novel therapeutic challenges in cerebellar diseases

Novel Therapeutic Challenges inCerebellar Diseases 106Antoni Matilla-Duenas, Carme Serrano, Yerko Ivanovic, RamiroAlvarez, Pilar Latorre, and David Genıs

Abstract

In the last decade, substantial scientific progress has enabled a better under-

standing of the pathogenesis of cerebellar diseases and the improvement of their

diagnoses. Extensive preclinical work is expanding the possibilities of using

experimental models to analyze disease-specific mechanisms and to approach

candidate therapeutic strategies to create a rationale for clinical trials that might

finally lead to successful treatment. At present, drug treatment of cerebellar

disorders has shown limited effectiveness and current treatment is primarily

A. Matilla-Duenas (*)

Department of Neurosciences, Basic, Translational and Molecular Neurogenetics Research Unit,

Health Sciences Research Institute Germans Trias I Pujol (IGTP), Universitat Autonoma de

Barcelona, Ctra. de Can Ruti, Camı de les escoles s/n, 08916 Badalona (Barcelona), Spain

e-mail: [email protected], [email protected]

C. Serrano

Neurology Service, Hospital de Martorell, 08760 Barcelona, Spain

e-mail: [email protected]

Y. Ivanovic

Monte Alto Rehabilitation Medical Center, (Madrid), Private Practice, Calle Monte Alto 25,

28223, Madrid, Spain

and

National Reference Care Centre for People with Rare Diseases and Their

Families–CREER–(Burgos), IMSERSO, Calle Bernardino Obregon, 09001 Burgos, Spain


R. Alvarez • P. Latorre

Neurodegeneration Unit, Neurology Service, University Hospital Germans Trias i Pujol

(HUGTP), Badalona (Barcelona), Spain


D. Genıs

Neurodegenerative Diseases Unit, University Hospital of Girona Dr. Josep Trueta, Girona, Spain

e-mail: [email protected]

M. Manto, D.L. Gruol, J.D. Schmahmann, N. Koibuchi, F. Rossi (eds.),

Handbook of the Cerebellum and Cerebellar Disorders,DOI 10.1007/978-94-007-1333-8_106, # Springer Science+Business Media Dordrecht 2013

2371

supportive. Until effective and selective pharmacological treatment leading to

better quality of life as well as increased survival of patients with cerebellar

diseases is found, physical and sensory rehabilitation techniques are revealing

effective approaches for improving the patient’s quality of life. The objective of

this chapter is to provide an updated summary of the treatments currently

available for cerebellar disorders, in particular for spinocerebellar ataxias, and

to discuss the new emerging therapeutic strategies that are resulting from the

intensive ongoing basic and translational research devoted to cerebellar diseases.

Introduction

Damage to the cerebellum has been associated with a wide range of movement

disorders including incoordination, reduced manual dexterity, postural instability,

and gait disturbances (Manto 2008). Because ataxia is the most common neurolog-

ical deficit resulting from dysfunction of the cerebellum, this chapter will mostly

focus on treatment of ataxic disorders.

Cerebellar ataxic movement patterns result from the impairment of the timing

and duration of muscle activation or the magnitude and scaling of force production

during voluntary movement, as the cerebellum is thought to be instrumental in these

crucial elements of motor control. Drug treatment of cerebellar diseases has shown

limited effectiveness, and therefore treatment is primarily supportive. With very

few exceptions, such as in those ataxias associated with vitamin E and CoQ

deficiencies, there are no disease-modifying therapies for cerebellar diseases.

However, medications such as 5-hydroxytryptophan, clonazepam and others that

will be discussed herein have been reported to have limited benefits in a few

cerebellar conditions (Ogawa 2004; Matilla-Duenas et al. 2006; Ferrara et al.

2009; Manto and Marmolino 2009; Trujillo-Martin et al. 2009; Table 106.1).

Very recently there have been encouraging advances in clinical ataxia research.

Collaborative study groups throughout the world have developed and validated

ataxia rating scales and instrumented outcome measures and have begun to rigor-

ously define the natural history of these diseases, thus laying the foundation for

well-designed clinical trials (Schmitz-Hubsch et al. 2010). Hereditary ataxias may

have certain clinical features that respond very well to symptomatic medical

therapy. Parkinsonism, dystonia, spasticity, urinary urgency, sleep pathology,

fatigue and depression are all common in many of the different ataxia subtypes

and very often respond to pharmacologic intervention as in other diseases. Much of

the clinical interaction between the neurologist and the ataxia patient focus on

identifying and treating these symptoms. As in the cases of infarctions, hemor-

rhages and neoplasms, surgical and medical treatment, radiotherapy or chemother-

apy to treat the original cause of the cerebellar diseases is commonly followed by

physical therapy. Treatment of the core clinical feature of these diseases – ataxia –

is thus predominantly rehabilitative (reviewed in Watson 2009). The value of good

physical therapy far exceeds any potential benefit from medications that a physician

might prescribe to improve balance and coordination. Furthermore, speech and

2372 A. Matilla-Duenas et al.

Table 106.1 Summary of the existing treatments in the spinocerebellar ataxias. Only those

treatments in clinical trials or about to be tested in patients have been included

Ataxia Treatment Status Conclusions/observations

Autosomal recessive ataxias

Friedreich’s ataxia Idebenone 5–20 mg/kg/

day

Completed Stabilization and possible

reduction of the left ventricular

mass. Reduction of the

progression of cerebellar

manifestations during the early

stages of the disease, but this

evidence appears controversial

Idebenone 500 mg/kg/

day

Completed No effects on cardiomiopathy or

neurological symptoms

Pioglitazone Ongoing clinicaltrials.gov

Deferiprone Completed Mild clinical improvement

Erythropoeitin Completed Ataxia rating scales and frataxin

levels improved

CEPO Ongoing clinicaltrials.gov

HDACis Pre-

clinical

A study to evaluate the

pharmacokinetic and safety

profiles will be initiated shortly

Replacement strategies Pre-

clinical

TAT-fused frataxin

Polyamides Pre-

clinical

Increase frataxin levels in vitro

Gene therapy Pre-

clinical

Under experimentation

Ataxias with vitamin E

deficiency

Vitamin E Treatment

of choice

Ataxia and mental retardation are

reversed if treated early. In older

individuals, disease progression

can be halted

RR-a-tocopherol Completed Stabilization of clinical

symptoms with 800 mg/kg/day

Ataxias with

Coenzyme Q10

deficiency

Coenzyme Q10 Treatment

of choice

Slows progression of ataxia

Abetalipoproteinemia Vitamin E together with

a-tocopherolTreatment

of choice

Initial treatment is crucial to

avoid progression of the disease.

Massive oral doses of a-tocopherol (100–150 mg/kg) are

required

Cerebrotendinous

xanthomatosis

CDCA 15 mg/kg/day Treatment

of choice

Decreases cholestanol levels

leading to improvement of

neurological symptoms

Refsum’s disease Westminster-Refsum

diet

Treatment

of choice

Lowers phytanic acid levels and

improves symptoms

(continued)

106 Novel Therapeutic Challenges in Cerebellar Diseases 2373

Table 106.1 (continued)

Ataxia Treatment Status Conclusions/observations

Autosomal dominant ataxias

SCA1 Lithium Completed Clinical benefits. Adverse effects

SCA2 NMDA antagonists,

Deep brain stimulation

Completed Some benefits regarding ataxic

symptoms

Amantadine,

dopaminergic,

anticholinergic drugs

Completed Alleviate tremor, bradkykinesia

or dystonia

SCA3 Clonazepam, Buspirone,

Hydroxytryptophan,

Lamotrigine,

Tandospirone


symptoms

Amantadine,

dopaminergic,

anticholinergic drugs

Completed Alleviate tremor, bradkykinesia

or dystonia

Varenicline Ongoing

SCA6 Acetazolamide,

Gabapentin


symptoms

FXTAS Varenicline Ongoing

Memantine Ongoing

Dystonia Botulinum toxin Completed Clear benefits. Small dosage

Intention tremor Benzodiazepines,

b-blockers, chronic

thalamic stimulation

Completed Symptoms ameliorate

Muscle cramps Magnesium, quinine,

mexiletine

Completed Symptoms ameliorate

Myoclonus Piracetam Completed Symptoms ameliorate. Also used

to treat dementia/cognitive

decline

Restless legs

syndrome

Dopaminergic treatment,

rotigotine, tilidine

Completed Clear benefits

Saccadic intrusions Memantine Completed Clear benefits

Spasticity Baclofen, memantine,

tizanadine with

dopamine treatment


Botulinum toxin Completed Clear benefits. Small dosage

Episodic ataxias

EA1 Carbamazepine, valproic

acid, ACTZ


EA2 ACTZ Treatment

of choice

Clear benefits. It should not be

prescribed to patients with liver,

renal or adrenal insufficiency

4-aminopyridine, CHZ Completed Clear benefits

3,4-diaminopyridine Completed Improves down-beat nystagmus

Attack rates Carbazepine, sulthiame Completed Reduce the frequency of attacks,

but the response is heterogeneous


swallowing are often affected. In more severe cases, aspiration risk can be very

significant and life threatening. Routine monitoring of swallowing by speech thera-

pists, often including modified barium swallowing tests, is indicated in most patients.

Treatments for Autosomal Recessive Spinocerebellar Ataxias

The heterogeneity of this group of diseases, which includes an extraordinary variety

of gene mutations originating from different pathogenic mechanisms, places the

task of reviewing all the potential or hypothetical future treatments beyond the

scope of a single chapter. Therefore this chapter limits the review to the most

common autosomal recessive ataxias together with those in which successful

therapeutic options have been explored.

Friedreich’s Ataxia (FA)

Biochemical investigations have revealed the role of frataxin, the protein associated

with FA, in the assembly of iron–sulfur clusters (ISCs) in the mitochondrion

(reviewed in Pandolfo and Pastore 2009). A GAA-triple repeat expansion in intron

1 of the frataxin (FXN) gene inhibiting frataxin expression is the most common

type of mutation causing FA. As a consequence of frataxin deficiency, iron is

accumulated in mitochondria leading to a loss of mitochondrial function. Cells

from patients with FA become highly sensitive to oxidants causing further mito-

chondrial damage and respiratory chain dysfunction. Therefore, antioxidants such

as idebenone, coenzyme Q10 and iron chelators such as deferroxiamine have been

used in attempting to reduce oxidative stress (Pandolfo 2008; Schulz et al. 2009).

Erythropoietin (EPO) is now being employed as a treatment for frataxin deficiency

whereas histone-deacetylase inhibitors and gene therapy are experimental treat-

ments currently being investigated.

Idebenone is the antioxidant that has been the most widely used drug in FA

treatment since the initial report of its successful use in the reduction of the left

ventricular mass of three FA patients with cardiac hypertrophy (Rustin et al. 1999).

In one of the first open-label trials in which nine patients were treated with 5 mg/kg/

day, cerebellar improvement was considered to be notable in mildly symptomatic

patients after the first 3 months of therapy. Treatment during the early stages of the

disease was found to reduce the progression of cerebellar manifestations (Artuch

et al. 2002). A prospective open trial designed to study cardiac hypertrophy in FA

patients found a reduction in the left ventricular mass of more than 20% in 50% of

patients (Hausse et al. 2002). Another prospective study showed that idebenone did

not halt the progression of ataxia, but significantly reduced the cardiac hypertrophy

in six of eight patients as revealed by cardiac ultrasound studies (Buyse et al. 2003).

In a 1-year, randomized, placebo-controlled trial of idebenone in 29 FA patients,

significant reductions of interventricular septal thickness and left ventricular mass

in the idebenone groupwere found (Mariotti et al. 2003). A randomized, double-blind,


placebo-controlled trial comparing the effects of three different doses of idebenone

(5, 15 and 45 mg/kg) over a 6-month period did not find significant differences

between any of the employed clinometric scale total scores (Di Prospero et al. 2007).

However, when wheelchair-bound patients were excluded, a significant improve-

ment in the ICARS score was obtained suggesting a dose-related response in scales

scores. Another large open-labeled prospective survey studying 104 FA patients

during a median period of 5 years (88 treated with idebenone at 5 mg/kg/day)

found that the total ICARS score worsened over the follow-up period in both the

treated and non-treated groups (Ribai et al. 2007). The left ventricular mass index

decreased in the treated group as well as the ejection fraction suggesting that

idebenone may not have significantly altered the neurological progression. Even

the beneficial effects of idebenone on cardiomyopathy in this study were

questioned and are still currently an object of debate.

In an open-labeled prospective study with 24 FA patients treated at different

doses of idebenone ranging between 5 and 20 mg/kg/day and a long-term follow-up

of between 3 and 5 years, differences were found between pediatric and adult

patients (Pineda et al. 2008). While no changes were found in the clinical scale

results and cardiac measurements of children after 5 years of follow-up, ICARS

scores in adult patients increased after 3 years and cardiac echographic measure-

ments remained stable. The authors concluded that idebenone leads to the stabili-

zation of cardiomyopathy in both the groups albeit only pre-pubertal children

obtain neurological benefit from the drug. Based on the results of this study, the

age of therapy initiation would therefore appear to be an important factor. Less

optimistic results were obtained in another study of a cohort of 35 patients over

a 5-year period (Rinaldi et al. 2009). The authors reported that at the end of the

study period the group without left ventricular hypertrophy (LVH) before treatment

therapy had increased interventricular septum and posterior wall thickness while

there was no change in the group with LVH before treatment. A Cochrane review

concluded that no RCTs using idebenone or other drug therapy have shown

significant benefits in the neurological symptoms associated with Friedreich’s

ataxia (Kearney et al. 2009). Idebenone, on the other hand, showed a positive effect

on left ventricular mass of the heart. In a 6-month randomized, double-blind,

placebo-controlled intervention trial of 70 patients three arms of treatment, low

dose idebenone, high dose and placebo, were compared (Lynch et al. 2010).

Although there were differences between both placebo and treated groups favoring

idebenone treatment, they were not statistically significant. The most recent

reported results are obtained from the MICONOS study, a large, randomized,

double-blind, placebo-controlled trial testing the efficacy and safety of the three

doses of idebenone (Catena®/Sovrima®) and placebo over a 12-month treatment

period. The primary endpoint of the study, mean change in the ICARS score from

baseline, has not revealed significant differences between the active dose arms and

placebo. Secondary endpoints also failed to reveal statistically significant differ-

ences between the placebo and active dose groups, and even cardiac benefit could

not be proved. Although there are a few completed and ongoing studies with

idebenone in FA (http://clinicaltrials.gov/) it seems clear that a significant response


http://clinicaltrials.gov/

of neurological parameters to high doses of the drug will not be obtained, although

an effect on cardiomyopathy might be expected in some cases. Simultaneous

treatment with both coenzyme Q(10) and vitamin E in low and high doses were

compared in a randomized, double-blind clinical trial in 50 patients over a 2-year

period. Serum CoQ(10) and vitamin E levels, which had previously been deter-

mined to be low in these patients, reached normal values as a result of the treatment.

The primary and secondary end points were not significantly different between the

therapy groups. Comparison of the ICARS scores with cross-sectional data showed

an overall 49% improvement. There were no differences between both the groups in

the end points. The best predictor of a positive clinical response to this double

therapy was low serum CoQ(10) and vitamin E levels (Cooper et al. 2008).

A 2-year prospective, randomized double-blind trial of pioglitazone versus

placebo is currently ongoing (http://clinicaltrials.gov/). Pioglitazone is a peroxi-

some proliferator-activated receptor g (PPARg) ligand that induces the expression

of enzymes involved in the mitochondrial metabolism, including the superoxide

dismutase. This drug appears to counteract the disabled recruitment of antioxidant

enzymes in FA patients.

Iron chelators such as deferiprone have been used in a short study of nine

patients in which this drug successfully reduced labile iron levels in the dentate

nuclei (Boddaert et al. 2007). The noted clinical improvement was mild. A larger

scale study has been undertaken (Velasco-Sanchez et al. 2010). Iron chelators such

as 2-pyridylcarboxaldehyde 2-thiophenecarboxyl hydrazone (PCTH) appear more

effective than conventional radical scavengers in in vitro assays (Lim et al. 2008),

albeit their efficacy needs to be proven in patients. After finding that recombinant

human erythropoietin (rhuEPO) significantly increases frataxin expression levels in

in vitro studies (Sturm et al. 2005), an open-label clinical pilot study to evaluate the

safety and efficacy of rhuEPO was designed. Eight adult FA patients received

2,000 IU rhuEPO three times a week subcutaneously for 6 months. The scores in

different ataxia rating scales and frataxin levels improved significantly after

treatment, and the values measuring oxidative stress decreased (Boesch et al.

2007; Boesch et al. 2008). Because of the side effects of EPO on hematopoiesis

and tumor growth, efforts to develop EPO derivative molecules avoiding binding

the erythropoietin receptor resulted in the synthesis of carbamylated erythropoie-

tin (CEPO). This drug has proven neuroprotective and increases the production of

frataxin to the same levels as rhuEPO. A safety study on this drug is in process

(http://clinicaltrials.gov/).

Varenicline is a partial nicotinic receptor agonist which has been recently used in

a clinical trial to investigate its effects on neurological clinical features in FA

(Zesiewicz et al. 2009). However, the study with this drug was halted before

completion due to concerns about its safety and insufficient evidence of efficacy

in patients.

Histone deacetylase inhibitors (HDACi) revert silent heterochromatin to an

active chromatin conformation and therefore have been evaluated as molecules

reverting gene expression. HDAC inhibition is a persistent reversible phenomenon

which in theory should permit the intermittent administration of the drug. Such




a regimen would minimize toxic side effects by reducing drug exposure while at the

same time allowing sustained up-regulation of frataxin protein levels. This is an

important consideration since uncommon but serious side effects had been reported

with the use of other HDACi in the past. HDACi have been proven to increase

frataxin protein levels in FA cells with a silent mutant frataxin gene (Herman et al.

2006; Rai et al. 2008, 2010). Among these HDACi, pimelic diphenylamide HDACi

have stood out as efficient up-regulators of frataxin expression (Rai et al. 2010).

A study to evaluate the pharmacokinetic and safety profiles of this new generation

of HDACi will be initiated shortly in FA patients.

The HIV-1 transactivator of transcription (TAT), an arginine-rich cell penetrant

peptide, is being exploited in replacement therapy strategies for transducing full-

length proteins not only across the cell membrane, but also into intracellular

organelles including the mitochondrion (Del Gaizo and Payne 2003; Vyas and

Payne 2008; Rapoport and Lorberboum-Galski 2009). Very recently, a pre-clinical

trial has proven successful in delivering synthetic TAT-fused frataxin (TAT-

frataxin) to the mitochondrial matrix in FA mice. After the treatment, TAT-frataxin

did not induce inflammatory response in FA mice when injected chronically over

2 months, and FA mice increased their life span significantly (R.M.Payne,

unpublished results).

Based on the empiric observations that some polyamide compounds such as

beta-alanine-linked pyrrole-imidazole polyamides bind GAA/TTC tracts with high

affinity and disrupt the intramolecular DNA-associated regions, they were tested to

examine their ability to increase frataxin gene transcription in cell cultures. This has

proven to increase frataxin protein levels (Burnett et al. 2006). Similar effects have

been obtained with pentamidine and related small molecules (Grant et al. 2006;

Gottesfeld 2007). Different approaches have focused on the high capacity of the

herpes simplex virus type 1 (HSV-1) amplicon vectors expressing the entire 80 kb

FRDA genomic locus to successfully transduce onto FA patient frataxin-deficient

fibroblasts in a FA mouse model (Gomez-Sebastian et al. 2007; Lim et al. 2007).

Other innovative strategies designed to place exogenous frataxin protein into the

mitochondria of patients include the intravenous administration of frataxin previ-

ously encapsulated with peptides in nanoparticles.

Ataxias with Vitamin E and Coenzyme Q10 Deficiencies

The treatment of choice for the ataxia with vitamin E deficiency is lifelong high-

dose oral vitamin E supplementation. Some symptoms including ataxia and mental

deterioration can be reversed if treatment is initiated early in the disease process. In

older individuals, disease progression can be stopped, but deficits in proprioception

and gait unsteadiness generally remain (Gabsi et al. 2001; Mariotti et al. 2004).

With treatment, plasma vitamin E concentrations can become normal. No thera-

peutic studies have been performed on a large cohort to determine optimal dosage

and evaluate outcomes. Reported doses of vitamin E range from 800 mg to 1,500 mg

or 40 mg/kg body weight in children.


The used vitamin E preparations are the chemically manufactured racemic form,

all-rac-a-tocopherol acetate or the naturally occurring form, RRR-a-tocopherol.It is not currently known whether affected individuals should be treated with all-rac-a-tocopherol acetate or with RRR-a-tocopherol. It is known that alpha-tocopherol

transfer protein (alpha-TTP) stereoselectively binds and transports 2R-a-tocopherols.For some ATTP mutations, this stereoselective binding capacity is lost and affected

individuals cannot discriminate between RRR- and SRR-a-tocopherol (Traber et al.1993; Cavalier et al. 1998). In this instance, affected individuals would also be

able to incorporate non-2R-a-tocopherol stereoisomers into their bodies if they

were supplemented with all-rac-a-tocopherol. Since the potential adverse effects ofthe synthetic stereoisomers have not been studied in detail, it seems appropriate to

treat with RRR-a-tocopherol, despite the higher cost. Several studies have reportedthe stabilization of the clinical symptoms and even some improvement with twice

daily doses of 800 mg of RRR-a-tocopherol in patients presenting ataxia with

vitamin E deficiency (Amiel et al. 1995; Yokota et al. 1997; Martinello et al.

1998). Furthermore, fat-enriched meals are recommended in these patients.

Oral antioxidant therapy with CoQ10 has slowed the progression of ataxia in

patients who are specifically deficient in those components (Hirano et al. 2006;

Pineda et al. 2010).

Abetalipoproteinemia

The disease in patients with abetalipoproteinemia is directly related to vitamin E

deficiency (reviewed in Kayden 2001). Substitution therapy with vitamin E

presents complex problems due to severe intestinal misabsorption and requires

a close dietetic control to take into account all the aspects involved in the

management. In this disease, the lipoproteins transporting a-tocopherol are

missing. An early onset treatment with vitamin E is crucial to avoid or halt the

progression of the neurological symptoms. Initial parenteral administration of

vitamin E is recommended followed by massive oral doses of a-tocopherol at100–150 mg/kg. Plasma levels of vitamin E often fail to reflect the whole body

content of vitamin E and the adequacy of vitamin replacement may be difficult to

gauge from serum concentrations. However, this dose has been shown to improve

the overall neurological state of the patient if treatment is started early (Zamel

et al. 2008). Vitamin A, D and K and other dietary supplements must be given.

The disease requires lifelong controls to avoid or minimize secondary nervous

system damage.

Cerebrotendinous Xanthomatosis (CTX)

Cerebrotendinous xanthomatosis (CTX) is a lipid storage disease in which several

bile alcohols, particularly cholestanol, are accumulated. Treatment with

chenodeoxycholic acid (CDCA) decreases the cholestanol levels and this leads to


the improvement of cognition, psychiatric, motor clinical and neurophysiological

parameters (Berginer et al. 1984). As observed with other metabolic ataxias, earlier

treatment usually results in better results. The recommended doses are 15 mg/kg/

day in three daily doses. Other treatments include the use of pravastin, a 3-hydroxy-

3-methylglutaryl (HMG)-CoA reductase inhibitor or a combination of both

chenodeoxycholic acid and pravastin (Salen et al. 1994; Verrips et al. 1999).

More aggressive treatments of CTX with LDL-apheresis have shown contradictory

results (Ito et al. 2003; Dotti et al. 2004).

Refsum’s Disease

Refsum’s disease features are directly related to the progressive deposition of

phytanic acid in different tissues. Thus, the main objective for treatment has been

to lower the phytanic acid levels mainly by providing the Westminster-Refsum diet

(Baldwin et al. 2010). As patients with Refsum’s disease may suffer with severe

clinical exacerbations, therapeutic lipapheresis has been considered in these con-

ditions (Gutsche et al. 1996; Weinstein 1999). Liver cell transplantation is under

consideration as a treatment option in Refsum’s disease patients (Sokal et al. 2003;

Najimi and Sokal 2005).

Treatments for Autosomal Dominant Spinocerebellar Ataxias

There are currently no known effective pharmacologic treatments to reverse or even

substantially reduce motor disability caused by cerebellar degeneration in most of

the autosomal dominant spinocerebellar ataxias (SCAs) or related cerebellar disor-

ders, although some benefits on ataxic and non-ataxic symptoms have been reported

in a few therapeutic clinical trials (extensively reviewed in Ogawa 2004; Matilla-

Duenas et al. 2006; Manto and Marmolino 2009; Trujillo-Martin et al. 2009). Some

benefits regarding ataxic symptoms have been reported with acetazolamide and

gabapentin in SCA6 (Nakamura et al. 2009), 5-hydroxytryptophan, clonazepam,

buspirone or tansodpirone, sulfamethoxazole/trimethoprim or lamotrigine in SCA3,

NMDA modulators or antagonists, and deep brain stimulation in SCA2 with tremor

or FXTAS (Ferrara et al. 2009). Amantadine, dopaminergic and anticholinergic

drugs have been used to alleviate tremor, bradykinesia or dystonia in SCA2 and

SCA3 (Botez et al. 1991; Tuite et al. 1995; Buhmann et al. 2003). Varenicline is

currently being tested in SCA3 (Zesiewicz and Sullivan 2008) and FXTAS. Rest-

less legs and periodic leg movements in sleep usually respond to dopaminergic

treatment, tilidine or rotigotine (Schols et al. 1998; Hening et al. 2010; Zintzaras

et al. 2010). Spasticity in SCAs is effectively treated with the GABA analogue

baclofen, tizanadine or memantine when combined with dopaminergic treatment.

In selected cases where other treatments have failed, botulinum toxin has been

successfully used to treat dystonia and spasticity in SCA3 (Freeman and Wszolek

2005), although caution and small dosage are recommended since unusually severe


https://www.researchgate.net/publication/223028163_Comparative_effects_of_lovastatin_and_chenodeoxycholic_acid_on_plasma_cholestanol_levels_and_abnormal_bile_acid_metabolism_in_cerebrotendinous_xanthomatosis?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

https://www.researchgate.net/publication/8176807_Normalisation_of_serum_cholestanol_concentration_in_a_patient_with_cerebrotendinous_xanthomatosis_by_combined_treatment_with_chenodeoxycholic_acid_simvastatin_and_LDH_apheresis?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

https://www.researchgate.net/publication/23711644_Effectiveness_of_physiotherapy_for_adults_with_cerebellar_dysfunction_a_systematic_review_Clin_Rehabil?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

and long-lasting muscular atrophy occurs in some SCA3 patients with this treatment

because of subclinical involvement of motor neurons in the anterior horn in the

degenerative process. Intention tremor has been ameliorated with benzodiazepines,

b-blockers or chronic thalamic stimulation. Muscle cramps, which are often present

at the onset of the condition in SCAs 2, 3, 7, and DRPLA, are alleviated with

magnesium, quinine or mexiletine (Kanai et al. 2003). Piracetam have been used to

treat myoclonus and/or dementia/cognitive decline (De Rosa et al. 2006; Kanai

et al. 2007; Ince Gunal et al. 2008). In spite of the lack of effectiveness in the

treatment of ataxia symptoms in most SCAs, treatment in some spinocerebellar

ataxias has proven successful. Furthermore, most autoimmune cerebellar ataxias,

such as anti-glutamic acid decarboxylase (GAD)-antibody-positive cerebellar

ataxia and gluten ataxia, have proven to be treatable with intravenous immuno-

globulin administration (Lock et al. 2006; Nanri et al. 2009). In the remaining

ataxias, physiotherapy is currently being used as an effective treatment alternative.

Ataxia improves with daily autonomous training of gait and stance in combination

with physiotherapy. Other neurological symptoms such as dysarthria and dysphagia

warrant logopedic treatment to maintain the ability to communicate and to prevent

pneumonia from aspiration.

A clinical trial with the aim of assessing the safety, tolerability and the effects of

lithium in SCA1 has recently been completed, and patients are being recruited to

assess lithium carbonate therapy in SCA2 and SCA3. Albeit there are clinical

benefits with lithium treatment, common side effects include muscle tremors,

twitching, ataxia and hypothyroidism. Long-term use of lithium has been linked

to hyperparathyroidism, hypercalcemia (bone loss), hypertension, kidney damage,

nephrogenic diabetes insipidus (polyuria and polydipsia), seizures, and weight gain

(Tredget et al. 2010). Although lithium or a bioactive analogue may have promising

potential to benefit ataxia patients, clinical and biological responses to a range of

doses throughout an extended time period need to be carefully evaluated and

monitored in any forthcoming clinical trial.

Other ongoing clinical trials in SCAs include the NMDA receptor antagonist

memantine in fragile X tremor and ataxia syndrome (FXTAS). Memantine has

been successfully used to treat saccadic intrusions in spinocerebellar ataxias (Serra

et al. 2008).

Treatments for Episodic Ataxias

Several different drugs are reported to improve symptoms in EA1 and EA2, but so

far there have been no controlled studies documenting or comparing efficacy of

these different drugs. Carbamazepine, valproic acid and acetazolamide (ACTZ)

have proven effective for EA1 (Eunson et al. 2000; Klein et al. 2004); and ACTZ

(Griggs et al. 1978), 4-aminopyridine (Strupp et al. 2004; Strupp et al. 2008) and

chlorzoxazone (CHZ) (Alvina and Khodakhah 2010a) have been effective in EA2

cases. The response to acetazolamide is often dramatic in EA2 (Griggs et al. 1978;

Jen et al. 2004), and is considered the treatment of choice. ACTZ should not be


prescribed to individuals with liver, renal or adrenal insufficiency. Acetazolamide,

a carbonic-anhydrase (CA) inhibitor, may reduce the frequency and severity of the

attacks in some but not all affected individuals with episodic ataxias. Chronic

treatment with ACTZ may result in side effects including paresthesias, rash and

formation of renal calculi.

Antiepileptic drugs (AEDs) such as carbamazepine may significantly reduce the

frequency of the attacks in responsive individuals; however, the response is het-

erogeneous as some individuals are particularly resistant to drugs (Eunson et al.

2000). Anticonvulsant drugs such as sulthiame may reduce the attack rates. During

this treatment, abortive attacks were still noticed lasting a few seconds and trou-

blesome side effects were paresthesias and intermittent carpal spasm (Holtmann

et al. 2002).

The potassium channel blocker 4-aminopyridine has been found to be effective

in stopping attacks in patients with EA2 (Strupp et al. 2004; Alvina and Khodakhah

2010b). Furthermore, 3,4-diaminopyridine was demonstrated in a placebo-

controlled study to improve down-beat nystagmus, which is often observed in

patients with EA2 (Strupp et al. 2003).

Emerging Therapeutic Strategies

In the last decade, intensive scientific research has been devoted to identify

molecular pathways underlying cerebellar neurodegeneration (Matilla-Duenas

et al. 2010) with the aims of discovering and establishing effective and selective

therapeutic strategies to treat cerebellar diseases. Among them, a few innovative

approaches yielding promising results are being investigated at the preclinical and

in some cases at the clinical level including the use of RNA interference (RNAi)

aiming to inhibit the expression of mutated polyglutamine-proteins in those SCAs

caused by expanded polyglutamine mutations, prevention of protein misfolding and

aggregation by over-expression of chaperones and by pharmacological treatments,

and the regulation of gene expression by treatment with histone deacetylase inhib-

itors (HDACi). Intracerebellar injection of vectors expressing short hairpin RNAs

was shown to selectively decrease the expression of mutant proteins and profoundly

improve motor coordination, restore cerebellar morphology and prevent the char-

acteristic intranuclear aggregated inclusions in Purkinje cells in SCA1 transgenic

mice (Xia et al. 2004). While these results show that RNAi therapy improves

cellular and behavioral characteristics in pre-clinical trials, its application in

patients to protect or even reverse disease phenotypes shall be delayed until proper

toxicity tests are assessed. Another target, molecular chaperones provide a first line

of defense against misfolded, aggregation-prone proteins. Many studies have ana-

lyzed the effects of chaperone over-expression on inclusion body formation and

toxicity of pathogenic polyQ fragments in cell culture, and it is clear that over-

expression of molecular chaperones might prove beneficial for the treatment of

cerebellar diseases (Muchowski and Wacker 2005). They prevent inappropriate


interactions within and between non-native polypeptides, enhance the efficiency of

de novo protein folding, and promote the refolding of proteins that have become

misfolded as a result of the mutations and cellular stress (Chan et al. 2000).

Chemical and molecular chaperones might also prevent toxicity by blocking inap-

propriate protein interactions, by facilitating disease protein degradation or seques-

tration or by blocking downstream signaling events leading to neuronal dysfunction

and apoptosis. The first proof of concept studies supporting such idea was

performed using Congo Red, thioflavine S, chrysamine G and Direct Fast yellow

which proved to be effective in suppressing molecular aggregation in vitro and

in vivo and ameliorate symptoms (Heiser et al. 2000; Sanchez et al. 2003), albeit

their efficacy in vivo is limited by their variable abilities to cross the blood–brain

barrier and bioviability such that proper pharmacologic analogues may need to be

developed for further clinical considerations. Other low molecular mass chemical

chaperones, such as the organic solvent dimethylsulfoxide (DMSO) and the cellular

osmolytes glycerol, trimethylamine n-oxide and trehalose, appear to ameliorate cell

death triggered by mutant ataxin-3 by increasing its stability in their native confor-

mation (Yoshida et al. 2002). Trehalose was identified in an in vitro screen for

inhibitors of polyglutamine aggregation, and its administration reduces brain and

cerebellar atrophy, improves motor dysfunction and extends the lifespan of mice

resembling the polyglutamine disorder Huntington’s disease (Tanaka et al. 2004).

In vitro experiments suggest that the beneficial effects of trehalose result from its

ability to bind and stabilize polyglutamine-containing proteins. More recently,

a new generation of small chemical compounds that directly target polyQ aggre-

gation without significant cytotoxicity have been identified in high-throughput

screens using cell-free assays or by targeting cellular pathways (Heiser et al.

2002; Zhang et al. 2005). These compounds decrease molecular aggregation in

cultured cells and brain slices and can rescue neurodegeneration in a drosophila

model, although no effect was detected in mouse models possibly due to

bioviability issues of the compounds. By a different mechanism, a small molecule

that acts as a co-inducer of the heat shock response by prolonging the activity of

heat-shock transcription factor HSF1, arimoclomol, significantly improves behav-

ioral phenotypes, prevents neuronal loss, extends survival rates and delays disease

progression in a mouse model of neurodegeneration (Kieran et al. 2004). Similarly,

activation of heat-shock responses with geldanamycin inhibits aggregation and

prevents cell death (Rimoldi et al. 2001). This suggests that pharmacological

activation of the heat shock response may therefore be an effective therapeutic

approach for treating neurodegenerative diseases. However, excessive up-

regulation of chaperones might lead to undesirable side effects, such as alterations

in cell cycle regulation and cancer (Mosser and Morimoto 2004). Therefore,

a delicate balance of chaperones will likely be required for a beneficial

neuroprotective effect. For instance, chemical or molecular chaperones, used in

combination with a pharmacological agent that up-regulates the synthesis of

molecular chaperones, might be a valid therapeutic approach for treating

spinocerebellar ataxias caused by polyglutamine expansions. Aggregate formation

has also been successfully targeted with inhibitors of transglutaminase, such as


https://www.researchgate.net/publication/11636727_Analysis_of_heat_shock_transcription_factor_for_suppression_of_polyglutamine_toxicity?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

cystamine, which reduces apoptotic cell death and alleviates disease symptoms

(Dedeoglu et al. 2002; Karpuj et al. 2002).

Compounds directly targeting mitochondrial function such as coenzyme Q10

(Shults 2003); creatine (Ryu et al. 2005) and tauroursodeoxycholic acid (TUDCA)

(Keene et al. 2002); or autophagy, such as the mTor inhibitor rapamycin and

various analogous (Ravikumar et al. 2004), have proven effective at reducing

cellular toxicity in animal models, and are currently being tested in clinical trials

in a few ataxia subtypes (Menzies and Rubinsztein 2010). Caspase activation,

which usually precedes neuronal cell death, has been targeted by inhibiting their

expression, recruitment and consequent activation onto “apoptosome-like signaling

structures” or by enzymatic inhibitors all of which include minocycline, zVAD-

fmk, CrmA, FADD DN and cystamine (Ona et al. 1999; Sanchez et al. 1999; Lesort

et al. 2003). In general, the inhibitors of the different caspases have been shown to

decrease microglia activation, prevent disease progression, delay onset of symp-

toms, enhance inclusion clearance and extend survival rates in several mouse and

cell models of neurodegeneration (Ona et al. 1999; Chen et al. 2000; Lesort et al.

2003). Other agents promoting the clearance of mutant proteins in the CNS or

which are Ca2+ signaling blockers and stabilizers, such as specific inhibitors of the

NR2B-subunit of N-methyl-D-aspartate glutamate receptors, blockers/antagonists

of metabotropic glutamate receptor mGluR5 and inositol 1,4,5-trisphosphate recep-

tor InsP3R1 such as remacemide; intracellular Ca2+ stabilizers such as dantrolene;

dopamine stabilizers such as mermaid-ACR-16; dopamine depleters and agents

inducing anti-excitotoxic effects such as riluzole; or agents which alleviate cogni-

tive components such as horizon-dimebon; appear to be at least partially beneficial

for the treatment of some neurological symptoms in spinocerebellar ataxias

(Gauthier 2009; Liu et al. 2009; Mestre et al. 2009). A recent clinical trial with

riluzole showed a reduction of the ICARS score in patients with a wide range of

cerebellar disorders (Ristori et al. 2010). Neuroprotective drugs such as olesoxime

have proven to increase microtubule dynamics, reestablish neuritic outgrowth,

improve myelination and prevent apoptotic factor release and oxidative stress in

amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA) (Bordet

et al. 2007), and are potential drugs to be tested in ataxias. Inhibition of potassium

channels with 3,4-diaminopyridine has proven efficient in normalizing motor

behaviors in young SCA1 mice and in restoring normal Purkinje cell volume and

dendrite spine density and the molecular layer thickness in older SCA1 mice.

Aminopyridines, such as fampridine and diaminopyridine, increase PC excitability

and are also efficient for treating down-beat nystagmus (Strupp et al. 2008; Alvina

and Khodakhah 2010b; Tsunemi et al. 2010). Peroxisome biogenesis dysregulation

has been identified as the underlying causative deficits in some cerebellar diseases

in which bile acid supplements and dietary restriction of phytanic acid are indica-

tive (Regal et al. 2010), and therefore treatment targeting this pathway has the

potential of being explored.

The roles that some proteins implicated in cerebellar diseases play in transcrip-

tion and, more importantly, the effects mediated by some of their co-transcriptional

regulators in the suppression of cytotoxicity are being used as targets to modulate


the pathological effects, thus opening the path for new therapeutic strategies for

treating some spinocerebellar conditions. Recent progress in histone deacetylase

(HDAC) research has made possible the development of inhibitors for specific

HDAC family proteins and these compounds could prove effective candidates for

the treatment of spinocerebellar ataxias (Dokmanovic and Marks 2005; Thomas

et al. 2008). Neuroprotective and neurorestoration strategies addressing specific

bioenergetic defects might hold particular promise in the treatment of

spinocerebellar conditions. Drugs, such as rasagiline, a selective irreversible mono-

amine oxidase B inhibitor, have been shown efficient in protecting neuronal cells

against apoptosis through induction of the pro-survival Bcl-2 protein and

neurotrophic factors providing an experimental rationale for rasagiline as

a disease-modifying molecule (Naoi et al. 2009). Rasagiline is expected to enter

a few phase 3 clinical trials shortly. Recent alterations of the insulin growth factor

(IGF-1) pathway have been reported to be implicated in SCA1, SCA3 and SCA7

(Gatchel et al. 2008; Saute et al. 2010), suggesting that in vivo neuroprotection

exerted by IGF-1 potentially through the PP2A-regulated PI3K/Akt signaling

pathway, could potentially be used to halt cerebellar neurodegeneration (Fernandez

et al. 2005; Leinninger and Feldman 2005). Clinical trials with IGF-1 on AT and

SCA3 patients are underway.

Gene therapy and stem cell and grafting approaches are being experimentally

considered for treating spinocerebellar neurodegenerations (Chintawar et al. 2009;

Erceg et al. 2010; Louboutin et al. 2010). Delivery of proteins or compounds by

viral vectors onto the cerebellum represents one such gene therapeutic approach

(Louboutin et al. 2010). Vectors used are capable of transducing neurons and

microglia very effectively and thus can be used for gene delivery targeting the

cerebellum in vivo. Neural cell replacement therapies are based on the idea that

neurological functions lost during neurodegeneration could be improved by intro-

ducing new cells that can form appropriate connections and replace the function of

lost neurons. This cell replacement therapeutic strategy, although potentially effec-

tive, is still in early experimental stages (Erceg et al. 2010), since the use and the

process for reprogramming human somatic cells from accessible tissues, such as

skin or blood, to generate functional “disease- and patient-specific” neurons from

embryonic-like induced pluripotent stem cells (iPSCs) present several technical

challenges (Saha and Jaenisch 2009; Tenzen et al. 2010). Since neurogenesis does

occur in the adult nervous system, another approach is based on the stimulation of

endogenous stem cells in the brain, cerebellum or spinal cord to generate new

neurons. Studies to understand the molecular determinants and cues to stimulate

endogenous stem cells are underway (Gage 2002). A recent study by Lee and

colleagues suggested slowed progression of patients presenting the cerebellar

subtype (MSA-C) of multiple systemic atrophy who had been treated with

mesenchymal stem cell grafts (Lee et al. 2008). Although promising and further

preclinical work is necessary to define the molecular mechanisms underlying

these effects, one is only starting to learn the potential and challenges of these

emerging therapies, especially their efficacy in treating human cerebellar

neurodegeneration.


https://www.researchgate.net/publication/38055577_Genome_Modification_in_Human_Embryonic_Stem_Cells?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

Physical Therapy in Cerebellar Diseases

The cerebellum integrates sensory input, mainly proprioceptive and vestibular, with

voluntary motor action to assure coordinated and automated timing, duration and

amplitude of muscle activity in normal movement. It guarantees equilibrium and

vestibular-oculomotor control (midline cerebellar structures), accurate limb move-

ment (cerebellar hemispheres and outflow tracts) and modulated speech

(paramedian structures). It also plays a role in motor learning.

Cerebellar damage typically results in varying degrees of instability of stance

and gait, clumsy target maneuvers, slowed alternating movements, postural or

action tremor of trunk or limbs, decreased muscle tone, slurred speech, dizziness,

and nystagmus or saccade inaccuracies among other oculomotor signs. In addition,

bladder/sphincter dysynergia causes frequent or urgent incontinence. SCA patients

may suffer all symptoms or just some of them but unfortunately they will be

progressive in most patients. Since few pharmacological options are available,

most treatments rely heavily on rehabilitation therapy including exercise/physical

therapy programs and speech and swallow evaluation and training. However, the

cerebellum is known to play a crucial role in both motor control and motor learning;

therefore, the benefit of physiotherapeutic training has been long time under dispute

for patients with degenerative ataxia. In this regard, impairment of cerebellar

patients in practice-dependent motor learning has been shown for various motor

tasks (Maschke et al. 2004). Additionally, most of the research has been done with

case studies or case series with heterogeneous populations, interventions and

outcomes (Martin et al. 2009) and no information regarding the long-term effec-

tiveness of physiotherapy is available. Nevertheless, rehabilitation programs

clearly improve quality of life and motor performance and reduces ataxia symp-

toms in SCA patients (Class III evidence) (Ilg et al. 2009), however, and because

of the low prevalence of these diseases, no double-blind, randomized, controlled

trials have been performed to demonstrate the actual value of such interventions

and there is insufficient evidence to support the efficacy of any specific therapy.

Based on the principle that symptomatic treatments can be useful independent of

the etiology of the problem, much of the work done with Friedreich’s ataxia

patients and much of the progress achieved in this disease is currently applied to

treat SCA patients.

Physical Therapy Examination

A comprehensive natural history is a critical feature when examining SCA patients

since these diseases can involve multiple systems, thus data about previous inter-

ventions and surgeries should be collected and cardiovascular and musculoskeletal

systems carefully reviewed (Maring and Croarkin 2007). Additionally, gaining

insights into the psychosocial factors is essential in the interview process since

the progressive nature of the symptoms could subjectively influence an individual’s

perception of his or her quality of life to various degrees (D’Ambrosio et al. 1987).


https://www.researchgate.net/publication/5934340_Presentation_and_Progression_of_Friedreich_Ataxia_and_Implications_for_Physical_Therapist_Examination?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

https://www.researchgate.net/publication/23711644_Effectiveness_of_physiotherapy_for_adults_with_cerebellar_dysfunction_a_systematic_review_Clin_Rehabil?el=1_x_8&enrichId=rgreq-e389971a-5744-4cb8-9852-166bb86e0d2e&enrichSource=Y292ZXJQYWdlOzIzMzQyNDgyOTtBUzo5NzE5NDk1ODkxNzYzNEAxNDAwMTg0NDkyMzIx

The examination should consist of a complete history, a throughout review of the

systems, and the implementation of the best available tests and measures to describe

patients’ impairment and functional limitations. In routine clinical settings, tradi-

tional measurements of symmetry, range of motion and muscle strength are good

indicators of specific impairments of the musculoskeletal system. Cranial nerves

should also be tested for signs of impairment of ocular movements, acuity and

visual field deficits, hearing loss, dysarthria and dysphagia. A complete test of

sensory system is recommended since sensory neuropathy may be present and may

contribute to the ataxia symptoms (Perlman 2004; Maring and Croarkin 2007).

Finally, testing velocity and the independence of the gait are easy to achieve and

represent important functional measurements in SCA patients. Such a complete

physical therapy exam would eventually set the risk of falling and would prevent

accompanying injuries and erosion of self-confidence (Perlman 2004).

Composite rating scales have been proposed in order to improve reliability and

validity of performance measures including the International Cooperative Ataxia

Rating Scale (ICARS), the Ataxia Clinical Rating Scale, the Ataxia Functional

Composite Scale, the Brief Ataxia Rating Scale, the Functional Ataxia Scoring

Scale, the Inherited Clinical Rating Scale, the Northwestern University Disability

Scale and the Scale for the Assessment and Rating of Ataxia (SARA). All of them

show good interrater and test–retest reliabilities. Among them, only the Interna-

tional Cooperative Ataxia Rating Scale, the Ataxia Clinical Rating Scale, and the

Inherited Ataxia Clinical Rating Scale demonstrated a good relationship

between score and disease duration (Maring and Croarkin 2007). ICARS is

the more widely used clinical scale up to date and it has been correlated with

cerebellar volume measures in patients with pure cerebellar degeneration (Richter

et al. 2005). However, internal validity is unclear and newer scales such as SARA

can be completed faster and may have better construct validity (Schmitz-Hubsch

et al. 2006).

Other tools reported in single cases follow-up or cohort studies include the Berg

Balance Test, the timed unsupported stance test, the Functional Ambulatory Cate-

gory (FAC) test, the 10-m walk test, the Outpatient Physical Therapy Improvement

in Movement Assessment Log (OPTIMAL), the transverse abdominal thickness,

and the kinematic analysis and isometric endurance (Maring and Croarkin 2007;

Freund and Stetts 2010). Recently, quantitative movement analysis of the gait,

and static and dynamic balance tasks have revealed a specific behavior in patients

with degenerative ataxia and intensive coordinative training. Essentially, patients with

cerebellar ataxia showed significant improvement in intralimb coordination, bal-

ance control in gait and balance tasks as opposed to patients with afferent ataxia.

Physical Therapy Intervention

The aim of physical therapy is to maintain the individual’s independence in all

environmental contexts for as long as possible. The physical therapist will contrib-

ute to educate patients and family members about the effects of the disease on




function of life style, potential interventions and realistic expectations about them.

However, there is little evidence regarding specific physical therapy interventions

in these patients, therefore programs shown to be beneficial in other patient

populations with ataxia could be reasonably recommended (Sliwa et al. 1994;

Perlmutter and Gregory 2003; Harris-Love et al. 2004). Those programs include

aerobic fitness, maintenance of biomechanical alignment and counseling for assis-

tive or adaptive devices which would preserve independence of mobility.

Most authors agree that the main working goals in physical therapy are to

develop strategies to optimize sensorial information, to improve balance in stance

by postural reaction and postural stabilization, to develop strategies for an inde-

pendent gait, to improve the quality and control of movement in different body

postures, to exercise against resistance to improve hypotonia as well as to adjust

motor control, to calibrate the motor control of speech and to improve coordination.

Motor coordination can be trained using the Frenkel’s method (Vaz et al. 2008;

Martin et al. 2009). Essentially, Heinrich Sebastian Frenkel designed a method

to improve motor control through repetitive exercises. In general, treatment is

recommend early in the course of the disease, the patient should start with easy and

wide exercises and once they are perfectly performed, the next level of complexity

would be recommended. All exercises should be performed with open and closed

eyes, fast movements should precede the slow ones and proximal joints and trunk

should be approached from the beginning. A report of progression should be

registered.

Frenkel’s method should be complemented with a Bobath concept approach to

physiotherapy. The Bobath concept incorporates a bio-psycho-social approach and

is based upon recovery as opposed to compensation (Graham et al. 2009). The main

principles are: (1) human motor behavior is based upon continuous interaction

between the individual, the environment and the task; (2) the individual focuses

on the goal rather than the specific movement in the acquisition of motor skills; and

(3) learning and adaptation of motor skill involve a process associated with practice

and experience. Contemporary practice in the Bobath concept utilizes a problem-

solving approach to the individual’s clinical presentation and personal goals.

Treatment guides the individual toward efficient movement strategies for task

performance. The method in Bobath concept focuses particularly in two

interdependent aspects: the integration of postural control and task performance

and the control of selective movement for the production of coordinated sequences

of movement. Intervention is directed at analyzing and optimizing all factors

contributing to efficient motor control. The Bobath concept also seeks to utilize

appropriate sensory input to influence postural control and the internal representa-

tion of a postural body schema. One of the main strategies for improving postural

control in relation to gravity and the environment is the alignment of body segments

in relation to each other and the base of support. Selective movement and move-

ment patterns will be accessed by facilitating task-specific patterns of muscle

activation and the therapist aims to utilize afferent input to re-educate the internal

reference systems to enable the patient to have more movement choices and greater

efficiency of movement.


In addition to both the Frenkel method and Bobath concept, single case

reports have shown the benefit of trunk stabilization training and loco motor

training using body-weight support on a treadmill (Cernak et al. 2008; Freund

and Stetts 2010).

In conclusion, individualized physical therapy, including traditional and bio-

psycho-social methodology, is proposed as one of the main symptomatic treatments

for SCA patients. Therapy will have reasonable goals since small steps may

represent a great motivation and may increase adherence to treatment leading to

a real and sustainable change in patients’ lives and their families.

Concluding Remarks and Future Directions

As with other cerebellar diseases, the spinocerebellar ataxias are devastating neu-

rological diseases for which currently there are no effective and selective pharma-

cological treatments available that reverse or even substantially reduce motor

disability caused by the cerebellar neurodegeneration. The recent progress on the

understanding of cerebellar diseases has been possible through the combined efforts

of worldwide international academic networks. However, further experimental and

clinical research is needed to further understand their pathogenesis, validate and

define the role of the updated clinical diagnostic criteria, and to enhance the

assessment of the disease. This research will also help to develop novel supportive

neuroimaging methods and other clinical investigations that might improve the

diagnostic precision and facilitate early diagnosis and treatment. Importantly, more

effort is necessary to define disease-modifying therapeutic strategies. Currently,

physical therapy is the sole form of intervention that can improve walking ataxia in

affected individuals and effectiveness of physiotherapy for adults with cerebellar

dysfunction is currently under assessment (reviewed in Watson 2009). A more

recent study where patients with variable forms of cerebellar degenerative disease

were subjected to “intensive coordinative training” showed improvement in the

ataxia and balance clinical scales, indicating that rehabilitation may be of real

benefit to ataxic individuals (Ilg et al. 2009). Similarly, in a specific rehabilitation

program including foot sensory stimulation, and balance and gait training, 24 ataxic

patients with clinically defined sensory ataxia improved their balance with better

results in dynamic conditions (Missaoui and Thoumie 2009). These studies are of

particular interest because they showed how individuals with cerebellar damage can

learn to improve their movements, recover the control of their balance and propri-

oceptive contributions enabling them to achieve personally meaningful goals in

everyday life after proper training. Until effective and selective pharmacological

treatment which ultimately should lead to better quality of life and increased

survival of patients with cerebellar diseases, physical and sensory rehabilitation

are meanwhile revealing effective approaches for improving the patient’s quality of

life. Taken together, all the data resulting from the most recent intensive research

highlight that providing effective treatments to ataxia patients is no longer an

utopia, but it is possible in the foreseeable future.


Acknowledgments Dr. Ivelisse Sanchez’s helpful comments and suggestions are kindly

acknowledged. Dr. Antoni Matilla’s scientific research on ataxias is funded by the Spanish

Ministry of Science and Innovation (BFU2008-00527/BMC), the Carlos III Health Institute

(CP08/00027), the Latin American Science and Technology Development Programme

(CYTED) (210RT0390), the European Commission (EUROSCA project, LHSM-CT-2004-

503304), and the Fundacio de la Marato de TV3 (Televisio de Catalunya). We are indebted to

the Spanish Ataxia Association (FEDAES), the Spanish Federation for Rare Diseases (FEDER),

and the ataxia patients for their continuous support and motivation. Antoni Matilla is a MiguelServet Investigator in Neurosciences of the Spanish National Health System.

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