Excerpt from Olivopontocerebellar Atrophy

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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)

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. This classification then evolved in the classification of SCAs. According to Paulson and Ammache from 2001, it includes all well-understood types of dominant OPCA and many other dominant ataxias. 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)

In addition, 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. 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. These inclusions are also different from the alpha-synucelinopathic 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. For the genetic OPCAs, the primary molecular lesion is related to the gene that defines the genetics, rather than alpha-synuclein.

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 cause 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. The cerebellum is small with loss of Purkinje cells, but the dentate nuclei are well preserved. The middle cerebellar peduncles also are 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 frequently are 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).

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