Isolated idiopathic hypomagnesemia presenting as aphasia and seizures

Isolated hypomagnesemia of the idiopathic form is a rare condition that is known to present as generalized motor seizures in children. This report describes a 4-year-old African-American male who presented with a predominant symptom of sudden onset aphasia and no clear initial motor seizure activity. An evaluation revealed an isolated and severe hypomagnesemia (initial serum magnesium levels <1.0 mg/dL) and inappropriate renal handling of magnesium (fractional excretion of magnesium >40% under conditions of hypomagnesemia). The child had subsequent generalized tonic-clonic seizures that were brought under control with valproic acid therapy and magnesium supplementation. Six months after the diagnosis, he had regained 50-60% of his speech and had no further staring spells or motor seizure activity after the initial episode. Isolated and idiopathic hypomagnesemia caused by defective renal reabsorption of magnesium is a rare familial condition with variable inheritance. Aphasia as the solitary presenting symptom has not been described before. The exact pathophysiology of hypomagnesemic aphasia and seizures is not known but may relate to disinhibition of specific types of glutamate receptors. In the present case, neuronal depolarization may have been localized to language areas in the temporal lobes.     

Neonatal seizures

In childhood, the risk for seizures is greatest in the neonatal period. Currently used therapies have limited efficacy. Although the treatment of neonatal seizures has not significantly changed in the past several decades, there has been substantial progress in understanding developmental mechanisms that influence seizure generation and responsiveness to anticonvulsants. This review includes an overview of current approaches to the diagnosis and treatment of neonatal seizures, identifies some of the critical factors that have limited progress, and highlights recent insights about the pathophysiology of neonatal seizures that may provide the foundation for better treatment.     

Neonatal cocaine-related seizures

Cocaine abuse is associated with a variety of severe acute neurologic complications typically occurring in the abusers themselves. These include ischemic stroke, subarachnoid and intraparenchymal hemorrhage, headaches, syncope, seizures, and death. Sixteen pediatric patients with presumed cocaine-related seizures secondary to maternal consumption are reported. They were evaluated only because of requests for neurologic consultation. All were seen during the 1987 calendar year at the King/Drew Medical Center and Urban Comprehensive Epilepsy Program of Los Angeles. The cohort had similar maternal pregnancy histories and uniformly presented with postdelivery tremulousness, irritability, and excessive startle responses. Shortly after birth, each patient began having stereotypic episodes with ictal electroencephalographic confirmation in seven. Eight of these neonates continued to have seizures after the initial month of life.     

Neonatal seizures and brain damage

There are four unresolved clinical issues at bedside with respect to the recognition, differential diagnosis, prognosis, and treatment of infants who present with seizures. There is also an overriding fifth question which bridges these four clinical issues, based on a laboratory researcher's perspective at the “bench”. Given the increasing understanding of the neurobiologic and pathophysiologic explanations for seizures in animal models, one must consider the question of whether neonatal seizures cause brain injury or are a surrogate of injury resulting from other etiologies.     

Neonatal seizures and their treatment

PURPOSE OF REVIEW: Neonatal seizures continue to present a diagnostic and therapeutic challenge to paediatricians worldwide, and are a worrying sign for both parents and clinicians alike. The present review summarizes recent evidence regarding the diagnosis, aetiology and treatment of neonatal seizures. It is timely because there is new evidence that seizures are damaging to the neonatal brain, and because prolonged electroencephalographic recordings during treatment have provided information that challenges established treatment regimens. RECENT FINDINGS: Neonatal seizures can permanently disrupt neuronal development, induce synaptic reorganization, alter plasticity and "prime" the brain to increased damage from seizures later in life. Phenobarbitone remains the mainstay of treatment and is effective in about one-third of cases; babies who respond tend to have a smaller seizure burden and a relatively normal background electroencephalogram. Their prognosis is better than in those who require second-line treatments. Phenytoin and lignocaine (membrane stabilizing drugs) are probably more effective than any of the benzodiazepines as second line, but very few evaluation studies have been reported. Babies who require second-line treatments are more likely to have hypoxic ischaemic encephalopathy, an abnormal background electroencephalogram and a large seizure burden, and have a worse prognosis than do those who respond to a single agent; most have significant disability at follow up. SUMMARY: The search for an effective antiepileptic regimen in the newborn must continue. Whether better control of neonatal seizures leads to a reduction in neurodisability in childhood cannot be determined until more effective treatments are found. Meanwhile, electroencephalography remains the most useful investigation for diagnosis and prognosis.     

Benign familial infantile seizures

In recent years, numerous publications have reported localization-related epilepsy with onset during early infancy, idiopathic etiology and favourable outcome. In 1963, Fukuyama reported cases occurring in the first 2 years of life characterized by partial seizures, absence of etiologic factors and benign outcome. Watanabe studied the localization and semiology of seizures. Later Vigevano and coworkers directed attention to the presence of cases with a family history of convulsions with benign outcome during infancy, with autosomal dominant inheritance, suggesting the term 'benign infantile familial convulsions' (BIFC). Similar cases have been described by several authors confirming that this is a new syndrome. In the last ILAE proposal of Classification of Epilepsy Syndromes this entity is called benign familial infantile seizures. Benign infantile seizures are divided now into familial and non-familial forms, although the two forms can overlap. Genetic studies led to the identification of a marker on chromosome 19. This was not confirmed by later studies, and genetic heterogeneity was hypothesized. Recently Malacarne studying eight Italian families with BIFC mapped a novel locus on chromosome 2. In 1997, Szepetowski described the association between BIFC and a later occurrence of paroxysmal choreoathetosis. Following the identification of a specific marker on chromosome 16, this entity constitutes a variant of the familial forms, called infantile convulsions and choreoathetosis. The age at onset, the semeiology of the seizures and the genetic data distinguish the benign familial infantile seizures from the benign familial neonatal seizures. Recent data suggested that this type of epilepsy would be due to a channellopathy.     

Nonprogressive familial leukoencephalopathy with porencephalic cyst and focal seizures

Two siblings with a similar white-matter disease but different clinical symptoms are described. The first sibling suffers from nonprogressive spastic hemiparesis secondary to a congenital periventricular porencephalic cyst. Her brother has focal epilepsy. On magnetic resonance imaging, both patients show diffuse white-matter involvement predominantly of the posterior periventricular area. We suggest that this is a familial white-matter disorder with minimal symptoms and no progression in early childhood.     

Neonatal seizures in two sisters with incontinentia pigmenti

Familial incontinentia pigmenti (IP) (OMIM #308300) is a rare genetic disorder which segregates in an X-linked dominant way. The female-to-male ratio ranges from 20 to 37 : 1. In affected females IP causes highly variable abnormalities of the skin, hair, nails, teeth, eyes, and central nervous system (CNS). Cardiovascular anomalies, cerebral infarction, and immune dysfunction are rare complications of IP. The pathogenesis of cerebral changes in IP remains elusive. We report the case of two IP-affected sisters who presented in each case with neonatal seizures on the fifth day of life. Via cranial magnetic resonance tomographic imaging (MRI) different types of lesions in both hemispheres were demonstrable in both patients. To date the pathogenetic mechanisms for the cerebral lesions are not fully understood. However, multiple microscopic infarcts could serve as a possible explanation. The clinical course and the neurological development of the older child are favorable and so far the younger sibling appears to be developing normally, which is uncommon for patients with early onset of neurological symptoms. Symptomatic seizures in IP are an important differential diagnosis in benign non-familial and familial neonatal seizures.     

Neonatal seizures: diagnosis and treatment

Neonatal seizures are a frequent problem encountered in neonatal nurseries, but their significance is controversial. Some investigators regard newborn seizures as simply epiphenomena and reflective of brain injury, whereas others note associated metabolic and physiologic aberrations suggesting that seizures per se are injurious to the central nervous system. The proper approach to the treatment of neonatal seizures depends on the etiology because treatment differs if seizures are of metabolic, toxic, or structural origin. Most studies reporting the efficacy of anticonvulsant agents neither define the seizure characteristics being treated nor use electroencephalographic documentation of seizure activity. The choice of anticonvulsants has been based on tradition rather than on the proven superiority of one agent over another. Although several anticonvulsants are available, phenobarbital remains the drug most frequently chosen as the initial agent in treatment. The important pharmacologic considerations of anticonvulsants include route of administration, ability to achieve therapeutically efficacious and predictable plasma levels rapidly, drug distribution, the availability and affinity of receptor sites, protein-binding characteristics, effects on brain growth, and cardiovascular toxicities. At the present time, critical questions remain regarding the effects of both seizures and anticonvulsants on the developing central nervous system.     

Neonatal seizures and neonatal epileptic syndromes

The neonatal period is defined as the first 28 days of life of a term infant; for premature infants the limit of this period is 44 completed weeks of the infant's conceptional age (CA)-defined as the chronological age plus gestational age (GA) at birth. The clinical and electroencephalographic (EEG) manifestations of seizures during this period are determined primarily by the development features of the immature brain at the time of seizure onset, but are also related to the type and diversity of etiologies and risk-factors for seizures neonates may face early in life. Neonatal seizures may be strikingly different from the clinical and electrical seizures of older children and adults. In addition, findings from basic science investigations suggest that immature animals are more likely to experience seizures in response to injury than more mature animals, although the developing brain is less susceptible to seizure-induced injury.     

Neonatal seizures: a reappraisal

Sixty-three infants with neonatal seizures were studied in terms of etiology, seizure type, electroencephalograms, and outcome. Twenty-nine percent were normal when followed for up to five years; twenty-nine percent were brain damaged, and twenty-five percent expired. In spite of improved obstetrical care, the occurrence of neonatal seizures may be associated with significant morbidity and mortality.     

Neonatal seizures with tonic clonic sequences and poor developmental outcome

Seizures consisting of a tonic followed by a clonic phase have rarely been described in neonates and are not included in the current classifications of neonatal seizures. Our video archive of 105 neonates with seizures or suspected seizures revealed six neonates with such tonic clonic or tonic myoclonic sequences. Two of those neonates had pyridoxine dependent seizures. The other four neonates had drug refractory seizures and demonstrated similarities in electro-clinical pattern, clinical course and outcome. Their seizures started with tonic posturing and after 10-20s tonic posturing was superimposed by focal or multifocal cloni or myocloni. Ictal EEG started with voltage attenuation followed by bilateral or alternating focal epileptic discharges. The interictal EEG was abnormal. One child died, while the other three children became seizure free but had severe motor delay and mental retardation. In one of those three children, a de novo missense mutation was detected in the voltage gated potassium channel gene KCNQ2, indicating a genetic relationship between drug refractory neonatal seizures of unknown etiology with tonic clonic or myoclonic sequences and the well-known syndrome of benign familial neonatal convulsions (BFNC).     

Neonatal seizures and disruption to neurotransmitter systems

<正>Seizure disorders and epilepsies are well documented to be associated with long-term neurological and cognitive deficits in the adult and pediatric patients,but what about seizures in the newborn?The neonatal brain is highly susceptible to seizures,with hypoxic-ischemic encephalopathy(HIE)the most com-     

Neonatal seizures: electroclinical dissociation.

Electroclinical dissociation is a phenomenon in which the clinical component of a seizure occurs at times with or without an electrical correlate. The epidemiology of this observation was studied in a neonatal intensive care unit from July, 1983 to December, 1988. Infants demonstrating electroclinical dissociation were compared to those having exclusively electroclinical seizures. Sixteen percent of infants with electrographically-confirmed seizures and 19% of 243 analyzed seizures demonstrated electroclinical dissociation. The two groups revealed very few differences with respect to perinatal factors, etiology, and outcome. The subsequent electroencephalographic background was more disturbed in the electroclinical dissociation group, but did not correlate with clinical outcome. Extremity movements occurred at a statistically significant higher rate during electroclinical seizures. Electroclinical dissociation seizures arise from foci not consistently reflected in surface electrodes.     

Neonatal seizures: a clinician's overview

Seizures are the most frequent neurological event in newborns (NBs), provoked often by noxae not apt to cause them in later life. This is because receptor families of excitatory amino acids (EAA) are overexpressed at this stage of brain ontogenesis, which is also why most neonatal seizures rapidly abate, even when neurological deficits persist. The brain's immaturities dictate distinct seizure phenotypes. A classification proposed in the late 1960s has been criticized, and a new one has been advocated, based on correlations between EEGs and behaviors, leading to a classification of seizures into ‘epileptic’ and ‘non-epileptic’. The taxonomic pitfalls of these classifications are discussed, and the notion advanced that many seizures fail to fulfil the criteria to label them as epileptic. While etiological factors have changed in time, the striking dichotomy in outcome has persisted. Many etiologies, often multifactorial, are unique in NBs, and they are discussed with reference to diagnosis and therapies. Four syndromes of NB seizures, accepted into the International Classification of the Epilepsies, are critically analyzed, some appearing to rest on fragile grounds.Controversies persist whether seizures per se are injurious to the immature brain. Clinical studies suggest that neither duration in days or length of seizure phenotypes correlates with outcomes, the most valid prognostic indices being offered by etiologies and by patterns of EEG polygraphy. However, because most seizures are symptomatic, it may be difficult to distinguish morbidity due to underlying pathology from that possibly added by seizures. Animal experiments suggested that they are injurious. The theory of energy failure, postulated to cause a cascade of events leading to inhibitions of DNA, proteins, lipids and disrupted neuronal proliferation, synaptogenesis, myelination, has largely been disproved. Brains of immature animals have been shown to have the oxidative machinery needed to fulfil energy demands, even during status convulsivus. They are also capable of using anaerobic metabolism and require less ATP when aerobic energy production ceases.Recent explanations for the injurious consequences of hypoxic ischemia and of prolonged convulsions postulate that neuronal damage occurs from excessive release of EAA which, by binding to their ligand-gated ionic receptors, cause a large influx of Ca²⁺, resulting in cell death. Because of the overabundance of EAA receptors in early ontogenesis, the excitotoxic hypothesis would appear attractive, but some observations militate against it. Among these is the dissociation found between the focal neurotoxicities induced by EAA injected into the brain and their absence following the concomitant convulsions. The latter are not blocked by pretreatment with EAA antagonists, while these prevent injuries caused by the injected EAA. There is no convincing evidence that excessive release of EAA occurs during NBs' seizures. Even if it does occur, it has been shown that immature neurons have a better capacity to self-protect from increased Ca²⁺ influx, and also that direct application of glutamate to immature neurons leads to significantly lower Ca²⁺ influx. These data raise doubts about the postulated excitotoxicity caused by NBs' seizures, being consistent with the fact that no one, so far, has observed neuronal damage from drug-induced convulsive states in NBs. Lack of overt neuronal injuries does not preclude that long-term subtle changes might be induced by noxae apt to provoke transient ictal events. Thus models developed in our laboratories demonstrate that long-term epileptogenicity results following postnatal O₂ deprivation without evidence of neuronal injuries or of long-term behavioral or electrophysiological alteration. However, both age at which hypoxia occurs and specific proconvulsant methods used strictly determine whether increased epileptogenicity will occur. Difficulties in bridging the gaps between various experimental paradigms and between the latter with the clinical context are analyzed, and some ways to minimize them are indicated for future research.