Disclosures Recent Advances in Neurology Case Presentation Educational grant support: Medtronic Inc., Merz, Inc., Allergan, Inc. Clinical trial support: Ceregene Inc., MRI Interventions Inc., St. Jude Medical Inc.; Boston Scientific Inc. Jill L. Ostrem, MD Professor of Neurology UCSF Department of Neurology 1 2 Case: Fall 2008 7 year old previously healthy boy was stuck in the back at school. Developed severe back pain and seen at ER and released with no significant concerns. One week later he began limping and was stooped over due to worsening pain. Symptoms worsened where he could not walk more than a few blocks. He had scissoring of his legs and fatigue. Feb 2009- routine blood work normal, leg EMG was normal. Spring 2009 he required a wheelchair. At the age of 9, he began having trouble writing with his right hand. He reported his hand would tense-up. At the age of 9 ½ his left arm developed involuntary movements requiring him to place his arm behind his head to control the movements. Case (cont) No pain when lying down, but when sitting up, he had pain in the upper back and legs when he moved. He had lost weight. The muscles in his legs were notably smaller and his arms were are about the same size. Shoulders and trunk were also smaller. There was concern for neck extensor muscle weakness. He had no sensory deficits or paresthesias. He had no problems with speech, swallowing, or facial expression. He continued to have good grades in school, and his mother denied any concerns from his teachers about his behavior. Prior notes mentioned previous depression and one prior suicide attempt. 3 4 1
Case 1 (cont): 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. MRI Brain and C-Spine 5 6 Question 1 What is the most likely diagnosis of the patient? A. Delayed onset choreoathetoid cerebral palsy B. Conversion disorder C. Primary torsin dystonia D. Juvenile ALS E. Neuroacanthosytosis 13% 2% 50% 4% 32% Delayed onset choreoat... Conversion disorder Primary torsin dystonia Juvenile ALS Neuroacanthosytosis 8 2
Dystonia Defined as a movement disorder characterized by sustained or intermittent muscle contractions causing abnormal, often repetitive movements, postures, or both. Dystonic movements are typically patterned, twisting, and may be tremulous. Often initiated or worsened by voluntary action and associated with overflow muscle activation. Dystonia Consensus Update (Jinnah, Delong, Hallett. Movement Disorders. 2013.) Dystonia Classification New Axis I- Clinical features Age of onset (from infancy to late adult onset) Body distribution (focal forms, segmental, generalized) Temporal pattern (static or progressive disease course ) Isolated or combined with another movement disorder (parkinsonism, myoclonus, or other neurological manifestations) Isolated dystonia Onset in children = progress to generalized Onset adulthood = remain focal or segmental Axis 2- Etiology Inherited (DYT, others) Acquired (brain injury, tardive syndromes) Question 2: Which the following are usually NOT clinical features of a patient with dystonia? A. Stereotyped and patterned postures B. Sustained muscle contractions C. Tremor and myoclonus D. Muscle rigidity E. Geste antagoniste Stereotyped and patter... 10% Sustained muscle contrac... 16% Tremor and myoclonus 23% Muscle rigidity 29% 21% Geste antagoniste Clinical Features of Dystonia Stereotyped abnormal movements and postures Repeatedly involves the same muscle groups Sustained postures (as opposed to chorea) Tremor and jerks are often present Rigidity/hypertonia are usually absent Often activated by voluntary movements May even be task-specific Sensory tricks (geste antagoniste) 3
Difficulties in Dystonia Diagnosis Physicians are unfamiliar with dystonia (relatively rare) Bizarre and variable clinical features Often called psychogenic Many causes Few useful diagnostic tests Generalized dystonia (childhood) Diagnosis is often missed early It is often misdiagnosed a CP, neurodegenerative, or scoliosis Adult-onset focal dystonia is often misdiagnosed Question 3: Which of the following is NOT a useful test for identifying the etiology of a patient s generalized dystonia? A. Response to a trial of L-dopa treatment B. DYT1 or DYT6 testing C. Electromyography D. Serum ceruloplasmin E. MRI of the brain Response to a trial of L-... 5% 3% DYT1 or DYT6 testing Electromyography 67% Serum ceruloplasmin 7% 18% MRI of the brain Dopa Responsive Dystonia (DYT 5) Childhood onset; females >males Diurnal fluctuations L-dopa responsive at low doses Variable expression Gait disorder in children ( CP, myopathy ) Developmental delay/spasticity Kyphoscoliosis Focal or multifocal dystonia in adults Parkinsonism in adults Primary Torsion Dystonia (DYT1) (Early onset, generalized, persistent, isolated, inherited, and dominant) Old terminology dystonia musculorum deformans GAG/glutamate deletion in gene for Torsin A Autosomal dominant gene with 30% penetrance Age of onset < 26 years; usually limb onset Generalizes but often spares cranial muscles May cause focal limb involvement in adults Jewish (90% DYT1); non-jewish (45% DYT1) 4
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 Symbol Phenotype Gene or linkage (if known) Mode of inheritence DYT1 Earlet primary torsion dystonia TOR1A AD DYT2 Early-onset primary dystonia with prominent cranio-cervical involvement Not known AR DYT3 Adult onset dystonia-parkinsonism, prevalent in the Philippines. TAF1 X-linked DYT4 Whispering dystonia (adult onset spasmodic dysphonia) with generalization and hobby horse gait TUBB4A DYT5a Progressive DOPA-responsive dystonia with diurnal variation GCH1 AD DYT5b DYT6 Akinetic rigid syndrome with DOPA-responsive dystonia or complex encephalopathy Adult-onset torsion dystonia with prominent cranio-cervical and laryngeal involvement 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. TH THAP1 DYT7 Adult-onset primary cervical dystonia 18 p AD DYT8 Paroxysmal non-kinesigenic dyskinesia MR-1 AD DYT10 Paroxysmal kinesigenic dyskinesia PRRT2 AD DYT11 Myoclonic dystonia (often with alcohol responsiveness) SGCE AD DYT12 Rapid onset dystonia parkinsonism and alternating hemiplegia of childhood ATP1A3 AD (often de novo) 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 DYT16 Early-onset dystonia-parkinsonism PRKRA AR DYT17 Primary focal dystonia with progression in one Lebanese family 20p11.2-q13.12 AR DYT18 Paroxysmal exercise-induced dyskinesia ± epilepsy SLC2A1 AD DYT20 Paroxysmal non-kinesiogenic dyskinesia 2, in one large Canadian family 2q31 AD DYT21 Adult-onset mixed dystonia with generalization in one Swedish family 2q14.3-q21.3 AD DYT22 Reserved, but not published?? DYT23 Autosomal dominant, often tremulous cranio-cervical dystonia ±upper limb tremor ANO3 AD AR AD AD Question 4 Which one of the following is not a form of focal dystonia? A. Blepharospasm B. Torticollis C. Hemifacial spasm D. Spasmodic dysphonia E. Writer s cramp Blepharospasm Torticollis Hemifacial spasm 66% 11% 9% 11% 3% Spasmodic dysphonia Writer s cramp Charlesworth et al. Brain. 2013;136:2017-2037. For educational purposes only. 18 Hemifacial Spasm Adult-Onset Focal Dystonias Early-to-late adulthood Focal or segmental Persistent Isolated Sporadic or familial Synchronous clonic/tonic twitching of facial nerve innervated muscles on one side Can be bilateral Usually idiopathic, but check for structural lesion, demyelination in brainstem or compression of CN VII Can look like: blepharospasm, seizure, tics, facial synkinesis after paralysis (Bell s palsy) Treatment: Botulinum toxin, carbamazepine, clonazepam Estimated penetrance of 12% to 15% and therefore may appear sporadic 19 5
Question 5: What is the least helpful treatment for generalized dystonia? Blephrospasm Oromandibular Dystonia A. Botulinum toxin injections B. Oral baclofen C. Trihexiphenidyl D. Deep brain stimulation E. Clonazepam 53% 19% 16% 7% 4% Cervical Dystonia Limb Dystonia- Writer s Cramp Botulinum toxin injections Oral baclofen Trihexiphenidyl Deep brain stimulation Clonazepam 21 22 Case (cont) The patient was given a trial Levodopa to r/o DRD. He had only a mild benefit. Trihexiphenidyl resulted in more improvement. Later baclofen was added but caused sedation at higher doses. DBS therapy was recommended as he still had significant dystonia and disability. The patient had GPi DBS surgery in 2009 using a newer interventional MRI method for placing brain leads (allowing the patient to be asleep). Deep Brain Stimulation for Dystonia 2003 HDE approved for dystonia Indicated for unilateral or bilateral stimulation of the GPi or the STN to aid in the management of chronic, intractable (drug refractory) primary dystonia in patients seven years of age and above, including: Generalized dystonia Segmental dystonia Hemidystonia Cervical dystonia (torticollis) Estimated about 3,000 dystonia patients implanted since 2003 (80% are adults) 23 6
New method of surgery Interventional MRI for DBS lead placement- Asleep DBS Developed at UCSF (ClearPoint system) Allows patients to be asleep during the procedure Surgical procedure is faster with fewer brain penetrations 88% improvement 26 Factors/Predictors of DBS Responsiveness Fixed contractures do not respond to DBS Shorter disease duration correlates with improved outcomes Case: Happy ending Jan 2015 5 years after Gpi DBS Severe spinal deformity (DYT1) UCSF experience Generalized dystonia DYT1+ Markun L, et al. Neurosurgery 71:325 330, 2012 6 months after Gpi DBS 28 7
UCSF and SFVA Movement Disorders Team Surgical Movement Disorders Center Jill L. Ostrem, MD, Medical Director Philip Starr, MD, PhD, Surgical Director Neurology Jill Ostrem, MD Nicholas Galifianakis, MD Marta San Luciano, MD Maya Katz, MD Caroline Tanner, MD, PhD William J. Marks, Jr., MD Robert White, MD, PhD James Maas, MD, PHD Chadwick Christine, MD Michael Aminoff, MD Robert Edwards, MD Ken Nakamura, MD, PhD Alexandra Nelson, MD, PhD Michael Geschwind, MD Neurosurgery Philip Starr, MD, PhD Paul S. Larson, MD Edward F. Chang, MD Daniel Lim, MD, PhD Krzysztof Bankiewicz, MD, PhD Coralie De Hemptinne, PhD Nicki Swann, PhD Nathan Rowland, MD Neuropsychology Caroline Racine Belkoura, PhD Nursing Monica Volz, FNP, MS Robin Taylor, FNP, MS Susan Heath, MS, RN Elaine Lanier, MS, RN Karen Merchant, RN Jeverly Calaunan, MA Fellows Melanie Lising, MD Robert Coleman, MD Jennifer Chen, MD Erica Byrd, MD Svjetlana Miocinovic, MD, PhD Physical Therapy Nancy Byl, PT, PhD Research/Support Staff Nathan Ziman, BA Sarah Wang, PhD Salman Qasim, BS Mary McCormick Lorna Beccaria, NP Shatara Blackmon Yasmeen Gonzalez Julie Noury Monica Eisenhardt, LCSW 29 8