DEGENERATIVE DISEASES AFFECTING MOTOR NEURONS

These are a group of inherited or sporadic diseases that, in variable degrees of severity, affect:

• Lower motor neurons in the anterior horns of the spinal cord

• Lower motor neurons in certain cranial nerve motor nuclei (V, VII, IX, XII) but not those that control eye movements (III, IV, VI)

• Upper motor neurons (Betz cells) in the motor cortex

The disorders occur in all age groups, and the course of the illness is extremely variable, ranging from slowly progressive or nonprogressive to rapidly progressive and fatal in a period of

months or a few years. Denervation of muscles from loss of lower motor neurons and their axons results in muscular atrophy, weakness, and fasciculations; the corresponding histologic

changes in nerve and muscle are discussed in Chapter 27 . The clinical manifestations include paresis, hyperreflexia, spasticity, and extensor plantar responses (Babinski sign). Sensory

systems and cognitive functions are unaffected, but types with dementia do occur.

Amyotrophic Lateral Sclerosis (Motor Neuron Disease)

Amytrophic lateral sclerosis (ALS) is characterized by neuronal muscle atrophy (amyotrophy) and hyperreflexia due to loss of lower motor neurons in the anterior horns of the spinal

cord and upper motor neurons that project in corticospinal tracts, respectively.[223] The disease affects men slightly more frequently than women and becomes clinically manifest in the

fifth decade or later. Five per cent to 10% of cases are familial, mostly with autosomal-dominant inheritance.[224]

Pathogenesis.

The etiology and pathogenesis of amyotrophic lateral sclerosis are unknown. For a subset of the familial cases, the genetic locus has been mapped to the copper-zinc superoxide

dismutase gene (SOD1) on chromosome 21.[225] A wide variety of missense mutations have been identified that appear to generate an adverse gain-of-function phenotype. Among the

mutations, the A4V mutation is the most common (approaching 50% of cases), is associated with a rapid course, and rarely has upper motor neuron signs.[226] [227] A recessive locus on

chromosome 2 has been mapped to a gene encoding a protein termed alsin that has structural homology to proteins involved in GTPase regulation.[228] [229] Other genetic loci for ALS

have been mapped but not yet cloned. There is also evidence of roles of glutamate toxicity and protein nitration in the development of ALS pathology.[224] The basis for the selective

involvement of motor neurons remains uncertain.

Morphology.

On macroscopic examination, the anterior roots of the spinal cord are thin; the precentral gyrus may be atrophic in especially severe cases. Microscopic examination demonstrates a

reduction in the number of anterior horn neurons throughout the length of the spinal cord with associated reactive gliosis and loss of anterior root myelinated fibers. Similar findings are

found with involvement of the hypoglossal, ambiguus, and motor trigeminal cranial nerve nuclei. Remaining neurons often contain Bunina bodies: PAS-positive cytoplasmic inclusions

that appear to be remnant of autophagic vacuoles. Skeletal muscles innervated by the degenerated lower motor neurons show neurogenic atrophy. Destruction of the upper motor neurons

leads to degeneration of myelin in the corticospinal tracts, resulting in pale staining that is particularly evident at the lower segmental levels but traceable throughout the corticospinal

system with special studies ( Fig. 28-39 ).

Clinical Features.

Early symptoms include asymmetric weakness of the hands, manifested as dropping objects and difficulty in performing fine motor tasks, and cramping and

Figure 28-39Amyotrophic lateral sclerosis. Spinal cord showing loss of myelinated fibers (lack of stain) in corticospinal tracts. The anterior roots are smaller than the posterior roots.

Figure 28-40Metachromatic leukodystrophy. Demyelination is extensive. The subcortical fibers in the cerebral hemisphere are spared (Luxol fast blue PAS stain for myelin).

Figure 28-41Alcoholic cerebellar degeneration. The anterior portion of the vermis (upper portion of figure) is atrophic with widened spaces between the folia.

Figure 28-42Well-differentiated astrocytoma. A, The right frontal tumor has expanded gyri, which led to flattening (arrows). B, Expanded white matter of the left cerebral hemisphere

and thickened corpus callosum and fornices.

Figure 28-43 A, Computed tomographic (CT) scan of a large tumor in the cerebral hemisphere showing signal enhancement with contrast material and pronounced peritumoral edema.

B, Glioblastoma multiforme appearing as a necrotic, hemorrhagic, infiltrating mass.

Figure 28-44Glioblastoma. Foci of necrosis with pseudopalisading of malignant nuclei.

Figure 28-45Pilocytic astrocytoma in the cerebellum with a nodule of tumor in a cyst.

Figure 28-46Ependymoma. A, Tumor growing into the fourth ventricle, distorting, compressing, and infiltrating surrounding structures. B, Microscopic appearance of ependymoma.

Figure 28-47Medulloblastoma. A, CT scan showing a contrast-enhancing midline lesion in the posterior fossa. B, Sagittal section of brain showing medulloblastoma destroying the

superior midline cerebellum. C, Microscopic appearance of medulloblastoma.

Figure 28-48 A, Parasagittal multilobular meningioma attached to the dura with compression of underlying brain. B, Meningioma with a whorled pattern of cell growth and psammoma

bodies.

TABLE 28-4-- Paraneoplastic Syndromes

Date: 2016-04-22; view: 641