Treatment and management issues in ataxic diseases

Handbook of Clinical Neurology, Vol. 103 (3rd series) Ataxic Disorders S.H. Subramony and A. Du¨rr, Editors # 2012 Elsevier B.V. All rights reserved

Chapter 46

Treatment and management issues in ataxic diseases SUSAN L. PERLMAN* David Geffen School of Medicine at the University of California at Los Angeles, Los Angeles, CA, USA

INTRODUCTION The progressive ataxias are a diverse group of neurological diseases that share features of degeneration of the cerebellum and its inflow/outflow pathways, but differ in etiology, pathophysiology, course, and associated non-cerebellar system involvement. Some will have treatable causes; however, for most, the targets for disease-modifying therapy are incompletely known. Treatment strategies can include: 1) definitive therapy when available, 2) symptomatic treatment and prevention of complications, and 3) rehabilitation and support resources. The physician will have to decide whether to introduce or approve the use of therapies based on as yet unproven mechanisms or the use of complementary medicine approaches. There are as of yet no FDA-approved drugs for the treatment of the progressive ataxias and relatively few candidate disease-modifying therapies, but symptomatic and rehabilitation interventions can greatly improve the quality of life of individuals with these disabling neurodegenerative disorders.

DISEASE-MODIFYING THERAPIES The explosion of research in the pathophysiology and molecular genetics of the progressive cerebellar disorders will lay the foundation for the development and clinical testing of candidate drugs aimed at the neural degenerative process or the molecular mechanism itself (Table 46.1). Experience with these proposed treatments will conversely shed light on the underlying mechanisms of the disease and on the normal behavior of the system in health.

Acquired insult or deficiency that targets cerebellar neurons/pathways Direct neuronal damage, due to congenital, traumatic, vascular, infectious, inflammatory/immune-mediated, toxic, nutritional, hormonal, or neoplastic cause, can be addressed by eliminating or modifying the cause if possible. Hormone stabilization, nutritional correction, chelation therapy, anti-inflammatory treatment, antibiotic use, and vascular interventions can all potentially turn a progressive cerebellar deficit into a static one, amenable to rehabilitation and symptomatic management. The CNS complications of Langerhans cell histiocytosis (diabetes insipidus, cerebellar ataxia) may have delayed onset relative to the systemic manifestations and may not respond as well to treatment (Idbaih et al., 2004; Imashuku et al., 2004; Martin-Duverneuil et al., 2006). Immune-mediated processes have received increasing attention, with several anti-cerebellar antibodies being identified (Vianello et al., 2003; Fong, 2005) and attempts at immunosuppressant management being reported. Antigliadin antibodies (seen in gluten enteropathy/celiac disease) have been of special interest, due to their presence in both idiopathic and hereditary cerebellar degeneration, often without the enteropathy (Hadjivassiliou et al., 2003a; Shill et al., 2003). The gluten-free diet may be therapeutic and has undergone study both in Europe and at the NIH with variable results (Hadjivassiliou et al., 2003b; Briani et al., 2005; Volta et al., 2006). Immunomodulating therapies that have been used for both paraneoplastic and non-paraneoplastic cerebellar syndromes include corticosteroids (Bataller et al., 2001; Birand et al., 2006), plasmapheresis (McCrystal et al., 1995; Yeh et al., 1999; Miyamoto et al., 2002; Meloni

*Correspondence to: Susan L. Perlman, MD, Clinical Professor of Neurology, David Geffen School of Medicine at the University of California at Los Angeles, 300 UCLA Medical Plaza, Suite B200, Los Angeles, CA 90095, USA. Tel: 310/794-1225, Fax: 310/ 794-7491. E-mail: [email protected]

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Table 46.1 Disease mechanisms that are candidates for therapeutic intervention 1. Acquired insult or deficiency that targets cerebellar neurons/pathways 2. Direct neuronal damage 3. Congenital, traumatic, vascular, infectious, inflammatory/immune-mediated, toxic, nutritional, hormonal 4. Inborn errors of metabolism – loss of function 5. Inborn errors of DNA repair/cell cycle control – a. loss of function b. ataxia–telangiectasia and related disorders, SCAN1 6. Inborn errors of mitochondrial function – loss of function and acceleration of reactive oxygen species (ROS) reactions 7. Polyglutamine disorders – gain of function, transcriptional dysregulation, haploinsufficiency (SCA types 1, 2, 3, 6, 7, 17, Huntington’s disease) 8. Neuronal component regulation (SCA5) 9. Channelopathies (SCA6, SCA13, EA1, EA2) 10. Repeat expansions outside of coding region that may alter gene expression (SCA8, SCA10, SCA12, Huntington like disorder-2) 11. Other mechanisms (SCA types 4, 9, 11, 14–16, 19, 21, 22)

et al., 2004; Taniguchi et al., 2006), intravenous immunoglobulin (Daaboul et al., 1998; Abele et al., 1999; Go, 2003; Dalakas, 2005; Phuphanich and Brock, 2007), and standard chemotherapy agents that target B-cells (mycophenolate mofetil). Results with these modalities seem better for the non-paraneoplastic conditions, than for those associated with a neoplasm (which may respond to treatment of the underlying cancer). Rituximab, a chimeric mouse/human anti-CD20 monoclonal antibody, which selectively reduces B-cell activity and immunoglobulin production, may be more effective in the paraneoplastic cerebellar ataxias (Pranzatelli et al., 2003; Smitt et al., 2003). The use of these agents is briefly summarized in Table 46.2. Consultation with a specialist in hematology/ oncology or rheumatology may be necessary to design and monitor an immunosuppressant program.

2006), adrenomyeloneuropathy (Moser, 2006), cerebrotendinous xanthomatosis (Clemen et al., 2005), familial vitamin E deficiency (Mariotti et al., 2004), maple syrup urine disease (Morton et al., 2002; Strauss et al., 2006), pyruvate dehydrogenase deficiency (Klepper et al., 2004; Kaufmann et al., 2006; Stacpoole et al., 2006; Berendzen et al., 2006), Refsum’s disease (Wierzbicki et al., 2002; Ruther, 2005), and Wilson’s disease (Das and Ray, 2006). These readily identifiable disorders have been well reviewed with respect to diagnosis (Gray et al., 2000) and treatment (Gomez, 2001). Management typically relies on dietary modification, vitamin/cofactor supplementation, or, more recently, substrate reduction therapy (Aerts et al., 2006). Plasmapheresis has been used to control elevated levels of phytanic acid in Refsum’s disease (Hungerbuhler et al., 1985). Effective enzyme replacement therapy of type I Gaucher disease, based on chronic intravenous administration of mannose-terminated recombinant human glucocerebrosidase, has been available since 1990. Substrate reduction therapy, now available in the United States for type 1 Gaucher disease, is based on partial reduction of the synthesis of glucosylceramide and hence of subsequent metabolites. Oral administration of an inhibitor of glucosylceramide synthesis (N-butyldeoxynojirimycin, registered in Europe since 2002 as miglustat [Zavesca]), is effective in reversing clinical symptoms in type 1 Gaucher patients. Substrate reduction therapy, in conjunction with enzyme replacement therapy, may play an important role in the future clinical management of patients suffering from type 1 Gaucher disease. Clinical trials are underway that should reveal the value of substrate reduction for maintenance therapy of type 1 Gaucher disease and for treatment of neuronopathic variants of Gaucher disease, Niemann–Pick disease type C, late-onset Tay–Sachs disease (Platt et al., 1997), and Sandhoff disease. An innovative approach using gentamicin, to induce translational “read-through” of premature stop codons and allow the expression of full-length protein, has been explored in vitro and in clinical studies of cystic fibrosis (Wilschanski et al., 2003), Duchenne muscular dystrophy (Politano et al., 2003; Kimura et al., 2005), ataxia–telangiectasia (Lai et al., 2004), and lysosomal storage disease (Brooks et al., 2006).

Inborn errors of metabolism These recessive or X-linked genetic diseases typically result in decreased production of key enzymes, yielding a “loss of function” – diminished activity in critical metabolic pathways, resulting in the lack of a required substrate or cofactor or accumulation of a precursor or metabolite. Typical treatable examples are abetalipoproteinemia (Granot and Kohen, 2004; Clarke et al.,

Inborn errors of DNA repair/cell cycle control Ataxia–telangiectasia (A-T) is the classic example of this unique family of “loss of function” mutations. The mutated (ATM) protein is a PI-3 serine–threonine kinase, which phosphorylates more than a dozen distinct substrates, including itself, and p53, MDM2,

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Table 46.2 Use of immunomodulating therapies for antibody-mediated neurologic syndromes of various types – common treatment regimens Agent

Initial dose

Maintenance

Monitor

Risks

Corticosteroid Solumedrol

1 g IV qd
3–5 d

1 g IV/wk
1 mo, then q 2 wk
2 mo Slowly increase interval between doses

Weight, BP, blood sugar, electrolytes, ocular exam

50–100 mg qd for up to 3 mo or until clinical improvement is seen 1 g po bid

Taper by 5 mg every 2–6 weeks Alternate day regimen can be sought

As above

Weight gain, hypertension, diabetes, glaucoma, infection, osteoporosis, myopathy, pseudotumor, skin changes, mood change As above

1 g po bid

CBC q wk
1 mo, biw
2 mo, then q mo

Rituximab

375 mg/m2 IV weekly
2 wk

375 mg/m2 IV q 10 wk

Plasmapheresis

5 exchanges over 8–10 days

Benefits short-lived May repeat after a few weeks, but risks increase with repeat treatment Benefits short-lived May repeat every 4–6 weeks, aiming for increasing intervals

CBC, electrolytes, glucose, creatinine, CD3 and CD19, autoantibody titers Electrolytes, calcium

Prednisone

Mycophenolate mofetil (CellCept)

Intravenous 2 g/kg over 2–5 immunoglobulin days.

CHEK2, nibrin, H2AX, SMC1, Pin2/TRF1, FANCD2, BRCA1, IkBa kinase, and p53BP1. These substrates function in cell signaling to control the cell cycle, repair double-strand DNA breaks, respond to oxidative stress, and regulate transcription (Shiloh, 2003). The normal A-T gene product may have neuroprotective effects, and increasing attention is being paid to the role of oxidative stress in the pathophysiology of A-T (Barlow et al., 1999; Lee et al., 2001; Barzilai et al., 2002). Ataxia with oculomotor apraxia types 1 and 2 are caused by mutations in the genes for aprataxin and senataxin, respectively, proteins involved in DNA repair (Moreira et al., 2001) and RNA processing (Moreira et al., 2004). Another recessive disease – spinocerebellar ataxia with

No significant concerns

Diarrhea, vomiting, GI bleeding Leukopenia, sepsis (CMV, HSV, HZV, Candida) Secondary malignancy Avoid use of liveattenuate vaccines Avoid in pregnancy, PKU, and Lesch–Nyhan Absent B-cells. Allergic reaction Avoid use of anti-HTN medicine 12 h before dose BP instability, electrolyte imbalance, infection

Headache, back pain, increased risk of vascular sludging, cost

axonal neuropathy (SCAN1) (Takashima et al., 2002) – affecting an enzyme involved in DNA repair during transcription, may cause loss of post-mitotic neurons by similar mechanisms or by inducing apoptosis. Studies of antioxidant/free radical scavengers and iron chelators in vitro in A-T have been suggestive of benefit (vitamin E [Marcelain et al., 2002], alpha-lipoic acid [Gatei et al., 2001], iron chelators [Shackelford et al., 2004]) – but in vivo clinical trials have not yet been done to show improvement in the progressive neurologic features. Translational “read-through” of premature stop codons may allow the expression of full-length protein, providing a treatment alternative for patients with those mutations (Lai et al., 2004). High-throughput assays of

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other classes of candidate agents may reveal additional promising drugs (Shiloh et al., 2004).

Inborn errors of mitochondrial function These diseases are characterized by the loss of function of mitochondrial pathways (decreased oxidative energy supply, to which the cerebellum is very sensitive) and the acceleration of reactive oxygen species (ROS) reactions (leading to further cellular and mitochondrial disruption). Included are the usually maternally inherited “mitochondrial diseases”, with various point mutations (MERRF, MELAS, NARP) and deletions (Kearns– Sayres syndrome) (DiMauro and Moraes, 1993). While there have as yet been no large, randomized, doubleblind, placebo-controlled trials in homogeneous groups of patients with mitochondrial disease, several smaller studies have suggested benefits of certain antioxidants/metabolic stimulators in these disorders, such as creatine (Tarnopolsky et al., 1997; Tarnopolsky and Martin, 1999; Komura et al., 2003), and coenzyme Q10 (Di Giovanni et al., 2001; Artuch et al., 2006). Other candidate therapies have yet to be formally studied (Mahoney et al., 2002). The recessively inherited Friedreich ataxia (FRDA) has been established as a mitochondrial disorder, the reduced levels of gene product (frataxin) leading to altered mitochondrial iron handling, decreased iron/ sulfur cluster assembly, and alterations in the electron transport chain and energy production (Gerber et al., 2003), and the production of reactive oxygen species, which cause dysfunction of the inner mitochondrial membrane, oxidative stress, and neuronal death (Lynch et al., 2002). Coenzyme Q10, its synthetic analog idebenone, and vitamin E, as lipid-soluble antioxidants that protect the mitochondrial inner membrane, have been ideal candidates for study in Friedreich ataxia. Open-label (Rustin et al., 1999; Hausse et al., 2002; Buyse et al., 2003; Hart et al., 2005) and controlled trials (Schols et al., 2001; Mariotti et al., 2003) of these agents have shown some benefit for cardiac and muscle parameters, but no significant improvement in ataxia. An NINDS-sponsored phase 2 study of higher doses of idebenone has been completed and the data analyzed, and an industry-sponsored phase 3 study is in data analysis. A phase 1/2 study of mitoquinone (ubiquinone conjugated to a lipophilic cation that will enhance its mitochondrial uptake) (Kelso et al., 2002; Jauslin et al., 2003) has been considered . The use of mitochondrially targeted iron chelators has also been proposed (Richardson, 2003), and deferiprone is now in an industry-sponsored phase 2 study. Commonly cited antioxidants are summarized in Table 46.3.

Gene replacement (Fleming et al., 2005) or upregulation of native frataxin production (Ghazizadeh, 2003; Turano et al., 2003; Sturm et al., 2005) are promising future approaches. The GAATTC expansion has been felt to interfere with transcription of frataxin mRNA by forming triplex structures (Ohshima et al., 1998; Sakamoto et al., 1999; Grabczyk and Usdin, 2000) or highly condensed, histone-containing heterochromatin structures, which are associated with silencing of nearby genes (Saveliev et al., 2003). Gottesfeld’s group (Herman et al., 2006), following up the observation that the class of histone deacetylase inhibitors (HDACi) might revert silent heterochromatin to the active chromatin conformation (Di Prospero and Fischbeck, 2005), identified and optimized an HDACi (compound 4b) that specifically reversed the transcription repression of frataxin, bringing frataxin levels in cultured FRDA lymphocytes to the level of untreated carrier lymphocytes. This compound is now being readied by industry for a phase 1 study. An updated pipeline of drug development for FRDA can be found on the website for the Friedreich’s Ataxia Research Alliance (www.curefa.org).

Polyglutamine disorders This group of inherited ataxias represents the majority of autosomal dominantly inherited cerebellar disorders in North American and European populations (Perlman, 2003). Included are spinocerebellar ataxia (SCA) types 1, 2, 3, 6, 7, and 17, and dentatorubral–pallidoluysian atrophy (DRPLA). They are characterized by exonic CAG repeat expansions within their respective genes, which do not seem to interfere with transcription and translation of the gene product, although the total amount of normal gene product (all from the nonexpanded allele) is reduced to 50% and may play a role in reduced normal gene product function (“haploinsufficiency”) (Dragatsis et al., 2000). However, the expanded polyglutamine (polyQ) tract within the abnormal protein seems to actively contribute to a regionally specific neurodegeneration – a “gain of function” (Albin, 2003). The common mechanism of pathogenesis is felt to involve transcriptional dysregulation (polyQ interactions with transcription factors [Ross, 2002]), altered proteosome activity (polyQ fragment interactions within the proteosome), or some excitotoxic or pro-apoptotic effect of the neuronal intranuclear inclusions containing polyQ fragments. Mitochondrial dysfunction with associated decreases in energy production and increases in reactive oxygen species (Chou et al., 2006; Wang et al., 2006a) and inflammatory changes (Evert et al., 2001) are also seen.

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Table 46.3 Use of antioxidants and metabolic stimulators Agent

Doses cited in research reports

Monitor

Risks

Alpha lipoic acid Coenzyme Q10

150–1800 mg/day 400–1200 mg/day

No particular concerns LFTs Cholesterol levels PT/PTT

Creatine

5–10 g/day Lower doses are recommended in patients on cimetidine, diuretics, NSAIDs, probenecid, and trimethoprim 50–45 mg/kg/day

Creatinine

No particular concerns Mild GI changes May interfere with the activity of cholesterol-lowering medications or oral anticoagulants Should not be used in patients with kidney disease Avoid dehydration

Idebenone

L-carnitine (D-carnitine should not be taken). N-acetylcysteine Omega-3 fish oil/ EPA (eicosapentaenoic acid) Selenium Vitamin E (d-alpha tocopherol succinate)

White blood cell and absolute neutrophil count Chemistry panel Carnitine levels

Mild nausea Urine discoloration

60 mg/kg/day 2 g/day

No particular concerns No particular concerns

Mild GI changes Bruising/bleeding

50–100 mg/day (not to exceed 400 mg/day) 300–1200 IU/day

No particular concerns

Diarrhea, hair/nail/skin changes, fatigue, neuropathy Diarrhea, abdominal pain, bruising/ bleeding, possible blood clots in patients on estrogens

250–1250 mg/day

PT/PTT in patients on oral anticoagulants

Work in Huntington’s disease (a non-ataxic polyQ disorder), involving in vitro and animal studies and human clinical trials, has served as a springboard for similar work in the polyQ ataxias. The first human clinical trial in the SCAs has been done at NINDS, a phase 1 study of safety and tolerability of lithium in SCA1 (based on observations of improved neuronal function and hippocampal dendritic arborization in the SCA1 mouse model). Modifiers of the final common pathways for neuronal death ( Mattson, 2003; Schon and Manfredi, 2003) – free radical scavengers (alpha-lipoic acid, N-acetylcysteine/NAC, riboflavin, selenium, vitamin E), mitochondrial cofactors/stabilizers (coenzyme Q10, creatine, ethyl-eicosapentaenoic acid/ethyl-EPA, L-carnitine, tauroursodeoxycholic acid/TUDCA), and anti-excitotoxicity/anti-glutamate agents (remacemide, amantadine, and memantine – NMDA receptor blockers; riluzole – reduced glutamate release) – have shown suggestive benefits in animals (Kaemmerer et al., 2001), but less dramatic improvement in human studies (Peyser et al., 1995; Group, 2001; Seppi et al., 2001; Tabrizi et al., 2003). There is some thought that AMPA-type glutamate

Mild GI changes

receptor blockers might offer more potent anti-excitotoxicity effects (Ikonomidou et al., 2000; Van Damme et al., 2003). Caspase inhibitors (minocycline, ethyl-EPA), that may interrupt apoptosis or reduce the formation of polyQ fragments, and agents that may modify polyQ aggregation (minocycline, anti-transglutaminases – cystamine, other molecular chaperones) have also been studied (Deigner et al., 2000; Cummings et al., 2001; Yoshida et al., 2002; Steffan and Thompson, 2003), but with contradictory results (Bonelli et al., 2003; Smith et al., 2003). More recent studies of the mechanisms of transcriptional dysregulation have focused on the histone deacetylase inhibitors (suberoylanilide hydroxamic acid/SAHA, phenylbutyrate, valproic acid) as candidate agents to upregulate genes whose expression might have been suppressed by the polyQ gene product (Steffan et al., 2001; Hockly et al., 2003). Small interfering RNA (siRNA) technology, targeted to the disease mutation or a linked singlenucleotide polymorphism, has been shown to selectively silence the mutant SCA3 allele, while sparing the wild-type allele (Miller et al., 2003), and will hopefully be further

640 S.L. PERLMAN studied in the available animal models of the polyQ ataxias SYMPTOMATIC TREATMENT and ultimately in human clinical trials. Treatment of primary cerebellar symptoms – An interesting new line of research into the use of ataxia, action tremor, dizziness, nystagmus, nerve growth factors has shown the rescue of cerebellar and fatigue Purkinje cells in the SCA1 mouse using intranasal insulin-like growth factor-1 (IGF-1) (Fernandez et al., 2005; The cerebellum is one of the best understood areas in Vig et al., 2006). the brain with respect to its anatomy and physiology, neurochemistry, and neuropharmacology (Oertel, 1993). Channelopathies Attempts have been made to correlate various cerebellar degenerative processes to particular neuronal/neurochemDominantly inherited ion channel dysfunction causes two ical subsystems and to design drug trials on the basis of forms of episodic ataxia (EA) (EA1 – various missense this information, but, as yet, no definitive pharmacotheramutations in the KCNA1 potassium channel subunit gene; pies based on neurotransmitter mechanisms have proven EA2 – point mutations in the CACNA1A calcium channel acceptably successful (Perlman, 2000, 2004; Ogawa, subunit gene), and may play a role in the pathophysiology 2004; Colosimo et al., 2005). Medications that have shown of SCA6, a polyQ disorder with the CAG expansion in some benefits may affect symptoms from more than one the same gene as EA2, suggesting both a polyQ mechanism cerebellar region or influence more than one neurotransand an ion channel mechanism (Frontali, 2001; Piedrasmitter, if their mechanism of action is known at all. Drugs Renteria et al., 2001; Kubodera et al., 2003). Symptomatithat modify monoamine transmission (from cerebellar cally, EA1 responds to standard doses of anticonvulsants afferents) and continue to have off-label use for cerebellar (phenytoin, carbamazepine, valproic acid) and EA2 to acetataxia, based on results of open and controlled studies, azolamide (250–1000 mg per day in divided doses) or the include amantadine (increased release of brain monoapotassium channel blocker 4-aminopyridine (Strupp et al., mines) (Peterson et al., 1988; Filla et al., 1993; Botez 2004). Cases of SCA6 with episodic features and some et al., 1996), buspirone (5-HT1A receptor agonist) (Lou cases of EA1 have also improved with the use of acetazolet al., 1995; Friedman, 1997; Trouillas et al., 1997; amide (Lubbers et al., 1995; Jen et al., 1998; Jen, 2000; Yabe Holroyd-Leduc et al., 2005), tandospirone (5-HT1A recepet al., 2001). A small controlled trial of branched-chain tor agonist) (Takei et al., 2004, 2005), and ondansetron amino acid supplements (1.5–3 g per day) reported benefit (5-HT3 receptor antagonist) (Rice et al., 1997; Mandelcorn in SCA6 (Mori et al., 2002). (Of interest, a trial of tetrahyet al., 2004). L-5-OH tryptophan, a serotonin precursor, drobiopterin, a cofactor in amino acid synthesis, reported has also been studied in patients with genetic and acquired benefit in SCA3 [Sakai, 2001], possibly on the basis of modataxias, with mixed results (Trouillas et al., 1988, 1995). ified Purkinje and granule cell activity, reinforcing attenGamma-aminobutyric acid (GABA) transmission tion to the possible role of non-antioxidant supplements (intracerebellar, e.g., Purkinje cells, and efferents to in the treatment of these disorders.) inferior olive) can be modulated by benzodiazepines (GABA-A receptor), e,g., clonazepam, but they may lead Repeat expansions outside of the coding to long-term worsening of cerebellar function. Baclofen, region that alter gene expression a GABA-B agonist, also tends to increase ataxia. GabaThree dominantly inherited disorders (SCA8, SCA10, pentin and other anticonvulsant drugs have been SCA12) are characterized by repeat expansions within reported, in small open studies, to improve cerebellar non-coding regions of the gene locus (SCA8 – CTA/ signs in patients with isolated cerebellar cortical atrophy CTG, SCA10 – ATTCT, SCA12 – CAG). The pathogenesis and with cerebellar and brainstem atrophy (Gazulla of neurodegeneration in these disorders is incompletely et al., 2003; Gazulla and Benavente, 2005; Liu et al., understood, although it may include transcriptional dysre2005; Gazulla and Tintore, 2007). Similar small studies gulation, altered mRNA processing, or haploinsuffiwith zolpidem have suggested efficacy (Clauss and Nel, ciency (Albin, 2003). Disease-modifying approaches 2004; Clauss et al., 2004). Thyrotropin-releasing hormone have not yet been investigated and will depend on reliable (TRH) may also modulate GABA receptors and has in vitro or animal models. shown mild efficacy in animal studies and class I trials (Sobue et al., 1983; Filla et al., 1989; Waragai et al., Other mechanisms 1997; Shirasaki et al., 2003; Nakamura et al., 2005). Tanabe Seiyaku Co., Ltd., has marketed an oral TRH forSCA types 4, 9, 11, 14–16, 19, 21, and 22, and EA-3 mulation (Ceredist) since September 2000, approved in and EA-4 have as yet unknown molecular mechanisms, Japan as an orphan drug for spinocerebellar ataxia. More and disease-modifying therapies will have to await the recently, the anti-smoking drug varenicline has been elucidation of these basic processes.

TREATMENT AND MANAGEMENT ISSUES IN ATAXIC DISEASES reported to improve balance in patients with ataxia, in an anecdotal fashion (Zesiewicz and Sullivan, 2008; Zesiewicz et al., 2009). Studies that have attempted to improve ataxia as a symptom are summarized in Tables 46.4–46.6. Physical therapy interventions for pain (stretching, manual mobilization), strengthening, and aerobic conditioning (Fillyaw and Ades, 1989) can be beneficial for those needs in the ataxic patient. For gait ataxia, published studies demonstrate improvement with rehabilitation strategies, including rhythmic, repetitive exercise for neuromuscular re-education (Armutlu et al., 2001; Perlmutter and Gregory, 2003; Perez-Avila et al., 2004); balance retraining (Balliet et al., 1987; Cattaneo and Cardini, 2001); visual feedback techniques (Baram and Miller, 2006); and assessment for the use of adaptive devices (Gillen, 2002). In patients with a primary mitochondrial process, care may need to be taken to avoid fatigue-producing exercise regimens, as these individuals may be at greater risk for exercise intolerance and myoglobinuria (DiMauro, 1999; Vorgerd et al., 2000). Small studies are also now being done to assess the role of complementary medicine approaches in cerebellar ataxia, such as acupuncture (Wang et al., 2006b). Cerebellar tremor (Lambertand Waters, 1999) and nystagmus (Averbuch-Heller, 1999; Tusa, 1999) have had similar symptomatic approaches explored. Drugs studied for cerebellar-mediated essential-type and

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action tremor target the same neurotransmitter systems mentioned for ataxic symptoms above: carbamazepine (Sechi et al., 1989); clonazepam (Biary and Koller, 1987; Koller et al., 1987); gabapentin (Onofrj et al., 1998); isoniazid (Hallett, 1985; Hallett et al., 1985); levetiracetam, piracetam (Agarwal and Frucht, 2003; De Rosa et al., 2006; Striano et al., 2006); ondansetron (5-HT3 receptor agonist) (Rice et al., 1997; Gbadamosi et al., 2001; Bier et al., 2003); primidone; propranolol; topiramate (Sechi et al., 2003); valproic acid (Sotaniemi, 1982; Borggreve and Hageman, 1991; Meldrum, 1986); zonisamide (Takigawa et al., 1997). Botulinum toxin injections into muscles generating severe postural (and vocal) tremor have been a viable alternative to oral medication (Pacchetti et al., 2000), despite the risk of muscle weakness (Brin et al., 2001). Neural stimulation techniques – dorsal column stimulation, vagal nerve stimulation, transcranial magnetic stimulation (Shimizu et al., 1999; Shiga et al., 2002), and thalamic stimulation (Bryant et al., 2003; Schramm et al., 2005) – have been tried for cerebellar tremor and truncal instability, where medical interventions have failed, but may have serious complications (bleeding, infection, stroke) and high cost (upwards of $25 000). In nystagmus, drugs targeting GABAergic receptors – baclofen (Halmagyi et al., 1980; Averbuch-Heller et al., 1997; Lee and Lessell, 2003), benzodiazepines (McConnell et al., 1990; Yamamoto et al., 1992; Young

Table 46.4 Trials of cholinergic neurotransmitter based therapy of ataxia

Reference

Drug

Design/patient #/ diagnosis/duration

Kark et al., 1977 Lawrence et al., 1980

Physostigmine Choline Cl

DB/8/various/3 months DB/14/various/6 weeks

Sehested et al., 1980 Kark et al., 1981

Choline Cl Physostigmine

Reding et al., 1981 Livingstone et al., 1981 Filla and Campanella, 1982 Finocchiaro et al., 1985 Sorbi et al., 1988 Wessel et al., 1997

Lecithin Choline Cl Ph-ch

DBCO/6/various/4 days DBTCO/21/familial/3 months DBCO/2/various/5 weeks DBCO/20/various/6 weeks O/23/familial/6 months

Lecithin

O/11/various/3 months

Clinical scale

Ph-ch Physostigmine patch Varenicline

O/44/various/4 years DBCO/19/various/4 weeks O, case reports

Zesiewicz et al., 2008, 2009

Assessment

Result

Clinical exam, videos Clinical exam, writing, peg-board Clinical exam Clinical exam

Effective Not effective Not effective Effective

Clinical exam Clinical exam

Not effective Mild effect in some

Clinical scale

Clinical scale Clinical, PG

Mild effect in early disease Minimal effect with low drug levels Not effective Not effective

Clinical exam, videos

Effective

CO ¼ crossover; DB ¼ double blind; O ¼ open label; PG ¼ posturography; Ph-ch ¼ phosphatidylcholine; TCO ¼ triple crossover.

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Table 46.5 Trials of serotoninergic neurotransmitter-based therapy for ataxia

Reference

Drug

Trouillas et al., 1988 Wessel et al., 1995

L-5HTP L-5HTP

Trouillas et al., 1995 Lou et al., 1995 Manto et al., 1997 Trouillas et al., 1997

L-5HTP/FA Buspirone L-5HTP Buspirone

Bier et al., 2003 Monte et al., 2003 Takei et al., 2004

Ondansetron Fluoxetine Tandospirone

Design/patient #/diagnosis/ duration DB/30/various/4 months DBCO/39/various/ 10 months DB/19/FA/6 months O/20/various/8 weeks O/6/various/6 months DB/19/sporadic ataxia/ 4 months DB/45/various/7 days O/13/MJD/2 weeks O/10/MJD/7 weeks

Assessment

Result

Clinical scale Clinical scale

Effective for total and kinetic scores Not effective

Clinical scale Clinical, PG Clinical Clinical, PG

Effective for kinetic score Effective in early disease Not effective Effective

Clinical Clinical scale Clinical scale (ICARS), PG

Not effective Not effective Effective

CO ¼ crossover; DB ¼ double blind; FA ¼ Friedreich ataxia; L-5HTP ¼ L-5-hydroxytryptophan; MJD ¼ Machado–Joseph disease; O ¼ open label; PG ¼ posturography.

Table 46.6 Trials of miscellaneous agents in ataxia Reference

Drug

Design/patient #/ diagnosis/duration

Assessment

Results

Sobue et al., 1983

TRH

DB/254/various/2 weeks

Clinical scale, VAS

Banerjee et al., 1984

Lithium

O/10/various/2 weeks

Quantitated tasks

Peterson et al., 1988 Filla et al., 1993 Sakai et al., 1995

Amantadine Amantadine S-T

SB/16/FA/60 min DBCO/12/FA/90 min DBCO/8/MJD/4 weeks

Sakai et al., 1996

THBPT

DBCO/5/MJD/10 days

Schulte et al., 2001 Yabe et al., 2001 Shiga et al., 2002 Ogawa et al., 2003 Liu et al., 2005

S-T Acetazolamide TCMS D-cycloserine Lamotrigine

DBCO/22/MJD/6 months O/6/SCA6/88 weeks DB/74/various/3 weeks SB/15/various/2 weeks O/6/MJD/8 weeks

Clinical scale Clinical scale Clinical scale, timed tests Clinical scale, timed tests Clinical scale, PG Clinical scale Quantitated tasks Clinical scale Stance and tandem gait

Effective, more in cerebellar forms Effective, esp. in combination with choline Cl Effective Not effective Timed tests better Timed tests better Not effective Effective Effective Effective Effective

CO ¼ crossover; DB ¼ double blind; FA ¼ Friedreich ataxia; MJD ¼ Machado–Joseph disease; O ¼ open label; SB ¼ single blind; SCA6 ¼ spinocerebellar ataxia 6; S-T ¼ trimethoprim-sulfa; TCMS ¼ transcranial magnetic stimulation; VAS ¼ visual analog scale.

and Huang, 2001), gabapentin (Averbuch-Heller et al., 1997; Fabre et al., 2001), valproic acid (Williams et al., 1988) – serotoninergic receptors (Macleod, 2000), and cholinergic receptors (Schmitt and Shaw, 1986; Leigh et al., 1991; Lauter et al., 1999) have shown some success in individual cases. Carbamazepine has also been reported to be helpful in one case of nystagmus and

vertigo on a vestibular nuclear basis (Lawden et al., 1995). Recent controlled trials of the potassium channel blocker, 3,4-diaminopyridine, which increases the excitability of Purkinje cells, showed significant improvement of downbeat nystagmus (Strupp et al., 2003; Sprenger et al., 2006). Ocular rehabilitation exercises and devices (Carlow, 1986) and vestibular rehabilitation

TREATMENT AND MANAGEMENT ISSUES IN ATAXIC DISEASES exercises (beneficial for peripheral vestibular dysfunction, but not yet studied for central vestibular effect) (Tokumasu et al., 1993; Baloh, 1994) may provide nondrug approaches to nystagmus. Acetazolamide, a brain carbonic anhydrase inhibitor, lowers the threshold for P/Q-type voltage-gated calcium channel activation (Wan et al., 2003) and has been dramatically effective, in open studies, in controlling features of episodic ataxia/vertigo in EA2 and in SCA6 with episodic features (Jen et al., 1998; Yabe et al., 2001), which are caused by mutations in a gene encoding for the Cav2.1 subunit of that channel (Jen and Baloh, 2002). The use of these agents is summarized in Table 46.7.

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Treatment of associated non-cerebellar neurologic symptoms – spasticity, rigidity, involuntary movements, paresthesias and pain, bowel and bladder dysfunction, sexual dysfunction, orthostasis, cognitive and emotional disturbances, seizures While the impact of non-cerebellar symptoms on quality of life in patients with cerebellar ataxia has not been formally assessed, it is likely that these could be more bothersome than difficulties with balance and coordination. There are many widely used, FDA-approved, drug and non-drug approaches to the management of these symptoms, which should be treated aggressively, with

Table 46.7 Use of drugs employed in patients with ataxia Indication

Agent

Dose

Monitor

Risks

Imbalance Incoordination

Acetazolamide

250 mg–4 g/day in divided doses (bid–qid) Avoid use in hepatic or renal failure or with sulfa allergy

Kidney stones (15–36% of users), GI upset, nausea, metallic taste, paresthesias, weight loss

Amantadine

25–150 mg bid Lower dose for children and in renal insufficiency

Buspirone

Titrate up from 5 mg bid to as much as 30 mg bid Avoid use in hepatic or renal failure or with MAO inhibitors

Gabapentin

Titrate up from 300 mg tid to as much as 1600 mg tid Lower dose in renal insufficiency or the elderly

CBC Electrolytes Suggested to obtain renal ultrasound after 6 months of use Taper off, if discontinuing, to avoid neuroleptic malignant syndrome Creatinine LFTs PT/PTT in patients on oral anticoagulants Blood pressure CBC

L-5-OH tryptophan

600 mg–1 g per day

LFTs

Thyrotropin-releasing hormone

2–4 mg IM qd (oral formulation is available in Japan) 100–400 mg tid Has the potential for multiple drug interactions

TFTs

Action tremor

Carbamazepine

CBC, LFTs, Na, BUN, RUA, TFTs, blood levels Eye exam

Anticholinergic Livido reticularis Pedal edema Refractoriness after 6–12 months of use Dizziness, nausea, headache

Behavior or mood changes, dizziness, ataxia, fatigue, somnolence, hyperkinesia, joint pain, bruising, peripheral edema, weight gain Eosinophilia–myalgia syndrome Nausea, headache, hypersensitivity, hyperthyroidism Hypersensitivity Aplastic anemia Cardiovascular Dizziness, asterixis, drowsiness, nausea Continued

Table 46.7 Continued Indication

Agent

Dose

Monitor

Risks

Clonazepam

0.5–2 mg qd Lower dose in renal insufficiency Some drug interactions See above Up to 600 mg bid with 100 mg B6 qd Severe or fatal hepatitis more common in patients over age 35 or using alcohol Titrate up from 500 mg bid to as much as 1500 mg bid Reduce starting dose to 250 mg bid in renal insufficiency or the elderly Titrate up to 4–8 mg tid Do not exceed 8 mg per day in patients with liver dysfunction Use with caution in patients with impaired gastric motility Titrate up from 125 mg qhs to as much as 500 mg tid As little as 75 mg qd in the elderly Has the potential for multiple drug interactions Titrate up from 40 mg bid to as much as 240 mg per day Should not be used in patients with PR<70 bpm, CHF, WPWS, or asthma Should be used with caution in diabetes, impaired hepatic or renal function, or h/o severe anaphylaxis Should be tapered slowly if discontinuing Has the potential for multiple drug interactions Titrate up from 25 mg qd to as much as 300 mg bid Maintain adequate fluid intake Reduce dose in renal dysfunction or the elderly May interfere with oral contraceptive Titrate up from 250 mg qd to as much as 1000 mg bid Reduce dose in the elderly Has the potential for multiple drug interactions

CBC, LFTs Taper off if discontinuing

Drowsiness, hypersalivation

See above LFTs monthly CBC

See above Peripheral neuropathy, optic neuritis, other CNS, GI, hematologic, hypersensitivity, and lupuslike reactions Dizziness, fatigue, headache, irritability, and somnolence

Gabapentin Isoniazid

Levetiracetam.

Ondansetron

Primidone Tremor in cerebellar disease that has features of essential tremor may respond to this medication Propranolol Tremor in cerebellar disease that has features of essential tremor may respond to this medication

Topiramate

Valproate

CBC

LFTs

Extrapyramidal reactions, rash or more severe hypersensitivity reactions

CBC LFTs

Cognitive/mood dysfunction, dizziness, ataxia, hyperkinesias, insomnia, neuropathy, sedation, skin rash

Pulse rate, blood pressure CBC LFTs BUN

Circulatory changes, various CNS and GI complaints, bronchospasm, skin rash, impotence, fatigue, depression

CBC

Kidney stones (1.5%), decreased sweating (in children), cognitive slowing, fatigue, somnolence, emotional lability, dizziness, paresthesias, nosebleeds, glaucoma, weight loss Dizziness, tremor, drowsiness, hair loss, nausea, weight gain

CBC LFTs, ammonia Amylase

Continued

Table 46.7 Continued Indication

Nystagmus Dizziness or other central vestibular symptoms

Agent

Dose

Monitor

Risks

Zonisamide

Titrate up from 100 mg qd to as much as 300 mg bid Maintain adequate fluid intake Avoid in sulfa allergy

CBC LFTs

Acetazolamide

See above

See above

Kidney stones (1.9–4%), decreased sweating (in children), agitation, cognitive slowing, somnolence, dizziness, headache, nausea, skin rash, weight loss See above

Baclofen

Titrate up to 5–40 mg tid Use with caution in patients with epilepsy, diabetes, liver dysfunction, peptic ulcer disease, porphyria, psychiatric disease, respiratory disease, stroke, urinary retention Reduce dose in renal insufficiency and the elderly Avoid abrupt withdrawl Has the potential for multiple drug interactions Titrate up to 5–10 mg taken four to five times per day, maximum 80 mg per day

Blood sugar LFTs

Ataxia, confusion, dizziness, drowsiness, dry mouth or eyes, hallucinations, headache, hypotension, muscle weakness, nausea, rash, seizures, sweating, tremors Baclofen may disturb autonomic control of circulation during general anesthesia

No particular concerns

Carbamazepine Clonazepam Gabapentin Meclizine

See above See above See above 25 mg up to four times daily Use with caution in patients with asthma, glaucoma, or prostatic hypertrophy Alcohol use to be avoided

See above See above See above No particular concerns

Ondansetron Promethazine

See above 25 mg bid Use with caution in patients on MAOIs or with asthma, glaucoma, prostatic hypertrophy Alcohol use to be avoided Reduce dose in the elderly Not to be used in children under 2

See above Blood sugar CBC LFTs

Nausea, perioral and digital paresthesias Rarely cardiac arrhythmia (with overdose), confusion, seizures See above See above See above Drowsiness, dry mouth, visual blurring These side effects could worsen the symptoms of ataxia and dysarthria, even if the dizziness improves See above This phenothiazine derivative may cause apnea or fatal respiratory depression, severe CNS depression, hallucinations, lowered seizure threshold, bone marrow depression, acute extrapyramidal syndromes including neuroleptic malignant syndrome Alternative drugs should be sought

3,4-diaminopyridine

Continued

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Table 46.7 Continued Indication

Agent

Dose

Monitor

Risks

Scopolomine Transdermal patch

1.5-mg patch applied every 3 days Use with caution in patients with glaucoma; pyloric, other GI, or bladder neck obstruction; or with a history of seizures or psychosis Use with caution in the elderly or in patients with liver or kidney dysfunction Not to be used in children Titrate from 1 mg per day up to 5 mg twice a day Use with caution in patients with glaucoma; pyloric, other GI, or bladder neck obstruction; or with a history of seizures or psychosis Use with caution in the elderly and in patients with liver or kidney dysfunction See above

No particular concerns

Drowsiness, dry mouth, mental confusion or agitation, visual blurring These side effects could worsen the symptoms of ataxia and dysarthria, even if the dizziness improves

No particular concerns

Drowsiness, dry mouth, mental confusion or agitation, visual blurring These side-effects could worsen the symptoms of ataxia and dysarthria, even if the dizziness improves

See above

See above

Trihexyphenidyl

Valproate

the help of appropriate consultants if necessary. Oral agents for spasticity typically include ataxia as a side effect, so alternative approaches such as an intrathecal baclofen pump (Ben Smail et al., 2005), botulinum toxin injections (Freeman and Wszolek, 2005), and surgical releases may have to be sought. Cerebellar syndromes with associated basal ganglia features (e.g., multiple system atrophy) may respond to L-dopa or dopamine agonists. Associated cognitive dysfunction (typically subcortical and often subtle) may respond best to behavioral management and treatment of comorbid depression or fatigue. While cholinesterase inhibitors have shown some efficacy in the vascular dementias (Black et al., 2003; Corey-Bloom, 2003; Gabelli, 2003), they have not been studied in other forms of subcortical dementia and may have side effects and drug interactions that would warrant prudent use in this population (Bentue-Ferrer et al., 2003).

cardiomyopathy/arrhythmia/embolic consequences, skeletal deformities, diabetes; ataxia–telangiectasia – immunodeficiency, neoplasia), rather than by the course of the cerebellar degeneration, necessitating consultation and collaboration with experienced specialists. The standard drug treatments for these associated conditions may worsen ataxic symptoms or damage other neurologic systems. The stress and immobilization that accompany surgical interventions may also lead to a functional decline that may not recover to the prior baseline. Patients with ataxia–telangiectasia and neoplasm should follow cancer treatment protocols that are minimally radiomimetic, due to increased radiation sensitivity in this disorder (Sandoval and Swift, 1998).

PREVENTION OF COMPLICATIONS Falls

Treatment of associated non-neurologic symptoms – cardiac changes, skeletal deformities, diabetes, adrenal insufficiency, immunodeficiency, neoplasia Ultimate morbidity and mortality in certain ataxic conditions may be determined by these medical features (e.g., Friedreich ataxia and other mitochondrial disorders –

Fall risk assessment (by history or rehabilitation/physical therapy consultant), with preventive intervention, should be obtained on all ataxic patients. The presence of impaired vision, leg weakness or sensory loss, postural instability, and dementia increase the risk of falling (Sharma and MacLennan, 1988). Cardiovascular factors, orthostasis, syncope, transient ischemic attacks,

TREATMENT AND MANAGEMENT ISSUES IN ATAXIC DISEASES and otologic vertigo may have to be evaluated and ruled out in the older patient (O’Mahony and Foote, 1998), as well as the use of medication that may promote falls (e.g., diuretics, sedative/hypnotics) (Sobel and McCart, 1983). Prescription and training in the use of appropriate assistive devices and eliminating hazards in the home and environment could be helpful in reducing the occurrence of falls, with their accompanying injuries and erosion of self-confidence.

Immobility, deconditioning, weight gain, skin breakdown, infection, venous thromboembolism Disorders of mobility, by definition, lead to immobility and all of its attendant risks – which themselves promote further immobility. The use of exercise and assistive devices to keep the ataxic patient “on his feet,” or at least moving, help interrupt this downhill slide. Nutritional consultation for weight loss and careful medical monitoring can pick up problems before they become insurmountable. Venous thromboembolism prophylaxis may need to be considered if multiple risk factors are present (Anderson and Spencer, 2003).

Bulbar dysfunction, including declining speech, choking/nutritional issues, altered breathing, obstructive and central sleep apneas, parasomnias Progressive bulbar dysfunction occurs in most forms of ataxia and can lead to difficulty eating and drinking (with subsequent weight loss and aspiration/choking), as well as to alterations in breathing and sleep disturbance. In multiple system atrophy, the terminal event may be a cessation of breathing during sleep, due to increasing stridor. Instructions to patient and family, as to what to look for and report, can aid in the early identification of problems. A baseline radiographic swallowing study and nocturnal polysomnogram can lead to preventative interventions (dietary modifications, medications for parasomnias, positive pressure airway devices during sleep, consideration of a G-tube or tracheostomy).

WHAT DOES THE PATIENT WANT? Information is the most commonly sought commodity in the spinocerebellar ataxias. Patients want to know what they have, what is the cause, what is the risk for their children, will it get worse (and how fast), is there a cure, and is there any research being done. The tempo of research has done much to fan the flames of hope, but effective disease-modifying therapies may still be decades away.

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A detailed and ongoing treatment plan for each patient should be formulated and modified as circumstances dictate. The goals will be to treat any identifiable causes; improve symptoms, performance, and quality of life; prevent complications; and (ultimately) modify disease progression. The treatment plan should include symptomatic medication; physical, occupational, and speech therapy interventions; use of appropriate aids to gait and ADL; safety assessment of the home and daily environment of the patient at work, at school, and in the community; nutritional assessment; resources for in-home health assistance and caregiver respite; genetic counseling; psychosocial counseling; referral to support groups; and referral to legal aid for issues of power of attorney and conservatorship. Choking, falling, changes in weight, sleep disturbance, and changes in memory, mood, or behavior must be screened at each visit. When the ataxic disorder is associated with nonataxic complications (ocular/auditory, cardiac/blood pressure, respiratory/sleep, bowel/bladder, orthopedic, endocrine/metabolic, immune/neoplastic), these also must be monitored from visit to visit and appropriate sub-specialty consultation obtained. Symptomatic and rehabilitation strategies can greatly improve the quality of life in individuals with these disabling neurodegenerative disorders.

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