Revised Criteria for the Diagnosis of Amyotrophic Lateral Sclerosis

On this page:

• Requirements for Diagnosis
• Clinical Studies in the Diagnosis of ALS
• Clinical Types and Patterns of ALS
• Electrophysiological Studies
• Neuroimaging Studies
• Clinical Laboratory Studies
• Neuropathological Studies
• References

REQUIREMENTS FOR THE DIAGNOSIS OF ALS

The diagnosis of Amyotrophic Lateral Sclerosis [ALS] requires:

A - the presence of:

(A:1) evidence of lower motor neuron (LMN) degeneration

by clinical, electrophysiological or neuropathologic examination,

 

(A:2) evidence of upper motor neuron (UMN) degeneration

by clinical examination, and

 

(A:3) progressive spread of symptoms or signs within a region or to other regions,

as determined by history or examination,

 

together with

B - the absence of:

(B:1) electrophysiological and pathological evidence of other disease

processes that might explain the signs of LMN and/or UMN degeneration, and

 

(B:2) neuroimaging evidence of other disease processes that might explain the

observed clinical and electrophysiological signs.

 

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CLINICAL STUDIES IN THE DIAGNOSIS OF ALS

A careful history, physical and neurological examination must search for clinical evidence of UMN and LMN signs in four regions [brainstem, cervical, thoracic, or lumbosacral spinal cord] (see Table 1) of the central nervous system [CNS]. Ancillary tests should be reasonably applied, as clinically indicated, to exclude other disease processes. These should include electrodiagnostic, neurophysiological, neuroimaging and clinical laboratory studies.

Clinical evidence of LMN and UMN degeneration is required for the diagnosis of ALS.

The clinical diagnosis of ALS, without pathological confirmation, may be categorized into various levels of certainty by clinical assessment alone depending on the presence of UMN and LMN signs together in the same topographical anatomic region in either the brainstem [bulbar cranial motor neurons], cervical, thoracic, or lumbosacral spinal cord [anterior horn motor neurons]. The terms Clinical Definite ALS and Clinically Probable ALS are used to describe these categories of clinical diagnostic certainty on clinical criteria alone:

Clinically Definite ALS is defined on clinical evidence alone by the presence of UMN, as well as LMN signs, in three regions.

 

Clinically Probable ALS is defined on clinical evidence alone by UMN and LMN signs in at least two regions with some UMN signs necessarily rostral to (above) the LMN signs. The terms Clinically Probable ALS - Laboratory-supported and Clinically Possible ALS are used to describe these categories of clinical certainty on clinical and criteria or only clinical criteria:

 

Clinically Probable - Laboratory-upported ALS is defined when clinical signs of UMN and LMN dysfunction are in only one region, or when 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.

 

Clinically Possible ALS is defined when clinical signs of UMN and LMN dysfunction are found together in only one region or UMN signs are found alone in two or more regions; or LMN signs are found rostral to UMN signs and the diagnosis of Clinically Probable - Laboratory-supported ALS cannot be proven by evidence on clinical grounds in conjunction with electrodiagnostic, neurophysiologic, neuroimaging or clinical laboratory studies. Other diagnoses must have been excluded to accept a diagnosis of Clinically possible ALS.

 

Clinically Suspected ALS it is a pure LMN syndrome, wherein the diagnosis of ALS could not be regarded as sufficiently certain to include the patient in a research study. Hence, this category is deleted from the revised El Escorial Criteria for the Diagnosis of ALS.

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Clinical Types and Patterns of ALS

There are a number of ALS and ALS-like syndromes that must be recognized.

1. Sporadic ALS - ALS occurring alone or present incidentally with other preexisting disease processes.
2. Genetically-determined [Familial, Hereditary] ALS - ALS, present in one or more generations, associated with different modes of inheritance and defined pathogenic mutations such as superoxide dismutase-1 [SOD-1] mutations or hexoseaminidase A/B deficiency.
   
   ALS may occur as a genetically determined disease. In some cases, the pathogenic mutation has been determined, e.g., mutations of the SOD-1 gene. When there is a family history of such a defined pathogenic mutation, the diagnosis may be upgraded to
   Clinically Definite Familial - Laboratory-supported ALS - ALS presenting with progressive upper and/or lower motor neuron signs in at least a single region (in the absence of another cause for the abnormal neurological signs).
   
   However, in genetically determined cases where the gene has not been identified (even if linkage is established), the criteria for the diagnosis of sporadic ALS apply.
3. ALS Plus Syndromes (Appendix 1) - ALS present in association with clinical features of other neurological diseases which develop in addition to the phenotype of ALS which develop in parallel with the ALS, e.g., extra-pyramidal features or dementia.
4. ALS with Laboratory Abnormalities of Uncertain Significance (Appendix 2) - ALS present in association with laboratory-defined abnormalities that are of uncertain significance to the pathogenesis of ALS.
5. ALS-Mimic Syndromes - These syndromes occur as a consequence of other, non-ALS pathogenic processes, and do not represent other forms of ALS. ALS-Mimic Syndromes include the post-poliomyelitis syndrome, multifocal motor neuropathy with or without conduction block; endocrinopathies, especially hyperparathyroid or hyperthyroid states; lead intoxication; infections; and paraneoplastic syndromes.

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ELECTROPHYSIOLOGICAL STUDIES IN THE DIAGNOSIS OF ALS

Patients in whom the diagnosis of ALS is considered on clinical grounds should have electrophysiological studies performed to:

• confirm LMN dysfunction in clinically affected regions,
  
• detect electrophysiological evidence of LMN dysfunction in clinically uninvolved regions

and

• exclude other pathophysiological processes.

These electrophysiological studies should be performed by qualified physicians according to established standards. It is essential to interpret the electrophysiological results in conjunction with the clinical and other ancillary findings (Appendix 3).

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NEUROIMAGING STUDIES IN THE DIAGNOSIS OF ALS

Neuroimaging studies should be selected in order to exclude other conditions which may cause UMN and/or LMN signs that may simulate sporadic ALS (Appendix 4).

There are no neuroimaging tests which provide positive support for the diagnosis of ALS, although there are neuroimaging methods (e.g. NMR spectroscopy) that may in the future support the diagnosis of UMN involvement. Rarely, brain T2-weighted MRI may show increased signal in the corticospinal tracts.

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CLINICAL LABORATORY STUDIES IN THE DIAGNOSIS OF ALS

The diagnostic process employed to confirm the diagnosis of sporadic ALS, when the diagnosis is uncertain, includes repeated clinical examinations to document progression, repeated electrophysiological and/or neuroimaging examinations to exclude structural disorders and clinical should utilize laboratory examinations to exclude other disorders or support the diagnosis of ALS-Plus Syndromes, ALS-Mimic Syndromes, or ALS with Laboratory Abnormalities of Uncertain Significance. (See Appendix 5.)

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NEUROPATHOLOGICAL STUDIES IN THE DIAGNOSIS OF ALS

The diagnosis of sporadic ALS may be supported or excluded by muscle and/or biopsy studies in the living patient.

The diagnosis of sporadic ALS may be proven or excluded by autopsy examination. (See Appendix 6.)

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REFERENCES

• Subcommittee on Motor Neuron Diseases of World Federation of Neurology Research Group on Neuromuscular Diseases, El Escorial "Clinical Limits of ALS" Workshop Contributors (1994). El Escorial World Federation of Neurology criteria for the diagnosis of amyotrophic lateral sclerosis, Journal of the Neurological Sciences 124 : 96-107.

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