Disclosures Educational grant support: Medtronic Inc., Merz, Inc., - - PowerPoint PPT Presentation

2/13/2015 1

Jill L. Ostrem, MD

Professor of Neurology UCSF Department of Neurology

Recent Advances in Neurology Case Presentation

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Disclosures

Educational grant support: Medtronic Inc., Merz, Inc., Allergan, Inc. Clinical trial support: Ceregene Inc., MRI Interventions Inc., St. Jude Medical Inc.; Boston Scientific Inc.

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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.

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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.

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2/13/2015 2 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.

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MRI Brain and C-Spine

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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

8 D e l a y e d

• n

s e t c h

• r

e

• a

t . . . C

• n

v e r s i

• n

d i s

• r

d e r P r i m a r y t

• r

s i n d y s t

• n

i a J u v e n i l e A L S N e u r

• a

c a n t h

• s

y t

• s

i s

13% 2% 32% 4% 50%

2/13/2015 3 Dystonia

• Defined as a movement disorder

characterized by sustained or intermittent muscle contractions causing abnormal,

• ften 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

S t e r e

• t

y p e d a n d p a t t e r . . . S u s t a i n e d m u s c l e c

• n

t r a c . . . T r e m

• r

a n d m y

• c

l

• n

u s M u s c l e r i g i d i t y G e s t e a n t a g

• n

i s t e

10% 16% 21% 29% 23%

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)

2/13/2015 4 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”,

• r 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-... DYT1 or DYT6 testing Electromyography Serum ceruloplasmin MRI of the brain

5% 3% 18% 7% 67%

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)

2/13/2015 5

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 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. 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 AD DYT5a Progressive DOPA-responsive dystonia with diurnal variation GCH1 AD DYT5b Akinetic rigid syndrome with DOPA-responsive dystonia or complex encephalopathy TH AR DYT6 Adult-onset torsion dystonia with prominent cranio-cervical and laryngeal involvement THAP1 AD 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

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

18 B l e p h a r

• s

p a s m T

• r

t i c

• l

l i s H e m i f a c i a l s p a s m S p a s m

• d

i c d y s p h

• n

i a W r i t e r ’ s c r a m p

11% 9% 3% 11% 66%

Hemifacial Spasm

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• 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

Adult-Onset Focal Dystonias

Early-to-late adulthood Focal or segmental Persistent Isolated Sporadic or familial Estimated penetrance

• f 12% to 15% and therefore may

appear sporadic

2/13/2015 6

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Blephrospasm Oromandibular Dystonia Cervical Dystonia Limb Dystonia- Writer’s Cramp

Question 5:

What is the least helpful treatment for generalized dystonia?

• A. Botulinum toxin injections
• B. Oral baclofen
• C. Trihexiphenidyl
• D. Deep brain stimulation
• E. Clonazepam

22 B

• t

u l i n u m t

• x

i n i n j e c t i

• n

s O r a l b a c l

• f

e n T r i h e x i p h e n i d y l D e e p b r a i n s t i m u l a t i

• n

C l

• n

a z e p a m

53% 19% 4% 7% 16%

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).

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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)

2/13/2015 7

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

New method of surgery

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88% improvement

Severe spinal deformity (DYT1)

Fixed contractures do not respond to DBS

Factors/Predictors of DBS Responsiveness

Shorter disease duration correlates with improved outcomes

UCSF experience Generalized dystonia DYT1+

Markun L, et al. Neurosurgery 71:325–330, 2012

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Case: Happy ending

6 months after Gpi DBS Jan 2015 – 5 years after Gpi DBS

2/13/2015 8

UCSF and SFVA Movement Disorders Team

Surgical Movement Disorders Center Jill L. Ostrem, MD, Medical Director Philip Starr, MD, PhD, Surgical Director

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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 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 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 Fellows Melanie Lising, MD Robert Coleman, MD Jennifer Chen, MD Erica Byrd, MD Svjetlana Miocinovic, MD, PhD Physical Therapy Nancy Byl, PT, PhD