INTRODUCTION	Section 2 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

Background: Doctors who study olivopontocerebellar atrophy (OPCA) quickly learn that it is not a single entity. Its nosology is confusing. The OPCA classification system overlaps with those for the autosomal dominant spinocerebellar atrophies (SCAs) and the autosomal dominant cerebellar atrophies (ADCAs), which, in turn, overlap with each other. Nondominant hereditary cases, including recessive and X-linked types, are also described. Finally, sporadic cases of OPCA have been reported, at least some of which are a subset of multiple system atrophy (MSA). No wonder the subject is confusing.

Good reasoning, however, is behind the complexity. The study of the neurodegenerative ataxias, of which the OPCAs are a part, has continually drawn from the exciting interplay between clinical observations, neuropathological analysis, and, more recently, biochemistry and molecular genetics. Initially, clinical observation combined with pathology were the dominant methods of carving out disease entities from the welter of clinical observations. The first ataxia to emerge was not an OPCA, but Friedreich ataxia (Friedreich, 1863), which Nicolaus Friedreich (1825-1882) managed to separate from numerous other conditions, including especially multiple sclerosis (then called disseminated sclerosis) and neurosyphillis.

Thirty years later, Pierre Marie described another grouping of hereditary cerebellar ataxias (Marie, 1893). In essence, he proposed a classification to include all the non-Friedreich ataxia cases and suggested the name "heredoataxia cerebelleuse.” This included what is now termed the OPCAs and several other varieties. In some families, the ataxia was either totally or almost totally cerebellar. These would currently not be considered OPCA cases. Other families had different features, including brainstem and/or spinal cord involvement, peripheral neuropathies, or retinal problems. Some of these would be termed OPCAs based on later standards.

In 1907, Holmes described a family with a pure cerebellar form of ataxia and the term Holmes ataxia or ataxia of Holmes was born and stuck to this category for decades. Later (1922), Marie, Foix, and Alajouanine reported a similar family that probably had the same disease. Thus, both Holmes ataxia and the ataxia of Marie, Foix, and Alajouanine are pure cerebellar ataxias. Neither would be considered a type of OPCA. Sometimes, the term Marie ataxia is also used interchangeably with ataxia of Marie, Foix, and Alajouanine to designate a pure cerebellar ataxia. In other cases, Marie ataxia may refer to a member of the larger group from the 1893 paper, and, in this case, it may refer to an OPCA. As used in practice, the term has generally been ambiguous.

In 1900, Dejerine and Thomas identified cases that combined purely cerebellar problems with evidence of brainstem pathology. They coined the term OPCA. The name was accepted by the neurological community, and many cases were collected under this rubric. Gradually, researchers realized that both sporadic and hereditary (mostly autosomal dominant) cases comprised this group, and, broadly speaking, the neuropathology typically showed degeneration of the cerebellum with extensive cerebellar white matter degeneration. Major neuronal loss occurs in the inferior olivary nuclei and the pontine and arcuate nuclei. Actual Purkinje cell loss in the cerebellum is also common but is more variable. The white matter loss is probably due to dying back of axons from the degenerating neurons rather than a primary attack on myelinated tracts.

Menzel (1890) also had described a similar case. Through the years, both Dejerine-Thomas ataxia and Menzel ataxia have been used as terms for certain cases of either hereditary or sporadic OPCA.

Disputes in the clinic, on paper, and in conferences have occurred about the usage of these terms, such as fine distinctions between Menzel ataxia and ataxia of Dejerine-Thomas, but they are mainly now of historical interest only. OPCA type 1 (OPCA-I), to be described below, is synonymous with SCA type 1 (SCA-1) and is sometimes referred to as Menzel type ataxia. Dejerine-Thomas ataxia might be used for any of the 6 major phenotypic OPCAs, which are better defined below. However, the authors recommend against applying either of these terms to any new cases of ataxia. These terms are mentioned here only so that the reader may understand where they came from if they are encountered in other (hopefully much older) literature.

Over time, other genetic syndromes were also elucidated, such as ataxia-telangiectasia, originally described by Syllaba and Henner in 1926, who reported 3 adolescent siblings with progressive ataxia, choreoathetosis, and ocular telangiectasia. This syndrome was examined clinicopathologically by Boder and Sedgwick in 1957, who named it ataxia-telangiectasia. This is not an OPCA.

In 1954, Greenfield proposed a new clinicopathological classification, as follows:

• Type 1 - Predominantly spinal and includes Friedreich ataxia, abetalipoproteinemia, and hereditary spastic paraparesis

   

• Type 2 - Predominantly cerebellar and includes ataxia-telangiectasia, late-onset cerebellar atrophy (Holmes type), and Marinesco-Sjögren-Garland disease (Mendelian Inheritance in Man [MIM] #248800; cerebellar dysfunction, congenital cataracts, and mental retardation)

   

• Type 3 - Combined spinocerebellar plus other parts of the neuroaxis such as the brainstem; includes the OPCAs, hereditary spastic ataxia, Ramsay Hunt syndrome, and hereditary periodic ataxia

This classification embraced a mixture of genetic modes of transmission. The Greenfield categorization was elaborated in 1982 by Harding, who used a combination of anatomical, pathological, and biochemical approaches; at the time, it was considered very advanced and up-to-date. As applied to the purely dominant ataxias, this produced the ADCA classification, as follows:

• Type 1 ADCA (ADCA-1) - Ataxia and noncerebellar findings (eg, pyramidal or extrapyramidal dysfunction and ophthalmoplegia)

   

• Type 2 ADCA (ADCA-2) - Similar to ADCA-1 but includes retinal degeneration

   

• Type 3 ADCA (ADCA-3) - Includes relatively pure cerebellar dysfunction

In the ADCA grouping, the OPCAs are found in ADCA-1 and ADCA-2.

Harding was well aware that this was essentially a phenotypic grouping that lumped a number of different genetic diseases into 3 classes. However, the system was very valuable for further genetic and other scientific work, in which Harding herself has been a significant contributor.

Working on a somewhat separate but related track, in 1970, Konigsmark and Weiner attempted to bring some order to the heterogeneity found among the OPCAs. The proposed classification was based on clinical, genetic, and anatomic factors, as follows:

• OPCA-I (Menzel-type OPCA) - Autosomal dominant

   

• OPCA type 2 (OPCA-II or Fickler-Winkler type OPCA) - Autosomal dominant

   

• OPCA type 3 (OPCA-III or OPCA with retinal degeneration) - Autosomal recessive

   

• OPCA type 4 (OPCA-IV or Schut-Haymaker type OPCA) - Autosomal dominant

   

• OPCA type 5 (OPCA-V or OPCA with dementia and extrapyramidal signs - Likely autosomal dominant

   

• OPCA type X (OPCA-X) - X-linked OPCAs (added to classification at later date)

	CLINICAL	Section 3 of 10
Author Information Introduction Clinical Differentials Workup Treatment Medication Follow-up Miscellaneous Bibliography

History:

• Dysphagia and dysarthria (and occasionally anarthria) are common manifestations of OPCA.

• Respiratory stridor from vocal cord paralysis has been reported.

• Dementia can appear at any age; it is especially common later in the disease.

• Urinary incontinence occurs late in the course of the disease.

• Sleep disturbances are common in persons with OPCA.

Physical: Cerebellar signs and extrapyramidal signs are the predominant signs of OPCA. In addition, peripheral neuropathy is common. Ophthalmoplegia, retinopathy, and parkinsonism may be present.

• Usually, the initial sign in OPCA is a broad-based cerebellar ataxic gait. A parkinsonian gait is a less common but recognized variant.

• One of the other prominent features is dysarthria that is distinctly cerebellar in nature. The patient's speech has a poorly modulated and slurred quality, similar to that of a person intoxicated with alcohol. Other cerebellar findings include nystagmus, dysmetria on finger-to-nose testing, and ataxia on heel-to-shin testing.

• The pyramidal finding that is most uniformly present is a bilateral extensor plantar response. Hyperactive deep tendon reflexes and spasticity due to pyramidal tract dysfunction are often masked by a concomitant peripheral neuropathy.

• Nystagmus, slow saccades, and abnormal funduscopic examination findings are present in varying degrees.

• Hyperactive vestibuloocular reflex also has been reported.

• In some cases, limitation of extraocular movements, particularly of the upward gaze, also is present.

• Reflexes generally are hyperactive early in the course of the disease but are lost later, especially reflexes of the Achilles tendon.

• Position sense and vibratory function are reduced secondary to neuropathy.

• Cogwheel rigidity, bradykinesia, and, occasionally, tremor may be the dominant physical manifestations.

• The clinical manifestations of OPCA typically consist of a slowly progressive pancerebellar syndrome that usually begins in the lower extremities and then progresses to the upper extremities and the bulbar musculature. However, during the course of the disease, serial examinations may reveal noncerebellar signs.

• Parkinsonian symptoms with rigidity and akinesia may be the predominant picture in some cases of OPCA. In these cases, distinguishing OPCA from Parkinson disease may be difficult.

• The entire spectrum of cerebellar ocular motility disorders can occur in persons with OPCA. Retinal degeneration may be present. Nuclear or supranuclear ophthalmoplegia occurs more frequently in familial OPCA than sporadic OPCA.

• The clinical presentation may vary among the subtypes of OPCA. It includes the following:

• Abnormal movements are more frequent in familial OPCA. Abnormal movements may include myoclonus, spasmodic torticollis, chorea, and athetosis.

• Nonpyramidal signs, such as amyotrophy, fasciculations, peripheral neuropathy, lightning pains, and pes cavus, are more common in sporadic OPCA than familial OPCA.

• Autonomic failure is often seen, especially if sensitive methods of detection such as heart rate variability analysis are used. Severe autonomic impairment is more common in sporadic OPCA, which frequently evolves to a full-blown MSA.

• Postural hypotension may predominate among the clinical features.

Causes: A unifying etiology of OPCA has not been established. In the sporadic cases, abnormalities of alpha-synuclein (which is found as inclusion bodies in degenerating neurons) appear to play a significant role. In any of the inherited cases, specific genes have been identified, although in most cases the precise way in which the genes exert a pathological influence is not known. Many of the abnormal genes are of the expansion repeat variety. For example, in OPCA-I (or SCA-1), the SCA1 gene is on chromosome 6. It is a triple nucleotide repeat, with age of onset correlating with the length of repeat. The SCA2 gene is on chromosome 12.