Neonatal Neurology

Breda C. Hayes

Kalpathy S. Krishnamoorthy

Janet S. Soul

INTRACRANIAL HEMORRHAGE

Intra-axial Hemorrhage

Germinal Matrix/Periventricular-Intraventricular Hemorrhage (IVH)

Most common type of neonatal intracranial hemorrhage.

Incidence

Reported incidence in the preterm newborn ranges from 13% to 65%, but overall ˜20% to 25%.¹
- Risk of IVH correlates inversely with gestational age.
Varies among different hospitals and regions.
Newborns born to hypertensive mothers have a lower risk of IVH.²
Improvements in perinatal and neonatal care have led to a reduction in the overall incidence of IVH in the premature newborn; however, increased survival of the extremely premature newborn means that IVH remains a major source of mortality and morbidity in this population.
Incidence is much lower in term newborns than in preterm ones; the incidence of all types of intracranial hemorrhage in term newborns was 2.7/10,000 live births in one report.³^,⁴

Pathogenesis⁵

Intravascular Factors

Ischemia and reperfusion (e.g., following treatment of hypotension or hypovolemia)
Impaired cerebral autoregulation
Fluctuating cerebral blood flow
↑ Cerebral blood flow (e.g., due to hypercarbia, volume expansion)
↑ Cerebral venous pressure (e.g., with pneumothorax)
Coagulation abnormalities

Vascular Factors

Germinal matrix capillaries vulnerable to rupture: thin walls with large lumen
Arterial development immature: acute transition from large vessels to a capillary network without gradual arborization

Extravascular Factors

Increased fibrinolytic activity
Poor vascular support in cerebral tissue

Grading of IVH (per Volpe)⁵

Grade I: Hemorrhage confined to the germinal matrix.
Grade II: Hemorrhage within the lateral ventricle (10%-50% of ventricular area on sagittal view).
Grade III: Hemorrhage within the lateral ventricle (>50% of ventricular area or distends ventricle).
Periventricular hemorrhagic infarction (PHI)—parenchymal echodense lesion associated with large ipsilateral IVH; often referred to as Grade IV IVH.
- This venous infarction is caused by (usually) large IVH obstructing venous drainage of the periventricular white matter.

Management of IVH

Supportive care (including correction of coagulopathies, circulatory and respiratory support)
Daily monitoring of fontanelle and head circumference and serial head ultrasound (US) examinations in newborns with IVH ≥ Grade II to monitor for development of progressive ventricular dilation

Complications of IVH (Table 19.1)

Periventricular Hemorrhagic Infarction

As above, this is a complication of large IVH but is often referred to as Grade IV IVH.

Progressive Ventricular Dilation (PVD)/Posthemorrhagic Hydrocephalus

Occurs in 25% of preterm newborns.⁶
PVD usually caused by impaired reabsorption of the cerebrospinal fluid (CSF) by arachnoid villi.
Obstructive hydrocephalus rarely caused by obstruction of the aqueduct or foramen by clot.
PVD needs to be differentiated from stable ventricular dilation due to cerebral atrophy.

Death

Death may occur with catastrophic presentation of large bilateral IVH.
Mortality rate is higher in patients who develop PVD than in those without PVD.

Neurologic Sequelae in Survivors

There is a strong association between periventricular leukomalacia (PVL) and IVH. It is unknown to what degree the relationship is causal or whether the two entities develop in parallel because of common pathologic processes. There are data to suggest that IVH may exacerbate PVL, due to the presence of non-protein-bound iron in the CSF.⁷
The likelihood of later cerebral palsy, major neurosensory disability, and cognitive dysfunction increases with size of IVH, particularly with complications of PHI /or PVD.
PHI often results in mild, moderate, or severe hemiplegia.
Long-term cognitive impairments with school difficulties are frequent.
- Deficits in verbal learning and verbal memory particularly common.
- Subjects with IVH Grades III-IV score significantly lower than those with IVH Grades I-II in verbal learning, everyday memory, visuoconstructive and visuospatial abilities.
Sensory deficits (agnosia, tactile hypersensitivity, tactile hyposensitivity, dyspraxia) may also be associated with IVH.
Risk of visual impairments (strabismus, optic atrophy, retinopathy of prematurity) is increased in the presence of IVH, particularly with PHI.
PVD increases the likelihood of neurologic impairments and disabilities.
There are only a few small reports of neurologic sequelae of IVH with/without PVD in term newborns⁸^,⁹; alloimmune thrombocytopenia appears to be a poor prognostic factor (may be related to size of IVH).

TABLE 19.1 Complications of Intraventricular Hemorrhage (IVH) in the Preterm Newborn

Severity of IVH	Mortality (%)	Progressive Ventricular Dilatation (%)	Neurologic Sequelae (%)
Grade I	5	5	5
Grade II	10	20	15
Grade III	20	55	35
Periventricular hemorrhagic infarction	50	80	90

Management of PVD

Daily monitoring of head circumference, fontanelle, and serial head US examinations.
Approximately 38% of preterm newborns without treatment will have spontaneous arrest/and or resolution of PVD without treatment.⁶
Serial lumbar punctures (LPs) can be used to decrease ventricular volume ± increased intracranial pressure when there is evidence of rapidly progressive and/or persistent ventricular enlargement.
- Sufficient CSF should be removed to decrease ventricular volume and/or ICP (10-15 mL/kg body weight at each lumbar puncture).
- LPs should be continued until the ventricles stabilize or decrease in size on serial US studies or until surgical treatment deemed necessary and is feasible.
- Consider ventricular tap if LPs are unsuccessful (PVD may not be communicating).
Trials of fibrinolytics.
- Five randomized trials evaluated intraventricular administration of fibrinolytics in newborns with IVH and PVD, with no significant effect on rate of death or shunt dependence. Risks of treatment included meningitis and secondary IVH.
- A high-risk therapy called DRIFT (drainage, irrigation, and fibrinolytic therapy) was tested in an international randomized clinical trial. Although it did not significantly lower the need for shunt surgery, there was decreased mortality or risk of severe disability (54% vs. 71%) and decreased severe cognitive disability (31% vs. 59%) at 2 y.¹⁰ Due to high risks (e.g., secondary IVH), this therapy has not been widely adopted.

Intraparenchymal Hemorrhage

Intraparenchymal hemorrhage (IPH) refers to bleeding into the brain parenchyma.

Causes

Trauma (including nonaccidental trauma)
Coagulation abnormalities
Arteriovenous malformation (AVM), aneurysm, e.g., vein of Galen
Venous infarction
- Venous congestion or obstruction following large IVH.
- Venous congestion or obstruction following sinovenous thrombosis (SVT).

Neurologic Outcome

Depends on the location and size of parenchymal injury
Could include epilepsy and motor, cognitive, and/or sensory impairments

Extra-axial Hemorrhage

Subpial Hemorrhage (a type of subarachnoid hemorrhage—see below)

Hemorrhage between the pial layer and cortical surface, most often around temporal lobe.
Appears to be related to local trauma, e.g., with instrumented delivery.¹¹
On CT or MRI, appears as ribbon-like collections of blood following contours of gyri and sulci.
Seizures most frequent presenting sign, babies often otherwise well-appearing.

Subarachnoid Hemorrhage (SAH)

SAH is more commonly seen in conjugation with other types of intracranial hemorrhage, e.g., IVH, subdural hematoma, etc.
Primary SAH rarely leads to significant clinical signs unless large.
Small SAH may cause seizures in an otherwise well baby (see also subpial hemorrhage above).
Large SAH may result in hydrocephalus ± seizures.

Subdural Hematoma (SDH) & Epidural Hematoma

SDH and epidural hematoma most frequently related to trauma (e.g., birth trauma or nonaccidental injury) but epidural hematoma much less common.
Small SDH related to birth: common and inconsequential.
Rare causes of SDH are coagulation abnormalities and glutaric aciduria type 1.
Both large SDH and epidural hematoma may present with signs of raised intracranial pressure.
- Lethargy, vomiting, bulging fontanel, increased head size, highpitched cry, irritability, feeding difficulties, seizures, or loss of consciousness.
Characterized based on size, location, and age (i.e., acute, subacute, or chronic).
Early surgical evacuation may be lifesaving for large hematomas with signs of raised intracranial pressure and significant neurologic compromise.
Size, location, and age of SDH/epidural hematoma as well as the neurologic and medical condition of the patient determine the course of treatment and outcome.

Subgaleal Hematoma (SGH)

Prevalence of moderate-to-severe SGH is ˜1.5 per 10,000 births.¹²
SGH may form because of preexisting risk factors (e.g., coagulopathy).
Vacuum extraction predisposes a newborn toward subgaleal hemorrhage.
SGH must be considered in any newborn with a scalp swelling and a falling hematocrit.
In term babies, this subaponeurotic space may hold as much as 260 mL of blood.
Death can result from exsanguination and hypovolemic shock, caused by massive bleeding into the subgaleal space.
Close monitoring of vital signs, level of consciousness, hematocrit, blood gases, head circumference, and signs of tissue hypoperfusion is recommended.
Coagulation studies should be performed in all newborns with a diagnosis of SGH.

Cephalohematoma

Very common, usually does not require treatment or diagnostic testing.
Collection of blood beneath the periosteum.
Limited by suture lines (if no associated skull fracture).
Due to sliding/tearing forces during the birth process.
More common with forceps and vacuum extraction.
Generally benign, but if large, may exacerbate jaundice.
Takes weeks to months to resolve (outer edges may calcify, so center may resolve initially, leaving a “crater”-like appearance).
Large cephalohematomas may occur with coagulation abnormalities (vitamin K deficiency, factor 8 deficiency, etc.).

ENCEPHALOPATHY OF PREMATURITY/WHITE MATTER INJURY/PVL

Classical PVL consists of focal necrotic lesions and surrounding areas of gliosis, with cyst formation detectable typically 2 to 4 wk after birth.
Recent MRI studies have demonstrated a more diffuse form of non-cystic white matter injury.¹³
Both cystic and non-cystic forms are usually bilateral and symmetric.
Histology shows microglial activation and loss of premyelinating oligodendrocytes.
The periventricular white matter dorsolateral to the trigones and frontal horns of the lateral ventricles are areas most commonly affected by PVL.
Recent MRI and neuropathology studies strongly suggest that cerebral neuronal structures, as well as cerebellum, are also frequently injured.¹⁴^,¹⁵
Gray matter injury may reflect damage to subplate neurons, which appears early in cortical development and directs projections of afferent and efferent thalamocortical neurons.¹⁶
Diffuse loss of brain tissue in PVL results in ventriculomegaly, enlarged extra-axial CSF spaces, and immature gyral development.

Incidence

The reported incidence of cystic PVL has decreased over the past several years to ˜5% of very low birth weight newborns.
Diffuse non-cystic PVL is now recognized as the most common form of brain injury in preterm newborns; MRI studies at term show an incidence of up to 70%.¹⁷

Pathophysiology

Hypoxia, ischemia, and inflammation may all injure oligodendrocyte progenitor cells (preOL) in the periventricular white matter.

Hypoxia-ischemia
- “Border zone” in the white matter between penetrating cortical arteries and deep lenticulostriate arteries is susceptible to ischemia during periods of hypotension.
- Hypocarbia (a potent vasoconstrictor) is independently associated with PVL.¹⁸
Inflammation
- Free radical formation associated with hypoxia-ischemia and breakdown of red blood cells, e.g., with an associated IVH.
- Infection: PVL associated with premature rupture of membranes, maternal chorioamnionitis, postnatal infection, neonatal surgery, and necrotizing enterocolitis.

Diagnosis

Cranial US remains the preferred method of screening for and monitoring PVL due to safety, availability of bedside US, and reduced access, cost, and difficulty of performing MRI.
MRI, especially DTI, is more sensitive than US in detecting diffuse PVL.¹⁹ However, detection of more subtle PVL rarely alters management as all infants born preterm should receive close developmental follow-up and developmental services as indicated by physical findings and developmental progress.
Cystic PVL may be seen in the first postnatal week; however, cysts usually appear 2 to 4 wk after birth and are easily detected by US.
Diffuse PVL.
- Identified on cranial US or MRI by ex vacuo dilation of the ventricles (often associated with an abnormal shape of the lateral ventricles) and enlarged extra-axial spaces.
- The importance of diffuse excessive high signal intensity (DEHSI) is unclear.
  - Because of its high incidence in preterm newborns at term age, its absence after postmenstrual age of 50 weeks, and the sometimes normal neurologic outcome at a corrected age of 2 y, DEHSI may not be part of the spectrum of white matter injury, but rather a prematurity-related developmental phenomenon.²⁰
Punctate white matter lesions appear to be another form of white matter injury, but the neuropathology and clinical significance are currently unclear.¹⁹^,²¹
Recommended screening protocols suggest an initial cranial US within 3 to 5 d after birth, repeated at 7 to 10 & ˜30 days of age, and at 36-wk corrected gestational age and/or pre-discharge or term age equivalent.

Outcome—Encephalopathy of Prematurity

Depends on the severity and extent of PVL; however, rates of cognitive impairments, cerebral palsy or milder motor impairments, and visual perceptual or other sensory dysfunction are high.
Cystic PVL tends to damage more medial fiber tracts that control lower extremity function, leading to spastic diplegia, where upper extremity spasticity/dysfunction is less severe.
Extensive white matter involvement may result in quadriplegia and include facial weakness.
High incidence of subsequent cognitive deficits without prominent motor deficits may be explained in part by a reduction in the density of cerebral cortical neurons overlying areas of PVL.¹⁴
Cognitive and/or behavioral deficits may be very specific, such as visuomotor and perceptual disabilities, constructional dyspraxia, or attention-deficit disorders.
Attention deficits and impaired working memory may be associated with injury to the mediodorsal and reticular thalamic nuclei.¹⁵
Visual impairments: children with PVL may have visual perception difficulties or, with severe PVL, bilateral inferior visual field deficit.
Punctate white matter lesions and ventricular dilatation are significantly associated with cognitive and psychomotor developmental delay, motor delay, and cerebral palsy.²⁰

NEONATAL ENCEPHALOPATHY

Etiology

Intrapartum asphyxia with resultant hypoxic-ischemic encephalopathy
Infection
Drug exposure
Perinatal arterial ischemic stroke
Metabolic or other genetic disorders
Brain malformation, epileptic encephalopathy

The clinical history will determine the need for investigation to exclude these disorders.

TABLE 19.2 Distinguishing Features of the Three Clinical Stages of Hypoxic-Ischemic Encephalopathy in the Full-Term Newborn

@@	Stage 1	Stage 2	Stage 3
Level of consciousness	Hyperalert	Lethargic or obtunded	Stuporous
Neuromuscular control
Muscle tone	Normal	Mild hypotonia	Flaccid
Posture	Mild distal flexion	Strong distal flexion	Intermittent decerebration
Stretch reflexes	Overactive	Overactive	Decreased or absent
Segmental myoclonus	Present	Present	Absent
Complex reflexes
Suck	Weak	Weak or absent	Absent
Moro	Strong: low threshold	Weak, incomplete, high threshold	Absent
Oculovestibular	Normal	Overactive	Weak or absent
Tonic neck	Slight	Strong	Absent
Autonomic function	Generalized sympathetic	Generalized parasympathetic	Both systems depressed
Pupils	Mydriasis	Miosis	Variable; often unequal; poor light reflex
Heart rate	Tachycardia	Bradycardia	Variable
Bronchial and salivary secretions	Sparse	Profuse	Variable
Gastrointestinal motility	Normal or decreased	Increased; diarrhea	Variable
Seizures	None	Common; focal or multifocal	Uncommon (excluding decerebration)
Electroencephalogram findings	Normal (awake)	Early: low-voltage continuous delta and theta	Early: periodic pattern with isopotential phases
		Later: periodic pattern (awake)	Later: totally isopotential
		Seizures: focal 1-1½-hz spike-and-wave
Duration	<24 h	2-14 d	Hours to weeks
Sarnat HB, Sarnat MS. Neonatal encephalopathy following fetal distress. A clinical and electroencephalographic study. Arch Neurol. 1976;33(10):696-705.