Disorders of the Nervous System

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101 Disorders of the Nervous System

Ryan J. Felling, David A. Munson

The neonatal period is an important time for development of the nervous system. Interruption of normal development through disease or injury often leads to permanent neurologic sequelae. As our ability to care for critically ill neonates improves, neurologic disorders continue to be a significant cause of morbidity and mortality. It is crucial to identify neonates at risk for neurologic disorders through careful history taking and physical examination so that problems can be prevented or treated early.

Etiology and Pathogenesis

Hypoxic-Ischemic Encephalopathy

With dramatic advances in neonatal critical care, hypoxic-ischemic encephalopathy (HIE) has emerged as the primary cause of neurologic morbidity in the newborn period. This injury can occur both in premature neonates and term neonates. HIE is a consequence of poor delivery of oxygen to the brain, with hypoperfusion and ischemia likely being the most important mechanism. Much of the injury actually occurs during reperfusion of the ischemic brain. HIE can result from any mechanism that results in poor blood flow to the fetal brain in utero including chorioamnionitis, placental abruption, nuchal cord, and chronic maternal hypertension. It can also occur in the setting of severe postnatal cardiorespiratory compromise, including respiratory or cardiac arrest. In premature neonates, it is often associated with intraventricular hemorrhage (IVH).

Intraventricular Hemorrhage

Although the premature cerebrovasculature has reasonable capacity for autoregulation within the normal range of blood pressure, this mechanism quickly becomes inadequate as blood pressures fluctuate outside the norm, predisposing the brain to ischemic injury during times of hypotension and hemorrhagic injury during times of hypertension. The periventricular germinal matrix of the premature brain is at high risk for hemorrhagic injury because of the presence of a rich but relatively immature capillary network. This region is particularly critical because it harbors the neural stem and progenitor cell population that provides precursors necessary for future myelination and development of the brain. Figure 101-1 demonstrates patterns of hemorrhagic injury that can occur in both premature and term infants.

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Figure 101-1 Intracranial hemorrhage in a newborn.

Neonatal Seizures

Neonatal seizures are often a manifestation of underlying neurologic disease or injury (Table 101-1). In each case, the metabolic or structural abnormalities cause disorganized electrical activity that can lead to epileptogenic foci.

Table 101-1 Common Causes of Neonatal Seizures

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Neonatal Hypotonia

Hypotonia is a common sign of neurologic disease in newborns that can be caused by dysfunction anywhere along the neuromuscular axis. These may arise from genetic defects causing protein dysfunction in either nerve or muscle cells, loss of cerebral regulation of tone secondary to global central nervous system (CNS) dysfunction as in many chromosomal disorders or injuries, or disturbed signal transmission at the neuromuscular junction. The more common causes of hypotonia can be organized by the location of the primary defect (Figure 101-2).

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Figure 101-2 Primary sites of motor disorders.

Clinical Presentation

Hypoxic-Ischemic Encephalopathy

In his classic text, Volpe describes a “neurologic syndrome” that summarizes an infant who has sustained a hypoxic-ischemic insult to the brain. In severe cases, the infant progresses through several clinical phases. During the first 6 to 12 hours, the baby will have depressed consciousness and may even be comatose. This time is often characterized by apnea or periodic breathing and minimal movement, but the patient usually has intact pupillary and oculomotor reflexes. Seizures commonly occur during this initial period. The next 12 to 24 hours are often characterized by apparent clinical improvement. The newborn may appear more alert. Jitteriness is common and may be misinterpreted as seizures, although a considerable number of patients also develop true seizures during this time window. The apparent improvement is likely a consequence of excitatory neurotransmitter cascades that are characteristic of this phase of reperfusion injury. The next 24 to 72 hours often see a return of stupor or coma; respiratory failure; and more significant loss of central reflexes, including oculomotor disturbances.

Intraventricular Hemorrhage

In a premature baby in the first few days of life, acute IVH may be characterized by subtle signs such as new-onset apnea or decreased activity. However, a catastrophic bleed may make itself evident by a dramatic change in mental status along with cardiovascular collapse. If enough blood is lost into the brain, the baby may become anemic and develop severe hypotension and respiratory failure. Metabolic acidosis may become refractory to therapy if systemic perfusion is inadequate because of anemia and hypotension. Hydrocephalus is a common consequence of IVH as the blood obstructs the flow of cerebrospinal fluid (CSF). This manifests clinically as increasing head circumference, which may develop acutely or slowly depending on the size of the hemorrhage.

Neonatal Seizures

The newborn brain remains immature, particularly with regard to myelination. This immature anatomic organization makes neonatal seizures difficult to recognize and classify and often presents problems in selecting therapy and gauging efficacy. The fact that normal newborn infants often exhibit unusual movements confounds the diagnosis of neonatal seizures. With these difficulties, neonatal seizures often experience a paradoxical combination of overdiagnosis and underdiagnosis.

Neonatal seizures have a variety of manifestations and a variety of normal mimics (Box 101-1). Clonic seizures can occur either focally or multifocally and are repetitive high-amplitude, low-frequency jerking movements. Tonic seizures are constant stiffening of a portion of the body and may be focal or generalized. Myoclonic seizures include sudden extension or flexion of part of the body. Subtle seizures encompass other small abnormal movements that do not fit into the previously listed seizure types, including eye deviation, lip smacking, and tongue thrusting, among others. Subtle seizures and generalized tonic seizures often do not have electroencephalographic (EEG) correlates and are thought to emanate from deeper subcortical brain regions, a theory supported by animal studies.

Box 101-1 Appearance of Neonatal Seizures

Neonatal Seizure Classification

• Clonic

• Focal
• Multifocal

• Tonic

• Focal

• Generalized

• Myoclonic
• Subtle

Neonatal Seizure Mimics

• Jitteriness
• Benign myoclonus
• Opisthotonus
• Apnea

Several other unusual movements frequently seen in newborns must be considered in the differential diagnosis of seizures. These may occur in normal infants or may suggest other underlying disease. Jitteriness is a hypersensitivity to stimulus and may be suggestive of underlying abnormalities such as drug withdrawal; hypoxic-ischemic injury; or metabolic disease, particularly hypoglycemia. Benign myoclonus is a sudden, brief, jerking movement of the extremities that occurs during sleep in many normal infants. Opisthotonus is a tonic stiffening of the body, often resulting in arching of the back and neck. This is a common finding associated with gastroesophageal reflux (Sandifer’s syndrome). Neonatal apnea may or may not be associated with seizures, but it is frequently an independent clinical event in premature infants.

Neonatal Hypotonia

Hypotonia is a cardinal sign associated with many neurologic abnormalities that is characterized by decreased resistance of muscle to passive stretch. Hypotonia presenting in the newborn period has a similar clinical appearance regardless of where along the neuromuscular axis the disease originates. Figure 101-3 shows the characteristic appearance of hypotonic infants. These infants often appear in a frog leg posture with hips abducted and knees flexed when lying supine. Spontaneous movements are decreased compared with their healthy counterparts. Useful physical examination maneuvers to test for hypotonia are traction and prone suspension (Figure 101-4). With traction, a healthy full-term infant should demonstrate flexion at the shoulders and elbows and should be able to slightly flex the neck to keep the head in line with the body as it is brought up. Hypotonic infants show no flexion of the upper extremities, and their head fall to full extension as they are lifted. Similarly, in prone suspension, a healthy infant should show flexion of the extremities and some neck extension in an effort to maintain a horizontal position. Hypotonic infants lie draped over the examiner’s hand.

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Figure 101-3 Clinical presentation of neonatal hypotonia.

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Figure 101-4 Floppy infant.

Depending on the severity and duration of hypotonia in utero, neonates may have significant compromise at birth. Chest wall abnormalities caused by a lack of muscle tone necessary to keep the thoracic cavity expanded are frequently accompanied by respiratory distress. Infants with neuromuscular disease can also exhibit difficulty feeding because of a combination of easy fatigue and poorly coordinated suck and swallow function. This can also impede the body’s natural airway protection, leading to an inability to clear secretions and potentially aspiration. As hypotonia progresses and becomes more prolonged, musculoskeletal contractures may occur.

Evaluation and Management

Neurologic Assessment

History and Physical Examination

Many neurologic disorders share a common set of symptoms in the neonatal period; therefore, the tools for evaluating these infants are discussed here collectively. A thorough history and physical examination should always be the initial investigation into an infant with neurologic disease. The history should encompass the pregnancy, including gestational age and the results of any prenatal testing. Details of any previous pregnancies are also helpful. Frequent pregnancy losses could suggest the presence of an underlying genetic abnormality or a hypercoagulable disorder that may cause placental insufficiency. The neurologic examination of a neonate is an art that requires practice; however, numerous studies have demonstrated its value for both localization of pathology and prognosis. The clinician should always measure the head circumference and examine the fontanelles, sutures, and general shape of the head. Molding of the skull, overlapping sutures, and extracranial hemorrhages including caput succedaneum and cephalohematomas are common abnormalities but do not portend underlying brain anomalies. A tense fontanelle and widely patent sutures are suggestive of hydrocephalus or infection. Testing of cranial nerves should focus on pupillary responses, extraocular movements, sucking, and swallowing. The motor examination includes assessment of overall tone and spontaneous movements as well as primitive reflexes, including the Moro, grasp, and asymmetric tonic neck reflex. All three reflexes should be present by 28 weeks of gestation but become stronger as the infant nears term. The sensory examination should describe the type of stimulus and characterize the response. For example, whereas flexion of an extremity to a painful stimulus may be a reflex response, crying and specific withdrawal to such stimulus indicate intact cortical processing of pain.

Details obtained from the history and physical examination can help prioritize the use of adjunctive studies to determine the underlying cause of the disease. For example, whereas a history of fetal depression in utero might indicate HIE as the source of symptoms, a normal pregnancy with a particularly difficult delivery could suggest the possibility of an intracranial hemorrhage. Dysmorphic features often raise concern for a genetic syndrome that may involve structural brain anomalies.

Electroencephalography

As discussed in the Clinical Presentation section, neonatal seizures are difficult to identify and thus present a diagnostic dilemma for clinicians. A critical tool in the evaluation of suspected seizures is EEG. EEGs measure electrical activity between electrodes placed in an array over the scalp. These can be combined with video monitoring to correlate the brain’s electrical activity with the clinical presentation of the patient. This is an indispensable tool for distinguishing seizure activity from other nonepileptic movements and for quantifying seizure activity. EEG can also identify particular brain regions that are prone to epileptic activity. Certain types of epilepsy exhibit characteristic patterns on EEG. Examples of this include burst-suppression in Ohtahara’s syndrome and hypsarrhythmia in infantile spasms.

Lumbar Puncture

Analysis of the CSF is an important test for several reasons. Sepsis must always be near the top of the differential diagnosis list for ill neonates. Meningitis is indicated by a pleocytosis in the CSF, and culture of the CSF can help to identify a pathogen and direct antimicrobial therapy. Furthermore, blood in the CSF that does not clear can demonstrate the presence of a subarachnoid hemorrhage. Other CSF measurements can also be helpful. A significantly low glucose relative to serum glucose level may be indicative of GLUT-1 (glucose transporter protein type 1) transporter deficiency, and an elevated lactate level could suggest metabolic disease or indicate the presence of hypoxic-ischemic injury to the brain.

Neuroimaging

Neuroimaging offers many modalities that are of use in assessing the neonatal brain. Ultrasound is a readily available tool that can identify the presence of hemorrhage in the neonatal brain; however, it provides relatively poor anatomic definition. Magnetic resonance imaging (MRI) has become more common in the neonatal neurologic assessment. This modality provides excellent anatomic resolution and more precisely defines the location of pathologic lesions. Furthermore, it can provide metabolic information through the use of MR spectroscopy and vascular anatomy with MR angiography or venography. The ability to use MRI can be limited by availability and the clinical stability of the patient; however, ultrasound can be easily performed at the bedside. Computed tomography is rarely used in neonates because of the increasing availability of MRI, the ease of ultrasound, and the risks associated with radiation exposure to the newborn brain.

Additional Testing

Many additional studies are helpful in the diagnosis of neurologic disorders but are less commonly used. These are particularly relevant to infants with seizures or hypotonia of uncertain etiology. Genetic and metabolic studies can help identify inherited disorders. The proliferation of gene array studies has been helpful in this regard, although if specific disorders are suspected, targeted gene studies are more helpful. Typical metabolic screening tests include plasma amino acids, lactate, pyruvate, and urine organic acids. CSF can also be analyzed with these studies. Nerve conduction studies and electromyography can be performed to help localize the source of hypotonia. Finally, nerve and muscle biopsies can be helpful to identify particular myopathies and metabolic disorders.

Management

Hypoxic-Ischemic Encephalopathy

Early identification of neonates at risk for HIE is important to optimize management. One of the more recent advances that has shown promise in term infants with HIE is hypothermia. Hypothermia reduces the cerebral metabolic demand and may interrupt the excitatory cascade contributing to brain injury in the 72 hours that follow the inciting event. Several trials have demonstrated beneficial outcomes of this therapy, and large centers throughout the world are continuing to evaluate its efficacy. Other management issues focus on addressing the comorbidities associated with HIE. Seizure management may provide protection against further injury by reducing metabolic demand (excitotoxic injury) and preserving oxygenation of the brain.

Intraventricular Hemorrhage

Little can be done to help a baby after significant IVH has occurred, so prevention is the mainstay. Limiting fluid boluses and carefully adjusting medications to maintain normal blood pressure may help in this regard. The use of prophylactic indomethacin for closure of patent ductus arteriosus in the smallest babies (those <1000 g) has been shown to decrease the rate of severe IVH. Its use remains controversial, however, because this decrease has not yet correlated to improved long-term outcome.

If a baby does develop IVH, acute management is focused on supporting the baby through the cardiovascular collapse. If the patient survives, he must be monitored closely for the development of hydrocephalus over the ensuing weeks. This is routinely done through serial head circumference measurements and intermittent cranial ultrasound. In severe cases of hydrocephalus, neurosurgical intervention may be required through placement of a ventricular shunt to divert the flow of CSF. Babies who have had severe IVH are at significant risk for neurodevelopmental impairment, so long-term follow-up is necessary. Supportive services such as physical therapy, occupational therapy, and speech therapy are invaluable in terms of maximizing the patient’s future functionality.

Neonatal Seizures

Although the field of epilepsy overall has robustly expanded its armament of therapeutics, the treatment of neonatal seizures has been comparatively slow to evolve. The difficulty of accurately identifying neonatal seizures and the risk associated with many antiepileptic medications fueled controversy in the past regarding how aggressive clinicians should be in treating neonatal seizures. Accumulating evidence suggests, however, that repeated seizures in the neonatal period are independently associated with poor neurologic outcomes. These data and the tremendous improvements in neonatal care warrant early therapy.

Treatment of neonatal seizures should always focus on correction of the underlying etiology if possible. Transient metabolic disturbances should be addressed specifically. In the absence of such abnormalities, phenobarbital continues to be the mainstay of treatment for neonatal seizures by both neonatologists and neurologists. Second-line agents include phenytoin (or its preferred precursor fosphenytoin) and benzodiazepines, with lorazepam being the most common medication chosen from the latter class. Typical doses are listed in Table 101-2. The most significant risks associated with these drugs are sedation, respiratory depression, and hypotension, and neonates should be monitored closely during initiation these therapies. Clearance of these drugs from the neonatal system is notoriously variable, and infants must be closely monitored for signs of toxicity with clinical observation and drug levels.

Table 101-2 Intravenous Dosages of Common Antiepileptics in Neonates

  Loading Dose Maintenance Dose
Phenobarbital 20 mg/kg 3–4 mg/kg/day divided BID
Fosphenytoin 20 mg/kg 3–4 mg/kg/day divided BID
Lorazepam 0.05 mg/kg repeated loading as needed

BID, twice a day.

The use of traditional antiepileptics provides moderate control of seizures at best, and given concerns regarding the effect of these medications on the developing brain, it is essential to develop more effective treatments. Newer antiepileptics are available, but data on their safety and effectiveness in neonates are scarce. In animal models, several of these, including topiramate and levetiracetam, appear to have fewer detrimental effects on the CNS than the traditional antiepileptics, but further investigation is necessary. It is also important to consider some of the rarer causes of refractory seizures in neonates, particularly if there are no identifiable risk factors. Some of these children may respond to alternative therapies such as pyridoxine or the ketogenic diet, although in-depth discussion of these topics is beyond the scope of this text.

Neonatal Hypotonia

The treatment of neonatal hypotonia generally involves managing the comorbidities associated with the underlying disease. Ventilatory support is sometimes required and generally infers a poor prognosis. Nutritional support through tube feeding while continuing to encourage oral feeding is a necessity. Physical therapy is also an essential component of management to improve strength and feeding ability and to prevent contractures. Although clinicians can offer only supportive care for the vast majority of neuromuscular disorders of infancy, several diseases have specific treatment and therefore warrant mention here. The first is transient neonatal myasthenia gravis, which can be treated with neostigmine (0.05–0.1 mg/kg intramuscularly before feeding). Patients with congenital myasthenic syndromes can benefit from different therapies depending on the underlying defect (acetylcholinesterase inhibitors, 3,4-diaminopyridine, and acetylcholine receptor blockers). Finally, patients with disorders with evidence of neuropathy may benefit from steroid treatment (prednisone 2 mg/kg/d divided twice daily).

Future Directions

Basic science has provided extraordinary information regarding the nervous system in recent decades, and clinicians have seen tremendous benefit in terms of diagnostic potential. Much of this information, however, has yet to be translated into therapeutic interventions. Clearly, clinical studies of newer antiepileptics in newborns are necessary to improve the management of patients with seizures. Neuroprotection is another active area of research, and further understanding will help identify strategies to reduce morbidity and mortality associated with neurologic injury. Regenerative medicine is a rapidly developing area as well, and research on neural stem cell physiology will hopefully yield therapies targeted to improve development after neurologic injury. Genetic medicine also holds promise for inherited disorders such as spinal muscular atrophy in which the underlying genetic defects have been identified.

Suggested Readings

Aranda JV, Thomas R. Systematic review: intravenous Ibuprofen in preterm newborns. Semin Perinatol. 2006;30(3):114-120.

Booth D, Evans DJ: Anticonvulsants for neonates with seizures. Cochrane Database Syst Rev (4):CD004218. 2004.

Fenichel GM. Clinical Pediatric Neurology—A Signs and Symptoms Approach, ed 5. Philadelphia: Elsevier; 2005.

Glass HC, Glidden D, Jeremy RJ, et al. Clinical neonatal seizures are independently associated with outcome in infants at risk for hypoxic-ischemic brain injury. J Pediatr. 2009;155(3):318-323.

Jacobs S, Hunt R, Tarnow-Mordi W, et al: Cooling for newborns with hypoxic ischaemic encephalopathy. Cochrane Database Syst Rev (4):CD003311, 2007.

Painter MJ, Scher MS, Stein AD, et al. Phenobarbital compared with phenytoin for the treatment of neonatal seizures. N Engl J Med. 1999;341(7):485-489.

Schmidt B, Davis P, Moddemann D, et al. Long-term effects of indomethacin prophylaxis in extremely-low-birth-weight infants. N Engl J Med. 2001;344(26):1966-1972.

Volpe JJL. Neurology of the Newborn, ed 5. Philadelphia: Elsevier Saunders; 2008.

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