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Chapter 21 Ataxia

Pathophysiology and clinical syndromes

Ataxia is the type of clumsiness produced by dysfunction of the cerebellum or cerebellar pathways. The pathophysiology of the signs and symptoms has been detailed in the earlier chapter on motor control (Chapter 2). The core symptoms are difficulty with balance and gait, clumsiness of the hands, and dysarthria. The differential diagnosis is very long and includes all types of neurologic pathologic processes. While most patients presenting with ataxia will have a sporadic disorder, recently there has been increased attention on the genetic ataxias because of rapid advances in research.

Sporadic ataxia

Table 21.1 lists the principal categories. A series of 112 patients with sporadic ataxia with the following criteria were studied: (1) progressive ataxia; (2) onset after 20 years; (3) informative and negative family history (no similar disorders in first- and second-degree relatives; parents older than 50 years); and (4) no established symptomatic cause (Abele et al., 2002). Thirty-two patients (29%) met the clinical criteria of possible (7%) or probable (22%) multiple system atrophy (MSA). With genetic testing, Friedreich ataxia was found in five patients (4%), the spinocerebellar ataxia (SCA) 2 mutation in one (1%), the SCA3 mutation in two (2%) and the SCA6 mutation in seven (6%). The disease remained unexplained in 65 patients (58%). Antigliadin antibodies were present in 14 patients, 10 patients with unexplained ataxia (15%) and 4 patients with an established diagnosis (9%); this interesting aspect will be discussed further below.

Table 21.1 Categories of sporadic ataxia

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.


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).


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.


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).

Genetic ataxia

One of the most active areas in movement disorders and genetics is in determining the genes for numerous types of hereditary ataxias. Additionally, we are beginning to understand some of the mechanisms of neurodegeneration. On the other hand, specific therapies are still in the future. Many of the genes can be tested commercially. This is helpful, but it is important to remember that genetic testing can have significant consequences, both emotionally and socially – and not only for the individual tested, but also for the family. Hence, testing should be done with care and clear informed consent (Tan and Ashizawa, 2001).

Moseley et al. (1998) determined the incidence of spinocerebellar ataxia (SCA) types 1, 2, 3, 6, and 7 and Friedreich ataxia (FA) among a large panel of ataxia families in the United States. They collected DNA samples and clinical data from patients representing 361 families with adult-onset ataxia of unknown etiology. Patients with a clinical diagnosis of FA were specifically excluded. Among the 178 dominant kindreds, they found SCA1 expansion at a frequency of 5.6%, SCA2 expansion at a frequency of 15.2%, SCA3 expansion at a frequency of 20.8%, SCA6 expansion at a frequency of 15.2%, and SCA7 expansion at a frequency of 4.5%. Among patients with apparently recessive or negative family histories of ataxia, 6.8% and 4.4% tested positive for a CAG expansion at one of the dominant loci, and 11.4% and 5.2% of patients with apparently recessive or sporadic forms of ataxia had FA expansions. Among the FA patients, the repeat sizes for one or both FA alleles were relatively small, with sizes for the smaller allele ranging from 90 to 600 GAA repeats. The clinical presentation for these patients was atypical for FA including adult onset of disease, retained tendon reflexes, normal plantar response, and intact or partially intact sensation. The incidence of the SCAs has also been explored in other countries, such as Australia (Storey et al., 2000), Taiwan (Soong et al., 2001), and Thailand (Sura et al., 2009). The pattern does differ somewhat in different countries (Schols et al., 2004). The epidemiologic patterns are updated in the supplementary material in Wardle et al. (2009).

Looking specifically at patients with onset at age 18 or later (“late onset”), a study in the southeast Wales population showed the most frequent defined diagnoses to be SCA6, dentatorubral-pallidoluysian atrophy (DRPLA), and SCA8 (Wardle et al., 2009).

A very detailed compendium of the genetic ataxic disorders can be found at:

Here, the principal disorders will be reviewed. There are several good reviews (Di Donato, 1998; Subramony et al., 1999; Evidente et al., 2000; Klockgether, 2000; Stevanin et al., 2000; Devos et al., 2001; Di Donato et al., 2001; Schols et al., 2004; Klockgether, 2008; Manto and Marmolino, 2009; Durr, 2010).

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

Name Protein
SCA1 Ataxin-1
SCA2 Ataxin-2
SCA3 (Machado–Joseph disease) Ataxin-3
SCA4 (with sensory axonal neuropathy)  
SCA5 (Lincoln ataxia) Beta III spectrin (SPTBN2)
SCA6 α1a component of the voltage-dependent calcium channel: CACNL1A4
SCA7 Ataxin-7
SCA8 (mutation is in noncoding region)
SCA10 Ataxin-10
SCA11 Tau tubulin kinase 2 (TTBK2)
SCA12 Protein phosphatase 2A, regulatory subunit B (PPP2R2B)
SCA14 Protein kinase Cγ (PRKCG)
SCA15, 16, 29? Inositol 1,4,5-triphosphate receptor, type 1 (ITPR1)
SCA17 (also called HDL4) TATA binding protein (TBP)
SCA18 (with sensorimotor neuropathy)  
(SCA24) Now SCAR4  
SCA25 (with sensory neuropathy)  
SCA27 Fibroblast growth factor 14 (FGF14)
SCA28 ATPase family gene 3-like 2 (AFG3L2)
SCA29 (congenital, non-progressive)  
SCA31 (Japanese form of SCA4) Pleckstrin homology domain-containing protein, family G, member 4 (PLEKHG4, puratrophin-1)
DRPLA Atrophin-1 or DRPLA protein

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

ADCA type SCA type
I (ataxia plus) 1, 2, 3, 4, 8, 9, 12, 17, 27, 28, DRPLA
II (with pigmentary maculopathy) 7
III (pure ataxia) 5, 6, 11, 14, 15, 16, 22, 26, 30, 31
Ataxia and epilepsy 10
Early onset with learning disability 13

Table 21.6 Clues to the SCAs

Age at onset Young adult: SCA1, 2, 3, 21
Older adult: SCA6
Childhood onset: SCA2, 7, 13, 25, 27, DRPLA
Prominent anticipation SCA7, DRPLA
Upper motor neuron signs SCA1, 3, 7,12
Some in SCA6, 8
Rare in SCA2
Slow saccades Early, prominent: SCA2, 7
Late: SCA1, 3, 28
Rare: SCA6
Extrapyramidal signs Early chorea: DRPLA
Akinetic-rigid, Parkinson: SCA2, 3, 12, 21
Generalized areflexia SCA2, 4, 19, 21, 22
Late: SCA3
Rare: SCA1
Visual loss SCA7
Dementia Prominent: SCA17, DRPLA
Early: SCA2, 7
Otherwise: rare
Myoclonus DRPLA, SCA2, 14, 19
Tremor SCA2, 8, 12, 15, 16, 19, 27
Seizures SCA10

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

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