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Ipsilateral loss of tactile discrimination
and position and vibration sensation from arm
Gracile fasciculus
Cuneate fasciculus
Spinocerebellar tract
Dorsal horn
Hypothalamospinal tract
4
THE SPINAL CORD
and position and vibration sensation from leg
Ipsilateral loss of tactile discrimination
Horner’s syndrome
Fig. 4.10 Clinical deficits associated with damage to the main ascending and descending pathways at the cervical spinal cord level. (Adapted
from Fix JD. (1995). High Yield Neuroanatomy. Williams and Wilkins, Philadelphia.)
from proprioceptors, nociceptors and descending pathway tracts such as the vestibulospinal and reticulospinal
tracts. The ventral SCBT seems to defy the ipsilaterality of the cerebellum because the fibres cross over in the
cord. However, they cross back before entering the cerebellum via the superior cerebellar peduncle. Therefore,
the cerebellum still receives information from the ipsilateral side of the body. Ventral SCBT cells have large RFs
and appear to act as comparators of descending inputs
and other inputs to motor neurons.
Summary of somatosensory pathways
Three main ascending somatosensory pathways each
carry a specific modality of sensation associated with
specific receptors. Each pathway is somatotopically
organized so that a complete representation of the body
is reproduced in each relay nucleus along the pathway.
Any sensory system going to the cerebral cortex decussates at some point because the cerebral cortex operates
on a contralateral basis. The discriminative touch system crosses in the medulla, and the pain system crosses
in the spinal cord. The proprioceptive system ascends to
the cerebellum and does not cross. There is some overlap
of modalities between the ascending tracts: some light
touch information travels in the STT so that lesioning the
dorsal column does not completely abolish touch and
pressure sensation; similarly, visceral pain fibres travel
in the dorsal columns and not the STT. Discriminative
proprioception also travels in the dorsal columns and
follows the medial lemniscus all the way to the cortex,
so there is conscious awareness of body position and
movement. The pain and temperature system, although
it does ascend to the somatosensory cortex, also has multiple targets in the brainstem and other areas. Knowledge
of the pathways, point of decussation and cortical areas
associated with conscious perception of sensation
provides a framework for understanding sensory deficits
after damage, as summarized in Fig. 4.10.
Corticospinal tract
Ventral horn
Spinothalamic tract
Table 4.3 Main descending spinal pathways
Pathway Function
Corticospinal Control of fine voluntary movement
Rubrospinal Regulates muscle tone in anti-gravity
Vestibulospinal Regulates neck muscles involved in head
Raphe spinal Pain modulation
Coeruleospinal Autonomic nervous system reflex modulation
Reticulospinal Postural control via regulation of flexor and
Tectospinal Head and neck postural reflex responses to
Hypothalamospinal Sympathetic nervous system control of
As well as conveying sensory information to supraspinal levels, the spinal cord white matter contains many
descending pathways (Table 4.3). The main descending
pathway is the corticospinal tract (CST), which regulates the control of voluntary movement. Damage to
this pathway produces hyperreflexia, hypertonia and a
positive Babinski sign (extensor plantar response). These
descending pathways and their dysfunction are more
fully covered in Chapter 9.
The hypothalamospinal tract is clinically important, as
damage to this pathway results in Horner’s syndrome,
which is characterized by miosis, ptosis and anhydrosis.
Signs are always ipsilateral. The pathway runs directly
from the hypothalamus to the ciliospinal centre, located
in the intermediolateral cell column of the T1–T2 spinal
cord. It descends through the lateral tegmentum of the
brainstem to run in the dorsolateral quadrant of the dorsolateral funiculus.
Ipsilateral spastic paresis
Ataxia
Contralateral loss of pain
and temperature sensation
one segment below lesion
Ipsilateral flaccid paralysis
in affected myotomes
(extensor) muscles
balance reflexes
extensor reflexes
auditory and visual cues
visceral activity
79THE NERVOUS SYSTEM
4
PSA PSA
ASA
THE SPINAL CORD
Fig. 4.11 Distribution of the main arterial supply to the spinal
cord. The yellow area demarcates the distribution of the PSA; the
remainder demarcates the ASA territory. ASA, Anterior spinal artery;
PSA, posterior spinal artery.
Blood supply to the spinal cord
Two posterior spinal arteries and a single larger anterior
spinal artery, which originate from the vertebral artery,
supply the spinal cord. Each posterior artery supplies
the ipsilateral posterior third of the cord, while the anterior spinal artery supplies the anterior two- thirds of the
cord (Fig. 4.11). However, this is not enough to maintain
an adequate blood supply to the spinal cord. At each spinal segment, these arteries are reinforced by segmental
radiculospinal arteries, which are branches of the body
wall arteries. In addition, the anterior spinal arteries give
rise to smaller penetrating arteries, which anastomose
with similar arteries from the posterior spinal arteries
within the spinal cord tissue. Radicular arteries supply
the dorsal and ventral roots. These do not connect to the
anterior or posterior spinal arteries and only supply the
roots. The venous drainage has a similar distribution to
the arterial supply. Three anterior and posterior spinal
veins drain along the nerve roots into the internal (epidural) and external vertebral venous plexus along the
vertebral column, and from this plexus to ascending
lumbar veins: the azygos vein and hemi- azygos veins.
Damage to the spinal cord
SCI commonly arises from trauma, degenerative diseases, ischemia or occlusion of spinal cord arteries,
metastatic cancer, and infectious, toxic or metabolic
disorders and should be treated as a medical emergency to limit any irreversible damage (Table 4.4). SCI
can either be complete, meaning that there is no voluntary movement or sensation below the level of the
lesion bilaterally, or incomplete, when there is a variable amount of function below the level of the lesion.
The level of the lesion is helpful in predicting the deficits in body function that might occur and how much
independence the patient might have after the injury
(Table 4.5). The location of the lesion must be at, or
Table 4.4 Some common causes of spinal cord injury
Cause of SCI Example
Trauma Acts of violence
Penetrating wounds
Compression injury (e.g. prolapsed disc)
Whiplash
Sporting accidents (e.g. diving)
Demyelinating disease Multiple sclerosis
Spinal muscular atrophy
Syringomyelia/Arnold-Chiari malformation
Poliomyelitis
Inflammatory (transverse) myelitis
Spina bifida
Infection AIDS
Spinal meningitis
Tuberculosis
Syphilis
Lyme’s disease
Abscess
Metabolic disorder Subacute combined degeneration
(vitamin B12 deficiency)
Vascular Anterior spinal artery occlusion
Spinal dural arteriovenous malformation
Tumour Primary or secondary cancer
above, the level of the highest neurological sign. (For
a better understanding of the impact of SCI, see the
discussion on the descending pathways in Chapter 9).
SCI is most often classified using the American Spinal
Injury Association (ASIA) impairment scale based on
neurological assessment of 28 dermatomes and 10 key
muscles groups, 72 hours after injury. SCI is graded
from category A to E (Table 4.6).
Cervical spondylotic myelopathy is the most common cause of spinal cord compression in people aged
over 55 years, causing progressive loss of neurological
function and may lead to tetraplegia if left untreated.
Traumatic injuries are also common and can be caused
directly by penetrating injuries such as gunshot or
stab wounds, or indirectly as a result of compression
or flexion/extension injuries of structures associated
with the vertebral column. This can lead to sensory,
motor or sphincter dysfunction or a combination of
these, depending on whether the lesion is uni- or bilateral. One of the earliest signs of SCI is pain. Motor
dysfunction also occurs early, resulting in hypotonia,
muscle wasting and paralysis. Depending on the level
of the lesion, there may be deficits in cardiovascular,
respiratory and autonomic (bladder, sweating and sexual) function, as well as a loss of protective functions
such as pain and temperature sensation (see Table 4.5).
These lead to a number of secondary problems such
as urinary infections and pressure sores, and a loss of
unconscious control mechanisms such as regulation of
CNS neuronal excitability.
80 SYSTEMS OF THE BODY
Table 4.5 Effects of spinal cord injury at different segmental
13
10
11
12
14
15
16
19
20
21
23
24
22
17
18
levels in humans
4
THE SPINAL CORD
1
Patient
Segment Consequence
C1–C2 Quadriplegia None
Requires ventilated
respiration
Acute sympathetic shock
syndrome (bradycardia,
hypotension, bilateral
Horner’s syndrome, and
loss of thermoregulation)
Reflex bladder (damage
to upper motor neuron
control of micturition)
C4–C5 Quadriplegia None
Impaired respiration Requires constant care
Reflex bladder (urinary
retention and
constipation)
C6–C7 Quadriplegia with impaired
arm control
C8–T1 Impaired respiration Requires personal
Reflex bladder Can drive a car with
Paraplegia
T2–T3 Impaired respiration Complete
Poor trunk control
Reflex bladder
Paraplegia
T12–L1 Paraplegia Complete
Reflex bladder
L4–L5 Paraplegia Complete
Reflex bladder
S2–S3 Non-reflex bladder (damage
to lower motor neurons
leading to failure to void)
independence
Often die at scene of
injury
Minimal
care
special braces
Complete
Imaging the spinal cord
In order to assess the possible causes of spinal cord damage, various imaging techniques are used. X- rays can
detect vertebral damage due to trauma or cancer, and the
radiographs are commonly viewed in the anteroposteral
(longitudinal) and lateral directions. X- rays do not visualize the spinal cord but infer damage by changes in the
alignment of the vertebral column or reduction in the size
of the vertebral canal. Computed tomography (CT) can
be used to visualize infarcts and tumours in neural tissue. Magnetic resonance imaging (MRI) can differentiate
between grey matter and white matter, so this method is
2
3
4
5
6
7
6
8
9
5
1. Medulla.
2. Dens of axis.
3. Tongue.
4. C2 vertebra.
5. Subarachnoid space.
6. Spinal cord.
7. Trachea.
8. L1 vertebra.
9. Conus medullaris.
10. Filum terminale.
11. L5 vertebra.
12. Intervertebral disc.
Fig. 4.12 Magnetic resonance image of the spinal cord in the sagittal
plane. Top: Cervical cord. Inset shows the cord imaged in the transverse
plane at the level of the dashed lines. Here (in this T2- weighted
image), the grey matter appears paler than the white matter and the
cerebrospinal fluid is white. In the remaining images the cerebrospinal
fluid appears black. Bottom left: A normal magnetic resonance image of
the thoracolumbar vertebral region showing the end of the spinal cord.
Bottom right: Magnetic resonance image showing metastatic intervertebral
disc herniation into the spinal canal and compressing the spinal cord.
13. Foramen magnum.
14. Atlas.
15. Vertebral body.
16. Cerebrospinal fluid.
17. Grey matter.
18. White matter.
19. T11 vertebra.
20. Herniated cancerous disc.
21. T12 vertebra.
22. Degenerating vertebrae.
23. L4 vertebra.
24. Epidural fat.
6
particularly sensitive for distinguishing CNS tissue. It is
particularly sensitive for imaging areas of focal demyelination and spinal cord lesions. It can provide axial as well
as longitudinal images of the entire spinal cord and is now
the method of choice for study of the spinal cord, nerve
81THE NERVOUS SYSTEM
4
roots, and disc spaces or signs of narrowing (stenosis) or
damage (e.g. disc herniation, Fig. 4.12).
Pathophysiology of spinal cord injury
Spinal cord damage induced by a traumatic injury occurs
in two phases:
THE SPINAL CORD
1. Primary damage resulting from cord compression,
contusion, laceration or haemorrhage, which occurs
immediately on injury.
2. Secondary damage that is initiated by the trauma
but occurs over a period of hours, days and months.
This mainly involves physiological alterations due to
trauma, hypoxia, ischemia and inflammation.
The cord is often swollen and congested after only mild
focal indentation or severe haemorrhagic disruption, usually above and below the level of the lesion (Fig. 4.13). The
swollen cord can occupy the entire vertebral canal, causing secondary ischemia when the swelling exceeds the
venous blood pressure. This ischemia is further exacerbated by loss of autoregulation of blood flow, causing systemic hypotension, leading to spinal shock (see Box 4.7)
and secondary damage through excitotoxicity.
In the acute phase of traumatic cord injury there are variable amounts of oedema, micro- haemorrhaging in the grey
matter, axonal swelling, ascending/descending tract disruption, and foci of infarction. In the first 24 hours, axons start
dying back from the point of injury and the area of the initial injury increases in size, growing further as the area of
hypoperfusion spreads from the grey matter into the white
matter. Clearly, this early period presents a period of therapeutic opportunity to limit lesion size if appropriate drugs
can be used. Damaged cells, axons and blood vessels release
Fig. 4.13 Macroscopic anatomy of spinal cord injury. (A) Sagittal
section of the spinal cord and vertebral column, showing focal
indentation of the ventral spinal cord at the C4 level. (B) Gross
anatomy of the cord following its removal from the vertebral column,
showing compression of the ventral horn (oval).
chemicals that cause reactive gliosis and damage neighbouring tissue. For example, the injury area is flooded with the
neurotransmitter glutamate, which then overstimulates adjacent neurons and glial cells, leading to a massive Na+ and
Ca2+ influx into cells (neurons and glia) that cause them to
swell and burst and release their cellular contents and free
radicals into the extracellular space. This excitotoxic cascade also affects the oligodendrocyte cells that myelinate the
CNS tracts. Vascular reperfusion of the damaged tissue also
evokes excitotoxicity via the production of oxidative stress,
excessive glutamate and ATP release. This leads to further
demyelination of surviving fibres and more dysfunction.
Over the following days and weeks, there is macrophage
infiltration and a gradual removal of degenerative debris
(e.g. axons, myelin). At the site of injury, the grey matter
becomes necrotic and may cavitate. As time progresses, there
is hypertrophy of astrocytes and infiltration by fibroblasts
forming scar tissue to spatially contain and isolate damaged tissue. However, reactive tissue repair mechanisms
fail to occur, and the scar becomes a barrier to regeneration.
Frequently, cavitation involves the ventral part of the dorsal columns, which is maximal at the site of injury but may
extend a few segments rostral or caudal to the injury. Finally,
Box
**
BA
Spinal cord shock and neurogenic
4.7
shock
Clinically, there is pain at the level of the injury and a variable amount of sensorimotor loss below the level of the
lesion. Severe spinal cord injuries often initially produce
spinal shock: a state of temporary loss of all of the functions, and muscle reflexes below the level of the lesion are
depressed or absent, due to the removal of all descending motor pathways, giving the impression of flaccid
paralysis of muscles and loss of sensation. If the lesion
occurs above the T6 spinal level, the sympathetic nervous
system is affected, and severe hypotension and thermodysregulation may occur as a result of loss of sympathetic
vasomotor tone. This is neurogenic shock (autonomic dysreflexia) and is characterized by hemodynamic changes;
spinal shock is not circulatory in nature, but symptoms
can include neurogenic shock when the injury is at high
thoracic or cervical levels. Spinal shock often lasts approximately 1 day but may persist for up to a month, after
which the spinal cord neurons gradually regain their excitability and the flaccid paralysis gives way to spastic paresis. The first reflexes to reappear are the flexion reflexes.
Even after these reappear, limbs are flaccid in the absence
of tonic stretch reflex activation. After several months, a
return of muscle tone and tendon reflexes may occur.
The presence of spinal shock can be determined by testing the integrity of the anal sphincter reflex (checking for
anal sphincter contraction after pulling of the glans penis
or clitoris or by pulling on an inserted Foley catheter).
However, a sacral cord lesion would nullify this test, as the
S2–S4 nerve supply may be damaged.
82 SYSTEMS OF THE BODY
4
123
456
days or weeks after the initial event, some cells undergo
apoptosis, whilst Wallerian degeneration of damaged axons
causes further gliosis and neuroinflammation that can result
in another wave of death that may affect up to four spinal
segments rostral or caudal to the injury site.
In almost all lesions, even in apparently complete SCI,
not all ascending or descending axons are severed and
a peripheral ring at the outer edge of the white matter
remains intact (Fig. 4.14).Forexample, if asfew as 10%
of the descending CST fibres survive, the patient may
beabletowalk,whereasiflessthan4%remain,theyare
unable to do so. However, surviving fibres often do not
look normal; they are stripped of their insulation and so
may not properly conduct nerve impulses.
The prognosis for SCI depends on whether the lesion
is extrinsic, that is, outside the substance of the spinal
cord (e.g. tumour, in which case, it can often be removed
surgically, resulting in recovery of function) or intrinsic
within the spinal cord. Research has shown that the most
important predictor of improved spinal cord outcome
is the retention of sacral sensation (S4–S5 dermatomes),
especially pin- prick sensation, 3–7 days after injury. In
general, most SCI patients may regain one level of motor
function and most of the recovery, if it occurs at all, is seen
within the first 6 months after injury. Ten to fifteen percent
of ASIA grade A patients may progress to grade B–D, but
very few regain functional strength below the level of the
lesion, whereas half of grade B patients will regain func-
tionalstrengthbelow the lesion,andnearly90%ofgrade
C and D patients recover sufficient strength to walk again.
as gliomas (glial cell carcinomas). Pressure arising from any
of these causes may interfere with the arterial or venous
blood supply, causing ischemia or oedema and conduction
blockage in fibres in the white matter, which, if prolonged,
may cause focal demyelination. Compression may also
cause blockage of CSF flow and changes in the composition
of CSF below the level of the lesion. One of the earliest signs
of compression injury is pain, which may be restricted to
one or more spinal nerves and is made worse by exercise,
coughing or sneezing, or lying down. Motor dysfunction
occurs early, resulting in paralysis, spasticity and exaggerated reflexes below the level of the lesion. The degree
of sensory loss will depend on the nerve tracts involved.
Surgery to remove the extradural and extramedullary
causes is usually successful at reversing the symptoms, provided that irreversible damage due to compromised blood
flow has not occurred.
Fig. 4.15 details six distinct spinal cord syndromes
caused by destructive lesions; the functional losses associated with these syndromes are predictable from knowledge
of the anatomy of the spinal cord. The clinical symptoms
associated with these syndromes are detailed below. In the
first three, the characteristic symptoms appear after the initial period of spinal shock (see Box 4.7) has ended.
THE SPINAL CORD
Spinal cord syndromes
Spinal cord compression is most often caused by extradural
problems, such as spondylitis, disc herniation or primary
or secondary vertebral tumours or abscesses (see Fig. 4.12).
Tumours that arise outside the spinal cord, such as meningiomas or nerve fibromas, may compress the cord; those
originating in the cord are rarer and include tumours such
Fig. 4.14 Transverse section showing spinal cord compression. Note
the distortion of the grey matter on the side of compression and
demyelination at the lateral edge of the white matter of the cord on
the injured side (arrows).
Fig. 4.15 Schematic representations of areas of damage in distinct
spinal cord syndromes. 1, Complete cord transection; 2, spinal cord
hemi-section; 3, anterior cord syndrome; 4, amyotrophic lateral
sclerosis; 5, infectious diseases; 6, syringomelia.
Table 4.6 ASIA impairment scale
Grade Description
A Complete SCI; no preservation of sensory or motor
function in S4–S5 cord
B Incomplete; sensory but not motor function below
the neurological level and extending through to
S4–S5 cord
C Incomplete; motor function preserved below the
lesion site; most key muscles have strength of <3
(Medical Research Council [MRC] grade score)
D Incomplete; motor function preserved below the
lesion site; most key muscles have strength of >3
E Normal sensory and motor function
83THE NERVOUS SYSTEM
4
Complete cord transection
Here, there is complete loss of all sensory, voluntary
movement and autonomic functions below the level of
the lesion. Thus there is bilateral lower motor neuron
paralysis and atrophy at the damaged level, bilateral
spastic paresis and Babinski signs below the lesion, loss
of bladder and bowel function, and bilateral loss of all
THE SPINAL CORD
sensation below the level of the lesion. If the injury is a
vertebral fracture dislocation at L2–L3 or below, then
no cord injury occurs; damage is confined to the cauda
equina, and there are no upper motor neuron signs of
damage, the only damage being to sensory, motor and
autonomic nerve fibres.
Spinal cord hemisection (Brown–Séquard syndrome)
This can be caused by penetrating trauma injuries, for
example, a stab or gunshot wound, or by vertebral damage. A pure hemisection results in ipsilateral loss of all
sensations and voluntary muscle movement at the level
of the lesion, ipsilateral spastic paresis below the level of
the lesion, ipsilateral loss of discriminative (light) touch,
vibration sensation and proprioception, and a contralateral loss of pain and temperature sensation below the
level of the lesion. Damage to the hypothalamospinal
(descending sympathetic pathway) tract at T1 or above
produces an ipsilateral Horner’s syndrome. Such pure
lesions are rare and incomplete hemisections are more
common.
Anterior cord syndrome
This can be caused by fracture dislocation of vertebrae,
herniation of vertebral discs or occlusion of the anterior
spinal artery by a tumour. It results in bilateral motor
paralysis at the level of the lesion and bilateral spastic
paresis below the level of the lesion. There is a dissociated sensory loss with bilateral loss of temperature and
pain below the level of the lesion but no loss of light
touch or vibration sensation (supplied by the posterior spinal arteries). Damage to the hypothalamospinal
(descending sympathetic pathway) tract at T1 or above
produces a bilateral Horner’s syndrome, and damage to
the parasympathetic centres at S2–S4 results in loss of
voluntary control of bladder and bowel function.
Amyotrophic lateral sclerosis
This is a chronic progressive disease of which approxi-
mately 90% of cases are sporadic (unknown aetiology),
whilst10%haveageneticcomponent(seeChapter 9, Box
9.7). Onset occurs in late middle age and is often fatal
within 2–6 years of onset, although a small minority of
people, such as Stephen Hawking, can survive well over
10 years from onset. It causes the death of both upper
and lower motor neurons, resulting in symptoms such
as muscle atrophy, weakness and fasciculation, spasticity
and Babinski signs. There are no sensory deficits.
Infective diseases: poliomyelitis and syphilis
Polio is an acute viral infection that destroys the lower
motor neurons of the spinal cord and brainstem, leading
to progressive paralysis and muscle wasting. The lower
limbs are more often affected than the upper limbs, and
in severe cases, respiratory function may be threatened.
The advent of immunization during the 1950s greatly
reduced the incidence of this disease; however, postpolio syndrome can occur in those patients who have
had the disease (see Chapter 9, Box 9.8). It is characterized by progressive weakness, fatigue and atrophy of
previously affected muscles. In tabes dorsalis (neurosyphilis), the large- diameter myelinated fibres are
affected. It results in chronic inflammation of the dorsal
roots and spinal ganglia, causing pain and paraesthesia
of affected dermatomes. The cells die, resulting in degeneration of the axons within the dorsal columns. The peak
incidence of the disease occurs 15–20 years after the initial infection. It is a purely sensory disease and results
in bilateral loss of discriminative sensation. If the gracile
fasciculus is affected, a positive Romberg sign, indicating
sensory ataxia, occurs.
Syringomyelia
This is a developmental abnormality that results in cavitation within the spinal cord around the central canal and is
common in the cervical spinal cord. Thus it interrupts the
STT bilaterally, resulting in loss of pain and temperature
sensation below the level of the lesion, particularly in the
hands. As the cavity enlarges, there is progressive bilateral flaccid paralysis as the lower motor neurons become
affected. Horner’s syndrome may become apparent if the
descending sympathetic fibres that run in the lateral white
matter are affected. Tactile discrimination, vibration and
conscious proprioception remain intact.
A similar pattern of damage is seen in the central
cord syndrome, which can be caused by whiplash injury
(hyperextension of the cervical cord region). The cord
is compressed by the vertebral body (on the anterior
aspect) and the ligamentum flavum (on the posterior
aspect), causing damage to the central part of the cord.
There is bilateral muscular atrophy and paralysis at the
site of injury and bilateral spastic paresis with a characteristic sacral sparing, as the sacral fibres of the CST
are located furthest laterally and are thus least affected.
The lower limbs are less affected than the upper limbs.
Similarly, there is bilateral loss of pain and temperature
sensation, again with sacral sparing, and a greater effect
in the upper than in the lower limbs.
Management of spinal cord injury and future therapies
Any patient suspected of having a cervical spinal injury
has their neck immobilized to prevent any potential bone
fragments from penetrating or compressing the cord and
causing further damage. Imaging of the cord and vertebral column is performed using X- rays, CT or MRI. The
84 SYSTEMS OF THE BODY
4
main aims of medical and surgical treatments in SCI
patients are to prevent further damage and limit the area
of secondary injury. Surgically, this can be achieved by
removing fragments of damaged bone, discs and ligaments to decompress the cord. Pharmacologically, early
administration of anti- inflammatory drugs appears beneficial by targeting the secondary effects of SCI (by reducing oedema, inflammation, glutamate release, and free
radical accumulation). Clinical trials showed that highdose steroids such as methylprednisolone were effective
in preserving motor function if given within 8 hours of
injury and continued for 48 hours, but their use remains
controversial in some countries. Other promising pharmacological compounds that target immune cells that
might be suitable for clinical trials are the tetracycline
antibiotic minocycline, the omega- 3 polyunsaturated
fatty acid docosahexaenoic acid and peroxisome proliferator activated receptor gamma (PPARγ) agonists. Indeed,
minocycline, when given within 12 hours and twice daily
for a week, improved ASIA scores over 3–12 months. The
other main treatment is rehabilitation medicine, which is
used to help the patient make the most of what residual
function they have left through functional retraining, and
to prevent medical complications from occurring that
often lead to re- hospitalization such as bladder infections, skin lesions and musculoskeletal problems.
Substantial progress has been made in understanding the cellular, genetic and molecular consequences
of SCI, their spatial and temporal profile and how
axons find their way to appropriate targets during normal development. Successful repair of SCI will involve
overcoming (hierarchical) obstacles in four main areas:
reducing cell death; promoting CNS axon regeneration
or enhancing plasticity of residual, spared neural circuits; remyelination of damaged and regenerating fibres;
and restoration of appropriate connectivity (Table 4.7).
Consequently, researchers are now translating some of
this knowledge to clinical trials. For example, the drug
fampridine (4- aminopyridine)—a K+ channel blocker
that restores action potential conduction in demyelinated fibres—reduced spasticity whilst increasing sensory
and motor functions in some patients in phase 3 trials.
Likewise, riluzole—a drug licenced for ALS—is in phase
II and III trials. Giving riluzole orally twice a day for 2
weeks after SCI showed beneficial effects in terms of
neurologic recovery, functional outcomes and quality of
life outcomes.
The CNS environment, unlike the PNS, is hostile to
regeneration because CNS neurons have a low intrinsic ability to regenerate and damage fails to stimulate
growth- promoting molecules. More importantly, the
damaged CNS is very inhibitory to axonal regeneration
because it produces molecules that cause growth cones
to collapse. One major source of the inhibition is myelin.
At least three inhibitory proteins are known to exist:
Nogo- A, myelin- associated glycoprotein and oligodendrocyte myelin glycoprotein. These molecules bind to a
common receptor complex comprising the Nogo receptor (NgR1) and the p75 low- affinity neurotrophic factor
Table 4.7 Strategies for spinal cord repair
Level of
difficulty Objective Technique
Low Neuroprotection Pharmacological, e.g.
methylprednisolone, glutamate
receptor antagonists, ion
channel blockers
Prevention of
demyelination
Preventing scar
formation
Suppression of
CNS inhibitory
molecules
Promoting axonal
regeneration
Provision of
permissive
environment
Replacement of
lost cells
High Appropriate re-
connectivity
Pharmacological, e.g.
4- aminopyridine
Targeting glial reaction, e.g.
enzyme digestion
Neutralizing antibodies,
vaccines, specific receptor
antagonists
Use of growth factors or
stimulation of intrinsic
growth potential
Cellular bridges, e.g. nerve
grafts, biodegradable
conduits, Schwann cells, glial
cell transplants
Stem cells
Ensure specific target
recognition
receptor, which activates the Rho signalling pathway to
mediate growth cone collapse. Antibodies to Nogo- A
have been shown in rodents to promote neuronal regeneration of the CST, both of injured and uninjured axons.
Blocking the Nogo- A protein using antibodies or the
NgR1 with drugs or decoy proteins (AXER 204) to trap
myelin-associated inhibitors have all been tested in nonhuman primate models of SCI. Nogo- A antibodies and
AXER 204 are now undergoing clinical trials for SCI.
Damage to the CNS produces a glial scar within a
few weeks of injury that appears to have two opposing
functions: to protect tissue and prevent repair. The scar
is now recognized as a complex structure formed of several cell types with different functions. It is well known
that the glial scar inhibits regeneration. Experimental
therapeutic strategies use pharmacological, genetic,
and surgical methods to reduce scar formation or block
inhibitory extracellular matrix molecules like chondroitin sulphate proteoglycans (CSGPGs), which induces
growth cone collapse. Enzymes that digest the CSPG
side chains promote CNS regeneration. Alternatively,
bridging of the scar region with biodegradable conduits
that can be seeded with various trophic factors or cells,
or nerve grafts, has provided limited regeneration across
the injury site.
Another more controversial approach involves transplantation of Schwann cells, olfactory ensheathing cells
(OECs), or neural progenitor or mesenchymal stem cells
into humans. Cellular transplantation for SCI has been
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85THE NERVOUS SYSTEM
4
tried over the past 30 years, initially using embryonic tissue to bridge the lesion site and act as a relay between
disconnected neurons. However, such approaches raised
important ethical questions such as the source of the
cells, delivery method, immunogenicity and control
of growth that have largely precluded their incorporation into clinical practice. The early studies, especially
with OECs, showed the feasibility of this methodology,
THE SPINAL CORD
as transplants were incorporated into the host tissue
and produced some functional benefit in rodent models.
OECs have been transplanted into human SCI patients
in Portugal, Australia, China and Poland, with variable
success in Poland and China, and it is unclear whether
the transplants are directly responsible for the improvements. Inducible pluripotent stem cells (iPSCs) may circumvent the ethical issues associated with embryonic/
foetal tissue use. Neural progenitor cells generated from
iPSCs showed beneficial effects after transplantation in
preclinical models of SCI, but it remains unclear whether
meaningful differentiation into neurons occurs or if they
only play a supportive role. A critical safety issue for the
use of iPSCs is the risk of tumorigenicity.
It is highly unlikely that a single therapy will successfully treat SCI and lead to recovery of function.
Multiple therapeutic approaches that target the different
aspects detailed in Table 4.7 will be needed in a progres-
sive and coordinated fashion to initiate, maintain, and
guide appropriate regeneration from the injury site and
to re- establish functional connections. Sadly, of 19 published clinical trials, none have translated into general
clinical practice, aside from those countries that offer it
as a form of medical tourism for non-validated therapies.
However, an alternative strategy currently showing clinical promise is the use of functional electrical stimulation
and brain computer interface (BCI) machines to recover
function. Major advances (and failures) in neurosurgery,
robotics, computational neuroscience and neuroengineering have populated SCI medicine with wearable
and implantable neurotechnologies to enable and augment function, such as speaking or moving paralysed
limbs via prosthetics. They share two common themes:
to capitalize on the intrinsic capacity of spared circuits to
produce movement, and their remarkable ability to reorganize with rehabilitation training to enhance recovery.
The next generation BCIs aim to re- establish bidirectional
communication between the brain and denervated body
parts using wireless technology and implantable (miniature) CNS/PNS devices that will provide significant
improvements in patient quality of life. SCI research has
moved on from making people walk again, as for most
SCI patients, walking is not at the top of their wish list
for progress. It is the absence of bowel and bladder control and hand use, and the levels of neuropathic pain
that emerge after injury, which control the quality of
their lives. There are drugs that control incontinence and
sexual dysfunction, pain and spasticity. For example, in
rehabilitation medicine, oral or intrathecal baclofen—a
GABAB receptor agonist—is used to reduce muscle spasticity by increasing general CNS inhibition via reduced
neurotransmitter release and motor neuron activity. It
also has effects on bladder function by decreasing hyperactive contracture of the external urethral sphincter.
Next- generation implantable wireless technologies offer
much hope for improving these adverse consequences
post- injury.
Comments on the case history
Humpty Dumpty suffered spinal cord damage resulting
in a Brown–Séquard syndrome. The level of the lesion is
at T10—the highest level of neurological deficit on the
right side. This syndrome results in dissociated sensory
loss below the level of the lesion due to damage to the
DCML and STT, and the Babinski sign is an indicator of
damage to the CST. Humpty Dumpty’s cord will not be
put back together again!
Self- assessment case study
While on holiday, a 17- year- old boy playing with some
friends dived off the rocks into the sea. He emerged
motionless, face down in the water. His friends immediately rescued him, and on returning to shore, applied
artificial resuscitation while the emergency services were
called. The boy was put in a neck brace and flown by air
ambulance to the nearest neurological trauma centre,
where he underwent a complete neurological assessment
and was sent for MRI. The MRI scan showed a complete
fracture dislocation at C4, which had severed the spinal
cord. The parents arrive and ask about his condition and
what the prognosis is.
After studying this chapter, you should be able to
answer the following questions:
1. Is it possible to give an accurate prognosis at this
stage?
No, because after a major traumatic injury, an initial
period of spinal shock sets in, whereby all physiological
function of the cord is severely depressed, and this may
last for up to 4 weeks after the initial injury. After this
period has elapsed, signs associated with damage to various neuronal structures and pathways become evident.
Depending on the exact nature of the injury, there may
be some recovery of function.
2. What are the consequences of the lesion in terms of
functional disability?
There is complete loss of all sensory, voluntary
movement and autonomic functions below the level
of the lesion. The patient is likely to be paraplegic with
impaired respiration requiring artificial ventilation
(due to damage to the phrenic nerve supplying the diaphragm). There is bilateral lower motoneuron paralysis
and atrophy of the C4 dermatome innervating the pos-
86 SYSTEMS OF THE BODY
4
terior neck and shoulder muscles and bilateral spastic
paresis and Babinski signs below the lesion, loss of bladder and bowel function and bilateral loss of all sensation
below the level of the neck. A bilateral Horner ’s syndrome will also be present.
3. What are the medical complications associated with
the scenario?
The patient will have no independence of life and will
require constant care. Medical complications that can
occur are: (1) bedsores over bony protuberances due to
loss of sensation and inability to move; (2) bladder infections due to loss of bladder reflex control mechanisms;
(3) muscle spasms due to loss of inhibitory control mechanisms leading to hyperactivity of gamma motoneurons
that control the muscle spindles; (4) spontaneous neuropathic pain that is of a burning or shooting quality due
to deafferentation of spinal cord neurons; and (5) nutritional deficiency due to the injury.
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87THE NERVOUS SYSTEM
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