Acute Neurology

Status epilepticus – Treatment

This document reflects current procedures for the treatment of status epilepticus and includes recommendations regarding intensive care.

Background and definition

Status epilepticus (SE) is a condition involving abnormally prolonged or frequently recurring seizures, which in some cases pose a risk of long-term effects.¹ The overall mortality rate in SE is up to 20%, depending on factors like the patient’s age, comorbidities, seizure type, level of consciousness, and in some cases, the timing of treatment initiation. However, the cause of SE is the most decisive prognostic factor.² Most patients with SE do not have previously diagnosed epilepsy, underscoring the importance of an acute etiological investigation.² The treatment of SE follows established protocols in defined steps, with the next drug being added if SE does not cease.

Treatment of convulsive status epilepticus

Convulsive SE (or generalized tonic-clonic SE) is the most severe form of SE, characterized by a generalized tonic-clonic seizure lasting more than 5 minutes or repeated generalized tonic-clonic seizures within the same period without regaining consciousness between seizures. This time limit is based on the fact that most generalized tonic-clonic seizures stop spontaneously before this point. After 30-60 minutes of seizure activity, there is a risk of neuronal damage, which is why the goal should be to control symptoms within 60 minutes.¹

The clinical diagnosis is usually straightforward, but with prolonged convulsive SE, motor symptoms often become less prominent over time. An important differential diagnosis of convulsive SE is psychogenic non-epileptic seizures, which, if confused with SE, can lead to risky overtreatment.³ Brainstem-induced tonic spasms can also be mistaken for SE.

The treatment protocol below can be applied to convulsive SE in most clinical situations. In specific cases, such as intensive care or early postoperative settings after neurosurgery, early initiation or reintroduction of anesthetics is often justified.⁴

STABILIZATION PHASE (0-5 minutes from seizure onset)

Initial actions:

• Note the time of seizure onset.
• Assess and secure vital functions.
• Initiate continuous ECG and blood pressure monitoring.
• Observe symptoms, consider differential diagnoses.
• Take capillary blood glucose: if hypoglycemia is present, administer 50 ml 30% glucose IV and 100 mg thiamine IV.
• Administer oxygen via nasal cannula or mask.
• Establish two venous access points (minimum pink needles).
• Take blood samples: P-glucose, Hb, LPK, TPK, CRP, electrolyte status including Ca, albumin, liver function, lactate, serum concentrations of current antiepileptic drugs, intoxication tests.
• If meningitis/encephalitis is suspected, prepare cultures and empirical treatment (in cases of RLS >4 and/or focal neurological deficits, lumbar puncture is performed only after brain CT).

STEP 1: EARLY STATUS EPILEPTICUS (about 5-30 minutes from seizure onset)

As soon as SE has lasted >5 minutes, administer one of the following options:

• Diazepam (Stesolid^® novum 5 mg/ml) 10 mg IV (5-7.5 mg if the patient weighs <40 kg), injection time about 2 minutes.
• Lorazepam (Ativan^® 4 mg/ml, general SU-license) 4 mg IV (2 mg if the patient weighs <40 kg), injection time about 2 minutes.

If the patient lacks venous access, administer first:

• Midazolam (Midazolam^®) 10 mg intranasally or 10 mg intramuscularly (5 mg if the patient weighs <40 kg). Intranasal midazolam is administered in two equal doses into each nostril using a syringe with a luer-lock and atomizer (nasal olive/MAD).

If the patient lacks venous access, administer second:

• Midazolam (Buccolam^®) 10 mg buccally
• Diazepam (Stesolid^®, Diazepam) 10 mg rectally via enema or rectal solution

If SE has not ceased 5 minutes after a given dose of diazepam or lorazepam and the patient has not received prehospital treatment, the dose can be repeated once. In this case, parallel preparation of treatment according to step 2 below should be initiated.

Comment: According to randomized controlled trials, diazepam and lorazepam are safe and effective for breaking early SE both pre-hospital and in-hospital.¹⁰ The same applies to IM midazolam for pre-hospital use.¹¹ There is also support for intranasal midazolam, but the evidence is weaker for adults than for children.¹² The doses given vary between different studies, making direct comparisons between preparations difficult.^8,10 Lorazepam’s effect may last longer than other preparations due to pharmacokinetics, and some studies have concluded that it is more effective than diazepam.¹⁰ However, the difference is small, and others have judged the preparations as equivalent.⁸ It is important to administer benzodiazepines in sufficiently high doses. All benzodiazepines can cause respiratory depression, but the risk of respiratory depression is higher for untreated convulsive SE than for SE actively treated with benzodiazepines.¹³ Some guidelines recommend weight-based dosing for benzodiazepines,¹⁴ but most use fixed standard doses for adults.^4-6,8,9

STEP 2: ESTABLISHED STATUS EPILEPTICUS (about 20-60 minutes from seizure onset)

If SE continues, administer fosphenytoin or sodium valproate, alternatively levetiracetam. Note contraindications. For all preparations, doses may need to be reduced due to age and comorbidities, but in the first instance, a full dose should be given. Give half a dose if the patient is already on the preparation in question. Continuous monitoring of pulse and blood pressure is necessary for the infusion of fosphenytoin and advisable for sodium valproate and levetiracetam. Note contraindications.

Phenytoin (Pro-Epanutin) treatment

Fosphenytoin (Pro-Epanutin^® 50 mg FE/ml) 20 mg FE/kg, max 1500 mg FE, diluted with NaCl 0.9% or glucose 5%, and administered as an infusion at a rate of 150 mg FE/min. Note that fosphenytoin is prescribed in phenytoin equivalents (FE). Blood pressure drop or bradycardia that may occur during the ongoing infusion can often be managed with a reduced infusion rate and/or simultaneous infusion of fluids via another access.

Contraindications: AV block II-III, SA block, heart rate <50/min, systolic blood pressure <100, porphyria, progressive myoclonic epilepsy.

Sodium valproate treatment

Sodium valproate (Ergenyl^®, one ampoule = 400 mg) 40 mg/kg, max 3000 mg, administered over 10 minutes. Note: avoid combination with meropenem due to interaction. Contraindications: pregnancy, known mitochondrial disease, known urea cycle disorder, porphyria. Caution in liver disease.

Levetiracetam treatment

If contraindications or complex interactions exist, administer Levetiracetam (Keppra^®, Kevesy^®, Levetiracetam, Matever^®) 60 mg/kg, max 4500 mg, over 10 minutes. Keppra^® and generic Levetiracetam are available as 100 mg/ml infusion concentrate, mixed with NaCl 0.9%. Kevesy is available as a ready-to-use solution in packages containing 100 ml and doses of 500, 1000, or 1500 mg of levetiracetam per package. Dose reduction may be necessary in severe renal insufficiency.

Serum concentrations of S-phenytoin and S-valproate are measured 1-2 hours after the end of the infusion, and if necessary, a top-up dose is administered. Maintenance treatment is given twice daily based on daily serum concentrations, with trough values before the morning dose, but the clinical course is decisive. For levetiracetam, 1500 mg x 2 is usually an appropriate maintenance dose. During maintenance treatment, the drugs can be given as a slow injection/infusion, for fosphenytoin 25-50 mg FE/min with monitoring of pulse and blood pressure every 5 minutes. For patients already on antiepileptics, these should be prescribed in parallel.

In parallel with treatment, etiological investigation continues.

• Prepare CT brain if the cause of SE is not obvious (e.g., medication discontinuation in known epilepsy).
• Prepare lumbar puncture if meningitis/encephalitis is suspected.

Comment: Evidence for antiepileptics in treating status epilepticus after benzodiazepines comes mainly from open studies. There is support for using the recommended preparations above, but it is unclear whether any preparation is more effective or safer than others.^10,15 We recommend fosphenytoin and sodium valproate over levetiracetam due to more extended experience with the former in convulsive SE. Recommended doses are consistent with current evidence-based guidelines.⁸ There is no evidence for effective serum concentrations in SE. It is reasonable to aim for high concentrations after the loading dose, around 100 μmol/L for S-phenytoin and 800 μmol/L for S-valproate. During maintenance treatment of SE, target trough values in the upper reference range for each preparation, S-phenytoin 70-90 μmol/L (normal 40-80 μmol/L), S-valproate 500-800 μmol/L (normal 300-700 μmol/L). This often corresponds to a maintenance dose of 4-5 mg FE/kg/day and 20-25 mg valproate/kg/day. For levetiracetam, there is no established dose-response relationship. S-levetiracetam can be analyzed acutely in suspected intoxication levels, e.g., in renal dysfunction. Both phenytoin and valproate have a high degree of protein binding, making total serum concentrations difficult to interpret in old age, low albumin, renal failure, liver failure, and combination therapy.

STEP 3: REFRACTORY STATUS EPILEPTICUS (>60 MIN)

If convulsive SE has not stopped within 10-20 minutes after treatment according to step 2, the patient is intubated, if not already done, anesthetic treatment is initiated, and the patient is placed on a ventilator. Management is carried out in collaboration with the anesthetist on call. The initial goal is to achieve and maintain clinical seizure freedom. If possible, initiate continuous EEG monitoring as soon as possible.

• If the patient has no clinical seizure symptoms and the EEG shows no remaining electrographic seizure activity or electrographic SE, consider waking and extubating or continuing anesthetic treatment after discussion with a neurology consultant.
• If the patient continues to have clinical seizure symptoms and/or the EEG shows continued electrographic seizure activity or electrographic SE, deepen anesthesia to maintain clinical and electrographic seizure freedom for at least 24 hours. This often involves aiming for a “burst suppression” pattern on EEG.

At the same time as anesthetic treatment, maintenance treatment with antiepileptics is given. For patients not previously on epilepsy medications, it is generally justified to treat with two or at most three antiepilept ics in relatively high doses. Refractory SE requires careful monitoring for the development of secondary organ damage and side effects from the treatment itself. In addition to basic intensive care, active normothermia or moderate hypothermia may be considered. Etiological investigation continues in parallel with treatment and usually begins with CT of the brain and lumbar puncture if this has not already been done.

Anesthetic treatment is usually started with propofol in most cases. This is preferably combined early with midazolam, as it is difficult to achieve the desired depth of sleep with propofol alone without exceeding recommended doses. With prolonged treatment, this anesthesia is sometimes supplemented with thiopenthone, but the propofol dose should then be reduced or discontinued. Ketamine may be considered in some cases.

Below are dosing suggestions for these preparations. The dose ranges are wide, and individual adjustments are necessary, as is close dialogue between the responsible neurologist, intensivist, and clinical neurophysiologist. Reading of continuous EEG and consideration of treatment regimen adjustments should occur at least twice daily, more frequently with thiopenthone treatment and in the few cases where the treatment goal is isolectric EEG. When the patient is weaned off anesthesia, this should be done gradually and under close monitoring for the return of clinical or electrographic seizure activity or abundant epileptiform activity.

• Propofol (Diprivan^®, Propolipid^®, Recofol^®, Propofol) bolus dose 2-3 mg/kg followed by infusion 1-3 mg/kg/h. Additional bolus doses of 1-2 mg/kg can be administered to deepen sedation. Max dose of 4 mg/kg/h should be avoided and should not be used for more than 48 hours due to the risk of propofol infusion syndrome.
• Midazolam (Dormicum^®, Midazolam) can be started early to complement propofol. Treatment can be initiated with a bolus dose of 0.2 mg/kg followed by infusion of 0.05-0.4(-2) mg/kg/h. Tachyphylaxis (increased dose requirement) develops over time.
• Thiopenthone (Pentocur^®, Pentothal^®) can be used alone or as an adjunct for a patient already sedated with propofol. An induction dose of 2-3 mg/kg is used for patients not already sedated. For other patients, the dose should be adjusted and possibly fractionated. Additional bolus doses of 50 mg every 2-3 minutes can be repeated until clinical and electrographic seizure control is achieved. Continued infusion is set at 2(-5) mg/kg. Note that after the desired depth of sedation is achieved, the infusion rate must be reduced to avoid overdose. In this situation, close contact is required between the responsible neurologist, intensivist, and clinical neurophysiologist.
• Ketamine (Ketalar®, Ketamine) is usually not the first choice but may be considered as an adjunct. An initial bolus dose of 0.5-3 mg/kg followed by continuous infusion of 0.5-5 mg/kg can be used.

Comment: Since prolonged convulsive SE poses a high risk for neuronal damage and systemic complications, international consensus recommends early intubation and anesthesia treatment.^2,5-8 Complications are common both as a result of the treatment provided and SE itself and require active monitoring. Metabolic acidosis is a natural consequence of SE and rarely needs correction.¹⁶ There are no controlled studies guiding drug selection, duration, or intensity of treatment. The above is based on practical experience and international expert recommendations.^2,17 Thiopenthone should be considered a second-line option due to its higher risk of complications.^2,17 Anesthesia treatment aiming for an isoelectric EEG carries a high risk of severe complications and should be reserved for selected cases after special consideration.

If SE continues or recurs 24 hours after initiation of anesthesia treatment, it is referred to as super-refractory SE. This occurs both in patients with apparent, severe acute brain injury (trauma, infection, stroke) and in patients without previously known epilepsy who develop SE without an obvious cause. In the latter case, extensive etiological investigation is crucial, as the etiology is decisive for prognosis. Autoimmune encephalitis should be considered, and immunological treatment should be initiated as soon as bacterial and viral meningoencephalitis are excluded, even if positive antibody results are not yet available.¹⁷ A wide range of treatment methods are used for super-refractory SE and should be considered on an individual basis. There is no evidence regarding antiepileptic treatment for refractory and super-refractory SE. International experts recommend limiting treatment to two high-dose antiepileptic drugs, avoiding frequent medication changes, and considering interaction and side effect profiles.¹⁷

Other Types of Status Epilepticus

For other forms of SE, management is more individualized, and treatment selection depends on both the type of SE and the patient’s general condition. The scientific support for treatment is more limited than for convulsive SE, and specific recommendations are often lacking in published guidelines. Compared to convulsive SE, it is less clear to what extent continued SE contributes to long-term effects.^2,18 Convulsive SE may transition to non-convulsive SE. This is a situation with high mortality and is treated according to the same protocol as convulsive SE described above.^2,5

Focal Non-convulsive SE

This condition involves varying degrees of altered consciousness combined with electrographic seizure activity. By definition, major motor manifestations are absent, although minor movements, such as myoclonus around the eyes, may occur. EEG is crucial for diagnosing focal non-convulsive SE, although the EEG pattern is often not entirely clear, requiring the clinician to consider the EEG, clinical symptoms, and treatment response in the assessment. Non-convulsive SE does not pose a risk for systemic complications, and it is unclear to what extent the seizure activity affects long-term prognosis and the patient’s condition beyond the underlying etiology.^2,5,18

According to international recommendations, non-convulsive SE should be treated as soon as possible with benzodiazepines and antiepileptics. Levetiracetam 2000-3000 mg IV can be considered an alternative to fosphenytoin and sodium valproate due to its favorable side effect and interaction profile. Another alternative with the same advantages but less supporting experience is lacosamide (Vimpat®) 200-400 mg IV. Oral treatment is sometimes possible. Anesthesia treatment should only be used in exceptional cases of focal non-convulsive SE that did not begin as convulsive SE, given the risk of complications and uncertain treatment benefit.^2,5,6,14,18

Focal Motor SE

Focal clonic jerks of long duration in adults are often part of epilepsy following stroke or traumatic brain injury. The patient is generally awake or mildly impaired in consciousness. Considering the level of consciousness and comorbidities, if one or two doses of diazepam or lorazepam do not terminate the SE, non-sedating antiepileptics with favorable side effect and interaction profiles should be administered. Sodium valproate, levetiracetam, or lacosamide can be used. Anesthesia treatment is not indicated.

Absence Status

Characterized by mild consciousness impairment or confusion, with EEG showing generalized spike-wave activity at a frequency of around 3 Hz. This condition has a very good prognosis and is usually successfully treated with benzodiazepines according to the convulsive SE protocol, or with a halved dose repeated as needed. If absence status is caused by the withdrawal of antiepileptics, these should be reinstated. Otherwise, sodium valproate is the first choice.¹⁸ Anesthesia treatment is not indicated.

SE after Cardiac Arrest

Among patients who have regained circulation after cardiac arrest, electrographic SE with or without clinical symptoms is common. For this situation, refer to the protocol on Cardiac Arrest – Intensive Care and Prognostication.

Authored by a working group led by Johan Bjellvi, Specialist in Neurology.

References

1. Trinka E, Cock H, Hesdorffer D, et al. A definition and classification of status epilepticus – Report of the ILAE Task Force on Classification of Status Epilepticus. Epilepsia 2015;56:1515-23.
2. Betjemann JP, Lowenstein DH. Status epilepticus in adults. Lancet Neurol 2015;14:615-24.
3. Hocker SE. Status Epilepticus. Continuum (Minneap Minn) 2015;21:1362-83.
4. Shorvon S, Baulac M, Cross H, Trinka E, Walker M, TaskForce on Status Epilepticus of the ICfEA. The drug treatment of status epilepticus in Europe: consensus document from a workshop at the first London Colloquium on Status Epilepticus. Epilepsia 2008;49:1277-85.
5. Meierkord H, Boon P, Engelsen B, et al. EFNS guideline on the management of status epilepticus in adults. Eur J Neurol 2010;17:348-55.
6. Brophy GM, Bell R, Claassen J, et al. Guidelines for the evaluation and management of status epilepticus. Neurocrit Care 2012;17:3-23.
7. Claassen J, Silbergleit R, Weingart SD, Smith WS. Emergency neurological life support: status epilepticus. Neurocrit Care 2012;17 Suppl 1:S73-8.
8. Glauser T, Shinnar S, Gloss D, et al. Evidence-Based Guideline: Treatment of Convulsive Status Epilepticus in Children and Adults: Report of the Guideline Committee of the American Epilepsy Society. Epilepsy Curr 2016;16:48-61.
9. Healthcare Improvement Scotland. SIGN 143: Diagnosis and management of epilepsy in adults. 2015.
10. Prasad M, Krishnan PR, Sequeira R, Al-Roomi K. Anticonvulsant therapy for status epilepticus. Cochrane Database Syst Rev 2014:CD003723.
11. Silbergleit R, Durkalski V, Lowenstein D, et al. Intramuscular versus intravenous therapy for prehospital status epilepticus. N Engl J Med 2012;366:591-600.
12. Arya R, Kothari H, Zhang Z, Han B, Horn PS, Glauser TA. Efficacy of nonvenous medications for acute convulsive seizures: A network meta-analysis. Neurology 2015;85:1859-68.
13. Alldredge BK, Gelb AM, Isaacs SM, et al. A comparison of lorazepam, diazepam, and placebo for the treatment of out-of-hospital status epilepticus. N Engl J Med 2001;345:631-7.
14. Läkemedelsbehandling av epilepsi – ny rekommendation. Information från Läkemedelsverket 2011:1-17.
15. Yasiry Z, Shorvon SD. The relative effectiveness of five antiepileptic drugs in treatment of benzodiazepine-resistant convulsive status epilepticus: a meta-analysis of published studies. Seizure 2014;23:167-74.
16. Hocker S. Systemic complications of status epilepticus–An update. Epilepsy Behav 2015;49:83-7.
17. Shorvon S, Ferlisi M. The treatment of super-refractory status epilepticus: a critical review of available therapies and a clinical treatment protocol. Brain 2011;134:2802-18.
18. Meierkord H, Holtkamp M. Non-convulsive status epilepticus in adults: clinical forms and treatment. Lancet Neurol 2007;6:329-39.

Prognostication after Cardiac Arrest

The number of patients admitted alive to hospitals after cardiac arrest is increasing. The degree of cerebral hypoxia/ischemia during the cardiac arrest is critical for the prognosis regarding whether other vital organs will regain stable function. European guidelines state that the neurological prognosis should not be assessed until at least three days after the cardiac arrest. Neurological prognosis assessment should rely on independent examination methods: clinical and neurophysiological examinations, imaging diagnostics, and biomarkers. If the prognosis assessment 3–4 days after the cardiac arrest does not clearly indicate a poor neurological outcome, further observation and reevaluation are recommended.

The neurological prognosis is very poor in the following combinations:

1. RLS 7-8 after 3 days from the cardiac arrest AND bilateral absence of pupil and corneal reflexes.
2. RLS 7-8 after 3 days from the cardiac arrest AND bilateral absence of SEP N20 potential.
3. RLS 7-8 after 4 days from the cardiac arrest AND at least two of the following:
   a. Status myoclonus < 48 hours after cardiac arrest
   b. NSE values above 60 µg/L at 48 hours and increasing after 24-48 hours
   c. Burst suppression or status EP on EEG
   d. Diffuse anoxic injury on MRI

Highly malignant EEG patterns associated with poor neurological outcome if recorded approximately 48 hours after cardiac arrest.

1. A) completely flat/suppressed background <10 μV,
2. B) completely flat/suppressed background with superimposed periodic discharges,
3. C) and D) burst suppression with >50% suppression time without (C) or with (D) superimposed epileptiform discharges.

Cerebrospinal Fluid Analysis

If meningitis, ventriculitis, or encephalitis is suspected, a lumbar puncture is often performed with cell analysis. During lumbar puncture, a small needle bleed may occur, which can be mistaken for subarachnoid hemorrhage. A needle bleed will result in abundant erythrocytes (the absence of xanthochromia (yellow-red discoloration) after centrifugation early after LP supports a needle bleed rather than subarachnoid hemorrhage).

Suspicion of infection in the cerebrospinal fluid arises if there is more than 1 white blood cell (granulocyte) per 1000 red blood cells (erythrocytes). In patients who have undergone surgery or have confirmed subarachnoid hemorrhage, infection is suspected if there are more than 1-10 white blood cells per 200 red blood cells.

Typical cerebrospinal fluid findings in fulminant bacterial meningitis with barrier damage are:

• High lactate, about 10 mmol/L.
• High albumin, significantly elevated around 800 mg/L. Normal < 320 mg/L.
• Leukocytes, high neutrophils, more than 500 x 10⁶/L
• Low glucose, about 60% of B-glucose. Normal is more than 2/3 of B-glucose.

In bacterial meningitis, there is often a marked increase in leukocytes (> 500-1000 x 10⁶/L), predominantly neutrophils; however, early in the course of the disease, leukocyte counts may be lower.

Sodium and Fluid Imbalances in Brain Injury

SIADH (Syndrome of Inappropriate Secretion of ADH)

SIADH causes water retention and results in hyponatremia, leading to euvolemic hyponatremia. It is due to excessive antidiuretic hormone (ADH) relative to serum osmolality. This condition is seen in CNS injury and as a paraneoplastic phenomenon.

Symptoms of SIADH:

• Hyponatremia
• Water retention
• Weight gain or lack of weight loss
• S-Osm < 270 mOsm/kg
• U-Na > 20
• U-Osmolarity 300-1400

Treatment

• Fluid restriction
• Diuretics
• Hypertonic saline
• Possibly dialysis

Diabetes Insipidus

This condition results in water loss, leading to hypernatremia, sometimes severe.

• Hypernatremia (> 150 mmol/L)
• Fluid loss
• S-Osm > 270 mOsm/kg
• U-Na < 20
• U-Osmolarity significantly reduced

Treatment for diabetes insipidus:

• Treated with minirin 0.4 microg/mL in small repeated doses of 0.25 mL = 1 microg.
• Hypotonic fluid intravenously.

CSWS (Cerebral salt wasting syndrome)

The patient loses sodium and water. They become hypovolemic and hyponatremic or require a high intake of sodium supplements.

• Hyponatremia
• Dehydration
• Weight loss
• Urinary osmolality is higher than serum osmolality
• Urine sodium > 100 mOsm/kg

Treatment

• Follow diuresis with Ringer’s acetate or Plasmalyte
• Tab Florinef 0.1 mg/tablet 1-2 times daily. An aldosterone agonist that conserves sodium and eliminates potassium.

Iatrogenic fluid imbalance

• Hyponatremia
• Hypotonic solutions/water intake
• A patient who is past their spasm risk must be allowed to regress in fluid balance if they have excess fluid – often seen as no weight loss during care.
• Common methods for calculating fluid balance are VERY imprecise!
• +/- 0 in fluid balance over time means the patient is accumulating fluid

Myasthenia gravis

Myasthenia gravis (MG) is an autoimmune disease that affects the transmission between nerve and muscle, impacting neuromuscular transmission (NMT) at the neuromuscular junction. The most common symptoms of MG include muscle fatigue that worsens with exertion but improves with rest. Typically, patients are strongest in the morning and weaken as the day progresses.

Between the nerve ending and muscle fiber is a neuromuscular junction. In this junction, acetylcholine (ACh) is released and crosses over to the muscle fiber, binding to acetylcholine receptors (AChR), which receive the nerve impulse. When enough acetylcholine receptors are activated simultaneously by acetylcholine, the muscle contracts. In myasthenia gravis, the number of receptors is significantly reduced due to antibodies that destroy or block these acetylcholine receptors. Up to 80% of MG patients have antibodies against the acetylcholine receptor. Most patients have antibodies against AChR, MuSK (5–8%), or LRP4 (a small percentage). In 10–15% of cases, no antibodies are found. In 10% of cases, there is a correlation with a thymoma tumor in the thymus, an important part of the immune system.

Myasthenic crisis

Muscle fatigue can affect the respiratory muscles, and up to 20% of patients experience respiratory issues severe enough to require intensive care and ventilator support. This condition is known as myasthenic crisis (respiratory failure). In two-thirds of cases, a clear trigger can be identified. It can be due to infection, sepsis, fever, or pneumonia, sometimes caused by lung aspiration. Physical stress such as surgery or trauma can also trigger the condition. Pregnancy, new medication, incorrect medication, or incorrect doses of acetylcholinesterase inhibitors (for MuSK-positive patients), or even botox treatment, can also cause a myasthenic crisis. This condition can lead to respiratory collapse due to muscular weakness in the respiratory muscles. The patient should be admitted to an intermediate or intensive care unit for appropriate monitoring and be prepared for respiratory support, starting with non-invasive ventilation (NIV/HFNC) and, in severe cases, intubation and mechanical ventilation. Note that blood gases may remain normal until the patient is almost unable to breathe.

Medication treatment

Plasmapheresis or immunoglobulin (IVIG) is used to reverse the course of a myasthenic crisis as quickly as possible.

Intravenous neostigmine can be administered and should be initiated early because the absorption of Mestinon in the intestines may be negatively affected by cholinergic side effects of the treatment. Treatment is started with an equivalent dose to the patient’s normal oral dosage and adjusted based on effect.

Single doses of 0.5 mg neostigmine IV (equivalent to 60 mg oral Mestinon) can be given to test whether a dose increase is beneficial. Anticholinergic drugs like Robinul (glycopyrronium) should be given regularly to counter muscarinic side effects like increased mucus production, e.g., 0.2 mg 3-4 times per day. Alternatively, pre-mixed Robinul-Neostigmine can be used, with dosage according to the neostigmine schedule.

Steroids should be administered immediately, but dosing should consider the risk of the patient becoming ventilator-dependent due to the worsening effect induced by steroids. This risk increases with higher doses. High-dose corticosteroids should be avoided unless the patient is already ventilator-dependent. In elderly or otherwise frail patients, consider increasing the Prednisolone dose by 10 mg daily from a starting dose of 20 mg to minimize the risk of respiratory failure and the need for ventilation.

It is a great advantage if the patient can be managed with NIV and avoid mechanical ventilation, as especially older patients are at risk for respiratory complications after just a few days of ventilator use (VAP). If the patient requires ventilation, consider reducing cholinesterase treatment if there are problems with excessive bronchial secretions.

Intravenous neostigmine treatment during myasthenic crisis

Neostigmine for a 12-hour infusion is mixed in 500 mL NaCl and administered via infusion pump. A suitable starting dose in a myasthenic crisis is to first administer 0.5 mg IV as an injection, then start an infusion at 1 mg/12 hours.

Corticosteroids

Steroid treatment should be considered for moderate myasthenic symptoms to allow for lower dosing of cholinesterase inhibitors and reduce the risk of developing myasthenic or cholinergic crises.

Steroids can either be given as a pulse treatment (methylprednisolone, Solu-Medrol, at doses up to 30 mg/kg body weight per day, or prednisone, Deltison, orally at doses of 500-1000 mg per day for two consecutive days) or as continuous administration with Prekortalon.

Pulse treatments provide faster onset effects but carry a risk of an initial worsening phase on days 2-3. Therefore, the first treatment should be performed in an inpatient setting with regular monitoring of clinical status, including PEF (respiratory monitoring). If the PEF value is <30% of expected, continued monitoring should occur in the intensive care unit, where ventilation care can be quickly initiated. Severe worsening in MG can occur rapidly, and blood gas analyses are of limited value in assessing impending respiratory failure in MG.

When treating with Prednisolone, 30 mg/day is a common initial dose, which can be increased to 60 mg/day if necessary. This dose is maintained until a clear clinical improvement is observed, after which the dose is reduced.

IVIG and plasmapheresis

If steroid treatment is inappropriate or insufficient, and symptoms are severe enough that immunosuppressive drugs’ effects cannot be awaited, plasmapheresis may be attempted with 3-5 treatments. For a rapid effect, the first three infusions can be given three days in a row.

IVIG at a dose of 1 g/kg body weight total, divided over two-three days, is an alternative to plasmapheresis for severe symptoms. These two treatments are considered equivalent, but IVIG has the advantage of being available in general neurology and is generally better tolerated than plasmapheresis. Approximately 60% of patients improve significantly within a week, but the effect is short-lived, so treatment should be combined with other immunosuppressive or immunomodulatory treatments. For long-term IVIG treatment, tolerability is better with a single infusion (20-40 g) at 4-12 week intervals than with multi-day dose courses.

Acute treatment during exacerbations or myasthenic crisis

During exacerbations and myasthenic crisis, either plasmapheresis, methylprednisolone, or high-dose intravenous immunoglobulin (IVIG), or a combination of these treatments, is used. When combining plasmapheresis with IVIG, IVIG should be given after, and not immediately before, plasmapheresis, while Solu-Medrol can be given concurrently with plasmapheresis. Plasmapheresis provides the fastest (but short-lived) improvement. IVIG treatment with a total dose of 1.2 g/kg (spread over 2-3 days) can also provide a relatively quick effect, but its impact is somewhat milder than plasmapheresis. High-dose intravenous or oral steroids also offer a relatively fast effect, although it may take 1-3 weeks for therapeutic response. In refractory cases of AChR-positive generalized myasthenic crisis that have not responded to the above treatments, a single-dose monoclonal IgG antibody may be considered (eculizumab).

Symptomatic Treatment

Cholinesterase inhibitors are the main treatment for myasthenia gravis and myasthenic crisis. There are two available options: pyridostigmine bromide (Mestinon, 10 mg/60 mg) and ambenonium (Mytelase, 10 mg) in tablet form. Additionally, there is neostigmine (Neostigmine) for parenteral administration. Mestinon’s duration of action is about 4 hours, while Mytelase lasts about 4-6 hours.

Cholinesterase inhibitors have variable and low bioavailability, short action duration, and are generally dosed 4-6 times daily. Individual doses are titrated for each patient. The requirement varies even in the same patient at different times. Pyridostigmine doses can range from 20 mg x 3-4 to 120 mg x 6. Higher doses are not recommended. A typical dose of Mestinon is 60 mg x 5-6 during waking hours. Most patients do not need cholinesterase inhibitors at night. Mytelase doses should not exceed 50-60 mg/day. Mytelase can be administered less frequently, 3-4 times daily, compared to Mestinon. MuSK-positive myasthenia responds poorly or may even worsen with cholinesterase inhibitors.

Neostigmine can be administered as an intravenous or subcutaneous injection where 0.5 mg neostigmine IV equals 60 mg pyridostigmine bromide (Mestinon). In myasthenic crisis, when the patient is unconscious, intubated, or otherwise unable to take oral cholinesterase inhibitors, continuous neostigmine infusion is administered. A conversion table from oral pyridostigmine bromide doses to equivalent neostigmine infusion doses is available in the national MG consensus document from 2020 on SNEMA’s website and displayed here in table format. Neostigmine can also be used as a diagnostic test in undiagnosed patients whose MG presents with a myasthenic crisis while intubated in the intensive care unit.

Muscarinic Side Effects

• Abdominal cramps
• Increased intestinal motility
• Diarrhea and gas
• Increased sweating, salivation, and tearing
• Bronchospasm
• Bronchorrhea

These symptoms can be managed with anticholinergic (antimuscarinic) medications, such as atropine and hyoscyamine (Egazil) that do not affect neuromuscular transmission.

Overdose

Mestinon doses exceeding 600-720 mg/day may be counterproductive and induce a so-called cholinergic crisis. This condition is characterized by paradoxically increased muscle weakness due to overstimulation of nicotinic ACh receptors, which can cause severe respiratory failure.

Additional Medications

Beta-receptor stimulants can be given in tablet form, e.g., ephedrine or salbutamol. Potassium chloride or potassium-sparing diuretics (spironolactone) have been used to maintain serum potassium levels at the upper normal limit. At high doses of pyridostigmine bromide, KCl is added to replace bromine ions with chloride ions. Note that not all potassium supplements are chloride potassium. Avoid Kajos mixture as a potassium supplement because it consists of potassium citrate.

Cholinergic Crisis

Overdose of cholinesterase inhibitors can cause depolarizing blockade at the neuromuscular junction, resulting in muscle weakness similar to MG. Other symptoms of a cholinergic crisis include fasciculations, miosis, increased tearing, salivation, bronchial secretion, abdominal pain, nausea, vomiting, diarrhea, sweating, and bradycardia. The simplest way to determine whether weakness is due to cholinesterase inhibitors is to temporarily discontinue treatment.

A cholinergic crisis is almost always a consequence of under-immunosuppression, leading to steadily increasing doses of cholinesterase inhibitors. Thus, high-dose steroids and other immunomodulating treatments, as in myasthenic crisis, are often indicated.

Contraindicated Medications

MG patients often do not receive appropriate treatment for other conditions due to concerns about worsening myasthenia. The risk information provided for medications contraindicated in myasthenia is often exaggerated and should mainly be considered in cases of unstable generalized or bulbar MG.

Contraindicated medications are substances that can induce neuromuscular transmission disorders:

• Botulinum toxin
• Certain muscle relaxants like vecuronium, succinylcholine among others.
• Intravenous benzodiazepines
• Ketamine
• Immune checkpoint inhibitors that block CTLA-4 or PD-1.
• D-penicillamine
• Alpha-interferon

The following medications can sometimes worsen myasthenia and are relatively contraindicated only in patients with unstable generalized myasthenia:

• Some antibiotics (aminoglycosides, lincosamides, fluoroquinolones, telithromycin, tetracycline, and macrolides)
• MgSO₄
• Lithium, carbamazepine, phenytoin, gabapentin and riluzole
• Quinine and chloroquine
• Beta-blockers and calcium antagonists
• Estrogen-containing birth control pills
• Contrast agents (especially iodine-containing ones). Note! Can be used safely in patients with purely ocular MG and stable patients with generalized or bulbar myasthenia.

Note that antimuscarinic drugs like atropine and similar can be used in myasthenia. Common antidepressants, except fluoxetine, can also be used.

Anesthesia for Patients with Myasthenia Gravis

Patients with myasthenia gravis (MG) present a group where anesthesia can be risky, particularly when using muscle relaxants. Anesthesiologists are usually aware of the potential problems during premedication and induction of anesthesia in patients with neuromuscular transmission disorders. In mild cases of MG, no special measures are needed, while severe MG can risk serious complications. MG patients are not at an increased risk for malignant hyperthermia during anesthesia.

Before planned surgery, the treating neurologist should be contacted to assess the severity of myasthenia and current medication.

The patient should continue with their usual dose of cholinesterase inhibitors and any oral corticosteroids up to the morning of the surgery.

• Whenever possible, choose spinal or local/regional anesthesia.
• Be aware of the increased risk of vagal reactions; administer atropine or glycopyrronium (Robinul) generously.
• Propofol (Diprivan) and remifentanil can be administered intravenously. Propofol and remifentanil have increasingly replaced inhalational anesthesia. For induction, a combination of propofol and remifentanil is sometimes used. At some centers, 10 mg of intravenous ephedrine is added to the induction regimen with propofol-remifentanil to reduce the risk of remifentanil-induced bradycardia and hypotension.
• Sevoflurane (Sevorane) can be used for inhalational anesthesia. Sevoflurane has a mild muscle-relaxing effect, which may be sufficient for certain surgeries without the addition of muscle relaxants.
• Muscle relaxants should preferably not be used, but if necessary:
  – administer non-depolarizing muscle relaxants in the lowest possible dose. Preferably use rocuronium, whose effect can be reversed postoperatively with sugammadex.
  Depolarizing muscle relaxants (succinylcholine-like) can potentially be administered, but many MG patients are resistant to depolarizing agents. Note that cholinesterase inhibitors prolong the effect of depolarizing drugs.

Preoperative Preparations

• Check cardiopulmonary function with anamnesis, ECG, vital capacity (VC), and peak expiratory flow (PEF).
• Rule out infection: CRP, blood status, temperature.
• Investigate electrolyte status, especially potassium (hypokalemia worsens myasthenia symptoms).
• Optimize medication:
  – Adjust the dose of cholinesterase inhibitors.
  – Discontinue azathioprine (Imurel) and mycophenolate mofetil (CellCept) 1 week before and 1-2 weeks after surgery, but continue cyclosporine.

Premedication

• Avoid benzodiazepines.
• Antihistamines can be given, e.g., promethazine (Lergigan) 25 mg p.o. Only administer when needed.
• Anticholinergics such as atropine 0.5 mg i.v. or glycopyrronium (Robinul) 0.2-0.4 mg i.v. should be given in cases of high-dose cholinesterase inhibitors.
• It is important to note that the patients are ‘cholinergic’ due to treatment with cholinesterase inhibitors. There is a risk of vagal reactions such as extreme bradycardia and asystole during intubation. In cases of high cholinesterase doses (Mestinon dose of 360 mg/day or higher), premedication with atropine is recommended.
• Use morphine and benzodiazepines (especially midazolam) cautiously.

Anesthesia Induction

• Propofol (Propofol) should be administered cautiously in a low dose. The patient is often hemodynamically unstable.
• Remifentanil can be given intravenously as in intravenous anesthesia.

Intubation

• Possibly use lidocaine (Xylocaine) in spray form on the nasal and pharyngeal mucosa.
• If muscle relaxation is needed, use rocuronium (Esmeron), or alternatively atracurium (Tracrium) in a reduced dose (or succinylcholine (Celocurin) 0.25-0.5 mg per kg). Often, no muscle relaxant is needed for intubation.
• Insert a gastric tube simultaneously, and leave it postoperatively. Cholinesterase inhibitors can be administered through the gastric tube perioperatively, along with enteral nutrition and KCl.
• Monitor muscle function with NMT measurements.

Stroke

Intracerebral Hemorrhage

• Intensive care is indicated if the patient has impaired consciousness or difficult-to-treat hypertension.
• Consider admitting the patient close to neurosurgical intervention if there is altered consciousness, ventricular breakthrough, presence of a spot sign, lobar location, or cerebellar location where neurosurgery may be necessary.
• CT angiography is often relevant, with a question about the bleeding source and the so-called spot sign.
• Atypical bleeding location, a patient without known hypertension, or a biologically younger patient strengthens the indication for CT angiography.
• Reverse the patient’s coagulation status if ongoing anticoagulation with NOAC or Warfarin treatment.
• Contact the neurosurgeon urgently in the event of a larger hemorrhage with impaired consciousness.
• Ask for the maximum blood pressure limit and take preventive measures, such as pain relief, antiemetics, urinary retention, and other stress factors.

Intravenous Thrombolysis

Indications

• Meets diagnostic criteria for brain infarction.
• Age ≥16 years.
• Symptom onset ≤ 4.5 hours before the start of thrombolysis.
• Imaging has ruled out intracranial contraindications (bleeding, extensive infarction >1/3 of the hemisphere, subacute infarction, malignant brain tumor/metastasis).
• The patient must consent to treatment. If the patient is not capable of decision-making, consent is assumed.

Absolute Contraindications

• Blood pressure ≥ 185/110 despite acute treatment with IV medication.
• Clear suspicion of a diagnosis other than ischemic stroke (subarachnoid hemorrhage, malignant brain tumor, metastasis, high fever).
• Clear suspicion of septic embolism/endocarditis or aortic dissection.
• Previous spontaneous intracerebral hemorrhage.
• Ongoing anticoagulant treatment.
• If the patient is on Warfarin and PK/INR is > 1.7.
• If the patient is on apixaban (Eliquis) or rivaroxaban (Xarelto) with intake within 48 hours and:
• Tablet intake less than 4 hours ago.
• Tablet intake more than 4 hours ago (with normal kidney function) and drug concentration >25 mcg/l.
• If the patient is on edoxaban (Lixiana) (intake within less than 48 hours).
• If the patient is on dabigatran (Pradaxa) with intake within less than 48 hours: reversal with Praxbind should be considered before thrombolysis. Decision by stroke duty doctor!
• If the patient is on high-dose heparin or similar (< 48 hours).

Relative Contraindications

• Suspicion of a diagnosis other than ischemic stroke (e.g., paresis due to hypoglycemia with B-glucose < 3 mmol/L; seizure with postictal paresis).
• Very mild symptoms (not disabling).
• Impaired consciousness RLS >2 not caused by the patient’s stroke.
• Stroke, intracranial surgery, or severe head trauma within 6 weeks.
• Previously known, untreated AVM or aneurysm intracranially.
• Gastrointestinal or urinary tract bleeding < 3 weeks ago.
• Major surgery or childbirth < 2 weeks ago.
• Known, uncorrected bleeding disorder. Platelet count < 100. Other increased bleeding risk. Ongoing major bleeding.
• Arterial puncture or other puncture at a non-compressible site (e.g., LP) < 7 days ago.

Thrombectomy

Indications

• Meets the criteria for brain infarction.
• Age ≥16 years (after consultation with pediatric medicine, individual assessment for younger individuals).
• Symptom onset <24 hours before the start of thrombectomy.
• Significant symptoms (NIHSS usually ≥6 points, individual assessment NIHSS 2-5).
• Neuroradiology has demonstrated central vessel occlusion.
• Imaging has ruled out hemorrhage.
• The patient must consent to treatment. If the patient is not capable of decision-making, consent is assumed.

Contraindications

Absolute Contraindications

• None

Relative Contraindications

• Mild symptoms.
• Comorbidity that makes the treatment not beneficial to the patient.
• Unfavorable radiological appearance.

Steroid Regimen for Adults (Corticosteroid Regimen)

Betapred dosing is individualized, weight-based, and determined by the surgeon. The Betapred regimen for children is recommended for those under 30 kg. For children weighing 30-60 kg, half the adult regimen is recommended. Children over 60 kg are considered adults and recommended the adult regimen.

Steroid Regimen (Corticosteroid Regimen) for Children

The Betapred regimen for children is recommended for those under 30 kg. For children weighing 30-60 kg, half the adult regimen is recommended. Children over 60 kg are considered adults and recommended the adult regimen.

Reaction Level Scale (RLS)

Definitions RLS-85

• RLS 1 Awake. No delayed reaction. Oriented.
• RLS 2 Drowsy or confused. Responds to mild stimulation such as verbal address, single calls, or touch.
• RLS 3 Very drowsy or confused. Responds to strong stimulation such as repeated calls, shaking, or pain stimulation. Can, for example, follow with the eyes, obey a command, say a few words, or withdraw from pain.

…………………………Threshold for unconsciousness ……………………………………………………………….

• RLS 4: Unconscious. Localizes but does not avert pain.
• RLS 5: Unconscious. Withdraws movement from pain.
• RLS 6: Unconscious. Stereotypical flexion movement in response to pain (decorticate posturing). The wrist, fingers, and elbow flex. The leg extends and internally rotates.
• RLS 7: Unconscious. Stereotypical extension movement in response to pain (decerebrate posturing). Opisthotonus, neck extension, clenched jaws, pronated, adducted, extended arms and legs.
• RLS 8: Unconscious. No response to pain.

Awake: Not drowsy, fully oriented. Intubated patient: No signs of delayed reaction.

Drowsy: The patient is drowsy if they feel or participate poorly and respond or react with delayed response.

Confused: If the patient answers incorrectly to any of the following three questions, they are considered confused: a) “What is your name?” (first and last name). b) “Where are you?” (place, e.g., the name of the city or “at the hospital”). c) “What year and month is it now?”

Responsive: Can be woken up. The patient can do any of the following: Speak or utter words – follow with their eyes – obey commands – avert pain.

Follow with eyes: Eye opening with eye contact and at some point, clear attempts to follow with the eyes.

Obey commands: On command, the patient performs a specific movement, e.g., “raise your arms”, “stick out your tongue”, or “close your eyes”.

Avert pain: The patient localizes the pain stimulation, actively grasps and tries to remove it.

Unconscious: Cannot be woken. Cannot perform any tasks in response to stimuli.

Localize pain: The patient is examined while lying on their back with their arms resting alongside the body. a) When pain is stimulated at the jaw angle, the patient moves a hand above the chin, or b) when pain is stimulated on the nail bed of one hand, the patient moves the other hand across the midline.

Withdraw movement: a) When pain is stimulated at the jaw angle, the patient turns their face away, or b) when pain is stimulated on the nail bed, the patient does not localize the pain but clearly withdraws the arm away from the body.

Stereotypical flexion movement: In response to pain, the patient slowly and mechanically flexes at the elbow and wrist but cannot localize or withdraw.

Stereotypical extension movement: In response to pain, the patient extends the arms or legs. If both flexion and extension movements occur, the flexion movement is noted as the best response.

No pain response: The patient neither moves their arms nor legs nor grimaces in response to pain stimulation.

Glasgow Coma Scale (GCS)

A consciousness grading scale that sums points from three different responses: eye opening, verbal response, and motor response. A score below 10 indicates unconsciousness.

Eye Opening

4: Spontaneous
3: On command
2: To pain
1: No response

Verbal Response

5: Oriented (best response)
4: Disoriented, confused
3: Incoherent but comprehensible words
2: Unintelligible sounds, grunting
1: No response

Motor Response

6: Obeys command (best response)
5: Localizes pain
4: Withdrawal movement to pain
3: Stereotypical flexion movement to pain
2: Stereotypical extension movement to pain
1: No response

Glasgow Coma Scale Children

Glasgow Outcome Scale

The Glasgow Outcome Scale (GOS) is a global functional outcome scale that categorizes a patient’s status into one of five categories: death, vegetative state, severe disability, moderate disability, or good recovery. The extended GOS (GOSE) provides more detailed categorization into eight categories by further dividing the severe disability, moderate disability, and good recovery categories into lower and upper levels:

CPC – Cerebral Performance Categories

Hunt & Hess – WFNS Grading

Clinical grading of a subarachnoid hemorrhage.

The Hunt and Hess scale describes the severity of subarachnoid hemorrhage, and is used as a predictor of survival.