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 1 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 2 Sixth Annual Intensive Update in Neurology 9/15-16/2016 What is ataxia? • Dysfunction of the cerebellum or cerebellar pathways • Core symptoms: • Balance & gait • Hand incoordination • Dysarthria • Oculo-motor abnormality 3 Sixth Annual Intensive Update in Neurology 9/15-16/2016 APPROACH TO THE ATAXIC PATIENT A detailed history and exam are always free! 4 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 5 Sixth Annual Intensive Update in Neurology 9/15-16/2016 Drugs & Dementia are common cause of falls in elderly 6 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 7 Sixth Annual Intensive Update in Neurology 9/15-16/2016 8 Sixth Annual Intensive Update in Neurology 9/15-16/2016 Questions to ask 1. Age of onset 2. Rate of disease progression 3. Family history 4. Systemic clues 9 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 10 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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? 11 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 12 Sixth Annual Intensive Update in Neurology 9/15-16/2016 CASE PRESENTATION 65 year old male with progressive ataxia… 13 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 14 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 15 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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. 16 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 17 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 18 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 19 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 20 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 21 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 22 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 23 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 24 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 25 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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) 26 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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 27 Sixth Annual Intensive Update in Neurology 9/15-16/2016 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