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Amyotrophic Lateral Sclerosis
11 September 2009

Motor neuron disease (MND), or amyotrophic lateral sclerosis (ALS) is a devastating degenerative disease of motor neurons. MND is not identical to ALS, because MND also comprises other disorders of lower motor neurons, such as progressive spinal muscular atrophy (PSMA), segmental spinal muscular atrophies and progressive bulbar palsy. Primary lateral sclerosis is a disorder only of the upper motor neurons and reflects the other end of the spectrum. The terms MND and ALS are, however, often used to denominate the same rapidly progressive disorder which is characterized by hypertonia, impairment of skilled movements and hyperreflexia due to involvement of upper motor neurons, and by fasciculations, muscle cramps, weakness and muscle atrophy as manifestations of involvement of lower motor neurons.


Authors

M.M. van der Graaff, M.D.
L.H. van den Berg, M.D., Ph.D.
J.H. Veldink, M.D.


Clinical features
In most studies the mean age of onset is between 55 and 60 years. When the initial symptoms arise from lower motor neuron dysfunction, the disease is heralded by weakness that is asymmetric. In such instances, the initial symptom, usually only recognized retrospectively, is volitional cramping that is most pronounced early in the morning. Muscle twitching from fasciculations may be another early manifestation. The most common site of onset is in the distal lower extremities. There may initially be foot-drop, first recognized when an individual trips over a low object such as a curbstone. If the disease first affects the hands, there is a subtle and progressive difficulty manipulating fine objects, such as keys or coins, or problems with buttons or pulling a wallet from a pocket. Lower motor neurons innervating bulbar muscles may be involved initially, in which case the presenting problems are flaccid dysarthria or difficulty chewing. Very rarely, the first manifestation of lower motor neuron pathology may be isolated diaphragmatic weakness. Read more

Natural course and prognosis

Although disease progression may vary between patients, the 50% survival probability after the first symptoms of ALS is three to five years. The prognosis of patients whose first complaints are of bulbar origin is worse than of patients who have limb-onset disease. Prognosis depends mainly upon the degree of respiratory insufficiency, which is also the main cause of death.


Epidemiology
The annual incidence of ALS is between 1.5 and 2.0 per 100.000, with a clear male predominance.

Pathophysiology / etiology
In 1993, a major breakthrough in ALS research was achieved by the discovery of mutations in the copper/zinc superoxide dismutase 1 (SOD1) gene on chromosome 21 in approximately 20% of all familial cases. 1 Currently, eight additional loci have been identified in familial ALS (see Genetics/ genetica). The majority of autosomal dominant familial ALS remains thus unexplained. Read more

Differential diagnosis

The diagnosis of ALS should be relatively straightforward, although it has been shown that false positive and false negative diagnosis occur frequently. Table 1 lists conditions that must be differentiated from classical ALS or variants thereof, including progressive spinal muscular atrophy (PSMA), segmental spinal muscular atrophies, progressive bulbar palsy, and primary lateral sclerosis.

Table 1. Differential diagnosis of ALS/MND (see Belsh and Schiffman: Amyotrophic Lateral Sclerosis; diagnosis and management for the clinician; Futura Publishing Company, Inc. 1996)

Lower motor neuron signs

Compressive radiculopathy (cervical, lumbosacral)

Plexus dysfunction (neurogenic thoracic outlet syndrome, cervical rib, brachial plexus neuropathy, diabetic amyotrophy)

Polyneuropathy (sensorimotor (CIDP), pure motor (MMN))

Mononeuropathy (entrapment, mononeuritis multiplex)

Neuromuscular junction defect (myasthenic syndromes)

Myopathy (polymysitis, inclusion body myositis, myotonic dystrophy, distal myopathies)

Kennedy’s disease

Primary hyperparathyroidism

Postpolio syndrome

Benign fasciculations

Postradiation motor neuron syndrome

Upper motor neuron signs

Multiple Sclerosis

HTLV-1 myelopathy

Hereditary spastic paraparesis

cerebro-tendinous xanthomatosis

adrenomyeloneuropathy

hypovitaminosis

galactocerebrosidase deficiency (Krabbe’s disease)

Stroke

Toxic spastic paraparesis (lathyrism, konzo)

Combination of upper and lower motor neuron signs

Cervical spondylosis

Spinal dural fistula

Spinal cord tumor/foramen magnum tumor

Thyrotoxicosis

Syringomyelia

HIV infection/AIDS

Spirochetal infections (Lyme, syphilis)

Multisystem degeneration

Hexosaminidase deficiency (predominantly in Ashkenazi Jews; mostly with cerebellar and cognitive deficits)

Adult polyglucosan body disease

Organophosphate toxic neuropathy/ lead and mercury toxicity

Motor Neuron Disease with paraproteinemia/ Hodgkin’s and non-Hodgkin’s lymphoma


Ancillary investigations

For the diagnosis of ALS, abnormalities of both lower and upper motor neurons (LMN and UMN) are required combined with the progressive spread of symptoms and signs within a body region or to other regions (Revised El Escorial criteria, see http://www.wfnals.org/oldsite/Articles/elescorial1998criteria.htm). Their presence can be established in the consulting room. In clinically unaffected muscles, electromyography can help to uncover denervation activity as a sign of subclinical involvement of lower motor neurons. For the clinical (revised) El Escorial criteria for ALS the human body is subdivided into four regions: head, arms, thorax and trunk and legs (table 2).

Table 2. The revised El Escorial criteria

Clinically Definite ALS

Is defined by evidence on clinical grounds alone of the presence of UMN as well as LMN signs in the bulbar region and at least two spinal regions or the presence of UMN signs in two spinal regions and LMN signs in three spinal regions.

Clinically Probable ALS

Is defined by evidence on clinical grounds alone of UMN and LMN signs in at least two regions with some UMN signs rostral (above) to the LMN signs.

Definite Familial ALS - Laboratory- supported

Is defined on clinical grounds, supported by electrophysiologic evidence in the presence of a defined pathogenic mutation when progressive UMN and/or LMN signs occur in a single anatomical region in the absence of another cause for the abnormal neurological signs.

Probable ALS - Laboratory-supported

Is defined on clinical grounds when the UMN and LMN signs are in only one region or UMN signs alone are present in one region and LMN signs defined by EMG criteria are present in at least two limbs; with proper application of neuroimaging and clinical laboratory protocols to exclude other causes.

Possible ALS

ALS cannot not be proven by evidence on clinical grounds alone or in conjunction with electrodiagnostic neurophysiologic, neuroimaging or clinical laboratory findings. In Possible ALS, UMN and LMN signs are found in only one region, UMN signs are found alone in two or more regions, or LMN signs are found rostral to UMN signs. Other diagnoses must have been excluded.

Suspected ALS

Pure LMN involvement: this category is deleted from the revised El Escorial Criteria for the Diagnosis of ALS (see progressive spinal muscular atrophy).

Definite and probable cases should not cause much diagnostic difficulty because they require upper motor neuron signs rostral of lower motor neuron signs, thereby excluding myelopathy, which is characterised by the reverse. Problems may arise when abnormalities are only regional, or when the signs are exclusively upper or lower motor neuron. Ancillary tests, such as nerve-conduction studies and neuro-imaging, are then usually indispensable.

Considering the differential diagnosis of ALS, ancillary laboratory tests should include: serum creatine kinase (unusual above ten times upper limit of normal), ALT, AST, Calcium, Phosphate, Paraproteines, TSH, CBC, and ESR. Hypochloremia and increased bicarbonate are related to advanced respiratory compromise.


Genetics

Both sporadic and familial forms of the disease exist, with familial ALS (FALS) accounting for 5-10% of cases. Familial ALS shows a mostly autosomal dominant pattern of inheritance. In 20% of familial cases, a mutation in the SOD1 gene is present. Testing for such a mutation is possible in Amsterdam (AMC) or Rotterdam (EMC).

A few additional loci have been found, however the genes involved have not yet been determined (table 3). Genetic testing, therefore, is not yet available for SOD1 negative familial cases.

Table 3. Loci/genes identified in familial ALS/MND

Disease Inheritance Locus Gene
ALS (ALS1) AD/AR 21q22.211 SOD1
ALS (ALS3) AD   18q2135  
ALS (ALS6) AD 16q1236  
ALS (ALS7) AD 20ptel37,38  
Juvenile ALS (ALS5) AR 15q15-2239  
Juvenile ALS (ALS2) AR 2q3340  ALS2
Juvenile ALS (ALS4) AD 9q3441  
ALS with FTD AD 9q21-2242  
ALS with D/P  AD 17q21.1143 Tau
Kennedy disease XR Xq11-Xq1244 Androgen receptor

Therapy
Current treatment is riluzole 50 mg bid.

References
Rosen D, Siddique T, Patterson D. Mutations in Cu/Zn superoxide dismutase gene are associated with familial amyotrophic lateral sclerosis. Nature 1993; 362:59-62. Read more