Ruth H. Walker, MB., Ch.B., Ph.D. Departments of Neurology, James J
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A flow chart for the evaluation of chorea Ruth H. Walker, MB., Ch.B., Ph.D. Departments of Neurology, James J. Peters Veterans Affairs Medical Center, Bronx, NY, and Mount Sinai School of Medicine, New York, NY [email protected] Patient with chorea Streptococcal? Age of Infant/child +ve Autosomal recessive/sporadic sore throat, rheumatic Sydenham's chorea Onset? heart disease ASO, anti-DNAse Lesch-Nyhan syndrome B titers Confirm with gene test Tardive dyskinesia Autosomal Adult X-linked Inheritance? Normal recessive Delayed Autosomal Medication- Yes Direct Check Yes Childhood onset, dominant Time course? gouty arthritis, MRI; normal induced? Immediate or side effect uric acid self-mutilation? Fe in basal dose related Calcium Acute infarct in ganglia ? deposition posterior limb of in basal internal capsule. ganglia. Diffusion- No No Pantothenate Phospholipase-associated CT scan weighted MRI Normal neurodegeneration kinase-associated Yes No Infantile bilateral neurodegeneration striatal necrosis •Mix blood 1:1 with 0.9% NaCl containing 10IU/ml heparin Yes Structural lesion; •Incubate at room temperature for 30-120 min on a shaker •Childhood onset PKAN: T2 weighted MRI Stroke, tumor •Take 5+ microphotographs from each wet preparation •Occasional later onset Yes Leigh’s syndrome, (phase-contrast microscope) •Pigmentary retinopathy MRI arteriovenous malformation, Lactate/ •Count cells with spicules: normal value < 6.3 % •Dystonia PANK2 Normal PLA2G6 other mitochrondial? Lubag •10% have acanthocytosis Ceruloplasmin? calcification (IBG1?), etc pyruvate No No Yes mutation? No mutation? Confirm with gene test Acanthocytosis? Filipino? Confirm with gene test Basal ganglia No No Typical phenotype = dystonia- necrosis? parkinsonism, but should be Other neurodegeneration considered in any Filipino with an Yes with brain iron unexplained movement disorder, Caudate Yes including women Yes Recent Post-infectious Accumulation disorder… nucleus FAHN, MPAN, BPAN… Yes infection? striatal necrosis •Full panel of 23 Kell abs usually available atrophy? Courtesy of Dr Hans H. Jung, Zürich at regional blood centers; •Ask to “exclude McLeod phenotype” Pseudo- Aceruloplasminemia dominant Yes Features •Iron overload suggestive of Yes inheritance? •Diabetes mellitus in 20’s (from pancreatic iron) Work-up for inherited metabolic Liver enzymes or Kx and Kell •Middle-age onset metabolic diseases; McLeod syndrome •Retinal degeneration (from iron deposition) disease? creatine kinase ags •Parkinsonism/dystonia, orofacial involvement is typical •Behavioural changes/ organic/amino acids, •Dementia usually later psychopathology •MRI may not show Fe accumulation (Skidmore et al. 2007) lysosomal enzymes •Seizures Fasano et al. 2008 •Peripheral neuropathy Gradient echo T2* skin biopsy etc Normal •Hyporeflexia No Normal •Cardiomyopathy No Normal •Hepatosplenomegaly ? Normal Kayser- McNeill et al 2008 Normal Fast spin echo Fleischer Ceruloplasmin? Creatine kinase Liver enzymes rings? Diagnosis Diagnosis Yes Ferritin 24hr Cu Lactate/ Normal Chorein mutations? chorein excretion? pyruvate Normal assay Normal Dobson-Stone et al. 2004 Normal Contact – [email protected] Recent Neuroferritinopathy No +ve liver +ve +ve disease? No •Middle-age onset Wilson’s disease Metabolic •Parkinsonism/dystonia Metabolic •Occasional ataxia, spasticity Ataxia? work-up (2) •Dementia rare •Dystonia/parkinsonism/dystonia more common Normal Anti-phospholipid ab Normal work-up (1) •Adolescent onset Electrolytes •Risus sardonicus SLE, other autoimmune Mitochondrial Chorea-acanthocytosis •Psychiatric disease Yes Polycythemia vera Glucose Yes huntingtin Celiac disease Pregnancy test disorder? Confirm with gene test HIV, B12, RPR TSH Confirm with gene test mutation? Normal Acquired hepatocerebral Pb •Behavioural changes/psychiatric disease But can be normal degeneration •Self-mutilation of lips, tongue, other body parts in pre-menopausal Frataxin women with Friedreich’s ataxia •Seizures mutation? •Hyporeflexia Ferritin level? neuroferritinopathy •Hepatomegaly No •Onset in childhood Huntington’s •Ataxia may be absent Chorea is a common movement disorder, the etiology of which is •Reflexes increased or decreased disease •Cardiomyopathy •Onset in childhood rarely identifiable from its appearance. The identification of genetic •Susceptible to radiation •Risk of malignancy, infection causes for some of the inherited choreas has facilitated their •Elevated α-feto-protein Courtesy Dr Jane Zheng, UNC-CH C9ORF2 C9ORF72 diagnosis, in addition to increasing the spectrum of phenotypes for Telangiectasia? Ataxia-telangiectasia mutation? disease other disorders in which chorea may occur less often. A number of Confirm with ATM mutation •Variable phenotype clues in the family and medical history, clinical examination, and •Often upper motor neuron signs laboratory findings may inform the diagnosis. Whilst we typically No •Reduced penetrance •Variable age of onset consider these simultaneously when evaluating the patient with chorea, there is a need for an algorithm to generate consideration α-feto- Senataxin Yes Ataxia with oculomotor of some of the rarer etiologies. protein mutation? apraxia type 2 African •Onset in childhood Huntington’s Yes Junctophilin-3 Yes ancestry? No •Peripheral neuropathy disease-like 2 mutation? (may be This flow chart aims to present the various factors which facilitate •Elevated creatine kinase Consider AD occult) making the correct diagnosis, and the appropriate testing to Consider AD spinocerebellar •Behavioural changes/psychiatric disease Aprataxin and X-linked •May have more dystonia/parkinsonism? consider depending upon previous test results. The list of ataxias mutation? pathways •10% have acanthocytosis e.g. homozygosity? No differential diagnoses of chorea is ever-evolving with advances in the molecular biology of movement disorders. This algorithm Yes Spinocerebellar ataxia MRI - Fe which is open to further development in the light of new Autoimmune Yes SCA/DRPLA No Yes Ataxia with oculomotor 1,2,3,17,? in basal knowledge. mutations? apraxia type 1 non-paraneoplastic DRPLA ganglia •Onset in childhood syndrome •Peripheral neuropathy •Ataxia, eye movement abormalities, peripheral This flow chart does not necessarily indicate the temporal course Neoplasm Negative workup •Elevated cholesterol neuropathy etc are typical, but may be pure HD evaluation; of the diagnostic work-up of chorea, especially if the family history •hypoalbuminemia phenocopy No Anti-Hu, Yo, +ve Paraneoplastic •DRPLA – myoclonus, dementia, dystonia typical Yes Huntington’s is not known, but should be used a guideline to generate the CRMP-5, GAD65 syndrome disease-like 1? consideration of various clinical entities in light of the available NMDA, VGCC Benign hereditary Caspr2, LGI-1 information. …….. Creutzfeldt-Jakob chorea Yes Non-progressive, No Prion Single Yes PLED’s? disease Confirm with TITF-1 +ve no dementia? mutation? case? -ve MRI findings? (chorea more common mutation, although other CSF 14-3-3 in new variant) genes implicated Consider atypical forms of No Confirmed by pathology No AD, X-linked or AR disorders, -ve ? depending upon inheritance .