“When the seizure doesn’t stop” – essentially a talk about refractory status epilepticus.
I’m I’ll go through what I guess most people see as the most important aspect – how you should manage it, both initially and in ICU, as well as some pitfalls and nuances. We will also talk about how these patients fare long term…
But first I want to go back in time, to put it all in perspective and I also think the historical perspective is fascinating.
So obviously fitting has been around for a while…
The first written description, probably of status was 700 BC on a cuneiform tablet from Babylon:
As you can read, it says…
‘If the possessing demon possesses him many times during the middle watch of the night, and at the time of his possession his hands and feet are cold, he is much darkened, keeps opening and shutting his mouth, is brown and yellow as to the eyes…It may go on for some time, but he will die’
So they had doom and gloom intensivists back then too…
And from that time forward epilepsy has generally had a fairly bad rep, even though the mortality for refractory status is more like 30% than 100% now…
Whether being out down to demonic possession, cursed by gods or caused by witchcraft epileptics have been harshly treated by society throughout time.
There were some glimmers of hope around 400 BC from the father of western medical thought – Hippocrates.
He had little time for mystical descriptions of the affliction and named it ‘The Sacred Disease’ ironically, because he was convinced that once we understood the disease, all these notions of divinity would fall away.
He didn’t have it all figured out and his theories involved phlegm flowing out of the brain, but at least he got that it was organic pathology…
For the next couple of thousand years we know those with seizure disorders received no effective treatments and were shunned by society.
The dark ages were truly dark with a nadir in the late 1400’s when a handbook on witch-hunting, Malleus Maleficarum, was written by two Dominican friars under Papal authority.
This stated said that one of the ways of identifying a witch was by the presence of seizures.
This book guided a wave of persecution and torture, which caused the deaths of up to 200,000 women thought to be witches.
To this day some cultures like the South American Chipaya people who believe seizures are caused by witchcraft that enters into the nose and the head, as a wind. This is treated with a ritual animal sacrifice called willancha, and by taking several dried insect infusions and bird’s blood….
As we got to the 1800’s Europe had moved on from Witch Hunting and sorcery but epileptics were treated in the same way as those with serious psychiatric disorders and those shunned by society. One of the more famous of these asylums was The hospital for the ‘epileptics and insane’ at the Salpêtrière, Paris, who housed “people, mainly women, with epilepsy, psychosis, melancholy and those who had children out of wedlock”
Epileptics only got their own “colonies” created as they were seen as a threat to the others – psych pts wouldn’t be able to stand seeing a seizure. These sort of clinics sound like hell and were immortalised in literature such as Dostoyevsky’s The Idiot.
However it was from these asylums that the first really good descriptions came of status epilepticus.
From the likes of Calmeil, who coined the phase “etat de mal” in 1824, Delasiauvre and Desire Magloir Bourneville were accurate descriptions of the phases of status, and first recognition that is was the associated systemics effects of the seizure that killed people.
And in London at Queen Square, the National Hospital for the paralysed and the epileptic where Gowers, Jackson and Turner were publishing on the epidemiology and described early treatments.
The history of these treatments is fascinating on its own merits.
Prior to 1912, the mainstay of treatment was potassium bromide – a drug that still used in dogs with epilepsy today and was famously mentioned by and even taken by Connan Doyle’s Sherlock Holmes. It makes you pretty sleepy.
I love some of the other remedies that have been tried including:
- Being covered in mustard flour
- Amyl Nitrate
- Cold showers
- Ketogenic Diet – the only odd one that is still used today
- And back in the days there was a serious obsession with the rectum, so
- Bowel irrigation with KBr
- Multiple enemae and full bowel irrigation
- Rectal digitalis
…were all given a shot.
In the 19th century, the high society party drug and hypnotic luminal – phenobarbital, was found to be much better at controlling seizures and was much less sedating than than bromide; its value as an anti-epileptic drug was proven as there was a mini-epidemic of post-traumatic epilepsy resulting from head-wounds after the first World War.
In 1924 Hans Berger, a German neurologist, used his ordinary radio equipment to amplify the brain’s electrical activity so that he could record it on graph paper. Interestingly Berger had become obsessed with the electrical powers of the mind after personal telepathy experience. This bizarre event led to a massive breakthrough in epilepsy diagnostics.
In 1938 Merrit and Putnam added to the armoury of treatments in an important way with the discovery of Phenytoin (Epanutin or Dilantin), a powerful new anti-epileptic drug.
It was to be several decades before the next few pharmacological treatments emerged Between 1960 and 1980 drugs such as Carbamazepine (Tegretol) and Valproate (Epilim), and ethosuxamide (Zarontin) and Diazepam (Valium) emerged as new treatments. After 1980, the pace of development rapidly increased such that there are now over 20 recognised and licensed drug treatments for epilepsy.
OK, modern day treatment…
So, the patient comes in fitting…
Obviously we’re going for simultaneous resuscitation and evaluation, with an aim of
- Terminating the seizures ASAP
- Trying to avoid iatrogenic harm
- Take out the underlying cause.
Make sure it is a fit and not another movement disorder, rigors or a pseudoseizure – or PNES as it’s now termed (psychogenic non epileptic seizures)
One question you must work out early on is “is this Generalised convulsive SE or is it focal complex/ myoclonic / absence SE. The tricky bit can be differentiating between subtle generalised SE and focal complex / myoclonic / absence status…
Essentially, if the LOC is diminished, you’re going to intubate to protect their airway initially and an EEG can help differentiate the tricky ones…
Things not to forget:
- If the BGL is low or you don’t know it, give Dextrose
- With thiamine 100 mg to prevent cord damage in the malnourished
OK, so we’re treating a seizure.
Chuck Norris once told me:
To be a master you need SPEED, POWER & TIMING
This applies to treating status….
Getting the drugs in quickly is crucial – I’ll explain why.
The timing of the medical treatment, especially if you’re giving phenytoin is also pivotal
And by power I mean you have to give enough
The first tier, the ONLY proven therapy, is the GABAa Agonist – a benzodiazepine
That can be loraz/midaz/clonaz/diaz
In Aus that means IV clonaz, diaz or midazolam usually, but in the US IV loraz is available. They all work, none are proven to be superior to the others, clonaz has some theoretical pharmaological advantages. More importantly is that your hospital has a protocol, the team knows it and you crack on and give a benzo.
With hard IV access Midaz can be given buccally, intranasally or IM and many pt prefer this to rectal diazepam…. except in France
The other drug in the first tier is good old phenytoin.
This sodium channel blocker limits repetitive firing of action potentials.
Here’s where timing and power come into play.
You must give enough. 1 g is almost never the 18-20 mg/kg that we need to give to adequately load this drug with a large volume of distribution.
You must monitor, don’t give faster than 50 mg/min. This is because even at this rate hypotension occurs in 50% and arrhythmias in 2%.
Fosphenytoin is a recommended alternative as it is not in the propylene glycol vehicule that really causes the problems with phenytoin. So it’s in in 10 minutes, but although in rats it looks like CSF levels don’t rise any faster than for phenytoin and it’s not proven to stop fitting faster for it’s increased cost.
So why is there any imperative to stop it quick?
The working definition of status is when it’s 5 minutes of continuous seizure activity or 2 or more discrete seizures with no intervening return of consciousness..
Well for one, we know the longer you fit, the more the brain is fried. And this is independent of just the potential hypoxic and hypotensive components of brain injury that can occur – in the 70’s, Meldrum famously induced status in 8 Senegalese female teenage baboons with IV bicuculline, and kept them ventilated and paralysed. He eloquently demonstrated that the neuronal damage visible on autopsy in the neocortex, hippocampus and thalamus was related to seizure activity alone.
A definition with 30 minutes of continuous or intermittent seizure activity was derrived from Meldrum’s baboon experiments showing neuronal damage was demonstrable in post mortem after this time, but we don’t hang around that long nowadays…
We also know that you need to get the drugs in quick if they’re going to work. The first line drug – benzodiazepines, which work on GABA a recpetors are much more effective in the first few minutes, and this is probably because the GABAa receptors get internalised into the neuronal cytoplasm
Now if the fitting still continues, this is now called refractory status epilepticus, and we’re on to second tier treatment…
And for generalised convulsive seizures, we’re now looking at general anaesthesia and up to level 2.
At this point you’re really committing, and if you’ve got an elderly patient with a known nasty underlying cause of the seizures, you may think about non-sedating AEDs and trying to avoid a prolonged ICU stay with the same outcome.
When ‘tubing, a midaz centred induction makes sense, but thiopentone and propofol also stop seizures. As in all intubations the doses and the precautions you take at induction are almost more important than the drugs themselves. We’ll mention ketamine later but probably not right as an induction agent.
Generally midaz and propofol in combination are sufficient to control things from here…
Midaz is still acting on the GABAa receptors and you get tachyphylaxis after 12-24 hours so the dose may need to go up. Propofol also hits GABAa receptors but in addition works on sodium and calcium channels. Whopper doses (like > 5mg/kg for >24h) increase the chance of PRIS. This catastrophic mitochondrial failure is rare but when it happens you never forget it.
You should be doing an EEG, ideally continuous EEG (the topic of another talk!) and initially titrating to burst suppression for 24 hours, then slowly tapering over 6-12 hours..
If you can’t get an EEG, a BIS is a poor compromise and arguably not better than nothing as it can lull you into a false sense of security.
If this fails, your heading upstairs once more –
WIth these additional agents, they seem either unlikely to work or to cause significant morbidity…
Levetiracetam is the plat du jour at the moment and certainly causes us few problems in ICU and is much cheaper than it used to be. Again, give a good dose like 2 g.
Other alternatives include IV valproate – which does work at times but is much more expensive than levetiracetam and more toxic.
Then you’re looking at a thio coma. These are often unpleasant and it’s more often in the contexts of other neurological catastrophes I’ve resorted to this. You’re looking at days to weeks of induced coma, increased vasopressor requirements, impressive hypokalemia that becomes hyperkalaemia when you stop it and a pretty much guaranteed ileus and VAP.
Other therapies with less experience and evidence include lacosamide, which has been helpful in this context anecdotally, can be given IV and is pretty safe, ketamine, magnesium, lignociane, and verapamil (interesting as it is not an AED but may improve uptake of other AEDs to the CNS).
More extreme measures include hypothermia – which works but causes morbidity and the seizures often return when you warm, surgery, ECT and classical music.
I finally want to mention prognostication, as these can be patients that spend a long time in ICU and this can be incredibly distressing for relatives, nursing and medical staff, not to mention the patient when they’re conscious.
Short term mortality for refractory status is between 16 and 39%
The biggest predictors of outcome are CAUSE and AGE
GOOD causes that are much more likely to do well include:
- Withdrawal from of low levels of AEDs
- Alcohol related seizures
- Systemic infection
BAD causes include things that are generally bad:
- large ischaemic stroke
- Hypoxic brain injury
- CNS infection
- severe systemic infection
- malignant brain tumour
- AIDS with CNS complications
- intracranial tumour
35 year old lady, previously well
- history of headaches, confusion, psychosis
- Then non convulsive SE
- Full work up for all causes, found to be anti-NMDA receptor with an associated ovarian tumour
- She remains in a thio coma for 5 months to stop her fitting
How will she do?
Near complete recovery, with only naming and memory deficits on neuropsych assessment at 6 months. No more seizures.
83 year old lady on warfarin for AF.
Large ICH with lots of ventricular blood.
RSE persists despite tier 3 AED’s
How will she do?
Not well in this case. Remained in status despite 3 AEDs, developed complications of being intubated in ICU and was extubated and subsequently palliated.
23 year old man, previously well
refractory status secondary to viral meningoencephalitis
every tier mentioned above used
105 days in ICU, discharged to ward with a mini trach and PEG, only grimacing to pain, pressure areas and incontinence.
How will he do: well – thumbs up? badly: thumbs down?
Take home points:
- Speed power and timing
- Find and treat the cause
- Cause and age prognosticate (more than duration of seizure) – so don’t give up on the young ones with a reversible cause!