Professional Documents
Culture Documents
Disorders
Benjamin Rix Brooks, Robert G Miller, Michael Swash & Theodore L Munsat
To cite this article: Benjamin Rix Brooks, Robert G Miller, Michael Swash & Theodore L
Munsat (2000) El Escorial revisited: Revised criteria for the diagnosis of amyotrophic lateral
sclerosis, Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders, 1:5, 293-299, DOI:
10.1080/146608200300079536
1
Conference Organizer for WFN Research
Committee on Motor Neuron Diseases
2
Chairman, WFN ALS Clinical Trials Consortium
3
Chairman, WFN Research Committee on Motor
Neuron Diseases
4
Chairman, WFN Research Committees
Airlie House “Current Issues in ALS Therapeutic
Trials’“ Workshop Contributors
Warrenton, Virginia April 2 – 4, 1998
Correspondence:
Benjamin Rix Brooks, MD
ALS Clinical Research Center
University of Wisconsin Hospital and Clinics
Clinical Science Center H6–563
Madison, Wl 53792–5132, USA
Tel.: (608) 263–9057
Fax: (608) 263–0412
Email: Brooks@neurology.wisc.edu
in four regions (brainstem, cervical, thoracic, or lum- 1. Sporadic ALS – ALS occurring alone or present inciden-
bosacral spinal cord) of the central nervous system (CNS). tally with other preexisting disease processes
Ancillary tests should be reasonably applied, as clinically 2. Genetically-determined (familial, hereditary) ALS –
indicated, to exclude other disease processes. These should ALS, present in one or more generations, associated
include electrodiagnostic, neurophysiological, neuroimag- with different modes of inheritance and dened patho-
ing and clinical laboratory studies . genic mutations such as superoxide dismutase-1
(SOD1) mutations or hexoseaminidase A/B deciency.
ALS may occur as a genetically determined disease. In
Clinical evidence of LMN and UMN degeneration
some cases, the pathogenic mutation has been deter-
is required for the diagnosis of ALS
mined, e.g. mutations of the SOD1 gene. When there is
The clinical diagnosis of ALS, without pathological conr- a family history of such a dened pathogenic mutation,
mation, may be categorized into various levels of certainty the diagnosis may be upgraded to Clinically De nite
by clinical assessment alone, depending on the presence of Familial ALS – Laboratory-supported: ALS presenting
UMN and LMN signs together in the same topographical with progressive upper and/or lower motor neuron
anatomic region in either the brainstem (bulbar cranial signs in at least a single region (in the absence of
motor neurons), or the cervical, thoracic, or lumbosacral another cause for the abnormal neurological signs).
spinal cord (anterior horn motor neurons). The terms However, in genetically determined cases where the
Clinically De nite ALS and Clinically Probable ALS are gene has not been identied (even if linkage is estab-
used to describe these categories of clinical diagnostic cer- lished), the criteria for the diagnosis of sporadic ALS
tainty on clinical criteria alone: apply.
Clinically De nite ALS is dened on clinical evidence 3. ALS-Plus Syndromes – ALS present in association with
alone by the presence of UMN, as well as LMN signs, in clinical features of other neurological diseases which
the bulbar region and at least two spinal regions or the develop in addition to the phenotype of ALS which
presence of UMN and LMN signs in three spinal regions. develop in parallel with the ALS, e.g. extra-pyramidal
Clinically Probable ALS is dened on clinical evidence features or dementia. (Appendix 1)
alone by UMN and LMN signs in at least two regions with 4. ALS with Laboratory Abnormalities of Uncertain Sig-
some UMN signs necessarily rostral to (above) the LMN ni cance – ALS present in association with laboratory-
signs. dened abnormalities that are of uncertain signicance
The terms Clinically Probable ALS – Laboratory-sup- to the pathogenesis of ALS. (Appendix 2)
ported and Clinically Possible ALS are used to describe 5. ALS-Mimic Syndromes – These syndromes occur as a
these categories of clinical certainty on clinical and criteria consequence of other, non-ALS pathogenic processes,
or only clinical criteria: and do not represent other forms of ALS. ALS-Mimic
Clinically Probable ALS – Laboratory-supported is Syndromes include the post-poliomyelitis syndrome,
dened when clinical signs of UMN and LMN dysfunction multifocal motor neuropathy with or without conduc-
are in only one region, or when UMN signs alone are tion block; endocrinopathies, especially hyperparathy-
present in one region, and LMN signs dened by EMG cri- roid or hyperthyroid states; lead intoxication;
teria are present in at least two regions, with proper appli- infections; and paraneoplastic syndromes.
cation of neuroimaging and clinical laboratory protocols
to exclude other causes.
Clinically Possible ALS is dened when clinical signs of Electrophysiological studies in the
UMN and LMN dysfunction are found together in only
one region or UMN signs are found alone in two or more
diagnosis of ALS
regions; or LMN signs are found rostral to UMN signs and Patients in whom the diagnosis of ALS is considered on
the diagnosis of Clinically Probable ALS – Laboratory- clinical grounds should have electrophysiological studies
supported cannot be proven by evidence on clinical performed to:
grounds in conjunction with electrodiagnostic, neurophys-
iologic, neuroimaging or clinical laboratory studies. Other conrm LMN dysfunction in clinically affected
diagnoses must have been excluded to accept a diagnosis regions,
of Clinically Possible ALS. detect electrophysiological evidence of LMN dysfunc-
Clinically Suspected ALS may be suspected in many set- tion in clinically uninvolved regions and
tings, where the diagnosis of ALS could not be regarded as exclude other pathophysiological processes.
sufciently certain to include the patient in a research These electrophysiological studies should be performed by
study. Hence, this category is deleted from the revised El qualied physicians according to established standards. It
Escorial Criteria for the Diagnosis of ALS. is essential to interpret the electrophysiological results in
conjunction with the clinical and other ancillary ndings.
Clinical types and patterns of ALS (Appendix 3)
Upper motor clonic jaw jerk, clonic DTRs, loss of supercial clonic DTRs,
neuron signs gag reex, Hoffmann abdominal reexes, extensor
pathologic spread of exaggerated reex, pathologic DTRs, plantar
reexes, clonus, etc. snout reex, pathologic DTRs, spastic tone response,
pseudobulbar spastic tone, pathologic DTRs,
features, preserved reex in spastic tone,
forced yawning, weak wasted limb preserved reex in
pathologic DTRs, weak, wasted limb
spastic tone
Table 1
Lower motor neuron and upper motor neuron signs in four CNS regions
Neuroimaging studies in the diagnosis dromes, or ALS with Laboratory Abnormalities of Uncer-
of ALS tain Signicance. (Appendix 5)
Glossary
De nite specic clinical and exclusionary criteria met; no other diagnosis possible on basis of clinical distribution or
laboratory ndings
Dementia progressive deterioration of specic cognitive functions
Extrapyramidal clinical features localizable to basal ganglia and/or midline cerebellum
Hyperre exia spread of deep tendon reex outside stimulated territory
Minor subjective and objective complaints conrmed by examination (utilization of instrumental sensory testing may
increase the detection of sensory abnormalities)
Onset time of rst subjective symptom noticed by patient which later is conrmed by examination
Possible specic clinical and exclusionary criteria met
Probable specic clinical and exclusionary criteria met
Radicular distribution conforming to particular nerve root
Region brainstem, cervical, thoracic or lumbosacral spinal cord levels (regional involvement is dened by either right or left
sided signs)
Required necessary or sufcient
Segment single brainstem or spinal cord level
Spread involvement of new anatomic segments or regions in the central nervous system
Support neither necessary nor sufcient, but may suggest
Systemic non-central nervous system
Weakness decreased isometric strength
Worsening increased weakness of muscles in previously affected segment
7. Full interference pattern in a clinically weak muscle. There is no clinical laboratory nding which, if present
8. Signicant abnormalities in autonomic function or with the proper clinical and electrophysiological signs of
electronystagmography. ALS and appropriate neuroimaging studies, rules out the
diagnosis of ALS.
Features that rule out the diagnosis of ALS or suggest the pres- Aggregates of neurolaments in perikarya of the motor
ence of additional disease: neurons (hyaline conglomerate inclusions)
1. Plaques of multiple sclerosis. Axonal spheroids with accumulation of masses of
2. A focal cause of myelopathy. neurolaments, Wallerian-like degeneration in the
anterior roots.
Features that are compatible with, and do not exclude, the dia-
Light microscopic studies gnosis:
Features required for the diagnosis: Variable involvement of Clarke’s nucleus and the spino-
1. Some degree of loss of both of the following neuronal cerebellar tracts; posterior root ganglia, the posterior
systems: large motor neurons of the anterior horns of columns of the spinal cord and peripheral sensory nerves;
the spinal cord and motor nuclei of the brainstem (V the brainstem reticular neurons and the anterolateral
motor, VII motor, IX and X somatic motor, and XII); columns of the spinal cord; the thalamus; subthalamic
and large pyramidal neurons of the motor cortex nucleus; and the substantia nigra.
and/or large myelinated axons of the corticospinal
Features that rule out the diagnosis or suggest the presence of
tracts.
additional disease:
2. The following cellular pathological changes in the
Major pathological involvement of other parts of the
involved neuronal regions described above: neuronal
nervous system, including: cerebral cortex other than the
atrophy with relative increase in lipofuscin and loss of
motor cortex; basal ganglia; substantia nigra; cerebellum;
Nissl substance. There should be evidence of different
cranial nerves II and VIII; dorsal root ganglia.
stages of the process of neuronal degeneration, includ-
ing the presence of normal-appearing neurons, even
The following cellular pathological changes in the
in the same region.
involved neuronal systems described above:
3. Evidence of degeneration of the corticospinal tracts at
the same level. Extensive central chromatolysis;
Extensive active neuronophagia;
Features that strongly support the diagnosis:
Neurobrillary tangles;
1. Lack of pathological change in the motor neurons of
The presence of abnormal storage material;
cranial nerves III, IV and VI, the intermediolateral
The presence of signicant spongiform change;
column of the spinal cord, and Onuf’s nucleus.
The presence of perivascular inammatory cell inltra-
2. The occurrence of one or more of the following cellu-
tion.
lar pathological changes in the involved neuronal
systems described above:
Electron microscopic studies
Ubiquinated intracytoplasmic inclusions in the motor Features required for the diagnosis:
neurons (skeins, Lewy body-like structures) Ultrastructural studies are not required for the diagnosis of
Bunina bodies ALS.