Download - Dystonia: Cases Victor Fungdystonia usually looks indistinguishable from that in degenerative disease • Most (but not all) dystonia secondary to neurodegenerative disease will have

Dystonia: Cases

Movement Disorders Unit, Department of Neurology,Westmead Hospital & University of Sydney, Sydney, Australia

Victor Fung

Acknowledgements• Movement Disorders Unit

– Sangamithra Babu– Florence Chang– Ainhi Ha– Mariese Hely (ret)– Samuel Kim– Ivan Lorentz (Emeritus)– Neil Mahant– John Morris (Emeritus)– Nigel Wolfe

– Russell Dale– Greg DeMoore– Shekeeb Mohammad– Michael Tchan

• Fellows– Alessandro Fois– Hugo Morales

Briceno

2016– Margaret Kit Kwan

Ma

• Nurses– Emma Everingham– Donna Galea– Jane Griffith– David Tsui

• Referring Neurologists– Peter Brimage– Paul Clouston– Paddy Grattan-

Smith– Mohammed Shaffi– Shaun Watson

Learning Objectives

• At the conclusion of the activity, participantsshould be able to:

1. Identify a patient with movement disorders

2. Differentiate between Parkinson’s disease andatypical parkinsonism

3. Understand Movement Disorders through casediscussions

Assessment of Dystonia:Clinical Challenges

• How to recognise dystonia?

• Dystonia due to secondary causes can looksimilar to idiopathic, non-degenerative disease

• How to know how far to go with investigations ineach patient presenting with dystonia

• How to make a specific aetiological or geneticdiagnosis

Diagnostic approach in movement disorders

• Phenomenology– What kind(s) of involuntary movements are present?– What is the nature of any impairment of movement?

• Clinical syndrome– What mix of phenomenology is present?– What other neurological or systemic features are present?

• Aetio-Pathological diagnosis– What are the potential diseases that cause that syndrome?

• Genetic diagnosis

• Phenomenology – “DYSTONIA”- What kind(s) of involuntary movements are present?- What is the nature of any impairment of movement?

• Syndromic diagnosis – “DYSTONIA”- What mix of phenomenology is present?- What other features are present?

• Aetio-Pathological diagnosis – “DYSTONIA”- What are the potential diseases that cause that

syndrome?

• Genetic diagnosis – “DYSTONIA”

The same term dystonia is usedfor differential levels




syndrome?


Syndromic diagnosis in dystonia

Dystonia is not a symptom…

• “I can’t ….”

• “My neck / arm / leg twists…”

• “My arm / leg cramps or spasms when I …”

• Stiffness / cramping / (pain)

• Tremor / involuntary movement

• Dystonia is defined as a movement disordercharacterized by sustained or intermittent musclecontractions causing abnormal, often repetitive,movements, postures, or both.

• Dystonic movements are typically patterned andtwisting, and may be tremulous.

• Dystonia is often initiated or worsened byvoluntary action and associated with overflowmuscle activation.

Therapy of Movement Disorders: A Case-Based Approach. S Reich & S Factor (eds) Springer 2018

35 yo, R handed, normal birth & development, 1-2 yr h/oprogressive difficulty writing associated with pain over wrist

moreso than forearm. Negative FH.

35 yo, R handed, normal birth & development, 1-2 yr h/oprogressive difficulty writing associated with pain over wrist

moreso than forearm. Negative FH.

Therapy of Movement Disorders: A Case-Based Approach. S Reich & S Factor (eds) Springer 2018

Writer’s cramp - adult onsettask-specific focal isolated dystonia

Nov 2002

Apr 2004 Jan 2005

• 15 yo• idiopathic generalised isolateddystonia from age 5

“Dystonic movements aretypically patterned...”

• 54 yo, 9/12 h/o R foot feeling as if it wanted to slip when standing,then progressive difficulty walking, worse on hard surfaces, betteron sand & grass, increasingly disabled.

2008

• 54 yo, 9/12 h/o R foot feeling as if it wanted to slip when standing,then progressive difficulty walking, worse on hard surfaces, betteron sand & grass, increasingly disabled.

2008

Task-specific gait dystonia -Idiopathic lower limb isolated dystonia

• Aug 2014: maintains 98% improvement since on tetrabenazine 12.5 dailycommenced Mar 2009. Previously worse with levodopa 300mg/day(needed crutches) and confused with benzhexol 3mg daily.

2014

• 41yo, 2 yr h/o abnormal kicking of R leg when walking down stairs,slight feeling that R knee bends more walking up stairs, no problems

walking on flat. No h/o drug exposure. Normal MRI brain & spine.

• 41yo, 2 yr h/o abnormal kicking of R leg when walking down stairs,slight feeling that R knee bends more walking up stairs, no problems

walking on flat. No h/o drug exposure. Normal MRI brain & spine.

Task-specific (downstairs) leg dystonia- adult onset focal isolated dystonia

Courtesy Michael Hayes, Sydney, Australia

2016

• 57yo, 17 yr h/o difficulty speaking

• 57yo, 17 yr h/o difficulty speaking

Tongue dystonia(as part of task-specific oromandibular dystonia)

73 yo, 12 mth h/o involuntary R ear movements, painful anddistressing, associated with R ant > post neck pain, intermittent

mild head tremor

2006

• 22 yo, developmental delay and behavioural disturbance

2008

• 22 yo, developmental delay and behavioural disturbance,treated with risperidone from 14 yo

• Dystonia is defined as a movement disordercharacterized by sustained or intermittent musclecontractions causing abnormal, often repetitive,movements, postures, or both.

• Dystonic movements are typically patterned andtwisting, and may be tremulous.

• Dystonia is often initiated or worsened byvoluntary action and associated with overflowmuscle activation.

Can dystonia manifest as tremorwithout abnormal posturing?

57 yo, 2 yr h/o involuntary twisting of neck to rightwith posterior right neck pain

78 yo, 7 yr h/o head tremor, stable for last few years.

39 yo, 12 yr h/o involuntary neck twitches associated withpost. neck pain, partly suppressed by touching chin or leaning

head back against wall

81 yo, involuntary truncal movements lasting one week 4 and 2 yearsago, now persistent for 6 months. Distressing but not disabling,not present during walking. No medical or psychiatric history.

22 yo with Wilson’s disease

Focal isolated dystonia

• Adult onset focal isolated dystonia mostcommonly presents as cervical, cranial orupper limb dystonia

• Focal isolated dystonia can affect almost anypart of the body

• Look for patterned abnormal posture ormovement that may be task or position specific,or a geste antagoniste

• The syndromes of late adult-onset focal isolateddystonia are usually sporadic without identifiablecause, and rarely progress to generalized dystonia,but can extend to contiguous body regions

Isolated dystonia syndromes:Red flags

Isolated dystonia syndromes:Role of imaging

• The phenomenology in idiopathic, non-degenerativedystonia usually looks indistinguishable from that indegenerative disease

• Most (but not all) dystonia secondary toneurodegenerative disease will have imagingabnormalities

9 yo, onset generalised dystonia aged 2, parents first cousins

7 yo, onset generalised dystonia aged 4,mother has cervical dystonia

• 9 yo, onset generalised dystonia aged 2, parents first cousins

Pantothenate Kinase AssociatedNeurodegeneration (PKAN)




syndrome?



Combined dystonia syndromes

• Combined dystonia:– Dystonia + another movement disorder

+/- involvement of other neurological systems+/- systemic disease

• Combined dystonia is more likely to be due to aneurodegenerative process than isolated dystonia

• Many (but not all) combined dystonias due toneurodegenerative disease will have imagingabnormalities that provide a diagnostic clue

2005(1/12 post-BTX1)

• 56 yo, 8 yr h/o intermittent head turn to R 3x/wk, 5 yr h/opersistent turn to R after waking from 45 min nap on a train.

Father with PD in 60’s.

2005

• 56 yo, 8 yr h/o intermittent head turn to R 3x/wk, 5 yr h/opersistent turn to R after waking from 45 min nap on a train.

Father with PD in 60’s.

Axis I: Adult onset, focal isolated dystoniaAxis II: Sporadic, idiopathic

2012

• 63 yo, 3 mthly BTX, 2-3 yr h/o increasing unsteadiness, no falls butusing stick. Her mother had “balance problems”, one of her sisters

diagnosed with orthostatic tremor, and another sister has adult onsetbalance and gait problems.

2012

• 63 yo, 3 mthly BTX, 2-3 yr h/o increasing unsteadiness, no falls butusing stick. Her mother had “balance problems”, one of her sisters

diagnosed with orthostatic tremor, and another sister has adult onsetbalance and gait problems.

Axis I: Adult onset, focal dystonia combined withcerebellar syndrome

Axis II: Familial (autosomal dominant?), degenerative

• DYTCA(dystonia & cerebellar atrophy)– SCA 17– SCA 6– idiopathic

Syndromes where minimalinvestigation are required

• Adult onset, focal isolated dystonia► Idiopathic, non-degenerative– Copper studies if

Using investigations to define thesyndromic diagnosis

• Assessment of other neurological systems:– Radiological (MRI including iron susceptibility

sequences, CT for calcification)– Ophthalmological (slit lamp, retinal exam, ERG)– Neurophysiological (NCS/EMG, evoked potentials)

• Assessment of systemic involvement– Screening blood tests (haematological, hepatic,

renal, endocrine, copper studies)– Organ imaging




syndrome?



Investigations to make anaetiological or genetic diagnosis• Targeted metabolic analysis• Targeted genetic testing

• Wilson’s disease• Autoimmune screen (incl. cell surface Ab)• Leucocyte lysosomal enzymes• Urine metabolic screen screen (aminoacidurias,

urea cycle disorders and mucopolysaccharidoses)• CSF neurotransmitters, Glc, folate• Biopsy (muscle, skin, conjunctival, rectal)

• Genetic screening (Next Generation Sequencing)

Genetic diagnosis of dystonia

• CGH microarray(large scale deletions or duplications)

• Dystonia gene panels(sequencing of lots of known dystonia genes)

• Whole exome sequencing

• Whole genome sequencing

• [ XXX Triplet repeat disorders XXX]

Conclusions

• The assessment of dystonia requires asyndromic approach– Phenomenology– Syndromic diagnosis– Aetiological / Genetic differential diagnosis to

guide investigations

2008

• 18yo, N milestones, 9/12 prior woke with speech impairment, L>Rslowness of hand movements and gait disturbance which partiallyrecovered. Stable since. MRI normal. No recreational drug, toxin or

medication exposure. No FH.

• 19yo, sister of previous patient. Age 16, after EtOH++ & walking 2 hours, developed overhours imbalance, vertigo and generalised weakness. Woke next day with slurred speech,

UL limb stiffness & ongoing gait disturbance. Worst in the first 48 hours and then partiallyrecovered over days. Exacerbation during 3rd trimester of second pregnancy.

2017

Videos courtesy of Dan Healy

Expanding phenotypic spectrum ofATP1A3 mutations

• Rapid onset dystonia-parkinsonism

• CAPOS (cerebellar ataxia, areflexia, pes cavus, opticatrophy, sensorineural hearing loss )

• Alternating hemiplegia of childhood

• Catastrophic infantile epilepsy with microcephaly

• Fever-Induced paroxysmal weakness and encephalopathy(mutations at residue 756)

• Overlap syndromes with partial features