Pathological Studies in the Living Patient with Sporadic ALS
Indications for biopsies
Biopsies of the skeletal muscle, peripheral nerve and other tissues are not required for the diagnosis of amyotrophic lateral sclerosis, unless the clinical, electrophysiological or laboratory studies have revealed changes that are atypical for ALS (e.g. inclusion body myositis). In addition, the muscle biopsy may be used to demonstrate LMN involvement in a body region that had not been shown to be involved by other techniques.
Muscle biopsy
Features required for the diagnosis:
- Evidence of chronic denervation/reinnervation in an affected muscle.
Features that are compatible with, and do not exclude the diagnosis:
- Scattered hypertrophied muscle fibers.
- No more than a moderate number of target or targetoid fibers.
- Fiber type grouping of no more than mild-to-moderate extent.
- The presence of a small number of necrotic muscle fibers.
Features that rule out the diagnosis or suggest the presence of additional disease:
- Significant monoclonal gammopathy, infiltration with lymphocytes and other mononuclear
inflammatory cells,
- Significant arteritis,
- Significant numbers of muscle fibers involved with the following structural changes: necrosis; rimmed vacuoles; nemaline bodies; central cores; accumulation of mitochondria (ragged red fibers),
- Large fiber type grouping
- Giant axonal swellings from accumulation of masses of neurofilaments, but not of PAS
positive bodies, in intramuscular nerves.
Pathological studies at autopsy
other than in patients surviving for prolonged periods on life support systems
Gross pathological changes
Features required for the diagnosis:
- There are no positive diagnostic features on gross pathological examination.
Features that rule out the diagnosis of ALS or suggest the presence of additional disease:
- Plaques of multiple sclerosis.
- A focal cause of myelopathy.
Light microscopic studies
Features required for the diagnosis:
- Some degree of loss of both of the following neuronal systems. Large motor neurons of the anterior horns of the spinal cord and motor nuclei of the brainstem (V motor, VII motor, IX and X somatic motor, and XII); and large pyramidal neurons of the motor cortex and/or large myelinated axons of the corticospinal tracts.
- The following cellular pathological changes in the involved neuronal regions described above: neuronal atrophy with relative increase in lipofuscin and loss of Nissl substance. There should be evidence of different stages of the process of neuronal degeneration, including the presence of normal- appearing neurons, even in the same region.
- Evidence of degeneration of the corticospinal tracts at the same level.
Features that strongly support the diagnosis:
- Lack of pathological change in the motor neurons of cranial nerves III, IV and VI, the
intermediolateral column of the spinal cord, and Onuf's nucleus.
- The occurrence of one or more of the following cellular pathological changes in the involved neuronal systems described above:
- Ubiquinated intracytoplasmic inclusions in upper and lower motor neurons (skeins, "Lewy body-like structures");
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- Aggregates of neurofilaments in perikarya of the motor neurons (hyaline conglomerate inclusions);
- Axonal spheroids with accumulation of masses of neurofilaments, Wallerian degeneration in the anterior roots.
Features that are compatible with, and do not exclude, the diagnosis:
- Variable involvement of Clarke's nucleus and the spinocerebellar tracts; posterior root
ganglia, the posterior columns of the spinal cord and peripheral sensory nerves; the
brainstem reticular neurons and the anterolateral columns of the spinal cord; the
thalamus; subthalamic nucleus; and the substantia nigra.
Features that rule out the diagnosis or suggest the presence of additional disease:
- Major pathological involvement of other parts of the nervous system, including: cerebral cortex other than the motor cortex; basal ganglia; substantia nigra; cerebellum; cranial nerves II and VIII; dorsal root ganglia.
- The following cellular pathological changes in the involved neuronal systems described above:
- Extensive central chromatolysis;
- Extensive active neuronophagia;
- Neurofibrillary tangles;
- The presence of abnormal storage material;
- The presence of significant spongiform change;
- The presence of perivascular inflammatory cell infiltration.
Electron Microscopic studies
Ultrastructural studies are not required for the diagnosis of ALS.
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