Occurrence and predictive factors of heterotopic ossification in

severely brain-injured patients with Disorders of Consciousness:

preliminary results from a multi-centric observational study

SIRN GCA & DoC Special Interest Group

Anna Estraneo, MD

Neurorehabilitation Unit and Laboratory for Disorder of Consciousness

Maugeri Clinical Scientific Institute, IRCCS

Telese Terme, BN, Italy

anna.estraneo@icsmaugeri.it

Heterotopic ossification

Benign formations of

mature lamellar bone in

extraskeletal soft tissues,

usually around joints.

• Congenital conditions (fibrodysplasia

ossificans progressiva);

• skeletal and soft-tissue traumatic

lesions;

• rheumatologic diseases (e.g. ankylosing

spondylitis);

• 10-53% of patients with traumatic

spinal cord injury

Heterotopic ossification in acquired brain injury

Source Design Subjects Observation period

(post injury) Aetiology Results

Bargellesi et al.,

2017

multicentre cross-

sectional survey (48

rehabilitation

institutes)

689 Time post-sABI (days):

mean= 209.5±108.4 ;

range= 37–613

Severe ABI:

TBI (n=178),

vascular (n=360),

anoxic (n=73),

other (n=78)

HO occurred in 94 pts (13.6%).

Risk factors: male gender, young age, PSH, spasticity, longer

duration of coma, ventilation and longer interval between

brain injury onset and admission to rehabilitation centre. No

etiology (16.3% TBI, 19.2% anoxic, 11.7% vascular, 11.5%

other).

Didzar et al.,

2013

retrospective cohort

study in

rehabilitation unit

151 TBI HO occurred in 56 pts (37.1%). Hip (73.2%) and knee (44.6%)

Risk factors: Time since injury and serum ALP and ESR levels,

degree of spasticity, pressure ulcer, presence of neurogenic

bladder and systemic infection.

Genet et al,

2011

retrospective study

on patients

undergoing surgery

for HO

357 Time post injury:

mean=15.7 months

TBI, spinal cord

injury, stroke,

anoxic

HO requiring surgery occurred more frequently after TBI

(55.7%), then SCI (24.0%), stroke (11.8%) and anoxic (8.6%).

Hip (60.9%), then the elbow (21.3%), knee (14.3%) and

shoulder (3.5%). Multiple HO occurred more frequently in

patients with CA (16/30) and TBI (74/199) than with SCI (29/86)

and stroke (10/42). Early surgery for HO is not a factor of

recurrence.

van Kampen et

al, 2011

prospective cohort

study on patients

admitted to

emergency

department

97 6 months after the

injury

Severe TBI HO occurred in 13 pts (13%). Risk factors: prolonged coma duration and mechanical ventilation, coexistent surgically treated bone fractures and clinical signs of autonomic dysregulation

No data about occurrence of HO in patients with DoC

Objectives:

1. to estimate occurrence of HO

in severely brain-injured

patients with DoC admitted to

23 intensive

neurorehabilitation units;

2. to identify possible risk factors

for HO.

GCA & DoC Special interest Group Multi-centric prospective study

Inclusion criteria:

1. clinical diagnosis of VS or MCS, according to standard diagnostic criteria (Giacino, 2002);

2. time from onset 1 -3 months;

3. age ≥16 years

Exclusion criteria:

1. severe pathologies independent from the brain injury (e.g., premorbid history of psychiatric, neurodegenerative diseases)

GCA & DoC Special interest Group Heterotopic ossification in DoC

Subjects

Brain injury

1 3 6 mos

Study entry: • Demographic information • Medical history (time since injury and etiology) • CRS-R • DRS • ERBI • Presence of ventilatory support • Presence of pressure sore

*

*

3 months

3 months after study entry: • Presence of HO: clinical evidence (i.e.

limited range of motion and/or joint pain and/or local inflammatory signs) confirmed by standard radiological and/or sonographic evaluation;

• Occurrence of paroxysmal sympathetic hyperactivity (PSH).

GCA & DoC Special interest Group Heterotopic ossification in DoC

Study design and procedures

Participating centres/Subjects

Participating centres: 23 Total DoC patients: 253

Centers Members

ICS Maugeri, Telese Terme Estraneo A, Masotta O, Pascarella A

Medicina Riab Int Osp Castel San Giovanni , (PC) Antenucci R

Ospedale Sacro Cuore Don Calabria, Verona Avesani R

Dip Riab. UGCA HABILITA, Care & Res Rehabil H, Zingonia Bartolo M, Aadis H

Centro Cardinal Ferrari, Fontanellato di Parma De Tanti A

ICS Maugeri, Pavia Nardone A, Berlusconi M

Fondazione Santa Lucia, Roma Formisano R

Ospedale riabilitativo di Marzana, Verona Gambarin M

Dipt Riabilitazione F.T. Camplani Cl Ancelle Carità, Cremona Gentile S

Istituto S. Anna , Crotone Lucca L

IRCCS Centro Neurolesi "Bonino-Pulejo”, Messina Marino S

Riabilitazione Ospedale AO Brotzu, Cagliari Diana A, Pilia F

Istituti Clinici Zucchi, Carate Brianza Perin C

Gruppo di Neuroriab O Maggiore Casa Risvegli, Bologna Piperno R, Casanova E

SC Riab Neuromotoria PO- Vimercate Premoselli S

Azienda Ospedaliera Universitaria Pisana- Dip Specialità Med SD GCA, Pisa

Carboncini MC

U.F. Riab Neuromotoria- Istituto Clinico Quarenghi, S. Pellegrino Terme

Pietro Salvi G

UO Riabilitazione Fondazione San Raffaele Giglio, Cefalù Sant’Angelo N

Dipt Neurologia UGCA Ospedale S. Giovanni Battista; Foligno Scarponi F, Patriarca E

Az socio sanitaria terr dei sette laghi- Pres riab neur; Varese Biacchi D, Bertoni M

IRCCS "Casa Sollievo della Sofferenza”, San Giovanni Rotondo

Intiso D

San Raffaele, Cassino Pistoia F, Sarà M

Don Gnocchi, Firenze Grippo A, Romoli A

GCA & DoC Special interest Group

*= p<.001

GCA & DoC Special interest Group Heterotopic ossification in DoC

Subjects

*= p<.001

Total sample HO + HO -

N. 253 31 (12,2%) 222 (87.8%)

Age, mean and (SD), in years 56.7 (17.8) 54.4 (16.2) 57.1 (18.2)

Sex F/M (n) 80/173 11/20 60/173

Clinical diagnosis

VS (n) 135 21 114

MCS (n) 118 10 108

Aetiology *

TBI n (%) 77 15 (19.5%) 62 (80.5%)

Vascular n (%) 109 4 (3.7%) 105 (96.3%)

Anoxic n (%) 50 7 (14.0%) 43 (86.0%)

Mixed n (%) 17 5 (29.4%) 12 (70.6 %)

GCA & DoC Special interest Group Heterotopic ossification in D0C

Results

HO as a function of clinical diagnosis

Thirty-one patients (12.2%) developed HO within 3 months after admission.

Occurrence

0

50

100

150

200

250

HO + HO -0

20

40

60

80

100

120

VS MCS

HO +

HO -

HO tend to be more frequent in VS (15.6%) than MCS (8.5%) patients (p>.05)

GCA & DoC Special interest Group Heterotopic ossification in D0C

Results

Total sample HO + HO -

N. 253 31 222

Time post injury, mean and

(SD) in days

137.4 (20.9) 138.2 (22.7) 137.3 (20.7)

CRS-R total score 8.2 (4.7) 7.1 (4.3) 8.3 (4.7)

ERBI total score -200.3 (54.1) -215.1 (49.3) -198.0 (54.5)

DRS category 24.9 (2.2) 8.3 (0.7) 7.9 (1.1)*

Pressure sore(s) (P/A) 115/138 12/19 103/119

Ventilatory support (P/A) 22/231 1/30 21/201

PSH (P/A) 67/186 22/19 55/167

*= p<0.05

GCA & DoC Special interest Group Heterotopic ossification in D0C

Results

HO might be underestimated because of:

• difficulty to detect them (e.g. radiological vs sonographic

examination)

No information about occurrence of HO in the acute phase

No information about additional possible risk factors (e.g. fractures,

spasticity, duration of coma, interval between brain injury onset and

admission to rehabilitation centre as possible risk factors) and HO site

Opportunities

Possibility of generalization across settings

Sharing assessment tools across settings

GCA & DoC Special interest Group Heterotopic ossification in D0C

Study limitations

Concluding remarks

HO developed in 12.2% of patients with DoC.

HO occurrence was significantly higher in patients with:

• mixed etiology (29.4%) than in patients with traumatic (19.5%), anoxic

(14.0%), or vascular etiology (3.7%);

• higher DRS category.

HO tends to occur more frequently in patients in VS with lower (but not

significantly) mean CRS-R total score.

No association with (some) risk factors for occurrence of HO in severely

brain-injured patients (e.g. young age, male gender, ventilation support,

PSH).

Further studies are necessary to investigate the role of early appropriate

rehabilitation pathways to reduce occurrence of HO.

Istituto Referenti

- ICS Maugeri, Telese Terme Estraneo Anna, Masotta Orsola

- Medicina Riab Int Osp Castel San Giovanni , (PC) Antenucci Roberto

- Ospedale Sacro Cuore Don Calabria, Verona Avesani Renato

- Dip Riab. UGCA HABILITA, Care & Res Rehabil H, Zingonia Bartolo Michelangelo, Aadis Hend

- Centro Cardinal Ferrari, Fontanellato di Parma De Tanti Antonio

- ICS Maugeri, Pavia Nardone Antonio, Berlusconi Marta

- Fondazione Santa Lucia, Roma Formisano Rita

- Ospedale riabilitativo di Marzana, Verona Gambarin Mattia

- Dipartimento Riabilitazione F.T. Camplani Clinica Ancelle Carità, Cremona Gentile Simona

- Istituto S. Anna , Crotone Lucca Lucia

- IRCCS Centro Neurolesi "Bonino-Pulejo”, Messina Marino Silvia

- Riabilitazione Ospedale AO Brotzu, Cagliari Diana Annarita, Pilia Felicita

- Istituti Clinici Zucchi, Carate Brianza Perin Cecilia

- Gruppo di Neuroriab O Maggiore Casa Risvegli, Bologna Piperno Roberto, Casanova Emanuela

- SC Riab Neuromotoria PO- Vimercate Premoselli Silvia

- Azienda Ospedaliera Universitaria Pisana- Dip Specialità Med SD GCA, Pisa Carboncini Maria Chiara

- U.F. Riab Neuromotoria- Istituto Clinico Quarenghi, S. Pellegrino Terme Pietro Salvi Giovanni

- UO Riabilitazione Fondazione San Raffaele Giglio, Cefalù Sant’Angelo Nino

- Dipartimento Neurologia UGCA Ospedale S. Giovanni Battista; Foligno Scarponi Federico, Patriarca E.

- Az socio sanitaria terr dei sette laghi- Pres riab neur; Varese Biacchi Daniela, Bertoni Michele

- IRCCS "Casa Sollievo della Sofferenza”, San Giovanni Rotondo Intiso Domenico

- San Raffaele, Cassino Pistoia Francesca, Marco Sarà

- Don Gnocchi, Firenze Grippo Antonello, Romoli Annamaria

Thanks to GCA & DoC Special interest Group

GCA & DoC

Special interest Group

Chairs:

Dr Anna Estraneo

Dr Antonio De Tanti

Our Mission: To provide a forum for exchange between professionals, as well as, neuroscientists on the study, assessment, and care of persons with severe brain injury and with disorders of consciousness, their families, and the systems serving them.

> 68 members 4 projects Website: http://www.sirn.net Contact: anna.estraneo@icsmaugeri.it or antonio.detanti@centrocardinalferrari.it

Multicentric longitudinal project on clinical complication on Disorder of Consciousness Multicentric observational study on PSH in GCA SIMFER-SIRN survey on heterotopic ossification SIRN-SINC sharing on diagnostic and prognostic procedures of patients with disorder of consciousness

Anna Estraneo, MD

Vincenzo Loreto MD

Angelo Pascarella MD

Pasquale Moretta, Psy

Orsola Masotta, Psy

Salvatore Fiorenza, TNPP

Luigi Trojano, MD

Thank you for your attention

Collaborations

Trojano L, Dept. Psychology, University Lugi Vanvitelli, Caserta, Italy

Soddu A., The University of Western Ontario, London ON, Canada

Schnakers C, UCLA Department of Neurosurgery, Los Angeles, California

Thibaut A, Gosseries O. Coma Science Group, Liège University, Belgium

Cavaliere C., SDN – Istituto di Ricerca Diagnostica e Nucleare, Napoli, Italy

Formisano R., Fondazione Santa Lucia - IRCCS, Roma

Research laboratory for DoC Telese Terme

anna.estraneo@icsmaugeri.it