Progression of Ataxia Susan L. Perlman M.D. Clinical Professor of Neurology Director, UCLA Ataxia Clinic Medical Director, National Ataxia Foundation
NAF AMM Las Vegas
The information provided by speakers in any presentation made as part of the 2014 NAF Annual Membership Meeting is for informational use only.
NAF encourages all attendees to consult with their primary care provider, neurologist, or other health care provider about any advice, exercise, therapies, medication, treatment, nutritional supplement, or regimen that may have been mentioned as part of any presentation.
Products or services mentioned during these presentations does not imply endorsement by NAF.
Susan L. Perlman M.D.
The following personal financial relationships with commercial interests relevant to this presentation existed during the past 12 months:
No personal relationships to disclose.
Research relationships include Edison Pharmaceuticals, ViroPharma, and Teva Pharmaceuticals.
UCLA ATAXIA/NEUROGENETICS CENTER
Founded--mid-1970’s as a research clinic for Friedreich’s Ataxia. Has a database of over 3000 neurogenetics patients, most with ataxic disorders, as well as a DNA bank. Works with two tissue banks. Evaluates about 75 new ataxia patients each year. Evaluates asymptomatic individuals at-risk for ataxia. Provides continuity care for many of these individuals. Multidisciplinary model (multi-specialty Physician, Nursing, Social Work, Psychology, PT, OT, Orthotics, Speech, Nutrition, Genetics). Is a member of the Cooperative Ataxia Group (www.cooperativeataxia-group.org) and the Collaborative Clinical Research Network for FA, and collaborates with other “ataxologists” across the USA and around the world. Provides educational programs and inservice training, as well as community outreach through the National Ataxia Foundation (www.ataxia.org) and Friedreich’s Ataxia Research Alliance (www.curefa.org).
UCLA ATAXIA CENTER DEMOGRAPHICS
Catchment area— southwestern US, remaining US, Mexico, Canada, Pacific Rim, providing great ethnic and cultural diversity (but few large pedigrees).
40% of cases have either Friedreich’s ataxia or a known SCA
60% of cases have unknown genotype or sporadic presentation, spurring the search for new genes and epidemiologic factors
SCA6 SCA7 Other SCA6 SCA1 11% SCA2 SCA3
Distribution of Dominant Cases
UCLA ATAXIA CENTER
1562 PATIENTS SEEN BETWEEN 1995 AND 2005 (CURRENTLY BEING UPDATED) GENETIC
Dominant (325) Known mutation 196 Unknown mutation 129 Recessive (250) Looks like FA but isn’t 112 X-linked or Mitoch (80) Looks like mitochondrial but isn’t 54
UNKNOWN GENE/SPORADIC (Total 904) Pure cerebellar (ILOCA) 233 SOPCA 97 With other complications 264 HSA/HSP 76 MSA 72 Known cause 162
OUR GOALS HAVE BEEN TO ANSWER THE QUESTIONS ASKED BY OUR ATAXIA PATIENTS TO MAXIMIZE THEIR QUALITY OF LIFE TO GET THEM INVOLVED IN RESEARCH And NOW TO BECOME A PLATFORM FOR CLINICAL TRIALS
WHAT DO I HAVE?
WHAT IS THE CAUSE?
ARE MY CHILDREN AT RISK?
WILL IT GET WORSE?
HOW BAD WILL IT GET? HOW SOON?
CAN IT BE TREATED?
CAN IT BE CURED?
IS THERE ANY RESEARCH BEING DONE? CAN I GET INVOLVED?
Facts about Cerebellar Ataxia
(If you Google “Ataxia” you get 2,820,000 hits— the Wikipedia entry comes up first, followed by the National Ataxia Foundation.)
If it is genetic, there are no cures at this time. The symptoms will progress.
If it is non-genetic (or minimally genetic), unless a treatable cause is found, the symptoms will progress.
If a treatable cause is found early enough, symptom progression can be halted and maybe recover a bit.
If the ataxia was caused by a one-time damage to the cerebellum, symptoms may improve slowly over time, but the effects of aging can cause worsening again.
Other medical or surgical illnesses, certain medications, poor diet, lack of exercise, sleep disturbances, vitamin deficiencies, toxic exposures, alcohol or recreational drug use, and depression can all worsen symptoms of ataxia.
Recent Questions to NAF
She is experiencing quite a bit of fear and anxiety regarding the progression of her condition
About how long can this condition last?
What are the symptoms for late stage ataxia?
I would like to know if you have any information regarding progression of disease.
I was wondering if you could provide me with some input of what the future could hold.
We would hope that the past week of exciting research presentations would help answer these questions--
Or shed some light on the future…
There have been good efforts made to determine the progression of ataxia
Knowing what to expect can help patients and their families become more proactive about their treatment and lifestyle.
Physician researchers knowing what to expect can design better clinical trials of new treatments.
Not all forms of ataxia progress at the same rate.
Not all forms of ataxia cause serious problems with speech, swallowing, hand coordination, bowel and bladder function, or memory.
All ataxias impair the ability to stand and walk and increase the risk of falls. It should be a shared goal to keep ataxans safely on their feet for as long as possible.
EuroSCA Falls Study
Inventory of Non-Ataxia Symptoms--
developed by EuroSCA --Jacobi, H., et al. 2013 More likely to be seen in certain SCAs, FA, and MSA. Less likely to be seen in idiopathic late onset cerebellar ataxia.
3 Extensor plantar
12 Resting tremor
13 Sensory symptoms
6 Muscle atrophy
14 Urinary dysfunction
15 Cognitive dysfunction
16 Brainstem Oculomotor
Exercise always helps (there have
been clinical trials done that prove this and more planned to find the best exercises for ataxia)
And there are an increasing number of clinical trials barreling toward us
Some Commonly Used Off-Label Ataxia Medications (do not forget all the nondrug strategies as well) 1. Immune—Corticosteroids, other
immunosuppressants, IVIG, plasmapheresis
4. Action tremor Carbamazepine *
2. Anti-Oxidants—there are many. The ones most studied are vitamin E, coenzyme Q10 (idebenone), omega fish oil, creatine, alpha lipoic acid. I usually recommend pick one or two and change them up every 6 months. And tell your doctor what you are taking. 3. Ataxia
Clonazepam * Gabapentin * Levetiracetam Primidone
Buspirone Gabapentin L-5-OH tryptophan
Zonisamide 5. Nystagmus Dizziness (including the *) Baclofen
Thyrotropin releasing hormone
Several others in very small trials based on
Natural History Studies
try to show the average changes of ataxia over time, are important for clinical trial design, and can provide a baseline against which to compare your own symptoms, but may not provide the whole answer
Spinocerebellar ataxia Friedreich’s ataxia Multiple system atrophy
Validated Scales used by Ataxia Researchers for Natural History Studies
Derived from the parts of the neurologic exam that best track changes in ataxia.
ICARS (International Cooperative Ataxia Rating Scale)
SARA (Scale for Assessment and Rating of Ataxia)
FARS (Friedreich’s Ataxia Rating Scale)
Plus Patient Related Outcome Measures that collect information about how the ataxia patient feels their symptoms are doing—required by the FDA. Can be general or symptom/task specific.
EuroSCA Natural History Study
Over 2 years, using the 40 point SARA scale, SCA1 worsened by 2.2 points, SCA3 by 1.6 points, SCA2 and SCA6 by 1.4 points. Progression was faster in SCA1 and SCA2 patients who had larger mutations and earlier age of onset.
Hmm…worsened by 2.2 points. Out of 15 points to start, that is 15% worse !!!
The USA CRC-SCA Natural History Study
Over 2 years, using the 40 point SARA scale, SCA1 worsened by 1.6 points, SCA2 by 0.7 points, SCA 3 0.65, and SCA6 by 0.87 points.
Predicted vs. Actual
NAF AMM Las Vegas
Progression of SCA1, 2, 3, 6
The annual rate of increase of the SARA Total Score is shown.
Black bar: Annual rate of increase of the SARA Total Score was estimated from cross-section SARA scores and the durations of the disease at the baseline visit.
Grey bar: The observed rate of increase of the SARA Total Score during the longitudinal study. (*: p = 0.003, **: p = 0.049, compared with SCA2, SCA3 and SCA6).
Not everything can be predicted
Many factors may influence the progression of Spinocerebellar Ataxia
Size of the mutation (may explain only 50% of progression).
Age of onset of first symptoms.
How the disease progressed in other family members.
How the disease progressed in you up till now.
Environmental or lifestyle factors that may help or undermine your brain’s ability to compensate.
Presence of other medical or surgical conditions.
CLINICAL OUTCOME MEASURES IN FRIEDREICH’S ATAXIA
In Friedreich’s Ataxia, change was most reliably seen over 1 to 2 years of follow up.
Two European Studies of the Natural History of MSA
In the 20 years from 1994 to 2013, the two studies showed 1994
Average age of onset 53
Average age of onset 56
About half started with Parkinsons and half with ataxia
Spasticity in 61%
Over 2 years patients got worse by 50% over baseline (cf. SCA worsened by 15%)
Autonomic sxx in 97%
Median survival 9.8y
Wheelchair bound by 5y
Median survival 9.5y
Shorter survival with severe Parkinsonism or bladder retention
NAF AMM Las Vegas
For other non-genetic ataxias, the rate of progression may give clues to the underlying cause, possibly treatable
Acute (minutes to hours)--traumatic, vascular, metabolic/ toxic, infectious, inflammatory
Sub-acute (days to weeks)--post-traumatic, metabolic/ toxic, infectious, inflammatory, neoplastic, paraneoplastic
Slowly progressive (months to years)--congenital, metabolic/toxic, infectious, inflammatory, neoplastic, paraneoplastic, degenerative, genetic
Episodic--vascular, metabolic-toxic, inflammatory, genetic
Static—congenital; residua of trauma, vascular insult, or infection
Research may not have the answers specific for you
But, we should be monitoring…
It is important for the patient and family to have some idea what to expect and to know what to watch for, to help them make decisions about long-term care and hospice care.
Untreatable rigidity, autonomic failure, and bulbar symptoms (central or obstructive apneas, stridor, choking/ aspiration) can lead to death in under a year.
Increased falling or becoming chair- or bed-bound may lead to life-threatening complications (injuries, decubiti, infection).
Dementia, behavioral problems, and depression make management, compliance, and care more difficult.
Pain and fatigue are treatable.
I believe we will see disease modifying treatments for ataxia in my professional lifetime.
In SCA, the first 5 years are manageable, the next 5 years may require medical intervention, and after 10 years there may be significant limitations to Quality of Life.
In Friedreich’s ataxia, there may be motor plateaus where nothing new happens, followed by falling off the plateau and then stabilizing again.
The literature says things like: death 10-20y after onset (SCA1, 2, 3); mean age of death 38 y/o (Friedreich’s, due to cardiomyopathy); but the exceptions can be more common than the rule…
Scott SCA2, age 46, onset age 25
Eighty percent of success is showing up. – Woody Allen
Thank you for helping to make this Annual Membership Meeting the success it has been.
Thank you for supporting each other.
Thank you for supporting the National Ataxia Foundation.
Thank you for supporting Ataxia Research by:
Signing up for the Registry.
Volunteering for Clinical Trials.
Keeping Ataxia Awareness high.
Partners in Neurogenetics Research at UCLA
Daniel Geschwind, M.D., Ph.D., Neurogenetics Program Director
Susan Perlman, M.D., Ataxia Clinic Director (Ataxia Database, Drug Trials)
Brent Fogel, M.D., Ph.D. (Molecular Genetics, Biospecimens bank)
Robert Baloh, M.D. (Neuro-Otology)
George Bartzokis, M.D. (Neuroimaging, Biomarkers)
Yvette Bordelon, M.D., Ph.D. (Huntington’s disease, Biomarkers, Drug Trials)
Stephen Cederbaum, M.D. (Medical Genetics, Metabolic Disorders)
Giovanni Coppola, M.D. (Molecular Genetics)
Ming Guo, M.D., Ph.D. (Drosophila)
Shamran Khamsa, M.D., Juan Alejos, M.D. (Cardiology)
Joanna Jen, M.D., Ph.D. (Episodic Ataxias, Drug Trials)
Arik Johnson, Psy.D. (Psychology)
William Oppenheim, M.D. (Orthopedics)
Noriko Salamon, M.D. (Neuroradiology)
Ernest Wright D.Sc., Ph.D, Vladimir Kepe Ph.D,, Jorge Barrio Ph.D. (Neuroimaging, Biomarkers)
Clinic Coordinator (310) 794-1195
Brian Clemente, Ph.D. Research Coordinator (310) 206-8153
Amy Zebberman, social work intern — Social Work Coordinator (310) 794-1225
National Ataxia Foundation— sponsor of grants for our internal database, our DNA bank, our webbased database project, and the SCA3 Chantix study.
The Collaborative Research Network for Spinocerebellar Ataxia— sponsor of the grant for the SCA Natural History Study. NINDS RC1 NS68897 and NIH Office of Rare Diseases Research
Muscular Dystrophy Association and Friedreich’s Ataxia Research Alliance— sponsors of the grant for the collaborative project on “Clinical Outcome Measures in Friedreich’s Ataxia”.
The Bettencourt Family Foundation The Norman Lapin Fund The Mariette Monnet Fund