Olivopontocerebellar Atrophy  (and Spinocerebellar Atrophy)

Author: Christina J Azevedo MD, Staff Physician, Department of Neurology, Dartmouth-Hitchcock Medical Center
Coauthor(s): Stephen A Berman, MD, PhD, Professor, Department of Internal Medicine, Section of Neurology, Dartmouth Medical School; Chief, Neurology Service, White River Junction Veterans Medical Center
Contributor Information and Disclosures

Updated: Feb 12, 2009

Background

Olivopontocerebellar atrophy (OPCA) is a neurodegenerative syndrome characterized by prominent cerebellar and extrapyramidal signs, dysarthria, and dysphagia. Those who study OPCA quickly learn that it is not a single entity, and that its nosology can be confusing. The umbrella term of OPCA includes common sporadic forms and uncommon genetic forms. In the genetic subgroup, all 3 major inheritance patterns (autosomal dominant, autosomal recessive, and X-linked) have been described. The classification scheme for autosomal dominant OPCA overlaps with that of autosomal dominant spinocerebellar atrophies (SCAs) and autosomal dominant cerebellar atrophies (ADCAs). In the sporadic type of OPCA, at least some of the cases are a subset of multiple system atrophy (MSA).

While the classification is seemingly convoluted, there is good reasoning behind the complexity. The study of neurodegenerative ataxias draws from the interplay between clinical observations, neuropathological analysis, and biochemistry and molecular genetics. Historically, however, one had to rely solely on the combination of clinical observation and neuropathology to describe the disorders. Because of this, the recognition of the OPCA as its own entity has evolved over time.

The first named ataxia to emerge as a clinical entity was not an OPCA, but Friedreich ataxia, which Nicolaus Friedreich (1825-1882) managed to separate from numerous other conditions, the most prominent being multiple sclerosis (then called disseminated sclerosis) and neurosyphilis.^{1, 2} Thirty years later, Pierre Marie described another grouping of hereditary cerebellar ataxias.³ Essentially, he proposed a classification to include all the non-Friedreich ataxia cases and suggested the name heredoataxia cerebelleuse. Some of these cases would now be termed OPCAs. 

In 1907, Holmes described a family with a purely cerebellar form of ataxia, and the terms Holmes ataxia and ataxia of Holmes stuck to this category for decades. In 1922, Marie, Foix, and Alajouanine reported a similar family that probably had the same disease.⁴ Thus, both Holmes ataxia and the ataxia of Marie, Foix, and Alajouanine (sometimes called Marie ataxia) are purely cerebellar ataxias. Neither would be considered a type of OPCA.

In 1900, Dejerine and Thomas identified cases that combined purely cerebellar problems with evidence of brainstem pathology.⁵ They coined the term olivopontocerebellar atrophy. The neurologic community accepted this name and collected many cases under this rubric. Gradually, researchers realized that both sporadic and hereditary (mostly autosomal dominant) cases comprised this group, and that, broadly speaking, these cases all had similar neuropathologic features that are described later in this article. Menzel (1890) also had described a similar case. Throughout 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) 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 case of ataxia. These terms are mentioned here only so the reader may understand where they came from if they are encountered in other literature.

In 1954, Greenfield proposed a new clinicopathological classification of OPCA.⁶ This was revised by Harding in 1982, based on anatomical, pathological, and biochemical features.⁷ As applied to the purely autosomal dominant ataxias, the classification is 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 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.⁸ 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)

These are detailed in Table 1 in Causes.

In 1974, Skre studied the hereditary ataxia diseases in western Norway and chose to consider all these disorders as members of a comprehensive group of diseases termed spinocerebellar ataxias.⁹ This classification then evolved in the classification of SCAs. According to Paulson and Ammache in 2001, SCAs include all well-understood types of dominant OPCA and many other dominant ataxias.¹⁰ Geneticists sometimes state that the OPCA classification has been replaced by the SCA classification. This does not mean that every currently defined SCA is also an OPCA. The SCAs that could typically be considered to be an OPCA are SCA types 1, 2, 3, 7, and possibly 17.

In addition to these major forms, which might be called the traditional or classic OPCAs, some extremely rare diseases also involve degeneration of the same, or very similar, anatomical regions. These are mainly infantile or childhood diseases. They are not what neurologists (even pediatric neurologists) usually call OPCAs. However, occasionally in the literature they are called infantile OPCAs and thus they are included in Table 2 in Causes.

Table 3 in Causes lists a large number of the known SCAs (no table of such diseases is ever totally up-to-date for long), and those that can be reasonably identified as OPCAs are noted.

Finally, the sporadic OPCAs are considered. According to current knowledge, sporadic cases can be classified into the 3 following categories, which may be modified later based on further research findings:

• Type 1 - A subtype; essentially the presentation of MSA
• Type 2 - Sporadic cases that are not part of an MSA, as presently understood
• Type 3 - De novo mutations that are actually genetic cases (but authorities do not realize they are genetic)

A separate but related question is whether the sporadic diseases are simply multigenetic, with the genetics being presently too complex to recognize as such.

A large percentage of the sporadic OPCAs are a subset of MSA. Some authorities have claimed that all sporadic OPCAs will progress to include significant autonomic and parkinsonian features and thus evolve into full-blown MSA if the patient lives long enough. According to this view, MSA typically starts as an ataxic OPCA form, an autonomic form (Shy-Drager syndrome), or a parkinsonian form (striatonigral degeneration). Motor neuron degeneration and dementia also eventually occur.

However, a large and careful study by Gilman et al published in 2000 showed that of the cases they selected for analysis, only 25% of the sporadic OPCAs converted to full-blown MSA within 5 years.¹¹ Nevertheless, all the sporadic OPCAs, Shy-Drager syndrome, striatonigral degeneration, and full-blown MSAs appear on the molecular level to be alpha-synucleinopathies; that is, they involve abnormalities of the protein alpha-synuclein. In addition, Jellinger reports in 2003 that the molecular pathology involves alpha-synuclein–positive glial (and less abundant neuronal) cytoplasmic inclusions in MSA and in all the purported subtypes.¹² These inclusions are also different from the alpha-synucleinopathic inclusions (eg, Lewey bodies), which are seen in other diseases.

The genetic OPCAs are all more pure in the sense that they do not evolve to an MSA picture. Many of the genetic forms are considered SCAs. Some genetic forms have additional characteristics such as retinal involvement, extrapyramidal degeneration, spinal cord degeneration, dystonia, dementia, and other neurological abnormalities dependent mainly on the genetic subtype but even showing variability within the same subtype. The genetic OPCAs are generally not alpha-synucleinopathies.

Clinical distinction of these entities is based on the dominant feature, which may be cerebellar ataxia (observed in OPCAs, SCAs, and MSA), parkinsonism (observed in MSA, striatonigral degeneration, and Shy-Drager syndrome), or autonomic failure (observed in MSA and Shy-Drager syndrome). Whatever the subtype, the term OPCA indicates a form of progressive ataxia distinguished by pontine flattening and cerebellar atrophy on brain imaging studies and at autopsy.

When faced with an adult having progressive ataxia suggestive of OPCA, the role of the clinician includes (1) excluding readily treatable alternative diagnoses, (2) discussing the value of genetic testing with patients in whom such testing is informative, (3) managing symptoms, and (4) advising the patient and family regarding the natural history and the need to plan for the future. No definitive therapy exists for OPCA.

Pathophysiology

The OPCAs are progressive neurodegenerative conditions. Sporadic forms involve abnormalities of alpha-synuclein, but that does not fully explain the abnormality that must involve many other yet unknown details. Many specific genes have been identified for the genetic forms, although how the genetic abnormalities lead to the clinical findings remains uncertain.

On the gross level, brains show some common characteristics in all cases of OPCA. The pons is diminutive, especially in the area of the basis pontis. Degeneration of the cerebellum occurs, especially in the white matter. This white matter loss is probably due to the dying back of axons from degenerating neurons rather than a primary attack on the myelinated tracts. Loss of Purkinje cells is common. Major neuronal loss occurs in the inferior olivary, arcuate, and pontine nuclei. Dentate nuclei are well preserved. The middle cerebellar peduncles are also atrophic, possibly secondary to degeneration of the basal pontine gray matter. The substantia nigra of the midbrain shows evidence of tissue loss. Cellularly, one sees neuronal degeneration in the arcuate, pontine, inferior olivary, pontobulbar nuclei, and the cerebellar cortex.

Additional areas of degeneration probably account for the difference in subtypes. In sporadic OPCA, oligodendroglial and neuronal intracytoplasmic and intranuclear inclusions characteristic of MSA are frequently seen. Many of these are accumulations of alpha-synuclein. In autosomal dominant OPCA, spinal cord lesions, especially in the posterior columns, spinocerebellar tracts, and anterior gray horn cells, are more common. The cerebellar features may be less prominent. However, so many variations of both the sporadic and genetic forms are described that one can find cases that appear to be exceptions to these generalizations.

Frequency

United States

The prevalence of OPCA is 3-5 cases per 100,000 individuals; this may represent approximately 5-6% of patients diagnosed with atypical Parkinson disease.

Mortality/Morbidity

The OPCAs are progressive neurodegenerative disorders that have no definitive treatment. Eventually, many patients become wheelchair bound. Severe dysarthria, anarthria, and dysphagia are not uncommon as the disease progresses.

• Morbidity increases significantly, including falls and aspiration pneumonia.
• Enteral feeding becomes necessary for many patients.
• Death commonly results from aspiration pneumonia.
• The duration of familial OPCA is approximately 15 years. The duration of sporadic OPCA is approximately 6 years.

Race

No apparent racial preference is observed in OPCA. This is unlike Machado-Joseph disease, which has a predominance in certain Azorean, Indian, and Italian families.

Sex

A male preponderance is observed in familial cases of OPCA, with a male-to-female ratio of 2:1. However, no such distinction is seen in sporadic cases.

Age

The mean age of onset of sporadic OPCA is 53 years. The mean age of onset of familial OPCA is 28 years (excluding the infantile forms in Table 2 in Causes).

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

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

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

Cerebellar dysarthria is also common. 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 entire spectrum of cerebellar ocular motility disorders can occur in persons with OPCA. Nystagmus, slow saccades, and abnormal fundoscopic examination findings are present in varying degrees. Hyperactive vestibulo-ocular reflex also has been reported. In some cases, limitation of extraocular movements, particularly of upward gaze, is also present. This nuclear or supranuclear ophthalmoplegia occurs more frequently in familial OPCA than in sporadic OPCA. Retinal degeneration may be present. 

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

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 present early in the course of the disease. These are often lost later, especially the ankle jerks, as part of a concomitant peripheral neuropathy.

Position sense and vibratory function are reduced secondary to neuropathy.

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.

To clarify the subtypes of the genetically determined OPCAs, the authors have placed them in tables. Table 1 below contains the most common types. Although the table is largely self-explanatory, a few points should be emphasized. The genetic OPCAs are now, at best, a subordinate category. Many neurogeneticists would say they are an obsolete category.

Where an OPCA represents a known mutation, it does do so because it is identified with a specific SCA (in the case of dominant mutations) or another specific genetically defined disease. For example, OPCA-IV was not previously genetically defined. However, OPCA-IV is now believed to be genetically the same as SCA-1. OPCA-I has also been found to be the same as SCA-1. Thus, no real distinction can now be made between OPCA-I, OPCA-IV, and SCA-1, except perhaps that in the historical cases of these syndromes, some differences existed in the phenotypic presentations of the same underlying disease.

Note also in the table that OPCA-2 and OPCA-II are not the same. This is unusual because for the other numbered OPCAs, the Arabic and Roman numbers can be used interchangeably. OPCA-2 is identical to SCA-2 and is autosomal dominant. OPCA-II, sometimes called Fickler-Winkler syndrome, is autosomal recessive and its gene is unknown. Separating the 2 types by using an Arabic 2 and a Roman II is not fully standard, and some books speak of the dominant versus recessive OPCA-2 (OPCA-II). Despite their similar names, the phenotypes are not very similar. In this text, Roman numerals are used for the OPCA types, with the exception of OPCA-X, which means X-linked OPCA, not OPCA type 10.

In the organization of the table, the first column contains the Online Mendelian Inheritance in Man number (OMIM#). The OMIM catalog was developed by Dr Victor McKusick and his colleagues at Johns Hopkins University, and the OMIM Web site is hosted by the US National Center for Biotechnology Information (NCBI) on what is essentially the same Web site as PubMed.

• In the table, both the OPCA specific names and other names for each condition are listed; also listed is the genetic pattern, including the mode of Inheritance, the locus (including the chromosomal region and the names of the gene and protein if available), and a concise description of the condition.Table 1. Most Common OPCAs With Alternative Names

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• In addition to what are considered the standard types of OPCA, some types are even rarer and more obscure. These are pediatric disease in which involvement of the cerebellum, pons, and the region of the inferior oliva is noted. They are not what most neurologists think of when they use the term OPCA. The only reason they are listed here is because the reader may encounter these and see them referred to as infantile OPCA or some variant thereof.Table 2. Extremely Rare Types of OPCAs

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• Although Table 1 gives the SCA equivalent for the OPCAs, many neurology residents have asked to see a table showing how the OPCAs fit into the larger SCA category. Table 3 gives that framework and the OPCAs are identified in the larger context.Table 3. Dominant SCAs with OPCAs Identified

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Finally, the question of how the OPCAs and SCAs fit with the 2 other systems of terminology is addressed: (1) the ADCAs and (2) the individual eponyms that honor the various physicians from the past who described the conditions that are now better (though still imperfectly) understood today.

Table 4 shows these correspondences. The first row consists of the SCAs because these represent the most accurate and finely divided category. The reader can then go down each column and find the ADCA number, the OPCAs, and the individual eponyms that are essentially equivalent.

In using this table, realize that all of these terms have been used inconsistently through the years. The SCAs are most closely linked to the actual genes involved. Although the ADCAs, with only 3 categories, represent a rather coarse division of these conditions, their phenotypic descriptions are rather simple and they have generally been used consistently in those cases in which they have been used. The use of the OPCA terms for diagnosis has been less consistent and it has been common to use the designation OPCA somewhat loosely. Finally, the eponyms have not been used very consistently, with the exception of Machado-Joseph disease (SCA-3) (which is not an OPCA). Thus, as one moves down the columns in the table, the names become less reliable.

The authors recommend against using the eponyms for fresh diagnoses. The ADCA and OPCA categories may be helpful for formulating ideas about the diagnosis, but one should try to think in terms of the SCA system in order to more readily connect the patient to a proper genetic diagnosis.

Table 4. Dominant Ataxia Nomenclature

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*SCA-13 is often said to not be part of ADCA classification. It is mainly a childhood mental retardation/ataxia syndrome. The ataxia is not accompanied by significant brainstem pathology, similar to ADCA-3. The mental retardation can be interpreted as a dementia, putting it in ADCA-1.
^† OPCA-IV (Schut-Haymaker OPCA) is now thought to be an SCA-1, which makes it OPCA-I (ie, strictly speaking, OPCA-IV no longer exists).
^‡ Menzel OPCA is sometimes taken much more broadly as virtually any OPCA except perhaps OPCA-III. Alternatively, it is taken as essentially the same as ADCA-1. In addition, it is sometimes applied to sporadic OPCAs that have similar presentations to any of the syndromes under ADCA-1.
^§ Sanger-Brown ataxia is sometimes taken more broadly. As expansively defined, the term could be used for virtually any of these.
^ll Holmes ataxia is sometimes applied to pure sporadic cerebellar ataxia of late onset.
^¶ This is sometimes used for most any of these syndromes, which seems to be the sense in which it was used in the original 1893 paper by Marie.
^# This is a very obscure term. It is most commonly used for conditions fitting ADCA-3.
**The authors found no papers calling SCA-3 Dejerine-Thomas ataxia, but Dejerine-Thomas ataxia is so broadly defined, the term could possibly be applied to SCA-3.

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