Chapter 10

Introduction

Neurodegenerative disorders in children pose a unique diagnostic challenge. Unlike many genetic syndromes, the clinical manifestations of childhood neurodegenerative diseases are often nonspecific and show considerable overlap. Pathognomonic clinical signs are rare. Many of these conditions are uncommon, and extensive clinical experience is generally lacking, even in tertiary referral centers. To further complicate matters, these children often present in the early stages of their illness, when evidence of progression is questionable and motor or cognitive impairment is relatively mild. It is only with extended observation that both clinical and neuroimaging abnormalities evolve to suggest a limited set of diagnostic possibilities. These children usually require repeated observation by a multidisciplinary team of neurologists, neuroimaging specialists, neuro-ophthalmologists, and geneticists before a specific diagnosis is established.199

Children with neurodegenerative diseases often present with a combination of motor and intellectual impairment. Although the definitive diagnosis of many of these disorders is made by testing for biochemical or genetic abnormalities, the differential diagnosis is based on the child’s physiognomy, systemic and neurological findings, neuro-ophthalmologic abnormalities, and the results of neuroimaging studies. The neuro-ophthalmologist is often called upon to look for ocular motility or retinal signs that suggest a specific diagnosis so that ancillary investigations can be directed appropriately.

It is inappropriate to investigate every child with developmental delay for neurodegenerative disease, and the complex interplay between development and degeneration may make the choice of which patients to be investigated, a difficult one. In this setting, visual system abnormalities may be among the most quantifiable and reproducible clinical features, and therefore figure prominently in the diagnostic decision-making process. In some circumstances, visual system abnormalities are the presenting sign of a neurodegenerative disease. The neuro-ophthalmological features of these conditions may include optic atrophy, retinal degeneration, nystagmus, ophthalmoplegia and other motility disturbances, and cortical

visual loss. In particular, the later-onset abnormalities (i.e., occurring after 5 years of age) may present with visual loss or the new onset of strabismus, ophthalmoplegia with ptosis, or nystagmus.

A traditional framework for categorizing neurodegenerative diseases is to divide them into disorders that involve primarily gray matter and those that involve primarily white matter. This classification system is useful primarily as a clinical and neuroimaging tool to aid in differential diagnosis. The definitive classification system for neurodegenerative disorders has yet to be established, and it appears that grouping diseases by the effected subcellular organelle (i.e., lysosomal, mitochondrial, and peroxisomal diseases) will eventually be supplanted by a genetic classification system. In this chapter, a combination of traditional and subcellular organelle classification systems will be used. The classification of each neurodegenerative disease under these systems is summarized in Table 10.1.

The primary involvement of gray versus white matter in neurodegenerative disease is often reflected in the early neurological abnormalities. Gray matter diseases present with intellectual deterioration, seizures, and involuntary movement disorders. Neuro-ophthalmologic abnormalities, when present, are dominated by retinal degeneration and supranuclear ocular motor disturbances (Table 10.2). White matter diseases usually begin with spasticity and optic atrophy. However, gray matter disorders may eventually spread to involve white matter and vice versa, and many neurodegenerative disorders involve both gray and white matter primarily.

Immaturity and poor motor control make behavioral evaluation of vision difficult in children with neurodegenerative disease. Accurate assessment of vision can be confounded by the child’s ambiguous response to visual stimuli. In this context, ancillary testing in the form of visual physiology and neuroimaging investigations may provide critical objective information.142 Electroretinography (ERG) is most likely to be abnormal in gray matter diseases, whereas the visual evoked potential (VEP) may provide early evidence of optic atrophy (Table 10.3) or intracranial white matter tract disturbance.

Neuroimaging findings are frequently nonspecific in neurodegenerative disorders of childhood. The presence of megelencephaly suggests Canavan disease or Alexander disease. Symmetrical changes suggesting edema in the basal ganglia or brainstem are characteristic of Leigh disease. Extensive bioccipital or bifrontal white matter edema with peripheral enhancement is characteristic of X-linked adrenoleukodystrophy with active demyelination. Although rarely diagnostic alone, neuroimaging of children with neurodegenerative diseases can narrow the differential diagnosis and direct genetic or biochemical investigations. Magnetic resonance (MR) imaging is particularly valuable in differentiating white matter from gray matter disease. These studies should be interpreted by an experienced observer because, even early in the course of gray matter disease, the cerebral white matter may show decreased volume because of Wallerian degeneration, and some white matter disorders have an inflammatory component that can cause a contiguous mass effect on adjacent gray matter.

White matter disorders such as adrenoleukodystrophy (ALD) and Alexander disease may show hypodensity (decreased attenuation) of central white matter on computed tomography (CT) scanning or prolonged T1 and T2 relaxation times on MR imaging (producing low signal on T1-weighted images and high signal on T2-weighted images) before any

atrophy is apparent. The site of early white matter involvement may provide additional diagnostic information. Neuroimaging specialists divide cerebral white matter into central and peripheral zones. Peripheral white matter is that which immediately underlies the cortex. Because these fibers follow the cortical gyri, they appear in the shape of a “U” on axial imaging of the brain. Disorders in which the abnormality is limited to white matter should undergo careful scrutiny of these subcortical “U fibers” because symmetrical involvement in a macrocephalic patient is strongly suggestive of Alexander disease. Bilateral symmetric peripheral white matter disease in a child who is not microcephalic should raise suspicion of galactosemia.17 Early involvement of deep white matter suggests a different group of disorders. Deep white matter involvement combined with thalamic involvement suggests Krabbe disease, whereas deep white matter involvement combined with corticospinal tracts involvement suggests peroxisomal disorders. A paucity of myelin without evidence of inflammation or injury to myelin is characteristic of Pelizaeus– Merzbacher disease.17

Gray matter disease may involve either cortical gray matter or deep gray matter nuclei. Gray matter diseases of the cortex include neuronal ceroid lipofuscinosis, gangliosidoses, and peroxisomal disorders. The MR abnormalities that suggest a peroxisomal disorder include focal migrational derangements