Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –

A draft by Alok Singla

Methods to study EEG and MRI and clinical outcomes during 6 month,12 month, 15 month and or 24
months Follow up
A draft by Alok Singla, MBBS ( Child Neurologist); NIH trained Physician Scientist

Objectives to prepare methods for the study :

1) evaluate the ability of early EEG, Apgar scores, cord pH, and severity of HIE 5,6 to predict adverse MRI

brain outcome in HIE newborns treated with whole-body TH

2) evolution of EEG background and investigate the EEG features progression7,10

3) early prognostic factors like S-W : Sleep wave cycle, IBIS interburst interval, VD voltage depression,

SW –sharp waves progression over the course of hypothermia 10

4) Severity of MRI 8

5) neurodevelopmental tools for 12m, 15m,24 m follow up of patients : CAT-CLAMS in early life, Clinical

follow up with CATS/CLAMS scale 9

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Methods

Study Designed drafted by Alok Singla submitted to IRB as draft and got approval

1) Retrospective cohort analysis of infants with moderate encephalopathy underwent Whole-body cooling

2) Inclusion meeting criteria according to National Institute of Child Health and Human Development (NICHD)

protocol5,6.

3) Data Collection and Outcome Measures: designed by Alok Singla

a. Demographics Table 1

b. Neurological exam at ≤6 hours of age as per Shankaran, et al. guidelines5,6 Table 2,

Table 1. Characteristics of all Included Infants : designed by Alok Singla

Clinical Characteristics Total (N=60)

Male sex, n (%) $

Gestational age at birth (weeks), Mean (SD) *

Birth weight (kg), median (range) *

Apgar Score @ 5 Min, median (range) $

Apgar Score @10 Min, median (range) $; First pH, mean (SD) $; C sec, Vaginal, vacuum$

Need of PPV or resuscitation >/= 10 minutes, n (%) $

Acute perinatal events, n (%)*

HIE (Sarnat) 10 grade, n (%)*

Therapeutic hypothermia, n (%)*

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Table 2: Documentation of Clinical findings as per Sarnart score5,6 : in a Table prepared by Alok Singla

Table 2. Severity of Clinical HIE Grading Neurological examination

S.no Parametes 1 2 3

1. LOC

2. Activity

3. Tone

A)decreased

b) Increased

4. Posture

Decorticate

Decerebrate

5. Primitive
reflexes

5.a Suck

5.b Moro

6. Autonomic
signs

6.a Pupils

6.b. HR

6.c RR

1. LOC : hyperalert=1,lethargic=2,stupor=3

2. Activity: Normal=0,decreased =1,none=2

3. Tone: hypotonia: 1=N ,2a=hypotonia-(partial/comp.),3a=flaccid 2B=hypertonia 3B rigid

3b

4. Posture: 1=N, 2=flaccid/decerebrate=3.distalflexion/complete extn

5. Primitive reflexes: a) Suck b) Moro : present =1, Incomplete =2, Abesnt =3

6a. Pupils : 1=normal, 2. Miosis , 3. Dialted or Variable/sluggish / fixed /unequal

6b. Heart rate : Bradycardia =1, Variable/Unstable =2

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

6c Respiration 1=Periodic Breathing, 2=Apnea, 3a: spon. Breath above PPPV

Early EEG Grading before cooling in HIE patients:

Figure 1.EEG classification modified as per mild adaptation

American Clinical Neurophysiology Society (ACNS) guidelines with some adaptation.7,10 All EEG background activity was graded for increasing

severity from 0 to 4 (Figure 1). –EEG Classification 7,10

Fig 1. Clear examples of EEG showing different grades of HIE5,6

Grade Leads EEG segment Description
C4- O2
F3- C3 Continuous background pattern with normal physiologic
0
C3 –O1 features such as anterior slow waves, SW<12 /50-60 min
T4 –C2
C4- O2
Mild: Continuous background pattern with mild
F3- C3
1 Will add picture asymmetry, mild Voltage depression poor S-W cycle,
C3 –O1
SW> 12/minute in record
T4 –C2
C4- O2
Moderate: Discontinuous activity with IBIs < 10 s, clear
F3- C3
2 Will add picture asymmetry or asynchrony, poor S-W cycle, SW>/6=10-
C3 –O1
60 s in record
T4 –C2
C4- O2
Major: Discontinuous activity with IBI 10–60 s, severe
F3- C3
3 depression, no wake/sleep cycles, or clear asymmetry or
C3 –O1
asynchrony, SW>/=6/ 10 sec
T4 –C2
C4- O2
F3- C3 Inactive: Background activity of or severe discontinuity
4 Will add picture
C3 –O1 of IBIs >60 s
T4 –C2

Table 3: EEG data collection table: designed by Alok Singla

Grade Initial EEG Abnormalities Parameters No of %

patients
Formatted Table
0 Continuous background pattern Normal physiological activity
SW<12 /50-60 min
1 Mild (Continuous background pattern with slightly Mild asymmetry
abnormal activity) Mild voltage depression
Poorly defined

Sharp waves > 12/record

2 Moderate Abnormalities Discontinuous activity
Inter-burst interval of < 10 s
No clear sleep-wake cycle
Clear asymmetry/ asynchrony
Sharp wave > 6/minute
3 Major Abnorm1alities Discontinuous back ground with inter-burst
interval of 10-60 s
Severe attenuation of background patterns
No clear sleep-wake cycle
EEG seizures
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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

SW >6 /10 sec

4 Inactive EEG findings Background activity < 10 uv
Severe discontinuity with ibi >60 s
S-W : Sleep wave cycle, IBIS interburst interval, VD voltage depression, SW –sharp waves

MRI

After TH was completed, MRI was performed. Images scored for abnormalities according to the basal ganglia (BG), watershed (W) and combined

basal ganglia/watershed (BG/W) system score of Barkovich et al.8 (Table 4) We defined normal to mild MRI injury as a BG score <2 and watershed

score <2, and moderate to severe MRI injury as a BG score ≥2 (involving both the thalamus and the lentiform nucleus) or watershed score ≥3

(involving both watershed cortex and white matter).8

Table 4: MRI Severity table developed by Alok Singla incorrespondance to the above basal ganglia/watershed

(BG/W) system score of Barkovich et al8

Sum US
mati G
on fin
Sn
(S) din
o.
Combined Arit gs
Of Basal
The watershed Basal hme obt
HIE ganglia (BG) Haemmorhage
(W) score ganglia/wate tic ain
su Score
rshed (BG/W) sum ed
bje
of bef
cts:
BG ore
and TH
W
Subdural(Tr Extr Intrav Scalp
0 1 2 3 4 0 1 2 3 4 5 0 1 2 3 4 ace, no adu entric hemat
mass effect) ral ular oma
Ph
<7
Ph
>7
Tot
al
pts

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Table5. Predictive values of early EEG (<6hrs of age) for post TH MRI outcomes in moderate HIE infants

Statistics % Overall EEG EEG Cord pH<7 Cord pH>7 Abnormal

(95%CI) G-2, 3 & 4 Early USG

Total pts.
Sensitivity
Specificity
PPV
Positive LH ratio
Disease prevalence
Accuracy

Results: pre draft design developed by Alok Singla

In total, newborns with GA ≥35 weeks with moderate HIE at birth were reviewed. Of the remaining infants,

n patients had mild encephalopathy or Sarnat stage 1 with normal early EEG and were not cooled.

Therapeutic Hypothermia Moderate Clinical HIE Stat EEG abn +Mild HIE Total patients
Qualifies
Disqualifies

The baseline demographic data and clinical risk factors as per NICHD protocol are shown in Table 1.

N= no of neonates with umbilical cord pH<7.0 were considered as moderately acidotic and 31(61%) with

pH>7.0 as mildly acidotic. In the moderately acidotic group, (n%) subjects had early EEG changes, while in the mildly

acidotic group (n%) subjects had abnormal early EEG (Table 8 ).

Early EEG

EEG background was abnormal in n (no. of patients) (n%). The early EEG background was mildly abnormal

(grade 1), moderately abnormal (grade 2) n (no. of patients) (n%) infants, and severely abnormal (grade 3 and 4)

in n (no. of patients) (n%).; Figure 1; Table 3.

MRI

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

MRI was performed at a median age of days [IQR= ] and an abnormal pattern of injury was noted in n (no. of patients)

(n%) infants: Basal Ganglia /thalamus (BG) score 2 = n, watershed cortex (W) score 1=n, Basal Ganglia/Watershed (BG/W)
score 1
= n & BG/W score 2=n. N (no. of patients) (n%) infants with watershed score < 2 were scored as normal on BG/W

classification.15 (Table 4,5,).

Table 5. Early EEG abnormality and post-therapeutic hypothermia

brain MRI in moderate HIE
MRI-Abnormal ( n
Early EEG (> 6 hr. of age) n=51 MRI –
10)
Normal
Grade Pts (n) BG or
Background (n 41) BG/W
(G) % W
Normal G0
Mild G1
Moderate G2
Severe G3
Inactive G4
MRI n 51 (% )

PPV of USg head – PPV of the early EEG with in infants who had abnormal early USG of head was not significant

(Table 6 ). table 6

Usg abn

USG abn Eeg n and mri n - true neg T-

Usg abn Eeg n and mri abn F-

Usg abn eeg abn mri n F+

Usg abn eeg abn mri abn T+

Severity of EEG background changes during TH and rewarming

Voltage depression (VD) and sleep-wake (S-W) cycle differentiation improved in (n)% of newborns and

(N)% ,Sharp wave changes study from 24 hours to 72 hours. MRI was normal /abnormal with VD and S-W cycle

differentiation and n % normal/ abnormal with improved IBIs as shown below.

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Which is best prognostic factor. Table 7 –designed by Alok Singla EEG MRI
finding Normal/ABN
EEG Parameters at 24 hr and 72 hr
1a(Improved) 1b 2 .No change
(worsen Voltage D
Asymmetry Sleep-
wake
Voltage depresiion
sleep/wake
differentiation SW
IB Interval IB interval

Table 8 demonstrates early EEG background abnormalities improved (n%) and n% with normal background

worsened. A total of (n )infants with abnormal MRI had normal early EEG. EEG worsened during TH in two infants

who had mild grade abnormalities (W<2) in post-TH MRI. However, the remaining one infant whose MRI had severe

abnormalities (W>2) irrespective of normal early EEG had significant thrombocytopenia and subdural hematomas.

In the moderately acidotic group (cord pH<7), early EEG background improved in n of infants and n (no. of

infants) of them had normal MRI versus in the mild acidotic group (cord pH>7) early EEG background improved in

(n)% of them normal MRI. The PPV of early EEG for MRI outcomes was if cord pH<7.0; PPV=, LR. A total of three

infants whose MRI were abnormal had normal early EEG background: TABLE 8

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Data collected in Microsoft excel file for analysis : prepared by Dr.Alok Singla and later data was collected

Basic rule: data collected informed as ( 1= present abnormality , 2 absent abnormality)

Sheet 1: HIE – subject no, Date of birth and medical record no.

Sheet 2: Demographics , Acute perinatal events as per NRN : data collected informed as ( 1= present abnormality , 2 absent abnormality)

Subje UA cord Birth Ge Gestati apga apga apga Mod Acute perinatal factors Resusc UA Basal
ct no. PH>/=/ weigh nde on age r@1 r@5 r@1 e as per NRN guidelines itation Cord deficie
<7 t r 0 of pH nt
deliv of UA
ery cord

Sheet 3: Abnormal EEG grading collected and arranged by Alok Singla (data collected informed as 1= present abnormality , 2 absent
abnormality)

Grading of Baseline EEG Discontinuous Background (Grade

Continuous Background (Grade 0,1)
Background Activity nopresent) 2,3,4)
2 4
0 1 3 Gr
(Mod (Inac
(Nor (M (Ma ad Grade 1 mild (m)abn Grade 2 (<10 sec- IB ) Mod abn
erate tive
mal) ild) jor ) e0
) )
4 (sharp 1. 2. 3.
1m 2(mild 3(poor 4. SW
ph waves clear volta sleep/wak
asym volt sleep/wak >
>7 >12/record asym ge e cycle
etry depress) e cycle) 6/min
) m abn abn
Ph
>/
=7

3 (IB =10-60 sec) 4 (IB>60 )

1. ASYMETRY 2. Volt/sver. Bckgr supp 3. sleep/wake unclear 4. seizures

ph>7

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Ph >/=7

Continue in below line

Sheet 4: MRI Severity table developed by Alok Singla, MD incorrespondance to the above basal ganglia/watershed (BG/W) system score of
8
Barkovich et al

Sharp waves/ record

Grade 0 Grade 1 Grade 2 Grade 3
<12 /50-60min >12/60 min >6/min >6/10sec
Sum USG
Sn matio findi
o. n (S) ngs
Combined
Of Arith obt
Basal ganglia The watershed (W) Basal
HIE metic Haemmorhage aine
(BG) Score score ganglia/watersh
subj sum d
ed (BG/W)
ects of BG befo
: and re
W TH

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

Intrave Scalp
Subdural(Trace, Extra
0 1 2 3 4 0 1 2 3 4 5 0 1 2 3 4 ntricula hemato
no mass effect) dural
r ma
Ph<
7

Ph>
7

Tot
al
pts

Sheet 5 and 6: Progression of EEG background and features during Theraputic hypothermia

At 24 hr -
Discontinuous Background (Grade 2,3,4) (1=changed from baseline EEG, 2= remained same)
d72 hr cooling

asymmetry voltage sleep/wake IB interval Sharp waves Seizures

ph>7 BG supression differentiation
1 1
HIE 1 present / 2 1 improved/ 2 1 improved/ 2 improved/ 1 improved/ 2 improved/
01 absent not improved not improved 2 not not improved 2 not
improved improved MRIabn

Ph
<7
>/=7

Sheet 6:

At 72 hr -
Discontinuous Background (Grade 2,3,4) (1=changed from baseline EEG, 2= remained same) d72
hr cooling

asymmetry voltage sleep/wake IB interval Sharp waves Seizures

ph>7 BG supression differentiation
1 1
1 present / 2 1 improved/ 2 1 improved/ 2 improved/ 1 improved/ 2 improved/
HIE 01
absent not improved not improved 2 not not improved 2 not
improved improved MRIabn
Ph
<7,>/=7

References drafted and added by Alok Singla

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 Methods to study EEG and MRI and clinical outcomes during 12 month, 15 month and or 24 months Follow up –
A draft by Alok Singla

1. Volpe JJ. Neurology of the Newborn. 5th ed. Philadelphia, PA: Saunders; 2008.

2. GBD 2013 Mortality and Causes of Death Collaborators. Global, regional and national age-sex specific all-cause and cause-specific
mortality for 240 causes of death, 1990–2013: a systematic analysis for the Global Burden of Disease Study. Lancet.
2015;385(9963):117-71.

3. Lai MC, Yang SN. Perinatal hypoxic-ischemic encephalopathy. J Biomed Biotechnol. 2011;2011:609813. doi:10.1155/2011/609813.

4. Spitzmiller RE, Phillips T, Meinzen-Derr J, Hoath SB. Amplitude-integrated EEG is useful in predicting neurodevelopmental outcome in
full-term infants with hypoxic-ischemic encephalopathy: a meta-analysis. J Child Neurol. 2007;22(9):1069–78.

5. Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, et al. Whole-body hypothermia for neonates with
hypoxic-ischemic encephalopathy. N Engl J Med. 2005;353:1574–84.

6. Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol.
1976;33(10):696-705.

7. Murray DM, Boylan GB, Ryan CA, Connolly S. Early EEG findings in hypoxic-ischemic encephalopathy predict outcomes at 2 years.
Pediatrics. 2009;124:e459-e467.

8. Barkovich AJ1, Hajnal BL, Vigneron D, Sola A, Partridge JC, Allen F, Ferriero DM. Prediction of neuromotor outcome in perinatal
asphyxia: evaluation of MR scoring systems. AJNR Am J Neuroradiol. 1998;19:143–149.

9. The infant neurodevelopmental assessment: A clinical interpretive manual for CAT-CLAMS in the first two years of life, part 1*
Author links open overlay panelArnold J.CaputeMD1Pasquale J.AccardoMD2

10. Tsuchida TN, Wusthoff CJ, Shellhaas RA, Abend NS, Hahn CD, Sullivan JE, Nguyen S, Weinstein S, Scher MS, Riviello JJ, Clancy RR.
American clinical neurophysiology society standardized EEG terminology and categorization for the description of continuous EEG
monitoring in neonates: report of the American Clinical Neurophysiology Society critical care monitoring committee. J Clin Neurophysiol.
2013;30(2):161-173.

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