic entity more than a century ago (1). The unique neuropathologic findings include anterior horn cell degeneration producing muscle atrophy or amyotrophy and degeneration and sclerosis of the corticospinal tracts. The clinical lower motor neuron (LMN) manifestations due to anterior horn cell loss include weakness, wasting, and fasciculation, with upper motor neuron (UMN) signs due to corticospinal tract degeneration recognized by hyperreflexia, spasticity, clonus, and Hoffmann and Babinski signs. The clinical spectrum of motor neuron disease (MND) is broad, with some patients manifesting LMN signs alone without signs of corticospinal tract dysfunction, so defining progressive spinal muscular atrophy (PSMA), and others demonstrating UMN without LMN signs in the syndrome of primary lateral sclerosis (PLS) (3). The signs of progressive bulbar palsy and bulbar-onset ALS reflect predominant motor neuron loss in the brainstem, supplying the lingual and pharyngeal muscles that leads to early or predominant dysarthria, dysphagia, and respiratory insufficiency (2). MND localized to a single limb is termed monomelic amyotrophy.

There is no marker that uniquely identifies the process of ALS during life; therefore, the diagnosis is absolutely confirmed at postmortem examination. However, in the presence -cf the classic clinical syndrome, confidence of the diagnosis probably approaches 98%. It is when portions of the clinical syndrome are missing that confidence decreases and the opportunity for other diseases masquerading o as ALS becomes a significant issue. Brisk reflexes in limbs exhibiting weakness, wasting, and twitching are probable UMN signs (2). Patients with probable UMN signs and PSMA have the greatest likelihood of having an alternative diagnosis, for example, multifocal motor neuropathy, lymphoma, paraproteinemia, or endocrinopathy. Patients with UMN signs alone and pseudobulbar palsy probably have PLS (3).

The World Federation of Neurology El Escorial Diagnostic Criteria (Table 1) (4) provide a useful scheme for the clinical classification ofALS. For classification purposes, LMN signs consist of weakness, atrophy, and fasciculation. UMN findings consist of overactive tendon reflexes, spasticity, Hoffmann and Babinski signs, and pseudobulbar features. The regions of the body are classified into bulbar, cervical, thoracic, and lumbosacral. Patients with definite ALS have UMN and LMN signs in three spinal regions or bulbar region and two spinal regions. Those with probable ALS have UMN and LMN signs in at least two regions. Possible ALS patients have UMN and LMN signs in one region and UMN signs alone in two or more regions. Suspected ALS has LMN signs in two or more regions. Prognosis is not clearly related to the particular clinical syndrome; however, long-term survival is best with PSMA followed by PLS, ALS, and bulbar palsy. The shortened survival of progressive bulbar palsy and bulbar-onset ALS is due to prominent involvement of swallowing and breathing.

In 5 to 10% of ALS patients, a genetic basis is demonstrable, so termed familial ALS (FALS). The mode of transmission is usually autosomal dominant. FALSautosomal dominant behaves in a stereotypic manner in successive generations with similar age at onset and course. In 30 to 40% of patients so studied, there is a mutation in the copper/zinc superoxide dismutase (Cu/ZnSOD) gene located on chromosome 21 (5).

CLINICAL PRESENTATION

The annual incidence of ALS is approximately 1 to 2 per 100,000 in developed countries (range, 0.5 to 2.4 per 100,000) (6). The average age at onset is 56 and is more common in men than women (1.3:1). It is less common below the age of 40 and rare below 30. The youngest patient I encountered was 17 years old. The average duration of illness is 3 to 5 years with a large variation in the duration of disease course (7,8), with some patients expiring weeks to months after diagnosis and others surviving decades. Most patients complain of weakness or some functional impairment that results from weakness, such as difficulty writing, buttoning, or holding onto objects indicative of involvement of the arms and frequent stumbling, tripping, and occasionally falls reflecting involvement of the legs. ALS can be misdiagnosed as painless radiculopathy before electromyography (EMG) studies are performed, especially when the signs and symptoms are restricted to a single limb or adjacent root. Occasional patients have isolated weakness of neck extension muscles leading to forward drooping of the head or floppy head syndrome. Hoarseness, slurred speech, and drooling precedes frank respiratory and pharyngeal muscle involvement in patients with bulbar involvement and can lead to complaints of sleep disruption and easy^atigability. Asymmetry and relentless progression of symptoms is diagnostically important. Although fasciculation is common, seldom is it the presenting complaint; rather, it is usually pointed out by the physician to the astonishment of the patient. Muscle twitching without focal weakness or bulbar complaints at presentation is more likely due to a benign disorder rather than ALS. The neurologic examination provides the foundation for the diagnosis of ALS and should demonstrate the combination of LMN and UMN signs already described. EMG and nerve conditions should be performed in all patients with suspected ALS to confirm the diagnosis .

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CHAPTER 32 - Amyotrophic
Lateral Sclerosis