Dr Sampaio still seemed concerned about (genetic) Mitochondrial diseases. He suggested that in the new year to conduct a skin biopsy, but to the parents he seemed a little too fixated on these diseases that if the results were returned negative, he would likely request for further biopsies for muscle, and then liver.
The parents were starting to notice this seemed to be an unstoppable crusade of his, unsupported by any medical or clinical evidence.
The parents asked for justification on why he even suspected a genetic disease at all. He could offer no reason at all.
Rasmussen’s disease was now suspected (towards the end of December) as the seizure activity was limited to the left side only, and to the Neurological team there were no other known explanations so far.
01/01
Ongoing arm twitching.
Alert, chatty, smiley, cheeky
Playing with mums purse and sitting up
Discussion re: potential diagnoses for Alina – Rasmussens, polG. Discussion re: prognosis. So far we can conclude this is a severe epilepsy.
Discussions were being made with Dr’s regarding Alinas schooling (following discharge) while suffering from [now] believed Rausmussens. Parents waiting patiently and nervously for the Surgeons to find time to remove her inflamed tonsils after their Xmas vacation.
- Rasmussens is a very rare condition. Although it is not known exactly how many people are affected, it is thought to be about 1 in 750,000. It may occur at any time during childhood but usually affects children aged 6 to 8 years. It may rarely happen in children as young as 2 to 4 years of age, or in adulthood
- In this condition, the brain cells in one part of one hemisphere (half) of the brain become inflamed and swollen. Very rarely, both hemispheres may be affected. The cause of this inflammation is not entirely known. There is no evidence of a viral infection in the majority of cases, although research has shown that sometimes a virus may be present. It is possible that a virus may trigger an antibody response in the brain – which then causes the inflammation. It is the inflammation that causes the nerve cells to malfunction. This is called an ‘auto-immune’ trigger in which the body’s antibodies can damage one or more organs in the body. In Rasmussen syndrome, the brain is the organ which is damaged by the body’s antibodies.
- The seizures may be very infrequent at the beginning of the condition but after a few weeks or months, they become very frequent. This means they may occur many times a day. The seizures are usually focal (partial) and can cause one side of the face or limbs to jerk rhythmically. This can become continuous and may last for many hours or even days. This is called ‘epilepsia partialis continua’. The seizures are usually very difficult and sometimes impossible to control with epilepsy medicines.
- All investigations are usually normal, except for the EEG (recording of electrical activity in the brain) and brain scans
- Medicines to stop, suppress or alter the immune system may also be used. These include steroids (prednisolone), immunoglobulins, azathioprine and tacrolimus. More recently, special medicines (called monoclonal antibodies) like rituximab and natalizumab which are powerful suppressors of immune responses have been used. These medicines may help to control the seizures. They may also slow its progression in some, but not all cases
Source: British Epilepsy Association website.
In other words, there is no current effective method for testing of Rasussens disease, other than clinical observations. It only effects one side of the body (the left)
- While the etiology is unknown, evidence supports an autoimmune basis. Although steroids, plasmapheresis, and intravenous immunoglobulin (IvIg) may afford limited benefit, standard of care for pediatric cases typically involves hemispherectomy. In this report, we present a case of adult-onset Rasmussen’s encephalitis with intractable epilepsy, ultimately responsive to a rituximab anti-B lymphocyte treatment protocol.
Source: Case Report: Rasmussen’s Encephalitis Treated Successfully with Rituximab – Juliana Lockman et al.
It was agreed to start reducing some of the medications as they were having little or no effect.
With Dr Lawson, Mum raises the question of the coincidence of the 18 month MMR, a week prior (in that week Alina showed marked deterioration; mount ulcers, tonsilitis & bad breath, coughing, irritable).
“…There’s a whole bunch of conditions that do happen after, immune diseases, that you are prone to. So you are prone to have it. Immunisation is a trigger for that… a quarter of all diseases we see are immune related”
Alina most certainly had an underlying condition, an unrecognised chronic virus.
02/01
Alina happy, alert, bright
Ongoing low amplitude non rhythmic L arm jerks
On 2 January, Alina was making significant progress, awaiting tonsillectomy, then looking to send the family home
On 3 January, with the quickly adjusted ketogenic diet and reduced medications Alina made significant improvements and the parents were allowed to take her away from the hospital, and into natural light for the first time in over a month.
The parents noticed that she had developed rings around her neck in the few weeks within the hospital, similar to her mum, and showed these to Dr Sampaio. Again, carefully explaining the family history of diabetes, changes occurring in line with Alina eating sugary foods (and the change of baby formula).
– Patirck is concerned whether this is potential indication of T2DDM
– dad reports concern that each of her seizures have been triggered by influx of sugars eg. sugar/change in formula etc
– Reassured that her changes in sugars over past week have not been near threshold of diabetic ranges
awake and playful
vocalisation attempts
fixes and follows
Preferences with Right hand with very limited activity with left hand. Does have active movements with left side, but limited.
Ongoing jerks with left side
Formal Sleep study before discussion regarding tonsilloidectomy Potential working discharge date 22nd January if all progressing well
“Tonsillar Crypt Epithelium is an Important Extra-Central Nervous System Site for Viral Replication in EV71 Encephalomyelitis”. Source: The American Journal of Pathology
On 4 January an additional eyesight test is done and a rare metabolic disease is suggested, due to further deteriorating eyesight
“Since overactivation of microglial cells may have deleterious effects in the retina, limiting IL-1β-mediated inflammatory processes could be a mechanism to prevent the progression of diabetic retinopathy”. Source: Mediators of Inflammation
slept better overnight – having increasing amounts of ‘jolt’s’ overnight- head drops and twitching of shoulders, awake and asleep(more than previously) – 1x vomit this morning- yellow like vomit following 0600 meds – nappy rash ++ secondary to loose stools- movicol withheld this morning
Alert smiley Moving all limbs Using L) hand less than usual Sandpaper like rash over abdomen- raised, non erythematous Head drops x3 when reviewed by EM, x2 with HS
ketones 3.9, 4.4, 4.6 last 24hr
Had a terrible night last night sleep-wise. Past 48 hours had had 8 hours of broken sleep. This morning had bilateral clonic jerking old R) arm, L) arm and head drops. Associated R) arm and head drops terminated after a dose of buccal midazolam. IV access attempted x1 by me but tissued immediately. Plan to give phenobarb load 20mg/kg orally 10mg/kg then another 10mg/kg an hour later. Multiple reviews during this time. Alina has ongoing high amplitude L) arm jerking and occasional head drops. Currently asleep.
Alina has had a settled day after this mornings seizures
Unfortunately, on 7 January on the ward, likely due to a large number of post Xmas/NY visitors an Adenovirus was spreading amongst the children. It was becoming clear to the parents that Alina had “caught something”, she was making very minor tremors now in her right arm (but resolved quickly with Midazolam). But was otherwise very interactive and sociable.
(Morning) Asleep upon handover and settled. Slept well in between disturbances.
Moving all four limbs and head and making appropriated eye contact. Neurologically
appropriate. Nil seizures noted
(afternoon) Pt appears in good spirits for most of the AM. Continues to have L) arm
jerking movements and head drop. Mo recording head drop episodes. Does not appear to be in pain.
Moving self independantly around bed however remains ustable sitting up.
(morning) Sleeping well overnight, easily rousable. Neurologically stable, nil changes. Mother has not reported any unusal seizure activity. Nil signs of pain.
Alina was quite lively, and playing with the nurses on 11 January, she even bumped her head slightly since she could be over enthusiastic with play, but thankfully this was of no consequence. She was in awe of the attention the nurses gave her. The parents both relieved for the extra support and to catch up on sleep since neither of them had family (although close friends had been very supportive) in the country and were waiting for granting of travel visa’s for relatives.
Minimal cncern re head bump this morning -monitor for any change in pattern of beahviour/neurology –
but looks alert and stable now
Alert and playing in nurse’s arms
Later reviewed walking around ward with mum
Saying ‘ball’
Reaching and grabbing with left arm
Smiling, symmetrical facial movements
Ongoing intermittent shaking of right arm – no change
(likely a typing error; reaching with right arm, intermittent shaking of left arm – no change)
Parents returned to the war at approx 1310hrs from the Ronald Mcdonald [care support house] as they noted bilateral clonic jerking of upper limbs, head dips and inspiratory gasps
Heart rate elevated this evening with distress from extended seizure activity. Unable to obtain
accurate blood pressure due to distress
Bilateral jerking of arms with occassional head drops have continued since 1330hours.
Right-sided jerking has progressively become more regular and succinct with left sided jerking. Alina distressed crying out for most of the evening. Multiple reviews and interventions as per neurology. Last buccal midazolam dose given as per SOS J.Tan at 2125hours, awaiting effect. All other regular medications given. SOS doctor to review approx. 2200 hours
At 3am on morning on 12 January, Alina literally burst into a full body seizure, it was vastly and clearly different from previous episodes, both shoulders and legs and face were expanding and contracting with incredible frequency, her whole body was like she was on electrical fire and every muscle was tensing for a fraction of a second then relaxing, she was massively distressed and yelping with pain as the whole body pulsed; it was horrifying, like an electrical mains switch had been turned on and she was being electrocuted.
Mum and Dad burst into tears, they could see their daughter in extreme pain having fought so hard against the incompetence, arrogance and delay of the Neurology team to recognise the symptoms and diet. The parents had tried so hard to have her infected tonsils removed and go home, but it was not classed as a priority. They just wanted to leave the hospital and seek better opinions as they knew they were in the worst place, and every medical professional they turned to (GP’s, Professors, online academics, even Doctors walking past in the corridor all said the same thing “they know what they’re doing, she’s in the right place!”)
Both Mum and Dad immediately knew this was likely the end of her chances and had done everything we could as parents to protect her and she had done everything she could to get this far. The parents were in tears panicking and just holding her tightly between them, very aware that this was their girl, daughter and life and she was in tremendous pain, things had dramatically changed and she was dying. She rested her head on Mum’s shoulder and tried to put her arms around her, she was terrified. Dad cuddled them both and all he could do was repeat saying when Mum was screaming their fears out and what they were holding “I know, I know”. When Ali closed her eyes, the parents saw their girl petrified and that was the last time they both saw their bean as she was ever before
Ongoing bilateral clonic seizure affecting arms today
KTG ratio increased to 4.5:1 this afternoon due to drop in ketones to 2.4-3.8 post seizure onset ?causative
PArents note high amplitude, synchronous rhythmic jerking of shoulders and arms
Associated with noisy breathing and difficulty settling to sleep
Currently; Asleep Synchronous bilateral clonic movements of shoulders and arms note
Overnight events noted.
Currently R) sided movements are higher amplitude
Has a temp currently, has high flow on. No other infective symptoms noted
Early L) pupil deviated inwards earlier as well. Now back to normal.
O/E
Pupils pinpoint, 3mm, reactive to light (minimally)
Sedated
IMPR
Worsening R) sided activity
Need to get EEG to see if new focus
Yesterday afternoon, twitching spread to right hand side in both arms, with both arms going upward in rhythmic pattern. Increasing drowsiness
Alina was admitted to ICU
At 0330 hours seizure intensified with all limbs and head jerking, eyes fixated and lip smacking. Pt in status not responding to voice or touch. Mild work of breathing due to pooling of secretions.
Began having brief desats and increased secretions at 0330 hours, commenced on 10L High Flow
Nasal Prongs 21% Fi02, maintaining Sp02 above 98% on High Flow. Midazolam Buccal given at 0505 hours, seizure continued but became less intense for approx 20mins then intensified again.
Regular 0600 medications given at 0530 hours. Reviewed constantly over course of shift by night SOS. Seen by neuro team and ICU at 0630 hours. Given further IV Midazolam at 0730 hours and STAT NGT Vigabactrim. Transported to ICU
Seizure activity continuing, twitching of trunk and arms, eased slightly post midaz dose on ward
Dr Sampaio was away watching the tennis in Melbourne and the parents asked desperately for his contact and advice via the ward on how to act – he didn’t respond directly; it was obvious even to them that Alina needed to be placed in a coma immediately. A video was sent of Alinas change in condition to him. The parents were trying their hardest to increase the use of Midazolam, which was the only effective drug, and to ease her pain
Clinical Neurophysiology Unit POWH/SCH (MURTAGH, Alina MRN 10450683; EEG; Recorded: 12-Jan-2018)
Detail:
A ward portable EEG was performed. The patient was sedated.
The background activity consisted of delta (1-4Hz) and beta rhythms, which were symmetrical and continuous.
Epileptiform activity arose repeatedly from Fz (frontal midline)
and was sometomes generalised. Isolated discharges occur, followed by runs of generalised spike discharges lasting 10-14s ie repeated electrical seizures associated with right arm and leg twitching and followed by brief attenuation (5s). The process repeats through the recording. Hyperventilation not done.
Photic stimulation not done.
Conclusion:
A very abnormal EEG with repeated electrical seizures, associated with right leg and arm jerking.
13/01
She has continued to have generalised clonic movements throughout the day with left and right arms twitching along with right leg twitching. She did have lip smacking to this morning with supsided and has ceased since the midazolam was commenced
14/01
Seizures:
Ongoing bilateral clonic seizures overnight on midazolam infusion 4mcg/kg/min
Given x6 boluses of midazolam overnight due to increasing amplitude of clonic movements
Right arm, leg and left clonic movements (asynchronous)
During night witnessed to have 2x episodes of bilateral limb jerking to both upper limbs and right leg, seems most pronounced to right arm and right leg. – on both occassions amplitude of jerking reduced with 2 x midazolam bolus and appear to settle
Pt required 4 x bolus’ of Midazolam from 0200-0500hrs instructed by CICU Registrar due to increased irritability and prolonged seizure activity, jerking of right and left upper limbs and R lower limb which eventually took good effect and reduced jerking movements
Remains vacant although eyes open spontaneously.
Temperature has continued to fluctuate throughout the day. Temperature 37-38.6
Has had one bolus of midazolam this evening due to increased HR and seeming agitated and settled post this and HR reduced and appeared to settle to sleep.
has continued to have generalised twitching movements to both arms and right leg along with her lips twitching today and appears more pronounced today
Alina was placed in an isolated ward on ICU, any noise made, however little would disturb her and would worsen the very aggressive seizure activity. Notification was posted outside the room requesting quiet as they worsened the seizures
For 5+ days until Dr. Sampaio returned, Alina faded slowly while in obvious pain, the seizure activity was now on both sides and constant, at most she slept for an hour a day due to her sensitivity to noise, during this period and the only thing the parents could do was to comfort and relax her with everything they possibly could to try and calm her. Her seizures were intense and through the whole body and constant
15/01
tepid cloths applied by parents during increased seizure activity to break fever
Ongoing seizure activity, however more pronounced when awake.
16/01
HR and temp rise with seizures – mum unsure whether fevers or seizure activity escalation comes first
Alina seems more settled tonight, ongoing seizure activity but much less pronounced than previous nights
No extra midazolam given
(Video 20180116.144)
17/01 (Dr Sampaio) Met with family to discuss negative genetic results. Broad panel with good coverage has not detected any mutations in POLG gene and other nuclear genes associated with EPC. May still be mitochondrial mutation or mutation on a gene not covered by panel. Will discuss with genetics where to from here – potentially biopsies or sequencing of genes not covered in panel. Negative gene panel does bring into question immune aetiology. Thus far no markers of immune cause. Spread to contralateral hemisphere makes rasmussens encephalitis very unlikely. Note antiGAD high, although this was post IVIG. Needs repeating. I have liaised with immunology. On balance worth a further course of IVIG. Notably parents concerned about mainatining ketosis. Should antiGAD levels have risen then steroids may be indicated but this would come at the cost of losing ketosis. We will order IVIG from the blood bank to make sure a preparation without glucose/carbohydrate is ordered
Alina has had ongoing seizures overnight, no change in activity to previous night.
18/01/2018
We are concerned that Alina continues to have seizures, she is minimally conscious and she is not getting better. EEG shows abnormal background and multifocal epileptiform discharges
Awake, unsettled with ongoing seizure activity, more vigorous than its been for the last few dys as per Mum
Eyes flickering and not fixing
R arm quite vigorous, L arm rhythmic movements but not as strong
R leg involved
19/01 (Discussion with Edwin Kirk / Caroline Ellerway)
– ?Trio exome
– Wouldn’t recommend a mito cocktail
– Not convinced this is a metabolic / mitochondrial process but always possible
19/01
Lactates all <1.5
– CSF lactate 1.3
– No lactate peaks on MRS
– UMS normal
– CGH normal
– POLG and mitochondrial panel (dels and dups pending) normal
– Fulgent epilepsy panel – no clearly pathogenic variants identified, variants of uncertain significance reviewed by Prof Kirk and deemed non-contributory
– CSF neurotransmitters normal
– Transferrin isoforms and carnitine profile normal
– Plasma amino acids normal
At this stage, although we cannot completely exclude a metabolic/mitochondrial cause, it is not likely
22/01
Patrick requested transfer of care to Dr Michael Cardamone
And second opinions from westmead children’s hospital
The family have been in contact with Dr Deepak Gill’s rooms, who have advised she can be seen in rooms when she is out of hospital
Joined by Dr Sampaio at 10:45 with Mum also Mum stated she is unhappy with progress, very teary, with in particular percieved delays in treatment such as giving thiopentone friday (17/1 at 17:10) rather than earlier
Dr Sampaio explained that thiopentione is risky and so we did not take this decision lightly and gave Alina time to see if midazolam worked in reversing seizure.
Dr Sampaio reflected that the treatments Alina have not had much benefit and there is no magic bullet treatment
Family and medical team agree that Ketogenic diet helpful but only part of the picture
Parents are very keen for complete copy of the records- they have requested same from HIU
Dr Sampaio currently making a summary of investigations, episodes and treatments throughout the course of her illness
As you can hear, Dr. Sampaio seems selective and generous to himself in the hospital notes regarding this conversation
He discussed her ketone level [which was had now finally established with the Neurology team as directly correlating to seizure activity]. How this was an altogether different type of seizure to the previous, and he tried to tell the parents that it wasn’t spontaneous but rather progressive over the course of the week. Mum corrected him, (it seemed he was trying to excuse himself for his delay).
Dr Sampaio was asked why he had ignored the parents requests for raising the level of the ketogenic diet, he agreed and confirmed it was the only thing working (or ‘valve’)
Download hospital letters here (PDF, 996k)
The light and recognition in her eyes faded over those days to just a glazed distant stare – this was agreed by both Dr Sampaio and the parents. The parents begged but couldn’t even get enough pain medications to calm her or even relieve her suffering as the Doctors and Nurses were likely under instructions from Dr. Sampaio not to intervene “even in the previous episodes, I do wonder if we gave her too much medicine sometimes” as his reason, in the context of implying that he had overreacted before with medications and on this occasion had misjudged the very different seizure type. For days Alina was kept awake so she could witness the agonising pain of her own cortex collapsing. The seizure had clearly spread from Focal to Generalised at a particular time – Saturday night at 3am, you didn’t need to be a Doctor to realise this
By the time Dr Sampaio returned, Alinas very different seizure had reduced her to nothing more than a constant full body EPC seizure, “no longer there” there was very little left of her otherwise determined and resilient spirit, the girl who was playing with nurses only a few days before and plans were being made to discharge the family.
An MRI at the end of the week showed that Alina had lost 50% of her cortex. Despite the claim in the Hospital notes that Dr Sampaio wished to see if Midazolam would work, in reality this had actually been reduced as can be heard from the Mothers complaint. Alina was kept awake for this generalised seizure with reduced pain medication.
Now please try to imagine the pain someone has when they have a migraine and how much of the brain this relates to, then I think you can only just glimpse and understand the incredible suffering Alina endured for 5 days before a coma was induced, and then consider just how quickly a coma was induced on previous focal episodes
The parents dismissed Dr Sampaio the following day, he had disgraced himself for not acting quickly and allowing Alina to suffer unnecessarily and in extreme pain for nearly a week.
He had spent his time trying to prove a genetic disease without reason, rather than attending to the actual symptoms as presented, viral symptoms; elevated temperatures, tonsillitis, croup and stridor, rashes, vomiting, as well as the disease indications from testing and advice from colleagues, all duplicates of her extensive medical history.
All because he was incapable of recognizing the symptoms of a very known illness (chronic) Herpangina or EV71, too arrogant to ring her GP and confirm the parents reporting of her history of the illness (he had even been given the phone number), Dr Sampaio did not include the parental email correspondence in the hospital notes (a virus so distinct its very likely another doctor would have recognised it immediately) all because he was oblivious that the CSF testing was ineffective for this particular virus once it reached the brain, in this situation the PCR tests are only 3% accurate and cannot distinguish between an acute +RNA Rhinovirus and -ve RNA Chronic Enterovirus. All things the parents would only find out after investigation, research and comparison of the hospital notes to the actual events, many months later.
Dismissing him was the only thing they could do.
And there was of course a very good reason why this episode seems to have been different, because it was a different set of circumstances.
Isolation of a subgenus B Adenovirus during a fatal outbreak of Enterovirus 71 associated with hand, foot, and mouth disease in Sibu, Sarawak.
- The agents isolated from ten (66·7%) of these 15 children were eventually identified as adenoviruses and were isolated mainly from clinically important sterile sites or tissues. All the enterovirus-positive children who died had this second agent
Source: The Lancet.
Believing that it was metabolic focused (Mitochondrial) is likely related to this evidence:
- Virus-induced mitochondrial dysfunction is not specific for EV71 and can be observed for other viruses… expression of human immunodeficiency virus (HIV) Tat protein, hepatitis B virus X protein, severe acute respiratory syndrome (SARS) coronavirus non-structural protein 10 results in mitochondrial depolarization
- These findings suggest that EV71 infection induces mitochondrial proliferation and changes in expression of mitochondrial proteins
- These findings suggest that mitochondrial ROS (reactive oxygen species) are essential to EV71 replication
- Oxidative stress and mitochondrial damage have been implicated in the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease, Parkinson’s disease and amyotrophic lateral sclerosis. Oxidative stress is characterized by the overproduction of reactive oxygen species, which can induce mitochondrial DNA mutations, damage the mitochondrial respiratory chain, alter membrane permeability, and influence Ca2+ homeostasis and mitochondrial defense systems.
Source: Oxidative stress, mitochondrial damage and neurodegenerative diseases – Chunyan Guo et al.
In other words, Enterovirus EV71 and Adenovirus combined has a documented and fatal outcome. EV71 places oxidative stress (= ROS) on mitochondria to alter proteins and repress aspects of the immune response (this is a known action for several viruses, including coronavirus), and linked to other nerve related chronic illnesses. You can only imagine how many other “auto-immune” diseases are simply chronic viral, but there is simply no effective method of medical testing, because the doctors do not routinely test for the -ve stranded Chronic Virus – a fact to be explained later. EV71 is a disease of the mitochondria, not a mitochondrial disease.
Dr. Sampaio wrote a paper on the subject of EV71 previously, with Prof. Russ Dale, so should be familiar with the disease, progression and associations, see Clinical Characteristics and Functional Motor Outcomes of Enterovirus 71 Neurological Disease in Children
Dr. Sampaio asked the advice of Prof. Russell Dale and other colleagues as to whether Alina’s illness could be metabolic or genetic, see emails here.
It is worth noting the following from a paper written by Prof. Russell Dale (who advised that this was not immunological as the OCB bands were absent and normal banding range of Neopterins and Biopterins):
“Neopterin levels are not elevated in Chronic progressive, metabolic or genetic. Nor Chronic Static”.
So it would be hard to argue that Alina had a chronic progressive disorder or, as Dr. Sampaio contributed, “definitely metabolic or genetic”
Furthermore:
- The cerebrospinal fluid (CSF) cell count was normal in 15% of all patients.
- Patients with normal CSF cell counts were older and less frequently had meningitis.
- PCR for enteroviruses may be useful in suspected central nervous system (CNS) infections without pleocytosis.
- Enteroviral CNS infections can manifest in the form of isolated cranial nerve involvement
- CSF cytology showed a predominance of neutrophils (≥50%) in 46% of patients
- CSF-specific oligoclonal bands indicating qualitative intrathecal IgG synthesis were present in 11% of patients
Further information can be found for infants with similar clinical presentations and low neopterins. The guide Prof. Dale used as for (baseline/control) comparison to evaluate the levels; Symptoms that Alina had an extensive and exact medical history of:
- These children initially were definitely not healthy but had a wide spectrum of diseases: cranial nerve palsy of unknown etiology, strong headache, first generalized seizure, acute strabismus [uncoordinated eye direction], transient gait disturbance, paresthesia of unknown etiology, acute confusional state due to migraine, benign paroxysmal vertigo, and progressive hypacusis [loss of hearing] of unknown etiology
In other words, the control group that consultant Prof. Russell Dale was comparing inflammation markers with and considered as the “normal”, had the same progressive metabolic/genetic disorders as Alina, as seen from her GP’s notes. Neopterins and Biopterins are only effective as elevated marker diagnosis by inflammation in acute cases.
The three images below show Alina’s test relevant results:
And the image below is the comparative table from the paper from Dr. Dale. Alina met the Chronic Progressive/Static range of biopterin levels
On 23 January there was a hand over to Dr Michael Cardamone, again briefly explaining the sequence of events propagating from the throat in a particular order, a distinct smell on her breath prior and during a seizure, constant night coughing for over a year from a repeating virus that the GP’s would ignore and just give Steroids (which would only work briefly)
The parents had seen Alina recover to some great degree previously, so they could only hope that this would happen again. There was no shortage of love, prayers and dedication for her from the parents, family and friends. Alina was very strong willed, resilient and determined to live, she loved life and adored people
At a meeting with parents and Dr. Cardomone on 24 January there was reassurance that the Neurology department works as a team
“We are actually working together… …we totally endorse so far what Hugo has done and his investigations…”
Question raised regarding possible immunodeficiency. Currently consider this unlikely as no significant personal or family history of infections.
Ability to clear viruses demonstrated this admission – in Dec 2017 cleared rhinovirus and bocavirus and in January 2018 cleared adenovirus on NPA.
Normal immunoglobulins and lymphocyte subsets
No evidence of cerebral inflammation on repeated CSF including low protein, no evidence of oligoclonal bands, normal neopterins in Nov 2017 and Jan 2018, CSF repeatedly negative for viruses on PCR. Repeat samples of CSF negative for autoantibodies. No pleocytosis on CSF.
Note that evolving changes on MRI – encephalitis cannot be excluded, however, lack of CSF inflammation unusual.
NK cell function not clinically indicated as no evidence of CNS inflammation.
If viral PCR positive on brain biopsy, then further immune investigations / genetic testing may be warranted but not currently.
And this was the source of the frustration the parents were having, like many of the explanations, symptoms and family history, Dr Hugo Sampaio had chosen not to document Alinas extensive history of a repeated viral infection, one which was even described in an email.
- The study shows that after the onset of symptomatic respiratory infection enterovirus RNA may take 2-3 weeks and rhinovirus RNA 5-6 weeks to disappear from nasal mucus.
- After entry into the CNS, glial cells which constitute part of the CNS innate immune system, detect the intracellular viral nucleic acid, and stimulate the release of IFN-1, causing apoptosis and inhibit viral replication. It is, however, important to note that collateral damage incurred upon activation of cytolytic T cells during an adaptive immune response within the CNS may be more damaging to neurons than the infection. Furthermore, both greater cytokine induced tissue destruction due to higher systemic levels of proinflammatory cytokines like IL-6, IL-1β, and TNF
- Even so, viruses have also evolved to escape host defence by producing viral proteins that inhibit host anti-viral response. For example, EV71 produces protein 3C which inhibits RIG-I like receptors and thus blocks host IFN-1, and protein 2C which inhibits IkB kinase beta phosphorylation, consequently blocking the TNF alpha activated NκB signaling pathway
- This results in suboptimal T and NK cell response as viral proteins inhibit IFN-1 synthesis and escape immune surveillance
- It is presumed as well that enterovirus will be detectable in the gastrointestinal (GI) tract, but in the case of chronic encephalitis, by the time the disease surfaces, the virus may have cleared from the GI tract and be undetectable in the stool. Additionally, due to low viral concentration, detection of viral RNA in the CSF early after manifestation may be challenging as well
- The tests currently available have a low diagnostic yield, even in the case of PCR which has high specificity and high sensitivity
- In utero, the BBB has not fully matured and viruses crossing into the placental circulation can also result in CNS infection.
- Furthermore, patients who suffer from neurogenic pulmonary edema have been reported to have lower absolute monocyte counts, CD4, CD8 and NK cells counts as compared to patients who had autonomic nerve system abnormalities and uncomplicated brainstem encephalitis
Source: Viral Encephalitis with Focus on Human Enteroviruses – Po-Ying Chia and Justin Jang Hann Chu.
Continually seizing still, more prominant movements with the right side- arm and leg twitching with some left movement as well, continual eye flickering.
Ongoing baseline seizures – eyes opened, mouth twitching, left and right UL, Rt LL
30/01 MRI shows significant damage to her brain
At the end of January 2018 the parents were approached by a Junior ICU Doctor Lily Foster, who for some unknown reason chose to approach the exhausted parents while they were attending to Alina one evening. She proudly told them the only option they had was to inject their daughter with morphine, until no longer able to support her lungs, and let her die. It would take anything from a few minutes to several hours, Dr. Foster said she was unaware if this was painless of not
Exhausted and with no family support, this Doctor chose to bully and hold an extremely distressing conversation in the same room and over their daughter. Dr Foster argued with them very forcefully, and when the parents said they would complain regarding this approach, she just simply didn’t care, that the parents complaints to the hospital were effectively meaningless. It was a terrify and massively unprofessional thing to do, especially over the bedside of the patient.
The parents complained the following day. Strangely this Doctor was not seen again on the ward and she was moved to North Shore. Later the hospital claimed this was a planned move, although the parents had been told earlier in the month (on two occasions, by different doctors) when they expressed concern that the rotation of staff, that she was one of two ICU Doctors specifically who would maintain their residence beyond the relocation of staff on the 31st January.
One Senior Doctor later remarked that “she was just showing off to her colleagues that she would have the conversation with you that the other Doctors were avoiding”
Complaints to ‘Patients Friend’ all but disappeared, and the conversation, even described verbatim, was diluted and diluted until it was believed “a shrugged apology” was sufficient.
The contempt for the family from many of the (Dr.) Medical staff was a daily battle for the parents, gaslightling often involves recruitment in support, which the parents had been subjected to