Olivopontocerebellar Atrophy

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.[2, 3] Thirty years later, Pierre Marie described another grouping of hereditary cerebellar ataxias.[4] 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.[5] 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.[6] 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.[7] This was revised by Harding in 1982, based on anatomical, pathological, and biochemical features.[8] 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.[9] 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.[10] 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.[11] 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, known as cerebellar subtype (MSA-C). 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 with spasticity and pyramidal weakness, and dementia also eventually occur.[12]

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.[13] 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.[14] 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.[15]

The OPCAs are progressive neurodegenerative conditions. Genetic and pathological evidence suggest that abnormalities of alpha-synuclein (αSYN) are important in the pathogenesis of these disorders. Many specific genes have been identified for the genetic forms, although how the genetic abnormalities lead to the specific αSYN abnormalities or to the specific clinical findings remains uncertain. Recently developed models using transgenic mice possessing the genes for human αSYN suggest that MSA involves dysfunction of the ubiquitin-proteasome system causing proteolytic stress that disrupts the oligodendroglial/myelintrophic support. Oligodendroglia in such models, as well as in pathological specimens of the human disease, have cytoplasmic inclusions of fibrillar αSYN.[16] There is also evidence for involvement of the ubiquitin-binding protein p62/sequestosome-1 in some cases of OPCA.[17]

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

The prevalence of olivopontocerebellar atrophy (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-, sex-, and age-related demographics

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.

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.

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).

Currently, no effective therapy is available for the neurodegenerative processes that constitute OPCA. Clinically, only supportive care can be given to patients with this progressive disease.

Dysphagia and dysarthria (and occasionally anarthria) are common manifestations of olivopontocerebellar atrophy (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.[18]

Generally, cerebellar signs and extrapyramidal signs are the predominant signs of olivopontocerebellar atrophy (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.

A unifying etiology of olivopontocerebellar atrophy (OPCA) has not been established.[19] 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 (Open Table in a new window)

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 (Open Table in a new window)

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 (Open Table in a new window)

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 (Open Table in a new window)

Falls are the primary complications in the early stages of olivopontocerebellar atrophy (OPCA).

Aspiration pneumonia is more common in later stages of OPCA.

Anti-Purkinje cell antibodies

Paraneoplastic cerebellar degeneration is an important entity in the differential diagnosis of olivopontocerebellar atrophy (OPCA). Ovarian cancer is one of the malignancies associated with this syndrome, and the paraneoplastic syndrome may manifest in the early and curable stage of cancer. Anti-Purkinje cell antibodies are the diagnostic marker for this entity, and an assay for these antibodies is commercially available. If the patient is a female who has not had oophorectomy and if the degenerative disorder is sporadic rather than clearly familial, additional screening for ovarian cancer is appropriate. Small cell cancer of the lung is also associated with this syndrome.

Vitamin E level

Although isolated vitamin E deficiency is exceedingly rare, the serum vitamin E level should be measured as part of the diagnostic workup.

MRI is the imaging study of choice in patients with olivopontocerebellar atrophy (OPCA) because CT scanning does not provide adequate resolution of the pons and cerebellum. MRI typically shows (1) pancerebellar and brainstem atrophy, with flattening of the pons; (2) an enlarged fourth ventricle and cerebellopontine angle; and (3) demyelination of the transverse pontine fibers. This demyelination of the transverse pontine fibers is responsible for the "hot cross bun" sign in a T2 weighted scan, which is thought to be highly specific for multiple system atrophy. Putaminal hyposignal intensity with hypersignal intensity rim in a T2 weighted scan represents putaminal atrophy also suggestive of a diagnosis of multiple system atrophy.[117, 118]

 

In the first year after the onset of cerebellar symptoms in patients with OPCA, MRIs may be normal; therefore, serial MRI examinations are necessary for detecting infratentorial atrophy.

Brain MRI is also useful in patients presenting with spinocerebellar syndromes to exclude the diagnoses of multiple sclerosis, cerebrovascular disease, and malignancy.

MRI also permits visualization of pontine atrophy, which distinguishes OPCA from other forms of genetic ataxias, and presentations of multiple system atrophy that do not yet heavily involve the pons. MRI findings in old patients with some late-onset genetic ataxias, such as spinocerebellar ataxia type 36 (SCA-36), may show similar pattern of OPCA.[119]

MR SPECT has been used in case reports and shows a decreased NAA/Cr ratio consistent with atrophy. The clinical use of this is not yet defined.[120]

Positron emission tomography (PET) scanning shows reduced metabolism in the brain stem and cerebellum. While this finding is of academic interest, PET scanning is not necessary for the diagnostic workup of a patient with OPCA, and the results do not distinguish subtypes of OPCA.

Table 3 in Causes lists whether genetic tests are available for the particular SCA. At present, commercial tests are available for SCA-1 (OPCA-I and OPCA-IV), SCA-2 (OPCA-2), SCA-3 (Machado-Joseph disease, not an OPCA), SCA-7 (OPCA-III), SCA-8 (an ADCA-1 but not an OPCA), SCA-10 (an ADCA-3, not an OPCA), SCA-12 (not an OPCA), SCA-14 (not an OPCA), SCA-17 (may be OPCA-V), and DRPLA (not an OPCA). In addition, a research test may be available for some others, such as episodic ataxia type 1, which is a dominant ataxia that is not an OPCA. Table 3 also provides the relevant chromosome and literature reference to the gene involved.

Sleep studies reveal lack of rapid eye movement and stage IV sleep in patients with OPCA. Apneic periods have also been observed.

Nerve conduction studies reveal a sensory neuropathy greater than motor neuropathy.

Evoked potentials may be delayed, especially visual evoked potentials.

EEG may show diffuse slowing and background disorganization.

None of the studies mentioned is necessary for the diagnostic workup of every patient with a progressive spinocerebellar syndrome.

Histologic findings vary among the subtypes of OPCA. The cerebellum shows predominant Purkinje cell loss. Sometimes, Purkinje cells are completely obliterated. Purkinje cell axon torpedoes are variably present. The molecular and granular layers are usually thin. The cerebellar white matter is depleted. The pons exhibits loss of transverse pontine fibers and pontine nuclei. Fibrous gliosis exists in the spaces created by the loss of fibers. Preolivary medullary fibers are reduced, and the arcuate nuclei may be so atrophic that they cannot be found. Some patients demonstrate olivary hypertrophy.

Degeneration of the dorsal columns and neuronal loss in the Clarke columns are present. In addition, dorsal root ganglia and anterior horn cells may be reduced.

Argyrophilic oligodendroglial cytoplasmic inclusions, which under light microscopy may resemble neurofibrillary tangles, are present in sporadic forms of OPCA. These typically contain alpha-synuclein.

Care of olivopontocerebellar atrophy (OPCA) is directed to the treatment of symptoms.

• Dopaminergic agents, such as levodopa, bromocriptine, or amantadine, have shown minimal benefit.

• Propranolol has been used for tremor, but the clinical response is generally minimal.

• Related to the fact that serotonin 5-hydroxytryptophan (5HT) 1-A receptor agonists modulate the serotonergic motor output from the cerebellum, a few small studies have focused on 5HT 1-A receptor agonists, such as tandospirone or buspirone, as a treatment for ataxia. Several such studies have indicated that such medications may produce modest improvement in ataxia caused by various neurodegenerative conditions, including OPCA.[121, 122]

• Another small trial concluded that buspirone is ineffective.[123]

• It had also been hypothesized that estrogen might potentiate the 5-HT1A effect because it is neuroprotective of the nigrostriatal system in some animal models.[124, 125, 126] It also appears to have a beneficial effect on the dopamine transporter.[127] Therefore, investigators undertook a trial of 18 patients to study the effect of combined estrogen and buspirone therapy for OPCA. Both groups showed significant improvements in finger-to-nose and rapid alternating movements at 1 month; however, at 12 months (which was the end of the study), there was no statistically significant improvement in any test of cerebellar function. Indeed, there was no evidence that the benefits lasted longer than 3 months. There were trends toward improvement in dysarthria, heel-to-shin testing, and gait speed. No benefit was seen by adding estrogen.[128]

• A small, brief randomized, double-blind pilot study of patients with cerebellar ataxia of different etiologies assessed the responses of 20 patients given riluzole versus 20 patients given a placebo. Assessment at 4 and 8 weeks showed Class I evidence that riluzole reduced the International Cooperative Ataxia Rating Scale (ICARS) score by at least 5 points.[129] The authors stated their belief that riluzole should now be tested in larger and longer studies. Also needed are studies that use more homogenous patient groups.

• Supportive care with gait-assisting devices is especially important to minimize falls.

At times, olivopontocerebellar atrophy (OPCA) patients may require enteral feeding to decrease the risk of aspiration.

Percutaneous endoscopic gastrostomy and jejunostomy tube (J-tube) placement may be necessary.

Consultations with physical and occupational therapists are helpful to increase mobility of patients with olivopontocerebellar atrophy (OPCA); the use of assistive devices can significantly increase functional ability. A case study using progressively more challenging static and dynamic balance tasks over a 12-week period produced significant improvement in balance in a patient with proven OPCA.[130] A swallowing evaluation can be a very important part of the early consultation.

Now that genetic testing is available, it can be performed to confirm the diagnosis of autosomal dominant OPCAs. These patients may not develop symptoms until after the onset of their reproductive years; therefore, family members must be evaluated early if a diagnosis of autosomal dominant OPCA is made. Referral for genetic counseling is advisable in these individuals. Not all patients wish to learn of their risks in the absence of an available treatment, while some individuals may use the information for family planning and other types of planning for the future.

As dysphagia progresses with olivopontocerebellar atrophy (OPCA), a pureed diet or enteral feeding may be required.

Activity in patients with olivopontocerebellar atrophy (OPCA) should be allowed ad libitum; however, appropriate measures should be used to minimize falls.

As previously stated, to date, medical therapy has provided only minimal benefits for olivopontocerebellar atrophy (OPCA). No medications are actually approved by the FDA for use in this condition. The medications mentioned here may be helpful in certain patients. Physicians should not prescribe these for OPCA unless they are familiar with the contraindications, interactions, precautions, and other potential problems and unless they discuss these with their patients. Brief summaries are listed, but more detail is provided in the package insert and in the literature.

Class Summary

Used to improve parkinsonian and tremor-related symptoms.

Levodopa/carbidopa (Sinemet)

Direct dopaminergic agent. Carbidopa prevents peripheral decarboxylation of levodopa, thus facilitating entry into CNS. Comes in different strengths of 25/100 mg, 25/250 mg, and 10/100 mg.

Amantadine (Symmetrel)

Unknown mechanism of action; may release dopamine from remaining dopaminergic terminals in Parkinson patients or from other central sites. Less effective than levodopa in treating Parkinson disease; slightly more effective than anticholinergic agents.

Class Summary

For OPCA, propranolol is used to help reduce the tremor. As with all medication, this pharmacologic therapy should be individualized based on a patient's age, race, known pathophysiologic variables, and concurrent conditions. The usual use of propranolol is to lower blood pressure and help ameliorate left ventricular hypertrophy. It can precipitate congestive heart failure, cause or worsen hyperlipidemia, worsen or precipitate asthma/COPD attacks, and mask hypoglycemia in diabetes. See the package insert for other precautions, interactions, and contraindications.

Propranolol (Inderal, Betachron E-R)

Nonselective beta-adrenergic agonist; mechanism of action for tremor suppression not fully known.

Class Summary

A modest improvement in ataxia has been observed in a few small clinical trials. One study showed no benefits. Another study showed benefits that were not sustained beyond 3 months.

Bupropion (Wellbutrin, Zyban)

Bupropion inhibits neuronal dopamine reuptake in addition to being a weak blocker of serotonin and norepinephrine reuptake.