Degenerative ataxia

MSA is likely the most common disorder, certainly in adults (Bhidayasiri and Ling, 2008; Gilman et al., 2008; Wenning et al., 2008). In addition to ataxia, patients have parkinsonism and autonomic dysfunction (including impotence). The disorder has also been called olivopontocerebellar atrophy when the emphasis is on ataxia, striatonigral degeneration when the emphasis is on bradykinesia and rigidity, and Shy–Drager syndrome when the emphasis is on autonomic dysfunction. Early falls are a prominent feature. Variable clinical features include pyramidal signs, tremor, dysarthria, dystonia, and mild dementia. There is typically a poor response to levodopa, but clearly at times there is some response, and this can be confusing. Responses are never dramatic and typically unsustained. The pathologic hallmark of the disorder, in addition to neuronal cell loss, is the glial cytoplasmic inclusion (GCI) (Yoshida, 2007). MSA is described in detail in Chapter 9.

Laboratory findings of value are particularly autonomic abnormalities. Studies include the skin sympathetic response, the Valsalva maneuver, and heart rate variation. Rectal sphincter electromyography (EMG) shows denervation, but this test must be done with caution. Women who have been through childbirth may have denervation secondary to their delivery. The specificity of this finding has been called into question. Magnetic resonance imaging (MRI) can show cerebellar and pontine atrophy. The hot-cross bun sign in the pons is due to degeneration of corticocerebellar fibers. Magnetic resonance spectroscopy (MRS) can show decreased N-acetyl aspartate signal in the cerebellum, and positron emission tomography (PET) can show decreased cerebellar metabolism.

Another degenerative cause is progressive myoclonic epilepsy since ataxia is typically a part of this syndrome. Often myoclonus and ataxia become difficult to separate. These syndromes are described in Chapter 20.

Strokes

There are a variety of strokes that produce ataxia. These can be due to lesions of the cerebellum or the cerebellar pathways.

Ataxic hemiparesis is characterized by both weakness and incoordination. Lesions can be in the thalamus and posterior limb of the internal capsule, upper basis pontis and cerebral peduncle, parietal lobe, and (debated) anterior internal capsule and frontal lobe.

Hemisensory loss and hemiataxia is typically due to a thalamic lesion.

Isolated gait ataxia can be seen with a lesion of the pontomedullary junction.

Ataxia (hemiataxia and/or gait ataxia) with variable cranial nerve involvement can be seen with involvement of several arteries. The superior cerebellar artery affects the upper pontine tegmentum; the anterior inferior cerebellar artery leads to damage of the lateral pontomedullary junction; and the posterior inferior cerebellar artery gives rise to the well-known lateral medullary syndrome.

Tumors

The tumors commonly affecting the cerebellum are listed in Table 21.2.

Table 21.2 Tumors producing ataxia

Toxic/metabolic

Toxic damage to the cerebellum can be caused by alcohol, both acute and chronic. The acute effects of alcohol appear to cause a true ataxia as measured by physiologic studies. In the chronic state, there can be irreversible cerebellar damage, particularly to the cerebellar vermis, leading to particular difficulties with stance and gait. There is also a characteristic prominent anterior-posterior sway when standing.

Hypoxia damages the cerebellum with a particular propensity for the Purkinje cells. These patients may also get myoclonus. Hyperthermia is another cause for Purkinje cell loss.

The childhood hyperammonemias are a cause of intermittent ataxia.

Celiac disease or sprue is an interesting cause of ataxia and possibly myoclonus as well (Hadjivassiliou et al., 1998). Celiac disease itself is a gluten-sensitive enteropathy with malabsorption. The gastrointestinal disorder can be reversed with a gluten-free diet, but the cerebellar degeneration does not necessarily get better. Curiously, it is now clear that up to 40% of patients with sporadic ataxia have antigliadin antibodies, but no sign of celiac disease (Pellecchia et al., 1999; Burk et al., 2001; Bushara et al., 2001; Hadjivassiliou et al., 2003, 2008c; Lin et al., 2010). This has been disputed, but the power of that study may have been too low (Abele et al., 2003). Antigliadin antibodies have also been seen in a similar percentage of patients with genetic ataxias (Bushara et al., 2001). This has also been disputed (Hadjivassiliou et al., 2003), but the percent abnormal may depend on the numbers of the specific SCA types. It is not clear what this means. In some of these patients, there are abnormalities of the white matter and prominent headache; at least these patients have some symptomatic response to a gluten-free diet (Hadjivassiliou et al., 2001). Antibodies to gangliosides were found in 64% of patients with mixed ataxias, suggesting that the increase in antigliadin antibodies may not be specific (Shill et al., 2003). In gluten-associated ataxia, there can also be antibodies directed to tissue transglutaminase, either type 2 (Hadjivassiliou et al., 2006) or, likely more specifically, type 6 (Hadjivassiliou et al., 2008a). Antigliadin antibodies in patients with ataxia bind to the neural antigen synapsin I (Alaedini et al., 2007). There may well be an increase in autoimmunity in sporadic cerebellar ataxia (Hadjivassiliou et al., 2008b).

There is open-label evidence that a gluten-free diet may benefit patients with antigliadin antibodies (Hadjivassiliou et al., 2008c). Intravenous immunoglobulin (IVIg) has improved the ataxia in three patients with overt celiac disease and ataxia (Souayah et al., 2008). IVIg therapy has appeared to help two patients, as well as two other patients with anti-GAD antibodies (see below for this entity), suggesting a role for immunotherapy (Nanri et al., 2009).

Vitamin deficiencies can cause cerebellar dysfunction including thiamine (vitamin B1), vitamin B12, and vitamin E. Zinc deficiency may also be a culprit.

In the endocrine area, hypothyroidism, hypoparathyroidism, and hypoglycemia (insulinoma) have been associated with ataxia.

Toxic drugs include thallium, bismuth subsalicylate, methyl mercury, methyl bromide, and toluene. Drugs include phenytoin, carbamazepine, barbiturates, lithium, cyclosporine, methotrexate, and 5-fluorouracil. Ataxia can be a component of the serotonin syndrome, from SSRIs (selective serotonin reuptake inhibitors).

Paraneoplastic

The paraneoplastic causes are very important to keep in mind (Anderson et al., 1988; Bolla and Palmer, 1997). The clinical syndrome is often a rapidly progressive one over a relatively short period of time and then a plateau without further change. What appears to be happening is a rapid destruction of Purkinje cells. Even if the cancer is found and successfully treated, the disorder may not improve because the cells are irreversibly damaged. Nevertheless, the best treatment is certainly treatment of the cancer.

In many cases, there will be detectable antibodies in the serum. These antibodies are markers of the cancer and are not specific for cerebellar syndromes. Some cases of paraneoplastic ataxia have no defined associated antibody.

There are three types of anti-Purkinje cell antibodies. Anti-Yo (PCA-1) is seen with tumors of breast, ovary, and adnexa. Atypical anticytoplasmic antibody (anti-Tr or PCA-Tr) is seen with Hodgkin disease, and tumors of the lung and colon. PCA-2 has been identified mostly with lung tumors; 3 of 10 patients had ataxia (Vernino and Lennon, 2000).

There are three antineuronal antibodies. Anti-Hu (ANNA-1) can be seen in possible conjunction with encephalomyelitis (Lucchinetti et al., 1998). It is associated with small-cell lung tumor, tumors of breast and prostate, and neuroblastoma. Anti-Ri (ANNA-2) is found with tumors of breast and ovary. Atypical anti-Hu is seen with tumors of the lung and colon, adenocarcinoma, and lymphoma.

Anti-CV2 (CRMP) antibody is associated with a syndrome of ataxia and optic neuritis (de la Sayette et al., 1998). It has been seen with small-cell lung carcinoma. The CV2 antigen is expressed by oligodendrocytes. Interestingly, this is one syndrome where improvement has been seen with removal of the tumor.

Antibodies directed to a serum protein, Ma1, have been found in patients with testicular and other tumors (Dalmau et al., 1999; Gultekin et al., 2000). The antibodies are anti-Ma and anti-Ta (Ta is Ma2). These patients may also have limbic encephalitis. Ma1 is a phosphoprotein highly limited to brain and testis.

Antibodies directed to amphiphysin are rarely associated with a cerebellar syndrome (Saiz et al., 1999). This is a marker for small-cell lung carcinoma. Antibodies to Zic4 are associated with cerebellar degeneration and small-cell lung cancer (Sabater et al., 2008).

Antibodies against a glutamate receptor can be seen with cancer, and this causes a pure cerebellar syndrome (Sillevis Smitt et al., 2000). Patients with Hodgkin disease can develop paraneoplastic cerebellar ataxia because of the generation of autoantibodies against mGluR1, and this is mediated both by functional and degenerative effects (Coesmans et al., 2003).

Other new antibodies are being identified (Jarius et al., 2010). Tests that are currently commercially available include Hu, Ma, Ta, Yo, Ri, amphiphysin, Zic4 and CV2.

In a series of 50 patients with paraneoplastic cerebellar degeneration out of 137 with any neurologic syndrome, 19 had anti-Yo, 16 anti-Hu, 7 anti-Tr, 6 anti-Ri, and 2 anti-mGluR1 (Shams’ili et al., 2003). While 100% of patients with anti-Yo, anti-Tr, and anti-mGluR1 antibodies had ataxia, 86% of anti-Ri and only 18% of anti-Hu patients had paraneoplastic cerebellar degeneration. In 42 patients (84%), a tumor was detected; the most common were gynecological and breast cancer (anti-Yo and anti-Ri), lung cancer (anti-Hu), and Hodgkin lymphoma (anti-Tr and anti-mGluR1). All patients received antitumor therapy and 7 had some neurologic improvement. The functional outcome was best in the anti-Ri patients, with 3 out of 6 improving neurologically; 5 were able to walk at the time of last follow-up or death. Survival was worse with anti-Yo and anti-Hu compared with anti-Tr and anti-Ri.

Autoimmune

Ataxia can be associated with anti-GAD antibodies (Saiz et al., 1997; Abele et al., 1999; Honnorat et al., 2001). There can be a pure ataxia syndrome and one with an associated peripheral neuropathy. In one series of 14 patients, 13 were women and 11 had late-onset diabetes (Honnorat et al., 2001). Anti-GAD antibodies are better known for association with stiff-person syndrome, but the relationship is not clear. In one case with antibodies in the cerebrospinal fluid, the antibody blocked GABAergic transmission in the rat cerebellum (Mitoma et al., 2000). As with stiff-person syndrome, patients can exhibit other forms of autoimmunity. IVIg therapy may be useful (Nanri et al., 2009).

Infectious/postinfectious

Infectious causes include rubella and Haemophilus influenzae. Acute postinfectious cerebellitis is generally a childhood condition, most common after varicella. Creutzfeldt–Jakob disease may have an ataxic form.

Demyelinating

Ataxia is common in multiple sclerosis. A patient with leukoencephalopathy with neuroaxonal spheroids (LENAS), a rare disease of cerebral and cerebellar white matter, had a 14-year course of progressive neurologic decline consistent with a clinical diagnosis of probable MSA, with prominent cerebellar dysfunction and dysautonomia (Moro-De-Casillas et al., 2004).

Other

Other syndromes include Chiari malformation, abscess, hydrocephalus, and superficial central nervous system hemosiderosis.

Ataxia of non-cerebellar origin

What looks like cerebellar ataxia can come from dysfunction outside the cerebellum. Most common causes include neuropathies such as the Miller Fisher form of Guillain–Barré syndrome (Lo, 2007) and spinocerebellar tract lesions.

Dominant ataxia

The dominant ataxias were divided into three clinical syndromes by Anita Harding, the autosomal dominant cerebellar ataxias, ADCA I, II, and III. ADCA I is a cerebellar syndrome plus other neurologic degenerations such as pyramidal, extrapyramidal, ophthalmoplegia, and dementia. ADCA II is a cerebellar syndrome with a pigmentary maculopathy. ADCA III is largely a pure cerebellar syndrome, with possible mild pyramidal signs. Subsequently, the genes were identified for these disorders, and they have been called the spinocerebellar ataxias, the SCAs. This terminology is much more common now in clinical use. The identified SCAs are growing rapidly and clearly there are more to be determined.

Table 21.3 gives the identified SCAs and their known genetic disorder. Many of them are due to expanded trinucleotide repeats. SCA3 is identical to Machado–Joseph disease and is often referred to as SCA3/MJD. DRPLA is often included in such lists. It shares the mutation disorder of CAG expansion and may have prominent ataxia as part of its manifestation. Some details about the proteins are known and these are listed in Table 21.4.

Table 21.4 The proteins that are affected in the SCAs

Commercial tests are available for SCA1, 2, 3, 5, 6, 7, 8, 10, 12, 13, 14, 17, and DRPLA (and this list is likely to expand).

Generally, the cerebellar syndrome is similar in the different disorders. Patients experience gradual onset of balance and gait difficulty, dysarthria and clumsiness of the hands. There may be visual symptoms such as blurry vision or diplopia. Age of onset is highly variable. Sometimes clinical features can help differentiate the different disorders. SCA12, for example, may be somewhat unique in that it may present with an action tremor that may look like essential tremor (O’Hearn et al., 2001). Other manifestations may help predict the genotype, but virtually any constellation of signs and symptoms can occur with any phenotype. Some guidelines are noted below.

Lining up the ADCAs and the SCAs gives a start (Table 21.5). Subramony has suggested some phenotypic clues (Subramony et al., 1999), and these are updated in Table 21.6.

Table 21.5 Relationship between ADCAs and SCAs

Table 21.6 Clues to the SCAs

DRPLA is most common in the Japanese. It is also known as the Haw River syndrome from an African-American family in North Carolina. In addition to ataxia, there may be myoclonus, epilepsy, chorea, athetosis, dystonia, dementia, psychiatric disorders, and parkinsonism.

The pathophysiology of the triplet repeat ataxias has been extensively studied (Koeppen, 2005; Paulson, 2007; Soong and Paulson, 2007; Zoghbi and Orr, 2009). It appears that the mutated protein is toxic to the cell. For example, in a mouse model of SCA1, the gene was made conditional; when the gene was turned off, the animals improved (Zu et al., 2004). Similarly, treatment of a mouse model of SCA1 with RNA interference (RNAi) can improve the disorder. Recombinant adeno-associated virus vectors expressing short hairpin RNAs were injected into the cerebellum with marked benefit (Xia et al., 2004).

There is no treatment for the SCAs. Lithium improved neurologic function and hippocampal dendritic arborization in a mouse model of SCA1 (Watase et al., 2007). Mode of action of lithium in this circumstance is not clear. Human studies have been initiated.

Then there are the autosomal dominant episodic ataxias (Table 21.7) (Evidente et al., 2000; Kullmann et al., 2001; Jen, 2008