Sixth Annual Intensive Update in Neurology 9/15-16/2016

THE WOBBLY PATIENT: ADULT ONSET ATAXIA

Rosalind Chuang, M.D. Movement Disorders Swedish Neuroscience Institute

September 15, 2016

Disclosure: none

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Objectives

• Review algorithm for work up of patients with ataxia • Review common forms of genetic ataxia • Understand which genetic tests to obtain and rationale for genetic testing

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What is ataxia?

• Dysfunction of the cerebellum or cerebellar pathways • Core symptoms: • Balance & gait • Hand incoordination • Dysarthria • Oculo-motor abnormality

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APPROACH TO THE ATAXIC PATIENT

A detailed history and exam are always free!

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Question to self: “Is it ataxia?” Other causes of imbalance  Visual: blindness  Vestibular: BPPV, Ménière syndrome  Cortical: dementia, medications  Musculoskeletal: muscle weakness, hip/knee joint problems  Proprioception/Sensory: sensory ataxia

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Drugs & Dementia are common cause of falls in elderly

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Cerebellar Exam: Scale for the assessment and rating of ataxia (SARA) 1. Gait 2. Stance 3. Sitting 4. Speech 5. Finger chase 6. Nose-finger 7. Fast alternating hand movements 8. Heel shin slide

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Questions to ask

1. Age of onset 2. Rate of disease progression 3. Family history 4. Systemic clues

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Approach to the ataxic patient

• Family history • Not limited to ataxia • Consider: • Dementia • Other movement disorders: Tremors, parkinsonism, chorea, dystonia • Epilepsy • Mental retardation, learning disability, autism • Psychiatric disease, history of suicide or alcoholism • History of institutionalization • “Cerebral palsy” • Vision loss • Premature ovarian failure • Autonomic dysfunction • Other medical diseases: DM II , deafness

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The detailed family pedigree

• Don’t accept “old age” as cause of death • Did parent remain ambulatory throughout? • Aunts, uncles, first cousins • Why was someone “institutionalized?” • “Really alcoholics?” • Children: any difficulty learning to walk? Learning disability? • Ethnicity • Ashkenazi Jewish ancestry? • French Canadians? • Possibility of consanguinity?

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Approach to the ataxic patient

• Cerebellar ataxia confirmed

• Always do MRI brain to exclude structural causes • Additional clues for another cause of ataxia

• Labs: (Fogel et al 2007) • Basic screen: Comprehensive metabolic panel, Vit B1, B12, E, CBC with smear, thyroid studies, ESR, CRP, ANA, immunofixation, RPR • Secondary screening labs: anti-GAD, cholesterol • If systemic clues are present: • paraneoplastic panel (with CT imaging), celiac, copper/ceruloplasmin • Imaging: MRI brain/C spine • Consults: neuro-ophtho, neuro-muscular

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CASE PRESENTATION

65 year old male with progressive ataxia…

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Case Presentation

• 65 year old gentleman with ataxia • PMH: DM II, HTN

• His wife noticed at breakfast that his speech was slightly slurred • Difficulty holding utensil at breakfast • Stumbled while walking

• Stable for past 3 months • Walking/stumbling has improved • Occasionally drops cups • Slurred speech resolved

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Acute onset, no progression 3. Family history • None 4. Systemic clues • Stroke risk factors

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Acute onset cerebellar ataxia

• Vascular (stroke) • Wernicke’s encephalopathy • Infections • More common in children • Trauma • Autoimmune: MS, ADEM, Miller-Fisher Syndrome) • Vestibular • Functional (psychogenic)

Cerebellarand Afferent Ataxias. Pandolfo, Massimo; Manto, Mario; MD, PhD. CONTINUUM:, October 2013.

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Case Presentation

• 65 year old male with progressive ataxia • Onset 4 months prior • Saw 2 prior physicians 2 months after onset of “dizziness” • Extensive work up…

• No family history, no risk factors (no tobacco, illicit drugs or alcohol history) • On initial exam: • SARA score of ~10 • Dysarthria • Abnormal saccades • Review of past work up: • CT chest with nodule: scar tissue • FDG-PET scan: “possible cerebellitis” • CSF: +EBV IgG

Referred for possible infectious cerebellitis

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Sub-acute, progressive with SARA of 10 over 4 month period 3. Family history • None 4. Systemic clues • None: no h/o fevers, chills, cough, malaise

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Case presentation #2: conclusion

• Referred to pulmonary consult for lung biopsy • Whole body PET scan positive • Biopsy: neuro-endocrine tumor

Paraneoplastic cerebellar ataxia

• Ataxia stable with chemotherapy/XRT • Had 3 rounds of IVIg with slight improvement with first round, no additional improvement with subsequent IVIg

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Paraneoplastic ataxia

• Most common malignancies: • SCLC • Breast, ovarian • Hodgkin’s • Usually sub-acute • Ataxia can precede identification of underlying tumor by 4 years

• Should everyone with ataxia have routine screening for paraneoplastic syndrome? • If rapid progression over months, yes. Also include CT Chest/abdomen/pelvis with contrast and whole body PET. • If negative initially, some still recommend Q6 month paraneoplastic panel

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Case presentation: Patient #3

• 65 year old computer engineer with no PMH until September 2015 • Awoke in middle of night with chest pains and sensory symptoms described as “electrical impulses” • New onset headaches causing insomnia from 10/2015-12/2015 • Spontaneously resolved December 2015 • Hyperacusis • Cognitive decline-not noticeable to colleagues or family but it “hurt” to think • His wife started to notice short term memory changes in February 2016 • Handwriting changes: messy, clumsy

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Case # 3 Physical exam February 2016

• Halting speech, repeating same stories, frequent word finding difficulties • CN: impaired smooth pursuit. But vertical gaze intact. No hypermetric saccades • Reflexes: areflexic • Sensation: Normal • Movement disorders: Excessive startle to facial stimuli No myoclonus UPDRS: slight neck rigidity, slight bradykinesia of all limbs, no tremors SARA 11.5

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Case # 3

• Labs: • RA, CRP, ESR, Hashimoto's Ab negative • Paraneoplastic Panel (serum) #1: negative • RPR non reactive • CSF November 2015: • Glucose 53, Protein 25, WBC 2, RBC 6, CSF ACE 1.7 (normal), IgG Index 0.5 (normal), Lyme negative, Oligoclonal Bands negative, VDRL non-reactive • EMG/NCS: negative • DaT scan: February 2016 • “Scintigraphic findings indicate nigrostriatal degeneration indicating Parkinsonian syndrome”

Referred to Movement Disorders for atypical parkinsonism

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Acute/Sub-acute, rapidly progressive with SARA of 11.5 3. Family history • None 4. Systemic clues • Sensory symptoms • Significant Cognitive changes

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Case # 3: Conclusion

Additional labs

• Whole body PET scan: • Progressive cognitive negative decline with agitation • CSF March 17, 2016 • Family consented for Brain • Paraneoplastic (Mayo Clinic) donation to Prion Center negative • Voltage gated K channel • Passed away May 11, requested, not done 2016

• CSF Tau total 6169 pg/ml • Autopsy confirmed prion • 14-3-3 to Prion Disease Center (Available April 2016) protein in brain tissue • Positive Sporadic CJD • RT-quic positive

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Sporadic CJD

• Peak age ~55-75 years old • Prodromal symptoms • Survival <1 year • 300 cases in USA/year

• First symptom: • Dementia (37 %) • Cerebellar (34 %) • Visual (15 %) • Psychiatric disturbances (14 %) • Extrapyramidal 4% (Krasniaski 2014)

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Sub-acute ataxia

• Paraneoplastic • Potentially treatable!

• Infection: • Prion disease • Infection precautions with brain biopsy/lumbar puncture • Send 14-3-3 to Case Western (Prion Surveillance Center) for RT-quic

• Auto-immune • Anti-GAD • SREAT • Gluten Ataxia

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Gluten Ataxia: brief word…

• Controversial

• Celiac related antibodies • Anti-gliadin (not recommended, high false positive) • Anti-TTG (tissue transglutaminase) • Anti-TG6 (transglutaminase 6) • Antibodies can also be present in ataxias with confirmed genetic cause • Gold standard: gut biopsy • Treatment: gluten free diet

• European Consensus Statement on ataxia does NOT recommend routine testing for gluten antibodies • It is potentially treatable, so if sub-acute onset, I send labs after 3-4 weeks of high carbohydrate diet • Or, just have patient go on gluten free diet for a few weeks and repeat exam

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SLOWLY PROGRESSIVE ATAXIA

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Slowly progressive ataxia

• Acquired • Toxin • Alcohol • Drugs: Lithium, phenytoin, carbamazepine, amiodarone • Structural: • NPH • Tumors • Vitamin Deficiencies: • Vit B1, B12, E, CoQ10 • Neuro-degenerative • Genetic

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Case # 4

• 65 year old male Onset of symptoms 1.5 years ago with gait changes • Had problems walking on the beach on vacation in Hawaii • Speech was slower • On exam, SARA score was 8 • On further questioning: • REM behavior disorder • Mild difficulty swallowing • Erectile dysfunction for 2 years • Orthostatic BPs: decrease of 20mmHg systolic

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“ILOCA”

• Idiopathic late onset cerebellar ataxia • Coined by Anita Harding in 1981

• Many cases have been reclassified since: • Spinocerebellar ataxias (SCAs) • Fragile X-Ataxia syndrome (FXTAS) • Friedreich’s ataxia (FA) • Multiple system atrophy (MSA)

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Slowly progressive over 1.5 years 3. Family history • None 4. Systemic clues • Urinary dysfunction • Orthostatic hypotension • REM behavior disorder

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Truly negative family history…now what?

• MSA, MSA, MSA (multiple system atrophy) • Consider this early and continue to evaluate at every clinic visit. • More rapid progression of SARA score • Check orthostatic BPs (supine and standing) at each visit • Review of systems every visit: Autonomic dysfunction, REM behavior • Findings of parkinsonism

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“24-36% OF LATE ONSET ATAXIA PATIENTS TRANSITION TO MSA-C IN 5-10 YEARS” DR. H. PAULSON, AAN 2008

• 29% per Abele et al. The aetiology of sporadic adult onset ataxia, Brain 2002

• 33% per Gilman et al. Evolution of sporadic OPCA into MSA. Neurology 2000

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Fig. 1 Prevalence of MSA, FRDA, SCA2, SCA3 and SCA6.

Fig. 1 Prevalence of MSA, FRDA, SCA2, SCA3 and SCA6. (A) Whole study population (n = 112). (B) Subgroup of patients with a disease duration of ≥4 years (n = 81).

M. Abele et al. Brain 2002;125:961-968

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Second consensus statement on the diagnosis of MSA (Gilman et al. Neurology 2008) Probable MSA  Autonomic failure involving urinary incontinence OR an orthostatic decrease of blood pressure within 3 minutes of standing by >30mmHg systolic or >15mmHg diastolic AND  Poorly levodopa responsive parkinsonism OR  Cerebellar syndrome Possible MSA  Parkinsonism OR cerebellar syndrome AND  At least one feature suggesting autonomic dysfunction that does not meet criteria AND At least one criteria of the following:

o Babinski

o Stridor

o Rapidly progressive parkinsonism

o Poorly responsive to levodopa

o Postural instability within 3 years of motor onset

o Ataxia, dysarthria, oculomotor dysfunction

o Dysphagia <5 years of motor onset

o Atrophy on MRI of putamen, MCP, pons, or cerebellum

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GENETIC ATAXIAS

~25% of ataxia patients with family history have positive genetic test

~10% of sporadic ataxia patients have positive genetic test

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Approach to the ataxia patient: The “negative” family history

• Early death of parents • Incomplete penetrance • Family estrangement or geography • Cultural barriers to discussing medical history • Adoption • Possibility of non-paternity

Consider genetic testing

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Have patient ask other relatives

SCA 8

Brusse et al. Clin Genet 2007

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Case Presentation

• 61 year old gentleman with ~3-5 years of cognitive changes and imbalance • Paranoia/delusions started ~5 years ago • Forgetting conversations ~3 years ago • Balance changes ~1-2 years ago with 1-2 falls/week

• Family history: • Parents: Mother: healthy. Father: died in war • Siblings: 1 brother with balance changes • Children: 1 daughter, healthy • Grandson: learning disability

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Slowly progressive over 3-5 years 3. Family history • Yes! Brother with ataxia • Also, grandson with learning disability 4. Systemic clues • Cognitive changes • Psychiatric changes

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FXTAS (Fragile X Ataxia Syndrome)

Clinical symptoms: • Late onset (>45 years old) • Action tremor (similar to ET with postural > intention) • Ataxia (axial and appendicular) • Parkinsonism • Peripheral neuropathy • Autonomic (orthostatic, impotence, urinary dysfunction) • Cognitive changes (fronto-executive) Imaging on MRI: MCP sign and hyper-intensities within corpus callosum Prevalence within sporadic ataxias: 1.5% in men, 0.2% in women

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FXTAS

• X chromosome • Females: • Pre-mutations with 55- • Premature ovarian 200 CGG repeats in failure with menopause FMR1 gene <40 years old • Carriers: • Males 1:813, Females 1:259

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FXTAS case conclusion

• Fragile X genetic testing April 2016 • 77 CGG repeats • Asymptomatic daughter: 69 CGG repeats • Grandson: >500 expansions

Genetic testing has implications for the entire family

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IF YOU HAVE A MALE WITH LATE ONSET TREMOR AND ATAXIA…

Think Fragile X ataxia pre-mutation carriers

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Case presentation

• 58 year old Caucasian gentleman • First symptom: Clumsy hands, dropping tools • Two years later, developed gait imbalance then falls. +dysarthria. • Reflexes normal • As part of work up, diagnosed with DM II • No clear neuropathy, mildly decreased vibratory sensation in toes • EMG/NCS normal

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Very slowly progressive 2+ years 3. Family history • None 4. Systemic clues • Possible neuropathy, DM II

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Classic Friedreich’s ataxia (FRDA)

• Most common form of inherited ataxia in Caucasians • 1/29,000 • 1:85 are carriers • Classic neurologic phenotype: • Ataxia • Dysarthria • Neuropathy (impaired vibration/proprioception) • Pyramidal weakness • Non-neuro symptoms: scoliosis, diabetes, cardiomyopathy

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Adult onset Friedreich’s ataxia

• Reflexes preserved or hyperreflexic • Generally don’t have cardiomyopathy • Generally die of cachexia or pneumonia

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AUTOSOMAL DOMINANT ATAXIAS

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Case presentation

• 65 year old gentleman with mild imbalance • Started to notice clumsiness ~8 years ago, attributed to ‘aging’ • Stopped drinking alcohol because more easily affected • When fatigued, speech is more slurred • Handwriting “messy” • No cognitive changes, no lightheadedness, urinary problems • Family History: no problems with balance • Exam: • Vibratory sensation: slightly reduced, normal pinprick • SARA score 6

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Clinical pearls for autosomal dominant ataxias • SCA 3 most common ~21% cases worldwide • SCA 2 is the second most common with quite variable phenotype • SCA 6 • “Pure” late onset cerebellar ataxia • “Sporadic” mutations occur more commonly than the other SCAs

• SCA 10 is associated with Hispanic population • But SCA 2 is still more common • SCA 31 and 36 in Japanese ancestry

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SCA 2 (ATXN2): great mimicker!

• CAG repeat expansion • Normal <31 • Intermediate 32-33 repeats • Full mutation >40 • Variable age of onset • Not dependent on number of CAG repeats • Anticipation phenomenon- • Earlier disease onset, more severe symptoms • Variable phenotype • ALS (~32/33 CAG) • Parkinsonism (34-39 CAG) • Dystonia or chorea (34-39 CAG) • Ataxia (>40 CAG)

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Table 7 -4 Non-Ataxia Signs and Symptoms Suggesting Specific Genetic Subtypes of Autosomal Dominant Spinocerebellar Ataxia

Cerebellar and Afferent Ataxias. Pandolfo, Massimo; Manto, Mario; MD, PhD

CONTINUUM: Lifelong Learning in Neurology. 19(5, Movement Disorders):1312-1343, October 2013. DOI: 10.1212/01.CON.0000436158.39285.22

© 2013 American Academy of Neurology. Published by American Academy of Neurology. 2

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Distinguishing features of autosomal dominant ataxias available by commercial testing

Disease Distinguishing clinical features in addition to ataxia SCA1 Pyramidal signs, neuropathy SCA2 Slow saccades, neuropathy, hyporeflexia, dementia SCA3 Pyramidal signs, parkinsonism, lid retraction, nystagmus, neuropathy SCA5 Slowly progressive SCA 6 Pure cerebellar, slowly progressive, downbeat nystagmus, mild neuropathy, late onset spasticity, “sporadic”

SCA 7 Visual loss SCA 8 Pure cerebellar, sometimes episodic SCA 10 Mexican families, seizures SCA 12 Slowly progressive, postural hand tremor, subtle parkinsonism (bradykinesia) SCA 13 Mild mental retardation, delayed motor development SCA 14 Can be pure cerebellar, myoclonus, myokymia, dystonia, vibratory loss SCA 17 Dementia, parkinsonism, dystonia, psychiatric, chorea, HD-like. Seizures. SCA 28 Slow ly progressive, hyperreflexia, nystagmus, and ophthalmoparesis

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Table 7 -2 Geographical Distribution of the Most Common Autosomal Dominant Spinocerebellar Ataxias Cerebellar and Afferent Ataxias. Pandolfo, Massimo; Manto, Mario; MD, PhD

CONTINUUM: Lifelong Learning in Neurology. 19(5, Movement Disorders):1312-1343, October 2013. DOI: 10.1212/01.CON.0000436158.39285.22

© 2013 American Academy of Neurology. Published by American Academy of Neurology. 2

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SCA 3 (Machado-Joseph Disease)

• ATXN3 gene, CAGs • Clinical phenotype: • Ataxia • Dystonia-rigid • Parkinsonian • Amyotrophy • Different subtypes: • Type I disease (13% of individuals) young onset • Spasticity, rigidity, bradykinesia • Minimal ataxia • Type II: disease (57%), • Ataxia, UMN signs (spastic paraplegia) • Type III disease (30%) • Later age ataxia and peripheral polyneuropathy. • Type IV disease • Dopa-responsive parkinsonism • Ask about Portuguese Azorean ancestry

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Back to Case:

• 65 year old gentleman with mild imbalance • Started to notice clumsiness ~8 years ago, attributed to ‘aging’ • Stopped drinking alcohol because more easily affected • When fatigued, speech is more slurred • Handwriting “messy” • No cognitive changes, no lightheadedness, urinary problems • Family History: no problems with balance • Exam: • Vibratory sensation: slightly reduced, normal pinprick • SARA score 6

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Case continued

• On further questioning of family history:

Still no family history of imbalance • Sister is undergoing speech therapy for “slurred speech”

• But no problems with balance • …except she uses a cane because of “knee problems”

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Questions to ask

1. Age of onset • Late… 2. Rate of disease progression • Very slow progression 3. Family history • Possible! Sister with dysarthria and possible imbalance 4. Systemic clues • Possible Sensory symptoms vs age related

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What genetic tests to perform for the sporadic ataxia?

• Most common in European population: SCA 6, SCA 2, 3 and Friedreich’s.

• Common autosomal dominant SCAs: SCA 1, 2, 3, 6, 7 available through genetic panel (relatively inexpensive but not always covered by insurance) • Fragile X: very inexpensive, usually covered by insurance • Friedreich’s: very inexpensive, usually covered by insurance

• In Asia: SCA 6, 3, 2, DRPLA, SCA 1 • DRPLA not so common in the USA

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Case conclusion

“Additional diagnostic test was performed”

SCA 6 positive!

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Ataxia labs

• University of Washington: • SCA 1, 2, 3, 6, 7 ($$) • Separate testing for Autosomal recessive: Friedreich’s and Fragile X ($) • Athena: • Full panel is $$$$ • University of Chicago Ataxia exome panel • $4800 (no insurance!) • Does not cover common autosomal dominant SCAs • See website for Excel spread sheet of genes tested: http://dnatesting.uchicago.edu/tests/ataxia-exome-panel • UCLA Ataxia Exome panel • Commercial labs: Invitae, Fulgent for whole exome sequencing (does not cover common autosomal dominant SCAs)

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ALL TESTS STILL NEGATIVE?

~40% of patients with sporadic, late onset cerebellar ataxia remain diagnostic mysteries…

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Resources

• Clin Gen https://www.clinicalgenome.org/ • “Gene Reviews” • Gene Tests: https://www.genetests.org/

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REMEMBER! Absence of limb ataxia does not mean the patient is not cerebellar dysfunction!

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REMEMBER! Always look at MRI brain…don’t trust radiology reports for cerebellar atrophy or diffusion abnormality

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REMEMBER!

• Rarely does genetic test result change outcome or management. • Rarely should genetic testing be the sent on first clinic visit. • Paraneoplastic panel and genetic test should never be sent on the same day.

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Resources 1. OMIM 2. Van de Warrenburg et al. “EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood” Euro J Neuro 2014 3. Corben et al. “Consensus clinical management guidelines for Friedreich’s ataxia” Orphanet 201 4 4. Pandolfo and Manto “Cerebellar and Afferent Ataxias” Continuum AAN October 2013 5. Van Gaalen & van de Warrenburg “Practical approach to late onset cerebellar ataxia: putting the disorder with lack of order into order.” Pract Neuro 2012 6. Brusse E. et al. (2007). Diagnosis and management of early and late onset cerebellar ataxia. Clin Genet 71: 12-24, 2007 7. Fogel and Perlman (2007) “An approach to the patient with late onset cerebellar ataxia” Nat Clin Pract Neurol 2: 629-635. 8. Durr, E. et al. “Clinical and genetic abnormalities in patients with Friedreich’s Ataxia” NEJM 1996

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