Spinal Cord (2010) 48, 2–9

& 2010 International Spinal Cord Society All rights reserved 1362-4393/10 $32.00
www.nature.com/sc

REVIEW

Brain death and the cervical spinal cord: a confounding factor

for the clinical examination
AR Joffe, N Anton and J Blackwood
Department of Pediatrics, Stollery Children’s Hospital, University of Alberta, Edmonton, Alberta, Canada

Study design: This study is a systematic review.

Objectives: Brain death (BD) is a clinical diagnosis, made by documenting absent brainstem
functions, including unresponsive coma and apnea. Cervical spinal cord dysfunction would confound
clinical diagnosis of BD. Our objective was to determine whether cervical spinal cord dysfunction is
common in BD.
Methods: A case of BD showing cervical cord compression on magnetic resonance imaging prompted
a literature review from 1965 to 2008 for any reports of cervical spinal cord injury associated with brain
herniation or BD.
Results: A total of 12 cases of brain herniation in meningitis occurred shortly after a lumbar puncture
with acute respiratory arrest and quadriplegia. In total, nine cases of acute brain herniation from various
non-meningitis causes resulted in acute quadriplegia. The cases suggest that direct compression of the
cervical spinal cord, or the anterior spinal arteries during cerebellar tonsillar herniation cause ischemic
injury to the cord. No case series of brain herniation specifically mentioned spinal cord injury, but many
survivors had severe disability including spastic limbs. Only two pathological series of BD examined the
spinal cord; 56–100% of cases had upper cervical spinal cord damage, suggesting infarction from direct
compression of the cord or its arterial blood supply.
Conclusions: Upper cervical spinal cord injury may be common after brain herniation. Cervical spinal
cord injury must either be ruled out before clinical testing for BD, or an ancillary test to document lack
of brainstem blood flow is required in all cases of suspected BD. BD may not be a purely clinical
diagnosis.
Spinal Cord (2010) 48, 2–9; doi:10.1038/sc.2009.115; published online 8 September 2009

Keywords: brain death; apnea test; spinal cord injuries

Introduction
Death is said to occur when there is an irreversible loss of The American Academy of Neurology writes that to
the integrative unity of the organism as a whole.1,2 Brain diagnose BD there must be ‘exclusion of complicating
death (BD) is accepted in most countries of the world as medical conditions that may confound clinical assessment.’7
death of the patient;3 this is because it purportedly shows They further write that ‘the clinical examination of the
that the supreme regulator of the body is dead, and therefore brainstem includes testing of the brainstem reflexes, deter-
all that is left is a disintegrated corpse.1,2 It is said that BD is mination of the patient’s ability to breath spontaneously,
fundamentally a clinical diagnosis made at the bedside.4–7 and the evaluation of motor responses (of the limbs) to
Using medically standardized tests that examine functions of painyAll clinical tests are needed to declare BD and are
the brainstem, one can diagnose the irreversible state of BD likely equally essential. (One should not prioritize individual
at the bedside. Ancillary or confirmatory radiological or brainstem tests). A confirmatory test is needed for patients in
electrophysiological testing is not required unless there are whom specific components of clinical testing cannot be
confounding factors interfering with the clinical bedside reliably evaluated.’9 Similarly, the Canadian Neuro-Critical
tests.4,6–8 Care Group wrote that there should be ‘no movementsy
arising from the brainyno confounding factors for the
application of clinical criteriay’; coma includes there being
Correspondence: Dr AR Joffe, Department of Pediatrics, 3A3.07 Stollery ‘no spontaneous or elicited movements’, and apnea testing is
Children’s Hospital, 8440 112 Street, University of Alberta, Edmonton, ‘to ensure that an adequate stimulus is presented to the
Alberta, Canada T6G 2B7.
respiratory center (in the medulla).’10 The more recent
E-mail: ajoffe@cha.ab.ca
Received 16 June 2009; revised 16 July 2009; accepted 26 July 2009; Canadian Forum wrote that minimum clinical criteria that
published online 8 September 2009 must be present in ‘brain arrest’ include ‘deep unresponsive
 Spinal cord in brain death
AR Joffe et al
3

coma with bilateral absence of motor responsesyabsent

respiratory effort on the apnea test; absent confounding
factors’; indeed, to do an ancillary test one must document
‘deep unresponsive coma.’4 High cervical spinal cord injury
would be a confounding factor.11 Other authors have written
that the clinical testing to diagnose BD is done to show
‘cerebral unresponsivity’;5 ‘absence of the brainstem func-
tions’12 and ‘loss of brainstem function; and signifies that
breath as an essential element of life has vanished from
man;’13 or ‘loss of the breath of life.’14
We present a case and review the literature to argue that
bedside testing cannot diagnose BD, because the cervical
spinal cord is often injured and dysfunctional after cerebellar
herniation, and therefore is a confounding factor. A test that
can differentiate lower brainstem irreversible loss of function
from upper cervical spinal cord loss of function should be
required, if the criterion of BD and the diagnostic standards
for it are to be taken seriously.

Case report
An 11-year-old boy had a history of months of morning
vomiting, headaches, lethargy, weight loss, and weeks of
ataxia and nystagmus. He presented with acute onset of
coma, and was intubated, hyperventilated, given mannitol,
started on an infusion of hypertonic saline and had an
urgent external ventricular drain inserted. Computed-tomo-
graphic scan before the ventricular drain showed acute
hydrocephalus with a posterior fossa mass. Magnetic reso-
nance imaging (MRI) after the ventricular drain showed
severe cerebellar tonsillar herniation with displacement of
the upper cervical spinal cord (Figure 1a), and injury of the
first cervical spinal cord segment (Figure 1b). Repeated
clinical testing was compatible with BD; however, because
of the MRI cervical spinal cord findings we did a 99mTc-ethyl
cysteinate dimer planar radionuclide blood flow test that
documented no uptake in the cerebrum or cerebellum
(Figure 2). The family consented to organ donation, which
was done. Figure 1 Magnetic resonance imaging (MRI) scans of the brain
showing cerebellar tonsillar herniation through the foramen mag-
num into the cervical spinal canal with (a) sagittal T1-weighted
image showing displacement of the upper cervical spinal cord, and
Materials and methods (b) axial T2-weighted image through the level of the first cervical
spinal segment showing hyperintense signal within the substance of
This case prompted us to question whether cervical spinal the spinal cord consistent with injury, and associated anterior
cord injury may be a common confounding factor in displacement by the cerebellar tonsils. The MRI scan did not image
diagnosing BD. As MRI is only rarely done in suspected BD, below this level.
cervical spinal cord involvement would rarely be identified
in usual practice. We searched MEDLINE and PubMed from
1965 to 2008 with any combination of the following search BD and pathology, and retrieved relevant publications. Any
terms: intracranial hypertension, quadriplegia, spinal cord report of spinal examination postmortem was considered
injuries, spinal cord compression, tentorial herniation, uncal potentially relevant, retrieved, and the reference lists were
herniation and brain herniation. All abstracts were reviewed, also reviewed.
and potentially relevant publications retrieved. Reference
lists of relevant publications were also reviewed and
potentially relevant publications retrieved. Any report
Results
mentioning quadriplegia, spinal cord injury or spinal cord
compression in the setting of intracranial hypertension or We identified 12 cases reported of brain herniation during
brain herniation was considered potentially relevant. We meningitis that resulted in quadriplegia (Table 1).15–25
also searched MEDLINE and PubMed from 1965 to 2008 for These reports have remarkable similarities: a patient with

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AR Joffe et al
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Figure 2 The 99mTc-ethyl cysteinate dimer brain blood flow study showing lack of uptake of tracer in (a) the cerebral hemispheres on the
static anterior view, and (b and c) cerebral and cerebellar hemispheres on the static lateral views.

an altered level of consciousness has a lumbar puncture, arteries intracranially’28), and direct spinal cord compression
and shortly thereafter has a respiratory arrest followed with local ischemia and venous obstruction.27,28
by high cervical spinal cord quadriplegia with variable There were some case series that reported outcomes after
partial later recovery. Two cases died and autopsy showed brain herniation (Table 3).29–35 Unfortunately, none of these
infarction of the upper cervical cord without evidence of specifically commented on whether the outcomes in survi-
arachnoiditis.19,24 Three cases had MRI and this showed vors were due to spinal cord injury. These series show that
swelling or compression of the upper cervical spinal cord.23–25 there is a high mortality after brain herniation, and that
Several of the reports specifically mention that the findings 25–50% of survivors are left with severe sequelae, including
were compatible with anterior spinal artery compression ‘spastic limbs.’29–35 In one series of traumatic transtentorial
resulting in high cervical spinal cord injury.15,17,19 herniation, cardiac arrest, flaccidity or bilateral fixed pupils
We identified nine cases reported of brain herniation after the herniation predicted worse neurological outcome.33
without meningitis that resulted in quadriplegia (Table 2).26–28 We found only two case series of BD that specifically
Six cases had sudden brain herniation and a respiratory commented on the pathological findings in the spinal cord
arrest, four of these shortly after a lumbar puncture. These (Table 4).36–38 The Cerebral Survival Study, the only
cases at autopsy had upper cervical spinal cord necrosis prospective study of BD ever reported, found that upper
(four) or tense spinal dura (two) most likely due to cervical spinal cord damage was present in 71/127 (56%)
‘compression of the spinal cord and possibly compromise of autopsies.36,37 In total, 54 cases had ‘localized edema,
of its vascular supply by the large amounts of displaced necrosis, infarction or hemorrhage at the cervicomedullary
cerebellar tissue.’26 Three cases had sudden brain herniation junction,’ and in another 17 cases ‘acute and chronic
from acute hydrocephalus and later variable partial recov- neuronal changes, and glial alteration were present in the
ery.27,28 These three cases at MRI had evidence of cord edema upper cervical spinal cord.’36,37 The authors wrote that
or infarction, and the pathophysiology was hypothesized to ‘because this is the location of tonsillar herniations and the
be due to arterial (anterior spinal artery) insufficiency boundary of cerebral and spinal circulation, it is susceptible
because of brain herniation (the vessels ‘descend through to the vascular changes produced by the cut-off of the
the foramen magnum after taking off from the vertebral vertebral blood supply which caused ‘demarcating reaction’

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 Table 1 Case reports of meningitis with acute brain herniation and quadriplegia from cervical spinal cord injury15–25

Author Age (year) Findings before LP Findings after LP Outcome MRI or autopsy result
15
DeSousa 3 Increasingly lethargic, After LP was unresponsive and with QP consistent Partial recovery F
developed seizures with ‘the anterior spinal artery syndrome’
at C2 level
Glista et al.16 2 Lethargic and For 24 h after LP had progressive decrease in Partial recovery F
generalized rigidity spontaneous activity, then RA, and QP with a
clinical ‘high cervical spinal cord lesion’
Swart and 15 Response to pain only 7 and 19 h after LP had RA with QP and findings Partial recovery F
Pye17 ‘compatible with an ischemic lesion at the
cervicomedullary junctionysuggested an infarct
of the upper cervical cord in the anterior spinal
artery territory’
Tal et al.18 3 Listlessness o8 h after LP had RA and QP Partial recovery F
3 Lethargy o3 h after LP had RA, dilated pupil and QP Partial recovery 1 month later: myelogram and vertebral angiogram
normal.
Norman19 6 Unresponsive 20 min after LP had RA and QP Death Autopsy 12 days later: infarction throughout C1
involving the pyramidal decussationa
Verghote20 15 Focal seizure and 11 h after LP had RA and QP Good recovery F
stuporous
Cabral et al.21 10 F Shortly after LP had RA, and ‘clinical assessment Partial recovery F
indicated an abnormality in the upper cervical
cord’
Phelan and 11 Drowsy Shortly after LP had RA and QP. Sensory level at Partial recovery Myelogram normal
Manson22 C1-2
Raps et al.23 47 Lethargy After LP had ‘progressive decline in Good recovery MRI: hydrocephalus with ‘anterior hydrostatic cervical
AR Joffe et al

consciousnessyflaccid QP’ cord compression;’ upper segments of the cervical

cord ‘compressed to less than 50% normal diameter.’
O’Farrell 25 Coma Over 12 h after LP pupils dilated and hemodynamic Death MRI: ‘increased signal intensity and expansion in the
et al.24 instability; 24 h later was alert but with C1 QP lower medulla, upper cervical cord and cerebellar
tonsilsyCSF of foramen magnum was effacedy’
Autopsy: ‘cystic infarction extending from the medulla
Spinal cord in brain death

to the upper cervical cord. An area of infarction, of

similar age, was noted bilaterally in the cerebellar
tonsils’
Ropper and 19 Lethargy and LP followed by progressive drowsiness and QP Partial recovery MRI: ‘cerebellar tonsillar herniation and swelling of the
Kanis25 confusion adjacent compressed cervicomedullary
junctionysignal changes within the upper cord.’
MRI 2 months later: ‘cavitation in the region of the
cervicomedullary junction [including] within the upper
cervical cord’

Abbreviations: C, cervical; CSF, cerebrospinal fluid; LP, lumbar puncture; MRI, magnetic resonance imaging; QP, quadriplegia; RA, respiratory arrest.
a
Norman19 writes: ‘the herniated cerebellar tonsils produced sufficient compression of structures in the foramen magnum to obstruct caudal flow in the vertebral artery branches which give rise to the anterior spinal
artery and thusy’

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Table 2 Reports of non-meningitis cases of acute brain herniation and quadriplegia from cervical spinal cord injury26–28

Author Age (year) Disease Description Outcome Autopsy or MRI result

Herrick and 1 Lead toxicity Lethargic, had LP, Death Spinal dura tense
Agamandolis26 o9 h later had RA
12 Reye syndrome Coma, had LP, Death Cervical necrosis of anterior posterior columns that
next day RA extended over most of the cervical enlargement
7 months Reye syndrome Coma, had LP, RA Death Spinal dura distended and tense
next day
4 Reye syndrome Seizures, LP, RA Death Cervical cord compressed, distorted, with
later that day vacuolated subpial white matter and necrosis
dorsal columns from cervical to upper thoracic
cord
18 Subdural empyema Coma, RA, Death Upper cervical cord necrosis involving one dorsal
then LP horn and adjacent dorsal column
17 Seizures and dialysis Clinical herniation Death Cervical white matter vacuolated and fragmented
with RA especially dorsal columns and adjacent lateral
columns
Sartoretti-Schefer 53 Haemangioglastoma of Ataxic Alive with MRI: ‘ycerebellar tonsils downward through
et al.27 vermis with acute recovery foramen magnumycentral grey matter and the
hydrocephalus directly adjacent white matter showed diffuse high
signal on T2-weighted images, extending from C3
to the upper margin of C7’
19 Late postmeningitic adhesive Decreased level of Alive with MRI: ‘yoedema was visible on T2-weighted
acute hydrocephalus consciousness recovery images in both cerebellar hemispheres and within
the grey matter and parts of the white matter of
the cervical spinal cord surrounding the dilated
central spinal canal’
Siu et al.28 24 Colloid cyst of third ventricle Suddenly Partial MRI: ‘abnormal signal change in the spinal cord
with acute hydrocephalus unresponsive with recovery centrally extending from C4 to T3 and consistent
extensor with a cord infarctiony’a
posturing and
then QP

Abbreviations: C, cervical; LP, lumbar puncture; MRI, magnetic resonance imaging; QP, quadriplegia; RA, respiratory arrest; T, thoracic.
a
Siu et al.28 write: the anterior spinal arteries ‘descend through the foramen magnum after taking off from the vertebral arteries intracraniallyywould lead to distal
watershed infarction in the thoracic region and with variable extension in a cephalad directiony’

Table 3 Case series of brain herniation describing outcomes suggestive of possible cervical spinal cord injury29–35

Author n Herniation Survivors of Severe disability Comments

(n) herniation (n) in survivors (n)

Meningitis case series

Horwitz et al.29 302 18 15 4 2/15 (13%) survivors of herniation had ‘severe residua,’ with
‘severe spastic hemiparesis’
Rosenberg et al.30 453 16 4 1 Spastic quadriplegia and late death in 1/4 (25%) survivors
Rennick et al.31 445 19 5 2 2/5 (40%) survivors of herniation with ‘severe neurologic impairment’
Pfister et al.32 86 7 2 1 1/2 (50%) survivors of herniation with ‘spastic limbs’

Traumatic head injury case series

Andrews and Pitts33 153 153 49 16 14 good recovery, 14 moderate disability, 15 severe disability
and 1 vegetative survivor. Cardiac arrest, flaccidity or bilateral
fixed pupils predicted worse outcome
Aarabi et al.34 323 Minority ? 429.4% All had decompressive craniectomy: 22.3% death; 29.4% severe
disability or vegetative; 48.3% GOS of 4–5
35
Salvatore et al. 80 80 68 8 10% severe disability; 20% moderate disability and 55% full recovery
with decompressive craniectomy. If decompressive surgery
delayed 46 h, 16% severe disability; 21% moderate disability,
and 42% full recovery

Abbreviation: GOS, Glasgow Outcome Score.

consisting of localized edema and laceration associated spinal cord.’ There was hemorrhagic necrosis of C1-C3/4
with petechial hemorrhages in the substance of the spinal shown by necrosis in 11 cases, and discoloration and
cord.’36,37 Similarly, Schneider and Matakas38 found in a softening in 4 cases.38 These authors wrote that the cervical
consecutive series of 15 cases ‘if the organism is kept alive, it cord is ‘supplied by arteries, arising from the intracranial
reacts in all cases identicallyydemarcation develops in the portion of the vertebral arteriesyit corresponds to the
anterior pituitary lobe, in the upper cervical segments of the marginal area of an ischemic infarction.’38 Other possible

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Table 4 Pathology series of brain death that include examination of the spinal cord36–38

Author n Cervical spinal Other spinal cord Comments

cord abnormal (n) abnormal (n)

Walker et al.36 and 127 71 (56%)a 51 54: localized edema, necrosis, infarction or hemorrhage of the
Walker37 cervicomedullary junction; 17: acute and chronic neuronal
changes and glial alteration were present in the upper cervical
spinal cord
Schneider and Matakas38 15 15 (100%) 15 Hemorrhagic necrosis of C1-C3/4 based on: necrosis in 11, and
discoloration and softening in 4

Abbreviation: C, cervical.
a
The report, in the section on spinal cord pathology, writes ‘y76 of the 127 cases in which spinal cord was examined were reported to be grossly normal.
Microscopically, in many cases, the substance of the spinal cord appeared normal. However, in about one-third of the cases, pathological alterations such as edema
(13.8%), petechial hemorrhages (5.7%), neurolysis of anterior horn cells (11.4%) were notedyAt the cervico-medullary junction, where the blood supply may be
derived from either vertebral or spinal arteries, myelopathy in the form of localized edema, necrosis, infarction, or hemorrhage, was present in 54 casesyIn an
additional 17 cases, acute and chronic neuronal changes were seen on microscopic examination of the upper cervical cord’(Walker;37 pp37). Similarly, in another
report it is written ‘54 cases had localized edema, necrosis, infarction, or hemorrhage at the cervico-medullary junctionyIn 17 additional cases, acute and chronic
neuronal changes and glial alterations were present in the upper cervical spinal cord’ (Walker et al.;36 pp 303). Therefore, cervical pathology occurred in 71/127
(56%) if the cervico-medullary junction is included, and in at least 51/127 (40%) if the cervico-medullary junction is not included.

etiologies that were hypothesized included ‘hindrance of models of BD showing demarcation at the C1/C2 cord
venous drainage’ and ‘cuff of necrotic cerebellar tissue segments.42
compressing the spinal cord.’38 Both pathological series note If cervical spinal cord injury is common after cerebellar
that other areas of the spinal cord can be affected by a herniation, one could argue that there should be more
different pathological process; specifically, necrotic cerebel- reports of this phenomenon. There are several possible
lar tissue that had sedimented, causing inflammatory reasons to believe that this is not a sound argument. First,
reaction in the marginal areas of spinal white matter of death usually occurs so quickly after herniation that
various parts of the spinal cord.36–38 Schroder did not quadriplegia is likely not recognized.19,28 Second, when
describe detailed spinal cord pathology but in his series quadriplegia is suspected after herniation, it is likely
wrote, ‘these [brain pathology] alterations decreasedy attributed to concomitant brainstem insult and followed
caudal (lower medulla, first cervical segment),’ implying by death.19,28 Third, severe sequelae in survivors of hernia-
some changes in the upper cervical spinal cord.39 tion are common, and likely attributed to other brain or
brainstem injuries, without investigation of the cervical
spinal cord.29–35 Fourth, in the setting of suspected BD, the
spinal cord is rarely investigated or suspected to be affected
Discussion
when testing for limb movement to pain or apnea.4–11 A
Brain death is said to be fundamentally a clinical diagnosis at final reason is that most patients are imaged with a CT scan
the bedside.4–7 Only when confounding factors make the of the brain, and this is often not adequate to show cerebellar
clinical examination of brainstem functions unreliable is an herniation, and not inclusive of the upper cervical spinal
ancillary test required.4–11 We report a case, and review the cord.43,44 To adequately show tonsillar herniation an MRI
literature, to make the suggestion that upper cervical spinal scan is required, and this is usually not done due to the
cord injury is a common result of brain herniation, and a hemodynamically unstable state of the patient.43–45
confounding factor in the clinical examination for BD. If One could argue that some of the spinal cord injury cases
unresponsive coma could be partly accounted for by the lack could be due to spinal arachnoiditis with vasculitis in the
of ability to move the limbs, and if apnea could be attributed setting of meningitis. There are several cases reported of
to absent respiratory muscle function, both due to upper spinal cord injury in meningitis due to this mechanism,
cervical spinal cord injury, then clinical testing for BD is proven at laminectomy or myelogram.46–52 These cases are
unreliable.11 Many case reports in the setting of sudden brain different from the ones reported here. The cases reported
herniation both with and without meningitis show that usually occurred later in the meningitis course, were not
permanent or partially reversible cervical spinal cord injury associated with sudden respiratory arrest, were not shortly
can occur, and the clinical, autopsy and MRI findings suggest after a lumbar puncture, and involved lower parts of the
this is due to direct compressive injury to the spinal cord, its spinal cord from C5 and lower.46–52 We found three cases of
arterial supply and its venous drainage.15–28 Furthermore, high cervical spinal cord injury in meningitis likely due to
the autopsy series of BD show that high cervical spinal cord arachnoiditis: a 24-week premature neonate with meningitis
injury is a common finding (56–100% of cases), and most who at 7 days of treatment became flaccid below the neck
likely due to compression of the upper cervical spinal cord despite being awake and having spontaneous movements; a
and its blood supply during cerebellar herniation.36–38 This is 33-week premature neonate with meningitis who at 4 days of
compatible with early pathological reports of BD in other treatment became flaccid and areflexic despite grimacing to
languages that found necrosis of the upper cervical segments pain, and autopsy showed extensive necrosis of the cervical
of spinal cord,40,41 and with early cat and baboon animal spinal cord with exudates and vasculitis; and a neonate with

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AR Joffe et al
8

meningitis who at 4 days of treatment was noted to be difficult, and in addition, the angiogram is invasive and has
areflexic with minimal movement of the upper extremities the potential to cause vasospasm and worsen the brain injury
and no movements of the lower extremities but was if BD has not yet occurred.58 Moreover, we are not aware of a
extubated 3 days later.50 These cases do not resemble the study showing that an angiogram can prove brain circulatory
cases discussed here of sudden herniation with respiratory arrest and rule out residual brain blood flow enough to
arrest and quadriplegia, and they do not explain the findings sustain some brain viability. Indeed, it has been shown that
in the non-meningitis cases. Banks and McCartney46 in 1942 electroencephalographic activity can remain in cases with
noted this when they described a variant of meningococcal clinical BD and absent flow on four-vessel angiography; this
meningitis that they called ‘focal encephalomyelitis,’ where suggests that the angiogram did not rule out residual blood
there was sudden fatal collapse and pathological changes flow sustaining viability of parts of the brain.59,60 Another
‘usually about the basal ganglia, midbrain, medulla, or upper study found that 13/43 (30%) of clinically brain-dead
cordypostmortem no satisfactory cause of death may be patients with absent conventional angiographic brain blood
found in these cases on macroscopic examination, since the flow had persistent cerebral perfusion by computed-tomo-
meningitis may have almost cleared upyit is only on careful graphic angiography.61
histological examinationy’. In conclusion, this review suggests a major limitation in
It could also be argued that some of the cases of spinal cord our ability to diagnose BD clinically at the bedside. Further
injury may be due to the hypoxemia and ischemia of the expert discussion is needed to resolve this difficult issue.
respiratory arrest event. This mechanism would be expected
to affect mostly the thoracic and lumbar spinal cord because
the border zone of arterial circulation is in the thoracic
cord.38,50 We note that, even if some cases of high cervical References
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