Hatem Samir Shehata, M.DProf. of NeurologyCairo University

December 2015

Movement Disorders Emergencies

• Movement disorders encompass disabling syndromes typically viewed as a realm of slowly progressive chronic disorders that are, in most cases, followed and treated without requiring emergent intervention

• Recently, this view has been challenged by the growing body of literature as well as clinical experience showing that movement disorders can also present acutely with more aggressive forms

• The criteria of movement disorders emergencies:– Acute/subacute evolving neurological disorder, in which the clinical

presentation is dominated by movement disorders and,– Failure to accurately diagnose and manage the patient may result in

significant morbidity or even mortality

Introduction

Six Main Topics

1. Emergency in PD:a) Severe motor fluctuation , super ‘OFF’b) Parkinsonism-hyperpyrexiac) Acute parkinsonismd) Acute psychosis in PD

2. Acute drug reactiona) Acute dystoniab) NMSc) Serotonergic syndromed) Malignant hyperthermia

3. Acute exacerbation of chronic MDsa) Status dystonicusb) Laryngeal dystonia in MSA and other conditionsc) Tic statusd) Wilson’s disease emergencies

4. Acute chorea and ballism5. Stiff-person syndrome6. Lethal catatonia

• Motor fluctuations in PD typically are not severe enough to need urgent interventions; however, some patients may have extremely disturbing “off” periods, especially when they occur suddenly, associated with prominent akinesia, dysautonomia, and psychiatric features, such as anxiety and panic

• Potential triggers or aggravating factors: (1) infections, (2) dopaminergic medication changes, and (3) use of antidopaminergic drugs

• Management involves combined approaches: – Fragmentation of daily doses of levodopa– Liquid forms (crushed tablets), controlled-release– Add SC dopamine agonists, MAO-B and COMT inhibitors– DBS

Severe Motor Fluctuations

• The “super OFF” is defined as an increase in motor disability scores in comparison to basal (OFF period) motor scores described in those experiencing MF

• So, the patients affected by this phenomenon have the sensation of being more symptomatic than their usual ‘OFF levodopa dose status’

• It is either; (1) a beginning-of-dose or, (2) an end-of-dose inhibitory effect. The phenomenon is often very distressing and disabling, lasting from minutes to hours

• Pathophysiology is probably linked either to presynaptic inhibition of firing and release of dopaminergic neurons, or from preferential stimulation of a subpopulation of postsynaptic DA receptors that have an inhibitory action on motor activity caused by low levels of levodopa in the rising or declining plasma level

• Clozapine can reduce the severity of ‘super OFF’ in those patients (as it could inhibit the inhibitory action of low plasma levodopa levels, leading to an apparent antiparkinsonian effect)

Super OFF phenomenon

• It mimics NMS in patients with PD, characterized by hyperthermia, dysautonomia, altered consciousness, severe rigidity, and elevated serum CK

• Triggers include: infections, hot weather, dehydration, and withdrawal of antiparkinsonian agents (specially L-dopa),

• Recurrent PHS was described after discontinuation of subthalamic nucleus DBS

• Complications include DVT, pulmonary embolism, aspiration pneumonia, and renal failure

• Treatment: supportive measures (+) reinstitution of adequate dopaminergic therapy. Occasionally, dantrolene is necessary

• Dyskinesia–hyperpyrexia syndrome (DHS) consists of severe dyskinesias leading to muscle exhaustion, hyperthermia, rhabdomyolysis, and confusion. It should be treated by cautiously reducing the dosage of dopaminergic drugs

Parkinsonism–hyperpyrexia syndrome (PHS)

Drug inducedNeuroleptics, Antidepressants, AnticonvulsantsAntiemeticsCytotoxic agents

IntoxicationsCarbon monoxide, MethanolOrganophosphates, Manganese, CyanideMPTP: 1-Methyl-1–4-phenyl-4-proprionoxypiperidine

StructuralSubdural hematomaHydrocephalusStrategic ischemic lesions

Infections/postinfectious/inflammatoryViral encephalitis, HIVPostinfectiousAutoimmune

MetabolicPontine and extrapontine myelinolisisHepatic encephalopathy, Diabetic uremia

GeneticRapid-onset dystonia parkinsonismAcute decompensation in Wilson's disease

• Acute severe de-novo parkinsonism is uncommon, and frequently caused by exposure to potent DRBs

• Acute worsening of motor symptoms in PD typically occurs because of concurrent medical conditions

• Treatment should be focused on resolution of underlying etiologies; occasionally, symptomatic treatment with dopaminergic agents is required

Acute Parkinsonism

• Psychosis occurs in up to ½ of cases with PD throughout the disease course, frequently triggered by medications targeted motor symptoms

• Manifestations include visual hallucinations, delusions, confusion, and agitation

• Acute clinical conditions (infectious, metabolic, or neurological disorders) may play a role, and should be treated promptly

• Withdrawal of potentially contributing agents is recommended, starting with anticholinergics, followed by MAO-B inhibitors, dopamine agonists, amantadine, and COMT inhibitors

• The use of antipsychotics (clozapine or quetiapine) may be necessary

Acute Psychosis in PD

• NMS is an idiosyncratic abrupt reaction to 'classic' neuroleptics; however, newer 'atypical' agents have all also been implicated, the safest being clozapine and quetiapine

• NMS can occur after abrupt withdrawal of dopaminergic agents

• Symptoms start during the first 2 weeks of treatment initiation or dosage change

• Risk factors include abrupt dose escalation, depot formulations, male sex, young age, use of lithium and SSRIs, fever, dehydration, EPS, and previous NMS episode

• Mortality remains high between 20 and 30% of cases

Neuroleptic Malignant Syndrome (NMS)

• Diagnostic criteria: A tetrad of hyperthermia, rigidity, altered mental status, and dysautonomia.

• Associated signs: tremor, dystonia, myoclonus, seizures, ataxia, and extensor plantars

• Laboratory changes include raised serum CPK (>1000 IU/l), impaired liver, renal, and coagulation status tests, leukocytosis, electrolyte disturbances, proteinuria, rhabdomyolysis, and myoglobinurea.

• Differential diagnoses: serotonergic syndrome, malignant hyperthermia, and catatonia

Diagnosis of NMS

1. Medication withdrawal

2. Supportive care (ICU admission)

3. Pharmacological interventions:– Dantrolene: loading 2.5 mg/kg IV bolus, then 1-2 mg/kg IV / 4 – 6 hours,

max: 10 mg/kg/d. Continue at least for 36 hr. – Benzodiazepines to reduce rigidity– Dopaminergic drugs (Bromocriptine ‘directly activate postsynaptic

receptors and offsets the central inhibition of DA’ / Levodopa / Amantadine)

4. Management of the underlying psychiatric condition can be then restarted with low doses, slow titration, avoiding lithium, and with close observation to prevent recurrence

Treatment of NMS

• It results from the combination of two or more agents that cause excessive brainstem and spinal cord serotonin or 5-hydroxytryptamine (5-HT) type 1A receptor stimulation

• This under-recognized syndrome presents with abrupt onset of agitation, mental status changes, myoclonus, ataxia, postural instability, hyperreflexia, rigidity, and dysautonomia after changes in serotonergic drug regimen. Fatality (10 – 20 %)

• Serum or CSF serotonin levels are useless for diagnosis, which is established on clinical grounds.

• The diagnostic criteria require:– Positive medication history along with any of the following: myoclonus,

agitation or diaphoresis; unexplained hyperthermia; hypertonia; and tremor– Seizures, renal failure, and coagulopathy may occur

Serotonergic Syndrome

Offender drugs

• A combination is usually needed, with greater risk for MAOI or SSRIs concomitantly used with any other serotonergic agent

• Although doses taken are commonly within therapeutic limits, 20% of cases occur secondary to overdose

• Other risky circumstances include rapid titration, addition or switch to a new agent without proper washout period, liver or renal disease, and old age

The most common implicated agents in SS

• Lab abnormalities include metabolic acidosis, rhabdomyolysis, leucocytosis, elevated serum aminotransferase and creatinine levels

• D.D. Cocaine or lithium overdose, anticholinergic poisoning, malignant hyperthermia, and NMS, each readily distinguished from serotonergic syndrome based on medication exposure history

• Treatment:– Medication withdrawal, enough to improve half of all cases– Persistent symptoms require pharmacologic treatment; (1) 5-HT receptor

blockers (cyproheptadine and methysergide), BZD, chlorpromazine, and propranolol

– Treatment of seizures, arrhythmias, coagulopathy, rigidity, and hyperthermia are necessary

• Reintroduction of treatment of the underlying psychiatric disorder requires close monitoring, low dose, and slow titration

Diagnosis and treatment of SS

• It is a rare genetic muscle disorder that occurs when a mutation-positive patient is exposed to inhalation anesthetics or depolarizing muscle relaxants

• Manifestations. Abrupt hyperthermia, fluctuations in blood pressure, hypercarbia, hyperkalemia, metabolic acidosis, rigidity, and rhabdomyolysis

Malignant Hyperthermia

• It results from uncontrolled calcium flux across muscle membrane due to a dominant mutation on the gene encoding skeletal muscle type-1 ryanodine receptor

• Dantrolene can be effective treatment, along with correction of metabolic and electrolyte abnormalities

NMS SS MH

Age/sex Young men None Children, young adults

Trigger Idiosyncracy Drug combination/overdose Gene mutation

Onset Acute Subacute Acute

Causative agents Classic/new neuroleptics, L-dopa withdrawal

SSRI, T3C, MAOIs, L-tryptophan, cocaine, amphetamine

Volatile anesthesia, succinylcholine

Fever +++ +++ +++

Confusion +++ +++ +

Dysautonomia +++ +++ +++

Motor features Tremor, rigidity Rigidity, myoclonus Rigidity

Diaphoresis +++ ++ +++

++ CK +++ ++ +++

++ transaminases +++ + -

Metabolic acidosis + + ++

Phamacotherapy Dantrolene, Bromocriptin

Cyproheptadine, methysergide

Dantrolene

• After exposure to DRB, typically within 24 h of exposure

• Risk is increased in men and when the dose is rapidly titrated

• Manifestations can combine blepharospasm, cervical, laryngeal or limbs dystonia, and oculogyric crisis

Acute dystonic reactions

• Life-threatening respiratory compromise can occur when the larynx or pharynx are affected

• Management includes parenteral anticholinergics or antihistamines, after the precipitating agent is discontinued

• A rare ‘but, under-reported’ life-threatening movement disorder emergency (only about 100 published cases, till 2014)

• It affects all age groups but up to 60% of patients are between ages 5 and 16 years

• Neurometabolic disorders such as glutaric aciduria type 1 may precipitate status dystonicus as early as 7 months of age [The extensor dystonia is mistaken for status epilepticus]

• Status dystonicus occurs at the end of a continuum of worsening dystonia

• Video recordings are important for diagnosis and follow-up of treatment response. The baseline neurological state (coexisting spasticity, etc.) should also be recorded

Status dystonicus(dystonic storm or dystonic crisis)

Phenomenology

• Characterized by frequent or continuous severe episodes of generalized dystonic spasms (contractions) and divided into: (1) tonic (sustained contractions) – worse outcome, (2) phasic (rapid and repetitive dystonic contractions) phenotypes

• It may overlap with other hyperkinesias such as choreoathetosis, which can make objective recognition complicated

• Patients have one or more of the following: (1) bulbar weakness compromising airway patency, (2) progressive impairment of respiratory function leading to respiratory failure, (3) metabolic derangements, and (4) exhaustion and pain

• Any form of dystonia has the potential to escalate into status dystonicus

• It usually emerges gradually after weeks or months in the patient with an underlying dystonia diagnosis, but it may present during new onset dystonic disorders without previous dystonic movements

• Some patients are prone to recurrent episodes

• The acquired dystonias (mostly CP) are the most common underlying dystonias leading to status dystonicus (38% of cases) followed by NBIA (neurodegeneration with brain iron accumulation) and Wilson disease

Aetiology

• Status dystonicus is often a triggered event

• The main triggers include infection (particularly gastroenteritis), medication adjustment, trauma, surgical procedures, anaesthesia, and stress. In about ⅓ of cases no obvious trigger

• Certain medications are triggering particularly DRB ‘pimozide and haloperidol’ [both are used to treat dystonia and chorea], and metoclopramide. Also Lithium and tetrabenazine withdrawal, ITB pump failure and DBS failure (hardware problems)

• In Wilson disease the introduction of chelation therapy with D-penicillamine, Zn sulphate, or trientine are triggers

Trigger factors

Complications

• Complications are at best painful and uncomfortable, and at worst life-threatening1. Severe generalized muscle spasms can cause severe metabolic

disturbances (rhabdomyolysis and acute renal failure)

2. Respiratory failure can be a function of dystonic bulbar spasms (pharyngeal, laryngeal), truncal-respiratory muscle spasm and diaphragm dystonia

3. Muscle spasm-induced hyperpyrexia and dehydration

4. Secondary complications such as thrombosis, gastric bleeding, injuries, fractures, and sepsis. Some patients require tracheostomy or gastrostomy

• Investigations (related to rhabdomyolysis):– ++ CPK (usually >5 times normal range, e.g. >1000 IU/L). Repeat if

negative due to a potential lag in elevation– Renal failure (electrolyte disturbances, dehydration ‘+ hematocrite’,

acidosis, coagulopathy, pancreatic dysfunction and arrhythmias)

• Differential diagnosis– NMS, serotonin syndrome, malignant hyperthermia– Paroxysmal autonomic instability with dystonia (PAID). Paroxysms of

agitation, diaphoresis, hyperthermia, HTN, tachycardia and tachypnoeawith hypertonia and extensor posturing (TBI due to brainstem injury)

– Acute dystonic reactions (drugs) may cause severe dystonic symptoms (e.g. oculogyric crisis, jaw opening, or closing dystonia).

Investigations and differential diagnosis

Screening for dystonia severity (grade) andDystonia Severity Action Plan (DSAP) to decidethe level of care of management of StatusDystonicus

2 - Sedating measures1- Supportive 3 – Dystonia specific2- Sedating measures

ventilation

Depolarizing agents, as suxamethonium, are associated with rhabdomyolysis

• Acute severe chorea can result from several factors leading to hyperthermia and rhabdomyolysis

– Chorea gravidarum is associated with a past history of rheumatic fever, SLE, or antiphospholipid antibody syndrome. It begins in the first trimester, and 1/3 of cases resolve spontaneously before delivery, and the remainder within hours after delivery. If persists, low-dose haloperidol can be used after the first trimester

• Ballism is large amplitude, coarse, forceful movements often occurring acute and unilaterally. Ballism and chorea may in fact represent a continuum of hyperkinetic movements differentiated by speed and amplitude

– The most common cause of hemiballism is vascular (contralateral STN). However, this topography is uncommon and lesions in multiple areas have been implicated (putamen, GP)

– NKH can result in unilateral or bilateral ballism, typically in elderly females, as a presenting feature of diabetes mellitus or in established cases

Chorea and Ballismus

Causesof Chorea

Vascular Ischemic/hemorrhagic strokeMalformations, Polycythemia veraCerebral anoxiaPostpump chorea

Metabolic Nonketotic hyperglycemia, HypoglycemiaUremic encephalopathyHyperthyroidism, Hypoparathyroidism

Structural Basal ganglia lesions, cerebellar massThalamotomy or subthalomotomy

Infectious Cryptococcal granuloma, TuberculomaToxoplasmosisHIV encephalitis

Autoimmune Postinfectious/Sydenham chorea/chorea gravidarumSLE, Polyarteritis nodosa, Antiphospholipid antibody syndromeScleroderma, Behcet disease, SarcoidosisMultiple sclerosisParaneoplastic (CV2/CRMP-5 antibodies)

Iatrogenic Anticonvulsants, LevodopaOral contraceptivesCocaine, Amphetamine, Morphine, Alcohol

• It usually occurs in the setting of schizophrenia, but may also follow infections as meningitis and encephalitis, head trauma, drug intoxication and metabolic disturbances (e.g., uremia, porphyria and WE)

• The diagnosis is clinical, and no paraclinical tests confirm the specific diagnosis.

• It is characterized by severe bahavioral disorders hyperthermia, autonomic instability and severe rigidity, which, if prolonged, can be followed by exhaustion, coma, renal failure, cardiovascular collapse and death

• MC differs from NMS by the severity of the behavioral abnormalities in the early stages, both syndromes may become indistinguishable in their more advanced stages

• Treatment includes high dose IV BZD, barbiturates and ECT. Other drugs (as dantrolene and bromocriptine) may have some utility

Lethal / malignant catatonia

• Myoclonus can present emergently in the following scenarios:– Toxic metabolic derangement– Drugs reaction (as in SS and NMS), added by opiates and GBP– Cerebral hypoxia: with 2 recognized syndromes (1) Myoclonus

status epilepticus (MSE): multifocal, poor prognosis, (2) Lance Adams syndrome (LAS), with stimulus sensitive and action-induced movements

• When myoclonus is particularly disabling, treatment may include clonazepam, valproic acid, and levetiracetam

Myoclonus

• A rare neurological disorder in which patients present with severe abrupt jerky painful spasms of the lumbar paraspinal muscles and lower limbs followed by tonic activity that slowly subsides over minutes (spontaneously or provoked by noise or movement). Rarely, these spasms last days (status spasticus)

• The affected muscles are hard to palpation with a board-like appearance, leading to hyperlordosis

• Spasms may be so forceful to produce femoral fractures, joint subluxations and herniation of abdominal contents

• Paroxysmal autonomic dysfunctions are common associates

• Autoantibodies to glutamic acid decarboxylase (anti-GAD) that limit GABA neuronal activity and lower the threshold for muscle spasms

• Treatment: GABA-ergic drugs (BZD, Baclofen, VPA, GBP, LEV)

Stiff person syndrome (SPS)