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

ck ee

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UNPUBLISHED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

2a

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

4a

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

6a

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.

8a

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

10a

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.

12a

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

l3a

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

l4a

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.

etiowaascad

COLA Pith « CRU NY

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sth siden pias oa se Girly

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 =

ee

:

‘

a

2

r]

|

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

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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 afebrile and not

clinically ill, causes infantile spasms.

*! according to Daubert v. Merrell Dow Pharmaceuticais Inc., 509 U.S. 579

(1993) (discussing admissibility of scientific evidence), “general acceptance’ can be

an important factor....” The court must focus on “the principles and methodology.” Id.

at 594-95. By espousing minority views as to statistical certainty or causation of

infantile spasms, Drs. Swann’s and Kinsbourne’s testimony, though admissible under

the broad directives of the Vaccine Program (which does not adhere to the Federal

Rules of Civil Procedure), is not as credible as the testimony of Drs. Lamm, Gomez,

and Osborne, who are in the mainstream in accepting statistical significance as the

appropriate standard or in opining that DPT does not cause afebrile seizures such as

infantile spasms

6la

Dr. Rita Lee, a pediatric neurologist, testified for

respondent. Tr. at 919. Tuber count is a very important, but not

the only, factor in prognosing a child’s ultimate outcome and

likelihood of seizures. Tr. at 928. In a seizure, the neurons

discharge abnormally. Id. A cortical tuber is a group of abnormal

neurons. Tr. at 929. Neurons are brain cells that transmit

messages. Id. The area around the tuber edge is decreased in

myelination. Tr. at 930. It has an increase in fibrillary material.

Id. The tuber or the area immediately adjacent to the tuber is the

origin of the seizures. Tr. at 931. One can see a correlation on

EEG between the discharges and the cortical tubers, although not

always. Tr. at 931-32.

Dr. Lee testified that TS is a neuronal migrational disease.

Tr. at 932. Precursor neurons begin their lives-just around the

ventricles. Id. They migrate radially to the cortex. Tr. at 933. In

TS, some cells do not get to the brain surface. Id. A tuber will not

conduct normally. Tr. at 933-34. Bad outcome is accepted as a

consequence of neuronal migration disorder. Tr. at 935. Dr. Lee

referred to R. Exs. DD (Bebin article)** and EE (Palmini article)*

as literature in support of the strong correlation between EEG

results and large tubers. Tr. at 935-36. She also referred to R. Ex.

G (Chugani article)** which recorded lesions on PET scan. Tr. at

937. The seizures stopped when the lesions were excised. Id.

The Bebin article, of which Dr. Gomez is a co-author,

states “Seizures are the initial sign in 92% of patients with TSC

{tuberous sclerosis complex]....” R. Ex. DD at 651. In all except

one of the nine patients under study, EEG confirmed that seizure

Bebin. E.M.. Kelly, P.J.. and Gomez, M.R.. “Surgical Treatment for

Epilepsy in Cerebral Tuberous Sclerosis,” 34 Epilepsia 65 1-57 (1993).

3pPalmini, A..~ “Focal Neuronal Migration Disorders and Intractable Partial

Epilepsy: A Study of 30 Patients,” 30 Ann Neur 741-49 (1991).

Shields, W.D., Shewmon, D.A., Chugani, H.T., and Peacock, W.J.,

“Treatment of Infantile Spasms: Medica! or Surgical?” 33 (Supp. 4) Epilepsia 526-531

(1992).

62a

discharges came from a single region corresponding to a

prominent neuroimaging sign on MRI. Id. at 652. After surgical

excision of a primary focus lesion, six of the nine are now

seizure-free. and the remaining two patients have decreased

seizures. Id. at 656. The authors conclude that removing the

primary focus lesion can also eliminate or silence secondary

epileptogenic activity. Id.

The Chugani article states that “[i]t is important to

recognize that infantile spasms are a manifestation of an

underlying brain disorder rather than a disease entity unto itself”

R. Ex. G at 526. “The most important predictor of outcome is the

underlying cause.... The probability of normal outcome for

children with symptomatic infantile spasms is only about 5%....”

Id. at 527.

Symptomatic means the underlying cause is known, e.g.,

TS. Id. The authors recount a patient with TS in 1987 who had

infantile spasms which resolved for seven months when his

primary focus lesion was resected. Id. at S29-S30. When he

resumed his normal anti-convulsants, he remained seizure-free.

Id. at S30. They treated by resection nine other patients with

infantile spasms, and seven of them remained seizure-free three

to six years after surgery. Id. at S30.

__ Dr. Lee stated that tubers cause seizures in TS. Tr. at 938.

One can often identify the tubers that cause the seizures by MRI.

PET scan, and EEG. Id. One can stop the seizures by surgically

removing the lesions. Id. In Dr. Lee’s opinion, one does not need

a catalyst for a TS child to start seizing. Tr. at 939. The tubers are

an adequate source of seizure initiation. Id. We do not know the

timing of seizures. Tr. at 939-40. Afebrile seizures are not due to

DPT, although a febrile seizure might be (but not subsequent

seizures ina TS child). Tr. at 940-41. She stated that it is possible

for one to have afebrile seizures due to DPT, but it is rare. Tr. at

945. But Dr. Lee said she could not imagine how to prove that

DPT causes infantile spasms because they do not occur as an

acute response to an acute insult. Id. Infantile spasms take time

to develop (at least three to four weeks). Tr. at 945-46. DPT does

63a

not cause infantile spasms in close temporal proximity to

vaccination. Tr. at 946. There is no evidence that DPT causes

infantile spasms three to four weeks after immunization. Id.

TS causes all types of seizure except petit mal or juvenile

absence seizures or benign Rolandic seizures. Tr. at 954-55. The

consensus in the medical community is that DPT does not cause

seizures other than acute, benign, febrile seizures. Tr. at 957-58.

There is a high concordance between identical twins over whether

and when they will develop epilepsy. Tr. at 962. Dr. Lee testified

that infantile spasms are associated with a high tuber count. Tr. at

976. She stated that Michael Hanlon has TS, but DPT did not

aggravate it. Jr. at 978. TS caused his first seizure. Tr. at 979. His

current condition is not a sequela of his first seizure. Tr. at 980-

81. He has ten cortical tubers, and he is better off than the

majority of TS children she has cared for, although she does not

know their tuber count. Tr. at 982-84. Michael Hanlon is not

severely or moderately retarded. Tr. at 984. She thinks that

Michael had infantile spasms, although he did not have

hypsarrhythmia on EEG to confirm that. Tr. at-1003. He began

with blinking spells. Tr. at 1008. By the age of six months, he had

nodding spells. Id. That he had stiffening, kicking, jerking, and

smiling at the end of a seizure without cyanosis or clonic

movements suggests to Dr. Lee that he had infantile spasms. Tr.

at 1008-09. Another respondent’s expert,** however, stated that

he had focal seizures, not infantile spasms, but Dr. Lee disagrees

with him. Tr. at 1029-30. Even if Michael Hanlon had a different

type of seizure than infantile spasms, her opinion about causation

is the same. Tr. at 1055-56. TS children have seizures other than

infantile spasms; it is common for them to have a mixed seizure

disorder. Tr. at 1056.

Dr. Lee subscribes to the clock theory, i.e., seizures begin

when there is a strong propensity without any sort of external

factor prompting them. Tr. at 103 8-39. Besides the Melchior

“SDr. Russel! Snyder. R. Ex. A.

64a

study-and Jozwiak study, common sense tells her that no added

factor is necessary when one has a disease that disrupts brain

function and structure. Tr. at 1040.

Dr. Lee relates Michael Hanlon’s mental retardation to his

TS. rather than to his seizures, where there are no long-term

intractable seizures occurring right after each other as in

prolonged status epilepticus.” Tr. at 1056-57.

Dr. Kinsbourne retook the witness stand to say that

Michael Hanlon did not have infantile spasms clinically. Tr. at

1099. He agrees with Dr. Gomez that seizures unleash a

dementing process. Tr. at 1119. Michael Hanlon eventually

substantially deteriorated, but not right away. Tr. at 1142. Now

he does not have seizures. Id.

Dr. Charles R. Fitz, a pediatric neuroradiologist, testified

for respondent about Rachel Plavin’s MRI.. Tr. at 1148. She has

43 tubers, some of which are unusually large. Tr. at 1152. She has

one of the most severe TS cases he has examined. Id. Based on

her 1990 MRI, between 20 to 30% of Rachel’s cortex and

subcortex are tubers. Tr. at 1168. He is sure that she has more

than 43 tubers. Ir. at 1169. Rachel’s MRI is in the top 5 of those

he has reviewed as far as severity of disease. Tr. at 1171. The

more tubers one has, the worse one Is. Tr. at 1172.

Dr. Mary Ann Guggenheim, a pediatric neurologist,

testified for respondent about Rachel Plavin. Tr. at 1175, 1194.

DPT did not significantly aggravate her. TS. Tr. at 1196. There

was chance temporal association, not causation, between DPT

and her onset of seizures. Id. Since neither of Rachel's parents

has TS, her 1S is caused by a change in her DNA (chromosomes).

“Children with tuberous sclerosis. all had high rates of mental retardation

and intractable epilepsy “ Kiukonen, R , “Long-Term Outcome of West Syndrome: A

Study of Adults with Infantile Spasms,” 37/4) Epilepsia 367-72, 371 (1996) R. Ex

“See also. Roach, ES . “Neurocutancous Syndromes,” 39(4) Ped Neur 59 1-620,

§94 (1992) “Seizures occur in an estimated 40% to 90% of recognized patients [with

TS} Infantile spasms are particularly common ” Roach continues, at 595, to state that

patients with severe cerebral disruption from TS (1.¢ , more tubers) are more likely to

develop both intractable seizures and severe mental retardation R Ex D

BREN eae

65a

Tr.

at 1196-97. There are at least two genetic loci established in TS.

Tr. at 1197. When there is neuronal proliferation (cell division)

and migration occurring, she had an error in the normal process,

producing tubers. Id.

The underlying physiologic change for seizures is an

increase in the degree and location of neuronal discharge. Tr. at

1198. There is an excessive amount of excitatory electrical

activity. Tr. at 1198-99. Tubers contain cells that are electrically

active. Tr. at 1200. Dr. Guggenheim knows of no aspect of

biological plausibility or experience to require a contributing

factor to cause a seizure in a TS child. Tr. at 1211-12. The clock

determines where and when epileptogenic discharges occur. Tr.

at 1212. A number of epileptic syndromes, such as febrile

seizures, benign Rolandic epilepsy, and juvenile myoclonic

epilepsy, have a predictable clock. Tr. at 1212-13.

DPT can cause local reactions, such as irritability, high-

pitched crying, and also febrile seizures, hypotensive-

hyporesponsive shock collapse, anaphylaxis, and rare cases of

acute global encephalopathy. Tr. at 1224-25. It is biologically

plausible for the structural and cellular changes in TS to account

for all the damage in a TS child. Tr. at 1230. One does not need

to recruit a second cause. Id.

Rachel Plavin’s course was due to TS; it was not due to

an acute encephalopathy but insidious, progressive, focal seizures.

Tr. at 124546. A lot of her brain tissue is abnormal. Tr. at 1246.

Rachel has a structural abnormality in her right cortex. Tr. at

1247. Hence, she had left focal seizures. Id. She also developed

a left hemiparesis. Id. Even if DPT caused Rachel's first seizure.

the rest of her seizures and outcome are due to TS. Tr. at 1248-49.

Dr. Kinsbourne testified in response to Dr. Guggenheim’ s

testumony. Tr. at 1300. He stated that no known neurophysiology

says masses in the brain have any particular effect on the way the

brain works. Tr. at 1304. The brain is a network. Tr. at 1305.

Different parts get into a particular pattern in firing; this pattern

could occur around inert matter. Id.

66a

DISCUSSION

Although early literature supported the hypothesis that

DPT causes infantile spasms, later literature, including more

extensive analysis, disputes this. The early articles depict an

extraordinary number of onsets of infantile spasms after DPT (9

out of 24, or 37.5%). If DPT truly caused all that many cases of

infantile spasms, then the number of children with infantile

spasms should number in the hundreds of thousands, if not

millions, considering that administration of DPT is universal in

this country.

Other analyses-belie these statistics. Firstly, the NCES and

the 1983 Bellman study both used the same data. They both found

that the incidence of onset of infantile spasms after DPT and after

DT was increased. But the NCES found that, overall, the risk of

serious, acute neurological illness after DPT was statistically

significant (which included more than infantile spasms, e.g.,

encephalopathy) but found that the risk of serious, acute

neurological illness after DT was not statistically significant.

Since the incidence of infantile spasms was the same after each

vaccination (DPT or DT), then the difference in statistical

significance had to have arisen because of the incidence of other

serious acute neuropathies, not infantile spasms, after DPT, which

did not occur after DT.

The 1983 Bellman study opined about the possibility of

trigger without analyzing how it is plausible that the same

incidence of onset of infantile spasms could occur after DT as

after DPT.

The whole literature, as well as the evidence presented in

this court, has been to the effect that the pertussis element of DPT

contains toxins (both endotoxin and exotoxin) which act upon

some immature brains in a deleterious manner, causing seizure

disorder, encephalopathy, etc. See P. Ex. 52, Menkes, J.H., and

Kinsbourne, M., “Workshop on Neurologic Complications of

Pertussis and Pertussis Vaccination,” 21 Neuropediatrics 171-76

67a

(1990), particularly its reference to the Cody article,*’ at 173, that

neither seizures nor shock-like symptoms followed DT, unlike

DPT. ,

Although Congress did not initially distinguish the type of

Table injury after DT or DPT (it subsequently revised its Table in

regulations effective March 10, 1995), this court has never heard

a case in which DT was alleged to have caused a seizure disorder.

If there is any credence to be attached to the theory of how

pertussis vaccine acts as a toxin in a child (and the court has

accepted this theory in one death case, Misenko v. Secretary.

HITS. No. 92-0013V, 1995 WL 76 1436 (Fed. Cl. Spec. Mstr.

Dec. 7. 1995)), then there can be no basis for assuming that DT

(without the pertussis vaccine) causes seizure disorders. Yet, the

results of the NCES data as reflected in the NCES analysis and

the 1983 Bellman paper point to equivalency of “reaction.” What

seems more likely to the court is that these are statistical artifacts

which. by themselves, have no statistical significance. (If they had

statistical significance, then the mere fact of the onset of infantile

spasms after DT would have elevated the risk of acute, serious

neurological reaction to DT to the level of statistical significance.)

The fact that children who develop infantile spasms do so

at the very ages they receive DPT vaccine has to mean that some

will develop infantile spasms in close proximity to their

vaccination. Although petitioners doubt the conclusion that

Melchior reached in his Danish paper, the data led him to believe

that altering the vaccine schedule did not change the age of onset

of infantile spasms. Dr. Kinsbourne queried whether, in the first

two months, there was a greater incidence of onset among

vaccinees, but the court has shown through an analysis of the

figures that the rate of onset of infantile-spasms was constant

"Cody, C.L., etal. “Nature and Rates of Adverse Reactions Associated with

DTP and DT Immunizations in Infants and Children,” 68(5) Pediatrics 650-60 (1981).

P. Ex. 81. The authors did a prospective study for reactions after 784 DT and 15,752

DPT immunizations given to children 0 to 6 years of age. Id. at 650. No infant among

over 16,500 vaccinees developed infantile spasms. Id. at 656.

68a

during the period when most of the children had their onset

whether or not the child could have had a DPT vaccination in a

reasonable period of time before the onset. Since the same rate of

onset occurred within each series of vaccinations (1957-67 and

1970-75), and within the same series (1970-75), one would be

hard pressed to show that DPT vaccine had any causative role.

Dr. Osborne doubted that DPT causes infantile spasms.

Dr. Gomez adopted the same opinion after reviewing the

literature respondent provided to the court (including the

Melchior study, and the twins studies). Moreover, Dr. Gomez, in

his 1991 testimony and in his book and 1982 article, was

maintaining the appropriately cautious stance of a practitioner in

the field of TS. One wants to do everything possible to avoid a TS

child’s starting to seize. If DPT is any risk at all, a responsible

doctor would not recommend it. But a court of law is not treating

a diseased child; it is trying to ascertain probabilities as to

causation. at least in a significant aggravation case in which

respondent’s burden is to prove that TS caused in fact the

vaccinee’s seizures.

Medical literature and anyone knowledgeable about TS

grant that the most prevalent expression of the disease is a seizure

disorder, most often, but not always, in the form of infantile

spasms. Two studies, one by a psychologist, Ann Hunt, and the

other by a doctor, S. Jozwiak, analyzed TS patients to determine

if there was an increased incidence of onset of infantile spasms

after receipt of DPT. Each author concluded that the evidence

showed no increased incidence. Interestingly, Ms Hunt’s data

showed an increased incidence after DT, rather than DPT, going

beyond the anomaly of equal occurrence after DPT and DT in the

NCES and 1983 Bellman data. Although she opined, as did

Bellman, as to the possibility of a trigger effect from DPT vaccine

(as well as from a host of other factors, including tever and

teething), these are pure speculations because the data do not

Support them.

It is particularly disturbing to the court that petitioners’

attempt to maintain the presumption of causality from the DPT

69a

vaccination rests upon Dr. Osborne’s opinion that DPT does not

cause afebrile seizures of any kind and Dr. Kinsbourne’s opinion

that DPT causes infantile spasms is a minority view. Dr. Gomez,

in his 1991 testimony, opined that the literature had associated

DPT and infantile spasms, but in light of his more thorough

education in the literature (courtesy of respondent), he has

changed his mind. The literature that petitiorers provided that

Dr. Osborne co-wrote specifies the lack of proof of a causal

relationship of infantile spasms with DPT as well as the majority

of TS patients’ having seizures and mental retardation (although

not all who seize are delayed).

The-court is most impressed with the testimony of Drs.

Gomez and Osborne. These men have devoted their professional

lives to the study of TS. Dr. Gomez is a pediatric neurologist,

whereas Dr. Osborne is a pediatrician. Not only because Dr.

Gomez is regarded as the world’s expert in TS, but also because

of his training and experience, the court must regard his testimony

as the more credible in the area. But he and Dr. Osborne do not

differ in opinion. TS is the overwhelming cause of seizures in a

child afflicted with the disease, unless he develops a fever or

some other well-recognized reaction to a vaccination.

When faced with the choice of whether TS caused in fact

an individual's seizure disorder so as to rebut the presumption

that DPT vaccination is the cause, the court must choose the

former over the latter in every case in which the vaccinee has no

symptom other than the seizure. It begs credulity to link DPT to

a seizure in a child who is not anorexic, insomniac, feverish,

crying, moody, irritable, depressed, vegetative, or behaves in any

other abnormal way that would lead a parent as well as a

physician to assume the child was unwell. The child need not

manifest all these symptoms, but in a case in which he does not

manifest any of them, one could hardly be reasonable, not

arbitrary, and not capricious to hoid that TS, a disease known to

produce seizures, and consequent mental retardation, autism, and

developmental delay, is not the cause and that respondent has

failed to rebut the presumption that DPT is the cause.

70a

. One may query why achild’s seizure begins at a particular

time (and, if right after a DPT vaccination, why that event is not

suspect). The answer lies in the genetic sphere, one in which all

the answers are not available. But, certainly the four twins articles

strongly indicate that there is a programmed aspect to seizure

onset.** These articles concerned monozygotic twins (just as the

Decker twins with whom Dr. Gomez was so impressed in his

1982 article). Without any precipitating factor, they seized in

close proximity to each other. No one knows how genes (and

genetic diseases) set up timetables. But they obviously do.

Respondent has attempted to show by its biomarker study

of cortical tubers that the greater number of tubers predicts a bad

outcome (which is possible only through the development of a

seizure disorder). While a large number of tubers is indeed a

factor (one that Dr. Gomez mentioned in his 1991 testimony and

to which all the witnesses agreed at the hearing), it is not the sole

factor. As Dr. Osborne and Dr. Roach (in his editorial to the

published cortical tuber count paper) as well as Drs. Shepherd,

Houser, and Gomez in their 1995 paper, stated, other factors

decisive in outcome are the tubers’ size and location. We do not

have all the answers yet. But, as Dr. Gomez said, biology is more

than statistics. The court cannot make a statistical determination

based solely on tuber count that a child would more likely than

not have his current condition.

By looking at the TS children whose cases are before me,

the court sees a child with 13 tubers who is vegetative, while one

with 17 tubers is planning to attend ‘college. And both have

seizure disorders.

It is indeed sad as well as tragic to have a brain-damaged

child. No one can be prepared for the heroic sacrifice that parents

must make when their child has TS and then develops a seizure

48.

{I]nfantile spasms become apparent at a special stage of brain maturation.”

Riikonen, R., and Donner, M., “Incidence and Aetiology of Infantile Spasms from 1960

to 1976: a Population Study in Finland,” 21 Develop Med and Child Neur 333.43, 333

(1979). P. Ex. 76.

T7la

disorder. And there are some TS children, i.e., Costa, Moon, who

do have reactions to DPT, which start them seizing. Put they had

obvious medical difficulties related to the vaccine. No one

expects a TS child to go into immediate status epilepticus

(prolonged seizure) or even coma as his first sign of a seizure

disorder. Where such an event occurs, the DPT vaccine is indeed

the cause.

| However, where a TS child receives DPT vaccine and

remains perfectly normal (in temperature, eating, sleeping, affect,

and activity) but has a seizure within three days, TS, not DPT, is

the cause in fact of that seizure. This is so whether or not the

initial seizure takes the form of an infantile spasm or some other

type of afebrile seizure such as Michael Hanlon and Rachel

Plavin had.

Under the principles that the U.S. Court of Appeals for the

Federal Circuit laid out in Whitecotton v. Secretary. HHS, 81

F.3d 1099 (Fed. Cir. 1996), petitioners initially satisfied their

burden of showing Table onset in those cases, such as Hanlon and

Plavin, in which the court has ruled that onset of seizures

occurred within Table time and their current condition is

obviously worse than their pre-vaccination status. However,

respondent has successfully rebutted that presumption by showing

that TS caused in fact their initial seizure as well as their current

condition. (Actually, if respondent had sought to prove solely that

petitioners’ current condition was due to TS, but that DPT caused

the initial seizure, they would also succeed in rebutting the

presumption of significant aggravation. But the court holds that

respondent has proven not only that the vaccinees’ current

condition is due to their preexisting TS, but also, in cases in

which a seizure is the only symptom, that TS is the cause in fact

of that seizure.)

To satisfy their burden of proving causation in fact,

respondent must offer “proof of a logical sequence of cause and

effect [for] the reason for the injury. A reputable medical or

scientific explanation must support this logical sequence of cause

and effect.” Grant v. Secretary, HHS, 956 F.2d 1144, 1148 (Fed.

724

Cir. 1992). Agarwsal v. Secretary. HHS, 33 Fed. Cl. 482, 487

(1995); see also Knudsen v. Secretary. HHS, 35 F.3d 543, 548

(Fed. Cir. 1994); Daubert v. Merrell Dow Pharmaceuticals. Inc..,

509 U.S. 579 (1993).

Respondent has proven by a logical sequence of cause and

effect that the presence of tubers in the cerebral cortex, which is

the hallmark of TS, leads to seizures in the majority of TS

patients. Moreover, most of those who have seizure disorders are

also mentally retarded. The effect of numerous tubers, as well as

their location and size, is a given. Not one witness disputes their

importance. Moreover, the epidemiology that is available (the

1983 Hunt and 1997 Jozwiak papers) supports the view that DPT

does not initiate seizures in TS patients. The studies on

monozygotic twins strongly suggest that there is a programmed

aspect (a biological clock) to the onset of seizures in children with

infantile spasms. The apparent administration of vaccinations at

the very peak of incidence of onset of infantile spasms creates the

suspicion, but no more than that, of a relationship. The NCES

data and the 1983 Bellman paper based on the same data show the

same incidence of onset of infantile spasms following DPT and

DT, the latter vaccination never being associated with seizures.

The lack of statistical significance in this phenomenon

accentuates its lack of importance in determining causation from

DPT. That surgical resection of cortical lesions results in the

alleviation permanently or for a time of seizures in afflicted

individuals reinforces the conclusion that seizures are linked to

brain lesions. Moreover, it makes sense (“a logical sequence of

cause and effect”) that brain cells that are disordered and form

lesions play a role in abnormal firing of those cells, or in the cells

that lie between the lesions and the normal cortex.

To apply these holdings to the Hanlon and Plavin cases in

which this court has ruled that Hanlon and Plavin are entitled to

compensation requires the court to reconsider its holdings.*°

“The court will issue orders in Hanlon and Plavin, as well as in any other TS

case in which it has already decided the issue of entitlement.

73a

Michael Hanlon had repetitive eye blinking occasionally between

the ages of two and four months. 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. He received DPT vaccinations when he

was two, four, and six months of age. Petitioners alleged that

onset occurred one day after the first DPT. In light of this court’s

above holdings, the onset of Michael’s seizures was coincidental

to his first DPT vaccination. By looking at the course of his

seizures, one can see that they were happening without any

reaction to an antigenic insult.

In Rachel Plavin’s case, Rachel’s parents stated that on the

day of her second DPT vaccination, at the age of three and one-

half months, she was staring, her left arm shook, and she drew her

legs up. Eleven days later, she was brought to the hospital. The

history the mother gave was that Rachel had been healthy until

she noticed occasional trembling of her ieft hand while she nursed

and one blank stare. The mother did not give an onset date. She

did. however, state that Rachel did not have a reaction to her DPT

vaccination ten days earlier. A subsequent history was that the

onset was at approximately two months with a shaking left hand.

By two and one-half months, these were apparently seizures. A

history two weeks later was that the first seizure occurred on the

day of the DPT vaccination while nursing. Rachel’s left arm

vibrated and she began shaking and staring.

Again, Rachel’s symptoms seem to be totally unrelated to

the DPT vaccination and purely coincidental. In her mother’s

mind, she was not having a DPT reaction. These symptoms are

typical of a TS child’s initial seizures. One should also note that

Rachel has 43 or more cortical tubers, making up a substantial

percentage of her cortex. Based on the court’s above holdings,

the onset of Rachel’s seizures was coincidental to her second

DPT vaccine.

CONCLUSION

Respondent has successfully rebutted petitioners’

presumption of significant aggravation of preexisting TS from

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DPT vaccine by proving that TS caused in fact both petitioners’

onset of seizures and current condition in all cases in which the

onset of seizures was unaccompanied by symptoms of a vaccine

reaction, such as fever, anorexia, insomnia, depressed affect,

shock, etc. The court will examine each case, even if already

decided on the issue of entitlement, to determine if they fall into

the category of Hanlon and Plavin, who are not entitled to

compensation.

IT IS SO ORDERED.

DATED: September 15, 1997 s/

Special Master

Laura D. Millman

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APPENDIX D: ORDER OF THE OFFICE OF SPECIAL

MASTERS OF THE UNITED STATES COURT OF

FEDERAL CLAIMS, DATED SEPTEMBER 18, 1997

UNPUBLISHED

In The United States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 90-1334V

September 18, 1997

JOHN HANLON and RUTH ANNE 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.

Karen P. Hewitt, Washington, DC, for respondent.

ORDER TO VACATE

MILLMAN, Special Master

On September 15, 1997, the court issued a decision in the

Omnibus TS proceedings. Barnes. et at. v. Secretary. HHS, No.

92-0032V, 1997 WL (Fed. Cl. Spec. Mstr. Sep.15,

1997). Pursuant to my holding in the TS Omnibus Decision, I

vacate my decision of May 31,1994 that found petitioners entitled

to an award.

This case is hereby dismissed with prejudice. In the

absence of a motion for review filed pursuant to RCFC Appendix

76a

J, the clerk of the court shall enter judgment accordingly.

IT IS SO ORDERED.

Date: September 18, 1997 s/

Laura D. Millman

Special Master

77a

APPENDIX E: ORDER OF THE OFFICE OF SPECIAL

MASTERS OF THE UNITED STATES COURT OF

FEDERAL CLAIMS, DATED SEPTEMBER 18, 1997

UNPUBLISHED

In The Unites States Court of Federal Claims

OFFICE OF SPECIAL MASTERS

No. 91-1555V

September 18, 1997

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.

Karen P. Hewitt, Washington, DC, for respondent.

ORDER TO VACATE

MILLMAN, Special Master

On September 15, 1997, the court issued a decision in the

Omnibus TS proceedings. Barnes. et at. v. Secretary. HHS, No.

92-0032V, 1997 WL (Fed. Cl. Spec. Mstr. Sep.15,

1997). Pursuant to my holding in the TS Omnibus Decision, I

vacate my decision of December 29,1994 that found petitioners

entitled to an award.

This case is hereby dismissed with prejudice. In the

78a

absence of a motion for review filed pursuant to RCFC Appendix

J, the clerk of the court shall enter judgment accordingly.

IT IS SO ORDERED.

Date: September 18, 1997 s/

Laura D. Millman

Special Master

= is ee ra ©

79a

APPENDIX F: OPINION AND ORDER OF THE UNITED

STATES COURT OF FEDERAL CLAIMS, DATED

MARCH 19, 1998

40 Fed. Cl. 609

In the United States Court of Federal Claims

No. 91-1555 V

(FILED: March 19, 1998)

MARC PLAVIN and TONI REISS, Parents and Next

Friends of RACHEL LEAH REISS-PLAVIN.

Petitioners,

V.

SECRETARY OF THE DEPARTMENT OF HEALTH AND

HUMAN SERVICES,

Respondent.

Robert T. Moxley and Richard Gage, Cheyenne, Wyoming, for

petitioners.

Mary Hampton Mason and Karen P. Hewitt, Washington, D.C.,

for respondent, with whom were Assistant Attorney General

Frank W. Hunger, Director Helene M. Goldberg, Deputy Director

John Lodge Euler, and Assistant Director Gerard W. Fischer

ORDER

TIDWELL, Judge:

This case is before the court on petitioners’ motion for

review: of the September 18, 1997 decision of Special Master

Millman denying compensation under the National Childhood

Vaccine Injury Act ("Vaccine Act”), 42 U.S.C. §§ 300aa-1 - 34

(1994). See Plavin v. Secretary of HHS, No. 91-1555V (Fed. Cl.

Sp. Mstr. Sept. 18, 1997) (dismissal order). In denying the

petition for compensation, the special master adopted the

‘in referring to petitioners’ motion for review, the court is also referring to

the accompanying memorandum of objections.

80a

reasoning of her “TS Omnibus Decision,” captioned in 22 cases,

including this case. Jd. (adopting Barnes, et al. v. Secretary of

HHS, slip op. (Fed. Cl. Sp. Mstr. Sept. 15, 1997, as amended

Sept. 18, 1997) (hereinafter “TS Omnibus Decision”)’). For the

reasons set forth below, the court grants in part and denies in part

petitioners’ motion for review. In doing so, the court reverses in

part, affirms in part, and remands the special master’s denial of

entitlement to compensation in Plavin.

BACKGROUND

On behalf of Rachel Leah Reiss-Plavin (“Rachel”),

petitioners filed a petition on October 30, 1991 for compensation

under the Vaccine Act. Rachel was born on June 8, 1989, in

Lexington Kentucky. Rachel received her first Diphtheria-

Pertussis-Tetanus (“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 old.

Rachel’s parents allege that later that day, Rachel 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 noted that Rachel had been

healthy until her mother noticed occasional trembling of her left

hand while she nursed, along with one blank stare. Dr. Campbell

concluded that Rachel was suffering from a seizure disorder, and

in her summary mentioned Rachel’s second DPT vaccination,

given 10 days before admission to the hospital, and that Rachel

had had “no reaction” to it.

In November 1989, Rachel was diagnosed with Tuberous

Sclerosis (“TS”), a neurocutaneous genetic disorder affecting the

skin and nervous system. TS causes lesions to appear on some

organs, including the brain. One type of lesion, located on the

cortex of the brain and called a “cortical tuber,” is responsible for

seizures, although not all TS patients with tubers have seizures.

>The court’s page references to the TS Omnibus Decision will refer to the

version issued by the special master on September 15, 1997, as amended September 1 8,

1997. ‘

8la

Other symptoms of TS include mental retardation.

Also in November, 1989, Dr. Robert J. Baumann, a

pediatric neurologist at the University of Kentucky Chandler

Medical Center, indicated in his records that at two months of

age, Rachel’s mother noticed that Rachel had begun to have

episodes where her left arm would shake, and by two and a half

months of age it was apparent that these were seizures.

On December 12, 1989, Rachel was seen by Dr. Bryan C.

Hall, the chief of the Division of Genetics and Dysmorphology

and Professor of Pediatrics at the University of Kentucky. Dr.

Hall recorded that Rachel! had her first seizure on September 15,

1989, following a DPT vaccination. Dr. Hall stated that while

Rachel was nursing, she pulled away from the nipple, and her left

arm vibrated for a short period. She also began shaking and

staring. A history given at the University of Kentucky Medical

Center on November 1, 1990 records an onset of seizures at three

and a half months.

Finally, on March 15, 1991, Dr. Campbell documented in

a letter the sequence of events leading up to the diagnosis of

Rachel’s seizure disorder and TS. Dr. Campbell wrote that on

September 15, 1989, Rachel’s mother called her to discuss

Rachel’s fussiness, apparent abdominal cramping, and occasional

brief arm tremor.

Presently, Rachel continues to suffer seizures and

developmental delay, and she is approximately two years behind

in gross and fine motor skills.

PROCEDURAL HISTORY

In their original petition, petitioners alleged that as a result

of her second DPT vaccination, Rachel suffered significant

aggravation of her pre-existing TS in the form of a residual

seizure disorder (“RSD”) within the Table time limits of the

Vaccine Act. See 42 U.S.C. §§ 300aa-14(a)(I)(D) and (E).

Respondent asserted that the onset of Rachel’s seizure disorder

occurred outside the Table time limits. In the alternative,

respondent claimed that Rachel’s seizure disorder was caused by

a factor unrelated, Rachel’s TS. No hearings were held, as the

82a

special master found that the records were sufficient to make a

determination. On December 29, 1994, the special master issued

her decision granting compensation to petitioners on the grounds

that Rachel had suffered an on-Table significant aggravation of

her TS. Plavin v. Secretary of HHS, No. 91-1555V (Fed. Cl. Sp.

Mstr. Dec. 29, 1994) (original entitlement order). In so deciding,

the special master took into account prior TS/DPT decisions and

the testimony elicited from t

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