Neurofibromatosis type 1

Neurofibromatosis type 1 has an incidence of 1 in 2500–4000 live births across all ethnic and racial groups. It is inherited in an autosomal dominant manner, with 98–100% penetrance, and similar neurocutaneous features may be found during examination of the parents’ skin. However, the new-mutation rate is high and accounts for about 30% of cases, so parents may not be affected (Reference AicardiAicardi, 1998). The appearance of the skin varies from minor coffee-coloured macules and axillary freckling to significantly disfiguring neurofibromas. Macrocephaly may be observed in up to 43% of those with this condition and short stature in about 27% (Reference NorthNorth, 1993).

Neurofibromas are benign tumours or hamartomas which may be located intracutaneously as violaceous nodules, subcutaneously along the nerve sheath, or in the iris as Lisch nodules. The criteria for the diagnosis of neurofibromatosis are shown in Box 1 (Reference AicardiAicardi, 1998). Clinicians should be alert to any reported change in vision in these patients, since optic nerve gliomas affect some 15–20% (Reference AicardiAicardi, 1998). However, lesions at the chiasm produce a bi-temporal hemianopia, which frequently goes unnoticed by the patient, making it mandatory to undertake a clinical assessment of visual fields.

Epilepsy is seen in up to 7% of children with NF1, with all seizure types represented. Although the presence of severe learning disability is rare, moderate learning disability occurs in 10% of cases and the IQ of patients with NF1 is, on average, lower than that of unaffected siblings. Specific learning difficulties affect 40–60% of patients and include visuospatial deficits, perceptual organisation difficulties, poor coordination, poor spatial and verbal memory, reading and writing difficulties and problems with numeracy (Reference Udwin, Dennis, O'Brien and YuleUdwin & Dennis, 1995). Up to 50% of children with NF1 have speech and language difficulties (Reference Udwin, Dennis, O'Brien and YuleUdwin & Dennis, 1995), including excessive nasality, breathiness and slow acquisition of vocabulary, although overall verbal abilities tend to be higher than non-verbal ones.

Attention difficulties in the absence of hyperactivity have been described (Reference AicardiAicardi, 1998) and, interestingly, distractibility and poor concentration seem more common in children with greater ability. Unhappiness and victimisation by bullying are frequently reported, as are anxiety, poor self-confidence and social withdrawal, and an excess of psychiatric morbidity such as anxiety and depression.

Tuberous sclerosis

The prevalence of tuberous sclerosis is reported to be of the order of 1 in 7000 of the population. It is an autosomal dominant condition with a very high rate of spontaneous mutations (58–68%). Hypomelanotic macules, commonly in an ash-leaf shape, are the most frequent cutaneous manifestation of tuberous sclerosis and are best seen using a Wood's light. Shagreen patches are yellow/brown elevated layers of epidermis with a granular surface seen in the lumbar region after the age of 2 years. Periungual fibromas, although pathognomonic, rarely appear before puberty. The best-known cutaneous manifestation of tuberous sclerosis is adenoma sebaceum, the papular, acneiform rash that appears in a butterfly distribution over the face between 3 and 15 years of age. Retinal astrocytomas or phakomas are round/oval lesions involving the optic nerve and retina which, when calcified, resemble mulberries.

The characteristic features of the syndrome are shown in Box 2 (Reference AicardiAicardi, 1998). It is a multi-system disorder with effects in the brain, heart, skin, kidneys and lungs. The most characteristic findings in those with tuberous sclerosis relate to the brain. They are cortical tubers, subependymal nodules and the subependymal giant cell astrocytomas that result in hydrocephalus. Seizures are the most common presenting complaint, occurring in 60% of individuals (Reference Webb, Fryer and OsborneWebb et al, 1991), with the most commonly described being infantile spasms. However, the full range of seizures may be seen, including complex partial, tonic and atonic attacks.

Fewer than 50% of those affected are thought to have a learning disability (Reference Webb, Fryer and OsborneWebb et al, 1991), although when present, this may be profound (IQ < 20). Cognitive performance seems to be adversely associated with epilepsy, particularly with seizure onset below the age of 2 years. A prevalence study in the west of Scotland (Reference Hunt and ShepherdHunt & Shepherd, 1993) showed that 43% of children with tuberous sclerosis fulfilled DSM–III–R (American Psychiatric Association, 1987) criteria for autism or pervasive developmental disorder. Reference Gillberg, Gillberg and AhlsenGillberg et al(1994) reported autism in 61% of those below 20 years of age with tuberous sclerosis and found many with attention-deficit hyperactivity disorder. Sleep disorder is common and particularly trying for the family. It is associated with the presence and severity of epilepsy. The behaviour seen in children with tuberous sclerosis means that they can rarely be left unsupervised as they may exhibit destructive behaviour. They seem impervious to verbal suggestion and appear to be in their own world (Reference Udwin, Dennis, O'Brien and YuleUdwin & Dennis, 1995). Attempts to redirect their activity provoke aggression and, in severe cases, the family may view trips out of the house as being too difficult to contemplate.

Eyes

The eyes can yield many clues for potential neurological diagnoses and, as far as possible, every patient should be examined. Table 4 lists some ophthalmological features in patients who might present to CAMHS, with associated diagnoses. The most obvious ophthalmological observation on first seeing the patient is that he or she is wearing thick spectacles. Bardet–Biedl syndrome, once referred to as Laurence–Moon–Biedl syndrome, has a variety of ocular features, including retinal dystrophy, astigmatism, glaucoma and retinitis pigmentosa. Other features include post-axial polydactyly, hypogonadism and obesity. Moderate learning difficulties are also seen, along with a shallow affect and inappropriate mannerisms (Reference JonesJones, 1997).

Table 4

Diagnostic clues from examination of the eyes

Acuity	Myopia is seen in Bardet–Biedl syndrome and Rubenstein–Taybi syndrome
Fields	Hemianopia or partial-field defects associated with hemiplegia, bitemporal hemianopia associated with lesions at the chiasm
Cornea/lens	Lisch nodules of neurofibromatosis, cataract in Lowe's syndrome, lens dislocation in homocystinuria and Marfan syndrome, telangiectasia in ataxia-telangiectasia aged >3 years, Kayser–Fleischer rings in Wilson's disease aged >8 years
Fundi
Optic atrophy	Leukodystrophy, gangliosidoses
Papilloedema	Evolution of hydrocephalus in neurofibromatosis or tuberous sclerosis
Phakomas	Tuberous sclerosis
Cherry-red spots	Gangliosidoses, sialidosis
Pigmentary changes	Mitochondrial disease, juvenile neuronal ceroid lipofuscinosis (Batten disease), Usher syndrome
Colobomas	Colomba, heart disease, atresia of the choanae, retarded growth and devlopment, genital abnormlaities and ear abnormalities, including deafness (the CHARGE association), Cat-eye syndrome
Eye movements and nystagmus	Juvenile Gaucher disease, ataxia telangiectasia, Niemann–Pick disease type C, spinocerebellar degeneration, Huntington's chorea.

It can be difficult to assess visual fields in young children or in those whose development has been delayed, but this should be attempted, especially in the presence of a motor deficit where a coexisting visual-field deficit may explain reduced visual awareness of material presented to that side. A useful method of assessment, if examining alone, is to hold two fingers out to either side within the child's lateral visual fields and midway between yourself and the child. Then call the child's name so that he or she looks at you and ask which fingers are moving. Move the fingers on one side and the child will either look or point at them. Call to the child again to bring attention back to your face and repeat the exercise for the other side and for the vertical plane. If an assistant is available a lighted torch can be introduced into the child's visual field from behind by one examiner while the other interests the child in looking forwards. The child will turn to the object when it has been sighted.

Table 4 contains examples of neurodegenerative disorders that might present later to CAMHS with a change in personality and/or behaviour, possibly associated with reduced academic performance and accompanied by evidence of visual failure. Deterioration in vision accompanied by personality change, intellectual deterioration or motor difficulties is very ominous and requires urgent further investigation. In these circumstances, fundal examination and the examination of eye movements may reveal clues as to the aetiology of the disorder.

In order to examine the fundi it is useful to ask a parent or carer to stand in front of the child and to ask the child to tell you if the adult is making faces behind your back. Most children will avidly concentrate on their parent/carer's face, allowing a view of the fundi to be obtained. Older children will usually voluntarily fix on a toy or picture but younger children or toddlers may need their interest to be captured by holding up a toy such as a teddy bear which is made to wave occasionally. Avoid using a toy that is too exciting, as the child will become upset if not allowed closer access to it and the opportunity will be lost. Pale optic discs indicative of optic atrophy, associated with evidence of visual failure, are a feature of neurodegenerative disorders such as leukodystrophy and other lysosomal enzyme disorders. These disorders are progressive and motor and mental deterioration occur before premature death. Cherry-red retinal spots may disclose the presence of GM1 gangliosidosis or, rarely, the ‘cherry-red spot-myoclonus syndrome’ (type 1 sialidosis). Pigmentary changes in the retina may be seen with mitochondrial disease.

Other significant neurological disorders are revealed by the presence of abnormal eye movements, which can be tested by moving a developmentally appropriate visual lure. Supranuclear ophthalmoplegia refers to a disturbance in the mechanisms controlling voluntary conjugate gaze, the cause of which lies above the level of those cranial nerve nuclei that control eye movements. Diffuse cerebral disease of any cause may affect both saccadic and pursuit eye movements. In affected children, voluntary side-to-side eye movements (saccades) are hypometric and slow, necessitating the use of a head thrust or forced blinking in order to relocate the gaze on a target. Pursuit movements in these children are small and jerky on following a target. The vestibulo-ocular brainstem reflex, which is independent of voluntary mechanisms, remains unaffected. Conditions producing a supranuclear ophthalmoplegia include juvenile Gaucher disease (supranuclear horizontal ophthalmoplegia), the adult form of GM2 gangliosidosis and type C Niemann–Pick disease (supranuclear vertical ophthalmoplegia). All of these autosomal recessive disorders are progressive, with variable rates of concurrent or subsequent deterioration in motor and intellectual function.

The disorder most familiar to a paediatric neurologist is that of ataxia-telangiectasia, a disorder with autosomal recessive inheritance. Clinical features include progressive cerebellar ataxia with choreo-athetosis in 25% of patients, progressive oculocutaneous telangiectasias, immunodeficiency and a high incidence of malignancy. Although the ataxia and apraxic eye movements are present after the age of 1 year, these might not have been recognised and the child may not be correctly diagnosed with the disorder until later in childhood, when up to one-third show mild learning difficulties (Reference AicardiAicardi, 1998). In most cases, dilated conjunctival vessels in the angles of the eye are noted after the age of 3 years and these spread medially. The course is relentless and the prognosis poor: children are wheelchair-bound by 10 to 15 years of age.

Nystagmus is an involuntary, rhythmical conjugate oscillatory movement of the eyes, it may occur in any plane and may be jerky or pendular, or both. It is important to differentiate true nystagmus from the roving eye movements of the blind child. The most common type is gaze-evoked nystagmus which is jerky and is produced by asking the patient to deviate his or her eyes to either side. This usually reflects dysfunction in the posterior fossa. Impairment of the vestibular tract anywhere from nucleus to end organ can also produce jerky nystagmus. Congenital nystagmus will have been present since shortly after birth and a history of this is usually readily obtainable from a parent or carer. It is usually seen as large-amplitude, pendular, horizontal nystagmus in a child who is otherwise neurologically normal, and it may be present in a parent.

Nystagmus is not a feature of cerebral palsy, including ataxic cerebral palsy, so it should not be accepted as such without further investigation. In boys, the presence of ataxia with nystagmus and variably progressive pyramidal weakness can indicate Pelizaeus–Merzbacher disease, an X-linked leukodystrophy, the first manifestation of which is rotatory nystagmus presenting in the first 3 months of life and variably beyond this time. Unfortunately, this is also a relentlessly progressive disorder and, as in all these disorders, the correct diagnosis is important for the genetic counselling of the parents and siblings and for discussion of the availability of prenatal diagnosis in subsequent pregnancies.

Remaining cranial nerves

Observations should be made of facial symmetry. In upper motor neuron facial weakness, movement of the eyelid, eyebrow and forehead is spared. In congenital hemiplegia, facial weakness is either absent or mild, in contrast with the more marked facial weakness in acquired hemiplegia (Reference Brown, Van Rensburg and WalshBrown et al, 1987).

Oromotor movements should be assessed in any child with a history of drooling and feeding problems along with impaired speech and in whom these problems are more severe than any motor impairments. Worster–Drought syndrome consists of congenital upper motor neuron bulbar palsy with mild pyramidal tetraplegia. Affected children dribble (86%), need a modified diet (80%) and use augmentative communication (80%) (Reference Clark, Carr and ReillyClark et al, 2000). Most affected children have significant comorbidity: 81% have learning difficulty, 41% neuropsychiatric problems and 28% epilepsy. The disease is a static disorder that falls within the spectrum of cerebral palsy, often associated with bilateral perisylvian cortical dysplasia.

Pyramidal signs

The presence of pyramidal signs refers to the finding of increased tone, weakness which is more obvious in the extensor muscle groups of the upper limb and in the flexor muscle groups of the lower limb, and brisk tendon reflexes with an extensor plantar response. This indicates dysfunction of the corticospinal (pyramidal) tracts anywhere from the cerebral cortex to the spinal cord. Cerebral palsy is ‘an umbrella term covering a group of non-progressive, but often changing, motor impairment syndromes secondary to lesions or anomalies of the brain arising in the early stages of development’ (Reference Badawi, Watson and PettersonBadawi et al, 1998). Thus, no progression of the motor impairment should be seen if the diagnosis of cerebral palsy is correct and, as a general rule, the impairment should not evolve to include ataxia, disordered eye movements or significant extrapyramidal features.

Congenital hemiplegia is associated with significant learning and behavioural problems, which should be anticipated in order to meet the child's needs in education and within the family. Children with such impairments have significant peer difficulties, which can be predicted from lower IQ and problems such as hyperactivity reported by teachers (Reference Yude and GoodmanYude & Goodman, 1999). Psychiatric problems are common and persistent, and in the school years hyperactivity again seems predictive of continuing psychiatric morbidity. Evidence suggests that of those requiring psychiatric help, 70% will still need this help in 4 years’ time (Reference GoodmanGoodman, 1998).

Ataxia

Ataxia is defined as incoordinated or inaccurate movement which is not due to paresis, alteration in tone, loss of postural sense or the intrusion of involuntary movements (Reference PattenPatten, 1998). However, ataxia may coexist with any of the abovementioned findings in a mixed rather than pure disorder. Evolution of ataxia alongside pyramidal-tract signs associated with even the mildest cognitive or behavioural decline is indicative of a progressive spinocerebellar degeneration. In boys, this should prompt a search for X-linked adrenoleukodystrophy, a disorder of the metabolism of very-long-chain fatty acids, which presents between the ages of 4 and 8 years with gait disturbance and subtle cognitive decline. The spasticity and dementia progress and death results within a few months to several years (Reference AicardiAicardi, 1998). Metachromatic and Krabbe leukodystrophies can present in a similar way. Juvenile- and adult-onset metachromatic leukodystrophy, in particular, may present with regressive behaviour and psychiatric disease.

Ataxic cerebral palsy is a non-progressive ataxia, mainly affecting the trunk and walking balance. It is a heterogenous condition with variable aetiology. Prenatal aetiology is the most common but inherited forms of non-progressive ataxia and those associated with structural malformations of the cerebellum are also described (Reference AicardiAicardi, 1998).

Involuntary movements

Involuntary movements include tics, stereotypies, chorea, dystonia and myoclonus. The evolution of any involuntary movement disorder requires close observation and further investigation.