CONTENTS

• Hypokinetic
  • Parkinson's disease
    • Managing Parkinson's medications in the ICU
    • Parkinsonism-hyperpyrexia syndrome
    • Acute parkinsonism
    • Psychosis in Parkinson's disease
  • Neuroleptic malignant syndrome (NMS)
  • Catatonia
  • Baclofen withdrawal
• Hyperkinetic
  • Acute ballismus or chorea
  • Akathisia
  • Myoclonus
  • Dystonia
    • Acute dystonia
    • Dystonic storm
  • Post-hypoxic myoclonus
  • Tetanus
  • Propofol frenzy
• Podcast
• Questions & discussion
• Pitfalls

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managing Parkinson's disease medications in the ICU

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general challenges

• (1) Parkinson's medications must generally be continued, to avoid parkinsonism-hyperpyrexia syndrome (discussed below). Medications which can be given via gastric tube are listed below. For patients unable to take oral medications, their medication regimen must be reformulated appropriately.
  • ⚠️ Consult neurology if there is any confusion about how to do this – it's extremely important.
• (2) Medications which inhibit dopamine transmission must be avoided (as listed below).
• (3) Monoamine oxidase-B inhibitors (MAO-B inhibitors; selegiline and rasagiline) have numerous drug-drug interactions. In particular, they interact with a variety of medications to increase the risk of serotonin syndrome.📖 MAO-B inhibitors should generally be continued, with caution regarding drug-drug interactions.

🛑 medications to avoid in parkinsonism

• Antidopaminergics:
  • Antipsychotics.
  • Prokinetics (e.g., metoclopramide).
  • Antiemetics (e.g., prochlorperazine, promethazine, chlorpromazine). (For antiemetics which don't affect dopamine receptors, see the antiemetics chapter.📖)
• Medications that interact with levodopa:(27907965)
  • Medications that decrease the effectiveness of levodopa: phenytoin, papaverine, amitriptyline, isoniazid, iron.
  • Linezolid reduces levodopa metabolism.

routes of administration of dopaminergic medications (Shutter 2019)

• Amantadine (unclear mechanism; weak NMDA antagonist):
  • Crushed/dissolved tablets or suspension can be given via gastric tube.
• Apomorphine (non-ergot dopamine agonist):
  • Available as subcutaneous injection.
  • May be used in patients unable to take oral medications, but it can cause significant nausea.(27907965)
• Entacapone (catechol-O-methyltransferase inhibitor prolongs half-life of levodopa)
  • Crushed/dissolved tablets can be given via gastric tube.
• Carbidopa/Levodopa (Levodopa is the precursor of dopamine; carbidopa inhibits peripheral metabolism of levodopa, limiting levodopa's side effects)
  • ⚠️ More levodopa (30-50%) is needed with sustained-release formulation than with immediate release formulation, so there may not be a 1:1 dose conversion.(27907965)
  • ⚠️ Avoid giving levodopa with food. This should be taken at least one hour before or two hours after food (including tube feeds).(27907965)
  • Sinemet immediate release may be crushed/dissolved and given via gastric tube (but not extended release forms). Duopa is an enteral carbidopa/levodopa suspension which can be given via gastric tube. Crushed/dissolved tablets of carbidopa can also be given via gastric tube.
• Pramipexole and ropinirole (non-ergot dopamine agonists):
  • Crushed/dissolved immediate release tablets can be given via gastric tube.
• Rotigotine (non-ergot dopamine agonist):
  • This is a transdermal patch.
• Rasagiline and selegiline (MAO-B inhibitors):
  • Crushed/dissolved tablets can be given via gastric tube.
  • Selegiline is also available sublingually (Zemplar) and transdermally (Emsam).

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Parkinsonism-Hyperpyrexia Syndrome

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basics

• Parkinsonism-hyperpyrexia syndrome is essentially a form of neuroleptic malignant syndrome (NMS) that results from rapid discontinuation of therapy for Parkinson's disease.
• The clinical features of neuroleptic malignant syndrome are further described here: 📖. Compared to other examples of neuroleptic malignant syndrome, extrapyramidal/parkinsonian features tend to be more pronounced and more routinely present (e.g., tremors, rigidity).(30743298)
  • Rigidity and tremor are often the first symptoms.
  • Hyperpyrexia and mental status changes may subsequently evolve.
• Symptoms may begin 18 hours to a week after changing therapy.(Shutter 2019)

causes of parkinsonism-hyperpyrexia syndrome include:

• Discontinuing dopaminergic medications, dose reduction, or nonadherence. For example:
  • Due to dysphagia.
  • Inappropriately holding medications prior to a procedure.
  • Following incarceration.
• Changing from immediate-release to extended-release formulations.
• Reduced absorption of levodopa due to coadministration with high-protein tube feeds.(Frucht 2022)
• Discontinuing anticholinergics or COMT inhibitors (e.g., entacapone).
• Dysfunction of a deep brain stimulator (if the patient has a device it should be immediately interrogated). (Shutter 2019; 27907965)
• Infection or dehydration.(26110802)

differential diagnosis

• Dyskinesia-hyperpyrexia syndrome results from an overdose of dopaminergic agents or occasionally physiological stress (e.g., infection, dehydration, heat exposure). This involves dyskinesias, rhabdomyolysis, hyperthermia, and confusion. Management requires a judicious reduction of dopamine agonists.(27907965)
  • Dyskinesia-hyperpyrexia syndrome is extremely rare, with only a few cases reported.(Freucht 2022)
  • Treatment involves aggressive supportive care and down-titration of Parkinson's medications.

management

• Supportive care 📖 .
• Reinstitution of dopaminergic therapy.
  • In patients who are strictly NPO, a transdermal or parenteral dopamine agonist may be needed (e.g., apomorphine 2 mg SC q3hr, or rotigotine).(Freucht 2022)
  • Additional medical therapy with bromocriptine 💉 (a dopamine agonist) should be considered, although there is no evidence regarding this.(Freucht 2022)
• Ensure that any deep brain stimulator is functioning properly.

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acute parkinsonism

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general

• There is no universal definition of acute parkinsonism, but the term may be used to refer to a bradykinetic-rigid syndrome developing over minutes to a few weeks.(Frucht 2022) Other Parkinsonian features such as tremor may also be seen.
• Acute parkinsonism may result from a variety of insults to the basal ganglia. Medications and toxins are the most common causes, but the range of causes is broad (listed below).

causes of acute parkinsonism (Shutter 2019, 30743298)

• Medications:
  • Amiodarone.
  • Antiepileptics (carbamazepine, lamotrigine, phenytoin, valproic acid).
  • Chemotherapeutic agents, cyclosporine.
  • Dopamine antagonists (including antipsychotics and some antiemetics).
  • Lithium.
  • Tricyclic antidepressants.
• Postencephalitic parkinsonism: Following infection with various viruses (coxsackie, EBV, HSV, CMV, VZV, HIV, influenza, Japanese B encephalitis, poliovirus, measles, western equine encephalitis, West Nile virus, lymphocytic choriomeningitis virus).
• Autoimmune/paraneoplastic:
  • Antiphospholipid syndrome.
  • Lupus.
  • Sarcoidosis.
  • Antibodies against LGI1, IgLON5, Dopamine D2-receptor, Ma2, or Ri.
• Toxins:
  • Carbon monoxide.
  • Cadmium.
  • Cyanide.
  • Methanol.
  • Ethanol withdrawal; disulfiram.
  • Manganese.
  • Organophosphates.
  • Designer drugs, such as MPTP.
• Metabolic:
  • Central pontine myelinolysis.
  • Hepatic encephalopathy.
  • Anoxic brain injury (may be delayed).
  • Acute decompensation of Wilson's disease.
• Structural brain lesions:
  • Stroke (especially in the basal ganglia, midbrain, supplementary motor area, or cingulate gyrus).(Frucht 2022)
  • Obstructive hydrocephalus.
  • Brainstem and posterior fossa tumors.
  • Subdural hematoma.
  • Central and extrapontine myelinolysis.

differential diagnosis includes

• Neuroleptic malignant syndrome.
• Underlying primary parkinsonism (e.g., Parkinson's disease or Lewy body dementia) exacerbated by anti-dopaminergic medications.
• Catatonia.
• Acute extrapyramidal symptoms due to medication.

management

• Any causative etiology should be identified and treated.
• Symptomatic management with dopaminergic agents may also be needed. A trial of levodopa may be better tolerated than postsynaptic dopamine agonists.(30743298) If levodopa fails, amantadine 200-400 mg/day may be trialed.(Frucht 2022)

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psychosis in Parkinson's disease

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clinical features

• Parkinson's disease psychosis requires at least one of the following features: illusions (misinterpretation of a real stimulus, such as seeing a tree as a person), false sense of presence, hallucinations, or delusions.(33896535)

causes of psychosis in Parkinson's disease

• Any of the usual causes of delirium (discussed further here 📖). In particular, common triggers may include:
  • Dehydration.
  • Infection (most often pneumonia or urinary tract infection).
  • Metabolic abnormality.
  • Sleep deprivation.
  • Polypharmacy.
• Psychosis may be provoked or exacerbated by Parkinson's medications. Ordered from most problematic to least problematic, these include: anticholinergics > amantadine > MAO-B inhibitors > dopamine agonists > COMT inhibitors > levodopa.(Shutter 2019)
• Underlying Lewy body dementia should be considered in patients who develop psychosis/hallucinations within a year of being diagnosed with parkinsonism. Such patients may respond poorly to neuroleptics, but respond better to cholinesterase inhibitors.(Freucht 2022)

management

• Investigate thoroughly for an acute trigger (as for any patient with delirium).📖
• Withdrawal of Parkinson's medications may be needed (starting with the worst offenders, as rank-ordered above). If removal of all medication other than levodopa is inadequate, then gradual reduction in the levodopa dose may be attempted.(33896535)
  • ⚠️ Medication withdrawal risks eliciting parkinsonism-hyperpyrexia syndrome (discussed above). This should be done carefully and ideally in consultation with a neurologist.
• Pimavanserin has been approved for the management of psychosis in Parkinson's disease. By acting predominantly at the 5-HT2A receptors, pimavanserin may have less risk of exacerbating Parkinson's disease than other antipsychotics.
• Alternatively, quetiapine may be very cautiously utilized (starting at 12.5 mg daily with gradual escalation to 50 mg daily at night or BID).(Shutter 2019)
• Clozapine may be effective at 6.25-50 mg daily (a dose much lower than is used for schizophrenia), but this requires regular monitoring of the blood count to detect agranulocytosis.(Shutter 2019)

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acute ballismus or chorea

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definitions

• Distinctions between chorea, athetosis, and ballismus (ballism) are somewhat arbitrary.(28168537) These disorders appear to have a common underlying pathology and treatment.
• Chorea is fluent, nonrhythmic, nonrepetitive, purposeless, involuntary movement. It often involves the distal extremities, causing dance-like movements.
  • Athetosis refers to a slow and distal form of chorea with a twisting or snake-like appearance (aka choreoathetosis).(28168537)
  • Ballismus is a very severe form of chorea involving the proximal musculature, leading to violent, flinging/flailing movements of an extremity. Ballism is classically associated with a lesion in the contralateral subthalamic nucleus, but ballism may also result from lesions elsewhere in the basal ganglia or contralateral cortex.(32299832, 30743298, 26110802)
• Hemiballismus or hemichorea refer to these movements involving half of the body, which is the most common distribution.

symptoms

• Acute ballismus or chorea is often unilateral.
• In severe cases, movements can be unrelenting and violent. This may cause physical injury, hyperthermia, and/or rhabdomyolysis.
• Movements generally disappear in sleep.(Freucht 2022)

causes

• Structural lesion:
  • Basal ganglia stroke is the most common cause.(30743298)
  • Multiple sclerosis.
  • Other space-occupying lesions (e.g., tumors, vascular malformations).
• Medication-induced, including:
  • Antiarrhythmics.
  • Antidepressants.
  • Antiepileptic medications.
  • Antihistamines.
  • Opioids (morphine, methadone).
  • Oral contraceptives.
  • Levodopa, dopamine agonists (e.g., causing dyskinesia-hyperpyrexia syndrome, discussed above 📖).(27907965)
• Toxins:
  • Carbon monoxide.
  • Metals (manganese, thallium, mercury).
  • Toluene.
  • Methanol.
  • Cyanide.
  • Cocaine, heroin, amphetamines.
• Metabolic:
  • Hypoglycemia or hyperglycemia – especially diabetic ketoacidosis or hyperglycemic hyperosmolar state (HHS).
  • Hypernatremia or hyponatremia.
  • Hypomagnesemia.
  • Hypocalcemia.
  • Thyrotoxicosis.
  • Chronic acquired hepatocerebral degeneration.
  • Uremic encephalopathy.
  • Wilson's disease.
  • Cerebral anoxia.
• Autoimmune/inflammatory:
  • Lupus.
  • Antiphospholipid antibody syndrome.
  • Chorea gravidarum (usually beginning within the first 12 weeks of pregnancy).(28168537)
  • Paraneoplastic (including: anti-CV2/CRMP5, anti-Hu, anti-NMDA receptor encephalitis).
  • Sydenham's chorea (status post beta-hemolytic streptococcal infection).
• Infections:
  • HIV.
  • Toxoplasmosis.
  • Cryptococcus.
  • Tuberculoma.
  • Mycoplasma.
  • Creutzfeldt-Jakob disease.

treatment

• Management of any underlying disorder (e.g., hyperglycemic hyperosmolar state, infection, metabolic abnormality).
• Spontaneous resolution generally occurs eventually (within three months), so treatment is not necessary if the symptoms are manageable.
• Padding may be needed to protect the limbs from injury.(32299832)
• Haloperidol 💉 may be used initially:
  • Only 0.5-1 mg IV BID may be sufficient.
  • In emergencies, 1-4 mg IV q4-6hr may be used.
• Risperidone 💉 is an alternative therapy, at 2-6 mg PO daily.(32299832)
• If ongoing treatment is needed for more than a few days, tetrabenazine may be preferable for maintenance therapy (given a lower risk of tardive dyskinesia). Attention is required for side effects (which may include depression, parkinsonism, akathisia, or orthostatic hypotension). Newer VMAT2 blockers, such as valbenazine or deutetrabenazine, may have fewer side effects.(Freucht 2022)

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akathisia

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basics

• Akathisia is an inner restlessness that often occurs as an extrapyramidal side effect due to the use of dopamine antagonists (e.g., antipsychotics). (27907965) This may manifest in a variety of ways (e.g., fidgeting, pacing, rocking, foot or finger tapping).
• Akathisia occurs within hours to days of drug initiation or uptitration.
• ⚠️ Inability to stay still may be misinterpreted as representing agitation due to delirium (which could lead to a vicious spiral of increased antipsychotic dosing).

management

• Discontinuation of antidopaminergic agents.
• Supportive care as needed to alleviate distressing symptoms, which may involve:
  • Anticholinergics (for dosing see the section above on acute dystonia: 📖).
  • Antiadrenergics (propranolol or clonidine).(27907965)
  • Serotonin antagonists (e.g., mirtazapine or trazodone).(27907965)

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myoclonus

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basics

• Myoclonus is defined as a sudden, brief, involuntary, shock-like, lightning-fast muscle contraction.
• Different forms of myoclonus can vary considerably, for example:
  • Synchronized, dramatic jerking of multiple limbs (e.g., post-anoxic myoclonus).
  • Asynchronous, multifocal twitching of individual muscles (multifocal myoclonus).
  • Asterixis (transient loss of muscle tone) is a form of negative myoclonus.
• Diffuse myoclonus without any focal abnormalities on neurological examination is most often due to metabolic abnormalities or medications. This is frequently encountered as a component of toxic/metabolic encephalopathy. Contrary to popular belief, myoclonus and asterixis (“negative myoclonus”) are not specific to hepatic dysfunction.

more common types of acute myoclonus encountered in an adult ICU (31356293, 28168537, 34446993)

• Metabolic (often multifocal & associated with asterixis):
  • Hepatic failure, hyperammonemia.
  • Renal failure, dialysis disequilibrium syndrome.
  • Hypercapnia, metabolic alkalosis.
  • Hyponatremia, hypernatremia, hyperosmolar hyperglycemic state.
  • Hypoglycemia.
  • Hypoxia and post hypoxia.
  • Hyperthyroidism.
  • Vitamin B12 deficiency, Vitamin E deficiency, Wernicke encephalopathy.
  • Hypomagnesemia.
• Medications:
  • Antidepressants (cyclic antidepressants, SSRIs, SNRIs, monoamine oxidase inhibitors).
    • Serotonin syndrome 📖
  • Lithium.
  • Antipsychotics (including tardive myoclonus from chronic exposure).
  • Antibiotics (e.g., penicillins; cephalosporins, especially cefepime; carbapenems; quinolones).
  • Gabapentinoids.
  • Opioids (morphine, fentanyl, tramadol).
  • Antiepileptics (phenytoin, valproate, carbamazepine, lamotrigine, vigabatrin, phenobarbital, primidone).
  • Lidocaine.
  • Midazolam, propofol.
  • Antiarrhythmics (e.g., amiodarone, flecainide).
  • Diltiazem, verapamil.
  • Parkinson's medications (levodopa, bromocriptine, amantadine, selegiline).
  • Anticancer drugs (chlorambucil, busulfan, cyclophosphamide, ifosfamide).
  • Withdrawal of medications (e.g., alcohol, benzodiazepine, or antiepileptic agents).
  • Sympathomimetic intoxication.
• Epileptic myoclonus (component of a seizure disorder):
  • Focal motor seizures (including epilepsia partialis continua).
  • Myoclonic epilepsy.
• Inflammation (e.g., infectious, postinfectious, paraneoplastic):
  • Viral encephalitis (arbovirus, HSV), postinfectious encephalitis.
  • Lyme, HIV, malaria, syphilis, cryptococcus, progressive multifocal leukoencephalopathy.
  • Hashimoto encephalopathy (aka, Steroid-Responsive Encephalopathy Associated with autoimmune Thyroiditis, SREAT).
  • Anti-NMDA-receptor encephalitis, paraneoplastic encephalopathies.
  • Voltage-gated potassium channel antibody (LGl1 and CASPR2 encephalitis).
  • Opsoclonus-myoclonus syndrome.
• Focal lesion:
  • Stroke, tumor.
  • Trauma.
  • Inflammation (e.g., multiple sclerosis).
  • Peripheral nervous system lesion (causing focal myoclonus).
• Basal ganglia degeneration:
  • Wilson's disease.
  • Parkinson's disease, progressive supranuclear palsy.
  • Multiple system atrophy.
  • Huntington's disease.
• Dementia:
  • Creutzfeldt-Jakob disease.
  • Alzheimer's disease.
  • Dementia with Lewy bodies.
  • Frontotemporal dementia, corticobasal degeneration.

patient evaluation: tests to consider

• Review of medication list & drug interactions.
• Electrolytes (including calcium and magnesium).
• Glucose.
• Liver function tests.
• Thyroid function tests.
• EEG to exclude seizure.(31356293)
• Neuroimaging.
• Workup for infection, if clinically indicated.

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acute dystonia

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definition

• Dystonia refers to a syndrome of involuntary muscle contractions, sustained or spasmodic, involving simultaneous contraction of opposing agonist and antagonist muscles.(28168537) Movements are usually slow and sustained, occurring in a repetitive and patterned fashion.(28168537)

epidemiology

• Acute dystonia is most often due to a medication.
  • Acute dystonia usually begins within a day of medication initiation, but there may be a lag of several days.(30743298)
  • Chronic use of neuroleptics may cause tardive dystonia. The investigation and acute management of tardive dystonia is largely similar to acute dystonia.
    • ⚠️ Tardive dyskinesia may be temporarily exacerbated by withdrawal of a neuroleptic medication (“withdrawal-emergent” dyskinesia).(28168537)
• Culprit medications include:
  • Most commonly, dopamine-inhibiting medications (e.g., neuroleptics, metoclopramide, prochlorperazine, promethazine).
  • Selective serotonin reuptake inhibitors, tricyclic antidepressants.
  • Carbamazepine, phenytoin, lamotrigine.
  • Gabapentin.
  • Lithium.
  • Ondansetron.
  • Tetrabenazine.
  • Various other medications (e.g., even calcium channel blockers).(30743298)
• Other causes may include:(Wijdicks 2021)
  • Exacerbation of Parkinson's disease or related disorders.
  • Bilateral paramedian thalamic infarction.
  • Multiple sclerosis.
  • Infection (neurosyphilis, acute herpetic brainstem encephalitis).
  • Paraneoplastic.
  • Traumatic brain injury.
  • Wilson's disease.

clinical presentation varies, including:

• Overall features:
  • Often affects the face and neck.(30743298)
• ☠️ Laryngeal dystonia:
  • May cause airway obstruction with stridor, which can be fatal.(30743298)
  • Simultaneous presence of other dystonias may help suggest the diagnosis (e.g., blepharospasm, torticollis, or opisthotonos).(Freucht 2022)
• Oculogyric crisis:
  • Often begins with fixed stare, followed by deviation of the eyes (usually upwards, or laterally).
  • May be associated with additional simultaneous dystonias (e.g., tilting back of the head, mouth opening with tongue protrusion, blepharospasm).(30743298) In severe cases, these may be associated with autonomic dysfunction (e.g., hypertension, tachycardia, mydriasis, diaphoresis).(Freucht 2022)
• Trismus, oromandibular dystonia (e.g., forced jaw opening).
• Tongue protrusion.
• Blepharospasm.
• Torticollis.

differential diagnosis (pseudodystonia)

• Localized tetanus.
• Deep neck space infection, peritonsillar abscess, meningitis.
• Atlantoaxial rotatory subluxation
• Stiff-person syndrome.
• Partial seizure causing abnormal posture.

management

• Dystonia is generally self-limiting, so no treatment is necessary if the dystonia is not distressful.
• Anticholinergic medications are generally first line:
  • Benztropine 1-2 mg IV with an additional dose as needed 20 minutes later is often effective. An oral course of benztropine tapering off over a week should be used to reduce the risk of recurrence.(Shutter 2019; Frucht 2022)
  • IV diphenhydramine (25-50 mg) is equally effective. Diphenhydramine may be more widely and rapidly available than benztropine.
• If anticholinergic fails, a benzodiazepine may be tried.(Frucht 2022)
• For patients failing therapy, reconsider the possibility of pseudodystonia (see the differential diagnosis above).
• For patients with parkinsonism, levodopa may be helpful.
• If airway obstruction occurs, intubation may be required.
  • If possible, flexible nasolaryngoscopy should be performed prior to intubation in order to secure the diagnosis (while excluding other forms of anatomic obstruction that could cause stridor).
  • Rapid sequence intubation with full paralysis may facilitate safe intubation. Note that if sedation-only intubation is attempted, dystonia may impair attempts at intubation (e.g., persistent vocal cord adduction may not allow passage of the endotracheal tube).
  • Patients with torticollis may have cervical spine instability, so caution should be taken during airway manipulation.

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dystonic storm, aka status dystonicus

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epidemiology

• Most often involves younger patients.
• Underlying causes of dystonia include:
  • Genetic dystonias.
  • Cerebral palsy.
  • Post-traumatic dystonia.
  • Wilson's disease.
  • Infectious or autoimmune encephalitis (e.g., anti-NMDA-receptor encephalitis).

presentation

• Dystonic storm is defined by the presence of generalized, continuous, and severe dystonic spasms.(33896535) This usually occurs in the context of pre-existing primary or secondary forms of dystonia (most often cerebral palsy).(30743298)
• Patients may have sustained, tonic muscle contractions or phasic dystonias that are rapid and repetitive (video below).
• Dystonic storm may result in dehydration, hyperpyrexia, rhabdomyolysis, aspiration pneumonia, respiratory failure, and even death.(33896535)

triggers of dystonic storm (32299832; Frucht 2022)

• (#1) Infection.
• (#2) Medication changes.
• Trauma/surgery.
• Hyperthermia.
• Dehydration, metabolic abnormalities.
• Penicillamine therapy for Wilson's disease (generally with initiation of therapy).
• Failure of a deep brain stimulator device.

differential diagnosis (30743298)

• Neuroleptic malignant syndrome, serotonin syndrome.
• Malignant hyperthermia (e.g., if occurring after surgery/anesthesia).
• Acute dystonic drug reaction.
• Acute parkinsonism.
• Paroxysmal sympathetic hyperactivity, which can cause tonic posturing.📖
• Intrathecal baclofen withdrawal.
• Status epilepticus.

treatment

• Any triggers should be treated.
• High-quality supportive care should be provided, e.g.:
  • Management of rhabdomyolysis 📖.
  • Multimodal management of pain 📖.
• Medical management may include:(33896535; Frucht 2022)
  • Antimuscarinic medications (e.g., trihexyphenidyl, benztropine).
  • Baclofen.
  • Benzodiazepines.
  • Clonidine.
  • Tetrabenazine.
• In medication-refractory cases, intubation and sedation may be necessary (e.g., with propofol). For the most refractory cases, paralysis is the last resort for initial stabilization.
• Recovery may take days or even weeks. In refractory cases, intrathecal baclofen or bilateral deep-brain stimulation may accelerate recovery.(33896535)

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tetanus

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pathophysiology

• Tetanus results from infection by Clostridium tetani, which secretes tetanus toxin (aka tetanospasmin). This enters peripheral nerves, is transported to the alpha motor neurons via retrograde axonal transport, and prevents the release of inhibitory transmitters – causing sustained motor neuron activity with muscle spasm and autonomic dysregulation.(30743297)
• Muscle spasms are due to GABA inhibition and glycine release within the spinal cord by tetanus toxin.(Wijdicks 2021)

epidemiology

• Tetanus is a vaccine-preventable illness that is largely restricted to unvaccinated populations (historically causing <50 cases/year in the United States).
• Infection usually involves the soft tissue, often after contact with soil or manure. Common examples include:
  • IV drug use.
  • Penetrating trauma with exposure to soil (e.g., gardeners or farmers).
  • Puncture injury (e.g., dirty nail).

clinical presentation

• The incubation period following inoculation into the soft tissue may range from a few days to several weeks.
  • Infection may occur at the site of a known, obvious injury (e.g., traumatic injury). Alternatively, the infection may appear trivial and be disregarded by the patient.
  • ~15% of patients have no history of any skin lesion.
• Prodrome:
  • Headache.
  • Trismus (painless lockjaw) is seen in most cases. This may associate with neck stiffness and difficulty swallowing.
  • Fasciculations may occur at the wound site.
• Full syndrome of tetanus:
  • Violent, paroxysmal spasms that may be generalized (e.g., leading to massive contraction of the back muscles, known as opisthotonos). Involvement of pharyngeal and/or thoracic muscles may cause respiratory arrest.(30743297)
  • Autonomic dysfunction may occur with sympathetic hyperactivity (marked by labile or sustained hypertension, tachycardia, tachypnea, hyperthermia, diaphoresis, and urinary retention).
  • Seizures may occur.(27907965)

diagnosis

• This is essentially a clinical diagnosis. Other differential diagnostic possibilities that should be considered include:
  • Trismus due to a dental infection.
  • Drug-induced dystonia.
  • Neuroleptic malignant syndrome.
  • Stiff-person syndrome.
  • Strychnine poisoning due to rat poison ingestion.
  • Hypocalcemia.
• Wound cultures for tetanus may be delayed and are often negative.
• Serum antibody titers against tetanus can be measured. If titers are >0.1 IU/ml, the diagnosis of tetanus should be reconsidered. (Louis 2021)

management

• Control of muscle spasms:
  • Benzodiazepine is commonly used.
  • Intubation with deep sedation (e.g., propofol) or even paralysis may be required in extreme cases.
• Management of dysautonomia (e.g., with esmolol infusion for management of sympathetic hyperactivity).
• Magnesium sulfate infusion has been shown to reduce the requirement for other medications to manage muscle spasms and cardiovascular instability.(17055945)
• Antitoxin may prevent additional toxin from affecting the nervous system (but it doesn't remove toxin which is already bound to neurons). Ideally, this is administered prior to manipulating the wound.
• Source control:
  • Infected site should be thoroughly irrigated and left open (noting that Clostridium tetani is anaerobic).
  • Debridement should ideally be done after administering antitoxin.
  • Antibiotic therapy (either with penicillin G or metronidazole; metronidazole may be preferred, given concerns that penicillin might potentiate the effect of tetanospasmin as a GABA antagonist).(27907965)
• Tetanus toxoid administration:
  • Clinical tetanus doesn't cause natural immunity!
  • Even if the patient had an episode of tetanus, they still need to be vaccinated.

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propofol neuroexcitation (“propofol frenzy”)

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clinical presentation (29101936)

• May occur in healthy patients undergoing conscious sedation.
• Following sedation, patients experience transient but repetitive violent motor activity with impaired consciousness (which will often be misdiagnosed as a seizure). Localization to pain seems to be preserved. Bizarre thrashing movements may help distinguish this from seizure (hence the term “propofol frenzy”).
• Spells of motor activity may last a few minutes, occurring repeatedly.

differential diagnosis

• Paradoxical agitation due to benzodiazepine (if benzodiazepines were administered).
• Medication-induced delirium (if longer-acting medications were used as well).
  • Serotonin syndrome (if multiple serotonergic agents were utilized; for example, fentanyl plus ondansetron).
  • Anticholinergic toxicity (if anticholinergics were coadministered during sedation).
• Status epilepticus.
• Pseudoseizure.

investigation

• Evaluation as appropriate for mental status change (e.g., with fingerstick glucose, electrolytes).
• Video EEG monitoring is desirable if possible, to provide reassurance that episodes are not seizures.

management

• Additional propofol administration should be discontinued.
• Trialing of numerous different medications should be avoided.
• Seizure precautions (e.g., padding on bed rails) should be used to prevent self-injury during episodes of hyperkinesis.
• Avoidance of stimulation may also be helpful.
• Sedation with dexmedetomidine might to be safe and effective, although this has been reported in only a couple cases. (29101936)

pathophysiology

• Propofol stimulates GABA receptors and also inhibits NMDA receptors. It's possible that propofol frenzy could reflect some residual inhibition of NMDA receptors as propofol wears off (reminiscent of emergence reactions following ketamine exposure, or anti-NMDA encephalitis).(29101936)

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To keep this page small and fast, questions & discussion about this post can be found on another page here.

• Avoid suddenly stopping Parkinson's medications, as this may provoke withdrawal (parkinsonism-hyperpyrexia syndrome).📖
• Be aware of propofol frenzy.📖 This can be quite dramatic and intimidating; a little awareness of the syndrome can go a long way.
• Be on the lookout for acute extrapyramidal side effects of medications (especially laryngeal dystonia – which may cause airway problems, and akathisia – which may cause patients to be restless/agitated). If recognized, these can generally be easily treated. Alternatively, failure to recognize these presentations may cause substantial problems (especially if akathisia is treated with further administration of antipsychotics, which exacerbates it in a vicious spiral).

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