2/13/2015 Disclosures Educational grant support: Medtronic Inc., Merz, Inc., Allergan, Inc. Clinical trial support: Ceregene Inc., MRI Interventions Inc., St. Jude Medical Recent Advances in Neurology Inc.; Boston Scientific Inc. Case Presentation Jill L. Ostrem, MD Professor of Neurology UCSF Department of Neurology 1 2 Case: Case (cont) • Fall 2008 – 7 year old previously healthy boy was stuck in the • No pain when lying down, but when sitting up, he had pain in back at school. Developed severe back pain and seen at ER the upper back and legs when he moved. and released with no significant concerns. • He had lost weight. The muscles in his legs were notably • One week later he began limping and was “stooped” over due to smaller and his arms were are about the same size. Shoulders worsening pain. Symptoms worsened where he could not walk and trunk were also smaller. There was concern for neck more than a few blocks. He had “scissoring of his legs” and extensor muscle weakness. fatigue. • He had no sensory deficits or paresthesias. • Feb 2009- routine blood work normal, leg EMG was normal. • He had no problems with speech, swallowing, or facial • Spring 2009 – he required a wheelchair. expression. • At the age of 9, he began having trouble writing with his right • He continued to have good grades in school, and his mother hand. He reported his hand would “tense-up”. denied any concerns from his teachers about his behavior. • At the age of 9 ½ his left arm developed involuntary movements • Prior notes mentioned previous depression and one prior requiring him to place his arm behind his head to control the suicide attempt. movements. 3 4 1
2/13/2015 Case 1 (cont): MRI Brain and C-Spine Additional History: • The patient was the product of a normal pregnancy and was born 2 weeks early a hospital in Guadalajara without any complications via normal vaginal delivery. • He did not require oxygen or have a prolonged hospitalization. • He had have jaundice, but was still able to go home and treated by taking him outside every afternoon. • He was healthy as an infant and started saying a few words at 8 months and started walking at 11 months. • Family history was negative for any neurological conditions. 5 6 Question 1 What is the most likely diagnosis of the patient? A. Delayed onset choreoathetoid cerebral palsy 50% B. Conversion disorder C. Primary torsin dystonia 32% D. Juvenile ALS E. Neuroacanthosytosis 13% 4% 2% S r a s . e i L i . d n A o s t . r o a o e t t l y o s s n i s e d i y o d e o r n v h n u t h o i n c i s J a s r c t r o a e e t s v o n n y r o r u o a e d C m N e i y r a P e l D 8 2
2/13/2015 Dystonia Classification – “New” Dystonia Axis I- Clinical features • Age of onset (from infancy to late adult onset) • Defined as a movement disorder characterized by sustained or intermittent • Body distribution (focal forms, segmental, generalized) muscle contractions causing abnormal, often repetitive movements, postures, or • Temporal pattern (static or progressive disease course ) both. • Isolated or combined with another movement disorder • Dystonic movements are typically (parkinsonism, myoclonus, or other neurological patterned, twisting, and may be tremulous. manifestations) • Often initiated or worsened by voluntary – Isolated dystonia action and associated with overflow muscle activation. • Onset in children = progress to generalized • Onset adulthood = remain focal or segmental Axis 2- Etiology – Inherited (DYT, others) Dystonia Consensus Update (Jinnah, Delong, Hallett. Movement Disorders. 2013.) – Acquired (brain injury, tardive syndromes) Clinical Features of Dystonia Question 2: Which the following are usually NOT • Stereotyped abnormal movements clinical features of a patient with dystonia? and postures • Repeatedly involves the same muscle groups A. Stereotyped and patterned postures 29% • Sustained postures (as opposed to B. Sustained muscle contractions 23% chorea) 21% C. Tremor and myoclonus • Tremor and jerks are often present 16% D. Muscle rigidity • Rigidity/hypertonia are usually 10% absent E. Geste antagoniste • Often activated by voluntary movements s y e • May even be task-specific t t . . u i . . n d s . c n i . a o i r g o e r c l i t t o r g t n e a a o y l t p c m c n s a d e u d e n c l n M • Sensory tricks (geste antagoniste) a s t a s d u e m r e o G p d m y t e e n o r e i T a r t e s t u S S 3
2/13/2015 Difficulties in Dystonia Diagnosis Question 3: Which of the following is NOT a useful test for • Physicians are unfamiliar with dystonia (relatively rare) identifying the etiology of a patient’s generalized • “ Bizarre ” and variable clinical features dystonia? • Often called “ psychogenic ” • Many causes 67% A. Response to a trial of L-dopa treatment • Few useful diagnostic tests B. DYT1 or DYT6 testing C. Electromyography • Generalized dystonia (childhood) D. Serum ceruloplasmin 18% E. MRI of the brain – Diagnosis is often missed early 7% 5% 3% – It is often misdiagnosed a CP , “ neurodegenerative”, DYT1 or DYT6 testing Electromyography Serum ceruloplasmin MRI of the brain Response to a trial of L-... or scoliosis • Adult-onset focal dystonia is often misdiagnosed Primary Torsion Dystonia (DYT1) Dopa Responsive Dystonia (DYT 5) (Early onset, generalized, persistent, isolated, inherited, and dominant) • Childhood onset; females >males • Diurnal fluctuations • Old terminology “ dystonia musculorum deformans ” • L-dopa responsive at low doses • GAG/glutamate deletion in gene for Torsin A • Variable expression • Autosomal dominant gene with 30% penetrance – Gait disorder in children ( “ CP,” “ myopathy ” ) • Age of onset < 26 years; usually limb onset – Developmental delay/spasticity • Generalizes but often spares cranial muscles – Kyphoscoliosis – May cause focal limb involvement in adults – Focal or multifocal dystonia in adults – Parkinsonism in adults • Jewish (90% DYT1); non-Jewish (45% DYT1) 4
2/13/2015 Genetic Classification of Some Dystonias The current DYT loci with brief description of associated phenotype, gene of linkage interval (where known), mode of inheritance and OMIM reference numbers Locus Phenotype Gene or linkage Mode of Symbol (if known) inheritence Question 4 TOR1A DYT1 Earlet primary torsion dystonia AD DYT2 Early-onset primary dystonia with prominent cranio-cervical involvement Not known AR TAF1 DYT3 Adult onset dystonia-parkinsonism, prevalent in the Philippines. X-linked Whispering dystonia (adult onset spasmodic dysphonia) with generalization AD TUBB4A Which one of the following is not a form of focal dystonia? DYT4 and ‘hobby horse’ gait GCH1 DYT5a Progressive DOPA-responsive dystonia with diurnal variation AD Akinetic rigid syndrome with DOPA-responsive dystonia or complex AR TH DYT5b encephalopathy 66% Adult-onset torsion dystonia with prominent cranio-cervical and laryngeal AD A. Blepharospasm THAP1 DYT6 involvement DYT7 Adult-onset primary cervical dystonia 18 p AD B. Torticollis MR-1 DYT8 Paroxysmal non-kinesigenic dyskinesia AD PRRT2 DYT10 Paroxysmal kinesigenic dyskinesia AD C. Hemifacial spasm SGCE DYT11 Myoclonic dystonia (often with alcohol responsiveness) AD ATP1A3 AD (often de novo ) DYT12 Rapid onset dystonia parkinsonism and alternating hemiplegia of childhood D. Spasmodic dysphonia DYT13 Early onset torsion dystonia in one Italian family 1p36.32-p36.13 AD DYT15 Myoclonic dystonia with alcohol responsiveness in one Canadian kindred 18p11 AD 11% 11% E. Writer’s cramp 9% PRKRA DYT16 Early-onset dystonia-parkinsonism AR 3% DYT17 Primary focal dystonia with progression in one Lebanese family 20p11.2-q13.12 AR SLC2A1 DYT18 Paroxysmal exercise-induced dyskinesia ± epilepsy AD DYT20 Paroxysmal non-kinesiogenic dyskinesia 2, in one large Canadian family 2q31 AD m s m p i a s l l s i m a o a n DYT21 Adult-onset mixed dystonia with generalization in one Swedish family 2q14.3-q21.3 AD o a p c p r s i s h c o r t p o l s r a s ’ a T i y r DYT22 Reserved, but not published ? ? h c d e a t p f c i e i i r m d W B l Autosomal dominant, often tremulous cranio-cervical dystonia ±upper limb AD e o m H s ANO3 a DYT23 tremor p S DYT9, DYT14, DYT19 are not included in the table as they are now known to be synonymous with DYT18, DYT5a, and DYT19 respectively. AD = autosomal dominant; AR = autosomal recessive; DYT = dystonia. Charlesworth et al. Brain . 2013;136:2017-2037. For educational purposes only. 18 Hemifacial Adult-Onset Focal Dystonias Spasm � Early-to-late adulthood � Focal or segmental � Persistent � Isolated � Sporadic or familial • Synchronous clonic/tonic twitching of facial nerve innervated muscles on one side Estimated penetrance • Can be bilateral of 12% to 15% and therefore may • Usually idiopathic, but check for structural lesion, demyelination in appear sporadic brainstem or compression of CN VII • Can look like: blepharospasm, seizure, tics, facial synkinesis after paralysis (Bell’s palsy) • Treatment: Botulinum toxin, carbamazepine, clonazepam 19 5
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