Learning objectives

MDS-ES Movement disorders emergencies • Recognize acute dystonias and treat !

Acute Dystonia and Status Dystonicus Dystonia • Status dystonicus and differential diagnosis an overview Diagnosis and treatment

Pr. Marie Vidailhet Department of NeurologySalpetriere Hospital, Sorbonne Université, Paris Brain Institute (ICM) Paris, France [email protected]

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combination of gastro- oesophageal reflux disease with torticollis and dystonic body movements Acute dystonia (s) with or without hiatal hernia.

Hypothesis the positioning of the head provides relief from abdominal discomfort caused by acid reflux.

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1 Dopa responsive dystonia

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• Parkinsonism and dystonia without dopaminergic denervation Mutations in the ATP1A3 gene encoding the subunit alpha 3 of Na-K-ATPase pump, Rapid onset dystonia parkinsonism ATP1A3 Autosomal dominant with reduced penetrance; De novo cases are frequent

- Abrupt onset within hours to week - In adolescence or early adulthood with no gradual worsening over years

Dystonia: rostral to caudal gradient (bulbar +) Bradykinesia and postural instability

Triggered by fever, alcohol binging, unusual physical exercise

No response to L-Dopa, DAT scan normal

At age 22, unusual alcohool intake, Abrupt onset, rapid evolution waked up : mutism, difficulties to move. then “static” Within a few days, gait disturbances, postural instability, axial dystonia, severe dysarthria, dystonic postures, bradykines. 7 8

2 Wilson’s disease Kayser Fleischer’s ring D-Penicillamine Trientine mutation of the ATP7B gene Oral Zinc inherited in an autosomal recessive manner Dietary recommendations Low ceruloplasmin relative exchangeable copper (REC)* Acute worsening if the treatment is interrupted High urinary copper

(REC) corresponds to the ratio between CuEXC and total serum copper - enables a diagnosis of WD with high sensitivity and specificity when REC>18.5%.

- CuEXC values at diagnosis are a marker of extrahepatic involvement and its severity.

A value of >2.08μmol/L is suggestive of corneal and brain involvement (Se=86%, Sp=94%), liver transplantation - D-penicillamine , trientine, Zinc, (lifelong) - liver transplant Asymptomatic carriers: -> detection,treatment 9 10

Status dystonicus Definition and generalities

• acute and persistent combination of generalized dystonia and chorea Status dystonicus • widespread severe muscle contractions and look alike • potentially life-threatening disorder • represents as an emergency • In primary or secondary dystonia

• Common triggers include general anesthesia, administration of drugs (e.g. neuroleptics), or infection and fever.

• Admission to the intensive care unit is usually advisable.

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3 Status dystonicus Cerebral palsy First line care

• hemodynamic and metabolic monitoring • Severe fever, rhabdomyolysis , myoglobinuria, risk of renal failure

• Sedation(muscle relaxant) lessens the severe spasms thereby decreasing muscle breakdown and preventing rhabdomyolysis • Use of Midazolam, propofol, thiopental, lorazepam • Sedation may require admission in ICU, sedation and ventilation

• if possible, treat the triggering factor • In some cases, consider DBS in emergency (benefit within days then gradual improvement).

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One example GNAo1 One example GNAo1 Pre op (2016) • GNAO1 recently identified to be involved in the pathogenesis of early infantile epileptic encephalopathy and movement disorders.

– global motor retardation, progressive hyperkinetic movement disorder – prolonged life-threatening exacerbations – refractory to most anti-dystonic medication.

– group of disorders with early-onset movement disorders • the GNAO1(G protein subunit alpha o1) • other G-protein related complexes encoded by related genes :GNAL (G protein subunit alpha L), GNB1 (G protein subunit beta 1) or ADCY5 (adenylate cyclase 5)

– MRI: pallidal hypo-intensity, cerebellar atrophy, cortical and sub-cortical atrophy

Deep brain stimulation is effective in pediatric patients with GNAO1associated severe hyperkinesia Koy A et al Journal of the Neurological Sciences, 2018

Courtoisy Dr N Dorison Neuropediatric, Fondation Rothschild Paris France

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4 Bilateral pallidal stimulation

Post-op 2017 June 2020 Moderate aggravation Bilateral GPi in the last months

Progressive atrophy (MRI) GNAo1)

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Marked worsening Admission in ICU August 2020 Has to be intubated At home Pa02 very low (50%) Laryngeal dystonia

Triggering factor of Dystonic storm : Viral infection

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5 Long list of disorders with possible status dystonicus

• Even in subtypes of dystonia with usually good beneficial effect of bilateral Gpi stimulation such as KMT2B

• Most of the secondary dystonia : metabolic disorders (e.g. methymalonic acidemia) mitochondrial disorders, PANK2 with life- threatening tongue protrusion

• Drug induced status-dystonicus: Phenytoin Induced Status Dystonicus

• Status dystonicus resembling the intrathecal baclofen withdrawal syndrome

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Bilateral pallidotomy Intrathecal baclofen withdrawal syndrome

• Bilateral pallidotomy can be an alternative to bilateral DBS • Baclofen delivered by an implantable pump system, • widely used for the treatment of refractory spasticity. • Review: 25 patients with status dystonicus (SD) • abrupt cessation of intrathecal baclofen infusion • In all but 2 the SD resolved after bilateral pallidotomy. • Relapse of SD n=7. median follow up: 12 months -> severe withdrawal syndrome • • Dystonia • bilateral pallidotomy is an effective and relatively safe procedure • autonomic dysfunction for certain types of dystonia, particularly in medication-refractory SD. • hyperthermia, • publication bias the underreporting of negative outcomes is very • organ failure and sometimes death. likely, bilateral pallidotomy is a reasonable alternative to DBS in selected dystonia patients. Abrupt withdrawal of intrathecal baclofen may simply precipitate an episode of status dystonicus in susceptible individuals. Centen et al Movement Disorders. 2021,

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6 Take home message Intrathecal baclofen withdrawal syndrome

• Withdrawal syndrome due to loss of GABAergic inhibition with Acute dystonia & status dystonicus triggered by various factors: predominantly excitatory effects (hyperexcitability and increased • disease related, spasticity). • infection, metabolic disorders • change in treatment, battery failure (DBS) • withdrawal symptoms appeared within 1 to 3 days after • pump failure (intrathecal baclofen) interruption of therapy. • Severe and life threatening • due to pump malfunction, programming error, catheter ->Emergency care obstruction or kink, dislodgement or leakage, empty battery, a may have severe complications : rhadomyolysis, renal failure unrecognized declines in pump reservoir drug level Can be related to the therapeutic device : battery failure in DBS, Pump • Treatment: dysfunction in intrathecal baclofen infusion • restoration of baclofen levels at or near the same levels as before therapy was interrupted, • Intensive care, metabolic, pain, sedation, ICU, antibiotics if needed • benzodiazepines, • Deep brain stimulation or pallidotomy in severe cases • propofol infusion. Relapses related to the undelying disease

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Thank you for your attention

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