Ординатура / Офтальмология / Английские материалы / Handbook of Pediatric Neuro-Ophthalmology_Wright, Spiegel, Thompson_2006
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32.Gottlob I, et al. Head nodding is compensatory in spasmus nutans. Ophthalmology 1992;99(7):1024–1031.
33.Gottlob I, Wizov SS, Reinecke RD. Spasmus nutans. A long-term follow-up. Investig Ophthalmol Vis Sci 1995;36(13):2768–2771.
34.Gottlob I, Wizov SS, Reinecke RD. Quantitative eye and head movement recordings of retinal disease mimicking spasmus nutans. Am J Ophthalmol 1995;119(3):374–376.
35.Gradstein L, et al. Relationships among visual acuity demands, convergence, and nystagmus in patients with manifest/latent nystagmus. J Am Assoc Pediatr Ophthalmol Strabismus 1998;2(4):218–229.
36.Gresty MA, Ell JJ. Spasmus nutans or INS? Classification according to objective criteria [Letter]. Br J Ophthalmol 1981;65(7):510–511.
37.Gresty MA, et al. Assessment of vestibulo-ocular reflexes in INS. Ann Neurol 1985;17(2):129–136.
38.Gresty MA, et al. Neurology of latent nystagmus. Brain 1992;115(pt 5):1303–1321.
39.Guo SQ, et al. Visual pathway abnormalities in albinism and infantile nystagmus: VECPs and stereoacuity measurements. J Pediatr Ophthalmol Strabismus 1989;26(2):97–104.
40.Halmagyi GM, et al. Treatment of periodic alternating nystagmus. Ann Neurol 1980;8(6):609–611.
41.Helveston EM. Dissociated vertical deviation—a clinical and laboratory study. Trans Am Ophthalmol Soc 1980;78:734–779.
42.Helveston EM. 19th annual Frank Costenbader Lecture—the origins of congenital esotropia [see comments]. J Pediatr Ophthalmol Strabismus 1993;30(4):215–232.
43.Hertle RW. Examination and refractive management of patients with nystagmus. Surv Ophthalmol 2000;45(3):215–222.
44.Hertle RW, Dell’Osso LF. Clinical and ocular motor analysis of INS in infancy [see comments]. J Am Assoc Pediatr Ophthalmol Strabismus 1999;3(2):70–79.
45.Hertle RW, Zhu X. Oculographic and clinical characterization of thirty-seven children with anomalous head postures, nystagmus, and strabismus: the basis of a clinical algorithm. J Am Assoc Pediatr Ophthalmol Strabismus 2000;4(1):25–32.
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47.Hu DN. Prevalence and mode of inheritance of major genetic eye diseases in China. J Med Genet 1987;24(10):584–588.
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49.Jan JE, et al. Visually impaired children with sensory defect nystagmus, normal appearing fundi and normal ERGS. Dev Med Child Neurol 1996;38(1):74–80.
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51.Kori AA, et al. Pendular nystagmus in patients with peroxisomal assembly disorder. Arch Neurol 1998;55(4):554–558.
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52.Leigh RJ. Clinical features and pathogenesis of acquired forms of nystagmus. Baillieres Clin Neurol 1992;1(2):393–416.
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54.Nelson LB, et al. Congenital esotropia. Surv Ophthalmol 1987;31(6): 363–383.
55.Norn MS. Congenital idiopathic nystagmus. Incidence and occupational prognosis. Acta Ophthalmol 1964;42(4):889–896.
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58.Pearce WG. INS—genetic and environmental causes. Can J Ophthalmol 1978;13(1):1–9.
59.Pike MG, Jan JE, Wong PK. Neurological and developmental findings in children with cataracts. Am J Dis Child 1989;143(6):706–710.
60.Pratt-Johnson JA. 18th annual Frank Costenbader Lecture. Fusion and suppression: development and loss. J Pediatr Ophthalmol Strabismus 1992;29(1):4–11.
61.Reinecke RD. Costenbader Lecture. Idiopathic infantile nystagmus: diagnosis and treatment. J Am Assoc Pediatr Ophthalmol Strabismus 1997;1(2):67–82.
62.Sakata E, et al. Recent development of the study on clinical significance of abnormal eye movement. Auris Nasus Larynx 1985;12(3): 169–182.
63.Selz PA, et al. Vestibular deficits in deaf children. Otolaryngol Head Neck Surg 1996;115(1):70–77.
64.Shallo-Hoffmann J, Petersen J, Muhlendyck H. How normal are “normal” square wave jerks? Investig Ophthalmol Vis Sci 1989;30(5): 1009–1011.
65.Shallo-Hoffmann J, Faldon M, Tusa RJ. The incidence and waveform characteristics of periodic alternating nystagmus in INS. Investig Ophthalmol Vis Sci 1999;40(11):2546–2553.
66.Stang HJ. Developmental disabilities associated with INS. J Dev Behav Pediatr 1991;12(5):322–323.
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68.Steinlin M, Zangger B, Boltshauser E. Non-progressive congenital ataxia with or without cerebellar hypoplasia: a review of 34 subjects. Dev Med Child Neurol 1998;40(3):148–154.
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71.Weissman BM, et al. Spasmus nutans. A quantitative prospective study. Arch Ophthalmol 1987;105(4):525–528.
72.Yee RD, et al. A study of INS: waveforms. Neurology 1976;26(4): 326–333.
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73.Yee RD, Baloh RW, Honrubia V. Study of INS: optokinetic nystagmus. Br J Ophthalmol 1980;64(12):926–932.
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10
Neurodegenerative
Conditions of Ophthalmic
Importance
Mark S. Borchert and Sarah Ying
The pediatric ophthalmologist is frequently asked to evaluate children with multiple neurological impairments for ophthalmic manifestations of heritable neurological diseases. Occasionally these are diseases with specific ocular findings such as Kayser–Fleischer rings in Wilson’s disease or cherry-red spots in Tay–Sachs disease. More typically, they are diseases with nonspecific findings such as optic atrophy or nystagmus. Such findings can be used to help direct the neurological workup. Less commonly, these children present to the ophthalmologist with ocular complaints primarily. The ophthalmologist must recognize those signs and symptoms that may be associated with neurodegenerative conditions and institute an appropriate workup. Although all these conditions are rare, a general ophthalmologist
is likely to encounter several of them in their career.
Most of the neurodegenerative conditions are metabolic and represent dysfunction of specific enzymes or enzyme systems. Many of these enzyme systems are associated with particular cellular organelles, allowing for the classification of these diseases according to the organelle that is disrupted. Examples of these are the lysosomal storage diseases, the mitochondrial disorders, and the peroxisomal diseases. Other neurodegenerative diseases have characteristic clinical and pathological findings without known enzyme defects. Clinically, these diseases each have their own stereotypical time and mode of onset, which allows for easy division of the neurodegenerative conditions into groups that present in infancy, early childhood, or late childhood (Tables 10-1 through 10-3).
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CHAPTER 10: NEURODEGENERATIVE CONDITIONS |
325 |
LYSOSOMAL STORAGE DISEASES AND LEUKODYSTROPHIES
The lysosomal storage diseases are caused by dysfunction of lysosomal enzymes involved in the catabolism of complex lipids and sugars normally present in tissues, resulting in accumulation of intracellular storage products. Substances that may accumulate in nerve cell bodies and ultimately cause neuronal degeneration include sphingolipids, mucopolysaccharides, mucolipids, and oligosaccharides.81
When the catabolic defect affects primarily myelin constituents, it results in white matter fibrosis known as leukodystrophy. The leukodystrophies typically have visual loss as a primary manifestation of the disease. Those that are caused by lysosomal enzyme defects include metachromatic leukodystrophy and globoid cell leukodystrophy (Krabbe’s disease). Adrenoleukodystrophy is now recognized to result from defects of peroxisomal function. Spongiform leukodystrophy (Canavan disease) and sudanophilic leukodystrophy (Pelizaeus–Merzbacher disease) are disorders of myelin production. The metabolic defect in other leukodystrophies remains obscure. Other lysosomal diseases with ophthalmic manifestations, including secondary visual loss, are covered elsewhere.
Krabbe’s Disease
Krabbe’s disease (globoid cell leukodystrophy, galactosylceramide lipidosis) is an autosomal recessive condition characterized by the accumulation of periodic acid–Schiff- (PAS-) positive material within microglial cells in the brain imparting a typical “globoid cell” appearance histologically. It is caused by a deficiency of the lysosomal enzyme galactocebroside -galactosidase (galactocerebrosidase), which is encoded on chromosome 14. The accumulation of galactocerebroside results in central nervous system and peripheral nervous system demyelination.
Typical infantile-onset Krabbe’s disease presents at age 4 to 5 months with irritability and muscular hypertonicity. Loss of vision or failure to develop vision is noted soon thereafter, as are recurrent low-grade fevers. Spasticity and opisthotonos rapidly supervene. Death usually occurs by age 2 years.186 The principal ophthalmoscopic finding is primary optic atrophy. Rarely, macular cherry red spots are seen.115
TABLE 10-1. Neurodegenerative Conditions with Onset in Infancy.
Defective organelle |
Condition |
Principal ophthalmic manifestation |
Principal systemic manifestations |
Biochemical defect |
Lysosome |
GM1 gangliosidoses |
Cherry-red spots, nystagmus, |
Hypotonia, seizures, dysmorphism, |
GM1 -galactosidase |
sphingolipidoses |
|
corneal opacities |
organomegaly |
|
|
GM2 gangliosidoses |
|
|
|
|
Tay–Sachs disease |
Cherry-red spots, optic atrophy, |
Abnormal startle reflex, hypotonia, |
Hexosaminidase A |
|
|
nystagmus |
seizures |
|
|
Sandhoff disease |
Cherry-red spots, optic atrophy, |
Abnormal startle reflex, hypotonia, |
Hexosaminidase A and B |
|
|
nystagmus |
seizures, organomegaly |
|
|
Krabbe disease |
Optic atrophy, cortical blindness |
Irritability, spasticity, fevers |
Galactocerebrosidase |
|
Gaucher disease type 2 |
Esotropia, ocular motor apraxia |
Irritability, spasticity, seizures, |
Glucocerebrosidase |
|
|
|
organomegaly |
|
|
Niemann–Pick disease |
Cherry-red spots, optic atrophy, |
Organomegaly, hypertonia, loss of |
Sphingomyelinase |
|
type IA (formerly |
nystagmus |
motor skills, seizures, failure to |
|
|
type A) |
|
thrive |
|
|
Sialolipidosis (formerly |
Corneal clouding, pigmentary |
Psychomotor retardation |
Ganglioside sialidase |
|
mucolipidosis IV) |
retinopathy |
|
(presumed) |
Lysosome |
Mannosidosis type 1 |
Spokelike cataracts, corneal |
Coarse facies, severe psychomotor |
-Mannosidase |
oligosaccharidoses |
|
opacities |
retardation, recurrent infections, |
|
|
|
|
organomegaly |
|
Lysosome |
Mucolipidosis II |
Corneal cloudiness |
Psychomotor retardation, coarse |
UPD-acetylglucosamine: |
mucolipidoses |
(I-cell disease) |
|
facies, kyphoscoliosis, |
lysosomal enzyme |
|
|
|
hyperplastic gingiva, |
N-acetylglucosaminyl- |
|
|
|
macroglossia, cardiomegaly |
1-phosphotransferase |
|
|
|
|
|
OPHTHALMOLOGY-NEURO PEDIATRIC OF HANDBOOK 326
Lysosome |
Infantile NCL |
Pigmentary retinopathy, optic |
Psychomotor delay, |
Palmitoyl protein |
ceroidoses |
(Santavouri–Haltia) |
atrophy |
choreoathetosis, seizures |
thioesterase (PPT) |
Peroxisome |
Neonatal |
Pigmentary retinopathy, flat ERG |
Hypotonia, seizures, adrenal |
Multiple proteins of |
|
adrenoleukodystrophy |
|
insufficiency |
peroxisome biogenesis |
|
|
|
|
(PEX family) |
|
Infantile Refsum’s |
Pigmentary retinopathy |
Dysmorphism, deafness, |
Multiple proteins of |
|
disease |
|
organomegaly |
peroxisome biogenesis |
|
|
|
|
(PEX family) |
|
Zellweger syndrome |
Pigmentary retinopathy, optic |
High forehead, hypotonia, seizures, |
Multiple proteins of |
|
|
atrophy, corneal clouding, |
psychomotor retardation, |
perixosome biogenesis |
|
|
cataract, glaucoma |
hepatomegaly, polycystic kidneys |
(PEX family) |
Mitochondria |
Leigh syndrome |
Nystagmus, optic atrophy, |
Hypotonia, seizures, psychomotor |
Multiple |
|
|
ophthalmoplegia |
retardation |
|
None |
Canavan’s disease |
Optic atrophy, nystagmus |
Hypotonia, seizures, enlarged head |
Aspartoacylase |
|
Pelizaeus–Merzbacher |
Nystagmus, optic atrophy |
Spasticity, psychomotor retardation |
Lipophilin |
|
disease |
|
|
|
Unknown |
Lowe syndrome |
Cataracts, glaucoma |
Hypotonia, mental retardation, |
Inositol polyphosphate-5- |
|
|
|
rickets, renal failure |
phosphatase |
|
|
|
|
|
327 CONDITIONS NEURODEGENERATIVE :10 CHAPTER
TABLE 10-2. Neurodegenerative Conditions with Onset in Late Infancy or Early Childhood.
Defective organelle |
Condition |
Principal ophthalmic |
Principal systemic manifestations Biochemical defect |
|
|
manifestation |
|
|
|
|
|
Lysosome |
Metachromatic |
Optic atrophy, nystagmus |
sphingolipidoses |
leukodystrophy |
|
|
Gaucher disease type 3 |
Abducens palsy, ocular |
|
|
motor apraxia |
|
Niemannn–Pick type IS |
Pigmentary maculopathy |
|
(formerly type B) |
|
|
Niemann–Pick type IIS |
Vertical gaze palsy |
|
(formerly type C) |
|
Lysosome |
Aspartylglycosaminuia |
Crystalline cataracts |
oligosaccharidoses |
Fucosidosis |
Tortuous conjunctival |
|
||
|
|
vessels |
|
Mannosidosis type II |
Spokelike cataracts, |
|
|
corneal opacities |
|
Schindler’s neuroaxonal |
Optic atrophy, nystagmus |
|
dystrophy |
|
Lysosome mucolipidoses |
Mucolipidosis III |
Corneal clouding, |
|
(pseudo–Hurler |
pigmentary retinopathy, |
|
polydystrophy) |
hyperoptic astigmatism |
Lysosome |
MPS 1H (Hurler) |
Corneal clouding, |
mucopolysaccharidoses |
|
pigmentary retinopathy |
|
MPS II (Hunter) |
Pigmentary retinopathy, |
|
|
corneal clouding (rare) |
Weakness, ataxia, dementia |
Arylsulfatase A |
Dysphagia, spasticity, dementia, |
Glucocerebrosidase |
myoclonus organomegaly, |
|
osseous lesions |
|
Organomegaly, mental retardation |
Sphingomyelinase |
Organomegaly, psychomotor |
NPC1 or HE1/NPC2 |
retardation |
product |
Coarse facies, mental retardation, |
Aspartylglycosaminadase |
diarrhea, recurrent infections |
-L-Fucosidase |
Coarse facies, psychomotor |
|
deterioration, dysostosis |
|
multiplex, angiokeratoma |
|
Coarse facies, psychomotor |
-Mannosidase |
deterioration, dysostosis, |
|
multiplex, deafness, recurrent |
|
infections |
|
Weakness, peripheral neuropathy, |
-N- |
psychomotor retardation |
Acetylogalactosaminidase |
Dysostosis multiplex, mental |
UPD-N-Acetylglucosamine: |
retardation, coarse facies (mild) |
lysosomal enzyme N- |
|
acetylglu-cosaminyl-1- |
|
phosphotransferase |
Dysostosis multiplex, |
-L-Iduronidase |
organomegaly, coarse facies, |
|
mental retardation |
|
Dysostosis multiplex, |
Iduronate sulfatase |
organomegaly coarse facies, |
|
psychomotor retardation |
|
OPHTHALMOLOGY-NEURO PEDIATRIC OF HANDBOOK 328
|
MPS III (Sanfilippo) |
Pigmentary retinopathy |
Severe mental retardation, mild |
Heparan N-sulfatase (MPS |
|
|
|
dysostosis multiplex, deafness |
IIIA) -L- |
|
|
|
|
Acetylglucosaminidase |
|
|
|
|
(MPS IIIB) |
|
|
|
|
Acetyl-Co-A: - |
|
|
|
|
glucosaminide |
|
|
|
|
acetyltransferase (MPS |
|
|
|
|
IIIC) |
|
|
|
|
N-Acetylglucosamine 6- |
|
|
|
|
sulfatase (MPS IIID) |
Lysosome ceroidoses |
Late infantile NCL |
Pigmentary retinopathy, |
Seizures, ataxia, spasticity, loss of |
Pepstatin-insensitive |
|
(Jansky–Bielschowsky) |
optic atrophy |
speech |
lysosomal peptidase |
Mitochondria |
MELAS syndrome |
Hemianopsia, cortical |
Seizures, lactic acidosis, |
Mitochondrial tRNAleu |
|
|
visual loss |
hemiparesis |
|
Peroxisome |
Adrenoleukodystrophy |
Cortical blindness, optic |
Quadriparesis, dysarrthria, |
Lignoceroyl CoA ligase |
|
|
atrophy |
cognitive decline, Addison’s |
|
|
|
|
disease |
|
Unknown |
Riley–Day syndrome |
Dry eyes, corneal |
Vomiting, motor delay, poor |
IKAP protein |
|
(familial |
hypoesthesia, band |
temperature control, postural |
|
|
dysautonomia) |
keratopathy, optic atrophy |
hypotension, emotional lability |
|
|
Chediak–Higashi |
Iris transillumination, foveal |
Oculocutaneous albinism, |
Unknown |
|
syndrome |
hypoplasia, nystagmus |
recurrent infections, ataxia, |
|
|
|
|
polyneuropathy |
|
|
Neuroaxonal dystrophy |
Optic atrophy, cortical |
Weakness, peripheral neuropathy, |
Unknown |
|
|
blindness, nystagmus, |
spasticity |
|
|
|
esotropia |
|
|
|
Ataxia telangiectasia |
Conjunctival telangiectasia, |
Ataxia, polyneuropathy, |
ATM protein kinase |
|
(Louis–Bar syndrome) |
dysmetric saccades, |
immunologic impairment |
|
|
|
nystagmus, optic atrophy |
|
|
|
|
|
|
|
329 CONDITIONS NEURODEGENERATIVE :10 CHAPTER
TABLE 10-3. Neurodegenerative Conditions with Onset in Late Childhood or Adolescence.
Defective organelle |
Condition |
Principal ophthalmic manifestation |
Principal systemic manifestations |
Biochemical defect |
Lysosome |
Metachromatic |
Optic atrophy |
Personality changes, ataxia, |
Arylsulfatase A |
sphingolipidoses |
leukodystrophy |
|
incontinence, gallstones |
|
|
(late onset) |
|
|
|
Lysosome |
Sialidosis (type I) |
Cherry-red spots, nyctalopia, |
Myoclonus, ataxia |
Neuroaminidase |
oligosaccharidoses |
|
cataracts |
|
(oligosaccharide sialidase) |
Lysosome |
Juvenile NCL |
Pigmentary maculopathy |
Behavioral problems, cognitive |
Palmitoyl protein |
ceroidosis |
(Spielmeyer–Vogt) |
|
decline, seizures, spasticity |
thioesterase and others |
Peroxisome |
Refsum’s disease |
Pigmentary retinopathy, |
Ataxia, hearing loss, cardiac |
Phytanic acid -hydroxylase |
(presumed) |
|
nyctalopia, cataracts |
arrhythmia |
|
Mitochondria |
Fukuhara’s disease |
Optic atrophy |
Myoclonus, ataxia, weakness |
Mitochondrial tRNAlys |
|
(MERRF) |
|
|
|
|
Chronic progressive |
Ptosis, ophthalmoplegia, |
Weakness, heart block, ataxia, |
Mitochondrial tRNAleu; |
|
external |
pigmentary retinopathy, |
hearing loss, endocrine |
multiple mitochondrial |
|
ophthalmoplegia |
nystagmus |
problems |
enzymes |
|
CPEO/Kearns–Sayre |
|
|
|
None |
SSPE |
Macular chorioretinitis, optic |
Cognitive decline, myoclonus, |
Immune response to |
|
|
atrophy, papilledema |
epilepsy, rigidity |
measles virus |
|
Hallervorden–Spatz |
Vertical gaze palsy, saccadic |
Rigidity, choreoathetosis, |
Pantothenate kinase |
|
disease |
pursuit, eyelid apraxia, |
dysarthria, dysphagia, |
|
|
|
pigmentary retinopathy |
dementia |
|
|
Wilson disease |
Kayser–Fleischer rings, sunflower |
Liver failure, choreoathetosis, |
Copper-transporting |
|
|
cataracts, saccadic pursuit |
renal stones, cardiomyopathy |
ATPase |
|
Myotonic dystrophy |
Ptosis, blepharospasm, cataracts, |
Myotonia, muscle atrophy |
Myotonic dystrophy |
|
|
pigmentary retinopathy |
|
protein kinase (DMPK) |
|
Friedreich’s ataxia |
Optic atrophy, nystagmus |
Ataxia, dysarthria, pes cavus, |
Frataxin |
|
|
|
kyphoscoliosis, proprioceptive |
|
|
|
|
loss, hyporeflexive joints, |
|
|
|
|
hearing loss |
|
|
|
|
|
|
OPHTHALMOLOGY-NEURO PEDIATRIC OF HANDBOOK 330