Cognitive Impairment

A correlation between MIC and mental retardation has been recognized since studies in the late 1800s, and subsequent research has explored the strength of this correlation in a number of ways, although rarely in a prospective manner among a broad sample of subjects. In reported studies, the incidence of MIC has varied, depending on the population studied. Prevalence estimates of MIC in institutionalized patients have reported a rate of MIC ranging from 6.5 percent [Krishnan et al., 1989] to 53 percent [Roboz, 1973]. In contrast, for children seen in neurodevelopmental clinics, the prevalence of microcephaly averages 24.7 percent (range 6–40.4 percent) [Smith, 1981; Martin, 1970; Desch et al., 1990].

Other studies have looked at the incidence and significance of MIC in children who were functioning normally or had normal intelligence. In one report of 1006 students in mainstream classrooms it was found that 1.9 percent had mild microcephaly (−2–3 SD) and none had severe microcephaly (below −3 SD) [Sells, 1977]. The microcephalic subjects had a similar mean IQ (99.5) to the normocephalic group (105), but lower mean academic achievement scores (49 vs. 70). Another report, looking at the records of 1775 normally intelligent patients aged 11–21 years, followed in adolescent medicine clinics, found 11 (0.6 percent) with severe MIC (below −3 SD) [Barmeyer, 1971]. Among a separate sample of 106 retarded adolescents, the incidence of severe MIC was 11 percent.

A related issue concerns the incidence of developmental disability in individuals with MIC. Several investigations based on the United States National Collaborative Perinatal Project (1959–1974) have data regarding the degree of developmental disability in children with MIC. In an early report, OFC measurements of less than 43 cm (−2.3 SD) for males and 42 cm (−2.4 SD) for females at 1 year of age were associated with IQ <80 at 4 years in half the individuals [Nelson and Deutschberger, 1970]. A second study using these data found congenital MIC (<2 SD) in 1.3 percent that was associated with a greater risk of mental retardation at 7 years (15.3 vs. 7 percent) in selected populations [Camp et al., 1998]. A third study found that, of normocephalic children, 2.6 percent were mentally retarded (IQ ≤70) and 7.4 percent had borderline IQ scores (71–80). Of the 114 (0.4 percent) children with mild microcephaly (2–3 SD), 10.5 percent were mentally retarded and 28 percent had borderline IQ scores [Dolk, 1991]. Severe MIC (below −3 SD) was found in 41 (0.14 percent) children, and 51.2 percent were mentally retarded and 17 percent had borderline IQ scores. These reports have been supported by findings in several other studies [O’Connell et al., 1965; Watemberg et al., 2002].

A number of additional studies of microcephalic children have examined other clinical factors. Available data are conflicting as to whether having proportionate MIC is less predictive of developmental and learning disabilities [Sells, 1977] or not [Nelson and Deutschberger, 1970]. Other studies have shown that early severe medical illness or acquired brain injury can be associated with MIC and a future risk of retardation [Avery et al., 1972]. The pattern of head growth can also be a significant predictor of outcome. Infants whose birth OFCs were normal but who acquired MIC by age 1 year were likely to be severely delayed. On the other hand, when MIC and developmental delay were acquired as a consequence of the combined deprivations of early childhood malnutrition, poverty, and lack of stimulation, as frequently occurs in emerging countries [Grantham-McGregor et al., 2007], significant potential for physical and cognitive recovery exists [Rutter, 1998].

There is also some evidence to support the generally held belief that there is a correlation between the severity of MIC and degree of developmental disability. One study of 212 children with MIC, seen in either a birth defects or a child development clinic, found a significant correlation between the degree of MIC and severity of mental retardation. Among the 113 subjects with mild MIC (2–3 SD below the mean), mental retardation was found in just 11 percent. The mean IQ of the children with the most normal OFC, between 2.0 and 2.1 SD below the mean, was 63. Mental retardation was diagnosed in 50 percent of the 99 subjects with more severe MIC (≥3 SD), and in all of those with an OFC more than 7 SD below the mean. The mean IQ of the children with an OFC between 5 and 7 SD below the mean was 20 [Pryor and Thelander, 1968].

The above studies all underscore the fact that MIC is common in developmentally disabled children, with the incidence greater in those more severely affected. Even in low-risk populations (e.g., children with normal school placements), 1.9 percent have MIC, and in many of these children, subtle cognitive deficits are detected. In addition, there is a 50 percent increased risk for being developmentally delayed in children with MIC compared to children without MIC (e.g., 15.3 vs. 7 percent), and a strong correlation between the severity of MIC and developmental outcome (i.e., mental retardation occurs in 10.5 percent of children with mild MIC [<2 SD] and in 51.2 percent of children with severe microcephaly [below −3 SD]). Because of these observations, it is important for serial developmental screening to be done in children with MIC to detect developmental disorders.

Epilepsy

The relation between MIC and epilepsy is of great clinical importance for several reasons:

One study involving 66 children with MIC (<−2 SD) found an overall prevalence of epilepsy of 40.9 percent [Abdel-Salam et al., 2000]. It has also been suggested that epilepsy is more common in postnatal-onset than in congenital MIC. In one study, epilepsy occurred in 50 percent of children with postnatal-onset microcephaly compared to only 35.7 percent of those with congenital MIC [Abdel-Salam et al., 2000]. A second study found that epilepsy was four times more common in postnatal-onset MIC [Qazi and Reed, 1973].

MIC also is a significant risk factor for medically refractory epilepsy [Berg et al., 1996; Chawla et al., 2002; Aneja et al., 2001]. In one study of 30 children, MIC was found in 58 percent of those with medically refractory epilepsy compared to 2 percent in whom seizures were controlled [Chawla et al., 2002].

Although children with MIC are at greater risk for epilepsy, many do not have epilepsy. There are, however, certain MIC syndromes in which epilepsy is a prominent feature. Knowledge of these disorders and their genetic basis can help establish a diagnosis and determine prognosis. Some of the more commonly recognized entities are summarized in Table 25-3.

Table 25-3 Severe Epilepsy and Microcephaly Associated Genetic Syndromes*

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. Data extracted from OMIM (http://www.ncbi.nlm.nih.gov/omim); the reader is referred to that source for updated information as new entries are added and data are revised. The reader can also go directly to GeneTests (http://www.genetests.org), to which OMIM links, for updated information regarding the availability of genetic testing on a clinical or research basis.

Studies have not examined the role of obtaining a routine electroencephalography (EEG) in children with MIC to determine their risk for developing epilepsy. In one study of children with MIC, EEG abnormalities were found in 51 percent of 39 children who either had no seizures or occasional febrile seizures [Abdel-Salam et al., 2000]. EEG abnormalities (focal, generalized, or mixed epileptiform discharges) were present in 78 percent of 18 children with medically refractory epilepsy.

Overall, it is important to be aware that epilepsy is more common in children with MIC, and when it occurs, it is more difficult to treat. Certain MIC syndromes are associated with a much higher incidence of epilepsy, and increasingly, genetic etiologies defining the relation between MIC and epilepsy are being reported. In addition, there are no systematic studies regarding EEG findings in children with MIC who have or do not have epilepsy.

Cerebral Palsy

Not unexpectedly, many children with MIC are diagnosed later in infancy with cerebral palsy, and likewise, children with cerebral palsy are frequently found to be microcephalic. Data from one study of 216 children with MIC and developmental disabilities found a rate of cerebral palsy of 21.4 percent compared to 8.8 percent in a population of normocephalic developmentally disabled children (p <0.001) [Watemberg et al., 2002]. In contrast, several studies have examined the incidence of MIC in children with cerebral palsy. Three studies of children with cerebral palsy found congenital MIC in 1.8 percent of cases [Croen et al., 2001; Pharoah, 2007; Laisram et al., 1992]. In three other studies, the combined incidence of congenital and postnatal-onset MIC ranged between 32.5 percent and 81 percent, and averaged 47.9 percent [Edebol-Tysk, 1989; Lubis et al., 1990; Suzuki et al., 1999]. In one of these studies, 68 percent were diagnosed with secondary (i.e., acquired microcephaly) and 13 percent had congenital MIC [Edebol-Tysk, 1989]. Others have shown that the yield of determining the etiology of cerebral palsy is improved if MIC is present [Shevell et al., 2003]. These data suggest that it is important for physicians and others caring for children with MIC to monitor for the development of cerebral palsy, so that appropriate physical and occupational therapeutic interventions can be initiated.

Ophthalmological Disorders

No studies have surveyed the incidence of vision loss or specific ophthalmological disorders in children with MIC. One study found an incidence of 145 cases of congenital eye malformations (microphthalmia, anophthalmia, cataracts, coloboma, etc.) in 212,479 consecutive births [Stoll et al., 1997]. MIC was among the malformations in 56 percent of these children. Another study (n = 360) with severe MIC (below −3 SD) found eye abnormalities in 6.4 percent, but in only 0.2 percent of 3600 age-matched normocephalic controls [Kraus et al., 2003]. Other reported eye abnormalities in children with MIC that have been reported when searching the OMIM database for MIC have found associations with anophthalmia, blindness or visual loss, cataracts, colobomas, microphthalmia, nystagmus, optic atrophy, ptosis, and retinal disorders. Table 25-4 lists some of the more common MIC syndromes associated with ophthalmological disorders.

Table 25-4 Microcephaly Disorders with Prominent Ophthalmologic Involvement*

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. From OMIM (http://www.ncbi.nlm.nih.gov/sites/entrez). Gene map loci are listed in each OMIM entry. Disorders are listed alphabetically; prevalence data are not known.

** CHARGE (Coloboma of the eye, Heart defects, Atresia of the choanae, Retardation of growth and/or development, Genital and/or urinary abnormalities, and Ear abnormalities and deafness.

Audiological Disorders

No studies have surveyed the incidence of hearing loss or audiological disorders in children with MIC. One study of 100 children with complex ear anomalies recorded that 85 had neurological involvement and 13 children had MIC [Wiznitzer et al., 1987]. Hearing loss is likely the most common audiological disorder associated with MIC, and Table 25-5 summarizes some of the common MIC syndromes listed in OMIM in which prominent audiological involvement is reported.

Table 25-5 Microcephaly Syndromes with Prominent Ear or Auditory Impairments*

* Adapted from Ashwal S, et al. Practice parameter: Evaluation of the child with microcephaly (an evidence-based review): report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society, Neurology 73:887–897, 2009. From OMIM (http://www.ncbi.nlm.nih.gov/sites/entrez). Gene map loci are listed in each OMIM entry. Disorders are listed alphabetically; prevalence data are not known.

** POR – cytochrome P450 oxido reductase deficiency.

*** GOMBO – Growth retardation, ocular abnormalities, Microcephaly, Brachydactyly and Oligophrenia.

Extrinsic Causes

Extrinsic injuries before birth or early in life can certainly lead to MIC. The developing nervous system is highly vulnerable to infections, including cytomegalovirus, toxoplasmosis, rubella, herpes simplex, and group B coxsackievirus. Intrauterine infections with these can result in MIC [Evrard, 1992; Norman et al., 1995; Volpe, 2000]. MIC also has been reported in infants of women exposed to ionizing radiation, as shown in studies following exposure to atomic bomb radiation or to radium implantation in the cervix during the first trimester [Dekaban, 1968; Wood et al., 1967]. Maternal metabolic disorders during pregnancy, such as diabetes mellitus, uremia, and undiagnosed or inadequately treated phenylketonuria, may result in neonatal MIC [Levy et al., 1996; Rouse et al., 1997]. Malnutrition, hypertension, and placental insufficiency may all result in intrauterine growth retardation and MIC.

Maternal alcoholism during pregnancy has also been linked with MIC as part of the fetal alcohol syndrome [Clarren et al., 1978; Loebstein and Koren, 1997; Ouellette et al., 1977; Spohr et al., 1993]. The clinical features include growth and mental retardation, midfacial hypoplasia, short palpebral fissures, epicanthal folds, and behavioral disturbances. Neuropathologic findings include MIC, heterotopia, widespread cortical and white-matter dysplasias, and defects of neuronal and glial migration [Wisniewski et al., 1983]. MIC has also been reported with maternal exposure to cocaine [Loebstein and Koren, 1997]. Some other reports are largely anecdotal, so the associations are often not proven.

Familial Mild Microcephaly

Mild MIC may have either complex (polygenic) or autosomal-dominant inheritance. The autosomal-recessive forms typically present with severe primary MIC and many reviews have not clearly separated patients with mild and severe MIC, often making clinical data difficult to interpret. The polygenic or autosomal-dominant forms are generally associated with mild to moderate cognitive problems, with epilepsy being uncommon. The risk of recurrence in siblings may be as high as 50 percent with the assumption of autosomal-dominant inheritance, but is probably lower, considering that polygenic inheritance may be involved. The genetic basis for familial mild MIC is not known, but several genes have been identified that cause mild MIC, as indicated in Table 25-6.

Severe MIC, which we define as birth OFC at or below −3 SD or later OFC at or below −4 SD, is more likely to be associated with a wide variety of genetic disorders, although exceptions are likely (but not well documented).

Patients with primary MIC tend to fall into two further, albeit somewhat heterogeneous, subgroups [Dobyns, 2002]. The first subgroup includes children with severe MIC but only moderate neurologic problems, usually with moderate mental retardation and with no spasticity or epilepsy. The second subgroup consists of severe MIC with a much more severe neurologic phenotype that consists of abnormal neonatal reflexes, generalized spasticity, and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999]. These children have poor feeding and recurrent vomiting, leading to poor weight gain, profound mental retardation, and severe spastic quadriparesis. Most of these children also have early-onset intractable epilepsy. The wide clinical spectrum suggests pathogenetically heterogeneous conditions, and several syndromes and genes have been identified (see Table 25-6).

Primary Microcephaly

When congenital MIC is the only abnormality on evaluation, the disorder has been designated primary MIC. As discussed previously, this designation becomes much more useful when restricted to children with birth occipitofrontal circumference below −3 SD. Most patients with primary MIC also have mild growth deficiency, with stature typically −2 to −3 SD, which may be part of the syndrome or partly nutritional. This deficiency is much less striking than their head size, which is typically −4 to −8 SD after early childhood. Most affected persons fall into one of two groups described below [Dobyns, 2002].

The first group is composed of children with extreme MIC but only moderate neurologic problems, usually with only moderate mental retardation without spasticity or epilepsy [Barkovich et al., 1998; Peiffer et al., 1999; Tolmie et al., 1987]. Their neonatal examinations are usually normal, except for MIC, but many children initially have poor feeding and weight gain. They may have normal tone or mild distal spasticity, but do not have moderate or severe spasticity. Seizures are uncommon and are easily controlled. Febrile seizures occur and should be managed as in any other child. Early development is only mildly delayed and many infants progress to walking between 1 and 2 years of age and develop limited language skills. Several genes have been identified from studies of patients with this disorder (see Table 25-6).

The second group consists of primary MIC with a severe neurologic phenotype that includes severe spasticity and epilepsy [Barkovich et al., 1998; Dobyns, 2002; Sztriha et al., 1999; ten Donkelaar et al., 1999; Tolmie et al., 1987]. Neonatal examination demonstrates abnormal neonatal reflexes and generalized spasticity, and these children subsequently develop impaired feeding and recurrent vomiting, leading to poor weight gain, severe developmental delay, profound mental retardation, and severe spastic quadriparesis. Most of these infants have early-onset intractable epilepsy. In addition to a simplified gyral pattern, brain magnetic resonance imaging (MRI) may demonstrate other abnormalities, as summarized above (see Figure 25-1). Children with Amish lethal microcephaly have this phenotype, except that hypotonia predominates rather than spasticity, and seizures are not prominent [Kelley et al., 2002; Rosenberg et al., 2002].

The term radial microbrain was introduced by Evrard to describe the brain in some patients with severe mental retardation, profound MIC, and early death, describing an abnormally small brain that has a normal gyral pattern, normal cortical thickness, and normal cortical lamination, although the number of cortical neurons was only 30 percent of normal [Evrard et al., 1989; Evrard, 1992]. He hypothesized that a decreased number of radial neuronal-glial units was responsible for this form of MIC. This subgroup fits into the lower-functioning group of patients with primary MIC, rather than comprising an independent syndrome. However, multiple causes with different pathologic changes and clinical courses are likely to emerge from this group.

Severe Microcephaly with Cortical Malformation

Although still incompletely delineated, several syndromes with severe congenital microcephaly and additional severe brain malformations are known. The combination of severe microcephaly and true lissencephaly (with an abnormally thick cortex) has been reported, with at least three different patterns [Barth et al., 1982; Dobyns and Barkovich, 1999; Sztriha et al., 1998]. The most common of these very rare syndromes is probably the Barth microlissencephaly syndrome, which consists of severe microcephaly, diffuse complete agyria, and severe brainstem and cerebellar hypoplasia [Barth et al., 1982; Kroon et al., 1996]. Severe microcephaly with diffuse periventricular nodular heterotopia has been described, and clearly differs from other forms of heterotopia [Robain and Lyon, 1972; Sheen et al., 2004]. Some patients with severe microcephaly also have had diffuse polymicrogyria [Dobyns and Barkovich, 1999].

Severe Microcephaly with Proportionate Growth Deficiency

Several syndromes with severe intrauterine and postnatal growth deficiency and proportionate MIC have been described, although the head size does not keep up with even slow body growth, leading to disproportionate MIC in childhood and later. The best known of these are Seckel syndrome, Majewski syndrome, microcephalic osteodysplastic primordial dwarfism type 1 (MOPD1), also known as Taybi–Linder syndrome and microcephalic osteodysplastic primordial dwarfism type 2 (MOPD2). Several other syndromes with severe growth deficiency and microcephaly have been described in a few patients, however, so it is likely that this group will become a large and complex group of syndromes. In some children, the skeletal changes may be absent or less prominent than in Seckel’s syndrome or the MOPD syndromes.

Seckel’s syndrome consists of severe intrauterine and postnatal growth deficiency and microcephaly, and abnormal facial features. including large eyes, beaklike protrusion of the nose, narrow face, and receding lower jaw [Majewski and Goecke, 1982; Seckel, 1960]. All affected individuals have severe mental retardation, although the severity varies considerably and some patients live to adulthood. Abnormalities of the brain seen on postmortem examination or brain imaging demonstrate pure microcephaly with deficient production of neurons and other cell types in some patients [Hori et al., 1987], whereas other patients have severe brain malformations, including lissencephaly [Capovilla et al., 2001; Shanske et al., 1997; Sugio et al., 1993]. Some patients have had various hematological disorders, such as pancytopenia or acute myeloid leukemia [Butler et al., 1987; Hayani et al., 1994].

MOPD1, or Taybi–Linder syndrome, consists of similar severe intrauterine and postnatal growth deficiency and microcephaly, combined with abnormal body proportions and short limbs. Typical skeletal changes consist of a low and broad pelvis with poor formation of the acetabulum, short and bowed humerus and femur, dislocated hips and elbows, retarded epiphyseal maturation, cleft vertebral arches, platyspondyly, horizontal acetabular roofs, and short long bones with enlarged metaphyses. Patients with MOPD1 also may have skin abnormalities, including hyperkeratosis and sparseness of hair and eyebrows [Meinecke et al., 1991; Sigaudy et al., 1998; Taybi, 1992]. Brain malformations, in addition to the severe microcephaly, are common and include lissencephaly, heterotopia, callosal agenesis, and cerebellar vermis hypoplasia [Klinge et al., 2002; Sigaudy et al., 1998].

MOPD2 consists of similar severe intrauterine and postnatal growth deficiency, proportionate microcephaly at birth that progresses to disproportionate microcephaly, shortening of the middle and distal segments of the limbs, a progressive bony dysplasia, abnormal facial appearance, including prominent nose and malformed ears, and a high squeaky voice [Hall et al., 2004; Majewski and Goecke, 1998; Majewski et al., 1982]. These patients may have dilated arteries in the brain that resemble aneurysms or moyamoya disease [Kannu et al., 2004; Young et al., 2004]. Although all affected individuals have severe microcephaly, no other brain malformations have been described [Fukuzawa et al., 2002].

Although these syndromes dominate the literature concerning intrauterine and postnatal growth deficiency and microcephaly, review of many reports suggests an overall substantial causal heterogeneity, with probable confusion among these and other syndromes in this group. In support of this likelihood, several novel syndromes have been reported [Kantaputra, 2002; Okajima et al., 2002].