Olivopontocerebellar atrophy (OPCA) was first described in 1900 by Dejerine and Thomas. OPCA is a group of dominant inheritance and sporadic neurological disorders characterized by a chronic, progressive, cerebellar ataxia that begins in middle age. The cerebellum and its connections are the primary sites of the disease in chronic progressive disorders that often occur in familial or hereditary patterns. Postmortem studies indicate an atrophy of the cerebellum, pons, and inferior olives. This neuropathological neuronal cell loss permits classification of OPCA as a non-Alzheimer’s neurodegenerative illness.

Gross postmortem inspection of the brains of patients with OPCA shows marked shrinkage of the ventral half of the pons, and disappearance of the olivary eminence on the ventral surface of the medulla. These brains also exhibit an atrophy of the cerebellum with degeneration of the middle cerebellar peduncles, and to a lesser extent, of the inferior peduncles. Thus, the cerebellum suffers mainly through atrophy of its afferent fibers. The neocerebellum and the olive undergo the primary degeneration. The purkinje cells of the cerebellar cortex are affected secondarily.

Histological examination shows severe degeneration of Purkinje cells, reduction in the number of cells in the molecular and granular layers of the cerebellar cortex, severe loss of the number of cells in the pontine nuclei and olives, and demyelination of the middle cerebellar peduncle. The cerebellar nuclei are well preserved. The tegmentum of the pons, the corticospinal tracts, and the restiform body are also usually unaffected. In clinical cases involving extrapyramidal symptoms, degenerative changes in the striatum, especially the putamen, and a loss of pigmented cells in the substantia nigra may be seen. Tubular structures and crystalline inclusions may be found with the electron microscopy. More wide spread degeneration of the central nervous system has been reported in dominant autosomal cases, and may involve the spinocerebellar fibers and the posterior columns.

The patient who presents with OPCA will most often be an adult or of late middle life up to the age of 60. The age of onset may be significantly earlier in familial cases, as distinct from sporadic cases. The clinical syndrome is characterized by classical cerebellar symptomology. OPCA presents with a chronic, slowly progressive ataxia that usually begins in the legs, and later also involves the trunk and upper limbs. The patient will exhibit impairment of equilibrium, illustrated by a positive Rhomberg sign, and walk with the typical cerebellar gait characterized by a wide stance and stiff-legged movements.

Disorders of speech and swallowing are present in the clinical picture of OPCA. Dysphasia often develops in tandem with dysarthria. Dysarthria occurs owing to ataxia of the muscles of the larynx. Articulation is jerky and the syllables are often separate and slurred. Dysarthria and dysphasia are both present from the early stages of the disease, although the signs are usually ignored until there is an obvious problem with chewing and swallowing and articulation becomes affected. The dysphasia is of major medical concern; a common cause of death in OPCA is aspiration bronchopneumonia.

Patients may also present with involvement of the muscles of the face and eyes. Nystagmoid jerks are often present, and can be considered simply, an ataxia of the ocular muscles. Other occulomotor involvement’s may also be present. The facial features will often be marked by facial palsies, and immobile faces. These symptoms again interfere with the processes of swallowing. Control of a liquid depends upon intact functioning of motor and sensory capacities of the lips, tongue, and buccal musculature. In OPCA, the function/coordination/sensory feedback is affected in the oral cavity and pharyngeal musculature. This dysfunction leads again to an increase in vulnerability to aspiration pneumonia, and problems in receiving adequate hydration. Tube feedings may be indicated in patients in the late stages of the disease.

OPCA patients may be characterized by a musculature hypotonia. The muscles lose resilience to palpation and there is diminished resistance to passive movements of the joints. Shaking the limbs produces excessive movements at the terminal joints and is attributable to a loss of cerebellar influence on the simple stretch reflex. In some cases, spasticity, exaggerated reflexes, and extensor planter responses rather than hypotonia occur. Impairment of sphincter function commonly occurs with urinary and fecal incontinence.

Parkinsonian symptoms may develop and OPCA patients may exhibit tremors. Oscillatory tremors of the head and trunk may be present. Intention tremors will occur when fine movements are attempted. A decomposition of movements is also seen as muscle groups fail to work harmoniously without the cerebellar control. These extrapyramidal symptoms will be seen as improperly coordinated movements, such as past--pointing.

The reflexes usually remain normal and voluntary power is well preserved. Occasionally, knee and ankle reflexes may be lost and extensor responses may occur. In these cases, the movement produced by tendon reflexes tends to continue for a longer period of time than normal. Normally, the reflex movement is self-limited by the stretch reflexes of the agonist and antagonist muscles. In OPCA, the influence on the stretch reflexes is lost and the movement continues as a series of flexion and extension movements.

Dementia is not rare in OPCA patients, but is normally mild. OPCA patients do not normally exhibit the severe global dementia of the Alzheimer type. Examinations of Alzheimer’s patients has consistently shown reduced levels of choline acetyltransferase activity (ChAT). The brains of patients with OPCA were measured for this enzyme. Examination of the OPCA brains also showed a ChAT deficit in the cerebral cortex and is attributed to a degeneration of cholinergic neurons projecting from the nucleus basalis of Mynert. This nucleus provides the cerebral cortex with most of its cholinergic innervation. The magnitude of the deficit was similar in Alzheimer's and OPCA patients. A less severe deficit of ChAT was seen in the hippocampus of OPCA patients (42%) as compared to Alzheimer’s patients (60 to 90%). This observation implies that the cholinergic neurons in the basalis-septum area innervating the hippocampus are less severely damaged. This may explain the absence of severe dementia in OPCA patients and illustrate that a marled cerebral cortical cholinergic depletion, as assessed by reduced ChAT levels, is itself insufficient to produce a severe dementia. It must be noted, however, that intellectual deterioration may be an unrecognized feature of OPCA patients who have, because of the nervous system dysfunction, lost much of their ability to communicate verbally and by coordinated limb movements.

It has been proposed that the cause of neurodegeneration in OPCA may involve an excitatory amino acid mechanism. Reductions in amino acid levels has been observed in patients of dominant autosomal OPCA. The reductions in glutamate and aspartate are not uniformly present throughout the brain. This provides evidence against the idea of a generalized disorder of excitatory amino acid metabolism in OPCA patients.

The biochemical changes do provide support for regionally selective disturbances as the magnitude of the change is greater than can be explained by neuronal loss. The loss of inferior olivary climbing fibers which utilize aspartate as a neurotransmitter explains part of the reductions in aspartate concentrations in the cerebellar cortex. The magnitude lost (70%), however, is greater than that seen in animal models after destroying the entire inferior olive Similarly, the reduction in glutamate (43%) can be partially explained by the loss of granule cell neurons utilizing glutamate as a neurotransmitter. However, the loss of granule cells in OPCA patients is mild. gamma-aminobutyric acid (GABA) levels are also reduced in several extra-cerebellar brain areas. The amino acid reductions could be explained by a failure of one of the enzymes involved in metabolism. For instance, alpha-ketoglutarate debydrogenase is involved in aspartate and glutamate metabolism. Reduced enzyme activity and depletion of the stores could explain the lowered brain levels

The neuronal cell death observed in brains of OPCA patients may be the result of an altered membrane phospholipid metabolism. The levels of glycerophosphoethanolamine (GPEA), a phosphodiester, have been shown to be significantly increased (37 to 69%) in OPCA brain regions except the hippocampus. Elevation throughout the brain areas suggests a generalized brain abnormality. Increased levels of this phosphodiester could be explained by above normal activity of the phosphatidylethanolamine catabolizing enzymes phospholipase A2 and/or lysophospholipase, or decreased activity of a GPEA specific phosphodiesterase. Alterations in membrane phospholipid metabolism could alter membrane composition and fluidity and lead to neuronal death. It cannot currently be determined, however, if these changes precede the neuronal cell death or are a result of the cell death.

Diagnosis depends upon differentiation of OPCA from other cerebellar ataxia’s. Criteria for diagnosis include the relatively late onset, absence of spinal cord disease, family history, symptoms presented, and the progressive nature of the disease. Current interventions are limited to treating the symptomology. Patients may be taught direct strategies to improve swallowing and prevent aspiration pneumonia, and may receive physical therapy to aid in coordination of movements. Most individuals with OPCA maintain normal mental capacity until near death

Bibliography:

Campbell-Taylor, I. Dysphasia in Familial Olivopontocerebellar Atrophy: Effects of Intervention on Patients and caregivers.

Kish, Stephen J. et. al.: Brain Choline Acetyltransferase Reduction in Dominantly Inherited Olivopontocerebellar Atrophy. Annals of Neurology: 22 (2), 272-275, 1987.

Kish, Stephen J. et. al. Non-Alzheimer-Type Pattern of Brain Cholineacetyltransferase Reduction in Dominantly Inherited Olivopontocerebellar Atrophy. Annals of Neurology: 26 (3), 362-367, 1989.

Kish, Stephen J. et. al.: Glycerophosphoethanolamine Concentration is Elevated in Brain of Patients with Dominantly Inherited Olivopontocerebellar Atrophy. Neuroscience Letters (submitted publication).

Kish, Stephen J. et al : Brain Amino Acid Abnormalities in Dominantly Inherited Olivopontocerebellar Atrophy. Revised manuscript in preparation for resubmission to J. Neurochemistry.

Kish, Stephen J. et. al. Cognitive Deficits in Olivopontocerebellar Atrophy: Implications for the Cholinergic Hypothesis of Alzheimer’s Dementia. Annals of Neurology: 24 (2), 200-206, 1988.

Rowland, Lewis P. (ed.): Merritt's Textbook of Neurology, eighth edition. Lea and Febiger. Philadelphia, 1959, pp. 630--631.

Snell, Richard S: Clinical Neuroanatomy for Medical Students. Little, Brown, and Company, Boston, 1957, pp. 220--222.