By chance Dr. Caroline Stewart returned to the ward after a months absence, one of the few Doctors outside of the Neurology team who had treated Alina before and after her seizure on the 12th Jan. On seeing her only before pre-Anakinra trial and now after, all she immediately said to the parents “she’s like a new girl!” regarding the very clear improvements. Her notes were as follows; no longer refractory seizures. They had reduced considerably from earlier in the month, and especially since the horrific seizure of 12th.
01/03
21mo EPC Alina
Ongoing twitching of face
Left arm improved this morning
02/03
(ICU notes)
Still having a high secretion load, requiring high level of physiotherapy
– Respiratory functiom remains stable on 1L/kg/min HFNP supplemental O2
– Nursing staff report that when asleep today, seizure activity does appear to some extent diminished
– Nuring staff also report improved cough
– Current tentative plan is for possible discharge to ward next week
(Neuro notes)
Much more settled
persistent facial twitching – frequency decreased from previous
Tone slightly decreased in arms and legs (more tone in legs > arms)
Head lag ++ on pulling up
Looking around and fixing on faces
Made slight movement left leg
Copious oral secretions
No cough
03/03
ICU notes
Seizures
on multiple AED’s
on ketogenic diet – aiming ketones 4-6
neurology team happy with BSLs 3.3 to 4.3
most responsive to phenobarbitone, aiming high levels 30-40
avoiding hyperthermia (worsens seizures)
on regular Mg – aiming Mg >1.0
No longer refractory clinical seizures – 2 x clinical seizures in last 24 hours, can be prolonged (45 minutes_
poor cough, very weak & ineffective, slow to trigger
nil drooling
C haemodynamically stable, unremarkable exam
D neuro – briefly fixing, fleetingly following
globally weak
moving all 4 limbs
right arm remains jittery require phenobarb to settle. ocassional tremmors in other arm. nil abnormal movements in legs noted or facial abnormalities.
Neuro notes
much more settled and alert
coughing overnight
- Phenobarbital reduces blood glucose and gluconeogenesis through down-regulation of phosphoenolpyruvate carboxykinase (GTP) gene expression in rats
04/03
Seizures continuously despite maximal therapy – confirmed on recent awake and asleep EEG. Clinically appear to reduce when asleep and there has only been 1 witnessed cluster today (04/03/18)
Today Alina has been well settled, however, PT and nursing staff have expressed concern regarding the invasive nature of the suctioning required to manage her secretions, which have become more tenacious.
Alina slept for consultation – no facial twitches noted
05/03
Currently febrile and tachycardic, exacerbating twitches
Otherwise alert, looking around, looks comfortable
06/03
Breif discussion between Prof Kirk and Dad. Discussion revolved around that genetic tests have been sent to Helsinki and will likely be reported in several weeks
Father in attendance, feels Alina is a lottle stonger each day and attempting to vocalise
Feels cough slowly improving
07/03
ICU Notes
Issues with Father, Patrick, becoming intimidating towards nurses and doctors, altering HFNP settings, yelling, demanding medications be changed/continued
he does not believe that seizures can be seen with an EEG
he does not believe that we are investigating the cause of her fevers
he believes that she is seizure free most of the time, is interactive and talks
Father feels cough has improvved, movements disorder not increasing since midazolam weaned
Do view the videos from the 4th and 5th, although ‘talking’ might be an overstatement, she was certainly interactive, aware and fixated on dad to her right, then adjusts to follow other people, even aware of the stethoscope. Also note the significant reduction in seizure activity that was so very constant, violent at times, and unabated whether awake or asleep (and marked in the notes towards the end of January) prior to the administration of Anakinra. Over the next week there were very visible periods with a complete lack of seizure activity, as noted by the Nurses and ICU Doctors
Neuro Notes
Overall pleased that Alina remains extubated. However she remains very dependant on physiotherapy and suctioning.
Cough is present and blunted. She would not be ready for further anaesthetic till cough is stronger and chest remains clear for several months.
Enteral Mg contains carbohydrate – this medication is not adding benefit and is reducing benefit of ketogenic diet
Advised parents that epilepsy panel was normal. The whole exome looks looks at all genes (epilpesy and non epilpesy). There are functional studies that will give us the likelihood for pathogenicity, with mutations
Clear that epileptiform activity is noted all throughout EEG. We have stressed that there is continous seizure activity on the EEG in wake and sleep (electrical and clinical). Some of these electrical discharges do not have a clinical correlate. In addition she has facial tremulousness
08/03
Patrick concerned about stopping the IV magnesium. Advised it is not having much benefit to Alina, we need to reduce the risk of infection with IV access lines and prioritise the ketogenic diet. Explained the combination we feel has been most beneficial to her is Perampenel, Phenobarbitone & ketogenic diet
- (MgSO4) is a cheap, safe, and readily available medication that is effective in managing tetanus-associated ANS dysregulation and has shown promise when used empirically in EV71-confirmed severe HFMD cases
10/03
Alina noted to temporarily track and follow balloon
Parents and family alternating at bedside, helpful with cares. Parents appear less stressed today
since Alina is sleeping, there’s no visible seizure activity while asleep and her obs are improving
12/03
ICU Notes
Very minimal seizure activity noticeable whilst asleep- will occasionally have a twitch on her cheek and R) arm, otherwise no other seizure activity visible whilst asleep
Neuro notes
Continues to have sz/EPC vs. movement disorder almost continually when awake – facial twitching and hand twitching
We will await form CARS2 result (parents not aware)
Anakinra has a short half-life. And the benefits were now starting to wear off, and pneumonia is affecting her lungs frequently from being bed bound.
On 13 March, Alina is intubated.
15/03
unable to gain seizure control – until most recent EEG has always had constant seizure activity on EEGs
16/03
Multiple episodes of apnoea and pauses in breathing requiring ventilator
Copious secretions with persistent desaturations
Agitated overnight unable to settle
Further episode of upper limb arm stiffness, twisting movement overnight, throwing her body around whilst awake 0030
Multiple of her usual seizures R sided upper limb and eye deviation
No episodes noted when asleep
2-3 buccal midazolam doses with no effect
Midazolam infusion for 6 hours overnight, stopped at 0700
Slept well this morning
Currently off midazolam and diazepam
No vomiting
Ketones 3.3
BSL 4.9
—
A slow record with prominent EMG artifact. Occasional epileptiform activity arose from a right
temporal focus. Frequent probable epileptiform activity arose from Cz (vertex).
Reported by: PROF J COLEBATCH
—
18/03
Patrick asked the following:
– Certainty of genetic result. Is it possible that this mutation is not disease causing? Are there other tests that could confirm it.
– Functions that mutations in this gene affect
19/03/2018
Explained when we get a gene it is described as pathogenic, likely pathogenic, variable insignificance. This is based on the level of evidence we have on the gene. Advised the lab dont have enough information yet to get the gene from variable to likely pathogenic. Explained Dr Kirk doesnt have a report yet and we are quite cautious about the reporting. Patrick asking if any other genes identified explained no other genes and we asked for secondary look to check specifically for respiratory or immunological genes.
Advised EEG last friday is back to baseline prior to Anakinra.Lots of artefact and lots of epileptic spikes. Parents confused because the last one was better. Explained she didnt have epileptic spikes but the background was very very flat and slow because she was unwell and unconsious at the time.
The benefits of Anakinra was almost complete, and the only other demonstrated effective medication IV Midazolam was withdrawn, as was Magnesium, to force the return of the heavy and constant seizures. The parents were very aware that the Neurologists had now withdrawn any care and would be intent on causing deliberate suffering, abuse and harm to a child to force a request of palliative care
Rather than an honest conversation with the parents regarding the likely or possible future for Alina, an admission of their error in failing to recognise a treatable illness, the Neurologists very quickly returned to the abandoned genetic cause for the seizures.
The Neurological team had jumped around with so many differing diagnosis for this unknown disease, and when it was clear an Autoimmune drug had shown great benefit and treatment was possible.
The database of +230k comparable gene samples did not find any fault, so one need to be created, one which matched Dr Sampaios initial hunch. A computer program was used to fabricate a possible relationship, using software that is openly known to perform the very same error required of “over reporting”. The Genetics team presented 2 similar examples of a very rare genetic illness (CARS2) and they clearly had very little overlap with Alinas presentation or medical history.
To the parents this seemed very convenient and contrived.
It would take very little research to later find that the genetic explanation was indeed fabricated and easily disproved. Further publications of identical or similar presentations would show this was the very same treatable illness (with full recovery) the parents had emailed and discussed at length on admission, with Anakinra as one of the suggested medications of use
The hospital was aware the parents would not seek an autopsy since the mum held strong religious beliefs
Alina had returned to her previous condition prior to Anakinra, (almost identical to the video at the end of January – 2018.01.29), of heavy and continuous seizures
22/03
Advised CARS2 gene the likely explanation for Alinas condition but if they want to confirm need skin/muscle/liver biopsies, whilst limiting number of GAs Alina has. Long discussion about CARS2 gene and function of mitochondria.
Planning for tracheostomy. Mum states she is not in favour of trache but doesnt want to take it away from Patrick, he carries the hope whereas Mum is focused on limiting suffering. mum states Patrick is not accepting of diagnosis.
mum stating Patrick asking about giving IVIg – explained there is significant risk of aspetic meningitis and we have no found any immunological/inflammatory genes
23/03
CARS2 gene identified as likely pathogenic. Parents likely unaffected carriers.
have recommended biopsy- as yet not performed. parents not convinced it will help, and will not consent to it as an individual procedure as they do not want to expose alina to risk of additional GA
As documented, these showed compound heterozygous variants in CARS2, a gene which encodes a mitochondrial tRNA synthetase. One variant had been thoroughly studied previously, but the other had not been reported. Both variants were interpreted as Likely Pathogenic by the laboratory. We had discussed the meaning of a Likely Pathogenic classification, which means that there is a high probability that the variants are pathogenic, but acknowledges a small chance that this is incorrect. We also discussed the remaining uncertainty, related to the small number of previous reports with overlapping but not identical phenotypes.
4 seizures overnight requiring IN midazolam
Felt to work better than buccal due to oral secretions
Ketones low today
24/03
Parents have been present throughout the day rotating. Both were very emotional and teary
this morning, Patrick got upset this morning and spoke about how he feels Alina is suffering like this and that it is hard for him to make the decision as to what to do, he mentioned that Alina was a daddy’s girl and its hard for him to keep that memory as does not feel she is right now.
Alina could now no longer recognise her parents when they came into the room, she had suffered enough from multiple lung failures. The parents felt the withdrawal of Anakinra, a decision made by the Neurologists and against the parents wishes, a medication that had made a clear difference. Alina returned to her previous state of continued seizures, she was suffering as a result and the parents felt strongly they were being bullied and manipulated into accepting palliative care, and then shortly after a fraudulent CARS2 gene diagnosis
26/03
Progress noted
Increasing seizure activity
Plan made with ICU and parents for extubation and palliation today
Dr Cardamone aware but unavailable in clinic this morning
Patrick and Mum present at bedside
Not wishing to engage in conversation
Refractory seizures – on multiple AEDs, ketogenic diet, does derive some benefit from IN midazolam
2) I+V – requirements for mandatory rate due to apnoeas
3) Palliative course anticipated in light of recent discussions
Alina was extubated in the fairy garden at around 1230 pm and placed in her mother and father's arms
Both parents are in agreement that this is where Alina would like to spend her final moments
Soon after this, several friends of Alina's parents arrived to offer their support.
Neurology Fellow – Macdonald
Alina passed away earlier this evening.
Visited parents on behalf of neurology. Dr Cardamone has also visited. Dr Sampaio also informed.
Our condolances to Alina's family, rest in peace Alina
Following months of unnecessary and avoidable suffering, palliative care was introduced, a high dose of morphine for several hours. Alina died in her Mothers arms at sunset
