COURT FILE NO.: CV-19-71115
DATE: 2024-12-30
ONTARIO
SUPERIOR COURT OF JUSTICE
BETWEEN:
SKYLER BROWN, by her Litigation Guardian Jennifer Brown, JENNIFER BROWN and JEFF BROWN
Plaintiffs
– and –
BRANDON MEANEY and GABRIEL RONEN
Paul Harte and Kristian Bonn, for the Plaintiffs
Darryl Cruz, Sam Rogers and Mogan Watkins for the Defendants
Defendants
HEARD: March 18-22, 25-28, April 2-4, 2024
M. Bordin J.
CONTENTS
A. OVERVIEW... 3
B. THE FACT WITNESSES – CREDIBILITY AND RELIABILITY.. 6
C. PYRIDOXINE EMIPRICAL TRIAL AND TREATMENT. 8
Positions of the Parties. 8
Pediatric Neurology at MCH.. 9
Skyler’s course of treatment 10
April 2003. 10
May 9-10, 2003. 11
May 11, 2003. 11
May 12 – 15, 2003. 16
May 16 – 19, 2003. 20
May 20, 2003. 22
May 26 – July 6, 2003. 24
July 6, 2003 - Admission to MCH.. 28
July 15, 2003 meeting. 31
After August 11, 2003. 33
- The Expert Witnesses. 35
Dr. Yager 38
Dr. Wiznitzer 39
Dr. Snead. 40
Dr. Prasad. 43
- Standard of Care: pyridoxine trial and treatment with pyridoxine. 44
Law on Standard of Care. 45
Knowledge of PDE in 2003. 50
Empirical Trials in 2003. 55
Dr. Ronen and Dr. Meaney’s Knowledge of PDE in 2003. 61
Expert opinions on whether the defendants met the standard of care. 62
- Analysis of Standard of Care in pyridoxine trial and treatment with pyridoxine. 64
May 11, 2003 treatment 64
Conduct of the pyridoxine trial 65
Differential diagnosis of focal cortical dysplasia. 66
Discontinuing pyridoxine with a three to four day monitoring period. 66
Response to the pyridoxine. 67
Discharge on May 20, 2003. 73
May 26 to July 6, 2003. 74
D. INFORMED CONSENT. 84
Positions of the Parties. 84
Law of informed consent 85
Facts and analysis of informed consent 87
Would the plaintiffs’ conduct have been different?. 93
E. CAUSATION: PYRIDOXINE AND INFORMED CONSENT. 95
Positions of the Parties. 95
Law of Causation. 96
Facts. 99
Skyler’s development 99
Skyler’s sister 102
- Expert Opinions. 102
The genetic disorder 105
Impact of seizures. 105
Statistical Outcomes. 106
Late onset of seizures. 108
Triple Therapy. 109
Head Circumference. 110
MRIs. 112
Comparison to Summer 113
- Causation analysis. 115
F. CONCLUSION.. 124
A. OVERVIEW
[1] In December 2020 Skyler Brown (“Skyler”) was born with a rare but well-known disorder, pyridoxine-dependent epilepsy (“PDE”). PDE causes seizures that cannot be controlled by antiepileptic medications but can be treated with pyridoxine. Pyridoxine is commonly known as vitamin B6.
[2] Skyler’s parents are Jennifer Brown (“Jennifer”) and Jeff Brown (“Jeff”). Together with Skyler they sue the defendants, Dr. Brandon Meaney and Dr. Gabriel Ronen for alleged negligence in Skyler’s care. Dr. Meaney and Dr. Ronen were pediatric neurologists at McMaster Children’s Hospital (“MCH”) who were consulted about and who directed the treatment of Skyler’s seizures.
[3] The plaintiffs allege that the defendants breached the standard of care in their treatment of Skyler between May 12, 2003, and July 6, 2003. They allege that the defendants breached the standard of care in conducting a pyridoxine trial and in failing to treat Skyler with pyridoxine when her seizures returned on and after May 26, 2003. Further, they allege that the defendants breached their duty to properly inform and obtain consent from Skyler’s parents.
[4] Skyler suffers from severe neurologic injuries and intellectual and developmental delay. The plaintiffs assert that the defendants’ breach of the standard of care and failure to properly inform and obtain consent caused or contributed to Skyler’s intellectual and developmental delay and the developmental challenges she currently faces.
[5] The defendants assert that they exercised appropriate clinical judgment in a complex and evolving situation over 14 weeks involving a rare and little-known condition. They assert that they were not negligent in Skyler’s treatment or in obtaining informed consent. In addition, the defendants assert that the plaintiffs have failed to establish causation.
[6] The parties have agreed on damages. Only liability is at issue.
[7] Jennifer, Jeff, Dr. Meaney, Dr. Ronen, and four expert witnesses testified at trial. The plaintiffs read in excerpts from the defendants’ examinations for discovery. The parties filed a lengthy Agreed Statement of Facts (“ASF”). The ASF was not intended to be a complete statement of the facts regarding the case and was filed without prejudice to the submissions the parties make about the relevance and weight that ought to be given to any fact. The parties also filed a Supplemental Agreed Statement of Facts.
[8] The parties filed a Joint Book of Documents but only referred to a limited number of the documents within it. As discussed and agreed to with the parties, I did not review the over two thousand pages of documents that the parties did not refer to at trial.
[9] At the outset of trial, the plaintiff filed a copy of their opening statement containing an extensive review of the law. Similarly, the defendants filed an extensive Principles of Law Memorandum. Both parties submitted lengthy written closing submissions. I have relied on the law contained in all the materials filed by the parties.
[10] The structure of these reasons is as follows. I begin with a brief discussion of the credibility and reliability of the fact witnesses. Then I consider the allegations of negligence pertaining to the pyridoxine trial and treatment. In doing so, I set out the positions of the parties on this issue, the facts concerning Skyler’s treatment, the evidence of the expert witnesses generally, the law on standard of care, my findings on the standard of care, and conclude with my analysis on whether there was a breach of the standard of care.
[11] In the next section of these reasons, I address the issue of informed consent. In doing so, I set out the positions of the parties on this issue, the law of informed consent and the relevant facts and findings. I conclude this section with my analysis of the issue, including whether the plaintiffs would have conducted themselves differently if, as they assert, they would have had they been provided with the appropriate treatment options and been apprised of the relevant risks and benefits.
[12] In the final section of these reasons, I address causation with respect to both the pyridoxine trial and treatment, and informed consent. I then set out the positions of the parties on this issue, followed by a discussion of the law, the facts, expert opinions, and my analysis of causation.
[13] As set out in detail in these reasons, I conclude that the defendants breached the standard of care in their treatment of Skyler and breached their duty to inform Skyler’s parents. I find that these breaches caused or contributed to the significant brain injury Skyler suffered and the intellectual and developmental delay and the developmental challenges she currently faces.
B. THE FACT WITNESSES – CREDIBILITY AND RELIABILITY
[14] Jennifer was Skyler’s primary contact with the physicians. She was an honest and forthright witness. Her evidence in chief was not undermined in cross-examination. Jennifer readily admitted things that were contrary to her interests. There are a number of examples of her doing so. She acknowledged that she could not recall every conversation with the physicians or details of every conversation. She does not recall specific conversations with doctors in May 2003 other than conversations about giving Skyler medication. She conceded that she does not recall the specific details of the timing of the medications given or the dosage. She acknowledged that she could not recall which doctor discussed B6 with her, but she believed it was Dr. Meaney. She acknowledged that she relied on the physicians and followed their advice.
[15] Jennifer remembered the conversations that stuck in her head. These memories were the kinds of details one would expect a parent in her situation to recall. She remembered those conversations even where they seemed to potentially undermine the claim. By way of example, Jennifer admitted that Dr. Meaney told her that he had concerns with neuropathy related to high doses of pyridoxine which he said could cause things like incontinence and trouble walking. She acknowledged that this concerned her. She admitted that she did not wean Skyler off pyridoxine or the ketogenic diet without Dr. Meaney’s recommendations. I found Jennifer’s evidence to be credible and reliable.
[16] Jeff did not recall many details of the events concerning Skyler’s medical interventions in 2003. Jennifer was home with Skyler while he was at work much of the time. He would sometimes attend doctor appointments. Jeff was not cross-examined.
[17] Dr. Meaney conceded that medical records should contain all clinically relevant information and should allow physicians to discern the medical history, treatment and other factors that impact the care of the patient. He agreed that ideally, the records should show the physician’s thought process. Dr. Meaney also agreed that it is vitally important for that medical documentation to reflect the understanding achieved by in-person communications between consulting doctors. In some cases, there are no records of important discussions between Dr. Meaney and Dr. Ronen, nor are there documents that show their thought processes. There are many things that Dr. Meaney and Dr. Ronen testified about, for which there are no notes or records. This undermines their evidence and impacts negatively on their credibility and reliability given that 21 years have passed since the primary events in issue.
[18] Dr. Meaney testified that he had some vague memories of treating Skyler but did not provide many specifics. Any specifics in his recollection were from the records and based on what would have been his usual practice. His evidence makes clear that he had no specific recollection of what he did or of discussions he had. Much of his evidence was given by using words such as “I would have”.
[19] Dr. Meaney repeatedly had difficulties directly answering questions put to him. He either could not or would not answer the question posed. He would routinely ask for clarification or provide answers that were not directly responsive to the question. On occasion he had to be asked the same question two or three times before he would answer. At times his responses gave the impression of seeking to buy time to answer the question. At times Dr. Meaney contradicted himself. At times he had to be confronted with his answers from his discovery to answer the questions put to him at trial. He would try to explain away inconsistencies in his evidence. He speculated about what other physicians might have known, might have done, or what they might have been thinking. He blamed others. These are some of the reasons I did not find Dr. Meaney’s testimony to be particularly credible or reliable.
[20] Dr. Ronen had no memory of treating Skyler nor could he recall any specific interactions with her. His evidence was based on the medical records and his habitual practice. He often testified about what he would have done or said. Notwithstanding this, he often expanded on what was in the medical records and appeared to be speculating. At times Dr. Ronen refused to answer questions and had to be asked up to three times before he would answer the question directly. At times his evidence was internally inconsistent. It was apparent from observing his testimony and considering it in its totality that he had very little recollection of what occurred and that at times he was reconstructing what he had come to believe had occurred 21 years earlier. On one occasion he modified his evidence based on evidence he had heard earlier in the trial from an expert who testified before him. These are some of the reasons that I did not find Dr. Ronen’s testimony to be credible or reliable.
C. PYRIDOXINE EMIPRICAL TRIAL AND TREATMENT
1. Positions of the Parties
[21] The plaintiffs allege that the defendants failed to properly conduct a pyridoxine empirical trial, failed to recognize and document the effect of the pyridoxine and failed to reinstate pyridoxine when Skyler’s seizures returned. The defendants submit that they met the standard of care and that they exercised their clinical judgment in assessing the effect of pyridoxine and in treating Skyler’s seizures. The defendants submit that they therefore cannot be held liable.
2. Pediatric Neurology at MCH
[22] MCH was a quaternary hospital facility in 2003. The pediatric neurology department had two physicians, Dr. Meaney and Dr. Ronen. They had a rotating call schedule of a week on and a week off. Handover typically occurred on Monday morning unless it was a holiday. At handover, it was their practice to meet in person. They would review a list of patients and discuss them one by one. Dr. Meaney testified that notes were not made of the handover.
[23] Dr. Ronen and Dr. Meaney often had residents working with them. Sometimes the resident would make the notes in Skyler’s chart. However, the notes reflected the views of Dr. Ronen and Dr. Meaney. Dr. Meaney acknowledged that he was responsible for the choice of antiseizure medication, not the resident.
[24] Pediatric neurology acted as a consulting service to pediatrics or the Pediatric Intensive Care Unit (“PICU”). One physician at MCH was designated as the Managing Responsible Physician (“MRP”). At the relevant times in 2003, neither Dr. Meaney nor Dr. Ronen were the MRP; Dr. Lloyd was the MRP. All orders and care decisions went through the MRP. Informed consent for treatment went through the MRP. MCH had a policy that only the MRP made the actual orders. In part this was for reasons related to consistency in messaging and internal hospital policy.
[25] Both Dr. Ronen and Dr. Meaney testified that they did not make any orders. By way of example, they testified that they did not order that the pyridoxine trial be undertaken, they did not order that Skyler be administered pyridoxine, they did not order that the pyridoxine be stopped, and they did not order that Skyler be given phenobarbital. They say that they simply made recommendations. The MRP could follow pediatric neurology’s suggestion or not. Dr. Ronen testified that usually the MRP followed his recommendation because he was more knowledgeable. However, the MRP made the final choice of orders to be made.
[26] There is no evidence before me that the suggestions made by Dr. Meaney or Dr. Ronen were not followed by the MRP. The decisions of Dr. Ronen and Dr. Meaney regarding Skyler’s treatment for her seizures, including the selection of medication and the use of pyridoxine, were implemented. The other physicians relied on their suggestions and implemented them. It was for internal policy reasons that orders were made by the MRP and not the defendants. I find that it was the defendants who made the decisions as to Skyler’s treatment which were then incorporated into orders by the MRP.
3. Skyler’s course of treatment
April 2003
[27] On April 4, 2003, Skyler had two episodes of jerky movements. Skyler was taken to the Greater Niagara General Hospital (“GNGH”). The emergency physician assessed Skyler and discharged her with a referral to a pediatrician. On April 7, 2003, a pediatrician assessed Skyler. The pediatrician’s impression was that Skyler had likely experienced benign myoclonic jerks. In late April 2003, Skyler experienced similar jerking episodes for about half an hour.
May 9-10, 2003
[28] On Friday, May 9, 2003, Skyler was taken to GNGH in status epilepticus. At this time, Skyer was four and a half months old. Among other treatments, Skyler was given multiple doses of benzodiazepines, Dilantin (an anti-epileptic) and phenobarbital, and was intubated to try to control her seizures. Skyler’s last seizure that day was recorded at around 19:27.[^1] Skyler was transferred to MCH.
[29] Skyler arrived at MCH shortly before midnight. She was admitted to the PICU by Dr. Lloyd. Dr. Lloyd ordered, among other things, that Skyler be started on IV Ativan (a benzodiazepine) every hour as needed. A CT scan was performed around 02:30 on May 10, 2003. Skyler had no documented seizures overnight.
[30] Sometime before 10:40 on May 10, 2003, Dr. Meaney recommended an electroencephalogram (“EEG”) and an MRI. At or around 10:40, an order was written that Skyler be started on phenobarbital 16 mg twice a day until further evaluation. Skyler was extubated around 22:50.
May 11, 2003
[31] Around 11:30 on May 11, 2003, the PICU resident observed in Skyler an approximately 20-30 second episode of right head deviation and gaze deviated to the right with slight nystagmus. These symptoms may have represented a seizure episode.
[32] Sometime before 12:00 on May 11, 2003, Dr. Meaney assessed Skyler. When he was first consulted about Skyler, Dr. Meaney reviewed the existing documentation from GNGH and from MCH. He obtained a first-hand history from Skyler’s parents, conducted a physical exam of Skyler and reviewed available laboratory assessments. Dr. Meaney’s May 11 note states that Skyler was a healthy-appearing four-month-old who was developmentally normal and who had some brief and some prolonged episodes of seizures. She had no convincing history of fever, lethargy, or encephalopathy prior to admission. She had normal responsiveness between seizures. Dr. Meaney’s examination notes indicate Skyler had a head circumference of 41 cm and that she was a large baby.
[33] Dr. Meaney’s initial impression of Skyler reflected in his note was that given her repeated seizures and otherwise normal health and development the “biggest” likelihood was of a focal dysgenetic cortical lesion. He based this on the fact that 50 percent of babies presenting as Skyler did would have focal cortical dysplasia. Focal seizures, without impairment in responsiveness or encephalopathy, suggested seizures from one part of the brain. There was no evidence of infection or metabolic abnormality based on the available basic metabolic investigations.
[34] Dr. Meaney recommended that phenobarbital be kept at a therapeutic level with Ativan to be provided if there were breakthrough seizures because he understood that when he first saw Skyler that she had received a loading dose of phenobarbital at GNGH. A loading dose or bolus was described as a one-time large dose of medication that will rapidly get the concentration of medication in the patient to a therapeutic range.
[35] Dr. Meaney was confronted with the PICU note of May 10 at 00:15 and the May 10 PICU admission note of 04:15. These notes do not indicate that Skyler had received phenobarbital. Dr. Meaney sought to explain this by saying that from time to time the doctors who transcribe what happened at another hospital do not do so with perfect accuracy because often the records are incomplete from another hospital. Dr. Meaney explained that because of this, it is possible that phenobarbital was not listed. He then speculated that he might have had a conversation with the intensive care physician at the time who may have told him that Skyler had received phenobarbital. He eventually agreed there was a “cloudiness about it”. Dr. Meaney then testified that he does not necessarily believe everything second or third hand that is written in a record is true.
[36] At or around 16:35, Skyler was noted to be crying, agitated, to have stiff legs, and to have eyes that deviated upward. Skyler was given an intravenous dose of 0.5 mg Ativan. Due to ongoing potential seizure symptoms, a further 0.5 mg dose of intravenous Ativan was given at 18:45 and another at around 18:55.
[37] At 19:10 on May 11, Dr. Meaney was consulted. He suggested STAT (meaning expedited turnaround time or immediately) phenobarbital levels and an additional half loading dose of phenobarbital. There is no indication in the records of when the phenobarbital level became available. Dr. Meaney could not say when it was received. He testified that the phenobarbital level he had ordered STAT could be useful to understand how close Skyler was to the supratherapeutic range to anticipate possible complications. He knew that Skyler would receive the half-load of phenobarbital, but if further successive full loads were to be given one after the other, he wanted to have the level. However, Dr. Meaney testified that it turned out that the phenobarbital level report was not important in the end, because the seizures later stopped. He said that the fact that a further full load of phenobarbital was given was not concerning to him.
[38] At around 20:30 Skyler had continued seizure activity. Skyler was given phenobarbital and three doses of Ativan (0.5 mg, 0.5 mg and 1 mg) at three to four minute intervals, and another loading dose of phenobarbital (two 10 mg/kg doses, 25 minutes apart). After 12 to 15 minutes of continued seizure activity, the decision was made to intubate Skyler using propofol. The purpose of the intubation was to control Skyler’s airway in the face of medications which could suppress her respiratory drive. Propofol was used to sedate her during intubation. Propofol was administered at 20:50 and 20:55. Phenobarbital was administered at 20:55. After the intubation, Skyler’s seizure activity stopped.
[39] At or around 21:30, Skyler received a dose of intravenous Ativan (1 mg). At or around 22:00, Dr. Lloyd noted that Skyler was deeply sedated and not experiencing seizures at that time.
[40] Dr. Lloyd and Dr. Meaney discussed Skyler’s case. They were going to treat her empirically for pyridoxine deficiency and possible herpes simplex virus (HSV) encephalitis even though both were unlikely. Dr. Lloyd recorded that the plan was to manage further seizures with more phenobarbital and a Versed infusion if necessary. Dr. Meaney testified that although encephalitis was quite unlikely because its clinical features such as fevers and a markedly decreased responsiveness were not present, Skyler was treated empirically for it because in the rare possibility that it was encephalitis, the treatment could be lifesaving.
[41] With respect to the pyridoxine empirical trial, Skyler had experienced recurrent episodes of seizures which appeared to have been occurring despite having been treated with the normal medications to control them. Dr. Meaney’s concern was that she might continue to have more seizures and not respond to the normal medication. He testified that he was still operating under the understanding that Skyler’s phenobarbital level was likely in the high therapeutic range. Dr. Meaney recommended 100 mg of pyridoxine twice a day, a dosage which was commonly referred to in the literature at the time, as it might have been the intervention that allowed the seizures to stop.
[42] Dr. Meaney believed at the time that it was unlikely that Skyler had PDE because it was exceedingly rare, especially a presentation at over four months of age. In his view, a presentation at that age would be an atypical variant of the baseline position. An empirical trial of pyridoxine was undertaken as there was not yet definitive proof of a condition and the pyridoxine might have stopped the seizures.
[43] Running the pyridoxine trial was within Dr. Meaney’s domain. He testified that diagnosing pyridoxine in 2003 required a trial of pyridoxine, with the hope that there would be a clear signal emerging that indicated there was a response to pyridoxine. He would be looking for a complete absence of the seizures while Skyler was on the pyridoxine. Typically, it would then involve withdrawing the pyridoxine and seeing whether the seizures reoccurred and whether the patient would again not be responsive to the usual anti-seizure medications. And then when the pyridoxine was re-instituted, the seizures would go away again. Dr. Meaney testified that ideally, the cessation of seizures would occur with pyridoxine as the only intervention to which one might attribute cessation of seizures. Dr. Meaney acknowledged that he was required to conduct the pyridoxine trial appropriately and that the incidence of PDE and its rarity is irrelevant to conducting a proper pyridoxine empirical trial.
[44] Dr. Meaney estimated it would have taken between ninety minutes and three hours for the pyridoxine to be at a sufficient serum level to have effect. He determined three days to be a reasonable period to administer the pyridoxine. Enough time was needed to observe how Skyler would react to the pyridoxine, then withdraw it and observe how she was off the pyridoxine.
[45] At or around 22:10, the PICU resident Dr. Gilleland wrote an order for pyridoxine 100 mg NG (by nasogastric tube) twice daily for three days, followed by a reassessment. At or around 22:55, Dr. Gilleland wrote an order for Ativan 1 mg q1h (every hour) for sedation, otherwise 1 mg q2h for regular dosing. At or around 24:00, Skyler was started on pyridoxine. Skyler was continued on maintenance doses of phenobarbital 16 mg, orally, twice daily and Ativan 1 mg q2h (every two hours).
[46] Although there is no evidence that both Dr. Meaney and Dr. Ronen were present at the time, both doctors testified that Skyler’s seizures stopped before the administration of pyridoxine. Dr. Meaney believes the seizures stopped post intubation (which occurred around 20:55) for three possible reasons. The first is that the load of phenobarbital which was to be administered over twenty minutes had taken effect. The second is that the propofol stopped them. The third possibility is that the seizures stopped spontaneously. In cross-examination Dr. Meaney agreed that after Skyler received pyridoxine, it was possible that it was having a contributing effect to controlling her seizures.
May 12 – 15, 2003
[47] On May 12, 2003, the PICU resident, Dr. Stephen Cheuk, noted “? Seizure activity this am 03:00 but short lived”.
[48] Dr. Ronen had previously answered an undertaking to advise of his position on whether there were seizures following the start of treatment with pyridoxine. His position was that there were seizures because according to a written note in the records there was “seizure activity” on May 12 at 03:00. At trial, Dr. Ronen testified that this was not the whole story because the medical records reflect that it was a possible seizure. Additionally, he explained that his evidence had changed because he heard Dr. Yager, the plaintiff’s expert, testify at trial that it was not a seizure.
[49] Dr. Meaney testified that he did not have “a strong position” about whether Skyler had a seizure at 03:00 on May 12. He agreed that the resident’s note does not contain enough information to determine this one way or another. He agreed that if it was a seizure it occurred in the face of all the medication that Skyler had received prior to that time.
[50] I find the evidence is inconclusive as to whether Skyler had a seizure at 03:00 on May 12.
[51] An EEG on May 12, 2003 showed no evidence of active seizures.
[52] Dr. Meaney handed over care to Dr. Ronen in the morning on May 12, 2003. There are no notes of the handover. Dr. Meaney testified that he did not know exactly when the STAT phenobarbital levels he had ordered came back, yet he is certain it was prior to handover to Dr. Ronen.
[53] Skyler’s phenobarbital level at 19:00 on May 11 was 25, below the reference or therapeutic range. When he received the result, Dr. Meaney testified that it was a moment of revelation; it was not that Skyler was not responding to the therapeutic phenobarbital and was not responding to the normal medication, it was that she was not getting the normal medication.
[54] Dr. Ronen testified that he and Dr. Meaney most likely did not discuss PDE at the handover. He has no recollection of discussing it. He believes that Dr. Meaney would have told him that Skyler was referred from GNGH and that they tried to abort her seizures but were unsuccessful. Dr. Ronen testified that he was probably told how Dr. Meaney was able to abort the seizures, what was done to investigate the underlying causes, about Dr. Meaney’s interactions with the family, and what Dr. Meaney expected would happen the week Dr. Ronen was on service.
[55] Dr. Meaney believes that during handover to Dr. Ronen he would have focused on Skyler’s focal seizures and lack of encephalopathy, and that a focal anatomic cortical lesion was most likely. Dr. Meaney testified that he would have spoken to Dr. Ronen about the pyridoxine. He testified that he would have indicated to Dr. Ronen that he had started it because he understood that she was having seizures despite the full therapeutic or high phenobarbital level. He testified that he would have told Dr. Ronen that it turned out GNGH did not give a phenobarbital load and Skyler was markedly subtherapeutic on phenobarbital. At discovery almost seven years earlier, Dr. Meaney testified he told Dr. Ronen only that he had started the pyridoxine trial. Dr. Meaney explained the difference in his evidence by saying that the case was not as fresh at discovery. However, he says that in preparing for trial, he did a deeper dive and saw the phenobarbital level. When seeing this, he remembered how unusual the level was which rekindled the realization that this was a very important result. He understood he had an obligation to correct his discovery answers, but he did not do so.
[56] Despite Dr. Meaney’s asserted revelation on receiving the phenobarbital level, he did not suggest that the pyridoxine be immediately stopped. The pyridoxine trial continued.
[57] There is nothing in the resident’s May 12 note about pyridoxine.
[58] Dr. Ronen could not recall the discussion with Skyler’s parents on May 12. He described his usual practice was to inform the family about the current condition. Dr. Ronen explained that he would have told them the seizures were fully controlled, that Skyler was significantly sedated and that the hope was to get her out of sedation. He would have told them that he still did not know the exact underlying mechanism and why he thought it was probably focal cortical dysplasia. There is no evidence of a discussion about PDE and the pyridoxine trial.
[59] Both doctors appeared to be speculating as to what they would have discussed at handover. They gave contradictory evidence as to whether they discussed PDE. Despite the passage of 21 years and the lack of notes, Dr. Meaney’s evidence at trial about his discussion with Dr. Ronen regarding the pyridoxine trial expanded considerably.
[60] Dr. Ronen’s assumption at the time was that it was extremely unlikely Skyler had PDE because in 2003 PDE was thought to be a metabolic condition. If Skyler had PDE, he said her seizures would be generalized. This would suggest that the seizures arise from many different areas in the brain. Skyler’s seizures were different. They started with a specific area of the brain. He does not remember the area. He testified that it was only later when Skyler was very sick that she had secondary generalized seizures (i.e., from both sides of the brain). At the time, Dr. Ronen was not aware of any known metabolic condition that had Skyler’s presentation. He felt the most likely underlying cause after the normal CT scan was focal cortical dysplasia. He felt PDE was an extremely remote possibility that did not come close to needing his closer consideration.
[61] Dr. Ronen suggested an MRI and a metabolic screen on May 12. He testified that even though he did not think Skyler had an underlying metabolic disease, he ordered a metabolic screen because he tended not to leave a stone unturned when there was a patient with undiagnosed abnormalities and seizures.
[62] Skyler was continued on maintenance doses of phenobarbital 16 mg PO (orally) bid (twice a day) and Ativan 1 mg q2h and pyridoxine 100 mg bid.
[63] On May 13, 2003, an MRI of Skyler’s head was performed. The MRI revealed no focus of abnormal signal intensity to account for a seizure focus. At or around 16:30 the standing order for Ativan was discontinued. Skyler remained on phenobarbital and pyridoxine.
[64] On May 14, 2003, Skyler was extubated without complication. At or around 13:30, Dr. Lloyd wrote an order to continue pyridoxine.
[65] On May 15, 2003, Skyler’s phenobarbital dose was reduced. At around 16:00 she was transferred from the PICU to the pediatric medicine floor. She continued to receive phenobarbital and pyridoxine.
[66] There is nothing in the neurology notes of May 13, 14 and 15 about pyridoxine.
May 16 – 19, 2003
[67] On Friday, May 16, 2003 at or around 16:00, Dr. Nakhla, the pediatric neurology resident, wrote an order with instructions to (1) discontinue pyridoxine, (2) if Skyler had a seizure over the weekend, to restart pyridoxine at 100 mg bid, (3) start the anti-convulsant medication Trileptal (oxcarbazepine) 40 mg bid, (4) wean the phenobarbital dose by 2 mg daily and discontinue phenobarbital after May 21, 2003.
[68] On May 16 at 16:00 the PICU resident Dr. Gilleland wrote that neurology suggested that the pyridoxine be discontinued and if seizures resume over the weekend, the pyridoxine was to be restarted at 100 mg PO (by mouth).
[69] Dr. Ronen testified that on May 16 he suggested that Skyler be weaned off phenobarbital and put on Trileptal because it was clear that phenobarbital was impacting her level of consciousness. He decided to switch a sedative antiseizure medication (phenobarbital) to a non-sedative antiseizure medication, Trileptal.
[70] Even though, as set out in the ASF, his resident wrote the order, Dr. Ronen denied that he made the decision to stop the pyridoxine. He said it was a recommendation only. He testified that he expected his recommendation to be followed because he was more knowledgeable, but it was the MRP who decided to stop the pyridoxine. He thought that if Skyler had PDE, the seizures would reappear.
[71] Dr. Ronen was taken to his answers at his discovery in August 2017, where he was asked why he stopped the pyridoxine trial. Those answers were somewhat different than his answers at trial. He testified that he provided additional evidence at trial and that he did not change his mind, he just expanded it. He was asked if he was telling the truth at his discovery; he answered: “I told them that was my impression at that time. Is that the truth, I don’t know what truth is but that was my impression at that time.” When asked if he understood that he had an obligation to update his answers, he said that that “the discoveries happened in 2017. And now it is now a number of years later and thinking about those questions I think I have a better answer than I gave in 2017.”
[72] Skyler was started on Trileptal and the phenobarbital was weaned.
[73] Dr. Ronen testified that he kept Skyler in the hospital over the May 2003 long weekend because she was still at higher risk of developing seizures and he did not want her to be in the community on the weekend in the event the seizures returned. Although he did not believe PDE was a diagnosis, he still took the diagnosis seriously and testified he did not want to leave any stone unturned. He suggested waiting several days to see if the seizures returned from pyridoxine dependency or perhaps due to the reduction of the phenobarbital. He chose this length of time because in his view pyridoxine-dependent seizures tend to recur shortly after withdrawal. However, he acknowledged that seizures could recur later.
[74] Dr. Ronen testified that he would likely have discussed with Skyler’s parents why he discontinued the phenobarbital and introduced a non-sedative antiseizure medication. He testified that he probably would have discussed the fact that he stopped the “vitamin” but put this “order” in place in the remote possibility that seizures would recur. Jennifer testified that such a discussion never occurred. No one spoke to her about discontinuing the pyridoxine. I accept her evidence.
May 20, 2003
[75] Dr. Ronen testified that when he handed over to Dr. Meaney on May 20, 2003, he would have discussed the plan he set out on May 16. He would have told Dr. Meaney that Skyler was improving, that she was still sedated and overreacting to the phenobarbital with excessive somnolence, that he decided to start the Trileptal, that he stopped the pyridoxine on Dr. Meaney’s direction but kept Skyler in hospital for observation and that she was ready to be discharged. None of this is recorded anywhere.
[76] Dr. Meaney testified that he would have spoken with the family at discharge but has no specific recollection of that discussion. He agreed that Jennifer would have understood that he had told her that the pyridoxine did not work.
[77] Jennifer’s unchallenged evidence is that she was told that the B6 did not work. She understood that B6 was a vitamin. Jennifer testified that if she had been told about the pyridoxine trial, she would have put Skyler back on the B6 right away at her next seizure and that if she had been told that Skyler’s seizures stopped on the B6, she would have insisted that the doctors keep Skyler on the B6. This evidence was not challenged in any significant way.
[78] Dr. Meaney was asked about Skyler being started on Trileptal at the time of discharge. He testified that phenobarbital is known to have an adverse impact on cognition if a patient is on it long term. If it is possible to get the patient on different medication, that would be better. Dr. Meaney was of the view that since the phenobarbital had worked to urgently control Skyler’s seizures, it would be beneficial if it could be held in reserve in the event there were flare ups. Dr. Meaney’s reason for switching phenobarbital for Trileptal differed from Dr. Ronen’s explanation.
[79] At about 18:00 on May 20, 2003, Skyler was discharged from MCH on Trileptal 40 mg bid, with instructions to continue to wean the phenobarbital dose and discontinue the phenobarbital after May 21, 2003. When Skyler was discharged, Dr. Meaney and Dr. Ronen did not have a diagnosis for the cause of her seizures.
[80] Dr. Meaney was of the view that the pyridoxine did not control the seizures primarily because the seizures stopped before pyridoxine was started. Dr. Meaney believed that the already low likelihood of PDE was diminished further by the late onset and diminished even further by Skyler’s response to phenobarbital. Finally, when pyridoxine was stopped the seizures did not rebound.
[81] There is nothing in the medical records reflecting an evaluation of the pyridoxine trial or a consideration of why the seizures stopped.
May 26 – July 6, 2003
[82] Skyler remained seizure free until the evening of May 26, 2003. Dr. Meaney was consulted when Skyler attended the ER at GNGH when she had a grand mal seizure (a seizure that involves the whole body) lasting six minutes. Dr. Meaney doubled the Trileptal dose to see if a higher dose would control the seizures. He did not restart pyridoxine because he felt that a single seizure 10 days later did not set off robust flags that it was a bad rebound from stopping pyridoxine. He said he thought it was from stopping the phenobarbital, but he did not start Skyler on phenobarbital. He testified that he could have restarted the phenobarbital but was not prepared to abandon the Trileptal yet.
[83] On May 28, 2003, Dr. Ronen was consulted by the physician at GNGH. He suggested an increase to Skyler’s dose of Trileptal to 80 mg tid (three times a day) because the medication was not controlling her seizures at the prior dose. He testified he did not suggest pyridoxine because Skyler’s initial seizures stopped with phenobarbital prior to receiving pyridoxine. Secondly, pyridoxine was given and discontinued, and no seizures occurred in the short period after it was discontinued. Finally, the clinical impression was of focal onset seizures.
[84] According to Jennifer, Skyler had a few seizure-like episodes on May 30 and 31, 2003.
[85] On June 2, 2003, Skyler arrived at GNGH at or around 03:36 in status epilepticus. She was given midazolam, phenobarbital and Dilantin. She was transferred to MCH around 10:57. Skyler had been given a phenobarbital load. Dr. Lloyd noted that Skyler had a fever. Dr. Meaney was on call. Around 17:50 Dr. Meaney ordered that Trileptal be increased to 100 mg tid and to start clobazam (an antiseizure medication) 2.5 mg PO bid. Dr. Meaney wanted to give the Trileptal a further chance at the maximal dose to see if Skyler would respond. He thought the clobazam might help.
[86] On June 5, 2003, Skyler had further seizures. Dr. Meaney testified he ordered a phenobarbital 20 mg/kg load and maintenance dose because it seemed to work for her.
[87] On June 6, 2003, Skyler had further seizures. In addition to Ativan, Skyler was given a loading dose of phenobarbital 140 mg over 20 minutes and given maintenance phenobarbital. Dr. Meaney testified that he felt the Trileptal was not working and was hoping to adjust the phenobarbital for Skyler’s size and weight. Dr. Meaney believed that phenobarbital on its own would work. He did not start pyridoxine because he felt that Skyler’s course continued to be in keeping with a child who had a diagnosis that was more likely something other than PDE. On June 8, 2003, Skyler’s phenobarbital dose was increased to 17 mg bid and the clobazam was discontinued. Trileptal was discontinued on June 9, 2003. Skyler was seizure free from June 7 to June 11, 2003. She was discharged from MCH on June 11, 2003, on 17 mg phenobarbital bid.
[88] Skyler had seizures on June 12, 2003, and was brought to GNGH. She had seizures on June 14, 2003. Dr. Meaney was contacted by the GNGH pediatrician on June 15, 2003. Dr. Meaney recommended an increase in phenobarbital. No further seizures were reported until June 24, 2003.
[89] Dr. Meaney saw Skyler at his clinic on June 24, 2003, and recommended giving Skyler a 50 mg dose of phenobarbital that day, and then an increase in Skyler’s maintenance dose of phenobarbital to 23 mg bid. Dr. Meaney was trying to be proactive to ensure the phenobarbital stayed in the therapeutic range. According to Jennifer, on the way home from the appointment, Skyler started seizing again.
[90] On June 24, 2003, Skyler was admitted to MCH and seen by Dr. Ronen who was on service. He started Skyler on Topamax at a dose of 15 mg od (once a day) for three days at bedtime, then increased to 30 mg od for 5 days. She was continued on phenobarbital at a dose of 19 mg PO bid. Dr. Ronen noted that the preference is to keep a patient on monotherapy for continuing seizures but sometimes seizures continue despite good levels of medication. Another drug is added in such a case. Topamax was such a drug. Dr. Ronen noted that Topamax was probably one of the most powerful antiseizure medications at the time.
[91] Dr. Ronen said that he did not restart pyridoxine during this hospital admission because: 1) the seizures stopped before Skyler received pyridoxine; 2) the seizures did not exacerbate in the short period following the discontinuation of pyridoxine as one would expect; and 3) the focal appearance of seizures was not compatible with a generalized metabolic condition.
[92] On June 25, 2003, Dr. Ronen referred Skyler to Dr. Mark Tarnopolsky at the Neuromuscular & Neurometabolic Clinic for a consultation because her seizures became difficult to control. Dr. Ronen began to think that maybe there was an underlying degenerative disease causing an increase in severity. He considered other conditions and needed Dr. Tarnopolsky to test to see if there were indirect markers of those conditions. Dr. Ronen testified that there was no evidence from Dr. Tarnopolsky’s investigations and assessment that Skyler had a metabolic or degenerative disease.
[93] Skyler had no further seizures during this admission and was discharged on June 27, 2003, on phenobarbital (19 mg PO BID) and Topamax (15 mg PO BID), and rectal Ativan (1 mg) as necessary.
[94] According to Jennifer, on June 30, 2003, Skyler experienced three seizure episodes at home. She was brought to the GNGH emergency department. Dr. Meaney was consulted by the GNGH pediatrician on July 1, 2003 and Dr. Meaney decided to give a bolus of phenobarbital 40 mg PO that day, followed by an increase in the daily dose of phenobarbital to 22 mg twice a day and an increase in Topamax to 30 mg x 2 at bedtime and 15 mg x 1 in the morning. Dr. Meaney felt the phenobarbital was still producing an effect but was not as optimally effective on its own, so the Topamax was increased.
[95] At no time during the stays at GNGH at the end of May and in June, and the two stays at MCH (10 days in early June and 3 days in late June) did Dr. Meaney and Dr. Ronen discuss with Jennifer the possibility of putting Skyler back on pyridoxine. Dr. Meaney testified that he was still of the view that the likelihood that Skyler had PDE was still extremely low because of its extreme rarity, the presence of multiple rare features, the late onset at four months old, seizures that responded to and were controlled by traditional antiseizure meds, and the absence of dramatic recurrence of seizures when pyridoxine was stopped.
[96] There is nothing in the medical notes regarding pyridoxine between May 26 and July 6.
July 6, 2003 - Admission to MCH
[97] On July 5, 2003, Skyler was seizing and was brought by ambulance to GNGH. She was given the following intravenous medications between 04:52 and 05:18: Ativan (0.75 mg), Ativan (0.4 mg), phenobarbital (22.5 mg) x2, and Dilantin (125 mg).
[98] Jennifer described Skyler’s seizures on July 5 and 6, 2003, as clusters of seizures which would not stop.
[99] On July 6, 2003, Dr. Meaney was consulted. He recommended increasing the phenobarbital and Topamax. Dr. Meaney advised the GNGH physician that the plan was to wean Skyler off phenobarbital as she was not responding and to put her on valproic acid.
[100] In the morning of July 6, 2003, Skyler experienced seizures and developed status epilepticus. A decision was made to transfer her to MCH. At or around 14:10, Skyler was transferred to MCH in status epilepticus. She was started on a midazolam infusion. Dr. Meaney assessed Skyler. He recommended stopping phenobarbital, maintaining Topamax and starting valproic acid later in the week.
[101] Dr. Meaney acknowledged that Skyler was in status epilepticus. Skyler had refractory epilepsy of infantile onset. Dr. Meaney also noted that a diagnosis had not yet been established and thus far Skyler has been keeping up developmentally. Dr. Meaney felt that historically, Skyler had responded to phenobarbital monotherapy, but her seizures were beginning to have a different complexion. She was having more seizures which required more treatment. Dr. Meaney’s July 6, 2003 note states “Pheno and Topamax have been insufficient to control her epilepsy.” He wanted to start valproic acid, but Skyler needed to be weaned off phenobarbital first. According to Dr. Meaney, valproic acid is one of the strongest antiseizure medications which has potential side effects in children under the age of two.
[102] Dr. Meaney handed off to Dr. Ronen on July 7, 2003. In the morning of July 7, 2003, Skyler was seen by Dr. Ronen and an EEG was completed. That afternoon, due to repeated breakthrough seizures, Dr. Ronen and Dr. Meaney made the decision to initiate a pentobarbital coma titrated to EEG burst suppression/silence for five to six days. The idea was to put Skyler’s brain at rest for a few days with the hope that when she came out of the coma she would no longer be in a cycle of seizures. Dopamine was used proactively to ensure that there would be no issues with heart function and blood pressure. Dr. Snead described a pentobarbital coma as a last resort to stop the seizures.
[103] Skyler’s parents were updated with the current plan of care. Jennifer testified that Skyler was put into a drug induced coma because Skyler’s seizures could not be controlled.
[104] Dr. Ronen testified that he recommended the pentobarbital coma because Skyler had recurrent seizures. Dr. Ronen assumes that Skyler had recurrent episodes of status epilepticus that did not respond to the medications she was given. Dr. Meaney had a much harder time admitting that Skyler was in status epilepticus at the time. He did acknowledge that the decision to induce a pentobarbital coma had to do with the frequency and unresponsiveness of Skyler’s seizures.
[105] When Skyler was put into the pentobarbital coma, pentobarbital was titrated to eliminate all seizures and Skyler was on continuous EEG monitoring at her bedside. In 2003, Dr. Meaney knew that pyridoxine could be administered intravenously and that a child with PDE should respond within seconds or minutes to pyridoxine administered intravenously if they were having ongoing seizures. Dr. Meaney acknowledged EEG monitoring with pyridoxine could have been done in 2003.
[106] On July 7, 2003, Dr. Tarnopolsky assessed Skyler. As part of his history, Dr. Tarnopolsky documented “pyridoxine trial with last admission Ø help”. Dr. Meaney testified that he did not think that Dr. Tarnopolsky got this information from him because he was not on call. Dr. Ronen does not know the source of Dr. Tarnopolsky’s comment in his report that Skyler was tried on pyridoxine with no clear benefit.
[107] On July 8, 2003, at or around 14:00 Skyler was started on folinic acid 5 mg bid and creatine.
[108] On July 11, 2003, Skyler was extubated and started to be weaned off pentobarbital. She was started on a 3.5:1 ketogenic diet (1/3 strength). Dr. Ronen testified that it was his experience that many patients without diagnosed metabolic diseases responded well to the ketogenic diet. Dr. Ronen would not agree that the ketogenic diet would not kick in for a couple of weeks. However, he acknowledged that he wrote the note of July 17, 2003, which stated, “Ideally we would like to wait a few weeks until the ketogenic diet clicks in.”
[109] Dr. Meaney acknowledged that when Skyler was taken out of the pentobarbital coma, her seizures came back.
[110] On July 14, 2003, at or around 15:30, the PICU resident noted that an EEG done that day was showing cortical electrical activity. The PICU resident noted that Dr. Ronen had been consulted and his plan was to: (1) treat clinical seizures by starting Skyler on vigabatrin 100 mg/kg/day x 2 doses/day, (2) discontinue the pentobarbital drip now; (3) hold all benzodiazepines; (4) perform a follow-up EEG; and (5) continue the ketogenic diet.
[111] The medical record indicates Skyler was having seizures on July 15, 2003. On July 15 at or around 02:00, the PICU physicians noted that Skyler continued to have seizures. She was given a dose of valproic acid and additional pentobarbital. She still had continuous seizure activity. Further doses of pentobarbital were given, and a continuous infusion of pentobarbital was started. The seizures settled with the increased pentobarbital. The ketogenic diet was held. At or around 08:00, the PICU physician, Dr. Writer, wrote an order to continue valproic acid 75 mg IV q6h and start a gradual weaning of the pentobarbital over the next three days. That day, Dr. Cheuk wrote an order to increase the dose of valproic acid to 150 mg q6h. At or around 13:05 the ketogenic dietitian wrote an order to start the ketogenic diet at 2/3 strength via NG tube.
[112] There is nothing in the medical notes regarding pyridoxine from July 6 to July 15, 2003.
July 15, 2003 meeting
[113] On July 15, 2003, a family meeting was held with Dr. Ronen, Dr. Writer, a social worker, and a dietician. Dr. Ronen informed Skyler’s parents that valproate was added due to emergence of the seizures.
[114] Jennifer recalls Dr. Ronen telling her at the meeting that Skyler would likely have seizures for days, weeks, or months and die. Jennifer provided him with a list of medications that she had researched. Dr. Ronen checked off the list and said there were no other drugs to try. She asked him about trying B6 and he responded by saying “it would not hurt”. She said she raised trying B6 because it was the only thing the doctors had not tried. She does not recall any other specifics of advice given to her at the meeting.
[115] Jeff recalls a meeting where he was told by Dr. Ronen that Skyler may not make it. None of the medications were working. He recalls Jennifer asking Dr. Ronen about putting Skyler back on B6. Dr. Ronen said it would not hurt.
[116] Dr. Ronen could not recall this discussion with Jennifer. He testified that he could neither confirm nor deny the conversation. He agreed that it could not have hurt to have tried Skyler on pyridoxine for the short term. Dr. Meaney also agreed that at this time in July 2003, it could not have hurt to have tried pyridoxine.
[117] On July 16, 2003, the ketogenic diet was advanced to a 4.5:1 ratio. At or around 10:00 on July 16, 2003, the first dose of pyridoxine 200 mg was given. Jennifer testified that after the B6 was started, Skyler’s seizures stopped. This evidence is uncontradicted.
[118] Dr. Meaney would not acknowledge that the pyridoxine is what stopped the seizures. He was prepared to agree that the only new agent added between July 15 and July 16 was the pyridoxine. However, he testified that it was “biologically plausible” that some of what had been added in the preceding days, such as ketosis, the valproic acid, the creatine, and the folic acid were beginning to have effect. He described it as a cloudy picture.
[119] On July 18, 2003, Skyler was fully weaned from the pentobarbital and at or around 18:00 on July 19, 2003, Skyler received her last dose of Topamax.
[120] Jennifer recalls the discussion referred to in a PICU note dated July 18, 2003, which states: “Parents have been regularly updated re: Skyler’s status including being prepared to anticipate/expect the low likelihood of return to previous state of neurological function and sequelae secondary either to seizures or prolonged periods of necessary coma.” Jennifer testified that Dr. Meaney told her at some point in July 2003 that Skyler had suffered a severe insult to her brain.
After August 11, 2003
[121] Skyler was discharged on August 11, 2003, with the plan to continue medications and supplements including pyridoxine (200 mg twice a day), folinic acid (5 mg twice a day), vigabatrin (250 mg twice a day), and valproex (125 mg every 8 hours). She remained on the ketogenic diet.
[122] On December 17, 2004, Dr. Meaney saw Skyler at a clinic appointment. Dr. Meaney noted that Skyler had no seizures since starting the ketogenic diet in July 2003. At that time, she was on a protocol that included pyridoxine, folinic acid and maintaining the ketogenic diet. Dr. Meaney’s plan was to take away only the pyridoxine. If she remained seizure free without the pyridoxine for six months, Dr. Meaney would possibly wean the ketogenic diet.
[123] Following Dr. Meaney's recommendation on December 17, 2004, Jennifer stopped administering the pyridoxine. Six days later, Skyler had a seizure. Jennifer reinstated the pyridoxine and the seizures stopped. Dr. Meaney was aware of this.
[124] Dr. Meaney saw Skyler again on January 28, 2005. As of January 31, 2005, Dr. Meaney was still of the view that there was no strong conclusive evidence that Skyler had PDE, but he was entertaining the possibility because of the recurrence of her seizures six days after stopping the pyridoxine the month before. He still was not sure that reinstating the pyridoxine stopped the seizures because sometimes seizures stopped on their own. He was still of the view that there were many atypical features of PDE. Dr. Meaney wanted to undertake further trials of discontinuation of pyridoxine to gain diagnostic clarity about whether Skyler had PDE. Because Skyler’s parents did not want to stop the pyridoxine, he came up with an alternative approach to test if Skyler had PDE – stop the ketogenic diet to see if the seizures came back.
[125] On April 28, 2005, Skyler started to wean off the ketogenic diet, which was completely weaned by September 19, 2005. On October 6, 2005, Skyler had a seizure and was taken by ambulance to GNGH in status epilepticus. She had symptoms of a respiratory infection and a fever upon arrival to the ER. She was transferred to MCH. On October 8, 2005, Skyler was reinitiated on her ketogenic diet at 1/3 strength. The ketogenic diet was increased to 2/3 strength on October 10, 2005. She was discharged from MCH on October 12, 2005.
[126] Jennifer researched PDE and found two specialists, Dr. Baxter and Dr. Gospe. She discussed her research with Dr. Meaney who told her he would look into it. Jennifer learned about the antiquitin gene related to PDE through her research. She reached out to Dr. Baxter about it in January 2006.
[127] On April 17, 2006, Skyler was seen in clinic by Dr. Meaney. She was noted to be on a 3.5:1 ketogenic diet and pyridoxine (250 mg twice a day). Skyler’s parents reported no new seizures. The ketogenic diet was reduced to 3.0:1.
[128] Jennifer’s uncontested evidence was that in a call with Dr. Meaney on October 23, 2006, Dr. Meaney acknowledged that Skyler’s secondary seizures were caused by her brain injury.
[129] In late 2006, following a discussion with Dr. Meaney, Jennifer began weaning the pyridoxine by reducing Skyler’s dosage from 500 mg per day to 400 mg per day until it was discontinued altogether by March 2007. On March 20, 2007, Skyler was taken by ambulance to GNGH. The physician at GNGH noted that upon arrival Skyler was having seizures, and she was given two doses of 2 mg intravenous Valium followed by phenobarbital 150 mg. The seizure activity stopped. She was discharged home that day. She remained on the ketogenic diet and was restarted on pyridoxine.
[130] On October 2, 2008, genetic testing definitively confirmed the diagnosis of PDE. Skyler started weaning off the ketogenic diet in early May 2009. The ketogenic diet was stopped completely in July 2009. Jennifer’s uncontested evidence was that ceasing the ketogenic diet did not impact Skyler’s seizures.
[131] Between 2008 and 2012, Skyler was noted to have had short seizures which were associated with infection and fever. In 2013 Skyler was started on a lysine-restricted diet. Around August 2014, Skyler was started on arginine supplementation. On October 6, 2015, Dr. Potter noted that Skyler had not had any seizures for approximately 17 months.
4. The Expert Witnesses
[132] The plaintiffs called two expert witnesses, Dr. Yager and Dr. Wiznitzer. The defendants called two expert witnesses, Dr. Snead and Dr. Prasad.
[133] Each party asserted that the other side’s expert witnesses were less experienced.
[134] The plaintiffs say that Dr. Snead had seen very few PDE patients in his 50 years of practice and had experience with no more than four or five pyridoxine trials. He had never treated a late onset PDE patient. Dr. Prasad has researched PDE but did not testify that he had ever been involved in a pyridoxine trial clinically.
[135] The defendants say their experts were more qualified and their evidence should be preferred over the evidence of the plaintiffs’ experts. The defendants submit that Dr. Prasad’s evidence is unassailable, that he provided the most detailed comprehensive and fair report and evidence in chief. The defendants submit that Dr. Prasad was precisely the type of expert the court should want to testify – not a professional expert, but a professional doctor providing evidence as an expert.
[136] All four experts were eminently qualified in their fields. All four experts had voluminous CVs. All but Dr. Yager were licensed as pediatric neurologists. However, Dr. Yager had been practicing as a pediatric neurologist for approximately 30 years. Each had varying and different amounts of or focus on clinical practice, research, teaching and leadership positions. Each had limited experience with actual PDE cases.
[137] Each party accused the other party’s experts of bias.
[138] The plaintiffs assert that Dr. Snead suffered from confirmation bias and that Dr. Prasad was biased. The defendants assert that Dr. Wiznitzer suffered from confirmation bias. To some extent, each of the experts’ testimony indicated possible confirmation bias to varying degrees. However, I make no express findings of confirmation bias.
[139] To varying degrees there were issues with the evidence and opinions of each of the experts.
[140] Dr. Yager reviewed an MRI from 2016, but he did not have or review the MRI from May 2003. He did not review the plaintiffs’ examination for discovery transcripts. Dr. Yager did not have the medical records of Skyler’s sister, Summer. The information he relied on regarding Summer came from Skyler’s records.
[141] Dr. Wiznitzer admitted that he did not have the transcripts of the examination for discovery of Jeff and Jennifer, nor did he have Summer’s medical records. He read the discovery transcripts of five treating physicians. He did not refer to them in his report. He referred to and relied on the medical records rather than the transcripts given by the defendants after they were sued. The defendants say that this demonstrates that Dr. Wiznitzer rejected the defendants’ evidence entirely, did not give the transcripts any weight, cherry-picked evidence in forming his opinion, became an advocate, and revealed himself to be biased. Specifics of the transcript evidence, or the alleged cherry-picking, were not put to Dr. Wiznitzer to question him as to whether it changed his opinion. Dr. Wiznitzer and the other witnesses were examined at length on the medical records. The records formed the backbone of the ASF and significant portions of the evidence. Further, as noted, the defendants did not have any recollection of the events other than as set out in their notes and their usual practice.
[142] Dr. Prasad did not refer to the sworn evidence of Skyler’s parents in his report or in his testimony in chief. Dr. Prasad also did not refer to the sworn evidence of other physicians involved in Skyler’s care and did not review or consider Summer’s medical records. He testified that nothing Skyler’s parents had to say was relevant to his opinion.
[143] Dr. Snead did not refer to the discovery evidence of Skyler’s parents when preparing his reports and did not refer to their trial evidence when testifying at trial. He relied on the evidence of the defendants. He had Summer’s medical records.
[144] I do not agree that not using or referring to the plaintiffs’ or the defendants’ discovery transcripts in these circumstances alone affects the weight of an expert’s opinion. Nothing material was drawn to the court’s attention that suggested that there was information in those transcripts which impacted the opinions given. For the same reasons I do not agree that, as suggested by the defendants, less weight should be given to the entire opinion of an expert who failed to consider the physicians’ discovery evidence, and more weight should be given to the entire opinion of an expert who did.
[145] These factors, together with the issues with the evidence of the experts identified below and throughout these reasons, form part of my assessment of the expert evidence.
Dr. Yager
[146] Dr. Yager is a full professor with tenure in the Department of Pediatrics at the University of Alberta. He was qualified to give expert evidence as a pediatric neurologist and clinical neuroscientist to provide opinion evidence in the areas of pediatric and newborn neurology, developmental disabilities, the assessment and treatment of infant epilepsy including PDE and was qualified to testify about the standards of care required for an empirical pyridoxine trial.
[147] Dr. Yager does not write about or specifically research PDE. However, PDE is something he has in mind as part of his clinical practice. Dr. Yager recalled running a PDE trial as a resident and recalled running another around 2000. Dr. Yager acknowledged that he had only ever seen two cases of PDE in his career.
[148] Dr. Yager does not cite any literature in his report. He did not review the literature on the topic of PDE in siblings. Dr. Yager testified that his report and opinion were based on a general assessment of the literature and were not directed to anything specific. He said this was because PDE in the late 90s and early 2000s was relatively rare, and the literature largely consisted of case reports. Further, he felt Skyler’s case was more about the continuation of the pyridoxine after it was recognized that PDE was part of the differential diagnosis, rather than the underlying aspects of PDE. He viewed Skyler’s case as being about the treatment of a seizure disorder that happens to be PDE.
[149] Dr. Yager’s report assumed that the seizures on May 11 stopped after pyridoxine was administered, not before.
Dr. Wiznitzer
[150] Dr. Wiznitzer is a full professor of Pediatrics and Neurology at Case Western Reserve University School of Medicine in Cleveland, Ohio. He was qualified to provide opinion evidence as an expert in the areas of pediatric neurology, neurodevelopmental disability, the assessment and treatment of infant epilepsy including PDE and was qualified to testify about the standards of care required in the assessment and treatment of intractable seizures in infants and the cause of brain injury in an epileptic pediatric population.
[151] Dr. Wiznitzer has seen hundreds of infant patients with intractable seizures where trials of two different families of antiseizure medications have been tried and failed. A trial of pyridoxine while running an EEG was part of the standard routine if a child continued to have seizures despite the use of pharmacologic therapy. Dr. Wiznitzer has diagnosed one case of PDE and participated in the care of two other children with PDE. Dr. Wiznitzer acknowledges that he is not an expert in PDE in the sense that he has not been found to be an expert in that area. However, Dr. Wiznitzer has expertise in PDE.
[152] Dr. Wiznitzer was knowledgeable and was familiar with both the literature and the medical records. He was not shaken much on cross-examination and except for rare exceptions, answered questions directly without much argument or repetition. He readily conceded facts that did not assist his opinion.
Dr. Snead
[153] Dr. Snead was qualified in pediatric neurology with expertise in epilepsy qualified to provide opinion evidence on standard of care and causation.
[154] Dr. Snead had not written on PDE prior to 2015. He had not treated a patient with late onset PDE.
[155] Dr. Snead’s report contained a number of errors including the following. Dr. Snead referenced EEG results on May 10 when there was no EEG that day. He says this does not impact his opinion. He incorrectly indicated that pyridoxine was started at 10:00 on May 12 – it was started at midnight the night before. He said he read the chart wrong. He testified that he has known of the error for some time but did not correct it. In his report, Dr. Snead indicates that after the pyridoxine trial began on May 12, the seizures abated over the next 24-36 hours on the combination of phenobarbital, Ativan, and pyridoxine. This timing is contrary to the evidence. Dr. Snead says that by abated he meant stopped. When he wrote his reports, Dr. Snead did not know when Skyler had her last seizure in relation to the pyridoxine. His assumption with respect to the timing of the pyridoxine discontinuance was also wrong. There were other dates for events that were acknowledged as being incorrect in his first report. The summary under his “June 2-11” heading contained incorrect information about Trileptal. Dr. Snead acknowledged that he read the wrong note in the records.
[156] The defendants submit that the deficiencies in Dr. Snead’s report were not material to his opinion.
[157] Dr. Snead was at times evasive, repeatedly providing long answers that did not always respond to the question. He often answered questions with caveats and the question would have to be repeated one or two times to get an answer. In providing answers to questions, Dr. Snead would speculate.
[158] Dr. Snead was resistant throughout most of his examination to the idea that there was even the possibility that Skyler had PDE at the relevant time. In part this can be seen from his opinion that the pyridoxine may not have been working in October 2005 when Skyler had a seizure after stopping the ketogenic diet. Dr. Snead provided this opinion even though Skyler had a febrile illness at the time, which can cause a seizure relapse for patients with PDE who are on pyridoxine.
[159] On July 27, 2016, Dr. Snead prepared an expert report on behalf of Dr. Ronen in response to Jennifer’s complaint to the College of Physicians and Surgeons. His opinion was the same in that report although he reviewed more information for his current opinion. Dr. Snead testified that less than two years later he did not recall any of the details about the opinion he provided to the College in the complaint when he prepared his first report in this action dated May 31, 2018. He testified that he did not have access to his prior report because his computer had crashed.
[160] Dr. Meaney graduated from a child neurology program that was directed by Dr. Snead. Dr. Snead was responsible for training Dr. Meaney. Dr. Meaney was one of almost one hundred clinical trainees listed on Dr. Snead’s CV from programs that he directed. Dr. Snead testified that he does not see Dr. Meaney routinely and has very little contact with him, though Dr. Snead has followed Dr. Meaney’s career. Dr. Snead sees Dr. Ronen at conferences. Dr. Snead and Dr. Ronen have both participated in research conducted by a third party. Dr. Snead agreed that he had particularly high regard for Dr. Meaney and Dr. Ronen prior to his involvement in this case.
[161] The plaintiffs chose not to oppose Dr. Snead’s qualifications because of his prior involvement with Dr. Meaney and Dr. Ronen. This involvement does not completely undermine his opinion. This factor, like other issues with the experts’ opinions, goes to the weight and assessment of the expert opinion.
[162] In closing submissions, the defendants state:
Unfortunately, Dr. Snead did not complete his evidence for legitimate reasons due to a medical emergency and resulting personal circumstances. Plaintiffs’ counsel had an hour and a half of cross-examination left. Had Dr. Snead completed his evidence, it is possible that he may have made some concessions, but not to the point of changing his opinion.
[163] I take nothing from Dr. Snead’s inability to complete his cross-examination in the unfortunate circumstances faced by him. The parties agreed that the plaintiffs would truncate their cross-examination of Dr. Snead and the defendants would forgo re-examination.
Dr. Prasad
[164] Dr. Prasad was qualified in pediatrics, pediatric neurology, neurogenetic and neurometabolic disorders with special expertise in epilepsy qualified to opine on both standard of care and causation.
[165] Dr. Prasad acknowledged that this was the first time he had provided an expert report and had been qualified to give an expert opinion. He is clearly a well-intentioned and thoughtful physician. He was constantly careful to provide caveats to many propositions put to him, even after initially agreeing to the proposition. In his evidence in chief, when providing his opinion, he left out important qualifications or limitations on his evidence and additional evidence which was favourable to the plaintiffs. It was not until his cross-examination that these qualifications and limitations were brought out and admitted. For example, Dr. Prasad testified that seizures would recur within a 48-to-72-hour interval after withdrawal of the pyridoxine, while knowing that this figure applied to neonatal PDE patients, not late-onset PDE patients for whom he knew reoccurrence of seizures could take many weeks. Dr. Prasad knew but did not disclose in chief that the late onset PDE phenotype[^2] was associated with a good developmental outcome. It was not until cross-examination that he conceded that late-onset PDE was a positive factor with respect to developmental outcome. I consider other instances below.
[166] When a point was raised from the literature or from his own work that was favourable to the plaintiffs, Dr. Prasad would attempt to qualify the favourable evidence by repeatedly saying that the broader statements regarding PDE did not necessarily apply to an individual case. He did not always say that they did not apply to Skyler’s case, but rather that the general could not necessarily be extrapolated to each individual case.
[167] Dr. Prasad’s opinion on the standard of care was at times based not on what the standard was, but on what the defendants had done, had concluded, had been thinking, or the level of experience they may have had with PDE. Dr. Prasad also repeatedly gave evidence based on Skyler not having come to the defendants with a pre-determined diagnosis of PDE even though it was the role of the defendants to treat and diagnose Skyler.
5. Standard of Care: pyridoxine trial and treatment with pyridoxine
[168] A successful action in negligence requires that the plaintiff demonstrate (1) that the defendant owed the plaintiff a duty of care; (2) that the defendant’s behaviour breached the standard of care; (3) that the plaintiff sustained damage; and (4) that the damage was caused, in fact and in law, by the defendant’s breach.[^3]
[169] There is no dispute that Dr. Meaney and Dr. Ronen owed Skyler a duty of care. The issues before me are:
a. What was the standard of care in 2003;
b. Whether Dr. Meaney and/or Dr. Ronen breached the standard of care; and
c. If there was a breach, whether it caused or contributed to Skyler’s injuries and damages.
[170] The parties have agreed that, to prove their case, the plaintiffs must establish a breach of the standard of care of either or both of the defendant physicians; and that as a result of the said breach(es) of the standard of care and in accordance with the legal principles of causation, Skyler suffered a significant brain injury resulting in the developmental challenges she currently faces.
Law on Standard of Care
[171] The standard of care required of a medical practitioner is to exercise a reasonable degree of skill and knowledge and the degree of care that could reasonably be expected of a normal, prudent practitioner of the same experience and standing.[^4] The plaintiffs must show, on a balance of probabilities, that the decisions and actions of Dr. Meaney and Dr. Ronen were not those which would have been taken by reasonable, competent pediatric neurologists in the circumstances.[^5]
[172] A specialist’s conduct must be assessed in light of the conduct of other ordinary specialists who possess a reasonable level of knowledge, competence and skill expected of professionals in Canada, in that field.[^6] A specialist must exercise the degree of skill of an average specialist in their field.[^7] As specialists in pediatric neurology, Dr. Ronen and Dr. Meaney were required to meet the standard of care of a pediatric neurologist in 2003 with a reasonable level of knowledge, competence and skill.
[173] The standard of reasonableness is not a standard of excellence that amounts to perfection.[^8] The Supreme Court has confirmed that “what must be asked is whether that act or omission would be acceptable behaviour for a reasonably prudent and diligent fellow professional in the same circumstances.”[^9] Or, as put by the Court of Appeal for Ontario, in any case where standard of care is at issue, the court must determine what is reasonably required to be done (or avoided) by the defendant in order to meet the standard of care.[^10]
[174] It has been held that as the degree of risk increases, the degree of care expected of the doctor also increases.[^11]
[175] The conduct of physicians must be judged in light of the knowledge that ought to have been reasonably possessed at the time of the alleged act of negligence. Courts must not, with the benefit of hindsight, judge too harshly doctors who act in accordance with prevailing standards of professional knowledge.[^12] Medical literature post-dating the care in question should not be used as evidence to determine the standard of care.
[176] A physician is not to be judged by the result. Medical professionals should not be held liable for mere errors of judgment which are distinguishable from professional fault.[^13] An error of judgment must be distinguished from an act of unskilfulness or carelessness due to lack of knowledge.[^14] A physician who acts in conformity with the standards of the profession will not be held liable for mere errors of judgment.[^15] A mistaken diagnosis alone is not sufficient to ground a finding of negligence.[^16] An adverse outcome alone does not imply that a physician breached the standard of care.[^17]
[177] Where there are different treatment techniques available, a physician is permitted to exercise their discretion in determining the best course of treatment for that patient.[^18] Although a court may prefer one “school of thought” over another, this preference cannot ground a finding of negligence.[^19] What must be found is that the course of action chosen by the defendant is not a choice which would have been made by a reasonable, competent physician in the circumstances.[^20]
[178] When a physician is faced with different diagnostic and/or treatment options, the fact that the ultimate decision reached later proves injurious does not mean that the treatment was negligent.[^21] If a reasonable doctor similarly situated could reasonably arrive at that conclusion, the act is only an error of judgment.[^22]
[179] In Lapointe v. Hôpital le Gardeur, the Supreme Court held that:
Given the number of available methods of treatment from which medical professionals must at times choose, and the distinction between error and fault, a doctor will not be found liable if the diagnosis and treatment given to a patient correspond to those recognized by medical science at the time, even in the face of competing theories. As expressed more eloquently by André Nadeau in “La Responsabilité Médicale” (1946), 6 R. du B. 153 at p. 155:
[TRANSLATION] The courts do not have jurisdiction to settle scientific disputes or to choose among divergent opinions of physicians on certain subjects. They may only make a finding of fault where a violation of universally accepted rules of medicine has occurred. The courts should not involve themselves in controversial questions of assessment having to do with diagnosis or the treatment of preference.[^23]
[180] While conformity with common practice will generally exonerate physicians of any complaint of negligence, there are certain situations where the standard practice itself may be found to be negligent. However, this will only be where the standard practice is “fraught with obvious risks” such that anyone is capable of finding it negligent, without the necessity of judging matters requiring diagnostic or clinical expertise.[^24] Put another way, this occurs only where the practice does not conform with basic care which is easily understood by the ordinary person who has no particular expertise in the practices of the profession.[^25] Where a custom of a profession ignores the elementary dictates of caution, it is open to a court to find the professional person negligent.[^26] Thus, even if a doctor practises in accordance with common professional practice, he will be liable if that practice is wanting.[^27]
[181] Courts should not involve themselves in resolving scientific disputes which require the expertise of the profession.[^28] Where a common and accepted course of conduct is adopted based on the specialized and technical expertise of professionals, it is unsatisfactory for a finder of fact to conclude that such a standard was inherently negligent.[^29] On the other hand, matters falling within the ordinary common sense of juries can be judged to be negligent.[^30] For example, where there are obvious existing alternatives which any reasonable person would utilize in order to avoid a risk, one could conclude that the failure to adopt such measures is negligent notwithstanding that it is the prevailing practice among practitioners in that area.[^31]
[182] As a general rule, where a procedure involves difficult or uncertain questions of medical treatment or complex, scientific or highly technical matters that are beyond the ordinary experience and understanding of a judge or jury, it will not be open to find a standard medical practice negligent.[^32] On the other hand, as an exception to the general rule, if a standard practice fails to adopt obvious and reasonable precautions which are readily apparent to the ordinary finder of fact, then it is no excuse for a practitioner to claim that he or she was merely conforming to such a negligent common practice.[^33]
[183] Record-keeping is a part of the duty to provide medical care that meets the standard of care. In order to be relevant in the standard of care analysis, record keeping must play a causative role on the adverse outcome.[^34]
Knowledge of PDE in 2003
[184] I have considered the evidence of the experts and of the defendant doctors as to the state of knowledge in 2003 with respect to PDE and treatment for intractable seizures. There are areas of agreement, and areas where the evidence and opinion diverge.
[185] Pyridoxine-dependent seizures occur when the body cannot properly metabolize B6. The seizures caused by PDE are not adequately controlled by conventional antiepileptic medications.
[186] By 2003, physicians were starting to gather evidence of the biochemical and genetic basis for PDE. There was some information that it had a genetic basis and a metabolic issue associated with it. However, there were no known biomarkers or genetic markers. The gene responsible for PDE was not identified until 2008. There were no guidelines in Canada for the treatment of PDE in 2003. The first guidelines for the management of PDE came out in 2011.
[187] Much of the information and knowledge about PDE came from a limited number of papers and articles. Most were case reports and studies considering reported cases in which children were treated. The defendants and experts generally agreed that Dr. Gospe was a leading expert on PDE in 2003. Another recognized leader in PDE was Dr. Baxter. Both had written papers that were tendered in evidence and which the experts and defendants recognized as leading papers in 2003. The experts referred to papers by Dr. Baxter or Dr. Gospe or both.
[188] PDE was considered a rare syndrome in 2003. There were different estimates in the literature as to the incidence of PDE, ranging from one in 20,000 to one in 783,000, depending on which source experts referred to. The defendants’ experts tended to favour the upper end of the range and the plaintiffs’ the lower end. Dr. Prasad testified that the incidence of PDE in 2003 was 1 in 783,000, but in cross-examination he admitted that the incidence had been reported to be as high as 1 in 20,000. Dr. Prasad stated that the lower incidence he cited in chief reflected definite cases of PDE, not probable or birth incidence cases where the incidence is much higher. Dr. Snead repeatedly cited an incidence of 1 in 780,000 from Dr. Gospe’s 2002 paper. Dr. Yager accepted the figures in the Dr. Baxter 2001 paper which suggested an incidence of between 1 in 20,000 and 1 in 700,000.
[189] Notwithstanding its rarity, PDE was part of a medical resident’s training before 2003. Dr. Meaney acknowledged that PDE was on the syllabus for the Royal College of Physicians and Surgeons examination that he wrote to be certified.
[190] I accept Dr. Snead’s evidence that doctors had to pay attention to the literature and incorporate an understanding of the literature in their exercise of judgment. This is supported by Dr. Prasad’s evidence that even an experienced pediatric neurologist who might have one or two cases of PDE in their career needed to draw upon the literature for direction.
[191] It was known in 2003 that the two different classes of anti-convulsant or anti-seizure medications did not stop or prevent seizures resulting from PDE. Pyridoxine was known to stop and prevent seizures in PDE patients. In 2003, PDE was commonly understood to be present where seizures were intractable and not responsive to antiseizure medications but were responsive to pyridoxine.
[192] One option for administration of pyridoxine in 2003 was to administer it orally. It was known that if administered orally, there was little risk to maintaining a patient on pyridoxine. Another option was to administer pyridoxine intravenously. In large doses over longer time periods there is a risk of reversible peripheral neuropathy. It was known that when using large pharmacologic doses of pyridoxine, the potential for long term neuropathy was monitored and steps were taken to minimize the risk.
[193] It was known in 2003 that status epilepticus and ongoing seizures were of significant concern. Dr. Snead testified that status epilepticus is a huge emergency and that he would have been worried sick that Skyler’s seizures would come back.
[194] Although PDE was rare in 2003, it was important and was considered in differential diagnosis when presented with a child under three who had intractable seizures which did not respond to anti-convulsant medications because it was a known, treatable epilepsy syndrome. It was known that PDE seizures responded to pyridoxine, a relatively low risk treatment for the dangerous condition of intractable seizures.
[195] Prior to 2003 doctors could treat PDE even though it was rare. It was treated and diagnosed based on empirical trials. Doctors could treat PDE without knowing the genetic basis of disease and could treat PDE even though there were no guidelines, and no standard approach to treatment.
[196] PDE was considered where a newborn or infant was not responding to conventional anti-seizure medications. Dr. Prasad testified that PDE would have been on the list of possible differentials. Dr. Snead agreed that although PDE was rare, it was important because it was treatable and because in 2003 early treatment was thought to affect outcome. Dr. Snead agreed with Dr. Gospe that in 2003 pyridoxine-dependent seizures remained a clinical diagnosis that needed to be routinely considered in the evaluation of young patients with intractable seizures with the caveat that the question is one of priority. Dr. Yager testified that PDE was considered in the differential diagnosis when a child presented with highly intractable seizures that were not responsive to typical medications. Dr. Wiznitzer testified that pyridoxine was used where there was a patient in the first three years of life with intractable epilepsy.
[197] It was known in 2003 that there was much variability in PDE and its presentation. The seizures associated with PDE varied. A variety of clinical seizure types may be witnessed in patients with pyridoxine dependency, including myoclonic seizures, atonic seizures, partial and generalized events and infantile spasms.[^35] It was known in 2003 that patients with PDE typically presented with either recurrent seizure clusters or status epilepticus, and it was not uncommon for PDE patients to demonstrate periods of restlessness, irritability and vomiting before the onset of each clinical occurrence of seizures.[^36] This was supported by the evidence of Dr. Wiznitzer and Dr. Prasad who testified that there was variation in seizures ranging from myoclonic jerks to myoclonic seizures (repetitive contraction of limb(s)), focal seizures involving one side of the body, eye deviations and movements which could progress to more serious status epilepticus.
[198] PDE could present in the neonatal period or later. The classic or typical presentation of PDE was understood to occur in the neonatal period – typically within days of birth but up to a month afterward. The atypical presentation of PDE occurred later and was known in 2003 to occur up to three years after birth. The experts gave a range of 60 to 75 percent of cases presenting as classic or typical cases and 25 to 33 percent of cases presenting as atypical cases. Skyler’s PDE was atypical in the above sense. None of the experts disputed this.
[199] Pediatric neurologists and experts in metabolic disease could be involved in the diagnosis and management of PDE in 2003.
[200] A ketogenic diet was not part of the standard of care in 2003. Lysine reduction and the supplementation of arginine were not known in 2003 and were not part of the standard of care.
Empirical Trials in 2003
Empirical trials and diagnosis
[201] I accept Dr. Prasad’s evidence that the practice with respect to PDE did not substantially change from 2000 to 2008 when the gene for PDE was discovered.
[202] It was understood in 2003 that PDE could be diagnosed with an empirical trial. There were similarities and some differences between the defendants and the experts as to the proper method to conduct an empirical trial and the role of an empirical trial.
[203] An empirical trial is essentially trial and error. It is an exercise in clinical judgment. It requires the application of knowledge, training, education, experience and common sense to signs and symptoms. I accept Dr. Wiznitzer’s evidence that an empirical trial was a well-known mechanism to establish the causal relationship between the medication and the response to the medication. This was sometimes referred to as a challenge and rechallenge.
[204] Dr. Wiznitzer testified that there was a standard as to how to treat intractable seizures where a specific reason for the seizures could not be determined; it was appropriate to properly conduct a pyridoxine trial.
[205] Dr. Snead’s evidence as to how to conduct a clinical trial in 2003 to establish a diagnosis of PDE was essentially the same as the evidence of the other experts. To diagnose PDE, a child was given pyridoxine, if the child responded to the pyridoxine, after a period of time, the pyridoxine was withdrawn. If the seizures returned, then the pyridoxine was restarted to see if the seizures came under control again. If they did, the child was treated chronically with daily doses of pyridoxine.
Methodology of the trial
[206] Dr. Snead repeatedly testified that in 2003 there was no algorithm, evidence, consensus-based guidelines or standard of care about how to conduct a pyridoxine trial on a child like Skyler who was in the midst of status epilepticus or who was actively seizing, was on high doses of barbiturates in an attempt to treat the status epilepticus and was receiving frequent doses of diazepam and propofol for intubation which had some anticonvulsant effect.
[207] Dr. Prasad also noted that there were no clear parameters for a pyridoxine trial in 2003 in terms of dosage, mode of administration of the pyridoxine, or the expected period of response. He testified that dosage of pyridoxine was variable in the case reports and while it was generally expected that seizures would stop very quickly on administration of pyridoxine as a monotherapy, there was variation.
[208] Dr. Yager testified that in 2003, pyridoxine could be provided intravenously with an EEG to monitor whether it reduced electrical activity. Similar evidence was given by the defendant’s experts. Dr. Snead agreed that in 2003 the trial could be done with EEG monitoring, but that this was difficult to do. Dr. Yager testified that the other way a pyridoxine empirical trial could be conducted, which was more common, was to administer the pyridoxine orally and monitor its effect. The latter approach was the favoured approach for late onset PDE.
[209] There was no clear consensus on the dose of pyridoxine to be administered in an empirical trial or the length of time the patient should be kept on pyridoxine.
[210] There was some difference in opinion as to how long an observation period was required to determine if the seizures returned after stopping the administration of pyridoxine. The defendant’s experts defended the three to four days chosen by the defendants and said there was no standard protocol and there was a lack of a well-defined period of observation after the withdrawal of pyridoxine. Dr. Prasad testified in chief that 48-72 hours was a reasonable period for observation. However, he agreed in cross examination that a 48–72-hour window for relapse was for the classic case of neonatal onset but in an atypical case like Skyler’s, it could be as long as weeks or months after withdrawal and that the literature indicated up to six weeks. Dr. Wiznitzer testified that seizures with PDE that start after the neonatal period like Skyler’s follow a different clinical course; patients may take more than 48 to 72 hours to relapse with some patients taking weeks to relapse.
[211] I find that in 2003 it was known that in atypical cases it could take much longer than three to four days for the seizures to relapse after withdrawal of the pyridoxine and that relapse could take weeks.
[212] There was evidence that when seizures were under control with pyridoxine, parents would be reluctant to stop the pyridoxine to see if the seizures start again.
Diagnosis vs treatment
[213] Dr. Snead and Dr. Prasad testified that a monotherapy trial was required to determine if a child had PDE. Dr. Wiznitzer testified that in patients with intractable seizures that are finally controlled by intravenous or oral pyridoxine, a definitive diagnosis of PDE in 2003 could only be confirmed by the discontinuation of daily pyridoxine supplementation. Dr. Prasad testified that diagnosing PDE in atypical cases was challenging because there could be a list of differentials that physicians would run in their mind.
[214] Dr. Yager testified that the goal was to treat the seizures. Dr. Wiznitzer testified that the objective with a patient with intractable seizures is to stop the seizures by whatever means possible. Dr. Snead testified that when a patient presented as Skyler did with status epilepticus (which he said is a real neurological emergency which can lead to severe irreversible brain damage and can cause patients to die) the primary focus is on stopping the seizures. The secondary focus is on figuring out what caused the seizures. Dr. Prasad testified that the first thing is to try and control the seizures and find something that works to stop them, and the second is to try and establish an etiology for the seizures; diagnosis comes later.
[215] Dr. Wiznitzer testified that monotherapy with pyridoxine was not required to determine if the pyridoxine treatment was working. If a physician was seeking to determine whether the patient was pyridoxine responsive, then the trial could be done in conjunction with other medications.
[216] Prior to the genetic test for PDE in 2008, Dr. Prasad’s algorithm for intractable epilepsy was to start with benzodiazepines and, if after ten or fifteen minutes, a patient was still seizing, having ruled out some metabolic disorders, they were to be given pyridoxine.
[217] Dr. Prasad agreed that if the cause of status epilepticus is not apparent, one should undertake a therapeutic trial with pyridoxine even though it is rare because one would always want to cover the possibility of a potentially treatable condition to control seizures. Dr. Wiznitzer gave similar evidence. Dr. Prasad agreed that a doctor should err on the side of caution in these circumstances. He testified that at times multiple trials had to be performed because patients would often be on antiseizure medications that could complicate the interpretation.
[218] Dr. Snead disagreed with Dr. Baxter’s suggestion in his 2001 paper that “it seems advisable that pyridoxine should be a third-line drug in the management of both acute status and of chronic intractable seizure disorders of any type in young children”. Dr. Snead’s position was based on the rarity of the disease and that Dr. Baxter’s article was just one article, although he agreed that doctors relied on articles like Dr. Baxter’s all the time. Dr. Snead also acknowledged that Dr. Baxter had more experience in the specific area of response to pyridoxine (but not intractable seizures generally). Dr. Snead referred to other leading authorities in 2003 that took a position different from Dr. Baxter’s.
[219] On the other hand, Dr. Prasad testified that pyridoxine is an adjunct therapy in many cases when there are very frequent and difficult to control seizures. Dr. Prasad agreed with Dr. Baxter’s position in his 2001 paper referenced in the previous paragraph.
[220] I find that a pyridoxine trial was the accepted means of obtaining a definitive diagnosis of PDE in 2003. A definitive diagnosis of PDE in 2003 typically required completing the pyridoxine trial on monotherapy, withdrawing the pyridoxine after the seizures were controlled to see if the seizures came back and if so, starting the pyridoxine again. If the seizures stopped and were controlled, PDE was confirmed. The pyridoxine could be administered intravenously or orally. Administering pyridoxine with an EEG to monitor whether pyridoxine reduced electrical activity was another possible means of diagnosis.
[221] I find that the standard of care in 2003 was to prioritize treatment for the seizures and to stop the seizures, with diagnosis of the underlying disorder being of secondary importance. The standard of care required that the seizures be treated by whatever means available to do so and to find something that stopped the seizures. I accept Dr. Prasad’s evidence that anti-seizure drugs in therapeutic doses are known to be harmful for the developing brain.
[222] I accept Dr. Wiznitzer’s opinion, supported by the literature and by the fact that Dr. Meaney directed an empirical trial of pyridoxine while Skyler was on anti-seizure medications, that in 2003 the standard of care for pediatric neurologists to determine whether the patient was pyridoxine responsive was that a pyridoxine trial could be done in conjunction with other medications.
[223] Further, I find that in 2003 if the cause of status epilepticus was not apparent, the standard of care required pediatric neurologists to undertake a therapeutic trial with pyridoxine, whether the child was already on anti-seizure medications or not, because a pediatric neurologist would always want to cover the possibility of a potentially treatable condition where seizures could be brought under control. I find that the standard of care was that at times multiple trials had to be performed because patients would often be on antiseizure medications that could complicate the interpretation of the effect of the pyridoxine. I find that a trial required the reinstating of the medication which had been removed if the seizures returned.
Dr. Ronen and Dr. Meaney’s Knowledge of PDE in 2003
[224] In 2003, Dr. Meaney understood that PDE was a rare condition that would present most typically in the newborn period. Dr. Meaney understood the incidence of PDE in 2003 to be between 1 in 500,000 and 1 in a million.
[225] Dr. Meaney knew that pyridoxine-dependent seizures would not respond with normal anti-seizure medications. He knew there were reports of atypical cases including cases presenting outside the newborn period and that there were different seizure presentations.
[226] Dr. Meaney understood that PDE was rare but important and that to treat PDE, pyridoxine was given. He said pyridoxine was like an antidote. He testified that to diagnose PDE in 2003, one first had to think of it, then a trial of pyridoxine would be undertaken with the hope that there would be a clear signal emerging from the noise that there had been a response to the pyridoxine. He understood how to run a pyridoxine trial, and that in an ideal situation, no other medications would be given. However, Dr. Meaney recommended a pyridoxine trial while Skyler was on phenobarbital and Ativan. He was clearly aware that it was possible to test pyridoxine responsiveness in such circumstances. Dr. Meaney testified that because seizures sometimes spontaneously end on their own, the trial may have to be done more than once. Dr. Meaney recognized that in May 2003 there was discussion in the PDE literature of periods of time longer than three or four days before seizures returned after cessation of pyridoxine.
[227] Until 2003 Dr. Meaney ran pyridoxine trials on a number of patients each year. Dr. Meaney estimates that in 2003 a PDE trial would be run three or four times a year. In 2003, he had yet to diagnose PDE. Dr. Meaney agreed that having decided to run a trial, he was required to do it appropriately.
[228] Dr. Ronen testified that in 2003 the only way to assess for PDE was to administer pyridoxine in monotherapy and watch the response to the withdrawal to get a precise answer. He knew in 2003 that the response time to pyridoxine was variable.
[229] Dr. Meaney and Dr. Ronen conceded that when administered at a low dose and over short periods there were no side effects of pyridoxine, but at pharmacological doses used in treatment of PDE, they acknowledged that there was a risk of peripheral neuropathy. Dr. Meaney agreed that the risks of treatment with pyridoxine are small compared to the potential benefit if the diagnosis is PDE. Dr. Meaney testified that the risk of neuropathy with pharmacologic doses of pyridoxine occurs after long use.
[230] Dr Ronen agreed that untreated PDE could be associated with bad neurologic outcomes and that pyridoxine is a relatively benign vitamin with little or no short-term risks if given orally. Dr. Ronen agreed that the incidence or rarity of PDE did not change from the time he decided to run the trial, to later dates when he was treating Skyler.
Expert opinions on whether the defendants met the standard of care
[231] Dr. Yager agreed that in their treatment of Skyler and in their assessment of the response to pyridoxine, Dr. Meaney and Dr. Ronen were engaged in an exercise of clinical judgment and making choices. His opinion is that Dr. Meaney and Dr. Ronen fell below the standard of care in failing to follow through on the pyridoxine trial.
[232] Dr. Wiznitzer agreed that in 2003 the treatment of intractable seizures by a pediatric neurologist was a matter of appropriate clinical judgment based on knowledge, experience and training. Decisions are made as to what medications to administer and steps to take. In Dr. Wiznitzer’s opinion, Dr. Meaney and Dr. Ronen fell below the standard of care in the following ways:
a. by failing to recognize the importance or the significance of the fact that Skyler’s seizures stopped in temporal association with the administration of pyridoxine;
b. by failing to recognize that seizures in pyridoxine-dependent epilepsy in late onset patients may take more than 48 to 72 hours to return after stopping pyridoxine and by not allowing enough time for Skyler to be off pyridoxine for the recurrence of seizures to be used to determine whether she had pyridoxine-dependent seizures;
c. in not completing the pyridoxine trial and giving Skyler pyridoxine when she came back to the hospital in June 2003 with seizure recurrence even though the anti-seizure medications given had proven to not really be helpful for sustained control of Skyler’s seizures;
d. by failing to start pyridoxine when Skyler was admitted to hospital in July 2003 when, after giving Skyler phenobarbital and benzodiazepines, she was not responding and the only medication which had a temporal association with a sustained response was pyridoxine.
[233] In Dr. Snead’s opinion, Dr. Meaney and Dr. Ronen were well within the standard of care in Skyler’s treatment in 2003.
[234] Dr. Prasad also concluded that the defendants met the standard of care. In his opinion, the decisions they made and the interventions that they provided were entirely appropriate for a child who presented for the first time with a focal seizure. Dr. Prasad’s opinion is that the defendants, having found that the pyridoxine introduction had not made a significant difference to the seizure control, did not fall below the standard of care in not re-starting pyridoxine.
6. Analysis of Standard of Care in pyridoxine trial and treatment with pyridoxine
May 11, 2003 treatment
[235] Dr. Snead testified that on May 11, 2003, the physicians were trying desperately to stop Skyler’s seizures because she was in and out of status epilepticus, a life-threatening neurological emergency that can lead to severe irreversible brain damage and can cause patients to die. The primary focus was on stopping the seizures. It required an exercise of clinical judgment, which was the synthesis of the defendants’ experience, training and interpretation of the literature. The defendants were trying various approaches to control the seizures.
[236] Dr. Prasad testified in chief that with Skyler presenting on May 9, 2003 with a focal onset seizure together with eye and head deviations of the left and right arm extension his first thought would be that this is a child who is presenting with a focal onset seizure that is possibly progressing and evolving into a generalized seizure and that pyridoxine-dependent epilepsy or pyridoxine-responsive seizures would have been low on the list of possible differentials.
[237] Despite the rarity of PDE, Dr. Meaney appropriately recognized the possibility of PDE and recommended a pyridoxine trial. None of the experts take issue with Skyler’s treatment to the point of putting Skyler on pyridoxine on May 11, 2003. None of the experts took issue with the dosage of pyridoxine or method of administration.
Conduct of the pyridoxine trial
[238] Dr. Snead agreed that having chosen to do the pyridoxine trial, Dr. Meaney was required to do it appropriately. However, in Dr. Snead’s opinion, it was impossible to conduct the pyridoxine trial appropriately in the circumstances faced by Skyler on May 11, 2003. Dr. Snead testified that Dr. Meaney could not have taken Skyler off the anti-seizure medication and watched her seize and put her on pyridoxine monotherapy to see if she would respond. He testified that Skyler was at great risk to have seizures if the doctors discontinued the one drug that worked and that it would have been a huge risk to Skyler to take her off phenobarbital. Because of the rarity of PDE, there was every possibility that Skyler would have gone into full blown status epilepticus and they would not have been able to control it, resulting in her being severely injured.
[239] Skyler was in fact taken off the Ativan beginning on May 13, 2003, and was weaned off the phenobarbital a week or so later even though these were the two drugs, in addition to the propofol used for intubation and the pyridoxine, which appeared to control her seizures. According to the ASF, after the Ativan was stopped, the only two treatments Skyler was receiving for her seizures were maintenance doses of phenobarbital and pyridoxine.
[240] Dr. Prasad also agreed that having decided to conduct the pyridoxine trial, irrespective of how rare the condition may have been, Dr. Meaney was required to do it appropriately “to a point”.
[241] I find that the defendants did not fall below the standard of care in not conducting a monotherapy trial prior to May 20, 2023.
Differential diagnosis of focal cortical dysplasia
[242] The defendants testified that in 2003, they concluded that focal cortical dysplasia was the most likely cause of Skyler’s seizures. As Dr. Meaney testified, based on the epidemiology, about 50 percent of infants who presented with Skyler’s story would have a focal cortical dysplasia.
[243] Dr. Ronen testified that as an epileptologist his approach was to first describe the seizures and where they were coming from, and then try to associate an underlying cause. He testified that in Skyler’s case, her seizures started with focal seizures. Therefore, after her normal CT scans he concluded that the most likely underlying cause was a focal cortical dysplasia.
[244] Dr. Snead testified that the belief that a focal cortical dysplasia was the most likely diagnosis for Skyler in May 2003 was reasonable for Skyler’s presentation. Dr. Prasad gave similar evidence. Neither defence expert was cross-examined on that opinion. However, this did not exclude the possibility of PDE given the known variability of PDE seizure presentation, that Dr. Meaney would have understood that about 50 percent of patients presenting as Skyler did would not have focal cortical dysplasia, and that Dr. Meaney recommended a pyridoxine empirical trial.
Discontinuing pyridoxine with a three to four day monitoring period
[245] The experts do not take issue with the discontinuance of the pyridoxine on May 16, 2003. The selection of a three to four day observation period is another matter.
[246] Dr. Snead did not take issue with the three to four day observation period. Dr. Prasad testified that discontinuing pyridoxine and monitoring Skyler for an additional four days to see whether seizures recurred, and if they did, to restart pyridoxine was a reasonable decision. However, he also testified that erring on the side of caution, a longer of period of observation was needed for atypical cases.
[247] In Dr. Wiznitzer’s opinion, Dr. Meaney and Dr. Ronen fell below the standard of care in failing to recognize that seizures in pyridoxine-dependent epilepsy in late onset patients may take more than 48 to 72 hours to return after stopping pyridoxine and by not allowing enough time for Skyler to be off pyridoxine for the recurrence of seizures to be used to determine whether she had pyridoxine-dependent seizures.
[248] The evidence confirms that a reasonably prudent and diligent pediatric neurologist in 2003 would have known that in atypical presentations such as Skyler’s, seizures could take weeks to recur after discontinuing the pyridoxine. The observation period of three to four days for recurrence of seizures prescribed by Dr. Meaney and implemented by Dr. Ronen was too short and not in keeping with what was known about atypical PDE in 2003. This was an error arising from an act of unskilfulness or carelessness or due to lack of knowledge on the part of the defendants. I find that Dr. Meaney and Dr. Ronen fell below the standard of care in setting and implementing an observation period of three to four days for recurrence of the seizures for an atypical presentation such as Skyler’s.
Response to the pyridoxine
[249] Dr. Meaney, Dr. Ronen, and the defendant’s experts all acknowledged that it was possible that the propofol stopped the seizures, rather than the phenobarbital. The propofol and intubation occurred immediately following the administration of phenobarbital and three doses of Ativan (0.5 mg, 0.5 mg and 1 mg) at three to four minute intervals, and another loading dose of phenobarbital (two 10 mg/kg doses, 25 minutes apart). After 12 to 15 minutes of continued seizure activity, the decision was made to intubate Skyler using propofol to sedate her during intubation. After the intubation, Skyler’s seizure activity stopped.
[250] In his evidence in chief, Dr. Wiznitzer testified that the seizures appeared to stop when Skyler was put on propofol. He testified that this was not surprising because propofol is a system suppressant which shuts everything down. The propofol would be expected to wear off within three to six hours.
[251] In his first report, Dr. Wiznitzer noted that Skyler had status epilepticus followed by recurrent seizure activity that started on May 9, 2003 and was not controlled on Ativan and phenobarbital and stopped almost immediately on May 12, 2003 after starting pyridoxine. Dr. Wiznitzer wrote that the first dose of pyridoxine was administered between 22:00 and 24:00 on May 11, 2003, and that there was no further seizure activity. He writes that Skyler showed an almost immediate response to pyridoxine with cessation of seizure activity. He does not say in his report that propofol had anything to do with the seizures stopping. When the timeline of medications and propofol was reviewed with Dr. Wiznitzer in cross-examination, he noted that the administration of Ativan after the propofol suggested ongoing seizures. He conceded that there were no notes of ongoing seizures.
[252] The defendants submit that Dr. Wiznitzer’s failure to mention in his report that propofol may have stopped the seizures undermined his opinion that the seizures responded to the pyridoxine. I do not agree. Dr. Wiznitzer’s opinion was that before Skyler was put on pyridoxine she had multiple seizures that did not show a good response to the phenobarbital and Ativan given during the day. Dr. Wiznitzer’s opinion was that the seizures stopped in temporal association with the pyridoxine. This is supported by the fact that Skyler continued to be seizure free after receiving pyridoxine.
[253] Dr. Prasad testified that giving the pyridoxine in addition to the other drugs would possibly make it difficult to interpret whether the pyridoxine was doing anything. Importantly, he testified that his first recognition that there may have been an effect from the pyridoxine was when he considered the fact that there were no seizures for up to five days on May 16, 2003. In cross-examination Dr. Prasad agreed that it appeared that the pyridoxine together with the anti-seizure medications was successful in keeping Skyler seizure free. On May 14-16, 2003, the only anti-seizure medications being administered to Skyler were phenobarbital and the pyridoxine. In Dr. Prasad’s opinion, it was not an unreasonable option to have kept Skyler on phenobarbital and pyridoxine.
[254] Dr. Snead agreed that prior to starting pyridoxine, the seizures proved to be intractable and difficult to control with a high dose of phenobarbital and hourly Ativan until the dosage of 20 mg/kg body weight was given, which was the standard dose to stop seizures. Dr. Snead testified that the pyridoxine trial was confounded by the fact that Skyler was getting so many other drugs and one could not tell which drug was working and could not tell for sure whether the pyridoxine was having an effect. His opinion was that the effect of the pyridoxine was inconclusive. He says this because pyridoxine was given when Skyler was not seizing. In addition, he says that a few hours after the administration of pyridoxine, Skyler had a seizure. This is a reference to the possible but inconclusive seizure at 03:00 on the morning of May 12, 2003. The evidence and medical notes are not sufficient to determine whether Skyler had a seizure at that time. Even if she had a seizure, it could suggest that none of the drugs were working, not just the pyridoxine.
[255] In cross-examination, Dr. Snead agreed that whether pyridoxine had an impact on Skyler’s seizures could not be ruled in or out.
[256] In Dr. Wiznitzer’s opinion, giving a patient other medication in addition to pyridoxine is not confounding if the patient is on medications that have not been stopping the seizures, and if when pyridoxine is administered and the seizures stop, and when pyridoxine is withdrawn the patient’s seizures come back but stop again if the pyridoxine is restarted. Dr. Prasad accepted that one approach set out by Dr. Gospe in his 2002 paper was to continue the pyridoxine treatment and then withdraw it while the antiepileptic drugs are continued to see if the seizures relapse.
[257] The weight of the expert evidence is that it was not possible to determine with certainty whether the pyridoxine had been effective at controlling the seizures at least until the recurrence of seizures after the withdrawal of the pyridoxine. But neither could its effectiveness be ruled out. In other words, it was an open question at least until the recurrence of the seizures.
[258] Dr. Meaney’s evidence regarding his moment of revelation when he reviewed the STAT phenobarbital levels at some unknown time and handed over to Dr. Ronen on May 12 was that he had concluded that the reason that Skyler’s seizures continued until the administration of the propofol was that Skyler was not receiving the appropriate amount of therapeutic phenobarbital, not because of the pyridoxine.
[259] One of the defendants told Jennifer on May 20, 2003, that the B6 did not work. I find that it was Dr. Meaney who told Jennifer this.
[260] The defendants point to Dr. Meaney’s evidence in response to why he told Skyler’s mother that it was not the pyridoxine that stopped her seizures:
Well primarily because the seizures had evidentially stopped prior to it being started, and – and then the likelihood of pyridoxine-dependent epilepsy having been the diagnosis, began at a very low likelihood, was diminished further by the very late presentation, and then diminished even further by her responding to phenobarbital which she shouldn’t have if she had pyridoxine-dependent epilepsy. And then finally when the pyridoxine was stopped, the seizures didn’t dramatically rebound back as was commonly understood would happen. And so, there was a constellation of successive datapoints that suggested that it was not a supportable plausible idea that this was pyridoxine-dependent epilepsy.
[261] Dr. Meaney had testified that he had no recollection of what he discussed with Jennifer. He has no notes of his discussion.
[262] At another point in his evidence, Dr. Meaney testified that he understood that Skyler had been given the pyridoxine trial and that because she was not continued on pyridoxine, the treating physicians must have thought it had not been the pyridoxine that stopped her seizures.
[263] Dr. Ronen’s evidence was that on May 16 his “re-evaluation” did not suggest Skyler had pyridoxine dependency and if it was PDE, the seizures would reappear. At his examination for discovery, which was read in at trial, when asked why he stopped the pyridoxine, Dr. Ronen testified that Skyler had no seizures, and he did not want her to be on a medication that either did not work or one where they did not know whether it worked.
[264] The defendants point to Dr. Ronen’s evidence as to why he formed the view that PDE was unlikely, focusing on the nature of the seizures that Skyler experienced which in his view differed from the type of seizures she would have if she had PDE. He does recognize that “much later on when she got very sick, she had what we call secondary generalized seizures, meaning that the seizures occurred from both sides [possibly indicating PDE in his view], but initially the seizures occurred from one specific spot.” However, the evidence, which includes Dr. Prasad’s evidence, was that seizures associated with PDE were known to be varied and included myoclonic seizures, atonic seizures, focal, partial and generalized events and infantile spasms. I accept this evidence and it was known in 2003. The evidence is that Skyler experienced myoclonic jerks and focal seizures before May 12, 2003.
[265] The defendants point to their consultation with Dr. Potter of the neurometabolic and neurogenetic service. On May 15, 2003, Dr. Potter concluded that the neurometabolic and neurogenetic service did not think there was an underlying metabolic or genetic disorder as the cause of the seizures. Dr. Potter did not testify. The conclusion is simply evidence of his understanding at the time. There are other issues with the Dr. Potter report raised by the evidence.
[266] Dr. Snead testified that it was reasonable for Dr. Meaney and Dr. Ronen to consult with metabolic services on two separate occasions. Dr. Prasad agreed. The plaintiffs and their experts do not dispute the reasonableness of a consultation. However, Dr. Wiznitzer noted that the report does not comment on Skyler receiving pyridoxine, while other medications are reviewed. Dr. Snead agreed that it appears from the report that the genetic neurometabolic service was not apprised of the pyridoxine empirical trial when consulted on May 15, 2003. There is no evidence that they were.
[267] I find that Dr. Meaney’s and Dr. Ronen’s evidence at trial is an attempt to reconstruct, after-the-fact, what they might have been thinking 21 years ago between May 11, 2003 and May 20, 2003 to justify their conclusion on or before May 20, 2003, that the pyridoxine did not work and that Skyler did not have PDE.
[268] The records are clear that Dr. Meaney and Dr. Ronen intended to run a pyridoxine trial, a trial for which they set an insufficient timeline of three to four days for the recurrence of the seizures and that at the end of those four days at the latest, they concluded that the pyridoxine had no effect because the seizures had not returned.
[269] The effectiveness of pyridoxine at controlling Skyler’s seizures up to May 20, 2003, could not be determined. Pyridoxine’s effectiveness could not be ruled out. That determination could not be made until it was seen whether the seizures returned within a period of weeks following the cessation of the pyridoxine, not days. The understanding of a reasonably prudent pediatric neurologist in 2003 in the circumstances of the defendants would have been that the effectiveness of pyridoxine and therefore, PDE, could not be ruled out by May 20, 2003, in an atypical case presenting like Skyler’s. The defendants fell below the standard of care in concluding on or before May 20, 2003, that the pyridoxine had no effect.
[270] The error of setting too short an observation period for the return of the seizures after discontinuing the pyridoxine on May 16, 2003, together with Dr. Meaney and Dr. Ronen’s conclusion that the pyridoxine had not been effective as of May 20, 2003, affected the defendants’ clinical judgment moving forward.
Discharge on May 20, 2003
[271] Dr. Snead testified that discharging Skyler on May 20 with a recommendation of weaning the phenobarbital and replacing it with Trileptal with follow up in a month was eminently reasonable. Pediatric neurologists try to avoid chronic phenobarbital therapy in children; it is very effective but has significant behavioural and developmental effects. Dr. Prasad agreed. The plaintiffs’ experts did not take issue with the discharge.
May 26 to July 6, 2003
[272] Skyler received pyridoxine for four and a half days. In total she was seizure free for 14 days from the start of the pyridoxine to her next seizure. This was the longest time she was seizure free on any medications.
[273] As set out in more detail above, on May 26, 2003, Skyler attended GNGH when she had a grand mal seizure. Dr. Meaney was consulted. He doubled her Trileptal dose. In response to being asked why he did not start pyridoxine Dr. Meaney said that a seizure ten days after stopping pyridoxine did not “set off robust flags that it was a bad rebound from stopping pyridoxine”. He said he thought it was from stopping the phenobarbital, but he did not start phenobarbital again. He wanted to give the Trileptal more time to work.
[274] In cross-examination Dr. Meaney was specifically asked to confirm that he never considered restarting pyridoxine from May 20, 2003 to July 15, 2003. He confirmed that he did not consider restarting pyridoxine during that time frame. Having considered the evidence, I do not accept Dr. Meaney’s explanation for why he did not start pyridoxine on May 26. I find it is an after-the-fact reconstruction. Dr. Meaney had already decided that the pyridoxine did not work and did not consider the possibility of restarting pyridoxine again prior to July 15, 2003.
[275] As set out in more detail above, on May 28, 2003, Dr. Ronen was consulted by GNGH. He suggested an increase to Skyler’s dose of Trileptal because it was clear the medication was not controlling her seizures at the prior dose.
[276] In cross-examination, Dr. Ronen was asked to confirm that between May 20 and July he never considered restarting pyridoxine. Dr. Ronen responded stating that he was not her primary physician. He then said when he was called, he tried to address her acute conditions. Dr. Ronen did eventually agree that he never considered it. I find this was because he had already decided prior to this that the pyridoxine did not work. As a result, he never considered pyridoxine again until it was raised with him on July 15, 2003.
[277] As set out in more detail above, Skyler was admitted to GNGH on June 2, 2003, in status epilepticus. She was then transferred to MCH. Skyler had been given a phenobarbital load. Dr. Meaney ordered that Trileptal be further increased. He was giving Skyler a final chance to respond to the maximum dose of Trileptal although he suspected it was probably not going to be sufficient, so he recommended starting clobazam. On June 6, 2003, Skyler had further seizures. In addition to Ativan, Skyler was given a loading dose of phenobarbital and maintenance phenobarbital.
[278] Although Dr. Meaney testified that he did not start Skyler on pyridoxine during her June 2 to 11 admission because her course continued to be in keeping with other more likely diagnoses including focal cortical dysplasia, pyridoxine was not in fact considered by him. I do not accept his explanation.
[279] As set out in more detail above, Skyler had seizures on June 12 and 14, 2003; Dr. Meaney was contacted by GNGH on June 15, 2003, and recommended an increase in phenobarbital.
[280] On June 24, 2023, Skyler was admitted to MCH. Dr. Ronen started Skyler on Topamax and she was continued on phenobarbital.
[281] On June 30, 2003, Skyler experienced three seizure episodes at home. She was brought to GNGH. Dr. Meaney was consulted by the GNGH pediatrician on July 1, 2003. He decided to give a bolus of phenobarbital, followed by an increase in the daily dose of phenobarbital and in increase in Topamax.
[282] As set out in more detail above, on July 5, 2003, Skyler had a seizure and was admitted to GNGH. On July 6, she developed status epilepticus and was transferred to the MCH PICU. She was given Ativan, Dilantin and started on a midazolam infusion. Dr. Meaney was on call for the pediatric neurology service. Dr. Meaney recommended, once Skyler was stable on midazolam, to stop phenobarbital, maintain Topamax, and start valproic acid later in the week. On July 6, Dr. Meaney wrote that phenobarbital and Topamax had been insufficient to control Skyler’s epilepsy. On July 7, 2003, due to repeated breakthrough seizures, Dr. Ronen and Dr. Meaney decided to initiate a pentobarbital coma.
[283] At no point after May 20, 2003, when the defendants were consulted regarding Skyler or saw her at MCH, did Dr. Meaney or Dr. Ronen ever consider pyridoxine or PDE even though the recurrence of the seizures was within the window of time known in pediatric neurology in 2003 for recurrence in atypical PDE cases.
[284] Dr. Meaney ordered a neurometabolic consult for Skyler with Dr. Mark Tarnopolsky at the Neurometabolic and Neurogenetic Service. Dr. Tarnopolsky did not arrive at a diagnosis. Dr. Snead testified that it was reasonable for Dr. Meaney and Dr. Ronen to consult with metabolic services. Dr. Prasad agreed.
[285] In Dr. Wiznitzer’s opinion, Dr. Tarnopolsky’s July 7, 2003, report, which noted that Skyler did not appear to have a pyridoxine responsive type of seizure, was incorrect. He concludes that either Dr. Tarnopolsky did not interpret the results of the pyridoxine trial correctly or he was given the wrong information.
[286] Dr. Yager testified that whether it was PDE was a diagnostic issue, but whether the seizures were amendable to treatment was an issue for pediatric neurology. Further, where there is no diagnosis of the underlying issues the outcome of the neurometabolic consultation is of less import.
[287] There is no evidence of what information was provided to Dr. Tarnopolsky regarding the pyridoxine empirical trial. Dr. Tarnopolsky did not testify. As agreed between the parties, Dr. Tarnopolsky’s statement in his July 7 report that Skyler did not appear to have a pyridoxine responsive type of seizure is only evidence of what he thought at the time. No one could explain how Dr. Tarnopolsky came to his conclusion that Skyler did not appear to have a pyridoxine responsive type of seizure. I do not accept it as an admissible opinion. It may have been Dr. Tarnopolsky’s understanding at the time, but with no evidence as to the basis for this understanding, I would give it no weight in any event.
[288] I do not accept Dr. Prasad’s opinion that, given the list of differentials and diagnostic possibilities, and the defendants’ impression that PDE was still a low diagnostic consideration the standard of care did not require pyridoxine to be restarted. Dr. Prasad also testified that the standard of care “possibly or possibly [did] not” require restarting pyridoxine up to July 6, 2003, depending on the differentials considered by the defendants.
[289] I do not accept Dr. Snead’s opinion that there was no evidence suggesting that Skyler needed to be started on pyridoxine on or before July 6, 2003. Dr. Snead testified that it was necessary given the extreme risk posed by Skyler’s seizures to stop the seizures and to be aggressive and try various combinations of medications. His opinion that the defendants did not breach the standard of care between May 26 and July 6 rested in part on what the defendants said they did and considered. Dr. Snead’s opinion does not satisfactorily explain why no consideration was given to pyridoxine and PDE given it was known that seizures could reoccur in atypical cases during most of this period or why no attempt would be made after May 26, 2003, to use an innocuous vitamin that was part of the only cocktail that kept seizures at bay for a 14-day period.
[290] Both Dr. Prasad and Dr. Snead, but especially Dr. Prasad, based their opinions of the standard of care on the evidence of the defendants and what they considered. I have found that the defendants did not consider whether pyridoxine should be restarted at any time after May 20, 2003, and did not consider PDE in their diagnostic consideration and differentials.
[291] Dr. Prasad agreed in cross-examination that when dealing with status epilepticus and refractory seizures a clinician wants to err on the side of caution in terms of attempting therapy that might stop that seizure. He added that every time they face a child with status epilepticus or refractory seizures the main goal is to try and control the seizures. Dr. Snead seemed to accept that the defendants could have tried to administer pyridoxine again if Skyler seized again, with the caveat that no other drug could be stopped. Dr. Snead testified that the defendants were required to continue trying to keep Skyler seizure free. This is eminently reasonable. The standard of care required the defendants to stop the seizures. Finding a diagnosis was secondary.
[292] Dr. Prasad agreed that if the cause of status epilepticus is not apparent, one should undertake a therapeutic trial with pyridoxine even though it is rare because one would always want to cover the possibility of a potentially treatable condition where seizures could come under control. Dr. Wiznitzer gave similar evidence. Dr. Prasad testified that at times multiple trials had to be performed because patients would often be on antiseizure medications that could complicate the interpretation. Dr. Meaney understood that an empirical trial of pyridoxine might have to be done more than once. In cross-examination Dr. Snead agreed that a pyridoxine trial should have been thought of and tried as soon as possible and that adding pyridoxine to Skyler’s treatment could not hurt.
[293] Dr. Prasad conceded that it was not an unreasonable option to have kept Skyler on phenobarbital and pyridoxine. Dr. Snead eventually conceded in cross-examination that it was a reasonable alternative on May 16 to keep Skyler on pyridoxine. He eventually conceded that when Skyler returned on May 26 with seizures, starting pyridoxine was a reasonable alternative. In Dr. Wiznitzer’s opinion, even if the doctors believed that the probability of PDE was low, when the seizures started again the pyridoxine should have been restarted. I find this to be a reasonable alternative. I find the same would be true as Skyler continued to return with further seizures in June through July 6, 2003, when the defendants continued to tweak her anti-seizure medication. Dr. Meaney and Dr. Ronen never considered this reasonable alternative.
[294] In Dr. Wiznitzer’s opinion, Dr. Meaney and Dr. Ronen fell below the standard of care in not completing the pyridoxine trial, and in not giving Skyler pyridoxine when she came back to the hospital with seizure recurrence when the anti-seizure medications given had proven to not be truly helpful for sustained control of Skyler’s seizures. The cessation of seizures from May 12 when the pyridoxine was started, until May 26 was a significant change from what was occurring before the pyridoxine. In Dr. Wiznitzer’s opinion that should have signaled to Dr. Meaney and Dr. Ronen that they had to strongly consider that the pyridoxine was the reason for the seizures stopping.
[295] Dr. Yager’s opinion was that the defendants should have looked at the trend and timeline of the seizures and the effect of the medications on the seizures and reinstated the pyridoxine. He said the seizures were occurring frequently until the pyridoxine was started and the anti-seizure medications did not seem to be effective. In Dr. Yager’s view, after pyridoxine was administered, except for a brief seizure (the purported 03:00 May 12, 2003 possible seizure), the seizures stopped. Dr. Yager’s opinion was that because Skyler was seizure free after the administration of pyridoxine for 14 days, at that point it was clear that pyridoxine contributed to the treatment or therapeutic value of reducing Skyler’s seizures.
[296] It was clear to Dr. Yager that Skyler was on large doses of anticonvulsants that were not effective. His opinion is that a reasonable physician in Dr. Meaney and Dr. Ronen’s position would have looked back to consider why the seizures started again after 14 days to see if anything could be reinstated.
[297] Dr. Yager’s opinion is that Dr. Meaney and Dr. Ronen fell below the standard of care in failing to follow through on the pyridoxine trial. His opinion is that the pyridoxine should have been reinitiated to see if it stopped the seizures when they resumed and that it was not reasonable not to have restarted the pyridoxine when the seizures returned.
[298] As noted above, where there are different treatment techniques available, a physician is permitted to exercise their discretion in determining the best course of treatment for the patient. To ground a finding of negligence, the choice made must be a choice which would not have been made by a reasonable, competent physician in the circumstances. When a doctor is faced with different diagnostic and/or treatment options, as long as a reasonable doctor similarly situated could reasonably arrive at that conclusion, the act is only an error of judgment.
[299] Medical professionals should not be held liable for mere errors of judgment. Errors of judgment are distinguishable from professional fault. An error in judgment must be distinguished from an act of unskillfulness or carelessness or an act due to lack of knowledge.
[300] The facts and the expert evidence establish that there was, at a minimum, a realistic possibility that the pyridoxine had controlled or assisted in controlling Skyler’s seizures. As a result of their breach of the standard of care in establishing the proper observation period for the recurrence of seizures, Dr. Meaney and Dr. Ronen missed this realistic possibility. A reasonable pediatric neurologist in Dr. Meaney and Dr. Ronen’s circumstances would have considered this possibility after May 26, 2003 when the seizures returned. The defendants did not.
[301] Throughout their evidence Dr. Meaney and Dr. Ronen resisted the possibility that the pyridoxine might have been effective. For example, although he agreed it could not hurt to try pyridoxine in July, Dr. Meaney refused to acknowledge that the same was true in late May. One reason he gave for the alleged difference is that in mid-July Skyler had difficult-to-control seizures, and additional agents had been added to her treatment like folinic acid, creatine and other supplements. Dr. Meaney says that adding pyridoxine earlier posed a risk of confusing the medical picture and it would muddy the waters. However, Dr. Meaney added pyridoxine in May when Skyler was on other medications and the physicians were attempting to control her seizures.
[302] Another explanation that Dr. Meaney gave for not wanting to administer pyridoxine is that in therapeutic doses pyridoxine is not always benign and there is a risk of neuropathy. He did not want to expose Skyler to the long-term risks from pyridoxine. This contradicts his evidence about the low risk of pyridoxine administered orally if there is a diagnosis of PDE and that the risk of neuropathy is from long term pharmacological doses. Moreover, the evidence is that it was not necessary to give Skyler pyridoxine for a long time to determine if it controlled her seizures.
[303] It was understood in 2003 that the risk of injury to Skyler was significant if her status epilepticus and seizures could not be controlled. On the other hand, the risks created by orally administered pyridoxine were low. Pyridoxine is a relatively harmless substance in the doses required to determine if it would control the seizures. The potential upside was significant if the pyridoxine controlled the seizures.
[304] Skyler’s seizures proved to be intractable and difficult to control with various medications. Skyler’s seizures returned again and again, within the known window for the possible return of seizures, notwithstanding that the defendants used increasing doses of medication and treatments that were riskier as time went on. For example, Dr. Ronen, who testified that he would not leave a stone unturned, said he suggested valproic acid which, at the time was considered potentially toxic. However, he did not consider pyridoxine.
[305] I find that a reasonable pediatric neurologist in the circumstances of the defendants would at a minimum have considered the possibility that the pyridoxine contributed to the cessation of seizures. They would have recommended starting Skyler on pyridoxine, a virtually harmless vitamin and low risk alternative treatment which could avoid a very significant risk of harm to Skyler, when her seizures resumed between May 26 and July 6, 2003. This should have been done either as a step to complete a clinical trial, or as a new clinical trial which Dr. Prasad and Dr. Meaney recognized could be necessary. Dr. Meaney and Dr. Ronen never turned their minds the fact that they had not completed the empirical trial by reinstituting the pyridoxine after the seizures returned or that a second empirical trial might be necessary.
[306] As a result, the defendants could not have and did not exercise clinical judgment or discretion in choosing between different treatment options. One cannot make a judgment call between two reasonable alternatives if one does not consider one of the alternatives. While treating intractable seizures in 2003 was a matter of appropriate clinical judgment, the failure by Dr. Meaney and Dr. Ronen to consider pyridoxine and to consider restarting pyridoxine in the circumstances of Skyler’s case was not a choice that a reasonable, competent pediatric neurologist would have made.
[307] I find that Dr. Meaney and Dr. Ronen fell below the standard of care in not considering and not using pyridoxine for Skyler’s seizures when Skyler returned to their care with seizures on and after May 26, 2003.
[308] Conformity with common practice will generally exonerate physicians of any complaint of negligence unless the standard practice is “fraught with obvious risk” such that anyone is capable of finding it negligent, where there are obvious existing alternatives which any reasonable person would utilize in order to avoid a risk, or if a standard practice fails to adopt obvious and reasonable precautions which are readily apparent to the ordinary finder of fact.
[309] I find that to the extent that Dr. Meaney and Dr. Ronen’s conduct could be said to conform with common practice, in light of the evidence, including the expert evidence, it is a practice that was “fraught with obvious risk” such that anyone is capable of finding the failure to administer an innocuous vitamin in these circumstances when there was some indication that it worked and it could have addressed a condition with such serious risks without harming the patient, it is a negligent practice. Any reasonable person, having the knowledge of the defendants, would have administered the pyridoxine when the seizures returned.
D. INFORMED CONSENT
7. Positions of the Parties
[310] The plaintiffs assert that the defendants breached their duty to obtain informed consent by failing to provide the plaintiffs with information about the pyridoxine trial and taking Skyler off B6.
[311] The defendants submit that the plaintiffs did not plead that it was a breach of an obligation of informed consent to stop the pyridoxine and that it was Dr. Lloyd, who was released from the action by the defendants, who was responsible for obtaining informed consent and not the defendants. The defendants also submit that Skyler’s parents were told about the B6 trial.
8. Law of informed consent
[312] Informed consent is a distinct cause of action, separate from a breach of the standard of care.[^37] No medical procedure may be undertaken without the patient’s consent obtained after the patient has been provided with sufficient information to evaluate the risks and benefits of the proposed treatment and other available options.[^38]
[313] For the plaintiffs to establish a claim based on a failure to obtain informed consent, the plaintiffs must prove the defendant physicians failed to adequately disclose a material risk[^39] or an indicated treatment option.[^40]
[314] As explained by the Supreme Court of Canada, an objective approach should be taken in in deciding whether a risk is material and should be disclosed to the patient; the crucial question is whether a reasonable person in the patient’s position would want to know of the risk:
Reibl v. Hughes [1980 CanLII 23 (SCC), [1980] 2 S.C.R. 880] indicates that the disclosure which must be made to a patient will often be more than that which the medical profession might consider appropriate to divulge. Although expert medical evidence on this issue is still relevant, it is no longer decisive in determining whether or not sufficient information was given to a patient to enable that patient to make an informed consent. The test now focuses on what the patient would want to know. Laskin C.J. put the position in these words at pp. 894-95:
To allow expert medical evidence to determine what risks are material and, hence, should be disclosed and, correlatively, what risks are not material is to hand over to the medical profession the entire question of the scope of the duty of disclosure, including the question whether there has been a breach of that duty. Expert medical evidence is, of course, relevant to findings as to the risks that reside in or are a result of recommended surgery or other treatment. It will also have a bearing on their materiality but this is not a question that is to be concluded on the basis of the expert medical evidence alone. The issue under consideration is a different issue from that involved where the question is whether the doctor carried out his professional activities by applicable professional standards. What is under consideration here is the patient’s right to know what risks are involved in undergoing or foregoing certain surgery or other treatment.[^41]
[315] Whether disclosure of potentially available treatment options is required in the circumstances is a matter of clinical judgment. Physicians are not required to disclose a treatment option that is not indicated or that, in the physician’s judgment, is not a medically reasonable alternative for the patient.[^42] A plaintiff generally requires expert evidence to prove that those alternative treatment options were medically reasonable alternatives.[^43]
[316] Where more than one viable option to manage the patient’s medical condition is available, the patient is also to be informed of the relative and comparative risks and benefits between the options. The extent to which a doctor must disclose and discuss alternative treatments will depend upon what has been described as “a myriad of factual circumstances”.[^44]
[317] The Ontario Court of Appeal in Van Dyke affirmed the importance of a patient being equipped with the information necessary to make an informed choice between alternative courses of treatment:
The ultimate decision whether to proceed with a particular treatment rests with the patient and not the doctor. The doctor must equip the patient with the information necessary to make an informed choice. Where there is more than one medically reasonable treatment and the risk/benefit analysis engaged by the alternatives involves different considerations, a reasonable person would want to know about the alternatives and would want the assistance of the doctor’s risk/benefit analysis of the various possible treatments before deciding whether to proceed with a specific treatment. Put differently, a reasonable person could not make an informed decision to proceed with treatment “A” if that patient was unaware of the risks and benefits associated with treatment “B”, a medically appropriate alternative treatment.[^45]
[318] The plaintiffs must also prove causation, which is addressed below.
9. Facts and analysis of informed consent
[319] The defendants submit that the plaintiffs failed to particularize their informed consent claim in the Statement of Claim. Paragraph 33 of the last version of the plaintiff’s statement of claim filed at the commencement of trial on March 19, 2024, alleges that:
Skyler’s parents had not been told about the pyridoxine trial. In particular, they were not informed that it was necessary to restart the pyridoxine if Skyler experienced further seizure activity in order to properly complete the trial. In fact, Dr. Meaney specifically told Jen that the B6 was not responsible for stopping Skyler’s seizure activity.
[320] Paragraph 60 of the statement of claim alleges that Dr. Meaney and Dr. Ronen were negligent in failing to fully inform Jennifer and Jeff of the purpose and importance of the pyridoxine trial. The defendants acknowledge that the plaintiffs stated in their opening statement that the defendants “[f]ailed to obtain Skyler’s parents informed consent to stop the B6, and failed to inform them of the empirical trial and its result.”
[321] Bolstered by the opening statement, and the proceedings at trial, the pleadings were sufficient to put the defendants on notice of the informed consent issue.
[322] Jennifer recalls being told sometime during Skyler’s stay at MCH in May 2003, about B6 and that it was a vitamin the physicians were going to try. Jennifer believes it was Dr. Meaney who told her they would try the B6. Jennifer testified that Dr. Meaney did not discuss treating Skyler empirically for B6 deficiency. Nor did Dr. Ronen. Jeff does not recall any doctors saying anything to him while he was at MCH about Skyler’s seizures stopping while she was on B6. Jennifer recalls a conversation with Dr. Meaney that the B6 did not work. Skyler was sent home without a requirement to administer B6. Dr. Meaney testified that he would have spoken with the family at discharge and agreed that it was reasonable for Jennifer to understand that he told her that the pyridoxine did not work. I accept Jennifer and Jeff’s evidence.
[323] Jennifer does not recall a conversation with Dr. Lloyd about the empirical trial although Dr. Lloyd recorded a note about it. Dr. Lloyd’s note of May 11, 2003, contained in the Joint Brief of Documents states that the decision to treat Skyler empirically for PDE was discussed with Jennifer. It is one of a number of medical issues in the note that Dr. Lloyd states that he discussed with Jennifer.
[324] The plaintiffs’ position is that Dr. Lloyd’s note is not admissible for the truth of its contents. According to the ASF, the parties agreed that the documents in the Joint Brief of Documents are authentic copies of the originals. The parties agree that all of the records in the Joint Brief of Documents are business records as defined by the Evidence Act, R.S.O. 1990, c. E. 23. These business records are agreed to be evidence of such acts, transactions, occurrences or events as set out in the records, without prejudice to the right of any party to lead contrary evidence. Where the records contain a diagnosis or statement of opinion, those entries are admitted to establish the fact that the author(s) reached those diagnoses or opinions at the time, and not for the truth or accuracy of those opinions.
[325] Dr. Lloyd’s note is not an opinion. Accordingly, it is evidence of the event described therein. However, I cannot tell from the note what Dr. Lloyd meant by and what was explained, if anything, to Skyler’s parents about treating empirically for PDE.
[326] I find that Jennifer was told that Skyler was being put on pyridoxine. I find that Dr. Meaney and Dr. Ronen did not discuss the pyridoxine trial with Skyler’s parents. Skyler’s parents were not told why Skyler was given B6. Skyler’s parents were not told that Skyler was seizure free while on B6 in May 2003. They were not told that if the seizures returned B6 should be considered again or that it was an option to do so on and after May 26, 2003.
[327] The defendants assert that they were not responsible for obtaining informed consent from Skyler’s parents, that it was the MRP, Dr. Lloyd or the staff in the PICU and the pediatric physicians who were required to do so. This is contradicted by Dr. Meaney’s evidence.
[328] Dr. Meaney testified that it was his responsibility to provide the risks, benefits and alternatives to the parents so they could decide what was best for their child. He agreed that a patient makes their own decisions about which health care interventions they will or will not receive. For an infant this means the parents make the decisions, not the doctor. Dr. Meaney agreed he was obligated to convey relevant information about Skyler’s health to Skyler’s parents and the more serious the potential consequences of such information, the more important that the patient, in this case, the parents, be informed. Further, he agreed Skyler’s parents were entitled to complete disclosure of all relevant information that could potentially impact on her medical condition or her treatment. He agreed that Skyler’s parents had a right to know about any test results that were relevant to her medical treatment.
[329] Dr. Meaney agreed that the pyridoxine trial was relevant to Skyler’s medical treatment and conceded that Skyler’s parents needed to be told about the B6 trial. Dr. Meaney agreed that on discharge he had an obligation to ensure that important information was relayed to Skyler’s parents. Dr. Meaney does not assert that he had no responsibility in informing the parents.
[330] Dr. Wiznitzer testified that a reasonably prudent doctor would have discussed with Skyler’s parents the potential role of pyridoxine in stopping the seizures after May 12, 2003. They should have been told that they had to watch to see if there was a relationship between the pyridoxine and the cessation of seizures. If Skyler was sent home without pyridoxine, they should have been told that if the seizures restarted, pyridoxine should be administered again to see if the seizures would then stop. They should have been told that it could be weeks before the seizures restarted. I agree. Dr. Meaney and Dr. Ronen failed to do this.
[331] The defendants say that Dr. Wiznitzer did not identify a conversation with the parents after discharge and before July 6 when there was a failure to obtain informed consent and that Dr. Wiznitzer did not testify that a material risk or required alternative treatment was required to be disclosed. The defendants submit that Dr. Wiznitzer opined that the defendants should have disclosed an opinion that they did not hold and that Dr. Wiznitzer did not testify that the defendants failed to obtain informed consent at any point in time. I disagree.
[332] It is clear from Dr. Wiznitzer’s evidence that he was referring to the time surrounding the commencement of the pyridoxine trial, the discontinuance of the pyridoxine and Skyler’s discharge from hospital on May 20, 2003. He was referring to the alternative treatment of restarting Skyler on pyridoxine if the seizures returned. In any event, an expert opinion is not required to determine that the defendants failed to obtain informed consent. This is a conclusion for the court to draw from the evidence and the factual circumstances of the case.
[333] The defendants submit that the plaintiffs’ submission is that the plaintiffs should have been given the option of continuing pyridoxine despite the extremely low possibility that Skyler’s had PDE. The defendants submit that this is not anywhere near the threshold for materiality suggested by case law. The defendants submit that there was nothing more regarding pyridoxine that they were required to inform Skyler’s parents about because they had concluded that the pyridoxine had not stopped the seizures.
[334] It was the defendants’ breaches of the standard of care that led to their conclusion that the pyridoxine had not stopped the seizures and to their failure to consider pyridoxine when the seizures returned. The defendants cannot rely on their breaches of the standard of care to avoid a duty to inform and obtain consent.
[335] Keeping Skyler on phenobarbital and pyridoxine and starting pyridoxine on May 26 through July 6, 2003, when the seizures returned, were reasonable alternatives. They were not considered by Dr. Meaney and Dr. Ronen and so they could not and did not inform Skyler’s parents of these options.
[336] No information was provided to Skyler’s parents about these alternatives. They were not informed of the comparative risks and benefits of the alternative options for treatment. Skyler’s parents were not told that Skyler was seizure free while on B6 in May 2003. There was no discussion with Skyler’s parents about the risks and benefits of continuing Skyler on pyridoxine after May 16, 2003. There was no discussion with them about the risks of keeping her on pyridoxine compared to trying various anti-seizure medications. There was no discussion about the risks and benefits of trying pyridoxine on and after May 26, 2003. Any reasonable person in the position of Skyler’s parents would want to know this information.
[337] Skyler’s parents could not make an informed decision without understanding the potential role of pyridoxine in stopping the seizures, the alternative options of continuing or resuming the pyridoxine if the seizures returned and without being informed of the virtually non-existent risk of doing so compared to the very significant risks of not controlling the seizures. They were denied material information and the choice of possible reasonable alternative treatment options. Dr. Meaney and Dr. Ronen breached their obligations to the plaintiffs in failing to advise them of the options and the risks and benefits of the options.
10. Would the plaintiffs’ conduct have been different?
[338] A patient alleging lack of informed consent must not only prove that the information provided was inadequate but must also establish causation.[^46] Here I am referring to what Skyler’s parents would have done if they had been provided with the appropriate treatment options and the risks and benefits described above.
[339] As set out by the court in Stepita v. Dibble[^47] at paras. 84-87 [citations omitted]:
[84] Even if a plaintiff establishes that a physician failed to adequately disclose a material risk or treatment alternative, the informed consent claim will still fail if the plaintiff cannot prove the harm was caused by the procedure to which the patient consented. A plaintiff must also demonstrate on a balance of probabilities that she would not have consented to the procedure if adequate disclosure had been made.
[85] The test for informed consent contains both a subjective and objective component. The subjective component is based on what the particular patient would have agreed to if the risks were known. It will of necessity vary from patient to patient and take into account factors unique to the patient. The objective component is based on what a reasonable person in the patient’s position would have done. Evidence that other patients regularly consent to the proposed treatment when risks are adequately disclosed is relevant to assessment of the objective test.
[86] A patient’s own testimony is inherently unreliable: a patient who is bringing an action would not likely admit that she would have agreed to the procedure at issue. The Supreme Court of Canada has expressly cautioned courts against reliance on the patient’s own testimony in informed consent claims:
The plaintiff will invariably state with all the confidence of hindsight and with all the enthusiasm of one contemplating an award of damages that consent would never have been given if the disclosure required by an idiosyncratic belief had been made. This would create an unfairness that cannot be accepted.
[87] Rather, courts are to consider the issue objectively based on the “particular concerns” of the patient and any “special considerations affecting the particular patient.”
[340] The plaintiffs must establish that the failure to disclose caused material harm to them. This involves both a subjective and a modified objective inquiry. The plaintiffs must establish that they would not have agreed to stop the pyridoxine or would have started it upon return of the seizures, and that a reasonable person would not have agreed to stop the pyridoxine or would have restarted it in the same circumstances.[^48]
[341] Jennifer testified that had she been fully informed of the B6 trial she would not have consented to stopping the B6 and would have started B6 immediately when the seizures returned. Jennifer testified that in May 2003 her priority for Skyler was to stop the seizures. A diagnosis was not important to her at that time. It was Jennifer who, on July 15, 2003, suggested to the pediatric neurologists, Dr. Meaney and Dr. Ronen, that they consider pyridoxine. This supports Jennifer’s evidence that she would have in fact continued and/or restarted the pyridoxine.
[342] As noted above, Jennifer’s testimony must be regarding with degree of skepticism. The defendants seek to undermine her credibility by pointing to her evidence in cross-examination that she conceded that the reason why she did not restart Skyler on B6 in May 2003 is because she was “told it didn’t work” and that she was going to follow the advice of the doctors. They point to evidence that Jennifer consistently followed Dr. Meaney’s advice with respect to B6 and other medications. This misses the point. Jennifer should not have been told that the B6 did not work. She should have been told that the results were inconclusive. She should have been informed of the purpose of the pyridoxine trial and of the risks and benefits of discontinuing the B6. She should have been told that if the seizures restarted, Skyler should be restarted on pyridoxine, a virtually harmless vitamin.
[343] I find that any reasonable person, properly informed, would very likely have continued the B6 on May 16, 2003, not agreed to stop the B6, and certainly would have restarted the B6 or queried the doctors if it should be restarted when the seizures returned on May 26, 2003, and thereafter.
E. CAUSATION: PYRIDOXINE AND INFORMED CONSENT
11. Positions of the Parties
[344] The plaintiffs’ position is that the evidence supports the conclusion that the defendants’ breaches of the standard care caused Skyler’s developmental delay and disability. They point to the medical documentation and evidence showing Skyler’s normal development in May 2003, evidence supporting a change in Skyler’s presentation after July 2003, a comparison to Skyler’s sister, and expert evidence regarding the outcome of PDE patients treated with pyridoxine, particularly late-onset patients.
[345] The defendants submit that the plaintiffs cannot establish causation. They argue that the most likely cause of Skyler’s outcome is her PDE and that her outcome would not have been different with earlier pyridoxine supplementation. The defendants submit that the plaintiffs’ causation theory lacks a factual and legal basis for the following reasons:
a. The plaintiffs’ experts did not consider the relevant literature before assessing causation;
b. Seizure control does not improve neurodevelopmental outcome;
c. Neither plaintiff expert identified a sentinel event;
d. The literature and facts demonstrate that there is no reason to believe Skyler would have followed the developmental course of her sister Summer; and
e. The 2016 MRI and the head circumference measurements do not prove a July 2003 brain injury.
12. Law of Causation
[346] The parties agree that the test for causation is the “but for” test. The plaintiff must establish on a balance of probabilities that “but for” the defendants’ negligent act, the injury would not have occurred.[^49]
[347] The plaintiffs must prove that “but for” the breach of the standard of care by either or both defendants, or but for the lack of informed consent, Skyler would not have suffered a significant brain injury resulting in the developmental challenges she currently faces.
[348] As the Court of Appeal for Ontario explained in Donleavy v. Ultramar Inc.:
[72] Causation is made out under the “but for” test if the negligence of a defendant caused the whole of the plaintiff’s injury, or contributed, in some not insubstantial or immaterial way, to the injury that the plaintiff sustained. Causation requires a “substantial connection between the injury and the defendant’s conduct.”[^50]
[349] To meet the “but for” test in a medical negligence case, the plaintiff must lead evidence on how the defendants’ breach of the standard of care caused the plaintiff’s injury.[^51] The plaintiffs must prove on a balance of probabilities that the delay in treatment with pyridoxine caused or contributed to Skyler’s unfavourable outcome.[^52] The plaintiffs must prove on the balance of probabilities that, but for the doctors’ breach of the standard of care, the unfavourable outcome or injury would have been avoided with prompt treatment.[^53] Inherent in the phrase “but for” is the requirement that the defendant’s negligence was necessary to bring about the injury ― in other words that the injury would not have occurred without the defendant’s negligence.[^54] Loss of a chance is not compensable in medical malpractice cases.[^55] What is required is an actual link between the delay in diagnosis and treatment, and the plaintiffs’ injuries.[^56]
[350] The “but for” causation test must be applied in a robust common-sense fashion. There is no need for scientific evidence of the precise contribution the defendant’s negligence made to the injury.[^57] Causation need not be proven with scientific or medical certainty because the law requires proof of causation only on a balance of probabilities, whereas scientific or medical experts often require a higher degree of certainty before drawing conclusions on causation. Scientific causation and factual causation for legal purposes are two different things. Factual causation for legal purposes is a matter for the trier of fact, not for the expert witnesses, to decide.[^58]
[351] A trial judge may draw an inference, where a medical expert would not, based on common sense and a consideration of all the circumstances.[^59] Evidence connecting the breach of duty to the injury suffered may permit the judge, depending on the circumstances, to infer that the defendant’s negligence probably caused the loss. Where “but for” causation is established by inference only, it is open to the defendant to argue or call evidence that the accident would have happened without the defendant’s negligence.[^60]
[352] In taking a “robust and pragmatic” approach to the facts, courts may draw inferences of causation on the basis of “common sense”. The trier of fact may draw an inference of causation even without “positive or scientific proof” if the defendant does not lead sufficient evidence to the contrary. If the defendant adduces evidence to the contrary, then, in weighing that evidence, the trier of fact may take into account the relative ability of each party to produce evidence.[^61]
[353] The robust and pragmatic approach does not dispense with the requirement that plaintiffs lead some evidence of causal connection, whether the claim is based on negligence or on a breach of the duty of disclosure. Moreover, the approach is most robustly applied in cases in which the facts lie particularly within the knowledge of the defendant.[^62]
13. Facts
Skyler’s development
[354] Skyler was born on December 20, 2002, after an uneventful labour and delivery and was discharged home the next day. Jennifer testified that Skyler was developing normally until she was about three months old. She then became cranky and irritable. This was not challenged by the defendants.
[355] All the experts agreed that Skyler’s seizures were late onset and in the atypical category for PDE.
[356] Dr. Meaney’s May 11, 2003, note states that Skyler was a healthy-appearing four-month-old who was developmentally normal. Dr. Ronen agreed that apart from her seizures, Skyler did not have any unusual health issues in May 2003.
[357] In his June 24, 2003, letter to Skyler’s pediatrician, Dr. Meaney did not comment on Skyler’s development. He admitted that if he had concerns about her development at that time, he would likely have noted them in his consult letter. Dr. Meaney’s July 6, 2003, note states that thus far Skyler has been keeping up developmentally. There is no evidence to contradict this.
[358] Dr. Meaney testified that in July of 2003 he thought that if Skyler’s seizures could not be controlled, there was a significant risk of permanent brain damage and even death.
[359] Dr. Meaney discussed with Skyler’s parents the degree to which her course had worsened her prognosis overall as reflected in his note dated July 6, 2003, in which he wrote: “I did discuss with the parents the degree to which Skyler’s course has worsened her prognosis overall. They seem to appreciate the reduced change of … outcome for her”. At this time, Dr. Meaney felt that her developmental outlook was concerning.
[360] On July 18, 2003, Dr. Ronen noted that he suspected Skyler may develop to a vegetative state though it was too early to be definite about that suspicion.
[361] Jennifer testified that after Skyler came home from the hospital in August 2003, Skyler was different and did not seem to be the same. She was kind of out of it and non-responsive. Skyler was a different baby; she was lethargic, did not make eye contact, and was limp. Jeff testified that he felt like she was not there. This evidence was not challenged.
[362] Jennifer’s recollection was that when Skyler was discharged on August 11, 2003, she had suffered a brain injury and would not recover to how she was been before.
[363] On October 23, 2006, Dr. Meaney acknowledged to Jennifer that Skyler’s secondary seizures were caused by her brain injury.
[364] At the time of trial, Skyler was 21 years old. Her current cognitive and behavioral impairments are significant. She is non-verbal and has limited ability to express herself. She can make facial expressions and sounds denoting happiness (e.g., laughter and smiling), and unhappiness (e.g., screaming, crying and becoming visibly upset). She has some responsive understanding of language and speech and can understand and follow very simple directions.
[365] While in school, Skyler received 1:1 education assistant support. She understood basic routine auditory directions within the classroom. She is no longer attending school.
[366] Skyler requires assistance with all her activities of daily living. She is dependent upon assistance for all aspects of her personal care, including bathing, grooming and dressing. She was previously able to feed herself but now has had difficulty doing so due to her hands shaking. She has been on an all liquid or pureed food diet for years, as she will not eat solid food. She is incontinent and requires diapers.
[367] Skyler requires full time direct and supervisory care, including overnight supervision. She self-harms including biting her hands and pulling her hair. Skyler can participate in various supervised recreational activities.
[368] Skyler can ambulate independently. She can physically walk throughout her house without any apparent difficulty or need for mobility support. She is physically able to run, jump and walk up stairs. However, for safety concerns, she requires supervision when walking up stairs. She cannot leave the house without direct supervision. As Skyler is fully mobile but lacks insight, she is a flight risk and so, is fastened to her service dog.
[369] There is no prospect that Skyler’s condition will improve.
Skyler’s sister
[370] Skyler’s sister, Summer, was born on February 6, 2008. On February 11, 2008, she had “jitters” and was taken to GNGH overnight and then transferred to MCH. Jennifer said she suggested to the doctors that pyridoxine be considered given what transpired with Skyler. One of the hospitals started her on pyridoxine. Summer’s jitters improved over a few days. She was discharged on a daily dose of pyridoxine and has remained on it since. Summer had one seizure when she was 15 months old which was associated with a very high fever.
[371] In October 2008, genetic testing ordered by Dr. Meaney confirmed that Summer has two heterozygous mutations in the ALDH7A1 gene, confirming a diagnosis of PDE. Skyler has the same mutation.
[372] Jeff and Jennifer testified that Summer is doing well. Summer’s development has been very good; Summer does well at school, she plays piano and she is trying to teach herself guitar. Jeff testified that Summer looks after Skyler at times. Jeff has no concerns about Summer’s development. This evidence was uncontested.
14. Expert Opinions
[373] The defendants submit that only Dr. Snead and Dr. Prasad cited literature regarding the different outcomes of PDE patients. They say that Dr. Yager cited no literature at all and did not review the literature. The defendants submit that Dr. Wiznitzer testified that he had reviewed the literature, chose not to cite it, and confirmed it showed variation in outcome of PDE patients.
[374] The defendants rely upon Bauer v. Kilmurry[^63] for the proposition that where an expert supports his opinion with peer reviewed academic medical literature and the other expert does not produce such literature the court must prefer the opinion of the former. I do not accept that as a statement of the law which would bind trial judges in their review and assessment of expert evidence in all cases. Expert evidence is assessed and weighed based on a myriad of factors which are case dependent. This is but one factor.
[375] Dr. Wiznitzer’s opinion is that the failure to restart pyridoxine in the weeks before July 16, 2003, caused or contributed to Skyler’s developmental issues. The child who was admitted to the hospital on July 6 was not the child who was released from hospital on August 11, 2003. His opinion is that if Skyler had remained on pyridoxine at any time before her July 6, 2003, admission to the hospital, she would have avoided the vast amount of the damage that she suffered. She would have remained a functional human being and remained on pyridoxine treatment for the rest of her life.
[376] Dr. Wiznitzer’s opinion is based on a number of factors. He notes that Skyler demonstrated good developmental progression until her admission in July 2003 with no evidence of significant developmental delay to suggest she had any significant brain injury because of the PDE or prior seizures. Dr. Wiznitzer testified that if there is normal development, no significant brain injury has occurred to alter the developmental trajectory. Skyler had a normal brain MRI in May 2003 but her MRI in 2016 showed damage to her brain. Her head circumference growth decelerated after her July 2003 stay in hospital. She suffers from significant intellectual and developmental delay. Skyler's sister Summer who has the same genetic mutation and was treated for pyridoxine-dependent seizures from an early age has developed normally.
[377] Dr. Snead’s opinion is that Skyler’s outcome would have been no different if she had been diagnosed with PDE earlier or if the pyridoxine was started earlier. He bases his opinion primarily on the literature he reviewed, on the percentage of patients with PDE who suffer from IDD even with pyridoxine treatment, and the great variability of the operation of the genes in the disorder.
[378] Dr. Prasad opined that there was no definitive evidence to suggest that anything that the two physicians did was responsible for any brain injury. Dr. Prasad’s opinion is that even if Skyler had been treated with pyridoxine earlier, it would not have made any substantive difference to Skyler’s development. This is based on “collective experience” and observational studies that pyridoxine alone would not protect the child against the underlying risks of developing cognitive and other impairments that have been observed in other individuals with the same condition. It is also based on the percentage of patients with PDE who suffer from IDD even with pyridoxine treatment, the great variability of the operation of the genes in the disorder, and the mechanism by which the genetic disorder operates to create and accumulate neurotoxins in the brain which damage the brain.
[379] The defendants note that both defence experts opined that the 51 days between the earliest possible breach of the standard of care on May 26, and pyridoxine being restarted on July 16, did not make a difference to Skyler’s ultimate outcome.
[380] To assess the expert opinions and the issue of causation, it is necessary to consider various issues upon which the experts were extensively examined.
The genetic disorder
[381] The underlying genetic defect of PDE is a deficiency of an enzyme known as alpha-aminoadipic semialdehyde (a-AASA) dehydrogenase, or antiquitin. This enzyme is a type of protein that acts as a catalyst in various metabolic processes. The ALDH7A1 gene has the instructions or genetic information necessary to build and assemble the antiquitin enzyme.
[382] In individuals with PDE, the antiquitin enzyme's activity is deficient, leading to the accumulation in the brain and body fluids of (1) the enzyme; (2) the organic compound, pipecolic acid; and (3) Δ1-piperideine-6-carboxylate (a different manifestation of the antiquitin enzyme). In sufficient quantity these compounds, known as metabolites, may be harmful to the brain (neurotoxic) and are associated with the onset of seizures in infants and young children.
Impact of seizures
[383] Dr. Wiznitzer testified that status epilepticus can lead to brain damage. He testified that studies suggest that status epilepticus of 45 to 60 minutes will cause brain damage.
[384] Dr. Snead repeatedly testified about the emergency that status epilepticus represents and the damage it could do to a child’s brain. For example, he testified that when a patient presented as Skyler did with status epilepticus it is a real neurological emergency which can lead to severe irreversible brain damage and also can cause patients to die. He described the heroic doses of anti-epileptic drugs Skyler had been given to control her brain threatening status epilepticus. He testified about how the doctors were making treatment decisions minute to minute to try and obviate any potential injury that would be caused by the seizures and to try to save the child’s life and brain. Dr. Snead testified about how if Skyler had gone into full blown status epilepticus she would have been severely injured.
[385] Dr. Snead also testified that the literature indicates that seizure control has no impact on neurodevelopmental outcomes for patients with PDE. The defendants point to the evidence from the Consensus Guidelines that there is no correlation between outcome and seizure control, and that there are patients who have been treated very early with pyridoxine who remained seizure free but who nevertheless have IDD. Here, the defendants appear to refer to 3.2 Clinical Presentation in the Consensus Guidelines which indicates that the level of evidence for this section is low-quality evidence.
[386] Dr. Prasad agreed that status epilepticus or intractable seizures are unfavourable to cognitive outcome and that he failed to mention this in his evidence in chief. Dr. Prasad agreed that it was known that status epilepticus and intractable seizures can cause brain damage independent of the underlying etiology of the seizure disorder. Dr. Prasad agreed that most studies suggest that the outcome from convulsive status epilepticus is dependent on the etiology, however, all things being equal, individuals who have a seizure duration greater than 60 minutes are 5.5 times more likely to have development of neurologic sequelae independent of etiology.
Statistical Outcomes
[387] Dr. Prasad testified in chief that in 2003 it was understood that most children with PDE achieved delayed milestones; they would have varying degrees of motor dysfunction with cognitive difficulties particularly in verbal scores. These difficulties were typically identified when children with PDE started school. Dr. Prasad explained that comprehension skills were possibly better preserved compared to expressive language skills.
[388] The expert evidence is that approximately 75 percent of patients with PDE have some degree of IDD even with treatment with pyridoxine. The 75 percent figure comes from the Consensus Guidelines.
[389] Dr. Yager testified that with treatment, 25 percent of patients with PDE have a normal development, 25 percent have a minor disability, 25 percent have a medium disability, and 25 percent have a severe disability.
[390] In chief Dr. Prasad testified that pyridoxine supplementation alone is insufficient to achieve normal developmental outcome and that even when seizure control is achieved most such patients experience intellectual disability or developmental disability.
[391] In cross-examination Dr. Prasad admitted that there are a range of disabilities that present in this 75 percent; disability ranges from mild to very severe. Dr. Prasad refused to admit that the majority of PDE patients have normal development or are mildly delayed until in cross-examination he was referred to the Bok article[^64] which he referred to in his report. Dr. Prasad agreed that the Bok article indicates that 29 percent of PDE patients had normal development and 29 percent were mildly delayed. He agreed that 58 percent of patients referred to in the Bok article have no or mild IDD.
[392] Dr. Prasad also agreed that the Bok article was one of the studies that is the source of the 75 percent figure. He acknowledged that all the subjects in the Bok article are neonatal cases, not late onset cases. Dr. Wiznitzer testified that the 75 percent figure does not apply to Skyler because she had late onset PDE, not neonatal onset.
Late onset of seizures
[393] Dr. Yager testified that late seizure onset has been postulated as beneficial for the developmental outcome of people with PDE.
[394] Dr. Wiznitzer testified that IDD is mostly in neonatal onset as indicated in the references to the Consensus Guidelines. His opinion is that whether patients with PDE have IDD depends on when the seizures start. If they start in the neonatal period, there is a greater risk of disability. If they start later, there is less risk. He testified that late onset patients have better outcomes.
[395] In cross-examination Dr. Prasad agreed that late-onset is positive for cognitive outcome. He agreed that late seizure onset has been postulated as beneficial for the developmental outcome with several factors hypothesized to contribute to this outcome, including genetic and functional variation, variation of treatment regimen, absence of neonatal seizures, and unknown protective factors. He agreed that he did not testify to this in his examination in chief. He again noted that each case must be viewed individually because sometimes broad statements cannot be extrapolated to a particular case.
[396] Dr. Prasad agreed that the paper he and his co-authors wrote in 2022[^65] concluded that late-onset seizures is a significant predictor of developmental test results and that delay in diagnosis and treatment may be a main contributor to the poor developmental outcome for people with PDE. The paper considered eight late onset patients with a mean developmental score in the normal range of 92.2. At one point Dr. Prasad testified that two of those eight patients were treated with pyridoxine alone; at another point he said they all had triple therapy at some point, but some had pyridoxine monotherapy first for a time.
Triple Therapy
[397] Dr. Prasad testified that treatment recommendations for PDE were updated in 2014 to include the use of a lysine-restricted diet. In addition, pharmacologic doses of arginine were recommended. Pyridoxine remained a mainstay of therapy. Together, these three treatments are referred to as a triple therapy and are used to attempt to reduce harm from PDE.
[398] Dr. Yager testified that a lysine-restricted diet is not a “utopian therapy.” In his opinion, the addition of a lysine-restricted diet to pyridoxine in the treatment of PDE may add, but often does not add any particular benefit to the outcome. Dr. Wiznitzer agreed that lysine reduction therapies have been associated with improved long-term neurologic outcomes. He noted that there is disagreement among experts on the effectiveness of lysine-restricted diet and its impact on outcomes.
[399] Dr. Prasad testified that there is some support for suggesting that there would be an improved cognitive outcome as a result of triple therapy. Dr. Prasad conceded that Summer did not start a low-lysine diet until 2013 when she was 5 years old – long after the critical developmental window that Dr. Prasad identified had passed.
[400] Dr. Prasad was one of the authors of a paper in 2022[^66] directed at trying to establish an association between early introduction of triple therapy and cognitive outcomes based on 62 patients between 2014 and 2021. He testified as to its results. In cross-examination Dr. Prasad conceded that only 15 percent of the cases in his 2022 paper were late onset cases. Further, his paper indicates that given the association between late-onset seizures and relatively good developmental outcomes in patients who present with onset of seizures after two months of age, they may only require treatment with pyridoxine supplementation. He did not mention this in his evidence in chief. He defended himself by saying that further study is needed and that a general statement cannot be applied to all individual cases.
Head Circumference
[401] Measurements for Skyler’s head circumference were recorded in her medical records.
[402] Dr. Wiznitzer testified that head circumference tends to grow at a certain rate and remain consistent. If there is an injury to the brain, the head will not grow as fast as it would have without an injury.
[403] Dr. Wiznitzer compared Skyler’s head circumference measurement prior to her July 6, 2003, admission to MCH and her measurements at age 6 and 14. Her head circumference was within the normal range before July 6 – it was growing at the 30th percentile. After the July 2003 admission, there was a deceleration of the growth velocity of Skyler’s head. By age six Skyler was less than the first percentile, meaning that her head size was smaller than 99 percent of children. In Dr. Wiznitzer’s opinion, this information, taken together with other information in Skyler’s history means that the deceleration in head circumferences matches the time of the clinical injury. Dr. Wiznitzer says this was the result of the brain injury which was caused by the status epilepticus of the July admission.
[404] Dr. Prasad agreed that pediatric neurologists look at changes in head circumference percentiles over time. He agreed that up until July 6, 2003, Skyler’s head circumference trajectory was normal. He agreed that there appeared to be a deceleration in brain growth, which could be considered acquired microcephaly due to the underlying disorder. He was not aware of any PDE literature which demonstrates a drop off in head circumference such as that experienced by Skyler.
[405] In his second report Dr. Prasad cited Dr. Gospe’s 1999 paper[^67] which found that untreated pyridoxine-dependent seizures are associated with progressive cerebral atrophy. He agreed that, depending on the trajectory, if a patient had cerebral atrophy, you would expect them to develop acquired microcephaly, depending on the extent of the atrophy.
MRIs
[406] An MRI shows what the brain looks like at a point in time. An MRI does not show whether the brain is functioning properly.
[407] The evidence is that Skyler’s May 13, 2003, MRI was normal.
[408] On January 21, 2016, an MRI of Skyler’s brain showed evidence of previous white matter insult with thinning of the posterior white matter and increased signal on T2-weighted and FLAIR images within the periventricular white matter, particularly adjacent to the atria of the lateral ventricles, and thinning of the posterior corpus callosum. Dr. Wiznitzer testified that the January 21, 2016, MRI report indicated significant damage to the white matter of the brain.
[409] Dr. Wiznitzer testified that in children with PDE, there is hypoplasia of the posterior corpus collosum. Because the May 2003 MRI was normal, Skyler did not have hypoplasia; she later acquired damage to the posterior corpus collosum. Dr. Wiznitzer acknowledged that the 2016 MRI does not enable anyone to say when the brain damage occurred. However, in conjunction with the clinical history and the measures of head circumference, he testified that it can be determined.
[410] Dr. Prasad testified that concluding that the white matter injury on the 2016 MRI is consistent with the effects on Skyler’s brain of recurrent seizures that occurred in 2003 is not a tenable conclusion that can be drawn from two MRIs separated by 13 years. However, Dr. Prasad testified that generally, the kinds of changes that take place in the brain as a result of PDE which are seen in MRIs include abnormalities of the corpus callosum, cortical atrophy, white matter signal changes, incomplete or delayed myelination, and hypoplasia of the brain stem. Dr. Prasad testified that some of these changes, particularly the white matter changes that were referenced in Skyler’s MRI reports, are also included in the range or spectrum of abnormalities associated with PDE.
Comparison to Summer
[411] Skyler and Summer share the same underlying genetic abnormality and both sisters respond to pyridoxine. Dr. Yager testified that because of this fact, it is common sense that they would follow the same course if treated the same way. His opinion is that if Skyler was treated earlier with pyridoxine, her development trajectory would be better than it is today.
[412] Dr. Wiznitzer testified that Summer, who was treated with pyridoxine in the first days of her life and whose development was normal, is an example of what Skyler would have been like if she had received pyridoxine treatment. It is his opinion that if there is an identical genetic mutation in siblings, it will cause similar disruption to function and cause seizures. Dr. Wiznitzer also noted that Summer was not in the 75 percent of patients with neonatal PDE with some degree of IDD. In other words, Summer is in the rarer 25 percent of patients with neonatal PDE with no IDD.
[413] Dr. Wiznitzer agreed that although seizures are a defining feature of PDE, other disorder manifestations can vary widely even within the same family. However, lack of variation in the same family is also possible. In part it depends on when treatment begins. If the first child is not treated in time, but the second is, outcomes can be different. There are many variables. Dr. Wiznitzer testified that some of the PDE literature on siblings supports his opinion and the comparison of Skyler and Summer for causation purposes, and some does not.
[414] Dr. Snead does not agree that Skyler would have followed the same developmental trajectory as Summer if she had been treated earlier with pyridoxine because Summer’s seizures started neonatally whereas Skyler had atypical PDE, with seizures that did not start until almost four months of age. He testified that this means the genetic manifestations of the PDE were different in the two sisters. Dr. Snead also testified that the literature indicates that the outcomes of siblings with PDE can vary and siblings can present in a different way. As a result, it cannot be said that Skyler would have done better if she had been treated earlier because she had a different phenotype.
[415] Dr. Prasad does not agree that because Summer has no developmental issues, Skyler would not have had any developmental issues if she had been treated earlier. He testified that unlike Summer, Skyler does not have two identical genetic mutations; she has a genetic mutation and an intergenic deletion. How that affects the expression of the phenotype is variable, as is the variability of response to treatment. Family members do not have the same genes and genes work in concert with other genes. Within a family there is considerable genetic variation, even with the same genetic mutation. It is not uncommon to find different presentations and different responses to treatment. Dr. Prasad noted that Summer presented very early in life with a classic presentation, whereas Skyler presented much later with an atypical presentation, yet both carried the same mutation. For these reasons his opinion is that one would expect that the treatment response would also be very different.
[416] Dr. Prasad referred to two articles on siblings with PDE. The first was the 2012 paper he co-wrote entitled, “Pyridoxine-dependent epilepsy – Enduring Mystery and Continuing Challenges”[^68] concerning two siblings with PDE who shared the same genetic mutation and were treated with pyridoxine from early infancy. These siblings, despite the control of their epileptic seizures, differed very significantly in their cognition and intellectual outcomes. He testified that this highlights the variability of treatment response in family members who share the same genetic mutation.
[417] In his paper, Dr. Prasad cites a paper entitled “Variability of Phenotype in Two Sisters with Pyridoxine-Dependent Epilepsy.”[^69] That paper makes the point that there can be variation in presentation within the same family and illustrates the fact that both sisters were diagnosed and treated early with pyridoxine alone but one had mild intellectual disability and the other had very significant disability to the extent that she could not manage her activities of daily living independently. In cross-examination Dr. Prasad acknowledged that the two sisters in the study had a different genotype than Skyler or Summer. Unlike Skyler and Summer, they also required anti-seizure medications to control their seizures. Further, the sister with the milder intellectual disability had later onset of seizures.
15. Causation analysis
[418] The experts largely agreed that there is much that is still not known about PDE. The level of medical evidence available is not of the highest quality because of the nature of PDE and the obvious unlikelihood of conducting randomized control studies with patients. The Consensus Guidelines for the diagnosis and management of PDE that the experts referred to demonstrate that there is no high-quality evidence with respect to PDE. The evidence is of moderate quality or low quality.
[419] In support of their argument that “the reason why pyridoxine and seizure control are insufficient to prevent poor developmental outcomes is because PDE is now understood to be a complex neurological neurodevelopmental disorder” the defendants reference the following excerpt from the evidence of Dr. Prasad:
A. Yes. So, I’m quoting the sentence from this paragraph, “It is conceivable that much of brain development and connectivity may be impaired in the prenatal and perinatal interval until the infant presents with symptoms and seizures.” So, this goes back - as an explanation, this goes back to the fact that the genetic mutation is present in the affected individual right at the time of conception. And the effect of the antiquitin deficiency would likely be operative throughout the prenatal and perinatal periods interfering possibly with the development of the neuronal network in the brain. And the neuronal network in the brain is basically the, the infrastructure on which later cognitive development and all the other developmental milestones that an infant displays, would be founded on. So, if you have a disturbed neuronal network, at a critical point when it destabilizes, symptoms may appear, and seizures are just one manifestation. If you see the whole condition as a complex neurological neurodevelopmental disorder, seizures are just the tip of the iceberg. In my opinion, the rest of the comorbidity may take a long time to manifest itself. [Emphasis added].
[420] As the emphasized words demonstrate, there is much speculation in the quoted evidence of Dr. Prasad. In my view this evidence demonstrates that Dr. Prasad’s conclusion on this point is speculative, which is consistent with the evidence that there is much that is still not known about PDE and that the level of evidence available is not of the highest quality.
[421] The evidence is that Skyler was developing normally before and even after her seizures started and until at least July 6, 2003. The evidence on this is undisputed. The evidence does not support a finding that Skyler was suffering from impaired brain development before July 6, 2003. I find that Skyler was developing normally up until July 6, 2003, but her development changed after July 6, 2003.
[422] In forming their opinions, the experts all relied on their personal experience. They also relied to a varying degree on the literature and the studies contained therein. The literature reviewed with the experts indicates that a limited number of individuals were the subject of those studies.[^70] The experts referred to various studies which supported one side or the other.
[423] The evidence demonstrates that there is variability amongst individuals as to how they respond to PDE and as to their outcomes. A particular individual with PDE may respond differently depending on many variables. The point was made, particularly by Dr. Prasad, that the general does not necessarily apply to any individual and that it is not possible to determine with medical or scientific certainty whether the outcome of an individual with PDE would be different if they received pyridoxine earlier rather than later. In Dr. Prasad’s opinion, there are too many variables to arrive at such a conclusion in this case.
[424] The difficulty with the defendants’ position on causation is that given the current limited state of medical knowledge with respect to PDE, the unlikelihood of conducting randomized control studies with patients, the quality of the evidence available, and the inevitable variability caused by genetics amongst all individuals, it would never be possible to establish with certainty that an individual’s outcome was impacted by the late administration of pyridoxine. But medical or scientific certainty is not required to establish causation.
[425] I have more information before me about Skyler than information about the individuals in the literature and studies which were reviewed with the experts. I turn now to a consideration of the factors and evidence summarized above.
[426] Relying on the evidence of Dr. Wiznitzer, the plaintiffs say that Summer is the ideal comparator to determine Skyler’s outcome if she had been treated with pyridoxine earlier. The defendants say that no conclusion can be drawn from Summer’s outcome. The defendants submit that the evidence demonstrates that Summer’s genetic mutation affected her differently than Skyler. Skyler experienced “jerky movements” at approximately 3.5 months of life and her first seizures requiring a visit to the hospital occurred at 4.5 months of life whereas Summer began seizing on the fifth day of her life. Further, Summer started pyridoxine on her sixth day of life and remained on it thereafter – more than 4.5 months earlier than Skyler.
[427] The defendants cite the following passage from Dr. Prasad’s evidence as the best and most reliable explanation why, based on the literature, Skyler was unlikely to follow Summer’s course:
Intrafamilial variability is a well-recognized feature in genetic conditions, particularly if there are still presentation, evolution and progression and response to treatment. See, the genetic makeup of two individuals is not exactly identical unless they are identical twins. So, within a family there is considerable genetic variation that arises, even between – between members of the same family or between individuals affected across families with the same genetic conditions, same genetic mutation. And this is a well-established factor in genetics because this genetic variation – because genes don’t work singlely[sic], they work in concert with other genes. There is a whole gene-gene network and protein-protein interaction that occurs on a, on a broader note. As a result of which it’s not uncommon to find different responses to presentation, different responses to treatment. And I draw your attention to the situation here where Skyler’s sibling presented very early in life with a more, what would be considered as a classical presentation, as opposed to Skyler who presented much later, and they both carried the same mutation. Of course – similarly for the same set of reasons that I’ve just outlined, one would expect that the treatment response would also be very different.
[428] Skyler had late onset PDE and Summer had neonatal onset. The evidence is that late onset patients have better outcomes. Further, Summer is in the 25 percent of neonatal patients with no IDD. This is some evidence that suggests Skyler’s possible outcome if she had been treated earlier with pyridoxine. However, the comparison to Summer is attenuated by the fact that unlike Summer, Skyler has a genetic mutation and an intergenic deletion. Further, there is genetic variation as noted by Dr. Prasad. The limited available studies indicate that PDE manifestations and outcomes can vary widely even within the same family and even if they have the same mutation. At best, it can be said that Summer’s normal development is some potential evidence of causation, although not especially strong evidence or worthy of substantial weight.
[429] Skyler did not receive triple therapy during the critical early years of development. Neither did Summer. Although not the case in 2003, PDE is now treated with triple therapy. There is some indication that triple therapy improves outcomes for PDE patients. There is also evidence from Dr. Prasad that given the association between late-onset seizures and relatively good developmental outcomes in patients who present with onset of seizures after two months of age that these individuals may only require treatment with pyridoxine supplementation. The effect that triple therapy would have had on Skyler’s outcome, if any, is far from clear on the evidence.
[430] The defendants submit that neither of the plaintiffs’ experts identified any sentinel event that could have caused a brain injury in July 2003 and that Dr. Prasad testified that a sentinel event may occur during management of a patient in the intensive care unit for various reasons. The defendants acknowledge that although Dr. Wiznitzer testified that Skyler’s injury “was from the status epilepticus that occurred during the July hospital admission,” he did not identify when in the July admission the injury occurred, or how it occurred. In my view, this level of precision is not necessary for the court to determine causation on these facts.
[431] Although dismissive of Dr. Wiznitzer’s evidence, the defendants cite his evidence that most seizures do not cause brain injury and that status epilepticus needs to be prolonged – 45 minutes to an hour – before it can cause any injury. They say that Dr. Wiznitzer did not identify any such period in the record.
[432] As noted above, Dr. Prasad testified that status epilepticus or intractable seizures are unfavourable to cognitive outcome. He testified both that status epilepticus and intractable seizures can cause brain damage independent of the underlying etiology of the seizure disorder and that studies suggest that the outcome from convulsive status epilepticus is dependent on the etiology. However, he said that all things being equal, individuals who have a seizure duration greater than 60 minutes are 5.5 times more likely to develop neurologic sequelae independent of etiology. The evidence also indicates that there may be electrical activity in the brain representing seizure activity even when seizures are not observed.
[433] Between May 26 and July 6, 2003, Skyler suffered many seizures. The seizures caused Dr. Snead grave concern. Dr. Snead repeatedly testified about the severe risk and emergency posed by the status epilepticus and ongoing seizures experienced by Skyler during her treatment by the defendants.
[434] On July 7, 2003, due to repeated breakthrough seizures, the defendants took the extraordinary step of putting Skyler into a pentobarbital coma for five to six days to stop the seizures. The defendants and doctors warned Skyler’s parents about the very likely negative impacts of the events in July 2003. The evidence that Jennifer was told in July 2003 that Skyler had suffered a severe insult to her brain and was told by Dr. Meaney in October 2006 that Sk