PERINATOLOGY 41

Neonatal maladjustment syndrome: Its

NEONATAL maladjustment syndrome (Rossdale 1972) in phases of experimentation in mouse models (Hoppe, Tcrrell
foals has marked clinical similarities with the acute symptoms and Gottlieb 1984; Yusa, Crapo and Freeman 1984).
of hypoxic-ischaemic encephalopathy (Volpe 1987) in human One major problem in developing definitive treatments for
infants. Both conditions are characterised by seizures, abnor- neuronal salvage after a neonatal hypoxic-ischaemic insult is
mal or absent sucking reflexes, cortical blindness, muscle tone the difficulty of defining the severity of insult or even of
abnormalities and motor dysfunction. In both species, the syn- establishing a definite diagnosis of the neuropathology causing
drome evolves acutely for the first three or four days of life. In clinical signs. ‘Neonatal maladjustment syndrome’ and
survivors, the clinical signs stabilise, then gradually improve ‘hypoxic-ischaemic encephalopathy’ are both diagnoses that
over ensuing weeks. In foals, complete recovery is frequent, may be made when the real problem is something quite
and the long term prognosis for athletic competence appears to different. A broad spectrum of anatomical malformations,
be reasonably good (Baker, Drummond, Lane and Koterba congenital metabolic disorders (hypocalcaemia, hypog-
1986). In infants, and probably in foals, neurological outcome lycaemia or ‘inborn errors of metabolism’) and vascular
depends upon the severity of the initial insult and on quality of accidents can cause similar clinical signs in equine and human
the following resuscitation and after care. Moderately affected neonates (Adams and Mayhew 1985; Volpe 1987). Definitive
babies have a reasonable chance of complete neurological neurological diagnosis is exceedingly difficult in the early
recovery. More severely affected individuals are left with hours of life, because signs are often subtle and are frequently
sequelae, including seizure disorders, mental retardation, and obscured by generalised depression related to disease in other
motor dysfunction. Extremely severe perinatal hypoxic- organ systems. Available bedside tests such as neurological
ischaemic insults result in acute death o r evolve to existence in examination, spinal fluid analysis, and electroencephalog-
a life-long vegetative state. raphic recordings are non-specific in foals and infants, unless
The biochemical or pathophysiological evolution of post obvious bacterial meningitis is found. The predictive value of
natal brain dysfunction is poorly understood (Volpe 1987). these tests, as they are currently applied and interpreted, is
During the first 12 h after birth the human neonate, after a limited. Diagnostic specificity is extremely low.
period of initial depression, often appears remarkably normal, Newer techniques, permitting imaging of the brain, hold
though in a state frequently characterised as ‘hyper-alert’. The considerable promise for improving diagnostic accuracy
second phase of the process is heralded by the onset of (Rumak and Johnson 1984). Cranial ultrasound can be used at
seizures, and is associated with the development of cerebral the bedside in human neonatology, because a non-calcified
oedema. The vascular, cellular and biochemical processes that fontanelle allows a sonographic access point. Foals’ fontanelles
contribute to the changing clinical signs are largely unknown. are usually closed at birth and thus their brains are inaccessible
Definitive treatment to prevent or abort cellular destruction for ultrasonic imaging. Even in infants, the ultrasonic
after a hypoxic-ischaemic insult is theoretical and experimen- ‘window’ can image only the ventricles and basal structures.
tal. In human neonatology, ‘brain resuscitation’ measures have The cortex and subarachnoid spaces over the convexities of
not altered substantially since the begining of neonatal the brain cannot be seen. Cortical infarcts, oedema and
intensive care in the 1960s. Currently, accepted therapy in man subarachnoid haemorrhages cannot be diagnosed therefore by
and horses is directed toward control of energy-costly seizures, cranial ultrasound.
general respiratory, circulatory, metabolic and nutritional Newer techniques, such as computerised axial tomography
supportive measures (Adams and Mayhew 1985; Volpe 1987), (CT scans), require the patient to be moved to the scanner.
and fluid restriction to control cerebral oedema. Use of Because CTscans image the difference between tissue (water)
corticosteroids. mannitol, or barbiturate-induced coma have and fat (myelin) densities, the human neonatal cortex nor-
been proposed, and occasionally tried in individual human mally appears hazy and undifferentiated because of incom-
cases (Volpe 1987). No controlled, prospective study has yet plete myelination of cortical white matter. Even the normal
been published to ascertain the level of efficacy of either the human neonatal brain is frequently interpreted to be ‘oedemat-
commonly accepted, or the proposed, measures for neonatal ous’ by CT scan (Rumak and Johnson 1984). The CT scan can
brain resuscitation in any species. Definitive pharmacological find areas of acute haemorrhage, haemorrhagic infarcts and
treatments to abort or slow the post ischaemic necrotic process gross developmental o r structural abnormalities, such as lis-
are not available for use in man, and are only in the early sencephaly (developmental arrest of brain growth at an early
42 EQUINE VETERINARY JOURNAL SUPPLEMENT 5

foetal stage), prenatal vascular insults resulting in focal loss of (hypoxanthine and oxygen) are complete. The reaction prod-
brain (porencephalic cysts) andlor hydrocephalus. ucts include superoxide radical (07-1 which is directly tissue
The application of C T scanning to foal neurology may pro- toxic, and which stimulates the production of other, even more
vide a significant advance in pre-mortem differential diagnosis destructive reactive compounds, hydrogen peroxide and
of the neonatal maladjustment syndrome. Currently, this hydroxyl radical (HO.). Normally, protective enzymes
advance in the field of equine neonatal neurology awaits the (superoxide dismutase, catalase and glutathione peroxidase)
geographical proximity of a CTscanner and an equine neonatal clear these radical species as they are produced and lipid mem-
intensive care unit. Because the foal is born in an advanced branes, proteins, and nucleic acids remain intact. However, a
state of neurological maturation, and has much more complete massive burst of oxygen radical production during the reperfu-
cortical myelination than the human neonate (Volpe 1987; sion period may overwhelm the usual protective mechanisms.
Mayhew p28), the normal foal C T scan may be more clearly Cellular damage, as indexed by capillary leak of fluid and
disrupted when perinatal insults cause the development of proteins, organelle dysfunction, or development of cell death,
cerebral oedema. As yet, no report of application of CTscan- follows. Convincing evidence has emerged that post ischaemic
ning to either normal or neonatal maladjustment syndrome myocardial damage can be altered by scavenging oxygen- free
foals is available in the literature. radicals (Ambrosio et al1986; Przyklenk and Kloner 1986).
Two more functionally based imaging techniques are cur- Damage in the watershed areas (border zones between the
rently emerging from the research laboratories. Magnetic reso- end of fields of major arteries ) is the principal lesion following
nance imaging permits generation of precise functional and hypoxic ischaemic insults in full term human neonates (Volpe
anatomical pictures of internal soft structures, enabling very 1987). Unfortunately, experimental limitations have made it
precise diagnosis. The technique is limited by non-portability quite difficult to substantiate an important role for free radicals
of the magnetic imagers, and by the strong magnetic fields that in generating this distinctive damage pattern in the post
the processs generates. These magnetic fields preclude use of hypoxic-ischaemic brain (Siesjo, Rehncrona and Smith 1980;
metal restraint or support equipment within the imaging room. Korthuis and Granger 1986). If these pathways are shown to be
The magnetic resonance imaging scanners are large and very important in the neuronal cell collapse during the first 24 h
expensive. They have been available in human medicine for after birth, many ‘new’ therapeutic regimes may prove useful:
about five years. New generation scanners are beginning to use of allopurinol (a xanthine oxidase inhibitor), or mannitol
replace the initial equipment that was used in early human (a hydroxyl radical scavenger); limitation of overzealous deliv-
studies. Perhaps a fortunate veterinary centre will inherit a ery of extra oxygen; or infusion of exogenous radical scaveng-
magnetic resonance imaging scanner, and learn to use it for ing enzymes.
foal diagnosis. Thus, in the area of neonatal neurological dysfunction, the
Magnetic resonance spectroscopy permits detection of current state of the art is approximately equal in human and
organic and inorganic phosphate molecules in living tissues equine species. Both fields utilise empirical treatment, and
(Volpe 1987). In experimental settings, magnetic resonance ‘common sense’ support measures. Development and applica-
spectroscopy has been used to track the decay of phosphory- tion of the emerging diagnostic and therapeutic regimes out-
lated high energy compounds from adenosine triphosphate to lined above may herald a period of very rapid advance in under-
adenosine diphosphate to adenosine monophosphate to phos- standing appropriate measures for brain salvage. Equine
phate, during experimental hypoxic-ischaemic insults in ani- neonatologists have the advantage that their patients’ out-
mals (Delpy et a1 1982; Thulborn, du Boulay, Duchen and comes can be determined in six to 18 months, and that direct
Radda 1982) and in infants (Younkin et al 1984; Hope and experimentation on foals is theoretically possible. Human
Reynolds 1Y85). The technique as currently used is expensive, neonatologists currently have more available access to the
cannot be used in the presence of ferrous metal and requires a newly developing techniques for anatomical and functional
large area of tissue pathology (about 30 cm3). Such a requisite brain imaging. Perhaps on-going intellectual cross-fertilisation
sample volume exceeds the size of most infants’ infarcts, but between the two areas will provide impetus for rapid improve-
application to foals’ larger brains might be more reasonable. ment in understanding of the processes of brain injury and for
The equipment that magnetic spectroscopy requires is also development of treatments focussed on specific therapy to
bulky and non-portable. An even newer technique, positron alter those processes, before neuronal death supervenes.
emission tomography, permits measurements of blood flow,
cerebral metabolism, cerebral blood volume and biochemical References
function (Volpe 1987). This technique is limited by cost and
Adams, R. and Mayhew. I.G. (1985) Neurologic diseases in neonatal equine dis-
size of necessary equipment and by the need to transport the ease. Equine Practice Vet Clin. NorfhAm. 1, 209-223.
patient to the scanner. Ambrosio. G., Becker. L.C., Hutchins, G.M.. Weisman, H.F. and Weisfeldt,
The development of imaging techniques for non-invasive M.L. (1986) Reduction in experimental infarct size by recombinant human
study of evolving biochemical dysfunction at a cellular level superoxide dismutase; insights into the pathophysiology of reperfusion injury.
may permit research aimed at interrupting the pathological Circulafion 74, 1424-1433.
‘process’ after the inciting insult, but before neuron;, destruc- Baker, M.S., Drummond, W.H., Lane,T.J. and Koterba. A.M. (1986) Follow-up
study of equine neonatal intensive care. J . Am. vef. med. Assoc. 189, 1454-
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tion medicine and free radical biochemistry have developed Delpy. D.T.. Gordon. R.E.. Hope, P.L.. Parker. D.. Reynolds. E.O.R.. Shaw.
working theories of post-ischaemic cell death resulting, not D. and Whitehead, M.D. (1982) Noninvasive investigation of cerebral
from ischaemia per se, but from ‘reperfusion injury’. The cur- ischaemia by phosphorus nuclear magnetic resonance. Pediatrics. 70,310-313.
rently accepted working theory proposes that periods of Hope. P.L. and Reynolds, E.O.R. (1985) Investigation of cerebral energy
hypoxia and or ischaemia deplete high energy phosphate com- metabolism in newborn infants by phosphorus nuclear magnetic res~nance
spectroscopy. Clin. Perinafol. 12.261-275.
pounds. The final degradation product of adenosine triphos-
Hoppe. S.A.,Terrell, D.J.. and Gottlieh, S.F. (1984)The effect of allpurinol on
phate in man is hypoxanthine but species differences may exist. oxygen-induced seizures in mice. Aviar. Space. Environ. Med. 55,927-930.
Concomitantly with loss of oxidative phosphorylation, pro- Korthuia. R.J. and Granger, N.D. (1986) Ischaemia-reperfusion injury: role of
teolysis results in the production of the enzyme xanthine oxygen-derived free radicals. In: Physiology of Oxygen Radicals. Eds. A.E.
oxidase from xanthine dehydrogenase. When oxygen is returned Taylor. S. Metalon. and PA . Ward. American Physiological Society,
to the system, substrate requirements for xanthine oxidase Bethesda, Maryland p 240-241
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