# Appendix — Hanlon v. Shalala, 120 S. Ct. 2212 (2000) (No. 99-1223)

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## Record

- **Collection:** Supreme Court brief
- **Document type:** Appendix
- **Published:** January 1, 2000

## Text

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991223 JAN 19 200

OFFICE OF THE CLERK
No.

In The

Supreme Court of the United States

seh enineaaliaatll

October Term, 1999

JOHN HANLON AND RUTH ANN HANLON, PARENTS
AND NEXT FRIENDS OF MICHAEL HANLON, and MARK
PLAVIN AND TONY REISS-PLAVIN, PARENTS AND NEXT
FRIENDS OF RACHEL PLAVIN,

Petitioners,
-VS.-

DONNA E. SHALALA. SECRETARY OF THE
DEPARTMENT OF HEALTH AND HUMAN SERVICES,

Respondent.

On Petition for a Writ of Certiorari to the United
States Court of Appeals for the Federal Circuit

APPENDICES TO
PETITION FOR A WRIT OF CERTIORARI

RICHARD GAGE
Attorney for Petitioners
Gage & Moxley
623 West 20" Street
P.O. BOX 1223
Cheyenne, WY 82003-1223
(307) 632-1112

la
APPENDICES

APPENDIX A: DECISION OF THE OFFICE OF SPECIAL
MASTERS IN AND FOR THE UNITED STATES COURT
OF FEDERAL CLAIMS, DATED MAY 31, 1994

UNPUBLISHED
In the United States Court of Federal Claims
OFFICE OF THE SPECIAL MASTERS
No. 90-1334V
May 31, 1994

JOHN HANLON AND RUTH ANN HANLON, PARENTS
AND NEXT FRIENDS OF MICHAEL HANLON,

Petitioners,
VS.

SECRETARY OF THE DEPARTMENT OF HEALTH AND
HUMAN SERVICES,

Respondent.

Richard Gage, Cheyenne, WY, for petitioners.
Mary Hampton Mason, Washington, DC, for respondent.

DECISION
MILLMAN, Special Master
On behalf of Michael Hanlon (hereinafter, “Michael”),

petitioners filed a petition on September 25, 1990 for
compensation under the National Childhood Vaccine Injury Act

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of 1986' (hereinafter, the “Vaccine Act” or the “Act”.

Petitioners have satisfied the jurisdictional prerequisites
provided in § 300aa-l!(c) of the Act by showing that Michael has
not previously collected an award or settlement of a civil action
for damages arising from the vaccine injury, that they have
incurred $1,000 in unreimbursable medical expenses, and that the
DPT vaccination was administered to Michael in the United
States.

Petitioners allege that Michael suffered significant
aggravation of his pre-existing tuberous sclerosis (TS) in the form
of a residual seizure disorder within the Table time limits of the
Act. 42 U.S.C. § 300aa-14(a)(D) and (E). Respondent defends
with the assertion that the onset of Michael’s seizure disorder
occurred outside the Table time limits. In the alternative,
respondent claims that Michael’s seizure disorder was caused by
a factor unrelated: TS. 42 U.S.C. § 300aa-13(a) (1) (B).

Two hearings were held: October 21, 1991 (at the Mayo
Clinic) and May 6, 1994. Testifying for petitioners were Dr.
Manuel Gomez at the Mayo Clinic, Ruth Ann Hanlon, Patricia
Ditto, Ruth Leahy, and John Hanlon. Because of the superfluity
of medical testimony already amassed in TS cases before this
Special Master, and the pivctal question of whether indeed
Michael’s seizures began within three days of his DPT
vaccination, the local hearing was restricted to lay testimony.
Petitioners filed reports from their expert, Dr. Marcel Kinsbourne.
Respondent filed an expert report from Dr. Russell D. Snyder,
who stated that the onset of Michael’s seizure disorder did not
occur on-Table and that Michael’s TS was not sigmficantly
aggravated by DPT vaccine.

FACTS
Michael was born on March 30, 1978. He received his

'The statutory provisions governing the Vaccine Act are fcund in 42
U.S.C.A. § 300aa—! et seg. (West 1991). The National Vaccine Injury Compensation
Program comprises Part 2 of the Vaccine Act. For convenience, further reference will
be to the relevant subsection of 42 U.S.C. § 300aa.

SR eee ge ae a en eee nae Peet ee ee ares |

3a

first DPT vaccination on June 1, 1978 when he was two months
old. Med. Recs. at 15. Petitioner alleges he suffered his first
seizure one day later.

Michael received his second DPT vaccination on July 28,
1978 when he was four months old. On examination, Dr. Jackson
Erffmeyer noted that Michael was doing well. Med. Recs. at 15.

Michael received his third DPT vaccination on October 3,
1978 when he was six months old. On examination, Dr.
Erffmeyer noted that he had tic-like movements of his head and
neck and questioned whether he was doing well. Med. Recs. at
15. On November 2, 1978, Dr. Erffmeyer noted that Michael had
fewer tics. Med. Recs. at 17.

On December 28, 1978, Dr. Erffmeyer noted that Michael
had had more tics the prior week and was planning to see a
neurologist, Dr. Gaylord Bennett, that week. Med. Recs. at 17.

Michael saw Dr. Bennett on January 17, 1979. The history
he recorded indicates that between the ages of two and four
months, Michael had repetitive eye blinking occasionally.
Between the ages of four and six months, he had recurrent
blinking of the eyes associated with some jerking of the head to
the right. These episodes were unaccompanied by fever. Med.
Recs. at 22-23.

From March 26, 1979 to March 27, 1979, Michael was a
patient at St. Francis Hospital. The history recorded indicates that
at two months, Michael experienced blinking spells that later
developed into four to ten nodding spells daily. Occasionally,
Michael exhibited an exaggerated head jerk and lost his balance.
Med. Recs. at 26.

Michael received his fourth DPT vaccination on October
1, 1979. Med. Recs. at 17. Thereafter, he suffered four seizures
daily. He was rehospitalized at St. Francis from July 1, 1980 to
July 2, 1980. The history recorded indicates that the onset of his
seizure disorder occurred at two months of age. Med. Recs. at 29.

TESTIMONY

Dr. Manuel Gomez, the world’s expert in TS, testified on

October 21, 1991. Dr. Gomez’s testimony on TS was taken at the

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Mayo Clinic and is described in Costa v. Secretary of HHS, No.
90-1476V, slip op. at 10-17 (Cl. Ct. Spec. Mstr. Feb. 26, 1992).
(A description of Dr. Gomez’s textbook and article on TS is on
pp. 5-0 of the same opinion.)

Dr. Gomez testified that TS is not an encephalopathy.
Gomez Tr. at 99. Rather, TS is a genetic disorder which is either
inherited or results from a mutation. Gomez Tr. at 96. Brain
growth controls tuber growth. Tubers exist at birth and do not
multiply. Gomez Tr. at 97. The most common presenting
symptom in TS is seizures. Gomez Tr. at 100. There is a
demonstrable correlation between the presence of many low
attenuated lesions and the frequency and severity of seizures and
mental retardation in an infant less than one year old. Gomez Tr.
at 101.

| The most common age for an onset of seizures in TS
children is the first year of life. The most symptom of
presentation is infantile spasms. Infantile spasms are age-
dependent seizures
occurring between ages of three and eight months, regardless of
the cause. Gomez Tr. at 103.
DISCUSSION

The court ruled from the bench for petitioners. The
attached pages recount the testimony as well as the court’s
reasoning.

CONCLUSION

Petitioners are entitled to a Program award in an amount
yet to be determined. The court hopes that the parties will be able
to settle the damages portion of this case without a hearing, and
suggests petitioners and respondent retain a joint Life Care
Planner and file a Life Care Plan expeditiously. The court will
hold a telephone conference soon to see how the parties are
progressing in resolving the damages issue.

IT JS SO ORDERED.

DATED May 31, 1994 s/
Laura D. Millman
Special Master

Pepe ee eee ny ee tee

Sa

Bench Ruling by Special Master Laura Millman
No. 901334V April 6, 1994

THE COURT: It’s not often that I rule on the record but
I seem to be doing it more often lately and I feel comfortable
doing it now.

As you know, I have all of the tuberous sclerosis cases and
so I’ve become an expert, somewhat, in the medical records
pertaining to T.S. and I read medical records in every other case,
as well. And as you know, as well, when there’s a conflict
between what the parents are saying happened and the medical
records it immediately raises red flags as to what is really true and
the parents are perhaps less believable. But I don’t see a
remarkable difference, if any difference at
all, between what the parents are saying here and what is in the
medical records.

I would not be surprised if they didn’t relate the DPT
shots to the tics because they didn’t see a child that was feverish,
uncomfortable, screaming, in pain. They see a placid child,
who’s still the same child they know and he has a few eye tics.
If you go into the subway you'll probably see people with eye tics.
It happens every day. you don’t necessarily attribute something
serious to this condition, although, obviously when it recurred and
got worse with more symptoms, they became more alarmed.

And that’s manifested in the medical records too. The
pediatrician’s first note as a question mark, tic like movements,
head and neck. And that of course precedes the third DPT.

The medical records are not so precise that you could say
we don’t need the testimony of the Petitioners as was in the Costa
case, where it was blatantly there. Everything in the medical
records -- you didn’t have to hear from Mr. and Mrs. Costa. But
having heard from them, I find them believable, particularly, Mrs.
Hanlon, who has an excellent memory. I am not surprised that she

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would remember certain events, and gauge them toward the fact
that they had seen the doctor the day before these things and now
what is this. It’s a close family. She’s got matriarchy, I think you
referred to, Mr. Gage. supporting her, people visiting her every
day. Apparently the women are a little more precise than the men,
which is not surprising. And, you know, it’s all consistent.
There’s nothing whatever to raise in my mind a lack of
credibility. There’s nothing to raise in my mind that doctors were
told something which now the parents are saying did or didn’t
happen. Dr. Bennett is the first professional who is geared toward
examining this type of thing. The -- I’ll never pronounce this
man’s name -- the pediatrician who -- I’ve got it -- I just want to
find it --Dr. Erffmeyer, who is a

pediatrician, obviously was not sure what this was and
responsibly referred them to Dr. Bennett. Dr. Bennett has always
diagnosed these tics as seizures.

We know from other T.S. cases, where there are tics or
twitches, or whatever, that T.S. can begin in a rather subtle way.
You don’t know what you're looking at. It could be benign. And
unfortunately, due to the nature of the illness, they become more
severe, more repetitive. Whether or not the statement in the
affidavits of the increasing refers to number or duration of the
seizure or type of symptomatology doesn’t really impress me
because the initial time of the seizures was obviously on table.

I have no reason to doubt, not only Mr. and Mrs. Hanlon,
but Mrs. Ditto, as well as the grandmother, Mrs. Leahy, that at the
time of the reception for Mrs. Hanlon’s brother’s wedding, there
was this collection of ladies, all gathered around there looking at
this little baby. They would have looked at him even if he wasn’t
twitching. But he was twitching . And they said it will go away,
which you want to believe. You don’t want to look at a child and
say ah ha, this is a very serious neurologic illness. Take this child
to the doctor at once. No, it’s going to go away. And it did. And
it came back.

We know from numerous discussions that the program
does benefit the Petitioners if they show an on-table onset

Ta

ofseizure activity, particularly in a T.S. child. We know from the
Suel case that one seizure equals significant aggravation, that is
a judicial mandate as far as I’m concerned, coming from Judge
Merow in the Suel case and a dictum coming from Judge Tidwell
in the Costa case.

It may not be applicable in non-T.S. cases but it certainly
seems to be applicable in T.S. cases.

I don’t think from hearing Mr. Hanlon that the child is as
severe as some T.S. children, severely injured, as some T.S.
children and I would hope that to speed things along we could do
damages without life care plans but I would leave that up to the
counsel to see what they need because the child is attending
school although receiving special education and is on seizure
medication and still seizing. It is a pre-Act case so of course
compensation is limited to what the statute permits.

I find that the child, Michael Hanlon’s seizures began
within table time of his first DPT shot, administered June 1, 1978
and that his seizures have continued past six months. That those
seizures significantly aggravated his underlying T.S. so that
whereas prior to the DPT he had no seizures, subsequent to the
DPT he did and continues to have them to this day.

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APPENDIX B: DECISION OF THE OFFICE OF SPECIAL
MASTERS IN AND FOR THE UNITED STATES COURT
OF FEDERAL CLAIMS DATED DECEMBER 239, 1994

UNPUBLISHED
In the United States Court of Federal Claims
OFFICE OF THE SPECIAL MASTERS
No. 91-1555V_ |
December 29, 1994

MARC PLAVIN and TONI REISS, Parents and Next Friends
of RACHEL LEAH REISS-PLAVIN,
Petitioners,
VS.

SECRETARY OF THE DEPARTMENT OF HEALTH AND
HUMAN SERVICES, |
Respondent.

Richard Gage, Cheyenne, WY, for petitioners.
Richard A. Schollmann, Washington, DC, for respondent.

DECISION
MILLMAN, Special Master

On behalf of Rachel Leah Reiss-Plavin (hereinafter,
“Rachel’’), petitioners filed a petition on October 20, 1990 for
compensation under the National Childhood Vaccine Injury Act
of 1986? (hereinafter, the “Vaccine Act” or the “Act”) Petitioners
have satisfied the jurisdictional prerequisites provided in § 300aa-

>The statutory provisions governing the Vaccine Act are found in 42
U.S.C.A. § 300aa-I et seg. (West 1991). The National Vaccine Injury Compensation
Program comprises Part 2 of the Vaccine Act. For convenience, further reference will
be to the relevant subsection of 42 U.S.C. § 300aa.

WN DM Soren ee ate APM Kn APY ob Ho RH

9a

11(c) of the Act by showing that Rachel has not previously
collected an award or settlement of a civil action for damages
arising from the vaccine injury, that they have incurred $1,000 in
unreimbursable medical expenses, and that the DPT vaccination
was administered to Rachel in the United States.

Petitioners allege that Rachel suffered significant
aggravation of her pre-existing tuberous sclerosis (TS) in the form
of a residual seizure disorder (RSD) within the Table time limits
of the Act. 42 U.S.C. § 300aa-14 (a) (1) (D) and (B) Respondent
defends with the assertion that the onset of Rachel’s seizure
disorder occurred outside the Table time limits. In the alternative,
respondent claims that Rachel’s seizure disorder was caused by
a factor unrelated: TS. 42 U.S.C. § 300aa-13 (a) (1) (B)

No hearing was held in the instant matter because the
records are sufficient for the court to reach a determination on
entitlement. However, preliminary testimony was taken on
October 21, 1991 at the Mayo Clinic from Dr. Manuel Gomez on
the nature of TS, and the effect of DPT vaccine on TS children.
Petitioners filed the expert report of Dr. Marcel Kinsbourne, a
pediatric neurologist.

FACTS

Rachel was born on June 8, 1989. She received her first
DPT vaccination on August 4, 1989 at the age of two months. She
received her second DPT vaccination on September 15, 1989,
when she was three and a half months. Med. Recs. at 45. The
parents allege that, later that day, she was staring, her left arm
shook, and she drew her legs up.

On September 26, 1989, Rachel was brought to Humana
Hospital. Dr. Jacqueline Campbell took the history that Rachel
had been healthy until her mother noticed occasional trembling of
her left hand while she nursed and one blank stare. No date is
given for the onset. She did not have a reaction to her second
DPT ten days earlier. Med. Recs. at 49.

~ On November 29, 1989, Dr. Baumann at the University of
Kentucky Outpatient Clinic took a history of onset at
approximately two months with a shaking left hand. By two and

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a half months, these were apparently seizures. Med. Recs. at
132.On December 12. 1989, Drs. Ryan and Hall recorded that the
first seizure occurred on September 15, 1989 following a DPT
vaccination. While nursing, Rachel pulled away from the nipple,
and her left arm vibrated. She began shaking and staring. Med.
Recs. at 147.

A history given at the University of Kentucky Medical
Center on November 1, 1990 states an onset of seizures at three
and a half months. Med. Recs. at 156.

A letter dated March 15, 1991 from Dr. Jacqueline
Campbell states that Rachel’s mother called her on September 15,
1989 to discuss Rachel’s fussiness, apparent abdominal cramping,
and occasional brief arm tremor. Med. Recs. at 289.

TESTIMONY

Dr. Manuel Gomez, the world’s expert in TS, testified on
October 21, 1991. Dr. Gomez's testimony on TS was taken at the
Mayo Clinic and is described in Costa v. Secretary of HHS, No.
90-1476V, slip op. at 10-17 (Cl. Ct. Spec. Mstr. Feb. 26, 1992)
(A description of Dr. Gomez’s textbook and article on TS is on
pp. 5-10 of the same opinion.)

Dr. Gomez testified that TS is not an encephalopathy.
Gomez Tr. at 99. Rather, TS is a genetic disorder which is either
inherited or results from a mutation. Gomez Tr. at 96. Brain
growth controls tuber growth. Tubers exist at birth and do not
multiply. Gomez Tr. at 97. The most common presenting
symptom in TS is seizures. Gomez Tr. at 100. There is a
demonstrable correlation between the presence of many low
attenuated lesions and the frequency and severity of seizures and
mental retardation in an infant less than one year old. Gomez Tr.
at 103.

The most common age for an onset of seizures in TS
children is the first year of life. The most common symptom of
presentation is infantile spasms. Infantile spasms are age-
dependent seizures occurring between the ages of three and eight
months, regardless of the cause. Gomez Tr. at 103.

Dr. Gomez stated, “The timing is very important. You

lla

don’t want to provoke or bring on the seizure. If there is any way
to prevent that, you should try to prevent it.” Gomez tr. at 48-49.
. Dr. Gomez has never recommended giving pertussis vaccine to
any child he knows has TS. Gomez. tr. at 48.

Dr. Kinsbourne states in his report that Rachel’s onset of
symptoms was the same day as the second DPT vaccination. She
was admitted to the hospital eleven days later. Dr. Kinsbourne
diagnosed encephalopathy leading to seizures and cognitive
deficits. ©

Counsel took the deposition of Dr. Jacqueline Campbell.
Rachel's pediatrician. She recounted that Rachel’s mother called
her on September 15, 1989, the evening of the DPT vaccination
. she had administered. Campbell tr. at 2; Ps’ Ex. 6; Med. Recs. at
289. Rachel's mother complained that Rachel was cramping and
had an occasional hand tremor. Campbell tr. at 4.

Dr. Campbell stated that when she put “no reaction” in the
Humana Hospital records pertaining to Rachel after her second
DPT vaccination. she meant that Rachel did not have the usual
reaction of high fever, high pitched cry, and severe irritability
Campbell tr. at 6.

Dr. Campbell stated one does not make a diagnosis until
one have evaluated everything. In retrospect, “these tremors that
... the mother had mentioned in the past . . . were probably very
minor seizures. We did not appreciate that until this episode
happened and the story became much more clear.” Campbell tr.
at
6-7.

Dr. Campbell also stated that the hand tremors to which
Rachel’s mother referred in the phone call of September 15, 1989
were probably minor seizure activity. Campbell tr. at 7.

Petitioners submitted affidavits of fact witnesses to attest
to Rachel’s seizures beginning within three days of her DPT
vaccination: Lauri Vinick. Allison Brown-Rice, and Sandra L.
Hough. Petitioners’ initial and supplemental affidavits are
consistent with on-Table onset.

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DISCUSSION

The records and Dr. Campbell's testimony clearly support
a finding that Rachel's seizures began on-Table after her second
DPT vaccination. The earliest medical record at Humana is
ambivalent. But Dr. Campbell recorded that history and
subsequently clarified what she meant by writing “no reaction” to
the second DPT, i.e., she was looking for fever and inconsolable
crying. In addition, Dr. Campbell testified that Rachel’s mother
called her the evening of the second DPT vaccination to report
what Dr. Campbell later agrees are seizures. Subsequent medical
histories just a few months later are consistent with on-Table
onset as are the affidavits of individuals who were in contact with
petitioners at the time.

Petitioners have prevailed in satisfying their burden of
showing Rachel having an on-Table onset of seizures which
constituted a significant aggravation of her TS.

CONCLUSION

Petitioners are entitled to a Program award in an amount
vet to be determined. The court hopes that the parties will be able
to settle the damages portion of this case without a hearing, and
suggests petitioners and respondent retain a joint Life Care
Planner and file a Life Care Plan expeditiously. The court will
hold a telephone conference soon to see how the parties are
progressing in resolving the damages issue.

IT IS SO ORDERED.
DATED: December 29, 1994 s/

Laura D. Millman
Special Master

— Sere

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APPENDIX C: “TS OMNIBUS DECISION” OF THE
OFFICE OF THE SPECIAL MASTERS OF THE UNITED
STATES COURT OF FEDERAL CLAIMS, DATED
SEPTEMBER 15, 1997

1997 WL 602115 (Fed. Cl. Spec. Mstr.)

OFFICE OF SPECIAL MASTERS
PUBLISHED

Barnes 92-0032V
Barnes 90-1101V
Bradbary 90-2770V
Copeland 90-0867V
Decker 90-11 ISV
Decker 90-11 16V
Flanagan 90-1 126V
Gallagher 95-0191 V
Hanlon 90-1334V
Henkel 90-3314V
Hulbert 90-1335V
Johnson 90-311 OV
Kouba 90-3524V
Langford 91-0521V
Loney 90-0926V
Miller 90-2764V
Moody 91-0393V
Muller 90-2724V
Plavin 91-1555V
Schueler 91-0124V
Turner 90-3409V
Ulicny 95-0189V

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Robert Moxley and Richard Gage,’ Cheyenne, WY, for
petitioners.
Karen P. Hewitt and Mary H. Mason, Washington, DC, for
respondent.

TS OMNIBUS DECISION
MILLMAN, Special Master
Statement of the Case

The above-captioned cases all deal with a disease called
tuberous sclerosis (“TS”) and were filed under the National
Childhood Vaccine Injury Act, 42 U.S.C. §300aa-1 et seq (West
1991 & Supp. 1996) (“Vaccine Act”). Initially, other special
masters and the undersigned heard and decided the TS cases
individually. Subsequently, all the TS cases were transferred to
the
undersigned for disposition. As part of determining the common
issues in these cases, in an analogy to 28 U.S.C. §1407
(multidistrict litigation), the undersigned held an Omnibus
Hearing in two parts: October 8-11, 1996 and June 3-4, 1997.

The following TS cases were decided prior to
consolidation before the undersigned: Wilson v. Secretary. HHS,

' Mssrs. Moxley and Gage de not represent all the petitioners in the caption.
However, those attorneys who do represent non-Moxley/Gage petitioners agreed to the
Omnibus Proceedings with Mssrs. Moxley and Gage, who have the overwhelming
number of cases and considerable experience in the area of TS, representing all
petitioners. The undersigned. in each order she issued, afforded non-Moxley/Gage
counsel the opportunity to provide different evidence or approaches than Mssrs.
Moxley and Gage. None of the other attorneys chose to diverge from Mssrs. Moxley
and Gage. If. in the future, other petitioners’ counsel have different evidence on the
common issues the court evaluated at the Omnibus Hearing, the undersigned will
certainly receive it. It would be hard, however, to perceive how any more evidence
could be available. considering the six days of exhaustive testimony the court has heard
on the common issues.

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15a

No. 89-65V, 1991 WL 20064 (Cl. Ct. Spec. Mstr. Jan. 22, 1991)
(petitioners entitled to damages for on-Table residuai seizure
disorder [RSD]); Huber v.Secretary. HHS, 89-72V (Cl. Ct. Spec.
Mstr. Aug. 6, 1990; Apr. 5, 1991) (petitioners entitled to
damages; respondent did not present a defense); Murphy v.
Secretary. HHS No. 90-882V (Cl. Ct. Spec. Mstr. Apr. 25, 1991)
(petitioners’ testimony conflicted with the contemporaneous
medical records; petition dismissed); Copeland v. Secretary.
HHS, No. 90-867V, 1993 WL 12894 (Fed. Cl. Spec. Mstr. Jan. 7,
1993) (DPTsignificantly aggravated TS; damages pending and
reassigned to the undersigned special master).

On October 21, 1991, the undersigned heard the testimony
of Dr. Manuel Gomez, the world’s expert on TS, at the Mayo
Clinic, Rochester, MN. The intent of the undersigned was to
apply Dr. Gomez’s testimony to all TS cases. The first TS case
that the undersigned decided was Costa v. Secretary. HHS, No.
90-1476V, 1992 WL 47334 (Cl. Ct. Spec. Mstr. Feb. 26, 1992),
vacated and remanded, 26 Cl. Ct. 866 (1992), on remand, 1992
WL 365421 (Fed. Cl. Spec. Mstr. Nov. 5, 1992). In Costa this
court held that petitioners were entitled to an award of damages
based on their proof of an on-Table RSD.

Upon motion of respondent, this special master certified
the case for interlocutory appeal and respondent then filed a
Motion for Review on the issue of whether the undersigned erred
in analyzing the case as an on-Table RSD, rather than as an on-
Table significant aggravation.

The U.S. Claims Court (now the U.S. Court of Federal
Claims), per the Honorable Moody R. Tidwell, held that
respondent’s analysis was correct, and that petitioners were
entitled to damages because the DPT did significantly aggravate
the vaccinee’s TS. Id. at 871. The appellate court also held that
TS was a latent RSD and a latent encephalopathy. Id. Since
Stephen Costa did not have any seizures before he received his
DPT vaccination, and did seize within Table time after he
received DPT, the DPT significantly aggravated his TS. Id.

The undersigned evaluated the remaining TS cases solely

l6a

under a theory of significant aggravation. The next case this court
decided was Suel v. Secretary. HHS, No. 90-935V, 1993 WL
241430 (Fed. Cl. Spec. Mstr. June 18, 1993), rev’d and remanded,
31 Fed. Cl. 1(1993). The undersigned held that David Suel’s eyes
rolling back two days after his DPT vaccination, although a
seizure, was not of sufficient severity as to constitute a substantial
deterioration under the definition of “significant aggravation” in
the statute at 42 U.L.C. §300aa-33. The U.S. Court of Federal
Claims, per the Honorable James F. Merow, reversed and
remanded, holding that a single seizure in a previously

asymptomatic child was per se significant aggravation of his TS.
In two other TS cases, Moon v. Secretary. HHS, No. 90-

2495 (1994) (injury case), and Perkins v. Secretary. HHS, No. 90-
2141 (1995) (death case), the parties settled before the
undersigned determined entitlement. Costa, supra, also settled
damages after the decision on remand. Respondent did not further
appeal Costa.

In 1995, respondent asserted that it had additional
evidence previously unavailable which proves epidemiologically
(and is confirmed neurologically) that if a vaccinee has eight or
more tubers, he or she will inevitably develop seizures and
become moderately or severely mentally retarded. Respondent
offers as its basis an epidemiological meta-analysis of studies of
TS. In the hope of facilitating the disposition of all remaining TS
cases and any subsequent tag-along cases of TS,’the undersigned
held an Omnibus Hearing on October 8-11, 1996 to hear
respondent’s new evidence. At that part of the hearing,
respondent submitted an abstract of-a study ("the Jozwiak study")
which had not yet been written. The undersigned continued the
hearing until it would receive the completed Jozwiak study plus

*There is dictum to the effect that applying the decision of an Omnibus
Hearing to a tag-along case is inherently unfair. Johnson v. Secretary, HHS, 33 Fed. Cl.
712, 730 n.10 (Ct. Cl.1996). aff'd. 99 F.3d 1160 (1996). However, in the federal
district courts’ usage of multidistrict litigation, the applicability of a decision on
common issues to tag-along cases is part of the raison d’étre of the proceeding.

17a

other materials that were still outstanding.

Subsequently, the other materials were provided and
respondent filed the Jozwiak study’, an independent analysis of
106 TS children in Poland. The authors of the study conclude that
receipt of DPT did not affect the onset of seizures in TS children.
Jozwiak, May 13, 1997 draft at 13. The most important
determinant of severity of mental retardation was whether or not
the TS individual had infantile spasms. Id. at 14. Jozwiak, by
controlling for infantile spasms (an age-related seizure disorder
whose occurrence falls generally between the ages of three and
eight months) as a variable, also concluded that the age of onset
of seizures did not affect the severity of mental retardation in a
TS child. Id. The court heard testimony on this evidence on June
3-4, 1997.

Recently, the U.S. Supreme Court decided two cases that
are pertinent to the issues at hand: Daubert v. Merrell-Dow
Pharmaceuticals. Inc., 509 U.S. 579 (1993) (re: scientific
evidence admissibility with an extensive discourse of the nature
of valid scientific testimony) and Whitecotton v. Secretary, HHS,
514U.S. 268 (1995) (discussing onset), on remand, 81 F.3d 1099
(Fed. Cir. 1996) (discussing the criteria for proving significant
aggravation under the Vaccine Program). In essence, the Federal
Circuit asked if the vaccinee’s current condition was worse than
his or her pre-vaccination condition and, secondly, if the
significant worsening began within Table time of the vaccination.
81 F.3d at 1107. If the answer to these two questions is in the
affirmative, the burden passes to respondent to prove by a
causation in fact standard that the pre-existing illness, not the
vaccination, caused the significant worsening. Id.

By trying common issues together, including respondent’s
extensive meta-analysis of epidemiological studies of TS, the

3Jozwiak, S.etal., "Poor Mental Development in TSC Patients: Clinical Risk
Factors,” drafts dated February 12, 1997 and May 13, 1977. Hanlon, R. Exs. BBB,
EEE. (All references to exhibit numbers will come from the Hanlon case.)

18a

undersigned hopes to facilitate the disposition of over twenty

cases (even those in which entitlement had already been decided

but which were awaiting disposition of damages).
TESTIMONY

Dr. Manuel Gomez, the world’s expert in TS, testified on
October 21, 1991 as part of all TS cases. Dr. Gomez’s testimony
on TS was taken at the Mayo Clinic and is described in Costa v.
Secretary, HHS, No. 90-1476V, 1992 WL 47334, *5-*8 (Cl. Ct.
Spec. Mstr. Feb. 26, 1992), vacated and remanded, 26 Cl. Ct. 866
(1992), on remand, 1992 WL 365421 (Fed. Cl. Spec. Mstr. Nov.
5, 1992). Dr. Gomez, at the time of the taking of his initial
testimony, was a pediatric neurologist at the Mayo Clinic,
Rochester, MN. He was also a member of the Medical Advisory
Board and Research Committee of the National Tuberous
Sclerosis Association.* R. Ex. 111. He has edited Tuberous
Sclerosis (Raven Press, 1979; 2d ed., 1988; a third edition is
forthcoming) (P. Ex. 56; R Ex. C). He authored "Tuberous
Sclerosis Complex in Olmsted County, Minnesota, 1950-89," 48
Arch Neur 400-0 1 (April 1991) (R. Ex. E); "Tuberous sclerosis,
early onset of seizures, and mental subnormality: Study of
discordant [mono ]zygous twins," 32 Neur 604-11 (1982) (P. Ex.
57). As of the date of his initial testimony, Dr. Gomez had
authored 151 publications. Gomez Tr. at 6. Dr. Gomez’s textbook
on TS and his article about twins are described in the first opinion
in Costa.

Dr. Gomez had been practicing pediatric neurology for
thirty-one years at the time of his initial testimony. Gomez Tr. at
8. He has seen 150 out of the 380 TS patients the Mayo Clinic has
had. The Mayo Clinic has more TS cases than any other
institution. Gomez Tr. at 9.

Dr. Gomez testified that TS is not an encephalopathy.
Gomez Tr. at 99. Rather, TS is a genetic disorder which is either

Currently, Dr. Gomez is Emeritus Professor of Pediatric Neurology, Senior
Consultant in Pediatric Neurology at the Mayo Clinic

19a

inherited or results from a mutation. Gomez Tr. at 96. Brain
growth controls tuber growth. Tubers exist at birth and do not
multiply. Gomez Tr. at 97. The most common presenting
symptom of TS is seizures. Gomez Tr. at 100. There is a
demonstrable correlation between the presence of many low
attenuated lesions and the frequency and severity of seizures and
mental retardation in an infant less than one year old. Gomez Tr.
at 101.

The most common age for an onset of seizures in TS
children is the first year of life. The most common symptom of
presentation is infantile spasms. Infantile spasms are age-
dependent seizures occurring between the ages of three and eight
months, regardless of the cause. Gomez Tr. at 103.

The TS lesions or tubers are located on the cortex and,
depending on their location, one would expect seizures
characteristic of the function of that brain area. Thus, if there is a
tuber in the motor area of the brain, one would expect a motor
seizure in the upper side of the brain. If the tuber is in the
occipital area, one would expect a more sensory seizure. There
are certain parts of the brain where a lesion is more likely to
produce seizures, 1.e., the temporal lobes (as compared to the
frontal lobes). Gomez Tr. at 19.

When an individual has more than five lesions detectable
on MRI in the brain, most likely he or she will have seizures. We
do not see all the lesions. If we detect five, there are probably
twice as many. Gomez Tr. at 20. If an infant has extensive,
numerous lesions, he will probably have lots of seizures and also
be mentally retarded. Gomez Tr. at 32-33.

One of every 14,000 people has TS. Gomez Tr. at 22. We
do not know what percentage of people with TS will be mentally
retarded because we do not know how many people there are with
TS in the general population. Of the people coming to the Mayo
Clinic with TS (a biased population), 45 percent are mentally
retarded. Parents of children with TS may have TS themselves
and lead a normal life. Gomez Tr. at 23.

20a

The 45 percent includes both the patients and their
dependents. In 1966 or 1967, to Dr. Gomez’s great surprise, he
found that many TS cases were not mentally retarded as the books
said they should be. Probably one-third of them were normal with
normal intelligence. Gomez Tr. at 10. Dr. Gomez opined that the
incidence of mental retardation outside the Mayo patient
population is much lower than 45 percent. Gomez Tr. at 26. He
believes that Dr. John Osborne’s statement in his paper
"Epidemiology of Tuberous Sclerosis" (615 Annals of the New
York Academy of Science, 125-27 (Apml 1991); P. Ex. 55), that
a true frequency of mental retardation in TS is approximately 33
percent is a good statement. Gomez Tr. at 91. If we could find
everyone with TS, Dr. Gomez believes that the incidence of
mental retardation should be much lower than what he estimated
(45 percent) and perhaps even lower than what Dr. Osborne
estimated (33 percent). Gomez Tr. at 92. Dr. Gomez testified that
the true incidence of mental normalcy in TS people could even be
higher than 67 percent. He stated that as more people who are
clinically normal are examined and are discovered to have TS, the
incidence of mental retardation keeps declining. Gomez Tr. at 93.

Dr. Gomez testified that the purpose of his wniting the
paper in the journal, Neurology (P. Ex. 57), on the two sets of
twins was to indicate that seizures influence the outcome of the
disorder. Gomez Tr. at 29. Repetitive seizures do lasting brain
damage to infants. Gomez Tr. at 3 5-36. Infantile spasms are a
form of epilepsy. Gomez Tr. at 43: Infantile spasms tend to come
in clusters (ten, fifteen, or even one hundred). These children are
either severely retarded to begin with because of severe
pathology, or if they are not, they are going to be. Onset at the age
of five, six, or seven months is very damaging, more so than if
infantile spasms occurred later on. Infantile spasms rarely begin
after the age of one year. Gomez Tr. at 44.

Dr. Gomez testified that the incidence of complication of
DPT vaccination is 1 in 300,000. Gomez Tr. at 47. The chance of
both twins in a set having a seizure reaction is 1 in 90,000,000.

2la

Gomez Tr. at 47. Dr. Gomez stated that it is a good precaution not
to give anybody who has TS any chance of developing seizures.
Thus, he has never recommended giving pertussis medication to
a child that he knows has TS: "It is better not to take any chance."
Gomez Tr. at 48. Pertussis immunization has frequently been
cited as a triggering factor or a cause of infantile spasms. Dr.
Gomez differentiated between triggering factor and cause by
stating, "I think trigger is the easy way out. Triggering is credible;
causing is hard to prove." Gomez Tr. at 83.

The most common presenting symptom of TS is seizures.
Gomez Tr. at 100. The incidence of seizures is much higher in the
first year of life in TS than at any other time. Dr. Gomez testified,
"The timing is very important. You don’t want to provoke or
bring on the seizure. If there is any way to prevent that, you
should try to prevent it." Gomez Tr. at 4849.

When questioned by the court regarding how to choose
between TS and DPT vaccine as the cause of the seizures, Dr.
Gomez stated that it is clearly by the chronology of events. The
peak onset related to the DPT shot would be within 24, 48, or 72
hours after the shot and not much more after that. Gomez Tr. at
121. After 72 hours, Dr. Gomez would probably relate a seizure
in a TS patient to the TS rather than to a DPT inoculation. Gomez
Tr. at 122.

Dr. Gomez also stated there is no one-to-one correlation
between the degree of cortical involvement and the degree of
retardation. Gomez Tr. at 62. Dr. Gomez testified that he did do
an incomplete, unpublished study indicating a demonstrable
correlation between the presence of many low attenuated lesions
in infants less than one year old and the frequency and severity of
seizures and mental retardation. Gomez Tr. at 101. He believes
that if you do a brain scan of a child early in life, the more lesions
that a child has, the more likely that the child is going to have
seizures. The more cortical lesions the child has, the more likely
that child is going to have severe neurologic dysfunction. Gomez
Tr. at 102. If he took a subset of TS people with many multiple

22a

brain lesions, the percentage of mental retardation would be much
higher than 33 percent. Gomez Tr. at 104.

Dr. Gomez stated that DPT vaccine does not aggravate
TS, but may aggravate the symptoms or bring them on. DPT
impairs the vaccinee’s normal development, including
intelligence and the ability to acquire knowledge. Gomez Tr. at
88-89. TS can be very benign, so benign that a person does not
know he or she has it. Gomez Tr. at 89. Dr. Gomez stated that
pertussis immunization and infantile spasms have been linked for
years. However, the proof has never been presented; they are
linked by chronology. Gomez Tr. at 141.

Infantile Spasms

Respondent’s defense is that TS, not DPT, is responsible
for any seizures in a TS child if the child has eight or more tubers.
In addition, respondent’s defense is that DPT does not cause
infantile spasms or any afebrile seizures. Congress did not
differentiate among seizure types when it included RSD as a
Table injury following DPT vaccination.°

Significant Aggravation

Congress defined "significant aggravation" as "any change
for the worse in a preexisting condition which results in
markedly greater disability, pain, or illness accompanied by
substantial deterioration of health [emphasis added]." 42
U.S.C. §300aa-33(4). In order for this court to hold that DPT
vaccine significantly aggravated a child’s pre-existing TS, it must
find that the child experienced greater disability, pain, or illness
accompanied by a substantial deterioration of health whose onset
was within Table time of the vaccination.

‘Ina change of the Vaccine Table, effective March 10,1995, the U.S.
Department of Health and Human Services ("HHS") removed RSD as a Table injury
following DPT vaccination. 42 C.F.R. 100.1-100.3. In its discussion of infantile
spasms and afebrile seizures, HHS reiterated its position: "The IOM concluded infantile
spasms are not causally related to DTP vaccination. Therefore, there is no basis for a
legal presumption of causation for this condition when it follows DTP vaccination...
The IOM concluded that afebrile seizures are not causally related to DTP vaccine.” 60
Fed. Reg. 7678, 7690 (1995).

23a

Legislative history provides insight into Congress’
interpretation of "significant aggravation":

The committee has included significant

aggravation in the Table in order not to exclude

serious cases of illness because of possible minor

events in the person’s past medical history. This

provision does not include compensation for

conditions which might legitimately be described

as pre-existing (e.g., a child with monthly seizures

who, after vaccination, has seizures every three

and a half weeks), but is meant to encompass

serious deterioration (e.g., a child with monthly

seizures who, after vaccination, has seizures on a

daily basis).
H.R. Rep. 98, 99th Cong., 2d Sess. 15-16, reprinted in
U.S.C.C.A.N. 6344, 63 56-57. Apparently, Congress did not
intend compensation for a slight increase in seizure frequency
(from once monthly to once every three and a half weeks), but
intended compensation for a serious deterioration, i.e., a marked
increase in seizure frequency (from once a month to once a day).

Although Congress spoke in the above history of
compensating significant aggravation of a minor illness, this court
and others have held that petitioners may prevail even if their pre-
existing illness was major, not minor, as long as the vaccination
significantly aggravated it. Costa v. Secre HHS, No. 90-
1476V, 1992 WL 47334 (Cl. Ct. Spec. Mstr. Feb. 26, 1992),
vacated and remanded, 26 Cl. Ct. 866 (1992), on remand, 1992
WL 365421 (Fed. Cl. Spec. Mstr. Nov. 5, 1992); Suel v.
Secretary. HHS, No. 90-955V, 1993 WL 241430, *7 (Fed. Cl.
Spec. Mstr. June 18, 1993), rev'd and remanded on other grounds,
31 Fed. Cl. 1(1993); Green v. Secretary. HHS, No. 90-2847V,
1993 WL 141105, *9 (Fed. Cl. Spec. Mstr. April 19, 1993).

The language of the statute indicates that onset of an on-
Table significant aggravation must occur within three days of a
DPT vaccination. "Time period for first symptoms or

24a

manifestation of onset or of significant aggravation after vaccine
administration: ..3 days..." (emphasis added.) 42 U.S.C. §300aa-
14(a).

Testimony at Omnibus Hearing

As part of its hearing on the common issues of TS, the
court also heard in particular the cases of Michael Hanlon and
Rachel Plavin so as to have specific details to which to apply the
general defenses of respondent.

Michael Hanlon’s onset of seizures (which the court
previously held occurred within Table me of his DPT) occurred
at the age of two months. His seizures were not infantile spasms.
They were, however, afebrnle. Michael has at least ten cortical
lesions. Hanlon v. Secretary, HHS, No. 90-1013V, unpub. slip op.
(Fed. Ci. Spec. Mstr. May 31, 1994).

Rachel Plavin (whose onset the court also found occurred
within Table time) has forty abnormal cortical areas.° Her
seizures were also not infantile spasms. They were, however,
afebrile. Plavin v. Secretary. HHS, No. 91-1555 V, unpub. slip
op. (Fed. Cl. Spec. Mstr. Dec. 29, 1994).

Dr. Steven H. Lamm, a pediatrician and epidemiologist,
testified first for respondent during the October 8-11, 1996
Omnibus Hearing. Tr. at 55. He is board-certified in pediatrics,
preventive medicine, and occupational medicine. Tr. at 57. He is
a charter fellow of the American College of Epidemiology. Tr. at
58. He has done meta-analysis for ten years. Tr. at 62. His
primary clients are industnes, the government, and lawyers. Tr.
at 66. He has done prior studies in lead and infant formula,
leukemia in children, cholera in the Philippines, and birth defects
(including Bendectin: he submitted an affidavit in the Daubert
case). Tr. at 70-75, 88-89.

Dr. Lamm stated that to have evidence of causation
between exposure to something and outcome, one must seek to

atthe October 1996 hearing, Dr. Fitz testified that Rachel Plavin has at least
45 tubers

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explain the outcome by other factors and also show the outcome
is significant. Tr. at 76. Epidemiologists look for data consistent
with a causal hypothesis, unlike physicians, who, with a totality
of information, reach a causal judgment. Tr. at 77.
Epidemiologists look for 95% certainty. Tr. at 8 1-82.

As a medical epidemiologist, Dr. Lamm deals with the
hypothesis that exposure leads to a disease. Tr. at 92. He
organizes literature and data in the literature to see if there is a
consistent pattern. Tr. at 92-93.

There are two types of epidemiologic studies: (1) case
control studies, and (2) cohort studies. Tr. at 94. Case control
studies are retrospective. Tr. at 95. They compare those with a
disease to those without a disease and ask who was exposed to the
material in question. Id. They calculate what are the odds of the
case having or not having exposure. Id. Then they ask what are
the odds of the contro! having or not having exposure. Id. A
formula with the numerator consisting of the exposure odds of the
cases over the denominator consisting of the exposure odds of the
controls equals the odds ratio ("OR"):

exposure odds of cases (people with the disease)
exposure odds of controls (people without the disease) = OR
(Tr. at 99-100).

Cohort studies compare a group with exposure to a group
without exposure and follow the subjects forward in time to see
the ultimate outcome. Tr. at 94. They report the relationship
between the two groups as relative nsk ("RR"). Id.

The TS Omnibus Proceedings involve a case control study
(being retrospective). Tr. at 104. Normally, in an odds ratio (OR),
if exposure is the same in the case as in the control, the OR =1.
Tr. at 97. If the OR 1s statistically significantly greater than 1,
there is more likely an increased association between exposure
and outcome. Id. If the OR is less than one, the people with the
disease are less likely to have been exposed than the people
without the disease. Tr. at 101.

The P value also expresses certainty by measuring the

26a

probability that the results could have happened by chance alone.
Tr. at 103. If the P value is less than 05, the confidence level is
more than 95%. Tr. at 102.

"Statistical significance" 1s the standard terminology for
epidemiologic analysis. Tr. at 101. A P value of less than .05 is
statistically significant. Tr. at 102. Confidence limits are the same
as the confidence interval (C1). Tr. at 107-08.

Epidemiology permits comparison of ratios, for example,
comparing exposure odds of cases to exposure odds of controls.
Tr. at 112. This entails use of a "two-by-two" table wherein the
epidemiologist assigns someone to one of four cells in order to
develop comparison rates. Tr. at 113-14.

Two-By-Two Table

R. Trial Ex. B. depicts the cells as with the disease and
exposure on the top left, without the disease and with exposure on
the top ight, with the disease and without exposure on the bottom
left, and without the disease and without exposure on the bottom
nght:

with disease; with exposure without disease; with exposure
with disease; without exposure —_— without disease; without exposure

If cases are more likely to be exposed than non-cases, Dr.
Lamm then asks 1f the OR 1s statistically significant. Tr. at 116.

Dr. Lamm wrote two papers as a result of his work as an
expert in this case. The tirst is entutled "Cortical Tuber Count: a
Biomarker indicating Cerebral Severity of Tuberous Sclerosis
Complex," by M. Goodman, S.H. Lamm, A. Engel, C.W.
Shepherd, C.W. Houser, and M.R. Gomez’ ("Tuber Count >
article".) R. Ex. LL.

The second article is a draft dated September 19, 1996,
entitled "Temporal Relationship Between Date of Onset of

"This was subsequently published as Goodman, M. et al. “Cortical Tuber
Count: A Biomarker Indicating Neurological Severity of Tuberous Sclerosis Complex,"
12 J Child Neur 85 (1997). R. Ex. DDD. This was followed by an editorial entitled,
“Tuberous Sclerosis: Function Follows Form," by E.S. Roach, 12 J Child Neur 75
(1997). R. Ex. DDD

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27a

Infantile Spasms and Prior Immunization with DPT and/or DT:
An Analysis Based on the Data from the National Childhood
Encephalopathy Study," by M. Goodman, S.H. Lamm, and M.H.
Bellman. R. Ex. MM. ("Reevaluation of Bellman" article.)
Respondent has informed the court that this second article has
been accepted for publication by the journal Vaccine.*

To begin his analysis, Dr. Lamm and his staff performed
a TS literature review and eventually identified the best of the
population studies and of the clinical studies. Tr. at 132-33. He
found Dr. Osborne’s study to be the best population study.’ The
best clinic-based study is Dr. Gomez's study at the Mayo Clinic.'®
Dr. Lamm found that the two studies’ findings were analogous.
Tr. at 139. Of the 131 TS cases in Webb ‘96, 70 had a learning
disorder which equals 53.4%. Tr. at 137. Ninety-nine of the cases
had seizures, with 70 of the patients with a known age of seizure
onset having the onset within the first year of life (71%). Id.
The Mayo Clinic study included 75 TS patients and the findings
were that 41 of the 75 (55%) had mental impairment and 66% of
those whose age at onset of seizures was known had onset of their
seizures within the first year of life. Tr. at 139. The Mayo Clinic
study also includes an additional analysis—the relationship
between tuber count and mental disability, and tuber count and
seizure onset before age one. Id.

Dr. Lamm cut the Mayo Clinic data at the median number
of tubers for the TS cases, which was ten tubers. Tr. at 157. Of
the 75 cases, 39 had ten or more tubers and 36 had less than 10
tubers. Id. Based on his analysis, Dr. Lamm testified that

’Respondent file an earlier draft of the same Bellman reevaluation, dated
November 28, 1995. R_ Ex W

Webb et al., "Morbidity Associated with Tuberous Sclerosis: A Population
Study," 38 Develop Med and Child Neur, 146-5 | (1996) ("Webb °96"). P. Ex. 59

'OShepherd et_al., "MR Findings in Tuberous Sclerosis Complex and
Correlation with Seizure Development and Mental Impairment," 16 AJNR 149-55 (Jan.
1995) ("Mayo Clinic"). R Ex. 0.

28a

someone with bad TS, 1.¢., mental retardation, 1s four and one-
half times more likely to have a high tuber count (ten or more
tubers). Tr. at 158. The confidence interval is from 1.5 to 13.4;
thus, 1.0 is not in the confidence range and the results are
statistically significant. Tr. at 158-59. The risk may be as low as
1.5% or as high as 13.4% but the best estimate is 4.5%. Tr. at
159. The P value is less than 5°o which means that there 1s a less
than one in twenty chance that the numbers could have occurred
at random. Tr. at!60. The P value here is .004 which says that
there is a 1 in 250 chance that the association is random. Id.

Dr. Lamm also performed an OR for seizure status
(defined as onset prior to one year). Tr. at 162. For cases with ten
or more tubers, the OR was 9.7 with a lower confidence limit of
2.9 and an upper confidence limit of 35.1. Id. The narrower the
range of the confidence interval, the less uncertainty. Tr. at 163.

Dr. Lamm then cut the Mayo Clinic data at those having
eight or more tubers, and those having 0-7 tubers. Tr. at 165-66,
169. He and his colleagues concluded that seven tubers or less:
meant there was no statistically significant correlation between
tuber count and ultimate outcome (seizures and mental
retardation). Tr. at 169-70. Those with eight or more tubers had
a three times greater chance of mental retardation than those with
0-7 tubers, with an OR of 3.2 and a low range in the confidence
interval of 1.1 which is still statistically significant. Id., R Trial
Ex. C at 16.

The OR for people with eight or more tubers and seizure
status was 9.1 so that the TS cases at the Mayo Clinic with
seizures were more than nine times likely to have eight or more
tubers than the people without seizures. Tr. at 170, R. Tnal Ex. C
at 16.

Dr. Lamm concluded that cortical tuber count is a strong
factor relating to mental retardation and seizure status. Tr. at 171.
His conclusion is based on the OR and its confidence levels and
the P values; the sequential analysis at different cuts; and his
finding that his conclusion was characteristic of the data, and not

£8 Le ON Set A

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29a

characteristic of his analysis. Tr. at 179.

Dr. Lamm then went on to perform a meta-analysis to
determine if his finding was representative of the whole body of
information that exists. Tr. at 180. He teaches meta-analysis on
the graduate level. Tr. at 180. The ttle of his course is "Where the
Whole is Greater than the Sum of the Parts". Tr. at 180. He stated
that the medical community accepts meta-analysis basically,
although it 1s criticized within the profession. Tr. at 182. Meta-
analysis is very common in medicine. Tr. at 184. Dr. Lamm
started with the hypothesis that bad outcome of TS is associated
with a high tuber count. Tr. at 186. He then proceeded to find
studies which identified TS individuals with cortical tuber counts
by MRI, who were classified by mental impairment and seizure
status. Tr. at 186. Three cardinal words are inclusion, exclusion,
and independent as criteria for meta-analysis. Tr. at 188.

Inclusion means one starts out broadly with every study
with relevant data. Tr. at 188. He developed criteria for his
categories and separated out the studies that do not fit the cnteria
to engage in exclusion. Tr. at 189. If two studies included the
same population -he would not use both of them, thus maintaining
the independence of the cases. Id.

In discussing Dr. Lamm’s cortical tuber paper, the court
will refer to R. Ex. DDD (the published version in a peer-
reviewed journal) rather than R. Ex. LL (the draft from which Dr.
Lamm testified in October 1996). The authors found five studies
that met the criteria for examining the association between the
number of cortical tubers on MRI and severity of cerebral
dysfunction. Tr. at 191. Lamm et_al. conclude that the MRI-
detected cortical tuber count TS is six times more likely to be
above the median count (which 1s different in each study) for TS
patients with severe cerebral dysfunction than TS patients with
more mild affects. Tr. at 195. When they cut the data in all five
studies at eight or more tubers, they found that moderately to
severely affected TS patients were 5.3 times more likely to have
eight or more tubers than those with mild TS and those with

30a

seizures were 16 times more likely to have eight or more tubers
than those without seizures. Tr. at 196. The associations were
statistically significant. Id. The authors thus concluded that

cortical tuber count was a biomarker to predict the severity of

functioning and the presence of seizures in a TS patient. Tr. at
93

The five studies that were part of the meta-analysis were:
Roach etal.,'' Inoue et al.,'* Jambaque et al.,'* Menor et al.,'* and
Shepherd et al.”

In Roach’s 1987 paper, nine TS patients who had ten or
more cortical lesions had both severe developmental delay and
poorly controlled seizures. R. Ex. M, p. 303.

In Inoue’s 1988 paper, the severely mentally retarded
among ten TS patients tended to have more subcortical lesions. R.
Ex. AA, p. 379.

In Jambaqué’s 1991 paper, among 23 TS children, seven
were normal, ten were mentally retarded, and six were mentally
retarded with autism. R. Ex. L, pp. 699-700. The number of
tubers on MRI ranged from one to eight. Id. at 700. Eleven
children had more than eight tubers. Id. Among sixteen children

Roach, E.S., Willams, D.P., Laster, D.W., "Magnetic resonance imaging
in tuberous sclerosis,” 44 Arch Neur 301-03 (1987). RR. Ex. M

‘>

‘“Inoue, Y , Nakajima, S., Fukuda, T., etal, "Magnetic resonance images of
tuberous sclerosis. Further observations and clinical correlations,” 30 Neuroradiology
379-84 (1988) R Ex AA

' Jambaque, 1, Cusmal, K., Curatolo, P., et_at., "7NeuropsychologiCal
aspects of tuberous sclerosis in relation to epilepsy and MBJ findings,” 33 Dev Med
and Child Neur 698-705 (1991) R Ex L

'SMenor, F., Mart, B.L., Mulas, F, et a.,"Neurommaging in tuberous

sclerosis: A clinicoradiological evaluation in pediatric patients,” 22 Ped Radiol 485-89
(1992) R Ex. BB

'>Shepherd, C.W., Houser, 0.W., Gomez, M_R., “MR findings in tuberous
sclerosis complex and correlation with seizure development and mental impairment,"
16 AJNR 149-5 5 (Jan. 1995). R. Ex. 0

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with IQs of less than 65, one had one lesion and two had two
lesions, but most had multiple bilateral cortical tubers. Id. at 701.
All in this group had had partial seizures or persistent infantile
spasms and later developed severe or intermediate multifocal
epilepsy. Id.

Among those TS patients with four or more tubers was
one person who had an IQ of 85-110, six people who had an IQ
of 40-65, and seven people who had an IQ of less than 40. Id. at
702. Among those who had from zero to two tubers was one TS
patient with an IQ of less than 40, two with an IQ of 40-65, and
six with an [Q of 85-110. Id. The oniy TS patients with autism
were six who had four or more tubers. Id. Among those with four
or more tubers were six with severe epilepsy and seven with
intermediate epilepsy. Id. However, one TS patient with severe
epilepsy had from zero to two tubers. Id.

Jambaqué and his co-authors state that mental retardation
occurs in 47 to 56 percent of TS patients. Id. All reported TS
patients with severe mental retardation had early-onset epilepsy,
mainly West syndrome (which includes infantile spasms). Id.
Several attempts have been made to identify specific
topographical lesions with brain deficits such as autism. Id. at
703. The authors surmise that "[b]oth the number and the
topography of tubers seem to play an important role in mental
outcome. This supports the idea that both epilepsy and mental
retardation reflect the cerebral dysfunction caused by cortical
tubers.” Id.

In Menor’s 1992 paper, the authors concluded after
analyzing twenty-seven TS patients that there was no clear
relationship between radiological features and the patients’
neurological evolution. R. Ex. BB, p. 485. Among these
patients, 59 percent were retarded in mental development, 26
percent were borderline, and 15 percent were normal. Id. at 486.
Half the six patients with more than five cortical tubers and half
the twelve patients with more than ten cortical tubers showed a
good neurological evolution. Id. at 487. One patient without

32a

cortical tubers and one with fewer than five cortical tubers had
poor control. Id.

Menor and his co-authors state that central nervous system
manifestations often occur before one year of age. Id at 488.
Ninety-six percent of the patients had seizures as the earliest and
most common neurological manifestation of TS. Id. at 489.
Mental retardation, although variable, was usually in fifty percent
ofthe patients. Id. The authors conclude, "In patients with TS, it
is not possible to predict their clinical prognosis by
neuroimaging:" Id.

In Shepherd's 1995 paper, the authors (including Dr.
Manuel Gomez) conclude that the number and anatomic location
of cortical tubers may play an important role in the mental
development and thus the intelligence of TS patients. R. Ex. 0, p.
149. An additional correlate to mental disability is the age of
seizure onset. Id. at 149-50. Cortical tubers may be asymptomatic,
but often are associated with severe intractable seizures and
mental disability. Id. at 149.

Significantly more tubers were found in patients whose
seizures began before one year of age and who were mentally
disabled. Id. Patients who had infantile spasms had a greater
number of tubers as well. Id. They studied seventy-five patients.
Id. at 150. The number of tubers ranged from one to forty-six. Id.
at 152. The likelihood of a first seizure being an infantile spasm
increased with the total number of tubers. Id.

Twenty-seven of the twenty-nine patients with infantile
spasms had a median number of 4.4 tubers. Id. Twenty-five of
these twenty-seven patients were impaired. Id. Twelve of the
twenty-six patients with generalized seizures had a median
number of 3.3 tubers. Id. Thirteen of these twenty-six were
impaired. Id. Eight of the fifteen patients with partial seizures
had a median number of 1.3 tubers. Id. Six of these fifteen were
impaired. Id; Four of five patients with no seizures had a median
number of 1.8 tubers. Id. None of these five was impaired. Id.

Fourteen patients had seizure onset before the age of three

SL i an ads Ap Rade EA ASEAN ALAA ENED aa

Pe ety eRe ee eee

Ce ey eT, ee

33a .

months. Id. These fourteen had an average number of 19.2
cortical tubers. Id. Twenty-one patients had seizure onset
between the ages of three to six months. Id. These twenty-one
had an average number of 19.8 cortical tubers. Id. Eleven patients
had seizure onset from six to twelve months. Id. These eleven
had an average number of 15.7 tubers. Id. Sixteen patients had
seizure Onset from twelve to sixty months. Id. These sixteen had
an average number of 16 tubers. Id. Eight patients had seizure
onset at over five years of age (Over sixty months). Id. These
eight had an average number of seven tubers. Id.

The authors conclude from this data that patients with
seizure onset before six months of age had three times as many
tubers as patients whose seizures began after one year of age.'®
Id.

Forty-one patients were mentally disabled; they had an
average number of 18.2 tubers each. Thirty-four patients did not
have disability; they had an average of 9.9 tubers each. Id. at 152-
53. The authors state, "The possibility of a patient being
mentally disabled was directly related to the total number of
tubers." Id. at 153.

The MRI underestimated the number of cortical tubers. Id.
In the seven children younger than two years of age, the number
of tubers was lower than the actual number because the brain

©The data may prove too much, however, since respondent's position is that
having eight or more tubers leads to a bad outcome, yet testimony and the medical
articles state ihat if a child reaches one year of age without onset of seizures, he 1s much
better off clinically. In fact, according to the Shepherd data, eight children with an
average of seven tubers had seizure onset after the age of five years. R. Ex. 0 at 52 A
doctor would not expect a bad outcome in a brain that had developed normally for five
years. For example, petitioners’ expert, Dr. John Osborne, in one of his articles, states,
"It 1s our experience that individuals who reach 5 years of age with normal
deveiopment do not develop mental handicap from tuberous sclerosis..." Webb, D W.,
Thomson, J.L.G., Osborne, J.P., "Cranial magnetic resonance imaging in patients with
tuberous sclerosis and normal intellect," 66 Arch Dis Childhood 1375-77, 1376(1991)
P.*s Ex 65. The Shepherd cut-off for clinical abnormality is substantially higher in
tuber count (18.2 on average) than the respondent's number of eight or more. R. Ex
0 at 152-53

34a

needs greater myelination for MRIs to detect tubers and this
requires maturation beyond two years. Id. The authors found that
tubers cause epilepsy because there was clear topographic
correlation between EEG spike foci and areas of abnormal MRI
signals. Id.

The number of tubers found in the patients with TS were
largely different. Id. The frontal and parietal lobes were most
commonly involved. Id. The authors found more tubers in the
frontal, medial, panetal, and temporal lobes of TS patients who
had infantile spasms than in those TS patients with other types of
generalized seizures or partial seizures. Id. Statistically,
occurrence of infantile spasms and not another type of seizure
was related to the total number of tubers, not to geographic
location. Id. Eighty-six percent of the patients (twenty-five out of
twenty-nine) with infantile spasms were disabled. Id. The authors
conclude that the greater number of cortical tubers in TS patients
with infantile spasms "causes more cerebral disruption and
deficit." Id.

Patients with other types of generalized seizures had fewer
tubers than those with infantile spasms but more than those with
partial seizures. Id. Sixty percent of the patients (nine out of
fifteen) with-partial seizures were mentally disabled. Id. They
had fewer tubers in the frontal lobes than those with infantile
spasms. Id. at 153-54. There was a direct relationship between
number of tubers and possibility of mental disability. Id. at 154.

The authors also state that all TS patients with mental
disability had or have some type of seizure, usually generalized
and very often infantile spasms. Id. None of the five patients who
had never seized was mentally disabled. Id. Yet, they had a
median number of cortical tubers that was higher than that for the
patients with partial seizures. Id In addition, the average number
of frontal lobe tubers in the seizure-free group of five patients was
higher than for those with partial or generalized seizures,
excluding those with infantile spasms. Id. From these data, the
authors conclude that if a TS patient has mental disability,

EE —

35a

seizures are always associated with it, "suggesting that the
seizures themselves play a role in the pathogenesis of the mental
impairment."

Referring to Roach etal., the authors state that Roach was
unable to link directly intelligence and the number of tubers. Id.
The authors surmise part of the difficulty may lie in Roach’s use
of less sensitive equipment. Id. In criticism of Jambaqué, the
authors write that Jambaque’ did not state the total number of
tubers accurately in relating number of tubers to mental
development, especially in cases of infantile spasms. Id.
Jambaqué’s study had three patients with unfavorable outcome
who had fewer than two tubers. Id. Moreover, Jambaqueé’s study
did not give a complete picture because it did not describe anyone
with generalized seizure other than infantile spasms. Id.

Because MRIs were not done at the same time as seizure
onset, Shepherd and his coauthors could not assess how MRIs
could be used to predict future disability. Id.

In Dr. Lamm’s published paper based on these five
papers, he and his co-authors (including the three authors of the
Shepherd paper) state that severe mental retardation is seldom
seen in TS patients whose seizure disorder presents after infancy
and is not seen in those who do not seize. R. Ex. DDD at 85.
"The relationship between cortical tubers, seizures, and mental
retardation is not well defined." Id. at 86. The hypothesis Dr.
Lamm presented was whether the tuber count in the above five
studies of TS patients was predictive of the patients’
neurodevelopmental status (normal or abnormal) or seizure status
(normal or abnormal). Id. The studies demonstrate increased
severity of both developmental status and seizure status with
increased number of cortical tubers. Id. at 87.

Lamm and his co-authors conclude that TS patients with
more cortical tubers were about six times as likely to have
intermediate or severe developmental delay and about eighteen
times as likely to have poor seizure control than those with fewer
cortical tubers. Id. at 87-88. TS patients with eight or more tubers

36a

were about five times as likely to have intermediate or severe
developmental delay and about sixteen times as likely to have
poor seizure control than those with fewer cortical tubers Id at 88.

One of the articles in the area which Dr. Lamm and his co-
authors did not use because the subjects of the study with tuber
counts were of normal intelligence was "Cranial magnetic
resonance imaging in patients with tuberous sclerosis and normal
intellect," by David W. Webb, J.L.G. Thomson, and J.P. Osborne
(the last being petitioners’ witness) in 66 Arch Dis Childhood
1375-77 (1991). P. Ex. 65. Tr. at 234. In that study, Dr. Osborne
and his co-authors conclude that MRI count of tubers is "unlikely
to be a reliable predictor of clinical outcome." P. Ex. 65 at 1376.
_ A better predictor may be distribution and size of lesions. id.
None of their eleven patients under MRI analysis had more than
ten cortical tubers. Id. One of their patients, who was a bright
student, had nine cerebral tubers. Id. Others have been reported
with considerably fewer lesions but with severe mental handicaps.
Id.

In conclusion, Dr. Osbome and his co-authors state, "[o]ur
findings suggest that the wrong conclusions may be drawn if the :
number of lesions alone on cranial MRI is used to predict |
neurological outcome in tuberous sclerosis." Id. at 1377. They |
suggest that future studies include number, size, and distribution
of lesions. Id.
Dr. Lamm’s study includes only cortical tuber count, not
size or distnbution. R. Ex. DDD. The same criticism that Dr.
Osborne and his co-authors raised in their paper (P. Ex. 65) is
expressed in an editonal following Dr. Lamm’s paper on cortical
tuber count as a biomarker for neurological seventy: "Tuberous
Sclerosis: Function Follows Form," by E.S. Roach, 12 J Child
Neur 75-76 (1997). R. Ex. DDD (following the Lamm paper). Dr.
Roach states:
Given the vanability of both the neurologic
impairment and the brain pathology caused by
tuberous sclerosis, it seems reasonable that

Eteet karte sie el ae

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37a

children with more brain lesions should have
more severe neurologic impairment.... Despite a
trend toward greater severity with increasing
numbers of cerebral lesions..., individual patients
may not fit this pattem. Many of us have
encountered a well-functioning patient whose scan
1s quite abnormal or a child whose scan is only
mildly abnormal despite very impaired function.

{E]xtensive brain disruption by tuberous sclerosis

may predetermine which patients develop

intractable epilepsy and through this or other

mechanisms contribute to poor intellectual
development.
Id.. at 75-76.

Continuing in his cnticism, Roach states that although
Lamm’s analysis is convincing. "a correlation of this sort leaves
many unanswered questions. There is enough individual variation
of both the clinical outcome and the radiographic appearance that
the magnetic resonance scan alone generally cannot be used to
establish the prognosis for an individual patient." Id. at 76. In
addition, seizure control may not be the only influence on a
child's developmental outcome because distribution of brain
lesions in specific regions may affect behavioral or cognitive
patterns. Id. To determine this "will require careful comparison
of the number, size, and location of the cerebral lesions" of TS
together with detailed neuropsychological testing. Id.

The undersigned has or has had before me thirty TS cases.
I have a tuber count for 19 of those cases. The least number of

38a

tubers is four'’ the greatest number of tubers is forty-three.'* But
there is no clear-cut correlation between number of tubers and
developmental delay. For instance, Miller'® has ten tubers and has
serious developmental problems and substantial deficits. But
Destrv Decker’ has seventeen tubers, yet his IQ is in the low
normal range and he planned to graduate high school and attend
college. His brother, Damien Decker,*' however. has twenty-three
tubers and has elective mutism and mild retardation with
emotional problems. In comparison, Turner~ has thirteen tubers,
ten less thari Damien, but he cannot talk or feed himself and has
a stomach tube. In 1989 when he was 11 years old, he had a
mental scale of six months and a motor scale of fifteen months.
Drs. Osborne's and Roach’s separate criticisms of reliance solely
upon cortical tuber count in predicting neurological outcome,
without evaluating tuber location and size, seems appropriate.
This emphasis on size and location is in the Shepherd et al. paper
as well. R. Ex. 0.

The second major part of Dr. Lamm’s testimony dealt
with the question of whether DPT is a significant risk factor for
bad TSC. Tr. at 291.

In Dr. Lamm’s testimony, he referred to the Melchior

"Henkel. No. 90-33 14V. The child had infantile spasms, but is functioning
well albeit some significant delay in a couple of areas.

8 , ae ae
'SPlavin, No. 91-1555V. She is functioning at a low to moderately low level
and the latest development record shows her about two years behind in gross and fine
motor skills.
19 saa YU
No. 90-2764 V.
.
?°No0. 90-1115V.

2INo. 90-11 16V.

*2No0. 90-3409 V.

39a

study in 1977” as proof that DPT does not cause infantile spasms.
Tr. at 296. When Denmark changed the immunization schedule
from the fifth month to the second month, the onset of infantile
spasms remained the same. Id.

Before April 1, 1970, DPT was administered in Denmark
at five months, six months, and fifteen months of age. R. Ex. H
at 134. After April 1, 1970, pertussis vaccine was administered at
five weeks, nine weeks, and ten months of age. Id. Melchior
compared the onset of 86 cases of infantile spasms from 1957 to
1967 with the onset of 113 cases of infantile spasms from April
1, 1970 to March 31, 1975, and found “no significant difference”
in the age of onset. Id. at 134-35. He stated, however, there mig:it
be a few cases of causal connection from the vaccine. But, he
thought “time-coincidence the most likely factor.” Id. at 136.

Dr. Lamm’s second article concerned a re-evaluation of
the Bellman 1983 paper.** Bellman and his co-authors took the
269 infantile spasms cases reported in the National Childhood
Encephalopathy Study (NCES)** and conducted a case control

*3Melchior, J.C., "Infantile spasms and early immunization against whooping
cough. Danish survey from 1970 to 1975," 52 Arch Dis Childhood 134-37(1977). R.
Gx. i.

*4Bellman, M.H., Ross, E.M., and Miller, D.L., "Infantile Spasms and
Pertussis Immunization,” The Lancet 1031-34 (May 1983). P. Ex. 53.

*5 alderslade, K., Bellman. M.H., Rawson. N.S.B.. Ross, E.M.. and Miller,
D.L.. “The National Childhood Encephalopathy Study: A report on 1000 cases of
serious neurological disorders in infants and young children from the NCES research
team,” Department of Health and Social Security. Whooping Cough: Reports from the
Committee on the Safety of Medicines and the Joint Committee on Vaccination and
Immunisation (London Her Majesty's Stationery Office, 1981). P. Exs. 80 and 80A.
According to the Institute of Medicine (IOM), the NCES did not include infantile
spasms in its study of DPT because “post-hoc analyses show[ed] no association
between infantile spasms and earlier DPT immunizations.” DPT Vaccine and Chronic
Nervous System Dysfunction. A New Analysis, IOM (Washington, DC: National
Academy Press, 1994) at 8. P. Ex. 82A. Actually, this is an oversimplification. The
NCES did include infantile spasms, but found that the same incidence of onset occurred
after DPT as after DT and, since the overall number of onsets of neurological illness
after DT was not statistically significant, it could similarly not find the incidence of

40a

analysis. P. Ex. 53 at 1031. They found an antecedent factor that
may have caused infantile spasms in 34 percent of the cases. Id.
The two most common causes were perinatal hypoxia (38 cases)
and TS (16 cases). Id. The authors conclude that DPT does not
directly cause infantile spasms, but may precipitate their onset “in
those children in whom the disorder is already destined to
develop.” Id. at 1033.

Bellman and his co-authors classified the children into one
of three categories: symptomatic (92 children) for those with an
antecedent disorder that could cause the spasms: cryptogenic (163
children) for those with no apparent cause; and doubtful (14
children) for those whose prior development was not normal but
who had no definite antecedent factor. Id. at 1031. The
symptomatic group was subdivided into perinatal and postnatal
groups and a group with congenital or genetic conditions. Id. TS
was included in the congenital/genetic subgroup of which it was
the most common in that subgroup (16 out of 35 cases). Id.

The authors state that since the onset of infantile spasms
occurs when most infants are receiving immunizations, “a
temporal coincidence would be expected in a certain number of
cases.” Id. at 1033. In Denmark and Japan, when the age of
vaccination was reduced, the incidence of infantile spasms onset
did not change, suggesting that causal association was unlikely.
Id. The NCES did not show any significant association between
infantile spasms and DPT administered in the prior seven days.
Id.

However, there was a small excess (less than 10 percent)
in the number of cases over those in the control group in seven
days after vaccination, with a corresponding deficit in the next
three weeks, suggesting that both DPT and DT may trigger the
onset of spasms. Id. Most of the DPT-associated cases were
cryptogenic whereas most of the DT-associated cases were

infantile spasms bv itself after DPT statistically significant. P. Ex. 830A. Bellman’'s
1983 paper based on the NCES data shows the same result of equal incidence of
infantile spasms after DPT and DT P Ex. 53

ee et a oe a se ee

4la

symptomatic. Id. A high proportion of the TS (symptomatic)
cases were vaccine-associated. Id. This suggests TS cases were
associated with DT, rather than DPT, vaccine.

In Dr. Lammn’s re-evaluation of the Bellman paper, he
included Dr. Bellmam as a coauthor. R. Ex. MM. The data were
the same underlying the 1983 Bellman paper. The authors of the
1996 re-evaluation propose three models: triggering of a
hypothetical relatiomship between DPT or DT and the onset of
infantile spasms: (indistinguishable from causality); recruitment
(onset would have occurred anyway, but occurs sooner); and no-
effect. Id. at 8.

They found no association between DPT or DT exposure
in the prior month and the onset of infantile spasms. Id. at 9.
However, among this group with DPT or DT exposure in the
previous month, cases were most likely to be reported within one
week of exposure than within the other three weeks of the
preceding month. This observation fits within the recruitment
effect model. Id.

The authors included TS patients in the category of
previously abnormal. Id. at 10. The data for the previously
abnormal infantile spasm cases with DPT or DT exposure fall
into the noeffect model. Id. None of the data fit the triggering
model. Id.

Dr. Lamm referred in his testimony to an abstract of data
that Dr.-Sergiusz Jozwiak submitted. Tr. at 353, R. Ex. FF.°° In
the October 1996 portion of the Omnibus hearing, this was all the
information that respondent provided the court. Consequently. the
court asked that respondent file the full paper when available. As

~ aresult of the filing of this paper (with Drs. Larnm and Goodman

as co-authors), the court continued testimony on the Omnibus

*6 Jozwiak, S., Chmielik, J., and Michatowicz, K., “Seizures and Intellectual
Disability in Children with Tuberous Sclerosis,” 37 Supp. 4 Epilepsia | 26 (1996)

42a

issues in June 1997,°’

In the abstract, Dr. Jozwiak states that 85-90 percentof TS
patients have epileptic seizures, and frequently mental retardation.
R. Ex. FF at 126. From 1984-95, he and his coauthors examined
106 Polish children with T'S, 102 of whom had epilepsy. Id. In
almost 60 percent of the patients, onset of seizures occurred in the
first six months of life: in 75 percent of the children, onset

occurred within the first year. Id. Most frequently, onset of

seizures occurred between the ages of 2 and 6 months, usually as
infantile spasms. Id. Those children who seized early more often
had severe mental retardation. Id. To test whether or not DPT
affected onset of seizures, the authors separated out twenty
children who had not been vaccinated. Id. All of them developed

seizures, 16 of them between the ages of 3 and 5 months. Id. Of

86 TS children vaccinated with DPT, 82 of them developed
seizures at the same age as the unvaccinated T'S children. Id.

Although the Jozwiak data rely on a small number of
children and, thus, the data are not statistically significant, itis the
only medical study that deals specifically with TS children and
DPI vaceie. Tr. at 354-55, 36 1-62. It does not deal with tuber
counts or types of seizure. Tr. at 355, 357.

There is another study by a psychologist, Ann Hunt, in
1983 in England.”* = She sent out 150 questionnaires to TS
families and received 97 replies. R. Ex. K at 346. The TS
individuals ranged in age from one year to age 51. Id. Fifteen had
never seized. Id.

Infantile spasms were the first symptom in 66 of the 82
cases. Id. at 347. Ms Hunt divided the cases into four groups
according to their immunization status. Id, at 346. Group II

9
“ The paper was submitted on May 13, 1997 as R EX PEE Sergiusz

Jozwiak, Michael Goodman, and Steven H Lamm, “Poor Mental Development in TSC

Patients Clinical Risk Factors © It has been accepted for publication in Arch Neur

“Hunt, Ann, “Tuberous Sclerosis A Survey of 97 Cases. 1 Seizures,
Pertussis Immunization and Handicap,” 25 Devclopmental Medicine & Neurology
34049 (1983) R EX K

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Pe ne LS ine Sta ONS “be

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43a

(children immunized after seizure onset) was further divided
according to whether the vaccinee received DPT or DT. Id. at
348. She found that six of the 13 DT vaccinated children were
profoundly handicapped compared with two of the 14 DPT
vaccinated children. Id. She concluded that the severity of these
children’s condition had to be related to factors other than
pertussis vaccine.”” Id. Early onset of seizures was predictive of
poor outcome. Id. at 349. She opines that DPT as well as other
factors (teething, high temperature, polio vaccine, smallpox
vaccine, etc.) may act as triggers to seizure onset. Id.

In describing R. Ex. EEE, the Jozwiak paper, Dr. Lamm
testified on June 3, 1997 that Dr. Jozwiak sent him data which he
analyzed. Tr. at 1563-64. Among four risk factors (age at seizure
onset, gender, previous DPT immunization, and seizure type),
Jozwiak, Goodman, and Lamm concluded that only seizure type
had a statistically significant association with poor mental
development. R. Ex. EEF at 2. The authors also found that age
of seizure onset was significantly associated with poor mental
development untl they “adjusted for seizure type,” 1.¢..removed
infantile spasms from their calculations.” Id. at 13-14. Neither
vender nor pnior DPT vaccination was a risk tactor for poor
mental development. Id. at 14.

Poland's DPT immunization policy is that the first DPT
is administered at three months, the second six weeks later, and
the third six weeks after that. Id. at 4. The fourth DPT is given
between the ages of 1’: to 2 years. Id. The authors compared
seizure onset during the first tour months of life for those who
had prior DPT vaccinations with those who did not (20 patients).

%) =

*'Group Hl contained those people vaccinated within one month prior to
seizure onset Of these 17 people, onls two were protoundls retarded R Ex K at 346
348

The authors, s lewing infantile spasms as age-specific since they occur only
between three and eight months of age, removed them trom their calculations, leaving
seizure onset of the remaining seizure types, and found that these seizures (non-
infanule spasms) were unrelated to poor outcome Tr at 1592-94

44a

Id. at 7-8. Kighteen of the twenty infants with seizure onset and
no prior DPT had their seizure onset within their first: four
months, the same age as those infants with prior DPT
immunization. Id. at 11. The authors conclude that DPT has no
association to the onset of seizures in TS children. Id. at 13.

Kighty-five percent of patients who seized within the first
six months of life had infantile spasms. Id. at 13. The authors
conclude that the most important single clinical finding associated
with poor mental development is infantile spasms. Id. They
comment that the Webb etal. family-based study”' reports a lower
rate of mental abnormalities because the authors excluded from
their study spontaneous mutations, which cause approximately 60
percent of all TS cases. Id. at 12.

In his testimony in October 1996, Dr. Lamm stated that 55
percent of TS patients at the Mayo Clinic who had MRIs had
mental retardation, and 72 percent of those with ten or more
tubers were mentally retarded. Tr. at 449. In his testimony in June

1997, Dr. Lamm said that there is a fourfold increased risk of

moderate to severe mental retardation if a T'S child has intantile
spasms. Ir. at 1586-87.

Dr. John P. Osborne testified for petitioners in October
1996. Tr. at 460. He is a consultant pediatrician with a special
interest in pediatric neurology and TS. Tr. at 461-62. He has done
research in the morbidity of TS and is continuing to study TS
patients. Tr. at 466-68. He is also a medical adviser to the TS
Society of Great Britain. Tr. at 471-72.

Dr. Osborne testified that no one knows the causative
mechanism of seizures in TS. Tr. at 475. A TS child will be
neurologically handicapped only if he or she has seizures unless
there is another cause. Id. As the tuber count increases, in
general the risk of mental retardation increases. Tr. at 476-77.
However. he is not convinced that tuber count has as close a
relationship to bad outcome as Dr. Lamm testified. Id. Other

‘I Webb. DW. Fryer. A_E.. and Osborne, J.P.. “On the incidence of fits and
mental retardation in tuberous sclerosis.” 28 J Med Genet 395-97 (1991). P. Ex. 63

= a Se ee

45a

factors, such as gender, and size and location of the tubers, come
into play. Id.

Dr. Bellman used data from the NCES” in his 1983 paper.
Tr. at 486. The NCES was designed to examine the role of DPT
in the outcome, but not to look at infantile spasms, just at
encephalopathy. Jd, In Dr. Osborne's view, there was a gross
underestimate of the number of infantile spasms post-DPT
because they were not reported. Id. The number of TS children
in the study also grossly underestimated the number they should
have found over the study’s time period. Tr. at 487.

TS children have normal development before seizures. Id.
There is a great debate over which category to put non-
symptomatic TS children: normal or abnormal. Tr. at 487-88. Dr.
Osborne would look at TS cases separately, but there was too
small a group to have significant results from the NCES data. Tr.
at 488. Dr. Bellman’s 1983 paper was very good, but had its
problems and limitations. Tr. at 489.

In Dr. Osborne's opinion, anything might recruit seizures.
Tr. at 499. Itis difficult for him to say, however, that DPT causes
afebrile seizures in a TS child. Tr. at 500-01. It is possible that
whatever triggers seizures can be a cause, such as swelling at the
vaccine site. Tr. at 501-02. The general trend is that the more
tubers, the more the risk of seizures and mental retardation. Tr. at
510.

As a rare occurrence, DPT can cause encephalopathy in
normal children. Tr. at 512. DPT is a risk factor tor TS children
because one wants to avoid giving them a fever. Tr. at 516. The
earlier their seizures, the more risk of retardation. Tr. at 519. The
risk of a low IQ is higher with an earlier age of onset, i.e., within
the first vear. Tr. at 521. He has seen children who have TS and
are on anticonvulsants contract a fever and not seize. Tr. at 535.
He is uncertain if TS patients can withstand a fever without
seizing prior to treatment with anticonvulsants. Tr. at 535-36. He

32
See supra, note 25

46a

thinks Dr. Lamm’'s cortical tuber paper is misleading because it
omits confounding factors. Tr. at 536. It is difficult to answer in
an individual child whether DPT caused his or her seizures. Tr. at

548. There is no way of knowing. Id. He could not rule out DPT

as a cause, however. Tr. at 550. Half of TS children are likely to
have mental retardation; three-quarters of them are likely to have
seizures. Tr. at 555.

There are two gene sites (TSC 1 and TSC 2) for
chromosomes linked to TS: chromosome 9 and chromosome 16.**
Tr. at 565. Dr. Osborne stated that TS is not an idiopathic
condition. Tr. at 567. He does not think he has seen a child with
more than nine tubers who was normal. Tr. at 587.

Dr. Osborne testified that TS causes infantile spasms,
which can have an acute onset. Tr. at 593-94. There is clearly an
association with TS, but no one knows how TS causes infantile
spasms. Tr. at 594. TS also causes mental retardation. Tr. at 596.
In less than ten percent of the cases would he attribute the cause
of seizures ina TS child to something other than TS. Tr. at 596-
97. A febrile illness could cause seizures in a TS child. but it
would not have sequelae. Tr. at 596.

Seizures cause the damage in the TS child. Tr. at 609-10.
[hree to six months 1s the most common age for TS children’s
onset of seizures. Tr. at 611. To have onset of seizures at nine
months 1s better than at three months. Id. The number of tubers
does not fully predict the outcome. Tr. at 628. Age and gender
are risk factors for seizure onset. Tr. at 630. DPT is not the most
important variable and is not frequently the cause of seizures in
a TS child. Id. DPT has an influence in some children. Tr. at 631.
But in an individual. one cannot tell if DPT caused the seizure. Id.

See R Exs OO-ZZ. LLL (The TSC | {TSC = TS complex] gene is on
chromosome 9q34 The TSC 2 gene is on chromosome l6pl3. Ro Ex. LLL. van
Siegtenhorst, M.ct.al, “Identification of the Tuberous Sclerosis Gene TSC | on
Chromosome 9q34," 277 Science 805-08 (1997) The authors state “TSC can be a
devastating condition as the cortical tubers. frequently cause epilepsy, mental
retardation, autism, or attention deficit-hyperactive disorder, or a combination of these
conditions " Id at 80S )

| ee ee

——

47a

When asked if a child who seized within three days of
DPT would have a change in outcome, Dr Osborne answered he
could not say it definitely would, but it might and occasionally
does (however, not more likely than not). Tr. at 631-32. Dr.
Osborne testified that he has never said that DPT was the
probable or likely cause of a seizure in a TS child. but he has said
it was a possible cause. Tr. at 645. The effect of DPT might be as
overwhelming in a child with one tuber as with many. Tr. at 666.

Dr. Marcel Kinsbourne, a pediatric neurologist, testified
next for petitioners. Tr. at 674. It is unquestionable that the
number of tubers is a risk factor for outcome in TS. Tr. at 687-
88. He does not believe that the TS does the damage itself. Tr. at
694-95. Something else decides when the seizures begin. Tr. at
695. Tubers mean there is an electrical difference between the
tuber and the normal brain. Tr. at 705-06. There is no evidence
that TS predetermines the outcome because the outcome in TS
patients ranges so widely. Tr. at 709. Biological processes are
continuous. Tr. at 711. The younger a child is, the greater the risk.
Id.

Dr. Kinsbourne thought the number of cases included in
Dr. Lamm’s reevaluation of the Bellman 1983 paper was too
small to look for the unusual effect of DPT causing seizures in a
TS child since it happens only occasionally. Tr. at 725. TS causes
twenty percent of all cases of infantile spasms: Tr. at 726. In
Bellman’s use of the NCES data, he had 262 patients with
infantile spasms. Id. Dr. Kinsbourne would expect that fifty of
the infantile spasms cases would have TS, but there were only
sixteen. Id. He thinks that DPT and a high cortical tuber count is
worse than DPT and a low cortical tuber count. Tr. at 732. The
1983 Bellman paper had a limited point. Tr. at 762. You cannot
use the NCES data as evidence against a DPT recruitment effect
on TS patients. Tr. at 763.

Dr. Kinsbourne agreed that cortical tuber count is a strong
predictive factor of having seizures, including infantile spasms,
and that it is more likely that a TS child will have infantile
spasms. Tr. at 792. He did think it incoherent to say that TS alone

48a

causes a bad outcome. Tr. at-793. He thinks that DPT is an
infrequent cause of infantile spasms in a TS child, but the issue
has not been formally studied.* Tr. at 798.

Dr. Kinsbourne is relying on the Decker twins” as the
basis of his opinion that DPT causes infantile spasms in TS
patients. Tr. at 8 15-16. He thinks that DPT is a contributory
factor in only some, but not all, TS children. Tr. at 817. The
incidence of neurologic reaction in TS and non-TS children
should be the same, but the consequences are different. Tr. at 819.
One cannot tell if DPT has a trigger or recruitment effect. Tr. at
819-20. He testified that the opinion that DPT is an occasional
cause of infantile spasms is a minority view. Tr. at 827-28.

In 1994, the IOM issued a reevaluation of the NCES
conclusions, based on a follow-up ten vears later: “DPT Vaccine
and Chronic Nervous System Dysfunction. A New Analysis,”
(National Academy Press, 1994), P. Ex. 82A. Positing the theory
that DPT could trigger acute neurologic signs and symptoms in
children with underlying brain or metabolic abnormalities, the
[OM entertained that vaccinees who had serious, acute neurologic
illnesses after DPT might go on to have chronic nervous system
dvstunction. Id. at 13-14. However, if that theory were true, DPT
would not increase the overall or lifetime risk of chronic nervous
system dysfunction because they would eventually have reacted
in the same fashion to another type of acute illness. Id. at 14.
Another theory the IOM posited is that children with underlying
brain or metabolic abnormalities might eventually develop
chronic nervous system dysfunction even without an acute
neurologic illness. The IOM called this theory the “provocative
challenge unmasking the underlying abnormality.” Id. But in this

} . P .

“Dr Kinsbourne’s testimony in October 1996 was before the Jozwiak paper
was written and only the abstract (one paragraph) was in evidence. Dr Kinsbourne
estified again in June 1997 after the Jozwiak paper was produced

Destry and Damien Decker were part of Dr. Gomez's study of two sets of
wins with TS P Ex 57. The Deckers had DPT before the onset of their infantile
spasms Destry has 17 tubers, while Damien has 23 tubers

49a

scenario, the IOM would not consider the relationship between
DPT causal (unlike in the triggering scenario). Id, (The IOM also
concluded causation if DPT caused a serious acute neurologic
illness and subsequent chronic nervous system dysfunction in a
child who seemed to have no underlying disorder. Id.)

The IOM said the NCES data do not permit distinguishing
among the above three scenarios. Id. at 13-14. In the trigger
scenario, the IOM would not posit cause of the chronic
dysfunction. Id. at 15. Overall, the IOM stat«s that the NCES data
does not permit a conclusion of causation although their
theorizing posits its plausibility in some cases. Id.

This court, in a case arising under a causation in fact

_ analysis. has held that there is no difference between “trigger” and

“cause.” McMurry v, Secretary, HHS, No. 95-682V, 1997 WL
402407 (Fed. Cl. Spec. Mstr. June 27, 1997). That case did not
concern a TS child. but one who without any apparent neurologic
deficit experienced fever and seizures within a day of DPT
vaccination. Since petitioners filed after the effective date of the
new regulations. residual seizure disorder was no longer a Table
injury.”

Since the IOM’s 1994 report (P. Ex. 82A) does not deal
specifically with TS, using tts rather broad theories of relationship
is limited at best. The court accepts, per Drs. Gomez’s.Osborne’s,
and Kinsbourne’'s testimony, that the earlier a TS child seizes, the
worse his or her condition will be. Dr. Gomez's 1995 article with
Drs. Shepherd and Houser states as much. R. Ex. 0. Considering
that there are a whole host of possibilities for underlying
neurologic abnormalities, the court cannot comfortably rely upon
the IOM’s 1994 report as proof of causal relationship in this case,
particularly in light cf the highly-specitic evidence of both
clinical neurology and medical literature concerning TS.

Petitioners also submitted P. Ex. 54, Shepherd, C.W.,
Beard, C.M., Gomez, M.R., Kurland, L.T., and Whisnant, J.P..

36,.
See supra, notes

50a

“Tuberous Sclerosis Complex in Olmsted County, Minnesota,
1950-1989.” 48 Arch Neur 400-01 (April 1991). There were 12
patients in the study. Id. at 400. One had an intellectual disability
and seven had seizures. Id. at 401. With this small number,
estimation in general of the number of TS patients with
intellectual disability is precarious. Id.

P. Ex. 55, Osborne, J.P., Fryer, A., and Webb, D.,
“Epidemiology of Tuberous Sclerosis,” 615 Annals of the New
York Academy of Sciences, 125-27 (April 1991), recounts that
the only study of any size to report the frequency of mental
retardation in TS individuals was one from Oxford in 1984 which
reported 68 percent had mild or severe retardation. Id. at 125.
Osborne and his co-authors studied 2,830,921 individuals and
found 83 TS people. Id. at 126. Of these, 52.5 percent were
mentally retarded. Id. Eighty percent of the affected people had
seizures, which meant that 27.5 percent of individuals with
seizures had normal intelligence. _Id. (P. Ex. 62 1s the same as P.
Ex. 55.)

P. Ex. 58, Clarke, A., Cook, P., and Osborne, J.P.,
Cranial Computed Tomographic Findings in Tuberous Sclerosis
are not Affected by Sex.” 36 Develop Med and Child Neur 139-
145 (1996), found that more males than females with TS had
learning disorders, and that high tuber count did not sufficiently
explain the difference. ld. at 142. The authors speculated that
males may be more sensitive to seizures and especially to
infantile spasms. Id. at 144. (Jozwiak, however, found no higher
risk factor for mental retardation among males than among
females with TS. R Ex. EEE at 2,12, 15.)

In P. Ex. 59, Webb, D.W., Fryer, A.E., and Osborne, J.P.,
“Morbidity Associated with Tuberous Sclerosis: A Population
Study,” 38 Develop Med and Child Neur 146-55 (1996), the
authors studied age of onset of seizures in 131 TS patients. Id. at
147. Seizures occurred in 102 of them (78 percent). Id. Age of
onset was known in 99 cases and it was under one year for 70 of
them (69 percent) with a peak between three and six months. Id.
The peak age for infantile spasms was four months and 70 percent

SR ee ve =

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:
‘
a
2
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|

Sla

occurred between three and seven months. Id. In males, 33
percent had infantile spasms; in females, 18 percent. Id. In males,
22 percent had partial seizures, episodes of absence and tonic-
clonic seizures; in females, 31 percent. Id. Seven patients had
febrile convulsions as their first seizure, and two patients had
myoclonic seizures. Id. at 147-48. Six had episodes of status
epilepticus. Id. at 148. Seventy patients (53 percent) had a
learning disorder; all of them had a history of seizures, but »ot all
patients with seizures had a learning disorder. Id. at 148. The
authors state that individuals with TS have an increased risk of
seizures throughout life. Id. at 152.

P. Ex. 64, Osborne, J.P. and Fryer, A.E., “Tuberous
sclerosis (epiloia, Bourneville’s disease),” 2 Clinical Neurology
1526-32 (Swash and Oxbury, eds., 1991), states that the majority
of TS patients have seizures. Id. at 1526. Most series report
seizures in excess of 85 percent of TS cases, occurring usually in
early life, with up to 50 percent of them having infantile spasms.
Id. Many types of seizures occur in TS. Id. The role of DPT
immunization in initiating seizures is unclear. Id. Citing the Hunt
1983 paper (R. Ex. K), Drs. Osborne and Fryer state that “there
is no good supportive scientific evidence” to regard DPT as the
trigger of TS children’s problems. Id.

P. Ex. 66, Fryer, AL., Chalmers, A.H., and Osborne, J.P.,
“The value of investigation for genetic counseling in tuberous
sclerosis,” 27 J Med Genet 2 17-23 (1990) describes TS as “best
known for causing mental retardation and fits....” Id. at 217.

At the court’s insistence, Dr. Manuel Gomez testified on
June 3, 1997, after the writing and filing of the Jozwiak paper. Tr.
at 1392. Since his testimony in 1991, Dr. Gomez's opinion
(communicated through letter form to respondent’) appeared to
be changing concerning DPT as a trigger of seizures in TS
children. Since Dr. Gomez is the world’s expert on TS, the court
found it crucial to ask him what his opinion was, whether it had

"See R. Ex. N

S2a

changed, and why.

In the Hanlon case, Dr. Gomez, after reviewing the
records. opined that the cause of Michael Hanlon’s seizure onset
was the cortical lesions of his brain. Tr. at 1397. He stated that
DPT did not significantly aggravate his seizure onset, and that
Michael's current condition is due to his TS. Id. DPT was not a
catalytic factor in this case. Tr. at 1398-99. One can determine the
location of the tubers by the symptoms in the child. Tr. at 1400.
For instance, Damien Decker has tubers in his left temporal lobe,
a site that is correlated with autism (a condition that Damien has).
Tr. at 1401.

In the Plavin case, Dr. Gomez testified that the cause of
Rachel Plavin’s seizures is her cortical lesions. Tr. at 1408. TS is
manifested by seizures. Tr. at 1409. Recently, surgery has been
done where if one removes the tuber. the seizure stops. Id.
Literature describing seizure onset in twins indicates that they
have infantile spasms at approximately the same time. Tr. at
1419.

Respondent's Exs. HH, I, JJ, and KK are studies on
infantile spasms in monozygotic twins (the Deckers are
monozygotic twins). Respondent produced these studies as proof
that onset of seizures in twins occurs closely in time without a
preceding DPT vaccination.

In Pavone, L., Mollica, F., Incorpora, G., and
Pampiglione, G., “Infantile spasms syndrome in monozygotic
twins.” 55 Arch Dis Childhood 870-72 (1980), the authors
discuss the onset of infantile spasms in twins on the same day (a
few hours apart) at age six months. R. Ex. HH at 870. The spasms
occurred and recurred at intervals of several seconds with
episodes of 15 to 20 spasms. Id. The authors state, “The precise
mechanisms underlying the syndrome of infantile spasms are still
unknown despite the fact that a variety of genetically-determined
conditions (in particular tuberous sclerosis) have been described.”
Id. at 872. There was no “apparent external triggering factor. This
would suggest some kind of ‘preprogrammed’ type of disease.”
Id.

53a

Pavone, L., Mollica, F., Incorpora, G., and Pampiglione,
G., “Infantile spasms syndrome in monozygotic twins. A 7-year
follow-up,” 6 Italian J of Neur Science 503-06 (1985), continue
discussing the same twins. R. Ex. II. They had received oral polio
vaccine at the ages of three and four months. Id. at 503. At four
months, they seemed to lag in motor and psychomotor
development._Id. Their seizures at six months were initially
viewed as colic. Id. at 503-04. Treatment was begun two months
after onset. Id. at 505. One twin was first treated with
Clonazepam and later given ACTH followed by Phenobarbital,
and was attending normal school. Id. at 504. The other twin,
who was first treated with ACTH followed by Prednisolone and
Clonazepam, lagged his brother. Id. No cause was found for the
‘infantile spasms. Id. at 505.
Segal, R.A., Chapman, C., and Barlow, J., ““Monozygotic
Twins with Seizures. Shared Characteristics,” 48 Arch Neur
1041-45 (1991), discuss eleven sets of monozygotic twins with
idiopathic seizure disorders. R. Ex. JJ. Three sets of twins had
their onset of clinical seizures within one day of each other. Id. at
1041. The concordance of the clinical seizure pattern, the EEG
patterns, “and, most strikingly, the timing of onset of the first
clinical seizure implicate genetic determinants. “Id. The mean
interval between the onset of seizures in co-twins was less than
three months 'n the eight cases that could be analyzed. Id. In nine
sets of twins, both twins had at least one seizure, a very high
concordance rate of 82 percent. Id. at 1041, 1043. The actual
concordance rate was probably higher because, in one of the two
sets of twins in whom only one twin seized, the asymptomatic
twin had an abnormal EEG, showing a propensity to seize. Id. at
1043. The authors state, “The most striking feature in this series
of epileptic twins is the frequency with which the time of onset
was shared by the twins.” The twins who seized within a day of
each other were afebrile, ruling out the possibility of a shared
infection. Id. at 1044.
Fujiwara, I., Nakamura, H., Watanabe, M., Yagi. K..,
Seino, M., and Nakamura, H., “Clinicoelectrographic

S4a

Concordance Between Monozygotic Twins with Severe
Myoclonic Epilepsy in Infancy,” 31(3) Epilepsia 28 1-86 (1990),
discuss monozygotic male twins whose seizure onsets were at ten
months (Twin A) and eleven months (Twin B). R. Ex. KK at 281,
283. Fever precipitated Twin A's seizure, while immersion in hot
water precipitated Twin B’s seizure. Id. The twins had three
different seizure types occurring in the same sequence. Id. at 285.
The authors believed that genetic, rather than exogenous, factors
were the cause of the seizures. Id.

Dr. Gomez testified that he is not sure that DPT causes
seizures, but iTcould if there is an acute illness. r. at 1420.
However, in the instance of infantile spasms, there is no evidence
that DPT causes them. Id. As tor Dr. Lamm’s cortical tuber count
paper (of which Dr. Gomez is the last named author), Dr. Gomez
said one cannot be that precise on the number of tubers. Tr. at
1422, 1462. One cannot be so exact with biology: biology is not
a mathematical science. Tr. at 1425. The location and size of
tubers, besides their number, are very important, agreeing with
Dr. Roach’s editorial following the cortical tuber count published
paper. Tr. at 1426, 1462-63. Tubers contain abnormal cells that
fail to develop. mature, and migrate. Tr. at 1427. As far as those
with eight or more tubers are concerned, some will seize and
some will not. Tr. at 1433. One has to look at the specific case;
one cannot generalize. Id. :

Both Hanlon and Plavin did not have infantile spasms. Tr.
at 1435-36. They had complex partial (focal) seizures. Tr. at
1436. Their seizures did not become generalized. Id. DPT can
possibly cause afebrile seizures that are general. Tr. at 1441-43.

If an insult to the body were to cause infantile spasms, it
would take a period of time (sometimes six-weeks, three months,
six months or one year) between the time of the insult and the
onset of seizures. Tr. at 1444. Dr. Gomez could not say that
someone with eight tubers would be mentally retarded. Tr. at
1470. If someone had ten tubers, he would probably have
seizures. Tr. at 1472. If someone had twenty tubers, he would
surely have seizures. Id. The onset of seizures in the Decker

=

eee ee ee aS

i eo

5Sa

twins after DPT could be a coincidence. Tr. at 1473-74.

Dr. Peter Kellaway, an expert in electromyography with
forty-five years’ experience, never saw infantile spasms after a
lesion or insult. Tr. at 1475. Dr. Kellaway wrote to another
respondent's expert, Dr. Rita Lee, on October 7, 1996, stating that
in more than forty-five years of clinical and research studies of
infantile spasms involving several thousands of children referred
for EEG, he and his associate never saw a case of infantile spasms
“develop acutely in response to brain injury or acute disease.” R.
Trial Ex. N (Dr. Peter Kellaway and Dr. Richard A. Hrachovy)

Dr. Gomez testified that a child will be worse if his onset
of infantile spasms is at three months rather than at eight months.
Tr. at 1513. He stated that the Melchior study (R. Ex. H)
disproves the Jeavons and Bower study.**(P. Doc. #4 attached to
Dr. Kinsbourne’s Response to the Government's Ten Question
Supplementation Request, filed January 21, 1997: also filed
separately by petitioners on September 23, 1996). Tr. at 1517-18.

The Jeavons and Bower 1964 study states that in nearly 70
percent of cases of infantile spasms, onset is within the first six
months. and. in nearly 90 percent, within the first year of life.
Jeavons and Bower at 11. Among factors in the symptomatic
group is TS. Id. at 15. Jeavons and Bower discuss DPT as a factor
and discuss literature showing DPT immunization before onset of
spasms in 9 out of 24 children, but note there is other litérature
that views DPT as coincidental to onset. (In the pro-DPT-as-a-
factor literature, 2 of those 24 children had onset of infantile
spasms after smallpox vaccination.) Id.

In pursuing DPT vaccine as a causative factor, Jeavons
and Bower focused on onset within one week of vaccination. Id.
at 36. The authors believed immunization was a cause in some
cases, admitting that individual case histories prove little. Id. at
37. They recommended a “very large scheme for collection of

8jeavons, P.M.. and Bower, B.D., “Infantile Spasms. A Review of the
Literature and Study of 112 Cases,” 15 Clinics in Developmental Medicine 1-82 (1964)
(hereinafter “Jeavons and Bower’)

S6a

data to obtain statistical information to prove or disprove the
theory.” Id.

As if in answer to Jeavons’ and Bower's suggestion, the
NCES is the largest study of DPT and serious, acute neurological
illness in association with DPT in the literature. P. Ex. 80A;
supra, note 25. The authors did not exclude cases in which there
was evidence of another possible cause, even though it might
have the effect of overestimating risks. Id. at 141. They found no
statistically significant risk in DT vaccine of severe convulsions
or encephalopathy within seven days or 72 hours of vaccination,
unlike their findings for DPT. Id.

The authors emphasized that their findings “suggest, but
do not prove that immunization with DTP vaccine does cause the
development of serious neurological disorders in a small number
of children....” P. Ex. 80A at 143.

In Dr. Gomez’s opinion, regardless of the age of onset,
tubers cause the seizures in children who have TS. Tr. at 1545.

Also testifying in June 1997 was Dr. Kinsbourne, in
response to Dr. Gomez. Tr. at 1649. Crucial to his opinion of a
relationship between DPT and seizures ina TS child are the dates
of vaccination and onset of seizures. Tr. at 1650. He stated that
the brain is not ready for infantile spasms until it is three months
old. Tr. at 1653. He admitted that the opinion that DPT causes
infantile spasms is a minority view. Tr. at 1678.

In criticism of Dr. Melchior’s conclusions (R. Ex. H), Dr.
Kinsbourne stated that the two cohorts of vaccinated and
unvaccinated by the third month showed more children who were
vaccinated had infantile spasms earlicr. Tr. at 1693-94. Melchior
went out to 18 months in forming his conclusion that there was no
difference in onset of infantile spasms whether a child was
vaccinated under the old series or new series of vaccine
administrations. Tr. at 1694-95. If one compares the whole of the
two groups, there is no difference in onset of infantile spasms
between those vaccinated and those unvaccinated. Tr. at 1695.
But the early months show a difference. Tr. at 1696. Dr.
Kinsbourne stated that Dr. Melchior did a conservative test

Least trad Pe Saad lh

'
at On sok eO Abid tec oT ic: we ALE

57a

showing all vaccinees, whereas he is less conservative
(comparing early vaccinated with unvaccinated). Tr. at 1701. In
Melchior’s Table | (R. Ex. H, at p. 134), before the age of three
months, 10 children in the 1957-67 series (unimmunized) and 25
children in the 1970-75 series (immunized two times, once at 5
weeks and once at 9 weeks) had onset of infantile spasms. Id.
Melchior’s Table | is as follows:

Table 1. Age at the first infantile spasms in two Danish series

1957-67 1970-75

Age(m) n % n %
<2 5 6 13 12
F 5 6 12 1]
3 9 10 14 12
4 17 20 8 7
5 17 20 26 23
6 13 15 12 1]
7 4 5 9 8
8 5 6 8 7
9-] 1 8 9 6 5
12-17 3 3 5 4
Total 86 100 113 100

There were, however, a total number of 86 in the 1957-67
series through the age of 18 months and a total number of 113 in
the 1970-75 series through’the age of 17 months. Id. However,
Melchior’s data do not show how many of the thirteen who had
onset of infantile spasms before the age of two months in the
1970-75 series had their onset before the first vaccination at five
weeks. Id. Moreover, since the testimony and the literature
support an onset of infantile spasms most often in the window of
time between three and eight months of life, one wonders how
carefully the data depict the true nature of the seizures that
occurred before three months and after eight months.

If we examine the data just for the window of time that
had the most onsets of infantile spasms (four to six months), we
come to a very different conclusion than Dr. Kinsbourne, one

58a

consistent with Melchior’s conclusion that pertussis vaccination
had no effect on onset of infantile spasms. The total number of
onsets between four months and six months in the 1957-67 series
(vaccinated at five and six months), was 47 cases of infantile
spasms; in the 1970-75 series (vaccinated at 5 and 9 weeks), there
were 46 cases of infantile spasms. The numbers are practically
identical. Thus, it appears that Dr. Kinsbourne’s analysis that
more vaccinated children in the younger (below three-month)
group developed infantile spasms than in the series that was not
vaccinated at that age is not a sufficient or persuasive analysis
when one examines the greatest onset of infantile spasms in both
vaccination groups.

Moreover, if we compare the number of onsets of infantile
spasms from under two months of age to three months (39) with
the number from four to six months (46) in the 1970-75 series, we
see the number almost the same, yet the four to six months group
had not been recently vaccinated.

If pertussis vaccine were the causative agent, one would
expect that a greater number of onsets would occur in close
proximity to reeeipt of the vaccine. But Melchior’s data do not
suggest this. In the 1957-67 series, pertussis vaccine was
administered before the age of eight months (the terminus of
onset of infantile spasms) at ages five and six months. Id. But the
onset of infantile spasms among that group occurred just as often
at age four months (17 cases) before vaccination as at ages five
months (17 cases) and six months (13 cases) after vaccination. Id.
Similarly, in the 1970-75 series, pertussis vaccine was
administered before the age of eight months at ages five and nine
weeks. But the onset of infantile spasms among that group
occurred just as often at under two months (13 cases) which could
have been before or after vaccination; at two months (12 cases)
long after the first vaccination but before the second; three
months (14 cases) long after the first and second vaccinations; at
five months (26 cases), twice as many onsets and yet not in any
time relationship to the first or second vaccinations; and at 6
months (12 cases), not in any time relationship to the first or

heh eA cts

Rebbe Scott Mans at eC ni ”

59a

second vaccinations. Id. The Melchior data do not show any
relationship between pertussis vaccination whether by comparing
the two vaccination series (1957-67 and 1970-75) or by internally
comparing onsets within each series.

In Dr. Kinsbourne’s workshop with Dr. Menkes which,
though published, is not a peer-reviewed article but a recounting
of a discussion among pediatric neurologists of the effect of DPT,
Drs. Kinsbourne and Menkes review the literature pertaining, in
part, to DPT and infantile spasms. Tr. at 1697-98, P. Ex. 52.
They cite Bellman, relying on the NCES data, that there is no
positive evidence to link DPT and infantile spasms. P. Ex. 52 at
17,4. The relative risk of 2.46 for the onset of infantile spasms
within one week of DPT immunization was not significant,
especially when compared to a relative risk of 2.0 in DT
immunized children. Id. They also cite Melchior’s study and
Fukuyama’s study’? for the proposition that DPT is unrelated to
the onset of infantile spasms. Id. Dr. Kinsbourne thought,
however, that one could conclude that DP7 might cause the onset
of infantile spasms in cryptogenic (unknown etiology) cases,

**Fukuyania, T., Tomori, N., and Sugitate, M., "Critical Evaluation of the
Role of Immunization as an Etiological Factor of Infantile Spasms," 8(3)
Neuropadiatric 224-3 7 (1977). R. Ex. I. The authors took 1 10 cases of infantile spasms
with information about immunization. Id. at 224. In 44 cases (40%), the children had
not received vaccinations yet. Id. Another 44 cases (40%) had been immunized either
one month before or after onset of infantile spasms. Id. They studied the remaining 22
cases and found age of onset of infantile spasms ranged from 3 to 9 months, with peak
occurreiice at 4-5 months, exactly identical to patients with infantile spasms in general.
Id. The vaccinations they received were DPT (15 cases), smallpox (4 cases), polio (1
case), encephalitis (2). Id. By asking if there were no other causal factors, whether
psychomotor development before onset was normal, and whether the interval from
immunization to onset was within 48 hours of DPT or 18 days of smailpox,
encephalitis, or polio vaccines, they found only 8 "cuiapatible" cases (4.8%) and 2
"probable" cases (1.8%) fulfilling these criteria. Id. at 228-29,235. The authors
concluded that the occurrence of 5 compatible cases out of 110 cases was easily
explained by coincidence since the onset of infantile spasms occurs at the same time
as immunizations within the first year of life. Id. at 235. R. Ex. J is the Institute of
Medicine (IOM) chapter 4 from Adverse Effects of Pertussis and Rubella Vaccines
(National Academy Press, 1991), which did a literature search and found no causation
between DPT and infantile spasms. R. Ex. J at 77.

60a

although this is unproven.*° Id.

Dr. Shanna Swan, who is a Ph.D., not an M.D.., testified
about the Jozwiak paper to the effect that she did not think that
one could conclude from it that DPT does not cause seizures such
as infantile spasms in TS children because one cannot prove a
negative. Tr. at 1706-07, 1716. She admitted that there was no
statistically significant association between DPT and the onset of
seizures in these children, but she thought that the field of
epidemiology might move away from the standard of requiring
statistical significance and be satisfied with less certainty. Tr. at
1717-19, 1739-40. The court was not impressed with Dr. Swan’s
testimony.”

In attempting to buttress its epidemiologic defense (Dr.
Lamm’s meta-analysis), respondent called witnesses to testify in
the October 1996 portion in particular about Michael Hanlon and
Rachel Plavin. The first of these witnesses was Dr. Robert. L.
Zimmerman, a pediatric neuroradiologist. Tr. at 840. He testified
that Michael Hanlon had ten cortical tubers. Tr. at 893.

“Petitioners later submitted P. Ex. 77 as an article upon which Dr.
Kinsbourne relied in his testimony: Riikonen, R., and Dormer, M., “Incidence and
Aeuology of Infantile Spasms from 1960 to 1976: a Population Study in Finland,” 21
Develop Med and Child Neur 333-43 (1979). Petitioners indicate that the mention of
one case of infantile spasms occurring after febrile gastroenteritis (id. at 337) proves
that an acute insult (the febrile gastroenteritis) can cause infantile spasms. Ergo, DPT.
another acute insult, can also cause them. This conclusion is too facile for the court.
One case out of 107 children of infantile spasms occurring after an infection that
includes fever hardly proves that DPT, especially when a child is

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Source: Frix Law Library, https://www.frixlaw.com/law-library/documents/brief%3Amicro_IA40386004_0906%3A2. Public record. Not legal advice.